Imides : medicinal, agricultural, synthetic applications and natural products chemistry 9780128156759, 0128156759, 9780128156766, 0128156767

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Isolation and Identification of naturally-occurring imides (Includes Review of Techniques and Sources in the Isolation of Imide Natural Products)
Total Synthesis of Imide Natural Products (Review and Critique of Naturally-occurring Imide Total Synthesis)<
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Imides

Developments in Organic Chemistry

Imides Medicinal, Agricultural, Synthetic Applications and Natural Products Chemistry

Edited by

FREDERICK A. LUZZIO Department of Chemistry, University of Louisville, Louisville, KY, United States Series Editor

MICHAEL B. SMITH

Elsevier Radarweg 29, PO Box 211, 1000 AE Amsterdam, Netherlands The Boulevard, Langford Lane, Kidlington, Oxford OX5 1GB, United Kingdom 50 Hampshire Street, 5th Floor, Cambridge, MA 02139, United States Copyright © 2019 Elsevier Inc. All rights reserved. No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, recording, or any information storage and retrieval system, without permission in writing from the publisher. Details on how to seek permission, further information about the Publisher’s permissions policies and our arrangements with organizations such as the Copyright Clearance Center and the Copyright Licensing Agency, can be found at our website: http://www.elsevier.com/permissions. This book and the individual contributions contained in it are protected under copyright by the Publisher (other than as may be noted herein). Notices Knowledge and best practice in this field are constantly changing. As new research and experience broaden our understanding, changes in research methods, professional practices, or medical treatment may become necessary. Practitioners and researchers must always rely on their own experience and knowledge in evaluating and using any information, methods, compounds, or experiments described herein. In using such information or methods they should be mindful of their own safety and the safety of others, including parties for whom they have a professional responsibility. To the fullest extent of the law, neither the Publisher nor the authors, contributors, or editors, assume any liability for any injury and/or damage to persons or property as a matter of products liability, negligence or otherwise, or from any use or operation of any methods, products, instructions, or ideas contained in the material herein. British Library Cataloguing-in-Publication Data A catalogue record for this book is available from the British Library Library of Congress Cataloging-in-Publication Data A catalog record for this book is available from the Library of Congress ISBN: 978-0-12-815675-9 For Information on all Elsevier publications visit our website at https://www.elsevier.com/books-and-journals

Publisher: Susan Dennis Acquisition Editor: Emily McCloskey Editorial Project Manager: Michael Lutz Production Project Manager: Vignesh Tamil Cover Designer: Matthew Limbert Typeset by MPS Limited, Chennai, India

LIST OF CONTRIBUTORS R. Alan Aitken

EaStCHEM School of Chemistry, University of St Andrews, St Andrews, United Kingdom Pranjal P. Bora

Department of Chemistry, University of Louisville, Louisville, KY, United States Soong Chee-Leong

Division of Applied Life Sciences, Graduate School of Agriculture, Kyoto University, Kyoto, Japan Sachin Handa

Department of Chemistry, University of Louisville, Louisville, KY, United States Makoto Hibi

Laboratory of Industrial Microbiology, Graduate School of Agriculture, Kyoto University, Kyoto, Japan; Biotechnology Research Center and Department of Biotechnology, Toyama Prefectural University, Toyama, Japan Nobuyuki Horinouchi

Division of Applied Life Sciences, Graduate School of Agriculture, Kyoto University, Kyoto, Japan Clemens Lamberth

Chemical Research, Syngenta Crop Protection AG, Stein, Switzerland Jie Jack Li

Revolution Medicines, Inc. Redwood City, CA, United States Justin M. Lopchuk

Drug Discovery Department, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, United States; Department of Oncologic Sciences, Morsani College of Medicine, University of South Florida, Tampa, FL, United States Frederick A. Luzzio

University of Louisville, Louisville, KY, United States Rosmarbel Morales-Nava

Division of Medicinal and Natural Products, The University of Iowa, Iowa City, IA, United States Masutoshi Nojiri

Biotechnology Development Laboratories, Kaneka Corporation, Hyogo, Japan Jun Ogawa

Division of Applied Life Sciences, Graduate School of Agriculture, Kyoto University, Kyoto, Japan; Research Unit of Physiological Chemistry, Kyoto University, Kyoto, Japan

ix

x

List of Contributors

Horacio F. Olivo

Division of Medicinal and Natural Products, The University of Iowa, Iowa City, IA, United States Pravin C. Patil

Department of Chemistry, University of Louisville, Louisville, KY, United States Anna C. Renner

Department of Chemistry and Biochemistry, North Dakota State University, Fargo, ND, United States Mukund P. Sibi

Department of Chemistry and Biochemistry, North Dakota State University, Fargo, ND, United States Michihki Takeuchi

Laboratory of Industrial Microbiology, Graduate School of Agriculture, Kyoto University, Kyoto, Japan

PREFACE Comprehensive reviews which cover a specific functional group, structural type, or functional group reactivity are of great utilization in the synthesis of medicinally relevant compounds and natural products. The present volume is inspired by my perusal of the Elsevier Series Progress in Heterocyclic Chemistry and an earlier review on imides published in Science of Synthesis (Thieme). The imide functional group is found in a diversity of structures, both natural and synthetic, and is present in compounds which possess a range of biological activities. Since the imide group is easily formed and otherwise derivatized, it can also function as a central torus or connecting point for chiral auxiliaries and directing groups. Chapter 1, Synthesis of Cyclic Imides, (R. Alan Aitken) focuses on the synthesis of cyclic imides using high-yield general methods, including those which are fragmentbased and methods entailing ring expansion and ring contractions. Chapter 2, Oxidation of Lactams to Cyclic Imides, (Pravin C. Patil) covers the transformation of lactams to cyclic imides exclusively, whereby preformed cyclic amides are converted to the corresponding imides by numerous oxidation methods. Chapter 3, Microbial Cyclic Imide Metabolism and Its Biotechnological Application, (Junichi Ogawa) addresses the enzyme-mediated reactions of imides as exemplified by microbial transformations of cyclic imides such as succinimides, glutarimides, and phthalimides to the corresponding acyclic components such as carboxyamides and dicarboxylic acids. Chapter 4, Imides: A Special Chemical Entity in Rhodium Catalysis, (Sachin Handa) surveys the preparation and utilization of imide-derived ligands in rhodium catalysis, a method which has had numerous applications in the synthesis of natural products, agrochemicals, and medicinally relevant compounds. Chapter 5, Stereoselective Conjugate Additions of Hydrazines, Oximes, and Hydroxylamines to α,β-Unsaturated Imides, (Mukund Sibi) details the use of the imide functionality as part of a chiral reactive component in reactions such as conjugate additions with N N and N O nucleophiles. Consequently, the review demonstrates that the unsaturated imide-conjugate addition strategy has significant relevance in the synthesis of bioactive structures related to β-amino acids. Chapter 6, Chiral Sulfur-Containing Imide Auxiliaries in Medicinal Chemistry, (Horacio Olivo) cites synthetic strategies which utilize the 1,3-thiazolidine and 1,3-oxazolidine chiral auxiliaries derivatized xi

xii

Preface

with acyl groups which provide synthons than can participate in asymmetric versions of aldol reactions, Michael additions, and aldimine additions. Chapter 7, Imide Natural Products, (Justin Lopchuk) deals with the isolation, synthesis, and biological activity of imide natural products. The range of compound classes includes bisindoles, glutarimides, maleimides, polyketides, succinimides, and tetramic acids. The compounds covered are select but representative and includes those isolated from the early 20th century to present. Chapter 8, Synthesis and Applications of Cyclic Imides in Agrochemistry, (Clemens Lamberth) provides an overview of the cyclic imide structural class in agricultural chemistry/crop protection. Imide classes which represent herbicides, fungicides, and insecticides are discussed along with their chemical synthetic routes. Chapter 9, Imide-Containing Synthetic Drugs, (Jie Jack Li) covers imide medicines, more specifically cyclic imides as pharmacophores which includes compounds with therapeutic activities as antiepileptic, antipsychotic, antineoplastic, and antianxiety. Finally, Chapter 10, Thalidomide and Analogs, (Frederick A. Luzzio) encompasses the synthesis, biological activity, and medicinal importance of thalidomide and its synthetic analogs. Topics which are covered in Chapter 10, Thalidomide and Analogs, include the biological disposition of thalidomide, teratogenic effects of analogs, synthesis of metabolites and metabolic analogs, and synthesis of configurationally stable analogs. The biological activities and therapeutic applications of thalidomide and its analogs are surveyed and include the effects on tumor necrosis factor, antiangiogenic effects, antiinflammatory and immunosuppressive activities, and exploration and approval as cancer chemotherapeutic. Where possible, a heavy dose of contemporary organic syntheses accompanies the discussion on the many biological effects of the compound and its analogs. In closing I thank the Series Editor, Professor Michael B. Smith, for extending the invitation to me as the Volume Editor of Imides. In addition, Professor Smith’s experience and help in proofing each of the chapters was invaluable and much appreciated. I also wish to thank Emily McCloskey, Senior Acquisitions Editor, and Michael Lutz, Managing Editor, both of Elsevier, for their encouragement and assistance in preparing this volume. Frederick A. Luzzio February 25, 2019

CHAPTER 1

Synthesis of Cyclic Imides R. Alan Aitken

EaStCHEM School of Chemistry, University of St Andrews, St Andrews, United Kingdom

1.1 INTRODUCTION This chapter reviews the advances in the synthesis of cyclic imides over the period 2000
17. It is designed to complement and update a systematic review of imide synthesis, with literature coverage up to 2003 which appeared in 2005.1 Other recent reviews of relevance are a short survey of “atom-economical” approaches to cyclic imides,2 a review of microwavepromoted synthesis of cyclic imides,3 and a lengthy review on the chemistry of cyclic imides, including coverage of their synthesis.4 Within this chapter, the synthetic approaches are divided into three major types: (1) fragment-based ring synthesis, (2) synthesis from nonimide cyclic precursors already containing all the ring atoms, and finally (3) the functionalization of imides on both C and N.

1.2 FRAGMENT-BASED SYNTHESIS This remains the most common synthetic approach to cyclic imides. The methods are categorized according to the source of the final ring atoms as follows: (1) in an increasing order of the number of fragments used and (2) according to the nature of the fragments involved. Since the vast majority of methods covered involved five-membered ring imides, the classification is based on these, with products of other ring sizes included in the most relevant section.

1.2.1 Cyclization of a Single Fragment Containing All Five Ring Atoms 1.2.1.1 Formation of a C
C Bond In this method, the base-induced aldol cyclization of an appropriate amido ketone 1 is performed in air resulting in oxidation of the intermediate lactams 2 to afford the triarylmaleimides 3 in moderate to good yield (Scheme 1.1).5,6 Imides DOI: https://doi.org/10.1016/B978-0-12-815675-9.00001-1

© 2019 Elsevier Inc. All rights reserved.

1

2

Imides

Scheme 1.1 Direct oxidative cyclization of amido ketones to give triarylmaleimides.

1.2.1.2 Formation of a C
N Bond The 1,2-diacid monoamides, such as 4, are important intermediates in the reaction of cyclic anhydrides with amines to give imides as will be discussed in Section 1.2.2.1. A detailed mechanistic study, including kinetics and Hammett parameters, for their dehydrative cyclization to give phthalimides 5 has been published (Scheme 1.2).7 An efficient cyclization of

Scheme 1.2 Imide synthesis by cyclization of 1,2-diacid monoamides.

Synthesis of Cyclic Imides

3

maleic acid monoamides 6 to give the maleimides 7 is achieved by heating in propyl acetate in the presence of the ionic liquid catalyst 8.8 The succinic acid ester amides 9, readily formed by alkoxycarbonylation of enamides, undergo ready cyclization upon treatment with calcium hydride in dimethylformamide (DMF) to give the corresponding succinimides.9 Base-induced cyclization of the N-protected asparagine followed by Nbenzylation gives the corresponding succinimides 12 in variable yield.10 The reaction of the silica-supported benzoyl chloride 13 with succinic acid monoamides 14 is accompanied by cyclization to give the succinimides 15 and the supported benzoic acid 16, which is readily reconverted into 13 with thionyl chloride (Scheme 1.3).11

Scheme 1.3 Succinimide synthesis using silica-supported benzoyl chloride.

A second solid-supported method involves the diphenylphosphoryl azide-promoted cyclization of the aspartic acid residue formed by deprotection of 17 to give succinimide 18, which can then be N-deprotected and further functionalized (Scheme 1.4).12

Scheme 1.4 Solid-supported synthesis of a succinimide from a dipeptide.

4

Imides

1.2.2 Synthesis From Two Fragments 1.2.2.1 From C4 and N Fragments 1.2.2.1.1 From Cyclic Anhydrides The reaction of cyclic anhydrides with amines is perhaps the best established and most widely used method for the synthesis of cyclic imides. As befits its importance, there have been a large number of reports involving application of improved reaction conditions or catalysts to this method. Various new ammonia equivalents for the conversion of anhydrides into NH imides have been employed, including formamide with microwave heating,13,14 urea in DMF,14 potassium cyanate or sodium thiocyanate,15 a combination of ammonium chloride and 4-dimethylaminopyridine (DMAP) or ammonium acetate,16 and hydroxylamine hydrochloride with catalytic DMAP under microwave heating.17 A selection of new procedures and catalysts for the reaction of cyclic anhydrides with amines is shown in Table 1.1 along with an indication of their applicability to the synthesis of succinimides 19, maleimides 20, and phthalimides 21 (Scheme 1.5). A mechanistic study has shown that microwave-induced solvent-free synthesis of 21 only works if the amine or the anhydride is liquid at the reaction temperature.18 Table 1.1 New conditions and catalysts for imide formation Conditions Applicable No. of to examples

Microwave heating, DMF Grind solids with catalytic TsOH to get diacid monoamide and then grind it with DCC Catalytic Nb2O5, solvent-free 3-(Diphenylphosphoryl)oxazol2(3H)-one, Et3N Bmim PF6 or Bmim BF4 Bmim BF4 Microwave heating, solvent-free Microwave heating, catalytic DMF Grind solids with catalytic DABCO Heat in dioxane to get diacid monoamide and then heat it with (NH4)2S2O8 in DMSO

Yields (%)

References

19, 20, 21 19, 20, 21

18 18

65
97 65
79

19 20

19, 21 21

18 6

55
98 69
99

21 22

19, 20, 21 21 21 21

14 10 8 8

90
99 74
98 91
95 88
98

23 24 25 26

21

13

72
90

27

19, 20, 21

21

65
99

28

Synthesis of Cyclic Imides

5

Scheme 1.5 Synthesis of succinimides, maleimides, and phthalimides from anhydrides.

The direct synthesis of the succinimide 23 required for a natural product synthesis from methylsuccinic anhydride gave only a low yield, but the use of methylmaleic anhydride to prepare 22 followed by catalytic hydrogenation gave much better results (Scheme 1.6).29 Changing to the esters 24 with a more complex group actually required for the target compounds, however, meant that direct reaction with methylsuccinic anhydride proceeded smoothly to give 25.30 The reaction of the furan/ maleic anhydride Diels
Alder adduct 26 with a series of amino acids in water results in imide formation accompanied by retro-Diels
Alder loss of furan to give the corresponding maleimido acids.31

Scheme 1.6 Synthesis of some N-o-carboxyphenylsuccinimides.

The typical conditions used for the conversion of anhydrides into the corresponding imides are illustrated by four recent syntheses of

6

Imides

biologically active target molecules. The anhydride 27 is converted into maleimide 28 by treatment with urea and the N-hydroxyimide 29 by reaction with hydroxylamine (Scheme 1.7). All the three compounds are natural products obtained from a fungal species in Taiwan and show anticancer activity.32 The imide 30 required in the course of an aza-steroid synthesis was prepared by the treatment of 4methoxyphenethylamine with succinic anhydride followed by acetyl chloride.33

Scheme 1.7 Synthesis of imide natural products and an aza-steroid precursor.

The synthesis of a series of antibacterial agents with a novel mode of action involves the treatment of (S)-methylsuccinic anhydride with an amine in the presence of N,N0 -carbonyldiimidazole to give succinimides 31 (Scheme 1.8).34 The reaction of glutaric anhydride with the aromatic amine 32 in the presence of sodium acetate in acetic acid gives the imide 33 which has antiinflammatory activity.35 The corresponding succinimide, maleimide, phthalimide, and two isomeric nitrophthalimides were also prepared from 32 using the same method but proved to be less active.

Synthesis of Cyclic Imides

7

Scheme 1.8 Synthesis of imides for antibacterial and antiinflammatory agents.

The examples of succinimides 31 prepared included two from hydrazines (R 5 NMe2 and NMeCbz),34 and the reaction of the hydrazinoimidazoline 34 with phthalic anhydride gives imide 35, which was investigated for anticancer activity (Scheme 1.9).36 The direct conversion of phthalic anhydrides into N-hydroxyphthalimides 36 can be achieved by the treatment with hydroxylamine hydrochloride in pyridine with microwave heating (eight examples, 58%
99% yield),37 or by heating with hydroxylamine phosphate at 130°C in the presence of a limited amount of water (six examples, 67%
100% yield).38 Heating with hydroxylamine phosphate in water is also the final stage in the total synthesis of the N-hydroxymaleimide natural product himanimide C 37 from the corresponding anhydride.39 O-Alkylhydroxylamine salts may also be used and a sample of N-methoxysuccinimide for X-ray structure determination was prepared in 70% yield by brief microwave heating of an intimate mixture of dry succinimide and methoxyamine hydrochloride.40

Scheme 1.9 Synthesis of N-amino and N-hydroxyimides from anhydrides.

8

Imides

1.2.2.1.2 From Dicarboxylic Acids There have been several reports of improved methods and catalysts for condensation of diacids with amines to give cyclic imides. A “green chemistry” method involves heating phthalic acid with an amine in aqueous ethanol under high temperature and pressure conditions to directly give the crystalline phthalimides in good yield (12 examples, 51%
95% yield).41 Microwave heating under solvent-free conditions is effective in synthesizing imides 38
40, which all show significant anticancer activity, from the corresponding diacids and amines (Scheme 1.10).42 Similar conditions are involved in the conversion of N-phthaloyl-(S)-glutamic acid 41 into thalidomide 42 using thiourea as a nitrogen source.43 Two separate imide formations can be achieved at once by starting from a mixture of phthalic anhydride, (S)-glutamic acid, and thiourea and subjecting it to the same conditions to afford 42 directly in 63% yield.43 Niobium pentoxide is effective in catalyzing the condensation of a range of 1,2-diacids with amines in hexane to give the imides in 75%
98% yield with examples, including succinimides, glutarimides, maleimides, and phthalimides.44 The substituted succinimide 43 required for the synthesis of a range of new anticonvulsants for treatment of epilepsy was prepared in 67% yield by heating the diacid with aqueous ammonia under pressure at 190°C.45 A useful synthesis of N-(4-aminophenyl)imides involves treating the 4-nitroaniline 44 with succinic or glutaric acid and polyphosphoric acid as a dehydrating agent to give the imides 45, which can then be hydrogenated over Raney nickel (Scheme 1.11).46 A traceless solid-supported synthesis of phthalimides involves attachment of the phthalic acid to Wang resin under Mitsunobu conditions to give 46, which is then treated with

Scheme 1.10 Some medicinally important imides formed from diacids.

Synthesis of Cyclic Imides

9

Scheme 1.11 Further syntheses of imides from diacids.

the required amine and EDCI followed by final release of the product 47 under microwave conditions.47 A range of N-aminosuccinimides are effective anticonvulsants for the treatment of epilepsy and their synthesis is illustrated by the typical conditions for the formation of 4848 and 4949 from the diacids and arylhydrazines (Scheme 1.12).

Scheme 1.12 Synthesis of anticonvulsant N-aminoimides from diacids.

1.2.2.1.3 From Diacid Monoesters Particularly for the synthesis of N-phthalimido derivatives of amino acids, reaction with monomethyl phthalate provides an efficient and mild method. The reaction of 50 with α-amino acid amides 51 in the presence of the BOP peptide coupling reagent and Hünig’s base initially gives the coupled amide products 52 and these are readily cyclized with base to afford the imido acid amides 53 (Scheme 1.13).50 This method is also

10

Imides

Scheme 1.13 Synthesis of imides from diacid monoesters.

effective for α-amino esters and dipeptide amides and esters.50 Alternatively, ultrasonication of 50 and 51 with BOP reagent, Hünig’s base, and zinc chloride affords the products 53 directly.51 In a related method, the reaction of methyl 2-(succinimidoyloxycarbonyl)benzoate 54 with amino acids and other amines gives the corresponding phthalimides 55 in good yield.52 1.2.2.1.4 From Cyano Acids and Esters Distillation of an aqueous solution containing an amine and a β-cyanoβ-alkoxycarboxylic acid such as 56 or 58 gives the corresponding imides 57 and 59, respectively (Scheme 1.14).53 The multifunctional cyano esters 60 react in benzene by electrophilic aromatic substitution accompanied by imide formation to give the maleimides 61 and the reaction is also possible for other arenes such as 1,4-dimethoxybenzene, which gives 62.54 1.2.2.1.5 From Diols A remarkable and valuable synthetic approach to imides involves reaction of a diol with a transition metal catalyst that promotes dehydrogenation to give the dialdehyde in the presence of a nitrogen source. The process was first reported using RuH2(PPh3)4 in the presence of the N-heterocyclic carbene (NHC) derived from 1,3-diisopropylimidazolium bromide and sodium hydride, and this was able to convert butane-1,4-diol and a primary amine RCH2NH2 into succinimides 63 (13 examples, 36%
88% yield), benzene-1,2-dimethanol into phthalimides 64 (4 examples, 51%
74%),

11

Synthesis of Cyclic Imides

Scheme 1.14 Synthesis of imides from cyano acids and esters.

and pentane-1,5-diol into glutarimides 65 (2 examples, 48%
51%) (Scheme 1.15).55 In the process, hydrogen gas is actually evolved and this was later exploited in a variant using the same catalytic system but with a nitrile RCN as the nitrogen source giving succinimides 63 from butane1,4-diol (11 examples) and phthalimides 64 from benzene-1,2-dimethanol (3 examples).56 Most recently, a manganese catalyst 66, generated in situ from the corresponding bromide and potassium hydride, has also proved HO

HO ,

HO

RCH2NH2 cat.

NBut

O RCH2N

, HO

N

HO

HO

or RCN cat.

O 63

O ,

O

RCH2N

,

O

RCH2N O

64

Mn CO CO

PBut2 66

Scheme 1.15 Synthesis of imides from diols with amines or nitriles.

65

12

Imides

capable of converting butane-1,4-diol and an amine into the succinimides 63 (16 examples, 42%
92%) and in this case, no NHC is required.57 1.2.2.2 From C3N and C Fragments Transition metal-catalyzed carbonylation of amides leads directly to imides in a few specific cases. The N-(2-pyridylmethyl)benzamides 67 are carbonylated with a mixture of carbon monoxide and ethylene (which acts as a hydrogen acceptor) to give phthalimides 68 (Scheme 1.16).58 Palladiumcatalyzed carbonylation of 2-bromobenzamide 69 using molybdenum hexacarbonyl as the CO source gives phthalimide.59 Amides 70 bearing an N-perfluoro-p-tolyl group undergo palladium-catalyzed carbonylation to afford succinimides 71.60

Scheme 1.16 Synthesis of imides by carbonylation of amides.

1.2.2.3 From C3 and CN Fragments Rhodium-catalyzed aminocarbonylation of benzoic acids with isocyanates affords the phthalimides 72 (Scheme 1.17).61 Nickel-catalyzed reaction of methyl 2-iodobenzoate with isocyanates similarly gives the phthalimides 73 and the process has also been used with ethyl 2-iodoacrylate to give maleimides.62 In a related approach, a cascade rearrangement and

Synthesis of Cyclic Imides

13

Scheme 1.17 Synthesis of imides from isocyanates and isocyanides.

cyclization of the indolones 74 with the isonitrile 75 is promoted by boron trifluoride etherate to give the quinoline-fused imides 76.63 Zinc triflate
catalyzed interaction of allenic esters 77
80 with aromatic isonitriles in wet tetrahydrofuran results in a multistep process leading to cyclization to form the maleimides 81
84, respectively (Scheme 1.18).64

Scheme 1.18 Synthesis of imides from allenic esters and isocyanides.

14

Imides

1.2.2.4 From C2N and C2 Fragments Iodine-mediated oxidative dimerization of arylacetonitriles in the presence of sodium methoxide followed by acid hydrolysis leads to the formation of the diarylmaleimides 85 (Scheme 1.19).65 In a related process, sodium borohydride reduction of phthalodinitriles 86 in aqueous ethanol gives the corresponding phthalimides 87.66 Iridium-catalyzed reaction of nitriles 88 with α,β-unsaturated nitriles 89 in the presence of water gives the substituted glutarimides 90.67

Scheme 1.19 Synthesis of imides from nitriles.

1.2.3 Synthesis From Three Fragments 1.2.3.1 From C3, C, and N Fragments Palladium-catalyzed reaction of methyl 2-iodobenzoates 91 with amines under an atmosphere of carbon monoxide affords the phthalimides 92 in moderate to good yield (Scheme 1.20).68

Scheme 1.20 Synthesis of imides from a 2-halobenzoate, an amine, and CO.

1.2.3.2 From C2, CN, and C Fragments The ruthenium-catalyzed reaction of an alkyne and an isocyanate under 1 atm of carbon monoxide gives the substituted maleimides 93 in high yield (Scheme 1.21) and the reaction can also be used with 1,4-phenylenedi(isocyanate) yielding 1,4-phenylenebis(maleimides).69

Synthesis of Cyclic Imides

15

Scheme 1.21 Synthesis of imides from an alkyne, an isocyanate, and CO.

1.2.4 Synthesis From Four Fragments 1.2.4.1 From Alkynes The sequential treatment of iron pentacarbonyl with sodium borohydride, acetic acid, and an alkyne gives the iron carbonyl complex 94 and when this is reacted with a primary amine followed by cupric chloride, the trisubstituted succinimides 95 are formed (Scheme 1.22).70,71

Scheme 1.22 Synthesis of imides from an alkyne, an amine, and iron pentacarbonyl.

The method was later simplified and made catalytic in iron, and reaction of an alkyne with ammonia or a primary amine and catalytic Fe3(CO)12 under 20 atm of CO gives the trans-succinimides 96 in good to moderate yield (Scheme 1.23).72
74 By way of contrast, alkynes react

Scheme 1.23 Synthesis of imides from an alkyne, an amine, and carbon monoxide.

16

Imides

with 2-pyridylmethylamine and CO catalyzed by Rh4(CO)12 in the presence of triethyl phosphite to give the maleimides 97.75 1.2.4.2 From Dihalides Catalytic double aminocarbonylation of 1,2-dihalobenzenes 98 to give the corresponding phthalimides 99 (Scheme 1.24) has been achieved in various ways, including reaction of dibromides with PdCl2(PPh3)2, DBU, and CO in the ionic liquid trihexyl(tetradecyl)phosphonium bromide (14 examples, 63%
92% yield)76; reaction of diiodides with 10% Pd/C, DABCO, and CO in toluene (19 examples, 79%
98% yield)77; and reaction of dibromides with Pd(OAc)2, molybdenum hexacarbonyl as CO source, DBU, and di(1-adamantyl)butylphosphine (18 examples, 15%
84% yield).78 Similar reaction of 1,8-diiodonaphthalene with amines and CO in the presence of Pd(OAc)2 and Ph3P gives the ring-fused imides 100 (six examples, 69%
80% yield).79

X +

R1

2

H2N R

O

Pd cat., base, CO source

R N

O

N R2

R1

X 98 X = Br, I

O

99

O 100

Scheme 1.24 Double aminocarbonylation of 1,2-dihalobenzenes.

1.3 SYNTHESIS BY RING TRANSFORMATION 1.3.1 Oxidation Without Change of Ring Size 1.3.1.1 Oxidation of Pyrrolidines There have been few examples of this apparently attractive synthetic approach. In an isolated example, the tricyclic compound 101 was converted into imide 102 in low yield using manganese dioxide,80 and a more systematic study described cuprous chloride-catalyzed oxidation of isoindolines 103 with tert-butyl hydroperoxide to give the corresponding phthalimides 104 (Scheme 1.25).81

Scheme 1.25 Synthesis of imides by oxidation of pyrrolidines.

Synthesis of Cyclic Imides

17

1.3.1.2 Oxidation of Lactams The oxidation of lactams is a well-known method dating back over 50 years that has been covered in previous reviews and was also comprehensively reviewed again in 2011.82 For this reason, we include here only two examples of unusual recently reported methods. (1) Manganesecatalyzed peracetic acid oxidation of lactams 105
107 in ethyl acetate with microwave heating affords the corresponding imides 108
110 in good yield (Scheme 1.26),83 and (2) the high-yielding conversion of caprolactam 107 into adipimide 110 using ozone has been studied mechanistically with kinetic parameters and solvent effect reported.84

Scheme 1.26 Synthesis of imides by oxidation of lactams.

1.3.2 Ring Expansion 1.3.2.1 From β-Lactams The initial discovery of this novel and valuable approach to imides involved the organocatalytic ring expansion of imines 112 derived from 4-formyl-β-lactams 111 to give succinimide monoimines 113, which were subsequently hydrolyzed to succinimides 114 (Scheme 1.27).85 The requirement for imine formation was subsequently removed by moving

Scheme 1.27 Synthesis of imides by ring expansion of β-lactams.

18

Imides

to catalysis by thiazolium salt-derived NHCs as organocatalysts, thus allowing direct conversion of 111 into 114 (five examples, 62%
88% yield).86 Using imidazolium salt-derived NHCs, the scope was expanded to include 3,3-disubstituted-4-formyl-β-lactams 115 leading to succinimides 116 (11 examples, 78%
99% yield).87 By employing a chiral triazolium salt-derived NHC, kinetic resolution was possible with one enantiomer of racemic 115 being converted into the succinimide 116 and the unreacted enantiomer being reduced to the alcohol 117.88 Although 117 was obtained in excellent e.e., the e.e. of 116 was only moderate. The ring expansion of β-lactams into succinimides has also been studied in detail using theoretical methods.89 1.3.2.2 From Iminooxetanes The iminooxetanes 118, prepared as shown by a multicomponent reaction, undergo acid-catalyzed ring expansion to afford N-tosylmaleimides 119 (Scheme 1.28).90

Scheme 1.28 Synthesis of imides by ring expansion of 2-iminooxetanes.

1.3.3 Ring Contraction A single example of this uncommon approach is provided by reaction of the dicyanoglutarimides 120 either with sodium ethoxide and bromine, with bromine water, or electrochemically to afford the cyclopropanefused succinimides 121 (Scheme 1.29).91

Scheme 1.29 Synthesis of imides by ring contraction.

Synthesis of Cyclic Imides

19

1.4 SYNTHESIS BY FUNCTIONALIZATION OF IMIDES 1.4.1 Alteration of the N-Substituent Treatment with paraformaldehyde in DMF with microwave heating converts substituted phthalimides 122 into the N-hydroxymethyl derivatives 123 (Scheme 1.30).14 The conversion of N-hydroxymethylphthalimide 124 into N-arylaminomethyl derivatives 125 can be achieved by reaction with an aromatic amine either in hot methanol, with heating under solvent-free conditions, or using microwave heating.92 The reaction of succinimide 43 with the secondary amine 126 in aqueous formaldehyde results in direct formation of the active anticonvulsant 127.45

Scheme 1.30 N-Hydroxymethylation and aminomethylation of imides.

Various new methods have been developed for direct N-arylation of succinimide 128 and phthalimide 129 to give the corresponding products 130 and 131 (Scheme 1.31). Reaction with arylboronic acids, ArB(OH)2, and catalytic cupric acetate may be carried out, either in methanolic solution (nine examples, 72%
96% yield),93 or in the ionic liquid [Bmim] BF4 (eight examples, 80%
92% yield).94 A metal-free variant is provided by the oxidative arylation observed on treatment with iodobenzene O

O NH O 128

,

NH 129

ArB(OH)2, cat. Cu(OAc)2 or ArH, PhI(OAc)2

O

Scheme 1.31 N-Arylation of imides.

O

O NAr , 130

O

NAr 131

O

20

Imides

diacetate in the presence of arenes, Ar
H, such as benzene, toluene, and p-xylene which is effective in converting both succinimide 128 and phthalimide 129 into the products 130 and 131.95

1.4.2 Alteration of a C-Substituent 1.4.2.1 Ring Alkylation Palladium-catalyzed coupling of dihalomaleimides 132 and 133 with trialkylindiums occurs readily to afford the monoalkylated maleimides 134 and 135 (Scheme 1.32).96 These may then be further alkylated a second time in a similar way, and sequential one-pot double alkylation is also possible. The imides 31 derived from (S)-methylsuccinic acid are ring acylated by treatment with Boc-valine and N,N0 -carbonyldiimidazole followed by addition to lithium hexamethyldisilazide to give succinimides 136, which are precursors to a series of antibacterial agents with a novel mode of action.34

Scheme 1.32 C-Alkylation of imides.

1.4.2.2 Michael Addition A major focus of research in imide synthesis in recent years has been the asymmetric Michael addition of various nucleophiles to maleimides to afford the corresponding chiral succinimides. The volume of work is too extensive to cover in detail here, so only representative examples are given. Michael addition of secondary amines, such as diethylamine, piperidine, and morpholine, to N-arylmaleimides 137 gives products 138 (Scheme 1.33).97 There have been various studies on addition of arylboronic acids to maleimides 139 to give the succinimides 140. The use of a chiral rhodium catalyst provides a range of monoarylsuccinimides 140

Synthesis of Cyclic Imides

21

Scheme 1.33 Michael addition to maleimides.

(R1 5 H, 10 examples, 88%
98% yield, 88%
95% ee).98 With a carbon substituent already in place (R16¼H), the formation of products 140 bearing a quaternary stereocenter is possible using a rhodium Binap catalyst system (9 examples, 90%
98% ee).99 Rhodium-catalyzed addition to unsubstituted maleimide (R1 5 R2 5 H) gives products 140 efficiently either with conventional or microwave heating (11 examples, 34%
85% yield).100 A great deal of work has been done on asymmetric Michael addition of stabilized carbanions to maleimides and one paper101 contains a useful compilation of references to recent work (References 8
12 therein). Two more unusual examples of Michael-type addition to maleimides are the rhodium-catalyzed coupling with acrylamides 141 to give products 142,102 and [3 1 2]-cycloaddition with 143 catalyzed by a dipeptide-derived phosphine to give the bicyclic products 144.103

1.4.3 Kinetic Resolution and Enzymatic Formation of Chiral Imides Whole-cell preparations of Aspergillus fungal species have been effective in enantiospecific reduction of maleimides to give the corresponding succinimides. Both the N-phenyl compounds 145 and 146,104 and the compounds 147 and 148 with a saturated chain between nitrogen and the

22

Imides

Scheme 1.34 Asymmetric reduction of maleimides.

phenyl group,105 are effectively reduced as shown with all products formed in .99% ee (Scheme 1.34). Kinetic resolution is achieved in the borane reduction of racemic succinimides 149 with the oxazaborolidine catalysts 151 and 152, which leads to the recovery of the unreacted staring material enriched in one enantiomer 149 (up to 47% ee) while the other enantiomer is reduced to the lactam 150.106

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H and N
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19965. 96. Bouissane, L.; Sestelo, J. P.; Sarandeses, L. A. Synthesis of 3,4-Disubstituted Maleimides by Selective Cross-Coupling Reactions Using Indium Organometallics. Org. Lett. 2009, 11, 1285
1288. 97. Kolyamshin, O. A.; Danilov, V. A. N-Aryl-2-dialkylaminosuccinimides. Russ. J. Org. Chem. 2004, 40, 982
985.

28

Imides

98. Shintani, R.; Duan, W.-L.; Nagano, T.; Okada, A.; Hayashi, T. Chiral PhosphineOlefin Bidentate Ligands in Asymmetric Catalysis: Rhodium-Catalyzed Asymmetric 1,4-Addition of Aryl Boronic Acids to Maleimides. Angew. Chem. Int. Ed. 2005, 44, 4611
4614. 99. Shintani, R.; Duan, W.-L.; Hayashi, T. Rhodium-Catalyzed Asymmetric Construction of Quaternary Carbon Stereocenters: Ligand-Dependent Regiocontrol in the 1,4-Addition to Substituted Maleimides. J. Am. Chem. Soc. 2006, 128, 5628
5629. 100. Iyer, P. S.; O'Malley, M. M.; Lucas, M. C. Microwave-Enhanced RhodiumCatalyzed Conjugate
Addition of Aryl Boronic Acids to Unprotected Maleimides. Tetrahedron Lett. 2007, 48, 4413
4418. 101. Gómez-Torres, E.; Alonso, D. A.; Gómez-Bengoa, E.; Nájera, C. Enantioselective Synthesis of Succinimides by Michael Addition of 1,3-Dicarbonyl Compounds to Maleimides Catalyzed by a Chiral Bis(2-aminobenzimidazole) Organocatalyst. Eur. J. Org. Chem. 2013, 1434
1440. 102. Sharma, S.; Han, S. H.; Oh, Y.; Mishra, N. K.; Lee, S. H.; Oh, J. S.; Kim, I. S. Cross-Coupling of Acrylamides and Maleimides Under Rhodium Catalysis: Controlled Olefin Migration. Org. Lett. 2016, 18, 2568
2571. 103. Zhong, F.; Chen, G.-Y.; Han, X.; Yao, W.; Lu, Y. Asymmetric Construction of Functionalized Bicyclic Imides via [3 1 2] Annulation of MBH Carbonates Catalyzed by Dipeptide-Based Phosphines. Org. Lett. 2012, 14, 3764
3767. 104. Sortino, M.; Filho, V. C.; Zacchino, S. A. Highly Enantioselective Reduction of the C
C Double Bond of N-Phenyl-2-methyl- and N-Phenyl-2,3-dimethylMaleimides by Fungal Strains. Tetrahedron Asymm. 2009, 20, 1106
1108. 105. Sortino, M.; Zacchino, S. A. Efficient Asymmetric Hydrogenation of the C
C Double Bond of 2-Methyl- and 2,3-Dimethyl-N-phenylalkylmaleimides by Aspergillus fumigatus. Tetrahedron Asymm. 2010, 21, 535
539. 106. Barker, M. D.; Dixon, R. A.; Jones, S.; Marsh, B. J. Kinetic Resolution of Racemic Pyrrolidine-2,5-diones Using Chiral Oxazaborolidine Catalysts. Chem. Commun. 2008, 2218
2220.

CHAPTER 2

Oxidation of Lactams to Cyclic Imides Pravin C. Patil

Department of Chemistry, University of Louisville, Louisville, KY, United States

2.1 INTRODUCTION Cyclic imides exhibit an interesting broad spectrum of therapeutic activities and are considered to be privileged building blocks that have numerous applications in the synthesis of natural products, agrochemicals, pharmaceutical drugs, and polymers. Drugs, natural products, and agrochemicals such as phensuximide,1 ethosuximide,2 palasimide,3,4 Captan,5 staurosporine6 (inhibitor of protein kinase), arcyriaflavin7 (angiogenesis inhibitors), all have a five-membered succinimide scaffold as a core structure (Fig. 2.1), which is responsible for specific biological activities. Phensuximide and ethosuximide are known for antiepileptic activities while palasimide is useful to treat absence seizures (sudden lapses of consciousness mostly found in children) and Captan acts as a pesticide. The natural products staurosporine and arcyriaflavin are inhibitors of protein kinase and angiogenesis inhibitors, respectively. Glutarimide is another well-known cyclic imide known for its wide range of biological activities such as antibacterial, antitumor, antiinflammatory, and others.8 It also acts as a vector by transporting biologically active substituents through cell membranes.9 Natural products such as lamprolobine10 (alkaloid), julocrotine11 (antiproliferative), cycloheximide12,13 (eukaryote protein synthesis inhibitor), and lactimidomycin14,15 (antifungal, antiviral, and anticancer properties) have the glutarimide ring as a core scaffold and are known to deliver essential biological activities (Fig. 2.2). The phthalimide structural core is responsible for a broad array of biological activities such as analgesic,16 antiinflammatory,17 antitumor,18 antimicrobial,19 hypolipidemic,20 and anticonvulsant.21 Phthalimide derivatives are known as amino peptidase inhibitors22 and are known for the promotion of tumor necrosis factor alpha (TNFα) production.23,24 Drugs and natural products comprise an important research area, and thalidomide, Imides DOI: https://doi.org/10.1016/B978-0-12-815675-9.00002-3

© 2019 Elsevier Inc. All rights reserved.

29

30

Imides

O

O

N

O N H Ethosuximide

O Phensuximide H N O

N Ph

O

O

O Palasimide O

O N SCCl3 H N

O N

O

O Captan

N

O

Me

H

MeO

N H

NHMe

N H

Arcyriaflavin

Staurosporine

Figure 2.1 Succinimide-based drugs and natural products. O O

N H

O

HN

OH

O

O

N

O

Lamprolobine

O

Lactimidomycin

O HN

OH

O Cycloheximide

O HN

O O N O Julocrotine

Figure 2.2 Glutarimide core
based natural products.

pomalidomide, and apremilast are well-known examples of phthalimide analogs (Fig. 2.3). Thalidomide was initially used as a sedative but later it was withdrawn due to its teratogenic effect in humans. The interest in thalidomide has resumed due to its antiinflammatory activity in the treatment of erythema nodosum leprosum (ENL).25 Pomalidomide26 and apremilast27,28 are effective as an antiangiogenic and antiinflammatory agents, respectively.

Oxidation of Lactams to Cyclic Imides

31

OMe O

Me

O O

N

O

N

O

NH O

O Thalidomide

O

N

NH O

NH2 O Pomalidomide

NHAc O

O S O Me

Apremilast

Figure 2.3 Phthalimide-based drug and natural products.

As of this date, many reviews have been published on the synthesis of imides discussing the importance of imides in various research areas.29
32 This chapter will focus on applications of metal- and nonmetal-based oxidizing agents toward the selective oxidation of lactams to cyclic imides such as transformations of pyrrolidones to succinimides, piperidones to glutarimides, isoindolinones to phthalimides, and caprolactam (hexahydro2H-azepin-2-ones) to adipimide (azepane-2,7-dione).

2.2 RUTHENIUM-BASED OXIDATION OF LACTAMS Ruthenium-based oxidizing reagents such as RuO2, RuO4, and Ruporphyrin catalysts are widely used for the oxidation of various lactams such as pyrrolidones, piperidones, and their derivatives to the corresponding imides.

2.2.1 Ruthenium-Based Oxidation of Pyrrolidones Ruthenium-based oxidations of various pyrrolidones to the corresponding succinimides remains one of the most popular oxidative transformations first introduced in 1958. Some of the ruthenium-based methods for the synthesis of succinimides are discussed in the following sections. 2.2.1.1. In 1958 Berkowitz and Rylander reported the first method for the synthesis of succinimide by oxidizing 2-pyrrolidone (1) using ruthenium tetroxide.33 Although ruthenium tetroxide has powerful oxidizing properties in many solvents such as ketones, paraffins, esters, and water, the oxidation of 2-pyrrolidone required a solution of ruthenium tetroxide in carbon tetrachloride to obtain succinimide (2) in 49% yield (Scheme 2.1). The mechanism of the selective oxidation of 2-pyrrolidone to succinimide is postulated through the formation of α-hydroxylactam and was supported by experimental evidence.

32

Imides

RuO4, CCl4 O

O

N H 1

N H

O

2, 49%

Scheme 2.1 Oxidation of 2-pyrrolidone to succinimide.

RuO2 (cat.),10% NaIO4 (excess) (i)

O

N CH3 3

CCl4–water, rt, 28 h

O

N CH 3

O

4, 87% RuO2 (cat.),10% NaIO4 (excess)

(ii)

O

N C 2H 5 5

Ethyl acetate–water, rt, 15 h

O

N C2 H5

O

6, 93%

Scheme 2.2 RuO2/10% NaIO4-mediated synthesis of N-substituted succinimide derivatives.

2.2.1.2. As shown in Scheme 2.2, N-substituted lactams such as Nmethyl-2-pyrrolidone (3) was oxidized to N-methylsuccinimide (4) by using a combination of ruthenium dioxide with 10% aqueous sodium metaperiodate at room temperature in a carbon tetrachloride
water biphasic system.34 Similarly, N-ethyl-2-pyrrolidone (5) was converted to N-ethylsuccinimide (6) using the same reaction conditions except that carbon tetrachloride was replaced by ethyl acetate (Scheme 2.2). The modified method for selective oxidation is known to have the advantages of short reaction time and higher yields compared to previously known methods that used ruthenium tetroxide in carbon tetrachloride. The effects of ring size of corresponding lactams and substitution pattern were also studied. 2.2.1.3. In further studies of ruthenium-based lactam oxidation, Petride and coworkers disclosed a new method for the synthesis of benzyl-substituted succinimide from the corresponding benzyl-substituted 2-pyrrolidone.35 Using a combination of hydrated ruthenium dioxide with aqueous sodium metaperiodate in carbon tetrachloride, the authors demonstrated that N-benzylpyrrolidine (7) is converted to N-benzyl-2pyrrolidone (8) in 39.5% yields along with many oxidative side products (Scheme 2.3A)

Oxidation of Lactams to Cyclic Imides

O

(A)

+ O

N

Endocyclic attack

O

N

O

Ph

Ph

9, 1%

1.5%

Ph 8, 39.5%

O

N

COOH +

+

33

N

CHO

+ Unknown 5.5%

Ph 13.5%

CHO

N

RuO4

Exocyclic

NaIO4

attack O

Ph

+

N

7

Ph 10, 27%

4%

Other

+ Ph

N O

N H

6.5%

13.0%

O

(B) CHO

RuO 4 , NaIO 4 N

O Ph

8

CCl 4 , H 2O

O

N

O

+

Ph 9, 75%

10, 10%

Scheme 2.3 (A) RuO4/10% NaIO4-mediated oxidation of N-benzylpyrrolidine. (B) RuO4/10% NaIO4-mediated oxidation of N-benzyl-2-pyrrolidone.

In situ
generated N-benzyl-2-pyrrolidone (8) was subsequently reacted with the same reagent to give N-benzylpyrrolidine-2,5-dione (Nbenzylsuccinimide) (9) in 75% yield along with the formation of benzaldehyde (10) in approximately 10% yield as a side product, as a result of oxidation of benzylic methylene group (Scheme 2.3B). 2.2.1.4. In addition to ruthenium dioxide and ruthenium tetroxide, a Ru-porphyrin/pyridine-N-oxide system was established as a new method for the conversion of lactams to imides.36 The Ru-porphyrin catalyst [RuIV(TMP)Cl2] in combination with pyridine-N-oxide in benzene under argon atmosphere at 40°C is optimized for oxidation of N-methyl2-pyrrolidone (3) to N-methylsuccinimide (4) in excellent yield of 91% (Scheme 2.4). The importance of this newly developed catalytic oxidative system was demonstrated by conversion of N-acyl cyclic amines to N-acyl amino acids as well as an oxidation of N-acylproline to corresponding glutamates and hence could be applicable toward synthesis of diverse γ-and δ-amino acids.

34

Imides

Cl Ar

RuIV(TMP)Cl2 (0.6 mol%) 2,6-Dichloropyridine N-oxide (0.40 M) O

N CH3 3

Benzene, 40°C, Ar, 16 h, 2 days

N

N O

O N CH 3 4, 91%

Ru

Ar

N

N Ar

Ar RuIV(TMP)Cl 2 Where: Ar =

Cl

TMP = Tetramesitylporphyrinato

Scheme 2.4 RuIV(TMP)Cl2-catalyzed oxidation of N-methyl-2-pyrrolidone.

Examples 2.2.1.1. The ruthenium tetroxide solution (1.69 g of RuO4 in carbon tetrachloride) was added to the stirred solution of 1.33 g of 2-pyrrolidone in 10 mL of carbon tetrachloride while maintaining the reaction temperature at 10°C
15°C. A vigorous reaction was observed which immediately resulted in a black precipitate which developed overnight at room temperature. The precipitated ruthenium dioxide was removed by filtration and washed with carbon tetrachloride. The solid residue of ruthenium dioxide was extracted with chloroform and added to the filtrate. Evaporation of the combined organic solvents resulted in succinimide (0.5 g, 49% yield) which could be further purified by crystallization from acetone. 2.2.1.2. To a solution of 2-pyrrolidone (12 mmol) in ethyl acetate (40 mL) was added a mixture of ruthenium dioxide (120 mg) and 10% aqueous sodium metaperiodate (120 mL). The resulting reaction mixture was stirred vigorously using a mechanical stirrer with a glass blade at room temperature, and the reaction progress was monitored by TLC. After completion of the reaction (28 hours) and work up, succinimide was isolated in 87% yield. By following the same procedure, N-methylsuccinimide was isolated in 93% yield from N-methyl-2-pyrrolidone after 15 hours. 2.2.1.3. To a mixture of carbon tetrachloride (5 mL) and 10% aqueous sodium metaperiodate (10 mL, 0.4 M) was added ruthenium dioxide (10 mg) followed by N-benzylpyrrolidine (7) (1 mmol). The resulting reaction mixture was stirred for 2
10 hours at room temperature. After following the work-up procedure, N-benzylpyrrolidine-2,5-dione (9) (75% yield from N-benzyl-2-pyrrolidone) and benzaldehyde (10% yield from N-benzyl-2-pyrrolidone) were isolated along with other side products.

Oxidation of Lactams to Cyclic Imides

35

2.2.1.4. A solution of N-methyl-2-pyrrolidone (3) (0.5 mmol), 2,6dichloropyridine N-oxide (200 mg, 1.2 mmol), and RuIV(TMP)Cl2 (3 mg, 3 μmol) in benzene (3 mL) was stirred for 2 days under an argon atmosphere at 40°C. After completion of reaction, the solvent was evaporated under vacuum and the obtained crude residue was further purified by using column chromatography (eluent: dichloromethane
ethyl acetate) to furnish the corresponding N-methylsuccinimide (4) in 91% yield.

2.2.2 Ruthenium-Based Oxidation of Piperidones Ruthenium-based oxidizing reagents play an important role for the selective oxidation of piperidones to corresponding glutarimides as discussed in the following sections. 2.2.2.1. A combination of ruthenium tetroxide with aqueous sodium metaperiodate was developed for the selective oxidation of 2-piperidones to glutarimides33 (Scheme 2.5). The modified method utilized ethyl acetate as a solvent for the reaction as an aid toward improving the reaction time and yield of the products. It was discovered that the oxidative transformation of N-methyl-2-piperidone (11) to N-methylglutarimide (12) proceeded via the intermediacy of an α-hydroxylactam. Using the same protocols, N-ethyl-2-piperidone (13) was converted to N-ethylglutarimide (14) in 88% yields. RuO2 hydrate, 10% aq. NaIO 4 A

O

N CH 3

Ethyl acetate, 30h

O

11

O N CH 3 12, 92%

RuO2 hydrate, 10% aq. NaIO 4 B

O

Ethyl acetate, 9h

N

O

N

CH3

CH3

13

Scheme 2.5 RuO2/10% piperidones.

O

14, 88%

aqueous

NaIO4-mediated

oxidation

of

substituted

2.2.2.2. Another method based on RuO4-mediated oxidation was demonstrated for the transformation of N-benzylpiperidine (15) to Nbenzylglutarimide (17). When (15) was combined with hydrated RuO2, and 10% aqueous NaIO4 in CCl4, it formed several oxidative products

36

Imides

such as N-benzyllactam (16) (32.5%), N-benzylglutarimide (17) (1%), a 2,3-dioxo derivative (1%), and a ring-opening acid (42%) from endocyclic oxidation of the methylene groups of the piperidine ring.35 Beside, a few products were also observed due to exocyclic oxidation of the benzylic methylene group and they were identified as benzamide (2%), and benzaldehyde (10) (16%). The N-oxide compound was also observed in 4% yield (Scheme 2.6A). It was also reported that N-benzyllactam (16) formed in 32.5% yield from the selective oxidation of N-benzylpiperidine (15) can be converted to N-benzylglutarimide (17) in 76% yield during the course of reaction (Scheme 2.6B). COOH

(A)

O N

Endocyclic

O

+

O

N

Ph

attack

16 , 32.5%

O

+

+ O

N

Ph

Ph

17 , 1%

1%

N

CHO Ph

42%

CHO N Ph

RuO4

Exocyclic

NaIO 4 H 2O, CCl 4

attack

+

N O

Ph 2%

15

10 , 16%

Other

Ph

N O 4%

(B) CHO RuO 4, NaIO 4 O

N

H2O, CCl4, 2–10 h, rt. Ph

16

O

O

N

+

Ph 17 , 76%

10 , 10%

Scheme 2.6 (A) RuO4/10% aqueous NaIO4-mediated oxidation of N-benzylpiperidine. (B) RuO4/10% aqueous NaIO4-mediated oxidation of N-benzylpiperidone.

2.2.2.3. Higuchi and coworkers demonstrated a new method for the oxidative transformation of N-methyl-2-piperidone (11) to N-methylglutarimide (12) using a new Ru-porphyrin-based catalyst in combination with pyridine oxides.36 When N-methyl-2-piperidone (11) was subjected

Oxidation of Lactams to Cyclic Imides

37

Cl Ar Ru(TMP)Cl2 2,6-Dichloropyridine N-oxide O

N CH3 11

Benzene, 40°C, Ar, 16 h.

N

N Ru

Ar O

N O CH3 12, 21%

N

N Ar

Ar Ru IV(TMP)Cl 2 Where: Ar =

Cl

TMP = Tetramesitylporphyrinato

Scheme 2.7 Ru(TMP)Cl2-mediated synthesis of N-methylglutarimide.

to the optimized reaction conditions using the Ru(TMP)Cl2 catalyst, the corresponding N-methylglutarimide (12) was the isolated product in 21% yield after 2 days (Scheme 2.7). This oxidative system works better for conversion of 2-pyrrolidone to succinimide but in the case of sevenmembered lactam, ring-opening product was obtained. Examples 2.2.2.1. To a solution of substituted 2-piperidones (12 mmol) in ethyl acetate (40 mL) was added a mixture of RuO2 hydrate (120 mg) and 10% aqueous NaIO4 (120 mL). The reaction mixture was vigorously stirred using a mechanical stirrer at room temperature while monitoring the reaction progress by TLC. After completion of reaction and followed by work up, the corresponding N-methylglutarimide (12) and N-ethylglutarimide (14) were isolated in 92% and 88% yields, respectively. 2.2.2.2. To a mixture of carbon tetrachloride (5 mL) and 10% aqueous NaIO4 solution (10 mL, 0.4 M) was added RuO2 (10 mg) and Nbenzylpiperidine (1 mmol in 5 mL CCl4). The resulting reaction mixture was stirred for 2
10 hours at room temperature. After complete conversion of the substrate and followed by work-up procedure, all oxidation products were analyzed and identified.

2.2.3 Ruthenium-Based Oxidation of 2-(2-Oxopiperidin-3-yl) isoindoline-1,3-diones In addition to the importance in the synthesis of succinimides and glutarimides, the applications of ruthenium-based oxidizing reagents have been extended to the oxidation of substituted 2-(2-oxopiperidin-3-yl)isoindoline-1,3-diones to the corresponding thalidomide derivatives under mild conditions. Some of the applications of ruthenium-based oxidizing reagents in the synthesis of phthalidomide derivatives are described in the following sections.

38

Imides

2.2.3.1 Ruthenium-Based Oxidation of Fluorinated 2-(2-Oxopiperidin3-yl)isoindoline-1,3-dione While attempting the synthesis of fluorinated thalidomide (21), various efforts toward direct fluorination of thalidomide (18) were unsuccessful. Finally, a different strategy was discovered for the synthesis of (21) by Takeuchi and researchers. 3-Phthalimidyl-piperidin-2-one (18) underwent a sequence of reactions which involved protections/deprotection of Boc group to obtain (19) followed by fluorination to give (20) (Scheme 2.8). The imide-lactam (20) was then subjected to a selective oxidation by using catalytic amount of RuO2 in the presence of excess sodium metaperiodate in ethyl acetate
dichloromethane solvent system to provide racemic fluorinated thalidomide analog (21) in 90% yield 37 (Scheme 2.8). O

O (Boc)2O, DMAP, acetonitrile, rt, 92%

N

LiHMDS, FClO3 ,THF, –40°C, 71%

NH O

H N

O

N O

O

Boc

19

18 O

O F

TFA/ CH2Cl2 ,

RuO2 , NaIO 4

N rt, Quantitative

NH O

O

ethyl acetate, CH2Cl2, H2O, 90%.

20

F N

O NH

O

O

21

Scheme 2.8 RuO2/NaIO4-mediated synthesis of phthalidomide.

2.2.3.2 Ruthenium-Based Oxidation of Stereoselective Fluorinated 2-(2-Oxopiperidin-3-yl)isoindoline-1,3-dione In a report by Shibata, enantiomerically pure (R)-2-(3-fluoro-2-oxopiperidin-3-yl)-isoindoline-1,3-dione (22) was selectively oxidized to (R)-30 fluorothalidomide (23) in 72% yield using a combination of RuO2 and 10% aqueous NaIO4 in ethyl acetate
dichloromethane under reflux38 (Scheme 2.9). Under the same set of reaction conditions, enantiomerically pure (S)-2-(3-fluoro-2-oxopiperidin-3-yl)-isoindoline-1,3-dione (24) was also oxidized to (S)-30 -fluorothalidomide (25) in 62% yield38 (Scheme 2.10). The advantage of the RuO2/10% aqueous NaIO4 oxidizing system includes isolation of both the enantiomers in good yields with excellent enantiopurities of 99% as analyzed by HPLC technique.

39

Oxidation of Lactams to Cyclic Imides

N

O

O F

RuO2, 10% aqueous NaIO4

N

Ethyl acetate–dichloromethane, reflux

O O

F

O O

N H

22

N H

O

23, (R)-3⬘–Fluorothalidomide, 99% ee

Scheme 2.9 RuO2/10% aqueous NaIO4-mediated synthesis of (R)-3'-fluorothalidomide.

O

O F

N

RuO 2, 10% aqueous NaIO4

N

Ethyl acetate–dichloromethane, reflux

O O

N H

F

O O

N O H 25, (S)-3⬘-Fluorothalidomide, 99% ee

24

Scheme 2.10 RuO2/10% aqueous NaIO4-mediated synthesis of (S)-30 -fluorothalidomide.

2.2.3.3 Ruthenium-Based Oxidation of Difluoro and Trifluoro Analogs of 2-(2-Oxopiperidin-3-yl)isoindoline-1,3-diones In a report by Burger and researchers, 3-difluoromethyl-thalidomide and 3-trifluoromethyl thalidomide were synthesized by oxidizing the corresponding fluorinated precursors of 2-(2-oxopiperidin-3-yl)isoindoline1,3-diones, by using a combination of RuO2 hydrate and 10% aqueous NaIO4 under mild conditions.39 More specifically, 3-difluoromethyl-3(phthalimido) piperidin-2-one (26) and 3-trifluoromethyl-3-(phthalimido) piperidin-2-one (28) were exposed to optimized reaction conditions which were mediated by RuO2 hydrate and an excess of 10% aqueous NaIO4 at room temperature. The optimized conditions afforded the corresponding phthalidomide analogs, 3-difluoromethyl-3-(phthalimido) piperidin-2,6-dione (27) and 3-trifluoromethyl-3-(phthalimido)piperidin2,6-dione (29) in 65% yields, respectively (Scheme 2.11). O

NH O

O

RuO2 hydrate, 10% aqueous NaIO4(10.0 equiv.)

R1 N

R1 N

Dichloromethane, rt, 3 days

O

O

1

O

1

26, R = CHF2 28, R 1 = CF3

Scheme 2.11 Synthesis thalidomides.

O NH

27, R = CHF2 , 65% 29, R 1 = CF3, 65%

of

difluoromethyl

and

trifluoromethyl

analogs

of

40

Imides

2.2.3.4 Ruthenium-Based Oxidation of Deuterio-2-(2-Oxopiperidin3-yl)isoindoline-1,3-dione The application of the RuO2/10% aqueous NaIO4 oxidizing system was extended to a synthesis of a novel deuteriothalidomide analog by selective oxidation of its precursor lactam.40 In detail, (30) was subjected to a selective oxidation by using RuO2 hydrate (0.5 equiv.) and excess of 10% aqueous NaIO4 in a biphasic solvent system to provide racemic 2-(3-deuterio-2,6-dioxo-piperidin-3-yl)-isoindol-1,3-dione (31) in 95% yield (Scheme 2.12). The enantiomers of (31) were separated by chiral HPLC to obtain each enantiomer in 99% ee. O

O D

RuO 2 (0.5 eq), 10% aq. NaIO 4 (excess)

N N O O 30

H

Water/ethylacetate/dichloromethane, 40°C, overnight, 95%

D N

O N

O O 31

H

Scheme 2.12 Oxidation of deuterio-2-(2-oxopiperidin-3-yl)isoindoline-1,3-dione.

Examples 2.2.3.1 Typical Procedure for Selective Oxidation of Lactam (20) to Imide (21) To a mixture of 10% aqueous NaIO4 (10 mL) and RuO2 (90 mg, 0.676 mmol) was added a solution of 2-(3-fluoro-2-oxo-piperidin-3-yl)isoindol-1,3-dione (20) (350 mg, 1.34 mmol) dissolved in ethyl acetate (20 mL) and dichloromethane (5 mL). The resulting reaction mixture was stirred overnight at 40°C whereupon addition of small amount of 2propanol decomposed the excess reagent. The formation of insoluble material in the reaction mixture after overnight stirring was removed by filtration. The filtrate was poured into water (30 mL) and repetitively extracted with 200 mL of ethyl acetate. The organic layer was washed with 10% Na2S2O3 (30 mL), brine (30 mL), and dried over MgSO4. The organic layer was evaporated under vacuum and the resultant crude residue was recrystallized from ethanol to give the fluorothalidomide (21) (330 mg, 90% yield) as a colorless crystal. 2.2.3.2 Synthesis of (R)-30 -Fluorothalidomide (23) A solution of (R)-2-(3-fluoro-2-oxopiperidin-3-yl)-isoindoline-1,3dione (22) [63.6 mg, 0.243 mmol, dissolved in a mixture of ethyl acetate (6.4 mL) and 1,2-dichloromethane (1.6 mL)] was added to a solution of

Oxidation of Lactams to Cyclic Imides

41

RuO2 (16.1 mg, 0.121 mmol) and 10% aqueous NaIO4 (5.0 mL) at room temperature. The reaction mixture was heated to reflux for 1.5 hours before addition of a small amount of 2-propanol. The resulting reaction mixture was filtered to separate insoluble matter and the filtrate was extracted with ethyl acetate. The organic layer was washed with 10% aqueous solution of Na2S2O3 followed by brine solution. The organic layer was dried over anhydrous sodium sulfate and evaporated under reduced pressure. The product, (R)-30 -fluorothalidomide (23), was isolated as a white solid in 58.5 mg (87% yield) and 99% ee. Synthesis of (S)-30 -Fluorothalidomide (25) To a mixture of 10% aqueous solution of NaIO4 (2.1 mL) and RuO2 (7.0 mg, 0.053 mmol) was added a solution of (S)-2-(3-fluoro-2-oxopiperidin-3-yl)-isoindoline-1,3-dione (24) (27.6 mg, 0.105 mmol, 99% ee) dissolved in a mixture of ethyl acetate (2.8 mL) and 1,2-dichloromethane (0.7 mL). The reaction mixture was heated to reflux and the temperature was maintained for 2.5 hours before addition of small amount of 2propanol. The formation of insoluble matter in the reaction mixture was separated by filtration and the filtrate was extracted with ethyl acetate. The organic layer was washed with 10% aqueous solution of Na2S2O3 followed by brine solution. The organic layer was dried over anhydrous sodium sulfate and evaporated under vacuum to obtain the desired product (S)-30 -fluorothalidomide (25) in 89% yield (25.8 mg) with 99% ee as analyzed by chiral HPLC. 2.2.3.3 Typical Procedure for the Synthesis of 3-Difluoromethyl-3(phthalimido)piperidin-2, 6-dione (27) To dichloromethane (10 mL) was added 3-difluoromethyl-3-(phthalimido) piperidin-2-one (26) (25 mg, 0.294 mmol) and RuO2 hydrate. To this solution was added 10% aqueous NaIO4 (10 equiv.) and the resulting mixture was stirred for 3 days (room temperature). After satisfactory progress of the reaction, the layers were separated. The aqueous layer was extracted with dichloromethane (3 3 15 mL) and the fractions were combined with previously separated organic layer. To the combined organic layer, 0.1 mL of methanol was added to consume the excess oxidant. The mixture was then filtered and the filtrate was washed with 5 mL of 10% aqueous Na2S2O3. The solvent was removed under vacuum and the residue was further purified by column chromatography to give pure 3-difluoromethyl-3-(phthalimido)piperidin-2,6-dione (27) in 65% yield (14 mg). By following similar protocols, 3-trifluoromethyl-3-(phthalimido)piperidin-2one (28) (0.10 g, 0.32 mmol) was oxidized to 3-trifluoromethyl-3-(phthalimido)piperidin-2,6-dione (29) in 65% yield (68 mg).

42

Imides

2.2.4 Ruthenium-Based Oxidation of Caprolactams In addition to an effective role in the selective oxidation of pyrrolidones, piperidones, 2-(2-oxopiperidin-3-yl)isoindoline-1,3-diones, the ruthenium-based oxidizing system was also found applicable for a selective oxidation of caprolactams to corresponding adipimides (azepane-2,7diones). Yoshifuji and researchers have developed a new method for the selective oxidation of substituted caprolactams to the corresponding adipimides.34 When N-alkyl-substituted caprolactams such as N-methyl (32), N-ethyl (35), and N-isopropyl (38) were subjected to a selective oxidation by using a combination of RuO2 hydrate and 10% aqueous NaIO4 in ethyl acetate, the corresponding imides (33), (36), and (39) were obtained in 38%, 53%, and 89% yields, respectively, along with the formation of side products (34) and (37). The desired imides were formed due to the selective oxidation of endocyclic methylene groups while N-carbonyl substituted imides (34) and (37) were formed as side products due to oxidation of N-methylene group (Scheme 2.13). From the results obtained, it was concluded that the N-alkyl caprolactam bearing an exocyclic tertiary carbon attached to nitrogen (38) was found less susceptible to exocyclic oxidation as compared to the primary (in 32) and secondary carbons (in35) which were attached to the nitrogen.

RuO 2 hydrate, 10% aq. NaIO4 O

N CH 3

Ethyl acetate, rt

+ O

N O CH3

RuO 2 hydrate, 10% aq. NaIO4 O

O O

33, 38%

32

N

+

Ethyl acetate, rt

N

O H

34, 35%

+ O

N

O

N

O O

35

36, 53%

O CH 3

37, 40%

RuO 2 hydrate, 10% aq. NaIO4 O

N 38

Ethyl acetate, rt

O

N

O

39, 89%

Scheme 2.13 RuO2/10% NaIO4-based oxidation of N-alkyl caprolactams.

O

N CH3 32, 24%

Oxidation of Lactams to Cyclic Imides

43

2.3 MANGANESE-BASED OXIDATION OF LACTAMS Manganese-based salts are known in the literature for the selective oxidation of lactams to corresponding imides.

2.3.1 Manganese-Based Oxidation of Pyrrolidones Manganese salts such as manganese chloride and manganese perchlorate have been used for the oxidation of pyrrolidones to succinimides. 2.3.1.1. A new reaction system comprising peracetic acid (CH3COOOH) and manganese chloride (MnCl2) under microwave irradiation (90 W for 5 minutes), with ethyl acetate as a solvent, was developed for the selective oxidation of 2-pyrrolidone to succinimide41 (Scheme 2.14). By using this method, unsubstituted 2-pyrrolidone (1) was converted to the corresponding unsubstituted succinimide (2). This method has the advantages of better reaction velocity, higher yield, improved selectivity, and scalability when compared to other transition metal salt-based oxidizing systems. CH 3 COOOH, MnCl 2, O

N H 1

Microwave irradiation (90 W), ethyl acetate, 5 min.

O

N H

O

2, 70%

Scheme 2.14 Mn
peracid-catalyzed oxidation of 2-pyrrolidone.

2.3.1.2. Recently, Browne and coworkers reported a new method which involved a combination of manganese perchlorate (MnII(ClO4)2  6H2O), pyridine-2-carboxylic acid, butanedione, sodium acetate, and hydrogen peroxide for the selective oxidation of secondary alcohols to ketones and oxidation of alkanes to ketones. After obtaining encouraging results from these methods, the authors further demonstrated the selectivity toward the α-methylene over N-methyl C
H groups of N-methyl-2-pyrrolidone. The optimized oxidative method was found useful for the conversion of N-methyl-2-pyrrolidone (3) to the corresponding N-methylsuccinimide (4) with both good conversion of 83% and moderate yield (34%)42 (Scheme 2.15). The method has the Mn(ClO4)2·6H2O (0.01 mol%), pyridine-2-carboxylic acid (0.5 mol%), NaOAc (1 mol%), butanedione (0.5 equiv.), O

N CH3 3

50 wt% H2O2 (3.0 equiv.), acetonitrile, 12–16 h.

O

N

O

CH3 4, 34%

Scheme 2.15 Mn(ClO4)2-mediated selective oxidation of N-methylpyrrolidone.

44

Imides

advantage of being catalytic with high turnover numbers and utilizes a stoichiometric amount of hydrogen peroxide. The reaction is scalable up to 4 g, proceeds with high selectivity, and is compatible with various protecting groups. Examples 2.3.1.1. A solution of MnCl2 in ethyl acetate (1025 mol in 10 mL of ethyl acetate) and a solution of 2-pyrrolidone (0.025 mol in 20 mL of ethyl acetate) were mixed in a 100-mL Erlenmeyer flask. The solution was cooled to 0°C
5°C and peracetic acid (0.045 mol, 25% solution in ethyl acetate) was added dropwise with extreme caution, while maintaining a temperature of 0°C
5°C. After complete addition of peracetic acid, the reaction flask was placed in a microwave oven and irradiated at 90 W power for 5 minutes. After microwave irradiation, the solvent was evaporated under reduced pressure to give succinimide in 70% yield. 2.3.1.2. To a stock solution of Mn(ClO4)2  6H2O (0.1 mol%, 0.361 mg) and pyridine-2-carboxylic acid (1.0 mol%, 0.246 mg) in acetonitrile was added N-methyl-2-pyrrolidone to generate a concentration of 0.5 M. To the resulting mixture was added a solution of sodium acetate (aqueous 0.6 M, 2 mol%, 33.4 μL) and butanedione (1.5 equiv., 130.5 μL) to generate a final volume of 2 mL. The reaction mixture was cooled in an ice/water bath and then H2O2 (50 wt%, 4.0 equiv., 227 μL) was added while stirring. After 12
16 hours of stirring, brine (10 mL) was added to the reaction mixture which was then extracted with dichloromethane (3 3 10 mL). The organic layers were combined and concentrated to obtain a residue which was further purified by flash column chromatography on silica gel to give N-methylsuccinimide in 34% yield.

2.3.2 Manganese-Based Oxidation of Piperidones Selective oxidation of piperidones to the corresponding glutarimides was reported by using manganese salt such as manganese chloride. A new method for the selective oxidation of unsubstituted 2-piperidone (40) to glutarimide (41) was established by using a combination of peracetic acid with a manganese salt (MnCl2) under microwave irradiation in ethyl acetate.41 The reaction system was found advantageous by utilizing a shorter reaction time (5 minutes) and resulted in a higher yield (85%) and better selectivity (Scheme 2.16).

Oxidation of Lactams to Cyclic Imides

45

CH3COOOH, MnCl 2 , O

N H 40

Microwave irradiation (90 W), ethyl acetate, 5 min.

N H

O

O

41, 85%

Scheme 2.16 Oxidation of 2-piperidone using peracid
Mn salt.

Example 2.3.2. To a solution of MnCl2 in ethyl acetate was added piperidone (0.025 mol) dissolved in 20 mL ethyl acetate. The reactants were mixed in a 100-mL Erlenmeyer flask and cooled to 0°C
5°C. To this solution was dropwise added peracetic acid (0.045 mol) with extreme caution, maintaining a temperature 0°C
5°C. After complete addition, the reaction mixture was subjected to microwave irradiation at 90 W power for 5 minutes. The solvent was evaporated and the glutarimide was isolated in 85% yield after recrystallization.

2.4 MOLECULAR OXYGEN
BASED OXIDATION OF LACTAMS Lactams have been selectively oxidized to corresponding imides by using molecular oxygen as a choice of oxidant.

2.4.1 Molecular Oxygen
Based Oxidation of Pyrrolidones In addition to the importance of ruthenium and manganese metal complexes toward the synthesis of succinimide, the use of molecular oxygen for the same oxidative transformation was considered as an important metal-free alternative. 2.4.1.1 Molecular Oxygen in Combination With a Photolytic Irradiation The transformation of 2-pyrrolidone to succinimide using oxygenmediated photolytic irradiation has been known since the 1980s. Gramain and colleagues studied a photolytic transformation of unsubstituted and substituted pyrrolidones to the corresponding succinimides.43 When 2-pyrrolidone (1) was exposed to photolysis in the presence of benzophenone in tert-butanol and molecular oxygen, succinimide (2) was obtained in 60% yield. Similarly, N-methyl-2-pyrrolidone (3) was converted to N-methylsuccinimide (4) in 60% yield in tert-butanol (Scheme 2.17). The mechanism of oxidative transformation was postulated to involve radical formation.

46

Imides

Photolytic irradiation, Ph2CO, O2 O

N H 1

tert-BuOH 60%

O

O

N H 2

O

O N CH 3 4

Photolytic irradiation, Ph2CO, O2 O

N CH 3 3

tert-BuOH 60%

Scheme 2.17 Synthesis of succinimide derivatives by photolysis.

2.4.1.2 Molecular Oxygen in Combination With Photolysis and TiO2 A photolytic irradiation of 2-pyrrolidone (1) in the presence of oxygenated aqueous suspensions of TiO2 under a constant stream of oxygen resulted in a synthesis of succinimide (2)44 (Scheme 2.18). Control experiments confirmed that the oxidation required light, TiO2, and oxygen. There was no consumption of starting material either in the absence of TiO2 or in a nitrogen-purged suspension of TiO2. Both 2-pyrrolidone (1) and N-methyl-2-pyrrolidone (3) were successfully provided corresponding succinimides, (2) and (4), respectively, under the optimized reaction conditions. Photolytic irradiation, O2 O

N H 1

Aqueous suspension of TiO2, 48 h.

O

N CH3 3

Aqueous suspension of TiO2, 48 h.

O

N H 2

O

O

O N CH3 4

Photolytic irradiation, O2

Scheme 2.18 TiO2-mediated photolytic synthesis of succinimides.

2.4.1.3 Oxygen-Mediated Oxidation Under Pressure Molecular oxygen mediated the facile and uncatalyzed oxidative transformation of N-methyl-2-pyrrolidone (3) to N-methylsuccinimide (4), as reported45 by Drago and Riley in 1990 (Scheme 2.19). This newly

Oxidation of Lactams to Cyclic Imides

47

O2 (50 psi), 105°C O N CH3

36 h

O

N CH3

O

4

3

Scheme 2.19 Molecular oxygen
mediated synthesis of succinimide.

developed system was considered to be a better alternative to metal-catalyzed air oxidation methods, which suffer from low yields. The mechanism of this oxidative transformation involves the intermediacy of 5-hydroperoxo-1-methyl-2-pyrrolidinone. 2.4.1.4 Aerobic Oxidation of N-alkylamides Catalyzed by NHydroxyphthalimide A combination of N-hydroxyphthalimide (NHPI), Co(II) salt, and molecular oxygen is effective for the oxidation of a lactam under mild conditions to form an imide. The product distribution is mainly dependent on the nature of the N-alkyl group and on the reaction conditions. For example, primary N-benzylamides give imides and aromatic aldehydes at room temperature while amides without the N-benzyl substituent provided imides and carboxylic acids. When 2-pyrrolidone (1) was subjected to the optimized reaction conditions (80°C in 5 hours), succinimide (2) was obtained in an excellent yield of 93%46 (Scheme 2.20). N-OH-phthalimide (0.5 mmol) Co(OAc) 2 (0.025 mmol) O

N H 1

O2 atm, AcOH, 80°C, 5 h.

O

N H

O

2

Scheme 2.20 Molecular oxygen
Co(II) salt-mediated succinimide synthesis.

A mechanistic investigation supported the abstraction of an H atom from the substrate by the phthalimide-N-oxyl (PINO) radical, which was formed in situ from NHPI using a combination of molecular oxygen and Co (II) salt (Scheme 2.21).

48

Imides

+

CO (II)

.

(i)

CO (III)OO

O2

O

O

.+

CO (III)OO

HO N

CO (III)OOH

+

PINO

O

.

.

R

O N O

(ii)

O N O

O NHPI O R-H

+

.

+

HO N

(iii)

O NHPI

PINO

Scheme 2.21 Postulated mechanistic pathway for oxidative transformation.

2.4.1.5 Oxidation of Lactam by Laccase-Generated Aminoxyl Radicals When NHPI and 1-hydroxy-benzotriazole (HBT) were subjected to enzyme laccase (isolated from fungus Trametes villosa), the corresponding PINO and BTNO (benzotriazole-N-oxyl) radicals were generated, respectively. It was determined that the lactams were oxidized in the presence of these radicals under optimized reaction conditions (Scheme 2.22). According to this protocol, when N-benzyl-2-pyrrolidone (8) was subjected to optimized reaction conditions, using HPI, it provided N-benzylsuccinimide (9) in 19% yield after 24 hours.47 Imide (90 ) was also formed in 4% yield due to the oxidation of benzylic methylene group. Interestingly, when HBT was used instead of HPI, no imide formation

O

O

N OH O N-OH-Phthalimide (NHPI) N

N OH 1-Hydroxy-benzotriazole (HBT)

. R 2NO

+

Sub-H

N OH O Phthalimide-N-oxyl (PINO)

Enzyme-laccase from Trametes villosa

N

.

Enzyme-laccase from Trametes villosa

R 2NOH

+ Sub

.

Scheme 2.22 Route of oxidation via an aminoxyl radical.

N N N . O Benzotriazole-N-oxyl (BTNO)

O2

Sub OX

Oxidation of Lactams to Cyclic Imides

Enzyme-laccase from Trametes villosa O

O2, HPI or HBT, buffered soln (pH = 5) 25°C, MeCN, 24 h

N Ph 8

49

+ O

N

O Ph

9 19% by using HPI 0% by using HBT

O

N O

Ph

9' 4% by using HPI 0% by using HBT

Scheme 2.23 Laccase-mediated enzymatic synthesis of N-benzylsuccinimide.

(9 or 90 ) was observed (Scheme 2.23). The mechanism involves abstraction of H from endocyclic N-methylene group of pyrrolidone by PINO radical (formed from NHPI by reacting with laccase enzyme) followed by subsequent oxidation via hydroperoxide formation. Examples 2.4.1.1. Photolysis (medium pressure Hanovia mercury vapor lamp, 150-W, Pyrex reactor) of an oxygen-saturated solution of N-methyl-2pyrrolidone (2.0 g) in tert-BuOH (70 mL) and oxygen-saturated benzophenone (1.0 g), provided N-methylsuccinimide in 60% yield after column chromatography on silica gel. 2.4.1.2. Photolysis (200-W high-pressure Hg lamp/Pyrex filter) of 10 mL of 0.2 M aqueous solution of 2-pyrrolidone in the presence of 100 mg of suspended unreduced anatase TiO2 under a constant flow of oxygen for 48 hours gave succinimide in excellent yield. 2.4.1.4. In a three-necked flask was placed 2-pyrrolidone (5 mmol), NHPI (0.5 mmol), and Co(OAc)2 (0.025 mmol) in 10 mL of acetonitrile or acetic acid under an oxygen atmosphere. The reaction mixture was slowly heated to 80°C and stirring was continued for 5 hours. After completion of reaction, the catalyst was removed by filtration through silica gel and the filtrate was analyzed by gas chromatography. By following the above optimized protocol, 2-pyrrolidone was converted to succinimide in 93% yield.

2.4.2 Molecular Oxygen
Based Oxidation of Piperidones A clean, inexpensive, and environmentally benign process was developed by Kus and Kazaz in 2008 for the selective oxidation of 2-piperidone (40) to glutarimide (41).48 Increasing the yield of the oxidation product was found to be directly related to increasing the oxygen pressure (Scheme 2.24).

50

Imides

O2 Pressure (bar)

O2, subcritical water, O

N H

110°C, 4 h.

O

40

N H

O

41

41, % yield

5 10 15 20

45 45 50 60

Scheme 2.24 Oxidation of 2-piperidone to glutarimide in subcritical water.

2.4.3 Molecular Oxygen
Based Oxidation of Caprolactams The role of molecular oxygen as an oxidizing reagent was effective for the selective oxidation of caprolactam and was used for the synthesis of adipimide. When the caprolactam (42) was subjected to selective oxidation using molecular oxygen in subcritical water, the corresponding adipimide was obtained (43).48 The reaction was performed in 280 mL of water as a solvent, using 1 mol equiv. of the substrate and 2 mol equiv. of molecular oxygen. From the results obtained, it was concluded that by increasing the oxygen pressure from 5 to 20 bar, the yield of the adipimide was also increased linearly from 35% to 55% (Scheme 2.25). O 2 Pressure (bar)

O2, subcritical water O

N H 42

O

N H 43

O

5 10 15 20

43, % yield 35 40 42 55

Scheme 2.25 Molecular oxygen
mediated adipimide synthesis in subcritical water.

2.5 DIOXIRANE-BASED OXIDATION OF LACTAMS The role of dioxirane for oxidation of lactams to imides was considered as a nonmetal-based alternative approach for this transformation.

2.5.1 Dioxirane-Based Oxidation of Pyrrolidones Recently, D’Accolti, Zonta, and coworkers discovered a new approach for the oxidation of lactams to succinimides mediated by dioxiranes.49 The researchers studied the oxidation of 5
13-membered ring lactams using two different dioxirane derivatives such as dimethyl dioxirane (DDO) and methyl (trifluoromethyl) dioxirane (TFDO) under the same reaction conditions. Interestingly, this method allowed control of the oxidation of N
H versus C
H bonds in lactams by varying the dioxirane reagents. The TFDO preferentially led to N
H oxidation whereas DDO favored C
H oxidations in lactams. When 2-pyrrolidone (1) was subjected to optimized reaction conditions by using DDO, it provided succinimide (2) in excellent yield (99%) and none of the N
H oxidation of

Oxidation of Lactams to Cyclic Imides

H3C

O O

25°C, 48 h. O

O

H3C

O

N H

F 3C

O O

0°C, 3 h.

O O

Dimethyl dioxirane (DDO)

2, 99% N H 1

51

O O2N

F3C OH

O O

Methyl (trifluromethyl) dioxirane (TFDO)

44, 99%

Scheme 2.26 Dioxirane-mediated oxidations of pyrrolidone.

lactam was detected (Scheme 2.26). Alternatively, using the same set of reaction conditions and TFDO at 0°C, a nitroacid formed via N
H oxidation was selectively produced and none of the succinimide was observed. From the formation of succinimide (2) and nitroacid (44) from 2-pyrrolidone (1) by using DDO and TFDO, it was postulated that DDO favors 1e (1 electron) C
H oxidation whereas TFDO has the tendency toward the 2e (2 electron) N
H oxidation pathways. Example 2.5.1. To chilled acetone was added 2-pyrrolidone (0.5 mmol) and DDO (5
20 equiv.) at 0°C. The reaction mixture was slowly brought to room temperature with constant stirring. The reaction progress was monitored by TLC analysis using n-hexane/ethyl acetate as a mobile phase. After completion of the reaction, acetone was removed under reduced pressure and the resulting residue was further purified by column chromatography to obtain the pure succinimide in 99% yield.

2.5.2 Dioxirane-Based Oxidation of Piperidone In addition to oxidation of 2-pyrrolidone, the dioxiranes were found useful for oxidation of piperidone. The authors have demonstrated the effect of two different dioxiranes such as DDO and TFDO for the oxidation of 2-piperidone (40).49 The methodology has delivered interesting results whereby the type of dioxirane controls the formation of product. For example, when 2-piperidone (40) was reacted with DDO under optimized reaction conditions, glutarimide (41) was formed in 99% yield from oxidation of the C
H bond. Alternatively, when the same reaction was carried out by using TFDO, it provided the open chain nitro acid (45) (90% yield) obtained due to the oxidation of N
H bond (Scheme 2.27). Apparently, DDO and TFDO favored preferentially the C
H and N
H bond oxidation, respectively.

52

Imides

H 3C

O O

25°C, 48 h

O

N H 40

O

O N H 41, 99%

O O

H 3C

Dimethyl dioxirane (DDO) O O

F3 C F3 C

O O

0°C, 3 h

Methyl (trifluoromethyl) dioxirane (TFDO) OH

O2 N 45, 90% O

Scheme 2.27 Dioxirane-mediated oxidation of 2-piperidone.

2.6 POTASSIUM PERSULFATE
BASED OXIDATION OF LACTAMS A combination of potassium persulfate and dipotassium hydrogen phosphate was utilized for the selective oxidation of lactams to imides as discussed in the following sections.

2.6.1 Potassium Persulfate
Based Oxidation of Pyrrolidones Oxidation of pyrrolidones using a combination of potassium persulfate and dipotassium hydrogen phosphate to obtain a corresponding succinimides was reported by Needles and Whitfield during the 1970s.50 More specifically, when 2-pyrrolidone (1) or N-methyl-2-pyrrolidone (3) were subjected to a combination of potassium persulfate and dipotassium hydrogen phosphate in distilled water at 85°C
90°C, the corresponding succinimide (2) or N-methylsuccinimide (4) were obtained in 61% and 35%, respectively (Scheme 2.28). The mechanism of persulfate-mediated oxidation is postulated through free radical attack on the methylene 2K2S2O8, 4K2HPO4 O

N H 1

H2O, 85°C–90°C

O

O N H 2, 61%

2K2S2O8, 4K2HPO4 O

N CH 3 3

H2O, 85°C–90°C

O

N

O

CH 3 4, 35%

Scheme 2.28 Potassium persulfate
mediated synthesis of succinimide.

Oxidation of Lactams to Cyclic Imides

53

adjacent to the amide nitrogen. One of the noteworthy features of this method was the selectivity, where the N-methyl position remained unchanged and oxidation occurred only at the α-methylene position. Example 2.6.1. To a 500-mL round bottom flask was added 2-pyrrolidone (1) or (3) (0.05 mole), potassium persulfate (0.1 mole), dipotassium hydrogen phosphate (0.2 mole) followed by 250 mL of distilled water. Nitrogen gas was bubbled through the reaction mixture for an hour and the reaction mixture was kept under a nitrogen atmosphere throughout the course of the reaction. The reaction mixture was slowly heated to 65°C where an exotherm was observed up to 85°C
90°C. The elevated reaction temperature (85°C
90°C) was maintained for 30 minutes. After completion of reaction, the water was removed from the reaction mixture by distillation. The corresponding succinimides (2) or (4) were isolated after work up.

2.6.2 Potassium Persulfate
Based Oxidation of Piperidones Similarly to the oxidation of pyrrolidones, the combination of potassium persulfate and dipotassium hydrogen phosphate effected a selective oxidation of 2-piperidones to glutarimides.50 When 2-piperidone (40) (0.05 mole) was reacted with 2 moles of persulfate and 1 mole of dipotassium hydrogen phosphate in distilled water at 85°C
90°C, provided glutarimide (41) in 23% yield. Following the same protocols, N-methyl2-piperidone (11) provided N-methylglutarimide (12) in 47% yield (Scheme 2.29). 2K2S2O8, 4K2HPO4

O

N H

H2O, 85°C–90°C

O

40

N H

O

41, 23%

2K2S2O8, 4K2HPO4

O

N CH3 11

H2O, 85°C–90°C

O

N O CH3 12, 47%

Scheme 2.29 Potassium persulfate
mediated synthesis of glutarimides.

54

Imides

2.7 PERACID-BASED OXIDATION OF LACTAMS Peracid has been used for the selective oxidation of lactams to imides. The following are some oxidative transformations representing applications of peracid as a selective oxidizing reagent.

2.7.1 Peracid-Based Oxidation of Substituted 2-(2-Oxopiperidin-3-yl)isoindoline-1,3-diones The use of peracid for the selective oxidation of differently substituted 2-(2-oxopiperidin-3-yl)isoindoline-1,3-diones to the corresponding phthalidomide analogs is reported. 2.7.1.1. The m-chloroperoxybenzoic acid (m-CPBA) is one of the most widely used peracids due to its selective oxidizing properties as well as cheap and easy availability. In 1989 Knabe and Omlor have demonstrated an application of m-CPBA for the selective oxidation of alkyl substituted 2-(2-oxopiperidin-3-yl)isoindoline-1,3-diones analogs such as methyl (46), ethyl (48), and propyl (50) to the corresponding phthalidomides (47), (49), and (51), respectively51 (Scheme 2.30). O

O m-CPBA, CCl 4

R N NH O

R N

O

40°C, 24 h

NH

O

O

46 , R = CH 3, 47% 48, R = C 2H 5 , 16% 50 , R = C 3H 7 , 24%

47 , R = CH 3, 47% 49, R = C 2H 5 , 16% 51 , R = C 3H 7 , 24%

Scheme 2.30 m-Chloroperoxybenzoic phthalidomides.

acid-mediated

O

synthesis

of

alkyl

2.7.1.1 Peracid-Based Oxidation of Methyl-Substituted 2-(2-Oxopiperidin-3-yl)isoindoline-1,3-diones During the development of biological response modifiers (BRMs) based on thalidomide and further investigation of molecular mechanisms of thalidomide, Hashimoto and researchers found that a pure enantiomer of unsubstituted thalidomide undergoes racemization upon subjected to physiological conditions which was believed to be due to acidic proton at the α-position. To overcome this issue, the researchers attempted a synthesis of α-methylthalidomide (47) in 38% yield by oxidizing 2-(3-methyl-2-oxopiperidin-3-yl)isoindoline-1,3-dione (46) with m-CPBA

55

Oxidation of Lactams to Cyclic Imides

O

O m-CPBA

N NH O

N

O NH

38% O

O

46

O

47, Methylthalidomide

Scheme 2.31 m-Chloroperoxybenzoic α-methylthalidomide (47).

acid-mediated

synthesis

of

at room temperature.52 Later, it was concluded that substitution of the methyl group by replacing hydrogen at α-position was supportive toward stabilizing its configuration under physiological conditions (Scheme 2.31). 2.7.1.2 Peracid-Based Oxidation of Substituted Stereoselective 2-(2-Oxopiperidin-3-yl)isoindoline-1,3-diones To investigate the effect of electron-donating amino groups substituted on the phthaloyl moiety of α-methylthalidomides for related TNFα-production enhancing activity, Hashimoto and coworkers synthesized differentially substituted α-methylthalidomide analogs.53 The precursors of substituted 2-(2-oxopiperidin-3-yl)isoindoline-1,3-diones were selectively oxidized to thalidomide analogs using m-CPBA in CCl4 under mild conditions (Scheme 2.32). The thalidomide analogs bearing substitution, H (53), 4-NO2 (55), 4-NH2 (57), 4-F (59), 5-NO2 (61), 5-NH2 (63), 5Me (65), and 4,5,6,7-F (67) on the phthalimide ring were synthesized. It was reported that both the enantiomers for each substitution were synthesized and further biological activity was studied.

R

O Me N

m-CPBA, CCl 4 R

O Me N

NH O

O

52, R = H 54, R = 4-NO2 56, R = 4-NH2 58, R = 4-F 60, R = 5-NO2 62, R = 5-NH2 64, R = 5-Me 66, R = 4, 5, 6, 7-F

O NH

O

O

53, R = H 55, R = 4-NO2 57, R = 4-NH2 59, R = 4-F 61, R = 5-NO2 63, R = 5-NH2 65, R = 5-Me 67, R = 4, 5, 6, 7-F

Scheme 2.32 Synthesis of substituted stereoselective phthalidomides.

56

Imides

2.7.2 Peracid-Based Oxidation of Isoindolinones The oxidative properties of m-CPBA was further explored by Luzzio and coworkers by investigating the oxidation of N-substituted isoindolinones (or N-substituted phthalimidines) to the corresponding phthalimides using a combination of m-CPBA with 2,20 -bipyridinium chlorochromate (BPCC) in dichloromethane under mild conditions.54 Using optimized conditions, the N-substituted isoindolinones such as (68), (70), (72), (74), and (76) were selectively oxidized to the corresponding phthalimides (69), (71), (73), (75), and (77), respectively. The isoindolinones with N-benzyl substitution were selectively oxidized to the corresponding N-benzylsubstituted phthalimides and oxidation of benzylic methylene group was not observed under optimized reaction conditions (Scheme 2.33).

N R O 68, 70, 72, 74, 76,

R R R R R

= = = = =

O

2, 2⬘-Bipyridinium Chlorochromate (BPCC), m-CPBA, celite

N R

Dichloromethane, rt. 46%–76% yield

–CH2CH(CH3)2 –CH(CH3)Ph –CH2CH2Ph –CH2Ph –CH2(CH2)2CH2 OBz

O 69, 71, 73, 75, 77,

R R R R R

= = = = =

–CH2CH(CH3)2 : 76% –CH(CH3)Ph : 70% –CH2CH2Ph : 60% –CH2Ph : 55% –CH2(CH2)2CH2 OBz: 46%

Scheme 2.33 2,20 -Bipyridinium chlorochromate/m-chloroperoxybenzoic mediated oxidation of N-substituted isoindolinones.

acid-

2.8 HYPERVALENT IODINE-BASED OXIDATION OF LACTAMS Hypervalent iodine reagents are prevalent due to many types of selective oxidizing properties under mild conditions. Recently, various oxidizing reagents such as periodic acid and o-iodoxybenzoic acid (IBX) have been used for the selective oxidation of lactams to the imides.

2.8.1 Periodic Acid-Based Oxidation of Substituted 2-(2-Oxopiperidin-3-yl)isoindoline-1,3-diones Considering the importance of enantiomers of 3-methylthalidomide due to their enhanced TNF-α inhibition activity and configurational stability, a simple and stereoselective synthesis of the configurationally stable analog of thalidomide, (R)-3-methylthalidomide was developed by Haq and researchers. The methyl-substituted 2-(2-oxopiperidin-3-yl)isoindoline1,3-diones (78) were selectively oxidized to (R)-3-methylthalidomide

57

Oxidation of Lactams to Cyclic Imides

O

O H 5IO6 , AC 2O, CrO 3 N

N

CH3 CN, 0°C, 95% O

O O

N O H 79, (R)-3-methylthalidomide

N H

O

78

Scheme 2.34 Periodic acid-mediated synthesis of (R)-3-methylthalidomide.

using a combination of periodic acid with chromium trioxide in acetonitrile and provided the desired enantiomer (79) in 95% yield with excellent enantiomeric purity without using a chiral auxiliary (Scheme 2.34).55

2.8.2 o-Iodoxybenzoic Acid
Based Oxidation of Caprolactams In work directed toward the synthesis of benzo[c]azapines and benzo[c] azapinones, Csaba Szantay and coworkers have developed a novel synthesis of spiro-substituted benzo[c]azapinones with a saturated and unsaturated cyclohexanone ring containing one or two C
C double bonds.56 As part of the synthetic strategy, when spirolactam (80) was reacted with o-IBX for the purpose of generating the double bond in the spiro-substituted cyclohexanone ring, it was observed that the caprolactam core in (80) was also selectively oxidized to the imide giving the spiro-adipimide (81) under the optimized reaction conditions (Scheme 2.35). Subsequently, the compound (81) was converted to the targeted compound (82) by oxidation with SeO2 and tert-BuOH in refluxing acetic acid. O

O

O

IBX

SeO 2 O

PhF-DMSO, 85°C NH

NH

tert-BuOH, acetic acid, reflux

O NH

O

O

O

80

81

82

Scheme 2.35 o-Iodoxybenzoic acid-mediated oxidation of spirolactam.

The IBX-mediated methodology for oxidation of (80) to (81) was further extended toward synthesis of a benzofurobenzapine tetracycle, typical of the galanthamine-type alkaloids, by Csaba Szantay and

58

Imides

O

O MeO

IBX PhF-DMSO, 85°C

MeO

Argon atm, 77 h

O NH

NH O 83

O 84, 54% yield

Scheme 2.36 o-Iodoxybenzoic acid-mediated oxidation of methoxy-substituted spirolactam.

researchers.57 During the synthesis of the tricyclic benzapine, the intermediate spiroketone (83), (6-methoxy)-3,4-dihydrospiro[2-benzapine5,10 -cyclohexane]-1(2H), 4-dione when reacted with IBX in fluorobenzene
DMSO, provided 6-methoxyspiro[2-benzazepine-5,10 cyclohexan]-20 -ene-1, 3(2H,4H),40 -trione (84) after selective oxidation of caprolactam to the imide in addition to deoxygenation of cyclohexanone core (Scheme 2.36). Example 2.8.2 Typical Procedure for the Synthesis of Spiro[benzo[c]azapin0 5,1 -cyclohexane]-20 -ene-1 (2H), 3(4H),40 -trione (81) To a solution of spirolactam (80) (2.472 g, 10.16 mmol) dissolved in a mixture of fluorobenzene (34 mL) and DMSO (68 mL) was added o- IBX (11.1 g, 39.63 mmol). The reaction mixture was heated at 85°C under an argon atmosphere and the temperature was maintained for 76 hours. The solvent was evaporated under vacuum and the resultant residue was dissolved in dichloromethane (500 mL). The dichloromethane solution was washed with saturated NaHCO3 solution (2 3 150 mL), water (250 mL), and followed by brine (2 3 150 mL). The organic layer was dried over magnesium sulfate and evaporated under reduced pressure to afford the crude residue of (81) which was further purified by column chromatography on silica gel. The pure product (81) was obtained in 50.3% yield (1.306 g) as a solid.

2.9 OZONE-BASED OXIDATION OF LACTAMS Recently, the usefulness of ozone for oxidation of lactam to imide has been studied. A novel approach for oxidation of caprolactam (42) to the imide (43) (azepane-2,7-dione) using ozone (O3) in carbon tetrachloride was developed by Rasumovskii and researchers58 (Scheme 2.37). The

Oxidation of Lactams to Cyclic Imides

59

O 3, CCl4 N H 42

O

90%

O

N H

O

43

Scheme 2.37 Ozone-catalyzed oxidation of caprolactam to adipimide.

transformation is simple, fast, and provided 90% yield of the imide (43). The mechanistic and kinetics aspects were also studied to support the exclusive formation of (43).

2.10 OXONE-BASED OXIDATION OF LACTAMS 2.10.1 Oxone-Based Oxidation of Isoindolinones Recently, Oxone has been used for the selective oxidation of isoindolinone to the corresponding phthalimides. 2.10.1.1. Luzzio and Patil have discovered a novel approach for the synthesis of triazole-substituted phthalimides, by selectively oxidizing the triazole-substituted isoindolinones (85), (87), (89), (91), (93), and (95) to the corresponding phthalimides (86), (88), (90), (92), (94), and (96) using Oxone/KBr in acetonitrile.59 The importance of this oxidative transformation is significant due to the selective oxidation of methylene group in the isoindolinone moiety in comparison with oxidation of the methylene group adjacent to the triazole moiety. The mechanism of oxidative transformation is postulated to go through a radical bromination of the methylene group in the isoindolinone ring followed by nucleophilic displacement of Br with OH to obtain the hydroxylactam which was further oxidized to the phthalimides using the excess of Oxone. This onepot synthesis has provided good to excellent yields (72%
91%) of triazole-bearing phthalimides (Scheme 2.38). 2.10.1.2. In a continuation of their research in oxidative transformations, Luzzio and coworkers developed a new method for the selective oxidation of N-substituted isoindolinones to phthalimides using a combination of Oxone with KBr.60 The substituted isoindolinones (97), (99), (101), (103), (105), (107), and (109) were selectively oxidized to the corresponding substituted phthalimides (98), (100), (102), (104), (106), (108), and (110), respectively, in good yields (Scheme 2.39). 2.10.1.3. When substituted isoindolinone (111) was subjected to optimal reaction conditions, the bromination of the naphthalene ring was also

60

Imides

O

O

N N N

N

R OMe

N

55°C–60°C, 16 h.

R= R= R= R= R= R=

R OMe

O 85, 87, 89 , 91, 93, 95 ,

N N N

Oxone, KBr, MeCN/H2O (9:1)

O

O

n-hexyl n-octyl cyclopentyl cyclohexyl benzyl 4-F-benzyl

86, 88, 90 , 92, 94, 96 ,

R= R= R= R= R= R=

n-hexyl: 91% n-octyl: 91% cyclopentyl: 72% cyclohexyl: 76% benzyl: 87% 4-F-benzyl: 90%

Scheme 2.38 Synthesis of triazolyl-substituted phthalimides.

O

O R1

R1

Oxone, KBr

N OR O

N

MeCN–H2O, 40°C–45°C, 16 h. R = ethyl or tert-butyl

OR O

O

98 , R1 = H, 85% 100 , R 1 = methyl, 70% 102 , R 1 = ethyl, 70% 104 , R 1 = propyl, 98% 106 , R 1 = butyl, 80% 108 , R 1 = benzyl, 88% 110, R1 = 4-F-benzyl, 72%

97 , R1 = H 99 , R1 = methyl 101 , R 1 = ethyl 103 , R 1 = propyl 105 , R 1 = butyl 107 , R 1 = benzyl 109, R1 = 4-F-benzyl

Scheme 2.39 Oxone /KBr-mediated synthesis of phthalimides 98
110 from isoindolinones 97
109.

Br O

O Oxone, KBr/IBX

N R

MeCN–H2O, 40°C–45°C, 16 h

N R O

111, R = COOMe

Scheme 2.40 Oxone/o-iodoxybenzoic ne
phthalimide derivative.

112, R = COOMe, 80%

acid-mediated

synthesis of

naphthale-

observed in addition to the oxidation of isoindolinone to the phthalimide (112) in 80% yield60 (Scheme 2.40). The necessity of IBX was optimized for satisfactory conversion of the hydroxyl intermediate to the corresponding carbonyl.

61

Oxidation of Lactams to Cyclic Imides

O

N

Ph

O

O

Oxone, KBr O

N R

113, R = COOMe

Ph

MeCN–H2O, 40°C–45°C, 3 h

NH 2

N R

O 114, R = COOMe, 65%

Scheme 2.41 Synthesis of asparagine derivative by using Oxone/KBr system.

2.10.1.4. In the same study, when the oxazole-based isoindolinone (113) was treated with the Oxone KBr system, the oxidative cleavage of the oxazole ring gave the amide moiety in (114) in addition to the selective oxidation of isoindolinone to phthalimide (Scheme 2.41).60 This is an interesting result and would be useful for making various asparagine derivatives.

2.11 SUMMARY This chapter summarizes various methods for the selective oxidation of lactams to the corresponding imides, specifically, the transformation of pyrrolidones to succinimides, piperidones to glutarimides, 2-(2-oxopiperidin-3-yl)isoindoline-1,3-diones to phthalidomides, and caprolactams to adipimides. Some of these oxidizing methods are based on metals such as ruthenium, manganese, potassium while some are nonmetal-based oxidizing systems which are based on molecular oxygen, dioxirane, peracid, hypervalent iodine, and ozone. Most of these reported methods for oxidative transformations are clean and provide good to excellent yields of products under mild reaction conditions.

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3733.

CHAPTER 3

Microbial Cyclic Imide Metabolism and Its Biotechnological Application Jun Ogawa1,4, Soong Chee-Leong1, Nobuyuki Horinouchi1, Masutoshi Nojiri2, Michihki Takeuchi3 and Makoto Hibi3,5 1

Division of Applied Life Sciences, Graduate School of Agriculture, Kyoto University, Kyoto, Japan Biotechnology Development Laboratories, Kaneka Corporation, Hyogo, Japan Laboratory of Industrial Microbiology, Graduate School of Agriculture, Kyoto University, Kyoto, Japan 4 Research Unit of Physiological Chemistry, Kyoto University, Kyoto, Japan 5 Biotechnology Research Center and Department of Biotechnology, Toyama Prefectural University, Toyama, Japan 2 3

3.1 INTRODUCTION 3.1.1 Diversity and Versatility of Cyclic Amide and Cyclic Imide Metabolism in Microorganisms Various metabolisms of cyclic amide compounds such as cyclic ureides and cyclic imides were analyzed in detail and applied to biotransformations, such as D-amino acid production from DL-5-monosubstituted hydantoin.1 In nature, cyclic ureide transformation is generally related to nucleic acid base-transformation, which comprises the catabolism and anabolism of pyrimidines and purines.2 The metabolism of nucleobases such as pyrimidines and purines involves various cyclic amide hydrolases (EC 3.5.2.-), such as dihydropyrimidinase in reductive pyrimidine metabolism2 (Fig. 3.1C), barbiturase in oxidative pyrimidine metabolism3 (Fig. 3.1B), dihydroorotase in pyrimidine biosynthesis,4 and allantoinase in purine metabolism5 (Fig. 3.1G). Among these enzymatic activities, the cyclic ureide hydrolysis of five-membered ring hydantoins catalyzed by dihydropyrimidinase has gained enormous attention due to attractive industrial applications for the production of optically active amino acids, especially D-amino acids.6 8 Ogawa et al. investigated the pyrimidine-transforming activity in a typical hydantoin-transforming bacterium, Blastobacter sp. A17p-4, which was screened from soil as a hydantoin-assimilating bacterium for the purpose of D-amino acid production.9 During the course of studies on Imides DOI: https://doi.org/10.1016/B978-0-12-815675-9.00003-5

© 2019 Elsevier Inc. All rights reserved.

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Figure 3.1 Overview of microbial nucleic acid and related cyclic amide metabolisms: (A) nucleoside metabolism, (B) oxidative pyrimidine metabolism, (C) reductive pyrimidine metabolism, (D) hydantoin metabolism, (E) cyclic imide metabolism, (F) sulfur-containing cyclic amide metabolism, and (G) purine metabolism.

Microbial Cyclic Imide Metabolism and Its Biotechnological Application

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hydantoin metabolism in this bacterium (Fig. 3.1D), it was found that it showed not only hydantoin but also cyclic imide metabolizing activity.10 Succeeding studies revealed that the strain has not only hydantoinmetabolizing enzymes but also enzymes specific to cyclic imide derivatives, as described below (Fig. 3.1E). Based on the finding of cyclic imide hydrolyzing activity in Blastobacter sp. A17p-4,10 the metabolism of various cyclic imides by microorganisms has been investigated. Blastobacter sp. A17p-4 can metabolize various cyclic imides such as succinimide, maleimide, 2-methylsuccinimide, and glutarimide, and sulfur-containing cyclic imides such as 2,4-thiazolidinedione and rhodanine.11 Further investigation of the metabolic fate of these cyclic imides showed that they were metabolized through a novel metabolic pathway (Fig. 3.1E). This pathway comprises the hydrolytic ring-opening of cyclic imides into half-amides, hydrolytic deamidation of the half-amides to dicarboxylates, and dicarboxylate transformation similar to that in the tricarboxylic acid (TCA) cycle.

3.2 FINDING OF CYCLIC IMIDE HYDROLYZING ACTIVITY IN BLASTOBACTER SP. A17P-4 Blastobacter sp. A17p-4, which is a gram-negative, nonmotile, nonspore-forming, obligatorily aerobic, nonfermentative rod, shows high D-enantiomer-specific hydantoin-hydrolyzing activity.9 Two cyclic ureide compound hydrolyzing enzymes were found in Blastobacter sp. A17p-4, and partially purified. One of the enzymes hydrolyzed 5-substituted hydantoins D-stereospecifically and showed that it had dihydropyrimidinase activity (D-hydantoinase). The physicochemical properties suggested that the D-hydantoinase of this bacterium are identical to dihydropyrimidinase, which functions in reductive pyrimidine metabolism (Table 3.1). The D-hydantoinase was purified and its substrate specificity was studied in detail.13 Besides its conventional substrates, cyclic ureides, the D-hydantoinase also hydrolyzed cyclic imides (Table 3.2). The activity toward cyclic imides was observed with bulky cyclic imides but not simple cyclic imides. The enzyme also catalyzed the reverse reaction, that is, the cyclization of half-amides to cyclic imides.13 This newly found catalytic activity suggested that the 13 D-hydantoinase may also be involved in cyclic imide metabolism. Mammalian dihydropyrimidinases have been reported to hydrolyze cyclic imides, and show a wide substrate spectrum, including simple and bulky

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Table 3.1 Properties of D-hydantoinase, imidase, and half-amidase from Blastobacter sp. A17p-4 Properties D-Hydantoinase Imidase Half-amidase

Native Mr Subunit Mr (SDS-PAGE) Number of subunits Substrate specificity Most active Mildly active

Optimum pH for Hydrolysis Cyclizing dehydration Optimum temperature pH stability Thermal stability Metal ion requirement Inhibitor

200,000 53,000

105,000 35,000

48,000 46,000

4

3

1

Cyclic ureides

Half-amides

Bulky cyclic imides

Simple cyclic imides Sulfur-containing cyclic imides Nonsubstituted cyclic ureides

Middle chain amides Aromatic amides

9.0 10.0 5.0

7.5 8.0 6.5

9.4 10.0 2

60°C

60°C

35°C

5.0 8.5 ,60°C Activation (Ni21, Co21, Mn21) SH-inhibitors Hg21

6.0 9.0 ,60°C (Co21)

7.5 10.5 ,35°C None

SH-inhibitors Cu21, Zn21, Ag1, Hg21 Serine protease inhibitors Metal ion chelators

SH-inhibitors Cu21, Zn21, Ag1, Hg21 Serine protease inhibitors

Source: Reproduced/Adapted from Soong, C.-L.; Ogawa, J.; Shimizu, S. Cyclic Ureide and Imide Metabolism in Microorganisms Producing a D-hydantoinase Useful for D-amino Acid Production. J. Mol. Catal. B: Enzymatic 2001, 12, 61 70 [12] with permission from Elsevier.

cyclic imides and cyclic ureides.14 16 These mammalian enzymes are tetramers and their NH2-terminal amino acid sequences show good homology with those of bacterial D-hydantoinases, including the Blastobacter D-hydantoinase. The similarities in structure, genomic sequence, and catalytic function of these two groups of enzymes suggest that they are phylogenetically related and that they form a gene superfamily related to ureases.17 19

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Table 3.2 Substrate specificity of D-hydantoinase from Blastobacter sp. A17p-4 Vmax/Km Substrate Relative Km Vmax activity (%) (mM) (μmol/ (min mg))

Cyclic ureides Dihydrouracil Dihydrothymine Hydantoin DL-5-Methylhydantoin DL-5-(2-Methylthioethylene) hydantoin DL-5-Phenylhydantoin DL-5-(p-Hydroxyphenyl) hydantoin Cyclic imides 2-Methylsuccinimide 2-Phenylsuccinimide Phthalimide 3,4-Pyridinedicarboximide

100 73 140 54 48

2.6 8.8 3.2 11 9.2

2.5 2.2 1.1 1.8 0.58

0.95 0.25 0.36 0.16 0.063

29 1.6

11 0.62

1.2 0.020

0.12 0.032

9.6 5.2 2.1 9.6

5.0 6.7 2.1 9.4

0.23 0.15 0.077 1.02

0.046 0.023 0.037 0.11

Source: Reproduced/Adapted from Soong, C.-L.; Ogawa, J.; Shimizu, S. Cyclic Ureide and Imide Metabolism in Microorganisms Producing a D-hydantoinase Useful for D-amino Acid Production. J. Mol. Catal. B: Enzymatic 2001, 12, 61 70 [12] with permission from Elsevier.

The other was a novel enzyme which should be an imidase. The imidase preferentially hydrolyzed cyclic imide compounds such as glutarimide and succinimide more than cyclic ureide compounds, and produced monoamidated dicarboxylates (half-amide). The only enzyme that has previously been reported to hydrolyze cyclic imides was the dihydropyrimidinase from rat liver20 at that time. However, the imidase is distinct from rat liver dihydropyrimidinase in that the imidase does not hydrolyze compounds with some substitutents on their ring structures such as dihydrothymine and 5-substituted hydantoins, and in that the imidase prefers to hydrolyze cyclic imides rather than cyclic ureides.

3.3 CYCLIC IMIDE TRANSFORMATION PATHWAY IN BLASTOBACTER SP. A17P-4 The metabolism of cyclic imides has been studied in mammals in relation to the detoxification of the antiepileptic agents ethotoin and phensuximide.21 Dihydropyrimidinase, which is involved in pyrimidine metabolism, functions in cyclic imide hydrolysis in mammals.20 However, there

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had been no reports on the microbial transformation of cyclic imides. Based on the findings of cyclic imide hydrolyzing activity of the Dhydantoinase and a novel cyclic imide hydrolyzing enzyme, imidase, the metabolism of various cyclic imides by Blastobacter sp. A17p-4 was investigated. The fact that Blastobacter sp. A17p-4 grows well in a medium containing succinimide as a sole source of carbon indicates that the bacterium has a metabolic system for the assimilation of simple cyclic imides as energy sources and nutrients.11 The bacterium can metabolize various simple cyclic imides with structures similar to that of succinimide such as maleimide, 2-methylsuccinimide, and glutarimide; and sulfur-containing cyclic imides such as 2,4-thiazolidinedione and rhodanine, other than the bulky cyclic imide of phthalimide, which is a substrate of the D-hydantoinase.11,13 Further investigation of the metabolic fate of these cyclic imides showed that they were metabolized through a novel metabolic pathway (Fig. 3.2). This pathway involves in turn the hydrolytic ring-opening of cyclic imides to half-amides, hydrolytic deamidation of the half-amides to dicarboxylates, and dicarboxylate transformation similar to that in the TCA cycle. For example, succinimide is first hydrolyzed by imidase to succinamic acid, and the succinamic acid is deamidated by amidase to succinate. The succinate then enters the TCA cycle and is transformed to fumarate, malate, and pyruvate, in that order (Fig. 3.2). Two novel enzymes, imidase and half-amidase, and D-hydantoinase were found to function in this pathway. In the first step of this metabolic pathway, imidase is involved in the hydrolysis of simple cyclic imides, and D-hydantoinase is involved in the hydrolysis of bulky cyclic imides. The half-amide products were successively hydrolyzed by half-amidase in the second step of the pathway, followed by the TCA cycle-like transformation.11 The cyclic imide metabolism has practical potential for stereospecific and regiospecific production of half-amides and dicarboxylates, and also the production of high-value organic acids such as pyruvate from cyclic imides.

3.4 ENZYMES INVOLVED IN CYCLIC IMIDE METABOLISM IN BLASTOBACTER SP. A17P-4 3.4.1 Imidase Imidase, which was named according to its high activity toward cyclic imides, especially simple ones, was first purified and characterized from Blastobacter sp. A17p-4 (Table 3.1).22 This enzyme is involved in the first

Figure 3.2 Microbial metabolic pathway for cyclic imides.

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step of cyclic imide metabolism, catalyzing the ring-opening hydrolysis of cyclic imides to half-amides and also the reverse reaction, that is, the cyclization of half-amides to cyclic imides.22 It is a trimer with a relative molecular mass of 105,000, and its NH2-terminal amino acid sequence shows no homology with other known cyclic amide metabolizing enzymes. Imidase exhibited higher activity and affinity toward simple cyclic imides, which are not hydrolyzed by the D-hydantoinase from the strain, than toward the cyclic ureides of dihydrouracil and hydantoin (Table 3.3). Imidase is also active toward sulfur-containing cyclic imides such as 2,4-thiazolidinedione and rhodanine (Table 3.3). However, bulky cyclic imides or monosubstituted cyclic ureides, which are the substrates of D-hydantoinase or dihydropyrimidinase, were not hydrolyzed. Rat liver imidase20 catalyzes the hydrolysis of a variety of imides that include five-, six-, and seven-membered rings, as well as the open-chain diacetamide. In addition, phthalimide, dihydrouracil, hydantoin, and C5-substituted cyclic ureides, such as dihydrothymine and 5-methylhydantoin, served as substrates. Imidase from Blastobacter sp. A17p-4 is, therefore, different from bacterial D-hydantoinases or mammalian dihydropyrimidinases in structure and substrate specificity, and seems to have a specific function in cyclic Table 3.3 Substrate specificity of imidase from Blastobacter sp. A17p-4 Substrate Relative Km Vmax (μmol/ activity (%) (min mg)) (mM)

Cyclic ureides Dihydrouracil Hydantoin Parabanic acid Cyclic imides Succinimide Glutarimide Maleimide 2-Methylsuccinimide Sulfur-containing cyclic amides 2,4-Thiazolidinedione Rhodanine Thiohydantoin Pseudothiohydantoin

Vmax/Km

100 110 100

52 5.7 62

240 34 370

4.7 6.0 6.0

530 630 5800 150

0.94 4.5 0.34 nda

910 1000 5800 nd

970 220 17000 nd

79 680 68 7.4

33 31 23 nd

160 1700 130 nd

4.7 55 5.8 nd

a nd 5 not determined. Source: Reproduced/Adapted from Soong, C.-L.; Ogawa, J.; Shimizu, S. Cyclic Ureide and Imide Metabolism in Microorganisms Producing a D-hydantoinase Useful for D-amino Acid Production. J. Mol. Catal. B: Enzymatic 2001, 12, 61 70 [12] with permission from Elsevier.

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imide metabolism. Imidase activity is inhibited noncompetitively by succinate, an interlinkage compound between cyclic imide metabolism and the TCA cycle, with a Ki value of 1.44 mM, suggesting that the enzyme activity is downregulated by the metabolite of the pathway in relation with the TCA cycle.11,22

3.4.2 Half-Amidase Half-amidase, which was named according to its high activity toward half-amides, was first purified and characterized from Blastobacter sp. A17p-4 (Table 3.1).23 This enzyme is involved in the second step of cyclic imide metabolism, catalyzing the irreversible hydrolytic deamidation of half-amides to dicarboxylates.23 It is a monomer with a relative molecular mass of 48,000, and its NH2-terminal amino acid sequence shows no homology to known cyclic amide metabolizing enzymes or amidases. The enzyme exhibited the highest catalytic efficiency toward half-amides (Table 3.4), and did not act on the substrates of known amidases such as short-chain (C2 C4) aliphatic amides, long-chain (above C16) aliphatic amides, amino acid amides, aliphatic diamides, α-keto acid amides, N-carbamoyl amino acids, and aliphatic ureides. The narrow catalytic spectrum of half-amidase suggested that the enzyme specifically functions in the metabolism of cyclic imides together with imidase. Rat liver Table 3.4 Substrate specificity of half-amidase from Blastobacter sp. A17p-4 Substrate Relative Km kcat/Km kcat (s21) activity (%) (mM) (s21 mM21)

Half-amides Succinamic acid Glutaramic acid Adipinamic acid Middle chain amides Lactamide n-Valeramide n-Caproamide Crotonamide Aromatic amides Benzamide 2-Phenylpropioamide

100 64 41

6.2 2.8 8.0

5.76 2.23 0.36

0.93 1.62 0.046

12 11 25 8

3.7 5.1 17.0 8.8

0.11 0.18 0.18 0.10

0.033 0.037 0.011 0.012

8 11

6.5 3.1

0.13 0.078

0.020 0.026

Source: Reproduced/Adapted from Soong, C.-L.; Ogawa, J.; Shimizu, S. Cyclic Ureide and Imide Metabolism in Microorganisms Producing a D-hydantoinase Useful for D-amino Acid Production. J. Mol. Catal. B: Enzymatic 2001, 12, 61 70 [12] with permission from Elsevier.

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ω-amidase, which is considered to be a mammalian counterpart of this bacterial half-amidase, has been reported to hydrolyze succinamic acid and glutaramic acid, as well as α-ketoglutaramic acid and α-ketosuccinamic acid, which are not substrates of the half-amidase. Thus in contrast to the bacterial half-amidase, the rat ω-amidase possessed different substrate specificity and physiological role, namely, metabolism of glutamine and asparagine.24,25

3.4.3 Physiological Functions of Imidase and Half-Amidase in Cyclic Imide Metabolism of Blastobacter sp. A17p-4 The production of imidase and half-amidase was enhanced in cyclic imide grown cells compared to in sucrose-grown cells.11 Especially, the production of half-amidase was significantly enhanced by the addition of cyclic imides such as succinimide and glutarimide. The intermediates of cyclic imide metabolism of succinic acid also showed stimulatory effects. Blastobacter sp. A17p-4 was able to grow in minimum medium with succinimide or glutarimide as the sole source of carbon. With these cyclic imides as sole sources of carbon, the halfamidase activity increased approximately three to five times compared to that found with sucrose-grown cells, and succinimide supported good growth. Amide compounds which act as substrates and inducers of known amidase (acetamide and lactamide for the amidase of Pseudomonas aeruginosa26,27; benzamide for that of Aspergillus nidulans28; cyclic ureides for dihydropyrimidinase; ammonium chloride and L-glutamine for ω-amidase) were less effective or somewhat repressive on the production of half-amidase. The enhancement of imidase and half-amidase production was further investigated at the gene expression level using an RNA synthesis inhibitor, actinomycin D.23 The addition of a cyclic imide enhanced the expression of imidase and half-amidase, but when actinomycin D was added together with the cyclic imide, no enhancement of the production of these enzymes was observed. This was due to the inhibition of RNA synthesis, which prevented the gene expression of imidase and half-amidase. No significant enhancement of the production of these enzymes was observed on the addition of sucrose in a control experiment. These results showed that imidase gene expression and particularly half-amidase gene expression are upregulated by cyclic imides. All these results imply that imidase and half-amidase are produced for cyclic imide utilization.11,22,23

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3.5 DISTRIBUTION OF CYCLIC IMIDE METABOLIZING ACTIVITIES IN MICROORGANISMS The distribution of cyclic imide (succinimide) and cyclic ureide (dihydrouracil and DL-5-methylhydantoin) metabolism was investigated in microorganisms.29 Besides the well-known cyclic ureide metabolism, cyclic imide metabolism is also common and widely distributed among bacteria, yeasts, and molds.29 Other than Blastobacter sp., some bacteria (Bacillus, Arthrobacter, and Pseudomonas), yeasts (Saccharomyces), and molds (Penicillium and Fusarium) are able to grow on cyclic imides as sole sources of carbon, suggesting that a cyclic imide metabolizing system exists in various microorganisms.29 In bacteria, no correlation was observed among succinimide-, dihydrouracil-, and DL-5-methylhydantoin hydrolyzing activities, suggesting that cyclic imide and cyclic ureide transformation involve different enzyme systems as observed in Blastobacter sp. A17p-4.10 This may be common in prokaryotes. On the other hand, cyclic imide- and cyclic ureide hydrolyzing activity are apparently related in yeasts and molds. Yeasts and molds show lower cyclic imide metabolizing activity than bacteria. The relative activity of cyclic imide transformation to that of cyclic ureide transformation was similar in all fungi examined. Together with the reports that both cyclic imides and cyclic ureides are hydrolyzed by mammalian dihydropyrimidinases,14 16,20 the present findings suggest that these two activities are catalyzed by an identical enzyme system in eukaryotes. It was revealed that cyclic imide transforming activity commonly exists in microorganisms, and that cyclic imides can be utilized as an energy source for growth. Since a few natural cyclic imide compounds are known, the physiological role of cyclic imide transforming activity may be in the degradation of xenobiotics.15 The present findings clearly show that microorganisms can transform cyclic imides.

3.6 OVERVIEW OF CYCLIC AMIDE TRANSFORMATION IN BLASTOBACTER SP. A17P-4 Blastobacter sp. A17p-4 shows diverse cyclic amide transforming activities, including that toward cyclic ureides and imides (Fig. 3.3). Ogawa et al. reported that the bacterium produces three N-carbamoyl amino acid amidohydrolases, that is, N-carbamoyl-D-amino acid amidohydrolase, N-carbamoyl-L-amino acid amidohydrolase, and β-ureidopropionase.9,30

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Imides

Figure 3.3 Diversity of cyclic ureide and imide metabolism in Blastobacter sp. A17p-4.

β-Ureidopropionase has a broad substrate specificity, utilizing not only N-carbamoyl-β-amino acids but also N-carbamoyl-γ-amino acids and several N-carbamoyl-α-amino acids.31 The hydrolysis of N-carbamoylα-amino acids by β-ureidopropionase is strictly L-enantiomer specific.31 This strict stereospecificity makes these enzymes applicable to the production of optically active amino acids (Fig. 3.3). In cyclic ureide hydrolysis, the bacterium produces D-hydantoinase, which was determined to be identical to dihydropyrimidinase. D-Hydantoinase is useful for the production of D-amino acids from DL-5-monosubstituted hydantoins in combination with N-carbamoyl-D-amino acid amidohydrolase. D-Hydantoinase also hydrolyzes bulky cyclic imides other than cyclic ureides. Cyclic imide metabolism is categorized differently from cyclic ureide metabolism (Fig. 3.3). Cyclic imide metabolism, especially simple cyclic imides metabolism, involves two unique enzymes, imidase and half-amidase. Imidase and half-amidase show high activity toward cyclic imides and the ring-opened products of half-amides, respectively, suggesting that the two enzymes act cooperatively in the metabolism of cyclic imides. The production of both enzymes was enhanced by cyclic imides, indicating that these enzymes were produced for cyclic imide assimilation. At the gene expression level, half-amidase was more sensitively upregulated by cyclic imides than imidase, which is constitutively produced to some extent. On the other hand, the catalytic activity of imidase was downregulated by succinate, while the half-amidase activity was not affected. The coordination

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between the catalytic and genetic regulation of imidase and half-amidase confirms the physiological importance of these enzymes in cyclic imide metabolism. Cyclic imide hydrolysis has been studied for mammalian dihydropyrimidinases in relation to the detoxification of antiepileptic agents.14 16 Ogawa et al. showed that the microorganisms also hydrolyze cyclic imides, which involves two distinct enzymes, D-hydantoinase and imidase. The differences in substrate range exhibited by D-hydantoinase and imidase from Blastobacter sp. A17p-4, and mammalian dihydropyrimidinases are illustrated in Fig. 3.7. The catalytic action of mammalian dihydropyrimidinases is fully complemented by the combined activities of D-hydantoinase and imidase in the Blastobacter system; suggesting that the functions of single eukaryotic dihydropyrimidinases are found in two distinct enzymes in prokaryotes. These proposals were supported by the distributions of cyclic ureide and cyclic imide metabolism in microorganisms. In prokaryotic bacteria, there is no correlation between cyclic imide and cyclic ureide metabolism suggesting that it involves different enzyme systems. In eukaryotic fungi, however, these two activities show some similarity.29 Above all, bacterial cyclic ureide and imide metabolism involves a diverse group of enzymes with different metabolic functions. Besides the practical application of D-hydantoinase to D-amino acid production, the practical potential of cyclic imide transforming enzymes was investigated for fine enzymatic synthesis of useful compounds, and valuable organic acid production from cyclic imides and metabolic intermediates as described in the following Section 3.7.

3.7 APPLICATION OF CYCLIC IMIDE METABOLISMS AND THE INVOLVED ENZYMES 3.7.1 Pyruvate Production Cyclic imide metabolism has been applied to the production of a highvalue organic acid, pyruvate.32 The commercial demand for pyruvate has been increasing due to its use as an effective precursor in the synthesis of various drugs and agrochemicals in addition to its use as a component of mammalian-cell culture media. Pyruvate was effectively produced from fumarate by an active metabolic conversion system of a cyclic imide assimilating microorganism. Fumarate was transformed to pyruvate via malate through the similar

78

Imides

reactions with those found in the TCA cycle. To obtain a high accumulation of pyruvate, controls of wet-cell concentration, pH, and temperature of the reaction were important. Sufficient supply of oxygen by vigorous shaking was required for complete conversion especially for that of malate, an intermediate, to pyruvate. A succinimide-assimilating bacterium, Pseudomonas putida s52, was found to be a potent producer of pyruvate from fumarate. Using washed cells from P. putida s52 as catalyst, 400-mM pyruvate was produced from 500-mM fumarate in a 36-hour reaction.33 Bromopyruvate, a malic enzyme inhibitor, was found to prevent pyruvate production from fumarate and to inhibit the growth of P. putida s52 in the medium when fumarate was used as a sole carbon source, indicating that it played a crucial role in pyruvate synthesis from fumarate in this strain. Bromopyruvate was used for the selection of mutants with higher pyruvate productivity. A bromopyruvate-resistant mutant, P. putida 15160, was found to be an effective catalyst for pyruvate production. The recovery of P. putida 15160 in the bromopyruvate-containing medium might have been due to increased activity of the malic enzyme or to compensatory induction of other enzymes for the conversion of L-malate into pyruvate.33 P. putida 15160 was found to be an effective catalyst for pyruvate production. Under batch bioreactor conditions, 767 mM of pyruvate was successfully produced from 1000-mM fumarate in a 72-hour reaction with washed cells of P. putida 15160 as catalyst. The concentration of pyruvate produced with P. putida 15160 was much higher than with Torulopsis glabrata, a strain used in the industrial production of pyruvate, which produced 676-mM pyruvate from glucose.34 This higher productivity of pyruvate with P. putida 15160 should be helpful in increasing total amount and facilitating downstream processes of pyruvate production. Biosynthesis of L-valine and L-leucine is one of the major pyruvate assimilation pathways.34 L-Valine/L-leucine auxotrophs derived from P. putida 15160 would become more excellent pyruvate-producing strains. In a preliminary study, Ogawa et al. obtained auxotrophic mutants and tested them for pyruvate production. Under batch bioreactor conditions, 821 mM of pyruvate was successfully produced from 1000 mM fumarate in a 96-hour reaction with washed cells of a L-valine/ L-leucine auxotroph derived from P. putida 15160 as catalyst (Fig. 3.4).

Figure 3.4 Pyruvate production by succinimide-assimilating strain Pseudomonas putida s52, bromopyruvate-resistant mutant 15160, and L-valine and L-leucine auxotrophic mutant M29.

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Imides

3.8 STEREOSPECIFIC SYNTHESIS OF OPTICALLY ACTIVE α-MERCAPTO ACIDS BY IMIDASE-CATALYZING HYDROLYSIS OF SULFUR-CONTAINING CYCLIC IMIDES Based on the finding that imidase hydrolyzes sulfur-containing cyclic imides, enzymatic stereoselective conversion of thiazolidinedione derivatives to optically active α-mercapto acids was established in a fashion similar to the hydantoinase process for optically active α-amino acid production (Fig. 3.5).35 Similar to α-amino acids, α-mercapto acids, which contain a chiral center at α-carbon, received increasing attention as a novel chiral building block for the synthesis of pharmaceuticals. Brevibacterium linens C-1 and Pseudomonas sp. Y7 were found to produce (S)- and (R)-3-phenyl-2-mercaptopropionic acid, respectively, from racemic 5-benzyl-2,4-thiazolidinedione. The cyclic imide hydrolase purified from B. linens C-1 showed allantoinase activity, indicating a metabolic relation with purine base metabolism (Fig. 3.1F and G). The thiazolidinedione derivative hydrolyzing activity of allantoinase was also confirmed in the course of investigations on 3-substituted glutarimide hydrolysis for the production of optically active 3-substituted glutaric acid monoamide as described in Section 3.10.

Figure 3.5 Production of S-3-phenyl-2-mercaptopropionate by Brevibacterium linens C-1 (A) and reactions catalyzed by thiazolidinedione amidehydrolase B. linens C-1 (B).

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3.9 REGIOSELECTIVE HYDROLYSIS OF CYCLIC IMIDES FOR FINE SYNTHESIS OF HALF-AMIDES 3.9.1 3-Carbamoyl-α-Picolinic Acid Production by Imidase-Catalyzed Regioselective Hydrolysis of 2,3-Pyridinedicarboximide in a Water Organic Solvent Two-Phase System 3-Carbamoyl-α-picolinic acid (α-3CP) is one of the regioisomeric halfamides of 2,3-pyridinedicarboxylic acid (PDC) and serves as a versatile building block for the synthesis of pharmaceuticals. It is considered to be a promising intermediate for the synthesis of modern agrochemicals such as nicotinoid insecticides.36,37 The chemical synthesis of α-3CP from PDC via the dimethyl ester and methyl half-ester of PDC has been reported.38 But the synthesis consists of three steps, including troublesome regiospecific diester hydrolysis to the half-ester. α-3CP was also prepared by alkaline hydrolysis of 2,3-pyridinedicarboximide (PDI), which was easily synthesized from PDC and ammonia. But the hydrolysis occurred randomly at two amide bonds and resulted in the coproduction of 2-carbamoyl-β-picolinic acid (β-2CP). Enzymatic regiospecific hydrolysis of PDI (Fig. 3.6) is an attractive method for overcoming this problem with an α-3CP synthesis. Imidase and D-hydantoinase (dihydropyrimidinase) were found to hydrolyze aryl-substituted cyclic imides such as PDI, 3,4-PDI,

Figure 3.6 3-Carbamoyl-α-picolinic acid production by imidase-catalyzed regioselective hydrolysis of 2,3-pyridinedicarboximide in a water organic solvent two-phase system.

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Imides

and phthalimide.13 16 Based on these findings, potential imidases applicable to the regiospecific hydrolysis of a cyclic imide, PDI, to α-3CP were screened. Phthalimide-assimilating Arthrobacter ureafaciens O-86 was selected as the best strain and applied to the cyclohexanone water two-phase reaction system at pH 5.5, in which the spontaneous nonselective hydrolysis of 2,3-pyridinedicarboxyimide was avoided, while the enzyme maintained its activity. Under optimized conditions, with the periodical addition of 2,3-pyridinedicarboxyimide (in total, 40 mM), 36.6 mM α-3CP accumulated in the water phase with a molar conversion yield of 91.5% and a regioisomeric purity of 94.5%, in 2 hours at pH 5.5.39 A novel imidase, phthalimidase, with specificity toward phthalimide derivatives was found in A. ureafaciens O-86.40 Then, three types of imidases with different substrate specificities were found (Fig. 3.7). An imidase with specificity toward simple cyclic imides was purified from Blastobacter sp. A17p-4.22 This enzyme is also active toward sulfurcontaining cyclic imides such as 2,4-thiazolidinedione and rhodanine. Bulky cyclic imides are hydrolyzed by the D-hydantoinase of Blastobacter sp. A17p-4 and mammalian dihydropyrimidinases.13 Phthalimide derivatives are hydrolyzed by the phthalimidase of A. ureafaciens O-86 and by mammalian dihydropyrimidinases.13 Enzymatic hydrolysis of the N-iminylamide was investigated with N-iminylamidase from pig liver, which catalyzed the hydrolysis of 3-iminoisoindolinone bearing N-iminylamide functional group.40 This enzyme was active with the typical substrate of mammalian imidase, such as phthalimide, dihydrouracil, and maleimide. The typical substrate of some cyclic amidases and imidases were inactive for pig liver N-iminylamidase.

Figure 3.7 Substrate specificities of cyclic imide hydrolyzing enzymes.

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3.10 IMIDASE-CATALYZING DESYMMETRIC IMIDE HYDROLYSIS FORMING OPTICALLY ACTIVE 3-SUBSTITUTED GLUTARIC ACID MONOAMIDES FOR THE SYNTHESIS OF GAMMA-AMINOBUTYRIC ACID ANALOGS Several types of γ-aminobutyric acid (GABA) analogs, the pharmacological activities of which depend on their chirality as well as chemical composition, have been synthesized for human therapeutics. For example, arbaclofen [(R)-3-(4-chlorophenyl) GABA], a prodrug of baclofen, is a GABA type B receptor agonist that is currently under clinical development for the treatment of spasticity, autism spectrum disorders, and Fragile X syndrome.41,42 Pregabalin [Lyrica API; (S)-3-isobutyl GABA] is a lipophilic GABA analog that was developed to improve epilepsy, neuropathic pain, anxiety, and social phobia.43 High purity, optically active 3-substituted glutaric acid monoamides can easily be converted to their corresponding GABA derivatives through Hofmann rearrangements, making them valuable synthetic intermediates.44 46 It was promising to develop a novel chemoenzymatic process for obtaining an optically active 3-substituted glutaric acid monoamide with an enzyme capable of asymmetrically hydrolyzing 3-substituted glutarimide in a stereoselective manner. The screening of microorganisms for imidases capable of transforming the key intermediates in the synthesis of arbaclofen, 3-(4-chlorophenyl) glutarimide (CGI), or in the synthesis of pregabalin, 3-isobutyl glutarimide (IBI), through imide desymmetrization (Fig. 3.8) was carried out. The bacteria Alcaligenes faecalis NBRC13111 and Burkholderia phytofirmans DSM17436 were discovered to hydrolyze CGI to (R)-3-(4-chlorophenyl) glutaric acid monoamide (CGM) with 98.1% enantiomeric excess (ee) and 97.5% ee, respectively. B. phytofirmans DSM17436 could also hydrolyze IBI to produce (R)-3-isobutyl glutaric acid monoamide (IBM) with 94.9% ee (Fig. 3.8).47 BpIH, an imidase, was purified from B. phytofirmans DSM17436 and found to generate (R)-CGM from CGI with specific activity of 0.95 U/mg. The amino acid sequence of BpIH had a 75% sequence identity to that of allantoinase from A. faecalis NBRC13111 (AfIH) (Fig. 3.9). The purified recombinant BpIH and AfIH catalyzed (R)-selective hydrolysis of CGI and IBI (Fig. 3.10). In addition, a preliminary investigation of the enzymatic properties of BpIH and AfIH revealed that both enzymes act on 3-substituted glutarimides, phthalimides, thiazolidinedione, and allantoin

Figure 3.8 Microorganisms producing (R)-IBM from IBI through desymmetrizing hydrolysis.

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Figure 3.9 Comparison of the amino acid sequences of the BpIH, AfIH, and PuuE. Identical amino acids among the sequences are marked in black. BpIH, an urate catabolism protein of Burkholderia phytofirmans DSM17436 (GenBank: ACD16728.1), AfIH, an allantoinase of Alcaligenes faecalis NBRC13111 (GenBank: KGP00466.1), PuuE, an allantoinase of Pseudomonas fluorescens (GenBank: ACA50280.1).

Figure 3.10 Bioconversion of CGI to (R)-CGM, and IBI to (R)-IBM by purified recombinant BpIH and AfIH.

(Table 3.5). BpIH and AfIH were stable in the range of pH 6 10, with an optimal pH of 9.0, stable at temperatures below 40°C, and were not metalloproteins.47 These results indicate that the use of this class of hydrolase to

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Table 3.5 Substrate specificities of recombinant BpIH and AfIH Relative activity (%) Substrate

BpIH

AfIH

3-(4-Chlorophenyl)glutarimide 3-Isobutylglutarimide Phthalimide cis-1,2,3,6-Tetrahydrophthalimide Allantoin 2,4-Thiazolidinedione Hydantoin Dihydrouracil Glutarimide Succinimide

100 3 157 22 50 22 Not Not Not Not

100 3 174 15 58 8 Not Not Not Not

detected detected detected detected

detected detected detected detected

Source: Reproduced/Adapted from Nojiri, M.; Hibi, M.; Shizawa, H.; Horinouchi, N.; Yasohara, Y.; Takahashi, S.; Ogawa, J. Imidase Catalyzing Desymmetric Imide Hydrolysis Forming Optically Active 3-Substituted Glutaric Acid Monoamides for the Synthesis of Gamma-Aminobutyric Acid (GABA) Analogs. Appl. Microbiol. Biotechnol. 2015, 99, 9961 9969 with permission from Springer Nature.

generate optically active 3-substituted glutaric acid monoamide could simplify the production of specific chiral GABA analogs for drug therapeutics.

3.11 CONCLUSION Reactions found through detailed observation of microbial cyclic imides together with cyclic ureides have paved the way to new bioprocesses for the production of organic acids, half-amides, and optically active α-mercapto acids.3,6,12,48,49 Modern society requests the development of processes exhibiting environmental harmonization, and economical efficiency. This trend is causing the application of biological reactions to a greater variety of industries. However, the feasibility of new bioprocesses will often be determined by the availability of biocatalysts, the search for which needs patience for steady research but has a deep impression when a new biocatalyst is encountered. Recently, some rational methods creating new biocatalysts have been rapidly developed. Modern gene technology, crystal structure analysis, and bioinformatics enable the modulation of enzyme function through site-directed mutagenesis, DNA shuffling, etc. However, “rationality” is not the only answer for developing new biocatalysts. Classical screening based on microbial diversity and versatility is still important. Such screening is something like a midnight walks without moonlight; however, detailed observation and deep insight with a

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well-considered strategy will lead to a discovery of new biocatalyst. This philosophy has now been succeeded by in vitro random evolution technology.50 Thus it is important to increase the catalog of biocatalysts waiting to be examined for practical purposes.35

ACKNOWLEDGMENTS The authors acknowledge the copyright licenses of Figs. 3.1 and 3.7 to John Wiley and Sons (license number, 4442330412341 and 4442330566884, respectively) and Figs. 3.6, 3.8, and Table 3.5 to Springer Nature (license number, 4442330775645, 4442340346159, and 4442340154609, respectively).

REFERENCES 1. Ogawa, J.; Horinouchi, N.; Shimizu, S. Hydrolysis and Formation of Hydantoins. In Enzyme Catalysis in Organic Synthesis; Drauz, K., Groger, H., May, O., Eds.; Wiley-VCH: Weinheim, 2012, 651 674. 2. Vogels, G. D.; Van der Drift, C. Degradation of Purines and Pyrimidines by Microorganisms. Bacteriol. Rev. 1976, 40, 403 468. 3. Soong, C.-L.; Ogawa, J.; Sakuradani, E.; Shimizu, S. Barbiturase, A Novel ZincContaining Amidohydrolase Involved in Oxidative Pyrimidine Metabolism. J. Biol. Chem. 2002, 277, 7051 7058. 4. Ogawa, J.; Shimizu, S. Purification and Characterization of Dihydroorotase from Pseudomonas putida. Arch. Microbiol. 1995, 164, 353 357. 5. Bongaerts, G. P. A.; Vogels, G. D. Uric Acid Degradation by Bacillus fastidiosus Strains. J. Bacteriol. 1976, 125, 689 697. 6. Ogawa, J.; Shimizu, S. Diversity and Versatility of Microbial HydantoinTransforming Enzymes. J. Mol. Catal. B Enzymatic 1997, 2, 163 176. 7. Shimizu, S.; Ogawa, J.; Kataoka, M.; Kobayashi, M. Screening of Novel Microbial Enzymes for the Production of Biologically and Chemically Useful Compounds. Adv. Biochem. Biotechnol. 1997, 58, 46 87. 8. Syldatk, C.; Muller, R.; Pietzsch, M.; Wagner, F. Microbial and Enzymatic Production of D-amino acids from D, L-5-Monosubstituted Hydantoins. Biocatalytic Production of Amino Acids and Derivatives; Hanser: Munich, 199275 128. 9. Ogawa, J.; Chung, M. C.-M.; Hida, S.; Yamada, H.; Shimizu, S.; Thermostable. Ncarbamoyl-D-amino acid Amidohydrolase: Screening, Purification and Characterization. J. Biotechnol. 1994, 38, 11 19. 10. Ogawa, J.; Honda, M.; Soong, C.-L.; Shimizu, S. Diversity of Cyclic Ureide Compound-, Dihydropyrimidine-, and Hydantoin-Hydrolyzing Enzymes in Blastobacter sp. A17p-4. Biosci. Biotechnol. Biochem. 1995, 59, 1960 1962. 11. Ogawa, J.; Soong, C.-L.; Honda, M.; Shimizu, S. Novel Metabolic Transformation Pathway for Cyclic Imides in Blastobacter sp. Strain A17p-4. Appl. Environ. Microbiol. 1996, 62, 3814 3817. 12. Soong, C.-L.; Ogawa, J.; Shimizu, S. Cyclic Ureide and Imide Metabolism in Microorganisms Producing a D-hydantoinase Useful for D-amino acid Production. J. Mol. Catal. B: Enzymatic 2001, 12, 61 70. 13. Soong, C.-L.; Ogawa, J.; Honda, M.; Shimizu, S. Cyclic-imide-hydrolyzing Activity of D-Hydantoinase From Blastobacter sp. Strain A17p-4. Appl. Environ. Microbiol. 1999, 65, 1459 1462.

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14. Dudley, K. H.; Butler, C. T.; Bius, D. L. The Role of Dihydropyrimidinase in the Metabolism of some Hydantoin and Succinimide Drugs. Drug Metab. Dispos. 1974, 2, 103 111. 15. Maguire, J. H.; Dudley, K. H. Dihydropyrimidinase. Metabolism of Some Cyclic Imides of Different Ring Size. Drug Metab. Dispos. 1978, 6, 140 145. 16. Yang, Y. S.; Ramaswamy, S.; Jakoby, W. B. Rat Liver Imidase. J. Biol. Chem. 1993, 268, 10870 10875. 17. Hamajima, N.; Matsuda, K.; Sakata, S.; Tamaki, N.; Sasaki, M.; Nonaka, M. A Novel Gene Family Defined by Human Dihydropyrimidinase and Three Related Proteins With Differential Tissue Distribution. Gene 1996, 180, 157 163. 18. Matsuda, K.; Sakata, S.; Kaneko, M.; Hamajima, N.; Nonaka, M.; Sasaki, M.; Tamaki, N. Molecular Cloning and Sequencing of a cDNA Encoding Dihydropyrimidinase From the Rat Liver. Biochim. Biophys. Acta 1996, 1307, 140 144. 19. May, O.; Habenicht, A.; Mattes, R.; Syldatk, C.; Siemann, M. Molecular Evolution of Hydantoinases. Biol. Chem. 1998, 379, 743 747. 20. Kikugawa, M.; Kaneko, M.; Fujimto-Sakata, S.; Maeda, M.; Kawasaki, K.; Takagi, T.; Tamaki, N. Purification, Characterization and Inhibition of Dihydropyrimidinase From Rat Liver. Eur. J. Biochem. 1994, 219, 393 399. 21. Dudley, K. H.; Buis, D. L.; Waldrop, D. Urinary Metabolites of N-methylα-methyl-α-phenylsuccinimide (Methsuximide) in the Dog. Drug Metab. Dispos. 1974, 2, 113 122. 22. Ogawa, J.; Soong, C.-L.; Honda, M.; Shimizu, S. Imidase, A DihydropyrimidinaseLike Enzyme Involved in the Metabolism of Cyclic Imides. Eur. J. Biochem. 1997, 243, 322 327. 23. Soong, C.-L.; Ogawa, J.; Shimizu, S. A Novel Amidase (Half-Amidase) for HalfAmide Hydrolysis. Appl. Environ. Microbiol. 2000, 66, 1947 1952. 24. Hersh, L. B. Rat Liver Omega-Amidase. Purification and Properties. Biochemistry 1971, 10, 2884 2891. 25. Meister, A.; Levintow, L.; Greenfield, R. E.; Abendschein, P. A. Hydrolysis and Transfer Reactions Catalyzed by ω-Amidase. J. Biol. Chem. 1955, 215, 441 460. 26. Kelly, M.; Clarke, P. H. An Inducible Amidase Produced by a Strain of Pseudomonas aeruginosa. J. Gen. Microbiol. 1962, 27, 305 316. 27. Maestracci, M.; Thiery, A.; Arnaud, A.; Galzy, P. The Amidases From a Brevibacterium Strain: Study and Applications. Adv. Biochem. Eng. Biotechnol. 1988, 36, 67 115. 28. Hynes, M. J.; Pateman, J. A. The Use of Amides as Nitrogen Sources by Aspergillus nidulans. J. Gen. Microbiol. 1970, 63, 317 324. 29. Soong, C.-L.; Ogawa, J.; Sukiman, H.; Prana, T.; Prana, M. S.; Shimizu, S. Distribution of Cyclic Imide-Transforming Activity in Microorganisms. FEMS Microbiol. Lett. 1998, 158, 51 55. 30. Ogawa, J.; Kaimura, T.; Yamada, H.; Shimizu, S. Evaluation of Pyrimidine- and Hydantoin-Degrading Enzymes Activities in Aerobic Bacteria. FEMS Microbiol. Lett. 1994, 122, 55 60. 31. Ogawa, J.; Shimizu, S. β-Ureidopropionase From N-Carbamoyl-α-L-amino acid Amidohydrolase Acitivity From an Aerobic Bacterium, Pseudomonas putida IFO 12996. Eur. J. Biochem. 1994, 223, 625 630. 32. Ogawa, J.; Soong, C.-L.; Ito, M.; Shimizu, S. Enzymatic Production of Pyruvate From Fumarate: An Application of Microbial Cyclic-Imide-Transforming Pathway. J. Mol. Catal. B: Enzymatic 2001, 11, 355 359.

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33. Hibi, M.; Horinouchi, N.; Tu, W.; Soong, C. L.; Ito, M.; Segawa, T.; Mu, X.; Hagishita, T.; Yokozeki, K.; Shimizu, S.; Ogawa, J. Breeding of a Cyclic ImideAssimilating Bacterium, Pseudomonas putida s52, for High Efficiency Production of Pyruvate. Biosci. Biotechnol. Biochem. 2013, 77, 1650 1654. 34. Miyata, R.; Yonehara, T. Breeding of High-Pyruvate-Producing Torulopsis glabrata and Amino Acid Auxotrophic Mutants. J. Biosci. Bioeng. 2000, 90, 137 141. 35. Ogawa, J.; Soong, C.-L.; Kishino, S.; Li, Q. S.; Horinouchi, N.; Shimizu, S. Screening and Industrial Application of Unique Microbial Reactions Involved in Nucleic Acid and Lipid Metabolisms. Biosci. Biotechnol. Biochem. 2006, 70, 574 582. 36. Kagabu, S.; Moriya, K.; Shibuya, K.; Hattori, K.; Tsuboi, S.; Shiokawa, K. 1-(6Halonicotinyl)-2-nitromethylene-imidazolidines as Potential New Insecticides. Biosci. Biotechnol. Biochem. 1992, 56, 362 363. 37. Moriya, K.; Shibuya, K.; Hattori, Y.; Tsuboi, S.; Shiokawa, K.; Kagabu, S. Structural Modification of the 6-Chloropyridyl Moiety in the Imidacloprid Skeleton: Introduction of a Five-membered Heteroaromatic Ring and the Resulting Insecticidal Activity. Biosci. Biotechnol. Biochem. 1993, 57, 127 128. 38. Luc, I.; Spiessens, M.; Marc, J.; Anteunis, O. Preparation and Structural Assignments of Some Isomeric 2,3-Disubstituted Pyridines. Bull. Soc. Chim. Belg. 1980, 89, 205 231. 39. Ogawa, J.; Soong, C.-L.; Ito, M.; Segawa, T.; Prana, T.; Prana, M. S.; Shimizu, S. 3Carbamoyl-α-picolinic acid Production by Imidase-catalyzed Regioselective Hydrolysis of 2,3-Pyridinedicarboximide in a Water-Organic Solvent, Two-phase System. Appl. Microbiol. Biotechnol. 2000, 54, 331 334. 40. Huang, C. Y.; Yang, Y. S. Discovery of a Novel N-iminylamidase Activity: Substrate Specificity, Chemicoselectivity and Catalytic Mechanism. Protein Expr. Purif. 2005, 40, 203 211. 41. Lal, R.; Sukbuntherng, J.; Tai, E. H.; Upadhya, S.; Yao, F.; Warren, M. S.; Luo, W.; Bu, L.; Nguyen, S.; Zamora, J., et al. Arbaclofen Placarbil, A Novel R-Baclofen Prodrug: Improved Absorption, Distribution, Metabolism, and Elimination Properties Compared With R-Baclofen. J. Pharm. Exp. Ther. 2009, 330, 911 992. 42. Hampson, D. R.; Adusei, D. C.; Pacey, L. The Neurochemical Basis for the Treatment of Autism Spectrum Disorders and Fragile X Syndrome. Biochem Pharmacol. 2011, 81, 1078 1086. 43. Tassone, D. M.; Boyce, E.; Guyer, J.; Nuzum, D. Pregabalin: A Novel Γ-Aminobutyric Acid Analogue in the Treatment of Neuropathic Pain, Partial-Onset Seizures, and Anxiety Disorders. Clin. Ther. 2007, 29, 26 48. 44. Chênevert, R.; Desjardins, M. Chemoenzymatic Enantioselective Synthesis of Baclofen. Can. J. Chem. 1994, 72, 2312 2317. 45. Caira, M. R.; Clauss, R.; Nassimbeni, L. R.; Scott, J. L.; Wildervanck, A. F. Optical Resolution of Baclofen via Diastereomeric Saltpair Formation Between 3-(pChlorophenyl)glutaramicacid and (S)-(2)-α-Phenylethylamine. J. Chem. Soc. Perkin Trans. 1997, 2, 763 768. 46. Hoekstra, M. S.; Sobieray, D. M.; Schwindt, M. A.; Mulhern, T. A.; Grote, T. M.; Huckabee, B. K.; Hendrickson, V. S.; Franklin, L. C.; Granger, E. J.; Karrick, G. L. Chemical Development of CI-1008, An Enantiomerically Pure Anticonvulsant. Org. Process. Res. Dev. 1997, 1, 26 38. 47. Nojiri, M.; Hibi, M.; Shizawa, H.; Horinouchi, N.; Yasohara, Y.; Takahashi, S.; Ogawa, J. Imidase Catalyzing Desymmetric Imide Hydrolysis Forming Optically Active 3-substituted Glutaric Acid Monoamides for the Synthesis of GammaAminobutyric Acid (GABA) Analogs. Appl. Microbiol. Biotechnol. 2015, 99, 9961 9969.

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48. Soong, C.-L.; Ogawa, J.; Shimizu, S. Novel Amidohydrolytic Reactions in Oxidative Pyrimidine Metabolism: Analysis of the Barbiturase Reaction and Discovery of a Novel Enzyme, Ureidomalonase. Biochem. Biophys. Res. Commun. 2001, 286, 222 226. 49. Soong, C. L.; Ogawa, J.; Sakuradani, E.; Shimizu, S. Barbiturase, a novel zinccontaining amidohydrolase involved in oxidative pyrimidine metabolism. J. Biol. Chem. 2002, 277, 7051 7058. 50. Arnold, F. H. Combinatorial and Computational Challenges for Biocatalyst Design. Nature 2001, 409, 253 257.

CHAPTER 4

Imides: A Special Chemical Entity in Rhodium Catalysis Pranjal P. Bora and Sachin Handa


Department of Chemistry, University of Louisville, Louisville, KY, United States
Corresponding author e-mail: [email protected]

4.1 INTRODUCTION In organometallic catalysis, rhodium has a unique place as its estimated natural (earth) abundance is 0.0001 parts per million.1 Therefore, it is considered as one of the most precious metals. Rhodium has 24 isotopes; however, its naturally occurring, nonradioactive, and most stable isotope is 103 Rh. Although the most common oxidation state of Rh is 13, the 11, 12, and 13 oxidation states of rhodium are all utilized in catalysis.2 The binding of diatomic hydrogen with Rh(III) and its subsequent cleavage to form a rhodium hydride species was one of the unusual activities reported in the early years.3,4 The Rh-mediated asymmetric hydrogenation of olefins and its application in the synthesis of L-3,4-dihydroxyphenylalanine (L-dopa) was among the vital catalytic transformations in the late 20th century.5 Since then, many novel Rh-catalyzed pathways have been reported2; the important catalytic pathways are hydrogenation of arenes,69 hydroformylation of olefins,1013 olefindiene codimerization,1416 carbonylation of methanol to acetic acid,1719 and CH activation2023 (Fig. 4.1). The most commonly used ligands in rhodium catalysis are phosphines,2426 imides,27 carboxylates,28,29 N-heterocyclic carbenes (NHCs),3032 acyclic diamino carbenes (ADCs),33 phosphoramidites,3436 oxazolines,37 mixed PS and PN ligands,38 and ferrocene-based ligands.39 The use of the nonracemic versions of these ligands in asymmetric catalysis allows for the synthesis of desired compounds in an enantioselective fashion.40,41 The increasing demand for the preparation of enantiomerically pure compounds as reaction intermediates in the pharmaceutical industry highlights one of the many applications of asymmetric catalysis.42 Applications of rhodium in asymmetric catalysis are broad in this regard, especially in the highly challenging transformations involving Imides DOI: https://doi.org/10.1016/B978-0-12-815675-9.00004-7

© 2019 Elsevier Inc. All rights reserved.

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Figure 4.1 Applications of imides in the rhodium catalysis.

CH activation.41 The use of various ligands in rhodium catalysis is also a broad topic. In this chapter, the focus will be on imidocarboxylates in rhodium catalysis with particular attention on highly efficient and atomeconomical reaction pathways.

4.2 CATALYSIS WITH N-IMIDO-AMINO ACIDDERIVED RHODIUM (II)-CARBOXYLATES 4.2.1 RhodiumImidocarboxylate as a Catalyst Metallocarbenoids are one of the most widely employed intermediates in organic synthesis, which are commonly generated from the corresponding

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Figure 4.2 The general mechanism for the formation of rhodium carbenoids.

diazo compounds.43,44 Owing to their dual electrophilic and nucleophilic character, these intermediates participate in a wide array of useful transformations. Among the various metallocarbenoids, rhodium carbenoids undergo a wide range of reactions, including cyclopropanation, CH insertion, Cheteroatom insertion, ylide formation, and cycloaddition (Fig. 4.2).45,46 The successful applications of the rhodium carbenoids in useful catalytic processes are due to the binding of the carbenoid to only one rhodium in the dirhodium complex while the second rhodium atom acts as an electron sink to enhance the electrophilicity of the carbene moiety. This selective binding facilitates the cleavage of the rhodiumcarbene (RhC) bond on the reaction completion.47 This kind of supporting role of one metal atom/ion in the bimetallic species is not available in monometallic carbenoid complexes, for example, a copper-carbenoid species. Among the different dirhodium catalysts, N-phthaloyl amino acidsderived homochiral rhodium(II)-carboxylate catalysts are widely used in various asymmetric carbene-transfer reactions. In 1990 Hashimoto and coworkers developed the first two catalysts of this series (Scheme 4.1), namely dirhodium tetrakis[N-phthaloyl-(S)-phenylalaninate] [Rh2(Sptpa)4] (2a) and dirhodium tetrakis[N-phthaloyl-(S)-alaninate] [Rh2(Spta)4] (2b).48 The rhodium (II)-carboxylates were prepared by a ligand exchange reaction of Rh2(OAc)4 with N-phthaloyl-(S)-amino acids (1ad) in refluxing chlorobenzene. Two years later, following a similar method of synthesis, the authors reported two more catalysts, named dirhodium tetrakis[N-phthaloyl-(S)-valinate] [Rh2(S-ptv)4] (2c) and dirhodium tetrakis[N-phthaloyl-(S)-tert-leucinate] [Rh2(S-pttl)4] (2d).49 The authors have also demonstrated the catalytic activity of these complexes for the enantioselective intramolecular CH insertion of α-diazo β-keto esters 3ad to obtain chiral cyclic β-keto esters 4ad with good to excellent yields. Upon demethoxycarbonylation in 4ad, cyclic ketones 5ad were obtained in poor enantioselectivity, that is, 24%46% as determined in 4ad.

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Scheme 4.1 Synthesis of imido carboxylate (IC)dirhodium complexes and their application.

Hashimoto and coworkers further fine-tuned the above complexes with the use of fused-benzophthalimide ligand 8ad, which were prepared by a reaction of 6 with amino acid 7 in dimethylformamide (DMF) at 140°C. Complexes 9ad were obtained in a modest yield upon reaction of rhodium acetate dimer with ligand 8 in refluxing chlorobenzene (Scheme 4.2). The resulting complexes were abbreviated

Scheme 4.2 Synthesis of ICrhodium complexes and their activity in the asymmetric cycloaddition reaction.

as [Rh2(S-bptpa)4], [Rh2(S-bpta)4], [Rh2(S-bptv)4], and [Rh2(S-bpttl)4]. The catalytic activity of these complexes exhibited better enantioselectivity for the intermolecular 1,3-dipolar cycloaddition of α-diazo ketone 10 with dimethyl acetylenedicarboxylate (11). Depending upon the type of catalyst used in this transformation, the resulting bridged cyclic ether 12 was obtained in 79%83% yield and 65%90% enantioselectivity.

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Among these catalysts, [Rh2(S-bptv)4] furnished the best results with 90% enantioselectivity and 79% yield.50 Furthermore, these authors also developed the complexes 16a and 16b, which are halogenated versions of 2d, that is, [Rh2(S-pttl)4]. Complex 16a is abbreviated as [Rh2(S-tfpttl)4] and 16b as [Rh2(Stcpttl)4]. These complexes were prepared via a ligand exchange reaction of Rh2(OAc)4 with N-tetrafluorophthaloyl- and N-tetrachlorophthaloyl(S)-tert-leucines, respectively. Compared to its nonhalogenated counterpart, these halogenated complexes displayed improved enantioselectivity in the catalytic CH amidation of indane (13) with [(4-nitrophenyl)sulfonylimino] phenyliodinane, NsN 5 IPh (14). Enantioselectivity in the product 15 was improved from 29% to 66% with the use of catalyst 16b (Scheme 4.3).51

Scheme 4.3 Improved selectivity with the halogenated ligands.

In 2003 Muller and coworkers developed a new series of dirhodium (II) carboxylate complexes derived from naphthalenediimide carboxylate ligands 18 (Scheme 4.4). These complexes were synthesized in a similar

Scheme 4.4 Synthesis and applications of [Rh2(S-nttl)4] and its derivatives.

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manner as Hashimoto’s approach. The chiral ligands 18aa18bc were prepared by a condensation of 1,8-naphthalic anhydride 17a or 17b and L-leucinebased amino acids, which on refluxing with Rh2(OAc)4 in chlorobenzene afforded the catalysts 19aa19bc. These complexes were abbreviated as [Rh2(S-ntpa)4] (19aa), [Rh2(S-ntv)4] (19ab), [Rh2(S-nttl)4] (19ac), and [Rh2(S-4-Br-nttl)4] (19bc). The authors investigated the activity of these catalysts for the enantioselective cyclopropanation of olefins with the Meldrum’s acid (20)derived phenyliodonium ylide 21. Among these catalysts, tert-leucinate protected with 4-Br substituted 1,8naphthalic anhydridederived complex [Rh2(S-4-Br-nttl)4] (19bc) provided the best enantioselectivity in cyclopropanation of styrenes. Consequently, product 22 was obtained in 75% yield and 82% ee.52,53 Inspired by the success of Hashimoto’s catalyst [Rh2(S-pttl)4] containing tert-butyl side chain compared to other rhodium phthalimidocarboxylate catalysts containing smaller side chains, Davis and coworkers developed a new rhodium phthalimidocarboxylatebased complex 23, that is, dirhodium(II) tetrakis[N-phthaloyl-(S)-adamantylglycine], abbreviated as [Rh2(S-ptad)4]. In this complex, the ligand possesses a much bulkier and rigid adamantane ring. Synthesis of this complex involved [Rh2(S-dosp)4]-catalyzed enantioselective CH functionalization reaction of adamantane with phenylvinyldiazoacetate (Scheme 4.5).54 The resulting coupling product was further recrystallized to obtain .99% enantioselectivity. Upon its reduction with LiAlH4, corresponding alcohol was obtained. The resulting alcohol was protected with the N2 H COOMe

COOMe Rh2(S-dosp)4 (0.5 mol%) hexane, 69 oC

H

LiAlH4 (0.5 equiv.)

TBS–Cl (1.1 equiv.) imidazole (1.1 equiv.) DMAP (15 mol%)

o

o

o

>99% ee after recrystallization

H

OTBS

O 74%

O

96%

H O HN

O

H

Ba(OH)2•H2O (5 equiv.) Dioxane:H2O(2:1) reflux

OH NH2

95%

65%

O

H

O R

OTBS

o

96%

DPPA (1.08 equiv.) Et3N (1.1 equiv.) TFA (2.5 equiv.) Toluene,reflux

O

R

R

OH

H

CH2Cl2, 0 C–23 C

THF, 0 C–23 C

RuCl3.H2O (2.2 mol%) NaIO4 (4.1 equiv.) CH3CN:EtOAc:H2O (1:1:1) rt

R

OH

H

OH N

RuCl3•H2O (2.2 mol%) NaIO4 (4.1 equiv.)

O

O

DMF, 140oC

R R R

CH3CN:EtOAc:H2O (1:1:1) rt

OH N

Rh2(OAc)2 R

R

R

R = H 80% R = Cl 80%

O

O

R

R

R = H 65% R = Cl 68%

H O

Rh

O

Rh

O N

Chlorobenzene 150 oC

R R

O R

4 R 23 R = H [Rh2(S-ptad)4] 60% 24 R = Cl [Rh2(S-tcptad)4] 62%

Scheme 4.5 Synthesis of [Rh2(S-ptad)4] and its chlorinated derivative.

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tert-butyldimethylsilyl (TBS) group before an oxidative cleavage to obtain the resulting carboxylic acid. With the one-pot transformations, that is, Curtius rearrangement and TBS deprotection, adamantyloxazolidin-2-one was obtained, which upon hydrolysis with Ba(OH)2 afforded 2-amino-2adamantylethanol. Its reactions with phthalic anhydride followed by oxidation of the resulting intermediate generates the N-phthaloyl amino acid. The ligand exchange reaction between the N-phthaloyl amino acid and Rh2(OAc)4 in refluxing chlorobenzene afforded [Rh2(S-ptad)4]. This catalyst afforded better or comparable selectivity as [Rh2(S-pttl)4] for asymmetric cyclopropanation and intermolecular CH insertion with diazo phosphonates. Using a similar synthetic protocol, they have also developed the chlorinated analog 24, which is abbreviated as [Rh2(Stcptad)4].55

4.2.2 Applications of RhodiumImidocarboxylate Complexes in Catalysis 4.2.2.1 Asymmetric Cyclopropanation Cyclopropane is the smallest cyclic hydrocarbon and has broad applications in synthetic and medicinal chemistry (Fig. 4.3). The cyclopropane ring is also found in a large number of bioactive compounds, including natural products and drugs. An opening of this highly strained ring can lead to many synthetically useful intermediates which serve as building blocks in the synthesis of complex molecules. Among the various

Figure 4.3 Some bioactive compounds containing cyclopropane rings.

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approaches, a rhodium-catalyzed reaction of diazo compounds with alkenes is an efficient way to achieve asymmetric cyclopropanations. The decomposition of diazo compounds in the presence of a dirhodium salt generates rhodium carbenoid species with a loss of molecular nitrogen. In situgenerated rhodium carbenoids also undergo concerted addition to alkenes to afford cyclopropanes. Muller and coworkers explored N-naphthoyl-tert-leucinederived dirhodium catalyst 19ac [Rh2(S-nttl)4] for the asymmetric cyclopropanation of styrene with (silanyloxyvinyl)diazoacetates 25 to afford cyclopropane 26 (Scheme 4.6).56 They have examined various dirhodium catalysts,

Scheme 4.6 [Rh2(S-nttl)4] as a catalyst for cyclopropanation.

including imide-based catalysts [Rh2(S-pttl)4], [Rh2(S-ptpa)4], and [Rh2(S-ntv)4]. Although all the imide-based Rh(II) catalysts examined provided very good diastereo- and enantioselectivities, [Rh2(S-nttl)4] afforded the best selectivity with 95% de and 98% ee. The scope of this protocol was also explored for the cyclopropanation of dihydrofuran and dihydropyran with 25 to afford bicyclic cyclopropanes 27 and 28. Excellent diastereoselectivity and enantioselectivity was obtained. Notably, [Rh2(S-nttl)4]-catalyzed cyclopropanation of styrenes with alkyl diazo(trialkylsilyl)acetates (29) was less selective and poor ee as well as de were observed during the catalytic synthesis of 30.57

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Davis and coworkers employed their imide-based dirhodium catalyst 23 [Rh2(S-ptad)4] for the asymmetric cyclopropanation of electron-rich olefins with 2-diazo-2-phenylacetonitrile. Various electron-rich olefins underwent cyclopropanation with 2-diazo-2-phenylacetonitrile to furnish synthetically useful nitrile-substituted cyclopropanes with high diastereoselectivities and enantioselectivities. Although cyclopropanation of 2,3-dihydrofuran was less enantioselective, it provided very good diastereoselectivity and reaction yield.58 Charette and coworkers also made some excellent contributions toward asymmetric Rh(II)-catalyzed cyclopropanation chemistry with employment of imide-based dirhodium carboxylate catalysts. In 2008 they explored the trans-directing ability of the amide group to develop a highly enantio- and diastereoselective cyclopropanation of olefins with α-amido diazoacetates 31 (Scheme 4.7). Among the various chiral dirhodium

Scheme 4.7 Asymmetric cyclopropanation of olefins with α-amido diazoacetates.

catalysts tested, 19ac [Rh2(S-nttl)4] offered the best stereoselectivities for the preparation of 32. Catalytic cyclopropanation of various alkenes afforded the cis-cyclopropanes in good yields with excellent diastereo- and enantioselectivities (32ac).59 Continuing their exploration of cyclopropanation chemistry, the authors found that an additive could significantly influence the stereoselectivities of cyclopropanation of α-cyano diazoacetamide 33 with alkenes.60 The use of TfNH2 as an achiral hydrogenbond donor significantly improved the stereoselectivities in 34. However,

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the authors did not provide an exact mechanism for how the TfNH2 enhanced the stereoselectivity. The 13C NMR analysis and control experiments suggested a possible interaction of TfNH2 with the cyano moiety to improve the stereoselectivity. In another study, Charette and coworkers explored the Rh(II) carboxylate-catalyzed enantioselective cyclopropanation of alkenes with α-nitro diazoacetophenones 35 for the enantioselective synthesis of ciscyclopropane α-amino acids (Scheme 4.8).61 Based on the screening of

Scheme 4.8 Asymmetric diazoacetophenones.

cyclopropanation

of

olefins

with

α-nitro

different phthalimide-based dirhodium catalysts, the use of [Rh2(Stcpttl)4] was found to be optimal, affording the nitrocyclopropane derivatives 36ad in good yields with excellent diastereoselectivity and up to 94% ee. As a representative example, N-tert-butoxycarbonyl (Boc)protected cis-cyclopropane α-amino acid 37 was synthesized from nitrosubstituted cyclopropane over four steps with minimum loss of optical purity, using BaeyerVilliger oxidation, indium-catalyzed reduction of nitro group followed by hydrolysis of ester, and Boc protection of the amino group. To gain more insights into the reaction mechanism on reaction selectivity, single crystal X-ray structure of catalytic species and 1 H13C heteronuclear nuclear overhauser effect spectroscopy (NOESY) experiments were performed. From these experiments, it was confirmed that the “all-up” conformation of the phthalimide-based Rh(II) carboxylate was a reactive conformation for the cyclopropanation. Based on the structureactivity relationship between the substrates and the catalyst, the

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p-methoxyphenyl ketone (PMP-ketone) fragment was determined to be a crucial partner to obtain excellent diastereo- and enantioselectivities.62 The PMP-ketone group enabled good diastereocontrol through a stereoelectronic effect in the transition state, while π-stacking with the catalyst’s tetrachlorophthaloyl groups afforded excellent enantioselectivity. The synthesis of organofluorine compounds is of great importance as they have been widely used as pharmaceuticals and agrochemicals. Introduction of fluorine atom(s) can beneficially modulate the chemical and physical properties of organic compounds. In this context, Davis and coworkers synthesized chiral cyclopropanes decorated with the trifluoromethyl group via Rh(II)-catalyzed asymmetric cyclopropanation of styrenes with 1-phenyl-2,2,2-trifluoro-diazoethane. Both the catalysts 2d [Rh2(S-pttl)4] and 23 [Rh2(S-ptad)4] were effective for the cyclopropanation of styrene with 1-phenyl-2,2,2-trifluoro-diazoethane in trifluorotoluene to furnish trifluoromethylated cyclopropane 38 in excellent yields with excellent diastereo- and enantioselectivity (Scheme 4.9).63 These

Scheme 4.9 Asymmetric synthesis of trifluoromethylated cyclopropanes.

authors also performed a two-step strategy for cyclopropanation of styrene with an air- and moisture-stable hydrazone to avoid the difficulties of handling diazo compounds. This approach involved oxidation of a hydrazone with MnO2 in trifluorotoluene followed by the cyclopropanation. Along the same lines, Charette, Jubault, and coworkers developed the first asymmetric synthesis of highly functionalized difluoromethylated cyclopropanes (Scheme 4.10).64 The cyclopropanation of α-difluoromethylstyrene with an α-nitro diazoketone in the presence of 16a [Rh2(S-tfpttl)4] or 16b [Rh2(S-tcpttl)4] afforded good enantioselectivity and average yields. However, the cyclopropane-based rhodium dicarboxylate catalyst [Rh2(S-btpcp)4] provided optimum yields and selectivity. The [Rh2(S-btpcp)4]-catalyzed cyclopropanation of difluoromethylated olefins 40 with α-aryl diazoacetates or α-nitro diazoketones 39 afforded a wide range of functionalized difluoromethylated cyclopropanes

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Scheme 4.10 Asymmetric synthesis of difluoromethylated cyclopropanes.

41ag in good to excellent yields with high diastereo- and enantioselectivities. In an application of cyclopropanation for the synthesis of natural product derivatives, Davies, Reiser, and coworkers explored the cyclopropanation of furans for the enantioselective synthesis of novel paraconic acid derivatives (Scheme 4.11).65 Notably, paraconic acids and their structurally related compounds are of great interest due to their broad spectrum pharmacological and biological activities, including antitumor, antibiotic, antifungal, and antibacterial properties. The authors optimized the challenging enantioselective cyclopropanation of methyl 2-furoate with methyl phenyldiazoacetate using various dirhodium catalysts. The chlorinated analog of [Rh2(S-pttl)4], which is, [Rh2(S-tcpttl)4] provided the monocyclopropanated furan 42 in good yields with excellent enantiopurity. Further optimization of the reaction condition showed that a catalyst loading of 0.001 mol% [Rh2(Stcpttl)4] could afford 42 in 88% yield with 96% enantiopurity, which crystallized directly from the reaction mixture and could be isolated by simple filtration. The monocyclopropanated furan 42 was synthetically transformed into novel paraconic acid derivatives 43 and 44 in 18.5% and 15.2% overall yields, respectively. The synthesis involved a highly diastereoselective allylation/retroaldol/lactonization cascade as a critical step. Due to the electrophilic nature of metal-bound carbenes, their cyclopropanation with electron-deficient alkenes is more challenging. It is

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Scheme 4.11 Rhodium-catalyzed asymmetric synthesis of novel paraconic acid derivatives.

much less explored compared to the cyclopropanation of electron-rich and electron-neutral olefins, especially with rhodium catalysts. In 2013 the Davies group reported the first highly enantioselective cyclopropanation of acrylates with aryl and vinyldiazoacetates catalyzed by adamantylglycine-derived catalyst 24 [Rh2(S-tcptad)4] (Scheme 4.12).66

Scheme 4.12 Asymmetric cyclopropanation of electron-deficient alkenes.

For this particular transformation, chlorinated catalysts such as [Rh2(S-tcptad)4], [Rh2(S-tcpttl)4], and [Rh2(S-tcptv)4] exhibited better enantiocontrol over their nonhalogenated counterparts. Various acrylates underwent cyclopropanation with a range of aryldiazoacetates and

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vinyldiazoacetates in the presence of 24 furnished the corresponding cyclopropane derivatives 45ag with good to excellent diastereo- and enantioselectivities. Cyclopropanation of aryldiazoacetates possessing strong electron-withdrawing group resulted in relatively lower reaction yields and diastereoselectivities, although good enantioselectivity was documented. Notably, the reaction of unsaturated aldehydes and ketones with aryldiazoacetates resulted in epoxidation with poor enantioselectivity. The authors have also tried to shed light on the mechanism of this intriguing cyclopropanation of highly electrophilic rhodium-bound carbenes with the help of density functional theory (DFT) studies. Based on the computational studies, the authors proposed that the weak interaction between the carbenoid and the substrate carbonyl facilitated the reaction. 4.2.2.2 CH Activation Rhodium(II)-catalyzed CH functionalization mainly involves insertion of a rhodium-bound carbene or nitrene into a CH bond, resulting in the formation of new CC and CX (heteroatom) bond(s). Owing to the inherent chirality associated with the N-imido-amino acidderived rhodium(II)-carboxylates, they can easily facilitate stereoselective CH functionalization. The Davies, Fox, and Murakami groups made excellent contributions toward the development of this research area. With the computational tools, Nakamura and coworkers investigated the mechanism of rhodium(II)-catalyzed CH activation for CC bond formation (Scheme 4.13).47 Accordingly, the CH activation and CC bond R

R

R N

O

O

Rh

Rh

N

N R1

R2

O

O

Rh

Rh

N

O

O

Rh

Rh

R1 R2

I

R1 R2

II R3 R4 R5

H

R R1

R5 R2

R

R3 R4

R3 R4 O

O

Rh

Rh

R5

H R1 R2

R3 R4

O

O

Rh

Rh

H

R5

R1 R2

III

Scheme 4.13 Proposed mechanism for rhodium(II)-catalyzed CH functionalization.

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formation process are initiated with the formation of rhodiumcarbene complex II from the reaction of dirhodium carboxylate catalyst I with the diazo compound. One of the two rhodium atoms works as a carbenebinding site while the other assists the CH insertion reaction. The CH activation/CC formation proceeds in a single step through the formation of three-centered hydride transfer-like transition state III. The unbound rhodium atom then facilitate the cleavage of the rhodiumcarbon bond by enhancing the electrophilicity of the carbene moiety. Fox and coworkers reported an unprecedented enantioselective C3H functionalization of indoles. N-Imido-(S)-tert-leucinatederived rhodium(II)-carboxylates [Rh2(S-nttl)4]catalyzed CH insertion of α-alkyl-α-diazo esters at C-3 position of indoles afforded α-alkyl-α-indolylacetates in high yields with very good to excellent enantioselectivities (Scheme 4.14).67 Diazoesters bearing different α-alkyl substituents such as

Scheme 4.14 Enantioselective CH functionalization of indoles.

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methyl, ethyl, butyl, and isopentyl afforded functionalized indoles with high yield and enantioselectivity. Likewise, indoles with a variety of functionalities (46ah) such as fluoro-, bromo-, methoxy-, siloxy, Bocprotected aniline, and ester functional groups were well tolerated. Although, N-aryl or N-alkyl indole derivatives afforded excellent results, indoles having strongly electron-withdrawing groups on nitrogen (e.g., acetyl or Boc) failed. From the DFT calculation, the authors proposed the formation of oxocarbenium-type rhodiumylide intermediate while the asymmetric induction was achieved either by an approach of the indole to the si-face of rhodiumcarbene, with subsequent aromatization and protonation or via dynamic kinetic resolution of a rhodium enolate intermediate. The Yu and Davies groups collaboratively developed an excellent approach for the enantioselective synthesis of 2,3-dihydrobenzofurans by employing two sequential C 2 H functionalizations (Scheme 4.15). This

Scheme 4.15 Enantioselective synthesis of 2,3-dihydrobenzofurans.

approach merged the Davies group’s enantioselective intermolecular benzylic C 2 H insertion68 with the Yu group’s C 2 H activation/C 2 O cyclization.69 The [Rh2(S-pttl)4]-catalyzed intermolecular benzylic CH insertion of various benzyl TBS ethers with aryldiazoacetate afforded CH functionalized product 47 with excellent diastereo- and enantioselectivities. The optically-enriched CH functionalized products 48, after TBS deprotection, exposed the hydroxyl group for Pd-catalyzed cyclization to afford 2,3-dihydrobenzofurans 49af (representative examples) with good regioselectivity and without any racemization.70 In another collaborative effort, the Davies and Itami groups developed a sequential CH functionalization approach for the concise synthesis of dictyodendrin A and F (Scheme 4.16).71 The dictyodendrins are pyrrolo

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Scheme 4.16 Synthesis of dictyodendrin A and F.

[2,3-c]-carbazole-based natural products, which exhibit interesting inhibitory activities toward telomerase and β-site amyloid precursor protein (APP) cleaving enzyme 1, and are potential chemotherapy agents and neurodegenerative probes. The synthesis involved a rhodium-catalyzed regioselective double CH functionalization. The first step involves the formation of 51 from 50 with the catalytic use of rhodium complex. Second CH functionalization involves the catalytic reaction of 51 with diazo compound 52 followed by bromination to afford 53 in 70% yield. This step was optimized with different dirhodium carboxylate catalysts along with varying reaction conditions. The [Rh2(S-tcptad)4] provided 53 with excellent regioselectivity when the catalyst and aryldiazoacetate were added in two fractions. The Pd-catalyzed SuzukiMiyaura coupling between 53 and 54 yielded a key intermediate 55, which upon treatment with lithium diisopropylamide (LDA) furnished the pyrrolo[2,3-c]carbazole 56. It was then transformed to dictyodendrin F over three steps 57, via formation of intermediate 58. For the synthesis of dictyodendrin A, pyrrolo[2,3-c]carbazole 56 on methylation and sequential Boc

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deprotection and debenzylation in one-pot furnished 58, which was then used as an intermediate for the synthesis of dictyodendrin A.72 The challenging site-selective CH functionalizations commonly rely on the substrate control strategy, where the substrate has one inherently more reactive CH bond or contains a directing group to favor a particular CH bond. The catalyst-control approaches are comparatively less selective and rare. Davies and coworkers recently reported the development of a catalyst-controlled approach for CH functionalization of the most accessible unactivated secondary and tertiary CH bonds (Scheme 4.17).73,74 The bulky dirhodium catalysts with triphenylcyclopropanecar-

Scheme 4.17 Site-selective CH functionalization.

boxylate (tpcp), Rh2[R-3,5-di(p-t-BuC6H4)tpcp]4 was found to be highly active for site-selective CH functionalization at the most sterically accessible secondary CH bond. While less sterically encumbered dirhodium catalyst, [Rh2(S-tcptad)4], catalyzed the site-selective CH functionalization at the most sterically accessible tertiary carbon. The reactions typically proceeded between diazo ester 59 and long-chain hydrocarbons 60. Good regio- and enantioselectivities were obtained in the substrate scope (61af). To demonstrate the efficiency of their approach for functionalization of natural products, cholesteryl acetate and vitamin-E acetate were functionalized at the most accessible tertiary CH bond at the end of the side chain with excellent diastereoselectivity.

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In 2015 Hashimoto and coworkers explored the imido-rhodium(II) catalyzed intramolecular CH insertion for the asymmetric synthesis of (2)-E-δ-viniferin (Scheme 4.18).75 (2)-E-δ-viniferin is a modest cytotoxic

Scheme 4.18 Asymmetric synthesis of (2)-E-δ-viniferin.

natural product isolated from the roots of Rheum maximowiczii and also exhibits inhibitory activities for a diverse array of enzymes, including cyclooxygenase I and II, lipoxygenase, and α-glucosidase. The [Rh2(Stfpttl)4]-catalyzed intramolecular CH insertion in diaryldiazomethane 62 afforded a key intermediate cis-2,3-diaryl-2,3-dihydrobenzofuran 63 in 96% ee with excellent cis-selectivity. To obtain .99% ee in 63, it was further recrystallized. Enantiomerically pure 63 was subjected to HeckMizoroki reaction with 3,5-diacetoxystyrene (64) with one-pot sequential epimerization at the C-2 position to obtain coupled product 65, which was then subjected to global deprotection with BBr3 to obtain (2)-E-δ-viniferin with .99% enantiopurity. 4.2.2.3 Cycloaddition Reactions Tropanes (8-azabicyclo[3.2.1]octane) are interesting scaffolds found in a wide range of natural products and pharmaceutical agents. Leveraging the catalytic efficacy of imido-rhodium(II) catalyst such as [Rh2(S-ptad)4], the Davies group achieved asymmetric [4 1 3]-cycloaddition of vinyldiazoacetate 67 with pyrroles 66 to access tropanes (8-azabicyclo[3.2.1]octane) 68.76 The rhodium-catalyzed formal [4 1 3]-cycloaddition involved

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tandem cyclopropanation/Cope rearrangement of vinylcarbenoids and pyrroles. The [Rh2(S-ptad)4]-catalyzed [4 1 3]-cycloaddition of 67 with various N-substituted-pyrroles furnished tropanes 68ad in good yields and excellent enantioselectivities (Scheme 4.19). For the substrate scope,

Scheme 4.19 [Rh2(S-ptad)4]-catalyzed asymmetric [4 1 3]-cycloaddition.

N-Boc and N-phenylsubstituted pyrroles along with 2,3- and 2,5disubstituted pyrroles afforded tropanes in good yields with excellent enantioselectivity. The reaction temperature played a crucial role in these transformations, and 50°C was found to be optimal for maximum ee and yields. In another example of cycloaddition chemistry, the Davies and Williams groups teamed up to undertake the total synthesis of (2)-5-epivibsanin E, a natural product isolated from the Japanese fish poison plant Viburnum odoratissimum. The approach exploited the Davies group’s rhodium-catalyzed enantioselective formal [4 1 3]-cycloaddition of vinylcarbenoids and dienes and the synthetic end-game strategies was developed by the Williams group. The key step involved [Rh2(S-ptad)4]catalyzed formal [4 1 3]-cycloaddition of vinyldiazoacetates 69 and dienes 70 which involved tandem cyclopropanation of dienes with vinyldiazoacetate-derived rhodium carbenoid to form divinylcyclopropane followed by a Cope rearrangement to afford functionalized cycloheptane 71 (Scheme 4.20).77 The [Rh2(S-ptad)4] also facilitated asymmetric

Scheme 4.20 Total synthesis of (2)-5-epi-vibsanin E.

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induction in forming the quaternary stereogenic center with excellent enantioselectivities. The cycloheptane 71 was then converted to the (2)-5-epi-vibsanin E over 17 synthetic steps. In another interesting application of formal [4 1 3]-cycloaddition in the total synthesis of natural products, the Sarpong and Davies groups developed a synthetic strategy for the total synthesis of (1)-barekoxide and (2)-barekol (Scheme 4.21).78 The [Rh2(R-ptad)4]-catalyzed formal

Scheme 4.21 Total synthesis of (1)-barekoxide and (2)-barekol.

[4 1 3]-cycloaddition of bicyclic diene 72 with diazo compound 73 afforded tricyclic compound 74 as a pure diastereomer after recrystallization. The tricyclic compound 74 was transformed to (1)-barekoxide over the six steps, including olefin reduction (75), reduction and oxidation (76), reduction of ketone (77), and epoxidation to form (1)-barekoxide. After acid-catalyzed isomerization, it afforded (2)-barekol. 4.2.2.4 Asymmetric Amination In 2006 the Davies group studied both intermolecular and intramolecular CH amination with their new phthalimide-based rhodium(II)carboxylate complex, [Rh2(S-tcptad)4] (Scheme 4.22).55 Interestingly, [Rh2(Stcptad)4] gave exceptionally better enantioinduction as compared to its nonchlorinated counterpart [Rh2(S-ptad)4]. The [Rh2(S-tcptad)4] efficiently catalyzed the benzylic amination with NsNH2 in the presence of PhI(OAc)2 to afford various amines (78ae) in good yields with average enantioselectivities. A periodinane was synthesized by a reaction of NsNH2 with PhI(OAc)2, which in the presence of rhodium(II)carboxylate formed the rhodiumnitrene intermediate. The rhodiumnitrene

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Scheme 4.22 Rhodium-catalyzed asymmetric amination.

then underwent benzylic CH insertion to give amines with good asymmetric induction. The synthetic utility of the selective CH amination was demonstrated in the enantioselective synthesis of the (R)-enantiomer of the anti-Parkinson agent rasagiline from intermediates 78e and 79. Furthermore, the authors also studied the intramolecular CH amination of N-tosyloxycarbamates. [Rh2(S-tcptad)4] catalyzed the intramolecular CH amination of N-tosyloxycarbamates to furnish oxazolidinones in good yields with average enantioselectivities. Rhodium(II)-catalyzed stereoselective intermolecular sp3-CH amination was also reported by Dauban and coworkers (Scheme 4.23).79 Screening of various chiral rhodium (II)-carboxylates revealed the requirement of optimal steric hindrance in the catalyst, that is, N-naphtholyl imino alaninederived [Rh2(S-nta)4] catalyst found to be the optimal. Mixed solvents such as methanol and tetrachloroethane were best for optimal activity. About 3 mol% [Rh2(S-nta)4] efficiently catalyzed the amination of a range of hydrocarbons with sulfonimidamides in the presence of PhI(OCOt-Bu)2 at benzylic or allylic positions with excellent stereoselectivities (80ah). Aminations of various cycloalkanes were also successfully performed, and good yields and stereoselectivities were achieved. Notably, the amination of linear alkanes such as 2methylbutane resulted in lower yields. A reaction between sulfonimidamide and PhI(OCOt-Bu)2 in situ generates iminoiodane, which further

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Scheme 4.23 Stereoselective intermolecular CH amination.

reacts with the rhodium(II) catalyst to generate a rhodiumnitrene intermediate followed by CH insertion. The authors also used their protocol to develop a highly enantioselective catalytic CH amination protocol via kinetic resolution of sulfonimidamides. By employing racemic sulfonimidamides 81, asymmetric benzylic CH aminations were achieved to obtain products 82ae with excellent diastereo- and enantioselectivities (Scheme 4.24). Notably,

Scheme 4.24 Asymmetric CH amination via kinetic resolution of sulfonimidamides.

[Rh2(S-nta)4]-catalyzed aminations only consumed the (S)-sulfonimidamide 81 while unconsumed R-enantiomer was a mismatch to the catalyst. Typically, in these kinds of transformations, hypervalent iodine is used as an oxidant, which generates iodine (I) as a byproduct, leading to poor atom economy. To circumvent this issue, Dauban and coworkers recently used the in situgenerated aryl iodide byproduct as a coupling partner in

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Scheme 4.25 Sequential CH amination and sila-SonogashiraHagihara coupling.

the sila-SonogashiraHagihara coupling (Scheme 4.25).80 The approach involved two tandem catalytic cycles, [Rh2(S-nta)4]-catalyzed CH amination with sulfonimidamides in the presence of ArI(OR)2 followed by Pd/Cu-catalyzed sila-SonogashiraHagihara coupling with in situgenerated ArI. In the first cycle, sulfonimidamides reacts with iodine(III) oxidant in the presence of [Rh2(S-nta)4] to generate metallonitrene and iodoarene. The metallonitrene undergoes CH insertion leading to the amination product. The amination product containing the TMSacetylene group further leads the Sonogashira couplings with the in situgenerated iodoarene in the second cycle. With this tandem rhodium(II)/palladium(0) catalysis, many substrates containing benzylic and allylic groups were transformed to complex nitrogenous molecules 83af in very good yields and excellent stereoselectivities. 4.2.2.5 Applications of RhodiumImidocarboxylate for the Generation of Rhodium Carbenoids From Sulfonyl Triazoles Compounds containing the 1,2,3-triazole fragment are highly important for many chemical subdisciplines along with their extensive applications in medicinal chemistry, biochemistry, and material science. Recent

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pioneering studies by the Fokin, Gevorgyan, Murakami, and Davies groups demonstrated 1-sulfonyl-1,2,3-triazoles as an air-stable precursor of transient metallocarbenes (Scheme 4.26).81 Treatment of 1-sulfonyl-1,2,3-

Scheme 4.26 Decomposition of sulfonyl-1,2,3-triazoles for the generation of rhodium(II) iminocarbenes.

triazoles 84 with rhodium(II) catalysts leads to ring opening with subsequent generation of imino-carbene 85. The Lewis acidic nature of rhodium(II) catalyst facilitates the ring-chain isomerization of the triazole, and the subsequent diazo decomposition forms rhodium(II) imino-carbene 86. In this context, the various N-imido-amino acidderived rhodium(II)carboxylates were widely explored for a range of transformations, including enantioselective reactions. Following this concept, Fokin and coworkers reported the [Rh2(Snttl)4]-catalyzed highly diastereo- and enantioselective cyclopropanation of alkenes with N-sulfonyltriazolederived imino metallocarbenes (Scheme 4.27).82 A wide variety of alkenes reacted with N-mesyl triazoles

Scheme 4.27 Asymmetric cyclopropanation of alkenes with N-sulfonyl triazoles.

to give mesylimines 87. Upon hydrolysis, the resulting 87 afforded the corresponding cyclopropyl carboxaldehydes 88 in good yields with excellent diastereo- and enantioselectivities, while reduction with LiAlH4 furnished N-sulfonyl homoaminocyclopropanes 89 with good yield and enantioselectivity. In a separate report, they demonstrated that the reactions could also be performed with the readily accessible NHtriazoles via in situ sulfonylation with the triflic anhydride.83 Interestingly, when

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electron-rich olefins such as methoxy styrenes were employed, the reaction led to transannulation resulting in the formation of 2,3-dihydropyrroles with moderate enantioselectivities.84 Fokin and coworkers also reported the [Rh2(S-nttl)4]-catalyzed reaction of aldehydes with 1-mesyl-1,2,3-triazoles furnishing the 3sulfonyl-4-oxazolines with excellent enantioselectivities (Scheme 4.28).85

Scheme 4.28 Asymmetric synthesis of oxazolines.

The 1-mesyl-1,2,3-triazolederived Rh(II)-stabilized imino metallocarbenes formed ylide (90) intermediates with aldehydes, which then underwent an intramolecular cyclization with the pendant sulfonyl imine to provide oxazolines. A variety of aromatic aldehydes afforded the corresponding oxazolines 91ad in excellent yields and high enantioselectivities. However, only a trace amount of product formation was detected when an aliphatic aldehyde was used. In a subsequent report, the authors demonstrated the formation of ylide-type intermediate in the formal [3 1 2]-cycloaddition of 1-mesyl-1,2,3-triazoles with isocyanates and isothiocyanates toward the synthesis of imidazolones and thiazoles.86 The enantioselective CH insertion of unactivated alkanes with Nsulfonyl triazolederived rhodium(II) imino carbenes has also been reported with the catalytic use of [Rh2(S-nttl)4] (Scheme 4.29).87 The CH insertion reaction of rhodium(II) imino carbenes to alkanes resulted in the formation of chiral imines, which on reduction with NaBH4 or LiAlH4 generated chiral-protected amines 92ae with excellent enantioselectivities. However, hydrolysis of the imines with K2CO3 to the corresponding carbaldehyde resulted in racemization due to the high acidity of the hydrogen atom at the stereocenter. Rhodium(II) imino carbenes derived from different sulfonyl triazoles underwent CH insertion with a number of alkanes and cycloalkanes to afford various protected amines in good yields with excellent enantioselectivities. Interestingly, the rhodium

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Scheme 4.29 Enantioselective CH insertion of unactivated alkanes.

(II) imino carbenes showed better chemoselectivity toward insertion into tertiary CH bonds over secondary CH bonds compared to that of the traditional rhodium(II) carbenoids generated from diazoacetates. The pyrroloindoline scaffold is the core structure of a subclass of alkaloid natural products known as pyrroloindoline alkaloids, which exhibit promising anticancer, antinociceptive, antibiotic, and antiinflammatory activities. Davies and coworkers developed an efficient [Rh2(S-ptad)4]catalyzed enantioselective formal [3 1 2]-cycloaddition of 4-aryl sulfonyltriazoles and C-3 substituted indoles toward the synthesis of chiral pyrroloindolines (Scheme 4.30).88 In their report, selection of solvent and

Scheme 4.30 Enantioselective formal [3 1 2]-cycloadditions.

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Imides

catalyst was found to be crucial for improved reaction yield and selectivity. Optimal yield and selectivity were observed in cyclohexane as a solvent. No desired product formation was observed using CHCl3, trifluorotoluene, and ethyl acetate while the reaction in toluene and heptane gave average yields with good enantioselectivities. The use of other catalysts such as [Rh2(S-pttl)4], [Rh2(S-nttl)4], [Rh2(S-btpcp)4], and [Rh2(S-dosp)4] were less effective. A range of C-3 substituted indoles underwent transannulation with various mesyltriazoles having electronwithdrawing and electron-donating aryl-substituents furnishing pyrroloindolines 93ah in good yields with high enantioselectivities. Indoles with bulkier (TBS, Bn) or electron-withdrawing [e.g., p-toluenesulfonyl (Ts), CO2Me, Boc] groups on the indolic nitrogen were not suitable for desired reactivity. The use of bulkier 1-(ethanesulfonyl)-1,2,3-triazoles resulted in poor yield and enantioselectivity. The authors also reported the intramolecular annulation of indoles with 1-sulfonyl triazoles in the substrates 94 with the catalytic use of N-phthalimido-tert-butyl leucinederived Rh(II)-carboxylates [Rh2(S-pttl)4].89 A variety of sulfonyltriazoles tethered to indole through four-membered linkers at the C-3 position underwent dearomatizing annulation in the presence of [Rh2(Spttl)4] to furnish polycyclic spiroindolines 95 in good yields, albeit with low enantioselectivities. In another report of transannulation, Davies and coworkers synthesized highly functionalized pyrroles with [Rh2(S-ptad)4]catalyzed reactions between furans and triazoles.90 The reaction involved an [3 1 2] annulation of rhodium-stabilized imino-carbenes with furans followed by ring opening to generate polyfunctionalized pyrroles. The alkenyl N-sulfonyl triazoles could participate in rhodium-catalyzed formal [4 1 3]-cycloaddition with dienes in a similar manner to alkenylsubstituted diazoacetates to afford seven-membered rings (Scheme 4.31).91

Scheme 4.31 Enantioselective formal [4 1 3]-cycloaddition for the formation of fused carbocycles.

Imides: A Special Chemical Entity in Rhodium Catalysis

119

After screening of various N-imido-amino acidderived rhodium(II)-carboxylates, [Rh2(S-nttl)4] was optimal for the enantioselective formal [4 1 3]-cycloaddition of alkenyl-substituted sulfonyltriazoles with dienes via tandem cyclopropanation/Cope rearrangement. Various dienes underwent formal [4 1 3]-cycloadditions with 4-alkenyl 1-sulfonyl triazoles forming a range of cycloheptenyl derivatives (96ad) decorating with synthetically useful α,β-unsaturated imine moiety with good yields and excellent stereoselectivities. When vinylcyclohexene or triazoles bearing an α-fused arene substituent was used, the fused tricyclic compounds (96cd) were also formed in high yields and good stereoselectivities.

4.3 APPLICATIONS OF IMIDES AS SUBSTRATES FOR RHODIUM-CATALYZED REACTIONS 4.3.1 Rhodium-Catalyzed Asymmetric Hydrogenation Rhodium-catalyzed asymmetric hydrogenation is widely used for the formation of chiral compounds and building blocks. The importance of asymmetric hydrogenation was recognized with the 2001 Nobel Prize in Chemistry awarded to Knowles and Noyori. In catalytic asymmetric reduction, the presence of a secondary chelating group near the unsaturated double bond facilitates high selectivity. This observation is also true for functionalized substrates containing an amine residue. The N-protecting groups in the substrates not only mask the amine but also assists the catalytic path by coordinating with the metal center during the catalytic cycle. In this context, the phthalimide moiety has emerged as an interesting option as it can coordinate very well with the metal center and then be cleaved under mild conditions without racemization of the resulting product. With this approach, chiral β-amino acids could be efficiently prepared. β-Amino acids and their derivatives are the prominent structural component of various natural products, β-peptides, and pharmaceuticals. In this context, Zhang and coworkers developed the rhodium-catalyzed asymmetric hydrogenation of phthalimide-based acrylates 97 (Scheme 4.32).92 The combination of Rh(COD)2BF4/BoPhoz-type ligand 98 efficiently catalyzed the asymmetric hydrogenation of many α-substituted or unsubstituted β-(phthalimidomethyl) acrylates under 10 atm hydrogen pressure at room temperature. The hydrogenation was more selective in the case of α-unsubstituted β-(phthalimidomethyl) acrylates with over 99% ee, while the α-substituted acrylates afford 99ac in up to 94% ee. The

120

Imides

Scheme 4.32 Asymmetric hydrogenation of phthalimide-based acrylates.

synthetic utility of the hydrogenation was also demonstrated by the highly enantioselective synthesis of β2-amino acids (S)-(2)-α-benzyl-β-alanine. Similarly, Lei and Zhang and coworkers also reported the rhodiumcatalyzed asymmetric hydrogenation of N-phthaloyl dehydroamino acid esters to N-phthaloyl amino acid esters employing the rhodium/ TangPhos catalytic system.93 Zhang and coworkers explored the rhodium-catalyzed asymmetric hydrogenation of 3-substituted maleinimides (100) for the synthesis of chiral 3-aryl or alkyl succinimides (102ae).94 Based on the screening of various ligands and solvent systems, a combination of Rh(NBD)2BF4/ bisphosphinethiourea (ZhaoPhos) in dioxane under hydrogen (30 bar of pressure) was determined as the optimal condition (Scheme 4.33). The bisphosphinethiourea ligand 101 facilitated ligation with rhodium and also synergistically acted as an organocatalyst. The thiourea motif activated the carbonyl group via hydrogen-bonding interaction, enabling highly efficient asymmetric reduction with phosphine-bound rhodium species. Under the optimum conditions, several 3-substituted maleinimides were reduced to the corresponding 3-aryl or alkyl succinimides in excellent yields and enantioselectivities. Succinimides with either electron-rich or electron-deficient aryl substituents at 3-position afforded the corresponding 3-arylmaleinimides with 98% . 99% ee while 3-methylmaleinimides were achieved with 83% ee. The synthetic utility of the protocol was demonstrated with the synthesis of a potent α-2-adrenoceptor antagonist analog 104 via reduction of the two carbonyl groups of maleinimide 103.

121

Imides: A Special Chemical Entity in Rhodium Catalysis

Scheme 4.33 Asymmetric hydrogenation of 3-substituted maleinimides.

4.3.2 Rhodium-Catalyzed Conjugate Addition Addition of a nucleophile to the appropriate α,β-unsaturated carbonyl compound is commonly employed for CC bond forming reactions in organic synthesis. Among the various approaches toward conjugate addition, rhodium-catalyzed asymmetric 1,4-addition of boronic acids to α,β-unsaturated carbonyl compounds have been widely explored. Hayashi and coworkers investigated the rhodium-catalyzed asymmetric 1,4-addition of boronic acid to substituted maleimides for the construction of the quaternary carbon stereocenter (Scheme 4.34).95 The choice

O NBn

+

O

2.5 mol% [RhCl(C2H4)2]2 2.75 mol% (R)-H8-BINAP

ArB(OH)2

0.5 equiv. KOH Dioxane/H2O (10:1)

R O

R Ar

NBn O Major

NBn

NBn NBn

O

O

O NBn O

O

O Cl 105a 98%, 90% ee Major:minor >98:2

O Minor O

O

NBn

NBn

+ R

O

O

O Ar

105b 95%, 97% ee Major:minor = 98:2

MeO 105c 90%, 96% ee Major:minor = 86:14

105d 95%, 96% ee Major:minor = 86:14

105e 85%, 98% ee Major:minor = 97:3

Scheme 4.34 Rhodium catalysis for the construction of stereocenters at the quaternary carbon.

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Imides

of an appropriate ligand enabled the creation of a stereocenter at a quarternary carbon. The conjugate addition of boronic acid to 3-substituted maleimides was achieved with the catalytic use of (R)-H8-BINAP/rhodium. The resulting 3,3-disubstituted succinimides were obtained in high regio- and enantioselectivity. Owing to the steric interaction of the 3substituent of the maleimide and phenyl moiety of the phosphorus atom of (R)-H8-BINAP, maleimide coordinates with the rhodium in a way to keep these substituents away from each other, resulting in the formation of the desired product (105ae) in higher selectivity. Nishimura, Hayashi, and coworkers also explored the rhodiumcatalyzed asymmetric 1,4-addition of boronic acid to β-phthaliminoacrylate esters toward the synthesis of chiral β-amino acids (Scheme 4.35).96 They employed a hydroxorhodium/chiral diene

Scheme 4.35 Asymmetric 1,4-addition of boronic acid to β-phthaliminoacrylate esters.

complex to effectively catalyze the conjugate addition of various boronic acid to β-phthaliminoacrylate esters resulting β-aryl-β-N-phthaloylamino acid esters 106ad in high yields and enantioselectivities. The resulting compound 106 or 107 could be easily transformed into biologically relevant β-aryl-β-amino acids by treatment with hydrazine followed by basic

Imides: A Special Chemical Entity in Rhodium Catalysis

123

hydrolysis without loss of enantiomeric purity. They demonstrated this approach with the synthesis of 108, a natural product isolated from the mushroom Cortinarius violaceus. Prabhu and coworkers successfully replaced the expensive boronic acids with a readily available and cheap carboxylic acid for the rhodiumcatalyzed conjugate addition.97 The approach involved rhodium-catalyzed CH activation at the ortho-position of carboxylic acid (Scheme 4.36).

Scheme 4.36 Conjugate addition via CH activation.

The carboxylate group acted as a traceless directing group. Under the optimized reaction conditions [10 mol% RhCp
(OAc)2 and 5.0 equiv. acetic acid at 100°C in dichloroethane (DCE)], various aromatic acids and heteroaromatic acids were coupled with maleimides containing different N-substitutions to obtain 3-aryl succinimides (109ad). The approach was also applicable to the decarboxylative conjugate addition of acrylic acid derivatives to maleimides affording 3-vinyl succinimides in good yields (109eh). Owing to the expensive and unstable nature of vinyl boronic acids, the rhodium-catalyzed conjugate vinylation is rare. The success of this approach is based on the use of readily available, cheap, and bench-stable acrylic acid derivatives as surrogates of the expensive and unstable alkenyl boronic acid derivatives.

4.3.3 Rhodium-Catalyzed Aromatic CH Activation Glorius and coworkers explored the rhodium(III)-catalyzed aromatic CH activation toward ortho-selective bromination and iodination of arenes with N-bromo(iodo) succinimide (Scheme 4.37).98 Notably, rhodium

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Imides

Scheme 4.37 Rhodium(III)-catalyzed CH activation for ortho-selective halogenation.

(III)-catalyzed carbonhalogen bond formation was not documented before this report. The amide group was a key in the substrate 110. The catalytic system [RhCp
Cl2]2/AgSbF6 efficiently brominated and iodinated a variety of benzamides at the ortho-position in high yield (111aj). Many sensitive functionalities such as nitro, ester, cyano, iodo, chloro, trifluoromethyl, etc. were well tolerated. The arenes with other directing groups such as carbamate, ketone, and ester also afforded ortho-halogenated products, albeit, in relatively lower yields. Based on the control experiments, they proposed two pathways for the ortho-selective halogenation. The rhodium catalyst coordinate with the O-atom of amide moiety of a substrate, leading to C 2 H activation via formation of a rhodacycle. The rhodacycle can either undergo nucleophilic addition to N-bromosuccinimide (NBS) to afford the brominated product or be oxidized to rhodium(V), which on reductive elimination gave the product with regeneration of the rhodium(III) catalyst. Extending this work, Li and coworkers developed rhodium-catalyzed CH activation for the amidation of arenes with N-OTs imides (Scheme 4.38).99 In the presence of the [RhCp
Cl2]2/AgSbF6 catalytic

Imides: A Special Chemical Entity in Rhodium Catalysis

125

Scheme 4.38 Amidation of arenes with N-OTs imides.

system, various pyridyl- and pyrimidyl-functionalized arenes as well as thiophenes gave selective mono CH amidation at ortho-position with N-OTs phthalimides possessing electron-donating and electronwithdrawing substituents. Desired products such as 112ae were obtained in moderate yields. Interestingly, no reaction occurred for N-OAc and NOC(O)Ph phthalimides. CH amidation with N-OTs succinimides was also demonstrated. However, reaction yields were lower. Kim and coworkers utilized maleimides as coupling partners for various rhodium-catalyzed C(sp2)H and C(sp3)H activation strategies. Succinimide, chromones, naphthoquinones, and xanthones moieties are very common in the various biologically relevant compounds. Due to the importance of such fragments, the authors explored rhodium(III)-catalyzed, ketone-assisted, site-selective CH functionalizations of chromones, 1,4-naphthoquinones, and xanthones with various maleimides to afford a range of biologically relevant compounds (Scheme 4.39).99 The CH functionalization of different chromones with maleimides occurred selectively at C-5 position and provided the C-5-succinimidecontaining chromones in good yields. Likewise, naphthoquinones and xanthones were also monoalkylated with maleimides to furnish a vast array of succinimide derivatives. All the products 113ai were also tested for in vitro anticancer activity against human breast adenocarcinoma cell lines [Michigan Cancer Foundation-7 (MCF-7)]. Interestingly, succinimidecontaining naphthoquinone derivatives 113h and 113i showed high cytotoxic activity which is comparable to the well-known anticancer agent doxorubicin. In a similar approach, Pan and You and coworkers developed C-7 alkylation of indolines with maleimides via rhodium-catalyzed CH activation.100 Kim and coworkers also documented the rhodium-catalyzed C(sp3) H activation for C(sp3)-H alkylation of 8-methylquinolines with

126

Imides

Scheme 4.39 CH functionalization of chromones, 1,4-naphthoquinones, and xanthones.

maleimides (Scheme 4.40).101 Couplings of various 8-methylquinolines containing different substituents at C-5, C-6, and C-7 position with maleimides led to the C(sp3)-H functionalized quinolines 114ag in good yields. However, the reaction with sterically congested 8-ethylquinoline was unsuccessful under their optimized reaction conditions. Based on the control experiments and kinetic isotope effect (KIE) experiments, the authors proposed a mechanism which involved the formation of fivemembered and seven-membered rhodacycle intermediates. The cationic rhodium(III) catalyst coordinates with quinoline N-atom and activates the C(sp3)H bond forming a five-membered rhodacycle intermediate. The five-membered rhodacycle intermediate on coordination with maleimide and migratory insertion form a seven-membered rhodacycle intermediate which on protonation with acid afforded the alkylation product along with regeneration of active catalytic species. For further developments toward the CH functionalization of alkenes, Rovis and coworkers documented the synthetic utility of rhodium(III)-catalyzed CH activation of enoxyphthalimide for novel cyclopropanation (Scheme 4.41).102 The rhodium(III)-catalyzed reaction of

Imides: A Special Chemical Entity in Rhodium Catalysis

127

Scheme 4.40 C(sp3)H alkylation of 8-methylquinolines.

enoxyphthalimide with alkenes in CF3CH2OH (2,2,2-trifluoroethanol, TFE) led to the highly diastereoselective cyclopropanation of alkenes with the release of phthalimide. The substrate scope was sufficiently broad, and yields in most of the cases were moderate. The functional group tolerance was also reasonably broad. In this transformation, the choice of base and ligand played a crucial role. Cesium acetate as a base and isopropyl cyclopentadienyl as the ligand were found to be the best for the desired activity. Representative examples 116ag are described in Scheme 4.41. The authors also investigated the CH activation of enoxyphthalimide for the novel carboamidation of alkenes. The use of more polar nucleophilic solvents such as methanol could facilitate the ring opening of the phthalimide group to form an amido ester. The resulting amido ester

128

Imides

Scheme 4.41 Cyclopropanation of alkenes with enoxyphthalimide.

could chelate with the rhodium catalyst to further enhance the stereoselectivity. With this approach, stereoselective syn-carboamidation of alkenes was achieved (Scheme 4.42).103 The generality of the protocols was

R1

O O Ar

O

N

+ R1

R2

5 mol% [Cp*tBuRh(CH3CN)3](SbF6)2 Ar 2 equiv. AdCO2Cs

O

R2 N

O

O

R2

Ar

MeOH

O

R1 MeOH

O

118

O

O Ar

R1

N H O

R2

Ar

O N Rh O

OMe R1

116

OMe

R2 117

O

F

CO2Me CO2Me

O

NPhth

118a 70% (118a/116b = 14.9:1)

O

CO2Me CO2Me

O

NPhth

O

CO2tBu CO2tBu

O

CO2Et

NPhth

118b 30% (118b/116b = 6.7:1)

NPhth

118c 72% (118c/116c > 20:1)

118d 53% (118d/116d > 20:1) dr = 10:1

O O

NPh

O

O

O

NBoc

O NPhth 118e 74% (118e/116e > 20:1)

NPhth 118f 69% (118f/116f > 20:1) dr > 20:1

CF3

NPhth 25% (118g/116g > 20:1) dr > 20:1

Scheme 4.42 Carboamidation of alkenes with enoxyphthalimide.

Imides: A Special Chemical Entity in Rhodium Catalysis

129

demonstrated with various alkenes. The authors critically explained this interesting solvent-mediated chemoselectivity switch. In TFE, irreversible CH activation at the β-position of the double bond by active rhodium (III) catalyst and subsequent migratory insertion of the alkene generates σ-alkylrhodium(III) complex 115 where the coordinatively unsaturated rhodium ligates the enol alkene moiety (Scheme 4.41). The intermediate subsequently undergoes migratory insertion and oxidative addition resulting in cyclopropanation. Conversely, methanol, when used as a solvent, cleaves the CN bond in the phthalimide moiety, forming the amido ester which coordinates with rhodium as a bidentate directing group. The in situformed species stabilizes the intermediate 117, thus inhibiting migratory insertion into the enol alkene, which led to reductive elimination and carboamination 118 (Scheme 4.42).

4.4 CONCLUSION In summary, imides as ligands and substrates in the rhodium catalysis have an extremely important role. To date, many molecules are synthesized due to the catalytic pathways made possible by the rhodium species containing imides. Asymmetric hydrogenations, cyclopropanations, CH activation, and cycloadditions are among many useful transformations achieved by rhodium catalysis which have demonstrated value in the fine chemical and pharmaceutical industry. Many more challenging future transformations could be anticipated via rhodium catalysis. Due to the broader impact of rhodium in the organometallic catalysis, it can be regarded as the most precious metal for chemists.

LIST OF ABBREVIATIONS AdCOOH ADCs APP BAIB Boc Cp
DABCO DBU DCE DFT DIBAL-H DMAP

1-Adamantanecarboxylic acid Acyclic diamino carbenes Amyloid precursor protein Bis(acetoxy)iodobenzene tert-Butoxycarbonyl Pentamethylcyclopentadienyl 1,4-Diazabicyclo[2.2.2]octane 1,8-Diazabicyclo(5.4.0)undec-7-ene Dichloroethane Density functional theory Diisobutylaluminium hydride 4-Dimethylaminopyridine

130

Imides

DMF DMS DMSO DPPA (R)-H8-BINAP ICdirhodium complexes KIE LDA L-Dopa MCF-7 m-CPBA NBS NHCs NOESY PivOH PMP Rh(COD)2BF4 Rh(NBD)2BF4 Rh2(OAc)4 [Rh2(S-bpta)4] [Rh2(S-bptpa)4] [Rh2(S-bpttl)4] [Rh2(S-bptv)4] [Rh2(S-btpcp)4] [Rh2(S-4-Br-nttl)4] [Rh2(S-dosp)4] [Rh2(S-ntpa)4] [Rh2(S-nttl)4] [Rh2(S-ntv)4] [Rh2(S-pta)4] [Rh2(S-ptad)4] [Rh2(S-ptpa)4] [Rh2(S-pttl)4] [Rh2(S-ptv)4] [Rh2(S-tcpttl)4] [Rh2(S-tcptad)4] [Rh2(S-tfpttl)4]

Dimethylformamide Dimethyl sulfide Dimethyl sulfoxide Diphenylphosphoryl azide [(1R)-5,50 ,6,60 ,7,70 ,8,80 -octahydro-[1,10 -binaphthalene]-2,20 -diyl] bis[diphenylphosphine] Imido carboxylate (IC)dirhodium complexes Kinetic isotope effect Lithium diisopropylamide L-3,4-Dihydroxyphenylalanine Michigan Cancer Foundation-7 m-Chloroperoxybenzoic acid N-Bromosuccinimide N-Heterocyclic carbenes Nuclear overhauser effect spectroscopy 2,2-Dimethylpropanoic acid p-Methoxy phenyl Bis(1,5-cyclooctadiene)rhodium(I) tetrafluoroborate Bis(norbornadiene)rhodium(I) tetrafluoroborate Rhodium(II) acetate dimer Tetrakis[(S)-1,3-dihydro-α-methyl-1,3-dioxo-2H-benz[f]isoindole-2-acetato]dirhodium(II) Tetrakis[(S)-α-benzyl-1,3-dihydro-1,3-dioxo-2H-benz[f]isoindole-2-acetato]dirhodium(II) Tetrakis[(S)-α-(tert-butyl)- 1,3-dihydro-1,3-dioxo-2H-benz[f]isoindole-2-acetato]dirhodium(II) Tetrakis[(S)-1,3-dihydro-α-(1-methylethyl)-1,3-dioxo-2H-benz[f] isoindole-2-acetato]dirhodium(II) Tetrakis[(R)-(2)-(1R)-1-(4-bromophenyl)-2,2-diphenylcyclopropanecarboxylato]dirhodium(II) Dirhodium(II) tetrakis[N-(4-bromo-1,8-naphthaloyl)-(S)-tertleucinate] Dirhodium(II) tetrakis[1-[[4-alkyl(C11-C13)phenyl]sulfonyl]-(2S)pyrrolidinecarboxylate] Dirhodium(II) tetrakis[N-(1,8-naphthaloyl)-(S)-phenylalaninate] Dirhodium(II) tetrakis[N-(1,8-naphthaloyl)-(S)-tert-leucinate] Dirhodium(II) tetrakis[N-(1,8-naphthaloyl)-(S)-valinate] Dirhodium(II) tetrakis[N-phthaloyl-(S)-alaninate] Dirhodium(II) tetrakis[N-phthaloyl-(S)-adamantylglycine] Dirhodium(II) tetrakis[N-phthaloyl-(S)-phenylalaninate] Dirhodium(II) tetrakis[N-phthaloyl-(S)-tert-leucinate] Dirhodium(II) tetrakis[N-phthaloyl-(S)-valinate] Dirhodium(II) tetrakis[N-tetrachlorophthaloyl-(S)-tert-leucinate] Dirhodium(II) tetrakis[N-tetrachlorophthaloyl-(S)-adamantylglycine] Dirhodium(II) tetrakis[N-tetrafluorophthaloyl-(S)-tert-leucinate]

Imides: A Special Chemical Entity in Rhodium Catalysis

TBAF TBS TEMPO TFA TFE THF tpcp Ts

131

Tetra-n-butylammonium fluoride tert-butyldimethylsilyl (2,2,6,6-Tetramethylpiperidin-1-yl)oxyl oroxidanyl Trifluoroacetic acid 2,2,2-Trifluoroethanol Tetrahydrofuran Triphenylcyclopropanecarboxylate p-Toluenesulfonyl

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67. DeAngelis, A.; Shurtleff, V. W.; Dmitrenko, O.; Fox, J. M. Rhodium(II)-Catalyzed Enantioselective C 2 H Functionalization of Indoles. J. Am. Chem. Soc. 2011, 133 (6), 16501653. 68. Davies, H. M. L.; Hedley, S. J.; Bohall, B. R. Asymmetric Intermolecular C 2 H Functionalization of Benzyl Silyl Ethers Mediated by Chiral Auxiliary-Based Aryldiazoacetates and Chiral Dirhodium Catalysts. J. Org. Chem. 2005, 70 (26), 1073710742. 69. Wang, X.; Lu, Y.; Dai, H.-X.; Yu, J.-Q. Pd(II)-Catalyzed Hydroxyl-Directed C 2 H Activation/C 2 O Cyclization: Expedient Construction of Dihydrobenzofurans. J. Am. Chem. Soc. 2010, 132 (35), 1220312205. 70. Wang, H.; Li, G.; Engle, K. M.; Yu, J.-Q.; Davies, H. M. L. Sequential CH Functionalization Reactions for the Enantioselective Synthesis of Highly Functionalized 2,3-Dihydrobenzofurans. J. Am. Chem. Soc. 2013, 135 (18), 67746777. 71. Yamaguchi, A. D.; Chepiga, K. M.; Yamaguchi, J.; Itami, K.; Davies, H. M. L. Concise Syntheses of Dictyodendrins A and F by a Sequential CH Functionalization Strategy. J. Am. Chem. Soc. 2015, 137 (2), 644647. 72. Okano, K.; Fujiwara, H.; Noji, T.; Fukuyama, T.; Tokuyama, H. Total Synthesis of Dictyodendrin A and B. Angew. Chem. Int. Ed. 2010, 49 (34), 59255929. 73. Liao, K.; Negretti, S.; Musaev, D. G.; Bacsa, J.; Davies, H. M. L. Site-Selective and Stereoselective Functionalization of Unactivated CH Bonds. Nature 2016, 533, 230. 74. Liao, K.; Pickel, T. C.; Boyarskikh, V.; Bacsa, J.; Musaev, D. G.; Davies, H. M. L. Site-Selective and Stereoselective Functionalization of Non-Activated Tertiary CH Bonds. Nature 2017, 551, 609. 75. Natori, Y.; Ito, M.; Anada, M.; Nambu, H.; Hashimoto, S. Catalytic Asymmetric Synthesis of (2)-E-δ-Viniferin via an Intramolecular CH Insertion of Diaryldiazomethane Using Rh2(S-TFPTTL)4. Tetrahedron Lett. 2015, 56 (29), 43244327. 76. Reddy, R. P.; Davies, H. M. L. Asymmetric Synthesis of Tropanes by RhodiumCatalyzed [4 1 3] Cycloaddition. J. Am. Chem. Soc. 2007, 129 (34), 1031210313. 77. Schwartz, B. D.; Denton, J. R.; Lian, Y.; Davies, H. M. L.; Williams, C. M. Asymmetric [4 1 3] Cycloadditions Between Vinylcarbenoids and Dienes: Application to the Total Synthesis of the Natural Product (2)-5-epi-Vibsanin E. J. Am. Chem. Soc. 2009, 131 (23), 83298332. 78. Lian, Y.; Miller, L. C.; Born, S.; Sarpong, R.; Davies, H. M. L. Catalyst-Controlled Formal [4 1 3] Cycloaddition Applied to the Total Synthesis of (1)-Barekoxide and (2)-Barekol. J. Am. Chem. Soc. 2010, 132 (35), 1242212425. 79. Liang, C.; Collet, F.; Robert-Peillard, F.; Müller, P.; Dodd, R. H.; Dauban, P. Toward a Synthetically Useful Stereoselective C 2 H Amination of Hydrocarbons. J. Am. Chem. Soc. 2008, 130 (1), 343350. 80. Buendia, J.; Darses, B.; Dauban, P. Tandem Catalytic C(sp3)H Amination/SilaSonogashiraHagihara Coupling Reactions With Iodine Reagents. Angew. Chem. Int. Ed. 2015, 54 (19), 56975701. 81. Davies, H. M. L.; Alford, J. S. Reactions of Metallocarbenes Derived From NSulfonyl-1,2,3-Triazoles. Chem. Soc. Rev. 2014, 43 (15), 51515162. 82. Chuprakov, S.; Kwok, S. W.; Zhang, L.; Lercher, L.; Fokin, V. V. RhodiumCatalyzed Enantioselective Cyclopropanation of Olefins With N-Sulfonyl 1,2,3Triazoles. J. Am. Chem. Soc. 2009, 131 (50), 1803418035. 83. Grimster, N.; Zhang, L.; Fokin, V. V. Synthesis and Reactivity of Rhodium(II) NTriflyl Azavinyl Carbenes. J. Am. Chem. Soc. 2010, 132 (8), 25102511. 84. Kwok, S. W.; Zhang, L.; Grimster, N. P.; Fokin, V. V. Catalytic Asymmetric Transannulation of NH-1,2,3-Triazoles With Olefins. Angew. Chem. Int. Ed. 2014, 53 (13), 34523456.

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102. Piou, T.; Rovis, T. Rh(III)-Catalyzed Cyclopropanation Initiated by CH Activation: Ligand Development Enables a Diastereoselective [2 1 1] Annulation of N-Enoxyphthalimides and Alkenes. J. Am. Chem. Soc. 2014, 136 (32), 1129211295. 103. Piou, T.; Rovis, T. Rhodium-Catalysed Syn-Carboamination of Alkenes via a Transient Directing Group. Nature 2015, 527, 86.

FURTHER READING Han, S. H.; Kim, S.; De, U.; Mishra, N. K.; Park, J.; Sharma, S.; Kwak, J. H.; Han, S.; Kim, H. S.; Kim, I. S. Synthesis of Succinimide-Containing Chromones, Naphthoquinones, and Xanthones Under Rh(III) Catalysis: Evaluation of Anticancer Activity. J. Org. Chem. 2016, 81 (24), 1241612425.

CHAPTER 5

Stereoselective Conjugate Additions of Hydrazines, Oximes, and Hydroxylamines to α,β-Unsaturated Imides Anna C. Renner and Mukund P. Sibi

Department of Chemistry and Biochemistry, North Dakota State University, Fargo, ND, United States

5.1 INTRODUCTION The development of enantioselective transformations remains a major objective in synthetic organic chemistry; the ability to selectively obtain one enantiomer of a product is key to the efficient preparation of many pharmaceuticals and natural products. Of particular note here is the use of amide-based auxiliaries/templates, such as oxazolidinones, for enantioselective conjugate additions to α,β-unsaturated carbonyl compounds. Installment of the auxiliary yields an imide that can coordinate to Lewis acids via its carbonyl oxygens, not only increasing the electrophilicity of the β carbon but also potentially restricting rotation around the amide bonds and thereby enforcing an s-cis conformation of the alkenoyl group to avoid steric interactions with the auxiliary. The chirality of the product can be derived from the use of a chiral reagent, a chiral auxiliary/template, a chiral ligand for the Lewis acid, or preexisting chirality within the substrate. While enantioselective reactions have been developed for conjugate additions of many different nucleophiles to carbonyl compounds, this chapter focuses on conjugate additions to α,β-unsaturated imides by nucleophiles containing N
N and N
O bonds: hydrazines, oximes, and hydroxylamines. These compounds are exceptionally nucleophilic due to the α-effect: the presence of an unshared electron pair on the N or O next to the more nucleophilic heteroatom imparts enhanced nucleophilicity. The resulting heteroatom-containing products themselves are potentially useful for applications in medicinal chemistry or natural products Imides DOI: https://doi.org/10.1016/B978-0-12-815675-9.00005-9

© 2019 Elsevier Inc. All rights reserved.

139

140

Imides

synthesis, and the products’ heteroatom
heteroatom bonds may alternatively be reductively cleaved to afford additional, distinct structures such as β-amino acids and β-hydroxy imides. The past 25 years have seen numerous advances in the area of enantioselective conjugate additions of N
N and N
O nucleophiles to α,β-unsaturated imides, and in this chapter, we have sought to comprehensively review not only the development of methods enabling such transformations but also their application for the efficient synthesis of target structures. When relevant, asymmetric conjugate additions to other enoates are included. The following discussion of the literature is divided into sections for each type of nucleophile—hydrazines, oximes, O-substituted hydroxylamines, and N-substituted hydroxylamines—and is further organized to highlight strategies for stereoinduction and chronological trends. We conclude the chapter by summarizing the studies reported to date and the current state of the science with the hope that this review will inform future innovations in the development or application of asymmetric synthesis.

5.2 HYDRAZINES Stereoselective conjugate addition of hydrazines to α,β-unsaturated imides is underexplored. An early report of stereoselective hydrazine addition, albeit to α,β-unsaturated esters, was by Enders et al.,1 who employed as nucleophiles the enantiomeric hydrazines TMS-SAMP and TMS-RAMP (Scheme 5.1). TMS-SAMP and TMS-RAMP were readily prepared from (S)- and (R)-1-amino-2-(methoxymethyl)pyrrolidine (SAMP and RAMP, O R1

TMS-SAMP (1.3 equiv.) OR2

n-BuLi, THF, –78°C

OMe SiMe3 N O N R1

1 R1 = Alkyl R2 = Me, t-Bu

OR2 2

OMe N HN

SiMe3

OMe SiO2, Ethyl acetate

N NH O Quant. 32%–67% (two steps) R1 OR2 3 de = 93%–98% Raney Ni, H2 H2O, 60–75°C 50%–86%

TMS-SAMP NH2 O R1

OH 4 ee = 90%–98%

Scheme 5.1 Asymmetric conjugate additions of chiral hydrazines.1

Stereoselective Conjugate

141

known for their use as chiral auxiliaries), respectively. After deprotonation using n-butyllithium, TMS-SAMP reacted with β-alkyl-substituted alkyl esters 1 to afford conjugate addition products 2, although methyl esters also underwent 1,2-addition. Desilylation of the crude products using silica gel in ethyl acetate gave products 3 in low to moderate yields (32%
67% over both steps) and 93%
98% de, and subsequent hydrogenolysis over Raney nickel yielded the corresponding β-amino acids 4 in 50%
86% yield and 90%
98% ee. The same reaction sequence with methyl crotonate as substrate and TMS-RAMP as nucleophile afforded (R)-3-aminobutanoic acid in similar yield and selectivity. Enders and Wiedemann later employed asymmetric conjugate addition of TMS-SAMP to construct five-, six-, and seven-membered carbocyclic and heterocyclic β-amino acids and esters starting with ω-halidesubstituted α,β-unsaturated esters (Scheme 5.2, see conversion of 5
7 and 8
10).2 With different halide-substituted esters and reaction conditions, each conjugate addition product either directly formed a carbocycle by intramolecular alkylation of its enolate or was converted to an N-heterocycle in a one-pot procedure effecting desilylation followed by intramolecular N-alkylation. The resulting desilylated β-hydrazino esters were obtained in low to moderate yields but excellent diastereoselectivities and were readily converted to chiral β-amino esters and acids. To account for the products’ absolute stereochemistry, the authors proposed model 11 in which the bulky silyl group of TMS-SAMP would hinder a re-face approach of the nucleophile, thereby favoring nucleophilic attack from the si face of the enoate. Another example of asymmetric hydrazine addition under basic conditions was reported by Seki and coworkers, who used the (1S)(
)-2,10-camphorsultam-derived substrate 12 as the chiral source in conjugate additions of cycloaliphatic hydrazines to cinnamates (Scheme 5.3).3 Bicyclic products 15 and 16 that would result from conjugate addition and subsequent cyclization had previously been used in syntheses of the spermidine and spermine alkaloids (S)-celacinnine and (S,S)-homaline. To enantioselectively prepare 15, the authors first conducted the reaction in tetrahydrofuran with 5 equiv. of piperidazine 13 and varying amounts of n-butyllithium. Although the reaction gave 44% ee in the absence of n-butyllithium, the enantioselectivity increased with the amount of base, reaching 66% ee when 5 equiv. of n-butyllithium was used. In further experiments, diethyl ether gave the highest enantioselectivity (86% and 77% ee for 15 and 16, respectively) when evaluated in a screen of several

142

Imides

1. TMS-SAMP n-BuLi THF, –78°C

O X

OMe N

Ot-Bu 2. HMPA, –78°C (n = 3, 4) 3. NaHCO3, H2O

n 5

X

n

NH2

SiMe3

CO2H

CO2t-Bu

de = 96%–98% ee ≥ 98%

de ≥ 96% 1. TMS-SAMP n-BuLi THF, –78°C Ot-Bu

n–2

7

n–2

6

X = Br, I n = 2, 3, 4

O

N

OMe

2. NaHCO3, H2O

8 X = Cl, Br n = 2, 3, 4

N N

Me3Si X 9

H N

CO2t-Bu

CO2t-Bu n–2

10

n–2

ee = 97% (n = 2)

de ≥ 96%

Me N

Me Si

re-face

Me

N

O Li

Me R O

11

RO Me Me Si Me

si-face

N N Li O Me

Scheme 5.2 Synthesis of carbocyclic and heterocyclic β-amino acids using conjugate addition of a chiral hydrazine.2

O O S O2

NH NH

+

N

Ph 12

13 (5 equiv.)

Li

n-BuLi (5 equiv.) Et2O, 0°C, 24 h; rt, 24 h

N

NH

O N N

Ph

14 (5 equiv.)

si-face attack

N

18

NH NH

15

N N

or Ph

+ S 17 O2

16

NH

O

Conjugate addition

O S O O

or

O S O O 19

(S)

Cyclization

N N

N Li

N

N

Ph 20 (up to 86% ee)

Scheme 5.3 Stereoselective conjugate additions of cyclic hydrazines using camphorsultam auxiliary.3

143

Stereoselective Conjugate

ethereal solvents as well as toluene. The chiral auxiliary 17 could be recovered. Other cinnamates with electron-withdrawing and electrondonating groups gave low to excellent yields and 46%
64% ee in room temperature reactions with pyrazolidine 14 in diethyl ether/tetrahydrofuran without n-butyllithium. However, under the optimal conditions (5 equiv. of n-butyllithium in diethyl ether at 0°C), p-methoxy and p-nitro cinnamates were converted to the corresponding products with significantly higher yield from the p-methoxy cinnamate (88% compared with 12% previously obtained) and higher (86%) ee from the p-nitro cinnamate. To explain the observed stereoselectivity, the authors proposed a model in which the steric influence of the auxiliary would favor si-face attack of the hydrazine to the cinnamate (see 18
20). In 2007 Sibi and Soeta reported chiral Lewis acid
catalyzed conjugate additions of monoalkyl-substituted hydrazines 22 to achiral 21 to yield chiral pyrazolidinones (Scheme 5.4).4 In these reactions, the formation of a single optically pure product required not only enantioselectivity but also chemoselectivity: either nitrogen of the alkylhydrazine could attack the enoate’s β carbon, potentially resulting in different stereoisomers and constitutional isomers. Several Lewis acids and crotonates (21, R1 5 Me) with different templates were screened in the reaction with benzylhydrazine using ligand 26 at room temperature, 230°C, and 250°C. The use of magnesium perchlorate and the benzimide template 25e at 250°C furnished the highest enantioselectivity of the major product, 23, formed via attack of the more-nucleophilic alkyl-substituted nitrogen. In an evaluation of enoate and hydroxylamine scope, good to excellent yields, high

O R2

+ Z

R1

N H

NH2

· 2HCl 21 R1 = Alkyl, Bn, CH2OBn, Ph, CO2t-Bu

Lewis acid/ligand 26 (30 mol%) Et3N, MS 4Å CH2Cl2

22 R2 = Bn, Alkyl O

Z= X

N

25a X = O 25b X = CH2

R1

N H

25d R = t-Bu 25e R = Ph

N R2 N H 24 X

Ph

X

O HN

N 26

R 25c

+

Mg O

O

N

N

R1

O

N H N R2 23

O N

O

O

H2N

N

O

N NH R2

R1

O 27

Scheme 5.4 Chemoselective and enantioselective conjugate additions of hydrazines to β-substituted acrylimides.4

144

Imides

isomer ratios (23/24 . 95:5), and good to excellent enantioselectivities were generally obtained, although lower yields and/or selectivities resulted in reactions of benzylhydrazine with enoates bearing template 25e and phenyl, isopropyl, and ester β substituents. Reactions of methylhydrazine and isopropylhydrazine with two of the substrates (21, R1 5 Me, CH2OBn) provided high enantioselectivities (up to 99% ee); the corresponding reactions of cyclohexylhydrazine afforded moderate to good ee. The authors noted that the major product’s absolute stereochemistry could be explained by conjugate addition to the substrate in its s-cis rotamer in an octahedral complex, 27.

5.3 OXIMES In conjugate additions, either heteroatom of an oxime can potentially react as the nucleophile: O-reactivity leads to the formation of oxime ethers while N-reactivity results in nitrone products. In 2002 Nakama and coworkers reported an enantioselective example of the latter reaction catalyzed by the aqua complex of Zn(ClO4)2  6H2O and the R,R-DBFOX/ Ph ligand 33 (Scheme 5.5).5 Noting the potential of oximes to strongly bind and possibly deactivate a catalytic metal complex, the authors surmised that aqua complexes of 33 with metal salts, which had previously demonstrated robust activity in the presence of strongly binding nucleophiles, might successfully catalyze the reaction. Indeed, complexes of 33 with various metal salts promoted the room temperature conjugate addition of benzaldoxime (28, R 5 Ph) to oxazolidinone crotonate 29, but the reactions gave insignificant enantioselectivity. The highest yield of the R O

O RCH = NOH +

28 R = Ph, 2-furyl, 2-thienyl, (E)-PhCH = CH-

Zn(ClO4)2·6H2O/33 (10 mol%)

N

X

N

O

O

O N

CH2Cl2

29 X = O 30 X = NPh

31 X = O 32 X = NPh O O

N Ph

33

N

O

Ph

Scheme 5.5 Enantioselective conjugate additions of oximes to yield nitrones.5

X

145

Stereoselective Conjugate

nitrones 31 or 32 resulted from the use of Zn(ClO4)2  6H2O when the reactants were slowly added simultaneously to a dichloromethane solution of the catalyst. Under these conditions, more-reactive 2-furyl, 2-thienyl, and styryl aldoximes formed the corresponding nitrone products in good yields but very poor enantioselectivity. Replacement of the oxazolidinone auxiliary with the more strongly coordinating imidazolidinone auxiliary 30 allowed for improved reactivity and enantioselectivity in the reactions of all four oximes, although enantioselectivities were generally still low. As the most successful example, the reaction of 2-furyl 28 at 0°C gave 64% ee; further lowering the temperature to 240°C for this reaction drastically decreased yield and only marginally increased enantioselectivity. Various other Lewis acid catalysts were evaluated in the reaction but afforded no improvements in enantioselectivity. Vanderwal and Jacobsen exploited the reactivity of oximes (35) as O-nucleophiles as a means to effect enantioselective formal hydration enabling the synthesis of chiral β-hydroxy carboxylic acid derivatives 38 (Scheme 5.6).6 Through screening a variety of oximes, (salen)aluminum

O R

OH

O N H

Ph

34

N

+

OH N

(R,R)-39b (5 mol%) Cyclohexane, 23°C, 48 h

OH

O

R

35

36

N H

Ph

H2, Pd(OH)2/C AcOH, EtOH, 23°C

R = Me, Et, i-Pr, O i-Pr O

OH O R

MOMO

37

O N H

Ph

Er(OTf)3 (cat.) EtOH, 4°C

TBSO MOMO (Salen)Al-X:

Me Me

O

O

O O

OH O H N

Me

H

R

N

t-Bu

O

O

OEt 38

Al t-Bu

X

MOMO

Me

t-Bu t-Bu 39a X = Me 39b X = O-Al(salen)

Scheme 5.6 Formal hydration strategy using enantioselective conjugate addition of salicylaldoxime.6

146

Imides

catalysts 39 (which had previously promoted enantioselective reactions of weakly acidic nucleophiles), and solvents, they identified optimal conditions—reaction with salicylaldoxime catalyzed by 39b in cyclohexane—that subsequently converted α,β-unsaturated benzimides 34 to the corresponding adducts 36 in excellent conversions and 97%
98% ee. Hydrogenolysis of the oxime adducts afforded the corresponding β-hydroxy imides 37 in 81%
93% isolated yields over the two steps. To demonstrate the potential utility of the conjugate addition in polyketide natural products synthesis, the authors used the (R,R) and (S,S) enantiomers of the catalyst to convert MOM- and acetonide-protected chiral imides to the corresponding formal hydration products in 70%
89% yields and 47:1 to .99:1 ratios of diastereomers. Finally, Er(OTf)3catalyzed ethanolysis of selected β-hydroxy imides gave the corresponding ethyl esters in 89%
98% yield.

5.4 O-SUBSTITUTED HYDROXYLAMINES Conjugate addition of O-substituted hydroxylamines to α,β-unsaturated imides has been an attractive approach notably for the synthesis of β-amino acid precursors. Stereoselective reactions of this type typically have been performed using α,β-unsaturated imides with either one β substituent or one α substituent. Whereas the reactions of β-substituted acrylimides require stereocontrol over the approach of the nucleophile, those of α-substituted acrylimides involve stereoselective protonation of the enolate resulting from conjugate addition. For the latter, asymmetric induction has been achieved with the use of chiral oxazolidinone auxiliaries, and the conjugate addition products have served as important intermediates in syntheses of pharmaceutically relevant compounds, often in industry settings. For the former, a greater number and variety of strategies have been developed and applied to achieve stereocontrol at the β carbon. As detailed in Section 5.4.1, methods have included the use of a chiral auxiliary with an achiral Lewis acid or an achiral auxiliary with a chiral Lewis acid; additionally, one report has described achiral Lewis acid
catalyzed conjugate addition to a chiral substrate with an achiral auxiliary, resulting in substrate-controlled diastereoselectivity.

147

Stereoselective Conjugate

5.4.1 Conjugate Addition to β-Substituted Acrylimides 5.4.1.1 Use of Chiral Substrates In a 2002 paper, Cardillo et al. described diastereoselective conjugate additions of O-benzylhydroxylamine to trans- and cis-enoates 40 and 41 derived from D-glyceraldehyde and bearing an oxazolidinone auxiliary (Scheme 5.7).7 The authors screened several Lewis acids in dichloromethane and/or THF at 210°C (or 260°C for AlMe2Cl). In the reaction of the trans enoate, the use of Sc(OTf)3 and MgBr2  Et2O afforded no diastereoselectivity while the use of Yb(OTf)3, Bu2BOTf, CeCl3  7H2O, and AlMe2Cl gave moderate diastereoselectivities. Interestingly, Yb(OTf)3 and Bu2BOTf afforded diastereoselectivities opposite to those obtained with CeCl3  7H2O and AlMe2Cl. The authors obtained better results in reactions with the cis enoate. Upon screening several Lewis acids, they achieved good to excellent yields and diastereoselectivities with CeCl3  7H2O, Cu(OTf)2, and MgBr2  Et2O, with the best results (yield . 98% and 42/43 . 99:1) obtained using MgBr2  Et2O. Further reactions promoted by different Lewis acids allowed product 42 to be selectively converted to diverse structures: ester 44, trans-aziridine 45, dihydro uracil 46, and lactone 47. BnO

1) Lewis acid CH2Cl2 and/or THF –10°C

O N

O

O

O O

O N

O O

O

42

O

+

2) BnONH2

BnO

40

NH

NH

BnO OMe

NH

BnO

O

O

O 47

O

O BnO N O

O 45

NH

HO

O

H O N O

O

O

O 42

N

41

N

44

O

O

43

O

O

O

N O

O

O

O

2) BnONH2

O

O

NH2 O

1) Lewis acid CH2Cl2 and/or THF –10°C

O

N

OH

N O

O O

46

Scheme 5.7 Lewis acid
catalyzed transformations of D-glyceraldehyde-derived imides.7

148

Imides

5.4.1.2 Use of Chiral Auxiliaries In 1993 Amoroso, Cardillo, and coworkers reported Lewis acid
promoted diastereoselective conjugate additions of O-benzylhydroxylamine to (4S,5R)-3-alkenylimidazolidin-2-ones 48 (Scheme 5.8).8 Several Lewis acids were tested and gave varying yields and diastereoselectivities. Higher diastereoselectivities and good yields were achieved with the use of TiCl4 and AlMe2Cl (up to 11:83 dr for 49/50 in AlMe2Cl-promoted reactions). Interestingly, these two Lewis acids gave opposite diastereoselectivities. To explain the diastereoselectivity obtained with AlMe2Cl, the authors invoked the formation of chelate 51 and preferential attack of O-benzylhydroxylamine at the s-cis conformation’s less-hindered Cβ-re face. To rationalize the opposite diastereoselectivity obtained with TiCl4, they suggested that the Ti
O
C bond lengths and angles in a chelate complex, if similar to those reported for TiCl4
ethyl O-acryloyllactate,9 would favor conformation 52 over 53 with Ti under the planes of the carbonyls, away from the bulky phenyl substituent, forcing the alkenoyl group above the carbonyl planes and thereby promoting si-face attack. Finally, the authors demonstrated the application of their methodology for the enantioselective synthesis of a β-amino acid, (1)-(S)-3-butanoic acid, which involved reductive cleavage of the N
O bond and hydrolysis to remove the auxiliary following the conjugate addition step. In 2000 Cardillo, Gentilucci, and coworkers described a similar but MgBr2-promoted conjugate addition of O-benzylhydroxylamine as an early step in their synthesis of a dipeptide fragment in the antibiotic Lysobactin (Scheme 5.9).10 In the presence of MgBr2  Et2O, a cinnamoyl O Me N

O N

Me

R

Ph

O

1) M(L)n dry CH2Cl2

Me N

2) BnONH2 dry CH2Cl2

Me

48

O

O

NHOBn

N

Me N +

R

Ph

Me

49

O

NHOBn

N

R

Ph 50

R = CH3, n-C3H7

Cl

Cl

Cl Ti H N N

O O

Al

AlCl2–

H

H si

re

N N

51

O Cl 52 Favored

O Ti

N

Cl H Cl

N O O

H H

Cl re

Cl 53 Disfavored

Scheme 5.8 Lewis acid
promoted conjugate additions and models explaining diastereoselectivity.8

149

Stereoselective Conjugate

O Me N

O N

Me

Ph

Ph

O

NH2OBn MgBr2•Et2O

Me N

CH2Cl2 90%

Me

O

O

NHOBn

N

Ph

+

Ph

54

NHOBn

O

Me N

N

Me

Ph

55

56 O

O O Me N

O N

Me

O

NHOBn Ph

AlMe2Cl

Me N

TEA, CH2Cl2 60%

Ph

O N

Me

55

H N

O

Ph

Ph

CH2Cl2 65%

O

HN Ph 59

Me N

O

O Me

Ph N

Me

1) LiOOH, THF/H2O MeO 2) CH2N2 75%

HN 60 O

Ph FMOC N H 58

TEA, DMAP, CH2Cl2 75%

Ph NHFMOC Me

O N

NH Me FMOC

OH

N

Me

Me

Cl

57

BF3•Et2O Me N H2O, piperidine

(80:20 dr)

Ph

O

Me Me

OH Ph NHFMOC Me Me

Scheme 5.9 Use of MgBr2-promoted conjugate addition for the synthesis of a dipeptide fragment.10

derivative of the chiral template (4S,5R)-1,5-dimethyl-4-phenylimidazolidin-2-one 54 underwent conjugate addition by O-benzylhydroxylamine to its less-hindered face, affording a 90% yield of the readily separated diastereomers 55 and 56 in 80:20 dr. Treatment of each product with AlMe2Cl and triethylamine in dichloromethane gave the corresponding trans aziridines 57, which were subsequently coupled to N-protected acid chlorides derived from leucine. Each aziridine underwent regioselective and stereoselective ring expansion to the corresponding oxazoline. Conditions for oxazoline ring opening were investigated with the (40 R,50 S) oxazoline and later applied to its diastereomer (40 S,50 R)-58 to yield the ring-opened compound 59. Removal of the chiral auxiliary followed by methylation of the free acid led to the final dipeptide fragment 60 present in Lysobactin. In a 2001 paper,11 Hanessian et al. also described diastereoselective conjugate additions of O-benzylhydroxylamine to 61 en route to aziridines, which they desired as precursors to aziridine-based constrained analogs of their recently reported acyclic matrix metalloproteinase inhibitors. They screened several Lewis acids and chiral auxiliaries, including AlMe2Cl, TiCl4, and the auxiliary used in Cardillo et al.’s 1993 paper (see 54). Although they obtained generally good yields, they were unsatisfied with the diastereoselectivities; as one of the best results, a 73:27 ratio of inseparable diastereomers 62/63 (R 5 i-Pr) was obtained with Cardillo et al.’s methods using AlMe2Cl. Drawing from Cardillo et al.’s

150

Imides

stereochemical models (Scheme 5.8) and considering the use of planar Bu2BOTf complexes in auxiliary-based asymmetric aldol reactions, the authors tested Bu2BOTf as a potentially more-effective Lewis acid in the conjugate addition reaction. Bu2BOTf-promoted reactions afforded 62/63 in 88%
93% yield and $ 95:5 dr (Scheme 5.10). Continuing their work toward the stereoselective synthesis of β-hydroxy-α-amino acids, Cardillo et al. described methodology for the preparation of oxazolines 69 as precursors of syn-hydroxyleucine, an amino acid in the antibiotic Lysobactin (Scheme 5.11).12 As in Scheme 5.9, their strategy was based on diastereoselective conjugate addition of O-benzylhydroxylamine to 64 followed by aziridine formation (67 or 68) and ring expansion, with the final stereochemistry depending on that introduced in the conjugate addition step. Using the auxiliary (4S,5R)1,5-dimethyl-4-phenylimidazolidin-2-one, the authors compared AlMe2Cl, BF3  Et2O, MgBr2  Et2O, Sc(OTf)3, and TiCl4 in the conjugate addition. The best results—9:1 dr and .95% yield of 65/66—were obtained with the use of BF3  Et2O. The authors had expected BF3 to give the opposite stereoselectivity, the reverse of that obtained with AlMe2Cl, MgBr2  Et2O, and Sc(OTf)3; they presumed that BF3, with only one coordination site, would not form a chelate with the two carbonyls as the other Lewis acids could. In a further investigation,13 Cardillo et al. performed 1H, 13C, and 11B NMR analysis of imides 70 (Scheme 5.12A) in the presence of BF3  Et2O. In the 1H NMR spectra for each imide, they identified signals for a complex present when either 1 equiv. or 2 equiv. of BF3  Et2O was used. Taking this to be the complex responsible for the observed

O

O N

N Me

then BnONH2 –78°C

R Ph 61 R = Alkyl, O

Bu2BOTf CH2Cl2

Me

Me

O N Bu2B O OTf

BnO

Me N re

NH

62

Ph

Me

+

R OPh

N Me

N R

si

BnONH2

O

O

BnO

NH

O

O N

N Me

R 63

Ph

Me

Scheme 5.10 Diastereoselective conjugate additions promoted by dibutylboron triflate (Bu2BOTf).11

151

Stereoselective Conjugate

O N

O N 64

Ph

NH2OBn Lewis aci d O N

O

NHOBn

N

N

O

67

69

R

R = Me, Ph

TEA

O

NHOBn N

N 66

Ph

O MeO

Ph

AlMe2Cl

O

H N

N

+ O

O N

65

Ph

N

O

O

H N

N Ph

68

Scheme 5.11 Oxazoline synthesis beginning with diastereoselective conjugate addition of O-benzylhydroxylamine.12

(A)

BF3 BF3 O N

O

O BF3·Et2O

R

N Ph

70a, R = Me 70b, R = i-Pr

N

O N

R BnONH2

Ph O

(B) Cβ-si face (hindered O due to LA)

N N

O

NHOBn

N Ph

N BnONH2

LA

O

Steric interaction between LA and Ph group

LA = BF3 or AlMe2Cl

Scheme 5.12 Models by Cardillo (A) and Duarte (B) for coordination of N-alkenoylimidazolidinones to Lewis acids.13,14

152

Imides

diastereoselectivity, the authors considered three possibilities: (1) chelation of one BF3 by both carbonyls, resulting in pentacoordinate boron; (2) chelation of one BF3 by both carbonyls, displacing F2 and forming BF42; and (3) coordination of the carbonyls to two different BF3 molecules, with the carbonyls in a parallel orientation due to electrostatic attraction. From the 11B NMR spectra of 70a-BF3  Et2O obtained at multiple temperatures and equivalents of BF3  Et2O, the authors concluded that the third possibility was the most likely, involving tetracoordinate boron without BF42 formation. Later, Duarte and coworkers14 challenged the coordination mode proposed by Cardillo et al. In their explanation, Duarte et al. applied their previously described alternative to Evans’ rationalization of stereoselectivities obtained in Lewis acid
catalyzed Diels
Alder reactions of alkenoyloxazolidinones. Their approach for analyzing Cardillo’s conjugate additions included NMR studies and computational methods. The NMR data agreed with Cardillo’s results and also demonstrated that complete complexation of the substrate (coordination of both carbonyls) occurred with 1.0 equiv. of Mg(ClO4)2 (previously shown to effectively chelate N-acyloxazolidinones) but required 2.0 equiv. of AlMe2Cl or BF3. At lower Lewis acid concentrations, the alkenoyl carbonyl was preferentially complexed first. Furthermore, NOESY experiments indicated that the carbonyl groups in the AlMe2Cl and BF3 complexes were antiparallel, and theoretical data agreed with the experimental results regarding the conformations and coordination modes of complexes. The computational results further demonstrated that chelated complexes of AlMe2Cl or BF3 would afford very low stereoselectivity and that parallel carbonyl bicomplexes, as proposed by Cardillo for BF3, would result in selectivity opposite that observed. Duarte’s findings supported a model with antiparallel carbonyls; the Lewis acid on the alkenoyl carbonyl, because of steric repulsion with the auxiliary’s phenyl substituent, would partially shield the Cβ-si face, favoring nucleophilic attack at the Cβ-re face and leading to the observed diastereoselectivity (Scheme 5.12B). 5.4.1.3 Use of Chiral Lewis Acid Catalysts In 1996 Falborg and Jørgensen reported chiral Lewis acid
catalyzed enantioselective conjugate additions of O-benzylhydroxylamine to N-alkenoyloxazolidinones 71 to provide 72 (Scheme 5.13).15 The authors first screened TiCl2-TADDOLate complexes, including 73 and TiCl2BINOLate complex 74, in the reaction of an oxazolidinone crotonate

153

Stereoselective Conjugate

R

Ph

O

O N

73 or 74 (10 mol%) O

+

Ph

O

NH2

O

N

H

R *

O

O N

71

72

R = Me, Pr, Ph

R = Me, Pr, Ph

O

Ph Ph Me Me

O O

O TiX2 O

O TiCl2 O

Ph Ph 73a X = Cl 73b X = OTf

74 (TiCl2-BINOL)

Scheme 5.13 Conjugate additions of O-benzylhydroxylamine catalyzed by chiral titanium-based Lewis acids.15

(71, R 5 Me) at 0°C and then studied reactions of propyl- and phenylsubstituted imides (71, R 5 Pr, Ph) promoted by 73 at room temperature. They also performed reactions at 220°C with each alkenoyloxazolidinone but found that temperature did not significantly affect enantiomeric excess. In the catalyst screening, catalysts 73a and 73b gave some of the best ee’s (29% and 28%, respectively), but the use of 73b resulted in greater conversion, which the authors attributed to greater Lewis acidity imparted to the catalyst by the presence of triflate ligands rather than chloride ligands. In the reactions of propyl- and phenyl-substituted substrates, the triflate catalyst gave 94% and 69% conversion and 35% and 42% ee, respectively. The chloride catalyst gave lower conversion with the phenyl substrate, similar to the result seen in the solvent screening. The authors determined the crotonate addition product’s β carbon configuration to be S, meaning that the conjugate addition predominantly occurred via si-face approach of O-benzylhydroxylamine. They proposed that the alkenoyloxazolidinone underwent bidentate coordination to the Lewis acid, forming a hexacoordinate titanium center in the active catalyst, but noted that the relatively low enantioselectivities did not allow them to identify which of five possible complexes (with different relative positions of ligands) might be involved. Chiral Lewis acid
catalyzed conjugate additions of O-benzylhydroxylamine with higher ee’s were reported by Sibi et al. in 2002.16 A notable feature of these reactions, catalyzed by a chiral bisoxazoline
MgBr2 complex, was that opposite product enantioselectivities resulted at different temperatures. Initially, conjugate addition to

154

Imides

crotonates 75 with various oxazolidinone and pyrrolidinone templates and chiral ligand 26 (Scheme 5.14) was investigated at 0°C and 260°C. The addition products 76 were obtained in 43%
71% ee with no significant improvement in enantioselectivity at lower temperature. Strikingly, however, the addition product of the 4,4-dimethyloxazolidinone crotonate (X 5 O, R1 5 Me, R2 5 Me) formed predominately with (R) configuration at 0°C but (S) configuration at 260°C. Repetition of the reaction at different temperatures showed that this reversal of selectivity occurred between 220°C and 240°C. The authors conducted additional experiments to determine the effects of the Lewis acid, the chiral ligand, the template structure, and the enoate’s β-substituent. The use of salts with more weakly coordinating counterions—Mg(ClO4)2, Mg(OTf)2, and MgI2—afforded no change in selectivity with temperature. Reactions catalyzed by ligands 77 gave low to moderate ee’s and no temperaturedependent selectivity change. Several oxazolidinone and pyrrolidinone templates with methyl and phenyl substituents at the 4-position all allowed for temperature-dependent selectivities and moderate to excellent yields, and different alkyl β-substituents provided similar, generally consistent results. To explain these results, Sibi et al. suggested that the selectivities might be due to a temperature-dependent change in the substrate
catalyst coordination complex. Assuming bidentate coordination of the substrate, they considered five- and six-coordinate complexes to be more likely than tetrahedral since the selectivity indicated by modeling the tetrahedral complex was opposite that actually obtained under conditions favoring low coordination number: high temperature, weakly coordinating counterion, and bulky ligand or substrate. The authors tentatively postulated O

O

O

O

NHOBn

MgBr2/ligand (30 mol%) X

N R1

R2 R1

O

75

X = O, CH2 R1 = H, CH3, Ph R2 = Alkyl

N

BnONH2, CH2Cl2 R1 O

O N

R1

76

O

N 26

R2

O N

R

N 77

R

R = t-Bu, Bn, Ph

Scheme 5.14 Conjugate addition of O-benzylhydroxylamine with temperaturedependent enantioselectivity.16

Stereoselective Conjugate

155

that the complex of a bulky 4,4-disubstituted oxazolidinone alkenoate with MgBr2 and bulky ligand 26 would be octahedral, with both bromides bound, at low temperatures but would be five-coordinate, with only one of the bromides bound, at higher temperatures, effecting different face selectivities in the conjugate addition. Previously, Sibi et al. had developed enantioselective conjugate additions of O-benzylhydroxylamine to N-alkenoyl-3,5-dimethylpyrazoles 78 catalyzed by complexes of MgBr2 and ligand 26, obtaining moderate to good yields and up to 97% ee in MgBr2-catalyzed reactions.17 To determine whether these reactions were reversible under the conditions employed, the authors subjected the racemic conjugate addition product from N-crotonoyl-3,5-dimethylpyrazole to the reaction conditions in the presence of oxazolidinone crotonate 79 (Scheme 5.15). Only the starting materials—no crossover product formed by conjugate addition of O-benzylhydroxylamine to the oxazolidinone—were recovered, indicating that the conditions did not allow for any significant reversibility. As a control experiment, the oxazolidinone crotonate alone was subjected to the same conditions in the presence of O-benzylhydroxylamine; after 22 h, the conjugate addition product 80 was obtained in 82% yield and 28% ee (Scheme 5.15), similar to the results obtained by Falborg and Jørgensen using TiX2-TADDOLate catalysts (Scheme 5.13). In 2006 Kikuchi and coworkers investigated rare-earth (RE) metal complexes with chiral pybox-based ligands 84 and 85 as catalysts for the conjugate addition of O-benzylhydroxylamine to N-alkenoyloxazolidinones (Scheme 5.16).18 The authors screened different RE metals, substituents on the pybox ligand, and structures of the alkenoyloxazolidinone substrate. Reactions of an oxazolidinone crotonate (81, R1 5 Me, R2 5 H) using an i-Pr-pybox ligand (84, R 5 i-Pr) and various RE O N

N

NHOBn CH3

O + O

78

O N

MgBr2/26 (1 equiv.) CH3

CH2Cl2, –60°C, 3 h

O

X

O

O N

79 O O

N

CH3 79

CH3 80

BnONH2 MgBr2/26 (1 equiv.)

O

NHOBn

CH2Cl2, –60°C, 22 h

O O

O N

NHOBn * CH3

80

Scheme 5.15 Crossover experiment and control reaction to assess reversibility of conjugate addition.17

156

Imides

R1

N 81

BnONH2 RE(OTf)3/ligand (5 mol%)

O

O

O

MS 4 Å, CH2Cl2, 0°C

BnO

NH

R1

R2

N 82

R2 R1 = Alkyl R2 = H, Me O

84

R

O

+

NH

O

R1

N H

OBn

83

R2

O

N N

N

N

N R

O

O

N

R2

BnO

O

O

85

R = i-Pr, t-Bu, Ph, Bn, CH2OH

Scheme 5.16 Chiral RE complex
catalyzed enantioselective conjugate additions of O-benzylhydroxylamine.18

triflates gave excellent conversions and varying ratios of products 82 and 83, and the use of Sc(OTf)3 provided the highest enantioselectivity. The enantioselectivity of the reaction with Sc(OTf)3 was significantly lower at 220°C and 250°C and slightly lower at room temperature. When compared with other pybox ligands in the same reaction, the i-Pr-pybox ligand afforded the highest enantioselectivity. Finally, substrates with various β-alkyl substituents, in reactions using Sc(OTf)3 and the i-Pr-pybox ligand at 0°C, formed the corresponding products in good conversions (80% to .99%) and enantioselectivities (80%
91% ee of 82). Larger β-alkyl groups were correlated with higher 82/83 product ratios. Finally, the reaction of a 4,4-dimethyl-substituted oxazolidinone crotonate (R1 5 R2 5 Me) yielded only the corresponding conjugate addition product—no amidation side product—in 91% conversion and 80% ee. Didier et al. in 2011 studied samarium iodobinaphtholate 89 as an alternative catalyst for the conjugate addition of O-benzylhydroxylamine to N-alkenoyloxazolidinones 86 (Scheme 5.17),19 having previously reported its use for the same reaction with anilines as nucleophiles. In preliminary experiments, samarium diiodide gave better conversions than did other achiral catalysts. Samarium iodobinaphtholate
catalyzed reactions of an oxazolidinone crotonate (R1 5 Me, R2 5 H) gave the conjugate addition product exclusively at lower temperatures and afforded the maximum enantiomeric excess at 240°C, with lower ee’s below this point. The authors attributed the nonlinear variation in enantioselectivity to equilibria among various monomeric and dimeric catalytic species. In an examination of substrate scope, β-alkyl and β-ester substrates were converted to the corresponding conjugate addition products in generally good yields

157

Stereoselective Conjugate

O

O N

R1 86

BnO

BnONH2 catalyst (10 mol%)

R1

O CH2Cl2, –40°C

R2

NH

R1 = H, alkyl, CO2Et, Ph R2 = H, Me

N

87

BnO

O

O

+

O

NH

O

R1

R2

88

R2

N H

OBn

O Sm I · (THF)2 O 89

Scheme 5.17 Samarium iodobinaphtholate
catalyzed conjugate additions of Obenzylhydroxylamine.19

(76%
84%) and enantioselectivities (83%
88% ee) with lower yield (59%) and enantioselectivity (52% ee) from a β-isopropyl substrate. The reactions of β-phenyl and α-methyl substrates, conducted at room temperature, gave poor results: the β-phenyl substrate afforded the corresponding conjugate addition product 87 in moderate yield and low enantioselectivity, and only addition/amidation product 88 formed in the reaction of the α-methyl substrate.

5.5 CONJUGATE ADDITION TO α-SUBSTITUTED ACRYLIMIDES In 2001 Pratt et al. (from British Biotech Pharmaceuticals) reported the conjugate addition of O-benzylhydroxylamine to α-substituted acrylimide 90 (Scheme 5.18).20 They noted that they chose the dimethyl-substituted (S)-4-benzyl-2-oxazolidinone auxiliary for its lesser tendency to undergo ring opening compared with an (S)-4-benzyl-2-oxazolidinone lacking the methyl groups. The product 91 was formed with .90% diastereomeric excess and was isolated as a single diastereomer as its tosylate salt. Further reactions converted the product to BB-3497, a peptide deformylase (PDF) inhibitor with antibacterial activity in vivo. Bn

Bn BnONH2, rt

N O

O O

90

70%

BnO

H2 N

N O

TsO

O O

91

OH N

O

H N

O N

O

H BB-3497

Scheme 5.18 Diastereoselective conjugate addition of O-benzylhydroxylamine in the synthesis of BB-3497.20

158

Imides

In 2008 Liu and coworkers (Novartis) published their methods for the scale-up synthesis of LCD320, another PDF inhibitor (Scheme 5.19).21 Conjugate addition of O-benzylhydroxylamine to intermediate 92, using (S)-4-benzyl-2-oxazolidinone as the chiral auxiliary, featured as a key step in their route. The reaction gave B3
4:1 dr, but the product 93 was isolated in 60%
64% yield as its tosylate salt containing ,1% of the minor diastereomer. Upon scale-up in a pilot plant, much lower diastereoselectivity (3:1 to 2:3) resulted, and significant amounts of amidation product 94 formed. The authors determined that residual Li1 from the previous step (installment of the chiral auxiliary) was responsible for the poorer results; to solve this problem, they implemented three aqueous washes instead of one in the purification of 92, reducing the Li1 content to 1 ppm. Several other groups—Pichota et al.22 in 2008, Shi et al.23 in 2010, and Yang et al.24 in 2014—have also used the (S)-4-benzyl-2oxazolidinone auxiliary containing substrate 95, 98, and 101 for conjugate additions of O-benzylhydroxylamine and O-(p-methoxybenzyl)hydroxylamine to provide products 96, 99, and 102. The conjugate addition products were converted to structurally diverse PDF inhibitors 97, 100, and 103. Scheme 5.20 highlights these reactions and the target compounds with potential antibacterial properties. In 2008 Vögtle and coworkers (Novartis) reported scalable routes to perfluoroalkane-tagged 5,5-diphenyl-2-oxazolidinone (DIOZ) auxiliaries 104
106, enabling purification by fluorous solid-phase extraction, and demonstrated their use for the diastereoselective conjugate addition of O-benzylhydroxylamine in the synthesis of β2-N-Fmoc-phenylalanine 109 (Scheme 5.21).25 The authors prepared all three auxiliaries but chose

O

O N

O

2) TsOH·H2O ethyl acetate, rt Ph

O

O

1) BnONH2·HCl NaHCO3, toluene, rt

N

CHO N

O O N H

Ph

60%

F

93 +

HO

N

H2N TsO OBn

92

O

N N

LCD320

O N H

O

Ph

94

Scheme 5.19 Diastereoselective conjugate addition of O-benzylhydroxylamine in the synthesis of LCD320.21

159

Stereoselective Conjugate

Pichota et al.: O

1) BnONH2 (neat) 2) TsOH, ethyl acetate

O

R N 95

O OBn R HN

3) Na2CO3

O

96

Ph

O

OH N

O

O

O Ph

O

O

O

1) O-(p-methoxybenzyl)hydroxylamine 50°C, 24 h

O N

2) TsOH, Na2CO3, ethyl acetate/H2O Ph

58%

98

Y

O

MeO

N O

Ph

99

HO

O

Bu

N

N O

100

R1 N R2

O

NR1R2 = Various heterocyclic, carbocyclic, and aniline-based groups attached through N

Yang et al.: O

O

Bu

H N

H

1) O-(p-methoxybenzyl)hydroxylamine 45°C, 24 h 2) TsOH, ethyl acetate

O N

101

N

97 Y = NH or O R = Bu, Pr, pentyl, cyclopentylmethyl, or Bn

Bu

O

N

N

Shi et al.:

R3

R

Ph

3) aq. Na2CO3, ethyl acetate 60%

R3 O

MeO

O

H N

O N

O

102

Ph

R3 = n-Pr or cyclopentyl H HO

X=

O N

or

O N

O N

R3 X

N R5

R4

103 O NR4R5 = Various heterocyclic, carbocyclic, and aniline-based groups attached through N

Scheme 5.20 Conjugate additions of O-benzylhydroxylamine in the syntheses of other PDF inhibitors.22
24

106 for the synthesis since 106 was easiest to prepare yet displayed chromatographic properties similar to those of the other two auxiliaries. They synthesized both enantiomers of β2-N-Fmoc-phenylalanine by using opposite enantiomers of the chiral auxiliary. In each case, the diastereomeric conjugate addition products formed from addition to 107 to

160

Imides

O O

O

O N

BnONH2

R2

O

O N

R2

NH O

THF, 72°C, 24 h 70% 108

107 R2

R2

O

O O

O

NH

O NH

HO

R2

R1O

NH O

R 1O

R2

104 R1 = Si(CH(CH3)2)2CH2CH2C8F17 105 R1 = CH2(CF2)7CF2H

106 R2 = C2H4C6F13

O 109

Scheme 5.21 Use of perfluoroalkane-tagged chiral auxiliaries for the synthesis of β2N-Fmoc-phenylalanine.25

provide 108 as an B8.3:1 mixture, and the diastereomeric excess increased to 93% upon formation and recrystallization of the corresponding tosylate salt. The overall syntheses afforded each enantiomer of β2-NFmoc-phenylalanine with .95% ee.

5.6 N-SUBSTITUTED HYDROXYLAMINES Asymmetric conjugate addition of N-substituted hydroxylamines 111 to enoates 110 or 116 constitutes a route to chiral isoxazolidinones 115 and β-amino acids via intermediates 112
114 and 117. Compared with O-alkylhydroxylamines and simple alkylamines, N-alkylhydroxylamines react more rapidly in conjugate addition to alkenoates 110; to explain this reactivity difference, Niu and Zhao proposed a concerted mechanism in which the hydroxylamine adds to the double bond via a five-membered cyclic transition state (Scheme 5.22).26 In support of the proposed mechanism, deuterated N-methylhydroxylamine added to ethyl cinnamate with high diastereoselectivity to give product 118 with a cis relationship between the protons of the isoxazolidinone ring. Likewise, the reaction of α-deuterated esters 119 and 121 with N-methylhydroxylamine yielded the corresponding syn addition products. The authors also showed that the conjugate addition could be applied with various α,β-disubstituted alkenoates and N-alkylhydroxylamines to diastereoselectively provide the

161

Stereoselective Conjugate

H H

CO2Et + H N

R1

R2

110

O

CO2Et

R1 R2 H N H δ+ O δ−

H

111

H

CO2Et

R1 H N O

R2

112 O

Ph

MeNDOD•DCl

116

Ph H

OEt OD

ZnCl2 84%

117

R

OEt

(a) MeNHOH•HCl, R Et3N, THF H

O

O

O

119 R = Ph,

120

Ph H

O

O N O

OEt (a) MeNHOH•HCl, O Et3N, THF D

(b) ZnCl2

D

O 115

118

O

N O

N

D H O

N

R2

R1

114

D H

H D O

CO2Et R2 N H OH

113

Et3N, THF OEt

H

H R1

(b) ZnCl2

121

OD H O

H N O 122

O O

Scheme 5.22 Concerted alkenoates.26

mechanism

of

N-alkylhydroxylamine

addition

to

corresponding isoxazolidinones, affording control over the relative stereochemistry at the α and β carbons. As reported in a 1998 paper, Ishikawa et al. pioneered the use of chiral Lewis acid complexes to effect enantioselective conjugate additions of N-benzylhydroxylamine to enoates bearing achiral oxazolidinone auxiliaries leading to isoxazolidinones 124 or 127 (Scheme 5.23).27 They termed the Lewis acid
N-benzylhydroxylamine complex a “Lewis acidhydroxylamine hybrid reagent (LHHR)” and proposed the strategy shown in Scheme 5.23 for the reaction of generalized enoate 123. In their experiments, reactions of an oxazolidinone crotonate (125 or 126, R1 5 Me) using metala-1,3-dioxolane-type catalysts 128 gave, at best, moderate yield and low enantioselectivity of the (R) product, but those using metala-1,3-dioxepane-type catalysts 129 gave better results. With the same substrate, catalysts 129a and 129b each provided good yield and 63% ee. Reactions of benzyl-substituted (E)- and (Z)-enoates using catalyst 129a proceeded with low to moderate yields and 71% and 43% ee, respectively, while the reaction of a β-phenyl substrate yielded only a trace of the corresponding conjugate addition product. Sibi and Liu noted the lower reactivity of β-aryl enoates in chiral Lewis acid
catalyzed conjugate additions of nitrogen nucleophiles and conducted studies identifying factors that could enhance reactivity (Scheme 5.24).28 Employing chiral ligand 26 with MgBr2 as the Lewis

162

Imides

L

L O M L N H O

Bn O R1

LHHR

R1

X

Bn

N

M O

R1

X

L R1

O X

O N O

Bn

123

124 O

O N

R1

R1 O

or

N

125 R1 = Me, Bn, Ph

Z

O M ONHBn O

Z

O

126 R1 = Bn

O LHHR (1 equiv.) R1 * N O THF Bn 0-22°C, 23°C, or rt 127 R1 = Me, Bn, Ph R

Me Me TBSO O Al ONHBn O TBSO Me Me

Ph Ph O O M ONHBn O O Ph Ph

R2 Me

128 Z = CO2i-Pr, Ph, CONMe2 M = Al, B

O

O

129a M = Al, R2 = Ph 129b M = Al, R2 = Me 129c M = B, R2 = Ph

O Al ONHBn O R 129e R = H 129f R = SiPh3

129d

Scheme 5.23 Chiral Lewis acid
catalyzed enantioselective conjugate additions of N-benzylhydroxylamine.27

Lewis acid/ligand 26 (30 mol%) O R2NHOH (1.1 or 2.2 equiv.)

O Z

R1

CH2Cl2, –60°C

130 R1 = Me, aryl, heteroaryl Me

N

Z=

O

N

R2 O

R1 131 R1 = Me, aryl, heteroaryl

O

O N

N 26

O

N O

O N

N

N

Lewis acid = MgBr2, MgI2, or Mg(ClO4)2 R2 = PhCH2, (Ph)2CH, or 4-MeOC6H4CH2

Me A

B

C

D

Scheme 5.24 Enantioselective conjugate additions of N-benzylhydroxylamine to β-aryl-substituted enoates.28

acid at 260°C, they studied the conjugate addition of N-benzylhydroxylamine to crotonates (130, R1 5 Me) with several different achiral templates. The reaction of the 3,5-dimethylpyrazole crotonate allowed for a direct comparison with Sibi et al.’s previous work involving conjugate addition of O-benzylhydroxylamine to this substrate: N-benzylhydroxylamine reacted significantly faster than O-benzylhydroxylamine under the same conditions. Pyrrolidinone template C imparted comparatively high reactivity, afforded good yield and enantioselectivity of the conjugate

163

Stereoselective Conjugate

addition product, and subsequently served as the template for further experiments. In the same reaction, the alternative nucleophiles N-benzhydrylhydroxylamine and N-(p-methoxybenzyl)hydroxylamine formed the corresponding adducts 131 with similar ee but reacted more slowly than N-benzylhydroxylamine. Finally, the conjugate addition of N-benzylhydroxylamine was performed with β-aryl- and β-heteroaryl-substituted enoates as substrates and MgI2 and Mg(ClO4)2 (which promoted faster reactions than did MgBr2) as Lewis acids; overall, 53%
87% isolated yields and 60%
96% ee’s were obtained. Experiments using BnNDOD as the nucleophile as in Niu and Zhao’s study26 suggested that conjugate addition under these conditions occurred via a concerted mechanism. In 2001 Sibi and Liu again reported methodology for chiral Lewis acid
catalyzed conjugate additions to enoates, this time using pyrazolidinone-based templates bearing chiral relay groups (denoted by Z) for the addition of N-(p-methoxybenzyl)hydroxylamine (Scheme 5.25).29 Templates with diphenylmethyl and 1-naphthylmethyl relay groups, intended to amplify the chirality introduced by the chiral Lewis acid, afforded significantly greater ee’s at higher temperatures in reactions of crotonates (R2 5 Me) when compared with a nonrelay (unsubstituted pyrrolidinone) template. To develop this methodology for the conjugate addition reaction, the authors first evaluated chiral bisoxazoline ligands with Mg(ClO4)2 and Zn(OTf)2 as catalysts for the reaction of a crotonate with a benzyl relay group (132, R1 5 Me, Z 5 Bn, R2 5 Me) at 0°C. Although poor to moderate enantioselectivities for 133 resulted in most cases, the reaction catalyzed by the Zn(OTf)2/134 combination gave 70%

O

N H

O

OH

MeO R1

N N R1 Z

R2

O

Lewis acid/ligand (30 mol%) CH2Cl2, 0°C

132 R1 = Me, H Z = H, Et, Bn, 2-CH2-naphthyl, 1-CH2-naphthyl, CH(Ph)2 R2 = Me, Ph

O

N OMe

* R 2

133 R2 = Me, Ph

O

O N

N 134

O

O N

N 26

Scheme 5.25 Enantioselective conjugate additions using chiral relay templates.29

164

Imides

ee. The authors next screened different relay substituents in the reaction of crotonates at 0°C with Lewis acid/ligand combinations Zn(OTf)2/134 and Mg(ClO4)2/26. Strikingly, the reactions catalyzed by the magnesium and zinc complexes gave opposite selectivities, yielding the (R) and (S) enantiomers, respectively. The best overall yields (77% and 75%) and enantioselectivities (81% and 75% ee) resulted with the 1-naphthylmethyl relay group; the reaction with the diphenylmethyl relay group led to relatively high enantioselectivity (84% ee) with Mg(ClO4)2/26 but only moderate enantioselectivity (57% ee) with Zn(OTf)2/134. With these two relay groups, the reaction gave good enantioselectivities even at room temperature when Mg(ClO4)2/26 was used. With the 1-naphthylmethyl relay group at 225°C, the magnesium and zinc complexes afforded 96% ee of the (R) product and 83% ee of the (S) product, respectively. Finally, cinnamates (R2 5 Ph) with different relay groups underwent the conjugate addition catalyzed by Mg(ClO4)2/26 in good yields at 0°C, and a cinnamate with the diphenylmethyl relay group formed the corresponding (S) product in 88% ee. Although methods initially had been developed for enantioselective conjugate additions of N-substituted hydroxylamines to acrylimides with one β-substituent, Sibi and coworkers expanded the reaction scope to α,β-disubstituted acrylimides 135, enabling enantioselective syntheses of α,β-disubstituted-β-amino acids 137 (Scheme 5.26).30 The concerted mechanism of N-benzylhydroxylamine addition would facilitate

R4

BnNHOH MgX2/26 (5 or 30 mol%)

O

O N R3

O

O

N

Bn

R2

135 R1 = Alkyl, Ph R2 = Me, Et, Br, Ph R3 = H R4 = i-Pr

CH2Cl2, 25ºC or –40°C O

O

R2

O

H2, Pd/C

R1

HO

Dioxane 60°C

R1

NH2 R1

R2 137

136

N

N

X

26

X O

N

O

R4 NH

Mg O

R2

N R1

O

138

Scheme 5.26 Enantioselective conjugate additions of N-benzylhydroxylamine to α,β-disubstituted acrylimides.30

Stereoselective Conjugate

165

simultaneous control over both of the resulting stereocenters, but control over s-cis and s-trans enoate rotamers would be essential for high enantioselectivity as well as diastereoselectivity. The authors employed secondary imide (R3 5 H) templates, hypothesizing that such a template would provide rotamer control while also maximizing reactivity: steric interaction between the enoyl α-substituent and a larger R3 substituent would promote out-of-plane twisting that would break conjugation and decrease β-carbon electrophilicity. Using chiral ligand 26 (30 mol%), various achiral templates, and several magnesium-based Lewis acids (30 mol%), the authors systematically optimized the conjugate additions of N-benzylhydroxylamine to tiglates (R1 5 R2 5 Me). Poor yields of 136 resulted from the use of pyrrolidinone, oxazolidinone, and N-methyl templates; among secondary imide templates, R4 5 i-Pr led to good yield and the highest stereoselectivity (96% de, 96% ee) when used with Mg(NTf2)2 as the Lewis acid at 240°C. The optimized conditions with 5 mol% catalyst were then applied to evaluate the reaction with variously substituted substrates. In most cases, the reaction gave good to excellent yields, excellent diastereoselectivities, and good to excellent enantioselectivities; poor to moderate yields were obtained from substrates with isopropyl and phenyl β-substituents and moderate enantioselectivity (60% ee) from an α,β-diethyl-substituted substrate. Hydrogenolysis of selected products yielded the corresponding β-amino acids, and on the basis of the product stereochemistry, the authors proposed cis octahedral model 138.

5.7 CONCLUSION Stereoselective conjugate additions of N
N and N
O nucleophiles to α,β-unsaturated imides, together with subsequent transformations, have enabled the construction of diverse structures, including pyrazolidinones from alkylhydrazines as nucleophiles; nitrones, oxime ethers, and β-hydroxy carboxylic acid derivatives from oximes; chiral aziridines, oxazolines, and β-amino acids from O-substituted hydroxylamines; and isoxazolidinones and β-amino acids from N-substituted hydroxylamines. Most of these reactions have involved conjugate addition to acrylimides with only one α or β substituent and have achieved control over the configuration at the single new stereocenter, but the concerted mechanism of N-alkylhydroxylamine addition, together with chiral Lewis acid catalysis, has allowed for configurational control of the two new stereocenters resulting from addition to α,β-disubstituted acrylimides. A variety of chiral

166

Imides

ligands, most notably bisoxazolines, have been used with various Lewis acids to promote stereoselective reactions of achiral substrates. Auxiliaries have included chiral and achiral oxazolidinones, pyrrolidinones, imidazolidinones, acyclic imides, and pyrazolidinones; the use of achiral pyrazolidinones with chiral relay substituents effectively amplified the chirality imposed by a chiral Lewis acid
bisoxazoline complex for N-(p-methoxybenzyl)hydroxylamine addition. Together, the methods and applications reviewed in this chapter demonstrate the broad scope and potential utility of these reactions for the synthesis of structurally diverse and potentially bioactive compounds.

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569. 13. Cardillo, G.; Gentilucci, L.; Gianotti, M.; Tolomelli, A. NMR Investigations on Boron Complexes in the Conjugate Addition on α,β-Unsaturated Imides. Org. Lett. 2001, 3, 1165
1167. 14. Duarte, F. J. S.; Bakalova, S. M.; Cabrita, E. J.; Gil Santos, A. Lewis Acid Catalyzed Reactions of Chiral Imidazolidinones and Oxazolidinones: Insights on the Role of the Catalyst. J. Org. Chem. 2011, 76, 6997
7004. 15. Falborg, L.; Jørgensen, K. A. Asymmetric Titanium-Catalysed Michael Addition of O-Benzylhydroxylamine to α,β-Unsaturated Carbonyl Compounds: Synthesis of β-Amino Acid Precursors. J. Chem. Soc., Perkin Trans. 1 1996, 23, 2823
2826. 16. Sibi, M. P.; Gorikunti, U.; Liu, M. Temperature Dependent Reversal of Stereochemistry in Enantioselective Conjugate Amine Additions. Tetrahedron 2002, 58, 8357
8363. 17. Sibi, M. P.; Shay, J. J.; Liu, M.; Jasperse, C. P. Chiral Lewis Acid Catalysis in Conjugate Additions of O-Benzylhydroxylamine to Unsaturated Amides. Enantioselective Synthesis of β-Amino Acid Precursors. J. Am. Chem. Soc. 1998, 120, 6615
6616. 18. Kikuchi, S.; Sato, H.; Fukuzawa, S. Asymmetric Conjugate Addition of O-Benzylhydroxylamine to α,β-Unsaturated 3-Acyloxazolidin-2-ones Catalyzed by Sc(OTf)3/i-Pr-Pybox Complex. Synlett 2006, 1023
1026. 19. Didier, D.; Meddour, A.; Bezzenine-Lafollée, S.; Collin, J. Samarium Iodobinaphtholate: An Efficient Catalyst for Enantioselective Aza-Michael Additions of O-Benzylhydroxylamine to N-Alkenoyloxazolidinones. Eur. J. Org. Chem. 2011, 2678
2684. 20. Pratt, L. M.; Beckett, R. P.; Davies, S. J.; Launchbury, S. B.; Miller, A.; Spavold, Z. M.; Todd, R. S.; Whittaker, M. Asymmetric Synthesis of BB-3497—A Potent Peptide Deformylase Inhibitor. Bioorg. Med. Chem. Lett. 2001, 11, 2585
2588. 21. Liu, Y.; Prashad, M.; Ciszewski, L.; Vargas, K.; Repiˇc, O.; Blacklock, T. J. Practical Synthesis of a Peptide Deformylase (PDF) Inhibitor. Org. Process Res. Dev. 2008, 12, 183
191. 22. Pichota, A.; Duraiswamy, J.; Yin, Z.; Keller, T. H.; Alam, J.; Liung, S.; Lee, G.; Ding, M.; Wang, G.; Chan, W. L.; Schreiber, M.; Ma, I.; Beer, D.; Ngew, X.; Mukherjee, K.; Nanjundappa, M.; Teo, J. W. P.; Thayalan, P.; Yap, A.; Dick, T.; Meng, W.; Xu, M.; Koehn, J.; Pan, S.-H.; Clark, K.; Xie, X.; Shoen, C.; Cynamon, M. Peptide Deformylase Inhibitors of Mycobacterium tuberculosis: Synthesis, Structural Investigations, and Biological Results. Bioorg. Med. Chem. Lett. 2008, 18, 6568
6572. 23. Shi, W.; Duan, Y.; Qian, Y.; Li, M.; Yang, L.; Hu, W. Design, Synthesis, and Antibacterial Activity of 2,5-Dihydropyrrole Formyl Hydroxyamino Derivatives as Novel Peptide Deformylase Inhibitors. Bioorg. Med. Chem. Lett. 2010, 20, 3592
3595. 24. Yang, S.; Shi, W.; Xing, D.; Zhao, Z.; Lv, F.; Yang, L.; Yang, Y.; Hu, W. Synthesis, Antibacterial Activity, and Biological Evaluation of Formyl Hydroxyamino Derivatives as Novel Potent Peptide Deformylase Inhibitors Against Drug-Resistant Bacteria. Eur. J. Med. Chem. 2014, 86, 133
152. 25. Vögtle, M. M.; Beck, D. A.; Leutert, T.; Ossola, F.; La Vecchia, L. Preparation of Perfluoroalkane-Tagged Chiral Auxiliaries and Their Application to Stereoselective

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26. 27. 28. 29. 30.

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Synthesis of a β2-Amino Acid Building Block. ARKIVOC (Gainesville, FL, U. S.) 2008, 15, 210
224. Niu, D.; Zhao, K. Concerted Conjugate Addition of Nucleophiles to Alkenoates. Part I: Mechanism of N-Alkylhydroxylamine Additions. J. Am. Chem. Soc. 1999, 121, 2456
2459. Ishikawa, T.; Nagai, K.; Kudoh, T.; Saito, S. Chiral Lewis Acid-Hydroxylamine Hybrid Reagent for Enantioselective Michael Addition Reaction Directed Towards β-Amino Acids Synthesis. Synlett 1998, 1291
1293. Sibi, M. P.; Liu, M. N-Benzylhydroxylamine Addition to β-Aryl Enoates. Enantioselective Synthesis of β-Aryl-β-amino Acid Precursors. Org. Lett. 2000, 2, 3393
3396. Sibi, M. P.; Liu, M. Enantioselective Conjugate Addition of Hydroxylamines to Pyrazolidinone Acrylamides. Org. Lett. 2001, 3, 4181
4184. Sibi, M. P.; Prabagaran, N.; Ghorpade, S. G.; Jasperse, C. P. Enantioselective Synthesis of α,β-Disubstituted-β-amino Acids. J. Am. Chem. Soc. 2003, 125, 11796
11797.

CHAPTER 6

Chiral Sulfur-Containing Imide Auxiliaries in Medicinal Chemistry Rosmarbel Morales-Nava and Horacio F. Olivo

Division of Medicinal and Natural Products, The University of Iowa, Iowa City, IA, United States

6.1 INTRODUCTION There is a great need to prepare complex molecules possessing one or more stereogenic centers in medicinal chemistry. Often, stereogenic centers present in natural compounds have been used as construction blocks to obtain new chiral moieties. However, these natural molecules are limited in most of cases, to specific configurations. Arguably, the best and most elegant method to synthesize these molecules is via asymmetric catalysis. However, many times no asymmetric methods are available for certain reactions, costly catalysts and ligands are necessary, and ligand and reaction conditions need to be optimized. For these reasons, the use of a chiral auxiliary can be the best practical solution for many applications. This review will focus on the application of chiral 1,3-oxazolidine-2thiones and 1,3-thiazolidine-2-thione auxiliaries in the preparation of natural products and biologically significant agents. Other reviews on this topic have appeared previously, therefore emphasis will be placed in more recent applications.1,2

6.2 PREPARATION OF CHIRAL OXAZOLIDINETHIONE AND THIAZOLIDINETHIONE AUXILIARIES Chiral sulfur-containing auxiliaries are easy to prepare from chiral β-amino alcohols or thiols. Initially, Nagao and Fujita reported the synthesis and applications of chiral 1,3-thiazolidine-2-thiones and 1,3-oxazolidine-2-thiones derived from cysteine and serine, respectively.3 The methyl ester derivatives of these aminoacids (1a and b) were treated with carbon disulfide and triethylamine in dichloromethane to afford the corresponding heterocycles 2a and 2b (Scheme 6.1).

Imides DOI: https://doi.org/10.1016/B978-0-12-815675-9.00006-0

© 2019 Elsevier Inc. All rights reserved.

169

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Scheme 6.1 Preparation oxazolidinethione.

of

(4R)-methyl

carboxylate

thiazolidinethione

and

Selective preparation of oxazolidinethiones and thiazolidinethiones from β-aminoalcohols depends on the type of base and the reaction conditions (Scheme 6.2).4 Oxazolidinethiones (3c
g) were obtained selectively when the corresponding aminoalcohol (1c
g) was reacted with stoichiometric carbon disulfide and trimethylamine in refluxing dichloromethane. While thiazolidinethiones (2c
g) were obtained under more drastic conditions and longer reaction times (16
24 hours), when the aminoalcohol was treated with an excess of carbon disulfide in a refluxing aqueous solution of potassium hydroxide. Oxazolidinethiones can also be prepared in excellent yield when the aminoalcohol is treated with 2 equiv of carbon disulfide, 1.5 equiv of hydrogen peroxide, and 0.5 equiv of potassium carbonate in anhydrous ethanol at 50°C.5 Microwave irradiation methods have been used to obtain oxazolidinethiones and thiazolidinethiones in reduced times and high yields.6 An organic synthesis protocol for the multigram synthesis of (4S)-IPTT 2e was reported by Romea and Urpí.7 S O

S NH

R3 R R1 2

CS2 , 1.2 equiv

HO

Et3 N, 1.2 equiv CH2Cl2 reflux

R 3 R R1 2

3c 63% 3d 50% 3e 62% 3f 87% 3g 60%

Scheme 6.2 Selective thiazolidinethiones.

NH2

CS2 , 5 equiv

1c R 1 = Bn, R 2 = R3 = H 1e R 1 = i-Pr, R2 = R 3 = H 1f R 1 = Me, R2 = Ph, R 3 = H 1g R1 = Bn, R 2 = R3 = Me

preparation

of

S

NH

1N KOH, 100°C

4-substituted

R3 R R1 2 2c 80% 2d 77% 2e 78% 2f 43% 2g 0%

oxazolidinethiones

and

A modified method for the preparation of 4-substituted oxazolidinethiones was reported by Wu (Scheme 6.3).5 These authors claim that trimethylamine is not the most practical base to use for the preparation of oxazolidinethiones. For this reason, they tested inorganic bases, such as NaHCO3, Na2CO3, and K2CO3. The best yields were obtained when

Chiral Sulfur-Containing Imide Auxiliaries in Medicinal Chemistry

−

171

–

Scheme 6.3 Preparation of 4-substituted oxazolidinethiones.

using 0.5 equiv of K2CO3, 2 equiv of carbon disulfide, and 1.5 equiv of H2O2 at 50°C. This method avoids the formation of the thiazolidinethione because when the aminoalcohol 1 reacts with carbon disulfide in the presence of K2CO3, the thiol anion of intermediate A is oxidized by H2O2 affording disulfide intermediate B. Finally, intermediate B releases molecular sulfide delivering the desired oxazolidinethione without any racemization. A new oxazolidinethione from (S)-valine was reported by Ortíz, Scheme 6.4.8 (S)-Valine methyl ester 4 was treated with trifluoroacetic anhydride to protect the compound from racemization. Ester 5 was treated with an excess of methyl Grignard followed by hydrolysis of the amide to deliver the aminoalcohol 6. Treatment of the tertiary alcohol with carbon disulfide in basic medium provided the desired dimethyl(4S)-diisopropyl-oxazolidinethione 7.

R

Scheme 6.4 Preparation of 5,5-dimethyl-(4S)-diisopropyl oxazolidinethione.

An (S)-valine-derived oxazolidinethione for auxiliary-based asymmetric aldol reactions was reported by Guz and Phillips (Scheme 6.5).9 Oxazolidinethione 8 was synthesized by a two-step sequence from 4 L-valine methyl ester hydrochloride 4 employing known methods.

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Scheme 6.5 Diphenyl-(4S)-diisopropyl oxazolidinethione.

Sterically encumbered chiral auxiliaries have been prepared. Crimmins reported the synthesis of both mesityl-substituted oxazolidinethione and thiazolidinethione chiral auxiliaries (Schemes 6.6 and 6.7).10 Oxazolidinethione 12 was synthesized from (R)-(1)-2-methyl-2-propanesulfinamide (9) and (4-methoxybenzyloxy)-acetaldehyde via CuSO4-mediated condensation. Imine 10 was treated with mesitylmagnesium bromide to give a single diastereomer of protected aminoalcohol. Concomitant removal of sulfinyl and PMB groups under acidic conditions gave the free aminoalcohol 11. Finally, treatment of aminoalcohol 11 with thiophosgene provided the desired mesityl-substituted oxazolidinethione 12. O

O H2 N

S

CuSO4

CMe3

NH2

1. Me3 C 6H 2MgBr toluene, –78°C

CMe3

10

O

Cl2C=S, Et 3N

H OH

N OPMB

H PMBO

9

S

2. HCl, MeOH

H O

NH 12

11 S

Scheme 6.6 Preparation of (4R)-mesityl oxazolidinethione.

Scheme 6.7 Preparation of (4R)-mesityl thiazolidinethione.

Chiral mesityl-substituted thiazolidinethione 14 was prepared modifying some reagents and conditions. The (R)-(1)-2-methyl-2-propanesulfinamide (9) was condensed with chloroacetaldehyde to give imine 13 (Scheme 6.7).

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Treatment of imine 13 with mesitylmagnesium bromide was followed by treatment with acid. Heating of the corresponding aminoalcohol with carbon disulfide and potassium hydroxide gave the desired chiral auxiliary 14. Phillips and Sammakia proposed that having a tert-butyl group on C4 would add high diastereoface selectivity in the enolate of the acetate aldol reaction (Scheme 6.8).11 The tert-butyl thiazolidinethione 17 was synthesized from tert-leucinol 15 in a 10 g scale by a slight modification of the two-step Le Corre’s procedure. Reduction of L-t-leucine (15) with sodium borohydride in the presence of iodine gave t-leucinol 16, which was treated with a large excess of carbon disulfide in a refluxing solution of potassium hydroxide to give the (4S)-tert-butyl thiazolidinethione 17.

Scheme 6.8 Preparation of (4S)-tert-butyl thiazolidinethione.

A new reagent, a functional equivalent of D-tert-leucine, was described by Sammakia, Scheme 6.9.12 The tert-butyl group was replaced with a protected tertiary alcohol. Synthesis began from cysteine ethyl ester (1a). The thiazolidinethione 2a was obtained in 90% yield when the cysteine 1a was treated with trimethylamine (1 equiv) and thionylcarbodiimidazole (1 equiv) in THF. Thiazolidinethione 2a was also obtained when cysteine was treated with trimethylamine and carbon disulfide in dichloromethane. Treatment of thiazolidinethione 2a with methyl lithium in the presence of cerium chloride gave the tertiary alcohol which was silylated to give the desired thiazolidinethione 18.

Scheme 6.9 Preparation of Sammakia’s thiazolidinethione.

Chlorodeoxypseudoephedrine hydrochlorides 19a and b were reacted with sodium dithiocarbonate in stirring ethanol at 0°C to obtain cis-substituted thiazolidinethiones 20a and b in high yields (Scheme 6.10). The

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Scheme 6.10 Preparation of 4,5-substituted thiazolidinethiones.

presence of the trans-substituted thiazolidinethione as a secondary product was explained by formation of cis-substituted aziridine.13 In our group, we set an important goal to prepare a chiral thiazolidinethione auxiliary that was sterically encumbered, easy to prepare, give excellent diastereoselectivities, and is inexpensive. Inspired in Ghosh’s oxazolidinone,14 we also thought the auxiliary should be prepared from commercially available trans-1-amino-2-indanol (21) (Scheme 6.11).15 We found out that the indene-based thiazolidinethione (IBTT) 22 can be obtained in excellent yield when trans-aminoindanol 21 is treated with sulfuric acid, and then the crude sulfated indanol is treated with potassium-ethyl xanthate and aqueous sodium hydroxide.

P

Scheme 6.11 Preparation of indene-based thiazolidinethione.

A camphor-based oxazolidinethione was prepared by Yan (Scheme 6.12).16 Synthesis of oxazolidinethione 26 required three high yielding steps from ketopinic acid 23. Isocyanate 24 was treated with sodium borohydride in methanol and 6N KOH to afford aminoalcohol 25 in excellent yield. Aminoalcohol 25 was treated with excess carbon disulfide in refluxing THF to give the desired camphor-based oxazolidinethione 26.

Scheme 6.12 Preparation of camphor-based oxazolidinethione.

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Jiang reported a practical and environmentally friendly procedure to obtain optically pure oxazolidinethiones from chiral amino alcohols (Scheme 6.13).17 Amino alcohol (1c
k), S8, CHCl3 and tert-BuOK in 2-ethoxyethanol/1,4-dioxane were added to CHCl3 dropwise at 0°C and heated to 50°C during 8
16 hours to deliver the desired oxazolidinethiones (3c
k). In this work, the construction of a thiocarbonyl group was oriented to the establishment of a carbon
sulfur double bond. Chloroform as a potential carbon source, and elemental sulfur as a natural abundant sulfur source were used to obtain the thiocarbonyl group via isocyanide intermediate.

Scheme 6.13 Preparation of (4S)-substituted oxazolidinethiones.

Large-scale production of 4,4-dimethyloxazolidine-2-thione (3l) was reported in kilogram scale (Scheme 6.14).18 This achiral oxazolidinethione was required for the synthesis of a key carbapenem intermediate. Carbon disulfide was added carefully to a solution of amino-methylpropanol 1l in toluene and vigorously stirred for 2 hours. The aqueous extract was then treated with a 10% NaOH solution and heated to 95
100°C for 2 hours. Crystalline oxazolidinethione 3l was produced upon cooling of the aqueous reaction mixture.

Scheme 6.14 Gram-scale preparation of oxazolidinethione.

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Imides

6.3 COUPLING OF ACYL GROUPS TO CHIRAL OXAZOLIDINETHIONE AND THIAZOLIDINETHIONE AUXILIARIES One of the most effective methods to prepare the N-acyl oxazolidinones and thiazolidinethiones is the N,N0 -dicyclohexylcarbodiimide (DCC)/4(dimethylamino)pyridine (DMAP)-mediated coupling of carboxylic acids with the heterocycle (Scheme 6.15).19 Very good results are obtained when using a light excess of carboxylic acid and DCC. The dicyclohexylurea byproduct is filtered and the excess carboxylic acid washed off with Na2CO3. Reaction is carried out at 0°C for the first 10 minutes and then at room temperature for just a few hours. A large number of N-acyl thiazolidinethiones 28 (X 5 S) and oxazolidinethiones 29 (X 5 O) have been prepared by this method. Carboxylic acid anhydrides can also be used to acylate these sulfur-containing auxiliaries in the presence of ZnCl2.20

Scheme 6.15 DCC coupling of carboxylic acids to oxazolidinethiones and thiazolidinethiones.

Modafinil, a small molecule possessing a chiral sulfoxide and amide, is a very unique CNS stimulant because it is devoid of any addiction liability.21 In an interest to study each enantiomeric form of modafinil, a chiral thiazolidinethione (4R)-PTT 2d was employed to resolve modafinic acid (30) (Scheme 6.16).22 The diastereomeric imides 31 and 32 were easily separated by silica gel column chromatography. An X-ray analysis showed the stereochemistry of the chiral sulfoxide in imide (2)-31. Both imides 31 and 32 were treated with a solution of CH2Cl2
MeOH
NH4OH (78:20:2) to deliver the enatiomeric pure forms of modafinil.

Scheme 6.16 Separation of diastereomeric imides.

Chiral Sulfur-Containing Imide Auxiliaries in Medicinal Chemistry

177

Compared to N-acyl oxazolidinones removal of the auxiliary in the thioimide auxiliary is generally easier. However, it is not always as trouble-free, particularly with the free β-hydroxy group, when the auxiliary carries large groups that hinder access to the carbonyl, or when fragile molecules. Wu reported a facile method to remove the thiazolidinethione auxiliary with benzyl alcohol-mediated by DMAP in dichloromethane.5 Usually, a 10 mol% of DMAP is required to catalyze the reaction.

6.4 PROPIONATE ALDOL REACTIONS Aldol reactions discovered independently by the German and Russian chemists Wurtz23,24 and Borodin,25 respectively, have played an important role in synthetic organic chemistry for making carbon
carbon bonds and the installation of stereogenic centers.26 Sn(II) metals were initially employed to create metal enolates of the sulfur-containing chiral auxiliaries. Paquette reported the X-ray analysis of the aldol product of N-propionyl (4S)-IPPT 33 and propionaldehyde to confirm the absolute stereochemistry of the aldol product.27 This aldol reaction was then performed with the highly complex aldehyde 34 with complete stereocontrol by the chiral thiazolidinethione auxiliary to give “non-Evans” syn-aldol product 35 (Scheme 6.17). The aldol product was transformed into the Weinreb amide, silylated, and then reduced to the corresponding aldehyde. This spiroketone-containing imide 35 was employed in the synthesis of the C1
C28 sector of spongostatin 1, one of the most potent antineoplastic agents identified.28

Scheme 6.17 N-Propionyl IPTT aldol reaction. Spongiostatin 1.

In the formal total synthesis of anticancer agent (1)-FR900482, Danheiser proposed the syn-aldol condensation with tin enolate of propionyl thiazolidinethione as a key step in the synthesis of the benzazocine core

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Imides

of (1)-FR900482.29 Acylation of (4S)-IPTT with 3-benzyloxypropionyl chloride gave N-acyl (4S)-IPTT 36, which was treated with tin(II) triflate and N-ethylpiperidine (NEP) at 278°C (Scheme 6.18). The resulting tin enolate was treated with acrolein at 278°C to obtain the “non-Evans” syn-aldol product 37 with more than 95% of selectivity of the desired diastereomer.

Scheme 6.18 N-Acyl IPTT aldol reaction. (1)-FR900482.

Miller studied the propionate aldol condensation of cysteine-derived thiazolidinethione with aromatic, saturated, and unsaturated aldehydes utilizing boron enolates.30 Generation of the boron enolate on N-propionyl thiazolidinethione 38 at 0°C and reaction with benzaldehyde at 278°C resulted in a single diastereomer 39 as observed by high-field NMR (Scheme 6.19). Methanolysis of the yellow “Evans” syn-aldol product 39 provided the corresponding methyl ester (1)-40 which optical rotation confirmed its absolute stereochemistry and required a transition state that does not involve metal chelation of the thione group of the chiral auxiliary. Miller repeated the aldol reaction replacing the boron for Sn(OTf)2. He observed that the same aldol product was obtained with the exact same properties than when utilizing the boron enolate.

Scheme 6.19 Boron-mediated N-propionyl thiazolidinethione aldol reaction.

Yan studied the propionate aldol condensation of the derived din-butylboryl enolate with various aldehydes affording the “Evans” syn-aldol product with good yields and excellent diastereoselectivity (Scheme 6.20).17 Only one diastereomer was observed in the analysis of the crude “Evans” syn-aldol product (42a
d). The absolute stereochemistry of the aldol products was determined by mild hydrolysis of the chiral auxiliary

Chiral Sulfur-Containing Imide Auxiliaries in Medicinal Chemistry

179

Scheme 6.20 Boron-mediated N-propionyl oxazolidinethione aldol reactions.

followed by methylation of the resulting β-hydroxycarboxylic acids with CH2N2 and comparison of their optical rotation with those reported in the literature. A nine-carbon unit was observed in several natural polyketides, for example, virginiamycin M1, mycoticin A, and roflamycoin. Helquist disclosed a synthetic sequence to prepare this unit utilizing a propionate aldol reaction employing a boron enolate (Scheme 6.21).31 The “Evans” synaldol product 43 was obtained as a single diastereomer when (4R)-oxazolidinethione ent-2b was reacted with isobutanal. Aldehyde 44 was obtained directly from the oxazolidinethione after silylation of the alcohol employing di-isobutylaluminum hydride (DIBAL-H).

Scheme 6.21 N-Propionyl oxazolidinethione aldol reaction. Virginiamycin M1.

Yan compared the propionate aldol condensation of the derived chlorotitanium enolates with the corresponding boron enolates (Scheme 6.22).17 Interestingly, his group found that the chlorotitanium enolate condensation affords the “non-Evans” syn-aldol product (45a
d), resulting from chelation control, opposite to the boron enolate which affords the “Evans” syn-aldol product through nonchelation control. Absolute configuration of aldol products was determined by mild hydrolysis followed by methylation and comparison with reported compounds. Yan’s group also reported a novel DMAP-promoted oxazolidinethione deacylation.32 Traditional oxazolidinones are cleaved by KOH/MeOH or K2CO3/MeOH. However, oxazolidinethiones were easily cleaved by

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Imides

Scheme 6.22 Titanium-mediated N-propionyl camphor-based oxazolidinethione aldol reactions.

nucleophilic attack of methanol, in the presence of DMAP. These reaction conditions did not cleave N-acyl oxazolidinones. The selectivity on the asymmetric aldol reactions for of titanium(IV) enolates of acyloxazolidinethiones for the preparation of the “Evans” or “non-Evans” syn-aldol products in high diastereomeric purity can be controlled simply by changing the stoichiometry of the Lewis acid and the nature of the amine base.33,34 Crimmins discovered that the “non-Evans” syn-aldol product is obtained when 1
2 equiv of TiCl4 and 1.1 equiv of Hunig’s, TMEDA, or (2)-sparteine base is used (Scheme 6.23). The titanium enolate coordinates with the aldehyde carbonyl oxygen and also with the chiral auxiliary thiocarbonyl sulfur atom forming a “closed” highly ordered chelated transition state.

Scheme 6.23 N-Propionyl oxazolidinethione aldol reactions. “Non-Evans” syn-aldol products.

Reaction of N-propionyl (4S)-BOxT 46 with benzaldehyde gave “nonEvans” syn-aldol product 47c in 50% yield during the synthesis of (1)-conagenin by Xie (Scheme 6.23).35 (1)-Conagenin is a small natural product isolated from the fermentation broth of Streptomyces roseosporus M1696-AF3, and it exhibits specific action on T cells without activation of macrophages.36

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When only 1 equiv of TiCl4 is used together with 2.5 equiv of TMEDA or (2)-sparteine, the resulting titanium(IV) enolate does not coordinate to the sulfur atom of the oxazolidinethione, but only to the aldehyde carbonyl oxygen forming an “open” transition state, Scheme 6.24. This transition state explains the “Evans” syn-aldol product. Several “Evans” syn-aldol products (48a
e) were prepared in high yields and diastereoselectivity ratios.

A

Scheme 6.24 N-Propionyl oxazolidinethione aldol reactions. “Evans” syn-aldol products.

Two consecutive efficient propionate aldol reactions were employed in the synthesis of callystatin A by Crimmins ( . 80% yield and .98:2 dr) (Scheme 6.25).37 Callystatin A is a highly cytotoxic polyketide isolated from the marine sponge Callyspongia truncata. Callistatin A showed remarkable in vitro cytotoxicity (IC50 5 0.01 ng/mL) against KB cells (cells that are positive for keratin by immunoperoxidase staining).38 The synthesis of the C13
C22 propionate fragment possessing four stereogenic centers required the application of the recently studied asymmetric aldol additions. Treatment of the N-propionyl (4S)-BOxT 46 with TiCl4 and (2)-sparteine followed by addition of S-2-methylbutanal 49 resulted

Scheme 6.25 N-Propionyl oxazolidinethione aldol reactions. Callystatin A.

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in the formation of the syn-aldol product 50 in very good yield and excellent diastereoselectivity. The aldol product 50 was silylated, reduced with lithium borohydride, and oxidized to the aldehyde 51 using Swern conditions. The second aldol reaction occurred under the same aldol reaction conditions affording the syn-aldol product 52 in very good yield and excellent diastereoselectivity. Apoptolidin was found in efforts to identify natural products with selective cytotoxicity against tumor cells.39 This polyketide isolated from actinomycete Nocardiopsis sp. was found to induce cell death in E1A transformed cells but not in normal cells. The Crimmins methodology was elegantly applied in one case to obtain the “Evans” and also the “non-Evans” syn-aldol products during the synthesis of the C(16)
C (28) fragment of apoptolidin by Sulikowski (Scheme 6.26).40 Utilizing inexpensive N-propanoyl (4S)-BOxT 46 and 1 equiv of TiCl4 and 1 equiv of (2)-sparteine reaction with aldehyde 53 gave the “Evans” syn-aldol 54. On the other hand, utilizing 2 equiv of TiCl4 and 2 equiv of (2)-sparteine, the same (4S)-BOxT 46 and aldehyde 55 gave the “non-Evans” syn-aldol product 56. The relative stereochemistry between C(25) and C(27) was assigned on the basis of the Rychnovsky method of an appropriate acetonide.41

Scheme 6.26 N-Propionyl oxazolidinethione aldol reactions. Apoptolidin.

Very similar reactions were carried by Crimmins in the synthesis of the C20
C28 fragment of apoptolidinone, where they showcased the versatility and utility of the thiazolidinethione chiral auxiliaries.42 One equivalent of TiCl4, (2)-sparteine and N-methyl-2-pyrrolidone (NMP) were employed for the formation of the “Evans” syn-aldol product 59 (dr . 98:2). The X-ray crystal structure of N-propionyl (4S)-benzylthiazolidinethione (BTT) 59 was reported by Vishweshwar.43 “Evans”

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183

syn-aldol product 59 was silylated and reduced directly to aldehyde 60 with DIBAL-H. In the second aldol reaction with the same chiral auxiliary, 1 equiv of TiCl4 and excess of diisopropylethylamine were used to obtain the “non-Evans” syn-aldol product 61 (Scheme 6.27).

Scheme 6.27 N-Propionyl thiazolidinethione aldol reactions. Apoptolidinone.

Sitophilure (63) is a small molecule that could be employed as a pheromone-baited insect trap (Scheme 6.28).44 The enantiomer of the most bioactive (4R,5S)-5-hydroxy-4-methyl-3-heptanone was prepared employing a chiral thiazolidinethione auxiliary by Lu.45 The titanium enolate of N-propionyl (4S)-BTT 57 was formed by adding 1 equiv of TiCl4, 1 equiv of di-i-propylethyl amine, and 2 equiv of 1-methyl-2pyrrolidinone. The “Evans” syn-aldol product 62 obtained was converted into (4S,5R)-sitophilure 63 after five more steps.

Scheme 6.28 N-Propionyl thiazolidinethione aldol reactions. Sitophilure.

Crocacins A
D are novel antifungals and highly cytotoxic metabolites isolated from the mycobacterial strains of Chondromyces crocatus and Chondromyces pediculatus.46 A synthesis of crocacin C started by the N-propionyl oxazolidinethione 46 aldol reaction with cinnamaldehyde (Scheme 6.29).47,48 The “non-Evans” syn-aldol product 64 was carefully reduced with 1 equiv of DIBAL-H to the corresponding aldehyde which was reacted with the stabilized ylide to obtain the α,β-unsaturated ester 65 without the need of protecting groups.

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Imides

Scheme 6.29 N-Propionyl oxazolidinethiones aldol reactions. Crocacins.

Stevastelins A, B, B3, and C3, isolated from a culture of Penicillum sp. NK374186, represent a family of cyclic depsipeptide immunosuppresants that inhibit the dual specificity phosphatase, VHR. A propionate aldol reaction was employed during the total synthesis of stevastelin B (Scheme 6.30). The “non-Evans” syn-aldol product 67 was obtained when N-propionyl BOxT 46 was reacted with chiral aldehyde 66.

Scheme 6.30 N-Propionyl oxazolidinethiones aldol reactions. Stevastelins.

Perkins employed a propionate aldol reaction to install the stereochemistry required in a synthon for the preparation of a spiculoic acid model.49 Reaction of the titanium enolate of N-propionyl (4R)-BTT ent57 with chiral aldehyde 68 in the presence of (2)-sparteine and NMP gave the desired “Evans” syn-aldol product 69 in good yield and good diastereoselectivity (Scheme 6.31). Wittig/Julia and Wittig/H. W. E. olefinations were employed to prepare trienes useful for intramolecular Diels
Alder reactions to construct the spiculoic acid models.

Scheme 6.31 N-propionyl thiazolidinethione aldol reactions. Spiculoic acid.

Shi et al. employed the TiCl4-mediated aldol reaction as a key step to create the stereogenic centers required in the syntheses of several 3,4-cisdialkyl substituted γ-lactones and 4,5-cis-dialkyl substituted δ-lactones.50

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They were discouraged to use the more commonly employed stoichiometric amounts of Bu2BOTf because of its cost and its high sensitivity to air and moisture. For this reason, they preferred to use the TiCl4 variant. Reaction of N-propionyl (4S)-BOxT 46 with n-heptaldehyde led to the “Evans” syn-aldol product 70 in 81% yield, and the analogous product 71 in 57% when the (4S)-BTT 57 was employed (Scheme 6.32). However, this shortcoming was partially compensated by the much more facile reductive cleavage of thiazolidinethione 71 than that of oxazolidinethione 70.

Scheme 6.32 N-Propionyl oxazolidinethione and thiazolidinethione aldol reaction. γ- and δ-lactones.

A synthesis of brefeldin A was reported by Wu et al., who studied the titanium-mediated aldol condensation between N-acyl (4S)-BTT 72 and aldehyde 73 (Scheme 6.33).51 Titanium(IV) was selected because it is much cheaper and easier to remove than Bu2OTf. Initially, these authors employed the analogous N-acyloxazolidinone auxiliary, but they found removal of the auxiliary to be extremely difficult. The stereoselectivity was strongly dependent on the base employed. The monoamine i-Pr2NEt often led to formation of two major products. But, the diamines such as TMEDA or TEPDA (N,N-tetramethylpropylenediamine), gave much better results than those observed with the original Crimmins’ substrates. The aldol product 74 was silylated followed by NaBH4 reduction; the resulting alcohol underwent an intramolecular Michael addition with the

Scheme 6.33 N-Acyl thiazolidinethione aldol reactions. Brefeldin A.

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Imides

α,β-unsaturated ester to give ether 75. A similar reaction was also performed with benzyl ether α,β-unsaturated aldehyde 76 to deliver aldol product 77. A propionate aldol reaction with a biaryl aldehyde was described by Gurjar et al. in the synthesis of eupomatilone-6.52 Eupomatilones are characterized by a biaryl system with a substituted γ-lactone ring attached to one of the aryl rings.53 Eupomatilone-6 exists as a mixture of fluctional atropisomers. N-Propionyl (4S)-BTT 57 was reacted with biaryl aldehyde 78 in the presence of 1 equiv of titanium tetrachloride and excess TMEDA to furnish the “Evans” syn-aldol product 79 (Scheme 6.34).

Scheme 6.34 N-Propionyl thiazolidinethione aldol reactions. Eupomatilone-6.

An aldol reaction was carried out with highly lipophilic compounds for the synthesis of nocardiolactone, a simple β-lactone isolated from pathogenic Nocardia strains.54 The long N-icosanoyl (4S)-PhTT 80 was treated with TiCl4 and TMEDA to form the titanium enolate which was treated with tetradecanal to give the “Evans” syn-aldol product 81 (Scheme 6.35). Displacement of the auxiliary with benzyl alcohol catalyzed by DMAP, followed by mesylation of the β-hydroxyester and treatment with a base gave the desired natural product.

Scheme 6.35 N-Acyl thiazolidinethione aldol reactions. Nocardiolactone.

Most of the α-CF3 ketone enolates such as Li enolates, react by defluorination, affording the corresponding α,β-unsaturated β,β-difluoroketones, whereas the titanium enolate counterparts react with aldehydes at 278°C, because of the weaker interaction of titanium with fluorine (Scheme 6.36).55 On this context, the aldol reaction of N-3,3,3-trifluoropropionyl

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Scheme 6.36 N-3,3,3-Trifluoropropionyl oxazolidinethione aldol reactions.

(4S)-BOxT 82 was reacted with 1 equiv of TiCl4 and excess of N,N-tetramethylethylenediamine (TMEDA) to form the enolate to react with p-nitrobenzaldehyde to furnish the “Evans” syn-aldol product 83. Salinomycin is a polyether ionophore antibiotic, and it is widely recognized by its remarkable antibacterial and anticoccidal properties.56 Urpí et al. proposed a propionate aldol reaction to create two contiguous chiral centers necessary for the construction of a pseudo-glycal (88).57 N-Propionyl (4S)-isopropyl-thiazolidinethione (IPTT) 33 was treated with 2 equiv of TiCl4 and 1 equiv of diisopropylethylamine to generate the titanium enolate which was reacted with chiral aldehyde 84 to furnish “non-Evans” syn-aldol product 85 (Scheme 6.37). This compound was transformed into pseudo-glycal 88 in six more steps.

Scheme 6.37 N-Propionyl thiazolidinethione aldol reactions. Salinomycin.

Erythromycins are polyketide macrolactones that have captured the interest of biologists, clinicians, and synthetic chemists.58 These molecules possess remarkable antibacterial properties and their architecture has been a challenge for the synthetic chemists. Crimmins described an impressive synthetic approach to 6-deoxyerythronolide B that showcases the utility of the acyl thiazolidinethione propionate aldol reaction to establish eight of the nine stereogenic centers in this molecule.59 He and his group employed the aldol reaction five times employing the same N-propionyl (4R)-BTT ent-57 to furnish the “Evans” or “nonEvans” syn-aldol products (Scheme 6.38). The “non-Evans” syn-aldol

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Imides

Scheme 6.38 N-Propionyl thiazolidinethione aldol reactions. Erythromycins.

product was obtained when using 1 equiv of TiCl4 and 1 equiv of base, and the “Evans” syn-aldol product was obtained when using 1 equiv of TiCl4 and an excess of base. Interestingly, all reactions were carried out at 0°C and gave the products in high yield and excellent diastereoselectivity. Schering
Plough Research Institute recently reported the isolation of a metabolite from Micromonospora sp., SCH-351448, a unique selective activator of LDL-R.60 The biological importance together with the novel diolide structure of SCH-351448 have made it an important synthetic target. Crimmins’ total synthesis of SCH-351448 employed two aldol reactions with highly complex N-acyl oxazolidinethiones.61 The aldol reaction of N-alkyl (4R)-BOxT 98 with aldehyde 99 gave the “nonEvans” syn-aldol product 100 in 81% yield and 15:1 dr (Scheme 6.39). The thioimide group was reduced after silyl protection to a methyl group in three more steps and the polyene underwent ring closing methathesis in the presence of a Ru catalyst.

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Scheme 6.39 N-Acyl oxazolidinethione aldol reactions. SCH-351448.

Valilactone was isolated from the MG 147-CF2 strain of Streptomyces and found to inhibit pancreas lipase three orders of magnitude lower than that of tetrahydrolipstatine, a molecule marketed under the name of Orlistat or Xenical, a drug to treat obesity.62 A new synthesis of valilactone was reported by Wu and Sun, where an N-acyl (4S)-BOxT 101 is utilized to set two of the three stereocenters found in the core of the molecule.63 N-Octanoyl (4S)-BTT 101 was treated with 1.2 equiv of TiCl4 and excess of base to obtain an enolate that was reacted with aldehyde 102 to furnish the “Evans” syn-aldol product 103 in good yield (Scheme 6.40).

Scheme 6.40 N-Acyl oxazolidinethione aldol reactions. Valilactone.

FR252921 is a novel immunosuppressive agent isolated from the cultured broth of Pseudomonas fluorescence No. 408813. Ma envisioned that the three stereocenters in this molecule could be elaborated via asymmetric aldol condensations.64 Thiazolidinethione auxiliaries were selected because it was known they could easily undergo transamination. N-Propionyl (4S)-BTT 57 was treated with TiCl4 and diisopropylethylamine to form the enolate that was reacted with Fmoc protected 2-aminoacetaldehyde to furnish “non-Evans” syn-aldol product 104 in 82% yield and .95:5 dr (Scheme 6.41). Aldol 104 was silylated and then reacted with an amine to displace the thiazolidinethione.

Scheme 6.41 N-Propionyl thiazolidinethione aldol reactions. FR252921.

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Imides

The “Evans” syn-aldol product 105 was employed by Toueg and Prunet for the synthesis of α-EWG-substituted enones, substrates for ring closing metathesis.65,66 N-Alkyl thiazolidinethione 105 was reduced directly to the aldehyde and transformed into β-ketoester 110 (Scheme 6.42). Knoevengel condensation of β-ketoester with acetaldehyde gave the diene substrate for the RCM reaction.

Scheme 6.42 N-Propionyl thiazolidinethione aldol reactions. Substrates for RCM.

Erogorgiane is a diterpene isolated from the West Indian sea whip Pseudopterogorgia elisabethae possessing promising antimycobacterial activity.67 It can inhibit the growth of Mycobacterium tuberculosis H37Rv at 12.5 μg/ mL, which makes it an interesting lead to develop new anti-TB agents. Yadav reported a total synthesis of this diterpene where an Evans aldol reaction was employed to set the stereochemistry of a benzylic position and a thiazolidinethione aldol reaction was employed to set two other stereocenters.68 The “non-Evans” syn-aldol product 108 was transformed into the tosylate 109, which upon desilylation followed by deprotonation of the alcohol underwent cyclization to form oxetane 110, Scheme 6.43. An intramolecular Friedel
Crafts reaction of oxetane 110 gave intermediate 111 possessing the three chiral carbons as found in erogorgiane.

Scheme 6.43 N-Propionyl thiazolidinethione aldol reactions. Erogorgiane.

Very good diastereoselectivities were reported utilizing the indenebased N-propionyl thiazolidinethione 112 (IBTT).16 Both “non-Evans” syn-aldol product 113 and “Evans” syn-aldol product 114 were obtained

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in very good yield and diastereoselectivities (Scheme 6.44). The chiral auxiliary was easily removed to deliver several valuable functionalities.

Scheme 6.44 N-Propionyl thiazolidinethione aldol reactions. Stereoselectivity in IBTT.

Aldolizations have been carried out with organoselenium compounds.69 Organoselenium compounds are used as intermediates in synthesis of numerous molecules. Asymmetric preparation of organoselenium compounds is challenging because protons α to the selenium atom are highly acidic and prone to epimerization. Both N-phenylselanylacetyl oxazolidinethiones 115 and thiazolidinethiones 116 were subjected to titanium enolization and reacted with different aromatic and aliphatic aldehydes giving the “Evans” syn-aldol products 117a
d and 118a
d in very good yields and excellent diastereoselectivities (Scheme 6.45). The oxazolidinethiones and thiazolidinethiones were reduced to alcohols after silylation and then treated with different isocyanates to deliver the corresponding carbamates.

Scheme 6.45 N-Acyl oxazolidinone and thiazolidinethione aldol reactions with selenium.

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Imides

Similarly to the N-phenylselanylacetyl oxazolidinones, N-thioglycolyl oxazolidinethiones worked well in aldol condensations with aldehydes.70 Reaction of the titanium enolate of N-thioglycolyl oxazolidinethione 119 with p-bromobenzaldehyde employing 2 equiv of TiCl4, 1 equiv of i-Pr2NEt, and 1 equiv of NMP gave solely the “Evans” syn-aldol product 120 (Scheme 6.46). Interestingly, when a large excess of TiCl4 was added, the “non-Evans” syn-aldol product 121 was preferentially obtained. However, this high selectivity was not observed with an α,β-unsaturated aldehyde (t-cinnamaldehyde), where diastereoselectivities were only modest.

Scheme 6.46 N-Thioglycolyl oxazolidinone aldol reactions.

Narbonolide is a 14-membered polyketide macrolide biosynthesized by the pikromycin polyketide synthase system of Streptomyces venezuelae ATCC 15439.71 Das employed three aldol reactions to install the C8
C9, C4
C5, and C2
C3 stereocenters of the C1
C10 intermediate.72 In the first aldol reaction, he employed (2)-sparteine and NMP as bases to obtain the “Evans” syn-aldol product 122 (Scheme 6.47). In the other two aldol reactions, diisopropylethylamine was used as base to obtain the “non-Evans” syn-aldol products 124 and 126.

Scheme 6.47 N-Propionyl thiazolidinethione aldol reactions. Narbonolide.

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In 1993, Gräfe reported the isolation and structure assignment of natural antibiotic pamamycin 621A from Streptomyces aurantiacus.73 Pamamycin 621A is a member of the macrodiolide homologous generated by various Streptomyces species.74 Wu and Ren reported a total synthesis of this bioactive natural product.75,76 During the total synthesis of this antibiotic, Wu et al. investigated the asymmetric aldol reaction of chiral aldehyde 127 and N-propionyl (4S)-BOxT 46 and ent-46 as chiral auxiliaries to provide the desired stereochemistry of C8 and C9 of pamamycin 621A (Scheme 6.48)77 The “Evans” syn-aldol product 128 was obtained in 85% yield and 10:1 dr when employing 2 equiv of TiCl4 and 1.1 equiv of (2)-sparteine. The “non-Evans” syn-aldol product 129 was obtained when only 1 equiv of TiCl4 and an excess of (2)-sparteine were employed in improved yield and dr. The authors noted the use of TMEDA under otherwise identical conditions led to much lower yields and stereoselectivity. Aldol product 128 was silylated and reduced with DIBAL-H to the corresponding aldehyde.

Scheme 6.48 N-Propionyl oxazolidinethione aldol reactions. Pamamycin 621A.

A number of bioactive polyether natural products have been isolated from the marine dinoflagellate Karenia brevis, the organism responsible for toxic red tides along Florida’s Gulf coast. The most well-known compounds isolated from K. brevis are a family of neurotoxins called brevetoxins. Related to this, (2)-brevenal was isolated from K. brevis and has been shown to counteract the toxic effect of brevetoxins and possesses specific activity in the treatment of cystic fibrosis.77,78 During the construction or ring A in (2)-brevenal,79 stereochemistry was created using a propionate aldol addition with N-propionyl (4R)-BTT ent-57 and aldehyde 130 to deliver “Evans” syn-aldol product 131, in excellent yield and diastereoselectivity (Scheme 6.49).

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Imides

Scheme 6.49 N-Propionyl thiazolidinethione aldol reactions. Brevenal.

Sabitha et al. reported the preparation of a C5
C13 tetrahydropyran ring system in a formal synthesis of (2)-brevisamide,80,81 a marine cyclic ether alkaloid obtained from K. brevis which was isolated and characterized by Wright.82 The stereochemistry of C9 and C10 was created by the aldol reaction of N-propionyl (4S)-BTT 57 and aldehyde 132 (Scheme 6.50). The “non-Evans” syn-aldol product 133 was obtained utilizing 1.1 equiv of TiCl4 and 1 equiv of (2)-sparteine in 90% yield as a sole product.

Scheme 6.50 N-Propionyl thiazolidinethione aldol reactions. (2)-Brevisamide.

Alkaloids from indolizidine class are found in compounds as those segregated by Dendrobates frogs skin for self-defense.83 Allopumiliotoxins belong to the indolizidine class of alkaloids that are characterized by a highly substituted 5,6-fused azabicyclic core (indolizidine frame), an exocyclic olefin and hydroxylated side chains. The synthesis of the indolizidine frame in allopumiliotoxin was reported by Chandrasekhar using a highly diastereoselective asymmetric aldol reaction as one of the key transformations.84 In this reaction, the titanium enolate derived from N-propionyl (4S)-BTT 57 was added to α-iodo-α,β-unsaturated aldehyde 134 to give the “Evans” syn-aldol product 138 as the major diastereomer in 78% yield and 98:2 dr (Scheme 6.51). Interestingly, the aldol product 135 underwent an SNi reaction with thionyl chloride to give the β,γ-unsaturated imides 137 and 138 in a 7:1 ratio, respectively. The allyl chloride of imide 137 was displaced by a substituted pyrrole without affecting the chiral auxiliary.

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Scheme 6.51 N-Propionyl thiazolidinethione aldol reactions. Allopumiliotoxin.

Catunaregin is an unprecedented norneolignan isolated from the stem bark of Catunaregam spinosa Tirveng.85 It was found to inhibit breast cancer F10 cell lines. Abe et al. reported asymmetric synthesis for (1)- and (2)-catunaregin.86 The synthesis of the levo isomer employed the aldol reaction of N-acyl (4S)-BTT 139 and benzaldehyde 140 (Scheme 6.52) The aldol reaction employed 2 equiv of TiCl4 and 1.1 equiv of TMEDA to deliver the “non-Evans” syn-aldol product 141. The authors employed a similar chiral oxazolidinone that gave the “Evans” syn-aldol product for the synthesis of the dextro isomer.

Scheme 6.52 N-Acyl thiazolidinethione aldol reactions. Catunaregin.

A total synthesis of (2)-pironetin was reported by Crimmins and Dechert in eleven steps from known chiral aldehyde (2S)-methyl 4-hexenal.87 This natural product was isolated from the fermentation broth of Streptomyces prunicolor PA-48153 and Streptomyces sp. NK-10958.88 (2)-Pironetin consists of an α,β-unsaturated δ-lactone possessing a linear alkyl chain containing four contiguous stereocenters and a trans-olefin. The two stereocenters contained in the δ-lactone were constructed via aldol reaction of N-butanoyl (4S)-BTT 142 and chiral aldehyde 143 (Scheme 6.53). The “Evans” syn-aldol product 144 was obtained in 65% yield and .20:1 dr.

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Imides

Scheme 6.53 N-Acyl thiazolidinethione aldol reactions.

A highly diastereoselective direct anti-aldol reaction with chiral acyloxazolidinones (148) and N-propionyl (4S)-BTT 57 promoted by catalytic amounts of MgCl2 in the presence of triethyamine and chlorotrimethylsilane was reported by Evans (Scheme 6.54)89 Reaction of acyloxazolidinones provide a different diastereomer (146) than the one obtained from acylthiazolidinones (147). Magnesium salts were selected because of their prior use in carbonyl-based enolization with tertiary amines. A strategy for turning over the metal center while improving the prospects for kinetic aldol diastereoselection was the metal aldol silylation.

Scheme 6.54 Diastereoselective anti-aldol reaction.

The proposed catalytic cycle is shown in Scheme 6.55. Magnesium salt forms a complex with the N-acyl thiazolidinethione which reacts with trimethylamine yielding the magnesium enolate.90 The enolate adds reversibly to the aldehyde forming the magnesium aldolate which is trapped irreversibly with trimethylsilyl chloride. To test the reversibility of the carbon
carbon bond forming step, a diastereomerically pure aldol product from p-methoxybenzaldehyde reacted with p-tolualdehyde under standard reaction conditions. In the crossover experiment, the silylated aldol product from p-methoxybenzaldehyde was isolated as the principal product together with silylated aldol product from p-tolualdehyde.

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Scheme 6.55 Catalytic cycle for anti-aldol reaction.

The silylated anti-aldol product 151 was employed by Crimmins in a very elegant synthesis of the C29
C37 bicyclic ether core of (1)-sorangicin A (Scheme 6.56).91 Sorangicin A, a 31-membered lactone featuring a tetrasubstituted tetrahydropyran, a trisubstituted dihydropyran, a (Z,Z,E)trienoate, and the signature C29
C37 bicyclic ether moiety, is highly active against a spectrum of both Gram-positive (MIC 0.01
0.3 μg/mL) and Gram-negative bacteria (MIC 3
25 μg/mL).92 Synthesis of the C29
C37 fragment started from the thiazolidinethione 148 which was obtained in 83% yield (91:9 dr). Thiazolidinethione 148 was directly reduced to an aldehyde and subjected to Brown’s asymmetric allylation protocol to furnish diol 149 ( . 95:5 dr).

Scheme 6.56 N-Propionyl anti-aldol reaction. Sorangicin A.

The chiral IBTT has also been shown to be effective in the anti-aldol reaction. N-Propionyl IBTT 112 was reacted with cinnamaldehyde under reaction conditions reported by Evans (Scheme 6.57).93 Only the antialdol product 150 was observed as the product. This product 153 was able to undergo hydrolysis, esterification, and ammonolysis without the need to protect the alcohol.

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Imides

Scheme 6.57 N-Propionyl IBTT anti-aldol reaction.

This IBTT was also reacted with formaldehyde, in the form of trioxane, to obtain simple chiral aldehydes (Scheme 6.58).94 N-Butanoyl IBTT 151 was treated with TiCl4 and trimethylamine to form the Ti enolate which was reacted with trioxane and then more TiCl4 was added, following reaction conditions reported by Evans, to deliver syn-aldol product 152.95 Stereochemistry was confirmed by X-ray crystallographic analysis of aldol compound 152. The aldol product 152 was silylated and reduced with DIBAL-H to obtain the desired aldehyde 153, which was later employed in the synthesis of simplactones, natural products isolated from the Caribbean sponge Plakortis simplex.96

Scheme 6.58 N-Acyl anti-aldol reaction. Simplactones.

Stemoamide is a tricyclic alkaloid possessing a pyrrolizidinone and a γ-lactone fused to an azepine ring with four contiguous stereocenters. Our group designed a synthesis of the alkaloid (2)-stemoamide employing the MgBr2 catalyzed anti-aldol reaction of a thiazolidinethione and cinnamaldehyde (Scheme 6.59)97 We envisioned that we could control the stereochemistry of three stereocenters by employing a chiral thiazolidinethione. Attempts to condense thiazolidinethione 154 with acrolein were unsuccessful. However, aldol reaction of thiazolidinethione 154 and cinnamaldehyde gave the anti-aldol product 155 possessing three contiguous stereocenters as found in the natural product. Direct reduction of the silylated thiazolidinethione 156 to the corresponding aldehyde (DIBAL-H) did not work in this case. The thiazolidinethione was removed and transformed into an aldehyde in two steps (NaBH4 reduction/TPAP oxidation). A total

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Scheme 6.59 N-Acyl anti-aldol reaction. Stemoamide.

synthesis of (2)-stemoamide was achieved in 11 steps from 5-acetoxyN-crotyl pyrrolidinone. Asymmetric catalysis is definitely an elegant strategy to prepare enantiomerically pure compounds. For this reason, Evans developed a catalytic enantioselective aldol reaction of N-propionyl thiazolidinethiones (Scheme 6.60).98 Reaction of nonchiral N-propionyl thiazolidinethione 157 with both alkyl and aromatic aldehydes resulted in syn-aldol product 158 very good yields (80%) and excellent enantioselectivity ( . 92%ee) and syn:anti ratio ( . 90:10). In the proposed catalytic cycle, the nickel coordinates to both sulfur thiocarbonyl and oxygen carbonyl forming the catalyst-substrate complex which is deprotonated by the base to yield the Z-enolate. Aldehyde is then added and enolate reacts to give the aldolate which is then silylated. This last step facilitates decomplexation of the aldol product and the catalyst turnover.

Scheme 6.60 N-Propionyl thiazolidinethione catalytic syn-aldol reaction.

6.5 ACETATE ALDOL REACTIONS Evans’ chiral oxazolidinones work with outstanding control when the acyl group on the nitrogen is a propionyl, but interestingly, when the propionyl group is replaced with the simpler acetyl group, no diastereoselectivity is observed, this is known as “the acetate aldol problem.”

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Imides

Several “solutions” to the acetate aldol problem appeared in the literature. For example, Miller reported the aldol reaction of thiophenyl derivative 159 with n-butanal (Scheme 6.61).99 Methanolysis of the “Evans” synaldol product 160 followed by reductive desulfurization with (n-Bu)3SnH and hydrolysis provided the β-hydroxyacid 161 in high optical purity (99%ee).

Scheme 6.61 Solving the “acetate aldol” problem.

Nagao and Fujita investigated the use of Sn(OTf)2 for the highly diastereoselective acetate aldol reaction utilizing chiral thiazolidinethione auxiliaries (Scheme 6.62).100 Aldol reactions were carried out with the N-acetyl (4S)-IPTT 162 in the presence of Sn(OTf)2 and N-ethyl piperidine. In the proposed transition state, the tin atom coordinates to the aldehyde, the oxygen enolate, and the sulfur of the thiocarbonyl of the IPTT delivering the acetate syn-aldol product 166 with very good diastereoselectivity (97:3 dr). Adding more than 1 equiv of base decreased diastereoselectivity and promoted β-elimination in the aldol product. But a slight excess of the Sn(II) did not affect the diastereoselectivity strongly.

Scheme 6.62 Tin triflate-mediated N-acetyl thiazolidinethione aldol reaction.

Mycothiazole was isolated from the marine sponge Spongia mycofijiensis and from Dactylospongia.101 Shioiri prepared both enantiomers of mycothiazole to determine which one belonged to the natural compound, which turned out to be the (R)-isomer (Scheme 6.63).102,103 Aldehyde 164 smoothly underwent the aldol reaction with (4S)-IPTT 162, using stannous triflate and NEP to give syn-aldol adduct 165 with good diastereoselectivity ( . 10:1). Preparation of the aldol enantiomer

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Scheme 6.63 Tin triflate-mediated N-acetyl thiazolidinethione aldol reaction. Mycothiazole.

was performed with the more expensive thiazolidinethione (4R)-IPTT ent-162 using Urpí and Vilarrasa’s conditions. The aldol product ent-165 was obtained in slightly better yield and better diastereoselectivity ( . 95:5). Phorboxazoles A and B, isolated from the marine sponge Phorbas sp., display highly potent activity against several NCI’s 60 human cancer cell lines with a mean GI50 of 1.58 nM.104 Because of their powerful biological activity, scarcity, and architectural complexity, they have been important synthetic targets. Paterson reported an acetate aldol reaction between N-acetyl (4S)-IPTT 162 and iododienal 166 during the synthesis of C33
46 fragment (Scheme 6.64).105 The use of the tin(II) enolate of N-acetyl (4S)-IPTT 162 resulted in the virtually exclusive formation of the desired diastereomer 167. Instead, the use of titanium(IV) enolate, as recommended by Urpí, Vilarrasa et al. proved less diastereoselective (5.5:1, dr).108

Scheme 6.64 Tin triflate-mediated N-acetyl thiazolidinethione aldol reaction. Phorboxazoles A and B.

Following the seminal work of Nagao in the use of diastereoselective acetate aldol reactions with tin(II),102 Urpí and Vilarrasa showed the practical advantages of using titanium enolates of chiral acetyl thiazolidinethione during the synthesis of macrolactin A (Scheme 6.65).106 Macrolactin A is the parent aglycone of a family of 24-membered polyene

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Scheme 6.65 Titanium-mediated Macrolactin A.

N-acetyl

thiazolidinethione

aldol

reaction.

macrolides isolated from a deep sea bacterium by Fenical.107 Aldol reaction between N-acetyl (4S)-IPTT 162 and benzaldehyde gave the syn-aldol product 168a in 90% yield and 9:1 dr. Aldol reaction with conjugated aldehyde gave the syn-aldol product 168b in lower yield but higher diastereoselectivity. An acetate aldol reaction utilizing (4S)-IPTT 162 was investigated by Crimmins during a synthesis of (1)-laurencin.108 The desired syn-acetate aldol product 170a was obtained in 83% yield as a 3.3:1 diastereomeric mixture when the aldehyde 169a possessed a triisopropylsilyl (TIPS) ether on C11 (Scheme 6.66). Diastereomers 170a and 171a were easily separable by simple flash chromatography. Interestingly, when the protecting group on C11 was a benzyl ether the stereochemistry of the aldol reaction was inverted. The major diastereomer was the anti-aldol product 171b and the minor one was the syn-aldol 171b (1:2.5 dr). It appears that aldehyde 169a showed an unanticipated preference for the Felkin addition of nucleophiles. The reversal of selectivity may be because of chelation of the C11 benzyl ether and the aldehyde carbonyl to the metal center, thus altering the selectivity.

Scheme 6.66 Titanium-mediated (1)-Laurencin.

N-acetyl

thiazolidinethione

aldol

reaction.

We were interested in applying the reaction conditions developed by Crimmins for the propionate aldol reaction of N-acyl thiazolidinethiones where a closed-transition state delivers the “non-Evans” syn-aldol products, and also the open-transition state conditions which deliver the “Evans” syn-aldol product in the acetate aldol reaction.109 When the

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203

closed-transition state conditions were applied [1 equiv of TiCl4 and 1 equiv of (2)-sparteine], the syn-aldol product 172a
i was obtained in all cases (Scheme 6.67). However, when the open-transition state conditions were applied [1 equiv of TiCl4 and 2 equiv of (2)-sparteine], diastereoselectivities were lower for the anti-aldol product 173, and in the case of benzaldehydes, biphenylacetaldehyde and pivalaldehyde, the major diastereomer was still the syn-aldol product (172d, g, and f). However, when the TiCl4 was replaced by PhBCl2 then the major diastereomer was the desired anti-aldol product (173d
g).

Scheme 6.67 Diastereoselective titanium-mediated N-acetyl thiazolidinethione aldol reaction.

High yields and diastereoselectivities (93:7 to 98:2) were obtained for aliphatic, aromatic, and α,β-unsaturated aldehydes when the more sterically encumbered auxiliaries were employed by Crimmins.11 When N-acetyl oxazolidinethione 174 carrying a mesityl group was treated with 2 equiv of TiCl4 and 2 equiv of i-Pr2Net and the corresponding aldehydes, the syn-aldol products 176a
f were obtained in high yields and

Scheme 6.68 Titanium-mediated N-acetyl oxazolidinethione and thiazolidinethione aldol reaction.

204

Imides

diastereoselectivities (Scheme 6.68). Similarly, when the N-acetyl thiazolidinethione 175 was treated with now 1 equiv of TiCl4 and 1 equiv of base and the corresponding aldehydes, the syn-aldol products 177a
f were obtained also in high yields and diastereoselectivities. Acetate aldol reactions were also carried with nonracemic aldehydes and excellent results were obtained. The chiral IBTT 178-IBTT auxiliary was designed to be a sterically bulky auxiliary, practically, and economically produced.16 N-Acetyl thiazolidinethione 178 was reacted with cinnamaldehyde employing 1 equiv of both TiCl4 and (2)-sparteine to furnish the syn-aldol product 179 (Scheme 6.69). This and other aldol products were all obtained in .90% yield and .93:7 dr.

Scheme 6.69 Titanium-mediated N-acetyl indene-based thiazolidinethione aldol reaction.

The N-acetyl IBTT 178 was also employed for the synthesis of aurisides.110 Aurisides A and B are two glycosylated macrolactones isolated from the sea hare Dolabella auricularia. We designed a synthesis of the polyketide aglycone employing two acetate aldol reactions with the IBTT. The first syn-aldol product was elaborated to construct the C1
C9 fragment

Scheme 6.70 Titanium-mediated Aurisides.

N-acetyl

thiazolidinethione

aldol

reaction.

Chiral Sulfur-Containing Imide Auxiliaries in Medicinal Chemistry

205

184 (Scheme 6.70). The titanium enolate of N-acetyl thiazolidinethione 178 was reacted with a hindered aldehyde to deliver the syn-aldol product 180. The thiazolidinethione was displaced with potassium-ethyl malonate to give β-ketoester 181 which was elaborated to the northern fragment of auriside aglycone 184. The same N-acetyl IBTT 178 was employed for the construction of the C10
C17 southern fragment of aurisides (Scheme 6.71). Titanium enolate of N-acetyl IBTT 178 was reacted with bromodienal to furnish syn-aldol product 185, which was elaborated in three steps to the desired alkyne fragment 186. Coupling of fragments 186 and 184 gave an ynone which was transformed into the auriside aglycone.

Scheme 6.71 Titanium-mediated Aurisides.

N-acetyl

thiazolidinethione

aldol

reaction.

N-Acetyl IBTT 178 was also employed to study the double diastereoselectivity of acetate aldol reactions.96 The aldol reaction was carried out with chiral aldehyde 187 and also with its enantiomer ent-187 (Scheme 6.72). We observed very good yields and high diastereoselectivity in aldol products 188 and 190 with both aldehyde enantiomers. The syn-aldol products 188 and 190 were treated with acid to obtain (3R,4S)simplactone 189 and (3R,4R)-simplactone 191, respectively.

Scheme 6.72 Double diastereoselectivity of titanium-mediated N-acetyl thiazolidinethione aldol reaction.

206

Imides

An acetate aldol reaction was employed successfully for the synthesis of the C1
C12 fragment of N-acetylcysteamine thioester of secoproansamitocin.111 The N-acetyl (4R)-IPTT ent-162 was treated with 1 equiv of TiCl4 and 1 equiv of diisopropylethylamine to generate the titanium enolate, which was reacted with unsaturated aldehyde 192 to furnish the syn-aldol product 193 in 77% yield and excellent diastereoselectivity (Scheme 6.73). Slightly higher yield (83%) was achieved when the reaction was carried out with Sn(II)triflate as the Lewis acid and NEP as the base. The authors preferred the method with the Ti(IV) because is less costly and less sensitive than the Sn(II) metal.

Scheme 6.73 Titanium-mediated N-acetyl thiazolidinethione aldol reaction. Secoproansamitocin.

Crimmins’ total synthesis of SCH-351448 employed an aldol reaction utilizing Phillips’ N-acetyl oxazolidinethione 194.10,61 N-Acetyl oxazolidinethione 194 was reacted with the complex and sensitive chiral aldehyde 195 (Scheme 6.74). The syn-aldol product was obtained and immediately protected as the methoxymethyl (MOM) ether in 84% yield for two steps and 10:1 dr. Oxazolidinethione 196 was transformed into an aldehyde in two steps (reduction/oxidation) and used in another aldol reaction with a complex N-alkyl oxazolidinethione, previously discussed.

Scheme 6.74 Titanium-mediated N-acetyl oxazolidinethione aldol reaction. SCH351448.

Luminacin D isolated from a fermentation broth of a soil bacterium showed promising angiogenesis inhibition (,0.1 μg/mL).112 This natural product contains a highly functionalized aromatic ring which is connected

Chiral Sulfur-Containing Imide Auxiliaries in Medicinal Chemistry

Scheme 6.75 Titanium-mediated Luminacin D.

N-acetyl

thiazolidinethione

aldol

207

reaction.

to a carbohydrate-like subunit. Luminacin D was synthesized by Maier utilizing two aldol reactions to form the carbohydrate section (Scheme 6.75).113 N-Acetyl (4S)-IPTT 162 was treated with 1.1 equiv of TiCl4 and diisopropylethylamine to form the enolate that was reacted with unsaturated aldehyde 197 to furnish syn-aldol product 198 in good yield. Aldol product 198 was transformed into the corresponding aldehyde in two steps (NaBH4 reduction/Swern oxidation) and utilized in an Evans’ oxazolidinone aldol reaction. The acetate aldol reaction of N-acetyl (4S)-IPTT 162 was carried out with acetaldehyde to obtain the syn-aldol product 199 which was employed in the synthesis of (2R,5S)-2-methyl-hexanolide (200), the sex pheromone of carpenter bee Xylocopa hirsutissima (Scheme 6.76).114 The synthesis of the pheromone was completed after five more steps.

Scheme 6.76 Titanium-mediated N-acetyl thiazolidinethione aldol reaction. (2R,5S)-2Methyl-hexanolide.

Yadav employed two consecutive acetate aldol reactions to install the two stereocenters found in the dihydropyranone (1)-dodoneine, isolated from Tapinanthus dodoneifolius, used as a remedy to treat cardiovascular and respiratory diseases.115 Reaction of the titanium enolate of N-acetyl (4S)BTT 201 with arylpropionaldehyde 202 gave the syn-aldol product 203, which was silylated and reduced to aldehyde 204 (Scheme 6.77). Again, titanium enolate of N-acetyl (4S)-BTT 201 with chiral arylaldehyde 204 gave syn-aldol product 205 which was elaborated into the target molecule in four more steps.

208

Imides

Scheme 6.77 Titanium-mediated (1)-Dodoneide.

N-acetyl

thiazolidinethione

aldol

reaction.

Guz
Phillips N-acetyl oxazolidinethione 195 was very effective in acetate aldol reactions (Scheme 6.78).10 The reaction of N-acetyl oxazolidinethione 195 with a variety of saturated and unsaturated aldehydes provided the syn-aldol products 206 in good yields (56%
90%) with excellent diastereoselectivities (92:8 to 99:1 dr). Guz and Phillips claimed that the oxazolidinethione derived from valine without the 5,5-diphenyl substituents reacts with minimal selectivity (dr values of 1.2
2.5:1), which suggests that diastereoselection can be affected by altering the population of rotamers around the auxiliary-enolate by decreasing the interactions between the ligands on titanium and the substituents on the auxiliary.

Scheme 6.78 Titanium-mediated Guz
Phillips auxiliary.

N-acetyl

oxazolidinethione

aldol

reaction.

An acetate aldol reaction was employed to set the stereochemistry of C13 in a valuable fragment for the synthesis of the side chain of the 14-membered macrolactones aurisides and callipeltosides.116 These natural products are halogenated and glycosylated macrolides isolated from the sea hare D. auricularia and the marine sponge Callipelta sp., respectively.117 Reaction of 1 equiv of titanium tetrachloride with N-acetyl (4S)-IPTT 162 and 1.2 equiv of Hunig’s base generated the titanium enolate that reacted with vinylbromo unsaturated aldehyde 207 giving only the syn-aldol product 208 in 75% yield (Scheme 6.79). Aldol product 208 was silylated and the thiazolidinethione group displaced with methyl (bis-methoxy)phosphonate and butyl lithium to furnish ketophosphonate 209.118

Chiral Sulfur-Containing Imide Auxiliaries in Medicinal Chemistry

209

Scheme 6.79 Titanium-mediated N-acetyl thiazolidinethione aldol reaction. Aurisides and callipeltosides.

Marensins belong to a family of dihydroxy containing products derived from polyunsaturated fatty acids.119 Maresin 1 is a potent antiinflammatory and proresolving lipid mediator derived from docosahexaenoic acid. Hansen investigated the acetate aldol reaction between N-acetyl thiazolidinethiones with different substituents on C4 and bromopentadienal 207 (Scheme 6.80).120 The best diastereomeric ratio was observed with N-acetyl (4S)-IPTT 162 utilizing TiCl4 and (2)-sparteine to generate the titanium enolate. The aldol product 209 was transformed into an aldehyde after silylation and utilized for the total synthesis of marensin 1.

Entry

R

1 2 3 4 5 6 7 8 9

Me i-Pr t-Bu t-Bu Ph Bn i-Pr i-Pr i-Pr

Lewis acid TiCl4 TiCl4 TiCl4 TiCl4 TiCl4 TiCl4 TiCl4 PhBCl2 Sn(OTf)2

Base i-Pr2NEt i-Pr2NEt i-Pr2NEt i-Pr2NEt i-Pr2NEt i-Pr2NEt (–)-sparteine (–)-sparteine 1-N-ethylpiperidine

dr (R:S) 7.9:1 15.3:1 2.8:1 7.0:1 4.5:1 9.8:1 1.8:1 3.2:1 10.6:1

Yield (%) 88 86 78 65 54 79 48 43 67

Scheme 6.80 Titanium-mediated N-acetyl thiazolidinethione aldol reaction. Maresin 1.

(1)-Rogioloxepane A is a nine-membered ring ether possessing two halogens and an acetylene-ene side chain.121 It is a representative member of the Laurencia-derived C15 acetogenins containing an α,α0 -trans-disubstituted oxepene ring. Crimmins reported an enantioselective total synthesis of (1)-rogioloxepane A in which his group employed successfully an acetate aldol reaction to create the C-6 stereochemistry.122 Although the aldol reaction was not satisfactory with N-acetyl thiazolidinethiones, the use of

210

Imides

Scheme 6.81 Titanium-mediated (1)-Rogioloxepane A.

N-acetyl

thiazolidinethione

aldol

reaction.

Phillips protocol led to improved yields and significantly improved diastereoselectivity (5:1) (Scheme 6.81). The diastereomeric mixture was silylated and reduced before the primary alcohols were readily separated by flash chromatography. (1)-Leucascandrolide A, isolated from the calcareus sponge Leucascandra caveolata,123 is an 18-membered macrocyclic lactone, was prepared in 20 linear steps from 1,3-propanediol by Crimmins.124 An acetate aldol reaction was employed to create alcohol C17 fragment (Scheme 6.82). Addition of the titanium enolate of acetyl thiazolidinethione 212 to α,β-unsaturated aldehyde 213 gave syn-aldol product 214 in high yield as a 93:7 mixture of diastereomers. The diastereomeric aldol adducts were readily separated by flash column chromatography and the diastereomer 214 was obtained in 67% purified yield.

Scheme 6.82 Titanium-mediated (1)-Leucascandrolide A.

N-acetyl

thiazolidinethione

aldol

reaction.

Spiruchostatin A is a potent histone deacetylase inhibitor isolated from a Pseudomonas extract. A total synthesis of spiruchostatin A was reported by Ganesan where his group employed an acetate aldol reaction to create the β-hydroxy lactone as found in the natural product.125 Reaction of aldehyde 218 with N-acetyl (4R)-IPTT ent-162 under Vilarrasa’s TiCl4 conditions was highly diastereoselective yielding the readily separable aldol product 216 and it diastereomer in 84% and 9.5:1 dr (Scheme 6.83). The same aldol product 216 was utilized by the same group in a total synthesis of FK228, a depsipeptide histone deacetylase inhibitor.126 A similar aldol reaction was reported during the synthesis of largazole, where the protecting group in the aldehyde was a silyl ether. Aldol product 218 was obtained in 83% yield and 14:1 dr.127

Chiral Sulfur-Containing Imide Auxiliaries in Medicinal Chemistry

Scheme 6.83 Titanium-mediated N-acetyl Spiruchostatin A, FK228 and Largazole.

thiazolidinethione

aldol

211

reaction.

Pateamine A (PatA), a marine metabolite from Mycale sp., is a potent inhibitor of the intracellular signal transduction pathway emanating from the T-cell receptor leading to the transcription of cytokines such as interleukin2.128 PatA possesses a thiazole, a dienoate, and a triene side chain. Romo described a total synthesis of PatA and simpler analogs employing an acetate aldol reaction to create C13 alcohol stereoselectively (Scheme 6.84).129 Romo et al. employed Vilarrasa’s conditions to obtain the aldol product 220 in 80% yield. The aldol reaction was readily performed on multigram scale to give the β-hydroxyimide 220, which was converted to the thioamide 221.

Scheme 6.84 Titanium-mediated Pateamine A.

N-acetyl

thiazolidinethione

aldol

reaction.

A highly diastereoselective acetate aldol reaction that utilizes tert-leucine-derived thiazolidinethione auxiliary and dichlorophenylborane was developed by Phillips and Sammakia.11 The boron enolate of N-acetyl (4S)-TBTT 222 is formed by addition of 1.3 equiv of dichlorophenylborane and 2.6 equiv of (2)-sparteine (Scheme 6.85). It is proposed that the addition undergoes an open-transition where the boron enolate coordinates with the aldehyde, but not with the sulfur of the auxiliary. Reaction with hydrocinnamaldehyde gave the anti-aldol product 223 in good yield and excellent diastereoselectivity.

Scheme 6.85 Titanium-mediated Phillips
Sammakia auxiliary.

N-acetyl

thiazolidinethione

aldol

reaction.

212

Imides

A “pseudoenantiomer” to the L-tert-leucine-derived reagent developed by Phillips and Sammakia was also developed by Sammakia and his group.13 Oxazolidinethione 224 is considered a “pseudoenantiomer” of (4S)-tertbutyl leucine, because it possesses the (4R)-stereochemistry, but it does not bear exactly a tert-butyl substituent. This new N-acetyl thiazolidinethione reagent 224 undergoes highly diastereoselective aldol reactions upon enolization with dichlorophenylborane and (2)-sparteine and subsequent treatment with a variety of aldehydes (Scheme 6.86). The (4S)-TLTT 222 and the (4R)-oxazolidinethione 224 reagents complement each other and deliver anti-aldol products with exquisitely high diastereoselectivity.

Scheme 6.86 Titanium-mediated Sammakia’s auxiliary.

N-acetyl

oxazolidinethione

aldol

reaction.

The first synthesis of (1)-Kavain, a psychoactive component of the Kava plant, was reported by Smith.130 Although better diastereoselectivities were found in an acetate aldol reaction when using Sn as the metal, the titanium counterpart provided useful yields of purified major diastereomers with less expense and operational complexity (Scheme 6.87). The (4S)-IPTT auxiliaries were successfully displaced by a carbon nucleophile without the need for protection of the free hydroxyl. Treatment of aldol adducts 226a
b with the potassium salt of monoethyl malonate and MgCl2 in the presence of imidazole led to β-ketoesters 227a
b.

Scheme 6.87 Titanium-mediated (1)-Kavain.

N-acetyl

thiazolidinethione

aldol

reaction.

Chiral Sulfur-Containing Imide Auxiliaries in Medicinal Chemistry

213

FR252921 is a novel immunosuppressive agent isolated from the cultured broth of P. fluorescens no. 408813. It was envisioned that the three stereocenters in this molecule could be elaborated via asymmetric aldol condensations by Ma.64 The first aldol was the preparation of dienol 229. N-Acetyl (4S)-BTT 201 was treated with 1 equiv of TiCl4 and diisopropylethylamine to form the enolate which was reacted with dodecanal 228 to furnish syn-aldol 229 in 68% yield and 95:5 dr (Scheme 6.88). The Fmoc-protecting group of an amine was liberated and reacted with aldol product 229 to displace the thiazolidinethione and deliver an amide.

Scheme 6.88 Titanium-mediated N-acetyl thiazolidinethione aldol reaction. FR252921.

(2)-Pladienolide is a 12-membered macrolactone isolated from the fermentation broth of Streptomyces platensis Mer-11107.131 This macrolactone inhibits hypoxia-induced vascular endothelial growth factor expression and proliferation of human cancer cell lines with low to nanomolar IC50 values. Skaanderup proposed the possible absolute stereochemistry of this natural product based on two other metabolites of the Streptomyces family.132 Skaanderup and Jensen synthesized the proposed structure utilizing an acetate aldol reaction and an osmium-catalyzed asymmetric dihydroxylation to install the three oxygenated stereocenters of the molecule. N-Acetyl (4S)-BTT 201 was reacted with 1 equiv of TiCl4 and diisopropylethylamine to generate the titanium enolate that reacted with aldehyde 230 to furnish the syn-aldol product 231 in 89% yield and 4:1 dr, (Scheme 6.89). The aldol product was transformed eventually into the desired macrolactone.

Scheme 6.89 Titanium-mediated (2)-Pladienolide.

N-acetyl

thiazolidinethione

aldol

reaction.

Herbarumin III is a phytotoxic nonelodide and 10-membered lactone isolated from the fungus Phoma herbarum when investigating for better potent herbicides.133 Yadav reported a total synthesis of herbarumin III

214

Imides

starting from butyraldehyde.134 Yadav prepared the N-acetyl (4S)-BTT auxiliary 201 and reacted it with butyraldehyde (Scheme 6.90). This time he used 2 equiv of base and obtained the anti-aldol product 232 in a 9:1 dr. This aldol product was employed for the synthesis of herbarumin III.

Scheme 6.90 Titanium-mediated Herbarium III.

N-acetyl

thiazolidinethione

aldol

reaction.

An acetate aldol reaction was required in the total synthesis of (2)-pironetin by Crimmins.89 Together with an acetal aldol reaction, the acetate aldol provided an intermediate with the four contiguous stereocenters as found in the side chain of the δ-lactone. Utilizing Crimmins N-acetyl (4S)-MTT 175 and chiral aldehyde 233 delivered the syn-aldol product 234 in 88% yield and 95:5 dr (Scheme 6.91). This aldol product was then silylated and reduced to an aldehyde which was employed in a Horner
Emmons reaction to access the α,β-unsaturated ester which was finally cyclized to the δ-lactone.

Scheme 6.91 Titanium-mediated (2)-Pironetin.

N-acetyl

thiazolidinethione

aldol

reaction.

Latrunculin B is a potent actin polymerization inhibitor which has called the attention of the synthetic community.135 Interestingly, this 14membered macrocyclic lactone possesses three olefins with different geometry, a tetrahydropyran ring system with a pending thiazolidinone heterocycle. Watson examined an olefin
olefin ring closing metathesis to prepare latrunculin B.136 The authors employed an acetate aldol reaction to install the sterocenter C11 of latrunculin (Scheme 6.92). N-Acetyl (4R)-BTT ent-201 was treated with TiCl4 and diisopropylethylamine to generate the Ti enolate which was reacted with chiral aldehyde 235 to deliver syn-aldol product 236 in 76% yield and 7:1 dr.

Chiral Sulfur-Containing Imide Auxiliaries in Medicinal Chemistry

Scheme 6.92 Titanium-mediated Latrunculin B.

N-acetyl

thiazolidinethione

aldol

215

reaction.

Crimmins reported several examples in the use of Ti acetate aldol reaction during the synthesis of spirofungins A and B.137 Due the required anti-substitution in C12
C11 this chain could not be accessed from thiazolidinethione-mediated propionate aldol reaction. Instead, this antidistribution was obtained via a diastereoselective TiCl4 (1.1 equiv)-mediated acetate aldol reaction between N-acetyl (4S)-MesTT 175 (1.1 equiv) and 3-butenal (1.0 equiv) to give the desired aldol adduct 237 in 81% yield and .20:1 diastereomeric ratio (Scheme 6.93).

Scheme 6.93 Titanium-mediated Spirofungins A and B.

N-acetyl

thiazolidinethione

aldol

reaction.

In Yadavs group, the titanium acetate aldol reaction has also been an important tool in the construction of chiral fragments for total synthesis of natural products. An important element in the synthetic strategy of the secondary metabolite (1)-polyrhacitide A is the utility of asymmetric aldol reaction to establish the initial asymmetry.138 The reaction between N-acetyl (4R)-BTT ent-201 and n-octanal in the presence of TiCl4 and DIPEA was used to install the stereochemistry in syn-aldol product 238 for the further construction of the side chain in (1)-polyrhacitide A (239) (Scheme 6.94). The aldol product 238 was isolated in 52% yield, together

Scheme 6.94 Titanium-mediated (1)-Polyrhacitide A.

N-acetyl

thiazolidinethione

aldol

reaction.

216

Imides

with the anti-aldol diastereomer (12%), N-acetoacetyl (4R)-BTT (15%), resulting from self-acylation of the N-acetyl auxiliary, and also N-H BTT (15%).139 In related works, Yadav’s group reported the use of same acetate aldol reaction in total synthesis of gingerol140 and α-pyrones.141 Umuravumbolide is a 5,6-dihydro-α-pyrone-containing natural product isolated from Tetradenia riparia.142 Venkateswarlu reported the synthesis of this lactone starting from valeraldehyde.143 A chiral aldehyde 240 was prepared in five steps from valeraldehyde utilizing a highly enantioselective zinc-mediated addition of a THP-protected propargyl alcohol. Aldehyde 240 was reacted with the titanium enolate of N-acetyl (4S)-BTT 201 to deliver the syn-aldol product 241 in 77% yield and 8.5:1.5 dr (Scheme 6.95). Diastereomeric syn- and anti-aldol products were easily separable.

Scheme 6.95 Titanium-mediated (2)-Umuravumbolide.

N-acetyl

thiazolidinethione

aldol

reaction.

Aculeatins A
D possessing epimeric spiroketal structures were isolated from the rhizomes of the plant, Amomum aculeatum RoxB. Simple and stereoselective syntheses of aculeatins were reported by Maram and Das.144 The synthesis is based on the acetate aldol reaction of N-acetyl (4R)-BTT ent-201 (Scheme 6.96). These spiroketals were prepared by an oxidative spirocyclization using iodine bis(trifluoroacetate) (PIFA) of a chiral β,δ-dihydroxyketone, which was prepared by two acetate aldol reactions, followed by Weinreb amidation, silyl protection, and Grignard addition. An initial acetate aldol reaction with tetradecanal provided the

Scheme 6.96 Titanium-mediated Aculeatins A, B, and D.

N-acetyl

thiazolidinethione

aldol

reaction.

Chiral Sulfur-Containing Imide Auxiliaries in Medicinal Chemistry

217

syn-aldol product 242. The syn-aldol product 242 was silylated and reduced directly to the corresponding aldehyde 243, which underwent a second acetate aldol reaction to furnish syn-aldol product 244. Other diastereomers were prepared by utilizing N-acetyl (4S)-BTT auxiliary. (1)-Goniothalesacetate, (1)-altholactone, (1)-gonioheptolide A, and (2)-goniofupyrone are representatives of the styryl lactones family.145 These four natural products possess a common tetrahydrofuran ring possessing four stereogenic centers. Sabitha employed an acetate aldol reaction to install a stereogenic carbon outside the tetrahydrofuran ring (Scheme 6.97).146 The syn-aldol product 246, obtained in 60% yield and 97:3 dr, was then treated with methanol and imidazole to displace the auxiliary and obtain the corresponding methyl β-hydroxyester, which was later deprotected to the natural product (1)-goniothalesacetate.

Scheme 6.97 Titanium-mediated N-acetyl thiazolidinethione aldol reaction. Styryl lactone family.

Largazole is a depsipeptide natural product isolated from the marine cyanobacterium of the genus Symploca.147 It has attracted a lot of attention because of its potent biochemical activity as a Class 1 Histone Deacetylase Inhibitor and consequent anticancer properties. Williams employed an acetate aldol reaction to install the stereochemistry of the octanoyl thioester side chain.148 The titanium enolate of N-acetyl (4R)-BTT ent-201 was reacted with α,β-unsaturated aldehyde 215 to give the syn-aldol product 247 in 76% yield (Scheme 6.98). The asymmetric aldol transformation occurred in very high diastereomeric purity. The aldol product 247 was submitted to cleavage of the chiral auxiliary using 2-(trimethylsilyl)ethanol in the presence of imidazole to obtain the corresponding ester.

Scheme 6.98 Titanium-mediated N-acetyl thiazolidinethione aldol reaction. Pyridylbased analog of largazole.

218

Imides

Peloruside A is a 16-membered lactone that was first isolated from the marine sponge Mycale. It displays potent antitumor activity against murine leukemia cells with an IC50 value of 10 ng/mL.149 Urpí and Romea prepared the C9
C19 fragment of peloruside A employing additions of titanium enolates of chiral thiazolidinethione auxiliaries.150 First, the addition of titanium enolate of N-acetyl (4R)-IPTT ent-162 to α,β-unsaturated aldehyde 248 gave the syn-aldol product 249 in 74% yield (Scheme 6.99). This aldol product was silylated, reduced, and converted into a dimethyl acetal to be used in a dialkyl acetal aldol reaction with the same N-acetyl chiral auxiliary ent-162.

Scheme 6.99 Titanium-mediated Peloruside A.

N-acetyl

thiazolidinethione

aldol

reaction.

Cryptomoscatone lactones isolated from Cryptocarya species have been shown to exhibit several biological activities such as antiinflammatory, antiproliferative activity, and inhibition of the growth of breast cancer cell.151 Among these lactones, cryptomoscatone F1 has been synthesized using two iterative TiCl4-mediated acetate aldol reactions to control 1,3syn diol stereochemistry into the side chain.152 The titanium enolate of N-acetyl (4S)-BTT 201 was reacted with trans-cinnamaldehyde to deliver the chromatographically separable syn-aldol product 250, obtained in 84% yield and 9:1 dr (Scheme 6.100). Silylation of aldol product 250 and reductive cleavage of chiral auxiliary delivered aldehyde 251. A second

Scheme 6.100 Titanium-mediated Cryptomoscatone F1.

N-acetyl

thiazolidinethione

aldol

reaction.

Chiral Sulfur-Containing Imide Auxiliaries in Medicinal Chemistry

219

acetate aldol reaction with the same thioimide 201 yielded the syn-aldol product 252 in more than 78% yield and 9:1 dr. Cryptomoscatone F1 was prepared from aldol product 252 after nine more steps. Disorazoles are macrolactones with extremely potent cytotoxic activ153 ity. Nicolaou described the first total synthesis of naturally occurring antitumor agents disorazoles A1 and B1.154 An acetate aldol reaction was employed to prepare an intermediate useful for the preparation of two different synthetic fragments (a vinyl boronic acid and an iodide with similar framework). Titanium enolate of N-acetyl (4R)-IPTT 162 reacted with chiral aldehyde 253 to deliver the syn-aldol product 254 in 89% yield and 12:1 dr (Scheme 6.101). The aldol product 254 was reduced to the corresponding alcohol using 5 equiv of DIBAL-H or to the corresponding aldehyde when 2.5 equiv of DIBAL-H was used.

A

Scheme 6.101 Titanium-mediated Disorazoles A1 and B1.

N-acetyl

thiazolidinethione

aldol

reaction.

Dihydropyrones are significant structural subunits in many biologically potent natural products. Two dihydropyrone rings are fused to a styryl skeletal in obolactone isolated from the fruits and the trunk bark of Cryptocarya obovate by Guéritte.155 Obolactone shows significant activity in vitro cytotoxic assays against KB cell line (EC50 5 3 μM). Kumar and Meshram reported that stereocontrolled total synthesis of obolactone from trans-cinnamaldehyde having as one of the key steps an acetate aldol reaction.156 The titanium enolate of N-acetyl BTT 201 reacted with chiral aldehyde 255 to deliver the syn-aldol product 256 in 78% yield and 9:1 dr (Scheme 6.102). This aldol product 256 reacted with methyl potassium

A

Scheme 6.102 Titanium-mediated Obolactone.

N-acetyl

thiazolidinethione

aldol

reaction.

220

Imides

malonate to deliver the corresponding β-ketoester without the need to protect the alcohol. Lagunamide C is a depsipeptide natural product with low nM cytotoxicity toward numerous lymphoma cancer cell lines.157 Particularly, lagunamide C presents cytotoxicity toward lung cancer, prostate cancer, ileocecal colorectal adenocarcinoma, and ovarian cancer, with IC50 values of 2.4, 2.6, 2.1, and 4.5 nM, respectively.158 Synthetically, lagunamide C was disconnected to a pentapeptide backbone and polyketide unit that possesses four stereocenters where two of them (C38 and C40) were in question. A synthetic study employs a highly selective aldol addition setting the C40 ester linkage by Rafferty et al. 159 These authors studied the aldol reaction of N-acetyl (4S)-IPTT 162 and butanal, screening different weak and strong bases and varying their amounts (Scheme 6.103). They found that the anti-aldol product 257 could be obtained in 79% yield and 20:1 dr when using 1 equiv of TiCl4 and equal molar ratio of lithium diisopropylamide and NMP. Further reactions gave the polyketide precursors alkenes 258a and 258b in 71% combined yield where stereochemistry in C38 and C40 has been defined.

Scheme 6.103 Titanium-mediated Lagunamide C.

N-acetyl

thiazolidinethione

aldol

reaction.

Two complementary chiral auxiliaries useful for the acetate aldol reaction were investigated by Zhang and Sammakia employing chiral aldehydes.160 The double diastereoselection between chiral N-acetyl (4S)-TT auxiliaries 222 and 224 were studied with several chiral aldehydes (a
e) (Scheme 6.104). In matched cases, useful increases in selectivities were observed, whereas mismatched cases caused small erosion in selectivity. In all cases, preferred selectivity was controlled by the chiral auxiliary. They found that the extent of double diastereoselection varies according to the position and nature of the stereocenter in the aldehyde. Aldehydes with an alkyl group at the α-carbon showed the greatest double diastereoselection and difference in selectivity of the matched and the mismatched reaction pairs.

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Scheme 6.104 Titanium-mediated N-acetyl thiazolidinethione aldol reaction. Double diastereoselection.

6.6 ALDOL ADDITION OF N-GLYCOLATES Crimmins demonstrated that α-alkoxy acyloxazolidinethiones also function well to give the “Evans” syn-aldol product.161 This reaction also works well with the corresponding oxazolidinones. Enolization of acyloxazolidinethione 262a with 1 equiv of TiCl4 and 2.5 equiv of (2)-sparteine at 278°C, followed by addition of 3-butenal solution, produced the synaldol adduct 262a with excellent diasteroselectivity ( . 98:2 ds, 90% yield at 30% conversion) (Scheme 6.105). At the same time, the corresponding acyloxazolidinone 262b could be enolized with the same Lewis acid and Hunig’s base followed by aldol reaction with 3-butenal to give 65% yield of the syn-aldol product 262b after purification. The chiral auxiliary of the aldol product was reductive cleaved by LiBH4 to the corresponding alcohol

Scheme 6.105 α-Alkoxy acyloxazolidinethiones and acyloxazolidinones. syn-Aldol product. (1)-Laurencin.

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Imides

and ring closing metathesis was followed to form an eight membered ring as found in (1)-laurencin. Laurencin is a representative marine natural product oxocene isolated from the red algae Laurencia sp.162 Interestingly, Crimmins and McDougall also developed a highly diastereoselective anti-aldol addition utilizing a variety of N-glycolyloxazolidinethiones.163 Enolization of an N-glycolyl OxT with TiCl4 and (2)-sparteine followed by addition of an aldehyde activated with additional TiCl4 resulted in highly anti-selective aldol additions (Scheme 6.106). The degree of anti-selection was highly dependent on the amount of TiCl4 used to activate the aldehyde. Saturated aldehydes gave higher selectivities using .2 equiv of TiCl4 to each equivalent of aldehyde, while α,β-unsaturated aldehydes required .3 equiv of TiCl4 for optimum results. Allyl-protected glycolyl OxT 263 demonstrated the highest levels of selection and yields, although O-benzyl and O-methyl glycolyloxazolidinethiones also performed well.

Scheme 6.106 Allyl N-glycolate anti-aldol reaction.

Amphidinoles, isolated from Amphidinium klebsi are mainly characterized, unlike polycyclic ethers isolated from other dinoflagellates, by two long carbon chains, one of them with multiple olefin groups and the other one polyhydroxylated. Among these compounds, amphidinol 3 showed the most potent antifungal and hemolytic activity.164 Because of its biological activity and challenging structure, amphidinol 3 has been targeted by several research groups, despite a total synthesis has not been accomplished today. The bis-tetrahydropyrane core present in amphidinol 3 was established as initial target for a total synthesis of this natural product.165 The stereochemistry in C43 and C44 was established using a glycolate anti-aldol reaction between aldehyde 265 and benzyl N-glycolyl OxT 266 to obtain the anti-aldol adduct 267 in 44% yield (10:1 dr) of separable diastereomers (Scheme 6.107). The anti-aldol product 267 was silylated and the oxazolidinethione auxiliary directly displaced with lithiated dimethyl methylphosphonate to deliver the β-ketophosphonate 268 in 81% for these two steps.

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Scheme 6.107 Benzyl N-glycolate anti-aldol reaction. Amphidinol 3.

Ircinastatin A (Psymberin) is a remarkably potent and selective cancer cell growth inhibitor isolated from the extracts of deep water sponges.166,167 Crimmins reported a total synthesis of ircinastatin A where psymberic acid, the side chain of ircinastatin A was prepared utilizing an N-glycolate anti-aldol reaction168 with the N-allyloxyglycolyl (4R)-BTT ent-263 and 3-methyl-but3-enal (Scheme 6.108).169 As noted above, an excess of TiCl4 provided a high anti-selectivity in the anti-aldol product 269 (64% yield, 87:2:11 dr). Psymberic acid chloride was prepared from adduct 269 in eight more steps.

Scheme 6.108 Allyl N-glycolate anti-aldol reaction. Ircinastatin A

Brevetoxin A is a structurally and biologically fascinating molecule of the ladder toxin natural products.170 The structure of brevetoxin possesses 10 rings (including 5-, 6-, 7-, 8-, and 9-membered oxacycles) fused in a linear array containing 22 stereogenic centers. Crimmins reported an enantioselective synthesis of brevetoxin A which is highly convergent.171 The anti-aldol product 269 was employed in the stereocontrolled synthesis of ring B of brevetoxin A (Scheme 6.108).

6.7 TITANIUM ENOLATE ADDITION TO DIALKYL ACETALS Romea and Urpí devised a direct method for the preparation of α-alkyl-β-alkoxycarbonyl compounds by addition of titanium enolates

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Imides

of chiral thiazolidinethiones to dimethyl acetals (Scheme 6.109).172 This method appeared attractive because alkylation of β-hydroxy carbonyl compounds might lead to β-elimination and this sequence could be reduced to one step. Urpí and his group developed an efficient methodology to gain access to the anti-α-methyl-β-alkoxy carbonyl structures. The titanium enolate of N-propionyl (4S)-IPTT 33 was added to benzaldehyde dimethyl acetal in moderate yield. They found two Lewis acids to enhance the electrophilicity of the acetal and promote the formation of the adduct, BF3  Et2O and SnCl4 (Scheme 6.109). The preferred anti-diastereomer 270 was formed with selectivities from 99:1 to 81:19 in very good yields. Stereochemistry of adducts 270 and 271 were unambiguously determined by X-ray crystallographic analysis. The observed stereochemistry can be explained by an open-transition state which involves the approach of an intermediate oxocarbenium ion to the less hindered face (Si face) of a chelated Z-enolate. The preferred formation of the anti-adduct can be rationalized through an antiperiplanar arrangement on the basis of stereoelectronic and steric considerations.

Scheme 6.109 Addition of N-propionyl enolate to dialkyl acetals.

Romea and Urpí reported a multigram organic synthesis protocol for the stereoselective synthesis of anti-α-methyl-β-methoxy carboxylic compounds.173 N-Propanoyl (4S)-IPTT 33 was treated with 1 equiv of TiCl4 and diisopropylethylamine to generate the titanium enolate which upon addition of BF3. OEt2 followed by dimethyl acetal 272 furnished the anti-adduct 273 in 89% yield and 95:5 dr (Scheme 6.110).

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Scheme 6.110 Addition of N-propionyl enolate to dialkyl acetals.

Rhizopodin is a polyketide isolated in 1993 from Myxococcus stipitatus, which exhibits potent cytotoxic activity against various cancer cell lines in low nanomolar concentrations.174,175 During total synthesis of rhizopodin in its protected form, Chakraborty et al. applied the Urpí’s diastereoselective anti-acetal aldol reaction for the direct installation of the anti-β-methoxyα-methylcarbonyl stereocenters.176 In this case, the titanium enolate of N-propionyl (4S)-IPTT 33 was prepared using 1 equiv of TiCl4 and 1 equiv of diisopropylethylamine, SnCl4 was used to activate the dimethyl acetal 274 which was then added to provide the anti-aldol product 275 in 86% yield and 93:7 dr (Scheme 6.111). Purification by column chromatography-delivered optically pure anti-adduct 275 in 79% yield. This adduct was treated with lithiated methyl dimethylphosphonate to furnish the corresponding β-keto phosphonate.

Scheme 6.111 Addition of N-propionyl enolate to dialkyl acetals. Rhizopodin.

An anti-acetal aldol reaction was also employed in the total synthesis of (2)-pironetin by Crimmins and Dechert.89 The acetal aldol reaction of N-propionyl (4S)-IPTT 33 and the dimethyl acetal 276 according to the conditions described by Urpí,188 provided the methylated anti-aldol adduct 277 in a 64% yield and 98:2 dr (Scheme 6.112). This reaction established the stereochemistry at C8 and C9 of (2)-pironetin.

Scheme 6.112 Addition of N-propionyl enolate to dialkyl acetals. (2)-Pironetin.

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Imides

Expansion of the titanium enolate addition to dialkyl acetals led to a study on addition to dimethyl ketals.177 This reaction presents a new approach to the stereoselective synthesis of tertiary methyl ethers and a contiguous stereocenter. Results proved that dimethyl ketals from aliphatic methyl ketones are suitable substrates for this kind of transformation provided that no electron-withdrawing groups are close to the ketal center. Titanium enolate of N-propionyl (4S)-IPTT 33 addition to methyl iso-propyl dimethyl ketal in the presence of SnCl2 gave the anti-adduct 278 in 74% yield and 95:5 dr (Scheme 6.113).

Scheme 6.113 Addition of N-propionyl enolate to dialkyl ketals.

The addition of chiral titanium enolates was also studied with α-substituted dimethyl and dibenzyl acetals.178 Dialkyl acetals containing other functional groups can participate in stereoselective coupling reactions with chiral titanium enolates. Particular interest was in the α-N-phthalate substituted dimethyl acetals for the preparation of α-methyl-β-hydroxy-γ-amino carboxylic acids, useful intermediate for the synthesis of bistramides and the novel immunosuppressant agent FR252921.179,180 The major diastereomer was the anti-adduct 279a
f and the minor diastereomer was the syn-adduct 280a
f (Scheme 6.114). The thiazolidinethione of the adduct containing a bromide was displaced with methanol and reduced to an alcohol and the bromide displaced with an azide.

Scheme 6.114 Addition of N-propionyl enolate to dialkyl acetals.

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An extension of this methodology was applied to the N-acetyl thiazolidinethione, where it is more difficult to achieve stereochemical control, with dimethyl acetals.181,182 Thus, the titanium enolate of N-acetyl (4S)IPTT 162 was treated with benzaldehyde dimethyl acetal in the presence of a Lewis acid (Scheme 6.115). The reaction proceeded with better diastereoselectivities when the Lewis acid was BF3  Et2O or SnCl4. The major diastereomer being the anti-aldol product 281. Similar results were also obtained when using dibenzyl acetals giving access to anti-β-benzyloxy-α-methyl carboxylic adducts in good yields and with diastereomeric ratios up to 99:1.183

Scheme 6.115 Addition of N-acetyl enolate to dialkyl acetals.

(2)-Hennoxazole A is an antiviral marine natural product isolated from a species of Polyfibrospongia sponge.184 Smith et al. reported an enantioselective, convergent total synthesis of (2)-hennoxazole from commercially available 4-methyloxazole-2-carboxylic acid.185 Synthesis of the C1
C15 pyran/bisoxazole fragment takes advantage of an aldol-like coupling between a dimethyl acetal and the N-acetyl thiazolidinethione for the direct, stereoselective installation of the C8-methoxy-bearing stereocenter. Smith et al. undertook a comprehensive study on the Lewis acid
mediated additions of N-acetyl thiazolidinethiones (carrying sterically bulky substituents on C4) to the dimethyl acetal 283 (Scheme 6.116). His studies revealed the ability of an oxazole ring to coordinate with the titanium and altered the stereochemical outcome of the additions and the undesired diastereomer was obtained in 80:20 dr in good yields. Employing Sammakia’s

Scheme 6.116 Addition of N-acetyl enolate to dialkyl acetals. (2)-Hennoxazole A.

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Imides

conditions, PhBCl2/(2)-sparteine followed by BF3  Et2O-mediated addition of the resultant boron enolate to dimethyl acetal 283 furnished the desired anti-adduct 284 in 53% yield and 86:14 dr. Urpí and his group designed a synthesis of the C9
C21 fragment of debromoaplysiatoxin and oscillatoxins A and D.186 These marine natural products were isolated from the sea hare Stylocheilus longicauda as well as the blue-green algae belonging to Oscillatoriaceae class. The approach relied on the cross-coupling of titanium enolates from N-acyl thiazolidinethiones and dialkyl acetals.187 The first cross-coupling between N-acetyl (4S)-IPTT 162 and dimethyl acetal 285 afforded a mixture of diastereomers (87:13 dr) that was purified by column chromatography furnishing pure adduct 286 in 82% yield (Scheme 6.117). In the more challenging second cross-coupling, the titanium enolate of N-propionyl (4S)-IPTT 33 to acetal 874 proceeded in highly stereoselective manner ( . 98:2 dr) delivering the anti-product 288 in 74% yield.

Scheme 6.117 Addition of N-acetyl and N-propionyl enolate to dialkyl acetals. Debromoaplysiatoxin and oscillatoxins A and D.

Evans reported a catalytic enantioselective method for the alkylation of metal enolates of N-acyl thiazolidinethiones.188 His group developed a Ni(II) (S)-Tol-BINAP-catalyzed orthoester alkylation with useful substrate scope and enantioselectivity. The optimized method requires 3 equiv of BF3  OEt2 to effectively ionize trimethylorthoformate in the presence of 3 equiv of 2,6-lutidine, and only a 5 mol% of the Ni(II) catalyst (Scheme 6.118). Reaction works well with saturated alkylsubstituted thiazolidinethiones 289 (51%
73% yields), and higher yields are obtained when the N-acetyl groups contains allyl, benzyl or aromatic groups (63%
92% yields), with excellent enantioselectivities ( . 90%).

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Scheme 6.118 Ni-catalyzed addition to trimethylorthoformate.

Urpí and Romea studied the highly stereoselective and efficient synthesis of C9
C19 fragment of peloruside A.189 (1)-Peloruside A is a polyketide macrolactone isolated from the marine sponge Mycale and exhibited extremely potent antitumor activity against P388 murine leukemia cells with an IC50 of 10 ng/mL.190 The synthesis started with the first catalytic aldol-type reaction of N-butanoyl (4S)-IPTT 291 and trimethylorthoformate (Scheme 6.119). The reaction was based on a catalytic addition of nickel(II) enolates to an oxocarbenium ion generated in situ. Commercially available (Me3P)2NiCl2 was used as a precatalyst and TESOTf was added to activate the orthoformate and create the truly active catalyst. Dimethyl acetal product 292 was obtained as a single diastereomer in 82% yield on a multigram scale from 291. This thioimide was converted into aldehyde 293 in six steps. An acetate aldol reaction employing N-acetyl (4R)-IPTT ent-162 was reacted with aldehyde 293 to furnish the syn-aldol product 294 (74% yield for three steps) and 85:15 dr.

Scheme 6.119 Addition of N-acetyl enolate to dialkyl acetals. (1)-Peloruside A.

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Imides

syn-Aldol product 294 was transformed into dimethyl acetal 295 and employed in another acetal aldol reaction with N-acetyl (4S)-IPTT 162 delivering syn-product 296 in 58% yield (for the last four steps) and 88:12 dr.

6.8 TITANIUM ENOLATE ADDITION TO GLYCALS A highly diastereoselective approach to provide enantiomerically pure C-glycosides, based on the Lewis acid
mediated cross-coupling reaction of glycals 297 and 298 to chiral titanium enolates of thiazolidinethiones was reported by Romea and Urpí (Scheme 6.120).191 They found that utilizing standard conditions, the stereochemistry of C-1 is defined by the stereochemistry of the chiral auxiliary. Results suggested that α- and β-C-glycosides can be prepared from glycal 297 when R 5 OOCR to afford glycosides 299 and 300 depending on the chirality of the auxiliary, whereas α-C-glycosides 301 and 302 are always obtained using glycal 298 when R 5 H or OTBS.

Scheme 6.120 Addition of N-propionyl IPTT to glycals. C-Glycosides synthesis.

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Scheme 6.121 Addition of N-acetyl IPTT to glycals. C-Glycosides synthesis.

Romea and Urpí investigated also the more difficult addition of N-acetyl IPTT to glycals.192 When the N-acetyl (4S)-IPTT 162 reacted with glycals 297 or 303, the product obtained afforded consistently the α-C-glycosides 304 and 306 (Scheme 6.121). But, when the N-acetyl (4R)-IPTT ent-162 was employed, there was a dramatic impact of the C6-protecting group, β-C-glycoside 305 was obtained when the group on C6 was an acetoxy and α-C-glycoside 307 was obtained when the protecting group was a silyl ether. Addition of a titanium enolate to a pseudo-glycal was used to obtain the necessary stereochemistry required in the synthesis of salinomycin by Urpí et al.59 Treatment of N-butanoyl (4S)-IPTT 291 with 1 equiv of TiCl4 and 1 equiv of DIPEA generated the titanium enolate which was reacted with the in situ generated oxonium from 308 to furnish the desired alkylated cyclic ether 309 (Scheme 6.122). Thiazolidinethione adduct 309 was treated with methanol to obtain the methyl ester 310, which is C1
C9 fragment of salinomycin.

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Imides

Scheme 6.122 Titanium enolate addition to a pseudo-glycal. Salinomycin.

6.9 INTRAMOLECULAR SULFUR TRANSFER IN N-ENOYL OXAZOLIDINONES Reaction of N-enoyl oxazolidinethiones in the presence of a Lewis acid, such as SnCl4, triggers the intramolecular Michael addition of the sulfur atom.193 The conjugate addition of the sulfur atom in N-enoyl OxT 311 takes place with excellent asymmetric induction to afford the β-mercapto alcohol oxazolidinone 312 after hydrolysis, in very good yield (Scheme 6.123). The reaction can also be carried out employing other Lewis acids such as TiCl4, Ti(i-PrO)4, BF3  Et2O, ZnBr2, Me2AlCl, Cu(AcO)2, and Cu(TfO)2, but higher yields are obtained when using SnCl4.

Scheme 6.123 Intramolecular sulfur transfer in N-enoyl oxazolidinethiones.

The relative stabilities of nonmetal coordinated N-enoyl systems containing oxazolidinethione and thiazolidinethione chiral auxiliaries were reported by Morales-Nava and Fernández-Zertuche in a systematic study including theoretical and NMR results.194 1H NMR studies showed the anti-s-cis structure as the most stable conformation compared to anti-s-trans, syn-s-cis, and syn-s-trans conformations. Density Functional Theory geometry optimizations were used to calculate the Gibbs-free energy differences between the most stable anti-s-cis conformation and the syn-s-cis conformation showing an average of 6 kcal/mol. The syn-s-cis conformation is widely used to explain structure and reactivity of these systems when they are not metal coordinated.

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Ortíz et al. studied the intramolecular sulfur transfer of N-enoyl oxazolidinethiones with other Lewis acids.9 They found that the sulfur transfer products have higher yields when using NbCl5 or TMSCl than when using SnCl4. Thiol products 314a and b were cleaved from the auxiliary in the presence of excess Sm(OTf)3 in methanol to the corresponding methyl ester 316 (Scheme 6.124).

Scheme 6.124 Intramolecular sulfur transfer in N-enoyl oxazolidinethiones.

Palomo et al. observed the intramolecular sulfur addition can also take place with several β,β-disubstituted N-enoyl oxazolidinethiones in the presence of Lewis acids.195 The most satisfactory results in terms of both reactivity and stereoselectivity were obtained with BF3  Et2O. This methodology was applied to a Z/E mixture of N-3-methylcinnamoyl OxT 319 to create the quaternary thiol 320 (Scheme 6.125). Strikingly, they found that the reaction diastereoselectivity was essentially the same regardless of the E/Z composition of the starting N-enoyl substrate 319.

Scheme 6.125 Intramolecular oxazolidinethiones.

sulfur

transfer

in

β,β-disubstituted

N-enoyl

A novel nucleophilic attack of oxazolidinethione was reported by the Ortíz group.196 A new product was formed when 2 equiv of oxazolidinethione and 2 equiv of NaH were used to attach crotonyl chloride to the auxiliary (Scheme 6.126). A reaction mechanism is proposed where the N-enoyl OxT 321 formed undergoes intramolecular sulfur addition

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Imides

Scheme 6.126 Intramolecular sulfur Michael addition and nucleophilic attack.

to intermediate A. Nucleophilic attack of an oxazolidinethiolate at the C-5 position of intermediate A leads to intermediate adduct B, which upon hydrolysis results in the new product 322 and oxazolidinone 323. When oxazolidinethione 324 was treated with sodium hydride and bromoacetyl bromide a rearranged product was observed by Ortíz (Scheme 6.127).197 It was proposed that the oxazolidinethione reacts with the acetyl bromide in the presence of sodium hydride to give N-bromoacetyl OxT 325. An intramolecular displacement of the bromide takes place by the sulfur atom and elimination of a proton gives the thiazolidinedione 326.

Scheme 6.127 Rearrangement of N-bromoacetyl OxT.

The initial intramolecular Michael addition of sulfur in N-enoylthioimides generating a chalcogenide was followed by an aldol reaction which alkoxide intermediate cyclized forming a cage-type scaffold (Scheme 6.128).198,199 This reaction can give up to three consecutive chiral centers and a quaternary carbon attached to heteroatoms. N-Cinnamoyl thiazolidinethione 327 was treated under the standard aldol reaction conditions

Scheme 6.128 Intramolecular sulfur addition/aldol reaction/cyclization.

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with p-chlorobenzaldehyde 328 delivering a mixture of tricyclic diastereomers 329a and 329b. Our group reported the cascade reaction of N-enoyl thiazolidinethiones as a thio-Michael-Aldol-Cyclization with aliphatic aldehydes and cyclic ketones.200 This cascade reaction was promoted by TiCl4 to deliver tricyclic adducts possessing a carbon tetrasubstituted with heteroatoms and up to four stereogenic centers. These reactions were carried out on with aliphatic aldehydes and N-crotonyl 4-phenyl-oxazolidinethione 330 using 2 equiv of TiCl4. We observed that the reaction with 2 equiv of n-butanal gave the desired product 331 in very good yield (Scheme 6.129).

Scheme 6.129 Intramolecular sulfur addition/aldol reaction/cyclization.

6.10 MICHAEL ADDITIONS Chen reported the asymmetric Michael addition of an organocopper reagent to N-crotonyl (4S)-BTT 332 (Scheme 6.130).201 This reaction was employed in the synthesis of (10R)-methyltridecan-2-one, the sex pheromone of the southern corn rootworm.202 Propylmagnesium bromide was added to N-crotonyl (4S)-BTT 339 in the presence of cooper bromide-dimethyl sulfide in THF. The addition product 333 was obtained in 91% yield as a pure stereoisomer. The thiazolidinethione 340 was reduced directly to the corresponding aldehyde using DIBAL-H.

Scheme 6.130 Asymmetric Michael addition of to an N-enoyl BTT.

Another reaction catalyzed by Ni(II) Tol-BINAP is the Michael addition to N-enoyl thiazolidinethiones.203 It was found that Ni(II) TolBINAP catalyzes the addition of tert-butyl acetoacetate (335) to N-crotonyl

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Imides

thiazolidinethione 334, in the absence of an amine base, to afford 336 as a 1:1 mixture of diastereomers (Scheme 6.131). Treatment of 336 with 1,8-diazabicyclo[5.4.0]undecane (20 mol%) resulted in the formation of enantioenriched dihydropyrone 337. A solvent survey showed that ethyl acetate was the preferred reaction medium in terms of reaction rate and enantioselectivity. The same Ni catalyst was useful for a Diels
Alder reaction of N-crotonyl thiazolidinethione 334 and cyclopentadiene furnishing the corresponding DA adduct in 83% yield and 97%ee.

Scheme 6.131 Catalyzed Michael addition tert-butyl acetoacetate.

We discovered the nucleophilic activity of oxazolidinethiones and thiazolidinethiones in intermolecular Michael additions with N-enoyl oxazolidinethiones and thiazolidinethiones.204 The nucleophilic character of these chiral auxiliaries was observed in their conjugated addition to N-crotonyl thiazolidinethiones 338a
c and oxazolidinethiones 340a
c in the presence of excess triethylamine in CH2Cl2. In these reactions, the Michael addition occurs with the nitrogen atom of the heterocycle (2c
e, 3c
e) and the additions proceed with high diastereoselectivities giving products 339a
c and 341a
c (Scheme 6.132). Also, was observed that the stereoselective addition takes place on the anti-s-cis conformation of the N-enoyl heterocycle. Continuing with the previous study, we focused our attention on the addition of both enantiomers of 4-POxT (3d and ent-3d) to 4-substituted N-crotonyl-oxazolidinones 342a
c (Scheme 6.133).205 When the Michael donor and acceptor possessed the same stereochemistry, a perfect match was observed; but when they possessed the opposite stereochemistry, a small mismatch was observed. The addition of (4S)-PTT 3d to N-crotonyl-oxazolidinones 342a
c gave exclusively one diastereomeric product 343a
c in good isolated yields (80%
85%). While addition of

Chiral Sulfur-Containing Imide Auxiliaries in Medicinal Chemistry

Scheme 6.132 Intermolecular oxazolidinethiones.

Michael

additions

of

thiazolidinethiones

237

and

Scheme 6.133 Michael additions of oxazolidinethiones to N-crotonyl-oxazolidinones.

(4R)-PTT ent-3d to N-crotonyl-oxazolidinones 342a
c gave observable mixture of diastereomeric products 344a
c and 345a
c. The addition of organocuprates to N-enoyl oxazolidinethiones gave preferentially the anti-diastereomer when the reaction takes place using an excess of a 1:2 mixture of CuBr  DMS or CuI  DMS and Grignard reagent, and excess TMSI. In our research group, we investigated the conformational preference in this reaction with indene-based and

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Imides

three different phenyl glycine
derived oxazolidinethiones.206 Addition of aryl organocopper reagents to N-crotonyl (4R)-POxT ent-340a gave the anti-Michael adduct 346a and b preferentially (Scheme 6.134). The nucleophile attacks the Michael acceptor when it adopts a syn-s-cis conformation in the transition state delivering the anti-addition product preferentially.

Scheme 6.134 Addition of organocuprates to N-enoyl oxazolidinethiones.

6.11 TITANIUM ENOLATE ADDITION TO ALDIMINES β-Amino carbonyl groups are important constituents of many biologically active natural products and therapeutics. Liotta et al. described the addition of titanium enolates of chiral thiazolidinethiones to non-enolizable imines.207 A reversal in selectivity from anti to syn can be achieved operationally by simply changing the group on the nitrogen and the reaction conditions (Scheme 6.135). Addition of titanium enolate from N-propanoyl (4S)-IPTT 33 to N-(4-methoxyphenyl)benzaldimine (348) yields (2R,3S)-(anti)-product 349 with good selectivity (6:1 to 18:1), while N-benzyloxycarbonylbenzaldimine 350 equilibrates and subsequently eliminates benzyl alkoxide under the reaction conditions to produce 2R,3R-(syn)-isocyanates 351 with excellent selectivity (95:5). NH

Scheme 6.135 Addition of titanium enolates to non-enolizable imines.

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Titanium enolates of thiazolidinethiones could also be added to aldimines in the presence of excess Lewis acid and at 0°C (Scheme 6.136).208 Aldimines exhibit lower reactivity than their parent aldehydes. For this reason, Liotta proposed to employ “imines” that are less prone to deprotonation, tautomerization, and oligomerization. An excess of Lewis acid was also suggested to overcome the moderate electrophilicity of the aldimines. Addition of the titanium enolate of N-propanoyl (4S)-IPTT 33 to O-methyl oxime 352 gave two products 353 and 364. Azetine 353 (R 5 Ph) was identified by X-ray crystallographic analysis. By using 4 equiv of TiCl4 and 2.5 equiv of (2)-sparteine azetine 353 was obtained as a single diasteromer. Interestingly, the reaction also worked with enolizable O-methyl oxime ether derived from hydrocinnamaldehyde and cyclohexane carboxaldehyde. Formation of the strained four-membered ring can be rationalized as being initiated by the combination of oxime and TiCl4 to give a highly electrophilic trichlorotitanium iminium intermediate which undergoes addition by the enolate followed by addition of nitrogen to electrophilic carbonyl coordinated to titanium to form an azacyclobutane. Elimination of bis-trichlorotitanium oxide triggers the formation of the azetines 353.

Scheme 6.136 Addition of titanium enolates of thiazolidinethiones to aldimines.

An efficient, diastereoselective one-pot procedure for preparing β-lactams starting from aromatic nitriles was also investigated by Liotta and Herold-Dublin.209 Titanium enolates of N-acyl thiazolidinethiones can react with nitriles which in situ are converted into N-metalloaldimines (Scheme 6.137). This strategy was showcased in the synthesis of SCH-48462, a novel cholesterol absorption inhibitor. N-Acyl (4S)-IPTT 355 was treated with TiCl4 and sparteine to form the titanium enolate. Phenyl nitrile 356 was first hydrometallated with Cp2ZrHCl, and another Lewis acid was then added to the reaction (pentamethylcyclopentadienyl titanium trichloride/titanium dichloroisopropoxide) to furnish β-lactam 357 in 71% yield. The β-lactam 357 was N-arylated by using copper catalysis to yield SCH-48462 358.

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Imides

Scheme 6.137 Synthesis of β-lactams starting from nitriles.

The addition of titanium enolates to preformed iminium salts is an important reaction for the synthesis of β-aminocarbonyl functionalities. We investigated the addition of the titanium enolate of N-acetyl (4S)-IPTT 162 to an N-substituted cyclic iminium ion 359 furnishing the corresponding Mannich-type anti-addition product 366 (Scheme 6.138).93 X-Ray analysis of adduct 360 confirmed the stereochemistry of the β-carbon. We found that good yields of adduct 360 could be obtained when employing 2 equiv of the TiCl4 and 1 equiv of diisopropylethylamine.

Scheme 6.138 Titanium enolate addition to an N-substituted cyclic iminium ion.

6.12 SODIUM ENOLATE MICHAEL ADDITION/ELIMINATION Key dienoic or dienal substructures of cytotoxic macrolides amphidinolide E and dictyostatin were prepared via Michael addition/elimination of chiral Na enolates on β-iodo derivatives of ethyl acrylate.210 Based on reports on the addition of Ti enolates of chiral N-propanoyl oxazolidinones to activated double bonds, Vilarrasa investigated the Michael addition/elimination of different metal enolates derived from oxazolidinethiones and thiazolidinethiones (Scheme 6.139). No reaction was observed when employing these thione auxiliaries. Excellent results were only obtained with sodium enolates formed from thiazolidinone 361. Thiazolidinone 361 was prepared by 2,3-dichloro-5,6-dicyano-p-benzoquinone oxidation of the corresponding thiazolidinethione. The geometry of the olefins 362Z and 362E was maintained and excellent diastereoselectivity was observed in products 363a and 363b.

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Scheme 6.139 Sodium enolate Michael addition/elimination.

6.13 RESOLUTION OF RACEMIC MIXTURES One of the oldest applications of an optically pure molecule is in the separation of enantiomeric mixtures forming diastereomeric salts or compounds which have different physical properties and are separable. Nagao applied his IPTT auxiliary for the resolution of racemic cis-benzoylcyclohexenecarboxylic acid rac-370 (Scheme 6.140).211 Reaction of (4S)-IPTT 2e with carboxylic acid 364 gave a mixture of diastereomeric thioimides 365a and 365b (24% and 40% yields, respectively). Reaction of (4R)IPTT ent-2e with carbocylic acid 364 gave a mixture of thioimides 366a and 366b (41% and 26% yields, respectively). These mixtures were completely separated on a silica gel column to give each pure thioimides as yellow solids. These optically pure thioimides were treated with hydrazine to yield 4-phenyl-cis-tetrahydrophthalazinones, a potent inhibitor of phosphodiesterase. Another interesting application is the differentiation between two chiral auxiliaries having a prochiral center.212

Scheme 6.140 IPTT chiral auxiliary in resolution of racemic mixtures.

Chiral oxazolidinethione and thiazolidinethione auxiliaries have been shown to be of extraordinary value in different C
C bond forming

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applications for the preparation of valuable synthetic intermediates. Among these applications, aldol reactions are in great way the most common and valuable examples. Some of these chiral auxiliaries are also easy to prepare and most reactions are carried out using practical and economical reagents. Transformations achieved with them have a high degree of diastereoselectivity and purified products are optically pure isomers of great value in medicinal chemistry. In addition, these thioimides have a distinct yellow color and in most cases their crystalline form facilitates analysis by X-ray crystallography. Cleavage of the chiral auxiliary is easy, convenient, and superior to other known chiral auxiliaries. For these reasons, we will continue to see more applications of these chiral auxiliaries in medicinal chemistry.

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Elimination Reactions of Chiral Enolates with Ethyl 3-Halopropenoates. Org. Lett. 2008, 10, 65. 211. Dang, T. V.; Jin, C. K.; Miyamoto, M.; Ikee, Y.; Masuda, T.; Sano, S.; Shiro, M.; Nagao, Y. Practical Synthesis of New Chiral cis-Phthalazinones with Potential for High Phosphodiesterase (PDE4) Inhibitory Activity. Heterocycles 2006, 68, 2133. 212. Nagao, Y.; Ikeda, T.; Yagi, M.; Fujita, E. A New Design for Chiral Induction: A Highly Regioselective Differentiation Between Two Identical Groups in an Acyclic Compound Having a Prochiral Center. J. Am. Chem. Soc. 1982, 104, 2079.

CHAPTER 7

Imide Natural Products Justin M. Lopchuk1,2 1

Drug Discovery Department, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, United States 2 Department of Oncologic Sciences, Morsani College of Medicine, University of South Florida, Tampa, FL, United States

7.1 INTRODUCTION The imide functionality is ubiquitous in nature and found in many structurally diverse natural products. The imides themselves are most often cyclic and the natural products containing them tend to be bioactive. Some imides, such as glutarimide, appear so frequently in highly potent, naturally occurring antibiotics, that they have come to be considered privileged scaffolds. The imide natural products covered in this chapter are grouped by a combination of the overall structural similarity of both the molecule and the type of imide itself; the groups include bisindoles, glutarimides, maleimides, polyketides, succinimides, and tetramic acids. Each individual natural product is further broken down by isolation, biological activity, and synthesis, where applicable. This chapter is not intended to provide comprehensive and exhaustive coverage of all known imidecontaining natural products. Rather, it will cover selected, representative natural products in a range of structural classes with initial isolation dates from the early 20th century up to 2018.

7.2 BISINDOLES 7.2.1 Arcyriacyanin A Isolation and Biological Activity: Arcyriacyanin A (1) is a green
blue pigment isolated from the sporangia of the slime mold Arcyria obvelata (formerly Arcyria nutans, Myxomycetes).1 The specific details of the isolation efforts appear to remain unpublished and are only mentioned in several reviews.2 Arcyriacyanin A (1) is representative member of many structurally similar bisindoylmaleimide alkaloids, including arcyriarubin A (2, a possible biogenic precursor), the isomeric arcyriaflavin A (3), and arcyroxepin A (4).3 Limited studies of the biological activity of arcyriacyanin A Imides DOI: https://doi.org/10.1016/B978-0-12-815675-9.00007-2

© 2019 Elsevier Inc. All rights reserved.

255

256

Imides

Figure 7.1

(1) showed weak inhibitory activity against a panel of 39 human cancer cell lines in addition to selective inhibition of protein kinase C and protein tyrosine kinase over protein kinase A or calmodulin-dependant protein kinase C (over 1
100 μg/mL) (Fig. 7.1).1,2 Synthesis: Despite modest biological activity, arcyriacyanin A (1) has been a popular target for total synthesis due in large part to the unsymmetrical C
C bond between the two indole heterocycles that differentiates it from compounds such as arcyriaflavin A (3), or arcyroxepin A (4). Steglich and coworkers reported the first total synthesis of arcyriacyanin A (1) by three discrete routes. Indole 5 was treated sequentially with lithium diisopropylamide (LDA) and Me3SnCl to afford stannane 6 in 76% yield. Bisindole 9 was constructed via the palladium-catalyzed crosscoupling of stannane 6 with bromoindole 7 followed by basic hydrolysis (57% over two steps). The addition of two equivalents of EtMgBr to bisindole 9 followed by heating with 3,4-dibromomaleimide (10) furnished arcyriacyanin A (1) in 41% yield (Scheme 7.1).4

Scheme 7.1

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The second approach began with the diazotation of aniline 11 followed by protection of the resulting phenol to give arene 12 (65% over two steps). The addition of dimethylformamide dimethyl acetal and catalytic amounts of pyrrolidine generated an intermediate enamine, which, upon hydrogenation, gave indole 13 in 60% yield. Indole 13 was sequentially treated with EtMgBr and bromomaleimide 14 to deliver bisindole 15. The penultimate triflate 17 was prepared in 76% yield by a two-step sequence comprised of acid-catalyzed hydrolysis and treatment with Nphenyltriflimide. An intramolecular palladium-catalyzed crosscoupling gave N-methyl arcyriacyanin A (18) in 81% yield (Scheme 7.2).4 Conversion of N-methyl arcyriacyanin A (18) to arcyriacyanin A (1) could be achieved by hydrolysis to the corresponding maleic anhydride followed by treatment with hexamethyldisilazane (HMDS).5

Scheme 7.2

Steglich and coworker’s third approach allowed for the formation of the final two C
C bonds in a single step via a domino Heck reaction. Treatment of bromomaleimide 14 with bromoindole 19 and a palladium catalyst afforded N-methyl arcyriacyanin A (18) in varying yields from 10% to 30% (Scheme 7.3).4

Scheme 7.3

258

Imides

A conceptually related approach to that shown in Scheme 7.1 was reported by Tobinaga and coworkers.6 4-Aminoindole 20 was diazotized with NaNO2 and treated with potassium iodide (KI) to afford iodoindole 21 in 84% yield. A protecting group swap was accomplished by cleavage of the tosyl group with NaOH and reprotection of the nitrogen with tertbutyldimethylsilyl chloride (TBSCl) (21 - 23, Scheme 7.4).

Scheme 7.4

In order to prepare the bisindole coupling partner, indole 24 was treated with n-BuLi and triethylborane to furnish an intermediate indolyl borate (not shown); the borate was allowed to react with iodoindole 25 in the presence of a palladium catalyst to afford protected bisindole 26 in 51% yield. A two-step deprotection with tetrabutylammonium fluoride (TBAF) followed by hydrogenolysis gave bisindole 9 in 83% yield (Scheme 7.5). The tert-butyldimethylsilyl (TBS) group on iodoindole 26 allowed for a superior yield during the crosscoupling when compared to indole 21 or 22 (46% and 38% yield, respectively).

Scheme 7.5

The synthesis of arcyriacyanin A (1) was completed by the double deprotonation of bisindole 9 with 2 equiv. of MeMgI, followed by the addition of 3,4-dibromomaleimide 27 to furnish the desired product in 46% yield (Scheme 7.6). A significant solvent/temperature effect was observed for this reaction; the use of refluxing benzene instead of refluxing toluene gave the desired product 1 in only 16% yield.6

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Scheme 7.6

Steglich and coworkers recently reported another synthesis of arcyriacyanin A (1) that relies on an unusual rearrangement to form the sevenmembered ring system. Exposure of ester 28 to hot dimethyl sulfoxide (DMSO) triggered a decarboxylation to afford nitroarene 29 in 34% yield (when the reaction was run without 2,6-di-tert-butyl-4-methylphenol (BHT) yields were c. 20%). The anion of arene 29 was treated with bromomaleimide 14 to afford cyclized product 30 in 48% yield. Sequential reduction of the nitro group (via hydrogenation) and the cyano group (via diisobutylaluminum hydride (DIBAL-H)) formed the final indole ring (32, 12% yield). Pyrolysis of the Boc group gave N-methyl arcyriacyanin A (18) in 80% yield (Scheme 7.7).7 Kraus and Guo reported a formal synthesis based upon a one-pot reaction of 2-substituted indoles from 2-aminobenzyl phosphonium salts. Treatment of phosphonium salt 33 with aldehyde 34 and acetic acid

Scheme 7.7

260

Imides

Scheme 7.8

under microwave conditions formed an intermediate imine; deprotonation with t-BuOK facilitated the cyclization to afford bisindole 9 in 87% yield (Scheme 7.8).8 7.2.1.1 Cladoniamides Isolation and Biological Activity: All seven members of the cladoniamides (A
G, 35
41) were isolated in 2008 by Andersen and coworkers from cultures of Streptomyces uncialis, which was found on the surface of the lichen Cladonia uncialis near the Pitt River, British Columbia.9 Initial in vitro testing showed cladoniamide G (41) was cytotoxic to human breast cancer cells (MCF-7) at 10 μg/mL.9 Cladoniamide A (35) and B (36) were later shown to be potent inhibitors of colon cancer cell line HCT-116 (IC50 of 8.8 and 10 ng/mL, respectively).10,11 A closely related natural product, BE-54017 (42), was isolated in 2000 from Streptomyces sp. A54017 and reported to have an IC50 of 0.11 μg/mL for P388 cells.12 The biosynthetic gene clusters that encode for compounds 35
42, containing a rare indolotryptoline core, have been extensively studied independently by both Brady and coworkers10 and Ryan (Fig. 7.2).13 Synthesis: Shibasaki and coworkers completed the first total synthesis of BE-54017 (42) and confirmed the absolute configuration of the alkaloid via a seven-step route starting from 5-chloroindole (43). Indole 44 was formed by stannylation of indole 43 after protection of the
NH with carbon dioxide (which also served to stabilize the subsequent α-carbanion). A carefully optimized palladium-catalyzed coupling of stannane 44 with methoxyacetyl chloride (45) furnished indole 46 in 74% yield. Treatment of indole 46 with phenylhydrazine in AcOH effected a Fisher indolization that afforded bisindole 47; since bisindole 47 proved to be unstable, it was immediately allowed to react with N-methylmaleimide (48) to give the Michael addition product 49 in 31% yield (over two steps). Indole 49 was heated to 200°C in the presence of a stoichiometric amount of palladium black to give indolocarbazole 50 in 48% yield. NMethylation of indole 50 with methyl iodide occurred in 70% yield set

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261

Figure 7.2

up the key dihydroxylation step. In the event, indole 51 was treated with 1.1 equiv. of OsO4 followed by a reductive workup to furnish racemic BE-54017 (42) in 37% yield. An HPLC resolution gave the pure enantiomers (Scheme 7.9).14

Scheme 7.9

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Imides

To confirm the absolute stereochemistry of BE-54017 (42), the natural product was prepared independently through cladoniamide A (35), whose absolute configuration was previously reported. Indolocarbazole 50 was dihydroxylated under the same conditions used earlier to complete the first total synthesis of cladoniamide A (35). After resolution of the enantiomers by HPLC, methylation gave (2)-BE-54017 (42), which was demonstrated to match the optical rotation of the natural product (Scheme 7.10).14

Scheme 7.10

7.3 GLUTARIMIDES 7.3.1 Cycloheximide Cycloheximide (52, also known as naramycin A or actidione) was first isolated in 1946 from Streptomyces griseus.15 It remains as one of the most famous glutarimide natural products and displays a wide variety of biological activities, including broad antibiotic, antifungal, antitumor, and amebicidal activities, as well as serving as an extremely potent rodent repellent.16 Most of the activity of cycloheximide (52) is derived from its ability to act as a protein synthesis inhibitor in eukaryotes and it is often used in experimental research studies for this purpose. Inactone (53), a closely related derivative of cycloheximide (52) was also isolated from cultures of S. griseus (Fig. 7.3).17 Actiphenol (54, also known as C-73) was first isolated concurrently from cultures of actinomycetes strain ETH 7796 and Streptomyces albulus.18 Compared to cycloheximide (52), actiphenol (54) displays minimal biological activity. Shen and colleagues have demonstrated that 52 and 54 are produced from Streptomyces sp. YIM65141 via a single biosynthetic machinery wherein actiphenol (54) may serve as the intermediate to the biosynthesis of cycloheximide (52).19 Actiketal (55) was first isolated from Streptomyces

Figure 7.3

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263

pulveraceus (subsp. epiderstagenes) and, though less active than cycloheximide (52), inhibits EGF-induced DNA formation in murine epithelial cells, the Con A-induced blast formation in spleen cells, and the incorporation of [3H]thymidine into EGF-stimulated Balb/MK cells (Fig. 7.3).20 Synthesis: Johnson and coworker’s synthesis of cycloheximide (52) began with cis-2,4-dimethylcyclohexanone (56), which was prepared from 2,4dimethylphenol by reduction with 10% Pd/C and hydrogen (not shown). Treatment of cyclohexanone 56 with morpholine and Dowex-50W resin in refluxing toluene for two days resulted in enamine 57 where the C2 position was epimerized to yield the trans compound. Acylation of enamine 57 with glutarimide 58 under rigorously dried conditions afforded 59, which was directly hydrolyzed to give 60 (30% yield from acid chloride 58). Reduction with PtO2 and hydrogen produced diol 61; this compound was converted to the corresponding chloroacetate 63, a strategy that resulted from a great deal of experimentation. Oxidation of the secondary alcohol furnished 64 and hydrolysis of the chloroacetate group afforded racemic cycloheximide (52). The same sequence was also used to generate the enantiopure natural product beginning with optically pure 56 (Scheme 7.11).16 The synthesis of several unnatural stereoisomers of cycloheximide (52) has also been reported.21

Scheme 7.11

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Imides

Johnson prepared actiphenol (54) in six steps beginning with commercially available dimethyl acetonedicarboxylate (65). Condensation of cyanoacetic acid (66) with 65 gave diester 67 in 54% yield. Hydrogenation of the product gave dimethyl 3-cyanomethylglutarate (68, 89% yield). Hydrolysis of glutarate 68 followed by heating furnished 3carbomethylglutarimide, which was treated with thionyl chloride to afford glutarimide 58. Acylation of 2,4-dimethylphenol (69) with 58 occurred upon heating in a solution of pyridine to afford ester 70. The final Fries rearrangement was induced by treatment with finely powdered AlCl3 and heating to 155°C to give actiphenol (54, Scheme 7.12).22

Scheme 7.12

Kiyota and coworker’s synthesis of actiketal (55) began with the palladium-catalyzed coupling of 5,7-dimethylbenzofuran (71) and dimethyl glutaconate (72), which furnished benzofuran 73 in 57% yield. The enone was selectively hydrogenated to give diester 74 in 98% yield. The glutarimide moiety was formed over a four-step sequence (62% yield) that included hydrolysis to the diacid, cyclization to the glutaric anhydride, ammonolysis to the corresponding acid amide, and finally cyclization to glutarimide 75. Oxidation of the C2
C3 double bond of benzofuran 75 delivered actiketal (55) in 33% yield (Scheme 7.13).23

7.3.2 Julocrotine, Cordiarimides, and Crotonimides Isolation and Biological Activity: Although first isolated in 1925 from Julocroton montevidensis,24 julocrotine (76) has been frequently found in many species of Croton plants, including Croton membranaceus, C. cascarilloides, C. cuneatus, and C. pullei var. glabrior Lanj.25 While the structure of

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Scheme 7.13

julocrotine (76) was first proposed on the basis of degradation studies in 1959,26 it was not confirmed until 2008 by X-ray crystallography.27 Despite being a component of trees used by native Venezuelan populations to treat gastrointestinal diseases as well as an antiinflammatory agent,28 no biological activity was known for julocrotine (76) until 2010 when it was reported to act as a potent antiproliferative agent against the promastigote and amastigote forms of Leishmania amazonensis (L.), a protozoan parasite that causes cutaneous leishmaniasis (Fig. 7.4).29 Cordiarimides A (77) and B (78) were recently isolated from the roots of Cordia globifera, collected in Nakhon Sawan Province, Thailand and represent the first instance of the isolation of glutarimide alkaloids from plants in the genus Cordia.30 Initial biological testing showed that cordiarimides A (77) and B (78) were weakly cytotoxic against the MOLT-3 cell line (145.3 and 44.5 μM, respectively) and inhibited superoxide anion radical formation in the xanthine/xanthine oxidase assay (IC50 5 54.1 and 21.7 μM, respectively). Neither compound was active against HepG2, A549, or HuCCA-1 cell lines (Fig. 7.5).30 Crotonimides A (79) and B (80) were isolated from the stems and stem bark of C. pullei var. glabrior Lanj., which was collected in the city of

Figure 7.4

266

Imides

Figure 7.5

Figure 7.6

Peixe-Boi, state of Pará, Brazil (Fig. 7.6).25a Crotonimide C (81) was isolated from the roots of C. alienus, collected from the Ngong Forest in Nairobi, Kenya. No biological activity has yet been reported for the crotonimides (Fig. 7.6).31 Synthesis: The first total synthesis of julocrotine (76) was reported by Silva and Joussef via a high-yielding route (41% overall) starting from Lglutamic acid (82). Protection of the nitrogen on 82 was followed by cyclization to afford oxazolidinone 84 (94% yield over two steps). Treatment with 2-phenethylamine led to ring-opening of the oxazolidinone and the resulting product was converted to the methyl ester 85. Glutarimide formation was achieved by exposing ester 85 to pTsOH in refluxing toluene (86, 64% yield). Removal of the Cbz group via hydrogenolysis followed by coupling with (S)-2-methylbutanoic acid furnished julocrotine (76) in 75%
89% yield over two steps (Scheme 7.14).32

Scheme 7.14

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267

Wessjohann and coworkers reported a formal synthesis of julocrotine (76) that began with L-Cbz-glutamine (87); N,N0 -dicyclohexylcarbodiimide (DCC) coupling of 87 with N-hydroxysuccinimide (88) allowed for the cyclization to occur and afforded glutarimide 89 in 76% yield. Alkylation could be achieved with base and the appropriate alkyl bromide, but this resulted in racemization of the product (Method A, Scheme 7.15). Instead, a Mitsunobu reaction with 2-phenylethanol gave optically pure intermediate (86) in 90% yield (Method B, Scheme 7.15), which constitutes a formal synthesis of julocrotine (76). Several analogs were made from 86 via a fourcomponent Ugi reaction.33

Scheme 7.15

A closely related synthesis was concurrently reported by Huang and coworkers where L-Boc-glutamine (90) was cyclized via an N-(3dimethylaminopropyl)-N0 -ethylcarbodiimide (EDC) coupling to afford glutarimide 91 in 70% yield (Scheme 7.16). As discussed earlier, alkylation via an alkyl bromide or Mitsunobu conditions led to intermediate 92, which intercepts the previous routes to julocrotine (76).34

Scheme 7.16

Cordiarimides A (77) and B (78) were prepared by the same intermediate (91) used for the julocrotine (76) synthesis. Glutarimide 91 was alkylated with 2-bromoacetophenone (93) to give ketone 94 in 87% yield. Cleavage of the protecting group with trifluoroacetic acid (TFA) was followed by acetylation to afford cordiarimide A (77) in 83% yield over two steps. A high pressure catalytic asymmetric hydrogenation (dr 5 6:1) was realized with (S,S)-Me-DuPhos (95) and a palladium catalyst to provide cordiarimide B (78) in 95% yield (Scheme 7.17).34 Hydrogenation without phosphine 95 resulted in a 1:1 mixture of diastereomers.

268

Imides

Scheme 7.17

Crotonimide A (79) and B (80) were readily synthesized from previously prepared glutarimide intermediate 92 (Scheme 7.16) via protecting group cleavage and coupling with either propionic anhydride [crotonimide A (79), 80% yield] or isobutyric anhydride [crotonimide B (80), 77% yield] (Scheme 7.18).34

Scheme 7.18

Alternatively, crotonimide A (79) was prepared from ketone 94; cleavage of the protecting group with TFA followed by coupling with propionic anhydride gave intermediate 96 in 75% yield. Complete reduction of the benzylic ketone via hydrogenation delivered crotonimide A (79) in 95% yield (Scheme 7.19).34

Scheme 7.19

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269

Figure 7.7

7.3.3 Lamprolobine Isolation and Biological Activity: Lamprolobine (97) was first isolated in 1968 from the leaves of Lamprolobium fruticosum Benth. (family Leguminosae), a bushy shrub commonly found in sandstone soils in northern Queensland, Australia.35 It comprised the bulk of the alkaloid material (c. 90%) found in the plant and represents an uncommon member of the quinolizidine alkaloids. Subsequently, lamprolobine (97) has been isolated from a variety of other leguminous plants, including Lupinus holosericeus, Sophora chrysophylla, S. velutina, Thermopsis villosa, and also from the root parasite Castilleja hispida.36 Epilamprolobine (98) was isolated from the fresh leaves of S. tomentosa, grown and collected in Japan.37 No significant biological activity has been reported for these compounds (Fig. 7.7). Synthesis: The first total synthesis of lamprolobine (97) was reported in 1970 by Goldberg and Lipkin.38 Diethyl ethoxymethylidenemalonate (100) was condensed with pyridine 99 to afford quinolizone 101 in 72% yield. Treatment with refluxing HCl caused hydrolysis followed by didecarboxylation to give 4-quinolizone (102). Reduction with PtO2 under hydrogen furnished 4-quinolizidone (103, 54% over two steps); further reduction with LiAlH4 gave quinolizidine (104) in quantitative yield (Scheme 7.20).38

Scheme 7.20

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Imides

Quinolizidine (104) was dehydrated with mercuric acetate in 52% yield. Treatment of 1,10-dehydroquinolizidine (105) with ethyl chloroformate and reduction with NaBH4 delivered intermediate 107 in 57% yield over two steps. Epimerization with base and reduction of the ester with LiAlH4 gave epilupinine (109, 76% over two steps). Conversion of the primary alcohol to the corresponding bromide 110 occurred in 75% yield upon treatment with PBr3. Displacement of the bromide with Npotassioglutarimide (111) afforded racemic lamprolobine (97) in 52% yield (Scheme 7.21).38

Scheme 7.21

Shortly following the first synthesis of lamprolobine (97), Wenkert and Jeffcoat published a route that began with the alkylation of nicotinonitrile (112) with 4-bromo-2-butanone ethylene ketal (113). Hydrogenation of the alkylated intermediate 114 followed by acidcatalyzed cyclization gave a separable mixture of diastereometic ketals 115 and 116. The nitrile groups were reduced to the corresponding amines with LiAlH4; Wolff
Kishner reduction subsequently removed the ketones (after hydrolysis of the ketals). Amines 117 and 118 were then treated with glutaric anhydride to furnish lamprolobine (97) and epilamprolobine (98) (Scheme 7.21).39 In the same year as the previous two syntheses (1970), Yamada, Hatano, and Matsui disclosed a route that begins with δ-valerolactam (120) and constitutes a formal synthesis of both lamprolobine (97) and epilamprolobine (98). Upon treatment with triethyloxonium fluoroborate, δ-valerolactam (120) was converted to iminoether 121 in 69% yield; this intermediate was then condensed with benzyl cyanoacetate (122) to afford

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piperidine derivative 123 (90% yield). The benzyl-protecting group was cleaved by hydrogenolysis and the addition of acid effected the desired decarboxylation to give 2-cyanomethylenepiperidine 125 as a mixture of isomers (97% over two steps). Cyclization with methyl acrylate furnished the quinolizidine system 126 in 77% yield (Scheme 7.22).40

Scheme 7.22

The reduction of quinolizidine 126 with NaBH4 in the presence of BF3  OEt2 gave nitriles 127 and 128 as a mixture of diastereomers. Trans isomer 128 was the major product, as well as the undesired isomer, and could be epimerized to cis isomer 127 in c. 80% yield. Reduction of the nitriles with LiAlH4 gave amines 118 and 117 and completed the formal synthesis of lamprolobine (97) and epilamprolobine (98) (Scheme 7.23).40

Scheme 7.23

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Imides

The most recent synthesis of lamprolobine (97) and epilamprolobine (98) was achieved by Michael and Jungman in 1992. Upon treatment with base, thiolactam 129 underwent conjugate addition to ethyl acrylate (130) to afford ester 131 in 99% yield. After the addition of bromoacetonitrile to ester 131, exposure to triphenylphosphine and triethylamine gave vinylogous cyanamide 132 in 85% yield. A sequence of reduction of the ester, tosylation of the resulting alcohol, and displacement of the tosylate formed the quinolizidine core 135 (Scheme 7.24, 52% yield over three steps).41

Scheme 7.24

Reduction of quinolizidine 135 with PtO2 and hydrogen gave the expected cis-reduced quinolizidine 128 in good yield. The use of NaBH3CN instead gave the desired trans-reduced quinolizidine 127 as the major product, albeit with a significant amount of the other isomer 128. Compared to LiAlH4, the use of a nickel
aluminum alloy and NaOH for the nitrile reduction gave cleaner reactions and higher yields of amines 117 and 118 and completed the formal synthesis (Scheme 7.25).41

Scheme 7.25

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Enantiopure (1)-epilamprolobine (98) was prepared from (2)-lupinine (136) via a short, four-step sequence. The primary alcohol was tosylated and displaced by ammonia at high temperature to afford amine 117. Reaction of amine 117 with glutaric anhydride gave (1)-epilamprolobine (98), the antipode of the natural product (Scheme 7.26).37

Scheme 7.26

7.3.4 Sesbanimides Isolation and Biological Activity: Sesbanimides A
C (138
140) were first isolated from the seeds of Sesbania drummondi, a legume native to the Gulf Coast Plains, US.42 Investigation of these seeds, which were known to be toxic to livestock, was prompted by the discovery that their extracts had shown significant antileukemic properties. Sesbanimide A (138) was later isolated from the seeds of Sesbania vesicaria43 and S. punicea.44 The origin of the sesbanimides is likely microbial in nature; sesbanimide A (138) was most recently isolated from marine Agrobacterium strain PH-103, while sesbanimide C (140) was produced from marine Agrobacterium strain PH-A034C.45 Sesbanimide A (138), in particular, has been reported to have potent antitumor properties and immunosuppressive activity. Against KB cells, 138 displayed an in vitro ED50 of 7.7 3 1023 μg/mL and gave in vivo T/C values of 140
181 in the 0.008
0.032 mg/kg range against PS lukemia.42a Sesbanimides B (139) and C (140) displayed similar activity, but required c. 10 times higher dosage levels (Fig. 7.8).42a

Figure 7.8

274

Imides

Synthesis: Given the potent biological activity of the sesbanimides, a significant amount of effort has been devoted to their synthesis. Schlessinger and Wood reported the first total synthesis of (2)-sesbanimide A (138), the antipode of the natural material.46 Their route began with aldehyde 141, a known compound that is readily prepared from D(2)-sorbitol. Aldehyde 141 was allowed to react with the sodium salt of phosphonate 142 to give α,β-unsaturated ester 143 in 87% yield. Malonate 144 was added to ester 143, which gave a 77% yield of diester 145. Glutarimide formation was achieved with NH4OH followed by heating up to 210°C (146, 68% yield over two steps). Selective hydrolysis of the primary alcohol-containing acetal was enabled by treatment of 146 with trifluoroacetic anhydride (TFAA) in acetic acid followed by a carefully pH-controlled workup; TBS protection of the secondary alcohol and DIBAL-H reduction of the primary acetate gave alcohol 147 in 84% yield over three steps. The alcohol was oxidized to the corresponding aldehyde and allowed to react with crotylstannane 149 in the presence of BF3  OEt2 to give a mixture of alcohol epimers 150 in 51% yield. Oxidation to the ketone and deprotection/cyclization formed the THF (tetrahydrofuran) ring and delivered (2)-sesbanimide A (138) in 63% yield over two steps (Scheme 7.27).46

Scheme 7.27

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Pandit and coworkers prepared both (2)-sesbanimide A (138) and (1)-sesbanimide A (138) from L- and D-xylose derivatives.47 Known aldehyde 141 was converted to α,β-unsaturated ester 152 via a Wittig reaction in 69% yield. The glutarimide ring was installed via basemediated cyclization with amide 153; the intermediate 154 was hydrolyzed with TFA and heating to trigger the decarboxylation to afford 146 in 45% yield over three steps. At this stage, one of the acetals was hydrolyzed and converted to the bis-acetate 155 (89% yield). After cleaving the acetates to reveal the diol, the alcohols were reprotected as a different acetal that could be removed under reductive conditions later in the synthesis (Scheme 7.28).

Scheme 7.28

Partial reductive cleavage of the acetal in intermediate 156 allowed for the primary alcohol to be subsequently oxidized to the corresponding aldehyde (158, 41% over two steps). Aldehyde 158 was allowed to react with allylsilane 159 in the presence of BF3  OEt2 and the resulting epimeric alcohols were oxidized to single ketone in 30% yield over two steps. A 2,3-dichloro-5,6-dicyano-p-benzoquinone (DDQ) oxidation revealed the secondary alcohol and treatment of the intermediate with acid, facilitated the cyclization to afford (2)-sesbanimide A (138). An identical route was used to prepare the natural enantiomer, (1)-sesbanimide A (138) (Scheme 7.29).47 Terashima and coworkers also used L- and D-xylose derivatives as a starting point for their synthesis of both (1)-sesbanimide A (138) and

276

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Scheme 7.29

(2)-sesbanimide B (139).48 Diol 161 was readily prepared in high yield over three steps from D-xylose. The diol 161 was bis-benzylated (NaH, then BnCl) and deprotected with acid to reveal a second diol. A Wittig reaction of the hemiacetal gave ring-opened α,β-unsaturated ester 162 in 61% yield over three steps. Installation of the required acetal was readily achieved with trimethylsilyl trifluoromethanesulfonate (TMSOTf) in dimethoxyethane (163, 79% yield). A Michael addition with the sodium salt of dimethyl malonate followed by demethoxydecarbonylation afforded diester 164 in 89% yield. A four-step sequence installed the glutarimide in 51% yield: Hydrolysis of the diester, activation of the acids with methyl chloroformate, ammonolysis to the corresponding amide acid, and dehydration to close the ring. Hydrogenolysis of the benzylprotecting groups furnished diol 166 in 95% yield (Scheme 7.30).

Scheme 7.30

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In order to protect the secondary alcohol, the primary alcohol was esterified and then reduced followed by TBS protection. Oxidation of the primary alcohol to the corresponding aldehyde was conducted under Collins conditions (167, 57% yield over four steps). A regioselective Reformatsky reaction was used to install the lactone in 73% yield; the lactone was reduced to the diol stepwise (DIBAL-H, then Luche reduction, 73% yield over two steps) and the primary alcohol protected with tertbutyl(chloro)diphenylsilane (TBDPSCl) to give alcohol 170 as a mixture of diastereomers. A final oxidation of the epimeric secondary alcohols and TBAF deprotection allowed the THF ring to cyclize and furnish (1)-sesbanimide A (138) and (2)-sesbanimide B (139) in 16% and 19% yield, respectively (Scheme 7.31).48

Scheme 7.31

A similar route was used by Koga and coworkers to prepare (1)-sesbanimide A (138) in 21 steps from D-glucose.49 Dithioacetal 171, prepared in four steps from D-glucose, was treated with base and dibromomethane to install the methylene acetal. Deprotection of the dithioacetal gave aldehyde 172 in 69% yield over two steps. A Witting reaction installed the α,β-unsaturated ester 173 in 99% yield, while the glutarimide ring was formed by reaction of the olefin with lithiated trimethylsilylacetonitrile, fluoride-promoted removal of the silyl group, hydrolysis of the nitrile to the amide, and cyclization (174, 34% yield over four steps). Treatment of the resulting product with acid gave a quantitative yield of diol 175 (Scheme 7.32). Oxidative cleavage of the diol followed by reduction gave primary alcohol 177 in 89% yield over two steps. A protecting group swap on the

278

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Scheme 7.32

secondary alcohol was completed in four steps (72% yield) followed by oxidation to the aldehyde to afford 148 in 95% yield constituting a formal synthesis. Coupling of aldehyde 148 with stannane 149 gave diastereomers 150 and 180 in 18% and 17% yield, respectively. As seen previously, oxidation and cyclization gave (1)-sesbanimide A (138) (Scheme 7.33).49

Scheme 7.33

Grieco and coworkers were the first group to complete a total synthesis of sesbanimide A (138) and B (139) that did not rely on sugars as their starting material.50 Lactone 183 was prepared on large scale in two steps by mixing glyoxylic acid (181) and cyclopentadiene (182) in water, followed by protection of the alcohol with chloromethyl methyl ether

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(MOMCl) (29% yield over two steps). A two-stage reduction both reduced the lactone and the olefin to diol 184 in 70% yield. The resulting primary alcohol was protected with TBSCl, followed by pyridinium chlorochromate (PCC) oxidation of the secondary alcohol to a ketone and Baeyer
Villiger oxidation to afford lactone 185 (68% yield over three steps). The enone was installed in two steps: addition of phenylselenyl chloride followed by oxidation to the corresponding sulfone and elimination (186, 70% yield over two steps). The installation of the γ-hydroxyl functionality with the correct stereochemistry required a four-step sequence. After migration of the olefin (187, 83% yield), dimethyldioxirane (DMDO) was used to generate the epoxide, which was then opened with triethylamine in dichloromethane (DCM) to afford 188 in 68% yield over two steps. (Scheme 7.34).

Scheme 7.34

Inversion of the γ-hydroxyl group to furnish alcohol 189 was realized via a Misunobu reaction in 75% yield. The methylene acetal 190 was isolated in 45% yield after a short reaction time with BF3  OEt2. The glutarimide ring was installed in three steps beginning with the conjugate addition of silyl ketene acetal 191 to the α,β-unsaturated lactone 190. The intermediate ester 192 was converted to bis-amide 193 upon exposure to ammonia in methanol; the ring-closing event occurred after heating to 259°C for 50 minutes to afford glutarimide 194 in 28% yield over three steps. After two protecting group manipulations, the attempt to silylate the secondary alcohol 195 resulted in tricyclic silyl ether 196 in near quantitative yield. A two-step redox operation converted the pivaloate to the required aldehyde 197 in 79% yield (Scheme 7.35).50

280

Imides

Scheme 7.35

The Schlessinger protocol (discussed earlier) was used to convert aldehyde 197 into a mixture of alcohols 198 and 199. The remainder of the synthesis follows previous route: Collins oxidation of the secondary alcohols to the corresponding ketones, followed by acidic hydrolysis of the silyl ethers and cyclization to afford racemic sesbanimide A (138) and B (139) (Scheme 7.36).50

Scheme 7.36

Panek and colleagues reported an asymmetric formal synthesis of (1)-sesbanimide A (138) based upon several key transformations, including a diastereoselective catalytic osmylation and chelation-controlled nucleophilic addition of vinyl Grignard reagents to forge three of the stereocenters.51 α,β-Unsaturated aldehyde 200 was treated with a lithiated silane to afford alcohol 201, which was subsequently oxidized to ketone

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202 (27% yield over two steps). Asymmetric reduction of ketone 202 with a chiral borane furnished secondary alcohol 203 in 76% yield and 92% ee. Acetylation followed by a diastereoselective osmium-catalyzed dihydroxylation in the presence of trimethylamine N-oxide (TMNO) afforded diol 205 in 92% yield with 4.0
4.4:1 anti:syn selectivity. Sequential protections of the diol as silyl and methoxymethyl (MOM) ethers gave intermediate 206 in 94% yield over two steps. The acetate was subsequently cleaved with DIBAL-H to reveal the secondary alcohol, which was then oxidized to furnish ketone 207 (86% yield over two steps). A selective hydrogenoloysis was achieved whereby the acyl silane functionality was converted to aldehyde 208 in 84% yield, while leaving the benzyl-protecting group untouched (Scheme 7.37).

Scheme 7.37

The addition of vinylmagnesium bromide to aldehyde 208 was achieved with good yield and diastereoselectivity (86%, 5:1 ratio). The reaction conditions were critical: High dilution and fast addition times for the Grignard reagent were found to give the best stereocontrol. Deprotection of the silyl group revealed the diol 210, which was converted to the required methylene acetal with bromochloromethane (211, 55% over three steps). Ozonolysis transformed the olefin into an aldehyde, which was allowed to react in a Wittig reaction to give α,β-unsaturated ester 212 in 74% yield. Conjugate addition and cyclization of t-butyl acetimidoacetate with 212 afforded glutarimide 213. Decarboxylation of the extraneous ester gave precursor 214 in 63% yield over two steps. A final

282

Imides

Scheme 7.38

three-step sequence of protecting group manipulations completed the formal synthesis of (1)-sesbanimide A (138) as advanced intermediate 216 intercepts Terashima’s route described earlier (Scheme 7.38).51 Honda and coworkers reported a formal synthesis of sesbanimides A (138) and B (139).52 The key step begins the synthesis and involves the chelation-controlled aldol reaction of a tetronic acid derivative 218 with glyceraldehyde derivative 217. The resulting alcohol was protected with chlorotriethylsilane (TESCl) to afford optically active lactone 219. Reduction of the olefin and a protecting group swap was achieved in three steps to furnish protected polyol 220 in 95% yield. The cyclic acetal was cleaved with TFA and the resulting diol oxidatively cleaved with sodium periodate. The newly revealed aldehyde was reduced to the corresponding alcohol with NaBH4 and protected with TBDPSCl (221, 58% yield over four steps). Lactone 221 was reduced to lactol 222 with DIBAL-H in 90% yield. Ring-expansion was achieved by the addition of thioacetal 223 and treatment of the intermediate with acid to give spirocycle 224 in 83% yield. The thioacetal was removed with sodium periodate to return lactone 225 in quantitative yield. A sequence of selenide addition
elimination installed the required olefin (226, 87% yield) and exposure of the α,β-unsaturated lactone 226 to BF3  OEt2 afforded methylene acetal 190 in 83% yield. This intermediate intercepts Grieco’s route and constitutes a formal synthesis of sesbanimides A (138) and B (139) (Scheme 7.39).52

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Scheme 7.39

7.3.5 Streptimidone Isolation and Biological Activity: Steptimidone (227) was first isolated from the cultures of a Streptomyces sp. in 195953 and has since been identified as a component in the culture broths and mycelial mats of Micromonospora coerulea strain Ao58.54 9-Methylsteptimidone (228) has been isolated from both Streptomyces sp. S-885 and E/887.55 As with the structurally similar cycloheximide (52), both natural products inhibit protein synthesis in eukaryotic cells and exhibit antiyeast, antifungal, antiprotozoal, and herbicidal activity.53,54 In contrast to cycloheximide (52), steptimidone (227) has not shown plant phytotoxicity in some studies, making it a candidate as a plant chemotherapeutic.54 The antiviral activity of 9methylsteptimidone (228) against poliovirus, vesicular stomach virus, and the Newcastle disease virus has also been reported (Fig. 7.9).55b Synthesis: The synthesis of steptimidone (227) and its diastereomers was reported by Kiyota and coworkers in 2000.56 Enantiopure ester 229 was converted by a known procedure to benzyl ether 230.57 Oxidation of the primary alcohol gave the corresponding aldehyde, which was treated with MeMgI to give a diastereomeric mixture of alcohols 231 in 73% yield. Protection of the alcohol with a silyl group followed by hydrogenolysis gave alcohol 233. The alcohol was oxidized to an aldehyde and

284

Imides

Figure 7.9

treated with phosphane oxide 234 to afford diene 235 in 67% yield. Removal of the TBS group with TBAF and oxidation with Dess
Martin periodinane furnished ketone 237 (Scheme 7.40).

Scheme 7.40

Intermediate ketone 237 was treated with LDA to form the required enolate, which then was allowed to react with aldehyde 238; the reaction resulted in a mixture of two unnatural diastereomers of streptimidone 239 and 240 in 28% and 19% yield, respectively (Scheme 7.41).

Scheme 7.41

Natural streptimidone (227) and the final unnatural diastereomer of streptimidone 242 were prepared in an analogous fashion from ester 229 using benzyl ether 241 as an intermediate (Scheme 7.42). From these synthetic studies it was reported that the natural stereochemical configuration of streptimidone (227) is required for antifungal activity.56

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Scheme 7.42

7.4 MALEIMIDES 7.4.1 Farinomalein Isolation and Biological Activity: Farinomalein A (243) was first isolated from the entomopathogenic fungus Paecilomyces farinosus HF599.58 The producing strain of fungus, in turn, was itself isolated from a lepidopteran larval cadaver collected on Mt. Tsukuba, Ibaraki, Japan. Farinomalein A (243) and its methyl ester 244 along with farinomaleins C
E (245
247) were also isolated from an unidentified endophytic fungus gathered from the inner tissues of healthy leaves of the mangrove plant (Avicennia marina, Oman).59 A closely related derivative, pestalotiopsoid A (248), was isolated from the endophytic fungus Pestalotiopsis sp. found on the Chinese mangrove plant Rhizophora mucronata.60 Farinomalein A (243) has potent activity against the plant pathogen Phytophthora sojae P6497 (5 μg/disk),58 while the methyl ester 244 has moderate cytotoxic activity against the mouse lymphoma cell line L5178Y (4.4 μg/mL).59 A subsequent study of synthetically prepared farinomaleins A (243), C
E (245
247), and various analogs showed that a lipophilic ester group enhanced antifungal potency against Cladosporium cladosporioides (e.g., 243 at 5 μg vs 245 at 0.5 μg) (Fig. 7.10).61

Figure 7.10

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Imides

Synthesis: Farinomalein A (243) was first prepared by Miles and Yan via a short, three-step sequence starting from isovaleraldehyde (249).62 γ-Hydroxybutenolide 250 was synthesized in 10 g batches in 65%
75% yield and exists in equilibrium with a small amount of open chain tautomer 251. Oxidation with Dess
Martin periodinane furnished anhydride 252; the crude intermediate was then treated directly with either β-alanine (253) or 254 to furnish farinomalein A (243) and farinomalein A methyl ester (244) (64% and 58% over two steps, respectively) (Scheme 7.43).

Scheme 7.43

Dallavalle and coworkers reported a more scalable route that intercepts the intermediate γ-hydroxybutenolide 252.63 A Horner
Wadsworth
Emmons reaction of butyrate 255 with triethylphosphonate 256 gave diester 258 in 80% yield. Hydrolysis with LiOH followed by cyclization with TFAA gave γ-hydroxybutenolide 252 in near quantitative yield over two steps to complete the formal synthesis (Scheme 7.44).

Scheme 7.44

Farinomalein C (245) and D (246) were readily prepared in good yield from farinomalein A (243) by esterification with the appropriate alcohol (92% yield and 54% yield over two steps, respectively) (Scheme 7.45).61 The same authors prepared farinomalein E (247), though the requisite alcohol requires seven steps to prepare (not shown).

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Scheme 7.45

7.4.2 Pencolide Isolation and Biological Activity: Pencolide was first isolated in 1963 from cultures of Penicillium multicolor Grigorrieva
Manilova and Poradielova (NRRL 4036).64 Although the stereochemical assignment was initially proposed to be (E),65 this was later corrected to (Z) by Olsen and coworkers.66 Subsequent isolations of pencolide (260) have been reported from P. sclerotiorum (Serra do Cipó National Park, Brazil)67 and P. citreonigrum (Joao Pessoa, State of Paraíba, Brazil).68 The biological activity of pencolide is still unclear. Takahashi and coworkers reported moderate activity (c. 13
17 mm zones of inhibition with 100 μg/disk) against Streptococcus pyogenese, Staphylococcus aureus, Salmonella typhimurium, Escherichia coli, and Candida albicans67; however, Cichewicz and coworkers observed no activity against 10 Gram-negative and Gram-positive bacteria and 5 fungi (including many of the same previously reported species) at up to 135 μg/disk (Fig. 7.11).68 Synthesis: Inspired by a biosynthetic proposal, Strunz and Ren prepared pencolide (260) in one step by mixing L-threonine (261) and anhydride 262 at 150°C for 3 hours to furnish pencolide (260) in 42% yield (Scheme 7.46). Racemic threonine could also be used in the reaction with similar results (260, 41% yield).69

Figure 7.11

Scheme 7.46

288

Imides

Figure 7.12

7.5 POLYKETIDES 7.5.1 Dorrigocin A and B Isolation and Biological Activity: Dorrigocins A (263) and B (264) were isolated in 1994 by researchers in Abbott Laboratories from a culture of Streptomyces platensis subsp. rosaceus strain AB1981F-75 (originally collected from soil on the Dorrigo plateau in New South Wales, Australia).70 Dorrigocin A (263) was reported to reverse the morphology of rastransformed NIH/3T3 cells; instead of inhibiting prenylation of protein synthesis, 263 inhibits the carboxylmethyltransferase in K-ras transformed cells.71 Shen and coworkers have demonstrated that dorrigocins A (263) and B (264) are not, strictly speaking, natural products, but instead shunt metabolites of isomigrastatin (Fig. 7.12).72 Synthesis: No total syntheses of dorrigocins A (263) and B (264) have been completed, though various analogs and congeners have been reported.73 Brazidec and coworkers prepared the C1
C13 fragment of 2,3-dihydrodorrigocin A (279) in a stereoselective fashion over 14 linear steps in a 2% overall yield.74 6-Bromohexanoic acid (265) was converted via a previously published route to sulfone 266, which was subjected to a Julia
Kocieñski olefination with aldehyde 267 in 76% yield as a 1:1 mixture of (E:Z) isomers. A 9:1 ratio of isomers [in favor of (E)] was obtained for olefin 269 after exposure to 2,20 -azobis(2-methylpropionitrile) (AIBN) and thiophenol. Deprotection of the silyl ether revealed the primary alcohol, which was subsequently oxidized with Dess
Martin periodinane to afford aldehyde 271 in 71% yield over two steps (Scheme 7.47). An aldol reaction was used to couple aldehyde 271 with chiral auxiliary 272 in 74% yield with excellent selectivity. The resulting secondary

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Scheme 7.47

alcohol was protected as the methoxymethyl ether (274, 79% yield), and the auxiliary removed with LiBH4 in methanol to furnish the primary alcohol in 70% yield. As before, the alcohol was oxidized to the corresponding aldehyde 275 with Dess
Martin periodinane in 86% yield (Scheme 7.48).74

Scheme 7.48

Diester 277 was prepared in 66% yield via the coupling of aldehyde 275 with stabilized phosphorilidene 276. Reduction of the ethyl ester followed by acidic hydrolysis of the t-butyl ester completed the synthesis of the C1
C13 fragment of 2,3-dihydrodorrigocin A (279) in 16% yield over the final two steps (Scheme 7.49).74

290

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Scheme 7.49

7.5.2 Isomigrastatin Isolation and Biological Activity: Isomigrastatin (280) was isolated from S. platensis strain NRRL 18993 by Kosan Bioscience in 2002, a species that also produces migrastatin (281) and dorrigocins A (263) and B (264) (Fig. 7.13).75 Isomigrastatin (280) is extremely unstable, both hydrolytically and thermally. Elegant studies by Shen and coworkers demonstrated that isomigrastatin (280) is the “true” natural product produced by Streptomyces sp. and that migrastatin (281) and dorrigocins A (263) and B (264) are shunt metabolites, formed by hydrolytic or thermal degradation of 280.72 Conversion to migrastatin (281) occurs via a 3,3-sigmatropic rearrangement (Pathway 1, starred carbon added for clarity) in the presence of water or heat. Hydrolysis of the ester involving migration of the olefin (Pathway 2) leads to dorrigocin A (263), while direct attack of water on the ester itself (Pathway 3), gives dorrigocin B (264) (Fig. 7.14).76 Synthesis: Despite the structural similarity between isomigrastatin (280) and migrastatin (281), Danishefsky and coworker’s routes toward the two

Figure 7.13

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Figure 7.14

compounds bear little resemblance, especially in the later stages.77 Lactol 284 was prepared from dihydropyrone 282 as discussed in the migrastatin (281) synthesis (see Scheme 7.62). Treatment of lactol 284 with 3chloroperbenzoic acid (mCPBA) afforded epoxide 284 in 43% yield; reductive ring-opening with LiBH4 gave diol 286 in excellent yield. Transient protection of the primary alcohol allowed for the preparation of MOM ether 287 in 75% yield over three steps (Scheme 7.50).

Scheme 7.50

Glutarimide Wittig reagent 290 was prepared in a straightforward manner from aldehyde 238. Wittig reagent 288 was mixed with aldehyde

292

Imides

238 to afford intermediate 289 in 70% yield. Reduction of the enone proceeded smoothly to give glutarimide Wittig reagent 290 in 95% yield (Scheme 7.51).77

Scheme 7.51

After oxidation of alcohol 287 to an intermediate aldehyde, Wittig reagent 290 was added to furnish enone 291 in 83% yield. The stereochemistry of the next reduction proved critical because the pending cuprate addition was found to occur with high antiselectivity. A stereoselective CBS reduction, followed by TBS protection, gave the required protected alcohol 292, with approximately 10:1 selectivity. Addition of the cuprate to allylic epoxide 292 afforded the desired diastereomer of allylic alcohol 293 in 80% yield (Scheme 7.52).77

Scheme 7.52

Esterification of allylic alcohol 293 with racemic carboxylic acid 294 proceeded with high kinetic resolution, giving an 8:1 mixture of diastereomers (at the selenide position) in 95% yield. The TBS group was

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293

Scheme 7.53

cleaved with HF  pyridine to reveal the secondary alcohol, which was subsequently oxidized to the corresponding ketone. The MOM group was removed to provide the ring-closing metathesis (RCM) precursor 296 in 68% yield over three steps. The ruthenium-catalyzed ring-closing metathesis afforded 21% of the desired (E) isomer, along with 36% of the (Z) isomer. Oxidation
elimination of the selenide gave the (E) isomer with good selectivity and completed the total synthesis of isomigrastatin (280) in 93% yield. Treatment of isomigrastatin (280) with trimethylphosphine rapidly and quantitatively isomerized the enone olefin from (E) to (Z), supporting the notion that 298 is more stable than 280 (Scheme 7.53).77

7.5.3 Lactimidomycin Isolation and Biological Activity: Lactimidomycin (299) was originally isolated by researchers at Bristol
Meyers Squibb in 1992 from the culture broth of Streptomyces amphibiosporus R310-104 (ATCC 53964).78 Initial

294

Imides

Figure 7.15

biological testing revealed 299 prolonged the survival time of mice transplanted with experimental tumors as well as some antifungal activity.78 Further studies showed that lactimidomycin (299) inhibits DNA and protein biosynthesis.79 Some reports suggest 299 is a potent cell migration inhibitor,80 while others report that no significant cell migration inhibition occurs at subtoxic doses.81 More recently, the mechanism of action for lactimidomycin (299) was reported to involve preventing binding of tRNA by 299 itself binding at the E-site of tRNA (specifically targeting the first elongation cycle) (Fig. 7.15).82 Synthesis: The only two total syntheses of lactimidomycin (299) reported to date have both been by Fürstner and coworkers, utilizing ring-closing alkyne metathesis as the key step.81,83 Treatment of ester 300 with LDA and methyl iodide, followed by protection with TESCl gave α-methyl ester 301 in excellent yield. After reduction of the ester to the aldehyde, olefination afforded α,β-unsaturated ester 302 in 92% yield over two steps. A two-step redox operation furnished α,β-unsaturated aldehyde 303 (77% yield), which was subjected to an aldol reaction with chiral auxiliary 304. The chiral auxiliary was converted to Weinreb amide 305 before being reduced to aldehyde 306 (Scheme 7.54).83b

Scheme 7.54

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Aldehyde 306 was converted to two different alkyne precursors: Alkyne 308 with Ohira
Bestman reagent 307 in 44% yield over three steps, and enyne 310 via Julia olefination with sulfone 309 in 59% yield over two steps (Scheme 7.55).83b

Scheme 7.55

Alkyne 308 proved unproductive in the ring-closing alkyne metathesis; only dimerization and oligomerization products were observed. In contrast, enyne 310, after coupling with acid 311 to afford diyne 312, smoothly underwent the desired ring-closing metathesis giving macrolide 314 in 95% yield. The reaction was even successful on gram-scale, delivering 1.2 g of 314 in 84% yield. The required (E) olefin was installed via a hydrosilylation/protodesilylation event in 64% yield over two steps. Conversion of the ketone to enone was achieved via selenation followed by oxidation
elimination (64% yield over two steps). One further oxidation with Dess
Martin periodinane furnished ketone 317 in 87% yield (Scheme 7.56).83b All that remained was to install the glutarimide moiety. In order to obtain the desired selectivity in the aldol reaction of ketone 317 with aldehyde 238, borane 318 was required. While other conditions led to unappealing mixtures, borane gave 318 as a single diastereomer. Deprotection under buffered fluoride conditions completed the synthesis of lactimidomycin (299) in 60% yield over three steps (Scheme 7.57).83b In a later effort Fürstner and coworkers used 1,3-diene 319 with catalyst 320 in order to improve the route surrounding the ring-closing event. The catalyst and position of the silyl group in 319 was critical to the outcome of the reaction; upon exposure to the reaction conditions 1,3-diene 319 was converted to a 95:5 mixture of macrolides 321 and 322 in 76%
78% yield, favoring the desired product. Macrolide 321 was deprotected and desilylated in 74% yield over two steps to intercept their own

296

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Scheme 7.56

Scheme 7.57

previous route and constitutes a formal synthesis of lactimidomycin (299) (Scheme 7.58).83a Nagorny and coworkers completed a formal synthesis of lactimidomycin (299) that relied on a zinc-mediated Horner
Wadsworth
Emmons

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Scheme 7.58

macrocyclization. The reaction was successful on a fairly large scale (423 mg) in 93% yield and gave only minor amounts (c. 3%) of dimerized product (which was a concern based upon model studies). Deprotection of the TBS group completed the formal synthesis. The same group has prepared numerous analogs and reported that compounds lacking the glutarimide side chain were significantly less toxic to human mammary epithelial cells (Scheme 7.59).84

Scheme 7.59

Nagasawa and Kuwahara used a key Stille coupling to forge the bond between vinyl iodide 324 and stannane 325 in 89% yield. The macrocyclization was successful after hydrolysis of the ester and exposure of the intermediate acid to Yamaguchi macrocyclization conditions. Treatment of selenide 328 with NaIO4 not only promoted the elimination (to give the enone), but also removed the TES group to complete the formal synthesis of lactimidomycin (299) (Scheme 7.60).85 Li and Georg are the most recent group to complete a formal synthesis of lactimidomycin (299). The key macrocyclization of advanced

298

Imides

Scheme 7.60

intermediate 330 was a copper-catalyzed ene-yne coupling/alkyne reduction tandem reaction. Interestingly, if the enone was installed prior to the ring-closing event, complete decomposition of the starting material occurred. Presumably, the increased flexibility afforded with vinyl iodide 330 allowed the reaction to occur smoothly, giving the macrolide in 83% yield. Deprotection with TBAF completed the formal synthesis of lactimidomycin (299) in 91% yield with a 93:7 mixture of epimers at the chiral center of the ester (Scheme 7.61).86

Scheme 7.61

7.5.4 Migrastatin Isolation and Biological Activity: Migrastatin (281) was first isolated by Imoto and coworkers from the cultured broth of Streptomyces sp. MK929-43F187 and later found in cultures of S. platensis strain NRRL 18993.75 Migrastatin (281) was reported to inhibit the spontaneous migration of human esophageal cancer EC17 cells independently of either cytotoxicity

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299

Figure 7.16

or the inhibition of protein synthesis. More recent studies have continued to support the potent inhibition of tumor cell migration of 281, while showing it has no effect on the biosyntheses of DNA, RNA, or protein in the same cells.87 Much like the dorrigocins, migrastatin (281) was found to be a shunt metabolite of isomigrastatin (Fig. 7.16).72 Synthesis: Given the potent biological activity of migrastatin (281), many reports have been published disclosing the synthesis of simplified analogs73,88 along with approaches toward its core structure.89 In this section, only the two completed total syntheses will be discussed in detail.90,91 Danishefsky and coworker’s synthesis of migrastatin (281) began with the DIBAL-H reduction of commercially available diester 331 to the corresponding dialdehyde; the intermediate was immediately treated with divinylzinc to afford diol 332 in a diasteroselective fashion (75% yield). Following methylation of the diol, the acetonide was cleaved with acid to furnish diol 333 in 80% yield. Glycol cleavage of 333 with Pb (OAc)4 gave aldehyde 334, which proved sensitive to handling, and so was directly treated with diene 335 in a chelation-controlled Lewis acid
catalyzed diene aldehyde cyclocondensation. This sequence afforded dihydropyrone 282 in 75% yield over two steps as a single diastereomer. Luche reduction converted the enone to an allyic alcohol; this was followed by a Ferrier rearrangement that transposed the
OH to furnish lactol 284. Reductive ring-opening furnished diol 336 in 44% yield over two steps from enone 282. Several protecting group manipulations and an oxidation afforded aldehyde 338 (Scheme 7.62).90 Adduct 339 was the exclusive product formed from the aldol reaction between aldehyde 338 and chiral auxiliary 272 (67% yield). The resulting secondary alcohol was protected with TESCl and the auxiliary cleaved with LiBH4 (340, 83% yield over two steps). To ultimately install the

300

Imides

Scheme 7.62

glutarimide ring, alcohol 340 was converted to phosphonate 341 followed by the Masamune
Roush variant of the Horner
Wadsworth
Emmons reaction with aldehyde 238 to forge enone 342 in 57% yield over two steps (Scheme 7.63).90

Scheme 7.63

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Enone 342 was reduced in a conjugate fashion by treatment with Stryker reagent, followed by selective cleavage of the TES group to give alcohol 343 in 82% yield. A Yamaguchi esterification allowed for the joining of acid 344 with alcohol 343 in 66% yield. The total synthesis of migrastatin (281) was completed following a ring-closing metathesis (70% yield) and deprotection (Scheme 7.64).90

Scheme 7.64

The only other total synthesis of migrastatin (281) to date was achieved by Reymond and Cossy. Methyl ester 346 was deprotected with acid and selectively protected on the primary alcohol with TBDPSCl to afford alcohol 347 in 67% yield over two steps. O-Methylation and reduction of the ester gave alcohol 348. Swern oxidation converted the alcohol to an aldehyde; direct treatment of the crude intermediate with stannane 349 furnished olefin 350 in 87% yield with a dr of 90:10. Esterification of the secondary alcohol followed by ring-closing metathesis gave α,β-unsaturated lactone 354 in 52% yield over two steps (Scheme 7.65).91

302

Imides

Scheme 7.65

Reductive ring-opening of lactone 354 gave diol 355 in 74% yield. Both alcohols were TBS protected followed by selective cleavage of the silyl group on the primary allylic alcohol to afford 356 in 56% yield over two steps. After oxidation of the allylic alcohol to α,β-unsaturated aldehyde 357, a selective crotylation with complex 358 and TES protection of the resulting alcohol delivered diene 359 in 72% yield. Oxidative cleavage of the terminal olefin was accomplished chemoselectively via a two-step sequence to furnish aldehyde 360 in 80% yield over two steps (Scheme 7.66).91

Scheme 7.66

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Treatment of aldehyde 360 with vinylmagnesium chloride followed by oxidation of the resulting alcohol installed the vinyl ketone (361, 73% yield over two steps). A ruthenium-catalyzed crossmetathesis of vinyl ketone 361 with glutarimide 363 gave intermediate 364 in 32% yield after 72 hours. Hydrogenation of the enone proceeded smoothly in excellent yield (Scheme 7.67).91

Scheme 7.67

Selective deprotection of the TES group in glutarimide 365 proceeded in 80% yield and was followed by Yamaguchi esterification with diene 366 to afford advanced intermediate 367 in 74% yield. A sequence of TBDPS deprotection, oxidation of the primary alcohol to an aldehyde, and olefination under Takai conditions delivered triene 345 in 44% yield over three steps, and intercepts a late-stage intermediate from Danishefsky’s route, thus constituting a formal synthesis of migrastatin (281) (Scheme 7.68).91

304

Imides

Scheme 7.68

7.6 SUCCINIMIDES 7.6.1 Methyllycaconitine Isolation and Biological Activity: Methyllycaconitine (368) is a complex C19 diterpenoid alkaloid that has been isolated from various Delphinium species, including D. brownii and D. elatum.92 It is highly toxic to both mammals and insects, and plants in this class are routinely responsible for a significant number of cattle deaths in North America.93 Given the toxicity of methyllycaconitine (368), its use is limited to a chemical and biological probe rather than a pharmaceutical or agrochemical. Methyllycaconitine (368) is considered to be the most potent nonprotein antagonist of the neuronal nicotinic acetylcholine receptor (nAChR) known; as such, most of the studies around 368 are in this arena and have implications in the treatment of various cognitive and neurodegenerative diseases (Fig. 7.17).94 Synthesis: Although no total syntheses of methyllycaconitine (368) have been reported, several groups have prepared analogs, synthesized subunits, or made attempts toward the overall core.95 A semisynthesis via the acylation of lycoctonine (372) was reported by Blagbrough and coworkers in 1994.96 The asymmetric hydrogenation of itaconic acid (369)

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305

Figure 7.17

gave chiral diacid 370 in 72% yield and .90% ee. Treatment of the diacid 370 with acetyl chloride furnished the optically active anhydride 371 (Scheme 7.69).96

Scheme 7.69

Lycoctonine (372) was regioselectively acylated with isatoic anhydride (373), which gave an isomeric mixture of half-acid amides that were not isolated (not shown). The mixture was treated with anhydride 371 followed by the addition of N,N0 -carbonyldiimidazole (CDI) to afford methyllycaconitine (368) in 55% yield (Scheme 7.70).96

Scheme 7.70

7.6.2 Palasimide Isolation and Biological Activity: Palasimide (374) was isolated in 1990 from the pods of Butea monosperma, a deciduous tree native to the tropical and subtropical regions of India and Southeast Asia.97 The tree is an abundant

306

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Figure 7.18

source of natural products, including various flavonoids, alkaloids, and terpenoids. The root, bark, leaves, flowers, fruit, and seeds are frequently used by local populations for medicinal purposes; for example, the roots and leaves are effective for diseases of the eye, while the bark is used for dysentery and ulcers.98 Although no biological studies have been reported for palasimide (374) itself, palasonin (375, isolated from seeds of the same tree), has been shown to have anthelmintic properties (Fig. 7.18).99 Synthesis: All synthetic work toward palasimide (374) was undertaken and completed before its isolation and while actually targeting palasonin (375). Palasimide (374) was first prepared by semisynthesis in 1967 by Bochis and Fisher as a means to confirm the structure of palasonin (375).100 Later, Meinwald and coworkers completed a total synthesis of palasimide (374) en route to palasonin (375).101 Anhydride 376 and furan underwent a Diels
Alder reaction in the presence of hydrogen and Pd/C to afford adduct 377 in 69% yield. Subsequent conversion to the N-phenylimide derivative and reduction with NaBH4 gave a mixture of diols 378 and 379 (49% and 10% yield, respectively). A selective oxidation of the secondary alcohols was achieved with cerium-catalyzed conditions and stoichiometric KBrO3. The primary alcohol of imide 380 was converted to the corresponding iodide by mesylation and displacement with NaI in 69% yield over two steps. Radical dehalogenation of iodide 381 furnished palasimide (374) in 96% yield (Scheme 7.71).101

Scheme 7.71

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307

Shortly thereafter, Dauban and coworkers reported a two-step synthesis of palasonin (375) that serves as a formal synthesis of palasimide (374). Anhydride 382 and furan engaged in a high-yielding Diels
Alder reaction when exposed to 8 kbar of pressure for 138 hours. Reduction of the resulting olefin under hydrogen with 10% palladium on carbon gave palasonin (375) in 99% yield (Scheme 7.72).102

Scheme 7.72

7.6.3 Salfredins C1
C3 Isolation and Biological Activity: Salfredins C1 (384), C2 (385), and C3 (386) were isolated from the fermentation broth of Crucibulum sp. RF-3817 by Kamigauchi and coworkers as part of a screening program for identifying pharmacologically active microbial products. The salfredins were thus identified as novel aldose reductase inhibitors. In particular, they were tested for inhibitory activity against rat lens aldose reductase where salfredin C2 (385) was found to be the most potent of the group (Fig. 7.19).103 Synthesis: To date, no syntheses have been reported for salfredins C1
C3 (384
386). The total synthesis of salfredin B11, a nonnitrogencontaining coumarin derivative, has been reported.

7.6.4 Versimide and Violaceimides A
E Isolation and Biological Activity: Versimide (387) was isolated by Brown in 1970 as a metabolite from the mold Aspergillis versicolor.104 More recently it has been isolated from the insect fungus Gibellula sp. BCC36964.105 Versimide (387) was originally reported to have insecticidal properties104

Figure 7.19

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Figure 7.20

Figure 7.21

and has since been demonstrated to be cytotoxic to various cancerous and noncancerous cell lines, including MCF-7 (IC50 5 3.59 μg/mL), KB (IC50 5 4.83 μg/mL), NCI-H187 (IC50 5 1.89 μg/mL), and Vero (IC50 5 2.49 μg/mL) (Fig. 7.20).105 Violaceimides A
E (388
390) were recently isolated from the sponge-associated fungus Aspergillus violaceus strain WZXY-m64-17, which was collected from the South China Sea. Violaceimides A (388) and B (388-OMe) were found to selectively inhibit the growth of human leukemia U937 and human colorectal cancer cell HCT-8, while displaying low cytotoxicity toward Vero cells (Fig. 7.21).106 Synthesis: The first published synthesis of versimide (387) was reported by Atkins and Kay.107 The sodium salt of succinimide 391 was allowed to react with dimethyl bromomalonate (392) to afford intermediate 393. After forming an anion at the activated tertiary carbon of 393, chloromethyl methyl sulfide (394) was added to give alkylated succinimide 395. Oxidation with KMnO4 converted the sulfide to the corresponding sulfone in intermediate 396; subsequent heating in the presence of KI effected the elimination of the sulfone and CO2 to furnish versimide (387) in 81% yield (Scheme 7.73).107 Brown and Smale achieved a two-step total synthesis of versimide (387), albeit in a lower-yielding sequence than described earlier.108 Serine methyl ester hydrochloride (397) was treated with anhydride 371 in the

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309

Scheme 7.73

presence of Et3N in refluxing dioxane to afford succinimide 398 in 26% yield. Elimination of the alcohol was completed with anhydrous potassium hydrogen sulfate in refluxing N,N0 -dimethylformamide (DMF), which gave versimide (387) in 21% yield (Scheme 7.74).108 No syntheses of violaceimides A
E (388
390) have been reported to date.

Scheme 7.74

7.7 TETRAMIC ACIDS 7.7.1 Malyngamides Isolation and Biological Activity: The malyngamides are a large class (. 35 members) of amide-containing fatty acids isolated primarily from marine cyanobacteria of the genus Lyngbya (recently reclassified as Moorea spp.).109 Several malyngamides have also been isolated from the extracts of sea hares, molluscs known to sequester toxic metabolites from their diet, and include malyngamides O and P (from Stylocheilus longicauda)110 and malyngamides S and X (from Bursatella leachii).111,112 As a group, the

310

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malyngamides display a wide range of biological activity, including anticancer, antiinflammatory, antimalarial, antitubercular, and toxicity to fish and crustaceans. A small subset of the malyngamides contain an imide functionality in the form of a N-acyl tetramic acid. Malyngamides A (399) and B (401) were first isolated in 1978 from shallow-water varieties of a marine blue-green alga, Lyngbya majuscula (Kahala Beach, Oahu, Hawaii).113 Subsequent studies showed that malyngamides A (399) and B (401) may have an antifeedant effect in some species of reef fish.114 Isomalyngamides A (400) and B (402), which differ from malyngamides A (399) and B (401) only by the conformation of the chloromethylene group, were isolated in 1999 in the same location (L. majuscula, Kahala Beach, Oahu, Hawaii).115 These compounds were found to be lethal to the crayfish Procambarus clarkii when administered by intraperitoneal injection. Notably, it appears that over the course of a decade the major constituents of L. majuscula have shifted from malyngamides A (399) and B (401) to isomalyngamides A (400) and B (402). The cause of this change is currently unclear (Fig. 7.22).115 Malyngamides Q (403) and R (404) were isolated from the lipid extract of the marine cyanobacterium L. majuscula, collected near Sakatia Island, Madagascar.116 Malyngamide Q (403) could not be subjected to biological studies since it decomposed shortly after characterization; however, malyngamide R (404) was shown to be moderately toxic to brine shrimp (LD50 5 18 ppm). Malyngamide X (405) was isolated from the sea hare B. leachii, which was collected from Sichang Island in the Gulf of Thailand.117 Initial biological testing of compound 405 showed moderate cytotoxicity against oral human epidermoid carcinoma of the nasopharynx (ED50 5 8.20 μM), human small cell lung cancer (ED50 5 4.12 μM), and

Figure 7.22

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311

Figure 7.23

breast cancer cell lines (ED50 5 7.03 μM), antitubercular activity against Mycobacterium tuberculosis H37Ra strain (MIC 5 80 μM) and antimalarial activity against Plasmodium falciparum K1 multidrug-resistant strain (ED50 5 5.44 μM) (Fig. 7.23). Malyngamide 4 (406) was isolated from the extracts of L. majuscula (renamed Moorea producens) collected from the Red Sea near Jeddah, Saudi Arabia.118 It was found to be modestly active against lung carcinoma (ED50 5 40 μM), colorectal cancer (ED50 5 50 μM), and breast adenocarcinoma (ED50 5 44 μM) cell lines and possessed weak antitubercular activity against M. tuberculosis H37Rv (17% inhibition at 12.5 μg/mL). The most recently disclosed (and currently unnamed) malyngamide 407 was isolated from M. producens (Kahala Beach, Oahu, Hawaii).119 Unique among the compounds in its class, malyngamide 407 has a free hydroxyl group at C7 (instead of OMe). This is suggested to explain at least some of the significant drop in potency when comparing 407 to isomalyngamides A (400) and B (402) in mouse L1210 leukemia cells (IC50 5 2900, 130, and 30 μM for 407, 400, and 402, respectively) and lethal toxicity to the shrimp Palaemon paucidens (LD100 5 33.30, 4.25, and 1.70 mg/kg for 407, 400, and 402, respectively) (Fig. 7.24). Synthesis: Of the imide-containing malyngamides described earlier, only Q (403), R (404), and X (405) have succumbed to total synthesis. Cao and coworkers recently reported an enantioselective convergent route to malyngamides O, P, Q (403), and R (404).120 Ethyl 4-chloro-3oxobutanoate (408) was converted to azide 409 by treatment with NaN3 in aqueous acetone (78% yield). Hydrogenation of the azide and protection of the resulting amine afforded ketone 410 in 71% yield. Both the ester and ketone were reduced in the presence of DIBAL-H and the

312

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Figure 7.24

primary alcohol was selectively protected with TBDPSCl (411, 68% yield over two steps). A 2-iodoxybenzoic acid (IBX) oxidation followed by a Wittig reaction gave vinyl chloride 412 in 72% yield over two steps with a 3:1 (Z:E) ratio for the olefin. Methylation of the Boc-protected amine furnished key intermediate 413 in 99% yield (Scheme 7.75).

Scheme 7.75

The tetramic acid moiety 416 was prepared in seven steps as shown in Scheme 7.76. Serine (397) was sequentially protected on both the amine and alcohol to give 414 in 90% yield over two steps. The pyrrolidone ring was formed by treatment of acid 414 with Meldrum’s acid followed by heating with MeOH; a Mitsunobu reaction followed by cleavage of

Scheme 7.76

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313

the Boc group with TFA afforded pyrrolidone 415t in 42% yield over four steps. A final acetylation provided building block 416 in 81% yield (Scheme 7.76).120 Intermediate 412 (prepared in Scheme 7.75) was deprotected and coupled with acid 417 in 86% yield over two steps. Reprotection of the nitrogen (93% yield) followed by TBAF-mediated deprotection of the alcohol (85% yield) gave amide 420 (Scheme 7.77).120

Scheme 7.77

Intermediate 421, destined to become malyngamide R (404), was prepared in an analogous fashion from vinyl chloride 413. A sequence of Boc deprotection, DCC coupling with acid 417, and deprotection of the silyl ether gave intermediate 421 in 85% yield over three steps (Scheme 7.78).120

Scheme 7.78

After oxidation of the primary alcohol to the corresponding aldehyde with IBX, vinyl chlorides 422 and 423 were treated with TiCl4 in the presence of pyrrolidine 416, which allowed the aldol reaction to occur, giving a diastereomeric mixture of alcohols [56% when R 5 Me (424), 57% when R 5 Boc (425), over two steps]. IBX oxidation of the secondary alcohols afforded ketones 426 and 427 in 73%
75% yield (Scheme 7.79).120

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Scheme 7.79

The total synthesis of malyngamide R (404) was completed in 52% yield by treatment of penultimate intermediate 426 with trimethyl orthoformate and catalytic sulfuric acid to both convert the ketone to the required methyl enol ether and cleave the TBS group (Scheme 7.80).120

Scheme 7.80

The total synthesis of malyngamide Q (403) was completed in a similar fashion. After conversion of the ketone to the methyl enol ether with concomitant removal of the TBS group, treatment with Mg(ClO4)2 facilitated the Boc deprotection to afford malyngamide Q (403) in 40% yield over three steps (Scheme 7.81).120

Scheme 7.81

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315

Isobe and coworkers completed the first total synthesis of malyngamide X (405) by a convergent route that allows for the rapid assembly of a series of structural analogs.112 Epoxide 428 was opened with a cuprate reagent derived from C6H13MgBr; the intermediate alcohol 429 was converted to the corresponding epoxide 430 after treatment with base (90% yield over two steps). The lithium acetylide of alkyne 431 opened epoxide 430 to give enantiopure alcohol 432 in 98% yield. Methylation of the secondary alcohol was achieved in 71% yield by treatment of 432 with MeI in a mixture of NaH
DMSO. The alkyne was reduced under dissolving metal conditions to afford the trans olefin; cleavage of the protecting group gave alcohol 434 in 81% yield over two steps. A final oxidation completed the synthesis of the fatty acid portion of the natural product (Scheme 7.82).112

Scheme 7.82

The required pyrrolidone ring was prepared in a similar fashion to the route shown in Scheme 7.76. Protected valine 435 was treated with Meldrum’s acid to form the ring, while Mitsunobu conditions converted the free hydroxyl group to the corresponding methyl ether. Deprotection of the amide and acylation of the nitrogen gave pyrrolidone 438 in 68% yield over four steps. Pyrrolidone 438 was converted to the (Z)-enolate by treatment with n-Bu2BOTf; once formation was complete, the addition of Boc-alaninal (439) and Et2AlCl allowed the aldol reaction to proceed and furnished the antiselective product 440 in 44% yield. Deprotection and coupling with amino acid 441 afforded peptide 442 in

316

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82% yield. The synthesis of malyngamide X (405) was completed in 44% yield with a final deprotection and coupling with previously prepared acid 417 (Scheme 7.83).112

Scheme 7.83

7.7.2 Palau’imide Isolation and Biological Activity: Palau’imide (443) was isolated from a “mixed collection” of Lyngbya sp. NIH309. The combined collection sites in Palau include Short Dropoff, Big Dropoff, Lighthouse Channel, Ngerkuul Pass, and Ngerkuul Lagoon. Palau’imide (443) was only found in the Lyngbya extracts collected in Palau and was absent from the same organism collected in Guam. Initial biological testing revealed that Palau’imide (443) is cytotoxic to KB and LoVo cells (IC50 of 1.4 and 0.36 μM, respectively) (Fig. 7.25).121

Figure 7.25

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317

Synthesis: The first total synthesis of Palau’imide (443) was completed by Huang and coworkers and served to establish the stereochemistry of the C20 methyl group, which was still ambiguous after isolation.122 Synthesis of pyrrolidone 450 began with the conversion of methyl 2methylacetoacetate (444) to methyl enol ether 445 in 80% yield over two steps via treatment with trimethyl orthoester and catalytic sulfuric acid followed by thermolysis of the intermediate acetal. Allylic bromination with N-bromosuccinimide (NBS) proceeded to give 446 in 86% yield. Phenylglycine derivative 447, serving as a chiral auxiliary, was heated with bromide 446 to afford tetramate derivative 448 in 78% yield. Formation of the anion with t-BuLi and quenching with benzyl bromide gave intermediate 449 in 62% yield; the diastereoselectivity was approximately 6:1 in favor of the desired product, while the positional selectivity (the desired C5 position vs reaction at C3) was approximately 4:1. Finally, the auxiliary was cleaved via a ceric ammonium nitrate (CAN)-mediated oxidation to furnish pyrrolidone 450 in 80% yield (Scheme 7.84).122

Scheme 7.84

After activation with C6F5OH, valine derivative 451 was coupled with pyrrolidone 452 in 85% yield. The synthesis of Palau’imide (443) was completed after deprotection of the amine and the EDC-mediated coupling of acid 455 (67% over two steps) (Scheme 7.85).122 Pettus and coworkers completed a formal synthesis of Palau’imide (443) by developing a mild route to 3-methyl tetramic acid derivatives. After protection, phenylglycine derivative 457 was coupled with

318

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Scheme 7.85

2-bromopropionyl bromide to afford a diastereomeric mixture of amides 459 in 42% yield over two steps. The key cyclization was achieved with SmI2 followed by diazomethane and maintains a high proportion of the original enantiopurity. The methodology is suitable for a range of C5 derivatives (e.g., phenyl, isopropyl, sec-butyl). In this way pyrrolidone was prepared in 65% yield with an er of 92:8. After cleavage of the protecting group a recrystallization delivered fully enantiopure intermediate 452 and completed the formal synthesis of Palau’imide (443) (Scheme 7.86).123

Scheme 7.86

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319

Figure 7.26

7.7.3 Sintokamides Isolation and Biological Activity: Sintokamides A
E (461
465) were isolated by Andersen and coworkers in 2008 from specimens of the sponge Dysidea sp., collected near Palau Sintok, Karimunjawa archipelago, Indonesia.124 Sintokamide A (461) was found to act as an antagonist of androgen receptor with a unique mode of activity, which has implications in the treatment of prostate cancer (Fig. 7.26).125 Synthesis: Sintokamide C (463) was the first member of the class to succumb to total synthesis.126 The route began with known acid 467, which has been previously prepared over a nine-step sequence starting with L-glutamic acid (82). Tetramic acid 468 was synthesized in 70% yield by treatment of acid 467 with DCC and Meldrum’s acid, followed by heating in EtOAc. The addition of diazomethane afforded the methyl enol ether 469; subsequent exposure to TFA gave the amide 470 in 69% yield over two steps (Scheme 7.87).126 Construction of amino acid derivative 477 began with a Horner
Wadsworth
Emmons olefination of aldehyde 472 with phosphonate 471 in 72% yield. After hydrogenation of the enone, amide 474

320

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Scheme 7.87

was treated with sodium bis(trimethylsilyl)amide(NaHMDS) to form the corresponding enolate; the addition of methyl iodide gave intermediate 475 in 68% yield with high diastereoselectivity. The chiral auxiliary was reductively cleaved and the resulting alcohol protected with TBDPSCl. After treatment with acid, alcohol 476 was isolated in 71% yield over three steps. A 2,2,6,6-tetramethylpiperidine 1-oxyl (TEMPO)-[bis(acetoxy)iodo]benzene (BAIB) oxidation converted the primary alcohol to the corresponding carboxylic acid 477 in 85% yield (Scheme 7.88).126

Scheme 7.88

Carboxylic acid 477 was protected as the benzoate, treated with TFA to reveal the free amine, and acylated to furnish amide 479 in 83% yield over three steps. Several further protecting group and activating manipulations gave amide 481 in three steps (Scheme 7.89).126

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321

Scheme 7.89

Upon treatment with lithium bis(trimethylsilyl)amide (LiHMDS), tetramic acid 470 was acylated with amide 481 to afford advanced intermediate 482 in 71% yield. The silyl groups were cleaved with HF  pyridine and the resulting diol oxidized to the corresponding dialdehyde (484, 55% yield over two steps). Both aldehydes were chlorinated using triphenyl phosphate and chlorine in 77% yield. A final deprotection furnished sintokamide C (463) in 73% yield (Scheme 7.90).126

Scheme 7.90

The only other total synthesis of the sintokamides reported to date is a unified, protecting group-free approach by Zakarian and coworkers that

322

Imides

allowed for the preparation of three members of the class.127 The route began with the asymmetric ruthenium-catalyzed trichloromethylation of oxazolidinone 486, which gave the desired product 487 in 96% yield and .98:2 dr. The chiral auxiliary was removed with LiAlH4 (78% yield) and the resulting alcohol was converted to the corresponding nitrile via a nucleophilic displacement to afford 489 in 75% yield over two steps. After reduction of the nitrile to a primary amine, it was transformed into sulfinimine 490, which served to direct the subsequent Lewis acid
catalyzed cyanation that furnished intermediate 491 in 73% yield over three steps (dr . 95:5). The sulfinimine moiety was cleaved via hydrolysis and the resulting free amine acylated with succinimide derivative 492 (Scheme 7.91).127

Scheme 7.91

Dichloromethyl building block 499 was prepared in a similar manner to 493, albeit with minor modifications. The asymmetric rutheniumcatalyzed dichloromethylation of oxazolidinone 486 proceeded in 64% yield with complete stereoselectivity. Instead of LiAlH4, NaBH4 was used for the removal of the chiral auxiliary and iododehydroxylation was employed to assist with installing the nitrile (496, 43% over three steps). Cyanation was achieved again via sulfinimine 497, but with a slightly lesser dr of 87:13 (86% yield). Hydrolysis of the chiral auxiliary afforded free amine 499 in 88% yield (Scheme 7.92).127 Chlorinated building blocks 499 and 493 were coupling using EDC in 91% yield and the methyl ester hydrolyzed with LiOH to give peptidic intermediate 500. Treatment with Meldrum’s acid, isopropyl chloroformate (501), and 4-(dimethylamino)pyridine (DMAP), followed by thermolysis and methylation crafted the tetramic acid moiety and completed

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323

Scheme 7.92

the synthesis of sintokamide A (461) in 48% yield, along with 24% of the epimer 503 (Scheme 7.93).127

Scheme 7.93

Sintokamides B (462) and E (465) were accessed in a similar fashion. Amines 505 and 506 were coupled with acid 493 in 91% and 92% yield, respectively. Installation of the tetramic acid portion completed the synthesis over three further steps to give sintokamides B (462) and E (465) in 60% (dr 5 . 95:5) and 65% yield (dr 5 67:33), respectively (Scheme 7.94).127

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Scheme 7.94

LIST OF ABBREVIATIONS AIBN BAIB BHT BINAP BPPM CAN CbzCl CDI CSA DBU DCC DCE DCM DDQ DEAD DIAD

2,20 -Azobis(2-methylpropionitrile) [Bis(acetoxy)iodo]benzene 2,6-Di-tert-butyl-4-methylphenol (1,10 -Binaphthalene-2,20 -diyl)bis(diphenylphosphine) (2S,4S)-1-tert-butoxycarbonyl-4-diphenylphosphino-2-diphenylphosphinomethyl-pyrrolidine Ceric ammonium nitrate Benzyl chloroformate N,N0 -Carbonyldiimidazole Camphor-10-sulfonic acid 1,8-Diazabicyclo[5.4.0]undecane N,N0 -Dicyclohexylcarbodiimide 1,2-Dichloroethane Dichloromethane 2,3-Dichloro-5,6-dicyano-p-benzoquinone Diethyl azodicarboxylate Diisopropyl azodicarboxylate

Imide Natural Products

DIBAL-H DMAP DMDO 1,2-DME DMF DMSO DMTMM dppp EDC HOAt HOBt HMDS HMPA IBX (2)-(Ipc) 2BCl IPCC KHMDS LDA LiHMDS mCPBA MOMCl MS MsCl NaHMDS NBS NMM NMO PCC PfpOH PTSA (S)-Me-CBS TBAF TBAI TBDPSCl TBDPSOTf TBSCl TBSOTf TEMPO TESCl TFA TFAA THF TMNO TMSCl TMSCN TMSOTf TsCl

Diisobutylaluminum hydride 4-(Dimethylamino)pyridine Dimethyldioxirane 1,2-Dimethoxyethane N,N0 -Dimethylformamide Dimethyl sulfoxide 4-(4,6-Dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride 1,3-Bis(diphenylphosphino)propane N-(3-Dimethylaminopropyl)-N0 -ethylcarbodiimide 1-Hydroxy-7-azabenzotriazole 1-Hydroxybenzotriazole Hexamethyldisilazane Hexamethylphosphoramide 2-Iodoxybenzoic acid (2)-Diisopinocampheylchloroborane Isopropenyl chloroformate Potassium bis(trimethylsilyl)amide Lithium diisopropylamide Lithium bis(trimethylsilyl)amide 3-Chloroperbenzoic acid Chloromethyl methyl ether Molecular sieves Methanesulfonyl chloride Sodium bis(trimethylsilyl)amide N-Bromosuccinimide 4-Methylmorpholine 4-Methylmorpholine N-oxide Pyridinium chlorochromate 2,2,3,3,3-Pentafluoro-1-propanol p-Toluenesulfonic acid (S)-2-Methyl-CBS-oxazaborolidine Tetrabutylammonium fluoride Tetrabutylammonium iodide tert-Butyl(chloro)diphenylsilane tert-Butyldimethylsilyl trifluoromethanesulfonate tert-Butyldimethylsilyl chloride tert-Butyldimethylsilyl trifluoromethanesulfonate 2,2,6,6-Tetramethylpiperidine 1-oxyl Chlorotriethylsilane Trifluoroacetic acid Trifluoroacetic anhydride Tetrahydrofuran Trimethylamine N-oxide Trimethylsilyl chloride Trimethylsilyl cyanide Trimethylsilyl trifluoromethanesulfonate p-Toluenesulfonyl chloride

325

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G, Tryptophan-Derived Alkaloids Produced in Culture by Streptomyces uncialis. Org. Lett 2008, 10, 3501
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4421. 15. a) Leach, B. E.; Ford, J. H.; Whiffen, A. J. Actidione, an Antibiotic From Streptomyces griseus. J. Am. Chem. Soc. 1947, 69, 474; b) Whiffen, A. J.; Bohonos, N.; Emerson, R. L. The Production of an Antifungal Antibiotic by Streptomyces griseus. J. Bacteriol. 1946, 52, 610
611. 16. a) Johnson, F.; Starkovsky, N. A.; Paton, A. C.; Carlson, A. A. The Total Synthesis of Cycloheximide. J. Am. Chem. Soc. 1966, 88, 149
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17. Preid’Homme, J.; Dubost, M. Handbook of 14th Int. Congr. on Pure and Applied Chemistry, Zurich, 1955, p. 382. 18. a) Rao, K. V. C-73: A Metabolic Product of Streptomyces albulus. J. Org. Chem. 1960, 25, 661
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86. Wonnacott, S.; Alberquerque, E. X.; Bertrand, D. Methyllycaconitine: A New Probe That Discriminates Between Nicotinic Acetylcholine Receptor Substrates. Method Neurosci. 1993, 12, 263
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95. a) Liu, M.; Cheng, C.; Xiong, W.; Cheng, H.; Wang, J.-L.; Xu, L. Total Synthesis of C19-Diterpenoid Alkaloid: Construction of a Functionalized ABCDE-Ring system. Org. Chem. Front. 2018, 5, 1502
1505; b) Carroll, F. I.; Ma, W.; Navarro, H. A.; Abraham, P.; Wolckenhauer, S. A.; Damaj, M. I.; Martin, B. R. Synthesis, Nicotinic Acetylcholine Receptor Binding, Antinociceptive and Seizure Properties of Methyllycaconitine Analogs. Bioorg. Med. Chem. 2007, 15, 678
685; c) Ismail, K. A.; Bergmeier, S. C. Structure
Activity Studies With Ring E Analogues of Methyllycaconitine. Synthesis and Evaluation of Enantiopure Isomers of Selective Antagonist at the A3 Nicotinic Receptor. Eur. J. Med. Chem. 2002, 37, 469
474; d) Baillie, L. C.; Bearder, J. R.; Li, W.-S.; Sherringham, J. A.; Whiting, D. A. Studies Into the Synthesis of a Sub-Unit of the Neurotoxic Alkaloid Methyllycaconitine. J. Chem. Soc., Perkin Trans. I 1998, 4047
4055; e) Baillie, L. C.; Bearder, J. R.; Whiting, D. A. Synthesis of the A/E/F Tricyclic Section of the Norditerpenoid Alkaloid Methyllycaconitine, A Potent Inhibitor of Neurotransmission. J. Chem. Soc., Chem. Commun. 1994, 2487
2488. 96. Blagbrough, I. S.; Coates, P. A.; Hardick, D. J.; Lewis, T.; Rowan, M. R.; Wonnacott, S.; Potter, B. V. L. Acylation of Lycoctonine: Semi-Synthesis of Inuline, Delsemine Analogues and Methyllycaconitine. Tetrahedron Lett. 1994, 35, 8705
8708. 97. Guha, P. K.; Poi, R.; Bhattacharyya, A. An Imide From the Pods of Butea monosperma. Phytochemistry 1990, 29, 2017. 98. Geeta, R.; Prakash, R.; Navgeet, S.; Neeru, V.; Sumit, J. Butea monosperma (Lam.) Kuntze: A Review. Int. Res. J. Pharm. 2011, 2, 98
108. 99. Raj, R. K.; Kurup, P. A. Isolation of Palasonin From the Seeds of Butea frondosa. Indian J. Chem. 1967, 5, 86
89. 100. Bochis, R. J.; Fisher, M. H. The Structure of Palasonin. Tetrahedron Lett. 1968, 9, 1971
1974. 101. Rydberg, D. B.; Meinwald, J. Synthesis of ( 6 )-Palasonin. Tetrahedron Lett. 1996, 37, 1129
1132. 102. Dauben, W. G.; Lam, J. Y. L.; Guo, Z. R. Total Synthesis of (2)-Palasonin and (1)-Palasonin and Related Chemistry. J. Org. Chem. 1996, 61, 4816
4819. 103. Matsumoto, K.; Nagashima, K.; Kamigauchi, T.; Kawamura, Y.; Yasuda, Y.; Ishii, K.; Uotani, N.; Sato, T.; Nakai, H.; Terui, Y., et al. Salfredins, New Aldose Reductase Inhibitors Produced by Crucibulum sp. RF-3817. I. Fermentation, Isolation and Structures of Salfredins. J. Antibiot. 1995, 48, 439
446. 104. Brown, A. G. Versimide, A Metabolite of Aspergillus versicolor. J. Chem. Soc. (C) 1970, 2572
2573. 105. Bunbamrung, N.; Intaraudom, C.; Supothina, S.; Komwijit, S.; Pittayakhajonwut, P. Antibacterial and Anti-Phytopathogenic Substances From the Insect Pathogenic Fungus Gibellula sp. BCC36964. Phytochemistry Lett. 2015, 12, 142
147. 106. Yin, J.; Zhang, C.; Huang, J.; Zhang, J.; Liu, D.; Huang, J.; Proksch, P.; Lin, W. Violaceimides A
E, Sulfur-Containing Metabolites From a Sponge-Associated Fungus Aspergillus violaceus. Tetrahedron Lett. 2018, 59, 3157
3160. 107. Atkins, P. R.; Kay, I. T. Synthesis of ( 6 )-Versimide. Chem. Commun. 1971, 430. 108. Brown, A. G.; Smale, T. C. Synthesis of ( 6 )-Versimide [Methyl α-(methylsuccinimido)acrylate] and Related Compounds. J. Chem. Soc. Perkin Trans. 1 1972, 65
68. 109. Burja, A. M.; Banaigs, B.; Abou-Mansour, E.; Burgess, J. G.; Wright, P. C. Marine Cyanobacteria—A Prolific Source of Natural Products. Tetrahedron 2001, 57, 9347
9377. 110. Gallimore, W.; Scheuer, P. J. Malyngamides O and P From the Sea Hare Stylocheilus longicauda. J. Nat. Prod. 2000, 63, 1422
1424. 111. Appleton, D. R.; Sewell, M. A.; Berridge, M. V.; Copp, B. R. A New Biologically Active Malyngamide From a New Zealand Collection of the Sea Hare Bursatella leachii. J. Nat. Prod. 2002, 65, 630
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112. Suntornchashwej, S.; Suwanborirux, K.; Isobe, M. Total Synthesis of Malyngamide X and Its 70 S-epi Isomer. Tetrahedron 2007, 63, 3217
3226. 113. a) Cardellina, J. H., II; Marner, F.-J.; Moore, R. E. Malyngamide A, a Novel Chlorinated Metabolite of the Marine Cyanophyte Lyngbya majuscula. J. Am. Chem. Soc. 1979, 101, 240
242; b) Cardellina, J. H., II; Dalietos, D.; Marner, F.-J.; Mynderse, J. S.; Moore, R. E. (2)-trans-7(S)-Methoxytetradec-4-Enoic Acid and Related Amides From the Marine Cyanophyte Lyngbya majuscula. Phytochemistry 1978, 17, 2091
2095. 114. Thacker, R. W.; Nagle, D. G.; Paul, V. J. Effects of Repeated Exposure to Marine Cyanobacterial Secondary Metabolites on Feeding by Juvenile Rabbitfish and Parrotfish. Marine Ecology: Progress Series 1997, 147, 21
29. 115. Kan, Y.; Sakamoto, B.; Fujita, T.; Nagai, H. New Malyngamides From the Hawaiian Cyanobacterium Lyngbya majuscula. J. Nat. Prod. 2000, 63, 1599
1602. 116. Milligan, K. E.; Márquez, B.; Williamson, R. T.; Davies-Coleman, M.; Gerwick, W. H. Two New Malyngamides From a Madagascan Lyngbya majuscula. J. Nat. Prod. 2000, 63, 965
968. 117. Suntornchashwej, S.; Suwanborirux, K.; Koga, K.; Isobe, M. Malyngamide X: The First (7R)-Lyngbic Acid That Connects to a New Tripeptide Backbone From the Thai Sea Hare Bursatella leachii. Chem. Asian J. 2007, 2, 114
122. 118. Shaala, L. A.; Youssef, D. T. A.; McPhail, K. L.; Elbandy, M. Malyngamide 4, A New Lipopeptide From the Rea Sea Marine Cyanobacterium Moorea producens (Formerly Lyngbya majuscula). Phytochemistry Lett. 2013, 6, 183
188. 119. Jiang, W.; Zhou, W.; Othman, R.; Uchida, H.; Watanabe, R.; Suzuki, T.; Sakamoto, B.; Nagai, H. A New Malyngamide From the Marine Cyanobacterium Moorea producens. Nat. Prod. Res. 2018, 32, 97
104. 120. Chen, J.; Fu, X.-G.; Zhou, L.; Zhang, J.-T.; Qi, X.-L.; Cao, X.-P. A Convergent Route for the Total Synthesis of Malyngamides O, P, Q, and R. J. Org. Chem. 2009, 74, 4149
4157. 121. Luesch, H.; Yoshida, W. Y.; Moore, R. E.; Paul, V. J. Structurally Diverse New Alkaloids From Palauan Collection of the Apratoxin-Producing Marine Cyanobacterium Lyngbya sp. Tetrahedron 2002, 58, 7959
7966. 122. Lan, H.-Q.; Ruan, Y.-P.; Huang, P.-Q. The First Enantioselective Synthesis of Cytotoxic Marine Natural Product Palau’imide and Assignment of Its C-20 Stereochemistry. Chem. Commun. 2010, 46, 5319
5321. 123. Bai, W.-J.; Jackson, S. K.; Pettus, T. R. R. Mild Construction of 3-Methyl Tetramic Acids Enabling a Formal Synthesis of Palau’Imide. Org. Lett. 2012, 14, 3862
3865. 124. Sadar, M. D.; Williams, D. E.; Mawji, N. R.; Patrick, B. O.; Wikanta, T.; Chasanah, E.; Irianto, H. E.; Soest, R. V.; Andersen, R. J. Sintokamides A to E, Chlorinated Peptides From the Sponge Dysidea sp. That Inhibit Transactivation of the N-terminus of the Androgen Receptor in Prostate Cancer Cells. Org. Lett. 2008, 10, 4947
4950. 125. Banuelos, C. A.; Tavakoli, I.; Tien, A. H.; Caley, D. P.; Mawji, N. R.; Li, Z.; Wang, J.; Yang, Y. C.; Imamura, Y.; Yan, L., et al. Sintokamide A is a Novel Antagonist of Androgen Receptor That Uniquely Binds Activation Function-1 in Its Amino-Terminal Domain. J. Biol. Chem. 2016, 291, 22231
22243. 126. Jin, Y.; Liu, Y.; Wang, Z.; Kwong, S.; Xu, Z.; Ye, T. Total Synthesis of Sintokamide C. Org. Lett. 2010, 12, 1100
1103. 127. Gu, Z.; Zakarian, A. Concise Total Synthesis of Sintokamides A, B, and E by a Unified, Protecting-Group-Free Strategy. Angew. Chem. Int. Ed. 2010, 49, 9702
9705.

CHAPTER 8

Synthesis and Applications of Cyclic Imides in Agrochemistry Clemens Lamberth

Chemical Research, Syngenta Crop Protection AG, Stein, Switzerland

8.1 INTRODUCTION During the last decades, intensive efforts have been undertaken to discover highly active chemicals with favorable toxicological and environmental properties for the selective control of weeds, insects, and fungal diseases. In several instances, cyclic imide derivatives have been found as promising agrochemical products. Many cyclic imides possess powerful biological activity, because on one side, such compounds belong to the big family of heterocycles, and on the other side, they can as well be counted to the huge group of carboxylic functions. Both structural motifs, the heterocylic rings and the carboxylic acid derivatives, play a very important role in agrochemistry, which has been recently summarized in two books.1,2 Approximately, two-third of all commercialized agrochemicals bear at least one heterocyclic ring, at least 50% of all crop protection products on the market derive from a carboxylic acid. Most of the cyclic imides with interesting activity against weeds, insects, and fungal diseases are pyrrolinediones or pyrrolidinediones. The only heterocyclic scaffolds, for which so far extensive reviews exist regarding their significance in crop protection chemistry, are pyrazole,3 oxazole,4 isoxazole,4 thiazole,5 isothiazole,5 pyridine,6 pyridazine,7 and pyrimidine.8 This chapter deals with all agrochemical aspects of cyclic imides. The main herbicidally, fungicidally, and insecticidally active imide classes are presented, together with their synthesis routes, modes of action, and biological spectrum. In addition, the role of cyclic imides as lead structure or as metabolite of nonimide crop protection agents is reported. Also the importance of imides as intermediates in the synthesis of other agrochemicals is covered.

Imides DOI: https://doi.org/10.1016/B978-0-12-815675-9.00008-4

© 2019 Elsevier Inc. All rights reserved.

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8.2 HERBICIDALLY ACTIVE CYCLIC IMIDES 8.2.1 N-Phenyltetrahydrophthalimide Herbicides Inhibiting Protoporphyrinogen IX Oxidase One of the most important herbicidal modes of action is the inhibition of protoporphyrinogen IX oxidase (PPO, protox), which is the last enzyme in the porphyrin pathway that is common to both chlorophyll and heme synthesis. In treated tissues, PPO inhibitors cause the accumulation of protoporphyrin IX. This tetrapyrrole is known to be a potent photosensitizer, generating high levels of singlet oxygen in the presence of sunlight. This oxygen modification induces peroxidation of unsaturated fatty acids in cell membranes, resulting in membrane leakage, pigment breakdown, and finally necrosis of the leaf. Therefore PPO inhibitors are also called peroxidizing herbicides.9,10 One of the important scaffolds, which has been successfully introduced into several commercialized PPO inhibitors, is the tetrahydrophthalimide bicycle, usually only substituted at the imide nitrogen with an aryl ring. Chlorphthalim (1) was the first example of this subclass which reached the herbicide market in 1981, it is specialized on the control of annual weeds in turf. Flumioxazin (2) was launched in 1994 and delivers preemergence control of annual broad-leaved weeds and some grasses in soybean, peanut, fruit trees, and grape. Flumiclorac-ethyl (3), which is a pre and postemergence herbicide for the control of broad-leaved weeds such as Xanthium strumarium (common cocklebur), Chenopodium album (lambsquarters), Ambrosia artemisiifolia (common ragweed), and Sida spinosa (prickly sida) in soybean and corn, has been commercialized in 1995. Cinidonethyl (4), a postemergence herbicide against annual broad-leaved weeds such as Galium aparine (cleavers) and Solanum nigrum (black nightshade) in cereals, is so far the youngest N-phenyltetrahydrophthalimide with a market entry in 1998 (Fig. 8.1).11 The two former structurally related developmental candidates flumipropyn (5)12 and S-2314213 (6) were foreseen to be applied as postemergence herbicides in wheat. The flumioxazin derivative B2055 (7), which is iodinated at the terminal alkyne position, is a powerful postemergence herbicide with better crop selectivity than flumioxazin (2) at the same use rate.14 The combination of high efficacy against several weeds, such as Abutilon theophrasti (velvetleaf), Amaranthus ascendens (Guernsey pigweed), and Digitaria sanguinalis (crabgrass) and a crop selectivity comparable to the structurally related flumioxazin (2) is also the strength of the phthalimide

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Figure 8.1 Commercialized tetrahydrophthalimide herbicides.

8.14 Soil-applied EK-5385 (9) shows good rice selectivity and potent herbicidal activity against Echinochloa crus-galli (barnyardgrass).15 The tetrahydrophthalimide-linked benzotriazole 1016 and benzimidazole 1117 both possesses strong postemergence herbicide activity against Ipomoea purpurea (morning glory) and A. theophrasti (velvetleaf). The phthalimide derivative 12 exhibits excellent efficacy against Amaranthus retroflexus (redroot pigweed) and C. album (lambsquarters).18 The benzothiazolesubstituted tetrahydrophthalimide 13 shows high herbicidal activity against A. retroflexus (redroot pigweed) and Eclipta prostrata (false daisy) in combination with good wheat selectivity.19 The N-benzyltetrahydrophthalimide 14 achieves interesting control of Sorghum halepense (Johnsongrass) and Setaria italica (green foxtail) under preemergence conditions (Fig. 8.2).20 Not only flumioxazin (2), but also several highly active experimental PPO inhibitors such as 7 and 8, possess a benzoxazinone linked via the phenyl ring to the tetrahydrophthalimide. The potent influence of this bicycle on the herbicidal activity is demonstrated by the comparison of the benzoxazinone derivative 16 with its ring-opened analog 15. The effective dose required to kill 85% of the available weeds of the two species A. theophrasti (velvetleaf) and I. purpurea (morning glory) is for the tetrasubstituted phenyl derivative 15 20-fold higher than for the benzoxazinone 16, although 15 possesses all structural features of the oxazinone in 16, an alkoxy group in the para-position of the tetrahydrophthalimide and a nitrogen-linked amide in the meta-position (Table 8.1).9,17 The herbicidal activity of N-aryl-3,4,5,6-tetrahydroisophthalimides such as 17 against Echinochloa utilis (sawa millet) results from the rapid

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Figure 8.2 Experimental phthalimide and tetrahydrophthalimide herbicides. Table 8.1 Preemergence herbicidal activity of two experimental herbicides Compound Abutilon theophrasti Ipomoea purpurea (morning (velvetleaf) (ED85 g/ha) glory) (ED85 g/ha)

2000

62.5

.4000

125

hydrolytic conversion into the corresponding tetrahydrophthalimide 6 in the presence of plant enzymes (Scheme 8.1).21

8.2.2 Miscellaneous Herbicidally Active Cyclic Imides The spirosuccinimide derivative 18 is closely related by structure to (1)-hydantocidin, a highly potent nonselective herbicide isolated from the fermentation broth of Streptomyces hygroscopicus. The replacement of the

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Scheme 8.1 Hydrolytic conversion of tetrahydroisophthalimide 17 to tetrahydrophthalimide 6.

Figure 8.3 Herbicidally active spirosuccinimide 18.

NH group in the hydantoin moiety of the naturally occurring hydantocidin by CH2 delivers the succinimide substructure of 18. An efficient synthesis of the 1-carba-hydantocidin 18, which contains four chiral centers, has been established starting from D-psicose (Fig. 8.3).22,23

8.3 FUNGICIDALLY ACTIVE CYCLIC IMIDES 8.3.1 N-Haloalkylsulfenylimide as Multisite-Inhibiting Fungicides The discovery of N-haloalkylsulfenylphthalimides and tetrahydrophthalimides in the 1950s at Standard Oil for the first time introduced synthetic organic chemistry as well as a formerly unknown level of activity to agrochemical diseases control. They are multisite inhibitors which block different essential enzymes. They act for instance by transformation with enzymatic thiol groups, whereby thiophosgene and hydrogen disulfide are formed. The highly reactive thiophosgene reacts further with two other enzymatic thiol functions to form trithiocarbonates. This unselective mode of action results in an unfavorable toxicological and ecotoxicological profile of these fungicides. The phthalimide derivative Folpet (19) and its corresponding tetrahydrophthalimide analog Captan (20) were reported in 1952.24 They have been used as foliar, protective fungicide against a broad spectrum of

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Figure 8.4 Commercialized N-haloalkylthioimide fungicides.

different plant diseases, such as downy and powdery mildew, early and late blight, leaf spot, rot and mold diseases in pome, stone, soft and citrus fruit, vine, olive, hops, tomato, potato, lettuce, cucurbits, onions, celery, carrots, and ornamentals. Captafol (21), the third commercialized active ingredient from this class, has been reported in 1962.25 As also the two earlier examples, it has been used against a wide range of phytopathogens, such as Venturia inaequalis, the causal agent of apple scab; Alternaria solani, the causal agent of potato early blight; Plasmopara viticola, the causal agent of grape downy mildew; and Rhynchosporium secalis, the causal agent of barley scald (Fig. 8.4).11 The synthesis of Captan (20) is easily possible by Diels Alder cycloaddition of maleic anhydride (22) with butadiene to the tetrahydrophthalic anhydride 23, which is then converted with ammonia to the tetrahydrophthalimide 24. Finally, alkylation of the imide nitrogen atom with perchloromethyl mercaptan delivers Captan (20) (Scheme 8.2).26 Also for some related analogs of Captan, Captafol, and Folpet, interesting fungicidal activity has been reported. The phthalimide 25,27 in which Folpet’s trichloromethyl group has been replaced by a fluorodichloromethyl function, and the O-sulfamoylated N-hydroxyphthalimide 2628 both show excellent control of Phytophthora infestans (potato late blight). The N-p-chlorophenylmercaptomethyl-phthalimide 27 has been described to be active against powdery mildew diseases (Fig. 8.5).26

8.3.2 N-(3,5-Dichlorophenyl)-Dicarboximide Fungicides In the early 1970s, a novel class of agrochemical fungicides has been discovered, in which a 3,5-dichlorophenyl ring is linked to a the nitrogen atom of a oxazolidin-2,4-dione, imidazolidin-2,4-dione (hydantoin), or pyrrolidin-2,5-dione (succinimide). These fungicides are not only effective against the same spectrum of especially fruit and vegetable diseases such as Botrytis cinerea (gray mold) and Sclerotinia sclerotiorum (white mold), but also show similar morphological changes to hyphae and germ tubes following

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Scheme 8.2 Synthesis of Captan (20).

Figure 8.5 Experimental phthalimide fungicides.

Figure 8.6 Commercialized dicarboximide fungicides.

treatment. Their mode of action is linked to interference with the signal transduction pathway regulating osmotic adaptation. The three cyclic imides, which have been commercialized within this mode of action class are Dimethachlor (28) (year of introduction: 1969), Procymidone (29) (year of introduction: 1976), and Metomeclan (30) (year of introduction: 1984) (Fig. 8.6).29 The synthesis of Procymidone (29) starts with the transformation of 3,5-dichloroaniline (31) with 1,2-dimethylcyclopropyl-1,2-dicarboxylic

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Scheme 8.3 Synthesis of Procymidone (29).

Figure 8.7 Experimental dicarboximide fungicides.

acid anhydride to the amide 32, which can be cyclized to Procymidone (29) in the presence of acetic anhydride (Scheme 8.3).30 The dicarboximide derivative 33, which carries an exocyclic methylene group at the cyclic imide, shows excellent control of S. sclerotiorum (white mold) and Cochliobolus miyabeanus (rice brown spot).31 The procymidone analog 34, in which procymidone’s meta-chloro substituents have been replaced by trifluoromethyl groups, is highly efficacious against B. cinerea (gray mold) (Fig. 8.7).32

8.3.3 Miscellaneous Fungicidally Active Cyclic Imides Also other imides not belonging to the mode of action classes of Nhaloalkylsulfenylimides and dicarboximides are known to possess fungicidal activity. The maleiimide derivative Fluoroimide (35) belongs, just like the N-haloalkylsulfenylimides, to the group of multisite inhibitors and controls a wide range of diseases especially of apple and citrus, such as Monilinia mali (apple leaf blight) and Diaporthe citri (melanose of citrus).33 The protein biosynthesis inhibitor cycloheximide (36) is highly active against a broad range of different phytopathogens such as Zymoseptoria tritici (wheat leaf blotch) and Guignardia laricina (larch shoot blight), but its use as agrochemical fungicide has been discontinued because of its relatively

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Figure 8.8 Fungicidally active cyclic imides.

high toxicity against plants and animals.34 Also the fungicidal activity of the bis-imide Dipymetitrone (37), which never reached the market, is resulting from its unselective (multisite) enzyme inhibition.35 The N-anilino imide 38, a close analog of the complex III inhibiting fungicide Famoxadone, possesses weak activity against P. infestans (potato late blight).36 The tricyclic imide 39, an analog of the natural product zopfiellin, controls very efficiently the oomycete diseases P. infestans (potato late blight) and Pythium ultimum (damping off) (Fig. 8.8).37 The multisite inhibitor dipymetitrone (37) can be obtained from succinic anhydride (40) following two completely different routes. One possibility is the oxidative chlorination of this starting material to the dichloromaleic anhydride 41, which via conversion to the corresponding maeliimide 42 and subsequent ring condensation with the aid of hydrogen sulfide delivers dipymetitrone (37).38 Alternatively, succinic anhydride (40) can be opened with methylamine to the succinamic acid 43. The treatment of 43 with thionyl chloride to the diisomaleiimide dithiine 44 and its subsequent rapid isomerization also leads to dipymetitrone (37) (Scheme 8.4).39

8.4 INSECTICIDALLY ACTIVE CYCLIC IMIDES 8.4.1 Pyrethroids Bearing a Cyclic Imide Tetramethrin (45) has been commercialized in the 1960s for the control of flies, cockroaches, mosquitos, wasps, and other insect pests in public health as well as home and garden use. Similar to the several other

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Scheme 8.4 Synthesis of dipymetitrone (37).

Figure 8.9 Insecticidally active tetramethrin (45).

synthetic pyrethroid insecticides, it acts on the voltage-gated sodium channel of the insects11 (Fig. 8.9). Also the closely related analogs 46 48, in which the cyclohexene moiety of tetramethrin (45) has been either aromatized, hydrogenated, or ring-opened, show strong insecticidal knockdown activity (Fig. 8.10).40

8.5 CYCLIC IMIDES AS LEAD STRUCTURES FOR NONIMIDE AGROCHEMICALS Some cyclic imide derivatives played an important role as lead compounds in the invention pathway of commercialized agrochemicals which do not contain imide substructures. An example is given in Scheme 8.5. The discovery of the imidazolinone herbicides, a class of acetohydroxyacid synthase inhibitors from which six examples have been commercialized, started with the screening of the phthalimide 49 which was originally prepared as a potential anticonvulsant. Compound 49 controlled a different weed species at the high dose of 4 kg/ha, therefore a synthesis program had been initiated, which resulted in the preparation of the chlorophthalimide AC 94377 (50). During the synthesis of this gibberellic acid mimicking plant growth stimulant, the tricyclic side product 51 formed by ring

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Figure 8.10 Experimental pyrethroid insecticides.

Scheme 8.5 Phthalimide lead structures of imidazolinone herbicides.

closure, which led through further exploration to the highly active imidazolinone herbicide imazamethabenz methyl (52) (Scheme 8.5).41,42

8.6 CYCLIC IMIDES AS METABOLITES OF NONIMIDE AGROCHEMICALS Cyclic imides were not only used as lead structures of significance for the imidazolinone herbicides, but they also play an important role for their selectivity. The impressive crop selectivity of imazaquin (53) is due to the

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Scheme 8.6 Cyclic imides as metabolism products of imazaquin (53) and pyrrolnitrin (54).

ability of corn and soybeans to rapidly metabolize it to nonphytotoxic forms. The tricyclic imide 54 acts as primary metabolite which further decomposes to different phthalamides.42 Pyrrolnitrin (55) was first isolated in 1964 from the bacterium Pseudomonas pyrrocinia. It was developed as an antimycotic for topical application in human medicine, owing to its rapid metabolism, it showed only weak activity after oral administration. Regarding its efficacy against plant pathogenic fungi, pyrrolnitrin showed in greenhouse as well as seed treatment assays interesting activity against several different phytopathogens, such as B. cinerea (gray mold) and Magnaporthe grisea (rice blast). However, when applied under field conditions, the activity disappears rapidly because of insufficient photostability. Exposure of pyrrolnitrin to sunlight causes the photooxidation of the pyrrole ring, leading to fungicidally inactive metabolites such as the maleimide 56 and the succinimide 57 (Scheme 8.6).43

8.7 CYCLIC IMIDES AS INTERMEDIATES IN THE SYNTHESIS OF NONIMIDE AGROCHEMICALS Another advantage of cyclic imide derivatives is that they facilitate the synthesis of several agrochemicals as intermediates even if they do not possess an imide substructure. The azaphthalimide 59, which can be obtained from the azaphthalic anhydride 58 in one pot, is used for the preparation

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of the imidazolinone herbicide imazapyr (62). After ring opening of the cyclic imide 59 to the amidoester 60, its N-acylamino acid amide moiety is cyclized under dehydrative conditions with phosphorus pentachloride and phosphorus oxychloride to the imidazolinone ring of the nicotinic ester 61. Ester saponification delivers the soybean herbicide imazapyr (62) (Scheme 8.7).41 Another regioisomeric azaphthalimide, chinchomeronimide (64), proved to be highly useful for the synthesis of the acaricidally active fenzaaquin analog 68. The imide 64, which was obtained from pyridine-3,4dicarboxylic acid (chinchomeronic acid, 63), can be regioselectively ringopened via Hoffmann rearrangement to 3-aminoisonicotinic acid (65). This azaanthranilic acid is then cyclized with formamide to 4-hydroxypyrido[3,4D]pyrimidine (66) under the conditions of the Niementowski reaction. The hydroxyl function of 66 is then exchanged via an intermediate chloride by a triazole group which is relatively stable but still activated for nucleophilic substitution. The triazole ring of 67 is finally replaced by the required phenylethanolate to deliver 68, an aza-analog of the complex I inhibiting acaricide fenazaquin (Scheme 8.8).8 Another cyclic imide intermediate appears in the synthesis of the insecticidally active tebufenpyrad analog 75. After Williamson reaction of the disubstituted benzene derivatives 69 and 70 to the diphenylether 71, its methyl group is brominated with N-bromosuccinimide. The bromine substituent of the resulting 72 is then exchanged by an amino function via the intermediate phthalimide 73. The resulting benzylamine 74 is then

Scheme 8.7 Synthesis of imazapyr (62).

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Scheme 8.8 Synthesis of the fenazaquin analog 68.

Scheme 8.9 Synthesis of the tebufenpyrad analog 75.

converted by amidation to the tebufenpyrad analog 75, which is highly active against Nephotettix cincticeps (green rice leafhopper) (Scheme 8.9).44 Phthalimide is highly useful not only for the introduction of an amine function (see Scheme 8.9) but also finds its application for the installation of a hydroxylamine group. This is demonstrated by the synthesis of the fungicidally active strobilurin derivative 82. Its synthesis starts with the transformation of o-toluidine (76) into the α-hydroxyiminobenzene

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Scheme 8.10 Synthesis of the strobilurin derivative 82.

acetate 77, followed by oxime methylation and benzylic bromination. The resulting benzyl bromide derivative 79 is then converted with N-hydroxyphthalimide into 80 which in turn is hydrolyzed to the O-benzylhydroxylamine derivative 81. This intermediate is then coupled to a persubstiuted pyrazole carbaldehyde to deliver the complex III inhibiting experimental fungicide 82, which shows excellent performance against B. cinerea (gray mold) and Rhizoctonia solani (rice sheath blight) (Scheme 8.10).45

8.8 CONCLUSION As seen in this chapter, many cyclic imide derivatives possess powerful efficacy against a broad variety of weeds, insects, and fungal diseases. Their structural diversity is impressive as well as the wide range of different

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modes of action involved. Furthermore, because of their easy accessibility, cyclic imides found application as lead structures in the discovery pathway and also as key intermediates in the synthesis route of different agrochemicals.

REFERENCES 1. Lamberth, C.; Dinges, J., Eds. Bioactive Heterocyclic Compound Classes: Agrochemicals; Wiley-VCH: Weinheim, 2012. 2. Lamberth, C.; Dinges, J., Eds. Bioactive Carboxylic Compound Classes: Pharmaceuticals and Agrochemicals; Wiley-VCH: Weinheim, 2016. 3. Lamberth, C. Pyrazole Chemistry in Crop Protection. Heterocycles 2007, 71, 1467 1502. 4. Lamberth, C. Oxazole and Isoxazole Chemistry in Crop Protection. J. Heterocycl. Chem. 2018, 55, 2035 2045. 5. Maienfisch, P.; Edmunds, A. J. F. Thiazole and Isothiazole Ring-Containing Compounds in Crop Protection. Adv. Heterocycl. Chem. 2017, 121, 35. 6. Guan, A.-Y.; Liu, C.-L.; Sun, X.-F.; Xie, Y.; Wang, M.-A. Discovery of PyridineBased Agrochemicals by Using Intermediate Derivatization Methods. Bioorg. Med. Chem. 2016, 24, 342 353. 7. Lamberth, C. Pyridazine Chemistry in Crop Protection. J. Heterocycl. Chem. 2017, 54, 2974 2984. 8. Lamberth, C. Pyrimidine Chemistry in Crop Protection. Heterocycles 2006, 68, 561 603. 9. Theodoridis, G.; Liebl, R.; Zagar, C. Protoporphyrinogen IX Oxidase Inhibitors. In Modern Crop Protection Compounds; Krämer, W., Schirmer, U., Jeschke, P., Witschel, M., Eds.; Wiley-VCH: Weinheim, 2012; pp 163 195. 10. Böger, P.; Wakabayashi, K., Eds. Peroxidizing Herbicides; Springer: Berlin, 1999. 11. Tomlin, C. D. S., Ed. The Pesticide Manual; British Crop Production Council: Alton, 2009. 12. Hamada, T.; Yoshida, R.; Nagano, E.; Oshio, H.; Kamoshita, K. S-23121 A New Cereal Herbicide for Broad-Leaved Weed Control. Proc. Brighton Crop Prot. Conf. Weeds 1989, 1, 41 46. 13. Sato, R.; Nagano, E.; Oshio, H.; Kamoshita, K. Diphenylether-Like Physiological and Biochemical Actions of S-23142, A Novel N-Phenyl Imide Herbicide. Pestic. Biochem. Physiol. 1987, 28, 194 200. 14. Huang, M.-Z.; Huang, K.-L.; Ren, Y.-G.; Lei, M.-X.; Huang, L.; Hou, Z.-K.; Liu, A.-P.; Ou, X.-M. Synthesis and Herbicidal Activity of 2-(7-Fluoro-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)isoindoline-1,3-diones. J. Agric. Food Chem. 2005, 53, 7908 7914. 15. Hwang, I. T.; Hong, K. S.; Choi, J. S.; Kim, H. R.; Jeon, D. J.; Cho, K. Y. Protoporphyrinogen IX-Oxidizing Activities Involved in the Mode of Action of a New Compound N-[4-Chloro-2-fluoro-5-{3-(2-fluorophenyl)-5-methyl-4,5-dihydroisoxazol-5-yl-methoxy}-phenyl]-3,4,5,6-tetrahydrophthalimide. Pestic. Biochem. Physiol. 2004, 80, 123 130. 16. Crews, A. D.; Condon, M. E.; Manfredi, M. C. Synthesis and Herbicidal Activity of Aryloxyphenyl and Heterocyclic Substituted Phenyl N-arylbenzotriazoles. In Synthesis and Chemistry of Agrochemicals V; Baker, D. R., Fenyes, J. G., Basarab, G. S., Hunt, D. A., Eds.; American Chemical Society: Washington, 1998; pp 40 47.

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17. Theodoridis, G.; Baum, J. S.; Chang, J. H.; Crawford, S. D.; Hotzman, F. W.; Lyga, J. W.; Maravetz, L. L.; Suarez, D. P.; Hatterman-Valenti, H. Synthesis and Herbicidal Activity of Fused Benzoheterocyclic Ring Systems. In Synthesis and Chemistry of Agrochemicals V; Baker, D. R., Fenyes, J. G., Basarab, G. S., Hunt, D. A., Eds.; American Chemical Society: Washington, 1998; pp 55 66. 18. Luo, Y.-P.; Jiang, L.-L.; Wang, G.-D.; Chen, Q.; Yang, G.-F. Syntheses and Herbicidal Activities of Novel Triazolinone Derivatives. J. Agric. Food Chem. 2008, 56, 2118 2124. 19. Jiang, L.-L.; Zuo, Y.; Wang, Z.-F.; Tan, Y.; Wu, Q.-Y.; Xi, Z.; Yang, G.-F. Design and Syntheses of Novel N-(benzothiazol-5-yl)-4,5,6,7-tetrahydro-1H-isoindole-1,3-(2H)dione and N-(benzothiazol-5-yl)isoindoline-1,3-dione as Potent Protoporphyrinogen Oxidase Inhibitors. J. Agric. Food Chem. 2011, 59, 6172 6179. 20. Konz, M. J.; Wendt, H. R.; Cullen, T. G.; Tenhuisen, K. L.; Fryszman, O. M. 3Benzyl-1-methyl-6-trifluoromethyluracils: A New Class of Protox Inhibitors. In Synthesis and Chemistry of Agrochemicals V; Baker, D. R., Fenyes, J. G., Basarab, G. S., Hunt, D. A., Eds.; American Chemical Society: Washington, 1998; pp 67 78. 21. Hoshi, T.; Koizumi, K.; Sato, Y.; Wakabayashi, K. Hydrolysis and Phytotoxic Activity of N-aryl,3,4,5,6-tetrahydroisophthalimides. Biosci. Biotech. Biochem. 1993, 57, 1913 1915. 22. Lamberth, C.; Blarer, S. Concise Approach to 1-Thiahydantocidin. Synth. Commun. 1996, 26, 75 81. 23. Sano, H.; Mio, S.; Tsukaguchi, N.; Sugai, S. Stereocontrolled Synthesis of Spirosuccinimide Derivative of (1)-Hydantocidin. Tetrahedron 1995, 51, 1387 1394. 24. Kittleson, A. R. A New Class of Organic Fungicides. Science 1952, 115, 84 86. 25. Thomas, W. D.; Eastburg, P. H.; Bankuti, M. D. Novel Fungicidally Active Tetrahydrophthalimides. Phytopathol. 1962, 52, 754. 26. Schlör, H. Chemistry of Fungicides. In Chemie der Pflanzenschutz- und Schädlingsbekämpfungsmittel; Wegler, R., Ed.; , Vol. 2; Springer: Berlin, 1970; pp 44 161. 27. Kühle, E.; Klauke, E.; Grewe, F. Fluorodichloromethylthio Derivatives and Their Use in Plant Protection. Angew. Chem. 1964, 76, 807 816. 28. Kühle, E.; Wegler, R. N-hydroxydicarboxylic Acid Imides and Their O-sulfonyl Derivatives: A New Class of Fungicides. Liebigs Ann. Chem. 1958, 616, 183 206. 29. Pommer, E.-H.; Lorenz, G. Dicarboximide Fungicides. In Modern Selective Fungicides; Lyr, H., Ed.; Gustav Fischer Verlag: Jena, 1995; pp 99 118. 30. Scheinpflug, H.; Schlör, H.; Widdig, A. Chemistry of Fungicides. In Chemie der Pflanzenschutz- und Schädlingsbekämpfungsmittel; Wegler, R., Ed.; , Vol. 4; Springer: Berlin, 1977; pp 117 238. 31. Fujinami, A.; Ozaki, T.; Nodera, K.; Tanaka, K. Studies on Biological Activity of Cyclic Imide Compounds. Part II: Antimicrobial Activity of 1-Phenylpyrrolidine-2,5diones and Related Compounds. Agr. Biol. Chem. 1972, 36, 318 323. 32. Takayama, C.; Fujinami, A. Quantitative Structure Activity Relationships of Antifungal N-phenylsuccinimides and N-phenyl-1,2-dimethylcyclopropanedicarboximides. Pestic. Biochem. Physiol. 1979, 12, 163 171. 33. Uesugi, Y. Fungicide Classes: Chemistry, Uses and Mode of Action. In Fungicidal Activity; Hutson, D., Miyamoto, J., Eds.; Wiley: Chichester, 1998; pp 23 56. 34. Buchenauer, H.; Walker, F. Fungicides Acting on Amino Acids and Protein Synthesis. In Modern Crop Protection Compounds; Krämer, W., Schirmer, U., Jeschke, P., Witschel, M., Eds.; Wiley-VCH: Weinheim, 2012; pp 693 706. 35. Jeanmart, S.; Edmunds, A. J. F.; Lamberth, C.; Pouliot, M. Synthetic Approaches to the 2010 2014 New Agrochemicals. Bioorg. Med. Chem. 2016, 24, 317 341.

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36. Sternberg, J. A.; Geffken, D.; Adams, J. B.; Pöstages, R.; Sternberg, C. G.; Campbell, C. L.; Moberg, W. K. Famoxadone: The Discovery and Optimisation of a New Agricultural Fungicide. Pest Manag. Sci. 2001, 57, 143 152. 37. Musso, L.; Dalavalle, S.; Farina, G.; Burrone, E. Natural Products as Sources of New Fungicides: Synthesis and Antifungal Activity of Zopfiellin Analogues. Chem. Biol. Drug Des. 2012, 79, 780 789. 38. Draber, W. Synthesis of 1,4-Dithiines From Maleiimide Derivatives. Chem. Ber. 1967, 100, 1559 1570. 39. Valla, A.; Cartier, D.; Zentz, F.; Labia, R. Atypical Oxidation Reaction by Thionyl Chloride: Easy Two-Step Synthesis of N-alkyl-1,4-dithiines. Synth. Commun. 2006, 36, 3591 3597. 40. Fujita, T. Similarities in Bioanalogous Structural Transformation Patterns. In Agrochemical Discovery; Baker, D. R., Umetsu, N. K., Eds.; American Chemical Society: Washington, 2001; pp 166 179. 41. Wepplo, P. Imidazolinone Herbicides: Synthesis and Novel Chemistry. Pestic. Sci. 1990, 39, 293 315. 42. Shaner, D. Pyridines Substituted by an Imidazolinone and a Carboxylic Acid as Acetohydroxyacid Synthase-Inhibiting Herbicides. In Bioactive Carboxylic Compound Classes: Pharmaceuticals and Agrochemicals; Lamberth, C., Dinges, J., Eds.; Wiley-VCH: Weinheim, 2016; pp 339 345. 43. Lamberth, C. Phenylpyrrole Fungicides. In Bioactive Heterocyclic Compound Classes: Agrochemicals; Lamberth, C., Dinges, J., Eds.; Wiley-VCH: Weinheim, 2012; pp 155 162. 44. Okada, I.; Okui, S.; Wada, M.; Fukuchi, T.; Yoshiya, K.; Takahashi, Y. Synthesis and Insecticidal Activity of N-(4-aryloxybenzyl)-pyrazolecarboxamide Derivatives. In Synthesis and Chemistry of Agrochemicals V; Baker, D. R., Fenyes, J. G., Basarab, G. S., Hunt, D. A., Eds.; American Chemical Society: Washington, 1998; pp 168 177. 45. Li, Y.; Zhang, H.-Q.; Liu, J.; Yang, X.-P.; Liu, Z.-J. Stereoselective Synthesis and Antifungal Activities of (E)-α-(methoxyimino)benzeneacetate Derivatives Containing 1,3,5-Substituted Pyrazole Ring. J. Agric. Food Chem. 2006, 54, 3636 3640.

CHAPTER 9

Imide-Containing Synthetic Drugs Jie Jack Li

Revolution Medicines, Inc. Redwood City, CA, United States

9.1 INTRODUCTION Imide as a pharmacophore in synthetic drugs rarely exists in its linear form. Rather, imides are present in medicines almost exclusively as a part of a ring mostly as a five-membered ring (1, pyrrolidine-2,5-dione, succinimide) or a six-membered ring (2, piperidine-2,6-dione). Ironically, the most notorious imide-containing synthetic drug, thalidomide (3), possesses both a succinimide moiety and a piperidine-2,6-dione motif. Due to intense interest in this potent teratogen, thalidomide (3) and its close analogs as viable cancer drugs are a focused subject of another separate chapter (Chapter 10: Thalidomide and Analogs) in this book.

9.2 ANTIEPILEPTIC DRUGS Some of the early imide-containing synthetic drugs were anticonvulsant drugs, also known as antiepileptic drugs (AEDs) or antiseizure drugs. Modern effective anticonvulsants owe their advent to phenobarbital (4, Luminal), prepared by Fischer in 1912.1 Despite its efficacy, phenobarbital (4) is tainted with sedative side effects. In 1939, working with Parke, Davis, and Company, Putnam and Merritt discovered phenytoin (5, Dilantin) as an efficacious treatment for epilepsy.2 Phenytoin (5) was the first anticonvulsant that was devoid of sedative side effects. It was revolutionary for treating epilepsy because it was the first drug that separated the Imides DOI: https://doi.org/10.1016/B978-0-12-815675-9.00009-6

© 2019 Elsevier Inc. All rights reserved.

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antiepileptic effect from the sedative action. Paradoxically, average doctors were reluctant to prescribe it because it lacked the pronounced sedation effect that plagued older AEDs.3,4

Via further manipulations of phenytoin (5), a chemical
biological research team at Parke
Davis in 1954 developed phensuximide (6, Milontin), an anticonvulsant for the control of absence (petit mal) epilepsy. In 1957, Parke
Davis introduced another epilepsy drug, methsuximide (7, Celontin). By then, Parke
Davis’s Dilantin (5), Milontin (6), and Celontin (7) covered each of the three major types of epileptic seizures. Parke
Davis solidly established its leadership position in the field of epilepsy treatment.2 In 1958, Parke
Davis’s tour de force in the field of AEDs was ethosuximide (8, Zarontin), which is still in use today for the treatment of absence seizure in children.4 The presence of the N-methyl group on the succinimide motif on both phensuximide (6) and methsuximide (7) is a strong indication that the free NH group is not required for the anticonvulsant effect since neither phenytoin (5) nor ethosuximide (8) are methylated. Unlike phenytoin (5), phensuximide (6), methsuximide (7), and ethosuximide (8) are imide-containing drugs, specifically succinimides. In terms of mechanism of action (MOA), succinimide AEDs such as 6
8 are “dirty” drugs, also known as “polypharmacologics,” modulating a number of pharmacological targets. It has been demonstrated that succinimide drugs 6
8 are capable of blocking cloned human T-type calcium channels at therapeutically relevant concentrations.5 Blocking T-channels would reduce the nerve cell excitability and could explain their antiepileptic effect. They may also modulate some other ion channels, block γ-aminobutyric acid (GABA) responses, and inhibit monoamine oxidase, among other possible mechanisms. Owing to their polypharmacology, it is not surprising that these drugs are often associated with certain toxicities such as neurotoxicities. None of them is the first-line treatment for

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epilepsy any longer. They have largely been replaced by more selective and thus “cleaner” and safer AEDs such as benzodiazepines, lamotrigine, gabapentin, pregabalin, and valproate, and so on. The pharmacokinetics of ethosuximide (8) in children was investigated.6,7 It is well-absorbed with its Cmax (the maximal drug concentration) attained within 3
7 hours, and its bioavailability is 95%
100%. The drug is minimally bound to plasma protein and is slowly eliminated with a half-life of 25
42 hours. The volume of its distribution has been reported as 0.7 L/kg. Approximately, 80% of ethosuximide (8) undergoes hepatic metabolism, which is mediated primarily by cytochrome P450 isoenzymes, with a major contribution from CYP3A. Hydroxylated metabolites 9
11 then form their corresponding glucuronides that are polar enough to be excreted.7,8

9.3 ANTIANXIETY DRUGS Antianxiety drugs are also known as sedative
hypnotic drugs. They are used interchangeably here in this chapter.

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Employing phenobarbital (4), a barbiturate, as the starting point, Ciba arrived at glutethimide (13, Doriden) in 1952 as a novel hypnotic although its superiority over barbiturates was not substantiated later on. While glutethimide (13)’s MOA has not been elucidated and is no longer of interest, its metabolism has been the subject of several informative investigations. In 1979, it was already known that, in humans, the lipophilic glutethimide (13) is oxidized by hepatic enzymes (i.e., CYP450s) to the corresponding hydroxylated metabolites 14
16, which subsequently form glucuronides before excretion.9 By 1993, it was reported that α-phenyl-γ-lactone (17) is a metabolite of glutethimide (13) and the mechanism of its formation was revealed to be via intramolecular cyclization from the corresponding 2-hydroxyethyl metabolite 18 (see the following figure).10

Glutethimide (13) is a mixture of two enantiomers, which behave differently in their metabolisms since the cytochrome protein (CYP) enzymes in liver are chiral.11 In dogs, the (S)-glutethimide is

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predominantly oxidized to the hydroxyethyl analog 18. On the other hand, the (R)-glutethimide is mostly converted to the corresponding 5hydroxyl derivative 19 in rats, dogs, and humans.

Introduced by Bristol
Myers Squibb in 1988, buspirone (20, Buspar) was considered groundbreaking for the treatment of general anxiety disorder (GAD), effectively treating anxiety without concomitant sedative, muscle relaxant, or anticonvulsant activities. As the first member of the azapirone family of drugs, buspirone (20) is believed to function as a partial serotonin agonist at the 5-hydroytryptamine (5-HT1A) receptor in the brain.12
15 The 5-HT1A receptors are the most studied and best characterized of the 5-HT receptor subtypes. Meanwhile, buspirone (20) also binds to dopamine D2, D3, and D4 receptors, but as an antagonist.16 Unlike benzodiazepines, it does not significantly interact with GABAA receptors. Buspirone (20)’s pharmacokinetics has been extensively studied.17
20 It has a Tmax (the time it takes to reach maximal drug concentration) of approximately 1 hour and its Cmax is B1.13 ng/mL for the 10-mg dose. Its mean systemic bioavailability is quite low, B4% due to its first-pass metabolism. Buspirone (20) has a volume of distribution of 5.3 L/kg, a systemic clearance of about 1.7 L/(h kg), an elimination half-life of about 2.5 hours, and its pharmacokinetics are linear over the dose range 10
40 mg. It is highly protein bound (more than 95%), interacting with both albumin and α-acid glycoprotein. Buspirone (20)’s metabolites include hydroxyl derivatives 21
24, which are readily excreted after glucuronidation. Another major metabolite, 1-(2-pyrimidinyl)piperazine (25, 1-PP), increased hypothalamic concentrations of 3-methoxy-4-hydroxyphenylethyleneglycol (MHPG) sulfate, the norepinephrine metabolite, which may have resulted from α-2 adrenoreceptor blockade.

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The metabolism of buspirone (20) may actually serve as a teachable moment on drug safety associated with reactive metabolites. One of buspirone’s (20) major circulating metabolites in humans is 5-hydroxylbuspirone (21), which is impervious to further CYP3A4 oxidation to the ultra-reactive metabolite in the form of quinone
imine 26. The absence of the quinone
imine reactive metabolite 26 may offer an explanation why buspirone (20) is not associated with idiosyncratic toxicity despite decades of clinical use. In contrast, nefazodone (27), a broad opioid receptor antagonist prescribed to treat alcohol dependence, has been associated with numerous cases (some so severe that liver transplantations or fatalities ensued) of idiosyncratic hepatotoxicity at the therapeutic range of 200
400 mg a day. As shown in the following figure, the aniline moiety of nefazodone (27) is oxidized by CYP3A4 to the corresponding parahydroxyl-nefazodone (28), which is further oxidized to the

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quinone
imine intermediate 29.21 Needless to say, intermediate 29, being such an excellent Michael acceptor, is vulnerable to nucleophilic attacks by either glucuronide (GSH) or water to form covalent bonds, thus leading to toxicities.

The second azapirone antianxiety drug tandospirone (30, Sediel) is only sold in China and Japan.22 The third azapirone antianxiety gepirone (31) is a close analog of buspirone (20). Bristol
Myers Squibb outlicensed it to Organon.23 Regrettably, the drug was rejected by the Food and Drug Administration (FDA) over concerns with its lack of efficacy. The azapirone antianxiety drug family also include binospirone (32), alnespirone (33), and zalospirone (34). But none of them has received the approval of governmental agencies to reach the market, to the best of my knowledge.

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9.4 ANTINEOPLASTICS

Aminoglutethimide (35, Cytadren), a close analog of glutethimide (13), was initially introduced as an anticonvulsant in 1960.24 It was withdrawn from the market in 1966 due to unacceptable toxicity profile. An idiosyncratic adverse drug reaction with aminoglutethimide (35)’s use is agranulocytosis, a condition characterized by severe neutropenia. A potential mechanism of agranulocytosis is that it induced protein-free radical

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formation on myeloperoxidase.25 In the ensuing years, one of aminoglutethimide (35)’s “side effect” was turned to therapeutic advantage. Since it inhibits several enzymes involved in the synthesis of corticosteroids as well as the aromatase enzyme which converts androgens to oestrogens,26,27 it was approved by the FDA for the treatment of breast cancer and other hormone-sensitive cancers in 1980. Although aminoglutethimide (35) is the first-generation aromatase inhibitor, it has its own unique pharmacodynamics and safety profile in comparison to other first-generation aromatase inhibitors such as exemestane (Aromasin), formestane (Lentaron), and atamestane, all three of them are steroid based. Conspicuous on the aminoglutethimide (35) molecule is the presence of the aniline functional group, now a notorious structural alert being associated with known hepatic toxicities. As a matter of fact, aminoglutethimide (35) has been even used as a model compound to study the hepatic effects as an aromatic amine!28 Therefore it is logical to switch the troublesome aniline moiety with a more innocuous bioisostere such as a pyridine group. The fruit of this exercise resulted in rogletimide (36). Indeed, aminoglutethimide (35) is an “ugly” drug, and rogletimide (36) is a “beautiful” drug. Alas, rogletimide (36) never made it to the market for its lack of efficacy possibly because it is a relatively weak aromatase inhibitor.29

9.5 ANTIPSYCHOTICS

The previous three sections surveyed some imide-containing drugs approved by regulatory agencies for marketing. Some imide-containing drugs were investigated in clinical trials but did not reach the marketplace due to either unacceptable toxicities or lack of efficacy. Compounds 37
41 were tested as potential antipsychotics. Succinimides fenimide (37), cyproximide (38),30 and morsuximide (39) are close analogs of methsuximide (7, Celontin). In fact, morsuximide (39) is an N-Mannich

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prodrug of fenimide (37). On the other hand, antipsychotic agent cinperene (40) is a direct derivative of glutethimide (13). Another imidecontaining drug tiospirone (41),31 a close analog of buspirone (20) was investigated as an atypical antipsychotic agent.

9.6 MISCELLANEOUS IMIDE-CONTAINING DRUGS Benzetimide (42) is a glutethimide (13) derivative developed as an antimuscarinic agent. It is a mixture of two enantiomeric isomers. The separation of the two enantiomers revealed that, as a muscarinic antagonist, the (S)-enantiomer dexetimide (43) is 1000-fold more potent than the corresponding (R)-enantiomer known as lexetimide.32 Dexetimide (43) was marketed by Janssen as an anticholinergic to treat drug-induced Parkinsonism in 1968 with a brand name Tremblex.33

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Among additional imide-containing drugs, cycloheximide (43) is a natural product discovered in the 1940s. It was widely used in studies of cell death without knowledge of its effects on protein synthesis.34 Since it is a eukaryote protein synthesis inhibitor, cycloheximide (43) has been used as an experimental tool in molecular biology to determine the halflife of a protein. On the other hand, Lilly’s ruboxistaurin (43) is a PKC-β inhibitor developed for the treatment of diabetic retinopathy,35 and ArQule’s tivantinib (44), as a selective MET kinase inhibitor, was investigated for treating hepatocellular carcinoma.36

In the 1950s, razoxane (46) was investigated as an antineoplastic agent but it was abandoned due to unfavorable toxicity profiles.37 In 2000 it was reported that dexrazoxane (460 ) offered amelioration of subcutaneous injuries caused by anthracyclines. Today, dexrazoxane (460 ) is used as a cardioprotectant in children receiving anthracyclines.38,39 The MOA of dexrazoxane (460 ) is serving a prodrug of ethylenediaminetetraacetic acid (EDTA), which is an iron chelator. Unlike EDTA, dexrazoxane (460 ) easily passes into cells. Upon hydrolysis, it opens into its EDTA-like form, which is a strong iron chelator that has the ability to displace iron from the anthracycline.

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In summary, imides are present in medicines almost exclusively as parts of rings such as succinimides or piperidine-2,6-diones if we discount the recent resurgence of thalidomide analogs. Imides were present in many older drugs before the demise of thalidomide. The last FDA-approved imide-containing drug was probably buspirone (20, Buspar) in 1988. Is this outcome a result of our cognitive bias or imides’ inherent inferiority as a pharmacophore? I suppose that we will never find out until we first solve the chicken and egg mystery.

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287. 19. Gammans, R. E.; Mayol, R. F.; LaBudde, J. A. Metabolism and Disposition of Buspirone. Am. J. Med. 1986, 80, 41
51. 20. Wong, H.; Dockens, R. C.; Pajor, L.; Yeola, S.; Grace, J. E.; Stark, A. D.; Taub, R. A.; Yocca, F. D.; Zaczek, R. C.; Li, Y. W. 6-Hydroxybuspirone is a Major Active Metabolite of Buspirone: Assessment of Pharmacokinetics and 5Hydroxytryptamine 1A Receptor Occupancy in Rats. Drug Metab. Dispos. 2007, 35, 1387
1392. 21. Bauman, J. S.; Frederick, K. S.; Sawant, A.; Walsky, R. L.; Cox, L. M.; Obach, R. S.; Kalgutkar, A. S. Comparison of the Bioactivation Potential of the Antidepressant and Hepatotoxin Nefazodone with Aripiprazole, a Structural Analog and Marketed Drug. Drug Metab. Dispos. 2008, 36, 1016
1029. 22. Nishitsuji, T. H.; Murakami, Y.; Kodama, K.; Kobayashi, D.; Yamada, T.; Kubo, C.; Mine, K. Tandospirone in the Treatment of Generalised Anxiety Disorder and Mixed Anxiety
Depression: Results of a Comparatively High Dosage Trial. Clin. Drug Investig. 2004, 24, 121
126. 23. Leslie, R. A. Gepirone. Organon. Cur. Opin. Investing. Drugs 2001, 2, 1120
1127. 24. Hughss, S. W.; Burley, D. M. Aminoglutethimide: A ‘Side-Effect’ Turned to Therapeutic Advantage. Postgrad. Med. J. 1970, 46, 409
416. 25. Siraki, A. G.; Bonini, M. G.; Jiang, J. J.; Ehrenshaft, M.; Mason, R. P. Procainamide, but not N-acetylprocainamide, Induces Protein Free Radical Formation on Myeloperoxidase: A Potential Mechanism of Agranulocytosis. Chem. Res. Toxicol. 2008, 21, 1043
1153. 26. Santen, R. J.; Brodie, H.; Simpson, E. R.; Siiteri, P. K.; Brodie, A. History of Aromatase: Saga of an Important Biological Mediator and Therapeutic Target. Endocr. Rev. 2009, 30, 343
375. 27. Lønning, P. E. Aminoglutethimide Enzyme Induction: Pharmacological and Endocrinological Implications. Cancer Chemother. Pharmacol. 1990, 26, 241
244. 28. Ng, W.; Metushi, I. G.; Uetrecht, J. Hepatic Effects of Aminoglutethimide: A Model Aromatic Amine. J. Immunotoxicol. 2015, 12, 24
32. 29. Dowsett, M.; Lønning, P. E. Anastrozole-A New Generation in Aromatase Inhibition: Clinical Pharmacology. Oncol. 1997, 54 (Suppl. 2), 11
14. 30. Sparano, B. M.; Brecher, M. P.; Gordon, G.; Iatropoulos, M. J.; King, C. D.; Gallo, P. Chemically Induced Hepatocellular Proliferative Changes in the Rat Without Evidence of Neoplastic Transformation. Toxicol. Pathol. 1982, 10, 175
187. 31. Cipollina, J. A.; Ruediger, E. H.; New, J. S.; Wire, M. E.; Shepherd, T. A.; Smith, D. W.; Yevich, J. P. Synthesis and Biological Activity of the Putative Metabolites of the Atypical Antipsychotic Agent Tiospirone. J. Med. Chem. 1991, 34, 3316
3328. 32. Laduron, P. M. Stereospecificity in Binding Studies. A Useful Criterion Though Insufficient to Prove the Presence of Receptors. Biochem. Pharmacol. 1988, 37, 37
40. 33. Zwanikken, G. J.; Oei, T. T.; Kimya, S.; Amery, W. Safety and Efficacy of Prolonged Treatment with Tremblex (Dexetimide), An Antiparkinsonian Agent. A Controlled Study. Acta Psychiatr. Belg. 1976, 76, 467
469. 34. Mattson, M. P.; Furukawa, K. Anti-Apoptotic Actions of Cycloheximide: Blockade of Programmed Cell Death or Induction of Programmed Cell Life? Apoptosis 1997, 2, 257
264.

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35. Schwartz, S. G.; Flynn, H. W., Jr.; Aiello, L. P. Ruboxistaurin Mesilate Hydrate for Diabetic Retinopathy. Drugs Today 2009, 45, 269
274. 36. Best, J.; Schotten, C.; Gerken, G.; Dechene, A.; Lohmann, G. Tivantinib for the Treatment of Hepatocellular Carcinoma. Exp. Opin. Pharmacother. 2017, 18, 727
733. 37. Langer, S. W. Dexrazoxane for the Treatment of Chemotherapy-Related Side Effects. Cancer Manage. Res. 2014, 36, 357
363. 38. Sepe, D. M.; Ginsberg, J. P.; Balis, F. M. Dexrazoxane as Cardioprotectant in Children Receiving Anthracyclines. Oncol. 2010, 15, 1220
1226. 39. Wiseman, L. R.; Spencer, C. M. Dexrazoxane: A Review of its Use as a Cardioprotective Agent in Patients Receiving Anthracycline-Based Chemotherapy. Drugs 1998, 56, 385
403.

CHAPTER 10

Thalidomide and Analogues Frederick A. Luzzio

University of Louisville, Louisville, KY, United States

10.1 INTRODUCTION The impact and legacy of thalidomide (1) have spanned several decades since its introduction in the late 1950s as a medication for treating nausea in pregnant women.1 The drug was cast into the public eye upon the discovery that its prenatal use resulted in limb malformations in newborn children.2
5 Although the drug was never approved in the United States for lack of proof that it was safe, elucidation of the potent human O N

O NH

O

O

1

embryotoxicity of thalidomide led to its immediate withdrawal from other markets. In fact, scrutiny from the then United States FDA inspector Frances Kelsey resulted in the nonavailability of the drug to American mothers, and newborn US children were relatively unscathed. Consequently, the culture of drug approval by the FDA changed with the passing of the Kefauver
Harris Drug Amendments Act that was responsible for tightly monitoring the safety assessment of pharmaceutical candidates.6 Indeed, the compound became the object of intrigue with regard to the mechanism of its effects, thereby spawning research efforts which continue to the present. As research on the teratogenicity of thalidomide continued, separate independent investigations revealed that it was an effective therapy for the symptoms of lepromatous leprosy (erythema nodosum leprosum, ENL) where it acts as an antiinflammatory.7 As thalidomide became available for treatment

Imides DOI: https://doi.org/10.1016/B978-0-12-815675-9.00010-2

© 2019 Elsevier Inc. All rights reserved.

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368

Imides

of ENL, it gradually gained status as an “orphan drug,” but was soon gaining attention as an immunomodulator since it was surmised that its probable mode of action on ENL was the lowering of excess levels of tumor necrosis factor-α (TNF-α).8
12 Thalidomide is a highly crystalline material which is sparingly soluble in most organic solvents and somewhat soluble in very polar solvents such as dimethylformamide (DMF), dimethylsulfoxide (DMSO), and pyridine. Its poor aqueous solubility along with its instability along the physiological pH range are factors which do have an effect on its bioavailability and excretion and have been roadblocks toward its development as a drug. For example, a pharmacokinetic study of thalidomide in a prostate cancer population (age range 55
80 years) required a daily dosing of 200
1200 mg/day (!).13 While the simplicity of its structure left little room for the design of analogues, active or otherwise, those which might shed light on its teratogenic action were investigated first, followed by analogues which served to elucidate configurational issues. Later, the TNF-α-inhibitory properties of the compound sparked interest in the development of immunomodulatory analogues, while angiogenesisinhibitory and metabolic analogues drew interest on the separate fronts of cancer research and molecular mechanism. The development of thalidomide analogues detailed in this chapter reviews research efforts toward stabilizing their configuration, identifying metabolites, enhancing bioavailability, and optimizing therapeutic effectiveness in cancer treatment and immunology. As always, within the context of discovery and optimization of any drug lead for a specific therapeutic response, there will remain questions regarding metabolic activation, the molecular target, and side effects points which are addressed herein where applicable to certain analogues. While a number of excellent reviews surrounding thalidomide and its analogues have been written over the years,14
24 the content herein is mainly focused on synthesis, but with due consideration to biological activity and therapeutic applications of the compounds described.

10.2 BIOLOGICAL DISPOSITION OF THALIDOMIDE Thalidomide exhibits a number of interesting chemical transformations in the biological system, namely, racemization, hydrolysis, and metabolism,

Thalidomide and Analogues

369

and these properties have made identification of the active components as well as the molecular target an arduous task. The in vivo and in vitro hydrolysis products first involve the ring-opening reactions of each of the respective phthalimide and glutarimide rings. Further hydrolysis results in complete decomposition of the drug to its basic components, o-phthalic and glutamic acids. Hence, on complete hydrolysis, each of the rings can yield acyclic amide derivatives which, in turn, can yield the carboxylic acid predecessors.25 The true metabolic profile of thalidomide includes those products of biochemical oxidation on the phthalimide (aromatic) ring and the glutarimide ring, and to complicate matters, those products can be involved in the hydrolytic cascade as well. Furthermore, the rapid racemization of 1 complicates the problem since it is vital to understand which antipode exerts a specific biological response.26 Since thalidomide exhibits biological activity in many potential therapeutic areas, the hydrolytic, metabolic, and stereoisomeric products are of interest to those who are working on analogues to target a specific therapeutic area. The hydrolytic cascade of thalidomide, along with its chiral inversion between enantiomers, is shown in Scheme 10.1. Glutarimide hydrolysis of 1 can result in both N-phthaloyl glutamine 2 and N-phthaloyl isoglutamine 3. Hydrolytic cleavage of either of the isomeric N-phthaloyl glutamines 2 or 3 can result in N-phthaloylglutamic acid 4, the so-called “PG acid” which was a suspected teratogenic component. Facile semi-hydrolysis of the N-phthaloyl group of 4 provides the carboxybenzamidic triacid 5 which can suffer further hydrolysis to give glutamic acid 6 and o-phthalic acid. In viewing the left-hand side of the cascade, 1 can suffer facile partial hydrolysis of the phthalimide ring to give the N-glutaryl carboxybenzamidic acid 7, followed by full hydrolysis to give o-phthalic acid and aminoglutarimide 8. On the right-hand side of the cascade, the N-phthaloyl isoglutamine 2 and the N-phthaloyl glutamine 3 are both hydrolyzed to the carboxybenzamidic derivatives 2a and 3a, respectively. In turn the carboxybenzamidic acid 3a is hydrolyzed to glutamine 9. One should note that aminoglutarimide 8, commercially available, is a key starting material in many thalidomide and thalidomide analogue syntheses. Hydrolysis of aminoglutarimide 8 will provide both glutamine 9 and isoglutamine 10 which result in glutamic acid 6, also available through the lefthand side of the cascade (Scheme 10.1). Apart from the in vivo hydrolytic

O H N O N H O COOH 7

O

O

NH

O

O

O

O

O

NH

O

OH

N

NH2

N NH2

O H N

OH

O

O

O 3

2

O

O

NH O O

COOH +

NH2

O

NH2

OH O 2a

OH

NH2

HN O

O 4

OH O 3a O

H2N

OH 9

O O OH

HN O O

+

OH

OH N

O

O

O

O O

O 8

H2N

–NH3 O

NH

H2N

COOH

O

1

O

NH2

OH 9

O 10

HN O OH O 5 –NH3 O OH COOH H2N

+ OH O 6

Scheme 10.1 Hydrolytic cascade of thalidomide along with its chiral inversion.

COOH

OH

OH

371

Thalidomide and Analogues

products of thalidomide, the true metabolites that result from biochemical oxidation of both the aromatic phthaloyl ring (11, 12) and the glutarimide ring (13, 14) are hydroxylated species.27,28 HOOC HO HO HO

O HO

O O O

O

N

N

NH O

O

12 OH

N

O NH O

O 13

O

O

11 O

O NH

O

OH

N H COOH

O NH O

14

The hydroxylated metabolites of thalidomide were some of the first compounds under study for teratogenic effects as it was thought that these compounds were responsible rather than the parent compound 1. The metabolites, 5-hydroxythalidomide 11 and 50 -hydroxythalidomide 13, were assayed for after incubation of 1 with human liver homogenate and administration of 1 to human volunteers. The biochemical glycosylation product of 11, thalidomide 50 -O-glucuronide 12, and the phthalimide hydrolysis product of 13, 50 -hydroxy-N-(o-carboxybenzoyl) glutamic acid imide 14 as well as 11 was detected in plasma and urine samples in mice after treatment with 1. In contrast, assay of urine samples of multiple myeloma (MM) patients using high performance liquid chromatography-mass spectrometry (HPLC
MS) indicated the presence of several hydrolysis products 2, 3, and 7 (see Scheme 10.1) but none of the metabolic products 11
14. The conclusion from studies of thalidomide therapy in MM patients and the associated bioassays was that the metabolites measured were not responsible for any of the therapeutic activity.29 50 -Hydroxythalidomide 13 has always been a source of interest as it was suspected of being the active metabolite in more than one type of biological response, and quite possibly the synthesis and administration of 13 to a biological test system may elicit the same responses as that produced from 1 in vivo. Although the teratogenicity of 13 was never confirmed,

372

Imides

several syntheses of this metabolite along with the bioassay work associated with the compound are discussed later in this chapter.

10.3 THALIDOMIDE ANALOGUES AND TERATOGENICITY The first series of thalidomide analogues described in the literature were those which were included in studies surrounding its teratogenic effects. The analogues investigated included those possessing intact phthalimide and glutarimide rings, saturated rings of varying sizes, and those having an array of substituents. Soon, it became apparent what the structural requirements were for the molecule to retain its teratogenic properties and such presumptions were based on the in vivo evaluation of analogues in a variety of test animals. The degree of teratogenicity of thalidomide and its analogues is species-specific. For example, many of the teratogenicity studies surrounded the thalidomide-sensitive marmoset monkey and revealed that a more potent thalidomide derivative might be available by removing one of the phthalimide carbonyls.30 Such a compound, 2-(2,6dioxopiperidine-3-yl)phthalimidine, termed EM-12 (15), become one O O

N NH O 15 (EM-12)

of the most widely bioassayed analogues in the thalidomide arena. When tested alongside thalidomide, the higher degree of teratogenic effects of EM-12 in the New Zealand white rabbit drew attention to the differential activity of thalidomide analogues with respect to the stereochemistry at 30 .31,32 As compared with thalidomide, the physiochemical properties of EM-12 are accompanied by a simpler in vivo hydrolytic profile due to the lack of one phthalimide carbonyl (Scheme 10.2). Only the glutarimide ring is easily hydrolyzed which gives rise to the isomeric N-isoindolinoyl glutamine 16 and isoglutamine 17, and in turn, both 16 and 17 may be hydrolyzed to the corresponding N-isoindolinoyl glutamic acid 18 (Scheme 10.2). While EM-12 has similar solubility issues to thalidomide, the simpler and hence straightforward hydrolytic profile of 1 renders this analogue an easier substrate to study in biological systems with respect to any associated metabolites as well as racemization issues.

Thalidomide and Analogues

373

15 H2O

H2O

O O

O NH2

O

N

OH

N OH

NH2

O

O 17

16 H2O

H2O

O O

OH

N OH O 18

Scheme 10.2 Hydrolytic profile of EM-12 (15).

In an early review, Jönsson listed a number of compounds 8 and 18
30 with a close structural relationship to thalidomide along with their teratogenic effects.33 The teratogenic activity of many of the compounds was organized according to fetal resorptions and malformations. The animals tested included the rabbit, chicken, and Wistar rat, although the chicken embryo presents inconsistencies due to lack of a placenta and any disparities in morphological development between avian and mammalian species. The aminoglutarimide 8 produces no resorptions or malformations in the rabbit, a thalidomide-sensitive species, while at the same time, one should note that it is one of the hydrolytic breakdown products of thalidomide. N- or 10 -methylthalidomide 18 does cause malformations in the rabbit, while the N-methoxy derivative 19 causes neither malformations or resorptions. In a separate communication by Wuest,34 N-hydroxythalidomide 20, once considered a plausible metabolite, is considered nonteratogenic. 4-Nitrothalidomide 22 and its reduction product, 4-aminothalidomide 21

374

Imides

O H2N

O

N

O NH

O O 18

O 8 NH2

NO2

O

O

N

O N CH3

O O 19

O

O N OCH3

N O OH

O

O

O 20

N OH

O

HO N

O

N

O

N O

H

O

O

21

O

H

O

O

O

O

H

O

O 25

N H

H

O N H

N

O

O 26

O

O

O

O 23

O

N

N H

O N

11

O

N

N

O N

22

O

O O 24

N

N

O

Ph

NH O

HN

N

O

27

O

Ph

O NH

NH

NH

NH O

O

Ph

O

O

O

28

29

30

(later to become the Celgene product, pomalidomide), both result in malformations and resorptions in the rabbit model. 4- and 5-Hydroxythalidomide (23, 11) both cause malformations in the chicken embryo whereas the 5-isomer 11 is an acknowledged metabolite in mammals. The cycloalkyl-fused or otherwise the tetrahydrophthalimide analogues 24 and 25 were found to be nonteratogenic. The 40 -phthalimido analogue of thalidomide 26 causes malformations in the chicken embryo but not the Wistar rat; however, in the rat, the compound does cause fetal resorptions. No detrimental responses to the N-succinimidoyl glutarimide 28 were recorded but malformations were noted in the chicken embryo when applying the N-benzoylglutarimide 27. Glutethimide 29, a widely used sedative does not elicit malformations in the rat or rabbit but does cause resorptions in the rat. The barbiturate 30 does cause both resorptions and malformations in both the rabbit and rat, but more specifically, the malformations that occur in the rabbit involve those of the skull and ribs and not the limbs. Early studies by a Bonn group which evaluated the effects of planarity of the phthalimide ring confirmed the lack of teratogenicity of Jönsson’s analogues 24 and 25 in mice. The same studies, which involve the partially planar analogues 30
32, confirmed the lack of teratogenicity in 30 and 31 while the dithia compound 32 was demonstrated to be teratogenic.35 To a degree, the Bonn group sought to prove or disprove the theory of

375

Thalidomide and Analogues

O

O

O S

N

O

N

O

N O

O

H

O

O

30

N H

N

O

S O

O

31

N H

32

DNA intercalation by the phthalimide group put forth by Jönsson. Researchers at the Grünenthal Research center evaluated the effects of compounds 15 (EM-12), 33 (EM-136), 34 (EM-8), 35 (EM-255), and 36 (CG-3033) on pregnant New Zealand white rabbits along with toxicity tests in mice.36 While the phthalimidine compound EM-12 (15) was included in the group of compounds tested, its teratogenicity was wellestablished earlier in thalidomide-sensitive primate models. The trend in teratogenic potency was O

O O

N

O

N NH

NH O

O

O

33 (EM-136)

15 (EM-12)

N S O2 O

O NH

34 (EM-8) O

O N NH O 35 (EM-255)

N S O2

NH O

36 (EM-87/CG-3033)

determined to be 15 . thalidomide  33 . 35 . 34 . 36. A number of interesting chemical points may be made from the Grünenthal (Helm) article. Compound 36 (CG-3033) was given a common name supidimide and could be a metabolic precursor to 35 (EM-8) through biochemical oxidation of the piperidinone moiety. The laboratory synthesis of 34 (EM-8) entailed the reaction of the sodium salt of benzo(d)isothiazole-3 (2H)-one 1,1-dioxide (sodium saccharin) and the bromoglutarimide 37 (Scheme 10.3). No yields were reported for the preparation of 34. Lenalidomide 38, an analogue of 1 and a close relative of the teratogenic EM-12 (15), is Celgene’s key anticancer drug for treatment of MM and myelodysplastic syndrome (MDS) and will be discussed later in the

376

Imides

O DMF

Br NNa

+

34

S O2

O

N H

140°C

O

37

Scheme 10.3 Synthesis of analog 34 from glutarimide 37.

chapter. The teratogenicity associated with the use of thalidomide in humans has been proven, leading to close scrutiny of the approved analogues before being administered to patients. While O O

N NH NH2

O

38 (Lenalidomide)

there are many other anticancer drugs that are teratogenic, the negative publicity that has surrounded thalidomide and its derived analogues over decades has prompted special and required protocols that preclude or accompany its usage. One program is the so-called “S.T.E.P.S.” an acronym for System for Thalidomide Education and Prescribing Safety, put into place by Celgene to ensure that women of childbearing age who received thalidomide as cancer treatment were closely monitored.37 Due to the teratogenicitiy of its close relatives, it was of concern to assess the potential teratogenic effects of lenalidomide in a relevant thalidomide-sensitive species. The commonly employed New Zealand White rabbits, used in many early studies of thalidomide analogues, were the subjects’ developmental toxicity studies of 38 along with thalidomide as a positive control. A study reported by Charles River Preclinical Services and Argus International disclosed that lenalidomide, administered to pregnant New Zealand White rabbits in the dosage range of 0
20 mg/(kg day) during 7
19 days gestation period, caused observations of necropsy, reduced maternal weight gain, and food consumption.38 When the administration of lenalidomide to the rabbits approached toxic levels, fetal malformations began to be apparent. While the substitution of fluorine on thalidomide which replaces the enolizable proton provides a substrate which is configurationally stable to racemization, the 30 -fluorothalidomides (R)-39 and its

Thalidomide and Analogues

O

377

O F

F

N

O

O

N

N O

N H

O

(R)-39

O

H

O

(S)-39

enantiomer (S)-39 proved to be a poor test compounds in vivo. Indeed, in contrast to thalidomide, the fluorothalidomides turned out to be maternally toxic to both rabbits and mice and yielded unidentified hydrolysis compounds. A dose of fluorothalidomide 39, apparently as the racemate, equal to that of thalidomide (427 mg/kg) given to pregnant New Zealand white rabbits resulted in pulmonary edema, renal tubular degeneration, macerated fetuses, and death 3 days after the end of the dosing period.39 Homothalidomides 40 and 41 were a source of interest from both the neurological and teratogenicity point of view as compared to thalidomide (1). Phthalimido succinimide 40 (2-(2,5-dioxopyrrolidin-3-yl)isoindoline1,3-dione) was not teratogenic or otherwise did not cause fetal malformations when administered to pregnant rats, but did cause an increase in fetal resorptions. Administration of the homothalidomide 41 [2-(2,7-dioxoazepan-3-yl)isoindoline-1,3-dione] to incubated eggs in the Hen’s Egg Test (HET) resulted in no malformations.40 Compound 40 exhibited a sedative effect in both rats and mice while 41 showed a higher sedative effect in mice as compared to thalidomide.41 O

O

N

NH O

O 40

O N O O 41

N H

O

The first synthesis of 50 -hydroxythalidomide 13 was reported by Eger and coworkers and was undertaken with the goal of identifying the compound as a modulator of TNF-α.42 Subsequently, the compound became of interest as an angiogenesis inhibitor as were many of the metabolites isolated from the thalidomide manifold were suspected teratogens. The synthesis begins with the N-carbobenzyloxy (CBZ)
protected lactone 42, a derivative of γ-hydroxyglutamic acid (Scheme 10.4). Treatment of 42 with ammonia in methanol gave the ammonium

378

Imides

H R N O

R OH NH3/MeOH O

O

42 R=carbobenzyloxy

NH

OH –

O NH3+

H2N O

Ac2O

R

H N O

O

CH3

O N H

43

O

O

44

1. H2/Pd-C 2. Phthalic anhydride O 13

PTSA MeOH

N

O

O O

N H 45

O

CH3 O

Scheme 10.4 The Eger Group synthesis of 50 -hydroxythalidomide 13.

salt of N-CBZ-4-hydroxy-isoglutamine 43. Treatment of the isoglutamine salt 43 with acetic anhydride in pyridine furnished the 5-(N-CBZ amino)-2,6-dioxopiperidin-3-yl acetate 44 which was N-deprotected (H2/Pd-C) and then N-phthaloylated to give the acetoxyglutarimide 45. Removal of the acetoxy group (p-toluenesulfonic acid/MeOH) gave the target 50 -hydroxythalidomide 13. The synthesis and utilization of glutamic acid derivatives have been a viable route to thalidomide analogues which bear a glutarimide ring. Therefore a synthesis of 50 -hydroxythalidomide 13 would utilize the intermediacy of 4-hydroxyglutamic acid, a compound that could be made in either enantiomeric or diasteriomeric forms.43 The synthesis starts with the commercially available (1)-(1R,3S)-4-cyclopentene-1,3-diol-1-acetate 46 (cyclopentenyl diacetate 46). Reaction of potassium phthalimide with 46 in the presence of Pd(PPh3)4/PPh3/tetrahydrofuran (THF) gave the (1)-(1S,4R) phthalimdo alcohol 47 (74%) which was esterified with pivaloyl chloride to give the cyclopentenyl phthalimide ester 48 (96%). Oxidative cleavage of 48 (OsO4/KIO4/CH3COOH then CH3COOOH) gave the intermediate dicarboxylic acid which was directly esterified to give the (1)-(2R,4S)-diester 49 (63% from 48). The remaining steps toward the hydroxyglutarimide 13 would entail hydrolysis of the diester 49 followed by amination of the resulting diacid and cleavage of the pivaloyl group (Scheme 10.5). The N-CBZ lactonic acid 42 proved to be useful in another synthesis of 13 whereby the major difference in the two syntheses was the

379

Thalidomide and Analogues

O NK OH

OAc

46 (+)-(1R, 3S)

O

O

O

N

O

O

COCl

OH

N

O

O DMAP

Pd(PPh3 )4 /PPh 3 47

48 1. OsO 4/KIO4/AcOH 2. CH 3COOOH O O

1. Amination 13

N O

O 2. Pivaloyl cleavage

O O

H 3CO

OCH3

49 (+)-(2R, 4S)

Scheme 10.5 Stereospecific route to 13 using diester intermediates. NHR HO

PMB-NH 2

O O

O Pyridine

HO

NHR

HOOC

42

O

Ac 2O

CONHPMB

(CF3CO) 2O

50

R=CBZ=benzyloxycarbonyl H3 CO

NH 2 = PMB-NH2

AcO

N O PMB 51 R=CBZ, PMB= 4-Methoxybenzyl O

CAN

O

13

Dowex-H+ MeOH

AcO

NHR

N

1. H 2/Pd-C

AcO

NHR

O O

N H 53

O

2. Phthalic anhydride

O

N H 52

O

Scheme 10.6 Synthesis of 13 using 4-methoxybenzylamine as an amination reagent.

employment of 4-methoxybenzylamine (PMB-NH2) was employed as a convenient amination reagent during the synthetic sequence (Scheme 10.6).44 Lactonic acid 42 was combined with 4-methoxybenzylamine in the presence of pyridine to give the N-4-methoxybenzyl (PMB) isoglutamine 50 (85%). The N-CBZ
N-PMB isoglutamine 50 was converted to the 3-acetoxy-N-PMB glutarimide 51 by heating in acetic/trifluoroacetic anhydride (68%). Following removal of the PMB group of 51 with ceric ammonium nitrate (CAN) in aqueous acetonitrile, the resultant N-CBZacetoxyglutarimide 52 was hydrogenated to remove the CBZ group

380

Imides

followed by phthaloylation [phthalic anhydride/triethylamine (TEA)]. The product 3-phthalimido-5-acetoxyglutarimide 53 was treated with Dowex (H1 form) in methanol to remove the acetyl group and furnish the target 13 in quantitative yield from 53. A formal “chiral pool”-derived route to 50 -hydroxythalidomide was detailed whereby the starting material was readily available L-aspartic acid and employed a Henry or nitroaldol reaction as a key step (Scheme 10.7).45 L-(S)-Aspartic acid was esterified (MeOH/chlorotrimethylsilane) followed by protection with tert-butoxycarbonyl anhydride (BOC anhydride) to deliver the N-BOC dimethyl aspartate 54 (80%). Installation of a second BOC group on 54 was effected with BOC anhydride in the presence of 4-dimethylaminopyridine (DMAP) to provide the di-N-BOCdimethylaspartate 55 (quantitative). The di-N-BOC diester 55 was reduced with diisobutylaluminum hydride (DIBAL) to afford the di-NBOC aldehyde-ester 56 (74%). The di-N-BOC aldehyde-ester 56 was combined with nitromethane in the presence of 1,1,3,3-tetramethyl guanidine (TMG) to give the di-N-BOC nitroalcohol 57 (79%). Treatment of the nitroalcohol 57 with tert-butyldimethylsilyl triflate (TBDMS-Trif) gave the di-N-BOC silyloxynitroester 58. Removal of both N-BOC groups followed by reaction with N-carbethoxyphthalimide gave the H

HO

O 1. MeOH OH TMSCl 2. (BOC)2O

NH 2

O

H

H 3CO

O

OCH3 NHBOC 54

O

Boc 2O DMAP

O

H

H 3CO

OCH3 N(BOC)2 55

O

DIBAL H

H O 2N TBDMS

O

OCH3 N(BOC)2

O

TBDMS-Trif

H

H O2 N

O

OCH 3 OH N(BOC) 2 57

58

H

CH 3NO2 H TMG

O

OCH3 N(BOC)2 56

O

1. TFA 2. Phthalic anhydride H

H O2 N TBDMS

O

O OCH 3

O

N

O

O

NaNO 2 AcOH

59

H

H

HO

O

O OCH 3

OH

N

MeOH

O TMSCl

O

60

H

H

H 3CO

O OCH3

OH

N

O

O

61

Scheme 10.7 Synthetic route to precursor 4-hydroxyglutamic acid from L-aspartic acid.

381

Thalidomide and Analogues

N-phthaloyl silyloxynitroester 59. Treatment of the silyloxynitro compound 59 with sodium nitrite/acetic acid (DMSO) gave the Nef-type product carboxylic acid ester 60 (51%) with concomitant removal of the silyl group. Esterification of the N-phthaloylester 60 with methanol and chlorotrimethylsilane furnished the N-phthaloyldiester 61 (90%) which was formally the diester analogue of 49. While the search for hydroxylated metabolites of thalidomide in human plasma may not be exhaustive or otherwise limited to the 50 -hydroxylated analogue 13. The set of enantiomers or diastereomers of the 40 -hydroxylated metabolite 62/63 does bear mention as it is a “metabolic analogue” and does carry the potential as an angiogenesis inhibitor. An entry into members of the 40 -hydroxyated series began with the application of the Sharpless asymmetric dihydroxylation reaction (Scheme 10.8).46 The 5-Nphthaloyl-α,β-unsaturated benzyl ester 64 was submitted to reaction with AD-mix-α, methansulfonamide, tert-butanol-H2O which gave (2R,3S) benzyl ester diol 65 (82%). Treatment of the benzyl ester diol 65 with 4nitrobenzenesulfonyl chloride followed by sodium azide in DMF furnished the (2S,3S) 2-azidoalcohol 66. Protection of the azidoalcohol 66 with TBDMS-Trif/2,4,6-collidine gave the trimethylsilyl-azidoalcohol 67. Removal of the N-phthaloylgroup of 67 with hydrazine in ethanol resulted in lactamization to give a mixture of 3-azido-4-O-TBDMS glutarimides 68 and 69 (3:1) in 90% combined yield. Staudinger reduction of the azido group of 68 with triphenylphosphine in acetonitrile/H2O followed by O

O OBn

N O

O

O OH

AD mix-α

OBn

N

64

O

NaN3

OH

O

OBn

N

O

CH3SO2NH2

OH

Nosyl chloride

N3

O 66

65

TBDMS-Trif OTBDMS N3

O

TBDMSO

1. PPh3

N O N H 70

O

OTBDMS N3 +

2. O-C6H4(COCl)2

N H 68

O

N H 69

O N2H4

HO NPhth

67

NPhth Phth=Phthaloyl

N H 71

O

O

N H 62

O

O

N H 63

O N3

O

HO NPhth

O

Scheme 10.8 Synthetic route to 40 -hydroxythalidomides 62/63.

TBDMS OBn

N

O

TFA

HO

O

382

Imides

phthaloylation with phthaloyl dichloride/DMAP afforded the N-phthaloylO-TBDMS lactam 70 (99%). Removal of the TBDMS group of lactam 70 with aqueous trifluoroacetic acid (TFA) provided the 40 -hydroxy-60 -desoxythalidomide 71 (70%). Numerous attempts to oxidize the 60 -methylene of lactam 71 or its derivatives failed to form the corresponding glutarimide en route to 62/63.

10.4 CONFIGURATIONALLY STABLE ANALOGUES OF THALIDOMIDE Thalidomide bears an enolizable α-proton at 30 and facile racemization under conditions occurs in vitro as low as physiological pH.47 Hence, the rate of racemization has been measured in several studies using the pure thalidomide enantiomers. The racemization issue has clouded investigations into the relationship of configurational preferences and biological activity whereby it was first postulated that one enantiomer only was responsible for its teratogenicity.48 Several correlations have been proposed based on bioassays using the pure enantiomers as well as nonracemic, configurationally stable analogues. Positioning a substituent other than a proton at 30 will preclude racemization and render the molecule configurationally stable. Consequently, a configurationally stable thalidomide analogue may help to elucidate any relationship between configuration and biological activity. Some of the substituents positioned at C-30 are deuterium (nonracemic), fluorine (nonracemic), methyl (nonracemic), and difluoromethyl/trifluoromethyl (racemic). There are also claims of configurationally stable thalidomide analogues having substituents at C-40 of the glutarimide ring rather than C-30 , with the idea that sterics play a role in preventing any inversion at C-30 . The syntheses of configurationally stable thalidomide analogues that have C-30 substituents are shown in Schemes 10.9 and 10.10. Shibata and coworkers synthesized (R)-(2) and (S)-(1)-30 -deuteriothalidomide (R)72/(S)-72 that utilized racemic 10 -N-BOC-N-phthalimidolactam 73 (Scheme 10.9).49 The racemic N-BOC lactam 73 is deprotonated with lithium hexamethyldisilazide (LHMDS) (278°C- 2 40°C) followed by a D2O quench to give the racemic-30 -deuterated lactams (R)-74/(S)-74 (80%). Following removal of the N-BOC group from the racemic Nphthalimido-N-BOC-lactams (R)-74/(S)-74 (TFA/dichloromethane) to give N-phthalimidolactams (R)-75/(S)-75 (83%), the racemic mixture of lactams were oxidized (RuO2/NaIO4) to provide the racemic glutarimides (R)-72/(S)-72 (95%). Chiral HPLC separation of racemic (R)-72/(S)-72

383

Thalidomide and Analogues

O

O H

O D

LHMDS

N

D

TFA

N N BOC

O

O

N N

D 2O O

O

73

N BOC

(R)-74/ (S)- 74

H

O O (R)-75/(S)-75 RuO2 NaIO 4

O

O D

O D

N

O

N

+

O

N

O

N

N O O (S)–(–) 72

D

DAICEL

H

N H

O O (R)-(+) 72

O O (R)-72/(S)-72

H

Scheme 10.9 Synthesis of 30 -deuterothalidomide (S)-(2)-72 and (R)-(1)-72.

O

1. LHMDS Cu(acac) 2

F N O

O

N BOC

O

1. LHMDS TMEDA

H N

2. DHQ/NFSI

O

O

(R)-76

O F N

N 2. DHQ/NFSI BOC

73

O O (S)-76

1. TFA 2. RuO 2/NaIO4

1. TFA 2. RuO 2/NaIO4 H

O

HO

F O

N O

O

(R)-39

N H

N BOC

N

O F O

N

H3 CO N DHQ

O O (S)-39

N H

Scheme 10.10 Synthesis of 30 -fluorothalidomides (R)-39 and (S)-39.

(DAICEL Chiralpak AD) afforded the separated enantiomers (R)-(2)-72 and (S)-(1)-72. Both α-deuterated thalidomide analogues (R)-(2)-72 and (S)-(1)-72 proved to be five times more stable than thalidomide itself when exposed to aqueous phosphate buffer solutions. The same racemic N-10 -BOC lactam 73 was employed by Shibata in a synthesis of (S)- and (R)-30 -fluorothalidomides (S)-39 and (R)-39 (Scheme 10.10).50 Racemic lactam 73 was treated with lithiumhexamethyl-disilazide/Cu(acac)2/2,2bipyridine followed by the chiral cinchona alkaloid ligand (dihydroquinine (DHQ)), and fluorinating agent, N-fluorobenzenesulfonimide (NFSI) to afford the (R)-fluorinated-N-BOC lactam (R)-76 (81%, 77% ee). Removal of the N-BOC group of (R)-76 (TFA/CH2Cl2) followed by oxidation of

384

Imides

the intermediate lactam (RuO2/NaIO4) provided the (R)-30 -fluorothalidomide (R)-39 (72%, 99% ee). The enantiodivergence of the synthesis is demonstrated when the starting racemic lactam 73 was treated with LiHMDS/ tetramethyl-ethylenediamine and then DHQ/NFSI to afford (S)-lactam (S)-76 (88%, 78% ee). The (S)-lactam 76 was then treated with excess TFA followed by the RuO2/NaIO4 oxidation to give antipodal 30 -fluoro(S)-39 (62%, 99% ee). The Hashimoto group reported a preparation of both antipodes of 30 -methylthalidomide (S)-77 and (R)-77 in 1994 in order to ascertain any configurational relationship in TNF activity between the two enantiomers (Scheme 10.11).51 The benzaldimine of alanine 78 was added to acrylonitrile under promotion with Triton B followed by hydrolysis (HCl) to give aminonitrile 79. The cyano group of the aminonitrile was reduced (H2/PtO2) to provide the cyclized aminolactam 80. Phthaloyation of aminolactam 80 (phthalic anhydride) gave the carboxybenzamidic acid (81, 94%) which was cyclized to the phthalimidolactam 82 by heating (89%). The 30 -methyl-30 -N-phthalimidolactam 82 was then oxidized to the corresponding racemic-30 -methylglutarimide (S/R)-77 by oxidation with m-chloroperbenzoic acid. Finally, the racemic-30 -methylthalidomide

Ph N

CN

1. Triton B H 2N 2. HCl

H3 COOC

H2 /PtO2

H 2N

COOCH 3

H

O 80

79

78

N

Phthalic anhydride O

O

O

O

MCPBA N

N

N

N

H

O O (S/ R)-77

O

O

81

O (S/ R)-77

O

O N

N O (S)-77

H

O

O

82

DAICEL

N

HN OH

H

O

H

+

O

N O (R)-77

N

H

O

Scheme 10.11 Synthesis of the configurationally stable 30 -methylthalidomides (R)-77 and (S)-77.

385

Thalidomide and Analogues

(R/S)-77 was separated to each enantiomer (S)-77 and (R)-77 using HPLC equipped with a Chiracel OD (DAICEL) column eluting with hexane/ethanol, 80:20. An interesting concept involving configurationally stable analogues of thalidomide entailed preparation of the 40 -substituted analogues. Hence, a substituent at the 40 -position would render the carbon at 30 configurationally stable since epimerization at the 30 would lead to the conformationally unfavorable cis-derivative. Enantiomerically and diasteriomerically pure 40 -methyl and 40 -phenyl thalidomide were prepared through the intermediacy of the appropriate pyroglutamic acid derivatives (Scheme 10.12).52 Base-mediated addition of the achiral nickel Schiff base derivative 83 utilizes either the 30 -methyl or 30 -phenyl-substituted enoyl-derived chiral auxiliary 84a/84b, whereby the chiral directing moiety is the (R)- or (S)-4-phenyl-1,3-oxazolidine-2-one. Using 1,8-diazabicyclo[5.4.0]undec7-ene (DBU), the diastereoselective Michael addition gave the adducts 85

N

O

O

O

Ni O

N

+

N

R

O

N DBU

N O

O

O

O

Ni O

Ph

N

O N

N R

O

Ph

84a , R=CH 3 84b, R=Ph

83

85, R=CH3 (2R, 3R) 86, R=Ph (2R, 3S) H+/H2 O

O

R

O O

N

1. Phthalic anhydride

COOH

O 2.Acetic anhydride

O

H 2N

R

HCl O

COOH

R

89, R=CH3 (2R, 3R) 90, R=Ph, (2R, 3S)

91, R=CH3 92, R=Ph

N

COOH

H 87, R=CH3 (2R, 3R) 88, R=Ph, (2R, 3S)

H2 O/acetone O

O

O OH

CF3 CONH 2

N

O NH

N

O

HOBt/EDCI O

R

O HO

93, R=CH3 94, R=Ph

O

R

95, R=CH3 (3S, 4R) 96, R=Ph (3S, 4S)

Scheme 10.12 Synthesis of configurationally stable thalidomide analogues 95 and 96.

386

Imides

and 86. Acid-mediated hydrolysis of the adducts 85 and 86 provided the (2R,3R)-3-methyl- and the (2R,3S)-3-phenyl pyroglutamic acids 87 and 88, respectively. Hydrolysis of the pyroglutamic acids 87 and 88 (6N HCl/reflux) afforded the corresponding (2R,3R)-3-methyl- and (2R,3S)3-phenylglutamic acids 89 and 90, respectively. The glutamic acids 89 and 90 were converted (phthalic anhydride, then acetic anhydride) to the corresponding N-phthaloylglutamic anhydrides (2S,3R)-91 and (2S,3S)92 accompanied by complete epimerization at C-2 (C-3 of the cyclic anhydride). Hydrolysis of the trans-(2S,3R) and (2S,3S) anhydrides (H2O/ acetone) gave the corresponding 3-methyl and 3-phenyl-N-phthaloylglutamic acids 93 and 94. Cyclization of acids 93 and 94 to the corresponding (3S,4R)-4-methyl- and (3S,4S)-4-phenylthalidomides 95 and 96 was accomplished using trifluoroacetamide/1-hydroxybenzotriazole (HOBt)/ 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI) in the presence of TEA. Configurationally stable analogues of thalidomide may also be explored by elimination of one of the glutarimide carbonyls thereby increasing the pKa of the α-proton at C-30 and enhancing configurational stability. The replacement of a glutarimide carbonyl with a spirocyclic oxetanyl group resulted in thalidomide and lenalidomide analogues 97 and 107 which exhibited increased in vitro stability in human plasma after incubation for 0.25
5 hours. The synthesis involved a complete skeletal design of the glutarimide ring (Scheme 10.13).53 Nitroaldol reaction of the 4-nitrobutanoate 98 with the oxetanone 99 in the presence of TEA followed by treatment with methanesulfonyl chloride gave the expected mesylate 101 along with alkenyloxetane elimination product 100 (41%). The mesylate 101 could be displaced with 4methoxybenzylamine (Et3N/THF) to install the nitrogen thereby affording the nitro-4-PMB aminooxetane 102. Conversion of the nitro group of 102 to the corresponding oxime 103 was effected using benzyl bromide/KOH and tetra-N-butylammonium iodide. Cyclization of oxime ester 103 to lactam 104 was done by heating in xylenes. Reduction of the oxime 104 (H2/Ni (R)/EtOH) gave the corresponding N-PMB lactam amine 105 which was phthaloylated (phthaloyl chloride/Et3N/DBU) to afford the N-phthaloyl-N-PMB spirocyclic lactam 106 (82%). Removal of the N-PMB group from the N-phthaloylspirocyclic lactam 106 using CAN in aqueous acetonitrile gave the oxetanylthalidomide analogue 107 (54%). The oxetanyl lenalidomide analogue was also prepared by simply changing the arylsynthon which comprised the phthaloyl group to that which is a nitroisoindolinone group (Scheme 10.13). Amino-N-PMB

387

Thalidomide and Analogues

O O

O O2 N

OCH 3

Et3N

O2 N

OCH 3

+ O 99

98

O O2 N

OCH3

+ OMs

O

O

101

100

OCH3

1. 4-Methoxybenzylamine 2. Bn-Br/KOH/n-Bu4NI

Et3N THF

H 2N

O HON HON

Xylene

O N PMB

O

O

O OCH3

NHPMB

n-Bu4NI

O

103

OCH3 NHPMB 102

104

H2/Ra-Ni

EtOH

O

COCl H 2N

O

O

N

COCl

O N

N Et3N/DBU

PMB O

O

N

CAN

O NH

PMB O 106

105

Et3N DMF 70°C

CH3CN H2O

O O 107

CO 2CH3 Br NO2 O

O CAN

N

PMB O 108

CH 3CN H 2O

O

N

O N

NO2

Bn-Br/KOH

O2N

O NH

NO2

H2/Pd-C

N

O NH

CH 3OH

O 109

NH2

O 97

Scheme 10.13 Synthesis of oxetano analogues 97 and 107.

lactam 105 was reacted with methyl-2-(bromomethyl)-3-nitrobenzoate (Et3N/DMF/70°C) to give the nitroisoindolinone in 108 in 73% yield. Removal of the N-PMB group of 108 (CAN/CH3CN/H2O) afforded the isoindolinone lactam 109, which was reduced (H2/Pd-C/CH3OH) to give the oxetano lenalidomide analogue 97 (108-97, 43%). The configurationally fixed but racemic 4-amino-30 -methyl analogue of thalidomide 110 was synthesized as part of Celgene’s TNF-α inhibitor program (Scheme 10.14).54 3-Methyl-N-CBZ glutamic anhydride 111 was reacted with ammonia in dichloromethane to provide a mixture of α-methylglutamines 112a and 112b. The mixture was treated with carbonyldiimidazole (CDI) in THF to provide the racemic-3-methylglutarimide 113. Removal of the CBZ group by hydrogenolysis (10% Pd-C) followed by treatment with 4N aqueous HCl gave the 3-amino-3-methylglutarimide hydrochloride

388

Imides

O

O O CBZNH

OH

NH 2

NH 3

CDI

+

O

CBZNH

O

CBZNH

OH

NH O

NH 2

113

O

O

111

O CBZNH

112a

112b 1. H 2/Pd 2. HCl

O O

1. O NO2 N NH NH 2

O –

O

O

Cl+H3 N

NH O

2. H 2/Pd-C

O

O

114

110

Scheme 10.14 Synthesis of a Celgene α-methylthalidomide analog 110.

H 1. n-BuLi Me3 Si

N

H2 N

F2 RC

SiMe3

N

2.

115

O

BOC OCH3 116, R=H 117, R=F

CF2R CO2 CH3 NHBOC 118 , R=H 119, R=F

RF2 C

H2 /Pd-C

O BocHN

NH 120, R=H 121 , R=F

TFA COCl O RF2 C N

O NH

O O 126, R=H 127 , R=F

RuO2

O RF2C N

NaIO 4

COCl NH

O 124, R=H 125 , R=F

RF 2C

O

O DMAP

H 2N

NH 122, R=H 123, R=F

Scheme 10.15 Burger’s synthesis of 30 -trifluoromethyl and 30 -difluoromethyl thalidomides 126 and 127.

114. Reaction of the glutarimide 114 with 3-nitrophthalic anhydride in refluxing acetic acid followed by reduction of the nitro group with hydrogen over Pd-C catalyst in acetone gave the racemic 4-aminothalidomide analogue 110. The Burger group prepared both configurationally fixed 30 -trifluoromethyl and 30 -difluoromethyl thalidomides 126, 127 from acyclic precursors (Scheme 10.15).55 Addition of the anion of N,N-bis(trimethylsilyl) prop-2-yn-1-amine 115 to either the difluoromethyl or trifluoromethyl N-BOC imino esters 116/117 gave the N-BOC-difluoromethyl or trifluoromethyl(aminomethyl)acetylenic esters 118 (81%) and 119 (89%),

Thalidomide and Analogues

389

respectively. Catalytic reduction (H2/Pd) of the triple bond of either 118 or 119 resulted in cyclization to the difluoromethyl/trifluoromethyl lactams 120/121 (85%/91%). Removal of the BOC group from 120/121 with TFA in dichloromethane gave the α-amino difluoromethyl/trifluoromethyl lactams 122/123 (68%/75%). The lactams were phthaloylated with phthaloyl dichloride and DMAP to give the difluoromethyl/trifluoromethyl phthalimidolactaams 124/125 (63%/50%). Finally, methylene oxidation of the lactams with ruthenium dioxide in the presence of sodium metaperiodate gave the corresponding difluoromethylthalidomide 126 (65%) or the trifluoromethylthalidomide 127 (65%). The configurational interconversion of pomalidomide 21 (ACTIMID) has been reported whereby the (S)-enantiomer (95% optical purity) racemizes rapidly in human plasma and phosphate-buffered saline.56 The compound presents similar configurational instability as thalidomide which led the Celgene researchers to determine that there was no advantage to developing a single enantiomer of the compound as a therapeutic. Even though chiral inversion of 21 was eminent, there was a need to examine the potential effectiveness of the configurationally fixed α-fluoro analogues of 21, 130. The synthesis of 130 starts with 4-nitrothalidomide 22 (see Johnsson analogues).57 The glutarimide nitrogen of 22 was protected with BOC anhydride [(BOC)2O]/DMAP which provided the nitrophthalimido-N-BOC glutarimide 128. Deprotonation of 128 with LHMDS followed by quenching with the fluorodiphenyldisulfonimide gave the N-BOC-fluoroglutarimide 129. The resulting N-BOC α-fluoro glutamide 129 was hydrogenated (H2/Pd-C) to reduce the nitro group of 129 and give the α-fluoropomalidomide analogue 130. Racemic α-deuteriothalidomide 72a/72b and α-fluorothalidomide 39 were prepared from N-BOC thalidomide 131 using the same deprotonation protocol followed by quenching with acetic acid-d4 or the bisphenylfluorosulfonimide ((PhSO2)2NF), respectively (Scheme 10.16). The biological implications of thalidomide’s stereoisomerism have always been intriguing despite the propensity toward facile racemization at physiological pH. Hence, the physiochemical properties of 1 and its analogues have endured rigorous stereochemical analysis. Shibata notes that both thalidomide and its 30 -fluoro analogue (R/S)-39 display the phenomenon of enantiomeric self-disproportionation whereby nonracemic mixtures of the compounds can be separated into fractions of varying enantiomeric distribution using achiral silica gel chromatography.58 The propensity of thalidomide 1 to form a heterochiral dimer enables the less

390

Imides

O

O

N

O O

O

N N NO2

22

O

O

BOC

F

LHDMS

O

DMAP

NH NO2

O

(BOC)2 O

N

O N

(PhSO2 )2 NF NO2

128

O

O

BOC

129 1. H 2/Pd-C 2. TFA

O

O F

N

O N

O

O 131

BOC

72a/72b and (R, S)-39

N

O N

NH2

O O 130

H

Scheme 10.16 Synthesis of racemic α-fluorinated pomalidomide 130, racemic 39 and 72.

polar (R)-1 (if (R)-1 is in excess) to elute first during simple silica gel column chromatography. Conversely, the propensity of the racemic-30 fluoro analogue (R/S)-39 to form a heterochiral dimer results in a lesspolar eluting species whereby the more polar monomeric (R)-39 was retained more and observed in the late chromatographic fractions.

10.5 INHIBITION OF TUMOR NECROSIS FACTOR-α The first “rescue” of thalidomide to attain orphan drug status was initiated by the discovery of its therapeutic usefulness in leprosy. One of the symptoms of infection by Mycobacterium lepra is ENL. ENL, commonly known as the lepra reaction, is characterized as an acute outbreak of painful skin lesions with accompanying inflammation and peripheral nerve damage. Jacob Sheskin pioneered the therapeutic use of thalidomide in leprosy patients in the mid-1960s and demonstrated in one of the initial cases that the drug caused the lesions to disappear completely along with a decrease in pain, pyrexia, and insomnia.59 It is interesting to note that the serendipitous discovery stemmed from the administration of thalidomide as a sedative to patients with severe ENL symptoms. Soon, the connection between symptoms of ENL in leprosy patients and elevated levels of the cytokine TNF-α was then established so it was surmised that the mechanism of action of thalidomide in ENL was the actual reduction of toxic levels of the cytokine.60 Consequently, experiments with thalidomide in vitro confirmed that the drug inhibits the production of TNF-α by

Thalidomide and Analogues

391

lipopolysaccharide (LPS)-stimulated human blood monocytes. A more detailed examination by the Kaplan group disclosed that in the inhibition of the LPS-induced TNF-α production, the inhibitory effect is through the degradation of TNF-α mRNA whereby the half-life of the molecule was reduced from 30 to 17 minutes in the presence of thalidomide.61 Concurrent research by the Kaplan group also revealed that thalidomide was a distinct inhibitor of human deficiency virus type I (HIV-1) activation in human peripheral blood mononuclear cells (PBMCs).62 The bioassays were done on blood of patients who tested positive for HIV-1 which contained the characteristic infected PBMCs. The inhibition of both virus activation and TNF-α suggests that the viral activation proceeds by a TNF-α dependent pathway, whereby the wasting characteristic of high levels of TNF-α is also a symptom of advance HIV infection. Interestingly, the inhibitory levels of thalidomide used in the LPSinduced human monocyte experiments are therapeutically relevant to the plasma levels (1.5 μg/mL) achieved in man after administration of 150 mg thalidomide daily. Toxic wasting associated with advanced stages of cancer, opportunistic infections associated with HIV, graft versus host disease (GVHD), sepsis, and pyrexia are accompanied by high levels of TNF-α in patients, so thalidomide or closely related analogues will prove to be useful in moderating these levels thereby improving their quality of life. The earliest reported efforts toward the synthesis and evaluation of thalidomide analogues for the suppression of TNF-α were those of He and coworkers.63 The work was directed at the development of therapeutics for GVHD but the researchers described the clinical relevance of TNF-α suppression in treating GVHD. The analogues were based on modifications of the phthalimide ring while keeping the glutarimide ring intact, and were aimed at improved bioavailability of the thalidomide core structure. The modifications were simple and entailed the addition of functional groups such as nitro, amino, and hydroxy (11, 21
23, 132
135) as well as those with a nitrogen within the phthalimide ring (134, 135). The syntheses of 11, 21
23, 132
135 were very straightforward and utilized 3-aminoglutarimide 8 and the appropriate substituted phthalic anhydride. The yields of the resulting thalidomide analogues reported by He were reported to be “good to excellent.” The compounds were bioassayed in vitro using human peripheral blood lymphocytes and also underwent in vivo bioassays in a GVHD animal model whereby a few of the compounds showed promising results.

392

Imides

NH2

O

NO2

O

OH

O

O

HO O

N

O

N

O

N

NH

NH O

O

O

22

O

O

NH

O

O

21

11

O

N

NH

O

O

O

23

O

O

H 2N

O2 N O

N

O

N

NH

N

O

O

N

N

NH

O

O 133

O 132

O

N

NH

NH O

O 134

O O 135

Kaplan and coinventor Sampaio first named thalidomide and analogues in their 1995 patent (Application WO 92/14455, 1992) entitled “Method of Treating Abnormal Concentrations of TNF-α.”64 Listed in the patent along with thalidomide and some of its simple N-glutarimide-substituted analogues were compounds 2, 2a, 3, 3a, 4, and 5 and these compounds were the actual proposed in vivo hydrolysis products of thalidomide (see Scheme 10.1). Also listed in the Kaplan patent is the structure of EM-12 15, one of the most potent of the teratogenic analogues. Several polyhalogenated phthalimides, including tetrafluorothalidomide 136, tetrachlorothalidomide 137, and tetrabromo-phthalidomide 138, were synthesized with the goal of an improved THF-α inhibitor over thalidomide itself.65 Tetrafluorothalidomide 136 was reported to inhibit TNF-α secretion from LPS-stimulated monocytes at an IC50 of 400 nM. Compared with thalidomide, which exhibited an IC50 of over 200 nM under the same conditions, a 500-fold increase of activity was observed. Both the tetrachloro analogue 137 and the tetrabromo analogue OCH 3 R

O

R

R N

O NH

R R

O

O

OCH 3

N

O

R R

136, R = F 137, R = Cl 138, R = Br

O

R

O

OCH 3

139, R = H 140, R = F

138 were much less active than the tetrafluoro derivative 136 using the TNF-α secretion assay. The tetrafluoro analogue 140 of the Celgene TNF-α inhibitor 13966,67 was prepared and observed to be 100-fold

Thalidomide and Analogues

393

more potent than 139 using the LPS-induced monocyte TNF-α secretion assay. A number of thionothalidomides or thalidomide analogues in which the oxygens of any of the four carbonyls were replaced with sulfur were prepared with the goal of evaluating these analogues as TNF-α inhibitors. The compounds were prepared directly from thalidomide using the Lawesson’s reagent (LR) under several different sets of conditions (Scheme 10.17).68 Thalidomide 1 was thionated with LR in refluxing toluene to afford dithio derivative 142 (1.6%) in which both carbonyls of the glutarimide were thionated, through an intermediate monothio analogue 141. Treatment of thalidomide with LR in pyridine gave not only 45% of the dithiothalidomide 142 but also dithiothalidomide 143, whereby one carbonyl of the phthalimide ring and one carbonyl of the glutarimide ring was thionated. Using LR together with a mixture of morpholine and toluene gave the trithionothalidomide 144 (65%) which had the two sulfurs on the glutarimide ring and one sulfur on the phthalimide ring replacing the oxygens (Scheme 10.17). Celgene’s isoindolinone (phthalimidine) analogue of thalidomide, lenalidomide 38 was prepared by starting with an array of number of nitro-substituted 2-(bromomethyl) benzoyl esters and 3-aminoglutarimide 8 (Scheme 10.18).54 The preparation of the glutarimide starts with CBZL-glutamine 145 which is cyclized with CDI and then deprotected by hydrogenation over palladium on carbon to afford the known aminoglutarimide 8. The reaction of the starting aminoglutarimide 8 with the nitro-substituted-2-bromomethyl benzoates 146
149 then provided the nitro-substituted EM-12 analogues which were then reduced with palladium on carbon to provide the corresponding amino-substituted isoindolinone analogues 38, 150-152. Within the same communication, the O 1

LR

S

O S

N

LR N

NH

LR

S

N

O O 141

O S 144

O S 142 S

H3 CO

S P

S

N

S

NH S LR

P S

OCH 3

S NH

NH

O O 143

Scheme 10.17 Synthesis of thiothalidomides 141
144 as TNF-inhibitors.

394

Imides

R4 H2 N

O

OCH 3

+

NH

R4

O

R3 R2 146 , 147 , 148 , 149 ,

R1

Br

R1=NO2, R2=NO2, R3=NO2, R4=NO2,

R2, R1, R1, R1,

O N

80°C

O 8

Et3N/DMF

R3 O

R2

NH O

R1 R 3, R 4=H R 3, R 4=H R 2, R 4=H R 2, R 3=H

H 2/10%Pd-C/ MeOH

R4

1. CDI/THF/reflux 2. H 2/10%Pd-C/EtOAc

O

R3

N

O

R2 O

O H 2N

NH

1

38 , R =NH 2, R , R , R4=H 150, R 2=NH2, R1, R 3, R 4=H 151, R 3=NH2, R1, R 2, R 4=H 152, R 4=NH2, R1, R 2, R 3=H

OH NHCBZ 145

R1

O +

O 2N

2

3

O

R2 8

O

R1

O

O

N NH

O 153, 3-Nitro 154, 4-Nitro

O

O

1

22, R =Nitro, R2=H 132, R2-Nitro, R1=H Catalytic reduction 21, 133

Scheme 10.18 Celgene’s TNF-inhibitor synthesis.

4- and 5-amino analogues of thalidomide 22, 132 were also described whereby the amino substituents were on the phthalimide ring. The same aminoglutarimide 8 was reacted with 3- or 4-nitrophthalic anhydride 153, 154 in acetic acid at reflux. The resulting 4- or 5-nitrothalidomides 22, 132 were reduced to the corresponding (and previously reported) 4or 5-amino analogues 21 and 133 using hydrogen and 10% palladium on carbon in acetone (Scheme 10.18). The conceptual details and preparation of the amino analogues and the corresponding nitro intermediates toward EM-12 were previously described by the same workers in a 1997 US patent which was the springboard for Celgene’s claims of the drugs lenalidomide (38)69 and pomalidomide (21), of which 21 was a known compound well before issuance of the patent. The utilization of halogenated thalidomide analogues in which the phthalimide ring contains the

Thalidomide and Analogues

395

halogen is an excellent expedient toward building thalidomide-derived scaffolds for applications in many potential therapeutic areas. A vast number of thalidomide analogues having carbon tethers or rings bound to the phthalimide core were prepared as candidates for inhibiting TNF expression. The synthesis made use of the 50 -bromothalidomide analogue 156, prepared from 4-bromophthalic anhydride 155 and the trifluoroacetate salt of 3-aminoglutarimide 8 (Scheme 10.19). Reaction of the 5bromothalidomide derivative 156 with an alkyne such as propargyl alcohol under Sonagashira conditions followed by oxidation afforded the 5alkynylthalidomide derivative 158.70 Similarly, using several phenylboronic acids as coreactants under Suzuki conditions, 156 gave the 5-arylsubstituted thalidomides 157. 3-Iodophthalic anhydride 159 and the glutarimide 8 gave the 4-iodothalidomide analogue 160 (Scheme 10.20) which also served as an ideal coreactant for coupling reactions at C-4. Using the 4-iodothalidomide and 5-bromothalidomide analogues 156 and 160, the Buchwald
Hartwig cross-coupling reaction was employed to fasten aniline or substituted anilines to the phthalimide ring in preparing analogues for evaluation of inhibition of TNF-α expression (Scheme 10.20). The synthetic products were compared to thalidomide and revlimide in terms of activity. Compound 161, which appears to be more closely related to pomalidomide 21 than lenalidomide 38, was ninefold more active than lenalidomide and 18-fold more active than thalidomide. Compound 162, having the nitrogen at the 5-position, was twofold more O O

O +

H3 N +

O

N

NH

Br O

O 155

O NH

Br O

8

O 156

1. Sonagashira 2. Oxidation O

Suzuki O

N

O

N

NH O H

O O 158

O NH

O

O O 157

Scheme 10.19 Synthesis of 4- and 5-substituted thalidomide analogues as TNF-α inhibitors.

396

Imides

O

O

O

PhNH2 O

+

8

N

O

I

I

159

N

O NH

O O 160

O NH

Pd 2(dba)3 XPhos

NH

O

O

161 O

O PhNH2

N

O NH

Br O O 156

N Pd 2(dba)3 XPhos

Ph

O NH

HN O O 162

Scheme 10.20 Buchwald
Hartwig reaction of halogenated thalidomides 156 and 159 with anilines.

potent than thalidomide at 10 μM, but the inhibition value was marginal in terms of confidence limits. A range of substituted anilines used as coreactants in the Buchwald
Hartwig reaction gave a variety of candidates for TNF expression inhibition studies.71 The structural core of EM-12 (15), along with its enhanced stability as compared to thalidomide, has served as a conceptual starting point for a great many more interesting analogues in addition to lenalidomide 38, the 4-amino analogue of 15. A 2013 Celgene publication detailed that selected substitutions on the isoindolinone ring delivers candidates which are of interest as TNF-α inhibitor, IL-2 costimulators and antiproliferative activity in a lymphoma cell-line assay.72 Two compounds 167 and 168 displayed exceptional activity in the inhibition of TNF-α in the LPSstimulated human peripheral blood mononuclear cells (hPBMC) assay. The synthesis of 167 and 168 entails the employment of the appropriate substituted o-toluic acids 163 and 164 (Scheme 10.21). Thus 2,3-dimethyl benzoic acid 163 is esterified with methanol followed by benzylic bromination of the ortho-methyl group. The bromomethyl methyl ester 165 is then reacted with 3-aminoglutarimide 8 to provide the 4-methyl EM12 analogue 167. The similar sequence is applied to 3-chloro-2methylbenzoic acid to afford the 4-chloro EM-12 analogue 168 through chloroester 166. The IC50 values for TNF-α inhibition exhibited by 167 were 0.010 μM, and for the chlorinated analogue 168, the value was 0.079 μM. The EC50 values measured for both compounds in the IL-2

Thalidomide and Analogues

O

397

O OH

1. CH 3I/NaHCO3

OCH 3

+

8

2. NBS/AIBN R 163 , R=CH 3 164, R=Cl

R Br 165, R=CH 3 166, R=Cl TEA/DMF O O

N NH R

O 167, R=CH 3 168, R=Cl

Scheme 10.21 Synthesis of 4-methyl and 4-chloro analogues of EM-12.

inhibition assay were in the range of 0.01
0.079 μM. Expounding upon the well-trodden theme of chirality versus activity in thalidomide analogues, a group at DeuteRx synthesized and compared both enantiomers of the deuterated cyclopropylcarboxamide thalidomide analogue (S)-173 and (R)-173 as inhibitors of TNF-α release by LPS-stimulated human PBMCs.73 The (S)-deuterated enantiomer (S)-173 (IC50 13.4 nM) was 10-fold more inhibitory than the (R)-deuterated enantiomer (IC50 123 nM) when tested using an in vitro human PBMC bioassay. The synthesis of (S)- and (R)-173 proceeds by way of a cycloaddition/aromatization of furfural N,N-dimethylhydrazone 169 and maleic anhydride which provided the phthalic anhydride 170. The reaction of anhydride 170 with either antipode of the α-deuteroglutarimide (S)-D-171 or (R)-D-171 gave the enantiomeric dimethylhydrazine thalidomide analogues (S)-172 and (R)-172. Catalytic reduction of the dimethylhydrazone moiety of (S)- and (R)-172 followed by treatment with cyclopropane carbonyl chloride and N,N-diisopropylethylamine (DIPEA) afforded (S)- and (R)-173.73 The same group also prepared both antipodes of the α-1H and α-2H quinoxaline-derived analogues 174, 175 (Scheme 10.22) with the goal of preparing, observing, and testing “stabilized” enantiomers of thalidomide

398

Imides

O O +

O

O

D O + H2 N

O TFA

O

D N

CH 3COOH

O

NH O

O

N NMe 2

O

N NMe 2

169

NH O

O N

(S)- 171 (R)-171

NMe2 (S)-172 (R)-172

170

1. H 2/Pd-C O 2.

NH 2

Cl DIPEA

O R N

O

O NH

N

D N

O (–)-174, R=D (+)-174, R=D (–)-174, R=H (+)-175, R=H

O NH

O O

O

N H (S)-173 (R)-173

Scheme 10.22 Quinoxaline-derived TNF-α inhibitors 174 and synthesis of a cyclopropyl carboxamidomethyl TNF-α inhibitor 173.

analogues. When tested for inhibition of TNF-α release using human PBMCs, (2)-D-174 was 20-fold more potent than (1)-D-174. While the antipodes of 174 and 175 were separated by chiral chromatography before bioassay, the absolute configurations of both antipodes of 174 and 175 were not determined.

10.6 ANTIINFLAMMATORY AND IMMUNOSUPPRESSIVE ACTIVITY As early as 1981, in the wake of Sheskin’s work with thalidomide in treating ENL, there were reports of thalidomide analogues that were under evaluation for both their antiinflammatory and immunosuppressive activities. Piper, Agrawal, and Hastings reported the activities of 3- and 4-hydroxythalidomide (23, 11, respectively) and 3- and 4-aminothalidomide (21, 133, respectively) in a carrageenan antiinflammatory model and PFC (plaque-forming cells) bioassay.74 One should be cautious when reviewing the Piper report as the

Thalidomide and Analogues

399

3- and 4-position numbering therein may be in fact be 4- and 5-numbering used in later nomenclature. Interestingly, the compounds investigated by He for GVHD activity were also included in the group evaluated by Piper and coworkers. In terms of biological activity and within the more specific context of immunomodulatory behavior, the common thread that unites thalidomide and its analogues are the “costimulatory” properties of 1. Apart from suppressing the immune responses toward the symptomatic effects of leprosy through the inhibition of TNF-α as stated earlier, the influence of compounds goes far beyond the inhibition of inflammatory cytokine production. While thalidomide itself has no direct effect on the responses of primary T cells, the compound was suspected of having an indirect effect, albeit elusive to detect, when assayed under conventional conditions or methods. During an examination of whether T cell responses induced by thalidomide will have an effect on the release of TNF-α, a Rockefeller group found that stimulation of purified T cells with antibodies to CD3, as well as thalidomide, resulted in a costimulatory response for T cell proliferation and lymphokine release.75 The costimulatory response elicited by thalidomide was more specific for the CD8 1 subset of T cells and is the first report of a synthetic small-molecule therapeutic which can function as a costimulator for T cells. Given that CD8 1 T cells can regulate an immune responses by a variety of mechanisms, the Rockefeller group postulated that the T cell costimulating effects of 1 may contribute to its clinical-immune modulating effects. The amino-substituted thalidomide analogue pomalidomide 21 was also found to exhibit potent costimulatory properties when bioassayed in a CT26 autologous murine model of ectopic colorectal cancer.76 Apparently it was the first report of a thalidomide analogue, albeit one with a simple modification, to promote T cell costimulation and subsequent immunity toward a live tumor challenge in an established cancer vaccine model. By comparison, bioassays in unvaccinated mice revealed that the analogue exhibited no effect which further demonstrated the synergistic effect between it and the tumor vaccination. The costimulatory properties of thalidomide analogues have been discussed in an earlier (2003) review.20 The cyclooxygenase enzymes (COX1 and COX-2 isoforms) occupy a prominent position in the inflammatory cascade. COX-2 has been implicated as an important molecular target in cancer treatment and prevention whereby its overexpression has been detected in various tumors as well as angiogenesis. Evaluation of COX-2 inhibitors in certain cancers, such as colon and prostate cancer, has been

400

Imides

undertaken with compounds such as sulindac and celexocib. Hashimoto and coworkers reported that thalidomide was found to possess significant, albeit weaker COX-1/COX-2 activity than aspirin and implies that the antiinflammatory activity of the compound may be attributed to its COX-inhibitory activity along with its TNF-α effects.77 The same workers, in the same communication, reported that the (R)-form of the Celgene compound 110, the α-methyl analogue of pomalidomide,54 also exhibited significant COX-2 selective activity. Therapeutic control of inflammation could also be through the mediation of 30 ,50 -cyclic adenosine monophosphate (cAMP) phosphodiesterases (PDEs) and cellular levels of cAMP. The principal enzyme found in monocytes, which are the major secretors of TNF-α is PDE4, and when mediated can inhibit TNF-α production. During their continuing search for TNF-α inhibitors, the Celgene group identified thalidomide analogue 176 as a potent PDE4 inhibitor which exhibited an IC50 of 0.23 (PDE4) and an IC50 of 0.70 (TNF-α).78 It is interesting to note that the structure of the Celgene inhibitor 176 contained the conserved phthalimide ring while at the same time, the dialkoxyphenyl moiety was a significant departure from the glutarimide ring characteristic of 1. OCH3 O

CH 2CH3

N

O CH 3 O

O 176

10.7 THALIDOMIDE AND CANCER The implications of thalidomide as a potential cancer therapeutic were known as early as the discovery of its antiangiogenic activity as well as its closely related analogue EM-12 (15).79 Angiogenesis is the generation and development of new blood vessels from preestablished vasculature. The relevance of angiogenesis in tumor growth and metastasis has driven research in the area of antiangiogenic agents as cancer therapeutics.80 Thalidomide as well as its suspected metabolites and analogues have

Thalidomide and Analogues

401

attracted considerable attention as angiogenesis inhibitors since its teratogenic activity initiated questions about its potential effect on neovascularization. D’Amato postulated that stunted fetal limb growth on exposure to thalidomide may be a secondary response to inhibition of developing vessels in the embryonic limb buds. Subsequent experiments by D’Amato and coworkers established that thalidomide was indeed antiangiogenic in the rabbit corneal micropocket angiogenesis assay when tested alongside analogues 4, 15, and 36. However, both thalidomide and EM-12 15 were reported to be inactive in the chicken chorioallantoic membrane (CAM) angiogenesis assay, the difference being that in the CAM assay, thalidomide is directly administered to the CAM while the corneal micropocket assay required administration of 1 to live rabbits thus suggesting a metabolic step to an active antiangiogenic species.81 While the initial development of the Celgene compounds was focused on immunomodulatory behavior, a study surrounding antiangiogenic properties revealed that these analogues are active in several angiogenesis assays. The idea that simple analogues of thalidomide may prove to be effective as angiogenesis inhibitors was continued by a group in the Molecular Pharmacology Section of the NCI in collaboration with a University of Leipzig group.82 After evaluating over 100 compounds prepared by the Leipzig group in the rat aortic ring (RAR) assay, seven were selected for further testing in preclinical assays such as the human umbilical vein endothelial cell (HUVECs) bioassay and cell proliferation assays such as the human prostate cell lines PC3 and androgen-sensitive human prostate adenocarcinoma cells (LNCaP). The seven most inhibitory compounds also underwent in vivo toxicity assays in the nude mouse model. The seven compounds evaluated fit broadly into two categories depending on structure. Four of the compounds 178
180 simply consisted of the thalidomide core bound to an amino acid through an ester linkage on the glutarimide ring nitrogen. The remaining three analogues 181
183 possessed a tetrafluorophthalimide ring with N-substitutions such as difluorophenyl 181, uracil 182 or barbituric acid-type moieties 183 which were meant to mimic the OQC
N
CQO arrangement of the glutarimide ring. Interestingly, the amino acid ester analogues 178
180 would release the N-hydroxymethyl thalidomide analogue 177 under hydrolytic conditions which in turn would convert to thalidomide itself. N-hydroxymethylthalidomide 177 and its phenylalanine ester 178 inhibited angiogenesis in the RAR assay at 25 μm. Significant inhibition ( . 60%)

402

Imides

was observed in with 179 and 180 in the RAR assay at 12.5 μM. The barbituric acid-tetrafluoro thalidomide analogue 183 inhibited microvessel outgrowth at 12.5 μM while the N-difluorophenyl-tetrafluorophthalimide 181 reduced HUVEC proliferation (60%) at 12.5 μM. The tetrafluoro analogue 182 did not inhibit microvessel growth when evaluated in the RAR assay. O

O N

O O

N

O O

N

O

N

N O

OH

O

N

O

O

178

177

O

O

O

O 179

NH2

O

O N

N Boc H

O N O

O

O

180 F

F

O

F

F

F

N NH

O 181

F

F

O

O 182

O

O

Ph N

Et N

O

F F

F

NH

F

NH 3+Cl–

O

F N

O

O NH

F F

O

O 183

A 5-carboxy-functionalized thalidomide analogue 184 was derivatized as a telomeric structure 185. The telomere possessing multiple thalidomide units was evaluated as an angiogenesis inhibitor in several bioassays.83 The carboxythalidomide was connected to the major part of the macromolecular scaffold, the tris(hydroxymethyl)acrylamidomethane (THAM) by a lysine spacer (in blue (gray in print version)). It was postulated that the THAM scaffold would act as an effective carrier for the thalidomide residues given the inherent problems with the bioavailability of thalidomide and its analogues. Not surprisingly, the cotelomeric thalidomide derivative 185 did not exhibit any inhibitory activity of new blood vessel growth in the CAM assay as well as no activity in the bFGF (basic fibroblast growth factor)-induced bovine capillary cell proliferation assay. Based on the purported requirement for metabolism, the cotelomer was submitted to the in vivo mouse corneal micropocket angiogenesis assay whereby the mice were allowed to ingest the compounds while angiogenesis was evaluated in the corneal micropocket. The telomere 185 exhibited 28% inhibition in the micropocket assay as compared to the thalidomide and carboxythalidomide 184 controls in the corneal micropocket assay.

403

Thalidomide and Analogues

C 8H 17-n

S

H 4 NH O

O OH

36 NH

O

THAM OH

O N

OH

O

OH

NH O 184

O

H3 CO 2C

O O

O N

O NH

O

O

185

One of the most widely studied thalidomide analogues is its teratogenic phthalimidine or deoxyphthalimide congener EM-12 (15). Along with thalidomide, EM-12 was one of the first analogues to be identified by D’Amato as antiangiogenic when tested in the rabbit cornea micropocket model. Having one less carbonyl at the reactive benzylic position, the question remains if there is a similar mode of activation as that of thalidomide. Direct addition of EM-12 to cultured RARs results in a minimal degree of antiangiogenic activity comparable to thalidomide (30% at 200 μM),84 thus demonstrating the requirement for metabolic activation.85,86 Several syntheses of EM-12 have been reported and all start with thalidomide which formally amounts to a deletion of one carbonyl group. The first synthesis demonstrates the selectivity of the aluminum amalgam reduction in reducing a benzylic imide (phthalimide) carbonyl to a hydroxylactam (Scheme 10.23). N-Phthaloylglutaric anhydride 186 is reacted with 4-methoxybenzylamine to give the N-PMB glutamine 187 followed by direct treatment with acetic/trifluoroacetic anhydride to afford the N-PMB thalidomide 188 (51% from the anhydride). Reduction of the N-PMB thalidomide 188 with aluminum amalgam in THF/H2O gives the hydroxylactam 189 which is then combined with thiophenol in the presence of p-toluenesulfonic acid to afford the 2-phenylthio-N-PMB thalidomide 190. Desulfurization of 190 with Raney nickel in ethanol at room temperature results in the formation of N-PMB EM-12 (191) (80% from 189). Removal of the PMB group from 191 was accomplished with CAN in acetonitrile/H2O thereby providing EM-12 (15) in 61% yield. In the same communication, an interesting route to 15

404

Imides

O O N

O

O

4-Methoxybenzylamine

NHPMB

N

O O

OH

O 186

O

O Ac 2O

N

O 187

O N

(CF3CO) 2O

O O 188

PMB

Al(Hg) SPh

H N

O

N

O 191

OH

O O 190

PMB

N

O N

N O

H Thiophenol

Ra-Ni

O N

PTSA O O 189

PMB

PMB

CAN 15

Scheme 10.23 Synthesis of EM-12 (15) through reduction of the N-PMB intermediate 188.

O

Bn O NH 3+Cl– 186

1. Al(Hg) N

O N

O O 192

O Bn

N 2. Et 3SiH/ (CF3CO) 2O

O O 193

O N O Bn

1. H 2/Pd-C 2. PhCOCH 2Cl/ TEA/DMAP 15

Scheme 10.24 Synthesis of EM-12 (15) through selective reduction of the N-benzyloxy intermediate of thalidomide 192.

was reported which also involves the application of aluminum amalgam in selective reduction of N-benzyloxythalidomide 192 to through the corresponding hydroxylactam (Scheme 10.24). Treatment of the N-phthaloyl glutaric anhydride 186 with benzyloxyamine hydrochloride in the presence of pyridine followed by acetic/trifluoroacetic anhydride gave N-benzyloxythalidomide 192 (97% from anhydride 186). The reaction of 192 with aluminum amalgam in THF/H2O gave the intermediate hydroxylactam which was directly treated with triethylsilane in trifluoroacetic anhydride to afford the intermediate N-benzyloxy derivative 193 of EM-12 (41% from 192). Removal of the N-benzyloxy group from 193 was facilitated by hydrogen gas and palladium-on-carbon followed by phenacyl bromide/ TEA/DMAP in acetonitrile to provide 15 (21% from 193). Direct conversion of thalidomide 1 to EM-12 (15) could also be

Thalidomide and Analogues

H

OH

Al(Hg) 1

405

O

N N O

O 194

H

Et3 SiH

15

CH 3COOH/ (CF3CO) 2O

Scheme 10.25 Synthesis of EM-12 (15) through selective reduction/deoxygenation of thalidomide 1.

effected in 66% yield by treatment of 1 with aluminum amalgam (THF/ H2O) followed by direct deoxygenation of 194 with triethylsilane in acetic acid/trifluoracetic anhydride (Scheme 10.25). The initial thoughts on the biological activation of thalidomide as a necessary step toward its antiangiogenic properties focused on the RAR bioassay of its confirmed metabolites. 50 -Hydroxythalidomide 13, the product of biochemical oxidation of 1 found in human plasma, was bioassayed by the Figg group at the NCI. Using the RAR angiogenesis assay, synthetic 13 was found to inhibit microvessel growth, albeit at high concentrations (50% inhibition of total microvessel outgrowth at 100 μM). 50 -Hydroxythalidomide was not inhibitory toward the human saphenous vein assay at concentrations comparable to the RAR assay. The conclusion that 50 -hydroxythalidomide is an inhibitor of angiogenesis may complement earlier work from the same group whereby metabolically activated 1 using a liver microsomal preparation was also inhibitory in the RAR assay.85,86

10.7.1 Multiple Myeloma and Myelodysplastic Syndrome The incidence of MM as compared to other hematologic cancers is 10% and the disease comprises 1% of all types of cancers. Melphelan or stemcell therapy does extend the overall survival rate although many conventional chemotherapy regimens are ineffective. The progression of neovascularization within the bone marrow correlates with the advanced stages of the cancer and a poor prognosis. An early (1999) study enlisting 84 patients who had refractory myeloma and underwent high-dose chemotherapy were administered thalidomide over an 80-day regimen. The starting dose was 200 mg of orally administered thalidomide per day with an increase of 200 mg every 2 weeks until a daily administration of 800 mg/day was attained. The duration of administration ranged from 2 to 465 days and the median of follow-up of the patients surviving the treatment was 13 months. Of note was a survival rate of 58% after

406

Imides

12 months of follow-up and an event-free survival rate of 22% after the same follow-up time. During the study, 30 patients died who did not exhibit a response and six patients died who did exhibit a response. Responses were measured by a drop in serum/urine paraprotein levels, decreased numbers of plasma cells in the bone marrow, and an increase in hemoglobin levels.87 The efficacy of thalidomide administration as well as a dual treatment regimen with thalidomide and dexamethasone 195 was reported in a later (2003) study of 28 patients with asymptomatic MM.88 The response rate for patients treated with thalidomide alone was 36% while the group treated with the dual OH O OH

HO

F O 195

regimen exhibited a 72% response rate. The group who were administered the dual regimen and exhibited the higher response rate included a group (16%) who experienced complete remission. Five of the patients in the study died as a result of MM, infection, or a thromboembolic event. While thalidomide administered alone was effective in patients with newly diagnosed MM, the administration with dexamethasone resulted in a higher frequency of response and a rapid onset of remission. Furthermore, there was a lower rate of irreversible toxicity since the severe side effects associated with the higher doses of thalidomide are avoided. These results laid the groundwork for future investigations and the acceptability and approval of thalidomide analogues and combination therapy for the treatment of MM.89 Lenalidomide (38, or Revlimide), the amino-substituted EM-12 analogue has been approved for administration in combination with dexamethasone as treatment for MM in patients who have received prior therapies.90 The FDA has also approved the lenalidomide/dexamethasone combination for patients who have newly diagnosed MM but are not eligible for an autologous stem-cell transplant. Prior to approval, one of the initial phase 3 studies confirmed that lenalidomide administered with 195

Thalidomide and Analogues

407

is more effective than high-dose dexamethasone alone (dexamethasone and placebo) in patients with relapsed or refractory multiple melanoma. The study entailed 351 patients who were given at least one prior therapy for MM whereby overall survival was significantly improved in the lenalidomide (plus dexamethasone) group of 176 patients. Noted side effects in the lenalidomide group were neutropenia, thrombocytopenia, and venous thromboembolism. A later (2013) phase 3 trial revealed that pomalidomide 21, the 4-amino analogue of thalidomide, when administered in conjunction with low-dose dexamethasone 195 given orally, was effective as a new treatment pathway for patients having refractory or both relapsed and refractory MM.91 The study was an open-label multicenter/multinational phase 3 trial which included patients diagnosed with refractory MM and have failed to respond to at least two previous treatments of bortezomib and lenalidomide 38. An overall survival analysis in the phase 3 pomalidomide study disclosed that the survival rate was markedly longer in the pomalidomide versus low-dose dexamethasone (12.7 months vs 8.1 months) than in the high-dose dexamethasone group. The most notable side effects in the low-dose dexamethasone group were infections and infestations, neutropenia, thrombocytopenia, and fatigue. As an immunomodulatory-type compound, lenalidomide has been proven effective in the treatment of patients suffering from MDS. Generally termed as a blood cancer, MDS are a group of disorders in which normal blood cell generation is retarded (cytopenia) along with observed morphological abnormalities of the bone marrow. Patients exhibit low red blood cell counts, low platelet counts, and low white blood cell counts (thrombocytopenia, neutropenia) along with chronic fatigue, anemia, easy bruising and subcutaneous hemorrhaging, and shortness of breath. MDS was associated with the term “preleukemia” since the MDS syndromes can progress to the chemotherapy-resistant acute myeloid leukemia.92 A subtype of MDS involves a cytogenetic abnormality termed the 5q 2 deletion syndrome whereby the q arm of chromosome 5 in bone marrow melanocycte cells characterizes the hematologic disorder. Lenalidomide is especially effective in treating MDS in transfusion-dependent patients exhibiting the 5q 2 deletion syndrome.93 The mechanism of selectivity of lenalidomide in treating MDS in 5q 2 patients has not been elucidated; however, the FDA has approved its use in lower risk MDS patients as a result of a multicenter phase 2 study where the participants exhibited prolonged transfusion independence.93

408

Imides

10.8 THALIDOMIDE AND CLICK CHEMISTRY While click chemistry can be employed to couple two biologically active fragments together to provide a molecule with enhanced activity, it can also be used to fasten entire scaffolds to aqueous-soluble components or even fluorescent tags. The glutarimide nitrogen makes an ideal contact point if one only desires to link macromolecules, tags, or aqueous-soluble moieties to the thalidomide core structure. The reactivity of the glutarimide nitrogen is easily accessed by deprotonation and any subsequent nucleophilic reactions to carbon are facile give the appropriate alkyl halides or sulfonates. An azidoethyl click partner of thalidomide 196 was prepared by deprotonation (NaH/DMF) followed by reaction with azidoethyl p-toluenesulfonate (Scheme 10.26). The click reaction of azide 196 (CuI/DIPEA) with the acetylenic naphthylimide 197 gave triazole 198 (49%) whereas when 196 was reacted with the N-propargylic benzoxadiazole 199, under the same click conditions, gave triazole 200 (98%). The excitation and emission spectra of both these fluorescently labeled triazoles were examined. Triazole adduct 198 exhibited maximum excitation/emission at 333/434 nm while triazole adduct 200 showed excitation/emission maxima at 476/513 nm.94 It has become apparent that analogues which involve substitution at every atom of the thalidomide core have been prepared and great many O 1

+

TsO

N

N3

O N

O

O 196

N3

NO 2 N H

N N O

O CuI/DIPEA

N

199

O 197

O N O NPhth

N N N

200

NO2 N H

N N O

N N

O N O NPhth

N

O N O

198

Scheme 10.26 Preparation of thalidomide coupling partner 196 and its click reaction.

409

Thalidomide and Analogues

of these have been evaluated for the wide spectrum of biological activities attributed to thalidomide. As mentioned previously, a number of structural features are characteristic of the most potent analogues having a wide range of biological activities. On viewing some of the most active analogues, one may consider the following: (1) an intact phthalimide or phthalimidine (lactam) ring at the C-30 position of the glutarimide; (2) the sixmember heterocyclic glutarimide required both carbonyls and not a single carbonyl at either C-20 or C-60 ; and (3) a free hydrogen at 10 , or otherwise, an unsubstituted N
H on the glutarimide ring. Even in the case of thalidomide prodrugs, the labile group at N-10 will give way to an unsubstituted glutarimide N
H. Given the structural requirements for activity, a “linker” could be placed between the phthalimide and glutarimide rings and the biological activity may still be retained as exemplified by structures 201
209. The idea of a linker between the two structures is very similar to the “fleximer” concept in nucleoside chemistry whereby an additional heteroatom or even scaffold is inserted between the nucleoside sugar and heterocyclic base. A number of “click” derivatives of thalidomide (201, 102) and its closely related analogue EM-12 (203, 204) were prepared which possess the required structural features for activity.95 The synthesis of the click triazole-linked O N

O

O

N

N N

N N

NH

O

N

O

N N

O 201

202

N

O N

O O

N

N 204

N N

N 207

O

NH N

F3C

205

NH

O

O

N N

O

206 O

O

O N N

O

F3C

NH

NH

N N

203

N

F

O

NH

O

O

O

O

N

NH

CF3

NH N

N N

208

O

F

NH N

N N

O

209

thalidomide analogues begins with the preparation of the azidoglutarimide 210 (Scheme 10.27), the “universal” click intermediate when reacted with a series of phthaloyl/isoindolyl alkyne click partners 211
214.

410

Imides

Br

Br2/CHCl3

O

N H

O

O

N H 37

N3

NaN3 O

O

N H 210

O

Scheme 10.27 Synthesis of 3-azidoglutarimide click partner 210.

N3

O

+

R ( )n

201–204

O

Sodium ascorbate THF/H2 O

210

211–214

CuSO4

NH

O

O

O

N

N

N

O 211

O N

O 213

212

214

Scheme 10.28 Click reactions of alkynylphthalimides 211, 212 and alkynyl isoindolinones 213, 214 with 210 to give click products 201
204.

Commercially available glutarimide was brominated using bromine in chloroform at 100°C to give the 3-bromopiperidine-2,6-dione 37 (see Scheme 10.3). Treatment of bromoglutarimide 37 with sodium azide in acetone at room temperature for 16 hours gave the azidoglutarimide click partner 210. The reaction products of 210 with the two N-phthaloyl alkynyl coreactants 211, 212 gave triazole products 201, 202 (83%, 67%), while the click reactions of 213, 214 gave triazoles 203, 204 (78%, 61%). The click reactions were accomplished under fairly standard reaction conditions (CuSO4/sodium ascorbate/THF/H2O) (Scheme 10.28). The acetylenes which bear the phthalimide or phthalimidine (isoindolinone) group 211
214 best approximate the thalidomide or EM-12 analogues in terms of complete structure and their preparation should bear mention herein. Within the group of four heterocyclic acetylenes are the N-ethynylphthalimide 211, the N-ethynylisoindolinone 213, the N-propargylphthalimide 212, and the N-propargylisoindolinone 214. The synthesis of the phthalimides/isoindolinones 211
214 acetylenic click partners begins with phthalimide and isoindolinone (Scheme 10.29). Phthalimide 215 is reacted with ethynyltrimethylsilane in the presence of anhydrous copper acetate, oxygen, pyridine, and sodium carbonate to

Thalidomide and Analogues

O

411

O Ethynyltrimethylsilane/

NH R

N Cu(OAc)2 /O2 /pyridine/ Na 2CO3

215, R=O 217 , R=H 2 Propargyl bromide/ Cs 2CO3 /MeCN O N R 212, R=O (69%) 214, R=H2 (65%)

TMS

R 216, R=O (59%) 218 , R=H 2 (22%) 1. R=O, TBAF/THF/AcOH; 2. R=H2 TBAF/THF O N

H

R 211, R=O (94%) 213, R=H2 (92%)

Scheme 10.29 Synthesis of N-ethynyl and N-propargyl phthalimides and isoindolinones 211
214.

provide the 2-(2-(trimethylsilyl)ethynyl)isoindoline-1,3-dione 216 in 59% yield. Using isoindolinone 217 with the same reaction/conditions afforded the 2-(2-(trimethylsilyl)ethynyl)isoindoline-1-dione 218 albeit in lesser yield (22%). Both the TMS acetylenic heterocycles 216, 218 were desilylated with tetra-N-butylammonium fluoride in THF to afford the corresponding acetylenes 211 and 213 in 94% and 92% yield, respectively. Both phthalimide and isoindolinone 215 and 217 were propargylated with propargyl bromide-cesium carbonate in acetonitrile to provide the products N-propargylphthalimide 212 and the 2-(prop-2-ynyl)isoindolin1-one (N-propargylisoindolinone) 214 in 69% and 65% yields, respectively. To establish the scope of the click reactions of azidoglutarimide 210, a range of aryl acetylene click partners 219
223 were investigated and the click yields of the corresponding triazoles 205
209 ranged from 76% to 98% (Scheme 10.30). The installation of azide groups on experimental therapeutics introduces the possibility of generating reactive nitrogen species for photoaffinity labeling as well as the means for conducting click reactions. An azidothalidomide analogue 224 was synthesized by the Brown group with the goal of creating an inhibitor in an endothelial cell proliferation assay.96 The synthesis uses readily available starting materials and reactions which typically afford high yields of the known intermediate products.

412

Imides

CuSO4

O

N3

R

+

205–209 (76%–98%)

NH O

219–223

Sodium ascorbate 210 F 3C

F

CF3

F

219

220

221

CF3

222

223

Scheme 10.30 Click reaction of arylacetylenes 219
223 with 210 to give triazoles 205
209.

O

O

O2 N N

O

H2/Pd-C

1. NaNO 2/HCl N

NH O O 132

O

H2N O NH

N3 N

O NH

2. NaN3

O O 133

O O 224

Scheme 10.31 Synthesis of azidothalidomide analog 224.

5-Nitrothalidomide 132 was reduced to the corresponding aminothalidomide 133 using hydrogen and palladium-on-carbon (80%). Treatment of 133 with sodium nitrite and hydrochloric acid followed by sodium azide provided the 5-azidothalidomide 224 (35%). Azido analogue 224 was then submitted to a human microvessel endothelial cell bioassay, conducted in the absence and presence of vascular endothelial growth factor (VEGF). In the human microvascular endothelial cell (HMEC) assay, 224 was more active than thalidomide (1) both in the presence and absence of VEGF exhibiting an IC50 value of 259 μM (with VEGF) and 239 μM (without VEGF). Control HMEC bioassays with racemic 1 gave IC50 values of .300 μM (Scheme 10.31). The purported binding of thalidomide to the protein cereblon (CRBN) influenced the design of functional biomolecules named “PROTACs” or proteolysis targeting chimeras. The molecules consist of a target protein binder 225 and a ubiquitin ligase binder 226 and a linker of varying lengths. The covalently bonded combination of all three units serves to mark a protein for destruction by using ubiquitin subunits connected to a target protein through an easily formed linker which may be optimized (Scheme 10.32). Subunit 226, devised by an Amgen group to use as the targeting ligand, served as the azide click partner while the

Thalidomide and Analogues

413

N3 HN

N N N

O O

N

S O

N NH O

O n

O

Cl 226

O

225

CuSO4/sodium ascorbate (67%-90%) O O

N N N

NH N

N N N N

O

S

Cl

O NH

O n

O

O

227, n=0–4

Scheme 10.32 Click synthesis of scaffolds 227 from thalidomide for inducing protein degradation.

hydroxythalidomide fitted with a glycol-linked propargyloxy group 225 served as the alkyne click partner. The click reaction utilized standard copper sulfate/sodium ascorbate/aqueous THF protocol. In the bioassays, the PROTAC with the longest linker length (227, n 5 4) was the most active (20 μM) in displaying protein degradation in H661 cells.97

10.9 WATER-SOLUBLE PRODRUG DERIVATIVES OF THALIDOMIDE Along with its complex hydrolytic disposition and configurational instability, another distinguishing factor pertaining to thalidomide is its poor solubility properties. A long-standing problem with thalidomide as well as many of its analogues is the limited aqueous solubility, a property which is directly related to and can hamper its bioavailability and therapeutic efficacy. For example, drugs formulated for intravenous administration require a high amount of aqueous or otherwise plasma solubility for safe

414

Imides

transport through the highly efficient circulatory system. Many strategies have been undertaken with the goal of rendering thalidomide more bioavailable, thereby lowering the effective dose and countering serious side effects such as peripheral neuropathy. Hess and collaborators devised a strategy for the design of water-soluble thalidomide prodrugs (180, 228
230) which entailed the connection of polar groups to the glutarimide nitrogen through a methylene linker.98 The valine derivative 180 inhibited secretion of TNF-α (88%) with an IC50 of 4.7 μM, while the glycine and N-methylalanine derivatives 228 and 229 exhibited only 54% and 12%, respectively. The glycyl-glycyl glycine analogue 230 did not inhibit secretion of TNF-α but actually increased release of the cytokine. The synthetic routes to 180, 228
230 consisted of preparing N0 hydroxymethylthalidomide 177 from thalidomide and formaldehyde followed by coupling small BOC-protected peptide residues to 177 using dicyclohexylcarbodiimide (DCC). The BOC group could be removed from these amino acid derived prodrugs using TFA to deliver the finished compounds. O

O

N

O

N

N O

O

O

O

O N

O

O

O

NH 3+Cl–

O

180

NH3 +Cl–

228 O

N

N

O

O O

229

O

O O

N O

O

N

O

O

CH 3

O

NH 3+Cl–

O

HN NH

230

O

NH3 +Cl–

Increased solubility and bioavailability have long been factors in the effective administration of thalidomide and in the development of its analogues. While conjoining the thalidomide molecule with polar scaffolds will certainly lead to a more water-soluble subset of derivatives, the socalled “prodrug” approach should also yield byproducts which are both innocuous and exhibit efficient excretory properties in the biological

Thalidomide and Analogues

415

system. The concept of installing nitrogen on board the thalidomide core, in the form of an amino group or within the phthalimide ring, has led early on to analogues with increased bioavailability, and with diverse biological effects as in the compounds reported by He for the treatment of GVHD.63 An interesting concept for rendering thalidomide more aqueous-soluble as well as improving the all-important hydrolytic stability,99 entailed the complexation of thalidomide with β-cyclodextrin (β-CD).100 Specifically, the concept of β-CD complexation was for the formulation of thalidomide so that the drug could be administered intravenously for the treatment of GVHD in leukemia patients. Hydroxypropyl β-CD (HP β-CD) was chosen as the test vehicle since it possesses a nearly 30-fold higher aqueous solubility as compared to β-CD. Consequently, the CD/thalidomide complex exhibited increased water solubility (50 μg/mL to 1.7 mg/mL) and increased stability toward the aqueous hydrolysis of 1.100

10.10 MISCELLANEOUS THALIDOMIDE SYNTHESES Most syntheses of thalidomide itself deal with the asymmetric aspects of the molecule, and are mostly aimed at producing larger quantities of either enantiomer so that more specific biological studies may be conducted. Soon after the initial disclosures which described and confirmed the potent human teratogenicity of 1, the speculation and experiments involving the differential bioactivity of the pure enantiomers required these compounds to be available in sufficient quantity. Shealy and coworkers prepared (S)-(2)-thalidomide (L-(2)-1, [α]D25 264°, c 2 DMF) from L-(S)-isoglutamine (S)-10, by mild phthaloylation using N-(ethoxycarbonyl)phthalimide 231 followed by cyclization of the resultant N-phthaloylisoglutamine (S)-2 using N,N0 -CDI (Scheme 10.33).101 While cyclization toward the glutarimide could be effected in high yield (70%
86%) using thionyl chloride, appreciable racemization resulted. A similar protocol was devised using the antipodal starting material N-phthaloyl-D-isoglutamine and gave D-(1)-thalidomide ([α]D20 1 64°, c 2 in DMF) in 86% yield. In contrast to experiments which employed the intermediate N-phthaloylglutamine intermediate 3, the isoglutamine derivative (S)-2 was less prone to racemization en route to thalidomide. A relatively more recent synthesis of racemic thalidomide entailed the well-known N-phthaloyl-L-glutamic acid (PGA) 4 (Scheme 10.34). PGA 4 was then esterified (methanol/ thionyl chloride/reflux) to give the N-phthaloyldiester 232 (71%). Treatment of 232 with sodium in liquid ammonia with a catalytic amount

416

Imides

COOH H H2N

O

O N

+ NH 2

COOH

H N

O

NH 2

O

O

O O (S)-2

O

(S)-10

231

CDI/DMF O H N

O NH

O O L-(-)-1

Scheme 10.33 Synthesis of L-thalidomide from L-isoglutamine.

O O

O OH

H

O CH 3OH

OCH3 H

N

Na/NH 3

N OH

O O 4

1 OCH 3

SOCl2 O O 232

Fe(NO2)3/–33°C 1. TFA/DCM 2. Phthalic anhydride

O

6

1. SOCl2 CH3 OH

O

OCH 3 NaNH 3 BOCHN

2. (BOC) 2O DMAP

NH

BOCHN OCH 3 O 233

Fe(NO2 )3

O 234

Scheme 10.34 Synthesis of thalidomide by Na/NH3-mediated ring closure of Nphthaloyl glutaric diester 232 or N-BOC glutaric diester 233.

of ferric nitrate gave thalidomide 1 in low yield (45%). The low yield of 1 was not surprising since the cyclization of the N-phthaloylglutaric diester 232 was conducted under the highly basic/nucleophilic conditions of Na/NH3, thereby compromising the integrity of the phthalimide ring. The Na/NH3-mediated ring closure was applied to N-BOC glutaric acid dimethyl ester 233 with better results albeit without the presence of the phthalimide ring. Esterification of glutamic acid 6 (methanol/SOCl2/ reflux) followed by reaction with BOC2O (dioxane/H2O/DMAP) provided the N-BOC diester 233 (88%). Cyclization of the N-BOC diester

417

Thalidomide and Analogues

233 with Na/NH3/Fe(NO2)3 at 233°C then provided the N-BOC glutarimide 234. Removal of the N-BOC group (TFA/dichloromethane) from 234 followed by phthaloylation (phthalic anhydride/acetic acid/ reflux) than afforded 1 (65%).102 The Robin synthesis of either antipode of 1 starts with (S)- or (R)-NBOC glutamic acid-γ-benzyl ester (R)-235/(S)-235 (Scheme 10.35).103 Esterification of (R)-235/(S)-235 with phenol mediated by DCC followed by debenzylation (H2/Pd) provided the N-BOC-phenyl esters (R)-236/(S)-236. Reaction of (R)-236/(S)-236 with O-benzylhydroxylamine in the presence of EDC and HOBt resulted in phenyl ester cleavage, cyclization to the glutarimides and loss of the BOC group to give (R)-237/(S)-237. Direct treatment of (R)-237/(S)-237 with phthalic anhydride/TEA gave the N-benzyloxythalidomides (R)-238/(S)-238 (70%). Removal of the N-benzyloxy group from (R)-238/(S)-238 to give (R)-1/(S)-1 first entailed catalytic hydrogenation (H2/Pd-C/methanol) followed by treatment of the intermediate N-hydroxyglutarimides (R)-20 or (S)-20 with phenacyl bromide in TEA/acetonitrile (80%). The Celgene group reported a scalable two-step synthesis of thalidomide from L-glutamine in contrast to syntheses which start from glutamic acid or isoglutamine (Scheme 10.36).104 Treatment of L-glutamine 9 with N-carbethoxyphthalimide 231 and sodium carbonate under aqueous conditions afforded N-phthaloyl-L-glutamine 3 in yields ranging from 50% to 70%. Treatment of L-3 with CDI in refluxing THF provided

Bn O O

HN

BOC

1. Phenol DCC/

HN HO

OPh

OH H

O

2.H2/Pd-

BOC

H

O

O

1. BnONH2 EDC/HOBt 2. TFA

H 2N

N H

O (R)-237 (S)-237

(R)-236 (S)-236

(R)-235 (S)-235

O

Et3N/THF

O

Bn

O O O

O

O (R)-1

H

PhCOCH 2Br

H2/Pd-C

N (S)- 1

O

H N

N

Et3N/CH3CN

O O (R)-20 (S)-20

OH

O O (R)-238 (S)-238

O N OBn

Scheme 10.35 Synthesis of both enantiomers of thalidomide from N-BOC glutamic acid derivatives (R)- and (S)-235.

418

Imides

O O

NH 2

1. Na2 CO 3 L-9

+

231

H OH

N 2. HCl O

CDI

1

O

L-3

Scheme 10.36 Celgene synthesis of racemic 1 from L-glutamine 9.

racemic 1 in yields ranging from 85% to 93% and in greater than 99% purity. While the Celgene synthesis did start with a chiral starting material, racemization to 1 was confirmed by chiral HPLC analysis.

10.11 MODE OF ACTION OF THALIDOMIDE—THE “NEVER ENDING TALES” Perhaps one of the longest lived chemical/biological queries in medical science, the mechanism of action of thalidomide, its metabolites or hydrolysis products continues to perplex medical research.105 Delineating the differences in teratogenic activity among species and even within strains or varieties of species, along with establishing reliable animal test models which will provide the approximate effects observed in humans has been a difficult task. In 2000 Stephens assembled a list of the proposed mechanisms of action of thalidomide whereby the reports cited span over two decades.106 An early and fundamental investigation by Fabro and coworkers entailed an evaluation of the derivatives of glutamic acid and glutamine, hydrolytic products of 1, as agents which will interfere with glutamate metabolism.107 The fetal toxicity of the hydrolytic congeners was also evaluated. (See the hydrolytic cascade of thalidomide, Scheme 10.1.) While glutamate metabolism may be relevant to the neurological issues presented by thalidomide and its well-documented, chromatographically separable hydrolysis products (which are glutamic acid congeners),108 administration of compounds 2, 2a, 3, 3a, 4, 5, 8 (as the HCl salt) to chinchilla or New Zealand white rabbits do not result in fetal malformations. A group at Johns Hopkins reported that thalidomide is transformed to a toxic arene oxide metabolite when the compound was incubated with hepatic preparations derived from maternal rabbits and rabbit, monkey and human fetuses.109 While it should be obvious that any phenolic metabolite should arise from further metabolism of the arene oxide via epoxide hydrolase (see compound 11), the report does not offer

Thalidomide and Analogues

419

any putative structures or confirm that these types of compounds are the causative agents. Neubert and coworkers proposed that EM-12, the teratogenic analogue of thalidomide, is teratogenic by way of downregulation of cell-surface adhesion receptors in embryonic tissues.110 EM-12 was chosen as the test compound due to its higher hydrolytic stability as compared with thalidomide together with its increased potency in the thalidomide-sensitive marmoset monkey, Callithrix jacchus. The downregulation of cell-surface receptors may possibly be linked to chemically altered cell
cell and cell
extracellular matrix interactions which leads to abnormal limb-bud morphogenesis, but has not been confirmed. The studies were conducted using the specifically bred marmoset monkey animal model, whereby the bioassayed cells were harvested from monkey embryos exposed to maternally administered EM-12. The list of suspected causative mechanisms of teratogenicity or mutagenicity related to 1 would not be complete if some type of DNA interaction or damage was not implicated. The observation of the binding of an engineered DNA aptamer to one enantiomer (R) of a thalidomide derivative was reported111; however, the relevance of the design and utilization of the test DNA toward genetic materials found in the actual cells of organisms affected by 1 was not mentioned. Furthermore, the thalidomide derivative utilized for the DNA binding assays was not evaluated for its configurational stability, and since the compound did not contain a group to stabilize its configuration at the α-position, one can only suspect that some racemization did occur112. The intercalation of 1 with DNA was postulated to occur through a planar π-complex with suitable juxtaposition so the reaction of one phthalimide carbonyl with a ring nitrogen of a deozyguanosine residue is favored. If indeed a covalent bond is formed between a phthalimide carbonyl of 1 and a DNA base, it would seem highly unlikely that the same type of bond would be formed between the base and the more teratogenic but less reactive EM-12. However, once the proposed covalent bond is formed between the causative agent and the nucleic acid, the link to abnormal morphogenesis is still unclear. According to a French/CNRS group, biochemical acylation could also involve the in vivo reaction of thalidomide with biologically important polyamines, as purported from results whereby newt eggs are treated with 1.113 Although the chemical reaction is favorable as in the case with nucleic acids (stated earlier), the specific structural nature of the polyamines or their acylated derivatives were not clarified. Also, factors such as hydrolysis of 1 were taken into account, but without a true

420

Imides

maternal system involved in the study as in mammalian systems, metabolism of 1 was not a consideration. Along with the intercalation, binding and otherwise covalent bonding to DNA are speculation surrounding thalidomide and its role in the generation of reactive oxygen species (ROS) with subsequent DNA damage.114 Using both pregnant rabbits and mice as test animals, a University of Toronto group assayed DNA isolated from both embryonic and maternal tissues for oxidized guanosine analogue residues. A higher DNA oxidation rate was detected in the rabbit as opposed to the mouse models which confirms a higher thalidomide sensitivity in the rabbit (as expected). Based on the premise that any ROS or otherwise radicals may be deactivated by the spin-trapping reagent, α-phenyl-N-tert-butylnitrone (PBN), rabbits were pretreated with PBN before thalidomide administration which reduced the incidence of fetal malformations and resorptions. Ito and coworkers have identified what they believe to be a partial pathway responsible for teratogenic effects of thalidomide, and the finding is related to what they observe in zebrafish and chicken embryos. The Ito group reported that CRBN is a protein that binds to thalidomide which then results in inhibition of a ubiquitin ligase complex with damaged DNA binding proteins (DDB1s).115 The inhibition of the ubiquitin ligase activity then results in the teratogenic effects. During the CRBN binding studies, affinity beads bearing thalidomide residues were prepared by attaching the 4-phenoxyacetic acid derivative to amine-functionalized ferrite-polyglycidyl methacrylate “FG” beads through amide bond formation. The resulting “Thal-immobilized” FG beads were utilized in binding and isolating thalidomide binding proteins which were isolated from HeLa cell extracts. Following elution with free thalidomide the pure binding proteins were analyzed and confirmed as CRBN and DDB1. The in vivo phase of the CRBN study involved the direct application of 1 by bathing the zebrafish embryos with thalidomide or otherwise directly applying the compound to the developing avian limb bud. On treatment of the zebrafish embryos with thalidomide over the first 3 days postfertilization, the researchers observed that it was apparent that the development of pectoral fins and otic vesicles was “disturbed.” The workers explain that zebrafish possess “zCRBN,” a CRBN-orthologous gene which is expressed in the developing fins and otic vesicles and is an interactor with DBB1. The inhibition of zCRBN function by thalidomide could be responsible for its teratogenicity, as exemplified by the overexpression of zCRBN which allows the embryos to develop in the presence

Thalidomide and Analogues

421

of 1. While there is claim that zCRBN has a 70% similarity to human CRBN, the route of administration of the compound, which avoids any metabolic pathway, coupled with species dissimilarity in morphogenesis renders any direct correlation with a mammalian response (a.k.a. humans or nonhuman primates) difficult as well as speculative. Crystal structures were later presented that were illustrative of a CRBN
DDB1 complex bound to thalidomide, lenalidomide, and pomalidomide.116 The crystal structure study utilized chicken CRBN whereby hydrogen bond interactions between the glutarimide moiety of (S)-1 and histidine 380, tryptophan 382, as a well as a hydrophobic effect between the glutarimide hydrogens and a “cage” formed by tryptophan(s) 402, 388, and phenylalanine 404.

10.12 SUMMARY Thalidomide and its analogues, together with the numerous proposals surrounding the modalities of its biological activity, continue to attract the attention of synthetic chemists and biomedical researchers. There always appears to be room for yet another theory which explains teratogenic action of 1 or whether the beneficial attributes of 1 are connected with its teratogenic activity. Over the past few years, the CRBN theory has been gaining press and support; however, one must note that the putative role of CRBN and its interaction with 1 is only part of the story. The employment and the evaluation of a wider range of analogues in CRBN interaction is needed for further confirmation as well as proof of its role in morphogenesis using a relevant mammalian system. While many of the metabolites of 1 have been identified, these compounds have been largely ignored in many of the bioassays which might elucidate at least part of the molecular mechanism in the therapeutic areas of interest. Considering that much effort has been expended toward the synthesis of the configurationally stable analogues of 1, one of these compounds has yet to be considered as a candidate for late-phase clinical trials. Thalidomide made its mark while making a “comeback” with the large amount of work in connection with TNF-α modulation and the physiological responses associated with sepsis and inflammation due to systemic infection. With the very limited numbers of reports of analogues of 1 as PDE4 or COX inhibitors, there appears to be ample room for development in the antiinflammatory area as the preliminary bioassays are straightforward and yield quick results. In the cancer area, most notably

422

Imides

the blood cancers MM and MDS, the administration of 1 and its analogues are becoming quite standard therapy along with the standard adjuvant dexamethasone. The relevance of angiogenesis where tumor growth and metastatic spreading through tumorigenic vasculature provided a proving ground for 1. However, thalidomide by itself failed to yield promising results as an antitumor agent, but trials which employ 1 as an antiangiogenic agent in combination with established antitumor agents are ongoing.117 While the click products of thalidomide have yielded good results when they have been conjugated with scaffolds to use as biological probes, the small-molecule triazole-derived click compounds have not been developed and have not offered as of yet, any promise as “standalone” drug candidates. Given the nominal or otherwise simple molecular architecture of thalidomide, which possesses only one stereocenter, a surprising number of syntheses, both stereoselective and racemic, have targeted 1 and its metabolites and analogues. It is well-expected that more syntheses surrounding the thalidomide core will arrive with the purposes of new therapeutic development, elucidation of mechanism or molecular target, and applications of new reactions and methodology.

LIST OF ABBREVIATIONS β-CD β-Cyclodextrin BOC tert-Butoxycarbonyl CAM Chicken chorioallantoic membrane cAMP 30 ,50 -Cyclic adenosine monophosphate CAN Ceric ammonium nitrate CBZ Carbobenzyloxy CD8 1 Cytotoxic T-lymphocytes CDI Carbonyldiimidazole COX Cyclooxygenase CRBN Cereblon DBU 1,8-Diazabicyclo[5.4.0]undec-7-ene DCC Dicyclohexylcarbodiimide DDB1 Damaged DNA binding protein DIPEA N,N-Diisopropylethylamine DMAP 4-Dimethylaminopyridine DMF N,N-Dimethylformamide DMSO Dimethylsulfoxide EDCI 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride ENL Erythema nodosum leprosum FG Amine-functionalized ferrite-polyglycidyl GVHD Graft versus host disease HOBt 1-Hydroxybenzotriazole

Thalidomide and Analogues

423

LHMDS Lithium hexamethyldisilazide LNCaP Androgen-sensitive human prostate adenocarcinoma cells LPS Lipopolysaccharide LR Lawesson’s reagent MDS Myelodysplastic syndrome MM Multiple myeloma PBMCs Peripheral blood mononuclear cells PBN α-Phenyl-N-tert-butylnitrone PC3 Human prostate cell lines—small cell neoendocrine carcinoma PDE Phosphodiesterase PGA N-Phthaloyl-L-glutamic acid PMB 4-Methoxybenzyl PROTACs Proteolysis targeting chimeras RAR Rat aortic ring TBDMS tert-Butyldimethylsilyl THAM Tris(hydroxymethyl)acrylamidomethane THF Tetrahydrofuran TNF-α Tumor necrosis factor-alpha VEGF Vasculoendothelial growth factor

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1350. 116. Fischer, E. S.; Bohm, K.; Lydeard, J. R.; Yang, H.; Stadler, M. B.; Cavadini, S.; Nagel, J.; Serluca, F.; Acker, V.; Lingaraju, G. M., et al. Structure of the DDB1CRBN E3 Ubiquitin Ligase in Complex With Thalidomide. Nature 2014, 512, 49
53. 117. Rehman, W.; Arfons, L. M.; Lazarus, H. M. The Rise, Fall and Subsequent Triumph of Thalidomide: Lessons Learned in Drug Development. Ther. Adv. Hematol. 2011, 2, 291
308.

INDEX Note: Pager numbers followed by “f” and “t” refer to figures and tables, respectively.

A Abutilon theophrasti (velvetleaf), 336 337 Acetate aldol reactions, 199 220, 200f cryptomoscatone F1, 218f double diastereoselectivity, 205f Guz Phillips auxiliary, 208f of N-acetyl (4S)-IPTT, 207 Phillips Sammakia auxiliary, 211f Sammakia’s auxiliary, 212f SCH-351448, 206f spirofungins A and B, 215f styryl lactone family, 217f titanium-mediated N-acetyl indene-based thiazolidinethione aldol reaction, 204f oxazolidinethione aldol reaction, 203f thiazolidinethione aldol reaction, 202f, 203f, 204f, 205f triflate-mediated N-acetyl thiazolidinethione aldol reaction, 200f 5-Acetoxy-N-crotyl pyrrolidinone, 198 199 3-Acetoxy-N-PMB glutarimide, 378 380 Acetylenic naphthylimide, 408 Actidione. See Cycloheximide Actiketal, 262 263 Actinomycin D, 74 Actiphenol, 262 264, 264f Aculeatins A D, 216 217, 216f Acyclic diamino carbenes (ADCs), 91 92 Acyl groups coupling to chiral oxazolidinethione and thiazolidinethione auxiliaries, 176 177 on nitrogen, 199 200 Acyloxazolidinethione, 221 222 Acyloxazolidinone, 221 222, 221f Adamantylglycine-derived catalyst, 102 104 Adipimide, 17 AEDs. See Antiepileptic drugs (AEDs)

Aerobic oxidation of N-alkylamides catalyzed by NHPI, 47 AfIH. See Alcaligenes faecalis NBRC13111 (AfIH) Agranulocytosis, 360 361 Agrochemicals, 29 fungicides, 340 343 Agrochemistry, 335 cyclic imides as intermediates in synthesis of nonimide agrochemicals, 346 349 as lead structures for nonimide agrochemicals, 344 345 as metabolites of nonimide agrochemicals, 345 346 fungicidally active cyclic imides, 339 343, 343f herbicidally active cyclic imides, 335 339 insecticidally active cyclic imides, 343 344 AIBN. See 2,2ʹ-Azobis (2-methylpropionitrile) (AIBN) Alcaligenes faecalis NBRC13111 (AfIH), 83 86 Aldehyde, 179, 185 186, 200 201, 222, 259 260, 283 284, 303 Aldimines, 238 240 β-lactam synthesis starting from nitriles, 240f titanium enolate addition to N-substituted cyclic iminium ion, 240f to non-enolizable imines, 238f of thiazolidinethiones to aldimines, 239f Aldol addition of N-glycolates, 221 223 allyl N-glycolate anti-aldol reaction, 222f Ircinastatin A, 223f benzyl N-glycolate anti-aldol reaction, 223f

431

432

Index

Aldolizations, 191 Alkaloids, 194 Alkenyl N-sulfonyl triazoles, 118 119 (4S,5R)-3-Alkenylimidazolidin-2-ones, 148 Alkyl phthalidomide synthesis, 54f Alkyl succinimides, 120 Alkylated cyclic ether, 231, 232f Alkynes, fragment synthesis from, 15 16 Alkynylphthalimides, 410f Allopumiliotoxin, 194, 195f Allyl-protected glycolyl OxT, 222 Alnespirone, 359 360 α-3CP. See 3-Carbamoyl-α-picolinic acid (α-3CP) α,β-disubstituted acrylimides, 164 165, 164f α,β-disubstituted-β-amino acids, 164 165 α,β-unsaturated aldehyde, 280 281 α,β-unsaturated benzimides, 145 146 α,β-unsaturated carbonyl compounds, 139 α,β-unsaturated ester, 275 α,β-unsaturated imides, 146 α,β-unsaturated nitriles, 14 α-C-glycosides, 231, 231f α-alkoxy acyloxazolidinethiones, 221 222, 221f α-alkyl-β-alkoxycarbonyl compounds, 223 224 α-C-glycosides, 231, 231f α-CF3 ketone, 186 187 α-amido diazoacetates, 99 100 α-amino acid amides, 9 10 α-cyanodiazoacetamide, 99 100 α-diazo β-keto esters, 93 α-hydroxyiminobenzene acetate, 348 349 α-methylglutamines, 387 388 α-methylthalidomide, 54 55 m-CPBA-mediated synthesis, 55f α-nitro diazoacetophenones, 100 101 α-phenyl-N-tert-butylnitrone (PBN), 420 α-phenyl-γ-lactone, 356 α-substituted acrylates, 119 120 α-substituted acrylimides, 157 160 Alternaria solani, 339 340 ( 1 )-Altholactone, 217 Amaranthus ascendens (Guernsey pigweed), 336 337

Ambrosia artemisiifolia (common ragweed), 336 Amidase, 73 74 Amide(s), 12 amide-based auxiliaries/templates, 139 amide-containing fatty acids, 309 310 Amido ketone, 1, 2f Amidoester, 346 347 Amino acids, 94 95 derivative, 319 320 Amino alcohol, 174 175 Amino peptidase inhibitors, 29 30 3-Amino-3-methylglutarimide hydrochloride, 387 388 2-Aminobenzyl phosphonium salts, 259 260 Aminoglutarimide, 368 371, 373 374 Aminoglutethimide, 360 361 3-Aminoisonicotinic acid, 347 Aminothalidomide, 373 374, 411 412 Amphidinium klebsi, 222 Amphidinoles, 222, 223f Androgen-sensitive human prostate adenocarcinoma cells (LNCaP), 400 402 Angiogenesis, 400 402 Anhydride, 5 6 synthesis of succinimides, maleimides, and phthalimides from, 5f Anti-aldol adduct, 222 223 product, 227 Anti-diastereomer, 223 224 (2R,3S)-(Anti)-product, 238 Antianxiety drugs, 355 359 Antibiotics, 255 lysobactin, 148 150 Anticonvulsant drugs. See Antiepileptic drugs (AEDs) Anticonvulsant N-aminoimides from diacids, 9, 9f Antiepileptic drugs (AEDs), 353 355 Antineoplastics, 360 361 Antipsychotics, 361 362 agent cinperene, 361 362 Antiseizure drugs. See Antiepileptic drugs (AEDs)

Index

Apoptolidin, 182, 182f Apremilast, 29 30 Aqueous sodium hydroxide, 174 Arcyria nutans, 255 256 Arcyria obvelata, 255 256 Arcyriacyanin A, 255 262, 256f cladoniamides, 260 262 Arcyriaflavin, 29, 256 Arcyroxepin A, 256 Aromatic amine, 6 Aromatic C H activation, rhodiumcatalyzed, 123 129 ArQule’s tivantinib, 363 3-Aryl succinimides, 123 5-Aryl-substituted thalidomides, 393 396 L-(S)-Aspartic acid, 380 381 Aspergillus fungal species, 21 22 Asymmetric amination, 111 114 asymmetric C H amination, 113f asymmetric cyclopropanation of alkenes, 115f asymmetric synthesis of oxazolines, 116f enantioselective C H insertion of unactivated alkanes, 117f enantioselective formal [3 1 2]cycloadditions, 117f enantioselective formal [4 1 3]cycloaddition, 118f rhodium-catalyzed, 112f sequential C H amination and silaSonogashira Hagihara coupling, 114f stereoselective intermolecular C H amination, 113f Asymmetric cyclopropanation, 97 104 asymmetric synthesis of difluoromethylated cyclopropanes, 102f of trifluoromethylated cyclopropanes, 101f bioactive compounds containing cyclopropane rings, 97f of electron-deficient alkenes, 103f of olefins with α-amido diazoacetates, 99f with α-nitro diazoacetophenones, 100f [Rh2(S-nttl)4]as catalyst for cyclopropanation, 98f

433

Asymmetric hydrazine addition, 141 143 Asymmetric hydrogenation, rhodiumcatalyzed, 119 120 asymmetric hydrogenation of phthalimide-based acrylates, 120f rhodium catalysis for stereocenter construction, 121f 3-substituted maleinimides, 121f Asymmetric ruthenium-catalyzed trichloromethylation, 321 322 Aurisides, 208, 209f Azaanthranilic acid, 347 Azaphthalimide, 346 347 Azapirone antianxiety drug, 359 360 gepirone, 359 360 Azetine, 239 3-Azido-4-O-TBDMS glutarimides, 381 382 (2S,3S) 2-Azidoalcohol, 381 382 3-Azidoglutarimide synthesis, 410f Azidothalidomide analog, 411 412, 412f Aziridine, 148 149 2,2ʹ-Azobis(2-methylpropionitrile) (AIBN), 288

B BAIB. See [Bis(acetoxy) iodo]benzene (BAIB) Barbiturate, 356, 374 375 Barbituric acid-tetrafluoro thalidomide analog, 400 402 Benzaldehyde, 33 34, 195 Benzene derivatives, 347 348 Benzetimide, 362 363 Benzimidazole, 336 337 Benzofuran, 264, 265f Benzoic acid, 3 Benzothiazole-substituted tetrahydrophthalimide, 336 337 Benzotriazole-N-oxyl radical (BTNO radical), 48 49 Benzoxazinone, 337 Benzyl bromide derivative, 348 349 Benzyl ester diol, 381 382 Benzyl ether α,β-unsaturated aldehyde, 185 186

434

Index

Benzyl N-glycolate anti-aldol reaction, 223f Benzyl N-glycolyl OxT, 222 Benzyl-substituted succinimide, 32 Benzylamine, 347 348 β,γ-unsaturated imides, 194 β-amino alcohols, 169 β-amino carbonyl groups, 238 β-C-glycoside, 231, 231f β-aryl-β-N-phthaloylamino acid esters, 122 123 β-CD. See β-cyclodextrin (β-CD) β-cyano-β-alkoxycarboxylic acid, 10 β-cyclodextrin (β-CD), 414 415 β-hydroxy-α-amino acids, 150 β-hydroxyimide, 211 β-ketoester, 190 β-lactam, 239 ring expansion from, 17 18 synthesis starting from nitriles, 240f β-mercapto alcohol oxazolidinone, 232 β-substituted acrylimides, 147 157 β2-N-Fmoc-phenylalanine, 160 161, 160f BHT. See 2,6-Di-tert-butyl-4methylphenol (BHT) Biaryl aldehyde, 186 Bicyclic diene, 111 Binospirone, 359 360 Bioactive polyether natural products, 193 Biological response modifiers (BRMs), 54 55 2,2'-Bipyridinium chlorochromate (BPCC), 56 Bis-imide Dipymetitrone, 342 343 Bis-tetrahydropyrane, 222 [Bis(acetoxy) iodo]benzene (BAIB), 319 320 Bisindoles, 258f, 260f arcyriacyanin A, 255 262 Bisphosphine thiourea ligand, 120 Blastobacter sp. A17p-4, 65 67 cyclic amide transformation in, 75 77 cyclic imide transformation pathway, 69 70, 71f cyclic imide hydrolyzing activity finding, 67 69, 68t substrate specificity of D-hydantoinase, 69t

enzymes involving in cyclic imide metabolism, 70 74 BOP peptide coupling reagent, 9 10 Borane reduction of racemic succinimides, 22 Botrytis cinerea (gray mold), 340 341 BPCC. See 2,2'-Bipyridinium chlorochromate (BPCC) BpIH, 83 86, 85f, 86t Brefeldin A, 185 186, 185f ( 1 )-Brevenal, 193 Brevetoxin A, 223 ( )-Brevisamide, 194, 194f BRMs. See Biological response modifiers (BRMs) 4-Bromo-2-butanone ethylene ketal, 270 2-Bromobenzamide, 12 Bromoindole, 257 Bromomaleimide, 257, 259 Bromomethyl methyl ester, 396 398 Bromopyruvate, 78 5-Bromothalidomide analogs, 393 396 BTNO radical. See Benzotriazole-N-oxyl radical (BTNO radical) Buchwald Hartwig reaction of halogenated thalidomides, 396f Burger’s synthesis, 388 389, 388f Burkholderia phytofirmans DSM17436, 83 Buspirone, 357 358 analog, 359 360 metabolism, 358 359

C C-73. See Actiphenol C-glycosides synthesis, 230, 231f C-substituent alteration, 20 21 Michael addition, 20 21 ring alkylation, 20 C(sp3)-H alkylation of 8-methylquinolines, 125 126, 127f C(sp3)-H functionalized quinolines, 125 126 C2N fragment synthesis, 14 C3N fragment synthesis, 12 Callipeltosides, 208, 209f Callyspongia truncata, 181 182 Callystatin A, 181 182

Index

Calmodulin-dependant protein kinase C, 255 256, 256f CAM. See Chorioallantoic membrane (CAM) cAMP. See 3ʹ,5ʹ-Cyclic adenosine monophosphate (cAMP) Camphor-based oxazolidinethione, 174, 174f CAN. See Ceric ammonium nitrate (CAN) Cancer, thalidomide and, 400 407 Caprolactam(s), 17 molecular oxygen based oxidation, 50 o-iodoxybenzoic acid based oxidation, 57 58 ruthenium-based oxidation, 42 Captafol, 339 340 Captan, 29, 340, 341f 1-Carba-hydantocidin, 338 339 3-Carbamoyl-α-picolinic acid (α-3CP), 81 82 production by imidase-catalyzed regioselective hydrolysis of PDI, 81 82 2-Carbamoyl-β-picolinic acid (β-2CP), 81 82 3-Carbomethylglutarimide, 264 Carbon (C) C-alkylation of imides, 20, 20f C2 fragment synthesis, 14 C3 fragment synthesis, 12 14 C4 fragment synthesis, 4 12 C C bond formation, 1 fragment synthesis, 12, 14 Carbon disulfide, 169 Carbon sulfur double bond, 175 Carbonyldiimidazole (CDI), 6, 305, 387 388 5-Carboxy-functionalized thalidomide analog, 402 403 Carboxylic acid, 319 320 Catalytic aldol-type reaction of N-butanoyl (4S)-IPTT, 229 230 Catalytic cycle, 196, 197f Catalytic enantioselective aldol reaction, 199 Catunaregin, 195, 195f

435

CBZ-L-glutamine, 393 396 CDI. See Carbonyldiimidazole (CDI) Celgene, 400 402 α-methylthalidomide analog synthesis, 388f isoindolinone (phthalimidine) analog, 393 396 TNF-inhibitor synthesis, 394f Celontin, 354, 361 362 Cereblon (CRBN), 412 413, 420 421 Ceric ammonium nitrate (CAN), 317, 378 380 Cesium acetate, 126 127 CG-3033, 374 375 CGI. See 3-(4-Chlorophenyl) glutarimide (CGI) C H activation, 104 109 enantioselective C H functionalization of indoles, 105f synthesis of 2,3-dihydrobenzofurans, 106f rhodium(II)-catalyzed C H functionalization, 104 105, 104f site-selective C H functionalization, 108f synthesis of dictyodendrin, 107f Chemoselective, 143 144, 143f Chenopodium album (lambsquarters), 336 Chinchomeronic acid, 347 Chinchomeronimide, 347 Chiral 1,3-oxazolidine-2-thiones, 169 Chiral 3-aryl succinimides, 120 Chiral acyloxazolidinones, 196 Chiral aldehyde (2S)-methyl 4-hexenal, 195 Chiral auxiliaries, 148 152 lewis acid promoted conjugate additions, 148f MgBr2-promoted conjugate addition, 149f Chiral cyclic β-keto esters, 93 Chiral IBTT 178-IBTT auxiliary, 204 Chiral imides, kinetic resolution and enzymatic formation of, 21 22 Chiral Lewis acid catalysts, 152 157 conjugate additions, 143 144, 153 154

436

Index

Chiral ligands, 95 96 Chiral mesityl-substituted thiazolidinethione, 172 173 Chiral oxazolidinethione, 241 242 Chiral oxazolidinethione and thiazolidinethione auxiliaries, 169 175 5,5-dimethyl-(4S)-diisopropyl oxazolidinethione, 171f diphenyl-(4S)-diisopropyl oxazolidinethione, 172f gram-scale preparation of oxazolidinethione, 175f (4R)-mesityl oxazolidinethione, 172f (4R)-mesityl thiazolidinethione, 172f (4R)-methyl carboxylate thiazolidinethione, 170f preparation of Sammakia’s thiazolidinethione, 173f (4S)-substituted oxazolidinethiones, 175f (4S)-tert-butyl thiazolidinethione, 173f 4-substituted oxazolidinethiones and thiazolidinethiones, 170f 4,5-substituted thiazolidinethiones, 174f Chiral rhodium catalyst, 20 21 Chiral substrates, 147 Chiral sulfur-containing imide auxiliaries acetate aldol reactions, 199 220 aldol addition of N-glycolates, 221 223 chiral oxazolidinethione and thiazolidinethione auxiliaries, 169 175 coupling of acyl groups to, 176 177 intramolecular sulfur transfer in N-enoyl oxazolidinones, 232 235 Michael additions, 235 238 propionate aldol reactions, 177 199 resolution of racemic mixtures, 241 242, 241f sodium enolate Michael addition/ elimination, 240, 241f titanium enolate addition to aldimines, 238 240 to dialkyl acetals, 223 230 to glycals, 230 231 Chiral thiazolidinethione, 241 242 Chiral-protected amines, 116 117 Chlorinated analog, 97

Chlorinated building blocks, 322 323 Chloroacetaldehyde, 172 173 Chlorodeoxypseudoephedrine hydrochlorides, 173 174 5-Chloroindole, 260 261 Chloromethyl methyl ether (MOMCl), 278 279 3-Chloroperbenzoic acid (mCPBA), 290 291 3-(4-Chlorophenyl) glutarimide (CGI), 83 Chlorophthalimide, 344 345 Chlorotriethylsilane (TESCl), 282 Chlorphthalim, 336 Chondromyces crocatus, 183 Chondromyces pediculatus, 183 Chorioallantoic membrane (CAM), 400 402 Cinidon-ethyl, 336 Cis-2,3-diaryl-2,3-dihydrobenzofuran, 109 Cis-2,4-dimethylcyclohexanone, 263 Cladonia uncialis, 260 Cladoniamides, 260 262, 261f Cladosporium cladosporioides, 285 Click chemistry, thalidomide and, 408 413 C N bond formation, 2 3 CN fragment synthesis, 12 14 ( 1 )-Conagenin, 180 Conjugate addition to α-substituted acrylimides, 157 160 to β-substituted acrylimides use of chiral auxiliaries, 148 152 use of chiral lewis acid catalysts, 152 157 use of chiral substrates, 147 rhodium-catalyzed, 121 123 C H activation, 123f Cordiarimides, 264 268 COX. See Cyclooxygenase enzymes (COX) CRBN. See Cereblon (CRBN) Crimmins methodology, 182 Crocacins, 183, 184f Crop protection, 335 Crotonimides, 264 268, 266f Cryptomoscatone lactones, 218 219 Crystalline oxazolidinethione, 175

Index

Cyanation, 322 Cyano acids, fragment synthesis from, 10 Cyanoacetic acid, 264 2-Cyanomethylenepiperidine, 270 271 3ʹ,5ʹ-Cyclic adenosine monophosphate (cAMP), 399 400 Cyclic amide diversity and versatility of metabolism, 65 67 transformation in Blastobacter sp. A17P-4, 75 77 Cyclic anhydrides, fragment synthesis from, 4 7 Cyclic ether, 94 95 Cyclic imide(s), 1, 29, 335, 340 341 cyclic imide metabolizing activities distribution, 75 derivatives, 344 347 enzymes involving in metabolism, 70 74 pyruvate production, 77 79 finding cyclic imide hydrolyzing activity, 67 69, 68t fragment-based synthesis, 1 16 hydrolysis, 75 77 as intermediates in synthesis, 346 349 as lead structures, 344 345 as metabolites, 345 346 oxidation of lactams to dioxirane-based oxidation of lactams, 50 51 hypervalent iodine-based oxidation of lactams, 56 58 manganese-based oxidation of lactams, 43 45 molecular oxygen based oxidation of lactams, 45 50 oxone-based oxidation of lactams, 59 61 ozone-based oxidation of lactams, 58 59 peracid-based oxidation of lactams, 54 56 potassium persulfate-based oxidation of lactams, 52 53 ruthenium-based oxidation of lactams, 31 42 succinimide-based drugs and natural products, 30f

437

pyrethroids bearing, 343 344 regioselective hydrolysis, 81 82 ring transformation synthesis, 16 18 synthesis by functionalization of imides, 19 22 transformation pathway in Blastobacter sp. A17P-4, 69 70 Cyclic ketones, 93 Cycloaddition reactions, 109 111 [Rh2(S-ptad)4]-catalyzed asymmetric [4 1 3]-cycloaddition, 110f total synthesis of ( )-5-epi-vibsanin E, 110f Cycloheptane, 110 111 Cycloheptenyl derivatives, 118 119 Cycloheximide, 29, 262 264, 342 343, 363 Cyclooxygenase enzymes (COX), 399 400 Cyclopentadiene, 278 279 Cyclopropanation, 97 104 of alkenes with enoxyphthalimide, 128f asymmetric, 97 enantioselective, 95 96 tandem, 110 111 Cyclopropane cyclopropane-fused succinimides, 18 derivatives, 102 104 Cyclopropyl carboxaldehydes, 115 116 CYP. See Cytochrome protein (CYP) Cyproximide, 361 362 Cytochrome protein (CYP), 356 357

D Damaged DNA binding proteins (DDB1s), 420 DBU. See 1,8-Diazabicyclo[5.4.0]undec-7ene (DBU) DCC. See Dicyclohexylcarbodiimide (DCC) DCE. See Dichloroethane (DCE) DCM. See Dichloromethane (DCM) DDB1s. See Damaged DNA binding proteins (DDB1s) DDQ. See 2,3-Dichloro-5,6-dicyano-pbenzoquinone (DDQ)

438

Index

Debromoaplysiatoxin, 228, 228f 1,10-Dehydroquinolizidine, 270 δ-valerolactam, 270 271 Density functional theory (DFT), 102 104, 232 6-Deoxyerythronolide B, 187 188 Dess Martin periodinane furnished ketone, 295 Deuterio-2-(2-oxopiperidin-3-yl) isoindoline-1,3-dione, ruthenium-based oxidation of, 40 41, 40f Dexamethasone, 405 407 Dexetimide, 362 363 Dexrazoxane, 363 364 DFT. See Density functional theory (DFT) Di-isobutylaluminum hydride (DIBAL-H), 179 Di-N-BOC aldehyde-ester, 380 381 dimethylaspartate, 380 381 nitroalcohol, 380 381 silyloxynitroester, 380 381 2,6-Di-tert-butyl-4-methylphenol (BHT), 259 3,5-Diacetoxystyrene, 109 1,2-Diacid monoamides, 2 3 Diacid monoesters, fragment synthesis from, 9 10 Dialkyl acetals, 226 N-acetyl enolate addition to dialkyl acetals, 227f, 228f ( )-hennoxazole A, 227f ( 1 )-peloruside A, 229f N-propionyl enolate addition to dialkyl acetals, 224f, 225f, 226f, 228f ( )-pironetin, 225f rhizopodin, 225f N-propionyl enolate addition to dialkyl ketals, 226f titanium enolate addition to, 223 230 Diaryldiazomethane, 109 Diarylmaleimides, 14 Diastereoselective conjugate additions, 147, 149 150, 150f 1,8-Diazabicyclo[5.4.0]undec-7-ene (DBU), 385 387 Diazo ester, 108

DIBAL-H. See Di-isobutylaluminum hydride (DIBAL-H) 3,4-Dibromomaleimide, 256, 258, 259f Dicarboximide derivative, 342 Dicarboxylic acids, fragment synthesis from, 8 9 2,3-Dichloro-5,6-dicyano-p-benzoquinone (DDQ), 275 3,5-Dichloroaniline, 341 342 Dichloroethane (DCE), 123 Dichloromaleic anhydride, 343 Dichloromethane (DCM), 278 279 Dichloromethyl building block, 322 Dictyodendrins, 106 108, 107f Dicyanoglutarimides, 18 Dicyclohexylcarbodiimide (DCC), 267, 413 414 Dienes, 110 111 Difluoro analogs of 2-(2-Oxopiperidin-3yl)isoindoline-1,3-diones, 39 Difluoromethyl phthalimidolactaams, 388 389 3ʹ-Difluoromethyl thalidomides, 388 389 Burger’s synthesis, 388f 3-Difluoromethyl-3-(phthalimido) piperidin-2-one, 39 3-Difluoromethyl-3-(phthalimido) piperidin-2,6-dione, 39 3-Difluoromethyl-thalidomide, 39 Digitaria sanguinalis (crabgrass), 336 337 Dihalides, fragment synthesis from, 16 1,2-Dihalobenzenes, 16 double aminocarbonylation, 16f Dihalomaleimides, palladium-catalyzed coupling of, 20 2,3-Dihydrobenzofurans, 106, 106f 2,3-Dihydrodorrigocin A, 288 L-3,4-Dihydroxyphenylalanine (L-dopa), 91 Dihydropyrimidinase activity (Dhydantoinase), 67 70, 68t, 75 77 Dihydropyrones, 219 220 Di-isobutylaluminum hydride (DIBAL-H), 259, 380 381 Diisomaleiimide dithiine, 343 Diisopropylethylamine (DIPEA), 396 398 Dimethachlor, 340 341 1,4-Dimethoxybenzene, 10

Index

Dimethyl acetal, 224, 227 230 Dimethyl acetonedicarboxylate, 264 Dimethyl dioxirane (DMDO), 50 51, 278 279 Dimethyl glutaconate, 264 Dimethyl sulfoxide (DMSO), 259, 368 Dimethyl-(4S)-diisopropyloxazolidinethione, 171 1-(3-Dimethylaminopropyl)-3ethylcarbodiimide hydrochloride (EDCI), 385 387 4-Dimethylaminopyridine (DMAP), 4, 176, 322 323, 380 381 5,7-Dimethylbenzofuran, 264 Dimethylformamide (DMF), 2 3, 94 95, 308 309, 368, 415 417 4,4-Dimethyloxazolidine-2-thione, 175 2,4-Dimethylphenol, 264 Diols, fragment synthesis from, 10 12 Dioxirane-based oxidation of lactams, 50 51 piperidone, 51 pyrrolidones, 50 51 2-(2,6-Dioxopiperidine-3-yl)phthalimidine. See EM-12 DIOZ. See 5,5-Diphenyl-2-oxazolidinone (DIOZ) DIPEA. See Diisopropylethylamine (DIPEA) 5,5-Diphenyl-2-oxazolidinone (DIOZ), 158 160 Diphenylether, 347 348 Dipymetitrone, 343, 344f Dirhodium catalysts, 93 Dirhodium tetrakis(N-phthaloyl-(S)alaninate) [Rh2(S pta)4], 93 Dirhodium tetrakis[N-phthaloyl-(S)phenylalaninate] [Rh2(S ptpa)4], 93 Dirhodium tetrakis[N-phthaloyl-(S)-tertleucinate] [Rh2(S-pttl)4], 93 Dirhodium tetrakis[N-phthaloyl-(S)valinate] [Rh2(S-ptv)4], 93 Dirhodium(II) tetrakis[N-(1,8naphthaloyl)-(S)-phenylalaninate] ([Rh2(S-ntpa)4]), 95 96 Dirhodium(II) tetrakis[N-(1,8naphthaloyl)-(S)-tert-leucinate] ([Rh2(Snttl)4]), 95 96, 95f, 98f, 99 100

439

Dirhodium(II) tetrakis[N-(1,8naphthaloyl)-(S)-valinate] ([Rh2(Sntv)4]), 95 96 Dirhodium(II) tetrakis[N-(4-bromo-1,8naphthaloyl)-(S)-tertleucinate] ([Rh2(S4-Br-nttl)4]), 95 96 Dirhodium(II) tetrakis[N-phthaloyl-(S)adamantylglycine] ([Rh2(S-ptad)4]), 96 97, 110 111 Dirhodium(II) tetrakis[Ntetrachlorophthaloyl-(S)adamantylglycine] ([Rh2(S-tcptad)4]), 102 104 Dirhodium(II) tetrakis[Ntetrachlorophthaloyl-(S)-tert-leucinate] ([Rh2(S-tcpttl)4]), 95, 101 102 Dirhodium(II) tetrakis[Ntetrafluorophthaloyl-(S)-tert-leucinate] ([Rh2(S-tfpttl)4]), 95, 101 102 “Dirty” drugs, 354 355 Disorazoles, 219, 219f 3,3-Disubstituted-4-formyl-β-lactams, 17 18 Dithioacetal, 277 Dithiothalidomide, 392 393 DMAP. See 4-Dimethylaminopyridine (DMAP) DMDO. See Dimethyl dioxirane (DMDO) DMF. See Dimethylformamide (DMF) DMSO. See Dimethyl sulfoxide (DMSO) ( 1 )-Dodoneine, 207, 208f Dorrigocin A and B, 288 289 Double diastereoselection, 220, 221f Drugs, 29

E ( )-E-δ-viniferin, 109, 109f EDC. See N-(3-dimethylaminopropyl)-Nʹethylcarbodiimide (EDC) EDCI. See 1-(3-Dimethylaminopropyl)-3ethylcarbodiimide hydrochloride (EDCI) EDTA. See Ethylenediaminetetraacetic acid (EDTA) Eger Group synthesis of 5ʹhydroxythalidomide, 377 378, 378f EM-8, 374 375

440

Index

EM-12, 372, 374 375, 392 396, 400 405, 404f, 408 410, 419 420 EM-136, 374 375 EM-255, 374 375 Enantioenriched dihydropyrone, 235 236, 236f Enantiomers, 260 261, 261f, 356 357 Enantiopure ( 1 )-epilamprolobine, 273 Enantiopure natural product, 263, 263f Enantioselective conjugate additions chemoselective and, 143f using chiral relay templates, 163f of N-benzylhydroxylamine to β-arylsubstituted enoates, 162f of oximes to yield nitrones, 144f Enantioselective transformations, 139 ENL. See Erythema nodosum leprosum (ENL) Enone, 301 Enzymes in cyclic imide metabolism half-amidase, 73 74, 73t imidase, 70 73, 72t physiological functions of imidase and half-amidase, 74 Epilamprolobine, 270 Erogorgiane, 190, 190f Erythema nodosum leprosum (ENL), 29 30, 367 368, 390 391 Erythromycins, 187, 188f Esterification of allylic alcohol, 292 293 Esters, fragment synthesis from, 10 Ethosuximide, 29, 354 355 Ethylenediaminetetraacetic acid (EDTA), 363 364 Eupomatilone-6, 186, 186f “Evans” syn-aldol product, 184, 190

F Farinomalein, 285 286 FDA. See Food and Drug Administration (FDA) Fenimide, 361 362 FK228, 210, 211f Flumiclorac-ethyl, 336 Flumioxazin, 336 337

Flumipropyn, 336 337 Fluorinated 2-(2-Oxopiperidin-3-yl) isoindoline-1,3-dione, Ruthenium-based oxidation of, 38 2-(3-Fluoro-2-oxo-piperidin-3-yl)isoindol-1, 3-dione, 40 (R)-2-(3-Fluoro-2-oxopiperidin-3-yl)isoindoline-1,3-dione, 38, 40 41 (S)-2-(3-Fluoro-2-oxopiperidin-3-yl)isoindoline-1,3-dione, 38, 41 Fluoroimide, 342 343 Fluorothalidomide, 40, 376 377 (R)-3'-Fluorothalidomide, 38 RuO2/10% aqueous NaIO4-mediated synthesis, 39f synthesis, 33 (S)-3'-Fluorothalidomide, 38 RuO2/10% aqueous NaIO4-mediated synthesis, 39f synthesis, 41 Food and Drug Administration (FDA), 359 360 4-Formyl-β-lactams, 17 18 FR252921 (immunosuppressant agent), 189, 189f, 213, 213f, 226 Fragment-based synthesis of cyclic imides, 1 16. See also Ring transformation synthesis of cyclic imides cyclization of single fragment C C bond formation, 1 C N bond formation, 2 3 from four fragments, 15 16 from three fragments, 14 from two fragments, 4 14 from C2N and C2 fragments, 14 from C3 and CN fragments, 12 13 from C3N and C fragments, 12 from C4 and N fragments, 4 12 Fungicidally active cyclic imides, 342 343 N-(3,5-dichlorophenyl)-dicarboximide fungicides, 340 342 N-haloalkylsulfenylimide as multisiteinhibiting fungicides, 339 340 Furan/maleic anhydride Diels Alder adduct, 5 Fused-benzophthalimide ligand, 94 95

Index

G

GABA. See γ-aminobutyric acid (GABA) GAD. See General anxiety disorder (GAD) Galium aparine, 336 γ-aminobutyric acid (GABA), 83, 354 355 γ-hydroxybutenolide, 286 γ-lactones, 184 185, 185f General anxiety disorder (GAD), 357 Glucuronide (GSH), 358 359 Glutamic acid, 368 371 Glutamine, 368 371 Glutarimide, 14, 29, 30f, 49, 51, 53, 255 cycloheximide, 262 264 julocrotine, cordiarimides, and crotonimides, 264 268 lamprolobine, 269 273 moiety, 264 potassium persulfate mediated synthesis, 53f sesbanimides, 273 282 streptimidone, 283 284 Wittig reagent, 291 292 Glutethimide, 356 357, 374 375 Glycals, 230 231 addition of N-propionyl IPTT to glycals, 230f titanium enolate addition to pseudoglycal, 232f Glycosides, 230 ( 1 )-Goniofupyrone, 217 ( 1 )-Gonioheptolide A, 217 ( 1 )-Goniothalesacetate, 217 Graft versus host disease (GVHD), 391 392 “Green chemistry” method, 8 GSH. See Glucuronide (GSH) GVHD. See Graft versus host disease (GVHD)

H 1

H NMR spectra, 150 152 H 13C heteronuclear NOESY, 100 101 Half-amidase, 73 74, 73t physiological functions, 74 1

441

Half-amides synthesis, 81 82 HBT. See 1-Hydroxybenzotriazole (HBT) ( )-Hennoxazole A, 227 228, 227f Hen’s Egg Test (HET), 376 377 Herbarumin III, 213 214, 214f Herbicidally active cyclic imides miscellaneous herbicidally active cyclic imides, 338 339 N-phenyltetrahydrophthalimide herbicides, 336 338 preemergence herbicidal activity, 338t HET. See Hen’s Egg Test (HET) Hexamethyldisilazane (HMDS), 257 Himanimide C, 7 HIV-1. See Human deficiency virus type I (HIV-1) HMDS. See Hexamethyldisilazane (HMDS) 5-HT1A receptor. See 5-Hydroytryptamine receptor (5-HT1A receptor) HOBt. See 1-Hydroxybenzotriazole (HOBt) Homothalidomides, 376 377 HP β-CD. See Hydroxypropyl β-CD (HP β-CD) Human deficiency virus type I (HIV-1), 390 391 Human umbilical vein endothelial cell (HUVECs), 400 402 Hünig’s base, 9 10 HUVECs. See Human umbilical vein endothelial cell (HUVECs) Hydrazines, 139 144 asymmetric conjugate additions of chiral hydrazines, 140f chemoselective and enantioselective conjugate additions, 143f stereoselective conjugate additions of cyclic hydrazines, 142f synthesis of carbocyclic and heterocyclic β-amino acids, 142f Hydrazinoimidazoline, 7 4ʹ-Hydroxy-6ʹ-desoxythalidomide, 381 382 1-Hydroxybenzotriazole (HBT), 48 49

442

Index

5ʹ-Hydroxy-N-(o-carboxybenzoyl) glutamic acid imide, 371 372 1-Hydroxybenzotriazole (HOBt), 385 387 2-Hydroxyethyl metabolite, 356 Hydroxyl derivatives, 356 358 Hydroxylactam, 403 405 Hydroxylamines, 139 140 Hydroxylated metabolites, 355 356 of thalidomide, 371 372, 381 382 5-Hydroxylbuspirone, 358 359 Hydroxypropyl β-CD (HP β-CD), 414 415 4-Hydroxypyrido(3,4-D)pyrimidine, 347 4-Hydroxythalidomide, 373 374 4ʹ-Hydroxythalidomide, 381 382 synthetic route, 381f 5ʹ-Hydroxythalidomide, 371 372, 377 378, 405 “chiral pool”-derived route, 380 381 Eger Group synthesis, 378f stereospecific route, 379f synthesis using 4-methoxybenzylamine, 379f 5-Hydroytryptamine receptor (5-HT1A receptor), 357 Hypervalent iodine-based oxidation of lactams, 56 58 o-iodoxybenzoic acid based oxidation of caprolactams, 57 58 peracid-based oxidation of substituted 2(2-oxopiperidin-3-yl)isoindoline-1,3diones, 56 57 spiro[benzo[c]azapin-5,1'-cyclohexane]2'-ene-1 (2H), 3(4H),4'-trione, 58

I IBI. See 3-Isobutyl glutarimide (IBI) IBM. See (R)-3-Isobutyl glutaric acid monoamide (IBM) IBX. See 2-Iodoxybenzoic acid (IBX) IC dirhodium complexes. See Imido carboxylate dirhodium complexes (IC dirhodium complexes) Imazapyr, 346 347, 347f Imazaquin, 345 346, 346f

Imidase, 70 73, 72t imidase-catalyzing desymmetric imide hydrolysis, 83 86 comparison of amino acid sequences of BpIH, AfIH, and PuuE, 85f microorganisms producing (R)-IBM from IBI, 84f substrate specificities of recombinant BpIH and AfIH, 86t physiological functions, 74 Imidazolinone herbicide imazamethabenz methyl, 344 345 Imide(s), 5 8, 29 30, 48 49, 150 152, 347, 353 for antibacterial and antiinflammatory agents, 7f application as substrates for rhodiumcatalyzed reactions rhodium-catalyzed aromatic C H activation, 123 129 rhodium-catalyzed asymmetric hydrogenation, 119 120 rhodium-catalyzed conjugate addition, 121 123 conditions and catalysts for imide formation, 4t functionalization, 19 22 imide-based dirhodium catalyst, 99 imide-containing drug miscellaneous, 362 364 tiospirone, 361 362 imide-containing synthetic drugs AEDs, 353 355 antianxiety drugs, 355 359 antineoplastics, 360 361 antipsychotics, 361 362 miscellaneous imide-containing drugs, 362 364 imide-lactam, 38 medicinally important, 8f N-arylation, 19f N-hydroxymethylation and aminomethylation, 19f natural products and aza-steroid precursor, 6f bisindoles, 255 262 glutarimides, 262 284

Index

maleimides, 285 287 polyketides, 288 303 succinimides, 304 309 tetramic acids, 309 323 oxidation procedure of lactam, 40 synthesis from alkyne, amine, and carbon monoxide, 15f from alkyne, amine, and iron pentacarbonyl, 15f from alkyne, isocyanate, and CO, 15f from allenic esters and isocyanides, 13f by carbonylation of amides, 12f from cyano acids and esters, 11f by cyclization of 1, 2-diacid monoamides, 2f from diacid monoesters, 10f from diols, 11f from 2-halobenzoate, amine, and CO, 14f from isocyanates and isocyanides, 13f by lactams oxidation, 17f from nitriles, 14f by pyrrolidines oxidation, 16f by ring expansion of 2-iminooxetanes, 18f by ring expansion of β-lactams, 17f Imido carboxylate dirhodium complexes (IC dirhodium complexes), 93, 94f Imines, 17 18 Imino-carbene, 114 115 Iminooxetanes, ring expansion from, 17 18 In situ generated N-benzyl-2-pyrrolidone, 33 Indane, 95 Indene-based thiazolidinethione (IBTT), 174, 174f, 190 191, 191f Indole, 257 258, 260 261 Indolones, 12 13 Insecticidally active cyclic imides, 343 344. See also Herbicidally active cyclic imides Intermolecular 1,3-dipolar cycloaddition of α-diazo ketone, 94 95 Intramolecular Friedel Crafts reaction of oxetane, 190

443

Intramolecular sulfur Michael addition and nucleophilic attack, 234 235, 234f transfer in N-enoyl oxazolidinones, 232 235, 232f, 233f addition/aldol reaction/cyclization, 234f, 235f β, β-disubstituted N-enoyl oxazolidinethiones, 233f rearrangement of N-bromoacetyl OxT, 234f Iodine-mediated oxidative dimerization of arylacetonitriles, 14 4-Iodothalidomide analogs, 393 396 2-Iodoxybenzoic acid (IBX), 311 312 Ircinastatin A, 223, 223f Iridium-catalyzed reaction of nitriles, 14 Iron carbonyl complex, 15 (R)-3-Isobutyl glutaric acid monoamide (IBM), 83 3-Isobutyl glutarimide (IBI), 83 Isobutyric anhydride, 268 Isocyanate, 174 Isoglutamine, 368 372 Isoindolines, 16 Isoindolinone, 393 396, 410 411 oxone-based oxidation, 59 61 peracid-based oxidation, 56 Isomigrastatin, 290 293 Isonitrile, 12 13 Itaconic acid, 304 305

J Julocrotine, 29, 264 268

K

( 1 )-Kavain, 212, 212f Kefauver Harris Drug Amendments Act, 367 368 Ketopinic acid, 174 Kinetic isotope effect (KIE), 125 126

L L-Boc-glutamine, 267 L-glutamic acid, 266, 319

444

Index

Laccase-generated aminoxyl radicals, oxidation of lactam by, 48 49 Lactams, 1 oxidation, 17 dioxirane-based oxidation, 50 51 hypervalent iodine-based oxidation, 56 58 manganese-based oxidation, 43 45 molecular oxygen based oxidation, 45 50 oxone-based oxidation, 59 61 ozone-based oxidation, 58 59 peracid-based oxidation, 54 56 potassium persulfate-based oxidation, 52 53 ruthenium-based oxidation, 31 42 selective oxidation procedure, 40 Lactimidomycin, 29, 293 298 Lactone, 147, 278 279, 282, 302 reductive ring-opening of, 302 Lactonic acid, 378 380 Lagunamide C, 220, 220f Lamprolobine, 29, 269 273 Lamprolobium fruticosum, 269 Largazole, 217, 217f Latrunculin B, 214, 215f Laurencia-derived C15 acetogenins, 209 210 Laurencin, 202, 221 222 Lawesson’s reagent (LR), 392 393 LCD320, scale-up synthesis, 157f, 158, 158f LDA. See Lithium diisopropylamide (LDA) Lenalidomide, 375 376, 393 396, 406 407 Lepra reaction, 390 391 Lepromatous leprosy, 367 368 ( 1 )-Leucascandrolide A, 210, 210f Lewis acid, 139, 152, 227, 232 chiral Lewis acid catalysts, 152 157 Lewis acid promoted conjugate additions and models, 148f nature of rhodium(II)catalyst, 114 115 Lewis acid-hydroxylamine hybrid reagent (LHHR), 161 Lexetimide, 362 363 LHHR. See Lewis acid-hydroxylamine hybrid reagent (LHHR)

LiHMDS. See Lithium bis(trimethylsilyl) amide (LiHMDS) Lipophilic glutethimide, 356 Lipopolysaccharide (LPS), 390 391 Lithium acetylide of alkyne, 315 Lithium bis(trimethylsilyl)amide (LiHMDS), 321 Lithium diisopropylamide (LDA), 106 108, 256 Long-chain hydrocarbons, 108 LPS. See Lipopolysaccharide (LPS) LR. See Lawesson’s reagent (LR) Luminacin D, 206 207, 207f Lycoctonine, 305 Lyngbya majuscula, 310

M m-Chloroperoxybenzoic acid (m-CPBA), 54 α-methylthalidomide synthesis, 55f alkyl phthalidomide synthesis, 54f Macrolactin A, 201 202, 202f Macrolide, 295 296 Maeliimide, 343 Maleic acid monoamides, 2 3 Maleic anhydride, 340 Maleimide(s), 2 6, 10, 285 287, 345 346 farinomalein, 285 286 pencolide, 287 synthesis from anhydrides, 5f Mammalian dihydropyrimidinases, 67 68 Manganese catalyst, 10 12 Manganese chloride (MnCl2), 43 Manganese perchlorate, 43 44 Manganese-based oxidation of lactams, 43 45. See also Ruthenium-based oxidation of lactams piperidones, 44 45 pyrrolidones, 43 44 Mannich-type anti-addition product, 240, 240f Maresin 1, 209, 209f Marine cyclic ether alkaloid, 194 MCF-7. See Michigan Cancer Foundation7 (MCF-7)

Index

mCPBA. See 3-Chloroperbenzoic acid (mCPBA) MDS. See Myelodysplastic syndrome (MDS) Mechanism of action (MOA), 354 355 Meldrum’s acid, 95 96 Mesityl-substituted oxazolidinethione and thiazolidinethione chiral auxiliaries, 172 1-Mesyl-1,2,3-triazole derived Rh(II)stabilized imino metallocarbenes formed ylide, 116 Mesylate, 385 387 Mesylimines, 115 116 Metallocarbenoids, 92 93 Methanol, 127 129 Methanolysis, 178 3-Methoxy-4hydroxyphenylethyleneglycol sulfate (MHPG sulfate), 357 358 4-Methoxybenzylamine (PMB-NH2), 378 380 (4-Methoxybenzyloxy)-acetaldehyde, 172 6-Methoxyspiro[2-benzazepine-5,1'cyclohexan]-2'-ene-1, 3(2H,4H),4'trione, 57 58 Methsuximide, 354 Methyl (trifluoromethyl) dioxirane (TFDO), 50 51 Methyl 2-(succinimidoyloxycarbonyl) benzoate, 9 10 Methyl 2-iodobenzoates, 14 Methyl ester, 233 3-Methyl tetramic acid derivatives, 317 318 2-(3-Methyl-2-oxopiperidin-3-yl) isoindoline-1,3-dione, 54 55 (R)-( 1 )-2-Methyl-2-propanesulfinamide, 172 (2R,5S)-2-Methyl-hexanolide, 207, 207f 3-Methyl-N-CBZ glutamic anhydride, 387 388 Methyl-substituted 2-(2-oxopiperidin-3-yl) isoindoline-1,3-diones, 56 57 peracid-based oxidation of, 54 55 Methyllycaconitine, 304 305 9-Methylsteptimidone, 283 3ʹ-Methylthalidomide synthesis, 384f

445

Metomeclan, 340 341 MHPG sulfate. See 3-Methoxy-4hydroxyphenylethyleneglycol sulfate (MHPG sulfate) Michael additions, 20 21, 21f, 235 238 asymmetric Michael addition of to Nenoyl BTT, 235f catalyzed Michael addition tert-butyl acetoacetate, 236f intermolecular Michael additions of thiazolidinethiones and oxazolidinethiones, 237f of organocuprates to N-enoyl oxazolidinethiones, 238f of oxazolidinethiones to N-crotonyloxazolidinones, 237f Michigan Cancer Foundation-7 (MCF-7), 125 Microbial cyclic imide metabolism application and enzymes, 77 79 Blastobacter sp. A17P-4 cyclic amide transformation, 75 77 cyclic imide transformation pathway, 69 70 cyclic imide hydrolyzing activity in, 67 69 enzymes involving in cyclic imide metabolism, 70 74 distribution of cyclic imide metabolizing activities, 75 diversity and versatility of cyclic amide and cyclic imide metabolism, 65 67 imidase-catalyzing desymmetric imide hydrolysis, 83 86 regioselective hydrolysis of cyclic imides, 81 82 stereospecific synthesis of optically active α-mercapto acids, 80 Microorganisms cyclic imide metabolizing activities distribution in, 75 diversity and versatility of cyclic amide and cyclic imide metabolism, 65 67 Microwave heating under solvent-free conditions, 8 microwave-induced solvent-free synthesis, 4

446

Index

Migrastatin, 298 303 Milontin, 354 MM. See Multiple myeloma (MM) MOA. See Mechanism of action (MOA) Molecular oxygen based oxidation of lactams, 45 50 caprolactams, 50 molecular oxygen mediated adipimide synthesis, 50f piperidones, 49 oxidation to glutarimide, 50f pyrrolidones, 45 49 MOMCl. See Chloromethyl methyl ether (MOMCl) Monoalkyl-substituted hydrazines, 143 144 Monoalkylated maleimides, 20 Monoarylsuccinimides, 20 21 Monocyclopropanated furan, 102 Morsuximide, 361 362 Multigram organic synthesis protocol, 224 Multifunctional cyano esters, 10 Multiple myeloma (MM), 371 372, 405 407 Multisite-inhibiting fungicides, Nhaloalkylsulfenylimide as, 339 340 Mycale sp., 211, 218, 229 230 Mycobacterium tuberculosis H37Ra strain, 310 311 Mycothiazole, 200 201, 201f Myelodysplastic syndrome (MDS), 375 376, 405 407 Myxococcus stipitatus, 225

N N,N-bis(trimethylsilyl)prop-2-yn-1-amine, 388 389 N,Nʹ-dicyclohexylcarbodiimide (DCC), 176, 176f N,N-tetramethylpropylenediamine (TEPDA), 185 186 N fragment synthesis, 4 12, 14 N-(2-pyridylmethyl)benzamides, 12 N-(3-dimethylaminopropyl)-Nʹethylcarbodiimide (EDC), 267 N-3-methylcinnamoyl OxT, 233

N-3,3,3-trifluoropropionyl (4S)-BOxT, 186 187 N-(3,5-dichlorophenyl)-dicarboximide fungicides, 340 342 N-(4-aminophenyl)imides, 8 9 N-(4-methoxyphenyl)benzaldimine, 238 N-4-methoxybenzyl (PMB), 378 380 N-PMB glutamine, 403 405 N-PMB thalidomide, 403 405 N-acetyl (4S)-IPTT, 200 201, 231 N-acetyl (4S)-TBTT, 211 N-acetyl enolate addition to dialkyl acetals, 227f, 228f ( )-Hennoxazole A, 227f ( 1 )-Peloruside A, 229f N-acetyl IBTT, 204 205 N-acetyl oxazolidinethione, 208 N-acetyl thiazolidinethione, 227 N-alkenoyl-3,5-dimethylpyrazoles, 155 N-acyl (4S)-BTT, 185 186, 195 N-acyl oxazolidinones, 177 N-acyl thiazolidinethione, 196 N-alkenoyloxazolidinones, 152 153, 156 157 N-alkyl thiazolidinethione, 190 N-alkyl-substituted caprolactams, 42 N-alkylhydroxylamines, 160 161, 161f N-amino synthesis, 7, 7f N-aminosuccinimides, 9 N-anilino imide, 342 343 N-aryl-3,4,5,6-tetrahydroisophthalimides, 337 338 N-arylaminomethyl derivatives, 19 N-arylmaleimides, 20 21 N-benzyl-2-pyrrolidone, 32, 48 49 RuIV(TMP)Cl2-catalyzed oxidation of, 34f N-benzylglutarimide, 35 36 N-benzylhydroxylamine, 161, 162f N-benzyllactam, 35 36 N-benzyloxycarbonylbenzaldimine, 238 N-benzyloxythalidomide, 403 405 N-benzylpiperidine, 35 36, 36f N-benzylpiperidone, 36, 36f N-benzylpyrrolidine, 32 RuO4/10% NaIO4-mediated oxidation of, 33f

Index

N-benzylpyrrolidine-2, 5-dione, 33 34 N-benzylsuccinimide, 33, 48 49, 49f N-benzyltetrahydrophthalimide, 336 337 N-BOC dimethyl aspartate, 380 381 N-bromosuccinimide (NBS), 317 N-butanoyl (4S)-BTT, 195 N-butanoyl (4S)-IPTT, 231, 232f N-butanoyl IBTT, 198 N-carbamoyl amino acid amidohydrolases, 75 77 N-carbobenzyloxy (N-CBZ) lactonic acid, 378 380 N-CBZ N-PMB isoglutamine, 378 380 N-CBZ protected lactone, 377 378 N-cinnamoyl thiazolidinethione, 234 235, 234f N-bromoacetyl OxT rearrangement, 234f N-crotonoyl-3,5-dimethylpyrazole, 155 N-crotonyl (4S)-BTT, 235, 235f N-crotonyl 4-phenyl-oxazolidinethione, 235 N-crotonyl thiazolidinethione, 235 236, 236f N-crotonyl-oxazolidinones, 236 237, 237f N-difluorophenyl-tetrafluorophthalimide, 400 402 N-enoyl oxazolidinones, intramolecular sulfur transfer in, 232 235, 232f, 233f N-enoyl OxT, 232 234 N-ethyl caprolactams, 42 N-ethyl-2-piperidone, 35 N-ethyl-2-pyrrolidone, 32 N-ethylglutarimide, 35, 37 N-ethylpiperidine (NEP), 177 178 N-ethylsuccinimide, 32 N-ethynylisoindolinone, 408 410 N-ethynylphthalimide, 408 410 N-glutaryl carboxybenzamidic acid, 368 371 N-glycolates, aldol addition of, 221 223 N-glycolyloxazolidinethiones, 222 N-haloalkylsulfenylimide as multisiteinhibiting fungicides, 339 340 N-heterocyclic carbene (NHC), 10 12, 91 92 N-hydroxyimide, 5 6 synthesis, 7, 7f N-hydroxymethyl derivatives, 19

447

N-hydroxymethylphthalimide, 19 N-hydroxyphthalimide (NHPI), 47 49 aerobic oxidation of N-alkylamides catalyzed by, 47 N-hydroxyphthalimides, 7, 348 349 N-hydroxysuccinimide, 267 N-hydroxythalidomide, 373 374 N-imido-amino acid derived rhodium (II)-carboxylates, catalysis with asymmetric amination, 111 114 cycloaddition reactions, 109 111 rhodium imidocarboxylate applications for rhodium carbenoid generation, 114 119 as catalyst, 92 97 complexe applications in catalysis, 97 119 N-isoindolinoyl glutamine, 372 N-isopropyl caprolactams, 42 N-methyglutarimide, 35 N-methyl arcyriacyanin A, 257, 257f, 259, 259f N-methyl caprolactams, 42 N-methyl-2-piperidone, 35 37, 53 N-methyl-2-pyrrolidone, 32 33, 35, 43 47, 52 53 N-methylglutarimide, 36 37, 53 Ru(TMP)Cl2-mediated synthesis, 37f N-methylhydroxylamine, 160 161 N-methylsuccinimide, 32 33, 45 47, 52 53 N-methylthalidomide, 373 374 N-naphthoyl-tert-leucine derived dirhodium catalyst, 98 N-p-chlorophenylmercaptomethylphthalimide, 340 N-phenyl compounds, 21 22 N-phenylselanylacetyl oxazolidinethiones, 191 N-phenyltetrahydrophthalimide herbicides, 336 338 commercialized tetrahydrophthalimide herbicides, 337f phthalimide and tetrahydrophthalimide herbicides, 338f N-phthaloyl amino acids derived homochiral rhodium(II)-carboxylate catalysts, 93

448

Index

N-phthaloyl glutamine, 368 371 N-phthaloyl glutaric anhydride, 403 405 N-phthaloyl isoglutamine, 368 371 N-phthaloyl silyloxynitroester, 380 381 N-phthaloyl-(S)-amino acids, 93 N-phthaloyl-(S)-glutamic acid, 8 N-phthaloyl-L-glutamic acid (PGA), 415 417 5-N-phthaloyl-α,β-unsaturated benzyl ester, 381 382 N-phthaloyldiester, 380 381 N-phthaloylester, 380 381 N-phthaloylglutamic acid, 368 371 N-phthaloylglutamic anhydrides, 385 387 N-phthaloylglutaric anhydride, 403 405 N-potassioglutarimide, 270 N-propanoyl (4S)-BOxT, 182 N-propanoyl (4S)-IPTT, 238 240, 239f N-propargylic benzoxadiazole, 408 N-propargylisoindolinone, 408 411 N-propargylphthalimide, 408 411 N-propionyl (4S)-BOxT, 181 182 N-propionyl (4S)-BTT, 183, 186, 196 N-propionyl (4S)-IPPT, 177, 187, 224 225 titanium enolate of, 223 224, 226 N-propionyl enolate addition to dialkyl acetals, 224f, 225f, 226f, 228f ( )-Pironetin, 225f rhizopodin, 225f N-propionyl enolate addition to dialkyl ketals, 226f N-propionyl IBTT, 197 N-propionyl thiazolidinethiones, 199 N-substituent alteration, 19 20 N-substituted cyclic iminium ion, 240, 240f titanium enolate addition to, 240f N-substituted hydroxylamines, 160 165 N-substituted isoindolinones, 56 N-substituted lactams, 32 N-substituted-pyrroles furnished tropanes, 109 110 N-succinimidoyl glutarimide, 373 374 N-sulfonyl homoaminocyclopropanes, 115 116 N-tert-butoxycarbonyl protected ciscyclopropane α-amino acid, 100 101

N-thioglycolyl oxazolidinethiones, 192 N-tosylmaleimides, 18 nAChR. See Neuronal nicotinic acetylcholine receptor (nAChR) NaHMDS. See Sodium bis(trimethylsilyl) amide (NaHMDS) Naphthalenediimide carboxylate ligands, 95 96 1,8-Naphthalic anhydride, 95 96 Naphthoquinone derivatives, 125 Naramycin A. See Cycloheximide Narbonolide, 192, 192f Natural products, 29, 255 cycloheximide, 363 enantiopure, 263, 263f glutarimide core based natural products, 30f imide and aza-steroid precursor, 6f bisindoles, 255 262 glutarimides, 262 284 maleimides, 285 287 polyketides, 288 303 succinimides, 304 309 tetramic acids, 309 323 NBS. See N-bromosuccinimide (NBS) Nefazodone, 358 359 NEP. See N-ethylpiperidine (NEP) Neuronal nicotinic acetylcholine receptor (nAChR), 304 NHC. See N-heterocyclic carbene (NHC) NHPI. See N-hydroxyphthalimide (NHPI) Ni-catalyzed addition to trimethylorthoformate, 229f Ni(II) Tol-BINAP, 235 236 Nicotinic ester, 346 347 Nicotinonitrile, 270 Niobium pentoxide, 8 Nitriles, iridium-catalyzed reaction of, 14 Nitroacid, 50 51 4-Nitroaniline, 8 9 Nitrocyclopropane derivatives, 100 101 4-Nitrothalidomide, 373 374, 411 412 NOESY. See Nuclear overhauser effect spectroscopy (NOESY) “Non-Evans” syn-aldol product, 177 180 Nonimide agrochemicals

Index

cyclic imides as intermediates in synthesis, 346 349 as lead structures for, 344 345 as metabolites, 345 346 Norepinephrine metabolite, 357 358 Nuclear overhauser effect spectroscopy (NOESY), 100 101, 152 Nucleobases metabolism, 65 Nucleophiles, 139 140, 144 145

O O-alkylhydroxylamine salts, 7 O-benzylhydroxylamine, 147, 151f, 153f, 154f, 156f, 157, 159f, 348 349 O-iodoxybenzoic acid based oxidation of caprolactams, 57 58 O-phthalic acid, 368 371 O-substituted hydroxylamines, 146 157 conjugate addition to β-substituted acrylimides, 147 157 O-sulfamoylated N-hydroxyphthalimide, 340 O-toluidine, 348 349 Obolactone, 219 220, 219f Olefins, 240, 241f Organocuprates addition to N-enoyl oxazolidinethiones, 238f Organoselenium compounds, 191 “Orphan drug”. See Erythema nodosum leprosum (ENL) Oscillatoxins A, 228, 228f Oscillatoxins D, 228, 228f Oxazaborolidine catalysts, 22 Oxazinone, 337 Oxazolidinethiones, 170, 234 intermolecular Michael additions of, 237f Oxazolidinone crotonate, 144 145, 152 153, 155 Oxazolidinones, 139, 266, 322 Oxazolines, 116, 150, 151f asymmetric synthesis, 116f Oxetano analog synthesis, 387f Oxidation, 277 of lactams, 17 oxidation elimination of selenide, 292 293 of pyrrolidines, 16

449

Oximes, 139 140, 144 146 Oxone-based oxidation of lactams, 59 61. See also Peracid-based oxidation of lactams isoindolinones, 59 61 2-(2-Oxopiperidin-3-yl)isoindoline-1,3diones, ruthenium-based oxidation of, 37 41 deuterio-2-(2-oxopiperidin-3-yl) isoindoline-1,3-dione, 40 41 difluoro and trifluoro analogs, 39 3-difluoromethyl-3-(phthalimido) piperidin-2,6-dione synthesis, 39 fluorinated 2-(2-oxopiperidin-3-yl) isoindoline-1,3-dione, 38 (R)-3'-fluorothalidomide synthesis, 33 (S)-3'-fluorothalidomide synthesis, 38 procedure for selective oxidation of lactam to imide, 40 stereoselective fluorinated 2-(2oxopiperidin-3-yl)isoindoline-1,3dione, 38 Oxygen-mediated oxidation under pressure, 46 47 Ozone-based oxidation of lactams, 58 59 Ozonolysis, 281 282

P p-chlorobenzaldehyde, 234 235, 234f p-methoxyphenyl ketone (PMP-ketone), 100 101 Paecilomyces farinosus HF599, 285 Palasimide, 29, 305 307 Palau’imide, 316 318 Palladium-catalyzed coupling of dihalomaleimides, 20 Pamamycin 621A, 192f, 193 Para-hydroxyl-nefazodone, 358 359 Paraconic acid derivatives, 102 Pateamine A (PatA), 211, 211f PBMCs. See Peripheral blood mononuclear cells (PBMCs) PBN. See α-phenyl-N-tert-butylnitrone (PBN) PCC. See Pyridinium chlorochromate (PCC) PDEs. See Phosphodiesterases (PDEs)

450

Index

PDF. See Peptide deformylase (PDF) PDI. See 2,3-Pyridinedicarboximide (PDI) Peloruside A, 218, 218f, 229 230, 229f Pencolide, 287 Peptide deformylase (PDF), 157 Peracetic acid (CH3COOOH), 43 Peracid-based oxidation of lactams, 54 56. See also Oxone-based oxidation of lactams isoindolinones, 56 substituted 2-(2-oxopiperidin-3-yl) isoindoline-1,3-diones, 54 57 Peripheral blood mononuclear cells (PBMCs), 390 391 Peroxidizing herbicides, 336 PFC. See Plaque-forming cells (PFC) “PG acid”. See N-phthaloylglutamic acid PGA. See N-phthaloyl-L-glutamic acid (PGA) Phenobarbital, 353 354, 356 Phensuximide, 29, 354 Phenylglycine derivative, 317 318 Phenyliodonium ylide, 95 96 2-Phenylthio-N-PMB thalidomide, 403 405 Phenytoin, 353 354 Phorboxazoles A and B, 201, 201f Phosphodiesterases (PDEs), 399 400 Photolytic irradiation, molecular oxygen in combination with, 45 Phthalidomide, RuO2/NaIO4-mediated synthesis of, 38f Phthalimide-N-oxyl radical (PINO radical), 47 49 Phthalimide(s), 2 4, 10 12, 19 20, 340, 344 345, 348 349, 410 411 derivatives, 29 30, 336 337, 339 340 experimental phthalimide fungicides, 341f lead structures of imidazolinone herbicides, 345f phthalimide-assimilating Arthrobacter ureafaciens O-86, 82 phthalimide-based acrylates, 119 120, 120f phthalimide-based drug and natural products, 31f

synthesis from anhydrides, 5f traceless solid-supported synthesis, 8 9 4ʹ-Phthalimido analog, 373 374 Phthalimido succinimide, 376 377 3-Phthalimidyl-piperidin-2-one, 38 Phthalodinitriles, sodium borohydride reduction of, 14 Phytopathogens, 339 340, 342 343 PINO radical. See Phthalimide-N-oxyl radical (PINO radical) Piperidine-2,6-dione, 353, 364 2-Piperidone, 49, 51, 53 dioxirane-mediated oxidation, 52f Piperidone(s) dioxirane-based oxidation, 51 manganese-based oxidation, 44 45 molecular oxygen based oxidation, 49 potassium persulfate based oxidation, 53 RuO2/10% aqueous NaIO4-mediated oxidation of substituted, 35f ruthenium-based oxidation, 35 37 ( )-Pironetin, 195, 214, 214f, 225f ( )-Pladienolide, 213, 213f Plaque-forming cells (PFC), 398 399 Plasmopara viticola, 339 340 PMB. See N-4-methoxybenzyl (PMB) PMB-NH2. See 4-Methoxybenzylamine (PMB-NH2) PMP-ketone. See p-methoxyphenyl ketone (PMP-ketone) Polycyclic spiroindolines, 117 118 Polyhalogenated phthalimides, 392 393 Polyketides dorrigocin A and B, 288 289 isomigrastatin, 290 293 lactimidomycin, 293 298 migrastatin, 298 303 Polypharmacologics. See “Dirty” drugs ( 1 )-Polyrhacitide A, 215 216, 215f Pomalidomide, 29 30, 389, 393 396, 406 407 Potassium persulfate-based oxidation of lactams, 52 53 piperidones, 53 pyrrolidones, 52 53 Potassium-ethyl xanthate, 174

Index

4-POxT, 236 237 1-PP. See 1-(2-Pyrimidinyl)piperazine (1-PP) PPO. See Protoporphyrinogen IX oxidase (PPO) Pregabalin, 83 Procymidone, 340 342, 342f “Prodrug” approach, 414 415 Propionate aldol reactions, 177 199 boron-mediated N-propionyl oxazolidinethione aldol reactions, 179f thiazolidinethione aldol reaction, 178f brevenal, 194f diastereoselective anti-aldol reaction, 196f N-3,3-trifluoropropionyl oxazolidinethione aldol reactions, 3, 187f N-acyl IPTT aldol reaction, 178f N-acyl oxazolidinone and thiazolidinethione aldol reactions, 191f N-acyl thiazolidinethione aldol reactions, 196f N-propionyl IBTT anti-aldol reaction, 198f N-propionyl IPTT aldol reaction, 177f N-propionyl oxazolidinethione aldol reaction, 179f, 180f, 181f, 183f N-propionyl thiazolidinethione aldol reactions, 186f N-propionyl thiazolidinethione catalytic syn-aldol reaction, 199f N-thioglycolyl oxazolidinone aldol reactions, 192f nocardiolactone, 186f simplactones, 198f spiculoic acid, 184f substrates for RCM, 190f titanium-mediated N-propionyl camphor-based oxazolidinethione aldol reactions, 180f valilactone, 189f Propionic anhydride, 268 Propylmagnesium bromide, 235 Proteolysis targeting chimeras (PROTACs), 412 413 Protoporphyrinogen IX oxidase (PPO), 336

451

inhibitors, 336 337 N-phenyltetrahydrophthalimide herbicides inhibiting, 336 338 Protox, 336 Pseudo-glycal, 187 Pseudoenantiomer, 212 Pseudomonas putida 15160, 78 Pseudomonas putida s52, 78 Psymberic acid chloride, 223 Psymberin. See Ircinastatin A Pyrazolidinones, 143 144 Pyrethroids bearing cyclic imide, 343 344, 345f Pyrexia, 391 392 Pyridine, 368 Pyridine-3,4-dicarboxylic acid, 347 2,3-Pyridinedicarboximide (PDI), 81 82 α-3CP production by imidase-catalyzed regioselective hydrolysis, 81 82 Pyridinium chlorochromate (PCC), 278 279 1-(2-Pyrimidinyl)piperazine (1-PP), 357 358 Pyrroles, 109 110, 345 346 Pyrrolidine-2,5-dione, 353 Pyrrolidine(s), 313 oxidation, 16 Pyrrolidinone, 153 154, 164 165 Pyrrolidone(s), 31, 32f, 45 46, 50 53, 317 dioxirane-based oxidation, 50 51, 51f manganese-based oxidation, 43 44, 43f molecular oxygen based oxidation, 45 49 aerobic oxidation of N-alkylamides catalyzed by N hydroxyphthalimide, 47 molecular oxygen in combination with photolysis and TiO2, 46 molecular oxygen in combination with photolytic irradiation, 45 oxidation of lactam by laccasegenerated aminoxyl radicals, 48 49 oxygen-mediated oxidation under pressure, 46 47 postulated mechanistic pathway for oxidative transformation, 48f

452

Index

Pyrrolidone(s) (Continued) route of oxidation via aminoxyl radical, 48f potassium persulfate based oxidation, 52 53 ruthenium-based oxidation, 31 35 Pyrrolnitrin, 345 346 cyclic imides as metabolism products, 346f Pyrrolo[2,3-c]carbazole, 106 108 Pyrroloindoline scaffold, 117 118 Pyruvate production, 77 79

Q Quaternary thiol, 233 Quinolizidine, 270 4-Quinolizone, 269 Quinone imine reactive metabolite, 358 359 Quinoxaline-derived TNF-α inhibitors, 398f

R Racemic 2-(3-deuterio-2,6-dioxopiperidin-3-yl)-isoindol-1,3-dione, 40 Racemic-3-methylglutarimide, 387 388 Racemic mixtures resolution, 241 242, 241f Rare-earth metal complexes (RE metal complexes), 155 156 Rat aortic ring assay (RAR assay), 400 405 Rat liver ɷ-amidase, 73 74 Razoxane, 363 364 RE metal complexes. See Rare-earth metal complexes (RE metal complexes) Reactive oxygen species (ROS), 420 Regioselective hydrolysis of cyclic imides, 81 82 α-3CP production by imidase-catalyzed regioselective hydrolysis of PDI, 81 82 Revlimide. See Lenalidomide Rh C. See Rhodium carbene (Rh C) Rhizophora mucronata, 285 Rhizopodin, 225, 225f

Rhodium (Rh), 91 carbenoid formation, 93f rhodium imidocarboxylate applications for, 114 119 catalysis catalysis with N-imido-amino acid derived rhodium (II)carboxylates, 92 119 imides application as substrates for, 119 129 ligands in, 91 92 Rh-catalyzed aminocarbonylation of benzoic acids, 12 13 Rh-catalyzed aromatic C H activation, 123 129 amidation of arenes with N-OTs imides, 125f C(sp3)-H alkylation of 8methylquinolines, 127f carboamidation of alkenes with enoxyphthalimide, 128f C H functionalization of chromones, 1,4-naphthoquinones, and xanthone, 126f cyclopropanation of alkenes, 128f rhodium(III)-catalyzed C H activation for ortho-selective halogenation, 124f Rh(COD)2BF4/BoPhoz-type ligand, 119 120 Rh(II) imino-carbene, 114 115 Rh(II)-catalyzed C H functionalization, 104 105, 104f Rhodium carbene (Rh C), 92 93 Rhodium imidocarboxylate as catalyst, 92 97 IC dirhodium complexes, 94f improving selectivity with halogenated ligands, 95f rhodium carbenoid formation, 93f synthesis of IC rhodium complexes and activity, 94f complexes in catalysis asymmetric cyclopropanation, 97 104 C H activation, 104 109

Index

Rhynchosporium secalis, 339 340 Ring alkylation, 20 Ring transformation synthesis of cyclic imides, 16 18. See also Fragment-based synthesis of cyclic imides oxidation without change of ring size, 16 17 ring contraction, 18, 18f ring expansion, 17 18 Ring-fused imides, 16 Robin synthesis, 417 418 ( 1 )-Rogioloxepane A, 209 210, 210f Rogletimide, 361 ROS. See Reactive oxygen species (ROS) Ruboxistaurin, 363 Ruthenium (Ru) Ru-porphyrin/pyridine-N-oxide system, 33 ruthenium-catalyzed ring-closing metathesis, 292 293 tetroxide, 31 Ruthenium-based oxidation of lactams, 31 42. See also Manganese-based oxidation of lactams caprolactams, 42 2-(2-oxopiperidin-3-yl)isoindoline-1,3diones, 37 41 piperidones, 35 37 pyrrolidones, 31 35

S S.T.E.P.S. See System for Thalidomide Education and Prescribing Safety (S.T.E. P.S.) (S)-Methylsuccinic anhydride, 6 Salfredins C1 C3, 307 Salicylaldoxime, 145 146, 145f Salinomycin, 187, 187f, 232f Samarium iodobinaphtholate catalyzed reactions, 156 157, 157f Saturated aldehydes, 222 Saturated alkyl-substituted thiazolidinethiones, 228 SCH-351448, novel diolide structure of, 188, 189f SCH-48462 synthesis, 239 Schlessinger protocol, 280

453

Sclerotinia sclerotiorum (white mold), 340 341 Secoproansamitocin, 206, 206f Sedative hypnotic drugs. See Antianxiety drugs Sepsis, 391 392, 421 422 Serine, 312 313 methyl ester hydrochloride, 308 309 Sesbania drummondi, 273 Sesbanimides, 273 282 Sida spinosa (prickly sida), 336 σ-alkylrhodium(III) complex, 127 129 (Silanyloxyvinyl)diazoacetates, 98 Silica-supported benzoyl chloride, 3 succinimide synthesis using, 3f Silylated anti-aldol product, 197 Sintokamides, 319 323 (4S,5R)-Sitophilur, 183 Sitophilure, 183, 183f Sodium bis(trimethylsilyl)amide (NaHMDS), 319 320 Sodium borohydride reduction of phthalodinitriles, 14 Sodium enolate Michael addition/ elimination, 240, 241f Sodium saccharin, 374 375 Solanum nigrum (black nightshade), 336 Solvent/temperature effect, 258 Sorangicin A, 197, 197f (2)-Sparteine azetine, 239, 239f ( 1 )-Sparteine, 182 183 Spiro[benzo[c]azapin-5,1'-cyclohexane]-2'ene-1 (2H), 3(4H),4'-trione, 58 Spiroketone, 57 58 Spirolactam, 57 Spirosuccinimide derivative, 338 339 Spiruchostatin A, 210 Staurosporine, 29 Stemoamide, 198 199, 199f Stereogenic centers, 169 Stereoselective conjugate addition, 140 141 of cyclic hydrazines, 142f Stereoselective fluorinated 2-(2Oxopiperidin-3-yl)isoindoline-1,3dione, 38 Stereospecific synthesis of optically active α-mercapto acids, 80

454

Index

Stevastelin B, 184, 184f Streptimidone, 283 284 Streptomyces albulus, 262 263 Streptomyces amphibiosporus, 293 294 Streptomyces griseus, 262 Streptomyces platensis Mer-11107, 213 Streptomyces pulveraceus, 262 263 Streptomyces roseosporus, 180 Streptomyces uncialis, 260 Streptomyces venezuelae ATCC 15439, 192 Strobilurin derivative, 348 349, 349f Stylocheilus longicauda, 228 Substituted 2-(2-oxopiperidin-3-yl) isoindoline-1,3-diones methyl-substituted 2-(2-oxopiperidin-3yl)isoindoline-1,3-diones, 54 55 peracid-based oxidation of, 54 57 substituted stereoselective 2-(2oxopiperidin-3-yl)isoindoline-1,3diones, 55 4ʹ-Substituted analogs, 385 387 4-Substituted N-crotonyl-oxazolidinones, 236 237 4-Substituted oxazolidinethiones, 170 171, 170f 3-Substituted maleinimides, 120, 121f Succinamic acid, 69 70, 73 74, 343 Succinic acid ester amides, 2 3 monoamides, 3 Succinic anhydride, 343 Succinimide(s), 2 4, 6, 10 12, 31, 45, 52 53, 69 70, 345 346, 353, 364 derivatives by photolysis, 46f drugs, 354 355 methyllycaconitine, 304 305 molecular oxygen Co(II) salt-mediated succinimide synthesis, 47f molecular oxygen mediated synthesis, 47f monoimines, 17 18 palasimide, 305 307 potassium persulfate mediated synthesis, 52f salfredins C1 C3, 307 solid-supported synthesis from a dipeptide, 3f

succinimide-assimilating bacterium, 78 synthesis from anhydrides, 5f using silica-supported benzoyl chloride, 3f TiO2-mediated photolytic synthesis, 46f versimide and violaceimides A E, 307 309 Sulfinimine, 321 322 Sulfonyl triazoles, 114 119 1-Sulfonyl-1,2,3-triazoles, 114 115, 115f Sulfur-containing cyclic imides, 70 73, 82 imidase-catalyzing hydrolysis, 80 Syn-adduct, 226 Syn-aldol adduct, 221 222 product, 229 230 Syn-s-cis conformation, 232 2R,3R-(Syn)-isocyanates, 238 Synthetic organic chemistry, 177 System for Thalidomide Education and Prescribing Safety (S.T.E.P.S.), 375 376

T t-leucinol, 173 Tandospirone, 359 360 Tapinanthus dodoneifolius, 207 TBAF. See Tetrabutylammonium fluoride (TBAF) TBDMS-Trif. See Tert-butyldimethylsilyl triflate (TBDMS-Trif) TBDPSCl. See Tert-butyl(chloro) diphenylsilane (TBDPSCl) TBS. See Tert-butyldimethylsilyl (TBS) TBSCl. See Tert-butyldimethylsilyl chloride (TBSCl) TCA. See Tricarboxylic acid (TCA) TEA. See Triethylamine (TEA) Tebufenpyrad analog, 347 348, 348f TEMPO. See 2,2,6,6Tetramethylpiperidine 1-oxyl (TEMPO) TEPDA. See N,Ntetramethylpropylenediamine (TEPDA) Teratogenicity of thalidomide, 372 382 Tert-butoxycarbonyl anhydride (Tert-BOC anhydride), 380 381 Tert-butyl acetoacetate, 235 236, 236f

Index

Tert-butyl thiazolidinethione, 173 (4S)-Tert-butyl thiazolidinethione, 173 Tert-butyl(chloro)diphenylsilane (TBDPSCl), 277 Tert-butyldimethylsilyl (TBS), 96 97 Tert-butyldimethylsilyl chloride (TBSCl), 258, 258f Tert-butyldimethylsilyl triflate (TBDMSTrif), 380 381 D-Tert-leucine, 173 TESCl. See Chlorotriethylsilane (TESCl) Tetrabromo-phthalidomide, 392 393 Tetrabutylammonium fluoride (TBAF), 258 Tetrachlorothalidomide, 392 393 Tetradenia riparia, 216 Tetrafluoro analog, 392 393, 400 402 Tetrafluorothalidomide, 392 393 Tetrahydrofuran (THF), 378 Tetrahydrophthalic anhydride, 340 Tetrahydrophthalimide, 339 340, 339f tetrahydrophthalimide-linked benzotriazole, 336 337 Tetramethrin, 343 344, 344f 1,1,3,3-Tetramethylguanidine (TMG), 380 381 2,2,6,6-Tetramethylpiperidine 1-oxyl (TEMPO), 319 320 Tetramic acids, 319 malyngamides, 309 316 moiety, 312 313 palau’imide, 316 318 sintokamides, 319 323 TFA. See Trifluoroacetic acid (TFA) TFAA. See Trifluoroacetic anhydride (TFAA) TFDO. See Methyl (trifluoromethyl) dioxirane (TFDO) “Thal-immobilized” FG beads, 420 Thalidomide, 8, 29 30, 353, 367 368 analogs and teratogenicity, 372 382 antiinflammatory and immunosuppressive activity, 398 400 biological disposition, 368 372 and cancer, 400 407 and click chemistry, 408 413 configurationally stable analogs, 382 390

455

hydrolytic cascade, 370f miscellaneous thalidomide syntheses, 415 418 mode of action, 418 421 multiple myeloma, 405 407 myelodysplastic syndrome, 405 407 TNF-α inhibition, 390 398 water-soluble prodrug derivatives, 413 415 Thalidomide 5ʹ-O-glucuronide, 371 372 THAM. See Tris(hydroxymethyl) acrylamidomethane (THAM) THF. See Tetrahydrofuran (THF) Thiazolidinethiones, 169 170, 191, 235 adduct, 231, 232f intermolecular Michael additions of, 237f titanium enolates of, 239 to aldimines, 239f Thiazolidinone, 240, 241f Thioacetal, 282 Thioimides, 241 Thiol products, 233 Thiothalidomide synthesis, 393f TiCl4-mediated aldol reaction, 184 185 Titanium dioxide (TiO2) molecular oxygen in combination with, 46 TiO2-mediated photolytic synthesis of succinimides, 46f Titanium enolate addition to aldimines, 238 240 to dialkyl acetals, 223 230 of N-propionyl (4S)-IPTT, 223 224, 226, 228 to glycals, 230 231 Titanium-mediated aldol condensation, 185 186 Titanium(IV), 185 186 TMEDA, 180 TMG. See 1,1,3,3-Tetramethylguanidine (TMG) TMNO. See Trimethylamine N-oxide (TMNO) TMSOTf. See Trimethylsilyl trifluoromethanesulfonate (TMSOTf) TNFα. See Tumor necrosis factor alpha (TNFα)

456

Index

Traceless solid-supported synthesis of phthalimides, 8 9 Trans-1-amino-2-indanol, 174 Trans-succinimides, 15 16 Transition metal-catalyzed carbonylation of amides, 12 Trialkylindiums, 20 Triarylmaleimides, 1 Triazole, 347, 408 Tricarboxylic acid (TCA), 67 Tricyclic diastereomers, 234 235, 234f Tricyclic imide, 342 343, 345 346 Triethylamine (TEA), 169, 378 380 Trifluoro analogs of 2-(2-oxopiperidin-3yl)isoindoline-1,3-diones, 39 Trifluoroacetamide, 385 387 Trifluoroacetic acid (TFA), 267, 381 382 Trifluoroacetic anhydride (TFAA), 274 Trifluoromethyl phthalimidolactaams, 388 389 3-Trifluoromethyl thalidomide, 39 3ʹ-Trifluoromethyl thalidomides, 388 389 Burger’s synthesis, 388f 3-Trifluoromethyl-3-(phthalimido) piperidin-2-one, 39 3-Trifluoromethyl-3-(phthalimido) piperidin-2, 6-dione, 39 Trifluoromethylated cyclopropane, 101, 101f Trimethylamine, 170, 198 Trimethylamine N-oxide (TMNO), 280 281 Trimethylsilyl trifluoromethanesulfonate (TMSOTf), 275 276 2-(2-(Trimethylsilyl)ethynyl)isoindoline-1dione, 410 411 2-(2-(Trimethylsilyl)ethynyl)isoindoline1,3-dione, 410 411 Tris(hydroxymethyl)acrylamidomethane (THAM), 402 403 Trisubstituted succinimides, 15 Trithionothalidomide, 392 393 Tropanes (8-azabicyclo[3.2.1]octane), 109 110 Tumor necrosis factor alpha (TNFα), 29 30, 367 368 inhibition, 390 398

U Umuravumbolide, 216, 216f Unsubstituted 2-pyrrolidone, 43

V Valeraldehyde, 216 L-Valine/L-leucine auxotrophs, 78 (S)-Valine methyl ester, 171 (S)-Valine-derived oxazolidinethione, 171 Vascular endothelial growth factor (VEGF), 411 412 Venturia inaequalis, 339 340 Versimide, 307 309 Vinylbromo unsaturated aldehyde, 208 Vinyldiazoacetate, 109 111 Vinylmagnesium bromide, 281 282 Violaceimides A E, 307 309

W Water-soluble prodrug derivatives of thalidomide, 413 415 Wolff Kishner reduction, 270

X X-ray analysis, 177 crystallography, 239, 264 265 Xanthium strumarium (cocklebur), 336

Y Ylide formation, 92 93

Z Zalospirone, 359 360 Zarontin, 354 zCRBN function, 420 421 Zinc triflate catalyzed interaction of allenic esters, 13 Zinc-mediated Horner Wadsworth Emmons macrocyclization, 296 297