[1st Edition] 9780128111253, 9780128111246

Table of contents :
Content:
CopyrightPage iv
ContributorsPage vii
PrefacePage ixHans-Joachim Knölker
Chapter One - The Rhazinilam-Leuconoxine-Mersicarpine Triad of Monoterpenoid Indole AlkaloidsOriginal Research ArticlePages 1-84Magnus Pfaffenbach, Tanja Gaich
Chapter Two - Flavoalkaloids—Isolation, Biological Activity, and Total SynthesisOriginal Research ArticlePages 85-115Lachlan M. Blair, Matthew B. Calvert, Jonathan Sperry
Chapter Three - Chemistry and Biology of the Pyrrole–Imidazole AlkaloidsOriginal Research ArticlePages 117-219Thomas Lindel
Cumulative Index of TitlesPages 221-231
IndexPages 233-236

Citation preview

Academic Press is an imprint of Elsevier 50 Hampshire Street, 5th Floor, Cambridge, MA 02139, United States 525 B Street, Suite 1800, San Diego, CA 92101-4495, United States 125 London Wall, London EC2Y 5AS, United Kingdom The Boulevard, Langford Lane, Kidlington, Oxford OX5 1GB, United Kingdom First edition 2017 Copyright © 2017 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: 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. ISBN: 978-0-12-811124-6 ISSN: 1099-4831 For information on all Academic Press publications visit our website at https://www.elsevier.com/books-and-journals

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CONTRIBUTORS Lachlan M. Blair University of Auckland, Auckland, New Zealand Matthew B. Calvert University of Auckland, Auckland, New Zealand Tanja Gaich University of Konstanz, Konstanz, Germany Thomas Lindel TU Braunschweig, Institute of Organic Chemistry, Braunschweig, Germany Magnus Pfaffenbach University of Konstanz, Konstanz, Germany Jonathan Sperry University of Auckland, Auckland, New Zealand

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PREFACE Volume 77 of the series The AlkaloidsdChemistry and Biology is covering in three chapters the recent developments in three unique classes of alkaloids. Chapter 1, written by Magnus Pfaffenbach and Tanja Gaich, summarizes the occurrence, biosynthesis, synthetic approaches, and pharmacology of the rhazinilam, leuconoxine, and mersicarpine alkaloids. These monoterpenoid indole alkaloids of the Aspidosperma class have been covered last time in our series by T.-S. Kam and K.-H. Lim in Chapter 1 of Volume 66, published in 2008. However over the past five years, these alkaloids have attracted considerable attention of many research groups which has culminated in more than 20 total syntheses. Thus, an update of this area was required. Pfaffenbach and Gaich present an outstanding compilation which is considering publications till the end of May 2016. Retrospectively, their review complements Volume 76 which has been a thematic volume focusing on indole alkaloids. Lachlan M. Blair, Matthew B. Calvert, and Jonathan Sperry describe in Chapter 2 the isolation, biological activity, and total syntheses of flavoalkaloids, isoflavoalkaloids, and neoflavoalkaloids. Thus, this article represents an update of one topic of a previous review in our series by Peter J. Houghton on “Chromone Alkaloids” which appeared as Chapter 3 in Volume 31 (published in 1987) and covered both flavonoid and chromone alkaloids. In Chapter 3, Thomas Lindel discusses the variety of structures, biogenesis, and recent progress in total synthesis of pyrrole–imidazole alkaloids as well as their biological activities. This class of alkaloids has been covered for the first time in our series, and I am very glad that one of the protagonists in the field has provided an excellent overview. Hans-Joachim Kn€ olker Technische Universit€at Dresden, Dresden, Germany

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CHAPTER ONE

The Rhazinilam-LeuconoxineMersicarpine Triad of Monoterpenoid Indole Alkaloids Magnus Pfaffenbach and Tanja Gaich1 University of Konstanz, Konstanz, Germany 1 Corresponding author: E-mail: [email protected]

Contents 1. 2. 3. 4.

Introduction Occurrence Biosynthesis Formal and Total Syntheses 4.1 Rhazinilams 4.2 Leuconoxines 4.3 Mersicarpine 4.4 Spectroscopy 5. Pharmacology 5.1 Natural Products 5.2 Rhazinilam Analogs 6. Perspectives References

2 9 9 16 16 39 50 59 66 66 75 78 79

Abstract The rhazinilam-leuconoxine-mersicarpine triad of monoterpenoid indole alkaloids comprises a variety of diverse natural products with unprecedented structural features and intriguing biological activities. This subfamily of Aspidosperma alkaloids has drawn significant attention from the synthetic community which is reflected by over 20 syntheses within the last 5 years. Numerous transformations and strategies have been developed to access the different key structural motifs such as the tetrahydroindolizine, a,b-unsaturated carbinolamide, diaza[5.5.6.6]fenestrane, and tetrahydro-2H-azepine frameworks. The present contribution comprehensively covers the abundant literature on this natural product class up to the end of May 2016, providing a detailed account of the formal and total syntheses which is complemented by an overview of their biosynthesis, spectroscopy, and pharmacology.

The Alkaloids, Volume 77 ISSN 1099-4831 http://dx.doi.org/10.1016/bs.alkal.2016.07.001

© 2017 Elsevier Inc. All rights reserved.

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2

Magnus Pfaffenbach and Tanja Gaich

1. INTRODUCTION The monoterpenoid indole alkaloids represent one of the largest classes of natural products featuring a diverse array of intriguing structural frameworks and interesting biological properties.1 Most of the over 2000 known members and their more than 42 skeletons have been isolated from the Apocynaceae, Loganiaceae, and Rubiaceae plant families.2 According to their carbon skeleton and biogenetic branch points, they are classified into five major subgroups: Aspidosperma, Ajmalan, Corynanthe, Iboga, and Quinoline alkaloids.3 Various pharmacologically valuable compounds have been identified which exhibit a broad range of biological activities including anticancer, antimalarial, and antiarrhythmic properties.4 Due to their combination of highly complex skeletons and promising biological activities, many of these alkaloids have gained prominence as attractive platforms for demonstrating the utility of novel synthetic methodologies and tactics. Among them, the rhazinilam-leuconoxine-mersicarpine triad of Aspidosperma5 alkaloids has garnered tremendous interest from the synthetic community which is reflected by over 20 syntheses within the last 5 years. ()-Rhazinilam (1) was first isolated in 1970 by Chatterjee et al.6 from Rhazya stricta Decaisne. Two years later, ()-1 has been identified7 as the previously isolated alkaloid Ld 82 from Melodinus australis.8 Over the decades, ()-rhazinilam (1) has also been found in various species of the Aspidosperma, Leuconotis, Kopsia, Vallesia, and Vinca genera (Table 1). The structure was unambiguously confirmed by X-ray analysis.9 ()-Rhazinilam (1) has been shown to be an artifact of plant extraction that arises from oxidative degradation of an Aspidosperma alkaloid precursor.7 As shown in Fig. 1, the rhazinilam subgroup is comprised of a variety of structural congeners. While ()-rhazinicine (2),10 ()-nor-rhazinicine (3),11 and 3oxo-14,15-dehydrorhazinilam12 (4) differ in either ring size or oxidation state of ring D, ()-rhazinal13 (5) and the ()-kopsiyunnanines C1eC314 (6e8) contain an additional carbon substitution at the pyrrole ring. Most of these tetracyclic compounds incorporate the unaltered tetrahydroindolizine ring system (highlighted in brown, Fig. 2). This structural element bears a quaternary carbon center, a conformationally restrictive heterobiaryl unit (phenyl-pyrrole), and a strained nine-membered ring lactam. Two natural products, namely ()-5,21-dihydrorhazinilam N-oxide11 (9) and 5,21dihydrorhazinilam (10),15 are devoid of the pyrrole moiety, the latter constituting a direct biosynthetic precursor of 1 (Scheme 2). ()-Rhazinilam (1)

Table 1 Rhazinilam-leuconoxine-mersicarpine alkaloids of plant origin MW Formula CAS registry number Compound name

C17H20N2O2

757967-34-3

()-Mersicarpine (16)

294.4

C19H22N2O

36193-36-9

()-Rhazinilam (1)

C18H18N2O2 C19H24N2O

1431863-99-8 109305-80-8

()-nor-rhazinicine (3) 5,21-Dihydrorhazinilam (10)

296.4 298.4

C19H24N2O C18H22N2O2

1432584-33-2 1895104-34-3

()-Leuconodine D (21) (þ)-Alstorisine A (26)

Alstonia rostrata Kopsia arborea Kopsia fruticosa Kopsia pauciflora Kopsia singapurensis Leuconotis griffithii Aspidosperma marcgravianum Aspidosperma quebrachoblanco K. arborea Kopsia jasminiflora K. pauciflora K. singapurensis Kopsia teoi Leuconotis eugenifolia L. griffithii Melodinus australis Melodinus henryi Rhazya stricta Decaisne Vinca major Vallesia glabra L. griffithii K. arborea K. singapurensis L. eugenifolia L. griffithii L. griffithii Alstonia scholaris

59 14,42 42 29 60 11 61 62 14,63 64 29 60,65,66 67e69 19 19 8 25,70 6 71 72 11 63 60,66 19 19 11 30 (Continued)

3

294.4 296.4

References The Rhazinilam-Leuconoxine-Mersicarpine Triad

284.4

Plant source(s)

Plant source(s)

References

306.4

C19H18N2O2

139955-87-6

A. quebracho-blanco

12

308.4

C19H20N2O2

197141-93-8

59 63 10,73 75

308.4

C19H20N2O2

1207530-25-3

(þ)-Melodinine E (17) (Formerly: epi-leuconolam)

310.4

C19H22N2O2

1514395-86-8

()-Leuconoxine (15)

312.4 312.4

C19H24N2O2 C19H24N2O2

1432584-34-3 1431864-00-4

59 19 12,19 25 59 27,31 63 73 46,76 29 60 26 24 11 11

322.4

C20H22N2O2

93710-27-1

()-Leuconodine E (22) ()-5,21-Dihydrorhazinilam N-oxide (9) ()-Rhazinal (5)

A. rostrata K. arborea Kopsia dasyrachis Rauvolfia Serpentina  R. stricta A. rostrata L. eugenifolia L. griffithii M. henryi A. rostrata A. scholaris K. arborea K. dasyrachis Kopsia griffithii K. pauciflora K. singapurensis K. teoi L. eugenifolia L. griffithii L. griffithii

324.4

C19H20N2O3

947251-84-5

(þ)-Leuconodine F (23)

324.4

C19H20N2O3

1431864-01-5

13,65 11 26 29 11

324.4

C20H24N2O2

1114474-90-6

()-3,14Dehydroleuconolam (14) ()-Kopsiyunnanine C3 (8)

K. singapurensis L. griffithii K. griffithii K. pauciflora L. griffithii K. arborea

14

4

Table 1 Rhazinilam-leuconoxine-mersicarpine alkaloids of plant origindcont'd MW Formula CAS registry number Compound name

3-Oxo-14,15dehydrorhazinilam (4) ()-Rhazinicine (2)

Magnus Pfaffenbach and Tanja Gaich

C19H22N2O3

93710-27-1

()-Leuconolam (11)

326.4 326.4

C19H22N2O3 C19H22N2O3

1432584-31-0 1236143-34-2

326.4 338.5 340.4

C19H22N2O3 C21H26N2O2 C20H24N2O3

1432584-32-1 1114474-87-1 109305-79-5

()-Leuconodine A (18) ()-Leuconodine B (19) (Scholarisine G) ()-Leuconodine C (20) ()-Kopsiyunnanine C1 (6) ()-21-O-methylleuconolam (12)

340.4

C20H24N2O3

160958-67-1

340.4

C20H24N2O3

926927-38-0

(þ)-N-methylleuconolam (13) (þ)-Arboloscine (24)

352.5 354.5

C22H28N2O2 C21H26N2O3

1114474-88-2 1636132-44-9

()-Kopsiyunnanine C2 (7) (þ)-Arboloscine A (25)

A. rostrata A. scholaris K. griffithii Kopsia hainanensis K. jasminiflora K. pauciflora K. singapurensis L. eugenifolia L. griffithii M. henryi L. griffithii A. scholaris L. griffithii L. griffithii K. arborea A. rostrata K. arborea L. eugenifolia L. griffithii R. stricta Decaisne

59 77,78 75,76 79 64 29 60,65 19,24 17,19 69 11 27 11 11 14 59 63 24 11 20

K. arborea L. griffithii K. arborea K. pauciflora

14,28 11 14 29

The Rhazinilam-Leuconoxine-Mersicarpine Triad

326.4

5

6

Magnus Pfaffenbach and Tanja Gaich

Figure 1 Members of the rhazinilam subgroup of Aspidosperma alkaloids.

Figure 2 Structural elements of ()-rhazinilam (1), ()-leuconolam (11),()-leuconoxine (15), and ()-mersicarpine (16).

has been identified as a unique mitotic spindle poison with high in vitro cytotoxic activity mimicking the effects of both, vinblastine and taxol.16 Encouraged by its excellent antimitotic properties, numerous synthetic transformations and strategies have been developed to access the target molecule (Section 4.1). Because of its lack of in vivo activity, a series of analogs that resemble the structure of rhazinilam have been prepared and investigated in regard of their activity on tubulin and various cancer cell lines (Section 5.2). ()-Leuconolam (11) was first isolated in 1984 by Goh et al.17 from Leuconotis griffithii. The structure and stereochemistry of this 2,7-seco

The Rhazinilam-Leuconoxine-Mersicarpine Triad

7

Aspidosperma alkaloid was unambiguously confirmed by X-ray analysis.18 The leuconolam derivatives including ()-21-O-methylleuconolam (12),19 (þ)-N-methylleuconolam (13),20 and ()-3,14-dehydroleuconolam11 (14) are characterized by their a,b-unsaturated carbinolamide subunit (highlighted in red, Fig. 2). To date, two total syntheses of 11 have been reported by Banwell et al.21 and Hoye.22 In 2014, X-ray analysis by Kam et al. revealed that the previously assigned epi-leuconolam is in fact (þ)-melodinine E (17).23 ()-Leuconoxine (15), first isolated by Abe and Yamauchi24 from Leuconotis eugenifolius, consists of a pentacyclic structure with three contiguous stereogenic centers including one that is quaternary and an aminal function. The natural product is also known as diazaspiroleuconolam and possesses a variety of structural congeners (Fig. 3) including (þ)-melodinine E (17), first isolated from Melodinus henryi in 2010,25 and the leuconodines AeF (18e 23), isolated from Kopsia griffithii in 2007,26 and L. griffithii in 2013.11 ()-Leuconodine B (19) has previously been isolated from Alstonia scholaris under the name of scholarisine G.27 While (þ)-arboloscine28 (24) and (þ)-arboloscine A29 (25) represent the only examples of secoleuconoxines, Ding and Luo recently reported the isolation of the first

Figure 3 Members of the leuconoxine subgroup and ()-mersicarpine (16).

8

Magnus Pfaffenbach and Tanja Gaich

nor-leuconoxine alkaloid, namely (þ)-alstorisine A (26), from A. scholaris.30 Biologically, ()-leuconoxine (15) stands out for its notable activity for inhibiting COX-2,31 the growth of human pancreatic cancer cell lines32 and, Mycobacterium tuberculosis,33 for which patents have recently been filed. Furthermore, ()-leuconodine E (22) displays moderate activity in reversing MDR in vincristine-resistant KB cells.11 The nondegraded leuconoxine derivatives share a common structural motif, a unique diaza[5.5.6.6]fenestrane skeleton (highlighted in blue, Fig. 2). Originally introduced by Georgian and Saltzman,34 the name fenestrane describes spirocompounds having bridges of carbon or hetero atoms that connect the a and a0 positions. All fenestrane structures have a central carbon atom which is shared with four rings.35 This motif is extremely rare among natural products (Fig. 4) and has for a long time been limited to terpenes including ()-laurenene (27),36 the penifulvins such as ()-penifulvin A (28),37 and ()-asperaculin A (29).38 Therefore, the leuconoxines represent the first alkaloid family containing a fenestrane skeleton. Although not consistent with the strict IUPAC nomenclature,39 santalin Y40 and isoschizogamine41 have also been described as fenestranes. The stereochemistry at the central fenestrane atom of ()-29 is not reported yet proposed to be consistent with that of the penifulvins due to their biosynthetic analogy. In 2004, ()-mersicarpine (16) was isolated from Kopsia fruticosa as well as Kopsia arborea.42 The natural product is characterized by a tetrahydro-2Hazepine ring system (highlighted in green, Fig. 2) incorporating a cyclic imine, a hemiaminal and a quaternary carbon center. Several formal and total syntheses have been accomplished since Kerr’s benchmark synthesis in 2008.43 The group of rhazinilam-leuconoxine-mersicarpine indole alkaloids has been reviewed in part in “The Alkaloids” series (2008, Chapter 1, subgroup of aspidospermine alkaloids).44 The natural products have also been the subject to several review articles.45 However, the number of known members

Figure 4 Natural products containing the fenestrane motif.

The Rhazinilam-Leuconoxine-Mersicarpine Triad

9

and reported syntheses thereof have grown remarkably in recent years so that the previous reports are relatively out-of-date. Therefore, the present contribution comprehensively covers the abundant literature up to the end of May 2016, providing a detailed account on the numerous formal and total syntheses which is complemented by an overview of their biosynthesis, spectroscopy, and pharmacology. Partial syntheses are not described in detail yet have been reported by Smith (31 / 1),46 Goh (11 / 12),15 Baudoin (11 / 15),47 Kam (11 / 15, 17, 18, 23),23 and Takayama (1 / 5e8).14 The organization of the chapter will be based on the alkaloid structure type along the lines of the progressing biosynthetic pathway (rhazinilam-leuconoxine-mersicarpine).

2. OCCURRENCE Members of the rhazinilam-leuconoxine-mersicarpine triad of alkaloids exclusively occur in the plant family Apocynaceae which consists of over 350 genera distributed among five subfamilies (Rauvolfioideae, Apocynoideae, Periplocoideae, Secamonoideae, and Asclepiadoideae).48 To date, these natural products have been found in the following genera: Alstonia, Aspidosperma, Leuconotis, Kopsia, Melodinus, Rhazya, Vallesia, and Vinca. The most often represented genera are Kopsia and Leuconotis. A detailed account of the distribution of rhazinilam-leuconoxine-mersicarpine indole alkaloids among different plant species is presented in order of increasing molecular weight in Table 1. The alkaloid structures with their melting points and [a]D values are presented in Table 2. The CAS registry numbers of individual compounds are indicated in both tables. The superscripts beside several of the natural products refer to alternative reports on melting points and optical rotation values.

3. BIOSYNTHESIS Nature’s biosynthetic machinery for the formation of complex, skeletally diverse monoterpenoid indole alkaloids can be divided into three stages: (1) fragment coupling, (2) cyclization, and (3) postcyclization.49 The first stage starts with the enzyme-catalyzed condensation of tryptamine and the iridoid glycoside secologanin, forming strictosidine in a PicteteSpengler type reaction. Deglycosylation, followed by primary cyclization and iminium ion reduction generates the Corynanthe alkaloid geissoschizine, which constitutes

N

10

Table 2 Rhazinilam-leuconoxine-mersicarpine alkaloid structures

N

N

O

N

OH H N

NH

NH

O

O

O

O a

(–)-Mersicarpine (16) [757967-34-3] Colorless oil42 [α]D –18 (c 0.28, CHCl3)42

NH

(–)-Rhazinilam (1) [36193-36-9] Mp. 214–215 °C (MeOH)9 [α]D24 –421 (c 0.97, CHCl3)8

(–)-Nor-rhazinicine (3) [1431863-99-8] Mp. 190–192 °C (CH2Cl2-hexanes)11 [α]D25 –285 (c 0.13, CHCl3)11

5,21-Dihydrorhazinilam (10) [109305-80-8] Mp. n.r. [α]D n.r.

O

O H

H N

N

N

N

HO

O (–)-Leuconodine D (21) [1432584-33-2] Mp. 100–105 °C (CH2Cl2-MeOH)11 [α]D25 –37 (c 0.10, CHCl3)11

N O (+)-Alstorisine A (26) [1895104-34-3] Amorphous30 [α]D25 +87 (c 0.1, MeOH)30

NH O 3-Oxo-14,15-dehydrorhazinilam (4) [139955-87-6] Amorphous12 [α]D n.r.

NH O (–)-Rhazinicineb (2) [197141-93-8] Light yellow oil10 [α]D –208 (c 0.13, CHCl3)10

Magnus Pfaffenbach and Tanja Gaich

N

The Rhazinilam-Leuconoxine-Mersicarpine Triad

(Continued)

11

Magnus Pfaffenbach and Tanja Gaich

n.r., not reported; a) Mp. 214e216 C (ether),62 Mp. 204e206 C,19 [a]D28 432 (c 1.25, MeOH),62 [a]D 147 (c 0.15, CHCl3)19; b) Mp. 201e204 C,75 [a]D 247 (c 0.3, CHCl3)75; c) Mp. 164e168 C (CH2Cl2-hexanes),23 [a]D25 þ271 (c 0.10, CHCl3)23; d) Mp. 210e215 C (MeOH),23 [a]D25 86 (c 0.7, CHCl3)23; e) Mp. 246e250 C (MeOH),23 [a]D25 þ94 (c 0.05, CHCl3)23; f ) Mp. 262e267 C,24 Mp. 178e180 C,23 [a]D 303 (c 0.8, CHCl3),23 [a]D 28 (c 0.70, MeOH)19; g) Mp. 134e136 C (EtOH),23 [a]D25 18 (c 0.03, CHCl3)23; h) Mp. 198e200 C (CH2Cl2-MeOH),11 [a]D25 48 (c 0.14, CHCl3)11; i) Mp. 214e218 C (MeOH),23 Mp. 140e150 C,24 [a]D25 240 (c 0.6, CHCl3).23

12

Table 2 Rhazinilam-leuconoxine-mersicarpine alkaloid structuresdcont'd

The Rhazinilam-Leuconoxine-Mersicarpine Triad

13

the key intermediate in the formation of the structurally more complex Aspidosperma, Iboga, and Strychnos alkaloids.50 Among those, the Aspidosperma subfamily bearing carbon framework A is proposed to be the biosynthetic origin for the rhazinilam-leuconoxine-mersicarpine group of alkaloids. A plausible skeletal rearrangement is depicted in Scheme 1. The biogenetic numbering of Le Men and Taylor51 is used throughout this chapter. Cleavage of the C2eC7 bond of A generates the nine-membered ring framework B which is characteristic of the rhazinilam-type natural products 1e14. Transannular cyclization with bond formation between N1 and C21 produces skeleton C, which is the diazafenestrane core structure of leuconoxines 15 and 17e26. Ring contraction/enlargement with N4 migration from C21 to C7 affords compound D, bearing resemblance to the 6-5-7 ring system and b-lactam unit of the chartellamides.52 Fragmentation of the fourmembered ring of D with loss of a two carbon atom fragment delivers the carbon skeleton E of ()-mersicarpine (16).42 Alternatively, C7eC16 connection in structure B leads to meloscine scaffold F, which is also accessible from architecture A by C7 migration from C2 to C16 (ring enlargement of the indole ring). Based on the isolation of both natural products along with many intermediates or their close derivatives from the same plant species, ()-rhazinilam (1) is postulated to be biosynthetically derived from (þ)-vincadifformine (30). As shown in Scheme 2, demethoxycarbonylation of (þ)-30 leads to (þ)-1,2-dehydroaspidospermidine (31) after tautomerization.53 Cleavage of the C7eC21 bond in the presence of acid forms iminium ion 32 which constitutes the core structure of

Scheme 1 Biosynthetic proposal for the rhazinilam-leuconoxine-mersicarpine group of alkaloids.

14

Scheme 2 Biosynthetic (þ)-vincadifformine (30).

Magnus Pfaffenbach and Tanja Gaich

cyclization/postcyclization

pathways

starting

from

quebrachamine-type alkaloids. Dihydroxylation of the indole double bond generates intermediate 33 which upon cleavage of the C2eC7 bond leads to the characteristic nine-membered lactam of the rhazinilams. Dehydration of 34 affords the natural product 5,21-dihydrorhazinilam (10) which upon oxidation to the pyrrole heterocycle forms ()-rhazinilam (1). The biosynthetic sequence is supported by Smith’s partial synthesis of ()-1 (30% yield) resulting from treatment of (þ)-31 with mCPBA, followed by aqueous FeSO4.46 In addition, 10 was found to be converted into ()-1 on prolonged exposure to air.15 In contrast to ()-1, the formation of ()-rhazinal (5) is proposed to arise from a one-carbon bridge (C22) between C5 and C16.53 The hypothesis is in analogy with the kopsan alkaloids that bear the same bridge between C6 and C16.54 Cleavage of the bridge by hydride reduction leads to the formyl oxidation level with overall transposition of C22 from C16 to C5. Construction of the typical nine-membered ring lactam in ()-rhazinal (5) is analogous to the steps described previously. Reduction of ()-5 gives access to the kopsiyunnanines C1eC3 (6e8) which has been demonstrated in Takayama’s semisynthesis.14 Moving forward within the cyclization events, ()-leuconolam (11) is formed by further oxidation of ()-rhazinilam (1). Transannular cyclization

The Rhazinilam-Leuconoxine-Mersicarpine Triad

15

of the N-acyliminium ion intermediate 35 derived from ()-11 is proposed to generate (þ)-melodinine E (17). This natural product constitutes the central biosynthetic precursor of the leuconoxine subgroup which occurs in various different oxidation states (Fig. 3). In addition, oxidative rearrangement of 17 with cleavage of a two carbon atom fragment yields ()-mersicarpine (16). Overall, the biosynthetic downstream diversification for this triad of indole alkaloids can be summarized in the following order: strictosidine / geissoschizine / preakuammicine / secodines / vincadifformine / rhazinilam (rhazinal) / leuconolam/melodinine E / leuconoxines / mersicarpine. The biosynthetic relationship described previously is supported by early reports on the formation of the leuconoxine skeleton either by oxidative rearrangement of ()-vincadifformine (30) or by treatment of ()-leuconolam (11) with acid and bromine. In 1974, ()-vincadifformine (30) and its derivatives were subjected to a series of oxidation events to prove the hypothesis by Wenkert et al.55 on the biosynthetic link between ()-30 and (þ)-vincamine (38). Interestingly, treatment of the N4-oxide 36 of ()-1,2-dehydroaspidospermidine (31) with TFAA under PolonovskiPotier conditions afforded the optical antipode of ()-leuconodine D (21)dalmost four decades before its actual isolation 56 (Scheme 3). Furthermore, the leuconoxine-type compound (þ)-37 was formed (yield not reported) upon treatment of ()-vincadifformine (30) with mCPBA in refluxing benzene.57 The stereochemistry at C7 and C21 has not been reported for structures (þ)-21 and (þ)-37. On the other hand, Goh et al.15,19 reported the formation of 6chloroleuconoxine 39 (initially named 6-chlorodiazaspiroleuconolam) as a

Scheme 3 First descriptions of the leuconoxine skeleton in 1974.

16

Magnus Pfaffenbach and Tanja Gaich

Scheme 4 Selected transformations of ()-leuconolam (11).

mixture of epimers by treatment of ()-leuconolam (11) with concentrated HCl (Scheme 4). The leuconoxine derivatives were presumably formed by transannular cyclization to the iminium ion derived from ()-11, followed by a nonstereospecific, anti-Markownikoff addition of HCl to the C6eC7 double bond. A similar ring closure/addition reaction was caused by treatment of ()-11 with bromine, producing the corresponding ()-6,7dibromoleuconoxine (40) in high yield.19,23 The exclusive formation of the cis-dibromo addition product might be a consequence of acid-catalyzed epimerization of the initially formed trans-adduct or from cis/trans mixtures formed via the intermediacy of the b-dibromocarbocation or the tribromide adduct.23,58 Interestingly, reaction of ()-11 with KOH in methanol was reported to result in the formation of meloscine derivative ()-41 as the sole product, provoking an alternative pathway for the biosynthesis of the Melodinus alkaloids.19 Compound ()-41 is likely formed by deprotonation at C16, followed by Michael addition to the C6eC7 double bond. In 2014, Kam et al. reinvestigated this transformation to verify the stereochemical assignments. After examining various bases, they found ()-41 to be produced in a maximum of 12% yield, accompanied by 3% of its C16 epimer and 20% of unreacted starting material. Both structures and their relative configurations were unambiguously confirmed by X-ray analyses.23

4. FORMAL AND TOTAL SYNTHESES 4.1 Rhazinilams In 1973, Smith et al. reported their landmark synthesis of ()-rhazinilam (rac-1) in 14 steps (10 steps longest linear sequence) and 14% overall yielddalmost three decades before the next synthetic endeavor.46 The key steps are comprised of a pyrrole N-alkylation with subsequent Lewis acid-mediated cyclization establishing the entire carbon skeleton in the first two steps (Scheme 5). The synthesis was straightforward

The Rhazinilam-Leuconoxine-Mersicarpine Triad

17

Scheme 5 First total synthesis of ()-rhazinilam (rac-1) by Smith in 1973.

and concise starting from building blocks 42 (4 steps, 13% yield from 2,2dimethoxyethylamine and 2-nitrophenylpyruvic acid) and 43 (4 steps, 22% yield from diethyl 4-ketopimelate). The synthesis commenced with the N-alkylation of sodium salt 42 with lactone 43 which on cyclization with anhydrous aluminum chloride and reduction afforded carboxylic acid 45 in 39% yield over three steps. Macrolactamization using dicyclohexylcarbodiimide generated 46 which upon basic saponification gave acid 47 in high yield. Finally, decarboxylation under low pressure and high temperature smoothly afforded the natural product ()-rhazinilam (rac-1) in 88% yield from 46. In 2000, the Sames group achieved the second total synthesis of ()-rhazinilam (rac-1) (18 steps, 5% overall yield) featuring a platinum complex-directed CeH bond activation/dehydrogenation reaction (Scheme 6).80 Two years later, the endgame was significantly shortened (13 steps, 9% overall yield) and the synthesis rendered enantioselective through the use of a chiral auxiliary.81 After heating the readily available cyclic imine 48 with o-nitrocinnamyl bromide (49) in the presence of silver carbonate, the initially formed iminium salt underwent cyclization to pyrrole 50 in 63% yield over two steps. The sensitive pyrrole moiety was temporarily protected by installation of a methyl carboxylate group, followed by reduction of the nitro group affording aniline 51 in 88% yield. Differentiation of the two enantiotopic ethyl groups was achieved by Schiff base formation between 51 and various chiral oxazoline ligands of type 52 (R ¼ Ph, c-Hex, iPr). Complexation with platinum through the reaction with stoichiometric amounts of

18 Magnus Pfaffenbach and Tanja Gaich

Scheme 6 Total synthesis of ()-rhazinilam (1) by Sames in 2002.

The Rhazinilam-Leuconoxine-Mersicarpine Triad

19

[Me2Pt(m-SMe2)]2 furnished dimethyl platinum complex 53 in high yields. Treatment of 53 with triflic acid led to spontaneous liberation of methane yielding a diastereomeric mixture (major isomer shown) of complex 54. Due to its unusual coordinative bonding between platinum and the pyrrole moiety, the heterobiaryl bond “a” was bent out of the plane rendering 54 distorted and labile (Scheme 6). Heating in 2,2,2-trifluoroethanol initiated the selective dehydrogenation under concomitant loss of a second molecule of methane forming alkenehydridoplatinum(II) complex 55. Demetalation using potassium cyanide afforded the corresponding Schiff base diastereoisomers (56 ¼ major isomer) in a maximum of 42% yield (R ¼ c-Hex, ds 4.4:1). After separation by HPLC and hydrolysis with hydroxylamine, a Pd-catalyzed hydroxycarboxylation of the alkene with in situ macrolactamization and subsequent ester saponification and decarboxylation furnished ()-rhazinilam (1). Mechanistically, a computational study by Ess et al. revealed that the key platinum-mediated CeH bond activation/functionalization step starts with activation of the primary CeH bond rather than the secondary. The diastereoselectivity was found to be induced by weak stabilizing interactions between the R group of the chiral oxazolinyl ligand and the carboxylate group.82 In 2001, the Magnus group accomplished the total synthesis of ()-rhazinilam (rac-1) in nine steps and 8% overall yield from commercially available d-valerolactam (57).83 Under retention of the oxidation state, the tetrahydroindolizine skeleton was constructed by elegant conversion of a lactam to a pyrrole via phenyl imidothioate 59 (Scheme 7). After stepwise alkylation of d-valerolactam (57), 2-piperidone 58 was converted into phenyl imidothioate 59 using phosphorus pentachloride and thiophenol. Various imino ethers derived from 58 proved to be

Scheme 7 Total synthesis of ()-rhazinilam (rac-1) by Magnus in 2001.

20

Magnus Pfaffenbach and Tanja Gaich

unsuitable substrates for the subsequent annulation step. Heating 59 with 2nitrocinnamyl bromide (49) followed by treatment with DBU initiated Nalkylation and pyrrole formation affording the desired tetrahydroindolizine 60 in 32% yield over four steps. The synthesis was completed by sequential oxidation of the allyl double bond to carboxylic acid 62, nitro reduction, and final macrolactamization forming ()-rhazinilam (rac-1) in good yields. In 2005, the Trauner group reported an 11-step (2% overall yield) synthesis of ()-rhazinilam (rac-1) by direct Pd-catalyzed intramolecular biaryl coupling (Scheme 8).84 The synthesis commenced with nucleophilic displacement of the tosyl group of Smith’s previously employed g-lactone 43 by sodium salt of 2carbomethoxy pyrrole (63), affording 64 in high yields. Intramolecular FriedeleCrafts alkylation using aluminum chloride formed carboxylic acid 65 in 55% yield harboring the tetrahydroindolizine moiety. Mukaiyama coupling with 2-iodoaniline and subsequent MOM protection of 66 furnished the desired key step precursor. After extensive screening, the intramolecular coupling was accomplished in 47% yield by heating the substrate with 10 mol% of DavePhos (67) and Pd(OAc)2 in the presence of K2CO3 as a base. Mechanistically, the strained nine-membered ring lactam 69 was formed by intramolecular nucleophilic attack of the pyrrole moiety onto the palladium center of species 68, followed by deprotonation and reductive elimination. Deprotection, subsequent saponification and decarboxylation generated ()-rhazinilam (rac-1) in two more steps. In 2006, Nelson et al. finished the total synthesis of ()-rhazinilam (1) in 13 steps (22% overall yield) by asymmetric Au(I)-catalyzed pyrrole addition

Scheme 8 Total synthesis of ()-rhazinilam (rac-1) by Trauner in 2005.

The Rhazinilam-Leuconoxine-Mersicarpine Triad

21

to an enantioenriched trisubstituted allene (Scheme 9).85 In this process, the axial chirality of the allene was efficiently translated to the incipient allcarbon quaternary center forming the tetrahydroindolizine core. The synthesis started with the O-trimethylsilylquinine (TMSQn)catalyzed cyclocondensation between propionyl chloride and 2-pentynal (70) affording b-lacton 71 in 72% yield and 99% ee. Nucleophilic attack of Grignard reagent 72 opened the four-membered ring in a copper-catalyzed SN20 reaction forming chiral allene 73 in high yields. After esterification, the use of 5 mol% of Ph3P$AuOTf at room temperature proved to be the optimal catalyst to trigger the desired pyrrole-allene addition generating tetrahydroindolizine 74 in excellent yields and virtually complete translation of chirality (94% de). The correct tether for lactamization was established in a sequence of regioselective carboxylation, oxidative olefin cleavage, olefination, and hydrogenation which formed ester 75 in good yields. Upon pyrrole iodination, Suzuki-Miyaura cross coupling of iodide 76 with a Boc-protected aminophenylboronate afforded the 3-aryl pyrrole 77 in 77% yield over two steps using Buchwald’s SPhos ligand. After chemoselective ester saponification and aniline deprotection, HATU-mediated lactamization yielded the corresponding nine-membered ring in 74% yield. Decarboxylation provided synthetic ()-rhazinilam (1) in 96% yield. In 2010, a second example of axial-to-central chirality transfer was realized by Gu and Zakarian86 in their total synthesis of ()-1 in 17 steps (13 steps longest linear sequence) and 10% overall yield. Conceptually different from every other synthesis, a late-stage Pd-catalyzed transannular Heck cyclization simultaneously formed both the quaternary carbon center and the nine-membered lactam (Scheme 10). Due to atrop chirality within the halogenated 13-membered macrocycles 82 and 83, both natural and unnatural rhazinilam have been prepared from simple, optically inactive starting materials. The synthesis started with selective halogenation of C2 of the pyrrole ring using pyridinium tribromide and trifluoroacetic acid to afford 79 in 87% yield. After N-alkylation with iodide 80, halogen exchange of the pyrrole bromide formed the requisite lactamization precursor 81 in high yields. Upon Mukaiyama coupling, the macro iodolactams were found to exist as a mixture of axial enantiomers (Ra)-82 and (Sa)-83 which can be separated by preparative chiral HPLC. Treatment of (Ra)-82 with 10 mol % of Pd(PPh3)4 and triethylamine at 100 C initiated a highly enantiospecific transannular cyclization forming the desired alkene 84 in 60% yield. Hydrogenation delivered the natural ()-rhazinilam (1) in quantitative yield.

22 Magnus Pfaffenbach and Tanja Gaich

Scheme 9 Total synthesis of ()-rhazinilam (1) by Nelson in 2006.

The Rhazinilam-Leuconoxine-Mersicarpine Triad

Scheme 10 Total synthesis of ()-rhazinilam (1) by Gu and Zakarian in 2010.

23

24

Magnus Pfaffenbach and Tanja Gaich

In 2012, Gaunt et al. reported the first total synthesis of ()-kopsiyunnanine C3 (rac-8) along with ()-rhazinilam (rac-1) in 11-step longest linear sequence (13e14% overall yield) by two selective metal-catalyzed CeH bond functionalizations of a simple pyrrole derivative (Scheme 11).87 Furthermore, rac-1 was also converted to aspidospermidine in 47% yield over three steps by a reductive transannular cyclization process thereby reversing the biosynthetic oxidative degradation pathway (not shown). The synthesis began with the selective Ir-catalyzed CeH borylation of pyrrole 85 which was followed by Suzuki coupling reaction with 86 forming the heterobiaryl fragment 87 in one flask and 63% yield. NAlkylation with iodide 88 furnished the desired precursor for Pd-catalyzed intramolecular CeH alkenylation reaction. After extensive optimization, treatment of 89 with 10 mol% Pd(OAc)2, 20 mol% NaOtBu, and 10 mol % DMF in pivalic acid at 110 C under a balloon of oxygen furnished olefin 90 in 60% yield. Hydrogenation, removal of the TSE ester, and macrolactamization provided Smith’s intermediate (46) in 70% yield over three steps. While standard saponification/decarboxylation finished ()-rhazinilam (rac-1), a DIBAL-H reduction completed the first synthesis of ()-kopsiyunnanine C3 (rac-8). In 2013, Tokuyama accomplished the first asymmetric total synthesis of ()-rhazinicine (2) along with ()-rhazinilam (1) in 12e14 steps and 9e 11% overall yield.88 The key tetrahydroindolizine motif was efficiently constructed by an Au-catalyzed cascade cyclization of a linear ynamide substrate (Scheme 12).

Scheme 11 Total synthesis of ()-rhazinilam (rac-1) and ()-kopsiyunnanine C3 (rac-8) by Gaunt in 2012.

The Rhazinilam-Leuconoxine-Mersicarpine Triad

Scheme 12 Total synthesis of ()-rhazinilam (1) and ()-rhazinicine (2) by Tokuyama in 2013.

25

26

Magnus Pfaffenbach and Tanja Gaich

Ketone 91, which was obtained using d’Angelo’s method for diastereoselective Michael reaction of 2-ethylcyclohexanone via the chiral enamine intermediate derived from (S)-1-phenylethylamine, was converted into epoxy ketone 92 in a three-step sequence. With the requisite quaternary stereocenter in hands, Eschenmoser-Tanabe fragmentation of the corresponding semicarbazone and subsequent Pinnick oxidation afforded carboxylic acid 93. Condensation with aminoacetaldehyde diisopropyl acetal and subsequent Sonogashira coupling with 2-bromoiodobenzene furnished the key ynamide 94. Extensive condition screening revealed that microwave irradiation (1 min  40 intervals) in the presence of 30 mol% [Au(PPh3)]NTf2, catalytic amounts of KHSO4 in isopropanol/ 1,4-dioxane provided the desired tetrahydroindolizinone 95 in 65% yield. After stepwise reduction of the N-acyl functionality using Luche conditions and sodium cyanoborohydride, aryl bromide 96 was converted into aniline 97 via a Cu-mediated reaction. Finally, a sequence of saponification and lactamization furnished ()-1. Applying the same conditions toward the completion of ()-rhazinicine (2) proved troublesome because of the highly reactive nature of the N-acylpyrrole functionality. Therefore, 95 was first converted into the corresponding carboxylic acid using TMSI and then into amide 98 by treating the CDI-activated acid with ammonium hydroxide. The crucial nine-membered lactam ring was formed via Cu-mediated intramolecular amidation generating ()-2 in 48% yield over three steps. In 2014, Lin and Yao developed a solvent-controlled switchable C2 or C5 alkenylation of 3-carboxy-4-aryl-pyrroles (Scheme 13).89 Their novel method was showcased in the total synthesis of ()-rhazinilam (rac-1) in 13 steps and 9% overall yield.

Scheme 13 Total synthesis of ()-rhazinilam (rac-1) by Lin and Yao in 2014.

The Rhazinilam-Leuconoxine-Mersicarpine Triad

27

The synthesis commenced with a van Leusen reaction between methyl 3(2-nitrophenyl)acrylate (99) and toluenesulfonylmethyl isocyanide forming 3,4-disubstituted pyrrole 100. After N-alkylation with known iodide 80, the Pd-catalyzed intramolecular oxidative Heck reaction selectively took place at the C5 position (C5:C2 ¼ 12:1) of the pyrrole heterocycle thus forming ester 102 in 56% yield. While DMSO led to the C5 alkenylation products, toluene favored the selective C2 alkenylations. The C3 carboxylate group caused the formation of two separable diastereoisomers of 102 in the ratio of 1.75:1. Nevertheless, the natural product was accessed through the same sequential reactions, since the biaryl axis is able to rotate after decarboxylation. Thus, hydrogenation of the double bond in 102 using Wilkinson’s catalyst and subsequent decarboxylation with phosphoric acid formed Magnus intermediate (62). Final hydrogenation of 62 and EDCI/DMAPmediated macrolactamization completed the synthesis of ()-rhazinilam (rac-1). In 2014, the Zhu group reported the total synthesis of ()-rhazinilam (1) (13 steps, 19% overall yield) via phosphoric acidecatalyzed desymmetrization of a bicyclic bislactone bearing the all-carbon stereogenic center (Scheme 14).90 Following the approach of Sames, a formal [3 þ 2] cycloaddition between o-nitrocinnamyl bromide (49) and cyclic imine 107 furnished the tetrahydroindolizine core. The synthesis commenced with conversion of dimethyl 4-ethyl-4-formylpimelate (readily available from reaction of butyraldehyde, pyrrolidine, and methyl acrylate) into the corresponding bislactone 103. Desymmetrization of 103 was best achieved using 10 mol% of a chiral imidodiphosphoric acid (derived from (S)-BINOL) and methanol (two equiv.) at room temperature which afforded monoacid 104 in 95% yield and excellent enantioselectivity. The aldehyde moiety of compound 104 was protected as 1,3-dithiolane. Then, the methyl ester was reduced to the corresponding alcohol with lithium borohydride. Subsequent esterification of the remaining carboxylic acid afforded 105 in 90% yield. After transforming the primary alcohol into the azide and dithiolane deprotection (IBX, TBAB, AcOH, DMSO/H2O), Staudinger reaction formed imine 106 in 50% yield. Heating of 106 with 49 initially gave the corresponding imminium salt which upon further heating in the presence of freshly prepared Ag2CO3 (two equiv.) furnished 107 in 60% overall yield. Standard hydrogenation of the nitro group, subsequent saponification using KOH, and lactamization provided ()-1 in 80% yield. In 2015, Tokuyama et al. reported their second total synthesis of ()-1 in 14 steps and 7% overall yield by a chiral pool strategy (Scheme 15).91 The

28 Magnus Pfaffenbach and Tanja Gaich

Scheme 14 Total synthesis of ()-rhazinilam (1) by Zhu in 2014.

The Rhazinilam-Leuconoxine-Mersicarpine Triad

29

Scheme 15 Total synthesis of ()-rhazinilam (1) by Tokuyama in 2015.

central tetrahydroindolizine skeleton was constructed by 1,3-dipolar cycloaddition between a chiral m€ unchnone intermediate and (2-nitrophenyl) acetylene. Known methyl pipecolate 108 bearing a chiral quaternary center was subjected to N-formylation and subsequent chemoselective ester hydrolysis which formed compound 109 in 81% yield. Refluxing 109 in acetic anhydride initiated the formation of m€ unchnone intermediate 111. The 1,3-dipolar cycloaddition with (2-nitrophenyl)acetylene (110) furnished tetrahydroindolizine 112 in excellent yields. After elongating the side chain by a sequence of ester reduction, oxidation to the corresponding aldehyde, and HWE olefination, the total synthesis of ()-1 was finished by standard end game. In the same year, Nakao et al. reported the formal synthesis of ()-rhazinilam (rac-1) via 1,3-arylcyanation by cooperative Ni/Al catalysis in 13 steps and 6% overall yield (Scheme 16).92

Scheme 16 Formal synthesis of ()-rhazinilam (rac-1) by Nakao in 2015.

30

Magnus Pfaffenbach and Tanja Gaich

The synthesis began with the conversion of aldehyde 114 into cyanide 115 via dehydration of the corresponding oxime. The requisite precursor 117 for intramolecular 1,3-heteroarylcyanation was formed by N-alkylation with known tosylate 116. Heating 117 in the presence of 5 mol% Ni(cod)2, 15 mol% P(4-MeO-C6H4)3, and 10 mol% AlMe2Cl afforded the desired tetrahydroindolizine moiety in 81% yield. The catalytic cycle for this reaction is proposed to involve the secondary alkylnickel intermediate 118 which is formed by nickel insertion into the CeCN bond, followed by carbometalation of the double bond. Intermediate 118 is proposed to undergo b-hydride elimination, followed by reinsertion into the resulting double bond to form a primary alkylnickel species. Subsequent reductive elimination formed 119, which was transformed to Nelson’s intermediate (75) by nitrile saponification and esterification. In 2016, Zhu et al. reported the divergent total synthesis of ()-1 (Scheme 17) together with (þ)-23 and ()-236 (Scheme 37) in 12e14 steps and 12e16% overall yield starting from known b-ketoester 120.93 Heteroannulation of tetrahydropyridine 124 with either bromoacetaldehyde or oxalyl chloride paved the way to the three skeletally different natural products. Following Stoltz’ method for Pd-catalyzed asymmetric decarboxylative allylation, 120 was transformed into (S)-2-allyl-2-ethylcyclopentan-1-one in 87% yield with 86% ee. A sequence of hydroboration oxidation and TBS protection afforded ketone 121. After conversion into the corresponding vinyl triflate, decarboxylative coupling (52%) with potassium carboxylate 122 generated 123 upon deprotection, mesylation, and azide formation. Ozonolysis of cyclopentene 123 is followed by one-pot Staudinger reduction/cyclization providing tetrahydropyridine 124. Stirring an acetonitrile solution of imine 124 and bromoacetaldehyde (125) at 70 C

Scheme 17 Total synthesis of ()-rhazinilam (1) by Zhu in 2016.

The Rhazinilam-Leuconoxine-Mersicarpine Triad

31

in the presence of a weak base (NaHCO3) triggered the desired heteroannulation. Tetrahydroindolizine 108 was formed in 76% yield from 123, presumably via initial N-alkylation to give enamine 126, followed by cyclization, dehydration, and tautomerization. Compound 108 was transformed into ()-rhazinilam (1) in 80% yield by their previously reported reduction/ hydrolysis/macrolactamization sequence. An overview on the racemic syntheses of ()-rhazinilam is given in Scheme 18, and on the asymmetric syntheses of ()-rhazinilam is given in Scheme 19. In 2003, Banwell et al.94 published the first total synthesis of ()-rhazinal (rac-5) in 13 steps and 7% overall yield from the potassium salt of pyrrole 127 and g-butyrolactone (128). The use of an intramolecular Michael addition of the pyrrole C2 position to an N-tethered acrylate furnished the key tetrahydroindolizine structural motif (Scheme 20). Without prolongation of the tether of intermediate 131, the B-nor-rhazinal congener was formed. The synthesis set out with N-alkylation of the potassium salt of pyrrole (127) with lactone 128. Subsequent Weinreb amide formation and treatment with ethylmagnesium bromide generated ketone 129 which was subjected to HWE olefination forming the desired unsaturated ester 130 in four steps from commercial materials. The acrylate geometry proved to be inconsequential for the subsequent AlCl3-mediated (five equiv., rt) intramolecular Michael

Scheme 18 Overview of the synthetic efforts toward ()-rhazinilam (rac-1).

32

Magnus Pfaffenbach and Tanja Gaich

Scheme 19 Overview of the synthetic efforts toward ()-rhazinilam (1).

addition affording ester 131 in high yield. A three-step sequence including reduction, mesylation of the primary alcohol, and addition of cyanide transformed 131 to cyanide 132. Hydrolysis, VilsmeiereHaack formylation, and subsequent regioselective iodination in the presence of Ag(OCOCF3) afforded iodide 133 in excellent yields. Suzuki-Miyaura cross coupling with the commercially available 2-aminophenylboronic acid and subsequent ester hydrolysis and macrolactamization gave ()-rhazinal (rac-5).

Scheme 20 First total synthesis of ()-rhazinal (rac-5) by Banwell in 2003.

The Rhazinilam-Leuconoxine-Mersicarpine Triad

33

Scheme 21 Total synthesis of ()-rhazinal (rac-5) by Trauner in 2009.

In 2009, the Trauner group published an extension of their Pd-catalyzed direct coupling strategy resulting in the total synthesis of ()-rhazinal (rac-5) in 14 steps and 1% overall yield (Scheme 21).95 The tetrahydroindolizidine core of the natural product was formed by an oxidative Heck coupling. The synthesis commenced with the nucleophilic substitution of tosylate 134 with the potassium salt of pyrrole (127) forming the N-alkylated pyrrole 135 in 67% yield. The key oxidative Heck cyclization was realized by using 10 mol% Pd(OAc)2 in the presence of a mixed solvent system (AcOH/ DMSO) and tert-butyl hydroperoxide generating the corresponding tetrahydroindolizine in 69% yield. Formylation, followed by chemoselective reduction using Crabtree’s catalyst formed ester 136 in high yields. A sequence of saponification with lithium hydroxide, coupling of the resulting acid with 2-iodoaniline, and MOM protection of the amide furnished the desired coupling precursor 137 in moderate yield. Applying the conditions previously optimized in the rhazinilam synthesis [Pd(OAc)2, DavePhos, K2CO3, heating] triggered the Pd-catalyzed coupling between the pyrrole and iodoamide moieties affording nine-membered lactam 138 in 43% yield. Deprotection with a large excess of boron trichloride at low temperatures gave ()-rhazinal (rac-5) in 45% yield. In 2011, Miranda et al. reported the formal synthesis of ()-rhazinal (rac-5) in seven steps and 4% overall yield) by a tandem radical additioncyclization process (Scheme 22).96

Scheme 22 Formal synthesis of ()-rhazinal (rac-5) by Miranda in 2011.

34

Magnus Pfaffenbach and Tanja Gaich

Commercially available 2-formylpyrrole (139) was first N-alkylated with mesylate 140 to form pyrrole 141 in 89% yield. Under Zard’s conditions (DCE, reflux), dilauroyl peroxide (DLP) initiated the desired radical addition-cyclization between alkene 141 and xanthate 142 affording Trauner’s intermediate (136) in only two steps. Starting the route from 5bromopentene instead of 140 allowed the completion of desethylrhazinal. In 2013, the Gu group accomplished the total synthesis of ()-rhazinal (rac-5) in 12 steps and 13% overall yield (7 steps from known acid 143) (Scheme 23).97 The synthesis featured a tandem Catellani-type orthoarylation/intramolecular Heck reaction efficiently furnishing the key tetrahydroindolizidine core. After selective reduction and tosylation of known acid 143, N-alkylation of pyrrole 145 was affected in high yields in the presence of potassium carbonate. Under PdCl2 catalysis, the desired arylation under CeH bond activation and Heck cascade process between 146 and 147 was achieved in 85% yield. Afterward, the double bond and the nitro group of the fully functionalized core structure 148 have been reduced. Due to the slow rotation of the pyrrole-phenyl bond at room temperature, the corresponding aniline exists as a pair of atropisomers (1:1). Upon removal of the tert-butyl group, standard macrolactamization with the Mukaiyama reagent smoothly formed ()-rhazinal (rac-5) in 80% yield over two steps. In 2015, the Chandrasekhar group reported a formal synthesis of ()-rhazinal (rac-5) in 19 steps and 1% overall yield from pyrrole (Scheme 24).98 Instead of using an N-alkylated pyrrole for cyclization, a readily orthosubstituted substrate formed the tetrahydroindolizine core by intramolecular amidation. Trauner’s intermediate (136) was formed in 14 steps and 13% yield.

Scheme 23 Total synthesis of ()-rhazinal (rac-5) by Gu in 2013.

The Rhazinilam-Leuconoxine-Mersicarpine Triad

35

Scheme 24 Formal synthesis of ()-rhazinal (rac-5) by Chandrasekhar in 2015.

Literature known pyrrole 150 was sequentially alkylated with ethyl iodide and allyl bromide using LDA and DMPU. After early installation of the quaternary center, the allyl double bond was converted to the corresponding methyl ester in 152 in good yield by hydroboration oxidation, TEMPO oxidation in the presence of (diacetoxyiodo)benzene to the acid, diazomethane treatment, and thermal Boc deprotection. Treatment of 152 with DBU resulted in intramolecular amidation which upon reduction with alane afforded tetrahyroindolizine 153 in 68% yield. Oxidation of 153 to the corresponding aldehyde, followed by Wittig olefination gave 154. Hydrogenation of the double bond and VilsmeiereHaack formylation furnished Trauner’s intermediate (136) in 87% yield. In 2008, Gaunt et al. established the first total synthesis of ()-rhazinicine (rac-2) in eight steps and 9% overall yield by iterative metal-catalyzed CeH bond functionalizations (11 steps from commercial materials).99 While the one-pot Ir(I)-catalyzed borylation and Suzuki coupling sequence formed the heterobiaryl fragment, an oxidative Pd(II)-catalyzed pyrrole cyclization rapidly delivered the tetrahydroindolizine core of the natural product (Scheme 25). The synthesis began with the microwave-assisted CeH borylation of the sterically less encumbered C4 position of the pyrrole ring of 155. Optimized to a one-flask process, subsequent Pd-catalyzed Suzuki coupling with 86 delivered 156 in 78% yield. Thermal removal of the Boc protecting group produced biaryl unit 157. N-Acylation of the lithium pyrrolate anion of 157 with the corresponding acyl chloride of 161 (prepared in three steps from diester 158) furnished alkene 162 in good yields. Treatment of 162 with 10 mol% Pd(O2CCF3)2 catalyst (less reactive Pd(OAc)2 proved inferior) and tBuOOBz as the oxidant resulted in cyclization to the C2 position of

36

Magnus Pfaffenbach and Tanja Gaich

Scheme 25 First total synthesis of ()-rhazinicine (rac-2) by Gaunt in 2008.

the pyrrole, forming 163 in 53% yield. Hydrogenation of the double bond and nitro group, AlC3-mediated cleavage of the silyl groups, and macrolactamization under Mukaiyama conditions finished the synthesis of ()-rhazinicine (rac-2). In 2006, the Banwell group achieved the first total synthesis of ()-leuconolam (11) and (þ)-melodinine E (17) (previously misassigned as epi-leuconolam) in 17 steps and 2% overall yield (15 steps to 5).21 The common tetrahydroindolizine 165 was obtained via organocatalyzed intramolecular Michael addition of a pyrrole to an a,b-unsaturated aldehyde (Scheme 26). The synthesis started with the reduction of previously employed ester 130 with DIBAL-H. Subsequent oxidation with barium manganate afforded the corresponding aldehyde in 69% yield over two steps. Exposure to MacMillan’s first generation organocatalyst (164) in a mixture of THF/ H2O at 20 C initiated the desired enantioselective intramolecular Michael addition. After reduction with sodium borohydride, tetrahydroindolizine 165 was formed in 81% yield and 74% ee. Attempts to further improve the ee’s using other organocatalysts remained fruitless. The natural product ()-rhazinal (5) was then completed by the previously described synthetic route (Scheme 20). Decarbonylation to ()-rhazinilam (1) was achieved in 89% yield by heating ()-5 with stoichiometric amounts of Wilkinson’s catalyst. In the presence of 4 Å molecular sieves and an excess amount of

The Rhazinilam-Leuconoxine-Mersicarpine Triad

37

Scheme 26 First total synthesis of ()-leuconolam (11) by Banwell in 2006.

PCC, ()-leuconolam (11) and (þ)-melodinine E (17) were produced as a separable mixture (17:11 ¼ 1.6:1). The transannular cyclization of 1 to yield 17 as the major product was presumably triggered by the acidic conditions resulting from the aqueous workup of excess PCC. In 2013, Hoye et al. reported a concise 14-step total synthesis of ()-leuconolam (rac-11) in 7% overall yield.22 The key feature was a regioselective and diastereoselective Lewis acidemediated allylative cyclization forming the carbinolamide subunit with two adjacent tetrasubstituted carbon centers in one step (Scheme 27). The synthesis commenced with the SN2-alkylation of the dianion of commercially available b-methallyl alcohol (166) with bromide 167. Primary alcohol 168 was further transformed to 170 by a three-step sequence including Swern oxidation, addition of Grignard reagent 169, and acetylation in 66% yield over three steps. An Ireland-Claisen rearrangement was followed by one-flask ethoxyethyl cleavage and methyl ester formation in the presence of acetyl chloride in methanol to afford E-alkene 171 in high yields. The alcohol was displaced in a Mitsunobu reaction with maleimide derivative 172 to furnish allyl silane 173 in good yields after thermolysis and sodium iodide treatment. Since the cyclizations of maleimides with the appropriate 2-nitrophenyl or 2-aminophenyl substitution in place proceeded with undesired regioselectivity, the authors changed the order of steps. Thus, 173 was submitted to HosomieSakurai type conditions to initiate the allylative ring closure. In the presence of MeAlCl2, the reaction

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Scheme 27 Total synthesis of ()-leuconolam (rac-11) by Hoye in 2013.

furnished carbinolamide 174 with high levels of both regioselectivity and diastereoselectivity. The Stille cross coupling of hindered halide 174 required the use of novel o-(trimethylstannyl)aniline (175) because conventional organostannanes failed to produce any of compound 176. In the end, the base-sensitive iodocarbinolamide 174 was successfully arylated in 74% yield by using palladium catalysis at room temperature. Saponification to the corresponding amino acid was followed by macrolactamization and hydrogenation, providing ()-leuconolam (rac-11) in 62% yield over three steps. An overview on the syntheses of rhazinal (5) and rhazicine (2) is given in Scheme 28.

Scheme 28 Overview of the synthetic efforts toward rhazinal (5) and rhazinicine (2).

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4.2 Leuconoxines In 2013, Zhu et al. published the first total synthesis of leuconoxine group alkaloidsdalmost 20 years after their initial isolation.100 In their elegant pioneering work, they accomplished a protecting group free, unified access to the structurally distinct mersicarpine-leuconoxine-leuconolam subfamily of Aspidosperma alkaloids in a maximum of 12 steps with 7% overall yield (Scheme 29). Their strategy involves the common cyclohexenone derivative 180 which was diversified into the different natural products by an unprecedented oxidation/reduction/cyclization processes. The key strategy toward the diazafenestrane skeleton was to take advantage of the specific nucleophilicity of N4 in the corresponding cyclization event. A sequence of hydroboration iodination of known (S)-2-allyl-2-ethyl cyclohexanone (177) was followed by azide formation to produce compound 178 in 74% yield. An excess of IBX in DMSO and subsequent treatment with iodine in the presence of DMAP furnished vinyl iodide 179 in 67% yield over two steps. A Suzuki-Miyaura coupling with 2-nitrophenyl boronic acid produced the functionalized cyclohexenone 180 in 75% yield which was further transformed to diketone 181 by ozonolysis. After extensive screening for reducing agents, Zhu et al. found that Pd-catalyzed hydrogenation of 181 instantly furnished mersicarpine (16) in 23% yield (path a, Scheme 29). For further improvement, they developed a one-flask protocol in EtOH starting with 10-mol% Pd/C to give indole 182 which underwent lactamization upon addition of potassium hydroxide. Purging the reaction mixture with oxygen probably formed peroxide 183 which was reduced with dimethyl sulfide to afford 16 in 75% overall yield. The leuconoxine

Scheme 29 First total synthesis of leuconoxine alkaloids by Zhu in 2013.

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skeleton was prepared from the same precursor 181 by hydrogenation with concomitant N-acetylation These conditions successfully prevented nucleophilic addition of N4 to the carbonyl carbon C21 until lactam and aminal formation were completed (path b, Scheme 29). Hydrogenation with Pd/C in the presence of acetic anhydride afforded the corresponding indolin-3d one which was directly oxidized to unstable compound 184 upon oxygen purging. Addition of potassium hydroxide afforded d-lactamization product 185 as a mixture of diastereoisomers. Without isolation, treatment of the mixture with TFA furnished tetracyclic aminal 186 as a single diastereoisomer in 50% overall yield from 181. A carefully optimized aldolization of 186 using excess tBuOK completed ()-leuconodine B (19) in 73% yield. Mesylation of the tertiary hydroxy group and subsequent elimination with DBU afforded (þ)-melodinine E (17) in 75% yield (Scheme 30). Diastereoselective double bond reduction furnished ()-leuconoxine (15) in 85% yield. In a reverse biomimetic fashion, 17 was converted to ()-leuconolam (11) under acidic conditions in 70% yield. Based on the same synthetic approach, the Zhu group also demonstrated a bioinspired diversification of (þ)-melodinine E (17).101 By selective introduction of a hydroxyl group to the C6, C7, and C10 positions of 17, the first total syntheses of ()-leuconodine A (18), ()-leuconodine C (20), and (þ)-leuconodine F (23) were achieved along with a new access to 19 (Scheme 31). Furthermore, their work revealed a strong self-induced diastereomeric anisochronism phenomenon for 18e20. The chemical shift differences observed in the 1H NMR spectra of the racemic and the enantioenriched natural products in an achiral environment were shown to result from different crystal packing of these two forms. The leuconoxines possess a D ring (piperidine) in a chair conformation. In contrast, the same ring in melodinine E (17) was found to adopt a

Scheme 30 Endgame for (þ)-melodinine E (17), ()-leuconolam (11), and ()-leuconoxine (15) by Zhu in 2013.

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Scheme 31 Total syntheses of ()-leuconodine A (18), (þ)-leuconodine F (23), and ()-leuconodine C (20) by Zhu in 2015.

strained, twisted-boat conformation in solid state. The natural product is therefore prone to degradation toward its more stable structural congeners. Under mild acidic conditions, the labile central aminal function in 17 is hypothesized to be in equilibrium with N-acyliminium ion 35. Fine tuning of the reaction conditions allowed the regioselective and stereoselective introduction of hydroxyl groups to various positions. Treatment of 17 with excess TFA in the presence of catalytic amounts of copper(II) 2-ethylhexanoate afforded the unstable trifluoroacetate 187 as a mixture of diastereoisomers. After workup with aqueous NaHCO3, ()-leuconodine A (18) was formed in 68% yield probably arising from a conjugate addition of a trifluoroacetate anion to 35, followed by protonation of the resulting enamine intermediate and transannular cyclization. Further oxidation of 18 by DMP formed (þ)-leuconodine F (23) in 83% yield. On the other hand, oxidation of the secondary amide function of 35 with a hypervalent iodine reagent generated intermediate 188 which was attacked by a triflate anion (path a, Scheme 31). After rearomatization and transannular cyclization, 10-OTf melodinine E (189) was furnished in 34% yield. Upon hydrolysis and hydrogenation, the first total synthesis of ()-leuconodine C (20) was completed in 91% yield. Treatment of 35 with Mn(dpm)3 [tris(dipivaloylmethanato)manganese] and PhSiH3 under O2 atmosphere converted 17 to ()-leuconodine B (19) in 90% yield.

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The regioselective transformation of an a,b-unsaturated amide to the b- rather than the a-hydroxy amide was unexpected. Presumably, reduction of 35 with an in situ generated manganese hydride species formed enamide 190 (path b, Scheme 31). Trapping 190 with molecular oxygen would form the hydroperoxide 191 which is subsequently reduced to 19. In 2014, the Tokuyama group accomplished the racemic route to ()-leuconoxine (rac-15) and ()-melodinine (rac-17) in 24 steps (21 steps longest linear sequence) and 6% overall yield.102 A stepwise oxidative cyclic aminal formation and a diastereoselective ring-closing metathesis reaction constituted the key steps for the construction of the characteristic diazafenestrane skeleton (Scheme 32). The synthesis started with the condensation of 2-iodoindole-3-ylacetate 193 and carboxylic acid 192, which was prepared in five steps (27% yield) from commercially available 1,4-cyclohexanedione. The quaternary carbon center together with the d-lactam ring was installed in 94% yield by an intramolecular MizorokieHeck reaction of 194 using palladium catalysis. After removal of the TBS group, GriecoeNishizawa dehydration established the gem-divinyl unit in 195 required for RCM reaction. Demethylation using a combination of TMSCl and NaI, followed by allyl amide formation afforded indole-3-acetamide 196 which was first examined for the crucial oxidative aminal formation. However, the d-lactamindole showed low reactivity toward oxidation reagents probably due to an insufficient electron

Scheme 32 Tokuyama’s total synthesis of leuconoxine group alkaloids in 2014.

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density at the indole ring. Tokuyama et al. solved this problem by cleaving the lactam ring and establishing a stepwise procedure for intramolecular aminal formation. Therefore, 196 was treated with NaOH, followed by TMSCHN2, to obtain the corresponding methyl ester which was then oxidized with DMDO to hydroxyindolenine 197 in 90% yield over three steps. In the presence of TMSOTf and 2,6-lutidine, the desired aminal product 198 was formed in 5 min and 93% yield. The choice of Lewis acid proved to be essential since BF3$OEt2 and Sc(OTf)3 exclusively afforded the corresponding rearranged 3,3-disubstituted oxindole. Next, treatment of 198 with tBuOK reclosed the d-lactam ring with concomitant TMS group removal. The resulting triene 199 was heated with HoveydaeGrubbs second generation catalyst, furnishing the fully established diazafenestrane framework. Hydrogenation of both double bonds completed the total synthesis of leuconodine B (19) which has been further converted into xanthate 200 in high yields. While BartoneMcCombie deoxygenation of 200 completed ()-leuconoxine (rac-15), the microwave-assisted elimination with DBU afforded ()-melodinine (rac-17). A racemic and divergent strategy for the synthesis of leuconoxine indole alkaloids was developed by Dai’s group in 2014.103 Therein, the authors reported the first synthesis of ()-leuconodine D (rac-21) in 14 steps (4% overall yield) starting from commercially available FischereBorsche product 201 (Scheme 33). The key transformation toward the diazafenestrane skeleton was a WitkopeWinterfeldt oxidative indole cleavage followed

Scheme 33 Dai’s first total synthesis of ()-leuconodine D (rac-21) in 2014.

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by transannular cyclization to provide intermediate 206 which served as platform for the construction of the different polycyclic structures. Compound 201 was converted to allyl ketocarboxylate 202 in a threestep sequence including Boc-protecton, a-carboxylation, and ethylation in 69% yield. Pd-catalyzed decarboxylative allylation and subsequent Boc deprotection produced ketone 203 in good yields. Hydroboration oxidation, followed by mesylation and azide replacement formed the WitkopeWinterfeldt precursor 204. Extensive screening of various conditions revealed that freshly purified mCPBA under anhydrous conditions was optimal for oxidative indole cleavage. After spontaneous transannular cyclization of the primary nine-membered ring lactam 205, tricyclic compound 206 was formed as a 2:1 mixture of diastereoisomers at C21. Since 206 was not stable toward silica, the crude product was directly submitted to Staudinger-aza-Wittig conditions to furnish mersicarpine (16) in 43% yield from 204. The natural product was formed as a single diastereoisomer, probably resulting from epimerization of the hemiaminal center under these reaction conditions. On the other hand, hydrogenation of 206 with in situ formation of the amide gave Zhu’s intermediate (186) in 30% yield upon acid-catalyzed cyclization (from 204). For the first time, ()-leuconoxine (rac-15) was converted to ()-leuconodine D (rac-21) by a chemoselective reduction of the five-membered lactam. The reaction was accomplished in the presence of the six-membered lactam by methylation with Meerwein’s salt and reduction with sodium cyanoborohydride. Kawasaki and Higuchi reported the asymmetric total synthesis of (þ)-melodinine E (17) and ()-leuconoxine (15) in 19 steps and 6% overall yield via chiral phosphoric acidecatalyzed desymmetrization of a prochiral diester (Scheme 34).104 Construction of the fenestrane framework was

Scheme 34 Total synthesis of ()-leuconoxine (15) by Kawasaki and Higuchi in 2014.

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achieved in two successive steps including N-acyliminium ion-mediated piperidine cyclization and g-butyrolactam formation using Bestmann’s ylide. The synthesis commenced with the acylation of tert-butyl acetoacetate by the acid chloride of compound 207 to give b-diketone 208 after acidcatalyzed removal of the tert-butoxy carbonyl group in 68% yield over three steps. Double Michael addition with methyl acrylate (209) afforded 210 which upon hydrogenation cyclized to indole 211 in 55% yield over two steps. With the prochiral diester in hands, the asymmetric lactamization using chiral phosphoric acids was examined. After extensive optimization, a solution of 211 and 10-mol% (S)-VAPOL phosphoric acid in toluene was heated for 4 days at 80 C to give lactam 213 in 94% yield and 74% ee. Generally, the authors observed better ee’s when nonpolar solvents with a high boiling point and sterically less bulky substituents on the chiral acids were applied. Using the ethyl derivative 212 substantially decreased the ee presumably due to the absence of hydrogen bonds between the phosphate and acetyl group of 211 in the cyclization process. Lactam 213 was then transformed to Kerr’s mersicarpine intermediate (214) by a known procedure. Treatment of 214 with Tf2O and 2,6-lutidine produced the desired aminal 215 via acyliminium ion formation and intramolecular cyclization in 56% yield without loss of chirality. Notably, mersicarpine (16) was formed quantitatively from 214 in the presence of PPTS in refluxing toluene. Finally, the g-butyrolactam formation was accomplished in one step (83%) by using Bestmann’s ylide to afford (þ)-melodinine E (17). Hydrogenation yielded ()-leuconoxine (15) which was recrystallized into its optically pure form (>99% ee). In 2015, Gaich and Pfaffenbach accomplished a protecting-group-free total synthesis of ()-leuconoxine (15) in 12 steps (0.5% overall yield) via a photoinduced domino Witkop macrocyclization/transannular cyclization (Scheme 35).105 This single transformation constructs three of the four rings of the diaza[5.5.6.6.]fenestrane skeleton providing a very short access to the alkaloid. The synthesis commenced with known b-ketoester 216, which was first converted to the corresponding bromoketone using NBS and then refluxed in SMe2 to provide ketosulfide 217 in 90% yield. A high-yielding Gassman indole protocol using freshly prepared tert-butyl hypochloride afforded 3(methylthio)indole 218. Selective removal of the sulfide group in the presence of the allyl double bond was accomplished (88%) with thiosalicylic acid in TFA. A sequence of DIBAL-H reduction, ParikheDoering oxidation, Wittig olefination, and Mg reduction furnished nitrile 220 in 62% yield.

46 Magnus Pfaffenbach and Tanja Gaich

Scheme 35 Total synthesis of ()-leuconoxine (15) by Gaich in 2015.

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Reduction with LAH produced the corresponding amine which was trapped with 2-chloroacetic acid to introduce the chloroacetamide moiety in 74% yield. Finally, hydroboration oxidation afforded the linear Witkop precursor 221. After extensive investigations, Gaich and Pfaffenbach found that UV-light irradiation of 221 directly generated the leuconoxine precursor 222 in 5% yield. The compound constitutes the cascade product of a Witkop photocyclization to the indole 3 position, followed by transannular cyclization. Unfortunately, irradiation of 221 generated two highly strained 11-membered ring indolophanes as the major products resulting from cyclization to the indole 4- and 7-positions, respectively. The reversal of the prevailing regioselectivity of the Witkop reaction (two-substituted indoles normally cyclize to the unsubstituted 3-position) resulted from the quaternary carbon center that excerted a strong ThorpeeIngold effect on the system. Final oxidative ring closure of 222 using a mixture of TPAP and/or NMO completed the synthesis of ()-leuconoxine (15). In the same year, Stoltz and Liang completed the synthesis of rac-11, rac15e17, and rac-19, in a maximum of 15 steps total and 7% overall yield (Scheme 36).106 The divergent approach relies on careful control of the cyclization conditions of diketone 228 in the Staudinger reaction. The synthesis begins with known lacton 223 which was converted to azide 224 in a sequence of hydroboration oxidation and Mitsunobu reaction using diphenylphosphoryl azide (DPPA). DIBAL-H reduction to the corresponding lactol, followed by OhiraeBestmann reaction produced alkyne 225 in 72% yield over two steps. Jones oxidation with concomitant esterification was followed by a Sonogashira coupling with tert-butyl (2iodophenyl)carbamate (226) to furnish 227 in high yields. The 1,2-diketone 228 is produced in a Ruthenium-catalyzed oxidation of the alkyne triple bond and Boc deprotection using TMSOTf. Similar to Zhu’s strategy, which is based on careful control of the N4 nucleophilicity, acyclic diketone 228 was used as the common intermediate to access the different polycyclic frameworks. Instead of a controlled hydrogenation/oxidation/polycyclization sequence, as seen in Zhu’s approach, diversification is achieved through a key Staudinger reaction. Therefore, treatment of 228 with PPh3 in a solvent mixture of THF and water furnished ()-mersicarpine (rac-16) in 66% yield forming all three remaining rings in one single operation. In the absence of water, the more favorable six-membered imine is formed by an AzaeWittig reaction, followed by aminal formation to give 229 (68%) as a diastereomeric mixture. Fortunately, treatment with sodium hydride in toluene at 50 C generated Kawasaki and Higuchi’s intermediate (215)

48 Magnus Pfaffenbach and Tanja Gaich

Scheme 36 Total synthesis of ()-mersicarpine (rac-16), ()-leuconoxine (rac-15), and ()-leuconolam (rac-11) by Stoltz/Liang in 2015.

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as a single isomer. Acylation and intramolecular Aldol reaction afforded ()-leuconodine B (rac-19) which was further transformed to chloride 230. Interestingly, the authors observed that ()-melodinine E (rac-17) was not directly formed by treatment of 230 with DBU. Instead, the unstable intermediate 231 was detected by 1H-NMR which collapsed to rac-17 upon treatment with water. Standard hydrogenation of rac-17 completed ()-leuconoxine (rac-15). On the other hand, acidic conditions furnished ()-leuconolam (rac-11) in 75% yield. In 2016, Zhu et al. achieved a divergent synthesis of (þ)-leuconodine F (23) and ()-leucomidine B (236) via cyclocondensation between imine 124 and oxalyl chloride (232) to furnish the common dioxopyrrole 233 (Scheme 37).93 Building block 124 is derived from the route described above for ()-rhazinilam (1) (Scheme 17). Heteroannulation of imine 124 with oxalyl chloride (232) afforded 233 after acidic workup in quantitative yield. Treatment of a methanol solution of 233 with DIPEA and subsequent trapping of the resulting enol with an excess amount of TMSCHN2 formed 234 in 93% yield. A three-step sequence including saponification of the methyl ester, hydrogenation of the nitro group, and macrocyclization provided the crude lactam as a mixture of diastereoisomers. Addition of TFA prompted a highly selective transannular cyclization affording (þ)-leuconodine F (23) in 53% yield. Common intermediate 233 was also transformed into leucomidine B (236) in three steps. After examining various reduction approaches, 233 was converted into the carboxylic acid which underwent a substrate-

Scheme 37 Total synthesis of (þ)-leuconodine F (23) and ()-leucomidine B (236) by Zhu in 2016.

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directed diastereoselective hydrogenation in the presence of Pd(OCOCF3)2, affording a mixture of aniline 235 and the corresponding indole (not shown). Heating the reaction mixture to reflux drove the reaction toward indole formation (dr 92:8). Addition of an excess amount of TMSCHN2 to the reaction mixture furnished 236 in 71% yield. The high selectivity is attributed to the coordinating ability of the carboxylic acid group since reduction under identical reaction conditions generated 235 and its C21 epimer without noticeable diastereoselectivity. An overview on the synthetic efforts towards leuconoxines is given in Scheme 38.

Scheme 38 Overview of the synthetic efforts toward leuconoxines.

4.3 Mersicarpine In 2008, the Kerr group accomplished the first total synthesis of ()-mersicarpine (rac-16) in 14 steps and 11% overall yield from commercially inexpensive indoline (237).43 The intricate azepine moiety was formed by late-stage oxidation of the indole core, while the d-lactam ring was established through a b-dicarbonyl radical cyclization (Scheme 39). In

The Rhazinilam-Leuconoxine-Mersicarpine Triad

Scheme 39 First total synthesis of ()-mersicarpine (rac-16) by Kerr in 2008.

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addition to their landmark synthesis, the reported structure was confirmed by X-ray analysis, and the sensitive 1H NMR behavior of the natural product with respect to solvent acidity was clarified. The first step of the synthesis was the acylation of indoline (237) using acryloyl chloride. Oxidation to the corresponding indole with DDQ furnished 238. After Michael addition of acetylacetone, the use of manganese (III) acetate in refluxing acetic acid triggered the desired b-dicarbonyl radical cyclization forming lactam 239 in 60% yield. After retro-Claisen condensation upon treatment with sodium bicarbonate in methanol, conjugate addition to acrylonitrile yielded methyl ketone 240 in 70% yield over two steps. Upon reduction to the secondary alcohol, deoxygenation was best achieved (73%) via Chugaev elimination of the intermediate xanthate to form 241. Hydrogenation over Adam’s catalyst reduced both the double bond as well as the nitrile which after Boc protection furnished carbamate 242. Oxidation of the N-acylindole was achieved in excellent yield with dimethyl dioxirane, prepared in situ from acetone and oxone, to afford 214 as a 1:1 mixture of diastereoisomers. Since the hemiaminal is easily epimerized, the result proved inconsequential and final amine deprotection and imine cyclization formed ()-mersicarpine (rac-16) in 76% from 242. One year later, Zard et al. finished a formal synthesis of rac-16 in nine steps and 21% overall yield (Scheme 40).107 The key reaction was an intermolecular radical additioneradical cyclization cascade which established the d-lactam ring and introduced all remaining atoms in one step. The synthesis commenced with tert-butylindole-3-carboxylate (243), which was converted (55%) to xanthate 244 via acylation with chloroacetyl chloride and subsequent nucleophilic substitution by potassium O-ethyl xanthate salt. Subjection of 244 and olefin 245 (three equiv.) to radical initiator DLP in refluxing DCE afforded the desired radical cascade forming lactam 246 in 78% yield. Mechanistically, initial xanthate decomposition generates a radical that attacks the double bond of 245. The resulting tertiary radical undergoes 6-exo cyclization to the indole 2-position. Stabilized by

Scheme 40 Formal synthesis of ()-mersicarpine (rac-16) by Zard in 2009.

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the ester moiety, the ensuing radical disproportionates into 246 and the corresponding indoline, which in turn is oxidized to 246 by MnO2. Kerr’s intermediate (242) was obtained in 84% yield after decarboxylation and reprotection of the amine as its tert-butyl carbamate. In 2010, the first enantioselective total synthesis of ()-mersicarpine (16) was achieved by Fukuyama et al. in 10 steps and 13% overall yield from known chiral ketoester 91.108 The synthesis features a Au-catalyzed indole formation as well as an elegant one-pot process for the construction of the cyclic imine and hemiaminal moieties (Scheme 41). Known ketoester 91 was transformed into semicarbazone 248 through a high-yielding three-step sequence including oxidation with IBX, epoxidation of the resulting enone, and reaction of 247 with semicarbazide hydrochloride. Upon oxidation with lead tetraacetate, 248 underwent Eschenmoser-Tanabe fragmentation to afford alkyne 249 in 60% yield. This Warkentin procedure proved to be the only solution since standard fragmentation conditions using tosyl or nosyl hydrazides only resulted in recovery of starting material or decomposition under harsh conditions. After reduction with sodium borohydride, Sonogashira coupling with 2iodoaniline furnished the corresponding alkynyl aniline which cyclized to 2-substituted indole 250 in the presence of NaAuCl4. Diazo coupling using benzenediazonium chloride installed the nitrogen atom at the indole 3position. Treatment with sodium hydride caused lactamization which was followed by mesylation of the primary alcohol affording 251 in excellent yields. Hydrogenolysis of 251 furnished the corresponding labile 3aminoindole, which was immediately cyclized to 252 in the presence of sodium bicarbonate in degassed refluxing iPrOH/CH2Cl2. Exposure to air-initiated autoxidation resulting in peroxide formation which upon reduction with dimethyl sulfide generated ()-mersicarpine (16) in almost quantitative yield from 251. In 2012, Tokuyama et al. also successfully implemented ketoester 91 in their nine-step total synthesis of optically active ()-mersicarpine (16) exhibiting an impressive 30% overall yield (Scheme 42).109 The azepinoindole core was constructed by a DIBAL-H-mediated reductive ringexpansion reaction starting from a simple oxime. The synthesis started with Fischer indole synthesis of ketone 91 with phenylhydrazine in 84% yield. Oxidation with DDQ furnished 253 which upon subsequent condensation with hydroxylamine hydrochloride formed oxime 254 in high yields. Treatment of 254 with eight equiv. of DIBAL-H at 78 C, followed by gradual warming of the reaction mixture to 0 C and

54 Magnus Pfaffenbach and Tanja Gaich

Scheme 41 First enantioselective total synthesis of ()-mersicarpine (16) by Fukuyama in 2010.

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Scheme 42 Enantioselective total synthesis of ()-mersicarpine (16) by Tokuyama in 2012.

then to room temperature initiated the desired reductive ring expansion. The resulting labile 3-aminoindole 255 was in situ Cbz protected to afford azepinoindole 256 in 74% yield over two steps. A combination of TPAP and NMO furnished d-lactam 257 in one step. Deprotection was achieved upon hydrogenolysis with Pd/C. Purging air through the reaction mixture resulted in autoxidation to hydroperoxide 183 which was reduced with dimethyl sulfide to generate ()-mersicarpine (16) in 91% yield from 257. In 2012, the Han group finished a formal synthesis of ()-mersicarpine (rac-16) from commercially available indole (259) and succinic anhydride (258) in nine steps and 19% overall yield (Scheme 43).110 The central quaternary carbon center was efficiently formed by a Lewis acidecatalyzed substitution reaction of indol-2-ylcarbinol 262 and silyl vinyl ether 263. Three years later, the authors reported a modified conversion of Kerr’s intermediate (242) to the natural product rac-16.111 The synthetic route started with the acylation of indole (259) using succinic anhydride (258) in quantitative yield. While FriedeleCrafts acylation

Scheme 43 Formal synthesis of ()-mersicarpine (rac-16) by Han in 2012/2015.

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formed the d-lactam ring in 261, addition of ethyl magnesium chloride formed tertiary alcohol 262. Then, the quaternary carbon center was installed via nucleophilic addition of silyl enol ether 263 (four equiv.) which was assisted either by Al(OTf)3 in 71% or Hf(OAc)4 in 85% yield. Removal of the nosyl protection group followed by a modified, one-pot WolffeKishner reduction completed Kerr’s intermediate (242) in 57% yield over two steps. In 2014, Liang et al. reported the total synthesis of ()-mersicarpine (rac16) starting from readily available building block 265 in nine steps and 6% overall yield.112 The pivotal quaternary center was constructed by an intramolecular cationic cyclization of carbamate 269 bearing a masked amine functionality (Scheme 44). After the addition of allyl magnesium bromide to ketone 265, Curtius rearrangement using DPPA and N-methylmorpholine followed by cyclization of the tertiary alcohol 266 afforded carbamate 267 in moderate yields. A sequence of hydroboration oxidation and Jones oxidation generated building block 268 in good yields. Acylation of 3-chloroindole with 268 under basic conditions formed the desired precursor 269 in 66% yield. Treatment of carbamate 269 with AlCl3 initiated the formation of the corresponding carbocation species under liberation of carbon dioxide. Subsequent intramolecular FriedeleCrafts alkylation efficiently formed the quaternary center as well as the d-lactam ring in 270 in one step. Careful oxidation of 270 generated intermediate 271 which upon pH adjustment led to ()-mersicarpine (rac-16) in 42% yield. In 2015, the Gaich group achieved the formal synthesis of rac-16 within 13 steps and 6% overall yield starting from commercially inexpensive ethyl 2-ethylacetoacetate (272).113 The indole core was established by a highyielding Gassman indole procedure which allowed the implementation of the quaternary center early in synthesis. Elongation of the tether chain as well as introduction of the nitrogen functionality was achieved by a Wittig reaction (Scheme 45). The synthetic route commenced with allylation of ethyl 2-ethylacetoacetate (272) with allyl bromide forming the quaternary center in the first step of the synthesis. The methyl ketone was then converted into the corresponding bromoketone with N-bromosuccinimide and subsequently refluxed in dimethyl sulfide to provide b-keto sulfide 217 in 74% yield. The Gassman indole protocol afforded 3-(methylthio)indole 218 in high yield. Selective removal of the sulfide group in the presence of the allyl double bond was accomplished by using thiosalicylic acid in TFA, which afforded the 3-unsubstituted indole in 88% yield. DIBAL-H reduction, followed by

The Rhazinilam-Leuconoxine-Mersicarpine Triad

Scheme 44 Total synthesis of ()-mersicarpine (rac-16) by Liang in 2014.

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Scheme 45 Formal synthesis of ()-mersicarpine (rac-16) by Gaich in 2015.

ParikheDoering oxidation generated aldehyde 219 which was transformed into nitrile 220 upon Wittig olefination and subsequent reduction (62% yield over four steps). Complete reduction to the amine with LAH and in situ Boc protection was followed by a sequence of hydroboration oxidation and dlactam formation completing Kerr’s intermediate (242). An overview on the syntheses of mersicarpine (16) is given in Scheme 46.

Scheme 46 Overview of the synthetic efforts toward mersicarpine (16).

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59

4.4 Spectroscopy The 1H NMR and 13C NMR spectral data for the rhazinilam-leuconoxinemersicarpine triad of alkaloids are presented in Table 3 and Table 4, respectively. High-field data (1H NMR 300 MHz; 13C NMR 100 MHz) is reported for all natural products except for 5,21-dihydrorhazinilam (10). In 2014, Kam et al. revealed that the previously assigned alkaloid epi-leuconolam is in fact (þ)-melodinine E (17). In the following, the main features in the NMR and mass spectra are noted. The leuconoxine subgroup has a characteristic quaternary carbon resonance at dC w90.5 ppm which corresponds to the C21 representing the central carbon atom of the diazafenestrane skeleton. The ethyl side chain is usually present at dH 0.90, 1.45, 1.68 ppm and dC 7, 29 ppm, respectively. Due to anisotropy induced by the proximate lactam carbonyl group, H12 of the ortho-disubstituted phenyl ring is deshielded toward dH 7.70e8.10 ppm. The benzylic H7 in 15, 18, 20, 21, and 23 is typically found around dH 3.69e4.23 ppm. While the C2 carbonyl group of the nine-membered ring lactam (rhazinilams) is generally found between dC 176.4e 179.1 ppm, the C2 of the d-lactam ring (leuconoxines) is shifted upfield to dC 172.2 ppm. In the rhazinilam-leuconolam series, four aromatic resonances (dH 7.27e 7.42 ppm) correspond to the unsubstituted phenyl group. The ethyl side chain is usually present at dH 0.70, 1.21, 1.45 ppm and dC 8.1, 30.1 ppm, respectively. The leuconolam congeners bear an additional C5 carbonyl in the a,b-unsaturated carbinolamide subunit which appears at dC 166.5 ppm. The quaternary carbon resonances of the lactam carbonyl and imine functionalities in mersicarpine (16) appear at dC 169.6 and 168.9 ppm, respectively. The quaternary carbon atom attached to both a nitrogen and oxygen atom is found at dC 93.8 ppm. The fragmentation pattern in the mass spectra of the rhazinilam-leuconoxine-mersicarpine alkaloids by electron impact ionization exhibits some common features. The most significant fragment peaks are usually caused by the initial loss of the ethyl group (MeCH2CH3), followed by the loss of a carbonyl group (MeCH2CH3eCO). The additional loss of an ethylene unit (MeCH2CH3eCH2]CH2eCO) is typical for the rhazinilam-type alkaloids. The 5,21-dihydrorhazinilam (10) is first converted to rhazinilam (1) by loss of two protons. The 5,21-dihydrorhazinilam N-oxide (9) and 3,14-dehydroleuconolam (14) show prominent fragment peaks for the elimination of water (MeH2O). Arboloscine (24) bears the fragment peak for the initial loss of the methyl (MeCH3) instead of the ethyl group. The base peak of mersicarpine at m/z 267 corresponds to a loss of OH.

60

Magnus Pfaffenbach and Tanja Gaich

Table 3 1H NMR chemical shifts and mass data for the rhazinilam-leuconoxinemersicarpine indole alkaloids

Mersicarpine (16)

H NMR (400 MHz, CDCl3): 0.74 (3H, t, J ¼ 7.5 Hz, H-18), 1.10 (1H, dq, J ¼ 14.5, 7.5 Hz, H-19), 1.32 (1H, dqd, J ¼ 14.5, 7.5, 1.5 Hz, H-19), 1.65 (2H, m, H-14), 1.65 (1H, m, H-17b), 1.75 (1H, dt, J ¼ 14.3, 3.5 Hz, H-15b), 1.89 (1H, dddd, J ¼ 14.0, 9.5, 7.8, 1.5 Hz, H-17a), 2.07 (1H, m, H-15a), 2.35 (1H, ddd, J ¼ 18.5, 8.8, 7.8 Hz, H-16b), 2.48 (1H, ddd, J ¼ 18.5, 9.5, 3.5 Hz, H16a), 3.87 (2H, m, H-3), 5.92 (1H, br s, OH), 7.09 (1H, td, J ¼ 8.0, 1.0 Hz, H10), 7.39 (1H, td, J ¼ 8.0, 1.0 Hz, H-11), 7.66 (1H, br d, J ¼ 8.0 Hz, H-9), 8.13 (1H, br d, J ¼ 8.0 Hz, H-12).42 EI MS: 284 (Mþ), 267 (100%).42 1

Rhazinilam (1)

H NMR (400 MHz, CDCl3): 0.71 (3H, t, J ¼ 7.3 Hz, H-18), 1.24 (1H, dq, J ¼ 14.2, 7.3 Hz, H-19), 1.46 (1H, dq, J ¼ 14.2, 7.3 Hz, H-19), 1.47 (1H, dd, J ¼ 12.5, 8.0 Hz, H-17), 1.54 (1H, dt, J ¼ 13.0, 3.0 Hz, H-15), 1.72 (1H, td, J ¼ 13.0, 3.0 Hz, H-15), 1.85 (1H, m, H-14), 1.95 (1H, dd, J ¼ 12.5, 8.0 Hz, H16), 2.22 (1H, qdd, J ¼ 13.0, 5.5, 3.0 Hz, H-14), 2.37 (1H, t, J ¼ 12.5 Hz, H16), 2.45 (1H, t, J ¼ 12.5 Hz, H-17), 3.78 (1H, td, J ¼ 13.0, 5.0 Hz, H-3), 4.00 (1H, br dd, J ¼ 13.0, 5.5 Hz, H-3), 5.75 (1H, d, J ¼ 2.7 Hz, H-6), 6.50 (1H, d, J ¼ 2.7 Hz, H-5), 6.77 (1H, s, NH), 7.20 (1H, dd, J ¼ 7.5, 2.0 Hz, H-12), 7.30 (1H, td, J ¼ 7.5, 2.0 Hz, H-11), 7.34 (1H, td, J ¼ 7.5, 2.0 Hz, H-10), 7.42 (1H, dd, J ¼ 7.5, 2.0 Hz, H-9).13,19 EI MS: 294 (Mþ), 293, 266, 265 (100%), 238, 237, 209, 197, 168, 149, 123, 118.19 1

Nor-rhazinicine (3)

H NMR (400 MHz, CDCl3): 0.72 (3H, t, J ¼ 7.3 Hz, H-18), 1.36 (1H, dq, J ¼ 14.0, 7.3 Hz, H-19), 1.50 (1H, dq, J ¼ 14.0, 7.3 Hz, H-19), 2.08 (2H, m, H16þH-17), 2.26 (1H, ddd, J ¼ 13.0, 10.0, 5.0 Hz, H-17), 2.37 (1H, ddd, J ¼ 13.0, 10.0, 5.0 Hz, H-16), 2.70 (1H, d, J ¼ 18.5 Hz, H-15), 2.95 (1H, J ¼ 18.5 Hz, H-15), 6.19 (1H, d, J ¼ 3.0 Hz, H-6), 7.00 (1H, d, J ¼ 3.0 Hz, H5), 7.12 (1H, br s, NH), 7.27 (1H, dd, J ¼ 7.3, 2.0 Hz, H-12), 7.34 (1H, td, J ¼ 7.3, 2.0 Hz, H-11), 7.37 (1H, dd, J ¼ 7.3, 2.0 Hz, H-9), 7.42 (1H, td, J ¼ 7.3, 2.0 Hz, H-10).11 EI MS: 294 (Mþ), 265, 237 (100%), 223, 209, 195, 182, 167, 154.11 1

5,21-Dihydrorhazinilam (10) 1

H NMR (90 MHz, CDCl3): 0.58 (3H, t), 1.25e3.10 (13H, m), 3.33 (1H, br s, H3b), 3.73 (1H, m, H-5a), 5.62 (1H, m, H-6), 7.20e7.28 (4H, m), 8.1 (1H, s, NH).15,19 EI MS: 296 (Mþ), 294, 279, 266, 265 (100%), 253, 238, 237, 209, 197, 171, 149, 123, 118.15,19

61

The Rhazinilam-Leuconoxine-Mersicarpine Triad

Table 3 1H NMR chemical shifts and mass data for the rhazinilam-leuconoxinemersicarpine indole alkaloidsdcont'd Leuconodine D (21)

H NMR (400 MHz, CDCl3): 0.73 (3H, t, J ¼ 7.3 Hz, H-18), 1.07 (1H, dq, J ¼ 13.0, 7.3 Hz, H-19), 1.21 (1H, td, J ¼ 13.0, 3.5 Hz, H-15), 1.30 (1H, dq, J ¼ 13.0, 7.3 Hz, H-19), 1.50 (1H, dd, J ¼ 13.0, 6.5 Hz, H-6), 1.61 (1H, m, H14), 1.70 (1H, m, H-17), 1.73 (1H, m, H-17), 1.79 (1H, m, H-15), 1.82 (1H, m, H-14), 2.34 (1H, ddd, J ¼ 14.0, 5.0, 2.5 Hz, H-16), 2.52 (1H, td, J ¼ 13.0, 3.5 Hz, H-3), 2.60 (1H, m, H-6), 2.72 (1H, dd, J ¼ 13.0, 6.5 Hz, H-5), 2.93 (1H, td, J ¼ 13.0, 6.5 Hz, H-5), 3.03 (1H, br d, J ¼ 13.0 Hz, H-3), 3.59 (1H, td, J ¼ 14.0, 8.0 Hz, H-16), 3.77 (1H, d, J ¼ 9.5 Hz, H-7), 7.00 (1H, td, J ¼ 7.3, 1.0 Hz, H-10), 7.13 (1H, br d, J ¼ 7.3 Hz, H-9), 7.16 (1H, td, J ¼ 7.3, 1.0 Hz, H-11), 8.11 (1H, br d, J ¼ 7.3 Hz, H-12).11 EI MS: 296 (Mþ), 268, 253 (100%), 151, 136.11 1

Alstorisine A (26)

H NMR (600 MHz, CDCl3): 0.79 (3H, t, J ¼ 7.5 Hz, H-18), 1.37 (1H, q, J ¼ 7.5 Hz, H-19), 1.44 (1H, q, J ¼ 7.5 Hz, H-19), 1.48 (1H, m, H-17), 1.55 (1H, m, H-14), 1.74 (1H, m, H-15), 1.86 (1H, overlapped, H-15), 1.87 (1H, overlapped, H-14), 2.46 (1H, m, H-16), 2.74 (1H, overlapped, H-16), 2.75 (1H, overlapped, H-17), 2.75 (1H, overlapped, H-3), 3.11 (1H, td, J ¼ 12.1, 3.3 Hz, H-3), 5.29 (1H, s, H-6), 5.69 (1H, s, H-6), 6.80 (1H, dd, J ¼ 8.7, 2.3 Hz, H-11), 6.92 (1H, d, J ¼ 2.3 Hz, H-9), 8.14 (1H, d, J ¼ 8.7 Hz, H-12).30 ESI MS: 299 [M þ H]þ, 321 [M þ Na]þ.30 1

3-Oxo-14,15-dehydrorhazinilam (4)

H NMR (500 MHz, CDCl3): 0.71 (3H, dd, J ¼ 7.4 Hz, H-18), 1.29 (1H, dddd, J ¼ 14.1, 7.4 Hz, H-19a), 1.81 (1H, dddd, J ¼ 14.1, 7.4 Hz, H-19b), 1.89 (1H, dd, J ¼ 13.7, 8.3 Hz, H-17a), 2.05e2.11 (2H, m, H-16a þ H-17b), 2.49 (1H, dd, J ¼ 13.7, 12.4 Hz, H-16b), 6.03 (1H, d, J ¼ 3.3 Hz, H-6), 6.23 (1H, d, J ¼ 9.9 Hz, H-14), 6.56 (1H, d, J ¼ 9.9 Hz, H-15), 6.80 (1H, br s, NH), 7.29 (1H, d, J ¼ 7.7 Hz, H-9 or H-12), 7.34e7.38 (2H, m, H-11þH-12 or H-9þH10), 7.43e7.46 (1H, m, H-10 or H-11), 7.53 (1H, d, J ¼ 3.3 Hz, H-5).12 EI MS: 306 (Mþ), 278, 277 (100%), 249, 235, 221.12 1

Rhazinicine (2)

H NMR (400 MHz, CDCl3): 0.74 (3H, t, J ¼ 7.3 Hz, H-18), 1.31 (1H, dq, J ¼ 14.5, 7.5 Hz, H-19), 1.47 (1H, dq, J ¼ 14.5, 7.5 Hz, H-19), 1.58 (1H, m, H17), 1.73 (1H, ddd, J ¼ 13.5, 5.0, 3.5 Hz, H-15), 2.12 (1H, td, J ¼ 13.5, 4.5 Hz, H-15), 2.12 (1H, m, H-16), 2.40 (1H, m, H-16), 2.44 (1H, m, H-17), 2.70 (1H, ddd, J ¼ 18.0, 4.5, 3.5 Hz, H-14), 2.93 (1H, ddd, J ¼ 18.0, 13.5, 5.0 Hz, H-14), 5.93 (1H, d, J ¼ 3.0 Hz, H-6), 6.75 (1H, s, NH), 7.37 (1H, m, H-11), 7.28 (1H, d, J ¼ 8.0 Hz, H-12), 7.41 (1H, m, H-9), 7.41 (1H, m, H-10), 7.42 (1H, d, J ¼ 3.0 Hz, H-5).10,73,74 EI MS: 308 (Mþ), 279 (100%), 251, 237, 223, 195.10,73,74 1

(Continued)

62

Magnus Pfaffenbach and Tanja Gaich

Table 3 1H NMR chemical shifts and mass data for the rhazinilam-leuconoxinemersicarpine indole alkaloidsdcont'd Melodinine E (17)

H NMR (500 MHz, CDCl3): 0.73 (3H, t, J ¼ 7.4 Hz, H-18), 1.05 (1H, m, H15b), 1.32 (1H, q, J ¼ 7.4 Hz, H-19b), 1.42 (1H, q, J ¼ 7.4 Hz, H-19a), 1.62 (1H, m, H-15a), 1.66 (1H, m, H-17b), 1.79 (1H, m, H-14b), 2.00 (1H, m, H14a), 2.09 (1H, m, H-17a), 2.59 (1H, m, H-16b), 3.04 (1H, m, H-16a), 3.21 (1H, m, H-3b), 4.42 (1H, m, H-3a), 6.20 (1H, s, H-6), 7.10 (1H, t, J ¼ 7.5 Hz, H-10), 7.31 (1H, t, J ¼ 7.5 Hz, H-11), 7.44 (1H, d, J ¼ 7.5 Hz, H-9), 8.14 (1H, d, J ¼ 7.5 Hz, H-12).23,25 ESI MS: 309 [M þ H]þ.23,25 1

Leuconoxine (15)

H NMR (400 MHz, CDCl3): 0.92 (3H, t, J ¼ 6.0 Hz, H-18), 1.38 (2H, qui, J ¼ 6.0 Hz, H-19), 1.60 (2H, m, H-14), 1.65 (1H, m, H-17), 1.70 (1H, m, H15), 1.84 (1H, ddd, J ¼ 14.0, 6.0, 1.0 Hz, H-17), 1.97 (1H, br t, J ¼ 12.0 Hz, H15), 2.48 (1H, ddd, J ¼ 19.0, 6.0, 1.0 Hz, H-16), 2.67 (1H, d, J ¼ 17.0 Hz, H-6), 2.75 (1H, m, H-16), 2.79 (1H, br t, J ¼ 13.0 Hz, H-3), 2.86 (1H, dd, J ¼ 17.0, 7.0 Hz, H-6), 3.81 (1H, d, J ¼ 7.0 Hz, H-7), 3.95 (1H, br d, J ¼ 13.0 Hz, H-3), 7.12 (1H, td, J ¼ 7.0, 1.0 Hz, H-10), 7.16 (1H, dd, J ¼ 7.0, 1.0 Hz, H-9), 7.25 (1H, td, J ¼ 7.0, 1.0 Hz, H-11), 7.77 (1H, dd, J ¼ 7.0, 1.0 Hz, H-12).23,24 ESI MS: 311 [M þ H]þ.23,24 1

Leuconodine E (22)

H NMR (400 MHz, CDCl3): 0.74 (3H, t, J ¼ 7.6 Hz, H-18), 1.14 (1H, dq, J ¼ 14.0, 7.6 Hz, H-19), 1.70 (1H, m, H-14), 1.74 (2H, m, H-15), 1.74 (1H, m, H-19), 1.77 (2H, m, H-17), 1.80 (1H, m, H-14), 2.08 (1H, dd, J ¼ 11.0, 6.0 Hz, H-6), 2.31 (1H, dt, J ¼ 14.0, 3.0 Hz, H-16), 2.70 (1H, m, H-5), 2.74 (1H, m, H6), 2.87 (1H, m, H-5), 2.96 (2H, m, H-3), 3.53 (1H, ddd, J ¼ 14.0, 12.0, 10.0 Hz, H-16), 7.08 (1H, td, J ¼ 8.0, 1.5 Hz, H-10), 7.23 (1H, td, J ¼ 8.0, 1.5 Hz, H-11), 7.27 (1H, br d, J ¼ 8.0 Hz, H-9), 8.11 (1H, br d, J ¼ 8.0 Hz, H12).11 EI MS: 312 (Mþ), 284, 269 (100%), 255, 228, 213, 207, 181, 132.11 1

5,21-Dihydrorhazinilam N-oxide (9)

H NMR (400 MHz, CDCl3): 0.67 (3H, t, J ¼ 7.5 Hz, H-18), 1.22 (1H, dq, J ¼ 14.0, 7.5 Hz, H-19), 1.35 (1H, dq, J ¼ 14.0, 7.5 Hz, H-19), 1.46 (1H, m, H16), 1.49 (1H, ddd, J ¼ 13.0, 10.0, 3.0 Hz, H-15), 1.71 (1H, td, J ¼ 13.0, 3.0 Hz, H-15), 1.81 (2H, m, H-14), 1.82 (1H, dd, J ¼ 15.0, 7.0 Hz, H-17), 2.02 (1H, br t, J ¼ 15.0 Hz, H-16), 2.21 (1H, dd, J ¼ 15.0, 7.0 Hz, H-17), 3.56 (1H, td, J ¼ 13.0, 4.0 Hz, H-3), 3.87 (1H, br d, J ¼ 13.0 Hz, H-3), 4.15 (1H, dd, J ¼ 15.0, 3.0 Hz, H-5), 4.43 (1H, s, H-21), 4.63 (1H, d, J ¼ 15.0 Hz, H-5), 5.87 (1H, br s, H-6), 7.20 (1H, dd, J ¼ 7.5, 2.0 Hz, H-12), 7.31 (1H, td, J ¼ 7.5, 2.0 Hz, H-10), 7.33 (1H, td, J ¼ 7.5, 2.0 Hz, H-11), 7.56 (1H, dd, J ¼ 7.5, 2.0 Hz, H-9)8.18 (1H, s, NH).11 EI MS: 294 (Mþ -H2O), 265 (100%), 237, 222, 209, 195, 167, 130.11 1

63

The Rhazinilam-Leuconoxine-Mersicarpine Triad

Table 3 1H NMR chemical shifts and mass data for the rhazinilam-leuconoxinemersicarpine indole alkaloidsdcont'd Rhazinal (5)

H NMR (400 MHz, CDCl3): 0.72 (3H, t, J ¼ 7.3 Hz, H-18), 1.26 (1H, dq, J ¼ 14.2, 7.3 Hz, H-19), 1.52 (1H, dq, J ¼ 14.2, 7.3 Hz, H-19), 1.54 (1H, m, H15), 1.54 (1H, m, H-17), 1.77 (1H, td, J ¼ 13.0, 3.0 Hz, H-15), 1.95 (1H, m, H14), 2.04 (1H, dd, J ¼ 12.5, 8.0 Hz, H-16), 2.19 (1H, qdd, J ¼ 13.0, 5.5, 3.0 Hz, H-14), 2.43 (1H, t, J ¼ 12.5 Hz, H-16), 2.50 (1H, t, J ¼ 12.5 Hz, H-17), 3.98 (1H, ddd, J ¼ 14.0, 13.0, 5.0 Hz, H-3), 4.77 (1H, dd, J ¼ 14.0, 5.5 Hz, H-3), 6.54 (1H, s, H-6), 6.80 (1H, s, NH), 7.26 (1H, br d, J ¼ 7.5 Hz, H-12), 7.35 (1H, br t, J ¼ 7.5 Hz, H-11), 7.40 (1H, dd, J ¼ 7.5, 2.0 Hz, H-9), 7.42 (1H, td, J ¼ 7.5, 2.0 Hz, H-10), 9.39 (1H, s, CHO).13 EI MS: 322 (Mþ).13 1

Leuconodine F (23)

H NMR (400 MHz, CDCl3): 0.92 (3H, t, J ¼ 7.4 Hz, H-18), 1.23 (1H, dq, J ¼ 13.0, 7.4 Hz, H-19), 1.49 (1H, dq, J ¼ 13.0, 7.4 Hz, H-19), 1.66 (1H, td, J ¼ 14.0, 6.0 Hz, H-17), 1.70 (1H, m, H-15), 1.70 (2H, m, H-14), 1.98 (1H, ddd, J ¼ 14.0, 6.5, 1.4 Hz, H-17), 2.05 (1H, m, H-15), 2.59 (1H, ddd, J ¼ 19.0, 6.0, 1.4 Hz, H-16), 2.86 (1H, ddd, J ¼ 19.0, 14.0, 6.5 Hz, H-16), 3.10 (1H, ddd, J ¼ 13.0, 11.0, 4.0 Hz, H-3), 4.11 (1H, ddd, J ¼ 13.0, 5.0, 2.3 Hz, H-3), 4.23 (1H, s, H-7), 7.16 (1H, td, J ¼ 7.6, 1.0 Hz, H-10), 7.22 (1H, dd, J ¼ 7.6, 1.0 Hz, H-9), 7.37 (1H, td, J ¼ 7.6, 1.0 Hz, H-11), 7.82 (1H, dd, J ¼ 7.6, 1.0 Hz, H-12).23,26 EI MS: 324 (Mþ), 308 (100%), 280, 279, 267, 256, 251, 237, 212, 181, 167, 149.26 1

3,14-Dehydroleuconolam (14)

H NMR (400 MHz, CDCl3): 0.50 (3H, t, J ¼ 7.0 Hz, H-18), 1.11 (1H, dq, J ¼ 14.0, 7.0 Hz, H-19), 1.41 (2H, m, H-17), 1.46 (1H, dq, J ¼ 14.0, 7.0 Hz, H19), 1.84 (1H, dd, J ¼ 18.0, 6.0 Hz, H-15), 1.99 (2H, m, H-16), 2.27 (1H, d, J ¼ 18.0 Hz, H-15), 4.98 (1H, s, OH), 5.04 (1H, br t, J ¼ 6.0 Hz, H-14), 6.01 (1H, s, H-6), 6.52 (1H, d, J ¼ 6.0 Hz, H-3), 7.19 (1H, d, J ¼ 7.0 Hz, H-12), 7.25 (1H, t, J ¼ 7.0 Hz, H-10), 7.32 (1H, t, J ¼ 7.0 Hz, H-11), 7.68 (1H, d, J ¼ 7.0 Hz, H-9), 8.48 (1H, s, NH).11 EI MS: 324 (Mþ) (100%), 306, 295, 277, 240, 212, 184, 145, 117, 95.11 1

Kopsiyunnanine C3 (8)

H NMR (500 MHz, CDCl3): 0.72 (3H, t, J ¼ 7.0 Hz, H-18), 1.26 (1H, m, H-19), 1.46 (1H, overlapped, H-19), 1.48 (1H, overlapped, H-17), 1.52 (1H, overlapped, H-15), 1.71 (1H, ddd, J ¼ 13.5, 13.5, 3.0 Hz, H-15), 1.90 (1H, overlapped, H-14), 1.96 (1H, dd, J ¼ 13.0, 6.5 Hz, H-16), 2.22 (1H, m, H-14), 2.38 (1H, overlapped, H-16), 2.46 (1H, overlapped, H-17), 3.72 (1H, ddd, J ¼ 12.5, 12.5, 5.0 Hz, H-3), 4.20 (1H, dd, J ¼ 12.5, 5.5 Hz, H-3), 4.51 (2H, s, H-22), 5.73 (1H, s, H-6), 6.60 (1H, br s, NH), 7.20 (1H, br d, J ¼ 7.5 Hz, H-12), 7.30 (1H, ddd, J ¼ 7.5, 7.5, 1.5 Hz, H-10), 7.34 (1H, ddd, J ¼ 7.5, 7.5, 1.5 Hz, H-11), 7.40 (1H, dd, J ¼ 7.5, 1.5 Hz, H-9).14 FAB MS: 347 [M þ Na]þ.14 1

(Continued)

64

Magnus Pfaffenbach and Tanja Gaich

Table 3 1H NMR chemical shifts and mass data for the rhazinilam-leuconoxinemersicarpine indole alkaloidsdcont'd Leuconolam (11)

H NMR (400 MHz, CDCl3): 0.55 (3H, t, J ¼ 8.0 Hz, H-18), 1.37e1.65 (7H, m, H-14, H-15a, H-17, H-19), 1.79 (1H, dt, J ¼ 12.5, 5.0 Hz, H-15b), 2.00 (1H, t, J ¼ 12.5 Hz, H-16b), 2.14 (1H, dd, J ¼ 12.5, 6.0 Hz, H-16a), 2.96 (1H, dt, J ¼ 12.0, 4.0 Hz, H-3b), 3.98 (1H, dd, J ¼ 12.0, 4.0 Hz, H-3a), 5.79 (1H, s, H6), 7.20 (1H, dd, J ¼ 6.0, 2.0 Hz, H-9), 7.33 (2H, dt, J ¼ 6.0, 2.0 Hz, H-10, H11), 7.89 (1H, br s, NH), 7.92 (1H, dd, J ¼ 6.0, 2.0 Hz, H-12).19,23 EI MS: 326 (Mþ) (100%), 308, 297, 279, 251, 186, 172, 145.19 1

Leuconodine A (18)

H NMR (400 MHz, CDCl3): 0.90 (3H, t, J ¼ 7.3 Hz, H-18), 1.49 (1H, dq, J ¼ 13.0, 7.3 Hz, H-19), 1.60 (1H, m, H-17), 1.64 (1H, m, H-15), 1.70 (2H, m, H-14), 1.92 (1H, m, H-15), 1.94 (1H, m, H-17), 1.96 (1H, m, H-19), 2.53 (1H, ddd, J ¼ 19.0, 6.0, 1.4 Hz, H-16), 2.78 (1H, ddd, J ¼ 19.0, 14.0, 6.0 Hz, H-16), 2.89 (1H, ddd, J ¼ 13.0, 11.0, 4.0 Hz, H-3), 3.90 (1H, s, H-7), 3.99 (1H, dd, J ¼ 13.0, 4.0 Hz, H-3), 4.51 (1H, s, H-6), 5.11 (1H, br s, OH), 7.13 (1H, td, J ¼ 7.8, 1.0 Hz, H-10), 7.25 (1H, td, J ¼ 7.8, 1.0 Hz, H-11), 7.27 (1H, td, J ¼ 7.8, 1.0 Hz, H-9), 7.87 (1H, dd, J ¼ 7.8, 1.0 Hz, H-12).11,23 EI MS: 326 (Mþ) (100%), 298, 283, 252, 237, 212, 171, 145, 117.11 1

Leuconodine B (19)

H NMR (400 MHz, CDCl3): 0.96 (3H, t, J ¼ 7.2 Hz, H-18), 1.56 (1H, m, H14a), 1.69 (1H, m, H-14b), 1.73 (1H, m, H-15b), 1.76 (1H, m, H-17a), 1.83 (1H, m, H-19), 1.98 (1H, m, H-15a), 2.16 (1H, m, H-19), 2.22 (1H, m, H-17b), 2.52 (1H, dd, J ¼ 18.8, 5.6 Hz, H-16b), 2.69 (1H, m, H-3a), 2.78 (1H, m, H16a), 2.82 (1H, s, OH), 2.96 (1H, d, J ¼ 16.4 Hz, H-6b), 2.99 (1H, d, J ¼ 16.4 Hz, H-6a), 3.98 (1H, ddd, J ¼ 13.6, 4.0, 2.4 Hz, H-3b), 7.22 (1H, t, J ¼ 7.6 Hz, H-10), 7.37 (1H, d, J ¼ 7.6 Hz, H-9), 7.40 (1H, t, J ¼ 7.6 Hz, H11), 7.82 (1H, d, J ¼ 7.6 Hz, H-12).11,27 EI MS: 326 (Mþ), 270 (100%), 255, 181, 152, 55.11 1

Leuconodine C (20)

H NMR (400 MHz, CDCl3): 0.86 (3H, t, J ¼ 7.0 Hz, H-18), 1.29 (1H, dq, J ¼ 13.0, 7.0 Hz, H-19), 1.53 (2H, m, H-14), 1.59 (1H, m, H-15), 1.59 (1H, m, H-17), 1.68 (1H, dq, J ¼ 13.0, 7.0 Hz, H-19), 1.78 (1H, dd, J ¼ 14.0, 5.0 Hz, H-17), 1.89 (1H, ddd, J ¼ 14.0, 12.0, 5.0 Hz, H-15), 2.41 (1H dd, J ¼ 19.0, 5.0 Hz, H-16), 2.56 (1H, d, J ¼ 17.0 Hz, H-6), 2.65 (1H, m, H-16), 2.70 (1H, m, H-3), 2.77 (1H, dd, J ¼ 17.0, 7.0 Hz, H-6), 3.69 (1H, d, J ¼ 7.0 Hz, H-7), 3.86 (1H, br d, J ¼ 12.0 Hz, H-3), 6.60 (1H, d, J ¼ 2.0 Hz, H-9), 6.64 (1H, dd, J ¼ 8.6, 2.0 Hz, H-11), 7.49 (1H, d, J ¼ 8.6 Hz, H-12).11 ESI MS: 327 [M þ H]þ.11 1

65

The Rhazinilam-Leuconoxine-Mersicarpine Triad

Table 3 1H NMR chemical shifts and mass data for the rhazinilam-leuconoxinemersicarpine indole alkaloidsdcont'd Kopsiyunnanine C1(6)

H NMR (500 MHz, CDCl3): 0.70 (3H, t, J ¼ 7.5 Hz, H-18), 1.21 (1H, m, H-19), 1.45 (1H, overlapped, H-19), 1.45 (1H, overlapped, H-17), 1.52 (1H, overlapped, H-15), 1.69 (1H, overlapped, H-15), 1.90 (1H, dd, J ¼ 14.0, 7.0 Hz, H-14), 1.96 (1H, dd, J ¼ 12.5, 7.5 Hz, H-16), 2.26 (1H, dd, J ¼ 14.0, 5.0 Hz, H-14), 2.38 (1H, overlapped, H-16), 2.45 (1H, overlapped, H-17), 3.66 (3H, s, OCH3), 3.68 (1H, ddd, J ¼ 12.5, 12.5, 5.0 Hz, H-3), 4.07 (1H, dd, J ¼ 12.5, 5.0 Hz, H-3), 4.31 (2H, s, H-22), 5.76 (1H, s, H-6), 6.58 (1H, br s, NH), 7.20 (1H, br d, J ¼ 7.5 Hz, H-12), 7.29 (1H, ddd, J ¼ 7.5, 7.5, 2.0 Hz, H-10), 7.34 (1H, ddd, J ¼ 7.5, 7.5, 2.0 Hz, H-11), 7.40 (1H, dd, J ¼ 7.5, 2.0 Hz, H-9).14 EI MS: 338 (Mþ), 277 (100%).14 1

21-O-Methylleuconolam (12)

H NMR (400 MHz, CDCl3): 0.55 (3H, t, J ¼ 7.5 Hz, H-18), 1.28 (1H, dq, J ¼ 13.6, 7.5 Hz, H-19b), 1.49 (2H, m, H-14), 1.50 (3H, m, H15b, H-16b, H17b), 1.54 (1H, m, H-19a), 1.75 (1H, m, H-17a), 2.05 (1H, ddd, J ¼ 15.0, 5.0, 2.0 Hz, H-15a), 2.17 (1H, td, J ¼ 15.0, 6.0 Hz, H-16a), 2.61 (1H, td, J ¼ 12.5, 4.0 Hz, H-3b), 3.15 (3H, s, 21-OMe), 4.18 (1H, td, J ¼ 12.5, 4.0 Hz, H-3a), 6.33 (1H, s, H-6), 7.26 (1H, ddd, J ¼ 7.5, 1.0, 0.5 Hz, H-9), 7.34 (1H, m, H-10), 7.41 (1H, m, H-11), 7.42 (1H, m, H-12),8.25 (1H, br s, NH).19,23 EI MS: 340 (Mþ), 326, 325 (100%), 309, 308, 297, 280, 279, 251, 201, 186, 172, 154, 144, 130.19,23 1

N-Methylleuconolam (13) 1

H NMR (300 MHz, CDCl3): 0.56 (3H, H-18), 1.29e2.19 (10H, 5xCH2), 2.60 (1H, H-3b), 3.15 (3H, s, NMe), 4.20 (1H, H-3a), 6.20 (1H, H-6), 7.24e7.40 (4H, H-9, H-10, H-11, H-12), 7.75 (1H, OH).20 EI MS: 340 (Mþ), 325 (100%), 307, 297, 279, 265, 251, 237, 215, 201, 189, 184, 172, 154, 144, 137, 128, 116, 109, 98, 95.20 Arboloscine (24)

H NMR (400 MHz, CDCl3): 0.82 (3H, t, J ¼ 7.5 Hz, H-18), 1.42e1.44 (1H, m, H-16), 1.45e1.51 (1H, m, H-19), 1.56 (1H, ddd, J ¼ 13.0, 7.0, 3.0 Hz, H-17), 1.60e1.62 (1H, m, H-14), 1.62e1.65 (1H, m, H-16), 1.66e1.74 (1H, m, H19), 1.81e1.89 (1H, m, H-14), 2.49 (1H, dd, J ¼ 16.9, 9.9 Hz, H-15), 2.68 (1H, ddd, J ¼ 13.0, 7.0, 1.0 Hz, H-17), 2.73e2.78 (1H, m, H-15), 2.78e2.81 (1H, m, H-3), 3.21 (1H, td, J ¼ 12.6, 3.3 Hz, H-3), 3.83 (3H, s, CO2Me), 6.51 (1H, s, H-6), 7.09 (1H, td, J ¼ 7.6, 1.0 Hz, H-10), 7.33 (1H, ddd, J ¼ 8.2, 7.6, 1.0 Hz, H-11), 7.43 (1H, dd, J ¼ 7.6, 1.0 Hz, H-9), 8.35 (1H, d, J ¼ 8.2 Hz, H-12).28 EI MS: 340 (Mþ), 325, 279, 284, 252, 224, 196, 178, 56 (100%).28 1

(Continued)

66

Magnus Pfaffenbach and Tanja Gaich

Table 3 1H NMR chemical shifts and mass data for the rhazinilam-leuconoxinemersicarpine indole alkaloidsdcont'd Kopsiyunnanine C2 (7)

H NMR (500 MHz, CDCl3): 0.70 (3H, t, J ¼ 7.0 Hz, H-18), 1.21 (3H, t, J ¼ 7.0 Hz, OCH2CH3), 1.25 (1H, overlapped, H-19), 1.43 (1H, overlapped, H-17), 1.48 (1H, overlapped, H-19), 1.51 (1H, overlapped, H-15), 1.69 (1H, ddd, J ¼ 13.5, 13.5, 3.5, H-15), 1.90 (1H, br d, J ¼ 13.5 Hz, H-14), 1.96 (1H, dd, J ¼ 13.0, 7.0 Hz, H-16), 2.20 (1H, m, H-14), 2.38 (1H, overlapped, H-16), 2.44 (1H, overlapped, H-17), 3.48 (2H, qd, J ¼ 7.0, 1.5 Hz, OCH2CH3), 3.71 (1H, m, H-3), 4.07 (1H, dd, J ¼ 12.5, 5.5 Hz, H-3), 4.35 (2H, s, H-22), 5.74 (1H, s, H-6), 6.55 (1H, br s, NH), 7.20 (1H, br d, J ¼ 7.5 Hz, H-12), 7.30 (1H, ddd, J ¼ 7.5, 7.5, 1.5 Hz, H-10), 7.33 (1H, ddd, J ¼ 7.5, 7.5, 1.5 Hz, H-11), 7.40 (1H, dd, J ¼ 7.5, 1.5 Hz, H-9).14 EI MS: 352 (Mþ), 323, 307, 277 (100%).14 1

Arboloscine A (25)

H NMR (400 MHz, CDCl3): 0.82 (3H, t, J ¼ 7.3 Hz, H-18), 1.35 (3H, t, J ¼ 7.3 Hz, H-23), 1.48 (1H, m, H-14), 1.48 (1H, m, H-19), 1.56 (1H, m, H17), 1.64 (1H, m, H-15), 1.70 (1H, m, H-15), 1.74 (1H, m, H-19), 1.84 (1H, m, H-14), 2.50 (1H, ddd, J ¼ 17.0, 10.0 Hz, H-16), 2.70 (1H, m, H-17), 2.74 (1H, m, H-16), 2.79 (1H, m, H-3), 3.22 (1H, td, J ¼ 12.0, 3.0 Hz, H-3), 4.28 (2H, m, H-21), 6.51 (1H, s, H-6), 7.09 (1H, t, J ¼ 8.0 Hz, H-10), 7.32 (1H, t, J ¼ 8.0 Hz, H-11), 7.43 (1H, d, J ¼ 8.0 Hz, H-9), 8.35 (1H, d, J ¼ 8.0 Hz, H-12).29 ESI MS: 355 [M þ H]þ.29 1

5. PHARMACOLOGY 5.1 Natural Products Molecules with a conformationally restrictive biaryl axis bind to a variety of proteins and have been proven to be highly active therapeutic agents.114 Among them, rhazinilam (1) has been identified as a unique mitotic spindle poison exhibiting strong cytotoxicity toward various cancer cells in the low micromolar range. In vitro, ()-1 induces the formation of abnormal tubulin spirals similar to vinblastine (Vinca alkaloid effect) and inhibits the cold-induced disassembly of microtubules such as paclitaxel (taxoid effect).16 Interestingly, the biological activity of ()-rhazinilam (1) is restricted to the naturally occurring enantiomer.115 The cytotoxic activity of ()-rhazinilam (1) and its structural congeners against various cell

Table 4

13

C NMR chemical shifts for the rhazinilam-leuconoxine-mersicarpine indole alkaloids

124.2

122.2 168.9 124.4

131.4

OH

34.3 39.3 21.1

93.8 133.2

146.5 N 116.7 169.6

O

25.4

128.0

H

127.5 133.7

47.0 N 97.6

123.5

N

143.0

123.5 114.5

O

172.6

127.6

142.2 107.1 128.8 84.8 153.6

27.1 39.3 37.2 20.2

HO

30.7

N

23.9

135.5

116.9 119.2

32.8

O

130.3

O

(+)-Alstorisine A (26) 150 MHz, CDCl330

37.5

8.2

34.1 N 36.9 164.2 121.5 123.4 44.5 16.7 93.5 124.3 26.0 N 30.4 148.5 131.5 115.8 33.1 O 173.5

(+)-Melodinine E (17) 100 MHz, CDCl323,25

H 123.8 135.1

170.7

41.9 N 92.5

125.5

N

127.9

142.0 120.1

O

172.8

44.4 49.6

7.3

27.3 36.8 20.1 38.1 26.7

HO 120.6 135.6

128.9

(–)-Leuconoxine (15) 100 MHz, CDCl323,24

91.8 N 95.3

123.8

27.0 29.4

120.5 154.8

29.0 38.4 176.6 27.6

9.36

21.1 26.3

29.2 27.4 179.1 37.2

6.8

O

125.8

20.5

29.6

(–)-Leuconodine E (22) 100 MHz, CDCl311

176.4 28.2

(–)-Rhazinicine (2) 100 MHz, CDCl310,73,74

7.4 28.9 49.5 41.5

N 32.3 141.2 115.2 31.9 O 173.2

50.3

116.6 O 114.6 N 167.9 130.0 121.9 137.1 29.0 128.9 133.2 38.2 31.7 127.8 7.9 137.1 NH 29.7 127.5 33.6

3-Oxo-14,15-dehydrorhazinilam (4) 125 MHz, CDCl312

O

O

O

44.3

N 75.9 41.2

5,21-Dihydrorhazinilam (10) 22.5 MHz, CDCl315,19

159.6

137.4 NH 130.5

29.3

169.2

O

N

58.3

141.0 136.2

H 138.7 NH 126.6

8.6

28.6 37.0

116.4 127.3 122.1 136.8 129.2

127.7

28.0

114.4

127.8

127.9

129.2

(–)-Nor-rhazinicine (3) 100 MHz, CDCl311

7.2

H N

170.5 47.8

137.0 NH 127.4 176.7

O

130.2

O

N

42.7

28.1

105.8

(–)-Leuconodine D (21) 100 MHz, CDCl311

176.0 118.1

8.1

30.1 36.6

110.7

131.1 117.4 135.2 129.0 141.4

33.0

140.3 NH 126.7 177.4

O

32.0

19.4

38.8

7.4

28.9

46.0

(–)-Rhazinilam (1) 100 MHz, CDCl313,19

(–)-Mersicarpine (16) 100 MHz, CDCl342

31.4 50.9 40.3 19.9

120.6

N

117.3 138.0 130.5

127.2

6.8

29.1

33.3 52.2

119.0

109.5

22.9

The Rhazinilam-Leuconoxine-Mersicarpine Triad

50.5

N

127.0 129.4

73.1

128.8 137.9 133.2

H 136.4 NH 126.3 O

O N

92.0 44.9

66.6 19.1 34.6

32.4 27.5 178.5 27.8

7.4

(–)-5,21-Dihydrorhazinilam N-oxide (9) 100 MHz, CDCl311

67

(Continued)

13

68

Table 4

C NMR chemical shifts for the rhazinilam-leuconoxine-mersicarpine indole alkaloidsdcont'd 178.7 130.2 125.4 131.3 129.0

CHO

141.3

127.3

39.6

8.1

29.8 36.5 28.0 176.5

126.3 129.4 126.6

155.6 133.1

N

19.7

93.6 44.9

24.5

27.3 25.4

6.9

124.5 132.1

129.9

49.9

MeO 135.7 NH 128.6 O

34.5

24.7 26.6 28.9 179.1

7.4

126.9

137.9

O

43.3

N

19.0 39.1

127.3

(–)-3,14-Dehydroleuconolam (14) 100 MHz, CDCl311

128.3

42.2

172.0 7.7 28.5 36.8 36.7 19.4

93.5

125.4

27.3

N

27.5

141.9 119.6

173.1

O

177.8 32.1

126.7 151.0 133.1

107.6

135.5 NH 127.2

O

HO

49.6 N

32.5

NH

30.1 36.6 28.1 177.3

8.2

(–)-Kopsiyunnanine C3 (8) 125 MHz, CDCl314

N

141.3

O

N 97.4 45.5

132.1

35.9 19.6 32.5

24.1 26.2

7.3

178.6 28.0

(–)-21-O-Methylleuconolam (12) 100 MHz, CDCl319,23

x,y ¼ signals may be interchanged.

127.1 128.8

126.8 150.7 133.4

O

27.2 25.5

173.6

111.3 134.3

93.1

HO

155.0

29.5

N 97.5 45.6

36.0 19.7 32.7

24.3 26.5

7.3

177.6 28.0

(+)-N-Methylleuconolam (13) 100 MHz, CDCl320

140.8 120.4 127.1 88.1 124.0 130.9

N

142.5 118.3

O

169.6

27.0 26.6

N

136.5 121.0

O

173.6

36.8 25.4

26.4

29.9

126.6 111.4 131.5 116.4 140.3 127.3 131.9 128.0 137.9 NH 126.8

(+)-Arboloscine (24) 100 MHz, CDCl328

O

177.2

127.3

132.1

39.0

32.5

30.2 36.6 28.1

8.2

(–)-Kopsiyunnanine C2 (7) 125 MHz, CDCl314

8.2

(–)-Kopsiyunnanine C1 (6) 125 MHz, CDCl314

168.7

140.1 120.5 127.3 88.1 124.1 130.9

N

142.5 118.5

O

61.7 14.2

CO2CH2CH3 7.1 H 26.3 N 40.4

110.1 19.1

32.5

30.2 36.7 177.3 28.2

64.9 15.2

43.3

19.1 39.1

NH

OCH2CH3

N

43.3

128.1 137.9 126.9

57.1

OMe

N

116.5 140.3

O

(–)-Leuconodine C (20) 100 MHz, CDCl311

30.3

131.5

29.3

64.3

CO2Me 6.95 H 20.1 N 40.3

126.3 111.8

42.2 N

168.9 110.4

171.6 7.4 26.3 37.0 38.3 20.2

37.7

H

(–)-Leuconodine B (19) (Scholarisine G) 100 MHz, CDCl311,26

166.7

HO Me 135.8 N n.r. 129.9

6.9

22.4 36.8 20.0 39.1

114.4

120.7

30.2

O

170.0

90.4

125.6

O

166.8

O

81.9N

122.9 137.4

129.4

(–)-Leuconodine A (18) 100 MHz, CDCl311,23

O

127.0

HO

130.2

O

75.1

H

35.3

(–)-Leuconolam (11) 100 MHz, CDCl319,23

131.9

26.3

118.2

N 92.6 43.6

OH

169.7

20.2

36.9

30.4 25.2 29.9

(+)-Arboloscine A (25) 100 MHz, CDCl329

Magnus Pfaffenbach and Tanja Gaich

O

129.3 156.4 133.7

127.2

129.6 110.4 131.4 116.6 140.1 128.0 132.2

166.6

66.1

HO

166.5

HO 135.0 NH

27.7 37.8 20.1 37.6

(+)-Leuconodine F (23) 100 MHz, CDCl323,26

O 128.1

128.7

7.3

N 26.6 142.6 121.0 29.5 O 172.2

129.9

(–)-Rhazinal (5) 100 MHz, CDCl313

129.3

53.4 N 88.0

125.9

31.9

137.6 NH

O

H

125.1 126.2

18.5

127.7

157.5

192.5

46.3

N

120.4 138.2

56.9

O

O

O

The Rhazinilam-Leuconoxine-Mersicarpine Triad

69

lines is summarized in Table 5. Despite its promising activity profile, ()-rhazinilam (1) showed no in vivo activity and is therefore not suited as a potential pharmacological agent. Presumably, the loss of activity is attributable to its fast oxidation at positions C3 and C5 leading to various much less active metabolites such as (3S)-hydroxyrhazinilam (273) and ()-leuconolam (11).47 For this reason, numerous analogs that mimic the structure of ()-rhazinilam (1) have been prepared and investigated for their activity on tubulin and various cancer cells (Table 6). It should be noted that KB cells are in fact HeLa cells generated by human cell line cross contamination. Although known for over 30 years, this false cell line continues to appear in many scientific publications.116 Apart from their anticancer profile, ()-leuconolam (11) was found to exhibit no antibacterial activity against Escherichia coli, Bacillus subtilis, Staphylococcus aureus, Erwinia carotovora, and Bacillus cereus with MIC values above 250 mg/mL.79 ()-Rhazinilam (1) showed no in vitro antiplasmodial activity (IC50 superior to 1 mg/mL) on Plasmodium falciparum.117 To date, 3-oxo-14,15-dehydrorhazinilam (4), ()-3,14-dehydroleuconolam (14), (þ)-21-O-methylleuconolam (12), (þ)-N-methylleuconolam (13), and ()-5,21-dihydrorhazinilam N-oxide (9) have not been investigated. Among the leuconoxine subgroup, ()-leuconodine B (19) and ()-leuconodine D (21) showed moderate to weak cytotoxicity toward KB cells (IC50 ¼ 36e55 mM), while ()-leuconodine E (22) showed moderate activity in reversing MDR in vincristine-resistant KB cells (IC50 ¼ 30 mM).11 Leuconoxine (15) has been evaluated for its anti-inflammatory activity and showed selective inhibition (>85%) of COX-2.31 In 2016, the natural product has been patented for inhibiting the growth of human pancreatic cancer cell lines PANC-1 and BXPC-3.32 Furthermore, 15 has been found to show notable activity for suppressing M. tuberculosis with good application prospect.33 (þ)-Melodinine E (17) was found inactive (IC50 values > 40 mM) against the A549, HL-60, SMMC-7721, and SKBR-3 cell lines.25 To date, ()-leuconodine A (18), ()-leuconodine C (20), and (þ)-leuconodine F (23) have not been investigated. Arboloscine (24) has been found to be more active (IC50 ¼ 11 mg/mL for KB/VJ300; IC50 ¼ 3.8 mg/mL for KB/VJ300*)63 in reversing MDR in vincristine-resistant KB cells than its ethyl ester congener 25 (IC50 > 30 mg/mL for KB/ VJ300; IC50 ¼ 6.4 mg/mL for KB/VJ300*).29 The C5-degraded nor-leuconoxine 26 showed no significant in vitro activity in regulating hippocampal neural stem-cell proliferation.30 No biological testing is reported for ()-mersicarpine (16).

70

Table 5 Activity of the rhazinilam subgroup on various cancer cell lines KBa Cell Line(s) MRC-5b Cell A549c Cell HT29d Cell IC50/mM Line IC50/mM Line IC50/mM Line IC50/mM Natural Product

HCT 116e Cell Otherf Cell Line IC50/mM Lines IC50/mM

/S: 0.50e0.70 1.87 /VJ300: 0.83 /VJ300*: 1.16

>97, 0.35

0.35

1.29

MDA-MB231: 1.97 PC-3, MCF7: >97

()-Rhazinal (5)

/S: 0.73, 0.25 0.62 /VJ300: 0.76 /VJ300*: 0.93

>97

nt

0.47

MDA-MB231: 0.49 PC-3, MCF7: >97

5,21-Dihydrorhazinilam (10) ()-Rhazinicine (2)

in

nt

nt

nt

nt

nt

/S: 4.06, 3.24 /VJ300: 8.12, 8.11 /VJ300*: 6.01, 5.99

13.62

>97

nt

5.84

()-nor-rhazinicine (3)

/S: 17.33, 36-55

64.55

>97

nt

21.40

MDA-MB231: >97 PC-3, MCF7: >97 NIH/3T3: 67.4g HL-60: >194g HeLa: 9.4g MDA-MB231: 41.44 PC-3, MCF7: >97

65,59,47,119 65 65 59,14 59 65,59 65 65 59 59 119 59,65 59,65 59,65 59 59 120 120 120 59,11 59

Magnus Pfaffenbach and Tanja Gaich

()-Rhazinilam (1)

References

nt

nt

5.38

4.67

nt

nt

14

nt

nt

7.44

6.39

nt

nt

14

nt

nt

8.21

8.89

nt

nt

14

in

nt

nt

nt

nt

nt

47,119

in, inactive (or IC50 not measurable); nd, no (exact) IC50 determinable (due to low solubility or very weak activity); nt, not tested; IC50, the concentration corresponding to 50% growth inhibition after 72-hour incubation. a KB/S: vincristine-sensitive human oral epidermoid carcinoma cell line; KB/VJ300: vincristine-resistant human oral epidermoid carcinoma cell line; KB/VJ300*: with added vincristine, 0.1 mg/mL (0.121 mM), which did not affect the growth of the KB/VJ300 cells. b MRC-5: normal human lung fibroblast. c A549: human lung carcinoma. d HT29 human colon adenocarcinoma grade II cell line. e HCT-116: human colorectal carcinoma. f MDA-MB-231: estrogen-sensitive human breast adenocarcinoma; NIH/3T3: normal mouse fibroblast cells; HL-60: human promyelocytic leukemia cells; HeLa: human cervical cancer cells; PC-3: human prostate carcinoma; MCF-7: estrogen-sensitive human breast adenocarcinoma. g CD50: concentration level of cytotoxicity of the compounds toward 50% of cell viability.

The Rhazinilam-Leuconoxine-Mersicarpine Triad

()-Kopsiyunnanine C1 (6) ()-Kopsiyunnanine C2 (7) ()-Kopsiyunnanine C3 (8) ()-Leuconolam (11)

71

72

Table 6 Activity of rhazinilam (1) and its unnatural analogs on tubulin and cytotoxicity Inhibition of Microtubule Inhibition of Disassembly Microtubule Cytotoxic KB IC50/mMa Assembly IC50/mMa Cell Line IC50/mMb Compound

Cytotoxic MCF7c Cell Line IC50/mMb

References

Natural products

()-Rhazinilam (1)

6.7 7.0 18.0 nt nt 6.6 nt nt 17 nt 110

0.6 0.5 0.7 2.0 nt nt 1.0 nt nt 0.73, 0.25 8.1

4.0 nt nt nt nt 0.97 nt nt 1.8 >97 nt

121,122 123 70 124e126 119 127 128 119 127 59,65 47

in

in

in

nt

47,119

nt nt a: 150, b: in, c: 6 a: 6, b-h: in

68 56 9a-c: nt a: 77, b: 154, c: 154, d: 42, e: 42, f: 63, g: 154, h: 126

nt nt a: 100, b: 44, c: 4 a: in, b: 16.5, c: 32.5, d: 2, e: 16.5, f: 4, g: in, h: 2.5

8.6 9.2 9a-c: nt a-h: nt

127 127 125 123

Phenylpyrrole analogs

274 275 276a-c 277a-h

Magnus Pfaffenbach and Tanja Gaich

(þ)-Rhazinilam (1) ()-Rhazinilam (1) ()-Rhazinal (5) (3S)Hydroxyrhazinilam (273)d Leuconolam (11)

3.7 3.0 2.0 3.0 0.5 nt nt in nt nt 16

281 282a-b 283a-b 284 285

nt z100 nd nd in

279a-m

nt a-b: nt nd nd 27

a: 3.5, b: 3.5, c: 2.5, d: in, e: 12.5, f: 1, g: in a-m: nt

a: 6, b: in, c: 15, d: 25, e: 75, f: 75, g: 4, h: 20, i: in, j: in, k: 60, l: in, m: in, n: in, o: 1, p: 10, q: in, r: 10, s: 3, t: 3, in a-b: nt in in 7

a-g: nt

123

a: 4, b: 3, c: 3, d: 4, e: >10, f: >10, g: 8, h: >10, i: >10, j: 4, k: >10, l: 2, m: 4, n: >10, o: >10

127

nt

119

nt a-b: nt nt nt nt

119 130 123 123 128,129

a-d: nt

126

The Rhazinilam-Leuconoxine-Mersicarpine Triad

280a-t

a: 6, b: 9, c: in, d: in, a: 3.5, b: 14, c: 77, e: in, f: 21, g: in d: 56, e: 154, f: 28, g: in a-m: nt a: 27, b: 28, c: 25, d: 20, e: >100, f: >100, g: 28, h: >100, i: >100, j: 21, k: >100, l: 11, m: 47, n: >100, o: >100 nt nt

278a-g

Biphenyl analogs

a: 24, b: in, c: 45, d: 9 a-d: nt

287a-h

(þ)-a: in, ()-a: 1.5, a: 3.4, b: in, c: in,

a: 22, b: 22, c: 80, d: 21 (þ)-a: 10, ()-a: 2, a: 1.1, b: 2.9, c:

122,126 73

286a-d

(Continued)

288a-f 289a-f

74

Table 6 Activity of rhazinilam (1) and its unnatural analogs on tubulin and cytotoxicitydcont'd Inhibition of Microtubule Inhibition of Disassembly Microtubule Cytotoxic KB IC50/mMa Assembly IC50/mMa Cell Line IC50/mMb Compound

Cytotoxic MCF7c Cell Line IC50/mMb

References

a: 6, b: 16, c: 18, d: 20, e: 6.5, f: 9, g: 8, h: 3 a-f: nt

131

d: 39, e: 200, f: 6.3, a: 6.5, b: 160, c: 190, g: 19, h: nd d: 40, e: 100, f: 12, g: 73, h: nd a: in, b: 60, c: 51, d: a-f: nt 24, e: 48, f: in a-f: in a: in, b: in, c: 160, df: in

>20, d: 19, e: 11, f: 3.7, g: 4.0, h: 5.5 a-f: nt

a: >100, b: 92, c: 32, a-f: nt d: 70, e: 16, f: >100

128

a: in, b: in, c: in, d: 29, e: 42, f: 18 a: nd, b: nd, c: in

a-f: nt

a-e: >16, f: 16

a-f: nt

124

a: nd, b: nd, c: in

a-c: in

a-c: in

121

Phenylpyridine analogs

290a-f

in, inactive (or IC50 not measurable); nd, no (exact) IC50 determinable (due to low solubility or very weak activity); nt, not tested. a IC50 ¼ concentration required to inhibit 50% of microtubule assembly or disassembly. b IC50 ¼ concentration corresponding to 50% growth inhibition after 72-hour incubation. c MCF-7: estrogen sensitive human breast adenocarcinoma. d 3-Hydroxy metabolite of rhazinilam.

Magnus Pfaffenbach and Tanja Gaich

291a-c

The Rhazinilam-Leuconoxine-Mersicarpine Triad

75

5.2 Rhazinilam Analogs A broad variety of rhazinilam analogs has been prepared by chemical modification of isolated ()-rhazinilam (1), semisynthesis from (þ)-1,2dehydroaspidospermidine derivatives or de novo synthesis to enhance cytotoxicity and tubulin-binding activity. To date, none of the synthesized derivatives were found superior to the natural product. In Table 6, the structure-activity-relationship (SAR) results are summarized, and the analog structures are shown in Figs. 5 and 6. Most of the compounds have been assayed as racemates and their activities should be carefully compared to that of (L)-1. In 2005, Morita et al.118 investigated the correlation between the antitublin activity of these derivatives and the steric and electrostatic factors by using the comparative molecular field analysis (CoMFA). The CoMFA model allows estimating the biological activity of novel analogs. In the series of phenyl-pyrrole analogs (Fig. 5), contraction (274) as well as expansion (275) of ring D was deleterious to both cytotoxicity and induction of tubulin spirals. Additional substitution in piperidine ring D with ethyl 276a or benzyl 276b groups clearly decreased activity. Notably, the unsaturated ()-14,15-didehydrorhazinilam (276c) was only two times less active than ()-rhazinilam (1). Oxidation at C3 (280set) was tolerated. Compounds 282aeb, devoid of the six-membered ring D as well as the alkyl groups in ring B, showed very low binding activity. Substitutions at N1 of ring B (277aeh, 280ken, 280peq) as well as at C10 of the phenyl ring A (280iej) led to a dramatic loss of activity. Substitution on the pyrrole ring C (280aeh) had less consequences leading to derivatives with activity levels close (280g) to ()-rhazinilam (1). Replacing the carbonyl with a thiocarbonyl (280r) was tolerated. The ring-opened aniline 281 was completely inactive. The nine-membered B ring analogs substituted at C16 (278aeg) position were all less active than rhazinilam on tubulin. Interestingly, analog 278f incorporating an alcohol group retained its very high affinity for the protein. All C16b analogs were less active than the C16a compounds because they adopt a different conformation than ()-rhazinilam (1). The corresponding 11- and 12-membered macrocycles 283aeb and 284 exhibited very low activity probably due to the excessive flexibility of ring B. Replacing the ethyl side chain with a variety of substituents (279aen) resulted in partial or total loss of activity in most cases. While the ethyl halides (279bed) showed only slight reductions in activity, all compounds with oxygen atoms (279e, 279f, 279h, 279m, 279n) in the side chain were inactive. Only analog 279l with a bulky (phenylthio)ethyl group was as active as ()-rhazinilam (rac-1).

76 Magnus Pfaffenbach and Tanja Gaich

Figure 5 Phenylpyrrole (A) analogs of ()-rhazinilam (1).

The Rhazinilam-Leuconoxine-Mersicarpine Triad

77

Figure 6 Biphenyl (B) and phenylpyridine (C) analogs of ()-rhazinilam (1).

78

Magnus Pfaffenbach and Tanja Gaich

Among the seven-membered biaryl lactams, phenylpyrrole 285 proved to be superior to their biphenyl derivatives 289aee in both activity and cytotoxicity. The eight-membered ring lactam 289f bearing no alkyl group was inactive. In the series of biphenyl analogs, the incorporation of a urethane 287a/ 286d instead of a lactam 286a group resulted in the largest increase of activity. Both functionalities were shown to be more active than their lactone 286b or urea 286c counterpart (urethane > lactam > lactone > urea). The unsubstituted biphenyl-urethane analog ()-287a was found as the most active analog generated to date, possessing doubled tubulin-binding activity compared to 1 as well as comparable in vitro cytotoxicities toward human cancer cell lines. The racemate 287a is as active as 1 on both microtubules formation and dissociation but twofold less cytotoxic toward KB and MCF7 cells. Consistent with ()-rhazinilam (1), where the biological activity is restricted to the naturally occurring atropisomer, (þ)-287a completely loses its binding activity to tubulin. Increasing the steric hindrance on ring A by the introduction of various substituents (287beh) has been harmful to the antitubulin activity and to the cytotoxicity. The nitro compound 287f proved to be an exception showing only a twofold increase in antitubulin activity. The introduction of bulky alkyl groups at C9 (288aee and 289aee) was beneficial for activity probably due to the decrease of their conformational freedom along the biphenyl axis. Substituents with oxygen such as 288f were inactive. In the series of phenyl-pyridine analogs, the cyclic carbamate 290f showed the best results being six times less active than the parent ()-rhazinilam (1). Compounds 291aec bearing the nitrogen atom in the aniline moiety together with sterically hindered substituents proved to be inactive. Overall, the SAR studies have demonstrated that substitutions on rings A, C, and D decrease activity suggesting a rather narrow tubulin-binding pocket. Furthermore, the retention of the boat-chair conformation of ring B was essential for binding so that any substitution at N1 or C16 lowered the activity. The incorporation of a gem-ethyl group at C9 of the lactam (or preferentially urethane) ring B proved beneficial, proposing a direct interaction of the alkyl groups with tubulin.

6. PERSPECTIVES The rhazinilam-leuconoxine-mersicarpine subfamily of Aspidosperma alkaloids is comprised of a variety of diverse natural products with

The Rhazinilam-Leuconoxine-Mersicarpine Triad

79

unprecedented structural features and intriguing biological activities. Inspired by their challenging frameworks, this group of indole alkaloids has garnered enormous attention from the synthetic community. Numerous transformations and strategies have been developed to access the different key structural motifs highlighting the creative possibilities that natural product synthesis allows. While most of the ingenious examples described in this chapter have been reported within only the last 5 years, the first total synthesis of a member of this natural product triad was achieved more than 40 years ago. Since that time, rhazinilam (1) and its structural congeners have posed an attractive target for testing new synthetic strategies and methodologies, metal-catalyzed CeH bond functionalizations in particular. With seven completed total syntheses within the last 3 years, striking progress was made in the leuconoxine group. A variety of elegant synthetic routes have been reported to successfully establish the structurally unique diazafenestrane framework. In addition, most groups managed to selectively target all three different polycyclic alkaloid skeletons from one common precursor. In terms of efficiency, the broad majority of the syntheses reported to date have been completed in 10e14 steps longest linear sequence with average overall yields of 10% (rhazinilams), 7% (leuconoxines), and 16% (mersicarpine). Surprisingly, yet giving further credit to the groundbreaking synthesis by Smith in 1973, the number of steps necessary to access rhazinilam from commercially available materials has remained similar over the period of more than 40 years. The synthetic endeavors enclosed in this chapter constitute the frontier of natural product synthesis and a fruitful inspiration for future synthesis and methodology development. Nevertheless, several members of this triad have not yet been addressed by total synthesis, and it is certain that further breakthroughs will be disclosed in the next years.

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10, 2501e2512. (f) Pfaffenbach, M.; Gaich, T. Chem. Eur. J. 2016, 22, 3600e3610. 46. Ratcliffe, A. H.; Smith, G. F.; Smith, G. N. Tetrahedron Lett. 1973, 14, 5179e5184. 47. Décor, A.; Bellocq, D.; Thoison, O.; Lekieffre, N.; Chiaroni, A.; Ouazzani, J.; Cresteil, T.; Guéritte, F.; Baudoin, O. Bioorg. Med. Chem. 2006, 14, 1558e1564. 48. For reviews on Apocynaceae, see: (a) Endress, M. E.; Bruyns, P. V. Bot. Rev. 2000, 66, 1e56. (b) Nazar, N.; Goyder, D. J.; Clarkson, J. J.; Mahmood, T.; Chase, M. W. Bot. J. Linn. Soc. 2013, 171, 482e490. (c) Ping-Tao, L.; Leeuwenberg, A. J. M.; Middleton, D. J. Flora of China 1995, 16, 154e 155. 49. (a) Fischbach, M. A.; Clardy, J. Nat. Chem. Biol. 2007, 3, 353e355. (b) Austin, M. B.; O’Maille, P. E.; Noel, J. P. Nat. Chem. Biol. 2008, 4, 217e222. 50. O’Connor, S. E.; Maresh, J. J. Nat. Prod. Rep. 2006, 23, 532e547. 51. Le Men, J.; Taylor, W. I. Experientia 1965, 21, 508e510. 52. For the chartellamides, see: (a) Anthoni, U.; Bock, K.; Chevolot, L.; Larsen, C.; Nielsen, P. H.; Christophersen, C. J. Org. Chem. 1987, 52, 5638e5639. (b) Lin, X.; Weinreb, S. M. Tetrahedron 2001, 42, 2631e2633. (c) Pinder, J. L.; Weinreb, S. M. Tetrahedron Lett. 2003, 44, 4141e4143. (d) Pauletti, P. M.; Cintra, L. S.; Braguine, C. G.; da Silva Filho, A. A.; e Silva, M. L. A.; Cunha, W. R.; Januario, A. H. Mar. Drugs 2010, 8, 1526e1549. 53. Szab o, L. F. ARKIVOC 2008, iii, 167e181. 54. Hajícek, J. Collect. Czech. Chem. Commun. 2007, 72, 821e898. 55. (a) Wenkert, E. J. Am. Chem. Soc. 1962, 84, 98e102. (b) Wenkert, E.; Wickberg, B. J. Am. Chem. Soc. 1965, 87, 1580e1589. 56. Hugel, G.; Lévy, J.; Le Men, J. Tetrahedron Lett. 1974, 15, 3109e3112. 57. Croquelois, G.; Kunesch, N.; Poisson, J. Tetrahedron Lett. 1974, 15, 4427e4430. 58. Herges, R.; Papafilippopoulos, A.; Hess, K.; Chiappe, C.; Lenoir, D.; Detert, H. Angew. Chem. Int. Ed. 2005, 44, 1412e1416. 59. Kim, J.-L.; Sim, K.-S.; Yong, K.-T.; Loong, B.-J.; Ting, K.-N.; Lim, S.-H.; Low, Y.Y.; Kam, T.-S. Phytochemistry 2015, 117, 317e324. 60. Subramaniam, G.; Hiraku, O.; Hayashi, M.; Koyano, T.; Komiyama, K.; Kam, T.-S. J. Nat. Prod. 2008, 71, 53e57. 61. Robert, G. M. T.; Ahond, A.; Poupat, C.; Potier, P.; Jolles, C.; Jousselin, A.; Jacquemin, H. J. Nat. Prod. 1983, 46, 694e707. 62. Lyon, R. L.; Fong, H. H. S.; Farnsworth, N. R.; Svoboda, G. H. J. Pharm. Sci. 1973, 62, 218e221. 63. Lim, K.-H.; Hiraku, O.; Komiyama, K.; Koyano, T.; Hayashi, M.; Kam, T.-S. J. Nat. Prod. 2007, 70, 1302e1307. 64. Kitajima, M.; Anbe, M.; Kogure, N.; Wongseripipatana, S.; Takayama, H. Tetrahedron 2014, 70, 9099e9106. 65. Subramaniam, G.; Hiraku, O.; Hayashi, M.; Koyano, T.; Komiyama, T.; Kam, T.-S. J. Nat. Prod. 2007, 70, 1783e1789. 66. Subramaniam, G.; Kam, T.-S. Helv. Chim. Acta 2008, 91, 930e937. 67. Varea, T.; Kan, C.; Remy, F.; Sevenet, T.; Quirion, J. C.; Husson, H. P. J. Nat. Prod. 1993, 56, 2166e2169. 68. Kam, T.-S.; Yoganathan, K. Phytochemistry 1996, 42, 539e541. 69. Kam, T.-S.; Yoganathan, K.; Chuah, C.-H. Tetrahedron Lett. 1993, 34, 1819e1822. 70. Kitajima, M.; Ohara, S.; Kogure, N.; Wu, Y.; Zhang, R.; Takayama, H. Heterocycles 2012, 85, 1949e1959. ́ ́

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71. Zhang, Z.-J.; Du, R.-N.; He, J.; Wu, X.-D.; Li, Y.; Li, R.-T.; Zhao, Q.-S. Helv. Chim. Acta 2016, 99, 157e160. 72. Zeches, M.; Mesbach, K.; Richard, B.; Moretti, C.; Nuzillard, J. M.; Le Men-Olivier, L. Planta Med. 1995, 61, 89e91. 73. Kam, T.-S.; Subramaniam, G.; Chen, W. Phytochemistry 1999, 51, 159e169. 74. Gerasimenko, I.; Sheludko, Y.; St€ ockigt, J. J. Nat. Prod. 2001, 64, 114e116. 75. Kam, T.-S.; Sim, K.-M.; Koyano, T.; Komiyama, K. Phytochemistry 1999, 50, 75e79. 76. Kam, T.-S.; Sim, K.-M. Phytochemistry 1998, 47, 145e147. 77. Yamauchi, T.; Abe, F.; Chen, R.-F.; Nonaka, G.-I.; Santisuk, T.; Padolina, W. G. Phytochemistry 1990, 29, 3547e3552. 78. Wang, F.; Ren, F.-C.; Liu, J.-K. Phytochemistry 2009, 70, 650e654. 79. Chen, J.; Yang, M.-L.; Zeng, J.; Gao, K. Phytochem. Lett. 2014, 7, 156e160. 80. Johnson, J. A.; Sames, D. J. Am. Chem. Soc. 2000, 122, 6321e6322. 81. Johnson, J. A.; Li, N.; Sames, D. J. Am. Chem. Soc. 2002, 124, 6900e6903. 82. Ellis, C. S.; Ess, D. H. J. Org. Chem. 2011, 76, 7180e7185. 83. Magnus, P.; Rainey, T. Tetrahedron 2001, 57, 8647e8651. 84. Bowie, A. L., Jr.; Hughes, C. C.; Trauner, D. Org. Lett. 2005, 7, 5207e5209. 85. Liu, Z.; Wasmuth, A. S.; Nelson, S. G. J. Am. Chem. Soc. 2006, 128, 10352e10353. 86. Gu, Z.; Zakarian, A. Org. Lett. 2010, 12, 4224e4227. 87. McMurray, L.; Beck, E. M.; Gaunt, M. J. Angew. Chem. Int. Ed. 2012, 51, 9288e9291. 88. Sugimoto, K.; Toyoshima, K.; Nonaka, S.; Kotaki, K.; Ueda, H.; Tokuyama, H. Angew. Chem. Int. Ed. 2013, 52, 7168e7171. 89. Su, Y.; Zou, H.; Chen, J.; Xu, J.; Wu, X.; Lin, A.; Yao, H. Org. Lett. 2014, 16, 4884e 4887. 90. Gualtierotti, J.-B.; Pasche, D.; Wang, Q.; Zhu, J. Angew. Chem. Int. Ed. 2014, 53, 9926e9930. 91. Sugimoto, K.; Miyakawa, Y.; Tokuyama, H. Tetrahedron 2015, 71, 3619e3624. 92. Yamada, Y.; Ebata, S.; Hiyama, T.; Nakao, Y. Tetrahedron 2015, 71, 4413e4417. 93. Dagoneau, D.; Xu, Z.; Wang, Q.; Zhu, J. Angew. Chem. Int. Ed. 2016, 55, 760e763. 94. Banwell, M. G.; Edwards, A. J.; Jolliffe, K. A.; Smith, J. A.; Hamel, E.; VerdierPinard, P. Org. Biomol. Chem. 2003, 1, 296e305. 95. Bowie, A. L.; Trauner, D. J. Org. Chem. 2009, 74, 1581e1586. 96. Paleo, E.; Osornio, Y. M.; Miranda, L. D. Org. Biomol. Chem. 2011, 9, 361e362. 97. Sui, X.; Zhu, R.; Li, G.; Ma, X.; Gu, Z. J. Am. Chem. Soc. 2013, 135, 9318e9321. 98. Sailu, M.; Muley, S. S.; Das, A.; Mainkar, P. S.; Chandrasekhar, S. Tetrahedron 2015, 71, 1276e1282. 99. Beck, E. M.; Hatley, R.; Gaunt, M. J. Angew. Chem. Int. Ed. 2008, 47, 3004e3007. 100. Xu, Z.; Wang, Q.; Zhu, J. J. Am. Chem. Soc. 2013, 135, 19127e19130. 101. Xu, Z.; Wang, Q.; Zhu, J. J. Am. Chem. Soc. 2015, 137, 6712e6724. 102. Umehara, A.; Ueda, H.; Tokuyama, H. Org. Lett. 2014, 16, 2526e2529. 103. Yang, Y.; Bai, Y.; Sun, S.; Dai, M. Org. Lett. 2014, 16, 6216e6219. 104. Higuchi, K.; Suzuki, S.; Ueda, R.; Oshima, N.; Kobayashi, E.; Tayu, M.; Kawasaki, T. Org. Lett. 2015, 17, 154e157. 105. Pfaffenbach, M.; Gaich, T. Chem. Eur. J. 2015, 21, 6355e6357. 106. Li, Z.; Geng, Q.; Lv, Z.; Pritchett, B. P.; Baba, K.; Numarjiri, Y.; Stoltz, B. M.; Liang, G. Org. Chem. Front. 2015, 2, 236e240. 107. Biechy, A.; Zard, S. Z. Org. Lett. 2009, 11, 2800e2803. 108. Nakajima, R.; Ogino, T.; Yokoshima, S.; Fukuyama, T. J. Am. Chem. Soc. 2010, 132, 1236e1237. 109. (a) Iwama, Y.; Okano, K.; Sugimoto, K.; Tokuyama, H. Org. Lett. 2012, 14, 2320e 2322.

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(b) Iwama, Y.; Okano, K.; Sugimoto, K.; Tokuyama, H. Chem. Eur. J. 2013, 19, 9325e 9334. 110. Zhong, X.; Li, Y.; Han, F.-S. Chem. Eur. J. 2012, 18, 9784e9788. 111. Zhong, X.; Qi, S.; Li, Y.; Zhang, J.; Han, F.-S. Tetrahedron 2015, 71, 3734e3740. 112. Lv, Z.; Li, Z.; Liang, G. Org. Lett. 2014, 16, 1653e1655. 113. Pfaffenbach, M.; Gaich, T. Eur. J. Org. Chem. 2015, 16, 3427e3429. 114. (a) Hamel, E. Med. Res. Rev. 1996, 16, 207e231. (b) Jordan, A.; Hadfield, J. A.; Lawrence, N. J.; McGown, A. T. Med. Res. Rev. 1998, 18, 259e296. (c) Shi, Q.; Chen, K.; Morris-Natschke, S. L.; Lee, K.-H. Curr. Pharm. Des. 1998, 4, 219e248. 115. Thoison, O.; Guénard, D.; Sévenet, T.; Kan-Fan, C.; Quirion, J.-C.; Husson, H.-P.; Deverre, J.-R.; Chan, K.-C.; Potier, P. C. R. Acad. Sc. Paris Série II 1987, 304, 157e160. 116. Masters, J. R. W. Nat. Rev. Mol. Cell Biol. 2000, 1, 233e236. 117. Passemar, C.; Saléry, M.; Soh, P. N.; Linas, M.-D.; Ahond, A.; Poupat, C.; BenoitVical, F. Phytomedicine 2011, 18, 1118e1125. 118. Morita, H.; Awang, K.; Hadi, A. H. A.; Takeya, K.; Itokawa, H.; Kobayashi, J. Biorg. Med. Chem. Lett. 2005, 15, 1045e1050. 119. David, B.; Sévenet, T.; Thoison, O.; Awang, K.; Païs, M.; Wright, M.; Guénard, D. Bioorg. Med. Chem. Lett. 1997, 7, 2155e2158. 120. Halomatussakdiah, S.; Amna, U.; Tan, S.-P.; Awang, K.; Ali, A. M.; Nafiah, M. A.; Ahmad, K. Int. J. Pharm. Sci. Rev. Res. 2015, 31, 89e95. 121. Bonneau, A.-L.; Robert, N.; Hoarau, C.; Baudoin, O.; Marsais, F. Org. Biomol. Chem. 2007, 5, 175e183. 122. Baudoin, O.; Claveau, F.; Thoret, S.; Herrbach, A.; Guénard, D.; Guéritte, F. Bioorg. Med. Chem. 2002, 10, 3395e3400. 123. Décor, A.; Monse, B.; Martin, M.-T.; Chiaroni, A.; Thoret, S.; Guénard, D.; Guéritte, F.; Baudoin, O. Bioorg. Med. Chem. 2006, 14, 2314e2332. 124. Pasquinet, E.; Rocca, P.; Richalot, S.; Guéritte, F.; Guénard, D.; Godard, A.; Marsais, F.; Quéguiner, G. J. Org. Chem. 2001, 66, 2654e2661. 125. Dupont, C.; Guénard, D.; Tchertanov, L.; Thoret, S.; Guéritte, F. Bioorg. Med. Chem. 1999, 7, 2961e2969. 126. Pascal, C.; Dubois, J.; Guénard, D.; Tchertanov, L.; Thoret, S.; Guéritte, F. Tetrahedron 1998, 54, 14737e14756. 127. Edler, M. C.; Yang, G.; Jung, M. K.; Bai, R.; Bornmann, W. G.; Hamel, E. Arch. Biochem. Biophys. 2009, 487, 98e104. 128. Baudoin, O.; Cesario, M.; Guénard, D.; Guéritte, F. J. Org. Chem. 2002, 67, 1199e 1207. 129. Dupont, C.; Guénard, D.; Thal, C.; Thoret, S.; Guéritte, F. Tetrahedron Lett. 2000, 41, 5853e5856. 130. Alazard, J.-P.; Millet-Paillusson, C.; Boyé, O.; Guénard, D.; Chiaroni, A.; Riche, C.; Thai, C. Bioorg. Med. Chem. 1991, 1, 725e728. 131. Pascal, C.; Dubois, J.; Guénard, D.; Guéritte, F. J. Org. Chem. 1998, 63, 6414e6420.

CHAPTER TWO

FlavoalkaloidsdIsolation, Biological Activity, and Total Synthesis Lachlan M. Blair, Matthew B. Calvert and Jonathan Sperry1 University of Auckland, Auckland, New Zealand 1 Corresponding author: E-mail: [email protected]

Contents 1. Introduction 2. Isolation, Biological Activity, and Total Synthesis of Flavoalkaloids 2.1 Pyrrolidine-Flavoalkaloids 2.1.1 Total Synthesis of Pyrrolidine-Flavoalkaloids

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2.2 Pyrrolidinone-Flavoalkaloids 2.3 Piperidine- and Piperidinone-Flavoalkaloids

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2.3.1 Total Synthesis of Piperidine-Flavoalkaloids

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2.4 Indole-Flavoalkaloids

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2.4.1 Total Synthesis of Indole-Flavoalkaloids

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2.5 Aminoglycoside-Flavoalkaloids 2.6 Other Flavoalkaloids 2.7 Aglains and Related Flavoalkaloids

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2.7.1 Total Synthesis of Aglain Derivatives

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3. Isolation, Biological Activity, and Total Synthesis of Isoflavoalkaloids 4. Isolation and Biological Activity of Neoflavoalkaloids 5. Conclusions References

108 111 112 113

Abstract The flavoalkaloids possess unique molecular frameworks that contain both a flavonoid and alkaloid component. Flavoalkaloids result from the convergence of distinct biosynthetic pathways, affording natural products that display a wide range of interesting biological activities that would not be expected for flavonoids or alkaloids alone. This chapter collates all the known flavoalkaloids up until early 2016, detailing their isolation, bioactivity, and successful total syntheses.

The Alkaloids, Volume 77 ISSN 1099-4831 http://dx.doi.org/10.1016/bs.alkal.2016.04.001

© 2017 Elsevier Inc. All rights reserved.

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1. INTRODUCTION Flavonoids are an enormous class of natural products that are widespread throughout the plant kingdom and are associated with a plethora of health benefits, most notably their antioxidant properties.1 A natural product is classed as a flavonoid if it possesses the 15-carbon arylchromane depicted in Fig. 1, with all flavonoids (flavanones, flavonols, flavanols, flavones, flavanonols, flavans and flavylium salts) sharing this common core structure. The isoflavonoids and neoflavonoids are less abundant than flavonoids, but still represent an important class of compounds with medicinal potential.2 In comparison to the flavonoids, flavoalkaloids are considerably less in number. Flavoalkaloids are a structurally intriguing class of natural products that possess both a flavonoid and an alkaloid component. Although the term “alkaloid” historically refers to a natural product that possesses a basic nitrogen atom,3 all natural products that contain a flavonoid framework in addition to one or more nitrogen atoms are considered herein to be a flavoalkaloid, neoflavoalkaloid, or isoflavoalkaloid depending on the structure of the flavonoid fragment. The isolation and synthesis of chromone alkaloids has been previously reviewed by Houghton in an earlier volume of this series3 and in a later review by the same author,4 with their isolation and bioactivity reviewed again in early 2012.5 This chapter collates all known flavoalkaloids up until early 2016, detailing their isolation, bioactivity, and successful total syntheses. To be as comprehensive and clear as possible, the flavoalkaloids have been segregated according to structural class and relevant compounds from the previously published review articles3,5 are included where appropriate.

2. ISOLATION, BIOLOGICAL ACTIVITY, AND TOTAL SYNTHESIS OF FLAVOALKALOIDS 2.1 Pyrrolidine-Flavoalkaloids The first natural products discovered that possess both a flavonoid skeleton and a nitrogen atom were ()-ficine (1) and isoficine (2), isolated in

Figure 1 Flavonoid, isoflavonoid, and neoflavonoid.

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Figure 2 Pyrrolidine-flavoalkaloids 1e6.

1965 from the fig tree Ficus pantoniana King (Fig. 2).6 ()-Ficine (1) and isoficine (2) are interconvertible through the WesselyeMoser rearrangement, and hence a dynamic equilibrium of the two isomers was achieved upon heating ()-ficine (1) in 70% hydrochloric acid.6 Although the optical rotation was not stated for either compound in the original report,6 an article published several years later revealed the optical rotation of natural ()-ficine (1) ([a]D ¼ 60).7 However, no optical rotation was made known for isoficine (2). A subsequent synthesis of ()-ficine (1) followed by separation of both enantiomers (chiral HPLC) enabled the absolute configuration of each to be elucidated by X-ray crystallography.8 Given the large difference in optical rotation values ([a]D ¼ 160 vs. 60) between the synthetic (>99% ee) and natural material, it is probable the latter exists as a scalemic mixture. The separation of synthetic ()-ficine also enabled biological evaluation of the two enantiomers; ()-ficine (1) was shown to be a potent inhibitor of the cyclin-dependent kinases CDK1 and CDK5 (IC50 of 0.04 mM against both isoforms),8 while the (þ)-enantiomer was less active (IC50 of 0.39 mM against

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CDK1 and 0.57 mM against CDK5). ()-Isoficine (2) was also prepared in this study, but displayed no significant activity in these biological assays.8 In 1980, the number of known flavoalkaloids rose to three when phyllospadine (3) was isolated from the Japanese sea-grass Phyllospadix iwatensis, collected in the Yamagata Prefecture (Fig. 2).9 The optical rotation of phyllospadine (3) was not reported, and hence its enantiopurity is unknown. A short time later, the fruit of the tropical tree Vochysia guianensis was shown to contain the flavoalkaloid vochysine (4), which occurs naturally as a single racemic diastereomer, the relative stereochemistry of which was not determined (Fig. 2).10 The epimeric L-proline-flavonoid hybrids prolinalin A (5) and B (6) were isolated from the shells of the silkworm Bombyx mori in 2006 (Fig. 2).11 Acid hydrolysis of both 5 and 6 produced D1-pyrroline-5-carboxylic acid, which was in turn reduced to L-proline with sodium borohydride and derivatized with Marfey’s reagent. HPLC was then used to confirm the configuration (by comparison to the retention times of L-proline and 11 D-proline derivatized with Marfey’s reagent). With this assignment of 00 configuration at C2 , NMR data was used to establish the relative configuration at C500 and hence the absolute configuration of the natural products, which was 200 S,500 S in 5, and 200 S,500 R in 6 (Fig. 2).11 However, the optical rotation was not reported for either compound. 2.1.1 Total Synthesis of Pyrrolidine-Flavoalkaloids Many of the pyrrolidine-flavoalkaloids have succumbed to total synthesis. The first was reported in 1965 by Anjaneyulu and Govindachari, who accomplished the total synthesis of ()-ficine (1) in nine steps from

Scheme 1 The first total synthesis of ()-ficine (1).

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1,3,5-trimethoxybenzene (7) (Scheme 1).12 Their strategy relied on an early-stage installation of the nitrogen heterocycle followed by assembly of the flavonoid component (Scheme 1). The reaction of 7 with g-aminobutyric acid followed by N-methylation and reduction gave pyrrolidine 8 (Scheme 1). Subsequent FriedeleCrafts acylation in the presence of polyphosphoric acid and selective demethylation gave ketone 9 which underwent base-mediated condensation with benzaldehyde to provide chalcone 10 (Scheme 1). Intramolecular conjugate addition followed by dehydrogenation and O-demethylation gave ()-ficine (1) (Scheme 1). In 1982, Leete reported the biomimetic total synthesis of both ()-ficine (1) and ()-isoficine (2).8 The phenolic Mannich reaction of chrysin (11) with N-methyl-D1-pyrrolinium acetate led to both natural products 1 and 2 in a single step, albeit in very low yield (Scheme 2A). A similar Mannich reaction was later used by Wang and coworkers using pyrroline 12, affording ()-isoficine (2) as the sole product and in good yield (Scheme 2B).13 Wang and coworkers repeated this reaction and discovered that upon heating to 80 C, both ()-isoficine (2) and ()-ficine (1) were formed in low yields (A)

(B)

(C)

Scheme 2 Biomimetic ()-vochysine (4).

syntheses

of

()-ficine

(1),

()-isoficine

(2),

and

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(13% and 7%, respectively).7 A similar method was employed by Koch and coworkers in the total synthesis of ()-vochysine (4) from flavan 13 (Scheme 2C).9

2.2 Pyrrolidinone-Flavoalkaloids A number of pyrrolidinone-containing flavoalkaloids have been isolated. (þ)-Lilaline (14) was discovered in 1987 from the flowers of Lilium candidum, also known as the Madonna lily, collected in Slovakia (Fig. 3).14 The absolute configuration of 14 was not elucidated. Three years later the diastereomeric davalliosides A/B (15) were isolated from the rhizomes of Davallia mariesii Moore, a fern that has found use in traditional Korean medicine (Fig. 3).15 The absolute configuration at C-100 , C-2, and C-3 was not

Figure 3 (þ)-Lilaline (14), davalliosides A/B (15), and ()-N-ethylpyrrolidinonyl theasinensin A (16).

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determined for either of the davalliosides. In 2005 the pseudodimeric ()-N-ethylpyrrolidinonyl theasinensin A (16) was isolated from commercially available black tea (Fig. 3).16 The R-configuration of the biphenyl moiety was assigned by comparing the circular dichroism (CD) spectra to those of a related atropisomer.16 The authors posit that 16 was formed during processing of the tea leaves and is not a genuine natural product, also acknowledging the dearth of naturally occurring pyrrolidinones present in black tea.16 To support this theory, the group also carried out a semisynthesis of 16 from the condensation of the parent flavonoid with N-ethyl-5-hydroxy-2-pyrrolidinone.16 The absolute configuration at C500 was not established. In 2008, dracocephins AeD (17e20) were isolated from the aerial parts of Dracocephalum rupestre, collected in the Shangxi Province, China (Fig. 4).17 All four of the dracocephins were separated into their individual enantiomers (16 in total), and the absolute configuration of each determined. In the same year, ()-8-(200 -pyrrolidinone-500 -yl)quercetin (21) and ()-8(200 -pyrrolidinone-500 -yl)isorhamnetin (22) were isolated from the perennial herb Senecio argunensis Turcz collected in the Jilin Province, China (Fig. 4).18 ()-8-(200 -pyrrolidinone-500 -yl)quercetin (21) was also later isolated from the aerial parts of the Chinese herb Emilia sonchifolia.19 In 2009, the flavoalkaloids 6-(2-pyrrolidinone-5-yl)-()-epicatechin (23) and 8-(2-pyrrolidinone-5-yl)-()-epicatechin (24) were isolated from the roots of Actinidia arguta, collected in Korea (Fig. 5).20 Both were isolated as a mixture of diastereomers (23; 5:3, 24; 2:1). The 8-isomer 24 was later isolated from the pericarps of the evergreen tree Litchi chinensis (Sonn) as a single undetermined diastereomer21 and was also isolated from the plant Phyllanthus cochinchinensis.22 Biological assays revealed that 23 and 24 inhibited the formation of advanced glycation end-products with IC50 values of 36.0 mM and 47.8 mM, respectively.20 The 8-isomer 24 also exhibited moderate antioxidant activity in various assays.21 Drahebephin A (25) and B (26) were isolated in 2012 from the perennial herb Dracocephalum heterophyllum Benth, with both occurring naturally as racemates (Fig. 5).23 ()-Drahebephin A (25) was tested against A549 lung cancer cells, but showed no promising cytotoxicity.23

2.3 Piperidine- and Piperidinone-Flavoalkaloids In 1984, the isolation of nine flavoalkaloids possessing a piperidine heterocycle was reported, all from various parts of the tropical tree Buchenavia sp.24 ()-Buchenavianine (27) and (þ)-N-demethylbuchenavianine (28) were

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Figure 4 Dracocephins AeD (17e20), ()-8-(200 -pyrrolidinone-500 -yl)quercetin (21), and ()-8-(200 -pyrrolidinone-500 -yl)isorhamnetin (22).

isolated from the leaves of Buchenavia macrophylla (Eichl.) (Fig. 6).24 The further analogs ()-O-demethylbuchenavianine (29), N,O-bis-(demethyl) buchenavianine (30), ()-N-demethylcapitavine (31), and ()-2,3dihydrocapitavine (32), alongside ()-buchenavianine (27), were isolated from the fruit of B. macrophylla (Eichl.) (Fig. 6).24 Finally, the seeds of Buchenavia capitata contain (þ)-capitavine (33), ()-40 -hydroxycapitavine (34), and (þ)-2,3-dihydro-40 -hydroxycapitavine (35) (Fig. 6).24 Compounds 27, 28, 31, and 33e35 are optically active, notably with low magnitudes ([a]D ranging from 11 to þ9) aside from 35 ([a]D ¼ þ51). On the other hand, 29 and 32 were reported to have no optical activity, and 30 could not be measured due to solubility issues.24 The absolute stereochemistry was not established for any of the optically active compounds. In 1992, 27, 29, and

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Figure 5 6-(2-Pyrrolidinone-5-yl)-()-epicatechin (23), 8-(2-pyrrolidinone-5-yl)()-epicatechin (24), and ()-drahebephin A (25) and B (26).

30 were again isolated from B. capitata.25 Interestingly, 29 was reported to be optically active ([a]D ¼ 30) despite being reported as racemic in the initial isolation report,24 and the optical rotation of 30 was also successfully established ([a]D ¼ 2), while the optical rotation of ()-buchenavianine (27) was similar to the initial report ([a]D ¼ 8 vs. 4).25 ()-Buchenavianine was later obtained from the Institut de Chimie des Substances Naturelles (ICSN) chemical library, and its optical rotation was once again measured, which differed again from previous reports ([a]D ¼ 20).8 Furthermore, chiral HPLC of the natural ()-buchenavianine (27) obtained from the ICSN chemical library revealed that the enantiomeric excess was only 20%, and the authors suggested that racemization may have occurred on account of the basic extraction conditions.8 It is possible this issue was a factor in the isolation of the other members of this family, raising doubts over the reliability of the reported optical rotations. The synthesis of ()-buchenavianine and ()-O-demethylbuchenavianine followed by chiral HPLC afforded enantiopure material, and subsequent X-ray crystallography revealed the absolute configurations of both 27 and 29 (Fig. 6).8 In antiviral assays ()-O-demethylbuchenavianine (29) exhibited moderate cytoprotective effects against HIV in cultured human lymphoblastoid cells, but did not show promising activity in correlative anti-HIV assays.25 Much later biological testing showed that like

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Figure 6 Piperidine- and piperidinone-flavoalkaloids 27e38.

()-ficine (1), enantiopure ()-O-demethylbuchenavianine (29) inhibits CDK1 (IC50 of 0.03 mM) and CDK5 (IC50 of 0.05 mM), while the (þ)-enantiomer is less potent (IC50 of 1.1 mM against CDK1 and 0.95 mM against CDK).7 In 1984, an unrelated piperidine-containing flavanol (þ)-kopsirachine (36) was isolated from the leaves of Kopsia dasyrachis Ridl26 and again in 1999 from the same species (Fig. 6).27 While the relative configuration of positions C2 and C3 in the flavonoid unit of 36 was established, the relative

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configuration of the remaining stereocenters in the alkaloid units remains unknown. Very recently, the piperidinone flavoalkaloids 37 and 38 were isolated from the aerial parts of Astragalus monspessulanus ssp. monspessulanus, collected from Rodopi Mountain, Bulgaria (Fig. 6).28 The absolute configuration of the stereogenic centers in the sugar moieties of 37 and 38 was established following acid-hydrolysis of the natural products, derivatization to the corresponding (2S)-2-butyl glycosides, and comparison to standards with GCMS.28 However the configuration at C400 of the 3-hydroxypiperidin-2-one moiety could not be established for either of the flavoalkaloids, and the optical rotation was not stated for 37 or 38. 2.3.1 Total Synthesis of Piperidine-Flavoalkaloids The total synthesis of several piperidine-flavoalkaloids has been accomplished. The phenolic Mannich reaction used by Wang and coworkers in their biomimetic synthesis of ()-isoficine (2) (see Section 2.1.1, Scheme 2B) was extended to other 6-substituted flavoalkaloids including ()-N-demethylcapitavine (31), and ()-capitavine (33) by employing the appropriate six-membered cyclic imine 39 or iminium precursor 40 in the process (Scheme 3A).13 Furthermore, a method to form 8substituted flavoalkaloid derivatives facilitated the total synthesis of ()-N,O-bisdemethylbuchenavianine (30) in a 3:1 ratio with ()-Ndemethylcapitavine (31) (Scheme 3B).13

2.4 Indole-Flavoalkaloids The first indole flavoalkaloid to be discovered was ()-licorice glycoside E (41), isolated in 1997 from the roots of Glycyrrhiza uralensis, known as Tohoku licorice (Fig. 7).29 Assignment of the absolute configuration of 41 was based on CD spectra.29 In 1999 the oxindole-flavoalkaloid (þ)-42 was isolated from the seeds of the horse chestnut Aesculus hippocastanum L. (Fig. 7).30 Identification of the sugar moieties was aided by acid-hydrolysis, derivatization, and subsequent gas chromatography: however, the assignment of the configuration at C30 was not stated.30 Later, 42 was reisolated from the same species, and mass spectrometric analysis located an ion consistent with the deoxy analog 43 (Fig. 7), but full spectroscopic data were not obtained.31 In 2002, (þ)-lotthanongine (44) was discovered in the roots of Trigonostemon reidioides Craib, a shrub found in Southeast Asia which has been used in traditional medicines for its antiseptic and emetic properties, the latter proving useful to treat mycetism (Fig. 7).32 The absolute stereochemistry of 44 remains unknown.

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(A)

(B)

Scheme 3 Biomimetic total syntheses of piperidine-flavoalkaloids ()-30, ()-31, and ()-33.

In 2005, yuremamine was isolated from the stem bark of Mimosa tenuiflora, a plant used to prepare the psychoactive beverage yurema that is consumed for medicoreligious purposes by the indigenous population of Northeastern Brazil.33 The root bark of M. tenuiflora contains the serotonin agonist N,N-dimethyltryptamine (DMT), which itself is not orally active due to rapid metabolism by monoamine oxidase (MAO) in the digestive system. As there have been no MAO inhibitors detected in M. tenuiflora, there is ongoing interest into how yurema exerts its visionary effects. Yuremamine was initially assigned the pyrrolo[1,2-a]indole structure 45,33 but a biomimetic synthetic strategy served to reassign yuremamine to the flavoalkaloid structure 46 (Fig. 8).34 The optical rotation of natural yuremamine was not reported, and the absolute configuration remains unknown. ()-Uncariagambiriine (47) was isolated in 2009 from the leaves of Uncaria gambir Roxb. collected in Indonesia,35 and comprises the dihydrogambirtannine residue linked to the A ring of the flavanol catechin (Fig. 8).36 The

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Figure 7 ()-Licorice glycoside E (41), oxindoles (þ)-42 and 43, and (þ)-lotthanongine (44).

assignment of the absolute configuration of 47 was based on analysis of the CD spectra. 2.4.1 Total Synthesis of Indole-Flavoalkaloids The total synthesis of ()-lotthanongine (44) was accomplished in 2005 by Suzuki and coworkers (Scheme 4).37 A Larock indolization was used to convert iodoaniline 48 to tryptophol 49, which was converted to the corresponding azide and subjected to a Staudinger ligation with coumaric acid 50 to assemble the protected alkaloid fragment 51 (Scheme 4). The flavonoid fragment 52 was prepared in racemic form according to literature procedures37,38 and the Lewis-acid promoted union of the two fragments gave the coupled product 53 as a diastereomeric mixture favoring the required b-isomer (Scheme 4). Separation of 53-b followed by deprotection completed the total synthesis of ()-lotthanongine (44) (Scheme 4).

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Figure 8 Putative (45) and revised yuremamine (46), and ()-uncariagambiriine (47).

Given the proposed biological activity and intriguing structure of the pyrrolo[1,2-a]indole 45 initially assigned to yuremamine, several groups pursued its total synthesis,39 including our own (Scheme 5).34 As previously discussed, our bioinspired strategy led to the structural revision of yuremamine to the flavoalkaloid 46, which we initially hypothesized to be a biosynthetic intermediate during the assembly of the proposed pyrrolo [1,2-a]indole 45. The biomimetic synthetic study was initiated with the condensation of benzaldehyde 54 and acetophenone 55 to give the chalcone 56, which underwent typical ring closure and reduction followed by Upjohn dihydroxylation to provide the racemic diol 57 (Scheme 5). The Lewis acidepromoted union of 57 and N,N-dimethyltryptamine (DMT) selectively gave the b-isomer, thus providing protected flavoalkaloid 58 (Scheme 5). At this stage we envisaged that debenzylation followed by skeletal rearrangement of 46 to 45 would complete the total synthesis, but were astonished to find that the spectroscopic data of 46 were indistinguishable from those of the natural product, which ultimately led to the serendipitous structural revision and total synthesis of ()-yuremamine (46) (Scheme 5).

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Scheme 4 Total synthesis of ()-lotthanongine (44).

2.5 Aminoglycoside-Flavoalkaloids In 1984, the aminoglycosylated flavone 59 was isolated from the leaves of Myoporum tenuifolium E. Foster, commonly known as “siempre verde” among Spanish locals (Fig. 9).40 In the following year, the four additional analogs 60e63 were isolated from the same species (Fig. 9).41 The absolute configuration for these aminoglycosides was not established, and their optical rotations also were not stated. In 1997, the structurally distinct aminoglycoside ()-actinoflavoside (64) was isolated from the fermentation broth of the marine-derived bacteria Streptomyces sp. CNB-689 (Fig. 9). ()-Actinoflavoside (64) occurs naturally as a 1:1 diastereomeric mixture, from which the optical rotation was obtained ([a]D ¼ 110) and is an exceedingly rare example of a bacterial flavonoid (Fig. 9).42,43

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Scheme 5 Bioinspired total synthesis and structural revision of ()-yuremamine (46).

Acid-hydrolysis of 64 provided the aglycone and established that 64 is epimeric at C2.42 Notably, this flavonoid contains a 5-hydroxymethyl group which cannot be accounted for by the typical biosynthetic pathway of flavonoids, and the rare deoxyamino sugar ristosamine.42 Biological testing against a panel of cell lines revealed that 64 possesses weak antibacterial activity.42 The synthesis of the actinoflavoside aglycon has been accomplished by Yamaura and coworkers.44

2.6 Other Flavoalkaloids There exists a cohort of flavoalkaloids that do not fall under any particular category described previously. Such is the case for the unusual nicotinic

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Figure 9 Aminoglycoside-flavoalkaloids 59e64.

acidecontaining flavoalkaloid 65, isolated from the seeds of the horse chestnut A. hippocastanum L. in 1999 (Fig. 10).30 Identification of the sugar moieties was aided by acid-hydrolysis, derivatization, and subsequent gas chromatography. Unfortunately, due to a lack of sufficient material the optical rotation could not be obtained for 65.30 In 2000 the urea-containing flavonoid cheliensisine (66) was isolated from the Chinese plant Goniothalamus cheliensis (Fig. 10).45 The optical rotation of 66 was not stated in the isolation report, and configuration of the stereocenter is unknown. A further two urea-containing flavoalkaloids, (þ)-aquiledine (67) and (þ)-isoaquiledine (68), were isolated in the following year from Aquilegia ecalcarata, an herb collected in the Si-Chuan Province, China (Fig. 10).46 Although this herb is commonly used in traditional Chinese medicine, no biological studies with either 67 or 68 have been performed.46 The absolute configuration was not determined for the C100 position in either (þ)-aquiledine (67) or (þ)-isoaquiledine (68). ()-Glymontanine A (69) and B (70) were isolated in 2005 from the twigs and leaves of Glycosmis montana and represent unusual examples of flavoalkaloids containing a thiocarbamate group (Fig. 11).47 The absolute configuration in both 69 and 70 was assigned based on CD spectra.47 The pseudodimeric flavoalkaloid 6-aminoacryloylchamaejasmin (71) was

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Figure 10 Nicotinic- and urea-flavoalkaloids 65e68.

Figure 11 Thiocarbamate, acrylamide, and nitroalkyl flavoalkaloids 69e72.

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isolated in 2012 from the roots of Ormocarpum kirkii collected in Tanzania (Fig. 11).48 The optical rotation of 71 was not stated in the report, and assignment of the absolute configuration was aided by CD spectra.48 An unusual example of a flavonoid containing a nitroalkyl group (72) was isolated from the roots of Indigofera stachyodes, collected in Guizhou Province, China (Fig. 11).49 This compound was tested for its ability to protect human liver cells from carbon tetrachlorideeinduced hepatotoxicity and proved to be significantly active (122% survival rate).49 The absolute stereochemistry was not conclusively established in the report.

2.7 Aglains and Related Flavoalkaloids The genus Aglaia consists of over a 100 species belonging to the Mahogany family that occur throughout Southeast Asia and the Pacific.50 These species are rich in structurally intriguing natural products, including a large subset possessing the cyclopenta[b,c]benzopyran framework shown in Fig. 12. These natural products are generally regarded as “aglains” or the regioisomeric “aglaforbesins,” named after the earliest examples.51 Proksch proposed a biosynthesis of the aglains that commences with the conjugate addition of a flavonoid 73 to a cinnamamide 74, forging the key CeC bond at the flavonoid C2, followed by an aldol cyclization and reduction to form the framework characteristic of these natural products (Scheme 6).50 A similar pathway involving the inverse approach of the cinnamamide 74 would result in the aglaforbesin derivatives and interestingly, this annulation can selectively deliver either enantiomer of the aglains/aglaforbesins. As the isolation and biology of these flavoalkaloids spanning 1996 to 2001 were covered previously by Proksch and coworkers,50 only examples not included in their review will be included herein.

Figure 12 The aglain and aglaforbesin frameworks.

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Scheme 6 Biosynthetic assembly of the aglains as proposed by Proksch.

()-Pyramidaglain A (75) and (þ)-pyramidaglain B (76) were isolated from the leaves of Abralia andamanica Hiern, collected in Thailand, and the absolute configuration was not established in either (Fig. 13).52 Glycosylated aglain derivative ()-77 and aglaforbesin derivative ()-78 were isolated in the following year from the leaves of Amoora dasyclada collected in the Yunnan Province, China, and their absolute configurations were not stated (Fig. 13).53 Closely related compounds were later isolated from the leaves of Acrosticta foveolata in 2007, and named ()-foveoglin A (79), (þ)-foveoglin B (80), (þ)-isofoveoglin (81), alongside an unusual lactam variant ()-cyclofoveoglin (82) (Fig. 13).54 ()-Foveoglin A (79) exhibited cytotoxicity against a panel of cancer cell lines (ED50 of 1.4e1.8 mM), while (þ)-isofoveoglin (81) and ()-cyclofoveoglin (82) were weakly cytotoxic (ED50 of 13.5e21 mM), and (þ)-foveoglin B (80) was inactive.54 Furthermore, ()-foveoglin A (79) is an active NF-kB inhibitor (IC50 of 0.37 mM).54 Curiously, the cyclofoveoglin analog ()-83 was later isolated from the mangrove Amoora cucullata, which has the same relative stereochemistry as 82, and is notably isolated from a non-Aglaia species (Fig. 13).55 The similar [a]D values reported for 82 and 83 (51.7 and 63.1, respectively) suggest that they probably have the same absolute configuration, which is yet to be conclusively established. The

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Figure 13 Aglain and aglaforbesin flavoalkaloids 75e88.

cyclofoveoglin analog 83 showed TRAIL-resistance overcoming activity in human gastric adenocarcinoma cells (1.25 or 2.5 mM of 83 led to 45 or 57% more growth inhibition compared to cells treated with 100 ng/ mL TRAIL).55 In 2008 (þ)-desacetylpyramidaglain A (84), ()-desacetylpyramidaglain C (85), and (þ)-desacetylpyramidaglain D (86) were isolated from the leaves of Archidendron forbesii, collected in Thailand (Fig. 13).56 Although the authors invoked biosynthetic considerations to propose the absolute stereochemistry of 84-86, only the relative stereochemistry was conclusively proven. Each was screened for antibacterial and antiviral activity, and (þ)-desacetylpyramidaglain D (86) was moderately active against Mycobacterium tuberculosis H37Ra (MIC of 25 mg/mL) and Herpes simplex

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virus type 1 at the noncytotoxic concentration of 50 mg/mL.56 In 2013, ()-perviridisin A (87) and (þ)-perviridisin B (88) were isolated from the leaves, twigs, and fruits of Aplastodiscus perviridis, collected in Vietnam (Fig. 13).57 Both were tested against human colon cancer cells (HT-29), and (þ)-perviridisin B (88) exhibited significant cytotoxicity (ED50 of 0.46 mM) with no significant effect on normal colon cells (CCD112CoN).57 Further testing revealed that 88 moderately inhibits NF-kB (ED50 of 2.4 mM).57 The absolute stereochemistry of 87 and 88 is unknown. In 2006 a series of aglains possessing a pyrrolidine moiety named ()-edulirin A (89), ()-edulirin A 10-O-acetate (90), ()-19,20dehydroedulirin A (91), (þ)-isoedulirin A (92), and (þ)-edulirin B (93) were isolated from the bark of Aglaia edulis collected in Indonesia (Fig. 14).58 While the relative configuration of the stereogenic centers in the cyclopenta[b,c]benzopyran skeleton of compounds 89e93 was established, the stereochemistry C-13 could not be determined. All members of the family (89e93) were tested against a panel of human cancer cell lines but had no significant activity.58 In the following year the structurally related ()-ponapensin (94) was isolated from leaves and stems of Aglaia ponapensis

Figure 14 Edulirins 89e93, ()-ponapensin (94), and ()-elliptifoline (95).

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(Fig. 14).59 Enzyme inhibition assays revealed that 94 potently inhibits NFkB (IC50 of 0.064 mM).59 Ponapensin (94) bears close structural resemblance to elliptifoline (95), isolated in 2001 from Aporusa elliptifolia (Fig. 14).60 The absolute configurations of ()-ponapensin (94) and ()-elliptifoline (95) were later established following the total syntheses of their (þ)-enantiomers by the Porco group.61 Additionally, Porco reassigned the relative configuration of C13 in ()-elliptifoline (95) and proposed insightful considerations on the biosynthesis of enantioenriched aglains through kinetic resolution mechanisms.61 Yet another series of aglain and aglaforbesin derivatives were isolated from the leaves of Aglaia odorata, collected in the Yunnan Province, China, named aglaodoratins AeH (96e103) (Fig. 15).62 A combination of X-ray crystallography and analysis of CD spectra enabled the assignment of the absolute configuration in ()-aglaodoratin A (96), and CD spectra was also used to assign the configuration of the stereogenic centers in 97e103, however, the configuration at C19 was not clearly stated for these members of the family.62 Note also that ()-aglaodoratin G (102) is epimeric at C13 and exists as a 1:1 mixture of diastereomer from which the optical rotation was obtained ([a]D ¼ 6).62 All eight analogs were screened against a panel of cancer cell lines, with aglaodoratin C (98) performing well against HT-29 (IC50 of 0.097 mM) and MG-63 cells (IC50 of 1.2 mM).62 Aglaodoratin D (99) demonstrated selectivity for MG-63 cells (0.75-fold), and ()-aglaodoratin E (100) was cytotoxic to SMMC-7721 cells (IC50 of 6.25 mM).62

2.7.1 Total Synthesis of Aglain Derivatives As previously noted, Porco and coworkers reported an elegant asymmetric total synthesis of the potent NF-kB inhibitor (þ)-ponapensin (94) and also (þ)-elliptifoline (95), the first of any member of the aglain family, which also led to the assignment of their absolute configurations and revision of 95 (Scheme 7).61 Using an enantioselective photocycloaddition, the simple flavonoid 104 was rapidly converted to the cyclopenta[b,c]benzopyran framework 105, which was then subjected to stereoselective reduction, furnishing the core 106 of both (þ)-ponapensin (94) and (þ)-elliptifoline (95) with high enantioselectivity (Scheme 7). Conversion of ester 106 to the amide 107 followed by acid-mediated cyclization in the presence of methanol or 2-methylbut-2-enamide completed the asymmetric synthesis of (þ)-ponapensin (94) and (þ)-elliptifoline (95), respectively (Scheme 7).

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Figure 15 Aglaodoratins AeH (96e103).

3. ISOLATION, BIOLOGICAL ACTIVITY, AND TOTAL SYNTHESIS OF ISOFLAVOALKALOIDS An early example of an isoflavoalkaloid was reported in 1989, following the isolation of pallimamine (108) from the whole herb of Corydalis solida ssp. Tauricola, collected in Taiwan (Fig. 16).63 Pallimamine (108) exists as a racemic mixture, and its relative configuration was determined by X-ray crystallography.63 Drimiopsis A (109) and B (110) were isolated in 2006, from Drimiopsis barteri collected in Cameroon (Fig. 16).64 These isoflavoalkaloids feature a rare heteroaromatic framework comprised of fused isoquinoline

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Scheme 7 Total syntheses of (þ)-ponapensin (94) and (þ)-elliptifoline (95).

and benzopyran units. In 2008, ()-tonkinensine A (111) and B (112) were isolated from the roots of Sophora tonkinensis, a plant used in traditional Chinese medicine to treat throat infections (Fig. 16).65 In both tonkinensines, the alkaloid component is derived from cytisine. The absolute configuration of

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Figure 16 Isoflavoalkaloids 108e113.

111 and 112 was established based on a combination of X-ray crystallography, CD spectra, and biogenetic considerations. Both were tested against human cervical carcinoma (HeLa) and human breast cancer (MDA-MB-231) cell lines, with only ()-tonkinensine B (112) exhibiting moderate activity (IC50 of 24.3 mM against HeLa and 48.9 mM against MDA-MB-231).65 ()-11-Azamedicarpin (113) was isolated as a racemate from the roots of Robinia pseudoacacia, the Black Locust tree, and is an interesting aza-analog of the pterocarpan medicarpin.66 This natural product was subjected to a battery of biological testing, including antioxidant, aromatase inhibition, and nematodicidal assays, but showed no promising activity.66 Further screening of 113 against human promyelocytic leukemia cells (HL-60) revealed modest activity (cell survival of 72% at 40 mM 113 and 27% survival at 200 mM 113).66 Notably, oxidation of 113 to the corresponding indole (not shown) improved cytotoxicity.66 A concise total synthesis of ()-11-azamedicarpin (113) was carried out by Speicher and coworkers, the group who are also responsible for its

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Scheme 8 Total synthesis of 11-azamedicarpin (113).

isolation.66 A condensation reaction between acetophenone 55 and dimethylformamide dimethyl acetal provided the enamine 114 (Scheme 8). Subsequent cyclization of the enamine 114 then formed the iodochromone 115, which underwent Ullman cross coupling with aryl bromide 116 to furnish the isoflavone 117 (Scheme 8). The synthesis was then completed by a series of hydrogenation steps effecting hydrogenolysis of the nitro group and subsequent condensationecyclization, debenzylation, and saturation to install the dihydrochromenoindole (Scheme 8).

4. ISOLATION AND BIOLOGICAL ACTIVITY OF NEOFLAVOALKALOIDS There are limited examples of natural products that can be classified as neoflavoalkaloids. In 2009, the hydroxyethylamine-containing neoflavoalkaloids ()-ammonificin A (118) and B (119) were isolated from the marine hydrothermal ventederived bacterium Thermovibrio ammonificans, itself

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Figure 17 Ammonificins AeD (119e122).

collected on the East Pacific Rise at a depth of 2500 m (Fig. 17).67 In 2012, the unsaturated analogs ()-ammonificin C (120) and D (121) were also isolated from the same species (Fig. 17).68 The absolute configuration of 118 and 119 was established based on CD spectra. All four ammonificins were subjected to an apoptosis-induction assay, and ()-ammonificin A (118) and B (119) were inactive while C (120) and D (121) induced apoptosis at 2 and 3 mM, respectively.68

5. CONCLUSIONS The flavoalkaloids comprise a diverse array of unique structures that result from the convergence of distinct biosynthetic pathways (shikimic acid to assemble the flavonoid fragment, with the “alkaloid” moiety originating from amino acids such as L-tryptophan, L-ornithine or L-lysine). As flavoalkaloids possess both phenols and a basic nitrogen atom, the isolation of these amphoteric compounds from aqueous solution is challenging, but often rewarded with natural products that possess an array of interesting biological activities that would not be expected for flavonoids or alkaloids alone. A pertinent example is the semisynthetic flavoalkaloid flavopiridol (also known as alvocidib), a CDK K9 kinase inhibitor under clinical investigation for the treatment of various cancers.69 In particular, flavopiridol shows real promise in the treatment of chronic lymphocytic leukemia70 and acute myeloid leukemia,71 with the outcome of stage III clinical trials eagerly awaited. When also considering their unique molecular architectures, flavoalkaloids represent appealing synthetic targets from which many new discoveries have been made. For example, our own work on yuremamine uncovered the biosynthetic origins of this hybrid natural product and also served to reassign its structure. Porco’s total syntheses of

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(þ)-ponapensin and (þ)-elliptifoline showcases some fantastic synthetic methodology that had to be developed to access these complex flavoalkaloids. This review contains many more structurally unprecedented natural products, and it is hoped further studies toward their synthesis and detailed biological evaluation are initiated.

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23. Wang, L.; Wang, S.; Yang, S.; Guo, X.; Lou, H.; Ren, D. Phytochemistry 2012, 82, 166e171. 24. Ahond, A.; Fournet, A.; Moretti, C.; Philogene, E.; Poupat, C.; Thoison, O.; Potier, P. Bull. Soc. Chim. Fr. 1984, 41e45. 25. Beutler, J. A.; Cardellina, J. H., II; McMahon, J. B.; Boyd, M. R.; Cragg, G. M. J. Nat. Prod. 1992, 55, 207e213. 26. Homberger, K.; Hesse, M. Helv. Chim. Acta 1984, 67, 237e248. 27. Kam, T.-S.; Choo, Y.-M.; Chen, W.; Yao, J.-X. Phytochemistry 1999, 52, 959e963. 28. Krasteva, I.; Bratkov, V.; Bucar, F.; Kunert, O.; Kollroser, M.; Kondeva-Burdina, M.; Ionkova, I. J. Nat. Prod. 2015, 78, 2565e2571. 29. Hatano, T.; Takagi, M.; Ito, H.; Yoshida, T. Phytochemistry 1998, 47, 287e293. 30. H€ ubner, G.; Wray, V.; Nahrstedt, A. Planta Med. 1999, 65, 636e642. 31. Kapusta, I.; Janda, B.; Szajwaj, B.; Stochmal, A.; Piacente, S.; Pizza, C.; Franceschi, F.; Franz, C.; Oleszek, W. J. Agric. Food Chem. 2007, 55, 8485e8490. 32. Kanchanapoom, T.; Kasai, R.; Chumsri, P.; Kraisintu, K.; Yamasaki, K. Tetrahedron Lett. 2002, 43, 2941e2943. 33. Veps€al€ainen, J. J.; Auriola, S.; Tukiainen, M.; Ropponen, N.; Callaway, J. C. Planta Med. 2005, 71, 1053e1057. 34. Calvert, M. B.; Sperry, J. Chem. Commun. 2015, 51, 6202e6205. 35. Yoshikado, N.; Taniguchi, S.; Kasajima, N.; Ohashi, F.; Doi, K.-I.; Shibata, T.; Yoshida, T.; Hatano, T. Heterocycles 2009, 77, 793e800. 36. Merlini, L.; Mondelli, R.; Nasini, G.; Hesse, M. Tetrahedron 1967, 23, 3129e3145. 37. Hatakeyama, K.; Ohmori, K.; Suzuki, K. Synlett 2005, 1311. 38. Kawamoto, H.; Nakatsubo, F.; Murakami, K. J. Wood Chem. Technol. 1989, 9, 35e52. 39. (a) Ohyama, T.; Uchida, M.; Kusama, H.; Iwasawa, N. Chem. Asian J. 2015, 10, 1850e1853. (b) Johansen, M. B.; Kerr, M. A. Org. Lett. 2008, 10, 3497e3500. (c) Dethe, D. H.; Boda, R.; Das, S. Chem. Commun. 2013, 49, 3260e3262. 40. Esta~ n, M. T. Rev. Agroquím. Technol. Aliment. 1984, 24, 529e532. 41. (a) Esta~ n, M. T. Rev. Agroquím. Technol. Aliment. 1985, 25, 369e372. (b) Esta~ n, M. T. Rev. Agroquím. Technol. Aliment. 1985, 25, 273e278. 42. Jiang, Z.-D.; Jensen, P. R.; Fenical, W. Tetrahedron Lett. 1997, 38, 5065e5068. 43. Elshahawi, S. I.; Shaaban, K. A.; Kharel, M. K.; Thorson, J. S. Chem. Soc. Rev. 2015, 44, 7591e7697. 44. Suzuki, K.; Tsuruga, T.; Hiranuma, K.; Yamaura, M. Synlett 2004, 116e118. 45. Gu, Z.-B.; Liang, H.-Q.; Chen, H.-S.; Xu, Y.-X.; Yang, G.-J.; Zhang, W.-D. Acta Bot. Yunnan. 2000, 22, 499e502. 46. Chen, S.-B.; Gao, G.-Y.; Leung, H.-W.; Yeung, H.-W.; Yang, J.-S.; Xiao, P.-G. J. Nat. Prod. 2001, 64, 85e87. 47. Wang, J.; He, H.; Shen, Y.; Hao, X. Tetrahedron Lett. 2005, 46, 169e172. 48. Xu, Y.-J.; Foubert, K.; Dhooghe, L.; Lemiere, F.; Maregesi, S.; Coleman, C. M.; Zou, Y.; Ferreira, D.; Apers, S.; Pieters, L. Phytochemistry 2012, 79, 121e128. 49. Qui, L.; Liang, Y.; Tang, G.-H.; Yuan, C.-M.; Zhang, Y.; Hao, X.-Y.; Hao, X.-J.; He, H.-P. Phytochemistry Lett. 2013, 6, 368e371. 50. Proksch, P.; Edrada, R.; Ebel, R.; Bohnenstengel, F. I.; Nugroho, B. W. Curr. Org. Chem. 2001, 5, 923e938. 51. Dumontet, V.; Thoison, O.; Omobuwajo, O. R.; Martin, M.-T.; Perromat, G.; Chiaroni, A.; Riche, C.; Païs, M.; Sévenet, T.; Hadi, A. H. A. Tetrahedron 1996, 52, 6931e6942. 52. Puripattanavong, J.; Weber, S.; Brecht, V.; Frahm, A. W. Planta Med. 2000, 66, 740e 745.

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53. Chaidir; Lin, W. H.; Ebel, R.; Edrada, R.; Wray, V.; Nimtz, M.; Sumaryono, W.; Proksch, P. J. Nat. Prod. 2001, 64, 1216e1220. 54. Salim, A. A.; Chai, H.-B.; Rachman, I.; Riswan, S.; Kardono, L. B. S.; Farnsworth, N. R.; Carcache-Blanco, E. J.; Kinghorn, A. D. Tetrahedron 2007, 63, 7926e7934. 55. Ahmed, F.; Toume, K.; Sadhu, S. K.; Ohtsuki, T.; Arai, M. A.; Ishibashi, M. Org. Biomol. Chem. 2010, 8, 3696e3703. 56. Joycharat, N.; Greger, H.; Hofer, O.; Saifah, E. Phytochemistry 2008, 69, 206e211. 57. Pan, L.; Acu~ na, U. M.; Li, J.; Jena, N.; Ninh, T. N.; Pannell, C. M.; Chai, H.; Fuchs, J. R.; Carcache de Blanco, E. J.; Soejarto, D. D.; et al. J. Nat. Prod. 2013, 76, 394e404. 58. Kim, S.; Chin, Y.-W.; Su, B.-N.; Riswan, S.; Kardono, L. B. S.; Afriastini, J. J.; Chai, H.; Farnsworth, N. R.; Cordell, G. A.; Swanson, S. M.; et al. J. Nat. Prod. 2006, 69, 1769e1775. 59. Salim, A. A.; Pawlus, A. D.; Chai, H.-B.; Farnsworth, N. R.; Kinghorn, A. D.; Carache-Blanco, E. J. Bioorg. Med. Chem. Lett. 2007, 17, 109e112. 60. Wang, S.-K.; Cheng, Y.-J.; Duh, C.-Y. J. Nat. Prod. 2001, 64, 92e94. 61. Lajkiewicz, N. J.; Roche, S. P.; Gerard, B.; Porco, J. A., Jr. J. Am. Chem. Soc. 2012, 134, 13108e13113. 62. An, F.-L.; Wang, J.-S.; Wang, H.; Wang, X.-B.; Yang, M.-H.; Guo, Q.-L.; Dai, Y.; Luo, J.; Kong, L.-Y. Tetrahedron 2015, 71, 2450e2457. 63. Lu, S.-T.; Hwang, J.-F.; Wu, T.-S.; McPhail, D. R.; McPhail, A. T.; Lee, K.-H. Phytochemistry 1989, 28, 1245e1249. 64. (a) Ngamga, D.; Tane, P.; Bezabih, M.-T.; Abegaz, B. M. Planta Med. 2006, 72, 1009. (b) Ngamga, D.; Bipa, J.; Lebatha, P.; Hiza, C.; Mutanyatta, J.; Bezabih, M.-T.; Tane, P.; Abegaz, B. M. Nat. Prod. Commun. 2008, 3, 769e777. 65. Li, X.-N.; Lu, Z. Q.; Qin, S.; Yan, H.-X.; Yang, M.; Guan, S.-H.; Liu, X.; Hua, H.-M.; Wu, L.-J.; Guo, D.-A. Tetrahedron Lett. 2008, 49, 3797e3801. 66. Dejon, L.; Mohammed, H.; Du, P.; Jacob, C.; Speicher, A. Med. Chem. Commun. 2013, 4, 1580e1583. 67. Andrianasolo, E. H.; Haramaty, L.; Rosario-Passapera, R.; Bidle, K.; White, E.; Vetriani, C.; Falkowski, P.; Lutz, R. J. Nat. Prod. 2009, 72, 1216e1219. 68. Andrianasolo, E. H.; Haramaty, L.; Rosario-Passapera, R.; Vetriani, C.; Falkowski, P.; White, E.; Lutz, R. Mar. Drugs 2012, 10, 2300e2311. 69. Senderowicz, A. M. Invest. New Drugs 1999, 17, 313e320. 70. Christian, B. A.; Grever, M. R.; Byrd, J. C.; Lin, T. S. Clin. Lymphoma Myeloma 2009, 9, S179eS185. 71. Zeidner, J. F.; Foster, M. C.; Blackford, A. L.; Litzow, M. R.; Morris, L. E.; Strickland, S. A.; Lancet, J. E.; Bose, P.; Levy, M. Y.; Tibes, R.; et al. Haematologica 2015, 100, 1172e1179.

CHAPTER THREE

Chemistry and Biology of the PyrroleeImidazole Alkaloids Thomas Lindel TU Braunschweig, Institute of Organic Chemistry, Braunschweig, Germany E-mail: [email protected]

Contents 1. 2. 3. 4.

Introduction Structures Biosynthesis Total Synthesis 4.1 Sceptrin 4.2 Ageliferin 4.3 Axinellamines 4.4 Massadine 4.5 Palau’amine 4.6 Proposed Structure of Nagelamide D 4.7 Agelastatin 4.8 Cyclooroidin and Hanishin 4.9 Ageladine A 4.10 Dibromoagelaspongin 4.11 Dibromophakellstatin and Dibromophakellin 4.12 Oroidin 5. Biological Activity 5.1 Anticancer Activity 5.2 Antimicrobial Activity and Action on Biofilms 5.3 Activity Against Cystic Fibrosis 5.4 Feeding Deterrence and Action on Channels 6. Conclusion References

118 119 129 135 135 140 146 152 157 165 167 178 186 188 191 198 202 202 206 208 210 210 212

Abstract More than a decade after our last review on the chemistry of the pyrroleeimidazole alkaloids, it was time to analyze once more the developments in that field. The comprehensive article focusses on the total syntheses of pyrroleeimidazole alkaloids that have appeared since 2005. The classic monomeric pyrroleeimidazole alkaloids have all been synthesized, sometimes primarily to demonstrate the usefulness of a new method, as in The Alkaloids, Volume 77 ISSN 1099-4831 http://dx.doi.org/10.1016/bs.alkal.2016.12.001

© 2017 Elsevier Inc. All rights reserved.

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j

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the case of the related molecules agelastatin A and cyclooroidin with more than 15 syntheses altogether. The phakellin skeleton has been made more than 10 times, too, with a focus on the target structure itself. Thus, some of the pyrroleeimidazole alkaloids are now available in gram amounts, and the supply problem has been solved. The total synthesis of the dimeric pyrroleeimidazole alkaloids is still mostly in its pioneering phase with two routes to palau’amine and massadine discovered and three routes to the axinellamines and ageliferin. In addition, the review summarizes recent discoveries regarding the biological activity of the pyrroleeimidazole alkaloids. Regarding the biosynthesis of sceptrin, a pathway is proposed that starts from nagelamide I and proceeds via two electrocyclizations and reduction.

1. INTRODUCTION Among nitrogen-containing natural products from marine sources, the pyrroleeimidazole alkaloids take a prominent position. The exploration of the pyrroleeimidazole alkaloids started in 1969, when ()-dibromophakellin (()-1, Fig. 1) was isolated from the marine sponge Phakellia flabellata. The biogenetic key metabolite oroidin (2) was described shortly after. Oroidin (2) functions as basis of structural diversity on the skeleton level by undergoing cyclization, dimerization, or reaction with other metabolites. Regarding its structural diversity, the oroidin family compares well with the benzyltetrahydroisoquinoline-derived alkaloids from terrestrial plants, of, which morphine constitutes the most prominent example. Even after almost 50 years of research, the isolation and structure elucidation of new pyrroleeimidazole alkaloids continues and has reached some maturity. On the synthesis side, different routes have accessed almost all of the smaller pyrroleeimidazole alkaloids efficiently, solving the supply problem in most cases. The higher pyrroleeimidazole alkaloids consisting of more than one oroidin unit continue to be attractive targets, such as palau’amine, which was synthesized O

O Br

N

Br

N Br

HN

N NH2

(–)-1: (–)-dibromophakellin (1969)

Br

NH2 N H

H N O

2: oroidin (1971)

N NH

N

H NH2

N HN

NH

H2N

HO N

NH

Cl

NH2 (–)-3: (–)-palau'amine (1993, revised relative configuration 2007)

Figure 1 The first, the parent, and the famous: ()-dibromophakellin (()-1), oroidin (2), ()-palau’amine (()-3).

Chemistry and Biology of the PyrroleeImidazole Alkaloids

119

in 2010 (()-3) and 2015 (rac-3). Toward the higher pyrroleeimidazole alkaloids, there is still a clear need for more efficient routes. The biological activity of the pyrroleeimidazole alkaloids has been explored to some extent, and there should be more to be discovered. Not unexpectedly, research progress on a hot topic such as the pyrrolee imidazole alkaloids has been reviewed several times, beginning with the 2001 article by Al-Mourabit and Potier1 who also outlined the possible biogenetic interrelationships between the pyrroleeimidazole alkaloids. We compiled a comprehensive review on the synthesis of the pyrrolee imidazole alkaloids in 2003,2 which was extended in 2005.3 Weinreb published a review on the synthesis of the pyrroleeimidazole alkaloids in 20074 and Papeo et al. published a review covering the period from 2005 until 2009.5 A comprehensive article was published in 2011 by Al-Mourabit et al. that outlines the possible biogenetic relationships of the pyrrolee imidazole alkaloids in detail, in addition to syntheses and biological activity.6 The most recent review article was published in 2014 by Chen et al. who discussed the synthesis and the biogenetic interrelations of the dimeric pyrroleeimidazole alkaloids.7 There are also review articles on particular topics such as the synthesis of the phakellin-type pyrroleeimidazole alkaloids and relatives by the Feldman group8 and by Nagasawa et al.9 the functionalization and reactivity of vinylimidazoles by the Lovely group,10 or a short review covering Baran’s first syntheses of ()-palau’amine (()-3) and the axinellamines.11 The present review addresses the developments since 2005, when our last review had appeared. The isolation and structure elucidation, total synthesis, biological activity, and the medicinal chemistry of the pyrroleeimidazole alkaloids are covered.

2. STRUCTURES The first pyrroleeimidazole alkaloid, ()-dibromophakellin (()-1, Fig. 1), was isolated in 1969 from the marine sponge P. flabellata.12,13 Since then, more than 220 members of that structurally diverse family of secondary metabolites have been discovered in marine sponges of the genera Agelas, Stylissa, Phakellia, Axinella, and Hymeniacidon. The parent compound of the family is oroidin from Agelas oroides (2, 1971, Fig. 1),14,15 the skeleton of which can undergo various cyclizations, dimerizations and even tetramerizations, as well as reactions with other metabolites. About one-third of the pyrroleeimidazole alkaloids contain two oroidin-derived units, about half

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contain one. ()-Palau’amine (()-3, 1993, Fig. 1) from Stylotella aurantium16 is the most famous pyrroleeimidazole alkaloid falling one pyrrole unit short of being a “dimer.” For reasons of simplicity, the pyrroleeimidazole alkaloids are often coined “monomers” (Figs. 2 and 3) and “dimers” (Figs. 47), which is not meant in a strict chemical sense, since such a “dimer” does not have to have the exactly doubled molecular formula of oroidin (2). The stylissadines (see below) are the only pyrroleeimidazole alkaloids constituted by four core units. There are no “trimers.” Figs. 17 give one example for every currently known type of pyrroleeimidazole alkaloid that contains at least one oroidin-derived unit. The subgroups are represented by their longest-known member. In addition, other structural motifs such as taurine may be incorporated in a pyrroleeimidazole alkaloid, which justifies including them in the list. The 2-aminoimidazole or 2-aminoimidazoline units are mostly given in their neutral form, although they may be

H2N

N

O

H N

HN

O

O N

Br Br

NH

N H

N

HN

NH2

O

4: debromo(–)-5: (–)-dibromohymenialdisine (1980) isophakellin (1986)

Br Br

H N

N

O

H N

NH

8: mauritamide A (rac, 1994)

N H

H N

Br H2N

O

NH HH NH

NH OH O

6: dibromoagelaspongin (rac, 1989)

(–)-7: (–)-agelastatin A (1993) NH

Br Br

N

N H

H N

HO

HN

NH HN

O

SO3

O3S

Br

N N

Br

NH2 NH

O

HO Br H N

N

H H N O

O

9: tauroacidin A (6:4 mixture of enantiomers, 1997) O

NH

H N

NH

N

N

NH2

OH

O

(+)-10: (+)-slagenin A (1999)

Br

Br

(–)-11: (–)-cyclooroidin (2000)

Figure 2 Pyrroleeimidazole alkaloids sharing one core unit, Part 1; for the structures of ()-dibromophakellin (()-1), 1969) and oroidin (2, 1971), see Fig. 1.

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Chemistry and Biology of the PyrroleeImidazole Alkaloids

O

H N

Br N

Br

Br Br

H

N

H N

N H

NH2

O

NH2 12: ugibohlin (2001)

Br

HO H N N

NH2

N H H SO3

HN

Br H N

N H

N

O

NH2 O

Br

Br

HN

N NH2

N H N

16: nagelamide W (rac, 2013) CO2H O

O

O

H N

N H HN

NH2

H2N

H2N

H N

NH

N N H H

O O3S

N H

SO3

15: (–)-nagelamide U (2013)

Br

N H

O

H N

Br

HO2C O H N

14: (–)-nagelamide N (2008)

13: (–)-nagelamide M (2008) NH2

Br

Br

O N

H2N 17: (+)-agelamadin C (2014)

Br Br

N N H

H N O

N N H

NH2

18: agelamadin F (2015)

Figure 3 Pyrroleeimidazole alkaloids sharing one core unit, Part 2.

protonated under physiological or isolation conditions. The pKa value of a 2-aminoimidazolium ion in water is about 8.5, whereas the pKa of a guanidinium moiety that is not incorporated in the aromatic imidazole ring may vary between 8.5 and 12.5, increasing with decreasing ring strain.17 After ()-dibromophakellin (()-1)12,13 and oroidin (2, structure revision in 1973),14,15 it took 9 years to find a new skeleton in debromohymenialdisine from P. flabellata (4, Fig. 2).18 ()-Dibromoisophakellin (()-5)19 from Axinella carteri and its enantiomer cantharelline,20 and the racemic dibromoagelaspongin (6)21 from Agelas sp. were the two other novel monomeric pyrroleeimidazole alkaloids found in the 1980s (Fig. 2). Among the monomeric pyrroleeimidazole alkaloids, the 1990s provided the first agelastatins (()-agelastatin A: ()-7) from Agelas dendromorpha,22 the taurine adducts mauritamide A (8) from Agelas mauritiana23 and tauroacidin A (9) from Hymeniacidon sp.,24 and, included here, (þ)-slagenin A ((þ)-10) from Agelas nakamurai (Fig. 2).25 After 2000, ()-cyclooroidin (()-11, Fig. 2) from A. oroides26 and ugibohlin (12, Fig. 3)27 from A. carteri

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H N Br

HN

Br

HN N H

NH2

H N

O

NH2

HN

H N

Br

HN

N

NH2

N NH2

N H

N H

Br N

H

NH HO N

Br

NH2 NH

Cl Br

(–)-21: (–)-styloguanidine (1995, revised relative configuration 2007) O N

O

H

H2N

NH HO N

NH

Cl

HN

H N

N O

O

N H

NH

H N

NH2

N

O

22: mauritiamine (rac, 1996) H N

H N

Br

N H

N HN

NH2

N H Br

NH2

Br

O

(–)-20: (–)-ageliferin (1990, revised absolute configuration 2014)

O

H2N

N

Br

(–)-19: (–)-sceptrin (1981, revised absolute configuration 2014)

HN

O

N

O

H N

HN

H N

Br

NH2 (–)-23: (–)-konbu'acidin (1997, revised relative configuration 2007)

O

H N

Br

HN

N

Br

HN

CO2H

N H

NH2

O

(–)-24: (–)-nakamuric acid (1999, revised absolute configuration 2014)

Figure 4 Pyrroleeimidazole alkaloids derived from more than one core unit, Part 1; for the structure ()-palau’amine (()-3), 1993), see Fig. 1.

were the only novel monomeric pyrroleeimidazole alkaloids that were not “hybrids” with another metabolite. In addition, Fig. 3 lists four hybrid-type nagelamides (M,28 the rearranged N,28 U,29 W29), and hybrid agelamadins C (17)30 and F (18),31 all from Agelas sp., as independent pyrroleeimidazole alkaloids sharing one core unit. Nagelamides M (13), N (14), and U (15) have incorporated a taurine moiety. In nagelamide U (15), the imidazole of the core unit has opened. Racemic nagelamide W (16) is, formally, formed by addition of guanidine to the alkene double bond of oroidin (2). In agelamadine C (17), a similar addition, this time of 3-hydroxykynurenine, has taken place, whereas in agelamadine F (18), the 2-aminoimidazole section of oroidin (2) has reacted in an oxidative manner with 3-hydroxypyridine.

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Chemistry and Biology of the PyrroleeImidazole Alkaloids

Br

Br

Br

HO NH Cl

O

N

O

NH2

N H

NH2

O

NH2

26: nagelamide A (rac, 2004)

NH2

Br

HO HN

H N

HN

Br NH

O

HO HN

HN

H NH

NH2

O

Br (–)-27: (–)-massadine (2006)

Br

N H

O N H

HH N

H H N N OCH3

O

HN

N NH2

(–)-29: (–)-nagelamide J (2007)

Br Br HN H2N

O

H

N

H N

N H

NH NH

HO N

Br Br

Cl

NH2 (–)-28: (–)-carteramine A (2007)

Br Br

O

H N

NH

H

O

H N

N

HN

Br

Br

NH2

N

H N H

Br

(–)-25: (–)-axinellamine A (1999)

Br

O

H N

NH

H N HO

HN

NH

HN

N H

Br Br

NH

Br

HN

Br NH2

H N

O

Br

HN

Br

HN

Br

N H

O

HN

NH2 N NH

N

NH HN

O3S

30: (–)-nagelamide K (2008)

Figure 5 Pyrroleeimidazole alkaloids derived from more than one core unit, Part 2.

In 1981, ()-sceptrin (()-19) from Agelas sceptrum was the first dimeric pyrroleeimidazole alkaloid (Fig. 4),32 followed by ()-ageliferin from Agelas sp. (()-20),33 ()-palau’amine (()-3)16 and the palau’amine regioisomer ()-styloguanidine (()-21)34 from S. aurantium, the racemic dimer mauritiamine (22)35 from Agelas sp., ()-konbu’acidin (()-23)36 from Hymeniacidon sp., ()-nakamuric acid (()-24)37 from A. nakamurai, and ()-axinellamine A (()-25, Fig. 5) from Axinella sp.,38 all discovered in the 1990s. The relative configurations of all pyrroleeimidazole alkaloids sharing the ring system with ()-palau’amine (()-3) have been revised in 2007. This is also true for the ()-styloguanidine (()-21, Fig. 4) series with an inverted pyrrole ring.

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Thomas Lindel

O

O Br

H N

Br

O

H N

Br

NH N

H2N

N H

HN

H N NH2

Br

NH N NH2

O

N H

31: nagelamide L (rac, 2008)

32: benzosceptrin A (2009)

NH2

H N

Br

NH

HN

NH2

Br

N

N H

Br

N

NH2

O

O

HN

HN

Br

Br NH

N

H N

H N

Br

O

NH

N

O3S

Br

N Br

NH

N

Br O

NH

O

NH2

N N H

HN

N NH2

Br NH2

33: nagelamide Q (2009) O

H2N

N H

H N N H2N

H N

N

NH

O NH

35: stylissazole A (2010)

Br NH O

N

NH N

HN

O

H2N Br

O N

34: nagelamide R (2009)

H2N

NH N

O NH

36: stylissazole B (rac, 2010)

Figure 6 Pyrroleeimidazole alkaloids derived from more than one core unit, Part 3.

The nagelamides from Agelas sp., practically a brand name by the Kobayashi group, are structurally versatile and exist AeZ. Nine of the dimeric pyrroleeimidazole alkaloids with a novel skeleton discovered after 2000 are named nagelamide (A (26),39 I (39),40 J (()-29),41 K (()-30),42 L (31),42 Q (33),43 R (34),43 X (38),44 Z (()-40),44 Figs. 5e7). In Figs. 57, only those dimeric nagelamides are shown, which possess a skeleton that was new at the time of isolation. For instance, the skeletons of nagelamides BeH had been published earlier or are covered by nagelamide A (26). Nagelamides L (31) and R (34) could also be artifacts formed from nagelamide A (26) by a reaction in DMSO and acid demonstrated for oroidin (2), which should be reattempted when having more materials in hands.45 Some of the nagelamides were shown to be racemic, sometimes the optical

125

Chemistry and Biology of the PyrroleeImidazole Alkaloids

NH

O

Br

NH H2N

N

Br

O

N

HN

N H

H N

N

NH

N H HN

Br

NH

HN

N H

O

N H

H2N

N

O O

H N

N H

HN

N

O

H N

Br

Br NH

NH

HN Br

H2N Br

NH2

N

H

HHN H

Br

NH

40: (–)-nagelamide Z (2013)

NH Br MeO HN

N H

O NH2

N

H N

O

H N

N N H

39: nagelamide I (2014)

N

Br

Br

NH2

Br

N H

O

38: nagelamide X (rac, 2013)

NH2 H N

Br

NH SO3

37: stylissazole C (rac, 2010)

HN

OH

H NH

NH

Br

NH2

N

O

Br

Br

HN

Br

HN

N N H X

NH2

N N

O

O HN

O

41: agelamadin A (rac, 2014)

H N

O

NH2 N H NH2

N

N

N

42: 15'-oxoadenosceptrin (2016)

Figure 7 Pyrroleeimidazole alkaloids derived from more than one core unit, Part 4.

rotatory power was weak, sometimes no optical rotation could be measured. In addition, Figs. 5e7 list ()-massadine (()-27)46 from Stylissa caribica as a close relative of the axinellamines, ()-carteramine A (()-28)47 from Stylissa carteri, benzosceptrin A (32)48 from A. mauritiana, the optically inactive stylissazoles A (35), B (36), and C (37)49 from S. carteri, agelamadine A (41)50 from Agelas sp., and the hybrid 150 -oxoadenosceptrin (42) from A. sceptrum.51 The stylissazoles (Figs. 6 and 7) are all adducts between debromohymenialdisine (4) and hymenidin, the monodebrominated version of oroidin (2). Overall, there are currently 17 types of pyrroleeimidazole alkaloids known with one oroidin core unit, and 25 with two units. Fig. 8 shows

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Br Br Br

Br

NH

HN H2N

O

HN

HN

N

O

HN

H HO N H2N

N H

N

NH2

O

NH

O

43: (–)-stylissadine A 44: (–)-stylissadine B

H H

(2006) NH

NH O

NH2

N OH H

NH

O

H N

O

HN Br

Br Br

Br

Figure 8 ()-Stylissadines A (()-43) and B (()-44), the only pyrroleeimidazole alkaloids composed of more than two core units.

the structure of the tetrameric ()-stylissadines A (()-43) and B (()-44) from S. caribica52 and Stylissa flabellata,53 which are condensed from two units of massadine with loss of water. Some of the pyrroleeimidazole alkaloids were isolated as racemic mixtures, among them several of the nagelamides, which points at the possibility of spontaneous formation. Not surprisingly, the pyrroleeimidazole alkaloids present in higher concentrations in the sponges have been discovered first and continue to be reisolated. Overall, there are more than 10 reports on the reisolation of each of the pyrroleeimidazole alkaloids oroidin (2), ()-sceptrin (()-19), hymenialdisine, ()-dibromophakellin (()-1), ()-dibromoisophakellin (()-5), and ()-ageliferin (()-20). Truncated pyrroleeimidazole alkaloids such as 4,5-dibromopyrrole-2-carboxylic acid, longamide A, or 2-bromoaldisine have also been reisolated frequently. The concentrations given in the literature refer to dry or wet weight of the sponge, making it difficult to compare the values. As a rule of thumb, the wet weight of a sponge is 10 times the dry weight. ()-Dibromophakellin (()-1), oroidin (2), ()-sceptrin (()-19), and a few others may reach concentrations around 3% of the dry weight, but not every time. Schupp et al. conducted an extensive study on Stylissa massa, which contained the alkaloids hymenialdisine (447, see Scheme 76), sceptrin (19), hymenidin (51, see Scheme 3), oroidin (2), and palau’amine (3) counting for 90% of the secondary metabolites. Some geographic variation of the contents was detected.54 Altogether, there are more than 500 reports on the isolation of any of the currently about 220 pyrroleeimidazole alkaloids. In about 20 cases, amounts of more than 1% of the dry weight (including cases calculated from the wet weight concentration) are reported, in about 50 cases the amount was between 0.1% and 1.0%, in 90 cases between 0.01% and 0.10%, in about 90 cases the concentration

Chemistry and Biology of the PyrroleeImidazole Alkaloids

127

was below 0.01%, in 260 cases no exact value was given. Recent new pyrroleeimidazole alkaloids have been present in concentrations below 0.001% of the dry weight. In 2012, Carroll et al. performed an interesting study on the distribution of different major pyrroleeimidazole alkaloids in the sponge tissue of S. flabellata employing matrix-assisted laser desorption/ ionization (MALDI)-mass spectrometry imaging of 20 mm cuts at 120 mm resolution.55 It became clear that sceptrin (19) is concentrated in the mesohyl, whereas dibromophakellin (1) is found in the external pinacoderm and internal network of the choanoderm chambers. The mesohyl is situated between the internal choanoderm and the external pinacoderm. Dibromopalau’amine and konbu’acidin B were also found in the choanoderm. The isolation and structure elucidation of the pyrroleeimidazole alkaloids has mostly followed standard protocols employing partitioning, gel chromatography, reversed phase high-performance liquid chromatography (HPLC), high-resolution mass spectrometry, and the suite of 2-D NMR experiments. The absolute configuration has not always been elucidated. Occasionally, quantum chemical calculations have aided the structure elucidation, for example, in the case of the agelamadines CeE (for agelamadine C (17) see Fig. 3), where both diastereomeric phenylglycine methyl esters were prepared of each agelamadine derivative and compared by NMR, providing the absolute configuration of the a-amino acidederived portion.30 For the determination of the two stereogenic centers at the pyrroleeimidazole alkaloid portion, Kobayashi et al. calculated the electronic circular dichroism (ECD) spectra employing the time-dependent density functional theory method. K€ ock et al. employed the fc-rDG/DDD method, which stands for “floating chirality-restrained distance geometry calculation combination with distance-bounds-driven dynamics,” for the determination of all eight stereogenic centers of the conformationally restricted pyrroleeimidazole alkaloids ()-axinellamine A (()-25, Fig. 5) and 3,7-epi-massadine chloride.56 Only four of the 128 diastereomers fulfilled the constraints, which were grouped into families with different deviation from the experimental data. The correct diastereomer was identified. Of course, this was only an exercise, since the result was known before. During the studies, it was observed that ()-massadine chloride (()-45) is converted to ()-massadine (()-27) in wet DMSO-d6 with loss of the chloro substituent (Scheme 1). The configuration at the carbon center is retained, pointing at the intermediacy of aziridine 46, thereby representing a good example for the classical neighboring group effect.57

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NH2 Cl HN RHN

RHN

N

N

H HO

NH2

O N

RHN H NH

DMSO-d 6, H2O

RHN

NH2 (–)-45: (–)-massadine chloride

HO HN

N

H HO

NH2

O N

RHN H NH

NH2 46

RHN

N

H HO

O N

H NH

NH2 (–)-27: (–)-massadine

Scheme 1 Solvolysis of ()-massadine chloride (()-45) to ()-massadine (()-27) via an aziridine intermediate (46, R]4,5-dibromopyrrol-2-ylcarbonyl). 57

An important event for the community was the 2007 revision of the relative configuration of ()-palau’amine (()-3, Fig. 1). Originally, rings D and E were considered cis-fused, because there had been no nuclear Overhauser effect spectroscopy (NOESY) or rotating frame nuclear Overhauser effect spectroscopy (ROESY) spectrum taken. In addition, it was generally expected that two cyclopentane rings should always be cisfused. The H,H-coupling constant between the two bridgehead hydrogens was 14 Hz, leaving both possibilities. Reinvestigations of the problem by K€ ock et al. (tetrabromostyloguanidine),58 Quinn et al. (palau’amine (()-3)),59 and Matsunaga et al. (()-carteramine A, (()-28))47 clarified the situation and secured structure 3 (Fig. 1), which differs from Scheuer’s original proposal also regarding the configuration of the chlorinated carbon center. Now, a modified biogenetic scheme could be drawn, which is not repeated here and connects all palau’amine relatives to a “preaxinellamine.”60 For palau’amine (()-3) and congeners, it was not only the relative configuration revised, but also the absolute configuration determined. Griesinger et al. calculated the ECD and optical rotatory dispersion spectra of dibromopalau’amine in DMSO (PCM) at the B3LYP-SCRF/6311G(d,p)// B3LYP/631G(d) level of theory, reaching good agreement with the experimental data.61 Another possibility was to use a series of model compounds representing the ABC tricycle of 3. It was shown that the CD spectrum of ()-palau’amine (()-3) can be explained based on the assumption that the pyrrolopyrazinone ABC partial structure of palau’amine (()-3) is planar, allowing the assignment of the absolute configuration.62 The ECD spectra of the tetracyclic pyrroleeimidazole alkaloids ()-dibromophakellstatin and ()-dibromophakellin (()-1, Fig. 1) have also been calculated.63 Moreover, the absolute configurations of the long-known dimeric pyrroleeimidazole alkaloids ()-sceptrin (()-19) and ()-ageliferin (()-20) have been revised in 2014. The original assignment was made by

Chemistry and Biology of the PyrroleeImidazole Alkaloids

129

Faulkner et al. (1981) on the basis of an X-ray analysis. That result was considered confirmed by Baran et al. who had synthesized both enantiomers of sceptrin and ageliferin in 2006/7, because the CD spectra of the isolated and synthesized samples were in agreement.64,65 In 2014, Ma et al. published a reinvestigation of the problem.66 A natural sample of ()-sceptrin (()-19) was recrystallized and resubmitted to X-ray analysis under state-of-the-art conditions, leading to revision of the absolute configuration of ()-sceptrin (()-19). There is no evidence that both enantiomers occur as natural products.

3. BIOSYNTHESIS The possible biosynthesis of the higher pyrroleeimidazole alkaloids like the axinellamines or palau’amine has been discussed and reviewed extensively,6,7 very recently in 2016,67 which is not repeated here. A look at the structures of the pyrroleeimidazole alkaloids immediately clarifies their structural interrelation. One can easily identify bonds that must have been formed when coming from the oroidin building block. Changes of the oxidation states and degree of bromination are also obvious. This does not mean that the biosynthesis of any of the pyrroleeimidazole alkaloids is proven on a mechanistic level. Still only very few experiments have been conducted in this respect. In 2012, the Molinski group, together with Romo, published the first experimental evidence for the long-standing assumption that oroidin (2) serves as biogenetic precursor of higher pyrroleeimidazole alkaloids (Scheme 2).68,69 A cell free extract of S. caribica was prepared from freshly collected sponge. An aqueous-organic suspension of the extract (0.2 mg/mL protein) in MeCN/sodium phosphate buffer (pH 7e9, 1:9) rapidly consumed dichloroclathrodin (47, 90% within 30 min). Using the dichloro analog 47 of dibrominated oroidin (2) allowed for mass spectrometry-based identification of metabolites newly formed by the cell free extract and not being present before. Chlorination had replaced isotopic labeling. In very good yield, Molinski et al. could isolate the oxidized tetrachlorinated metabolites 48 (52%) and 49 (21%) in amounts of about 1.5 mg, allowing complete characterization. Compound 48 exhibits the skeleton of the benzosceptrins, while compound 49 corresponds to nagelamide H. If NaHSO3 was added during workup, the reduced benzosceptrin derivative 50 (50%) was isolated instead of 48, which points at facile reduction of

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Thomas Lindel

Cl Cl

N H

cell free enzyme preparation from Stylissa caribica

N

H N

N H

O

NH2

pH 7, MeCN/0.1 M sodium phosphate buffer (1:9)

47: "dichloroclathrodin"

Cl

H N

NH

N H

NH

Cl

O

+ NH

HN

Cl Cl

N

N H

Cl

SO3

Cl

NH2

O

N NH2

O

Cl

48 (52%) Cl

Cl

H N

Cl

O

HN N H

NH

HN N H

49 (21%)

H N N H

N

NH NH2

NH2 N H

Cl Cl

H N

O

HN

O

H

H HO3S

N NH NH N NH2

50 (formed in 50% yield instead of 48 when worked up with 0.1 M NaHSO3)

Scheme 2 First experimental evidence for oroidin serving as biogenetic precursor of the dimeric pyrroleeimidazole alkaloids.68

benzosceptrin or at reduction of an intermediate before that would have the chance to undergo aromatization. Only cell-free extracts from the investigated sponges were able to induce the conversion, but neither were extracts from other sponges nor unrelated enzymes like horseradish peroxidase. This points at the existence of a specific biosynthetic machinery. The analogous experiment also worked with 15N-labeled oroidin, then providing the brominated natural products. Molinski et al. propose a radical mechanism, which branches after formation of the C9eC90 bond. Scheme 3 outlines the possible route to ()-sceptrin (()-19).69 Mechanistically, one reaction can be ruled out: the simple, nonassisted photochemical [2 þ 2] dimerization of oroidin (2) to sceptrin, which has been attempted by several research groups, without any success. Irradiation of oroidin (2) has only led to E/Z isomerization.70 The finding by Molinski et al. that the bisulfite adduct 50 is formed, if the product mixture is worked up in the presence of bisulfite, makes it a possibility that a hitherto unknown dihydrobenzosceptrin A (57, Scheme 4) takes part in the biosynthesis of the pyrroleeimidazole alkaloids. Scheme 4 gives a possible interrelation between 57 and nagelamide I (39) via two

131

Chemistry and Biology of the PyrroleeImidazole Alkaloids

Br

Br

NH2 H N

N H

9

N NH

SET oxidation N H

- e-

O 51: hymenidin

NH2

H

H N

N NH H

O 52 51

H N

O HN

Br Br

HN N H

H N

O

9 9'

NH2

N N N H

(–)-19: (–)-sceptrin

NH2

H N

O

HN

NH2 N

+ eSET reduction

Br

HN

H N

epimerization

Br

HN

N

N H

O

NH2

H

53

Scheme 3 One electron oxidation as initial step of the dimerization of hymenidin (51) to the higher pyrroleeimidazole alkaloids, to be followed by attack of another equivalent of monomer and single electron transfer (SET) reduction, shown here for ()-sceptrin (()-19)69.

subsequent electrocyclic reactions, which could take place reversibly and would explain the antiposition of the amidomethyl groups. The first step is would be a thermal 8p electrocyclization of nagelamide I (39) affording the cyclooctatriene 54 in a conrotatory manner. The amidomethyl groups will be put into an antiposition, as in sceptrin (19) and, mirrored, in the case of the axinellamines. Dihydrobenzosceptrin A (57) could be formed from intermediate 54 by disrotatory thermal 6p electrocyclization. For the conversion of the underlying hydrocarbon parent system octa-1,3,5,7tetraene to 1,3,5-cyclooctatriene and further to bicyclo[4.2.0]octa-2,4diene, Patel and Houk have calculated activation barriers of about 17 kcal/mol each.71 Toward ()-sceptrin (()-19), double single electron transfer (SET) reduction of cyclooctatriene 54 to 1,5-cyclooctadiene 55 could take place, followed by a [3,3] sigmatropic rearrangement to the cyclobutane ring of epi-sceptrin 56. The final step would be the epimerization of 56 to the more stable ()-sceptrin (()-19). Toward dibromoageliferin (61), nagelamide C (58) could serve as a precursor and undergo 6p thermal disrotatory ring closure that would again put the amidomethyl groups in the antiposition (Scheme 5). Reduction of 59 would afford the diastereomers 60 and 61, nagelamide G (60), and dibromoageliferin (61), respectively. This pathway would not require the conversion of sceptrin (19) to ageliferin (20), which was achieved thermally by Baran and coworkers.72 It remains to be investigated, whether the conversions shown in Schemes 4 and 5 are chemically possible or not.

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Thomas Lindel

N

RHN

NH2 NH NH

RHN

N

NH2

39: nagelamide I (2014)

NH

N H

or enantiomer, no meso compound

NH

RHN

Br

NH2

N

RHN

8π thermal conrotatory

N

NH2

54

=R O

2 H+, 2 eH N

NH2

O N H

Br

HN

Br N H

H

H

6π thermal disrotatory

N NH

RHN

NH

RHN

NH

H H

N

NH2

N

NH N

NH2

O

NH2

55

57: "dihydrobenzosceptrin A"

[3,3] H N

O

H N

Br

HN

N

Br

HN

N

N H

O

N H

(–)-19: (–)-sceptrin

H N

NH2 epimerization

NH2

H N

O

Br

HN

N

Br

HN

N

N H

N H

O

NH2

NH2

56

Scheme 4 Possible interrelation of nagelamide I (39) and ()-sceptrin (()-19) by 8p electrocyclization, reduction, [3,3] sigmatropic rearrangement, and epimerization.

The most recent modification of the putative biosynthesis of the higher pyrroleeimidazole alkaloids was triggered by the finding that the absolute configuration of the cyclobutane ()-sceptrin (()-19), originally assigned by Faulkner in 1981, was revised in 2014 by Baran and Chen. The same seems to be necessary for ageliferin. In contrast, the configuration of the axinellamines remained as originally assigned by Quinn. Thus, the formal [2 þ 2] and [4 þ 2] dimers sceptrin and ageliferin, respectively, exhibit a (9S,90 S) and the “[3 þ 2] dimeric” pyrroleeimidazole alkaloids such as the axinellamines possess (9R,90 R) configuration. A double interconversion of both stereogenic centers seems unlikely, which points at enantiodivergent biosyntheses. This would also mean that the axinellamines would not be

133

Chemistry and Biology of the PyrroleeImidazole Alkaloids

HN

NH2

RHN

N H

N

6 π thermal disrotatory

N

RHN

NH2

HN

N

NH2

RHN

H N

RHN

N

58: nagelamide C

NH2

59 HN

NH2

Br

N

2 H+, 2 eRHN RHN 60: X= 61: X=

X

H N N

Br NH2

N H

=R O

H : nagelamide G H : dibromoageliferin

Scheme 5 Possible interrelation of nagelamide C (58) and nagelamide G (60), dibromoageliferin (61).

formed by ring contraction of the ageliferin system, as suggested by several reactions found during total synthesis. Currently, there is no pyrrolee imidazole alkaloid known where only the C9eC90 bond is formed. There is also the possibility that the dimerization of oroidin (2) and congeners needs assistance by complexing agents. Al-Mourabit et al. conducted an experiment in the presence of diphosphonate salts and hexamethylphosphortriamide, which can be considered as a first biomimetic dimerization of oroidin (2, Scheme 6).73 On heating of oroidin (2) with bisphosphonate 62 (1 equiv.) in DMSO to 130 C, traces of dimers 63 and 64 were obtained as mixture of stereoisomers, which resemble some of the nagelamides. Together the dimers make almost 10% of the product mixture. What about oroidin (2) itself? Earlier, a few experiments had addressed the biosynthesis, beginning with a study by Kerr, Pomponi, et al. who observed low incorporation (0.022e0.026%) of the radioactively labeled amino acids [U-14C]proline, [U-14C]histidine, and [C514C]ornithine, but not [U-14C]arginine, into stevensine (hymenialdisine cyclization mode) by a cell culture of the marine sponge Teichaxinella morchella.74 More recent experiments by Al-Mourabit, Thomas, et al. employing 14C radiolabeled candidate amino acids and beta-imager autoradiography point at lysine and proline, but not histidine, being biogenetic precursors of oroidin.75 The whole sponge had been incubated with the putative precursors in seawater for 13 days before analysis, followed by HPLC separation and autoradiography. Genta-Jouve and Thomas point out that radiolabeling should be reactivated for biosynthetic studies with sponges.76

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Thomas Lindel

Br Br

NH2 N H

N

H N

OMe P O O

O O P MeO

62

2 n-Bu4N

NH

DMSO, HCl (0.5 eq), 130 °C, 6 h

O 2: oroidin

Br Br

Br

NH Br

O

NH2

NH

HN

O

NH2

N

O

NH O

HN NH2

H

N

N H

HN

Br

N

N +

N N H

HN

NH

HN NH2

Br

Br

Br

63 (1% E, 3% Z)

64 (5%, mixture of diastereomers)

Scheme 6 Tweezer-assisted dimerization of oroidin (2) at 130 C by Al-Mourabit et al.73

There have been natural products isolated from the relevant sponges that support open-chain precursors of the imidazole section, rather than histidine. However, the situation is still unclear, as Fig. 9 shows. While laughine (65)77 and compound 6678 exhibit a peptide linkage between the a-amino group and the pyrrole section, it is the ε-amino group in natural product 68.79 Compound 6779 is one carbon atom shorter, derived from arginine and could be an analogous biogenetic precursor of ageladine A (69)80 and latonduine A81 (70, Fig. 10). There is also (þ)-cylindradine A ((þ)-71) with the carbonyl group not attached to the 2-position of the pyrrole unit, but to the 3-position.82 Here, possible open-chain precursors have not been found as natural products.

Br

Br

N H

NH2

H N O

X

N n H

NH2

65: laughine (X=H, n=2) 66: X=CO2H, n=2 67: X=CO2H, n=1

X N H

H N

CO2H NH2

O 68

Figure 9 Bromopyrrole natural products from marine sponges derived from lysine and arginine.

135

Chemistry and Biology of the PyrroleeImidazole Alkaloids

N N H

HN Br

NH2

N

NH2

N

Br

69: ageladine A

O N

Br Br

Br

Br

N

N H

NH O

70: latonduine A

N H

HN

N NH2

(+)-71: (+)-cylindradine A

Figure 10 Ageladine A (69) and latonduine A (70) with only 10 carbon atoms, and (þ)-cylindradine A ((þ)-71), a derivative of pyrrole-3, not -2-, carboxylic acid.

4. TOTAL SYNTHESIS Key to further development of the pyrroleeimidazole alkaloids toward tools of biochemistry or even drugs will be their total synthesis. Even if the reactivity of an abundant pyrroleeimidazole alkaloid is of interest, stable access will be needed, which has to be independent from the collection of sponges. Once we thought we could isolate oroidin (2) from Agelas sp. and study its chemistry. Soon, we had to realize that the material was consumed. The efforts on the total synthesis of the pyrroleeimidazole alkaloids have been intense since 2005. With the exception of rac-sceptrin (rac-19) and rac-ageliferin (rac-20), none of the “dimeric” pyrroleeimidazole alkaloids had been accessed before 2005. Consequently, since 2005 there has been intense research aiming at the first, second, or third total synthesis of the higher pyrroleeimidazole alkaloids. Key results have been the total syntheses of palau’amine (3) and axinellamine A (25). On the other hand, the synthesis of the monomeric pyrroleeimidazole alkaloids, among them agelastatin A (7) and phakellin-type family members, is well-explored by now, and the supply problem has largely been solved.

4.1 Sceptrin Rac-sceptrin (rac-19) was synthesized for the first time in 2004, independently by Birman et al.83 and by Baran et al.84 as outlined in our 2005 review.3 The first enantioselective synthesis of ()-sceptrin (()-19) was published by Baran et al. in 2006.64,65 In 2014, Chen et al. published the synthesis of (þ)-sceptrin ((þ)-19),66 followed in 2015 by ()-sceptrin (()-19).85 For Scheme 7, the absolute configurations were kept as they were drawn in the original publications. With the 2014 revision66 in mind, all structures

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Thomas Lindel

pig liver esterase, acetone/phosphate buffer (pH 8), 7 d, 23 °C

MeO2C MeO2C

O

HO2C

quant.

i-PrO2C

80%

O

73 (ee 75%)

72

BnHN

1) DMT-MM, cat. DMAP, i-PrOH, 55 °C 2) LiOH, THF/H2O (1:1), rt 3) DMT-MM, BnNH2, THF, rt

MeO2C

O

O

BnHN

hν, THF, rt

H2SO4, THF/ MeOH (1:1), rt

Ac Ac

i-PrO2C

50%

i-PrO2C

O

O BnHN

76

O 75 MeO OMe 1) CH(OMe)3, p-TsOH, p-TsOH, MeOH, MeO2C Ac 1. MeOH, 50 °C HO PhMe, 105 °C 2) DIBAL, DCM, –78 °C Ac MeO2C quant. HO 77 1) AcOH, H2O, rt, 5 min MeO OMe H 78 O N 2) MsCl, pyridine, 0 °C MeO OMe 3) NaN3, DMF, 50 °C O R HN BTMA-ICl2, HN Br Cl 4) CH(OMe)3, p-TsOH, THF, 60 °C 1. MeOH, 50 °C 70% Br 97% HN 5) H2, Lindlar, HN Cl MeO OMe H 1. MeOH, rt R O O N N O 6) 79, MeCN, rt 81 80 H CCl3 Br 79 74

1) NaN(CHO)2, MeCN, 35 °C 2) HCl, MeOH, rt 3) NH2CN, H2O, 95 °C

H N

O

Br

HN

Br

HN

72% N H

O

X

H N

NH2

H2O, 200 °C, Br μw NH Br NH2 40–50% N X=OAc H

H N

NH

X

X=Cl: 19·2 HCl X=OAc: 19·2 HOAc

O HN HN

N H

O

HN

NH2 NH OAc H N NH2 N H OAc

20·2 HOAc: ageliferin·2 HOAc

Scheme 7 Enantioselective total synthesis of ()-sceptrin (()-19, (þ)-19 shown) and ()-ageliferin (()-20, (þ)-20 shown) by Baran et al. as published.64,65 According to the revision of the absolute configuration of ()-sceptrin (()-19) in 2014,66 all absolute configurations shown above must be inverted (see text). DMT-MM, 4-(4,6-dimethoxy1,3,5-triazin-2-yl)-4-methylmorpholinium chloride; BTMA, benzyltrimethylammonium.

of Scheme 7 have to be transposed to their mirror images. Key step of Baran’s approach64,65 is the acid-induced fragmentation of the chiral oxaquadricyclane 75, formed by irradiation of oxanorbornadiene 74, which afforded cyclobutane 76 in 50% yield. The four-step sequence to compound 74 starts with a desymmetrization step, the pig liver esterase-catalyzed enantioselective saponification of diester 72 to chiral monoester 73. The absolute

Chemistry and Biology of the PyrroleeImidazole Alkaloids

137

configuration of 73 was determined after cocrystallization with (S)-amethylbenzylamine, of a sample with only 75% ee. Here, the diastereomer formed with the minor enantiomer of acid 73 might have been submitted to X-ray analysis, leading to a misassignment of all compounds downstream. Interestingly, the synthesis still reached ()-sceptrin (()-19) with the expected optical properties. Finally, the problem was solved by a new Xray analysis and revision of the absolute configuration of naturally occurring ()-sceptrin (()-19) by Ma, Baran, Chen, et al. in a joint paper in 2014.66 By treatment of cyclobutane 76 with p-TsOH/MeOH in PhMe at 105 C, the C2-symmetrical cyclobutane 77 was formed. The ester groups of 77 were transformed in five steps to azidomethyl groups, followed by installation of the pyrrolylcarbonyl moieties (80). For the construction of the 2-aminoimidazole units an interesting a-chlorination of the dimethyl ketal partial structures employed BnNMe3ICl2 affording bis(achloroketone) 81. Baran et al. substituted the chloro substituents with the ammonia equivalent NH(CHO)2, followed by acidic hydrolysis and condensation with cyanamide affording the 2-aminoimidazole units and resulting in gram quantities of ()-sceptrin (()-19). It was noticed that the values of the optical rotations of sceptrin (19) and ageliferin (20) are reversed when changing the counterion from chloride to trifluoroacetate. The Baran group had shown earlier that rac-sceptrin (rac-19) could be converted to rac-ageliferin (rac-20) by heating an aqueous solution to 200 C in a microwave oven.72 That step was also employed in the enantioselective synthesis of ()-ageliferin (()-20, Scheme 7) with improved yields after changing the counterion from chloride to acetate. Houk, Baran, et al. propose that the thermal vinylcyclobutane rearrangement proceeds in a 6endo-trig manner via a dicationic diradical, corroborated by the fact that 10-epi-ageliferin (nagelamide E) is always a side product formed in the same ratio as found in nature.86 Starting from rac-sceptrin (rac-19), the Baran group also took the opportunity to synthesize rac-oxysceptrin (rac-83) and rac-nakamuric acid (rac-24, Scheme 8). Key intermediate was diol 82 (four diastereomers), which was synthesized by treating rac-sceptrin (rac-19) with peracetic acid (50%). On heating of 82 with HOAc, a 1:1 mixture of diastereomeric rac-oxysceptrins was formed by dehydration. Oxysceptrin also occurs as such a mixture in nature. Oxidation of 82 with sodium periodate afforded rac-nakamuric acid (rac-24) by glycol cleavage and hydrolysis. The 2015 synthesis of ()-sceptrin (()-19) by Chen et al.85 features an interesting photoredox-catalyzed cyclobutane formation to the substituted

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H N AcO2H, H2O rac-19: rac-sceptrin

50%

O

HO

Br

HN

HO

Br

HN N H

65% O

O

Br

HN

H

Br

HN N H

O

H N

60% H N

NH N H

NH2

NaIO4 (1.2 eq), pH 5 buffer

O

NH2

NH NH N H

NH2

NH

82, 4 diastereomers

aq HOAc, 140 °C, 30 min H N

O

H N

NH2

rac-83: rac-oxysceptrin (2 diastereomers)

Br

HN

CO2H

Br

HN

NH

N H

O

N H

NH2

rac-24: rac-nakamuric acid

Scheme 8 Conversion of rac-sceptrin (rac-19) to rac-oxysceptrin (rac-83) and racnakamuric acid (rac-24) by Baran et al.65

dioxacyclobuta[cd]pentalene 87 containing an acetal partial structure (Scheme 9). In 2014, (þ)-sceptrin ((þ)-19) had been obtained.66 As optically active starting material, 2,3-dihydrofuran 85 was reacted with the imidazolyl-substituted allylic alcohol 84 via activation of the vinyl ether with PhSeCl. The resulting acetal was subjected to oxidative deselenylation to the 3,4-dihydrofuran, followed by conversion of the imidazole-2-azido group to the iminophosphorane affording cyclization precursor 86. On irradiation with visible light in the presence of Ir(ppy)3 (3 mol%),87,88 the cyclobutane ring was formed, resulting in the formation of tricycle 87 as a mixture of C100 epimers (9:5). The authors provide evidence that an SET mechanism is at work, commencing with the conversion of the vinyl double bond to the radical cation. The reaction did not work in the presence of an azido group. Transthioketalization of 87 in the presence of TiCl4 opened the two tetrahydrofuran rings and afforded cyclobutyl-1,3-dithiane 88, which, after nine further steps, was converted to diazide 89. The second 2-aminoimidazole portion was constructed by condensation with Bocguanidine. Three further steps provided ()-sceptrin (()-19), the data of, which confirm the revision of its absolute configuration by the same group.66 Overall, sceptrin was synthesized in 20 steps from 84. In a similar approach, Chen et al. also synthesized rac-nakamuric acid (rac-24). The

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Chemistry and Biology of the PyrroleeImidazole Alkaloids

N N3

N BOM

OH

OTIPS 1) 85, PhSeCl, NEt3, DCM, –78 to –20 °C

N BOM

O

2) H2O2, pyridine, dioxane, 0 to 23 °C 3) PPh3, THF, 23 °C

O OTIPS

84 (2 steps)

86 PPh3 N TiCl4, HS(CH2)3SH, N DCM, –78 °C BOM

H

h ν (CFL), Ir(ppy)3, DMF, 23 °C

H 10'

H

O

HO H

S

25% (five steps)

OTIPS

O

H

S

87 (dr 9:5) 1) Ac2O, DMAP, pyridine, DCM, 23 °C 2) Hg(ClO4)2·3 H2O, CaCO3, H2O, THF, 23 °C 3) HOAc, THF, 23 °C 4) NaBH4, MeOH, 0 °C 5) NaOMe, MeOH, 0 °C 6) MsCl, pyridine, DCM, 23 °C 7) NaI, acetone, 56 °C 8) NaN3, DMF, 23 °C 9) HF-pyridine, pyridine, THF, 23 °C 45% PPh3 1) N

N BOM

H2N

N

90

N3 H MsO

OTIPS

88 PPh3 N

1) Dess-Martin periodinane, DCM, 23 °C 2) Boc-guanidine, TFA, DMF, 35 °C

N BOM

N3

HO

N BOM

3) H2, PtO2, t-BuOH

OH

26% 89

Br

H2N

N H

N

PPh3 N

N

N

N

PPh3 N

N

85

O

NH2

OH N H

H N

91

O EDC, HOBt, 2,6lutidine, DMF, 23 °C

2) BCl3, DCM, –10 °C; then NH4OH, MeCN, H2O, 23 °C 3) HCl, dioxane, H2O, 35 °C 26%

O

H N

Br

HN

N

Br

HN

N

N H

N H (–)-19: (–)-sceptrin

NH2

NH2

O

Scheme 9 Total synthesis of ()-sceptrin (()-19) by Chen et al.85 (CFL, compact fluorescence lamp, ppy, phenylpyridinato).

authors state that many of the aminoimidazole intermediates of their syntheses readily decomposed on exposure to acid or air. The photoredox-catalyzed formation of the cyclobutane ring of sceptrin comes close to the proposed biosynthesis of sceptrin. Chen et al. conducted density functional theory calculations of the Gibbs free energies of intermediates and transition states of a hypothetical dimerization of clathrodin (92), the nonbrominated analog of oroidin. The highest barrier (72 kJ/mol) was found for the, thus rate determining, first step forming the bond between C9 and C90 to radical cation 93D$, by reaction of clathrodin (92) with the

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Thomas Lindel

radical cation of clathrodin (92D$). Cyclization of 93D$ to the cyclobutane 94D$ should proceed via a much lower barrier (18 kJ/mol) than the reaction of 93D$ to the cyclohexane radical cation 95D$ (63 kJ/mol), perhaps explaining the natural ratio of sceptrin and ageliferin derivatives (Scheme 10).

4.2 Ageliferin Naturally occurring ()-ageliferin (()-20) has been obtained by Baran et al. from ()-sceptrin (()-19, Scheme 7, above).64,65 There were two more total syntheses of (þ)-ageliferin ((þ)-20) published by Chen et al.89,90 in 2011 and of rac-ageliferin (rac-20) by Harran et al.91,92 in 2013. Also included are intramolecular DielseAlder reactions of bis-vinylimidazoles by the Lovely group.93e95 For the synthesis of (þ)-ageliferin ((þ)-20), Chen et al. employed a Mn(III)-mediated radical cyclization of a chiral bimidazolyl-b-ketoester as the key step (Scheme 11).89,90 The authors also obtained (þ)-bromoageliferin with one of the pyrrole units carrying an additional bromo substituent and (þ)-dibromoageliferin with two dibrominated pyrrole units. The synthesis starts with the a-hydroxyalkylation of the chiral ester 97 (synthesized from Garner’s aldehyde in three steps) with BOM-protected H N

NH HN

H N

N H

O

92 •+ NH HN

H N O

H N

N H

NH

92

barrier ΔG≠ 63 kJ/mol

HN

NH

HN

N N H

O

NH2

NH2

barrier ΔG≠ 18 kJ/mol

H N

O H N N H NH

HN O

N

93 •+

HN

N H

barrier ΔG 72 kJ/mol

O

≠

+ N H

NH

HN 95 •+

NH

O

N

HN

NH

HN

NH

NH

N H

N H

O

NH2

NH

94•+

Scheme 10 Calculated free activation enthalpies (UB3LYP6311G(d,p)) of alternative dimerizations of clathrodin via the radical cation.85

Chemistry and Biology of the PyrroleeImidazole Alkaloids

141

Scheme 11 Total synthesis of (þ)-ageliferin ((þ)-20) by Chen et al. featuring a Mn(III)mediated single electron transfer cyclization.89,90

2-azidoimidazole carbaldehyde 96 (available in two steps from BOMe imidazole; introduction of the azido group by nucleophilic substitution of a chloro substituent). Oxidation provided b-ketoester 98, which was subjected to an interesting radical cyclization upon treatment with Mn(OAc)3 in HOAc at 60 C. The key step starts with a one-electron oxidation, followed by deprotonation of the resulting radical cation. The resulting dioxopentadienyl radical adds to the neighboring double bond forming a glactone moiety, followed by formation of the tricycle in a 5exo-6endo manner. A second one-electron oxidation/deprotonation afforded both diastereomers of lactone 99.

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Thomas Lindel

Decarboxylation was possible in a diastereoconvergent manner after treatment with LiOH. Three further steps afforded tetrahydrobenzimidazolone 100 with four stereogenic centers. Conversion of the azido group of 100 to the iminophosphorane, chemoselective hydrolysis of the oxazolidine and Boc removal (TFA), and installation of both pyrrole units afforded aminoalcohol 101. Treatment with doubly Boc-protected N-amidinopyrazole 102 afforded the guanidine, which cyclized to the Boc-protected 2-aminoimidazole 103 after oxidation of the primary alcohol. What remained was epimerization at C9 (TFA), sequential reduction of the keto to the methylene group (Ca(BH4)2, then NaBH3CN), and removal of the protecting groups. Overall, (þ)-ageliferin ((þ)-20) was synthesized in 21 steps and 0.5% overall yield from Garner’s aldehyde. A close structural analog of 101 was also employed to access a putative intermediate of the biosynthesis of palau’amine (()-3).105 Chen’s synthesis was achieved based on extensive model studies.90,96 For instance, the Mn(III)-mediated SET reaction of bimidazolyl-b-ketoester 104/105 depends on the substitution of its dibenzylated imidazolone partial structure (Scheme 12). If the imidazolone 4eposition is unsubstituted (104), the six-membered ring of product 106 is formed in a 5exo-6endo cyclization. The presence of a chloro substituent (105) guided the radical cyclization to the 5exo-5exo mode, affording spiro-hydantoin 107. This may become interesting for the synthesis of pyrroleeimidazole alkaloids of the axinellamine type, although a similar product can be obtained by oxidation of the 5exo-6endo product, as shown by the

O

O NBn

BnN

Mn(OAc)3, HOAc, 60 °C

X

X=H - 2 H·

O O

BnN

O

O O 106 (63%)

SET oxidation

X=Cl - 2 H·, + O

Bn N

O

O O

BnN

BnN O

H H

O

104 (X=H) 105 (X=Cl) Mn(OAc)3, x2 HOAc, 60 °C

NBn

H O O 107 (40%)

+

O O

NBn Cl

Cl H

O 108 (47%)

Scheme 12 Model study by Chen et al. on the outcome of the Mn(III)-mediated single electron transfer (SET) key reaction.90

Chemistry and Biology of the PyrroleeImidazole Alkaloids

143

authors themselves and earlier by Romo et al.97 and Lovely et al.98 The electron withdrawing chloro substituent stabilizes a radical in the a-position, which makes the spirocyclization competitive. Along with 107, the nontricyclic dichlorinated product 108 was formed in about equal amount, which is epimeric at C9. Apparently, if the trans-substituted g-lactone is formed in the first step, the second cyclization is prevented. The Chen group performed quantum chemical calculations, which are not detailed here. Originally, the authors had expected that the configuration of building block 98, derived from Garner’s aldehyde, would induce the opposite absolute configuration at C9. Chen et al. consider their approach biomimetic, which refers to the hypothesis that dimeric pyrroleeimidazole alkaloids are formed by radical processes. However, no pyrroleeimidazole alkaloid has been isolated to date containing a b-ketoester moiety. It is likely that the biosynthesis of the dimeric pyrroleeimidazole alkaloids proceeds via dimerization of oroidin (2) or less brominated analogs, followed by rearrangement and/or oxidation. However, as Harran et al. have shown in their original synthesis of rac-ageliferin (rac-20), it is possible to go the opposite way in chemical synthesis.91,92 Harran’s approach shares with the other syntheses that the central bond between C9 and C90 , the centers of the C3 chain of the monomers, is formed first. However, the synthetic intermediates are reduced step-by-step with a SmI2-mediated reductive ring enlargement being the last step (Schemes 13 and 14). Key intermediate is the bis spirocycle 116, consisting of two ACD subunits of the phakellin skeleton that are connected via C9/C9’. For the synthesis of 116, pyrrole-2-carboxhydrazide (109) was condensed with methyl 5-bromo-2-oxopentanoate (110), followed by conversion to the acid chloride and coupling with oxadiazine 111. Accidentally, it was found that oxalylchloride also induced ring closure to the tricyclic system 113. For solubility reasons, the pyrrole nitrogen was protected, before compound 114 was converted to the titanocene dienolate by treatment with [(i-PrCp)2TiCl2]/KHMDS. Oxidative coupling induced by Cu(OTf)2 led to g-homodimerization. After double Wilkinson hydrogenation and bromination of the pyrrole moieties, an almost 1:1 mixture of bistricycle 115 was obtained, albeit in only 21% yield. Deprotonation of the glycocyamidine a-position initiated ring contraction to the bisspiro-aminal 116 with cleavage of the labile NeN bond on both halves of the molecule. The authors expected formation of bisalkylidene products instead. Fortunately, it was not detrimental that a mixture of all diastereomers of 116 was obtained (Scheme 13).

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Thomas Lindel

1) HOAc, MeOH, 0 °C; 110, 0 °C to rt; K2CO3 to pH 6; 65 °C; LiOH (2 eq), THF/H2O, –10 °C

NH 109 + HN O NH2 O

CO2Me 110

(COCl)2, DMF (1 mol%), DCM, rt

Br

Br

N

Br

112

R N

O

Br

N N O N SEM N O

N

N

1) [(i-PrCp)2TiCl2] (1.05 eq), THF, –78 °C, 10 min; KHMDS (1.2 eq), –78 °C; Cu(OTf)2 (1.5 eq), –78 °C

113: R=H 114: R=

N

N

O

O

2) H2 (600 psi), [ClRh(PPh3)3] (0.6 eq), THF, 40 °C 3) NBS (4 eq), THF, 0 °C 21%

TMS Br

O H

KHMDS (4 eq), 18crown-6 (3.5 eq), THF, –78 °C; phosphate buffer pH 7.8 54%

O

115 (C2:meso 6:5)

O

111

NH

49% from 109 KOt-Bu, THF, –10 °C 60% Cl O TMS

O N

MeS O N N

O O

O SEM N N O N N N

H N

2) (COCl)2, DMF, DCM, rt SMe N

Br

N

Br

N SEM O O N HN N N O O

Br Br

N SEM

N HN O

N N

O

116, mixture of all diastereomers

Scheme 13 Total synthesis of rac-ageliferin (rac-20) by Harran et al. (Part 1).91,92

Treatment of the mixture (116) with 1,5,7-triazabicyclo[4.4.0]dec-5ene (TBD) induced an interesting rearrangement leading to the formation of a monoalkylidene spirocycle representing the connectivity pattern present in the axinellamines (Scheme 14). A cyclopentane ring had formed. Deprotection of the glycocyamidine units afforded product 117 as a mixture of two diastereomers. Toward rac-ageliferin (rac-20), both glycocyamidines had to be reduced, which was not as facile as it may seem. Use of excess of Myers’ lithium amidotrihydroborate (LiNH2BH3)99 was key to the selective reduction of the alkylidene glycocyamidine to the 2-aminoimidazole (118, obtained as a 2:1 mixture of diastereomers). The glycocyamidine unit of the spirocyclic system remained intact, and its reduction required employment of SmI2 in THF/water. The imine 119 was formed, which underwent immediate ring enlargement affording rac-ageliferin (rac-20). The Harran pathway might be considered as biomimetic as the other routes.

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Chemistry and Biology of the PyrroleeImidazole Alkaloids

Br Br

N SEM O O N HN N N O O

Br Br

N SEM

N HN O

N

TBD: N

N H 1) TBD (1.2 eq), THF, rt 2) NH4OH aq, DME/H2O (4:1), 120 °C; TFA, DCM, rt; NEt3, MeOH

NH

Br

H N

Br

O HN

Br

HN

Br

2) H2O, 180 °C (microwave), 15 min

NH

HN

NH O

O 117

116, mixture of all diastereomers

1) LiNH2BH3 (excess), THF, 60 °C; TFA/H2O (1:9) 39%

NH2 N

O

HN

Br

O

N

O

HN

HN

Br

43%

N

H N

Br

Br

NH

NH2

HN

N HN 14

NH

1) SmI2 (excess), THF/H2O, –40 °C to rt, 37%

NH O

2) TFAA, TFA, THF, 70 °C; 1 N HCl, 38%

O

118 (42%, +23% C14-epimer)

H N Br

O

HN

NHCOCF3 N HN

HN

NCOCF3 NH

HN

Br NH

O

O2CCF3 119

H N

O

Br

HN

Br

HN N H

O

HN

NH2 NH H N N H

NH2

2 O2CCF3

rac-20: rac-ageliferin

Scheme 14 Total synthesis of rac-ageliferin (rac-20) by Harran et al. (Part 2).91,92

Dispacamide A (444, vide infra), the alkylidene glycocyamidine analog of oroidin (2), also is an abundant natural product itself. Of course, it would have to be explained how the initial bond between C9 and C90 in the spirocyclic starting material 116 would be formed. There have been several studies on DielseAlder reactions of vinylimidazoles aiming at the dimeric pyrroleeimidazole alkaloids. In particular, the Lovely group added new examples since then, such as the reaction of N-oxamide 120, which underwent diastereoselective intramolecular cycloaddition on heating to 150 C.93 Scheme 15 also shows the three subsequent steps, which give access to spirocycle 122 after NeO cleavage, oxidation with the oxazirine 121, and reduction of the imidazolone to the imidazolidinone. A similar sequence was possible starting from alkynes with the triple bond conjugated to the carbonyl group.94 It was also found

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Thomas Lindel

Scheme 15 Intramolecular DielseAlder reactions aiming at the assembly of dimeric pyrroleeimidazole alkaloids by Lovely et al.93,95 (DMAS, dimethylaminosulfonyl).

that both vinylimidazole moieties could take the roles of diene and dienophile, as in the case of 123, which, upon heating to 130 C, formed the two regioisomers 124 and 125 in comparable yields.95 Mainly, the studies focused on imidazoles that were not aminated in the 2-position. It should be mentioned that in the presence of the pyrrole unit, oroidin (2) itself even underwent cyclization to rac-cyclooroidin (rac-11), but no dimerization.151

4.3 Axinellamines Based on their first-generation synthesis of rac-axinellamine A (rac-25) and B (rac-148),100,101 Baran et al. developed an enantioselective total synthesis of ()-25 and ()-148,102 which was later followed by a more efficient second-generation route to the racemic natural products.103,104 Chen et al. synthesized the ()-axinellamines A (()-25) and B (()-148) enantioselectively.105 The Harran group has achieved the synthesis of a racemic, dechlorinated axinellamine.91 Baran’s total syntheses of axinellamines A (25) and B (148), ()-massadine chloride (()-45), ()-massadine (()-27), and ()-palau’amine (()-3) are closely related to each other. Scheme 16 gives an overview of the overall approach by Baran et al. with some of the strategic intermediates and the number of steps. The trihalogenated cyclopentene precursor rac-127 was assembled over 13 steps by a DielseAlder/ozonolysis/intramolecular aldol

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Chemistry and Biology of the PyrroleeImidazole Alkaloids

Cl

13 steps

Cl N3

Cl

OTIPS

Br

N3

14 steps

Cl

O

N3

126

rac-127

NHBoc N3

Cl

(+)-127

NHBoc

NH2 Cl HN

N

N3

NH

Cl N3

O

3 steps

3 steps

BocN

Br

N3

2 steps N3

Cl

N Cl

NH3

O

O

N3

rac-128

rac-25: rac-axinellamine A

1) construction of 2-ai 2) aminohydroxylation of 2-ai 3) imidazoline hydroxylation ...

(–)-128 1) imidazoline hydroxylation 2) construction of 2-ai NH2

2 steps Cl HN N3

N3

1) dioxygenation of 2-ai ... 1 step

(–)-45: (–)-massadine chloride

NH OH NH

5 steps

(–)-25: (–)-axinellamine A

O

N3

(–)-129

7 steps, not via aminoketone

(–)-27: (–)-massadine

BocN

4 steps

HN (–)-130

NH2

5 steps

(–)-3: (–)-palau'amine

Scheme 16 Overview of some of the total syntheses of the Baran group in the palau’amine area (2-ai, 2-aminoimidazole).

reaction sequence starting from electron-rich diene 126, which eventually allowed synthesizing the optically active version (þ)-127 by employing a chiral dienophile. A problem was the low diastereoselectivity of the cyclizations to the spirocyclopentaimidazolines (128) from the corresponding guanidine precursors, which required separation. Compared to the first-generation synthesis of axinellamines A (25) and B (148), the newer versions construct the 2-aminoimidazole unit by reaction of an a-aminoketone and cyanamide, and not from the a-chloroketone and a protected guanidine. Once the spirocyclic key intermediate ()-129 had been reached, it was the order of steps that gave access to all title compounds. A 2-aminoimidazole unit is electron-rich and prone to facile oxidation. Thus, either the 2-aminoimidazole was to be assembled after the hydroxylation of the imidazoline system, or,

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Thomas Lindel

if assembled before, its C]C double bond had to be functionalized by aminohydroxylation (toward the axinellamines) or dioxygenation (toward massadine). All total syntheses have a length of about 25 steps. Most of the steps of the 2008 first-generation approach to rac-axinellamines A (rac-25) and B (rac-148) by Baran et al.100,101 reoccur in the synthesis of ()-palau’amine (()-3) or, for the second half, in the second-generation synthesis of the rac-axinellamines. Therefore, the first-generation synthesis of the rac-axinellamines is not detailed here separately, neither is the enantioselective total synthesis of ()-axinellamines A (()-25) and B (()-148).102 While the DielseAlder start was also employed for the enantioselective synthesis of ()-axinellamine A (()-25) and B (()-148),102 evaluation of the medicinal potential of the axinellamines required their availability in sufficient quantity. The existing first-generation route, which is similar to the synthesis of ()-palau’amine (()-3), had to be improved. The secondgeneration pathway to rac-axinellamine A (rac-25) and B published by Baran et al. in 2014 assembles the cyclopentane core by PausoneKhand reaction, followed by construction of the spirocyclic system (Schemes 17 and 18).103,104 For several of the reactions, new methodology had to be developed. In the beginning, the PausoneKhand reaction of in situ formed trimethylsilyl-protected (E)-2-butene-1,4-diol (135) and the intermediate cobalt complex 132 formed from Boc-protected propargylamine was difficult with yields around 20%. Addition of diethylene glycol-NMO improved the yield up to 45%, making it a diol N-oxide-assisted PausoneKhand reaction. Tertiary amine N-oxides have also been employed by Schreiber et al. in the stoichiometric PausoneKhand reaction.106 It is assumed that both ingredients help to generate a reactive cobalt complex. A second interesting step is the novel Zn/In-mediated Barbier reaction under aqueous conditions, which allowed the diastereoselective addition of 3-chlorocyclopentene 137 to N-trifluoroacetylated aminoacetaldehyde, obtaining 138. Compound 137 was obtained by Luche reduction of cyclopentenone 136 and treatment with NCS/PPh3 (Appel conditions). Nucleophilic substitution of both chloro substituents of 138 by azido groups required rather harsh conditions (10 equiv. of NaN3 in DMF at 85 C), probably due to steric hindrance. Goodman’s reagent (139) introduced the protected guanidino moiety affording 140. The conditions of the subsequent diastereoselective chloro spirocyclization (TfNH2/t-BuOCl in DCM) to spirocompound 141 have also been carefully optimized. Baran et al. discovered that the guanidine unit is chlorinated first, with TfNH2 functioning as a reductant toward overchlorinated species. Another guanidine-based chlorinating

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Chemistry and Biology of the PyrroleeImidazole Alkaloids

BocHN

BocHN Co2(CO)8

Co(CO)3 Co(CO)3

131 OH

OTMS OH

O

45%

OTMS

134 (7 eq), DCM, 40 °C

NHBoc

NMO-(HOCH2)2 (3 eq), DCM, rt

132

TMSO OTMS 136 (rac)

134 OTMS

NTMS

133

135 NHBoc

1) NaBH4 (4 eq), CeCl3 (1 eq), MeOH, 0 °C

Cl Cl

1) NaN3 (10 eq), DMF, 85 °C 2) i. TFA (50% in DCM), rt NTf ii. (1.5 eq), rt NHBoc 139 BocHN

H OH

Zn (16 eq), In (1.9 eq), THF, aq NH4Cl, rt

138

NBoc HN

O

NHBoc H OH

55% N3 N3

N H

CF3

i. TfNH2 (0.25 eq), DCM, t-BuOCl (2.0 eq), 0 °C

140

NBoc NBoc Cl H OH

HN

O N H

CF3

ii. DMP (1.2 eq), DCM/TFA (10:1), rt

NH2

141

O

NH Cl H O

81% (2 steps) N3 N3

N3 N3

CF3 O

Cl Cl

64%

137

HN

H N

BocHN

O

O (10 eq)

Cl

2) PPh3 (3.4 eq), NCS (3.4 eq), THF, rt 95%

H N

F3C

N H

CF3

CF3CO2

142

Scheme 17 Second-generation total synthesis of rac-axinellamines A (rac-25) and B (rac-148) by Baran et al. (Part 1).103,104

agent came out of this investigation, chlorobis(methoxycarbonyl)guanidine (CBMG, “Palau’chlor”), which proved to be very efficient. Dess-Martin periodinane oxidation of 141 afforded protected aminoketone 142 that was deprotected and condensed with cyanamide to assemble the second 2-aminoimidazole portion. Subsequent treatment of product 143 with DMDO/H2O led to dihydroxylation of the C4eC5 double bond, which reacted further to the tetracyclic core of the axinellamines by forming the N,N-acetal with the neighboring heterocycle (144). For

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Thomas Lindel

Scheme 18 Second-generation total synthesis of rac-axinellamines (rac-25) and B (rac148) by Baran and coworkers (Part 2).103,104 Purification was performed by RP-HPLC employing a TFA-containing mobile phase.

the oxygenation of the 2-aminoimidazoline unit of the spirocycle, Baran et al. employed silver(II) picolinate (145), a reagent that they had discovered earlier on development of the first-generation route. A good yield of 69% of bis-N,O-acetal 146 as a mixture of diastereomers was achieved. The azido groups were hydrogenated to the amines, followed by coupling with the pyrrolyl-2-carbonyl units. The reduction of the two azido groups of 146 was performed by hydrogenation instead of by treatment with 1,3-propanedithiol as in the first-generation synthesis. A mixture of rac-axinellamines A (rac-25) and B (rac-148) was obtained on a gram scale. Building up on their synthesis of ageliferin (20), Chen et al. were also able to develop a total synthesis of a mixture of ()-axinellamine A (()-25) and B (()-148, Scheme 19).105 Key step is the conversion of tetrahydrobenzimidazole 150 to spiroglycocyamidine 151 by ring contraction under oxidative conditions (Scheuer rearrangement). The starting material

Chemistry and Biology of the PyrroleeImidazole Alkaloids

151

Scheme 19 Total synthesis of ()-axinellamine A (()-25) and ()-axinellamine B (()-148) by Chen et al.105

149 shown in Scheme 19 had been obtained in 10 steps and about 10% yield from Garner’s aldehyde (see also Scheme 11). Five further steps to 150 included the regioselective Staudinger reduction of the imidazolyl azido group and the diastereoselective reduction of the ketone moiety. There was some loss of material due to incomplete epimerization of the a-carbon C12. Treatment of 150 with tert-butylhydroperoxide (TBHP) in the presence of Ti(Oi-Pr)4 induced the desired ring contraction to 151 diastereoselectively, guided by the hydroxy group. By exploiting the neighboring group effect of the imidazoline nitrogen, the hydroxy group was replaced with overall retention by chloride to give 152, presumably via an aziridine

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Thomas Lindel

intermediate. The second 2-aminoimidazole unit was constructed via the labile hydrated aminoaldehyde. Reduction of the carbonyl group of the spiroglycocyamidine unit of 153 proved difficult, as LiBEt3H also reduced the chloroalkane leading to loss of the chloro substituent. Treatment of 153 with BCl3 gave a mixture of N-chloromethyl and N-hydroxymethyl iminohydantoins because of incomplete removal of the BOM group (60% combined). Subsequent hydrolysis liberated the unprotected spiroglycocyamidine (81%). The 2-aminoimidazole moiety was oxidized with AD-mix-a or AD-mix-b, which led to formation of the desired tetracycle. The diastereoselectivity of that step was 37e18% in favor of the axinellamine B over the A configuration. Now, SmI2 in THF/H2O was able to reduce the glycocyamidine carbonyl group to the N,O-acetal, which was accompanied by the expected loss of the two 5-bromo substituents at the pyrrole section (67%). Rebromination (53%) with NBS completed the total syntheses of ()-axinellamine B (()-148, 1.5 mg), which was obtained together with rac-axinellamine A (rac-25). Branching from intermediate 118 of their ageliferin synthesis (see also Scheme 14), Harran et al. were able to obtain a racemic axinellamine congener lacking the chloro substituent at the cyclopentane moiety (155, Scheme 20).91 Treatment of 118 with the Davis oxaziridine 154 led to formation of the tetracycle, followed by treatment with SmI2 in THF/H2O to afford 155. As expected, the two 5-bromo substituents at the pyrrole rings were lost.

4.4 Massadine ()-Massadine (()-27) and ()-massadine chloride (()-45) differ from the axinellamines in that their N,O-acetal moieties share the oxygen atom,

Br Br

H N

O

HN

Br Br

NH

NH2

HN

HN

O 118

1)

N HN 14

NH NH

O

PhO2S

O N

NO2 154 (1.4 eq), TFA/H2O (1:9), 55 °C, 26% dr 4:1

2) SmI2 (excess), THF/H2O, –40 °C to rt, 45%

H N

O HN

Br

HO HN H N

O

NH

HN

HO

N H

NH2 NH H NH2

2 CF3CO2 Br

155

Scheme 20 Conversion of synthetic intermediate 118 to rac-bis(debromodechloro)axinellamine 155 by Harran et al.91

153

Chemistry and Biology of the PyrroleeImidazole Alkaloids

forming a tetrahydropyran ring. By changing the order of steps of the axinellamine synthesis, the Baran group was able to synthesize both 27 and 45 in racemic107 and enantiomerically pure form.102 The Chen group also managed to reach the goal,66 whereas Carreira et al. have contributed important studies.108,109 Baran’s synthesis (Scheme 21) proceeds via compound 130, which also served in the total synthesis of ()-palau’amine (()-3, Schemes 25 and 26).102 The 2-aminoimidazole unit of 130 is oxidized at its C]C double bond with DMDO, and the hydroxy oxygen attacks faster than the nitrogen that would lead to the axinellamine skeleton (Scheme 21). However, the diastereoselectivity was not in favor of the desired product 156 (15% yield, compared to 56% yield of the undesired C6 epimer). The following two steps provided ()-massadine chloride (()-45, 40%) in the correct configuration, together with ()-massadine (()-27, 20%), also in the correct configuration. ()-Massadine chloride (()-45) could be converted to ()-massadine (()-27) simply by treatment with water at 60 C NH2 Cl HN

NH OH

N3

NH

Cl HN N3

O

HO HN

N3

NH2

(21 steps from diene 126)

Br NH2 Cl HN

H N

H

O

HO HN

HN Br NH

O

H NH

1) PtO2 (0.3 eq), H2 (1 atm), TFA/H2O (1:19), 23 °C 2) 147 (16 eq), DIEA (16 eq), DMF, 23 °C

Br Br

6

NH2

156

(–)-130

HN

NH

H 10

15%

HN

N3

NH2

1) DMDO (1.3 eq), TFA/H2O (1:9), 0 °C 2) neat TFA, 23 °C; separation of diastereomers

NH O

NH2

Br H N

HN H

HO HN

HN Br

NH2

(–)-45: (–)-massadine chloride (40%)

H

O

+

NH

Br

HO HN

NH H2O, 60 °C, 4 h quant.

O

NH O

H NH

NH2

Br (–)-27: (–)-massadine (20%)

Scheme 21 Endgame to ()-massadine chloride (()-45) and ()-massadine (()-27) by Baran and coworkers.102 Purification was performed by RP-HPLC employing a TFA-containing mobile phase.

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Thomas Lindel

with retention of configuration at the carbinol center. Obviously, a neighboring group effect comes into play, and it is assumed that the nitrogen of the 2-aminoimidazole unit takes that role (see also Scheme 1). A tetrabrominated analog of the dibrominated intermediate of the ageliferin synthesis by Chen et al. (Scheme 11) is the protected 10’-oxodibromoageliferin (157), which served as starting material of the 2014 total synthesis of ()-massadine (()-27), Scheme 22).66 Reduction of 157 with LiBEt3H proceeded from the desired side and provided secondary alcohol 158. Ring contraction was induced by regioselective oxidation with TBHP/Ti(Oi-Pr)4 affording a spiroglycocyamidine, which was reduced immediately to the N,O-hemiacetal 159. Removal of the protecting groups afforded “premassadine” (160). The tetrahydropyran ring of massadine remained to be formed under oxidative conditions. Oxidation of with NBS in MeOH, followed by treatment with aqueous HCl worked to some extent and provided a mixture of ()-massadine (()-27, 15%, H N

Br Br

HN

Br

HN N H

Br

O

BOM LiBEt3H (16 eq), N THF, 0 °C N N PPh3 40% N

O

HN

Br Br

N HN

i. Ti(Oi-Pr)4 (2.4 eq), DCM, TBHP (3.2 eq), –20 °C

O

ii. Ca(BH4)2·2 THF (20 eq), –40 to 23 °C

Br

HN

Br

Br

NH

O

HO N

NH O HN

Br NH

HN

N 159

NH 2. HCl aq (1 N), 40 °C; then MeCN, aq NH4OH, 0 °C NH2 22% Br

NH

NH N

O

160: "pre-massadine"

H2N HN

OH

NH2

NH2

1. BCl3 (30 eq), DCM, –40 °C

Br

H

BOM N N N PPh3

N

O 158

OH

H2N HN

N H

OH

NBOM

H HN

Br

44%

Br

HN

PPh3

HO N

NH

O

Br

Br

NH2

157

Br

H N

Br

O

2. aq HCl (2 N), MeCN, 45 °C, 4 d

HO N

NH

1. NBS (0.9 eq), MeOH, –78 °C, 64%

O

H HN

Br NH

HO

NH O 7

3

NH

N

O

NH2

Br (–)-27: (–)-massadine (15%) + 161: 3,7-epi-massadine (29%)

Scheme 22 Endgame to ()-massadine (()-27) by Chen et al.66

Chemistry and Biology of the PyrroleeImidazole Alkaloids

155

0.014% overall yield from L-serine) and 3,7-epi-massadine (161, 29%). The absolute configuration of ()-massadine proposed by Fusetani et al.46 was confirmed. A norbornene rearrangement stands at the beginning of a synthetic study by the Carreira group, which finally afforded spirocycle 170 as synthetically most advanced, potential precursor of ()-massadine (()-27, Scheme 23).108,109 Carreira et al. have worked on that subject at least since 2000, as reviewed earlier. Starting material 162 was obtained by diastereoselective DielseAlder reaction of trimethylsilyl-cyclopentadiene and di-()-menthyl fumarate. After treatment of brominated norbornene 163 with AgNO3, the resulting, presumably nonclassical carbocation underwent a Fleming rearrangement,110 which again afforded a norbornene (165). The double bond of the product arises from elimination of the trimethylsilyl group after attack by methanol. The g-lactone ring also underwent methanolysis. It took 12 steps, including a Strecker aminocyanation of ketone 166, until the stage was set for an ozonolysis that cleaves the norbornene 167 to a highly substituted cyclopentane. Another 13 steps later, which are not detailed in Scheme 23, aldehyde 168 was obtained, which was subjected to a Henry reaction with nitromethane. After reduction of the nitro group to the amine (NaBH4$NiCl2$H2O), the first guanidino group was introduced, followed by oxidation to the ketone and deprotection of the NHCbz group. The second guanidino group is introduced forming 169, and the primary OTBS group is deprotected in the presence of the secondary by employing H2SiF6 in MeCN/H2O. IBX oxidation afforded the N,O-hemiacetal 170, which is described as being labile. The authors expect that from spirocycle 170 a total synthesis of massadine (()-27) should be possible, which remains to be shown. Already, the overall sequence needs 38 steps (0.9% yield) from trimethylsilyl cyclopentadiene. Carreira et al. also published an alternative shorter route to a potential cyclopentane precursor of massadine (()-27), which employs an Ugi four-component reaction and may gain importance in the future.111 Another study on the synthesis of a possible cyclopentane precursor of massadine was published by Daesung Lee et al. who synthesized dialdehyde 173 from cyclohexene 172 (five steps) that was in turn obtained by Dielse Alder reaction of silyloxydiene 171 and acrolein (Scheme 24).112 Ring closure of dialdehyde 173 to cyclopentenecarbaldehyde 174 was achieved under mildly acidic conditions (Bn2NH TFA), but did not proceed with proline as catalyst. Conversion of 174 to epoxyaldehyde 175 proceeded smoothly, and for the subsequent epoxide opening thiophenol/AlMe3

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Thomas Lindel

(–)-menthylO2C

(–)-menthylO2C (–)-menthylO2C

SiMe3

Br2, DCM, 0 °C

MeOH

O

99%

(–)-menthylO2C MeO2C (–)-menthylO2C

O

MeOH 164

90%

O 163

162

O

AgNO3, MeOH, 70 °C

SiMe3

165

HO

Br

AgI

1) (COCl)2, DMSO, NEt3, DCM 2) HC(OMe)3, MeOH, p-TsOH·H2O (cat.), 50 °C 3) LiAlH4, THF, 0 °C 4) t-BuOK, BnBr, dioxane 5) p-TsOH·H2O, THF/H2O 68%

BnO BnO

1) DMBNH2, p-TsOH·H2O (10 mol%), 4 Å MS, PhMe, 110 °C, then Me3SiCN, ZnCl2 (5 mol%), MeOH, rt 2) CF3CO2H/H2O/i-Pr3SiH (94:3:3; v/v/v), rt 3) NaN3, Tf 2O, CuSO4·5H2O, rt

O

166

14 steps, commencing with ozonolysis

OTBS 4) DIBAL-H, PhMe, –78 °C 47% 5) NaBH4, MeOH, 0 °C 6) TBSCl, ImH, DCM, 0 °C 167 7) PMe3, MeOH/DCM, then CbzCl, NaHCO3, acetone/H2O 1) NEt3, MeNO2 2) NaBH4, NiCl2·6H2O, MeOH CbzHN OTBS 3) N,N’-bis(Boc)-S-methylTBSO isothiourea, HgCl2, NEt3, DMF BocHN

13%

O

BocHN 168 BocHN NHBoc TBSO BocHN BocHN

N

OTBS

O

N H

NBoc NHBoc

1) H2SiF6, MeCN/H2O 2) IBX, DMSO

4) DMP, pyr, DCM 37% 5) H2, Pd/C, MeOH 6) N,N’-bis(Boc)-S-methylisothiourea, HgCl2, NEt3, DMF BocHN TBSO BocHN

N

NBoc OH

59% BocHN

169

NHCbz

BnO BnO

O

NBoc N H

NHBoc

170

Scheme 23 Assembly of the CD-spirocyclic potential synthetic precursor 170 of ()-massadine (()-27) by Carreira et al.108,109

had to be used affording 176 after silylation. After oxidation of the thioether and elimination, the cyclopentenecarbaldehyde 177 was obtained, with a shifted double bond compared to 174. The aminocyanation of formyl cyclopentene 177 was achieved by a diastereoselective formal 1,3-dipolar cycloaddition of lithium trimethylsilyldiazomethane, followed by NeN bond cleavage of the resulting pyrazoline 178. Overall, 16 steps with an

157

Chemistry and Biology of the PyrroleeImidazole Alkaloids

OTBS

acrolein, AlMe2Cl, PhMe, DCM, –78 to –30 °C 88%

1) DBU, DCM, rt 2) NaBH4, EtOH 3) TBSCl, NEt3, DCM

OTBS

4) OsO4, NMO, acetone, H2O 5) NaIO4, aq THF, pH 7

OHC 172

171

79% TBSO

CHO

O

+ – O NBn2H2 CF3CO2 PhH, rt

TBSO

TBSO

173

63%

174

1) AlMe3, PhSH, dr 6:1 O CHO 2) TBSCl, ImH, DMF, 80 °C

TBSO

3) DMP

OTBS

92%

1) NaBH4, EtOH 2) MCPBA, DCM

TBSO

CHO SPh

1) H2O2, HOAc, DCM dr 19:1 2) P(OMe)3, PhMe, rf

TBSO

75%

76%

OTBS

OTBS

175

176

TBSO

CHO

1) MnO2, NaCN, HOAc, MeOH 2) TMSCHN2, nBuLi, THF, -78 °C

TBSO

TBSO

CO2Me H N N

TBSO

65%

OTBS

OTBS

TMS

178

177 p-TsOH, DCM, K2CO3, 45 °C 90%

TBSO

TBSO

CO2Me NH2

179

CN OTBS

Scheme 24 Daesung Lee’s approach to the substituted cyclopentane 179 as potential synthetic building block toward ()-massadine (()-27).112

overall yield of 15% were needed to obtain hexasubstituted cyclopentane 179 from acrolein. It remains to be shown how efficient an overall synthesis of massadine will be, since there is still some way to go.

4.5 Palau’amine In 2010, the Baran group published the landmark first total synthesis of racpalau’amine (rac-3),113 to be followed in 2011 by the enantioselective version providing ()-palau’amine (()-3), which is presented here.102 In 2015, Namba, Tanino, et al. published the second total synthesis, of rac-

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Thomas Lindel

palau’amine (rac-3), which is longer.114 Two incomplete approaches towards palau’amine by Feldman et al.115,116 and by Chen et al.117 are also included. In its initial steps, the Baran synthesis (Schemes 25 and 26) follows the first-generation synthesis of the axinellamines. As a difference, an enantioselective copper-catalyzed DielseAlder reaction (ee 89%) was employed between the nonsymmetrical fumaric acid derivative 180 and electron-rich 1-silyloxydiene 126, employing the chiral bisoxazoline ligand 181 (Ishihara catalyst118). The reduction of oxazoline 182 proved to be difficult, because the carbamate reacted. Thus, thioester 183 was prepared, which was readily reduced to the alcohol. After mesylation, the introduction of the azido groups required heating in DMF. After desilylation and PMB protection, ozonolysis of cyclohexene 184 afforded diketone 185, which was a-brominated twice and underwent intramolecular aldol addition on warming in the presence of silica gel forming the cyclopentane ring (186). After conversion to the electrophilic trihalo compound 127 and reduction of the ketone, the first guanidine unit was installed by nucleophilic attack at the allyl bromide, forming cyclopentane 187. A key step of the sequence, which at the time was not diastereoselective, was the spirocyclization of 187 to the spirocyclopentaimidazoline, which was to become the spirocyclic partial structure of ()-palau’amine (()-3, Scheme 26). The step occurred after oxidation of the secondary allylic alcohol moiety of 187 to the enone, enabling an intramolecular Michael addition. The a-chloroketone was converted to the a-aminoketone, which was deprotected affording 129. An important finding was the use of Ag(II) picolinate for the oxidation of 2-aminoimidazoline to the N,O-acetal 189, which proceeded in the convincing yield of 69%. The oxidation had to take place before the construction of the electron-rich second 2-aminoimidazole unit, which now followed by condensation of the a-aminoketone with cyanamide. Product 130 was a branching point from which also ()-massadine became available (see Scheme 21). The five step sequence from the tricyclic precursor 130 to the hexacyclic structure of ()-palau’amine (()-3) proceeds via “macropalau’amine” 193. In the first step, the pyrrole unit was to be installed at the 2-aminoimidazole, which was possible after imidazole bromination to imidoyl bromide 190 (54%). The bromination step only worked in the presence of TFAA, which trifluoroacetylated the imidazole. In the absence of TFAA, addition to the C]C double bond occurred. The pyrrole-2-carboxylic acid was not introduced as a complete heterocycle, but rather by employing the linear primary amine 191. In the presence of TFA, cyclization to the pyrrole probably took place after formation of the

159

Chemistry and Biology of the PyrroleeImidazole Alkaloids

O

O O

O

OTIPS

N

O

MsHN

+

OEt

180

O

OTIPS

C12H25S

74%

EtO2C 183 1) NaH (2.0 eq), PMBCl (1.1 eq), TBAI (0.1 eq), DMF, 0 to 23 °C

N3 N3

PMBO N3

Br N3

O

N3

O

N3

3) SO2Cl2 (2.0 eq), 2,6lutidine (3.0 eq), DCM, 0 °C

186

182 (ee 89%)

OPMB

1) LiCl (3.3 eq), DMF, 23 °C 2) TFA/DCM (1:9), PhOMe (2.0 eq), 0 °C

Br

EtO2C

3) NaN3 (6.0 eq), DMF, 100 °C 4) TBAF (1.1 eq), THF, 23 °C 70%

86% OH

OTIPS

1) LiAlH4 (3.0 eq), Et2O, 0 °C 2) MsCl (4.0 eq), pyridine, 0 to 23 °C

2) O3, MeOH, –78 °C; DMS (3.0 eq), 23 °C

184

N O

84%

126

OH

O

NHMs

Cu(NTf2)2 (5.5 mol%), 181 (5 mol%), MeNO2, –20 to 4 °C, 15 h

O

C12H25SH (4.4 eq), n-BuLi (4 eq), THF, –78 to 0 °C

O 181

N

N

43%

DIEA (6.0 eq), TMSOTf (4.0 eq), 0 to 23 °C;

O

NBS (2.0 eq), THF, MeCN, 0 °C; SiO2, 50 °C

185

66%

Cl

Br

N3

Cl N3

O (+)-127 H2N

1) NaBH4 (1.0 eq), CeCl3·7 H2O (0.5 eq), MeOH, 0 °C 2) BocHN

Cl N3

E

NBoc NH2

(1.2 eq), DBU (1.2 eq), DMF, –20 to 0 °C 55%

N Boc

N3

NBoc

Cl OH 187

Scheme 25 Total synthesis of ()-palau’amine (()-3) by Baran et al. (Part 1, construction of cyclopentane ring E).102

imidazole-N-bond. Hydrogenation of both azido groups and coupling with the sterically more accessible amine with EDC closed the 9-membered ring of “macropalau’amine” (193). The distance between the amide nitrogen and the imidazole carbon, at which the final attack had to take place was 3.3 Å, and treatment TFA induced that step. ()-Palau’amine (()-3) was obtained as the correct enantiomer. The rather low overall yield of 0.026% was mainly caused by the final steps, e. g., 17% from 192 to ()-3, and the necessity of separating the diastereomers of 129.

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Thomas Lindel

NH2

1) IBX (2.0 eq), PhH, 83 °C 2) NaN(CHO)2 (1.5 eq), TBAI (0.1 eq), THF, 23 °C

187

Cl HN

NH

25%

N

O

O

188

NH3 N3

O

Ag

N3

3) TFA/H2O (1:1), 50 °C; separation of diastereomers

O

N

188 (2.5 eq), TFA/H2O (1:9), 23 °C

O (–)-129

69% NH2 Cl HN N3

NH2

NH OH

H2NCN (40 eq), pH 5, brine, 70 °C

NH3

Cl HN N3

N3

189

(–)-130

NH2 NH2

NH OH Br NH HN NH2 190

191

Cl HN

OMe

t-BuO2C

Cl HN

N3

OMe OMe

191 (3.0 eq), HOAc (3.0 eq), THF, 38 °C; TFA/DCM (1:30 to 1:1), 23 °C 44%

2) EDC (3.0 eq), DMF, 23 °C

Cl HN H3N

N N3

HN H2N

NH CO H 2 192

H2N NH OH H N

N

HN

NH OH

N3

H2N 1) Pd(OAc)2 (1.6 eq), H2 (1 atm), TFA/H2O (1:9), 23 °C

54%

HN

NH2

NH2 N3

TFAA/TFA (1:1); Br2 (2.0 eq); TFA/H2O (1:1), 38 °C, 1 h

NH

65%

O

N3

NH OH

NH2 neat TFA, H3N 70 °C, 24 h NH 17% (3 steps)

O 193: "macropalau'amine"

NH OH Cl HN F H NH2 E HN H D NH C N B N A O (–)-3: (–)-palau'amine

Scheme 26 Total synthesis of ()-palau’amine (()-3) by Baran and coworkers (Part 2).102 Purification was performed by RP-HPLC employing a TFA-containing mobile phase.

The total synthesis of rac-palau’amine (rac-3) by Namba, Tanino, et al. needed 45 steps starting from cyclopentenone (Schemes 27e29).114 Key step (74% yield) is the base-induced fragmentation of octahydrocyclopenta[c]pyrazole 204 (Scheme 28), which is believed to proceed along an E1cB mechanism. The NeN-bond of 204 is cleaved and the pyrrolecarboxamide nitrogen attacks at the resulting imine, forming the characteristic trans-fused octahydrocyclopenta[c]pyrrole core structure 205 of rac-palau’amine (rac-3). Before that reaction became possible, compound 204 was made available in 22 steps. Cyclopentenone (194) was hydroxyalkylated

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Chemistry and Biology of the PyrroleeImidazole Alkaloids

1) O

P(n-Bu)3 (10 mol%), THF O

AcO

2) Ac2O, Pyr, THF 3) NaBH4, CeCl3·7 H2O

1) TsNHNH2, EDC, DMAP, DCM 2) HOAc, H2O, THF

OTBS 3) PhMe, rf 4) THF, H2O

TBSO

49%

194

1) TBSOTf, NEt3, DCM 2) TBSCl, LHMDS, HO2C HMPA, THF, –78 °C

OTBS

OTBS TBSO

195

196

O Hg(OAc)2 (2 mol%), MeNO2, rt

TsN NH2

44% (six steps)

OH

HO

H

O TsN

84% (α:β 1:2)

N H

197

1) SO3·Pyr, NEt3, DCM 2) TMSI, HMDS, DCM 3) Pd(OAc)2, DMSO 78%

O TsN

N H

O 199

198 1) P(n-Bu)3 (40 mol%), aq H2CO, THF 2) tetramethylguanidine (43 mol%), MeNO2, 0 °C

H

OH

3) NaBH4, MeOH, –78 °C 91%

TsN

NO2

H

O

E N H

OH OH

200 (rac)

Scheme 27 Total synthesis of rac-palau’amine (rac-3) by Namba, Tanino, et al. (Part 1, construction of the fully substituted cyclopentane ring E).114

in a nonenantioselective BayliseHilman reaction, followed by eight steps to afford hydrazide 197 (Scheme 27). The allylic alcohol function of 197 was submitted to a Hg(OAc)2-catalyzed cyclization in nitromethane, which left a vinyl group at the bridgehead, later to be cleaved via the glycol.119 The cyclopentanol moiety of product 198 was decorated further via conversion to the cyclopentenone 199, a second BayliseHilman reaction, a Michaele Henry attack and reduction to 200. Three further steps afforded the octahydrocyclopenta[c]pyrazine 201, which was a-brominated (Scheme 28). Ring contraction of 201 to 202 occurred after methanolysis of the hydrazide. The pyrrolylcarbonyl unit was introduced and the stage was set for the key step. Treatment of 204 with lithium hexamethyldisilazide not only broke the NeN-bond and led to formation of the trans-fused five-membered rings (intermediate 205), but also led to further cyclization by attack of the deprotonated pyrrole nitrogen at the methyl ester function. As result, the ABCE subsystem of palau’amine (3) was formed in one step. For the construction of ring D, Namba et al. referred to Romo’s synthesis of dibromophakellstatin (385)120 by installing a thiourea unit, which was cyclized on a pyrrole-N,O-hemiketal (207), affording the ABCDE system 208 (Scheme 29) after three further steps.

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Thomas Lindel

NO2

H

O TsN

OH

N H

OH

200 (rac)

1) TBSCl, ImH (3 eq), DMF, 0 °C 2) i) SmI2 (10 eq), THF, MeOH, rt; air (workup) ii) FmocOSu (1.5 eq)

BocN

3) TBSOTf, 2,6-DTBP, DCM, –78 °C 4) Boc2O, DMAP, MeCN, 0 °C 68%

1) i) TESOTf (5 eq), DIEA (10 eq), DCM, –78 °C ii) NBS (1.2 eq), THF/ MeOH (1:1), –78 °C 2) K2CO3 (1 eq), MeOH, 0 °C

OTBS OTBS

N H

201

NHFmoc

MeO2C H H

NHFmoc

H

O

1) TFAA (10 eq), 2,6-DTBP (15 eq), DCM, 0 °C 2) i) piperidine/MeCN (1:19), rt ii) 203 (1.3 eq), 2,6-DTBP (3 eq), MeCN, rt

BocN N H

72%

OTBS OTBS

83%

CCl3 N H

203

O

202 HN

O

base

N

NH

MeO2C H H BocN N F3C

O

OTBS OTBS

LHMDS (3 eq), THF, –78 to 0 °C; HOAc (1 eq), –78 °C to rt

O

O

N H

H3CO BocHN

74%

F3C

OTBS OTBS

O

204

O BocHN

205

O

N N H

1) TMSOTf (5 eq), 2,6DTBP (6 eq), DCM, 0 °C to rt H

HN F3C

OTBS OTBS

O 206

H

N

2) CbzNCS (5 eq), 2,6DTBP (2 eq), DCE, 70 °C 3) NaBH4 (1 eq), EtOH, 0 °C 88%

HO

A N

O B

CbzHN S F3C

NH H HN

N C

H

E OTBS OTBS

O 207

Scheme 28 Total synthesis of rac-palau’amine (rac-3) by Namba, Tanino, et al. (Part 2, assembly of the ABCE ring system; FmocOSu: N-(9-fluorenylmethoxycarbonyloxy)succinimid).114

Ring F was assembled again via a thiourea, which was first converted to the differentially bis-protected guanidine moiety of 209 (Scheme 29). After dihydroxylation of the vinyl group and glycol cleavage, the hydroxy-2aminoimidazoline ring F was formed (210), completing the hexacyclic ring system. Seven functional group manipulations later, the synthesis of rac-palau’amine (rac-3) was complete, after 47 steps. The racemic pentacyclic ABCDE subskeleton (219) of palau’amine (3), lacking the spirofused ring F, was assembled by the Feldman group.115,116 The Pummerer approach had already been successful in the total synthesis of dibromophakellstatin (385, see there) and relies on the oxidation of a

163

Chemistry and Biology of the PyrroleeImidazole Alkaloids

1) MeI (6 eq), K2CO3 (6 eq), 0 °C 2) LHMDS (4 eq), THF, –78 °C; MsCl (4 eq), –40 °C 207

Cbz

3) i) DIBAL (2 eq), PhMe, –78 °C ii) CbzNCS (2 eq), DCE, rt

N

MeS CbzHN

N H

N N

OTBS OTBS

o-NB

42%

OTIPS

OH

NH

1) MCPBA (2 eq), DCE, 0 °C 2) (o-NB)NH2 (3 eq), Tf 2NH (3 eq), DCE, 50 °C

Cbz

CbzHN

N

H

N H

H

Cl N OH o-NB 212

N3

64%

O

N N H

N N

MeS

H

N

F OTIPS Cl N OH o-NB 210

1) HF-Pyr/THF (1:5); TMSOMe (workup) 2) MsCl (2 eq), Pyr, 0 °C 3) NaN3 (2 eq), 15-crown5 (2 eq), DMF, rt 45%

OTIPS Cl N OH o-NB 211

i) hν (Hg 400 W), MeOH, rt ii) H2, Pd(OAc)2 (1.5 eq), MeOH/TFA/H2O (2:1:1)

O

N CbzHN

N

N H

N

N

(o-NB)HN

N

(o-NB)HN

70%

N

O

N

Cbz

CbzHN

209

Cbz

55%

208

1) OsO4, TMEDA, DCM, –78 °C 2) NaIO4 (5 eq), MeOH/H2O 3) SO2Cl2, 2,6-lutidine, DCM, 0 °C

H

N

CbzHN

H

HN

1) (o-NB)NH2-HCl (6 eq), EDC (6 eq), DIEA (6 eq), DCE, 50 °C 2) i) HF-Pyr/THF (1:3), 0 °C, TMSOMe (workup) ii) TIPSOTf (2 eq), 2,6lutidine, 0 °C

O

N

MeS

N H

D N

S

49% Cbz

O

N

A N

O B

3 TFA N D C NH H H2N H E HN F NH2 H2N Cl N OH N

rac-3: rac-palau'amine

Scheme 29 Total synthesis of rac-palau’amine (rac-3) by Namba et al. (Part 3);114 o-NB: (o-nitrobenzyl).

phenylsulfanyl group rendering an electrophilic imidazole unit. The cyclopentane ring E was formed via light-induced Wolff ring contraction of an a-diazocyclohexanone moiety, which was obtained from the corresponding trans-disubstituted cyclohexene 215 (Scheme 30). That approach proved to be superior to the direct synthesis of the cyclopentane ring, which was possible, but did not allow the bicyclization. The cyclohexene ring of 215 was constructed by DielseAlder cycloaddition of 1,3-butadiene to electron-poor vinylimidazole 214 (45%) in the presence of hydroquinone.

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Thomas Lindel

1) BOMCl, K2CO3, MeCN, rt 2) n-BuLi, Ph2S2, THF, –78 °C

H N N

N H2N

N BOM

O

3) n-BuLi, DMF, THF, –78 °C 4) (EtO)2POCH2CONH2, KOt-Bu, THF, 0 °C to rt

213

SPh

1,3-butadiene, cat. hydroquinone, PhMe, 200 °C 45%

214

24% BOM N

1) POCl3, NEt3, MeCN, 0 °C to rt 2) AlCl3, DCM, –10 °C

SPh N

3) LiAlH4, Et2O, 0 °C 4) 147, Na2CO3, DMF, MeCN, rt

NH2

O

HN C N

55%

N B N

Br

O 217

Br

216

SPh

PhI(CN)OTf, 2,6lutidine, MeCN, 0 °C

SPh

N H N

O

35%

215

O

NH

H N

Br

Br

1) i) Hg(OCOCF3)2, HClO4 (cat), THF, H2O, rt ii) NaBH4, NaOH, 0 °C to rt 2) Dess–Martin periodinane, DCM, rt 3) LiN(TMS)2, CF3CO2CH2CF3, THF, –78 °C 12%, separation of

OH

regioisomers MeO2C

F3C

SPh HN N N

N

Br

O Br 218

i) MsN3, NEt3, MeCN, H2O, rt ii) 300 nm, MeOH 37%

E

SPh HN

D N C N B N Br A O Br 219 (rac, 1:1 mixture of diastereomers)

Scheme 30 Assembly of the pentacyclic ABCDE framework 219 of rac-palau’amine (rac-3) by Feldman et al.115,116

Compound 214 was accessible from imidazole within four steps. The pyrrole-2-carboxamide moiety was installed and the cyclization of 216 to pentacycle 217, which formed rings B and C, was induced after oxidation of the phenylsulfanyl group with PhI(CN)OTf. Further on toward 219 the separation of regioisomers became necessary. Oxymercuration of 217 was not regioselective. Nevertheless, demercuration was induced with NaBH4, followed by DesseMartin oxidation and a-trifluoroacetylation. Pentacycle 218 was obtained after separation of regioisomers. Diazotransfer (MsN3) to the sensitive a-diazoketone and irradiation led to ring contraction (Wolff rearrangement) affording 219 after methanolysis (Scheme 30). It remains to be seen whether 219 can be converted to rac-palau’amine (rac-3). In

165

Chemistry and Biology of the PyrroleeImidazole Alkaloids

addition, the DielseAlder reaction would have to be conducted enantioselectively. Originally, Feldman et al. had also targeted the wrong 1993 diastereomer of palau’amine, as did the Overman group.121 As a possible precursor of palau’amine (3), the Chen group also synthesized the hexacyclic model compound 221, which still would have to undergo oxidative ring contraction to the spirosystem (Scheme 31).117 As for the other synthesis of the group, Garner’s aldehyde served a starting material, which was converted to tetrahydrobenzimidazolone 220 in 13 steps. Reduction of the azido group and coupling with pyrrolyl trichloromethyl ketone 147 were followed by treatment with PhIO, which oxidized selectively the free imidazolone unit. Warming in DMSO led to the formation of the hexacyclic product 221 (0.5 mg). The overall yield for the final four steps was about 5%, leaving room for improvement.

4.6 Proposed Structure of Nagelamide D Lovely et al. completed the synthesis of what was thought to be nagelamide D (229), but had to realize that the data published by the Kobayashi group39 did not match the proposed structure (Scheme 32).122 The approach makes double use of dimethylaminosulfonyl (DMAS)-protected 4,5diiodoimidazole (222), which was converted to vinylstannane 223 and to vinyl-substituted iodoimidazole 224 in three and four steps, respectively. The hydrostannylation was not regioselective but still gave 223 in 57% yield. Stille coupling of 223 and 224 proceeded in more than 80% yield affording the bisimidazole section 226 of nagelamide D. For the installation of the pyrrolylcarbonyl units, Lovely employed the bicyclic hydantoin 227, which was reacted with 226 in a good-yielding Mitsunobu reaction (80%). DIAD had to be reacted with PPh3 prior to addition of the starting material 226 to prevent competing Staudinger reduction of the azido groups. Hydrolysis of the two hydantoin units of 228 proceeded regioselectively, liberating O N BOM N

CbzHN

BOM H N N H H N3

220 (13 steps from Garner's aldehyde)

O O 1) PPh3, H2O, THF, 80 °C 2) 147, NEt3, DMF, 70 °C

BOM O N

NH HN

BOM N H

3) PhIO, Na2CO3, TFE, 23 °C 4) DMSO, 50 °C ca. 5%

N N

H

Br Br

O

CbzHN 221

Scheme 31 Final steps of Chen’s study on the synthesis of the palau’amine skeleton (TFE, trifluoroethanol).117

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Thomas Lindel

N

I

N DMAS

I

1) EtMgBr, DCM; 2-PyN(CHO)Me 2) (EtO)2P(O)CH2CO2Me, KHMDS, THF, 0 °C

222

3) DIBAL, DCM 4) TBSCl, ImH

1) EtMgBr, DCM; H2O 2) propargylOTBS, Pd(PPh3)2Cl2, CuI, K2CO3, DCM 3) Pd(PPh3)2Cl2, n-Bu3SnH, THF

51%

49%

DMAS N

N

N

SnBu3

OTBS

N

N DMAS

Pd2dba3, PPh3, CsF, CuI, DMF, 55 °C; the TBAF, THF

OTBS 223

OH

N

224

I

N DMAS

N

DMAS

OH 225 Br

O N3 1) H2, Pd-C, EtOH, 34 °C 2) TBSCl, ImH, DCM

DMAS N

HN

N

3) n-BuLi, THF, –78 °C; TsN3 4) TBAF, THF 35% (6 steps)

N3

Br

O DIAD, PPh3, THF 80%

OH 226

Br

Br N3

N

O

N

O

N DMAS

N O 228

N

H2N

N N

N N3

Br

DMAS O

Br Br

1) NaOH, H2O, THF 2) i) HCl, MeOH ii) H2, Lindlar, MeOH; then TFA 27%

227

OH

N

N DMAS

N

NH

N HN

Br

O

N

HN

2 TFA H2N

HN

O N H

H N

Br Br

229: proposed structure of nagelamide D

Scheme 32 Synthesis of the proposed structure 229 of nagelamide D by the Lovely group.122

the pyrrolecarboxamide moieties. Removal of the dimethylaminosulfonyl (DMAS) group, followed by hydrogenation of the azido groups afforded structure 229. The reversed order of deprotection steps would not be possible, because the DMAS group could not be removed once the amino group was liberated.123 Unfortunately, the data of compound 229 did not correspond to the data published by the Kobayashi group. Lovely cites a doctoral thesis from the Horne group, which reports the same data as his own, indicating that the structure of the natural product needs to be redetermined.

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Chemistry and Biology of the PyrroleeImidazole Alkaloids

A study toward the total synthesis of nagelamide K (30) was published by Jiang et al. who employed a Ni(0)-catalyzed dimerization of an a-bromourocanic acid derivative (Scheme 33).124 The important amino groups at the imidazole section are still missing. After Wittig reaction of DMAS-protected imidazolecarbaldehyde 230 and in situ a-bromination with bromodimethylsulfonium bromide (BDMS), treatment with [Ni(cod)2] afforded the bisalkylidene succinic acid ester 231 in excellent yield (95%). On heating of 231 to 150 C in DMSO, cyclization to 232 took place with loss of one of the DMAS groups. Already when lowering the temperature 130 C, only 43% yield was reached. The endgame employs the masked pyrrolecarboxamide 227 and afforded model compound 233, which lacks the 2-amino groups and a taurine unit, when compared to nagelamide K (30).

4.7 Agelastatin Among the pyrroleeimidazole alkaloids, the cytotoxic agelastatin A (()-7) has been synthesized most frequently. Since 2006, successful routes have been published by 12 research groups with 2009 being the most productive year. In our earlier reviews, the syntheses by Weinreb et al.125 Feldman and Saunders126 Hale et al.127 and Davis and Deng128 have been covered and are not rediscussed here. Most of the syntheses still assemble ring C first by employing creative methodology, followed by appending the pyrrole section (ring A) and closing of the remaining rings. Ring B is often formed by Michael addition to a cyclopentenone version of ring C. A few of the

N OHC

DMAS

N

1) Ph3P=CHCO2Me, BDMS, Et3N

MeO2C

2) Ni(cod)2, Ph3P, MeCN 95%

N 230

N N MeO2C

N

N

MeO2C 232

MeO2C

Br

96% N

231

Br

DMSO, microwave, 150 °C

N N

1) LiAlH4 2) H2, Pd/C 3) (i) DEAD, Ph3P, 227 (ii) NaOH, THF, H2O 4) HCl, MeOH

DMAS

DMAS

DMAS

Br

H N

Br

HN

Br

HN

O N

NH 227 O

O

Br

N H

HN N N

N

O 233

65%

Scheme 33 Study on the synthesis of rac-nagelamide K (rac-30) by the Jiang group (BDMS, bromodimethylsulfonium bromide)124.

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Thomas Lindel

syntheses follow a different path, among them Movassaghi et al. who first make the AB system129,130 and the biomimetic approach by Romo et al. who make rings A and D first.131 Syntheses employing chiral saccharide starting materials are significantly longer. However, several of the total syntheses manage to access ()-agelastatin A (()-7) in 10 steps or less from basic chemicals. One can say that in the case of ()-agelastatin A (()-7) basic research in Organic Synthesis has convincingly solved the supply problem. The Ichikawa synthesis of ()-agelastatin A (()-7) starts from the chiral pool compound L-arabitol, which was converted to enal 234 (Scheme 34) in 9 steps (34%).132 Enal 234 was submitted to a Soai addition of Et2Zn, which gave the secondary alcohol with a de of 84%, to be converted to the carbamic

O

1) Et2Zn,

O CHO 234 (9 steps, 34% from L-arabitol)

O

1) CCl3C(O)NCO, DCM 2) K2CO3, aq MeOH

NCbz

3) PPh3, CBr4, NEt3, DCM

239

HO NHCbz H N

NH O

Br 241

NHCbz

76% 1) Cl3CCH2OH 2) Zn, HOAc, THF

O NCbz NCO 240

1) IBX, DMSO 2) i-Pr2NEt 3) H2, Pd-C (10%), EtOAc, NEt3 4) MeNCO 5) NBS, MeOH, THF

1) Dowex 50 W, MeOH, rf 2) Grubbs I catalyst (5 mol%), PhH, 60 °C 3) Me2C(OMe)2, CSA, acetone 4) silica gel, H2O, DCM

238

O

Br

236

2) n-Bu3SnOBn 78% (5 steps)

237

1) PPh3, CBr4, NEt3, DCM

O

2) CCl3CONCO, DCM 3) K2CO3, aq MeOH

O

NH2

O

235 hexane, 0 °C, dr 92:8

[3,3]

O

HO

O O

O

N

O

Ph Ph OH

N

Br

3) Br Br

CCl3

147

N H

O Na CO , DMF 2 3 4) Dowex 50 W x8, MeOH, rf 57% (7 steps) O N HO D NH C H (–)-7: (–)-agelastatin A H H N B NH A O

45%

Scheme 34 Total synthesis of ()-agelastatin A (()-7) starting from the chiral pool compound L-arabitol by Ichikawa et al.132

169

Chemistry and Biology of the PyrroleeImidazole Alkaloids

acid ester 236 in two further steps. Key step of the synthesis is a [3,3] sigmatropic rearrangement of in situeformed allyl cyanate 237, which was formed from allyl carbamate 236 under Appel-type conditions by treatment with PPh3, CBr4, and NEt3da dehydration that had been discovered by the main author in 1992.133 The allyl isocyanate, formed after rearrangement, was trapped as carbamate (238). Ring C was closed by olefin metathesis. The endgame is similar to earlier syntheses. Overall, ()-agelastatin A (()-7) was obtained in a rather long sequence of 29 steps with a high overall yield of 5%. In 2011, the group of Yasumasu Hamada streamlined the first part of Ichikawa’s synthesis of ()-agelastatin A (()-7).134 The late intermediate 241 became accessible in eight steps instead of 25 (Scheme 35). Key step is an asymmetric aziridination of cyclopentenone employing the Lwowski-type reagent, p-TsONHCbz, which had been employed for aziridinations in the presence of base earlier. As organocatalyst, N-neopentyl 1,2-diphenylethylenediamine (242) was employed providing Cbzprotected aziridine 243 in 75% yield and 95% ee. After conversion of 243 to the silyl vinyl ether, installation of the phenylselenyl group, and diastereoselective reduction to 244, regioselective opening of the aziridine by treatment with NaN3 was possible. Nickel borideecatalyzed reduction to the amine, amide coupling with pyrrole-2-carboxylic acid 245 and

OTMS 1) p-TsONHCbz, PhCO2H, NaHCO3, CHCl3 Ph

DBU (cat.), PhMe

CbzN

2) PhSeCl, PhMe, –78 °C 3) NaBH4, THF, H2O, –78 °C

NH2

O

O

75% Ph

N tBu H 242 (20 mol%)

194

75%

243 (95% ee)

1) NaN3, HOAc, MeOH, H2O, 7 d 2) NaBH4, NiCl2·6H2O (cat.), MeOH, –20 °C CbzN

SePh 3) EDCI, HOBt, DMAP, DCM OH 244

TMSN

Br

Br Br N H

H N O CbzHN OH

245 Br

OH N H

O 4) 30% H2O2, Pyr, THF

241 56%

Scheme 35 Hamada’s access to the Ichikawa intermediate 241 via asymmetric aziridination of cyclopentenone.134

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Thomas Lindel

oxidative elimination of the PhSe group afforded cyclopentene 241, and thereby formally ()-agelastatin A (()-7). In an even more efficient formal total synthesis of ()-agelastatin A (()-7), cyclopentene 251 was assembled in just five steps.135 The main focus of the work by Keiji Maruoka et al. is laid on the stereocontrolled synthesis of vicinal diamines by organocatalyzed Mannich reaction. In the case of the syn-diastereomer 248 that led to the natural product, use of L-proline as organocatalyst was sufficient for coupling aldehyde 246 and imine 247 (Scheme 36). The synthesis of the antidiastereomer, which is not discussed here, required the design of an axially chiral amino sulfonamide as organocatalyst. Aldehyde 248 was extended to compound 249 (both epimers, 1:1) via NozakieKishieHiyama coupling with (E)-1-bromopropene, followed by three further steps affording key intermediate 251, which had already served in the Ishikawa and Hamada syntheses of ()-agelastatin A (()-7). Compound 251 was obtained as a 1:1 mixture of diastereomers, which was oxidized to the ketone in the next step. Yoshimitsu, Tanaka, et al. published an enantioselective total synthesis of ()-agelastatin A (()-7) exploiting a radical aminobromination (Scheme 37).136e138 The key step goes back to work by Bach et al.139 and is induced by reacting the cyclopentenyl carbonazidate 255 with catalytic amounts of FeBr2 and stoichiometric amounts of trimethylsilyl bromide to form the b-brominated cyclic carbamate 256. The bromo substituent is introduced diastereoselectively from the face where the azide is located. It is assumed that the catalytic cycle commences with displacement of dinitrogen forming NBoc

O

69%

NHCbz

CbzHN

Ph

246

247

NHBoc

NH Cbz

NiCl2, CrCl2, DMSO Ph

73%

248 (98% ee, syn/anti 13:2)

HO NHCbz

1) TFA, DCM 2) 245, EDCI, HOBt, DMAP, DCM Br

Ph

H N

NH

3) NMes , PhMe

MesN 249

Br

MeCN, 0 °C

+

OH

NHBoc

O

L-proline (30 mol%),

Cl

Ru

250

Br 52%

O 251

Cl i-PrO

Scheme 36 L-Proline-catalyzed Mannich reaction as key step of the formal total synthesis of ()-agelastatin A (()-7) by Maruoka et al.135

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Chemistry and Biology of the PyrroleeImidazole Alkaloids

BocHN

OH

1) Mo(CO)6 (0.5 eq), NaBH4, aq MeCN

O

1) p-NO2-C6H4-CO2H, DEAD, PPh3, THF 2) TFA, DCM; then

2) lipase PS-C Amano II, MeO OMe vinylacetate, DCM O BocHN 252 3) aq LiOH, EtOH 253 3) CCl3C(O)NCO, DCM; then H+ (ee 99%) 30% 63% O O O O 1) K2CO3, MeOH, FeBr2 (0.1 eq), N3 DCM TMSBr (3 eq), MeCN H H NO2 2) CDI, THF; then 66% N NH2 N NH2 TMSN3, EtOAc, H2O 254 2 5 5 91% O O O O O N O O HO 1) aq MeNH2, DMSO, NH NH NH 130 °C H 2) TPAP, NMO, DMF NaH, DMF H H H Br H H Br N NH N NH2 91% N B NH 3) NBS, THF, MeOH O 256

O 257

22%

O (–)-7: (–)-agelastatin A

Scheme 37 Total synthesis of ()-agelastatin A (()-7) via radical aminobromination by Yoshimitsu et al.136,137

a radical with concomitant oxidation of Fe(II) to Fe(III). One of the bromide ligands and the nitrogen are transferred to the alkene, formally reducing Fe(III) back to Fe(II). Reaction with trimethylsilylBr liberates FeBr2 for the next cycle. From 256, ring B is assembled after deprotonation of the amide, followed by an established end game. The starting material of the synthesis is enantiomerically pure cyclopentene 253, obtained by reduction of the bicycle 252, kinetic resolution by enzymatically catalyzed acetylation of the resulting alcohol, and hydrolysis. Overall, ()-agelastatin A (()-7) was obtained in 13 steps and 2.2% overall yield. There was also an improved version of the agelastatin A synthesis published by Davis and coworkers.140 Wehn and Du Bois made use of their Rh(II)-catalyzed intramolecular aziridination of homoallylsulfamates, which converted cyclopentene 259 diastereoselectively to the isolable tricycle 260 (Scheme 38).141 The reaction proceeds with a very low catalyst load and very high yield (95%) with PhI(OAc)2 serving as oxidant. Nucleophilic ring opening of the aziridine by azide affording bicycle 261 is followed by nucleophilic attack of phenylselenide affording tetrasubstituted cyclopentane 262. The endgame assembles the pyrrole-2-carboxylic ester moiety by PaaleKnorr reaction,

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Thomas Lindel

OSO2NH2 1) Boc2O, cat DMAP, DCM

O HN 258

2) NaBH4, MeOH 3) ClSO2NH2, Pyr, DMA 77%

NaN3, i-PrOH, H2O BocHN

71%

1) TFA, DCM 2) 263, PPTS, DCE, 80 °C PhSe O 263 BnO2C

[Rh2(esp)2] (0.06 mol%), PhI(OAc)2, MgO, DCM 95%

BocHN

N

BocHN

259

260 PhSe

N3 O HN S O O 261 O

NHMe NH

CHO

3) Me3P, THF, H2O; then MeNCO 69%

O N S O O

NHCO2Et CO2Bn 264

N3

(i) (EtO2C)2O, cat DMAP, THF (ii) Ph2Se2, NaBH4, EtOH 93%

BocHN

NHCO2Et 262

1) (i) MCPBA, DCE, 0 °C (ii) Et3N, 80 °C 2) OsO4 (2.5 mol%), NaIO4, THF, H2O, 45 °C 3) KOt-Bu, t-AmOH, 45 °C 4) NBS, THF, MeOH 42%

O HO

Br

H N

N NH H H NH O

(–)-7: (–)-agelastatin A

Scheme 38 Total synthesis of ()-agelastatin A (()-7) via intramolecular aziridination by Wehn and Du Bois ([Rh2(esp)2]: bis[rhodium(a,a,a0 ,a0 -tetramethyl-1,3-benzenedipropionic acid], PPTS: pyridinium 4-toluenesulfonate).141

followed by four further steps to ()-agelastatin A (()-7, 14 steps from 258, 14% overall yield). The ()-agelastatin A synthesis by Chida et al. employs a sequential Overman/MisloweEvans sigmatropic rearrangement in the key step (Scheme 39).142 Since it starts from the saccharide chiral pool, the sequence is a little longer, reaching 21 steps and 1.6% overall yield. After formation of the bis(trichloroacetimidate) from diol 265, boiling in xylene in the presence of Na2CO3 induced the [3,3] sigmatropic events, resulting in two shifted trichloroacetamide moieties. Oxidation of the phenylsulfanyl group set the stage for a MisloweEvans rearrangement. Ring closing metathesis provided cyclopentene 266, which was converted in 10 further steps to the natural product. As in other syntheses, ring B is closed via Michael addition. Dickson and Wardrop, too, employed an Overman rearrangement in their total synthesis of rac-agelastatin A (rac-7).143 Starting from the dioxygenated cyclopentene 269 (two steps from cyclopentadiene) a trichloroacetimidate was installed, followed by the [3,3]-sigmatropic rearrangement (Scheme 40). A halonium formation and subsequent ring opening was induced by treatment with N-bromoacetamide, followed by dehydrobromination affording 270. After hydrolysis of the cyclic trichloroacetimidate

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Chemistry and Biology of the PyrroleeImidazole Alkaloids

SPh OH HO

1) Cl3CCN, DBU, DCM, –20 °C to rt 2) Na2CO3, o-xylene, 140 °C

OH

NHCOCCl3 4) p-TsOH·H2O, Pyr, H2O 5) DHP, PPTS, DCM

3) mCPBA, DCM, –20 °C 4) P(OMe)3, MeOH, rf 5) Grubbs I catalyst, DCM, rt

Br

267

NH

266 O

NHCOCl3 NH

NHCOCCl3

CO2H

265 (6 steps from (–)isopropylideneD-threitol, 29%) OTHP

Br

1) Ms2O, Pyr, DCM 2) DIBAL, DCM, –78 °C 3) 267, EDC, HOBt, Et3N, THF

NH

1) MeNHDMB, Na2CO3, DMSO, 100 °C 2) p-TsOH·H2O, MeOH 3) IBX, DMSO

HO

Br

NH H H H N B NH

4) Et3N, MeCN, –20 °C 5) CAN, MeCN, H2O, 10 °C

O

37%

268 (15% from 265)

N

O (–)-7: (–)-agelastatin A

Scheme 39 Total synthesis of ()-agelastatin A (()-7) by sequential Overman/MisloweEvans sigmatropic rearrangement (Chida et al.; DMB ¼ 2,4-dimethoxybenzyl).142

AcO

HO 269

1) CCl3CN, DBU, DCM, 0 °C 2) xylenes, rf 3) MeCONHBr, DCM, rf 4) DBU, PhMe, rf

3) N2H4, THF 4) EDC, DCM, 272 272 53% CO2H

N O

CCl3

p-TsOH, Pyr, H2O, 70 °C

AcO

Bn N

O NH NH

O 273

CCl3

O

93%

NH OH

270

AcO

NH

H

H

50%

1) DEAD, PhthNH, PPh3, THF 2) Bn(Me)NH, NaHCO3, DMF, 100 °C

N H

AcO

271 1) K2CO3, MeOH, DCM 2) IBX, DMSO 3) K2CO3, DMSO, 100 °C 4) H2, Pd(OH)2, THF 5) NBS, MeOH 20%

O HO Br

N

D NH

H H H N B NH O

rac-7: rac-agelastatin A

Scheme 40 Total synthesis of rac-agelastatin A (rac-7) by Dickson and Wardrop.143

affording 271, Mitsunobu inversion with PhthNH and three further steps gave the cyclization precursor 273, which was converted to rac-agelastatin A (rac-7) in five steps with assembly of ring B by Michael addition and construction of ring D after IBX oxidation and hydrogenolytic debenzylation of the urea function. From cyclopentene 269, the synthesis needs 14 steps with 5% overall yield. A similar Michael-oriented strategy was pursued by Duspara and Batey who developed an interesting first step (Scheme 41).144 Furfural (274) was

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Thomas Lindel

O CHO

HN(allyl)2, Dy(OTf)3 (2 mol%), MeCN, 4 Å

N(allyl)2

82%

274

1) DIBAL, PhMe, –78 °C 2) TBDPSCl, ImH (2 eq), DCM

O

3) NDMBA (4 eq), Pd(PPh3)4 (8.5 mol%), DCM, 45 °C 4) conc. HCl 80%

N(allyl)2 275

OTBDPS NH2

2 HCl

NH2

276

1) 277, TPTU, i-Pr2NEt (5 eq), DMF, 0 °C 2) 278, CsF (25 eq) O Br NH OLi N N H O 277 278 3) IBX (2 eq), DMSO 4) TFE, 40 °C

22%

O HO N Br

H N

N NH H H NH O

rac-7: rac-agelastatin A

Scheme 41 Total synthesis of rac-agelastatin A (rac-7) by Duspara and Batey (NDMBA, N,N’-dimethylbarbituric acid; TPTU, 2-(2-pyridon-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate; TFE, trifluoroethanol).144

reacted with diallylamine in the presence of Dy(OTf)3, forming the bis(diallylamino)-substituted cyclopentenone 275 in one step and 82% yield (de 90%). That step was coined as domino condensation/ring-opening/ Nazarov-like conrotatory 4p electrocyclization, which is thought to begin with the formation of the furfural-derived iminium salt (Stenhouse salt).145 The remaining steps are almost straightforward but still caused some trouble regarding the regioselectivity of the two coupling steps of diamine 276 with 277 and 278. In the end, rac-agelastatin (rac-7) was obtained in nine steps and 14% overall yield. Trost and Dong’s syntheses of ()- and of (þ)-agelastatin A (7) employ, not surprisingly, a Trost catalyst (Scheme 42) with a Pd-catalyzed asymmetric allylic alkylation (AAA) reaction being the key step.146,147 For the first time, pyrroles and N-alkoxyamides have been used as nucleophiles. Starting from achiral cyclopentadiene derivative 279 and the pyrrole-2-Nmethoxyamide 280, only six steps were needed to obtain ()-7 in 3.8% overall yield. The desymmetrizing key step proceeded in almost perfect enantioselectivity (ee of 97.5%, 282). For the allylic amination of 282, a regioselective SharplesseKresze reaction employing the NHCecopper complex 283 was used in moderate yield (47%). Movassaghi et al. managed to synthesize all agelastatins AF via coppermediated cross coupling of arylthioester 287 and stannylated triazone 288 (Scheme 43).129,130 Arylthioester 287 was synthesized in five steps from D-aspartic acid dimethyl ester via PaaleKnorr reaction to 285, bromination,

175

Chemistry and Biology of the PyrroleeImidazole Alkaloids

BocO

Pd2(dba)3-CHCl3 (5 mol%), 281 (15 mol%), HOAc (10 mol%)

OBoc 279

Br

H N

Br

+

82% O

NH HN OMe 280

H N OMe

O

O

O

281

NH HN

282 (ee 97.5%)

PPh2 Ph2P O

TsN=S=NTs (3 eq), 283 (0.2 eq), PhMe, 100 °C Br N

1) MeNCO, Cs2CO3 NHTs (0.2 eq), DCM 2) BH3-THF; then NaBO3 H N OMe 3) DMP, NaHCO3, DCM 4) SmI2, THF O 10%

H N

N CuCl

47% 283

N

HO

NH H H NH

H N

Br

O (–)-7: (–)-agelastatin A

284

Scheme 42 Total synthesis of ()-agelastatin A (()-7) by Trost and Dong.146,147

CO2Me 1) NBS, DTBMP, THF 2) ClSO2NCO, MeCN, 0 °C; Na(Hg), NaH2PO4 CO2Me

N

CO2Me Br N

73%

288

N N

Cy3Sn S OMe

Br N

N

O

N

N

O

N

Br

CuTC (1.5 eq), THF, 50 °C

NH

1) NaBH4, MeOH, 0 °C; p-TsOH·H2O, MeOH 2) HS-C6H4-p-Me, AlMe3, DCM, 0 °C 83%

CONH2 286

285

O

CO2Me

OMe O

N

NH

96% O

O 289 (99% ee)

287 O

HO

N NH aq HCl, MeOH, 65 °C

Br OMe

N

89%

NH

MeSO3H, H2O, 100 °C; MeOH (twice)

Br

H N

N

C

O NH

HH NH

ca. 60% O

O

290

(–)-7: (–)-agelastatin A

Scheme 43 Total synthesis of ()-agelastatin A (()-7) by the Movassaghi group (DTBMP, 2,6-di-tert-butyl-4-methylpyridine; CuTC, copper(I) thiophene-2carboxylate).129,130

176

Thomas Lindel

installation of the carboxamide functionality affording 286, reductive cyclization of 286, and AlMe3-mediated conversion of the remaining methylester moiety. After a series of experiments leading to a third-generation approach, it was realized that stoichiometric amounts of copper(I) thiophene-2-carboxylate (CuTC) at 50 C were already sufficient to construct ketone 289 from 287 and 288. Palladium catalysis was not necessary. Exposure of triazone 289 to methanolic hydrogen chloride under reflux cleaved both formaldehyde N,N-acetal moieties and led to cyclization to imidazolone 290 in 89% yield. The final, perhaps biomimetic step is a nucleophilic attack of the imidazolone moiety at the N,O-acetal position of ring B, which occurred in aqueous MeSO3H, affording ()-agelastatin A (()-7) as major product. Overall, ()-agelastatin (()-7) became accessible in just eight steps and an overall yield of about 30%. Bromination of ()-7 at the pyrrole ring afforded ()-agelastatin B. It was also possible to eliminate water or methanol from the CD bridge, followed by dihydroxylation to ()-agelastatin C. The formation of ring C was less effective, when the imidazolone unit was not N-methylated, probably because of diminished nucleophilicity. Here, Movassaghi et al. observed several products on treatment of 291 with MeSO3H, among, which was also the novel tetracycle 294 (20%, Scheme 44), representing a new mode of cyclization of the basic pyrrolee imidazole alkaloid building block. The cyclization occurred despite the 2-bromo substituent at the pyrrole ring, indicating initial protodebromination. The efficiency of their synthetic access to the agelastatins allowed the

HO Br

H N

O HN Br

NH OMe

N

NH O 291

MeSO3H, H2O, 100 °C; HCl, MeOH

H N

C

NH HH NH

MeO

O Br +

H N

O 292: (–)-agelastatin D (26%)

H N

O

NH HH NH O 293 (9%) +

O NH HN H

H

Br +

N

N

NH NH

O 294 (rac, 20%)

O 295 (20%)

Scheme 44 Formation of ()-agelastatin D (()-292) and side products in the absence of the N-methyl group at the imidazolone partial structure (Movassaghi et al.).130

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Chemistry and Biology of the PyrroleeImidazole Alkaloids

Movassaghi group to investigate the biological activity of the agelastatins in some detail. The total synthesis of rac-agelastatin (rac-7) by Reyes and Romo was inspired by the putative biosynthesis and features the cyclization of an oroidin-type imidazolone precursor containing a (Z)-double bond under acidic conditions (301, Scheme 45).131 The synthesis of rac-7 proceeded via the imidazolone carboxylic acid 297, which was converted to the protected aldehyde 298. BestmanneOhira reaction afforded the terminal alkyne, followed by ZnI2-mediated acetalization to 300. The coupling of 300 with the N-methoxypyrrolecarboxamide 280 proceeded in only 23% yield. At least, something of the starting materials was recovered. The NeO bond was reduced by treatment with SmI2, followed by hydrogenation to (Z)-alkene 301. The first step of the acid-induced biomimetic cyclization may be the formation of an iminium ion, which is attacked by the imidazolone ring. Alternatively, Nazarov cyclization of a pentadienyl cation is possible. For the second cyclization to ring B the Tse (p-toluenesulfonylethyl) protection group had to be removed. Rac-agelastatin A (rac-7) was obtained after 12 steps (1.1% overall yield).

O N H

OH OH

HO2C

N

54%

296

N

O MeO P MeO

NTse

SnCl4, DCM, –78 °C to rt

2) DIBAL, DCM, –78 °C 3) MnO2, DCM

85%

O N NTse

EtO

O 299

47% N2 2) ZnI2, CH(OEt)3, 110 °C

298

NH

297

1) (i) K2CO3, MeI (ii) K2CO3, TseOMs, DMF, 60 °C

1) 299, NaOMe, MeOH, DCM, –40 °C to rt

O OHC

NH

HO2C

H2SO4, 80 °C

CO2H

1) Br

O

NH2

EtO

300

NHOMe O

O 280

2) SmI2, THF 3) H2, Lindlar, THF, MeOH 15%

N

Br

NH

1) TFA, DCM, 78 to –30 °C; H2O NTse 2) KHMDS, THF, 60 °C OEt 3) neat on silica gel, NH 45 °C 34% O

301

O HO

N

NH H H H N B NH C

Br

O

rac-7: rac-agelastatin A

Scheme 45 Total synthesis of rac-agelastatin A (rac-7) by Reyes and Romo (Tse, p-toluenesulfonylethyl).131

178

Thomas Lindel

4.8 Cyclooroidin and Hanishin The pyrrolopyrazinone system of ()-agelastatin A (()-7) also occurs in ()-cyclooroidin (()-11), which lacks ring C of the agelastatins. The first synthesis of rac-cyclooroidin (rac-11) was published in 2005 by Papeo et al. starting from rac-longamide A (302).148 The first enantioselective synthesis of naturally occurring ()-cyclooroidin (()-11) was achieved by PellouxLéon, Minassian, et al. in 2006.149,150 Lindel et al. published an efficient, putatively biomimetic one-step conversion of oroidin (2) to rac-cyclooroidin (rac-11).151 Discussed are also the 2010 Lovely synthesis of (þ)-11152 and the 2014 Hoveyda synthesis of ()-11.153 Furthermore, this section includes the enantioselective synthesis of the related agesamides by Trost and Dong154,155 a study toward oxocyclostylidol by Lindel et al.156 and a study by Lovely et al. regarding the cyclization of oroidin-like alkynylimidazoles.157 Papeo et al. reacted the easily accessible N,O-hemiacetal rac-longamide A (302) with dimethylphosphonate 303 in an HWE approach, replacing the hydroxy group by an acetic acid ester side chain (304, 82%, Scheme 46).148 It has been known that the N,O-acetal is in equilibrium with the open-chain aldehyde, which has reacted here. In case of dibromination, the equilibrium clearly favors the N,O-acetal form. From longamide B methyl ester (304), five steps remained toward rac-cyclooroidin (rac-11), commencing with saponification, conversion to the acid chloride and chain elongation with trimethylsilyldiazomethane. Treatment with hydrobromic O

O

O MeO P MeO

NH

Br

N Br

O

303 OMe

NaH, THF, 0 °C to rt OH

NH

Br

N Br

82% 304

rac-302

1) LiOH, THF, H2O 2) SOCl2, PhMe, 90 °C

O 3) (i) TMSCHN2 (3 eq), THF, 0 °C to rt OMe (ii) HBr (5 eq), H2O, –5 °C O

O NH

Br

N Br

O Br rac-305

1) Boc-guanidine (3 eq), DMF 2) TFA, DCM 13% from 304

NH

Br

N Br

N

NH2 N H rac-11: rac-cyclooroidin TFA

Scheme 46 Synthesis of rac-cyclooroidin (rac-11) from rac-longamide A (rac-302) by Papeo et al.148

179

Chemistry and Biology of the PyrroleeImidazole Alkaloids

acid at 5 C afforded a-bromoketone rac-305, which reacted with Bocguanidine forming the aminoimidazole. Deprotection afforded rac-11 in six steps from rac-longamide A (302) and 11% overall yield. Several cyclooroidin syntheses assemble the pyrrole-N-C bond first, followed by construction of the lactam ring B. Starting from aspartic acid methyl ester 306, Pelloux-Léon, Minassian et al. assembled the pyrrole ring by PaaleKnorr synthesis and formed an N-benzylamide, which was reduced (BH3eTHF) to the N-alkylated chiral pyrrole derivative 307 (Scheme 47).149,150 Six further steps were needed to construct the lactam 308, which was converted to ()-longamide B (()-309) after four additional standard reactions. From there, the enantiomerically pure version of the Papeo intermediate (305) was reached in a similar manner, followed by two final steps to ()-cyclooroidin (()-11). An efficient conversion of a monomeric pyrroleeimidazole alkaloid to another was discovered by Lindel et al. when heating oroidin formate (2-HCO2H) in EtOH/water, which afforded rac-cyclooroidin (rac-11) in a

1) MeO H2N

CO2H CO2Me 306

B

NH

308

NHBn

DCE, H2O, 80 °C

N

2) i) CuCl2, HOBt, DCC, BnNH2, DMF ii) BH3, THF

4) i) H2, Pd(OH)2/C, MeOH ii) PhMe, rf 307

OH 35%

O

1) NBS, THF 2) BBr3, DCM 3) i) IBX, EtOAc

NH

Br

ii) NaClO2, NaH2PO4, 2-methylbut-2-ene, DCM 40%

OMe

1) BnBr, K2CO3, MeCN 2) NaH, MeI, THF 3) i) Cl3CCOCl, 2,6-lutidine, THF, rf ii) NaOMe, MeOH

OMe

31%

O

N

O

N Br

O

1) isobutyl chloroformate, NMM 2) CH2N2 3) aq HBr 70%

OH (–)-309: (–)-longamide B O

O NH

Br

N Br

O Br 305

1) Boc-guanidine 2) TFA 30%

A

Br

N

Br

B

NH

N

NH2 N H (–)-11: (–)-cyclooroidin TFA

Scheme 47 Synthesis of ()-longamide B (()-309) and ()-cyclooroidin (()-11) by Pelloux-Léon, Minassian, et al.149,150

180

Thomas Lindel

H Cl N NH2 N H

Br Br

H N

N H

O

Br

NCS, DMF, 0 °C to rt

Br

Cl N H

81%

O 311

(i) DMF, 100 °C (ii) HCO2H workup

Br

H N

N H

85%

HCO2

H N N H

O

H2O/EtOH NH2 (4:1), rf 93%

NH2

N H

310-HCl: dihydrooroidin-HCl Br

N

H N

O NH

Br

N H N

Br

NH2 N H rac-11: rac-cyclooroidin HCO2

2-HCO2H: oroidin-HCO2H

Scheme 48 Facile conversion of dihydrooroidin (310) to oroidin (2) and further on to rac-cyclooroidin (rac-11) by Lindel et al.159

single step and high yield (93%, Scheme 48).151 There was no sign of any oroidin dimer formed in that reaction. Scheme 48 also includes a convenient way of converting dihydrooroidin (310) to oroidin (2), which constitutes an improvement of Horne’s procedure, who used NCS in MeOH at room temperature.158 By replacing MeOH/m-xylene by DMF, the formation of rac-dihydrodispacamide was completely suppressed. It was also possible to isolate the chlorinated aminoimidazole 311, which lost HCl at 100 C in DMF, resulting in a two-step procedure with 69% overall yield.159 The chlorohydrin 312 was used as starting material of Lovely’s synthesis of (þ)-cyclooroidin ((þ)-11, Scheme 49).152 After condensation with O OH

O

1)

Cl NH

N

312

, THF, rt Cl 313

O

N

2) Cs2CO3, DMF, 75 °C

N DMAS

1) NaOMe, MeOH, rf 2) MsCl, NEt3, DCM 3) NaN3, DMF

N

30%

314

4) H2, Pd/C, MeOH N 5) NaH, THF 12% DMAS

O

O NH

N N

1) NBS, THF 2) LDA, THF, –78 °C; then TrisylN3 3) i) HCl, MeOH, 34 °C ii) H2, Lindlar, MeOH

N DMAS 315

15%

NH

Br

N Br

N

NH2 N H (+)-11: (+)-cyclooroidin

Scheme 49 Synthesis of (þ)-cyclooroidin ((þ)-11) by Lovely et al. (DMAS, dimethylaminosulfonyl).152

181

Chemistry and Biology of the PyrroleeImidazole Alkaloids

pyrrole-2-carboxylic acid chloride (313), the pyrrolooxazinone 314 was obtained in modest yield, which had to be converted to the pyrrolopyrazinone 315 in a five-step sequence. Four further steps afforded (þ)-11 (11 steps, 5% overall yield). Hoveyda et al. demonstrated the utility of a new synthetic method by synthesizing ()-cyclooroidin (()-11).153 An enantioselective NHCe Cu-catalyzed addition of the trimethylsilyl-protected propargylborane 317 to a phosphinoylimine was the key step that afforded the allene 319 in good yield (64%) and high ee (94%, Scheme 50). In the first step, the imine was formed in situ from 316. From allene 319, six further steps were necessary to reach ()-11, commencing with methanolysis and PaaleKnorr construction of the pyrrole (321), followed by dibromination of 321 and concomitant conversion of the trimethylsilyl allene to propargylbromide 322. After installation of an N,N0 -di-Boc-guanidine moiety by nucleophilic substitution, a novel Ag-catalyzed cyclization of 323 to the 2-aminoimidazole was employed and ()-cyclooroidin (()-11) was obtained in eight steps (11% overall yield).

Ph2P(O)HN 316

1) NaHCO3, DCM (1:1) 2) 318 (5.5 mol%), CuCl (5 mol%), 317 (1.5 eq), NaOt-Bu (10 mol%), i-PrOH (2 eq), THF, –30 °C

NHFmoc

Ph

Ts

317

62% (ee 94%) O

OEt N

Br2 (3 eq), HOAc

NHFmoc

320

OEt

Br

N

63%

322

321

Br

O

NHBoc

O NH

Br

N

(3 eq)

NHFmoc

Br

•

TMS O

NHBoc

319

318

O

51% O

HN

•

BF4

N

Mes iPr

1) MeOH, HCl (3 M) 2) 320, PhMe, aq HCl, 90 °C EtO2C

NHFmoc

TMS N

B(pin) TMS

Ph2P(O)HN

Ph

Br

1) AgOAc (10 mol%), MeCN 2) TFA/DCM (1:1)

NH

Br

N Br

K2CO3 (4 eq), DMF

NHBoc

62% N 323

NHBoc

90%

N

NH2 N H (–)-11: (–)-cyclooroidin

Scheme 50 Synthesis of ()-cyclooroidin (()-11) by Hoveyda et al.153

182

Thomas Lindel

A vinyl aziridine served as starting point of the total synthesis of the agesamides and several congeners, developed by Trost et al. (Scheme 51).154,155 Instead of the 2-aminoimidazole moiety of cyclooroidin (11), the diastereomeric agesamides A (329) and B (330) contain an alkylhydantoin partial structure, which is probably formed by hydrolysis and oxidation. Key step is the enantioconvergent, Pd-catalyzed allylic addition of pyrrole-2-carboxylic acid methyl ester 324 to vinyl aziridine 325 affording pyrrolopyrazinone 327 (ee 85%) with opening of the aziridine ring. Diphenylphosphinobenzoic acidederived ligands such as 326 were investigated. Five further steps were needed to access the agesamides as a mixture of diastereomers. Hydroboration, deprotection, and dibromination afforded the primary alcohol 328, which was efficiently converted to the hydantoin after oxidation to the aldehyde and treatment with KCN and ammonium carbonate. While the electron rich 2-aminoimidazole of oroidin (2) also occurs in the oxidized form of an imidazolone or alkylidene glycocyamidine, there is only one case where the pyrrole unit of a pyrroleeimidazole alkaloid is oxidized. The optically active natural product oxocyclostylidol (336) was discovered by Grube and K€ ock160 and contains a hydroxypyrrolone moiety and, interestingly, a nonoxidized, intact 2-aminoimidazole partial structure. So far, oxocyclostylidol (336) has not been synthesized. At least the oxidation of the pyrrole unit has been studied, leading to the discovery that Selectfluor (332) in MeCN/water is capable of performing the required oxidation in one step to the pyrrolo[1,2-a]pyrazine diones 333 and 335

Scheme 51 Synthesis of agesamides A (329) and B (330) by Trost et al.154,155

183

Chemistry and Biology of the PyrroleeImidazole Alkaloids

Cl N (3.0 eq) N 332 F 2 BF4

X Y

O

N

NH

HO

MeCN/H2O (4:1), 35 °C

331: X=Y=H rac-334: X=Br, Y=H (rac-mukanadin C) rac-302: X=Y=Br (rac-longamide A)

X O HO

N

OH O NH

333: X=H (64%) 335: X=Br (37% from 334, not formed from 336)

H O O NH

Br

336: oxocyclostylidol (optically active, absolute configuration unknown)

N O

N NH2 N H

Scheme 52 Study on the synthesis of the hydroxypyrrolone moiety of oxocyclostylidol (336) by Lindel et al.156

(Scheme 52).156 The reaction only works if no 2-aminoimidazole unit is present, which indicates that a synthetic route should assemble that unit later. The vinylimidazole portion of oxocyclostylidol (336) may eventually become accessible from alkyne precursors such as the nonbrominated compound 337 (Scheme 53), which was used by Lovely et al. as starting point for generating structural diversity.157 Treatment of 337 with a Au(III)

Scheme 53 Alkyne building block 337 as center of structural diversity (Lovely et al.).157

184

Thomas Lindel

precatalyst in 1,4-dioxane led to formation of the pyrroloazepinone 338 with a migrated carboxamide group. When the same molecule 337 was treated with Pd(OAc)2 in DMF that rearrangement also took place, but the cyclization afforded the pyrrolo[3,2-c]pyridinone 340 with an alkylidene side chain. The rearrangement, which could be interesting toward the synthesis of cylindradine (71), was avoided by replacing the N-methyl group at the pyrrole by hydrogen and by substituting Pd(OAc)2 by Cs2CO3. Now, the regioisomeric pyrrolo[1,2-a]pyridinone 341 was obtained in very good yield (81%). If the pyrrole and amide protecting groups of 337 were omitted and Pd(OAc)2 was employed in TFA, the alkylidene oxazoline 339 was formed (87%). Being related to cyclooroidin (11) and the agesamides (329, 330), truncated metabolites of the hanishin-type have been accessed several times, including the syntheses by Banwell et al.161 Scheme 54 outlines an approach by Wang, Hu, et al. who install the pyrrole moiety after reduction of an isoxazoline ring.162 Starting from aspartic acidederived 342, five standard steps lead to allylamine 343, which participates in a cycloaddition with a nitrile oxide formed in situ from 344. The NeO-bond of the resulting isoxazoline 345 is hydrogenated, together with Cbz removal, and liberates a reactive synthetic intermediate, which reacts further to pyrrole 346. Dibromination and closure of lactam ring B terminate the sequence to hanishin (()-347, 10 steps, 44% overall yield). A dehydro analog of hanishin with an additional endocyclic double bond in ring B has been accessed by Du, Zhang, et al. starting from dimethylaspartate. PaaleKnorr reaction and cyclization

Cbz

1) MsCl, DCM 2) NaN3, DMF, 80 °C 3) LiHMDS, BrCH2CH=CH2, DMF, –20 °C

H N

344 Cbz

OH CO2Et

N

4) PPh3, aq THF, –20 °C 5) Boc2O

342

NHBoc CO2Et

Cl

CO2Et

NaHCO3, EtOAc

343

62%

NOH

97% O

O O N CO2Et Cbz

N

NHBoc CO2Et 345

H2, Pd/C, aq MeOH, HOAc, 40 °C 92%

OEt N

1) NBS, THF 2) TFA, DCM

Br

N

NHBoc 3) TEA, PhMe, rf CO2Et 346

79%

B

Br

NH

O

OEt (–)-347: (–)-hanishin

Scheme 54 Synthesis of ()-hanishin (()-347) by Wang, Hu, et al.162

185

Chemistry and Biology of the PyrroleeImidazole Alkaloids

F3C

(10 mol%)

1)

CN Br

CF3 CF3

N H TMSO

NH

OTBDPS

+ O

Br

CF3

Br 348

CN

350

N

OTBDPS

Br

PhCO2H (40 mol%), PhMe

349

OH 2) NaBH4, EtOH

351 (76%, ee 93%)

O CN 1) Ag2O, MeI, MeCN, rf 2) HCl, MeOH

Br

N

OTs

Br

3) TsCl, Pyr

OMe

86%

1) NaN3, DMSO, 65 °C 2) NaOH, H2O2, Br MeOH, DCM 3) PPh3, H2O, THF, rf 4) BBr3, DCM

352

NH N Br OH 328

57%

Scheme 55 Synthesis of the key precursor 328 by Cho et al.164

afforded a pyrrolopyrazinedione, which was converted to the N,O-acetal from, which methanol was eliminated.163 Pyrrolopyrazinones of the hanishin type can also be constructed enantioselectively by employing organocatalysts, as shown by Cho et al. who performed a pyrrolidine-catalyzed (10 mol%) Michael addition of cyanopyrrole 348 to a,b-unsaturated aldehyde 349 in the presence of benzoic acid (Scheme 55).164 Reduction afforded alcohol 351 (ee 93%), which needed seven more steps to be converted to synthetic intermediate 328, which had already been passed through by Trost. Monosaccharides proved to be another suitable choice as starting material of a hanishin synthesis (Scheme 56).165 Boc-protected aspartate-derived (five steps) azide 353 was deprotected and reacted with D-ribose (354) in Et3N/DMSO/oxalic acid at 60 C. The pyrrole-2-carbaldehyde 355 was

BocHN

N3 CO2Et

353 (5 steps from L-Asp)

1) TFA, DCM 2) Et3N, DMSO, (COOH)2, 60 °C OH HO HO

OH 54% O

354

1) i) NaClO2, H2O2, NaH2PO4, MeCN, H2O ii) K2CO3, Br MeI, DMF

CHO N

O NH N

N3

Br O 2) i) H2, Pd/C, MeOH ii) PhMe, rf CO2Et OEt iii) NBS, THF 355 (–)-347: (–)-hanishin 43%

Scheme 56 Synthesis of ()-hanishin (()-347) by Koo et al.165

186

Thomas Lindel

obtained (54%), from which ring B was constructed in a straightforward manner via LindgrenePinnick oxidation, formation of the methyl ester, hydrogenation of the azide, cyclization, and dibromination to ()-hanishin (()-347). From L-aspartic acid, Koo’s approach needs 12 steps, from Dribose six steps (23%). In a Pd-catalyzed approach, rac-longamide B (rac-309) was synthesized by Chen et al. in six steps from the Weinreb amide 280 of 5-bromopyrrole-2carboxylic acid via double allylic alkylation of allylic biscarbonate 356 (Scheme 57).166 The authors also attempted to conduct the reaction enantioselectively employing, for instance Trost’s catalysts, but without success. The best ligand was P(Oi-Pr)3, of course leading to a racemic product. In this case, the yield of vinyl pyrrolopyrazinone 357 was good (72%). The methoxylated nitrogen reacted faster. Crudden’s Ir-catalyzed hydroboration ([Ir(COD)Cl]2, pinacolborane)167 circumvented the problem of reducing the amide when employing 9-BBN. Four additional steps afforded raclongamide B (rac-309) in six steps and 17% overall yield from 280.

4.9 Ageladine A Ageladine A (69) is one carbon atom shorter than the other pyrrolee imidazole alkaloids and features an imidazopyridine partial structure. Meketa and Weinreb developed two generations of a synthesis, which assembles the pyridine ring by 6p electrocyclization of N-vinylimidate 361 (Scheme 58), affording the imidazopyridine 362.168,169 The synthesis starts from BOMprotected tribromoimidazole (358) of which all bromo substituents were O N H

NH Br

OMe OBoc

280 + 356 OBoc

O

Pd2(dba)3-CHCl3 (10 mol%), P(Oi-Pr)3 (40 mol%), HOAc (10 mol%), PhMe

N

OMe

N Br

72%

357 1) (i) [Ir(cod)Cl]2, DPPB, pinacolborane (ii) aq NaOH, H2O2 2) SmI2, THF 3) NBS, MeOH 4) DMP, NaHCO3, DCM 5) NaClO2, NaH2PO4, 2methylbut-2-ene, DCM 23%

O NH

Br

N Br

O OH

rac-309: rac-longamide B

Scheme 57 Synthesis of rac-longamide B (rac-309) by Chen and coworkers166; DPPB, 1,4-bis(diphenylphosphino)butane.

187

Chemistry and Biology of the PyrroleeImidazole Alkaloids

Br

N Br BOM 358

CONH2

BOM N Br

N I

N

Br

1)

1) n-BuLi, THF, Me2S2, –78 °C 2) n-BuLi, THF, TMSCl, –78 °C 3) n-BuLi, THF, DMF, –78 °C 4) K2CO3, DCM, MeOH 5) Ph3PCH2I iodide, KOt-Bu, THF, –78 °C 79%

360 (3 steps from 1Hpyrrole-2-carbonitrile)

CuI (10 mol%), Cs2CO3, Br DMEDA, THF, 70 °C

2) Lawesson's reagent, PhMe, 100 °C 3) MeOTf, DCM 70%

SMe N BOM 359

N N BOM

SMe N BOM SMe

mesitylene, 145 °C

N Br Br

361

N N BOM

BOM N Br

N SMe

N

1) MCPBA, DCM, –78 °C to rt 2) NaN3, DMSO

NH2

N

N H

HN Br 362 (44%)

+ (E)-isomer of 361 (20%)

3) H2, Lindlar, THF, MeOH 4) AlCl3, DCM

Br

Br

44% 69: ageladine A

Scheme 58 Second-generation synthesis of ageladine A (69) by Meketa and Weinreb.168,169

replaced sequentially after Br/Li exchange. The introduced 5-trimethylsilyl group was removed by treatment with K2CO3 in MeOH, followed by a StorkeZhao olefination of the 4-formyl group to afford (Z)-iodoalkene 359. The pyrrolecarboxamide moiety was installed by Buchwald coupling in very good yield. The resulting enamide was treated with Lawesson’s reagent to afford the thionoamide and reaction with methyl triflate led to S-methylation. Under thermal conditions (mesitylene, 145 C), compound 361 indeed underwent electrocyclization and elimination to 362 (44%), which was accompanied by E/Z isomerization (20%). The final four steps to ageladine A (69) are needed for replacement of the thiomethyl by an amino group and for deprotection. In their first-generation approach, a nonbrominated pyrrole moiety had been introduced by Suzuki coupling after the electrocyclization, followed by rather unselective bromination.170 In the 13-step second-generation approach (10.7% overall yield), that latestage bromination is avoided. Shengule and Karuso developed a much shorter route to ageladine A (69), also in 2006 (Scheme 59).171 A PicteteSpengler condensation of

188

Thomas Lindel

N NH2

N H

CHO

N

NH2

N 1) Sc(OTf)3, EtOH 2) chloranil, CHCl3, rf

363

Boc N

29% 364

Br

Br

HN Br

Br

69: ageladine A 1) isobutyraldehyde, H2O, EtOH, Na2CO3

N

H2N

NH2

N H

N H

NH2

2) (i) Br2 (2 eq), MsOH, 110 °C 16% (ii) KOt-Bu, air, THF

365

N N

N

NH2

366

Scheme 59 Short synthesis of ageladine A (69) by PicteteSpengler condensation (Shengule and Karuso)171 and its adaptation by Horne et al.172

N-Boc-4,5-dibromo-2-formylpyrrole (364) with 2-aminohistamine (363) afforded the piperidine ring (diastereomers due to atropisomerism). Use of Sc(OTf)3 as catalyst accelerated the reaction, but was not required (44% of 69). Oxidation with chloranil simultaneously led to removal of the Boc group, affording the fluorescent natural product 69 in just two steps, when counted from 363 and 364, with an overall yield of 29%. Horne et al. used the PicteteSpengler approach by Karuso for the synthesis of a series of derivatives, including some with an azepine instead of the pyridine ring (366).172 Br2/MsOH, followed by KOt-Bu/air had to be used as oxidant, while for the six-membered series, chloranil could be employed (Scheme 59). The synthesis of aminohistamine 369 was addressed specifically by Ando and Terashima who started with the condensation of 3-bromo-1,1-dimethoxypropan-2-one (367) and Boc-protected guanidine (Scheme 60) obtaining the versatile building block 368, secured by X-ray analysis.173 Four further steps, including a Henry reaction, afforded 369, which was converted to the bis(trifluoroacetate) of ageladine A (69) by PicteteSpengler condensation.174

4.10 Dibromoagelaspongin There is only one synthesis of the natural product dibromoagelaspongin (6), which had been isolated as racemic mixture.21 Feldman and Fodor managed to assemble that pyrroleeimidazole alkaloid by oxidative cyclization of imidazopyridine 374, which was obtained by cyclization of sulfoxide 373 after

189

Chemistry and Biology of the PyrroleeImidazole Alkaloids

HN OMe MeO

Br

OMe

NHBoc

H2N

O

N

MeO

NHBoc

(3 eq), THF, 50 °C 62%

367

1) Boc2O (2 eq), NaHMDS (2 eq), THF, 0 °C 2) PPTS (cat.), acetone/H2O (3:2)

368

N H

3) NH4OAc, MeNO2, rf 4) LiAlH4 (3 eq), THF, 50 °C 55%

CHO SEM N

N

370 Br N NH2

NHBoc N H

369

Br

1) 370, EtOH, 50 °C 2) (i) IBX (1.5 eq), DMSO (ii) MnO2, DCM 3) (i) BF3-OEt2 (10 eq), DCM (ii) TFA, MeOH 50%

N

N H

HN Br

NH2

2 TFA Br

69: ageladine A

Scheme 60 Synthesis of ageladine A (69) by Ando and Terashima.174

electrophilic activation (Scheme 61).175,176 Starting from DMAS-protected 2-methylsulfanylimidazole (371), the SEM-protected dihydrooroidin derivative 373, which carries a methanesulfinyl group in the imidazole-2position, was assembled in five steps. Lithiation occurred ortho to the DMAS group. Exposure of 373 to Tf2O generated a sulfonium ion, which led to nucleophilic attack of the amide nitrogen at the imidazole, forming the tetrahydroimidazopyridine 374. The regioselectivity of that cyclization is governed by the DMAS group, since the unprotected imidazole afforded the spirocycle of the phakellin series. The second cyclization (NCS) to 375 let the pyrrole nitrogen participate and may again proceed via a sulfonium intermediate. This time, the activation of the thiomethyl unit takes place without prior conversion to the sulfoxide and is probably initiated by chlorination of the sulfur, followed by nucleophilic attack by chloride at the imidazole carbon. After deprotection of 375, an azido group replaced the methylsulfanyl after oxidation and treatment with trimethylsilylN3/ ZnI2 (376). Hydrogenation and hydrolysis afforded dibromoagelaspongin (6), which was overall obtained in 12 steps and 1.5% overall yield. Zaparucha, Al-Mourabit, et al. published a study on the synthesis of dibromoagelaspongin (6) that afforded analog 381 (Scheme 62) with a protected 2-aminoimidazoline partial structure.177 Key step of the sequence is the addition of 2-aminopyrimidine (379) to the tetrahydropyridine unit of synthetic intermediate 378, initiated by NIS. After dibromination, oxidation to the imidazole partial structure of 380 was best achieved by Ba(MnO4)2,

190

Thomas Lindel

N SMe N DMAS

1) n-BuLi, I(CH2)3Cl, THF, –78 °C to rt 2) K-phthalimide, DMF, 80 °C 3) MCPBA, DCM 4) N2H4, EtOH, rf

Br Br

5) 372, Na2CO3, DMF Br

371

372 Br

21%

1) Tf 2O, 2,6-lutidine, DCM, –78 °C 2) TFA, DCM 3) TBAF, THF, rf

N

H N

N SEM

N DMAS

O 373

CCl3

N SEM

O Br

Br O

Br

N H N

N

32%

O

NCS, DCM

N

92%

N DMAS 374

N

Br

Br O N

25%

1) H2, Pd/C, MeOH, THF

Br

N N

O N

B

A N

N D N HO H

2) H2O, 90 °C 3) TFA, MeOH

N3

N MeO H 376

Br

N

B

SMe N Cl DMAS 375

SMe

1) HCl, MeOH, THF, rf 2) (i) MCPBA, NaHCO3, DCM (ii) ZnI2, TMSN3, MeCN

O S

C

99%

Br TFA NH2

6: dibromoagelaspongin

Scheme 61 Total synthesis of dibromoagelaspongin (6) by Feldman and Fodor.175,176

NH2 OH

1)

N H

O

CCl3 203 , DCM

O

H2N 379 N 1) NIS (1.2 eq), N DMF, MeCN (2 eq)

N H

N

2) Br2 (2 eq), DCM 3) Ba(MnO4)2

2) IBX (1.5 eq), acetone 3) citric acid, PhMe 69%

377

O N

N H N N 380

18%

378 Br

Br Br 1) DMDO, acetone HCl 2) HCl, Et2O, –78 °C N

O

N N

N

HO

N

381

Br Br HCl

O D2O

N N

N

Br

ND N O N

382

Scheme 62 Study aiming at the synthesis of dibromoagelaspongin (6) by Zaparucha et al.177

191

Chemistry and Biology of the PyrroleeImidazole Alkaloids

albeit in modest yield (26%). Treatment of 380 with DMDO led to formation of ring B (381). By NMR experiment, it was found that target compound 381 was rather unstable and rearranged to ketone 382 in water. It was not possible to liberate the free 2-aminoimidazole unit from 381.

4.11 Dibromophakellstatin and Dibromophakellin Dibromophakellstatin (385) from Phakellia mauritiana178 differs from dibromophakellin (1) by the presence of a urea instead of a guanidine moiety in ring D (Scheme 63). Both natural products have been subject to several total syntheses, by either cyclizing a dihydrooroidin (311)-like precursor in an oxidative manner or by anellation of the imidazoline ring D to an ABC dipyrrolopyrazinone precursor. Rac-dibromophakellstatin (rac-385) and rac-dibromoisophakellin (rac-5) have been synthesized by Horne et al.179 and by Austin et al.180 whereas the (þ)-enantiomer ((þ)-385) has been obtained by Poullennec and Romo.120 Rac-dibromophakellin (rac-1) was, in 1982, the first cyclic pyrroleeimidazole alkaloid synthesized ever, accessed by an elegant oxidative cyclization of dihydrooroidin (311, B€ uchi et al.).181 All in 2007, Feldman et al. could extend their 2005 approach182 from rac-dibromophakellstatin (rac-385) to rac-dibromophakellin (rac-1),183 Chen et al. obtained rac-dibromophakellstatin (rac-385) in a similar manner with a different approach to the cyclization precursor,184 and Lindel et al. published the enantioselective total synthesis of ()-dibromophakellstatin (()-385),185 following their 2005 synthesis of rac-dibromophakellstatin (rac-385).186 (þ)-Monobromophakellin ((þ)-413) was synthesized by Romo et al., in 2008,187 (þ)-dibromophakellin ((þ)-1) by Nagasawa et al., in 2009.188 Tepe’s synthesis of rac-dibromophakellin (rac-1) was O Br Br

N H

N

H N

SPh

N H

O

PhI(CN)OTf, i-Pr2NEt, MeOH, DCM

N

Br

60—73%

N Br

HN 384

383 O CAN, H2O, MeCN (1:4), rf 80–93%

N Br

HN

SPh

O 1) Et3OBF4, NaHCO3, DCM

N

Br

N

NH O

rac-385: racdibromophakellstatin

2) EtCO2NH4, 135 °C 27%

Br

A Br

N

B

HN

N

C

D N

NH2 rac-1: racdibromophakellin

Scheme 63 Synthesis of rac-dibromophakellstatin (rac-385) and its conversion to racdibromophakellin (rac-1) by Feldman and Skoumbourdis.182,183

192

Thomas Lindel

published in 2011.189 This chapter also includes the 2014 Nagasawa synthesis of (þ)-cylindradine A ((þ)-71)190 and the 2009 conversion of rac-dibromophakellin (rac-1) to ugibohlin (12) via rac-dibromoisophakellin (rac-5) by the Lindel group.159 Feldman and Skoumbourdis developed a synthesis of rac-dibromophakellstatin (rac-385),182 which follows the assumed biosynthesis of the phakellin-type pyrroleeimidazole alkaloids. Scheme 63 gives the key cyclization step achieved by oxidation of phenylsulfanylimidazole 383 with Stang’s reagent (PhI(CN)OTf), which rendered the imidazole electrophilic and susceptible to nucleophilic attack by the remaining two nitrogen atoms. In a similar step the authors had also obtained dibromoagelaspongin (6, Scheme 61) if the imidazole nitrogen was DMAS-protected.175,176 The cyclization to tetracycle 384 was followed by oxidation of the sulfur with CAN, affording rac-dibromophakellstatin (rac-385). Conversion of the cyclic urea to the cyclic guanidine of rac-dibromophakellin (rac-1) was achieved in two further steps via O-ethylation with Et3OBF4 and ammonolysis.183 Rac-dibromophakellstatin (rac-385) was also synthesized by Chen et al. (Scheme 64).184 The synthesis is short (six steps), because the aminopropenylimidazole section 388 of the cyclization precursor proved to be accessible by Heck reaction between vinyl bromide 386 and unprotected imidazolone (387). Three further steps afforded 389, which was cyclized in almost quantitative yield to rac-385 by treatment with PhI(OAc)2. Thus, iodine(III) reagents were able not only to induce cyclization of a phenylsulfanyl imidazole precursor but also of an imidazolone.

Scheme 64 Synthesis of rac-dibromophakellstatin (rac-385) by Chen et al. (TFE, trifluoroethanol).184

193

Chemistry and Biology of the PyrroleeImidazole Alkaloids

The chiral pool total synthesis of ()-dibromophakellstatin (()-385) by Lindel et al. exploits a three-component reaction of chiral tricyclic enamine 393 with two equivalents of Lwowski’s reagent (394, Scheme 65).185 Starting from the dibrominated pyrrole-2-carboxylic acid 245, tricycle 393 was assembled in five steps incorporating hydroxyproline methyl ester (40% overall yield) and treated with excess of 394 in the presence of CaO in wet DCM.186 The tetracycle 395 of ()-dibromophakellstatin (()-385) was formed in acceptable yield (50%) and perfect diastereoselectivity. For good yields, the two bromo substituents, which served as protecting groups of the pyrrole, had to be removed. It is unclear whether a nitrene is formed from 394 by a-elimination, as it has been observed with Lwowski’s reagent. Possibly, the tosyloxime tautomer of 394 acts an electrophile in a Ca2þassisted manner. This assumption is corroborated by the fact that use of triethylamine instead of CaO/H2O did not afford tetracycle 395. The

Br

(i) SOCl2, MeCN, rf

O

H N

OH

(ii)

HN

MeO

Br

390 O Na2CO3

245

O N

OTBS

N

Br OH

N

64 %

394 O

O

MsCl, DBU, DCM, 0 °C

EtO

N

OTBS

N

(7 eq) NHOTs

CaO (7 eq), wet DCM, 15 °C 50%

393 O

N

O

2) DIBAL-H, DCM, –78 °C 3) H2, Pd/C, NEt3, MeOH/DCM 75%

392

OTBS

N EtO

OH

O

391

O

N

1) TBSCl, ImH DMF

Br MeO

84% OH

O

H N

N OTs O

N

1) NEt3·3 HF, THF 2) CBr4, PPh3, DCM 71%

395

EtO

N

N OTs O

O

SmI2 (12 eq), THF/MeOH (6:1)

Br

N

77%

396 O

O NBS (2 eq), THF/MeCN (5:1)

N N HN

NH O

397

47%

N

Br

N Br

HN

NH

O (–)-385: (–)-dibromophakellstatin

Scheme 65 Enantioselective total synthesis of ()-dibromophakellstatin (()-385) by Lindel et al.185

194

Thomas Lindel

two new nitrogens are found on the same side of the ring system. There is evidence that the antiproducts are also formed, which decompose in a reversible manner.191 For steric reasons, only the syn adducts can cyclize to the tetracycle. Deoxygenation of 395 was achieved after desilylation, Appel reaction to bromopyrrolidine 396, treatment with excess SmI2, and reintroduction of the two bromo substituents. The synthesis of ()-dibromophakellstatin (()-385) required 10 steps in 5% overall yield. The Tepe group (Scheme 66) discovered an efficient conversion of dipyrrolopyrazinone 398 to the tetracycle of dibromophakellin (1).189 By treatment of 398 with mono-Boc-guanidine in the presence of NBS, product 399 was formed, which was deprotected affording rac-dibromophakellin (rac-1) in just two steps (26%). Presumably, a brominated acyliminium ion serves as intermediate. The starting material 398, which had been synthesized before,192 was made in seven steps from pyrrole following a modified route (20%, not shown). Dibromophakellstatin was not accessible in that manner, since the addition of urea in the presence of NBS afforded the tetracyclic aminooxazoline 400 (50%). In an analogous manner, Tepe et al. also synthesized analogs of dibromophakellin (1) where the pyrrole was replaced by an indole moiety. Nagasawa et al. employed an Overman rearrangement in the course of a 19-step total synthesis of (þ)-dibromophakellin ((þ)-1, Scheme 67).188 Starting from trans-4-hydroxy-L-proline (403), the dipyrrolopyrazinone 402 was synthesized in four steps and oxidized in the a-position by

H2N

N

Br

N Br

NHBoc

N

Br

NBS, DMF, DCM

N Br

urea, NBS, DMF

89%

TFA, DCM O

N O

N NH2

400

N

Br

N Br

NHBoc

399

O Br

NH

N

29%

398 50%

O

NH

O

N Br

HN

N

HCl

NH2 rac-1: rac-dibromophakellin

Scheme 66 Conversion of pyrrolopyrazinone 398 to rac-dibromophakellin (rac-1) and to the aminooxazoline analog 400 by Tepe et al.189

195

Chemistry and Biology of the PyrroleeImidazole Alkaloids

HN HO2C

OH

401

N N

3) 272, EDC, DMAP, DCM 4) NaH, THF, 0 °C

O

O

IBX, Me3NO, DMSO OTBS

H

402 (dr 1:1)

70%

OH

272

O

1) SOCl2, EtOH, rf 2) TBSCl, ImH, DCM

NH 1) MsCl, NEt3, DCM 2) NaBH4, CeCl3·7 H2O, EtOH, THF, 0 °C

O N N O

OTBS

3) Ac2O, Pyr, DCM 4) HF-NEt3, THF

403 (dr 1:1)

404 (dr 1:1)

N

AcO O

O

1) K2CO3, MeOH 2) TBSCl, NaH, THF, 0 °C 3) DIBAL, PhMe, –80 °C

N

405

NH

N N

CCl3

90%

BocHN

NHBoc

406

72% O N

1) NBS, MeCN 2) aq HCl, MeOH

N N Boc

N

TBSO

4) H2, Raney-Ni, EtOH 5) NBoc=C(SMe)NHBoc, AgOTf, NEt3, MeCN

O 1) TBAF, THF, 0 °C 2) MsCl, NEt3, DCM, rf

OH

AcO

36% (from 402) O

48%

N N

OH

Cl3CCN, DBU, DCM, 0 °C to rt

O

DN

407

N Br

84% NHBoc

N

Br

HN

N

HCl

NH2 (+)-1: (+)-dibromophakellin

Scheme 67 Total synthesis of (þ)-dibromophakellin ((þ)-1) by Nagasawa et al.188

IBX/trimethylamine N-oxide affording hydroxyamide 403. Four further steps set the stage for the key reaction, which was induced by treatment of the tricyclic allylic alcohol 404 with trichloroacetonitrile and DBU in DCM. This led to the installation of one of the two nitrogens of ring D of the target molecule (405, 48%). In a competing reaction (50%), aromatization took place forming a second pyrrole moiety. Five further steps converted the acetoxy to a silyloxy group and installed the guanidine moiety of (þ)-1. Similar to an earlier observation by Romo et al. epimerization of the N,O-acetal carbon occurred on treatment with NaH. Ring closure to the aminoimidazoline ring D was possible after desilylation and mesylation with retention at the N,O-acetal, pointing at an equilibrium with an intermediate with an opened ring B. Boc removal and bromination of the pyrrole afforded (þ)-dibromophakellin ((þ)-1) in 6% overall yield.

196

Thomas Lindel

Toward the phakellin skeleton, anellation of the 2-aminoimidazoline unit can also be conducted by forming the Ctert-N bond in the second step, as shown by Wang and Romo (Scheme 68).187 The tricyclic precursor 408, which was available in three steps from L-proline, was converted to aminal 409 via replacement of the hydroxy by an azido group, followed by hydrogenation. Separation of the 3:4 mixture of diastereomers was possible, but not necessary, because the thermodynamically less stable N,N-acetal could be converted to 409 by warming with K2CO3 in MeOH. A trichloroethoxysulfonyl (Tces)-protected guanidine moiety was introduced by treatment with 410 using a procedure by Du Bois,193 and it was attempted to close the ring (412) by Rh(II)-catalyzed CH insertion. However, yields around 10% were obtained, being inferior to those obtained by employing PhI(OAc)2/MgO under microwave conditions (30e38%). Two further steps afforded (þ)-monobromophakellin ((þ)-413, 10 steps overall from L-proline). Nagasawa et al. have adapted the Romo route for their synthesis of (þ)-cylindradine A ((þ)-71, Scheme 69), which differs from the phakellin series by containing a pyrrole-3- instead of a pyrrole-2-carboxylic acid. Consequently, the synthesis starts from pyrrole-3-carboxylic acid, which is N-tosylated in this case (414).190 After six steps and one separation of diastereomers, the tricycle 417 was reached the OH group of which was replaced by an amino group in a very similar manner as that described by Romo (418). The key step is again the cyclization of ring D that started from guanidine 419 and proceeded a little better than earlier, affording tetracycle 420

Scheme 68 Total synthesis of (þ)-monobromophakellin ((þ)-413) by Wang and Romo; Tces, trichloroethoxysulfonyl (DPPA, diphenylphosphorylazide).187

Chemistry and Biology of the PyrroleeImidazole Alkaloids

197

Scheme 69 Total synthesis of (þ)-cylindradine ((þ)-71) by Nagasawa et al.; Tces, trichloroethoxysulfonyl; Boc-ON, 2-(tert-butoxycarbonyloxyimino)-2-phenylacetonitrile.190

in 65% yield. Four final steps completed the first total synthesis of (þ)-cylindradine A ((þ)-71, 15 steps from 414, 6% overall yield). Reaction of the enamide double bond of tricyclic systems like 398 with electrophiles always takes place at C10, since the pyrrole nitrogen is part of the aromatic system and, thus, the enamide character dominates. The existing approaches use the attack of a nucleophile as second step, leading to formal addition of an electrophile/nucleophile pair to the double bond. An epoxide has not been isolated. However, cyclopropanation with dichlorocarbene proved to be possible (Scheme 70, Lindel et al.).194 Tetracycle 421 was obtained in 85% yield, accompanied by compound 422 with the former pyrrole ring enlarged to the pyridine system. If the regioisomeric ABC tricycle 423 present in the isophakellin series was chosen as starting material, the central ring was enlarged to the unsaturated ε-lactam, forming the novel tetracycles 424 and 425. While the isophakellin-type ABC tricycle 423 had to be synthesized via a separate route, the ABCD tetracycle of rac-dibromoisophakellin (rac-5) proved to be accessible simply by heating rac-dibromophakellin (rac-1) under neutral conditions in water in almost quantitative yield (racemic series, Scheme 71, Lindel et al.).159 The reaction had worked also by heating in

198

Thomas Lindel

aq NaOH (50%), n-Bu4NBr (0.3 eq), CHCl3, 0 °C

O Br

7

N N

8

10

Br

Br

Cl

N N

Cl

Cl

O

421 (85%)

O

as above

422 (10%) O

N

N

Cl Cl

X

423: X=Br 426: X=H

X

+

X X

Cl

Cl

O

MeO N

X

+

N

10a

N

Br

N

Br

398 MeO

O

O

Cl

N

N

Cl

424: X=Br (21%) 427: X=H (79%)

Cl

Cl

X

Cl

425: X=Br (60%) 428: X=H (13%)

Scheme 70 Reaction of the tricyclic phakellin and isophakellin partial structures 398 and 423, 426 with dichlorocarbene (Lindel et al.).194 O N

Br

H2O, rf

N Br H

N

N

95 %

NH2

rac-1: rac-dibromophakellin

Br

O

H N A

B

Br H

N

N

C

D N

6 M HCl, rt 88 %

NH2

rac-5: rac-dibromoisophakellin

O

H N

N

Br Br

H

N

NH2

NH2 Cl 12: ugibohlin

Scheme 71 Conversion of rac-dibromophakellin (rac-1) to rac-dibromoisophakellin (rac-5) and further to ugibohlin (12) by Lindel et al.159

chlorobenzene in the presence of K2CO3 (Horne et al.).179 Under strongly acidic conditions (6 M HCl), rac-dibromoisophakellin (rac-5) underwent opening of the aminoimidazoline ring D, affording the natural product ugibohlin (12) in an efficient manner (88%).

4.12 Oroidin The synthesis of the parent compound of the pyrroleeimidazole alkaloids, oroidin (2), continues to be of interest, despite the existence of earlier routes. For instance, Ilas et al. replaced the unpleasant NaeHg reduction of ornithine derivatives to the a-aminoaldehyde by a three step procedure via the Weinreb amide (Scheme 72, 46% overall).195 The conversion of 430 to the eastern half 431 of oroidin (2) appears to be hampered by the presence of MeOH during the chlorination/dehydrochlorination step. Here, the authors could have used our procedure in DMF in the absence of MeOH.159 In addition, Ilas et al. made improvements of Al-Mourabit’s imidazopyridine

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Chemistry and Biology of the PyrroleeImidazole Alkaloids

O BocHN

OH

1) MeHNOMe-HCl, Et3N, BOP 2) Boc2O, DMAP, MeCN

NHBoc

3) LiAlH4, Et2O, 0 °C

429

1) HCl(g), Et2O 2) NH2CN, H2O, pH 4.5, rf 3) (i) NCS, MeOH, 2 h (ii) MeOH, xylene, 135 °C 11%

O Boc2N

NHBoc 430

46%

N NH2

H2N

N H 431

Scheme 72 Modified route to the eastern half 431 of oroidin (2) by Ilas et al. (BOP, (benzotriazol-1-yloxy) tris(dimethylamino)phosphonium hexafluorophosphate).195

route, which was discussed in our 2005 review,3 to oroidin (2) and congeners. The oroidin synthesis by Rasapalli, Lovely et al. embedded the 2aminoimidazole unit in an imidazopyrimidine bicycle (Scheme 73).196 An interesting step is the assembly of that bicycle by condensation of abromoketone 432 and N,N-dimethylamidine 433, which proceeded regioselectively affording the acyl heterocycle 434. The first step is likely to be a nucleophilic attack of a pyrimidine nitrogen at the a-carbon, which becomes a nucleophile itself after deprotonation. Reduction of the ketone moiety to the alcohol proceeded smoothly, which is difficult with the unprotected 2-aminoimidazole.197 After amide formation with 147, reduction of the ketone, and dehydration to 437, hydrazinolysis afforded oroidin (2) in seven steps from phthalimide (8% overall yield).

Scheme 73 Synthesis of oroidin (2) by Rasapalli, Lovely et al.196.

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There is also a synthesis of an isotopically labeled oroidin, developed by Molinski, Romo et al. with the aim of studying the biosynthesis of the pyrroleeimidazole alkaloids (Scheme 74, see also Scheme 2).198 The sequence starts from urocanic acid (436), which was converted to allylic alcohol 437 in six steps. The N label had to be introduced at a late stage, which was achieved by mesylation of 437 and reaction with 15N-labeled potassium phthalimide affording [15N]-438. Four additional steps provided [7-15N]oroidin ([7-15N]-2) in 12 steps (15% overall yield). Dihydrooroidin (311) has also been accessed from 4-azidobutyric acid, which was transformed to the acid chloride.199 Reaction with diazomethane and treatment with 48% HBr afforded 6-bromo-5-oxohexanoic acid methyl ester, which was reacted with Boc-guanidine to afford the 2-aminoimidazole. Melander et al. optimized the remaining N-acylation step by first hydrogenating the azide in THF, followed by in situ reaction with trichloromethylketone 147 and removal of the Boc group. In the absence of water, treatment of pyrrole 2-carboxamide derivatives with Selectfluor (332) in the microwave oven led to fluorination of the pyrrole unit, which allowed the synthesis of the first fluorinated derivative of a pyrroleeimidazole alkaloid, fluorohymenidin (441, Scheme 75).200 Starting from the monobrominated pyrrole derivative 79, fluorinated trichloromethylketone 439 was obtained in acceptable yield (43%), followed by condensation with the alkyl amino group of diamine 365. The fluorination did not work for 4,5-dibrominated pyrrole-2-carboxamides. When starting from nonbrominated pyrrole-2-carbonyl compounds, fluorination occurred at C5 and not at C4. This points at a radical mechanism

N HO2C

NH

H 15 N

N [15N]-438

N3

3) N2H4, EtOH, 50 °C 437

3) H2, Pd, Lindlar, MeOH, THF Br 147 Br

N H

CCl3 O

N Tr

HO

1) 147, Na2CO3, DMF 2) AcCl, MeOH, EtOAc

Tr N

1) MsCl, Et3N, THF 2) [15N]-PhthNK, DMF

N3 N

4) TBSCl, ImH 5) n-BuLi, TsN3, THF 6) TBAF, THF 57%

436

H

1) AcCl, MeOH, rf 2) TrCl, Et3N, DMF 3) DIBAL, THF

Br Br

N H

H N

15

N N H

NH2

O [7-15N]-2: [7-15N]-oroidin (26% from 437)

Scheme 74 Synthesis of 15N-labeled oroidin ([7-15N]-2) by Molinski, Romo, et al.198

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Chemistry and Biology of the PyrroleeImidazole Alkaloids

Cl N

Br

N F 2 BF4 332

4 5

CCl3

N H

F

79

N N H

O

NH2 N H · 2 HCl

365-2HCl

DMF, NEt3 (3 eq) (ii) MeOH-HCl

O

(i) NCS (1 eq), DMF (ii) 100 °C

Br H N

N

H2N

439

43%

F

(i)

CCl3

N H

MeCN, microwave, rf, 5 min

O

N H

Br

(1 eq)

NH2 · HCl

Br

73%

N H

N

H N

F

(iii) H2O/MeOH/ HCO2H

440-HCl

31%

NH2 N H · HCO2H

O

441-HCO2H: fluorohymenidin-HCO2H

Scheme 75 Synthesis of fluorohymenidin (441) by Lindel et al.200

taking place, since electrophilic bromination would have occurred at C4. Probably, addition of F at C5 is the first step. For the dehydrogenation of dihydrofluorohymenidin 440 to 441, a chlorination/dehydrochlorination sequence in DMF159 was employed. The earlier syntheses of the oxidized noncyclized pyrroleeimidazole alkaloids dispacamide A (444) and hymenialdisine (447) had already been very efficient. Nevertheless, slight variations have been published. In both cases shown in Scheme 76, an alkylidene glycocyamidine unit was installed by reaction of a dihydroimidazolone derivative with an aldehyde or a ketone. Starting from aldehyde 442, microwave conditions allowed a one-step transformation to dispacamide A (444) by reaction with H2N

N

Br Br

N H

H N

Br

O 443

HCl HN

Br

O NaOAc, HOAc, 120 °C, microwave

O 442

61%

O

1)

MeS HN

NH2

N H

H N

NH

O O 444: dispacamide A H2N

N

N

O 446

N O

HN

Br N H

NH O

445: aldisine

TiCl4, pyr, THF, –10 °C to rt

Br 63%

2) NH4OH, THF, 110 °C, sealed tube

N H

NH O

447: hymenialdisine

Scheme 76 Synthesis of dispacamide A (444) by Bazureau et al.201 and conversion of aldisine (445) to hymenialdisine (447) by Tepe et al.202

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Thomas Lindel

glycocyamidine (443),201 whereas the natural product aldisine (445) was converted to hymenialdisine (447) by TiCl4-assisted treatment with the Smethylated thiohydantoin derivative 446, followed by introduction of the nitrogen by treatment with NH4OH in a sealed tube (110 C).202 Bazureau et al. also used rhodanine and derivatives for the condensation reaction with aldehyde 442.203

5. BIOLOGICAL ACTIVITY A good part of the knowledge on the biological activity of the pyrroleeimidazole alkaloids has been discovered when the compounds were isolated for the first time and tested. Examples include agelastatin A (()-7) and ()-dibromophakellstatin (()-385), which were identified as being cytotoxic, or ()-palau’amine (()-3), which turned out to be immunosuppressive. This section focusses on studies after 2005, which go beyond initial biotests performed on isolation of the natural products.

5.1 Anticancer Activity Anticancer activities have been analyzed in some detail for ()-sceptrin (()-19), the agelastatins, ()-palau’amine (()-3), the phakellins, and the hymenialdisines. It was found that ()-sceptrin (()-19) inhibits the cell motility of cancer cell lines without being cytotoxic at comparable concentrations.204 Among other tested congeners such as nakamuric acid (24), ()-sceptrin (()-19) was the most potent compound in that respect. At 40 mM concentration of ()-19, the area covered by motion of the HeLa cell line was diminished to about 25%. Vuori et al. could also show that, as a possible cause, ()-sceptrin (()-19) binds to monomeric actin with an equilibrium dissociation constant (Kd) of 19 mM. The study also became possible, because the total synthesis by Baran et al. provided multigram amounts of material. Alternatively, ()-sceptrin (()-19) can be isolated from Agelas sp. in large amounts (1e2% of the dry weight). Actin binding of ()-sceptrin (()-19) is in agreement with an earlier interesting study by Rodríguez, Lear, and La Clair who had shown that sceptrin binds to MreB, the bacterial analog of actin, which is in turn in accordance with the fact that sceptrin disrupts the bacterial cell wall synthesis and induces the formation of spheroblasts.205 The method used to identify sceptrin as MreB binder makes use of a so-called bidirectional affinity approach. Hamann et al. found that addition of ()-sceptrin (()-19, 5 mM) to the

Chemistry and Biology of the PyrroleeImidazole Alkaloids

203

culture could change the metabolic profile of Pseudomonas sp. YPD5A, without identifying altered metabolites, however.206 On the basis of their multigram total synthesis of agelastatins AeF (see Scheme 43), Movassaghi et al. were able to assess the cytotoxic effects on a broader basis than before.130 The cytotoxicity of ()-agelastatin A (()-7), which had been discovered already in 1993 when the compound was first isolated by Pietra et al.22 could be confirmed. Against a standard panel of human cancer cell lines (U-937, HeLa, A549, BT549, IMR90), IC50 values in the single-digit micromolar range were observed for ()-7, and ()-agelastatin D (()-292) showed a slightly diminished activity. Agelastatins C and F were completely inactive. Particularly good activity was observed against leukemia and lymphoma cell lines (CEM, Jurkat, Daudi, HL-60, CA46), where ()-agelastatin A (()-7) was again the most potent with IC50 values between 20 and 187 nM. About three times less active was the N-demethylated ()-agelastatin D. Agelastatin C reached only singledigit micromolar IC50 values, whereas ()-agelastatin F was inactive. Interestingly, dibrominated ()-agelastatin B was 5e20 times less active than its monobrominated analog ()-7. Normal red blood cells are not affected by any of the natural products. Movassaghi et al. found that ()-agelastatins A (()-7) and D (()-292) induce apoptosis by activating procaspase-3 and cleavage of PARP-1. Cell cycle arrest is induced in the G2/M phase without affecting the tubulin dynamics. El Tanani et al. identified ()-agelastatin A (()-7) as effective inhibitor of osteopontin (OPN), an adhesive glycoprotein, at concentrations as low as 10 nM.207 ()-Agelastatin A (()-7) also inhibited the expression of b-catenin at the same concentration, which also plays a role in metastasis formation. Tun, Yoshimitsu, et al. have identified cytotoxic analogs of ()-agelastatin A (()-7) with similar cytotoxicity and suitable properties for CNS penetration.208 Synthetic access was possible based on the total synthesis of ()-agelastatin A (()-7) by Yoshimitsu, Tanaka, and coworkers. It was also possible to functionalize ()-agelastatin A (()-7) by Pd-mediated cross coupling at the bromopyrrole unit, obtaining analogs such as the cyclopropyl derivative 448, being about as cytotoxic as the natural product (Scheme 77). Molinski et al. investigated fluorinated agelastatin analogs and discovered the first derivative with comparable or even higher activity than the natural product against chronic lymphocytic leukemia cell lines (CLL1, CLL2).209 Trifluoromethylated compound 450 (Scheme 77) was obtained as major component of a mixture on treatment of ()-debromoagelastatin A (()-449) with NaSO2CF3 and TBHP, a method developed by Baran

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Thomas Lindel

HO Br

H N

N

HO

O BF3K

NH HH NH

H N

PdCl2(dppf), Cs2CO3, aq THF, rf 74%

O

H N

N

O

NH HH NH O

(–)-449: (–)-debromoagelastatin A

O

NH HH NH O 448

(–)-7: (–)-agelastatin A HO

N

HO NaSO2CF3, TBHP, H2O

X Y

H N

N

O

NH HH NH

O 450: X=CF3, Y=H (49%) 451: X=Y=CF3 (25%) 452: X=H, Y=CF3 (13%)

Scheme 77 Derivatization of ()-agelastatin A (()-7) by Yoshimitsu et al.208 and of ()-debromoagelastatin A (()-449) by Molinski et al.209

and coworkers.210 Formally, a trifluoromethyl group had replaced the bromo substituent of ()-agelastatin A (()-7). Only substitutions at that position were tolerated without loss of activity. The chloro analogs were also still active. The pyrrole b-position of ()-agelastatin A (()-7) was functionalized by cross coupling after having installed an iodo substituent by treatment with NIS (Romo et al.).211 From there, a series of cross-coupled derivatives was made. This led to loss of cytotoxicity by a factor of about 10 against CLL cells. The iodinated compound itself was inactive, whereas the chlorinated analog retained much of the activity of ()-agelastatin A (()-7). The cytotoxicity of the dibrominated agelastatin B was much lower. The hydroxy group must not be alkylated, as observed earlier. Diazirine and alkyne affinity probes were also synthesized and were about 100 times less active than ()-agelastatin A (()-7). Regarding ()-dibromophakellstatin (()-385), an structure-activity relationship (SAR) study by Lindel et al. not only varied the substitution pattern at the cyclic urea unit and the pyrrole section, but also investigated the functionalization of ring C (Fig. 11).212 Against a panel of 42 human cancer cell lines average relative IC50 values of 13.11 mM (()-385) and 3.67 mM for (12R)-dibromohydroxyphakellstatin (453, not found as natural product) were found, respectively. At higher doses, 12R-dibromohydroxyphakellstatin (453) showed complete cytotoxicity against almost all investigated cancer cell lines, whereas the more selective natural product 385 did

205

Chemistry and Biology of the PyrroleeImidazole Alkaloids

O debromination weakens/abolishes O cytotoxicity

N

Br

N Br HN

C

12

X = OH inactive X = OR weak or no activity X = OH cytotoxic X = OMOM weakly cytotoxic

N

Br Br

NH HN

X

O

453 D NH

O

urea must contain NHs

O

only (–)-enantiomer cytotoxic

guanidine derivative ((–)dibromophakellin) not cytotoxic

OH

N

N

Br

N Br

Cl Cl

(–)-385: (–)-dibromophakellstatin (X=H)

421, rac

Figure 11 Structure-activity relationship study on ()-dibromophakellstatin (()-385) by Lindel et al.212,213

not, indicating different mechanisms of action. The (12S)-diastereomer of 453 was not cytotoxic. Interestingly, the dichlorocyclopropane derivative 421, tested as racemic mixture, was cytotoxic still in the single-digit micromolar range.213 The (þ)-enantiomer ((þ)-385) of dibromophakellstatin, which had been obtained by separation of rac-385 on a chiral HPLC column, was not cytotoxic. Tepe et al. discovered that ()-palau’amine (()-3) and the smaller relatives rac-dibromophakellin (rac-1) and rac-dibromophakellstatin (rac-385) inhibit the human 20S proteasome (core particle), which is responsible for protein degradation.214 Inhibition of the proteasome opens possibilities for the treatment of immune diseases and inflammatory disorders, but also myeloma and mantle cell lymphoma. The effects were shown at single digit (()-palau’amine (()-3), rac-palau’amine (rac-3), IC50(b5c) 2.5 mM) or double-digit micromolar concentrations in the case of chymotrypsin-like and caspase-like activities. Trypsin-like activity was not inhibited. If ring D was absent, the activity was lost. It could further be shown that ()-palau’amine (()-3) binds to the 20S proteasome irreversibly, leading to accumulation of ubiquitinylated proteins in vivo. Groll, Tepe et al. obtained the first X-ray analysis (2.5 Å resolution) of a cocrystal of a phakellin-related molecule, the benzophakellin rac-455 (IC50(b5c) 3.5 mM), with yCP, the core particle with tyrosinase activity.215 Compound 455 binds exclusively and noncovalently in the S3 pocket of the chymotryptic like active site. A halogen bond was observed between the bromo substituent and the carbonyl oxygen of b5Thr21 (CeO$$Br angle

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Thomas Lindel

O

Br

N N

1) NBS, Bocguanidine, DCM, DMF 2) 5% TFA, DCM 49%

454

O

Br

N N N

HN rac-455

TFA

NH2

Scheme 78 Synthesis of benzophakellin rac-455 by Tepe et al.189,215

169 degrees, O$$Br distance 3.6 Å). The synthesis of rac-455 corresponds to Tepe’s approach to rac-dibromophakellin (rac-1, Scheme 66), but started from indole-2-carboxylic acid instead (Scheme 78).189 The X-ray analysis obtained by Groll et al. may also explain why only ()-dibromophakellstatin (()-385) is cytotoxic, whereas the (þ)-enantiomer is not, and why the introduction of large substituents at ring C has abolished the cytotoxicity. Cocrystals of pyrroleeimidazole alkaloids and proteins are very rare and had, until 2015, only been obtained for derivatives of the kinase inhibitor hymenialdisine (447). The kinase inhibitor hymenialdisine (447, Scheme 76), an ATP antagonist, continues to be subject of investigation. By now, at least four X-ray analyses of cocrystals with kinases (ACK1, Chk2, Chk1, CLK) have been obtained, making hymenialdisine (447) the biologically best-characterized pyrroleeimidazole alkaloid.216e219 Hymenialdisine (447) is a potent inhibitor of cyclin dependent kinases 1 (IC50 22 nM) and 2 (IC50 40 nM), and of glycogen synthase kinase 3b (IC50 10 nM). In the absence of the bromo substituent, that level of activity is almost retained. Indole analogs of hymenialdisine (447) have been synthesized, which themselves bind well to kinases and were also cytotoxic against cancer cell lines, e. g., leukemia T-cells (GI50 1.7 mM). The tetrahydroazepinone pharmacophore of 447 continues to be functionalized, e. g., by replacing the alkylidene glycocyamidine unit by oxime moieties, which did not provide more active analogs.220 The pyrroleeimidazole alkaloid hymenialdisine (447) has become a tool of biochemistry studying the cell cycle.

5.2 Antimicrobial Activity and Action on Biofilms The occasionally reported antimicrobial activity of some of the pyrrolee imidazole alkaloids was analyzed further for the axinellamines (25, 148). The antibiofilm activity of ageliferin (20) has initiated a successful optimization study, and there have been antimalarial activities reported. The second-generation total synthesis of the rac-axinellamines A (rac-25) and B (rac-148) on a gram scale by Baran et al. allowed a detailed assessment

207

Chemistry and Biology of the PyrroleeImidazole Alkaloids

of the antibacterial properties of those dimeric pyrroleeimidazole alkaloids.104 It turned out that the axinellamines, in contrast to earlier reports, have promising activity against both Gram-positive and Gramnegative bacteria via an interesting mode of action. The axinellamines appear to cause secondary membrane destabilization. Against MRSA strains from hospitals (N315) MIC values of 4 mg/mL were observed for both diastereomers rac-25 and rac-148. About the same activity was measured against Escherichia coli K-12, which reversibly changes its morphology to mostly elongated forms along the major axis. Perhaps, there is a relation to the MreB activity of another pyrroleeimidazole alkaloid, ()-sceptrin (()-19). Against fungi, the axinellamines were inactive. Ageliferin (20) became the first pyrroleeimidazole alkaloid in the field of biofilm inhibition and was simplified to the partially hydrogenated, diastereomeric 2-aminobenzimidazole derivatives 456 and 457 by Melander et al. (Fig. 12). Biofilms, which account for about 80% of all bacterial infections, are surface-attached bacterial communities, surrounded by a protective extracellular matrix. The bacteria can be up to 1000-fold less sensitive against antibiotics, thus constituting a serious health problem.221 Since the antibiofilm activities of 456 and 457 and of the natural products were still weak (IC50 H N

O

Br

HN

N

Br

HN

N H

N H

NH2

HN

H N O

N H

NH2

NH2

457

N

N N N

N N H

N

H2N H2N

NH2

456

NH2

Br

N H

N H

N

O

(–)-20: (–)-ageliferin

Br

N

H2N H2N

2: oroidin

N H

NH2

458

H N O

N N N

459

N N H

NH2

Figure 12 Biofilm-inhibiting 2-aminoimidazole derivatives discovered by Melander et al.222

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Thomas Lindel

value of oroidin (2) against Pseudomonas aeruginosa of only 190 mM222), a program on the synthesis of more active derivatives and analogs of the natural products was started, which continues to lead to promising candidates, with 2-aminoimidazole as key structural element. For instance, it was found that the triazole-containing 2-aminoimidazole 458 (Fig. 12), obtained by click reaction, inhibits and disperses bacterial biofilms of P. aeruginosa, Acinetobacter baumannii, Bordetella bronchiseptica, and Staphylococcus aureus without inducing cellular death. The triazole unit replaces the pyrrole. The IC50 values of 458 and congeners against biofilms were in the single digit micromolar range or even below.221 Furthermore, it could be shown that the resistance of multidrug resistant strains (MRSA, MDRAB) against antibiotics such as penicillin G, methicillin, or even ciprofloxacin is depleted at a concentration of 75 mM of 458.223 Compound 459 inhibits biofilm growth of MRSA with an IC50 of 2 mM.224 The noncytotoxic dihydrooroidin (311), active against Halomonas pacifica, was mixed with a marine-based paint (1 mM concentration) where it showed, qualitatively, antibiofouling effects.225 The mode of action of biofilm-inhibiting pyrroleeimidazole alkaloids is still unknown. Remarkably, ageliferin (20) and oroidin (2) have evolved to synthetic analogs with activities enhanced by a factor of roughly 100. Masic et al. derived from oroidin (2) the conformationally restricted analogs 460 and 461, among others. Compound 460 exhibited IC50 values of 20 mM against biofilms of S. aureus and Streptococcus mutans.226 Kikelj et al. also tried to convert the almost noncytotoxic227 and hardly antimicrobial parent compound oroidin (2) into apoptosis-inducing228 and antimicrobial229 derivatives, such as 461 (apoptosis induction). The most promising molecule is perhaps the 4,5,6,7-tetrahydrobenzo[d]thiazole 462, which contains the full 4,5-dibromocarboxamide moiety of oroidin (2). It was found that 462 inhibits the DNA gyrase of E. coli at nanomolar concentration (IC50 58 nM), whereas the DNA gyrase of S. aureus is not inhibited.230 Some of the pyrroleeimidazole alkaloids have also shown antiprotozoal effects with longamide B (309) and dibromopalau’amine being considered as promising trypanocidal and antileishmanial agents, and dispacamide B and spongiacidin B as potential antimalarial lead compounds. The observed activities did not reach those of standard agents such as chloroquine or podophyllotoxin.231

5.3 Activity Against Cystic Fibrosis Activity against cystic fibrosis was observed for latonduine A (70), which also lacks one carbon when compared to the other pyrroleeimidazole

Chemistry and Biology of the PyrroleeImidazole Alkaloids

209

alkaloids.232 Latonduine A (70) was identified as being able to correct a trafficking effect involved in cystic fibrosis, leading to functional correction in vivo. Cystic fibrosis is the most common lethal genetic disease. An alkynylated, benzophenone-containing derivative was synthesized (463, Scheme 79), incubated with cell lysate (CFBE41o cells) and irradiated. Employing click chemistry, the covalent adduct was biotinylated, followed by isolation and mass spectral analysis. Poly(ADP-ribose) polymerase (PARP-3) was identified as target protein in CFBE41o cell lines (coincubation), which is inhibited by the latonduines. Probably, latonduine A (70) binds directly at the catalytic domain of PARP-3.

Scheme 79 The chemical side of identifying poly(ADP-ribose) polymerase (PARP-3) as biochemical target of latonduine A (70, Carlile et al.).232

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Thomas Lindel

5.4 Feeding Deterrence and Action on Channels The only proven biological function of any of the pyrroleeimidazole alkaloids still appears to be the feeding deterrence of oroidin (2), the 4,5dibromopyrrole-2-carboxylic acid and a few congeners in Agelas sp., which occur in the sponge in the necessary concentrations and protect against predation by reef fish, such as Thalassoma bifasciatum. In 2000, an SAR study had shown that the pyrrole section is required for activity, which is enhanced by the presence of the eastern half of oroidin (2).233 Without the pyrrole, activity was lost. The dimeric pyrroleeimidazole alkaloids also revealed to be feeding deterrent.234 Perhaps related to feeding deterrence, ()-ageliferin (()-20) and bromoageliferin were found to inhibit the voltage-operated calcium entry in phaeochromocytoma PC12 cells at concentrations in the single-digit micromolar range and thereby to reduce intracellular calcium concentrations.235 The study was extended to in total 12 brominated pyrroleeimidazole alkaloids form the sponges S. caribica and Agelas wiedenmayeri including ()-massadine (()-27), the tetrameric ()-stylissadines A (()-43) and B (()-44), and tetrabromostyloguanidine, all of which showed that effect at similar concentrations.233 The monomeric pyrrolee imidazole alkaloids exhibited weaker effects. ()-Stylissadines A (()-43) and B (()-44) are also specific antagonists of the P2X7 receptor, an important inflammatory target.53 Ageladine A (69) is a fluorescent compound.80 Excited at 365 nm, ageladine A (69) shows emission at about 415 nm, which is most intense at pH 3 and almost disappears on the way up to pH 9. Bickmeyer et al. took advantage of that fact and identified low pH zones in the shrimp Macrobrachium argentinum and inside PC12 cells by fluorimetry.236 The bromo substituents should aid the membrane permeation of 69.

6. CONCLUSION At the end of our 2003 review, we depicted several structures, which could derive from the core dihydrooroidin (311) building block and would be even less strained than the natural product ()-dibromophakellstatin (()-385). We predicted that the next years would bring the isolation of pyrroleeimidazole alkaloid monomers with new skeletons, such as structures 466, 467, and 468. However, that prediction did not fulfill. None of the nagelamides AeZ, which occur in concentrations a hundred times

211

Chemistry and Biology of the PyrroleeImidazole Alkaloids

F3CO NH

H N

N H

N

NH2

N H

O

N

H N

N H

O

460

NH HCl

461 Br Br

N H

O

H N

S NH

O

CO2H

462

N

Figure 13 Conformationally restricted, biologically active compounds inspired by oroidin (2, Masic, We˛ grzyn, et al.)226,230

lower than oroidin (2), shares its skeleton with the putative molecules shown in Fig. 14 or others in the list. Apparently, the formation of cyclized pyrroleeimidazole alkaloid monomers does not only follow the criterion of product stability. In particular, participation of position 8 of the open chain precursor seems to be difficult. Instead, novel pyrroleeimidazole alkaloids show incorporation of other metabolites such as taurine or amino acid fragments. The low concentrations of the pyrroleeimidazole alkaloids isolated recently will make it difficult to investigate their biological properties, simply due to lack of material. Here, more total syntheses will be needed. With the exception of the putative structure of nagelamide D (229) and of nagelamide E, a diastereomer of ageliferin (20), none of the nagelamides has been accessed. On the other hand, the “classic” monomeric pyrroleeimidazole alkaloids have all been synthesized, sometimes primarily to demonstrate the usefulness of a new method, as in the case of the related molecules agelastatin A (7, 15 syntheses) and cyclooroidin (11). The phakellin skeleton has also been made 10 times, with a focus on the target structure itself. Some of

Br Br

O

N N HN O

N H

(–)-385: 26.7 kcal/mol

H N

Br

O N

O

O Br

H

H N HN

O

N H

466: 19.4

N H

O N

Br

Br

N H

H N

Br

NH O

467: 18.6

N H O

H

N H

468: 24.9

Figure 14 Strain energy of unknown modes of cyclization (MM2), compared with those of ()-dibromophakellstatin (()-385).

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the pyrroleeimidazole alkaloids are now available in gram amounts. The total synthesis of the dimeric pyrroleeimidazole alkaloids has had its pioneering phase with two routes to palau’amine (3) and massadine (27) discovered, and three to the axinellamines (25, 148) and ageliferin (10). Here, the consolidating phase has already started e.g., with the second-generation synthesis of rac-axinellamines A (rac-25) and B (rac-148) by the Baran group. The polarity of the pyrroleeimidazole alkaloids poses a particular challenge and often, new synthetic methodology had to be developed. There is still need for methods tolerating an unprotected 2-aminoimidazole unit. Interestingly, only a few interconversions of pyrroleeimidazole alkaloids are known. Despite enormous efforts on their total synthesis, the key biological activities of the pyrroleeimidazole alkaloids have first been described in the course of their isolation from natural sources. This is where we know from that ()-agelastatin A (()-7) and ()-dibromophakellstatin (()-385) are cytotoxic, for instance. To find more targets of the pyrroleeimidazole alkaloids, research has to increasingly include Chemical Biology, such as performed in the case of ()-sceptrin (()-19).

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CUMULATIVE INDEX OF TITLES A

Aconitum alkaloids, 4, 275 (1954), 7, 473 60), 34, 95 (1988) C18 diterpenes, 67, 1 (2009) C19 diterpenes, 12, 2 (1970), 69, 266–302 (2010) C20 diterpenes, 12, 136 (1970) Acridine alkaloids, 2, 353 (1952) Acridone alkaloids, 54, 259 (2000) experimental antitumor activity of acronycine, 21, 1 (1983) Actinomycetes, isoquinolinequinones, 21, 55 (1983), 53, 120 (2000) N-Acyliminium ions as intermediates in alkaloid synthesis, 32, 271 (1988) Aerophobins and related alkaloids, 57, 208 (2001) Aerothionins, 57, 219 (2001) Ajmaline-Sarpagine alkaloids, 8, 789 (1965), 11, 41 (1986), 52, 104 (1999), 55, 1 (2001) enzymes in biosynthesis of, 47, 116 (1995) Akuammiline alkaloids, 76, 171 (2016) Alkaloid chemistry marine cyanobacteria, 57, 86 (2001) synthetic studies, 50, 377 (1998) Alkaloid production, plant biotechnology of, 40, 1 (1991) Alkaloid structures spectral methods, study, 24, 287 (1985) unknown structure, 5, 301 (1955), 7, 509 (1960), 10, 545 (1967), 12, 455 (1970), 13, 397 (1971), 14, 507 (1973), 15, 263 (1975), 16, 511 (1977) X-ray diffraction, 22, 51 (1983) Alkaloids apparicine and related, 57, 258 (2001) as chirality transmitters, 53, 1 (2000) biosynthesis, regulation of, 49, 222 (1997) biosynthesis, molecular genetics of, 50, 258 (1998) biotransformation of, 57, 3 (2001), 58, 1 (2002) chemical and biological aspects of Narcissus, 63, 87 (2006) containing a quinolinequinone unit, 49, 79 (1997) containing a quinolinequinoneimine unit, 49, 79 (1997) containing an isoquinolinoquinone unit, 53, 119 (2000) ecological activity of, 47, 227 (1995) ellipticine and related, 57, 236 (2001) forensic chemistry of, 32, 1 (1988) histochemistry of, 39, 165 (1990) infrared and raman spectroscopy of, 67, 217 (2009) in the plant, 1, 15 (1950), 6, 1 (1960) of the Menispermaceae, 54, 1 (2000) plant biotechnology, production of, 50, 453 (1998) toxic to livestock, 67, 143 (2009) uleine and related, 57, 247 (2001)

221

j

222

Cumulative Index of Titles

with antiprotozoal activity, 66, 113 (2008) 153 Alkaloids from amphibians, 21, 139 (1983), 43, 185 (1993), 50, 141 (1998) ants and insects, 31, 193 (1987) Chinese traditional medicinal plants, 32, 241 (1988) Hernandiaceae, 62, 175 (2005) mammals, 21, 329 (1983), 43, 119 (1993) marine bacteria, 53, 239 (2000), 57, 75 (2001) marine organisms, 24, 25 (1985), 41, 41 (1992) medicinal plants of New Caledonia, 48, 1 (1996) mushrooms, 40, 189 (1991) plants of Thailand, 41, 1 (1992) Sri Lankan flora, 52, 1 (1999) Alkyl, aryl, alkylarylquinoline, and related alkaloids, 64, 139 (2007) Allelochemical properties of alkaloids, 43, 1 (1993) Allo congeners, and tropolonic Colchicum alkaloids, 41, 125 (1992) Alstonia alkaloids, 8, 159 (1965), 12, 207 (1970), 14, 157 (1973) Amaryllidaceae Amaryllidaceae alkaloids, 2, 331 (1952), 6, 289 (1960), 11, 307 (1968), 15, 83 (1975), 30, 251 (1987), 51, 323 (1998), 63, 87 (2006) Amphibian alkaloids, 21, 139 (1983), 43, 185 (1983), 50, 141 (1998) Analgesic alkaloids, 5, 1 (1955) Anesthetics, local, 5, 211 (1955) Annonaceae alkaloids: occurrence and a compilation of their biological activities, 74, 233 (2015) Anthranilic acid derived alkaloids, 17, 105 (1979), 32, 341 (1988), 39, 63 (1990) Antifungal alkaloids, 42, 117 (1992) Antimalarial alkaloids, 5, 141 (1955) Antiprotozoal alkaloids, 66, 113 (2008) Antitumor alkaloids, 25, 1 (1985), 59, 281 (2002) Apocynaceae alkaloids, steroids, 9, 305 (1967) Aporphine alkaloids, 4, 119 (1954), 9, 1 (1967), 24, 153 (1985), 53, 57 (2000) Apparicine and related alkaloids, 57, 235 (2001) Aristolochia alkaloids, 31, 29 (1987) Aristotelia alkaloids, 24, 113 (1985), 48, 191 (1996) Aspergillus alkaloids, 29, 185 (1986) Aspidosperma alkaloids, 8, 336 (1965), 11, 205 (1968), 17, 199 (1979) synthesis of, 50, 343 (1998) Aspidospermine group alkaloids, 51, 1 (1998) Asymmetric catalysis by alkaloids, 53, 1 (2000) Azafluoranthene alkaloids, 23, 301 (1984)

B Bases simple, 3, 313 (1953), 8, 1 (1965) simple indole, 10, 491 (1967) simple isoquinoline, 4, 7 (1954), 21, 255 (1983) Benzodiazepine alkaloids, 39, 63 (1990)

Cumulative Index of Titles

223

Benzophenanthridine alkaloids, 26, 185 (1985) Benzylisoquinoline alkaloids, 4, 29 (1954), 10, 402 (1967) Betalains, 39, 1 (1990) Biosynthesis C19 diterpene, 69, 362–374 (2010) in Catharanthus roseus, 49, 222 (1997) in Rauwolfia serpentina, 47, 116 (1995) isoquinoline alkaloids, 4, 1 (1954) pyrrolizidine alkaloids, 46, 1 (1995) quinolizidine alkaloids, 46, 1 (1995) regulation of, 63, 1 (2006) tropane alkaloids, 44, 116 (1993) Bisbenzylisoquinoline alkaloids, 4, 199 (1954), 7, 439 (1960), 9, 133 (1967), 13, 303 (1971), 16, 249 (1977), 30, 1 (1987) synthesis, 16, 319 (1977) Bisindole alkaloids, 20, 1 (1981), 63, 181 (2006), 76, 259 (2016) noniridoid, 47, 173 (1995) Bisindole alkaloids of Catharanthus C-200 position as a functional hot spot in, 37, 133 (1990) isolation, structure elucidation and biosynthesis of, 37, 1 (1990), 63, 181 (2006) medicinal chemistry of, 37, 145 (1990) pharmacology of, 37, 205 (1990) synthesis of, 37, 77 (1990), 59, 281 (2002) therapeutic uses of, 37, 229 (1990) Bromotyrosine alkaloids, marine, 61, 79 (2005) Buxus alkaloids, steroids, 9, 305 (1967), 14, 1 (1973), 32, 79 (1988) chemistry and biology, 66, 191 (2008)

C

Cactus alkaloids, 4, 23 (1954) Calabar bean alkaloids, 8, 27 (1965), 10, 383 (1967), 13, 213 (1971), 36, 225 (1989) Calabash curare alkaloids, 8, 515 (1965), 11, 189 (1968) Calycanthaceae alkaloids, 8, 581 (1965) Calystegines, 64, 49 (2007) Camptothecin and derivatives, 21, 101 (1983), 50, 509 (1998) clinical studies, 60, 1 (2003) Cancentrine alkaloids, 14, 407 (1973) Cannabis sativa alkaloids, 34, 77 (1988) Canthin-6-one alkaloids, 36, 135 (1989) Capsicum alkaloids, 23, 227 (1984) Carbazole alkaloids, 13, 273 (1971), 26, 1 (1985), 44, 257 (1993), 65, 1 (2008) biogenesis, 65, 159 (2008) biological and pharmacological activities, 65, 181 (2008) chemistry, 65, 195 (2008) Carboline alkaloids, 8, 47 (1965), 26, 1 (1985) b-Carboline congeners and Ipecac alkaloids, 22, 1 (1983) Cardioactive alkaloids, 5, 79 (1955)

224

Cumulative Index of Titles

Catharanthus alkaloids, 59, 281 (2002) Catharanthus roseus, biosynthesis of terpenoid indole alkaloids in, 49, 222 (1997) Celastraceae alkaloids, 16, 215 (1977) Cephalostatins and Ritterazines, 72, 153 (2013) Cephalotaxus alkaloids, 23, 157 (1984), 51, 199 (1998) Cevane group of Veratrum alkaloids, 41, 177 (1992) Chemistry of hapalindoles, fischerindoles, ambiguines, and welwitindolinones, 73, 65 (2014) Chemosystematics of alkaloids, 50, 537 (1998) Chemotaxonomy of Papaveraceae and Fumariaceae, 29, 1 (1986) Chinese medicinal plants, alkaloids from, 32, 241 (1988) Chirality transmission by alkaloids, 53, 1 (2000) Chromone alkaloids, 31, 67 (1987) Cinchona alkaloids, 3, 1 (1953), 14, 181 (1973), 34, 332 (1988) Colchicine, 2, 261 (1952), 6, 247 (1960), 11, 407 (1968), 23, 1 (1984) pharmacology and therapeutic aspects of, 53, 287 (2000) Colchicum alkaloids and allo congeners, 41, 125 (1992) Configuration and conformation, elucidation by X-ray diffraction, 22, 51 (1983) Corynantheine, yohimbine, and related alkaloids, 27, 131 (1986) Cularine alkaloids, 4, 249 (1954), 10, 463 (1967), 29, 287 (1986) Curare-like effects, 5, 259 (1955) Cyclic tautomers of tryptamine and tryptophan, 34, 1 (1988) Cyclopeptide alkaloids, 15, 165 (1975), 67, 79 (2009) Cylindrospermopsin alkaloids, 70, 1 (2011) Cytotoxic alkaloids, modes of action, 64, 1 (2007)

D

Daphniphyllum alkaloids, 15, 41 (1975), 29, 265 (1986), 60, 165 (2003) Delphinium alkaloids, 4, 275 (1954), 7, 473 (1960) C10-diterpenes, 12, 2 (1970) C20-diterpenes, 12, 136 (1970) Detection of through IR and Raman spectroscopy, 67, 217 (2009) Dibenzazonine alkaloids, 35, 177 (1989) Dibenzopyrrocoline alkaloids, 31, 101 (1987) Diplorrhyncus alkaloids, 8, 336 (1965) Diterpenoid alkaloids Aconitum, 7, 473 (1960), 12, 2 (1970), 12, 136 (1970), 34, 95 (1988) C18, 67, 1 (2009) C19, 69, 1 (2010) C20, 59, 1 (2002) chemistry, 18, 99 (1981), 42, 151 (1992) Delphinium, 7, 473 (1960), 12, 2 (1970), 12, 136 (1970) Garrya, 7, 473 (1960), 12, 2 (1960), 12, 136 (1970) general introduction, 12, xv (1970) structure, 17, 1 (1979) synthesis, 17, 1 (1979) Duguetia alkaloids, 68, 83 (2010)

Cumulative Index of Titles

225

E

Eburnamine-vincamine alkaloids, 8, 250 (1965), 11, 125 (1968), 20, 297 (1981), 42, 1 (1992) Ecological activity of alkaloids, 47, 227 (1995) Elaeocarpus alkaloids, 6, 325 (1960) Ellipticine and related alkaloids, 39, 239 (1990), 57, 235 (2001) Enamide cyclizations in alkaloid synthesis, 22, 189 (1983) Enzymatic transformation of alkaloids, microbial and in vitro, 18, 323 (1981) Ephedra alkaloids, 3, 339 (1953) Epibatidine, 46, 95 (1995) Ergot alkaloids, 8, 726 (1965), 15, 1 (1975), 38, 1 (1990), 50, 171 (1998), 54, 191 (2000), 63, 45 (2006) Erythrina alkaloids, 2, 499 (1952), 7, 201 (1960), 9, 483 (1967), 18, 1 (1981), 48, 249 (1996), 68, 39 (2010) Erythrophleum alkaloids, 4, 265 (1954), 10, 287 (1967) Eupomatia alkaloids, 24, 1 (1985)

F

Flavoalkaloids, 31, 67 (1987), 77, 85 (2017) Forensic chemistry, alkaloids, 12, 514 (1970) by chromatographic methods, 32, 1 (1988)

G Galanthamine history and introduction, 68, 157 (2010) production, 68, 167 (2010) Galanthus Galbulimima alkaloids, 9, 529 (1967), 13, 227 (1971) Gardneria alkaloids, 36, 1 (1989) Garrya alkaloids, 7, 473 (1960), 12, 2 (1970), 12, 136 (1970) Geissospermum alkaloids, 8, 679 (1965) Gelsemium alkaloids, 8, 93 (1965), 33, 84 (1988), 49, 1 (1997) Glycosides, monoterpene alkaloids, 17, 545 (1979) Guatteria alkaloids, 35, 1 (1989)

H Halogenated alkaloids biosynthesis of, 71, 167 (2012) occurrence of, 71, 1 (2012) Haplophyton cimicidum alkaloids, 8, 673 (1965) Hasubanan alkaloids, 16, 393 (1977), 33, 307 (1988) Hasubanan and acutumine alkaloids, 73, 161 (2014) Hernandiaceae alkaloids, 62, 175 (2005) Histochemistry of alkaloids, 39, 165 (1990) Holarrhena group, steroid alkaloids, 7, 319 (1960) Homalium alkaloids: isolation, synthesis and absolute configuration assignment, 74, 121 (2015) Hunteria alkaloids, 8, 250 (1965)

226

I

Cumulative Index of Titles

Iboga alkaloids, 8, 203 (1965), 11, 79 (1968), 59, 281 (2002) Ibogaine alkaloids addict self-help, 56, 283 (2001) as a glutamate antagonist, 56, 55 (2001) comparative neuropharmacology, 56, 79 (2001) contemporary history of, 56, 249 (2001) drug discrimination studies with, 56, 63 (2001) effects of rewarding drugs, 56, 211 (2001) gene expression, changes in, 56, 135 (2001) mechanisms of action, 56, 39 (2001) multiple sites of action, 56, 115 (2001) neurotoxicity assessment, 56, 193 (2001) pharmacology of, 52, 197 (1999) review, 56, 1 (2001) treatment case studies, 56, 293 (2001) use in equatorial African ritual context, 56, 235 (2001) Imidazole alkaloids, 3, 201 (1953), 22, 281 (1983) Indole alkaloids, 2, 369 (1952), 7, 1 (1960), 26, 1 (1985) ajmaline group of, 55, 1 (2001) biomimetic synthesis of, 50, 415 (1998) biosynthesis in Catharanthus roseus, 49, 222 (1997) biosynthesis in Rauvolfia serpentina, 47, 116 (1995) distribution in plants, 11, 1 (1968) Reissert synthesis of, 31, 1 (1987) sarpagine group of, 52, 103 (1999) simple, 10, 491 (1967), 26, 1 (1985) Indole diterpenoid alkaloids, 60, 51 (2003) Indolizidine alkaloids, 28, 183 (1986), 44, 189 (1993), 55, 91 (2001), 75, 1 (2016) 2,2’-Indolylquinuclidine alkaloids, chemistry, 8, 238 (1965), 11, 73 (1968) Infrared spectroscopy of alkaloids, 67, 217 (2009) In vitro and microbial enzymatic transformation of alkaloids, 18, 323 (1981) Ipecac alkaloids, 3, 363 (1953), 7, 419 (1960), 13, 189 (1971), 22, 1 (1983), 51, 271 (1998) Isolation of alkaloids, 1, 1 (1950) Isoquinoline alkaloids, 7, 423 (1960) biosynthesis, 4, 1 (1954) 13C-NMR spectra, 18, 217 (1981) Reissert synthesis of, 31, 1 (1987) simple isoquinoline alkaloids 4, 7 (1954), 21, 255 (1983) Isoquinolinequinones, 21, 55 (1983), 53, 120 (2000) Isoxazole alkaloids, 57, 186 (2001)

K

Khat (Catha edulis) alkaloids, 39, 139 (1990) Kopsia alkaloids, 8, 336 (1965), 66, 1 (2008)

Cumulative Index of Titles

227

L

Lead tetraacetate oxidation in alkaloid synthesis, 36, 70 (1989) Local anesthetics, 5, 211 (1955) Localization in the plant, 1, 15 (1950), 6, 1 (1960) Lupine alkaloids, 3, 119 (1953), 7, 253 (1960), 9, 175 (1967), 31, 116 (1987), 47, 1 (1995) Lycopodium alkaloids, 5, 295 (1955), 7, 505 (1960), 10, 305 (1968), 14, 347 (1973), 26, 241 (1985), 45, 233 (1994), 61, 1 (2005), 72, 1 (2013) Lythraceae alkaloids, 18, 263 (1981), 35, 155 (1989)

M

Macrocyclic peptide alkaloids from plants, 26, 299 (1985), 49, 301 (1997) Madangamine group alkaloids, 74, 159 (2015) Mammalian alkaloids, 21, 329 (1983), 43, 119 (1993) Manske, R.H.F., biography of, 50, 3 (1998) Manzamine alkaloids, 60, 207 (2003) Marine alkaloids, 24, 25 (1985), 41, 41 (1992), 52, 233 (1999) bromotyrosine alkaloids, 61, 79 (2005) Marine bacteria, alkaloids from, 53, 120 (2000) Marine bi-, bis-, and trisindole alkaloids, 73, 1 (2014) Maytansinoids, 23, 71 (1984) Melanins, 36, 254 (1989) chemical and biological aspects, 60, 345 (2003) Melodinus alkaloids, 11, 205 (1968) Mesembrine alkaloids, 9, 467 (1967) Metabolic transformation of alkaloids, 27, 323 (1986) Microbial and in vitro enzymatic transformation of alkaloids, 18, 323 (1981) Mitragyna alkaloids, 8, 59 (1965), 10, 521 (1967), 14, 123 (1973) Molecular modes of action of cytotoxic alkaloids, 64, 1 (2007) Monoterpene alkaloids, 16, 431 (1977), 52, 261 (1999) glycosides, 17, 545 (1979) Monoterpenoid bisindole alkaloids, 76, 259 (2016) Monoterpenoid indole alkaloids, 77, 1 (2017) Morphine alkaloids, 2, 1 (part 1), 161 (part 2) (1952), 6, 219 (1960), 13, 1 (1971), 45, 127 (1994) Muscarine alkaloids, 23, 327 (1984) Mushrooms, alkaloids from, 40, 190 (1991) Mydriatic alkaloids, 5, 243 (1955)

N

a-Naphthophenanthridine alkaloids, 4, 253 (1954), 10, 485 (1967) Naphthylisoquinoline alkaloids, 29, 141 (1986), 46, 127 (1995) Narcotics, 5, 1 (1955) Narcissus alkaloids, 63, 87 (2006) New Caledonia, alkaloids from the medicinal plants of, 48, 1 (1996) Nitrogen-containing metabolites from marine bacteria, 53, 239, (2000), 57, 75 (2001) Non-iridoid bisindole alkaloids, 47, 173 (1995) Nuclear magnetic resonance imaging, C19 diterpenes, 69, 381–419 (2010) Nuphar alkaloids, 9, 441 (1967), 16, 181 (1977), 35, 215 (1989)

228

Cumulative Index of Titles

O

Ochrosia alkaloids, 8, 336 (1965), 11, 205 (1968) Ourouparia alkaloids, 8, 59 (1965), 10, 521 (1967) Oxazole alkaloids, 35, 259 (1989) Oxindole alkaloids, 14, 83 (1973) Oxoaporphine alkaloids, 14, 225 (1973)

P

Pancratium alkaloids, 68, 1 (2010) Pandanus alkaloids chemistry and biology, 66, 215 (2008) Papaveraceae alkaloids, 10, 467 (1967), 12, 333 (1970), 17, 385 (1979) pharmacology, 15, 207 (1975) toxicology, 15, 207 (1975) Pauridiantha alkaloids, 30, 223 (1987) Pavine and isopavine alkaloids, 31, 317 (1987) Pentaceras alkaloids, 8, 250 (1965) Peptide alkaloids, 26, 299 (1985), 49, 301 (1997) Phenanthrene alkaloids, 39, 99 (1990) Phenanthroindolizidine alkaloids, 19, 193 (1981) Phenanthroquinolizidine alkaloids, 19, 193 (1981) b-Phenethylamines, 3, 313 (1953), 35, 77 (1989) Phenethylisoquinoline alkaloids, 14, 265 (1973), 36, 172 (1989) Phthalideisoquinoline alkaloids, 4, 167 (1954), 7, 433 (1960), 9, 117 (1967), 24, 253 (1985) Picralima alkaloids, 8, 119 (1965), 10, 501 (1967), 14, 157 (1973) Piperidine alkaloids, 26, 89 (1985) Plant biotechnology, for alkaloid production, 40, 1 (1991), 50, 453 (1998) Plant systematics, 16, 1 (1977) Pleiocarpa alkaloids, 8, 336 (1965), 11, 205 (1968) Polyamine alkaloids, 22, 85 (1983), 45, 1 (1994), 50, 219 (1998), 58, 83 (2002) analytical aspects of, 58, 206 (2002) biogenetic aspects of, 58, 274 (2002) biological and pharmacological aspects of, 46, 63 (1995), 58, 281 (2002) catalog of, 58, 89 (2002) synthesis of cores of, 58, 243 (2002) Polyhalogenated alkaloids in environmental and food samples, 71, 211 (2012) Pressor alkaloids, 5, 229 (1955) Protoberberine alkaloids, 4, 77 (1954), 9, 41 (1967), 28, 95 (1986), 62, 1 (2005) biotransformation of, 46, 273 (1955) transformation reactions of, 33, 141 (1988) Protopine alkaloids, 4, 147 (1954), 34, 181 (1988) Pseudocinchoma alkaloids, 8, 694 (1965) Pseudodistomins, 50, 317 (1998) Purine alkaloids, 38, 226 (1990) Putrescine and related polyamine alkaloids, 58, 83 (2002) Pyridine alkaloids, 1, 165 (1950), 6, 123 (1960), 11, 459 (1968), 26, 89 (1985)

Cumulative Index of Titles

229

Pyrrole–imidazole alkaloids, 77, 117 (2017) Pyrrolidine alkaloids, 1, 91 (1950), 6, 31 (1960), 27, 270 (1986) Pyrrolizidine alkaloids, 1, 107 (1950), 6, 35 (1960), 12, 246 (1970), 26, 327 (1985) biosynthesis of, 46, 1 (1995) Pyrrolo[2,1-a] isoquinoline alkaloids synthesis of 70, 79 (2011)

Q Quinazolidine alkaloids, see Indolizidine alkaloids Quinazoline alkaloids, 3, 101 (1953), 7, 247 (1960), 29, 99 (1986) Quinazolinocarbolines, 8, 55 (1965), 21, 29 (1983) Quinoline alkaloids related to anthranilic acid, 3, 65 (1953), 7, 229 (1960), 17, 105 (1979), 32, 341 (1988) Quinolinequinone alkaloids, 49, 79 (1997) Quinolinequinoneimine alkaloids, 49, 79 (1977) Quinolizidine alkaloids, 28, 183 (1986), 55, 91 (2001), 75, 1 (2016) biosynthesis of, 47, 1 (1995)

R

Raman spectroscopy of alkaloids, 67, 217 (2009) Rauwolfia alkaloids, 8, 287 (1965) biosynthesis of, 47, 116 (1995) Recent studies on the synthesis of strychnine, 64, 103 (2007) Regulation of alkaloid biosynthesis in plants, 63, 1 (2006) Reissert synthesis of isoquinoline and indole alkaloids, 31, 1 (1987) Reserpine, chemistry, 8, 287 (1965) Respiratory stimulants, 5, 109 (1995) Rhazinilam-leuconoxine-mersicarpine triad, 77, 1 (2017) Rhoeadine alkaloids, 28, 1 (1986)

S

Salamandra group, steroids, 9, 427 (1967) Saraine alkaloids, 73, 223 (2014) Sarpagan-Ajmalan-type indoles, 76, 1 (2016) Sarpagine-type alkaloids, 52, 104 (1999), 76, 63 (2016) Sceletium alkaloids, 19, 1 (1981) Secoisoquinoline alkaloids, 33, 231 (1988) Securinega alkaloids, 14, 425 (1973), 74, 1 (2015) Senecio alkaloids, see Pyrrolizidine alkaloids Sesquiterpene pyridine alkaloids, 60, 287 (2003) Simple indole alkaloids, 10, 491 (1967) Simple indolizidine alkaloids, 28, 183 (1986), 44, 189 (1993), 55, 91 (2001), 75, 1 (2016) Simple indolizidine and quinolizidine alkaloids, 28, 183 (1986), 55, 91 (2001), 75, 1 (2016) Sinomenine, 2, 219 (1952) Solanum alkaloids chemistry, 3, 247 (1953), 74, 216 (2015) steroids, 7, 343 (1960), 10, 1 (1967), 19, 81 (1981) Sources of alkaloids, 1, 1 (1950)

230

Cumulative Index of Titles

Spectral methods, alkaloid structures, 24, 287 (1985) Spermidine and related polyamine alkaloids, 22, 85 (1983), 58, 83 (2002) Spermine and related polyamine alkaloids, 22, 85 (1983), 58, 83 (2002) Spider toxin alkaloids, 45, 1 (1994), 46, 63 (1995) Spirobenzylisoquinoline alkaloids, 13, 165 (1971), 38, 157 (1990) Sponges, isoquinolinequinone alkaloids from, 21, 55 (1983) Sri Lankan flora, alkaloids, 52, 1 (1999) Stemona alkaloids, 9, 545 (1967), 62, 77 (2005) Steroid alkaloids Apocynaceae, 9, 305 (1967), 32, 79 (1988) Buxus group, 9, 305 (1967), 14, 1 (1973), 32, 79 (1988), 66, 191 (2008) chemistry and biology, 50, 61 (1998), 52, 233 (1999) Holarrhena group, 7, 319 (1960) Salamandra group, 9, 427 (1967) Solanum group, 7, 343 (1960), 10, 1 (1967), 19, 81 (1981), 74, 204 (2015) Veratrum group, 7, 363 (1960), 10, 193 (1967), 14, 1 (1973), 41, 177 (1992), 74, 204 (2015) Stimulants respiratory, 5, 109 (1955) uterine, 5, 163 (1955) Structure elucidation, by X-ray diffraction, 22, 51 (1983) Strychnine, synthesis of, 64, 104 (2007) Strychnos alkaloids, 1, 375 (part 1) (1950), 2, 513 (part 2) (1952), 6, 179 (1960), 8, 515, 592 (1965), 11, 189 (1968), 34, 211 (1988), 36, 1 (1989), 48, 75 (1996) Sulfur-containing alkaloids, 26, 53 (1985), 42, 249 (1992) Synthesis of alkaloids enamide cyclizations for, 22, 189 (1983) lead tetraacetate oxidation in, 36, 70 (1989)

T

Tabernaemontana alkaloids, 27, 1 (1983) Taxoids, 69, 491–514 (2010) Taxol, 50, 509 (1998) Taxus alkaloids, 10, 597 (1967), 39, 195 (1990) Terpenoid indole alkaloids, 49, 222 (1997) Thailand, alkaloids from the plants of, 41, 1 (1992) Toxicity to livestock, 67, 143 (2009) Toxicology Papaveraceae alkaloids, 15, 207 (1975) Transformation of alkaloids, enzymatic, microbial and in vitro, 18, 323 (1981) Tremogenic and non-tremogenic alkaloids, 60, 51 (2003) Tropane alkaloids biosynthesis of, 44, 115 (1993) chemistry, 1, 271 (1950), 6, 145 (1960), 9, 269 (1967), 13, 351 (1971), 16, 83 (1977), 33, 1 (1988), 44, 1 (1993)

Cumulative Index of Titles

Tropoloisoquinoline alkaloids, 23, 301 (1984) Tropolonic Colchicum alkaloids, 23, 1 (1984), 41, 125 (1992) Tylophora alkaloids, 9, 517 (1967)

U

Uleine and related alkaloids, 57, 235 (2001) Unnatural alkaloid enantiomers, biological activity of, 50, 109 (1998) Uterine stimulants, 5, 163 (1955)

V Veratrum alkaloids cevane group of, 41, 177 (1992) chemistry, 3, 247 (1952), 74, 216 (2015) steroids, 7, 363 (1960), 10, 193 (1967), 14, 1 (1973) Veratrum and Solanum alkaloids, 74, 201 (2015) Vinca alkaloids, 8, 272 (1965), 11, 99 (1968), 20, 297 (1981) Voacanga alkaloids, 8, 203 (1965), 11, 79 (1968)

W

Wasp toxin alkaloids, 45, 1 (1994), 46, 63 (1995)

X

X-ray diffraction of alkaloids, 22, 51 (1983)

Y

Yohimbe alkaloids, 8, 694 (1965), 11, 145 (1968), 27, 131 (1986)

231

INDEX ‘Note: Page numbers followed by “f” indicate figures and “t” indicate tables.’

A

D

Abralia andamanica, 104e106 Acetophenone, 110e111 Acrosticta foveolata, 104e106 Acrylamide flavoalkaloids, 101e103, 102f Actinidia arguta, 91 N-acyliminium ion-mediated piperidine cyclization, 44e45 Aesculus hippocastanum L., 95 Ageladine A, 186e188 Ageliferin, 140e146 Aglaia A. edulis, 106e107 A. odorata, 107 A. ponapensis, 106e107 Alkaloid, 86 Aminoglycoside-flavoalkaloids, 99e100, 101f 2-Aminoimidazoline, 120e121 Amoora A. cucullata, 104e106 A. dasyclada, 104e106 Anticancer activity, 202e206, 205f Antimicrobial activity, 206e208 Archidendron forbesii, 104e106 Aspidosperma alkaloids, 2, 6f Axinellamines, 146e152

Davallia mariesii, 90e91 Dibromoagelaspongin, 188e191 Dibromoageliferin, 131 Dibromophakellin, 191e198 Dibromophakellstatin, 191e198 Dilauroyl peroxide (DLP), 34 Dimethyl 4-ethyl-4-formylpimelate, 27 N,N-dimethyltryptamine (DMT), 98 Diphenylphosphoryl azide (DPPA), 47e49 1,3-Dipolar cycloaddition, 29 Dracocephalum D. heterophyllum, 91 D. rupestre, 91

B Bombyx mori, 86e88 Buchenavia B. capitata, 91e93 B. macrophylla, 91e93

C 15-Carbon arylchromane, 86 Chromone alkaloids, 86 Cyclooroidin, 178e184 Cyclopentene, 170 Cystic fibrosis, 208e209

E Emilia sonchifolia, 91 Enamine, 110e111 Ethyl 2-ethylacetoacetate, 56e58

F fc-rDG/DDD method, 127 Ficus pantoniana, 86e88 Flavoalkaloids acrylamide flavoalkaloids, 101e103, 102f aglains and related flavoalkaloids, 103e107, 103f, 105fe106f total synthesis, 107, 109 aminoglycoside-flavoalkaloids, 99e100, 101f biological activity, 86e107 indole-flavoalkaloids, 95e98, 97fe98f total synthesis, 97e100 isolation, 86e107 nicotinic- and urea-flavoalkaloids, 100e101, 102f nitroalkyl flavoalkaloids, 101e103, 102f

233

j

234 Flavoalkaloids (Continued ) piperidine-flavoalkaloids, 91e95, 94f total synthesis, 95e96 piperidinone-flavoalkaloids, 91e95, 94f pyrrolidine-flavoalkaloids, 86e90, 87f total synthesis, 88e90 pyrrolidinone-flavoalkaloids, 87f, 90e91, 92fe93f thiocarbamate flavoalkaloids, 101e103, 102f total synthesis, 86e107 2-Formylpyrrole, 34 FriedeleCrafts acylation, 55e56

G Glycyrrhiza uralensis, 95 (e)-Glymontanine, 101e103 Goniothalamus cheliensis, 100e101

H Hanishin, 178e184 Hydroboration iodination, 39e40

I Imine heteroannulation, 49e50 Indigofera stachyodes, 101e103 Indole-flavoalkaloids, 95e98, 97fe98f Indol-2-ylcarbinol, 55 Institut de Chimie des Substances Naturelles (ICSN), 91e93 2-Iodoindole-3-ylacetate, 42e43 Isoflavoalkaloids biological activity, 108e111, 110f isolation, 108e111, 110f total synthesis, 108e111, 110f

K Ketoester, 53 b-ketoester, 45e47 Ketone, 26, 53e55 Kopsia dasyrachis, 94e95

L Lactone, 31e32 (-)-Leuconolam, 6e7, 6f, 15e16 Leuconoxines, 39e50

Index

N-acyliminium ion-mediated piperidine cyclization, 44e45 Aspidosperma alkaloids, 39 b-ketoester, 45e47 diphenylphosphoryl azide (DPPA), 47e49 hydroboration iodination, 39e40 imine heteroannulation, 49e50 2-iodoindole-3-ylacetate, 42e43 melodinine E, 40e41 Ruthenium-catalyzed oxidation, 47e49 ThorpeeIngold effect, 45e47 Lilium candidum, 90e91 Litchi chinensis, 91

M Massadine, 152e157 Melodinine E, 40e41 Mimosa tenuiflora, 96e97 Monomers, 120e121, 120fe121f Myoporum tenuifolium E., 99e100

N Nagelamide C, 131 Nagelamide D, 165e167 Nagelamide I, 130e131 Natural products, 66e69, 70te74t Neoflavoalkaloids biological activity, 111e112, 112f isolation, 111e112, 112f Nickel borideecatalyzed reduction, 169e170

O Ormocarpum kirkii, 101e103 Oroidin, 198e202

P Palau’amine, 157e165 Pallimamine, 108e110 Phakellia flabellata, 118e122 Phyllanthus cochinchinensis, 91 Phyllospadix iwatensis, 86e88 Piperidine-flavoalkaloids, 91e95, 94f Piperidinone-flavoalkaloids, 91e95, 94f Preaxinellamine, 128

235

Index

PyrroleeImidazole alkaloids Agelas sp., 121e123 biological activity, 202e210 anticancer activity, 202e206, 205f antimicrobial activity, 206e208 biofilms action, 206e208, 207f cystic fibrosis, 208e209 feeding deterrence/action, 210 bisulfite, 130e131 cyclobutane (e)-sceptrin, 132e133 dihydrobenzosceptrin A, 130e131 dimers, 120e121, 122fe124f fc-rDG/DDD method, 127 isolation and structure elucidation, 127 monomers, 120e121, 120fe121f nagelamide I, 130e131 Phakellia flabellata, 118e119 preaxinellamine, 128 structures, 119e129 Stylissa caribica, 124e125 Teichaxinella morchella, 133 total synthesis ageladine A, 186e188 ageliferin, 140e146 axinellamines, 146e152 cyclooroidin, 178e184 cyclopentene, 170 dibromoagelaspongin, 188e191 dibromophakellin, 191e198 dibromophakellstatin, 191e198 hanishin, 178e184 ichikawa synthesis, 168e169 massadine, 152e157 nagelamide D, 166e167 nickel borideecatalyzed reduction, 169e170 oroidin, 198e202 palau’amine, 157e165 sceptrin, 135e140 truncated pyrroleeimidazole alkaloids, 126e127 Pyrrolidine-flavoalkaloids, 86e90, 87f Pyrrolidinone-flavoalkaloids, 87f, 90e91, 92fe93f

R Rhazinilam analogs, 75e78, 76fe77f Rhazinilam-leuconoxine-mersicarpine triad aspidosperma alkaloids, 2, 6f biosynthesis, 9e16 biosynthetic proposal, 9e13 cyclization events, 14e15 dihydroxylation, 13e14 isolation, 2e6 (e)-leuconolam, 6e7, 6f, 15e16 formal and total syntheses, 16e66 (e)-leuconoxine, 6f, 7e8 leuconoxines, 39e50 N-acyliminium ion-mediated piperidine cyclization, 44e45 Aspidosperma alkaloids, 39 b-ketoester, 45e47 diphenylphosphoryl azide (DPPA), 47e49 hydroboration iodination, 39e40 imine heteroannulation, 49e50 2-iodoindole-3-ylacetate, 42e43 melodinine E, 40e41 Ruthenium-catalyzed oxidation, 47e49 ThorpeeIngold effect, 45e47 mersicarpine tert-butylindole-3-carboxylate, 52e53 DIBAL-H-mediated reductive ringexpansion reaction, 53 ethyl 2-ethylacetoacetate, 56e58 FriedeleCrafts acylation, 55e56 indoline, 52 indol-2-ylcarbinol, 55 ketoester, 53 ketone, 53e55 silyl vinyl ether, 55 (e)-mersicarpine, 6fe7f, 8 occurrence, 3te5t, 9, 10te12t perspectives, 78e79 pharmacology natural products, 66e69, 70te74t rhazinilam analogs, 75e78, 76fe77f plant origin, 2, 3te5t

236 Rhazinilam-leuconoxine-mersicarpine triad (Continued ) (e)-rhazinilam, 2e6, 6f rhazinilams, 16e38 aldehyde, 30 N-alkylated pyrrole, 33 axial-to-central chirality transfer, 21 g-butyrolactone, 31 2-carbomethoxy pyrrole, 20 chiral auxiliary, 17 dilauroyl peroxide (DLP), 34 dimethyl 4-ethyl-4-formylpimelate, 27 1,3-dipolar cycloaddition, 29 2-formylpyrrole, 34 hydrolysis, 31e32 ketone, 26, 31e32 lactone, 31e32 macrolactamization, 17 o-nitrocinnamyl bromide, 17e19 Pd-catalyzed asymmetric decarboxylative allylation, 30e31 potassium cyanide, 17e19 pyrrole, 31 pyrrole N-alkylation, 16e17 tetrahydroindolizidine, 33 tetrahydroindolizine, 30e31 tetrahydroindolizine motif, 24 tetrahydropyridine, 30 O-trimethylsilylquinine, 21 d-valerolactam, 19e20 VilsmeiereHaack formylation, 35 spectroscopy, 59, 60te68t unaltered tetrahydroindolizine ring system, 2e6 Ruthenium-catalyzed oxidation, 47e49

S Sceptrin, 135e140 Senecio argunensis, 91 Siempre verde, 99e100 Silyl vinyl ether, 55 Spectroscopy, 59, 60te68t

Index

Stylissa S. caribica, 124e125, 129e130, 210 S. massa, 126e127 Stylotella aurantium, 119e120 Subsequent FriedeleCrafts acylation, 88e89

T Teichaxinella morchella, 133 Thermovibrio ammonificans, 111e112 Thiocarbamate flavoalkaloids, 101e103, 102f ThorpeeIngold effect, 45e47 Total synthesis ageladine A, 186e188 ageliferin, 140e146 axinellamines, 146e152 cyclooroidin, 178e184 cyclopentene, 170 dibromoagelaspongin, 188e191 dibromophakellin, 191e198 dibromophakellstatin, 191e198 hanishin, 178e184 ichikawa synthesis, 168e169 massadine, 152e157 nagelamide D, 165e167 nickel borideecatalyzed reduction, 169e170 oroidin, 198e202 palau’amine, 157e165 sceptrin, 135e140 Trigonostemon reidioides, 95 Truncated pyrroleeimidazole alkaloids, 126e127

U Uncaria gambir, 96e97

V d-Valerolactam, 19e20 Vilsmeier-Haack formylation, 35 Vochysia guianensis, 86e88