Amino Acids: Insights and Roles in Heterocyclic Chemistry: Volume 2: Hydantoins, Thiohydantoins, and 2,5-Diketopiperazines 177491154X, 9781774911549

Table of contents :
Cover
Half Title
Title Page
Copyright Page
About the Author
Table of Contents
Abbreviations
Acknowledgments
Preface
1. Heterocyclic Compounds
2. Hydantoin
3. Thiohydantoins
4. 2,5-Diketopiperazine
Index

Citation preview

AMINO ACIDS

Insights and Roles in Heterocyclic Chemistry Volume 2 Hydantoins, Thiohydantoins, and 2,5-Diketopiperazines

Amino Acids: Insights and Roles in Heterocyclic Chemistry, 4-volume set ISBN: 978-1-77491-150-1 (hbk) ISBN: 978-1-77491-151-8 (pbk) ISBN: 978-1-00333-019-6 (ebk) Amino Acids: Insights and Roles in Heterocyclic Chemistry, Volume 1: Protecting Groups ISBN: 978-1-77491-152-5 (hbk)

ISBN: 978-1-77491-153-2 (pbk)

ISBN: 978-1-00332-979-4 (ebk)

Amino Acids: Insights and Roles in Heterocyclic Chemistry, Volume 2: Hydantoins, Thiohydantoins, and 2,5-Diketopiperazines ISBN: 978-1-77491-154-9 (hbk)

ISBN: 978-1-77491-155-6 (pbk)

ISBN: 978-1-00332-983-1 (ebk)

Amino Acids: Insights and Roles in Heterocyclic Chemistry, Volume 3: N-Carboxyanhydrides, N-Thiocarboxyanhydrides, Sydnones, and Sydnonimines ISBN: 978-1-77491-156-3 (hbk)

ISBN: 978-1-77491-157-0 (pbk)

ISBN: 978-1-00332-987-9 (ebk)

Amino Acids: Insights and Roles in Heterocyclic Chemistry, Volume 4: Azlactones and Oxazolidin-5-ones ISBN: 978-1-77491-158-7 (hbk)

ISBN: 978-1-77491-159-4 (pbk)

ISBN: 978-1-00333-015-8 (ebk)

AMINO ACIDS

Insights and Roles in Heterocyclic Chemistry Volume 2 Hydantoins, Thiohydantoins, and 2,5-Diketopiperazines

Zerong Wang, PhD

First edition published 2023 Apple Academic Press Inc. 1265 Goldenrod Circle, NE, Palm Bay, FL 32905 USA 760 Laurentian Drive, Unit 19, Burlington, ON L7N 0A4, CANADA

CRC Press 6000 Broken Sound Parkway NW, Suite 300, Boca Raton, FL 33487-2742 USA 4 Park Square, Milton Park, Abingdon, Oxon, OX14 4RN UK

© 2023 by Apple Academic Press, Inc. Apple Academic Press exclusively co-publishes with CRC Press, an imprint of Taylor & Francis Group, LLC Reasonable efforts have been made to publish reliable data and information, but the authors, editors, and publisher cannot assume responsibility for the validity of all materials or the consequences of their use. The authors, editors, and publishers have attempted to trace the copyright holders of all material reproduced in this publication and apologize to copyright holders if permission to publish in this form has not been obtained. If any copyright material has not been acknowledged, please write and let us know so we may rectify in any future reprint. Except as permitted under U.S. Copyright Law, no part of this book may be reprinted, reproduced, transmitted, or utilized in any form by any electronic, mechanical, or other means, now known or hereafter invented, including photocopying, microfilming, and recording, or in any information storage or retrieval system, without written permission from the publishers. For permission to photocopy or use material electronically from this work, access www.copyright.com or contact the Copyright Clearance Center, Inc. (CCC), 222 Rosewood Drive, Danvers, MA 01923, 978-750-8400. For works that are not available on CCC please contact [email protected] Trademark notice: Product or corporate names may be trademarks or registered trademarks and are used only for identification and explanation without intent to infringe. Library and Archives Canada Cataloguing in Publication Title: Amino acids : insights and roles in heterocyclic chemistry / Zerong Wang, PhD. Names: Wang, Zerong (Daniel Zerong), author. Description: First edition. | Includes bibliographical references and indexes. | Contents: Volume 2: Hydantoins, Thiohydantoins, and 2,5-Diketopiperazines. Identifiers: Canadiana (print) 20220276242 | Canadiana (ebook) 20220276269 | ISBN 9781774911501 (set) | ISBN 9781774911549 (v. 2 ; hardcover) | ISBN 9781774911556 v. 2 ; softcover) | ISBN 9781003329831 (v. 2 ; ebook) Subjects: LCSH: Heterocyclic compounds. | LCSH: Amino acids. Classification: LCC QD400 .W36 2023 | DDC 547/.59—dc23 Library of Congress Cataloging-in-Publication Data Names: Wang, Zerong (Daniel Zerong), author. Title: Amino acids : insights and roles in heterocyclic chemistry / Zerong Wang, PhD. Description: First edition. | Palm Bay, FL : Apple Academic Press, 2023- | Includes bibliographical references and index. |

Contents: Volume 1. Protecting groups -- Volume 2. Hydantoins, Thiohydantoins, and 2,5-Diketopiperazines -- Volume 3. N-Carboxyanhydrides, N-Thiocarboxyanhydrides, and Sydnones -- Volume 4. Azlactones and Oxazolidin-5-ones. | Summary: “This first-of-its-kind four-volume book series, Amino Acids: Insights and Roles in Heterocyclic Chemistry, provides readers with up-to-date information on alpha-amino acids, the potential challenges in working with alphaamino acids, the protecting groups for the carboxyl, amino and side chain groups of the amino acids, and the most popular heterocyclic compounds that are originating from alpha-amino acids. These heterocyclic compounds include hydantoins, thiohydantoins (including 2-thiohydantoins, 4-thiohydantoins, 2,4-dithiohydantoins), 2,5-diketopiperazines, N-carboxyanhydrides, N-thiocarboxyanhydrides, sydnones, sydnonimines, azlactones, pseudoazlactones, and oxazolidin5-ones. This is the first resource to comprehensively collect all the heterocycles that can be directly prepared from alphaamino acids. In addition, almost all kinds of synthetic methods for a particular type of heterocycles from alpha-amino acids are include, along with the detailed mechanistic discussions and experimental procedures. In Volume 2: Hydantoins, Thiohydantoins, and 2,5-Diketopiperazines, the author has compiled the three IUPAC accepted nomenclature systems for heterocyclic compounds, which will be very useful for readers working in heterocyclic chemistry for giving synthesized molecules their correct names. In addition, three groups of heterocyclic compounds, i.e., hydantoins, thiohydantoins (including 2-thiohydantoin, 4-thiohydantoin and 2,4-dithiohydantoin), and 2,5-diketopiperazines, have been organized with updated literature information. Particularly, all three groups of heterocyclic compounds have demonstrated many important biological activities, particularly anticancer and antibacterial activities. On the other hand, these three groups of heterocycles can be applied as substrates to make other chemical derivatives, particularly novel unnatural amino acids. All their reactivities have been compiled and updated. These will be very valuable for the readers who have been working in this area or have interest in this area”-- Provided by publisher. Identifiers: LCCN 2022033373 (print) | LCCN 2022033374 (ebook) | ISBN 9781774911501 (set ; hardback) | ISBN 9781774911518 (set ; paperback) | ISBN 9781774911525 (volume 1 ; hardback) | ISBN 9781774911532 (volume 1; paper­ back) | ISBN 9781774911549 (volume 2 ; hardback) | ISBN 9781774911556 (volume 2 ; paperback) | ISBN 9781774911563 (volume 3 ; hardback) | ISBN 9781774911570 (volume 3 ; paperback) | ISBN 9781774911587 (volume 4 ; hardback) | ISBN 9781774911594 (volume 4 ; paperback) | ISBN 9781003330196 (set ; ebook) | ISBN 9781003329794 (volume 1 ; ebook) | ISBN 9781003329831 (volume 2 ; ebook) | ISBN 9781003329879 (volume 3 ; ebook) | ISBN 9781003330158 (volume 4 ; ebook) Subjects: LCSH: Amino acids. | Heterocyclic compounds. Classification: LCC QD431 .W36 2023 (print) | LCC QD431 (ebook) | DDC 547/.7--dc23/eng20220917 LC record available at https://lccn.loc.gov/2022033373 LC ebook record available at https://lccn.loc.gov/2022033374 ISBN: 978-1-77491-154-9 (hbk) ISBN: 978-1-77491-155-6 (pbk) ISBN: 978-1-00332-983-1 (ebk)

About the Author

Zerong Wang, PhD Professor of Chemistry, College of Science and Engineering, University of Houston–Clear Lake, Texas Zerong Wang, PhD, is a full Professor at the University of Houston-Clear Lake, Texas. Prior to that, he worked at the Institute for Biological Sciences of the National Research Council of Canada for several years. Through his career, the author has gained specific training and expertise in organic chemistry, particularly in physical organic chemistry and other subdisciplines that include photochemistry, spectroscopies, carbohydrate chemistry, sulfur chemistry, nucleosides and heterocycles, material science, reaction methodology, computational chemistry, among other. Dr. Wang has developed research projects relating to sulfur chemistry, computational chemistry, nucleoside analogs, heterocycle chemistry, materials science, and macromolecules (pillarene, calix[n]arene, and melamine-based dendrimers, etc.) and has received 22 research grants, including from NSF-MRI, NSFSTEM, Welch Research Grant, Welch Departmental Research Grant, and University of Houston-Clear Lake’s Faculty Research and Support Fund (FRSF) Grants. The author has developed two compendiums in organic chemistry: Comprehensive Organic Named Reactions, with Detailed Mechanism Discussions and Updated Experimental Procedures (3 volumes) (Wiley, 2009) and Encyclopedia of Physical Organic Chemistry (6 volumes) (Wiley, 2017), the PROSE Award winner in 2018. While conducting research activities, the author also teaches courses for both graduate and undergraduate students. To date, the author has taught courses on General Chemistry, General Chemistry Laboratory, Analytical Chemistry, Quantitative Chemical Analysis, Forensic Chemistry, Organic Chemistry, Organic Chemistry Laboratory, Advanced Organic Chemistry, Physical Organic Chemistry, Synthetic Organic Chemistry, Organometallic Chemistry, Biochemistry, Biochemistry Laboratory, Polymer Chemistry, Introduction to Chemical Engineering, Nutrition and Diet Chemistry, Green Chemistry, Introduction to NMR Spectroscopy, Chemistry Seminar, Graduate Research, and Chemistry for Non-Science Majors.

vi

About the Author

Dr. Wang earned his BS degree in Chemistry from Lanzhou University, PR China, and earned his MS and PhD degrees from the Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences. He conducted his post­ doctoral research at the Department of Chemistry, University of California Berkeley and York University (Canada).

Contents

Abbreviations .......................................................................................................... ix

Acknowledgments................................................................................................... xv

Preface ................................................................................................................. xvii

1.

Heterocyclic Compounds................................................................................. 1

2.

Hydantoin....................................................................................................... 39

3.

Thiohydantoins ............................................................................................ 117

4.

2,5-Diketopiperazine.................................................................................... 221

Index .................................................................................................................... 385

Abbreviations

AD ADMET ADT AITC ALS ALSR AR ATR-FTIR BAL BEMP BOP BOP-Cl BSA BTCA CDD CDI CDPS CMIA COMU COX CPG CRPC CS2 CVA21 DABCO DABITC DCC DCM

Alzheimer’s disease absorption, distribution, metabolism, elimination,

toxicity androgen deprivation therapy allyl isothiocyanate amyotrophic lateral sclerosis addition-cure liquid silicone rubber androgen receptor attenuated total reflectance Fourier transform infrared spectroscopy backbone amide linker 2-tert-butylimino-2-diethylamino-1,3-dimethylper­ hydro-1,3,2-diazaphosphorine (benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate bis(2-oxooxazolidin-3-yl)phosphinic chloride bovine serum albumin 1,2,3,4-butanetetracarboxylic acid cyclododecanone 1,1’-carbonyldiimidazole cyclodipeptide synthase carbonyl metallo immuno assay 1-[(1-(cyano-2-ethoxy-2-oxoethylideneaminooxy) dimethylaminomorpholino)]uronium hexafluoro-phosphate cyclooxygenase controlled pore glass castration-resistant prostate cancer carbon disulfide coxsackievirus-A21 1,4-diaza-bicyclo[2,2,2]octane 4-N,N-dimethylaminoazobenzene 4’-isothiocyanate dicyclohexylcarbodiimide dichloromethane

x

DCU DFT DHODH DIC DIEPA DKPs DMAP DMBA DMF DMHP DNITC DPTH DSC ECD EDC EDCI EEDQ EPN ETP FMN FMNH2 FPTase FT-IR GC/MS GC-NICI-MS GHIH GHRIH HABA HAPyU HATU HBTU HCTU HDAC6 hDHODH

Abbreviations

dicyclohexylurea density functional theory dihydroorotate dehydrogenase diisopropylcarbodiimide diisopropylethylamine 2,5-diketopiperazines 4-dimethyl-aminopyridine 7,12-dimethylbenz[a]anthracene N,N-dimethylformamide 5,5-dimethylhydantoin polyepoxide dimethylamino-1-naphthyl isothiocyanate 5,5-diphenyl-2-thiohydantoin differential scanning calorimetry electronic circular dichroism 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide ethyl-3-(3-dimethyl-aminopropyl)-carbodiimide N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline entomopathogenic nematodes epipolythiodioxopiperazine flavin mononucleotide dihydroflavin mononucleotide farnesyl protein transferase Fourier transform infrared spectroscopy gas chromatography/mass spectrometry gas chromatography-negative ion chemical ionizationmass spectrometry growth hormone-inhibiting hormone growth hormone release-inhibiting hormone (hydroxylamino)barbituric acid hexafluorophosphate O-(7-azabenzotriazol-1-yl)-N,N,N’,N’-tetramethylu­ ronium hexafluorophosphate O-(benzotriazol-1-yl)-N,N,N’,N’-tetramethyluronium hexafluoro-phosphate O-(6-chlorobenzotriazol-1-yl)-N,N,N’,N’-tetramethylu­ ronium hexafluorophosphate histone deacetylase 6 human dihydroorotate dehydrogenase

Abbreviations

HEICPSTH HIV-1 PR HOAt HOBt HONB HSV HTop1 HUVEC IDH IDO IQ IUPAC KSCN LC/MS LPS MDR MES MIC MRSA MRSE MTBI MTH-trp NaBH(OAc)3 NCA NCS NFTs NH4CN NH4SCN NMR NRPS NSAIDs OG PAI-1 PAI-2 PBS PCa PCl5 PD

xi

4-(2-hydroxyethylimino)-cyclopentanespiro-5-(2-thio­ hydantoin) HIV-1 PR aspartic proteinase 1-hydroxy-7-aza-benzotriazole 1-hydroxy-benzotiazole N-hydroxy-5-norbornene-2,3-dicarboxylic acid imide herpes simplex virus human Top1 human umbilical venous endothelial cells isocitrate dehydrogenase indoleamine 2,3-dioxygenase quinoline International Union of Pure and Applied Chemistry potassium thiocyanate liquid chromatography/mass spectrometry lipopolysaccharide multi-drug resistance maximal electroshock seizure minimum inhibitory concentration methicillin-resistant Staphylococcus aureus methicillin-resistant Staphylococcus epidermidis 4-(methylthio)-3-butenyl isothiocyanate methylthiohydantoin-tryptophan sodium triacetoxyborohydride N-carboxyanhydride N-chlorosuccinimide numerous neurofibrillary tangles ammonium cyanide α-amino acid and ammonium thiocyanate nuclear magnetic resonance non-ribosomal peptide synthetases non-steroidal anti-inflammatory drugs 8-oxo-7,8-dihydroguanine plasminogen activator inhibitor-1 plasminogen activator inhibitor-2 phosphate-buffered saline prostate cancer phosphorus pentachloride Parkinson’s disease

xii

PDE PDE5 PEG PGE2 PMH PMT PNT PNW POCl3 PS PSIBLAST PSMs PTC PTGS PV PXRD PyAOP PyBOP PyBrOP RIPK RONS ROS SEM SOCl2 SPE SPPS SPs SRIF SRIH SS NMR SST4 TACE TATU TBAB

Abbreviations

phosphodiesterase phosphodiesterase type 5 polyethylene glycol prostaglandin E2 phenylmethylene hydantoins peptide microtubes peptide nanotubes peptide nanowires phosphorus oxychloride polystyrene position-specific iterative basic local alignment search tool polymer surface modifiers phenylthiocarbamyl prostaglandin-endoperoxide synthase poliovirus powder X-ray diffraction (7-azabenzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate bromotri(pyrrolidin-1-yl)phosphonium hexafluorophosphate receptor-interacting protein kinase reactive oxygen and nitrogen species reactive oxygen species spectroscopy, scanning electron microscopy thionyl chloride solid-phase extraction solid-phase peptide synthesis senile plaques somatotropin release-inhibiting factor somatotropin release-inhibiting hormone solid state NMR somatostatin subtype 4 tumor necrosis factor-alpha converting enzyme O-(7-azabenzotriazol-1-yl)-N,N,N’,N’-tetra-methylu­ ronium tetrafluoroborate tetrabutylammonium bromide

Abbreviations

TBAI TBTU

xiii

tetrabutylammonium iodide O-(benzotriazol-1-yl)-N,N,N’,N’-tetramethyluronium tetra-fluoroborate TBuS-ITC tributylsilyl isothiocyanate TDBTU N,N,N’,N’-tetramethyl-O-(3,4-dihydro-4-oxo-1,2,3-ben­ zotriazin-3-yl)uronium tetrafluoroborate TLC thin layer chromatography TMOF trimethyl orthoformate TMP 2,4,6-trimethylpyridine TMSCN trimethylsilanecarbonitrile TMSOTf trimethylsilyl trifluoromethanesulfonate TNF tumor necrosis factor TNF-α tumor necrosis factor-alpha TNTU O-(5-norbornene-2,3-dicarboximido)-N,N,N’,N’tetramethyl-uronium tetrafluoroborate TPTU O-(1,2-dihydro-2-oxo-1-pyridyl-N,N,N’,N’-tetramethyl­ uronium tetrafluoroborate TRH thyrotropin-releasing hormone TSH thyroid-stimulating hormone TSTU O-(N-succinimidyl)-1,1,3,3-tetramethyl-uronium tetrafluoro-borate UHPLC-MS/MS ultra-high pressure liquid chromatography coupled to high resolution mass spectrometry VEGF vascular endothelial growth factor VREF vancomycin-resistant Enterococcus faecalis

Acknowledgments

Writing this book series was harder than I expected, even though I had already been through this process for my three-volume book, Comprehensive Organic Named Reactions, with Detailed Mechanism Discussions and Updated Experimental Procedures (2009, ISBN: 978-0-471-70450-8), as well as in editing the six-volume set, Encyclopedia of Physical Organic Chemistry (2017, ISBN: 978-1-118-47045-9), winner of 2018 PROSE Award for Multivolume Reference/Science. I’m eternally grateful to my wife, Xi Liu, and my daughter, Izellah, who have taken care of me so that I could focus on this book series in my spare time. It would not have been possible to complete these five books without their long-time support. A very special thanks to our librarians in the Newman Library of the University of Houston-Clear Lake, who helped me locate necessary references in a timely manner. Finally, I thank my colleagues and friends who have provided me with endless guidance.

Preface

This is the second book in the monograph series regarding a-amino acids and their simple heterocyclic derivatives. In general, four types of heterocyclic compounds can be formed from α-amino acids: ones with the heterocyclic ring formed from both the amino and carboxyl groups of amino acids, ones with the heterocyclic ring containing both the side chain functional group and either the carboxyl or the amino group, ones with the heterocyclic rings arising from either the amino group or the carboxyl group of amino acids, and lastly the heterocycles with the ring being generated from the side chain functional group only. This book series will be focused on the first type. The four chapters included in this book detail heterocyclic compounds, hydan­ toins, thiohydantoins, and 2,5-diketopiperazines. The book begins with a brief introduction on heterocyclic compounds in order to provide readers clarification on this type of molecule. Current book series and compendiums on heterocyclic compounds have also been compiled and summarized to provide easy access to additional resources. The nomenclature methods for heterocycles that are accepted by the Inter­ national Unione of Pure and Applied Chemistry (IUPAC), which include the commonly used Hantzsch-Widman nomenclature, common names and replacement nomenclature, have also been outlined. Chapter 2 focuses on hydantoins, the derivatives of a-amino acids, and a type of five-membered heterocycles of dense functional groups, including the carbonyl, amino, amido, imido, and urea groups. At the same time, it is only composed of a simple five-membered cyclic structure, as many as 32 synthetic approaches have been collected for this type of heterocycles, along with a general mechanism for its formation and several practical experimental procedures. Their biological activities as agonists and antago­ nists of protein receptors, inhibitors of proteins as well as anticancer and antimicrobial agents and medical applications, as well as other applications as the complexing agent in gold/silver electroplating environment, cosmetic preservatives, antibacterial agents, among others, have been detailed in this chapter. Chapter 3 involves thiohydantoins, the hydantoin analogs with one or both carbonyl oxygen atoms substituted with sulfur (e.g., 2-thiohydantoins, 4-thiohyantoins, and 2,4-dithiohydantoins). 2-Thiohydantoins are the most

xviii

Preface

common thiohydantoins, thus unless specified, mentions of thiohydantoins in this book refer to 2-thiohydantoins, which have properties similar to that of hydantoins. The preparative methods for 2-thiohydantoins, 4-thiohydan­ toins, and 2,4-dithiohydantoins have been compiled, with key experimental procedures. The chapter also covers the corresponding reactions of 2-thio­ hydantoins and 4-thiohydantoins, including the formation of 5-arylidene2-thiohydantoins, N- or S-alkylated 2-thiohydantoins, participation of 2-thiohydantoins in Diels-Alder reactions, Mannich reactions, as well as multi-component reactions and reductions. The final chapter details 2,5-diketopiperazines (DKPs), six-membered heterocycles are arising from the condensation of two a-amino acids. 2,5-Diketopiperazines are essentially cyclic dipeptides, which widely exist in nature due to their easy formation from the cyclization of two adjacent peptide fragments within proteins and/or peptides. More than 200 trypto­ phan, phenylalanine, or tyrosine-containing DKPs with associated biological activities have been assembled in different tables in this chapter. In addition, different preparation methods for DKPs, as well as the individual chemical reactivities at the 1,4-, 2,5- and 3,6-positions of DKPs have been summa­ rized, along with additional reactions for arylidene/alkylidene-DKPs. Overall, these three types of simple heterocycles (i.e., hydantoins, thiohydantoins, and 2,5-diketopiperazines) can be used in the preparation of unnatural amino acids. 2,5-Diketopiperazines, in particular, have been extensively explored as the Schöllkopf compounds for the synthesis of novel amino acids.

CHAPTER 1

Heterocyclic Compounds

1.1 INTRODUCTION TO HETEROCYCLIC COMPOUNDS Organic molecules are carbon-based compounds, for which over thousands of carbon atoms can be catenated in a linear or branched shape to form polymers or graphenes and carbon-nanotubes, or a few carbon atoms connecting together to form small organic compounds. Among the small organic molecules, when carbon atoms are linked together to form a ring-shaped structure, they are called cyclic molecules or carbocycles. Carbocycles can have as less as three to as many as more than 20 carbon atoms on one ring, or have more than one ring that shares one or more than one carbon atom. The small carbocycles such as cyclopropane or cyclobutane normally have ring strains, due to the deviation of the bond angles on the ring away from the typical bond angle of 109.5°. Similarly, when unsaturated double bond or triple bond is introduced into the carbocycles, potential ring strain may also arise due to the specific requirement of the bond angles for the corresponding double bond (120°) and triple bond (180°), resulting in strained carbocycles [1]. When carbocycles have only one cyclic structure, they are called monocyclic compounds. In contrast, carbocycles with more than one cyclic structure are known as polycyclic compounds or molecules, where the cyclic compounds with two rings that only share one common carbon atom are known as spiro-carbocycles [2], whereas the carbocycles with at least two rings sharing one common C-C bond (single or double bond) are classified as fused cyclic molecules [3], and the carbocycles with two rings sharing two carbon atoms instead of C-C bond are known as the bridged cyclic compounds [4]. Representative examples of a monocyclic compound and the three different carbocycles are displayed in Figure 1.1. All these cyclic molecules can be saturated or unsaturated. Many of the highly unsaturated carbocycles belong to aromatic compounds, for which the alternated double bonds and single bonds exist between carbon atoms on the coplanar ring(s) and the number of p electrons follows the Hückel’s rule (i.e., the p electrons = 4n + 2, where n = 0, 1, …) [5].

2

Amino Acids: Insights and Roles in Heterocyclic Chemistry, Volume 2

FIGURE 1.1 Different types of carbocyclic compounds.

Besides the pure carbocycles, organic molecules with cyclic structures exist more often as heterocycles or heterocyclic compounds, with at least one carbon atom on the rings being replaced with other elements, such as oxygen, nitrogen, sulfur, etc. The importance of replacing carbon atom(s) on the cyclic molecules can be rationalized by the fact that heterocyclic compounds exist widely as the primary metabolites, which are the building blocks of the four major macromolecules within the body, i.e., carbohy­ drates, lipids, proteins, and nucleic acids (DNA and RNA); as well as the secondary metabolites which have an even more diverse structural scaf­ folds, including alkaloids (e.g., morphine [6]), polyketides (e.g., Aflatoxin B1 [7], Jadomycin B [8]) and terpenoids (e.g., taxol [9] and limonin [10]), etc. (Figure 1.2). While all these structures demonstrate fused ring structures, taxol, and morphine also show bridged structural scaffolds, and limonin and another secondary metabolite griseofulvin [11] show spiral architectures. In addition to their wide distribution in natural products, heterocycles have been commonly used in the pharmaceutical/medicinal/agrochemical industry, for the following reasons. First of all, the cyclic structures in general would hold the geometries of molecules much better than the noncyclic structures as the latter have to fold into a specific conformation in order to achieve a complementary fit of pharmaceutical molecules to the binding site of proteins. Secondly, the heterocyclic molecules with carbon atoms replaced with other nonmetal elements (e.g., nitrogen, oxygen, sulfur) of higher electronegativity naturally introduce polarity into the molecules, which may facilitate the interaction between drug molecules and proteins due to the complementary match of polarity, hydrogen bonding and charge, which are absent in the purely carbocyclic molecules (totally non-polar in nature). Moreover, the heterocyclic moiety can function as an isosteric replacement of functional groups, alicyclic rings, or other heterocyclic rings to modify and optimize the expected biological properties of heterocyclic compounds. Furthermore, the presence of heteroatoms within the hetero­ cycles provides an opportunity to balance the lipophilicity and solubility

Heterocyclic Compounds

3

of the said heterocycles to the optimal level for the sake of pharmaceutical uptake and bioavailability. In addition, the presence of heteroatoms greatly enhances the availability of the heterocycles from the synthetic chemistry point of view, as the carbon-heteroatom bond is often the dissection point in the retrosynthetic design. Typically, the formation of a of carbon-heteroatom bond can be performed under less harsh conditions than the formation of a purely carbon-carbon bond in most synthetic practices. As a result, it is reported that approximately 70% of all the 2,400 pharmaceuticals listed in the online version of “Pharmaceutical Substances” bear at least one hetero­ cyclic ring [12], and a similar percentage of more than 1,000 agrochemicals listed on “Pesticide Manual” also are heterocyclic compounds. [13, 14] Interestingly, cheminformatic comparison between the structures of the 1,478 pesticides with clinical drug molecules based on physicochemical properties, usage frequency of molecular fragments, and chemical space distribution indicates that the pesticides generally possess lower molecular weights, higher lipid solubility, and significantly more F, Cl, and P atoms with respect to drug molecules [15]. This result also supports the necessity to replace the carbon with an alternative atom in order to achieve certain unique properties.

FIGURE 1.2 Representative secondary metabolites.

4

Amino Acids: Insights and Roles in Heterocyclic Chemistry, Volume 2

On the other hand, heterocyclic compounds provide the most diverse structural scaffolds to the pool of organic molecules, in terms of the varia­ tions in the size of rings, the replacement of one or more than one carbon atoms with different elements, degree of unsaturation, the connection mode (spiro, fused or bridged) of different rings, or any of these combinations. Such variations lead to the high complexity of nomenclature rules on hetero­ cyclic compounds. 1.2 SUMMARY OF LITERATURE REVIEWS ON HETEROCYCLES Due to the very high complexity in heterocyclic structures, as well as their wide applications in pharmaceutical, medicinal, and agrochemical indus­ tries, the literature relating to heterocycles has been extensively reviewed and constantly updated. Therefore, it is impossible to review all heterocycles within a short chapter, and the goal of this section is to provide readers a glimpse of different collections regarding heterocycles so that the readers can easily find multiple review articles for a unique type of heterocycles. The overall reviews on heterocycles can be classified into four categories: (a) compendium series, (b) chronological monographs, (c) individual books, and (d) extensive review articles on various journals. The most compre­ hensive summary of heterocycles should be the compendium series led by the late Alan R. Katritzky (Executive Editor), and three Editor-in-Chiefs (Christopher A. Ramsden, Eric F. V. Scriven, Richard J. K. Taylor) entitled “Comprehensive Heterocyclic Chemistry III,” with over 250 specialist reviews in 15 volumes, which was published in 2008 by ©Elsevier Limited (ISBN: 978-0-08-044992-0) after its initial publication in 1984. The topics related to the heterocycles covered in the individual volumes are listed below, which are further edited by well-known scientists as the volume editors, as listed in Table 1.1. TABLE 1.1 The Basic Volume Information for “Comprehensive Heterocyclic Chemistry III” Volume

Volume Title

Editors

1

Three-membered heterocycles, together with all fused systems containing a three-membered heterocyclic ring

Albert Padwa

2

Four-membered heterocycles together with all fused systems containing a four-membered heterocyclic ring

Christian V. Stevens

Heterocyclic Compounds

5

TABLE 1.1 (Continued) Volume

Volume Title

Editors

3

Five-membered rings with one heteroatom together with their benzo and other carbocyclic-fused derivatives

Gurnos Jones; Christopher A. Ramsden

4

Five-membered rings with two heteroatoms, each with their fused carbocyclic derivatives

John Arthur Joule

5

Five-membered rings: Triazoles, oxadiazoles, thiadiazoles, and their fused carbocyclic derivatives

Viktor V. Zhdankin

6

Other five-membered rings with three or more heteroatoms, and their fused carbocyclic derivatives

Viktor V. Zhdankin

7

Six-membered rings with one heteroatom, and their fused carbocyclic derivatives

David Black

8

Six-membered rings with two heteroatoms, and their fused carbocyclic derivatives

Alan Aitken

9

Six-membered rings with three or more heteroatoms, and their fused carbocyclic derivatives

Kenneth Turnbull

10

Ring systems with at least two fused heterocyclic fiveor six-membered rings with no bridgehead heteroatom

Ray Jones

11

Bicyclic 5–5 and 5–6 fused ring systems with at least one bridgehead (ring junction) N

Janine Cossy

12

Five- and six-membered fused systems with bridgehead (ring junction) heteroatoms concluded: 6–6 bicyclic with one or two N or other heteroatoms; polycyclic; spirocyclic

Keith Jones

13

Seven-membered heterocyclic rings and their fused derivatives

George R. Newkome

14

Eight-membered and larger heterocyclic rings and their fused derivatives, other seven-membered rings

George R. Newkome

15

Ring index (prepared by George Nikonov, with assistance of Alfred L. Finocchio)

–

Comparing to this latest version, there were only 11 volumes collected in the second edition of this compendium series (ISBN: 978-0-08-096518-5, by ©Elsevier Science Ltd, 1996), edited by Alan R. Katritzky, Charles W. Rees and Eric F. V. Scriven. This second version of the compendium updated the literature between 1982 and 1995. The volume titles of this series are listed in Table 1.2.

6

Amino Acids: Insights and Roles in Heterocyclic Chemistry, Volume 2

TABLE 1.2 The Basic Volume Information for “Comprehensive Heterocyclic Chemistry II” Volume

Volume Title

1A

Three-membered rings, with all fused systems containing three-membered rings

1B

Four-membered rings, with all fused systems containing four-membered rings

2

Five-membered rings with one heteroatom and fused carbocyclic derivatives

3

Five-membered rings with two heteroatoms and fused carbocyclic derivatives

4

Five-membered rings with more than two heteroatoms and fused carbocyclic derivatives

5

Six-membered rings with one heteroatom and fused carbocyclic derivatives

6

Six-membered rings with two or more heteroatoms and fused carbocyclic derivatives

7

Fused five- and six-membered rings without ring junction heteroatoms

8

Fused five- and six-membered rings with ring junction heteroatoms

9

Seven-membered and larger rings and fused derivatives

10

Author and ring indexes

In addition to this important and comprehensive summary about heterocycles, the representative chronological monographs on heterocyclic compounds can be found in a series of “Topics in Heterocyclic Chemistry” published by ©Springer since 2006, which presents critical reviews on present and future trends for the research of heterocyclic compounds. As of the time in preparation of this book, 57 volumes of monographs have been published already, and the basic information of these 57 volumes are listed in Table 1.3. TABLE 1.3 The Basic Volume Information of the “Topics in Heterocyclic Chemistry” Volume

Title

Editor(s)

Year

1

Microwave-Assisted Synthesis of Heterocycles

Erik Van der Eycken; C. Oliver Kappe

2006

2

Heterocyclic Antitumor Antibiotics

Moses Lee

2006

3

QSAR and Molecular Modeling Studies in Heterocyclic Drugs I

Satya Prakash Gupta

2006

4

QSAR and Molecular Modeling Studies in Heterocyclic Drugs II

Satya Prakash Gupta

2006

5

Marine Natural Products

Hiromasa Kiyota

2006

6

Bioactive Heterocycles I

Shoji Eguchi

2006

Heterocyclic Compounds

7

TABLE 1.3 (Continued) Volume

Title

7

Heterocycles from Carbohydrate El Sayed H. El Ashry Precursors

Editor(s)

Year 2007

8

Bioactive Heterocycles II

Shoji Eguchi

2007

9

Bioactive Heterocycles III

Mahmud Tareq Hassan Khan

2007

10

Bioactive Heterocycles IV

Mahmud Tareq Hassan Khan

2007

11

Bioactive Heterocycles V

Mahmud Tareq Hassan Khan

2007

12

Synthesis of Heterocycles via Cycloadditions I

Alfred Hassner

2008

13

Synthesis of Heterocycles via Cycloadditions II

Alfred Hassner

2008

14

Heterocyclic Polymethine Dyes: Synthesis, Properties, and Applications

Lucjan Strekowski

2008

15

Bioactive Heterocycles VI: Flavonoids and Anthocyanins in Plants, and Latest Bioactive Heterocycles I

Noboru Motohashi

2008

16

Bioactive Heterocycles VII: Flavonoids and Anthocyanins in Plants, and Latest Bioactive Heterocycles II

Noboru Motohashi

2009

17

Heterocyclic Supramolecules I

Kiyoshi Matsumoto

2008

18

Heterocyclic Supramolecules II

Kiyoshi Matsumoto; Naoto Hayashi

2009

19

Aromaticity in Heterocyclic Compounds

Tadeusz M. Krygowski; Michał K. Cyrański

2009

20

Phosphorous Heterocycles I

Raj K. Bansal

2009

21

Phosphorous Heterocycles II

Raj K. Bansal

2010

22

Heterocyclic Scaffolds I: b-Lactams

Bimal K. Banik

2010

23

Synthesis of Heterocycles via Multicomponent Reactions I

Romano V. A. Orru; Eelco Ruijter

2010

24

Anion Recognition in Supramolecular Chemistry

Philip A. Gale; Wim Dehaen

2010

25

Synthesis of Heterocycles via Multicomponent Reactions II

Romano V. A. Orru; Eelco Ruijter

2010

26

Heterocyclic Scaffolds II: Reactions and Applications of Indoles

Gordon W. Gribble

2010

8

Amino Acids: Insights and Roles in Heterocyclic Chemistry, Volume 2

TABLE 1.3 (Continued) Volume

Title

Editor(s)

Year

27

Halogenated Heterocycles: Synthesis, Application, and Environment

Jernej Iskra

2012

28

Click Triazoles

Janez Košmrlj

2012

29

Metalation of Azoles and Related Five-Membered Ring Heterocycles

Gordon W. Gribble

2012

30

β-Lactams: Unique Structures of Bimal K. Banik Distinction for Novel Molecules

2013

31

Metalation of Azines and Diazines

Michael Schnürch; Marko D. Mihovilovic

2013

32

Synthesis of Heterocycles via Metal-Catalyzed Reactions that Generate One or More CarbonHeteroatom Bonds

John P. Wolfe

2013

33

Synthesis and Modifications of Porphyrinoids

Roberto Paolesse

2014

34

Applications of Porphyrinoids

Roberto Paolesse

2014

35

Synthesis of Saturated Oxygenated Heterocycles I: 5and 6-Membered Rings

Janine Cossy

2014

36

Synthesis of Saturated Oxygenated Heterocycles II: 7to 16-Membered Rings

Janine Cossy

2014

37

Metal-Free C-H Functionalization of Aromatics: Nucleophilic Displacement of Hydrogen

Valery Charushin; Oleg Chupakhin 2014

38

Structure, Bonding, and Reactivity of Heterocyclic Compounds

Frank De Proft; Paul Geerlings

2014

39

Thiophenes

John A. Joule

2015

40

Chemistry of 1,2,3-Triazoles

Wim Dehaen; Vasiliy A. Bakulev

2015

41

Synthesis of 4- to 7-Membered Heterocycles by Ring Expansion: Aza-, Oxa-, and Thiaheterocyclic Small-Ring Systems

Matthias D’hooghe; Hyun-Joon Ha

2016

42

Transition Metal Catalyzed Carbonylative Synthesis of Heterocycles

Xiao-Feng Wu; Matthias Beller

2016

Heterocyclic Compounds

9

TABLE 1.3 (Continued) Volume

Title

Editor(s)

Year

43

The Chemistry of Benzotriazole Derivatives: A Tribute to Alan Roy Katritzky

Jean-Christophe M. Monbaliu

2016

44

Synthesis of Heterocycles in Contemporary Medicinal Chemistry

Zdenko Časar

2016

45

Synthesis and Modification of Heterocycles by MetalCatalyzed Cross-coupling Reactions

Tamás Patonay; Krisztina Kónya

2016

46

Au-Catalyzed Synthesis and Functionalization of Heterocycles

Marco Bandini

2016

47

Synthesis of Heterocycles by Metathesis Reactions

Joëlle Prunet

2017

48

Peptidomimetics I

William D. Lubell

2017

49

Peptidomimetics II

William D. Lubell

2017

50

Guanidines as Reagents and Catalysts I

Philipp Selig

2017

51

Guanidines as Reagents and Catalysts II

Philipp Selig

2017

52

Solid-Phase Synthesis of Nitrogenous Heterocycles

Viktor Krchňák

2017

53

Heterocyclic N-Oxides

Oleg V. Larionov

2017

54

Free-Radical Synthesis and Functionalization of Heterocycles

Yannick Landais

2018

55

Heterocycles as Chiral Auxiliaries in Asymmetric Synthesis

Manfred Braun

2020

56

Flow Chemistry for the Synthesis of Heterocycles

Upendra K. Sharma; Erik V. Van der Eycken

2018

57

Carbohydrate-SpiroHeterocycles

László Somsák

2019

Another series of chronological monographs named “Advances in Heterocyclic Chemistry” was launched by ©Elsevier Inc. in 1963, and there have been a total of 133 volumes published so far. The basic information of this book series is provided in Table 1.4. In addition, ©Elsevier Inc. has collected another monograph series of heterocyclic compounds known as

10

Amino Acids: Insights and Roles in Heterocyclic Chemistry, Volume 2

“Progress in Heterocyclic Chemistry” that provides a critical review of heterocyclic literature published in the previous year. This series has been launched in 1989, for which H. Suschitzky and E. F. V. Scriven were the editors for volume 1 to volume 7, H. Suschitzky and Gordon W. Gribble were the editors for volume 8 in 1996, Gordon W. Gribble and Thomas L. Gilchrist were the editors for volume 9 to volume 14 from 1997 to 2002, and then Gordon W. Gribble and John A. Joule have been the editors from volume 15 to 32 between 2003 and 2021. TABLE 1.4 The Publication Year and Length of Individual Volumes in “Advances in Heterocyclic Chemistry” Year

Volume*

Pages

Year

Volume*

Pages

Year

Volume* Pages

1963

1

476

1989

45

349

2006

90

350

46

339

91

314

47

467

92

267

2

458

1964

3

421

1965

4

462

48

393

93

223

5

395

49

474

94

317

1966

6

468

50

320

95

268

1967

7

511

51

301

2008

96

241

8

407

1991

52

304

2009

97

410

1968

9

491

1992

53

429

98

328

1969

10

348

54

452

99

284

1970

11

568

55

358

100

280

12

339

56

428

101

238

1971

13

439

57

411

102

300

1972

14

407

58

345

103

283

1973

15

350

59

369

104

502

1974

16

349

60

462

17

360

61

328

1975

18

486

62

418

1976

19

376

63

401

20

324

64

21

486

65

1977

1990

1993

1994

1995

1996

2007

2010

2011

105

369

106

239

107

231

108

300

368

109

326

374

110

246

2012

2013

1978

22

437

66

403

111

281

1979

23

387

67

438

112

246

24

461

68

432

113

317

1997

2014

Heterocyclic Compounds

11

TABLE 1.4 (Continued) Year

Volume*

Pages

Volume*

Pages

Year

Volume* Pages

1980

25

397

69

477

2015

114

392

26

247

70

508

115

354

27

331

71

378

116

364

28

367

72

412

117

376

29

405

73

395

118

314

30

408

74

253

119

326

31

350

75

389

120

352

32

404

76

323

121

302

33

336

77

394

122

324

34

450

78

313

123

370

35

456

79

318

124

336

36

416

80

324

125

365

37

368

81

303

126

262

1985

38

374

82

305

127

398

1986

39

393

83

257

128

576

40

320

84

353

129

426

41

376

85

380

130

367

42

410

86

358

131

420

43

353

44

396

1981

1982

1983 1984

1987 1988

Year

1998 1999

2000 2001

2002 2003

2005

2016

2017

2018

2019

2020

87

398

132

479

88

323

133

293

89

280

*Note: Alan R. Katritzky was the editor for Volumes 1–5, 30–46, 48–73, 75–113. Alan R. Katritzky and A. J. Boulton were the editors for Volumes 6–29. Alan R. Katritzky and Roger Taylor were the editors for Volume 47. Henk C. van der Plas was the editor for Volume 74. Eric F.V. Scriven, Christopher A. Ramsden are the editors for Volumes 114–133.

Similarly, John Wiley and Sons© has published a series of monographs known as “The Chemistry of Heterocyclic Compounds” since 1951 (Series online ISSN: 1935–4665, series DOI: 10.1002/Series 1079). This book series is distinctly different from the above two monograph series, as all aspects of a specific ring system, including its properties, synthesis, reactions, physiological, and industrial significance have been discussed in a specific volume. Additional literature information about the specific ring system after its initial publications have been updated in the supplementary volumes. As of today, there have been 64 volumes published already, where the contents

12

Amino Acids: Insights and Roles in Heterocyclic Chemistry, Volume 2

have been distributed in 101 books, and one cumulative index. This book series has collected approximately 2,700 systems of heterocycles [16]. The basic information of these book series is listed in Table 1.5. TABLE 1.5 The Basic Volume Information of the “The Chemistry of Heterocyclic Compounds” Volume

Topics

Editor(s)

Year

1

The Heterocyclic Derivatives of Phosphorous, Arsenic, Antimony, and Bismuth

F. G. Mann

1971

2

Six‐Membered Heterocyclic Nitrogen Compounds With Four Condensed Rings

C. F. H. Allen

1951

3

Thiophene and its Derivatives

Howard D. Hartough; F. P. Hochgesang; F. F. Blicke

1952

4

Five Member Heterocyclic Compounds L. L. Bambas with Nitrogen and Sulfur or Nitrogen, Sulfur, and Oxygen (Except Thiazole)

1952

5

Pyridazine and Pyrazine Rings: (Cinnolines, Phthalazines, and Quinoxalines)

J. C. E. Simpson

1953

6

Imidazole and Its Derivatives, Part I

Claus Hofmann

1953

7

Compounds with Condensed Thiophene Rings

H. D. Hartough; S. L. Meisel

1954

8

Heterocyclic Compounds with Indole and Carbazole Systems

Ward G. Sumpter; F. M. Miller

1954

9

Acridines, Second Edition

R. M. Acheson

1973

10

The 1,2,3‐ and 1,2,4‐Triazines, Tetrazines, and Pentazines

John G. Erickson; Paul F. Wiley; V. P. Wystrach

1956

11

Phenazines

G. A. Swan; D. G. I. Felton

1957

12

Six Membered Heterocyclic Nitrogen Compounds with Three Condensed Rings

C. F. H. Allen

1958

13

s‐Triazines and Derivatives

Edwin M. Smolin; Lorence Rapoport

1959

14

Pyridine and its Derivatives, Part 1

Erwin Klingsberg

1960

Pyridine and its Derivatives, Part 2

Erwin Klingsberg

1961

Pyridine and its Derivatives, Part 3

Erwin Klingsberg

1962

Pyridine and its Derivatives, Part 4

Erwin Klingsberg

1964

Pyridine and its Derivatives, Part 5

George R. Newkome

1985

Heterocyclic Compounds

13

TABLE 1.5 (Continued) Volume

Topics

Editor(s)

Year

Pyridine Metal Complexes, Part 6

Piotr Tomasik; Zbigniew Ratajewicz; George R. Newkome; Lucjan Strekowski

1985

Pyridine and its Derivatives, Supplement, Part 1

R. A. Abramovitch

1974

Pyridine and its Derivatives, Supplement, Part 2

R. A. Abramovitch

1974

Pyridine and Its Derivatives: Supplement, Part 3

R. A. Abramovitch

1974

Pyridine and Its Derivatives: Supplement, Part 4

R. A. Abramovitch

1975

Heterocyclic Systems with Bridgehead Nitrogen Atoms, Part 1

Williams L. Mosby

1961

Heterocyclic Systems with Bridgehead Nitrogen Atoms, Part 2

Williams L. Mosby

1961

The Pyrimidines

D. J. Brown; S. F. Mason

1962

The Pyrimidines: Supplement II

D. J. Brown; R. F. Evans; W. B. Cowden; M. D. Fenn

1985

17

Isoxazoles, Oxadiazoles, Oxazines, and Richard H. Wiley; Adolfo Related Compounds Quilico; Giovanni Speroni; Lyell C. Behr; R. L. McKee

1962

18

The Cyanine Dyes and Related Compounds

Frances M. Hamer

1964

19

Heterocyclic Compounds with Three‐ and Four‐Membered Rings

Arnold Weissberger

1964

20

Pyrazolones, Pyrazolidones, and Derivatives

Richard H. Wiley; Paul Wiley

1964

21

Multi‐Sulfur and Sulfur and Oxygen Five‐ and Six‐Membered Heterocycles, Part 1

David S. Breslow; Herman Skolnik

1966

Multi‐Sulfur and Sulfur and Oxygen Five‐ and Six‐Membered Heterocycles, Part 2

David S. Breslow; Herman Skolnik

1966

22

Pyrazoles, Pyrazolines, Pyrazolidines, Indazoles, and Condensed Rings

Richard H. Wiley; Lyell C. Behr; Raffaello Fusco; C. H. Jarboe

1967

23

Furopyrans and Furopyrones

Ahmed Mustafa

1967

24

Fused Pyrimidines, Part I, Quinazolines W. L. F. Armarego

15

16

1967

14

Amino Acids: Insights and Roles in Heterocyclic Chemistry, Volume 2

TABLE 1.5 (Continued) Volume

Topics

Editor(s)

Year

Fused Pyrimidines, Part II: Purines

J. H. Lister

1971

Fused Pyrimidines, Part III: Pteridines

D. J. Brown

1988

Fused Pyrimidines, Part IV: Pyridopyrimidines, Pyrano‐ and Thiopyranopyrimidines, Pyrimidopyrimidines, Pyrimidopyridazines, Pyrimidooxazines, Pyrimidothiazines, and Pyrimidotriazines

Thomas J. Delia; John C. Warner

1991

Indoles, Part 1

William J. Houlihan

1971

Indoles, Part 2

William J. Houlihan

1971

Indoles, Part 3

William J. Houlihan

1979

Indoles, Part 4, The Monoterpenoid Indole Alkaloids

J. Edwin Saxton

1983

26

Seven‐Membered Heterocyclic Compounds Containing Oxygen and Sulfur

Andre Rosowsky

1972

27

Condensed Pyridazines Including Cinnolines and Phthalazines

Raymond N. Castle

1973

28

Pyridazines

Raymond N. Castle

1973

29

Benzofurans

Ahmed Mustafa

1974

30

Special Topics in Heterocyclic Chemistry

Arnold Weissberger; Edward C. Taylor

1977

31

Chromenes, Chromanones, and Chromones

G. P. Ellis

1977

32

Quinolines, Part I

Gurnos Jones

1977

Quinolines, Part II

Gurnos Jones

1982

Quinolines, Part III

Gurnos Jones; John V. Greenhill

1990

Chemistry of 1,2,3‐Triazines and 1,2,4‐ Triazines, Tetrazines, and Pentazin

Hans Neunhoeffer; Paul F. Wiley

1978

25

33 34

Thiazole and Its Derivatives, Part 1

Jacques V. Metzger

1979

Thiazole and Its Derivatives, Part 2

Jacques V. Metzger

1979

Thiazole and Its Derivatives, Part 3

Jacques V. Metzger

1979

35

Condensed Pyrazines

G. W. H. Cheeseman; R. F. Cookson

1979

36

Chromans and Tocopherols

G. P. Ellis; I. M. Lockhart

1981

Heterocyclic Compounds

15

TABLE 1.5 (Continued) Volume

Topics

Editor(s)

Year

37

Triazoles 1,2,4

Carroll Temple Jr.; John A. Montgomery

1981

38

Isoquinolines, Part 1

Guenter Grethe

1981

Isoquinolines, Part 2, Second Edition

F. G. Kathawala; Gary M. Coppola; Herbert F. Schuster

1990

Isoquinolines, Part 3, Second Edition

Gary M. Coppola; Herbert F. Schuster

1995

39

Triazoles 1,2,3

K. Thomas Finley

1980

40

Benzimidazoles and Congeneric Tricyclic Compounds, Part 1

P. N. Preston

1981

Benzimidazoles and Congeneric Tricyclic Compounds: Part 2

P. N. Preston; M. F. G. Stevens; G. Tennant

1981

41

The Pyrazines

G. B. Barlin

1982

42

Small Ring Heterocycles, Part 1: Aziridines, Azirines, Thiiranes, Thiirenes

Alfred Hassner

1983

Small Ring Heterocycles, Part 2: Azetidines, b‐Lactam, Diaziridines, 3H‐Diazirines, Diaziridinones, and Diaziridinimines

Alfred Hassner

1983

Small Ring Heterocycles, Part 3: Oxiranes, Arene Oxides, Oxaziridines, Dioxetanes, Thietanes, Thietes, Thiazetes, and Others

Alfred Hassner

1985

Azepines, Part 1

Andre Rosowsky

1984

Azepines, Part 2

Andre Rosowsky

1984

Thiophene and its Derivatives, Part 1

Salo Gronowitz

1985

Thiophene and its Derivatives, Part 2

Salo Gronowitz

1986

Thiophene and its Derivatives, Part 3

Salo Gronowitz

1986

Thiophene and Its Derivatives, Part 4

Salo Gronowitz

1991

43 44

Thiophene and Its Derivatives, Part 5

Salo Gronowitz

1992

45

Oxazoles

I. J. Turchi

1986

46

Condensed Imidazoles: 5–5 Ring Systems

P. N. Preston

1986

47

Synthesis of Fused Heterocycles: Part 1 G. P. Ellis

1987

Synthesis of Fused Heterocycles: Part 2 G. P. Ellis

1992

16

Amino Acids: Insights and Roles in Heterocyclic Chemistry, Volume 2

TABLE 1.5 (Continued) Volume

Topics

Editor(s)

Year

48

Pyrroles, Part 1: The Synthesis and the Physical and Chemical Aspects of the Pyrrole Ring

R. Alan Jones

1990

Pyrroles, Part 2: The Synthesis, Reactivity, and Physical Properties of Substituted Pyrroles

R. Alan Jones

1992

49

Isoxazoles, Part 1

Paolo Grünanger; Paola Vita‐Finzi

1999

50

Bicyclic Diazepines: Diazepines with an Additional Ring

R. Ian Fryer

1991

51

Aza‐Crown Macrocycles

Jerald S. Bradshaw; Krzysztof E. Krakowiak; Reed M. Izatt

1993

52

The Pyrimidines

D. J. Brown; R. F. Evans; W. B. Cowden; M. D. Fenn

1994

53

Tellurium‐Containing Heterocycles

Michael R. Detty; Marie B. O’regan

1994

54

The Purines, Supplement 1

John H. Lister; M. David Fenn

1996

55

Quinazolines, Supplement I

D. J. Brown

1996

56

Monocyclic Azepines: The Synthesis and Chemical Properties of the Monocyclic Azepines

George R. Proctor; James Redpath

1997

57

The Pyridazines, Supplement 1

D. J. Brown

2000

58

The Pyrazines: Supplement I

D. J. Brown

2002

59

Synthetic Applications of 1,3‐Dipolar Cycloaddition Chemistry Toward Heterocycles and Natural Products

Albert Padwa; William H. Pearson

2002

60

Oxazoles: Synthesis, Reactions, and Spectroscopy: Part 1

David C. Palmer

2003

Oxazoles: Synthesis, Reactions, and Spectroscopy: Part 2

David C. Palmer

2004

61

Quinoxalines: Supplement II

D. J. Brown

2004

62

The Chemistry of 1,2,3‐Thiadiazoles

Vasiliy A. Bakulev; Wim Dehaen

2004

63

The Naphthyridines

D. J. Brown

2007

64

Cinnolines and Phthalazines: Supplement II

D. J. Brown

2005

Heterocyclic Compounds

17

Besides the above two types of literature, there have been a number of books devoted to the heterocyclic compounds. Several recently published books are: (a) “Heterocyclic Organic Corrosion Inhibitors: Principles and Applications” [17]; (b) “Modern Green Chemistry and Heterocyclic Compounds: Molecular Design, Synthesis, and Biological Evaluation” [18]; (c) “Metals and Non-metals: Five-membered N-Heterocycle Synthesis” [19]; (d) “N-Heterocyclic Carbenes in Organocatalysis” [20]; (e) “The Organo­ metallic Chemistry of N-Heterocyclic Carbenes” [21]; (f) “Transition Metal Catalyzed Pyrimidine, Pyrazine, Pyridazine, and Triazine Synthesis” [22]; (g) “Transition Metal-Catalyzed Pyridine Synthesis” [23]; (h) “Transition Metal-Catalyzed Heterocycle Synthesis via C-H Activation” [24]; and (i) “Fluorine in Heterocyclic Chemistry” [25]. In addition to the published compendiums and book series, there have been enormous literature reviews appearing in a variety of journals, including the reviewing journals such as Chemical Reviews, Chemical Society Reviews, Accounts of Chemical Research, Russian Chemical Reviews, Current Organic Synthesis, and Mini-Reviews in Organic Chemistry, etc. Moreover, there are two specific journals devoted to the heterocycles, which are the bimonthly “Journal of Heterocyclic Chemistry” published by Wiley-Blackwell and “Heterocycles” published by The Japan Institute of Heterocyclic Chemistry. A quick search via SciFinder© with “review on heterocycle” has identified more than 1,300 different articles, and even more articles can be located with “review on heterocyclic compounds.” However, it is impossible to list these review articles in this book, and it is not the goal of this book either. Interested readers can easily find the specific review articles via SciFinder© search. 1.3 GENERAL NOMENCLATURE RULES ON HETEROCYCLES Due to the very high complexity in heterocyclic structures, as indicated in the ring index of “Comprehensive Heterocyclic Chemistry III” [26] and the “Cumulative Index of Heterocyclic Systems” [16], it is almost impossible to name these heterocyclic compounds without clear nomenclature rules. Therefore, the heterocycle nomenclature rules are briefly summarized in this section. The International Union of Pure and Applied Chemistry (IUPAC) is an international federation for the advancement of chemistry. One of its sub-committees known as IUPAC’s Inter-divisional Committee on

18

Amino Acids: Insights and Roles in Heterocyclic Chemistry, Volume 2

Nomenclature and Symbols (abbreviated as IUPAC nomenclature) is the world authority to develop standards and rules for the naming of chemical compounds. For monocyclic heterocycles with the size of ring equal to or less than 10 ring members, the IUPAC rules allow three types of nomen­ clatures, including the Hantzsch-Widman Nomenclature, common names, and the replacement nomenclature. The latest revision on the extended Hantzsch-Widman System of Nomenclature was published in 1983 [27], based on the initial propositions put forward by (Karl) Oskar Widman in 1888 [28] and Arthur Rudolf Hantzsch. This latest revision has cited one of Hantzsch’s work in 1887 [29], which in fact is about elucidation of the structures of thiazole compounds, with no clue about the nomenclature of heterocyclic compounds. In order to find the work of Hantzsch regarding the nomenclature, a total of 540 publications prior to 1936 have been located from SciFinder© search with A. Hantzsch as the author, where only six articles relating to the nomenclature issues had been published between 1891 and 1906, respectively [30–35]. Likewise, only 66 items have been located from SciFinder© with Oskar Widman, with two more publications relating to the nomenclature rules [36, 37]. It is quite possible that SciFinder© has not collected all old literature prior to 1900 so it is not sure in which publication A. Hantzsch initiated the nomenclature issues. Similar to the latest extended Hantzsch-Widman System of Nomencla­ ture by IUPAC in 1983, Hantzsch’s work in 1887 [29] was also cited in Widman’s initial nomenclature proposition [28]. However, there have been several falsely cited literatures in this chapter, such as Hantzsch (Ber., 21, 946, the actual authors were Meyer, V. and Riecke, E.) [38] and L. Wolff (Ber., 20, 432, the actual author was Autenrieth, W.), and several citations are not retrievable from SciFinder©, such as Ber., 9, 220; Ber., 10, 1124; Ber., 11, 826; Ber., 15, 645; Ber., 18, 760; Ber., 20, 268; Ber., 21, 545; Ber., 21, 1258, etc. Nevertheless, Widman has criticized Hantzsch’s system of nomenclature and pointed out its weaknesses with respect to his own system [36]. In fact, Widman’s initial proposition on the nomenclature of nitrogencontaining molecules [28] had been challenged by Knorr for pronunciation issues such as “phenisoiazol” and “linguistic monstrosities” for compounds with several nitrogen nuclei connecting to one another. Considering the challenges from Knorr and the nomenclature rules suggested by Hantzsch for five-membered heterocycles, Widman updated his propositions on the nomenclature of heterocycles, such as numerical numbering the location of heteroatom within the ring rather than “ortho, meta” or “syn, anti,

Heterocyclic Compounds

19

amphi,” a fixed starting point in numbering the location for the divalent radical (especially for the five-membered heterocycles), designation of parent names based on simple structures that are distinguishable from others [36]. It sounds that Widman’s contribution to the heterocycle nomenclature is primarily focused on six-membered compounds, such as diazine, azosine, diazoxine [36], and tolupiazin, dipheniazin, anthranaphtopiazin [28], etc.; whereas Hantzsch’s contribution to the heterocyclic nomenclature is concentrated on the five-membered molecules, e.g., imidazole, oxazole, thiazole, etc. [29]. It should be pointed out that many other people had also contributed to the early development of nomenclature, such as for quinoxaline series [39], Williams, S. W. for alkaloidal salts [40], Graebe, C. for cyclic derivatives of naphthalene [41], Richter, M. M. for the ring systems [42], Jaubert, George F. for phenazine dyes [43], Voswinkel, Hugo for triazane derivatives [44], Stoermer, Richard for coumarone derivatives [45], Willgerodt, Conrad for quinopyridines [46], and chinopyridine and chinochinolines [47], just to name a few in the area of heterocyclic chem­ istry. Nevertheless, due to their pioneering contributions to the heterocyclic compounds, the overall nomenclature system for heterocyclic compounds has been known as Hantzsch-Widman System of Nomenclature which has been continually improved and updated over 100 years of development [27]. This system follows the initial suggestions on the nomenclature criteria proposed by Widman, including (a) the names should refer to the constitution, not to represent the structures; (b) the names are formed in such a way that the constitutions can easily be deduced from them; (c) analogy in the constitution must be made known through analogy in the formation of names; (d) when giving names, one has to follow the existing conditions as closely as possible; and (e) the names must be as short as possible. Therefore, it is necessary that the nomenclature system must be strictly systematic, in which every letter, if possible, acquires its special meaning [28]. In general, the extended Hantzsch-Widman System of Nomenclature applies to heteromonocyclic compounds of no more than 10 ring members, with a “prefix” to denote the substituting heteroatom and an ending “stem” to define the size of the ring and the presence or absence of double bonds. The stem names for heterocyclic compounds are listed in Table 1.6. In these stem names, the syllables that denote the size of the ring containing 3, 4, or 7–10 members are derived as follows: “ir” from tri, “et” from tetra, “ep” from hepta, “oc” from octa, “on” from nona, and “ec” from deca. In

20

Amino Acids: Insights and Roles in Heterocyclic Chemistry, Volume 2

addition, some “stem” names also indicate the state of hydrogenation for the heterocyclic compounds, as shown in Table 1.6. For example, the threemembered saturated compound with one nitrogen atom is known as “iridine” and the three-membered compound with one nitrogen atom and one double bond is called “irine.” For particular heterocyclic compounds where the “stem” names do not signify the state of hydrogenation (or the number of the double bond), the prefix “dihydro-,” “tetrahydro-,” etc., is put in front of the “stem” name to indicate the degree of unsaturation for the ring. Also, the prefix indicating the substituting element arises from the abbreviation of the element name but ends with “a.” However, when this prefix comes before the “stem” name starting with a vowel, the final “a” in the prefix is elided. It is assumed that all the heteroatoms within the ring should remain their normal valence as they are in the non-cyclic molecules. For example, halogens often form a single bond with carbon atoms but will have a posi­ tive charge when they connect to two carbon atoms in the cyclic molecules. Moreover, when more than two different heteroatoms coexist in the ring, there should be a priority to indicate the order of each heteroatom in the nomenclature. A general priority is followed according to the appearance of the heteroatom in the periodic table of elements. For example, the halogen is always prior to the chalcogen element, and the chalcogen element is prior to the nitrogen group element, then the group IV element. Within the same group, the priority of elements decreases from row two to higher rows. The prefixes to represent the heteroatom in heterocyclic compounds are listed in Table 1.7. It should be pointed out that the saturated suffix applies only to the completely saturated ring systems, and the unsaturated suffix applies to the rings incorporating the maximum number of non-cumulated double bonds. Systems between these two extreme cases which have a lesser degree of unsaturation would require an appropriate prefix, such as “dihydro” or “tetrahydro” as mentioned above. When more than one heteroatom exists in the ring, the heterocycle is numbered from the atom of the highest prefer­ ence as shown in Table 1.7 in such a way so as to give the smallest possible number to the other hetero atoms in the ring. Consequently, the position of substituent(s) if any plays no role in determining how the ring is numbered in such heterocycle. The core structures of some representative heteromonocyclic compounds with only one heteroatom are displayed in Figure 1.3. Similarly, some repre­ sentative monocyclic compounds with at least two heteroatoms are illus­ trated in Figure 1.4, and representative five- and six-membered heterocycles are demonstrated in Figure 1.5.

Heterocyclic Compounds

21

TABLE 1.6 Stem Suffixes for Hantzsch-Widman Nomenclature Rings with Nitrogen

Rings without Nitrogen

Ring Size

Maximum Unsaturation

One Double Bond

Saturated

Maximum Unsaturation

One Double Bond

Saturated

3

-irine

–

-iridine

-irene

–

-irane

4

-ete

-etine

-etidine

-ete

-etene

-etane

5

-ole

-oline

-olidine

-ole

-olene

-olane

6

-ine

–

(a)

-ine

–

-ane (b)

7

-epine

–

(a)

-epine

–

-epane

8

-ocine

–

(a)

-ocine

–

-ocane

9

-onine

–

(a)

-onine

–

-onane

10

-ecine

–

(a)

-ecine

–

-ecane

(a) Expressed by prefixing “perhydro” to the name of the corresponding unsaturated compound. (b) Only works for O, S, Se, Te, Bi, and Hg; whereas “-inane” is used for N, Si, Ge, Sn, Pb, B, F, Cl, Br, I, P, As, and Sb.

TABLE 1.7 The Prefixes for Heteroatoms in Hetero-Monocyclic Compounds Element

Prefix

Element

Prefix

Element

Prefix

Fluorine

fluora

Tellurium

tellura

Germanium

germana

Chlorine

chlora

Nitrogen

aza

Tin

stanna

Bromine

broma

Phosphorous

phospha

Lead

plumba

Iodine

ioda

Arsenic

arsa

Boron

bora

Oxygen

oxa

Antimony

stiba

Mercury

mercura

Sulfur

thia

Bismuth

bisma

Selenium

selena

Silicon

sila

Note: The priority of element decreases from top to bottom and from left to right.

It should be pointed out that in heterocyclic compounds, the position of a single heteroatom determines the numbering in a monocyclic compound, as shown by azocine (structure (a) in Figure 1.6). However, if there are more than one same heteroatoms in the monocyclic compound, the number of the same heteroatom is indicated by a “di-,” “tri-,” etc., placed before the appropriate prefix in Table 1.7. For these heterocyclic compounds, the numbering is chosen to give the lowest locants to the heteroatoms. When heteroatoms of different kinds are present, the locant 1 is given to the hetero­ atom of the highest priority as shown in Table 1.7. For example, the structure (b) in Figure 1.6 is called 1,2,4-triazine, but not 1,3,4-triazine; structure

22

Amino Acids: Insights and Roles in Heterocyclic Chemistry, Volume 2

(c) is numbered starting from the sulfur atom, instead of from the nitrogen atom, therefore, it is named 2H-1,5,2-dithiazine, but not 2,1,4-thiadiazine or 1,3,6-thiadiazine. Likewise, the structure illustrated by (d) in Figure 1.6 is named 6H-1,2,5-thiadiazine, rather than 1,3,4-dithiazine or 1,3,6-dithiazine.

FIGURE 1.3 Representative hetero-monocyclic compounds. Note: (a) The fully saturated five- and six-membered rings are derivatives of the corresponding heterocycles of the maximum unsaturation, such as tetrahydrofuran is the derivative of furan; (b) only representative heterocycles containing one B, N, O, S, P, or Se are listed.

Although the Hantzsch-Widman system has been generally followed, many five- and six-membered heterocyclic compounds have retained their names that do not obey this nomenclature rules [48], as shown by the structures shown in Figure 1.7. Possibly, these names have been given and popularized prior to the acceptance of the systematic nomenclature system.

Heterocyclic Compounds

23

FIGURE 1.4 Representative heteromonocyclic compounds of more than one heteroatoms. Note:

and

are not distinguishable as both share the same name of 1,2-diazete.

24

Amino Acids: Insights and Roles in Heterocyclic Chemistry, Volume 2

Furthermore, in addition to its default divalent form, sulfur, and selenium in the heterocycles may be tetravalent or even hexavalent. In this case, λ following a number in superscript is used to indicate such high valence. Similarly, when a cumulated double bond occurs within the heterocycles, a symbol of δ followed by a superscript number to indicate the atom between the cumulated double bonds. For example, structure “a” in Figure 1.8 with tetravalent sulfur is known as 1λ4,3-thiazine, where 1 indicates the location of sulfur as it is of higher priority than the nitrogen atom according to Table 1.7, number 3 tells the location of the nitrogen atom, and the superscript 4 demonstrates the valence of sulfur. Similarly, the structure “b” in Figure 1.8 is named as 1,1-dimethyl-1λ4,3-thiazine, structure “c” is known as 1λ4,3­ selenazine, structure “d” is known as 1λ6,3-selenazine and structure “e” is systematically known as 2λ4δ2,5λ4δ2-thieno[3,4-c]thiophene [48].

FIGURE 1.5 Representative five- and six-membered heterocycles.

FIGURE 1.6 Representative hetero-monocycles with more than one heteroatoms.

Heterocyclic Compounds

25

FIGURE 1.7 Representative heterocyclic compounds that do not follow the HantzschWidman nomenclature rules.

FIGURE 1.8 Heterocycles with high valent sulfur, selenium, or cumulated double bonds.

As the Hantzsch-Widman nomenclature is designed for the hetero-mono­ cyclic compounds of less than 10-membered rings, the Hantzsch-Widman nomenclature cannot be applied to heterocycles that are out of this scope. For this reason, the common names and replacement nomenclature are used. Many common names of heterocycles have been established and got popu­ larized prior to the adoption of the systematic nomenclature, which is still

26

Amino Acids: Insights and Roles in Heterocyclic Chemistry, Volume 2

widely used in nowadays literature, as represented in Figure 1.7. Besides the heteromonocyclic compounds, there are many fused heterocyclic compounds as well. If a heterocyclic ring is fused with a non-heterocyclic ring, then the heterocyclic ring will be the base structure for nomenclature, and the name of the fused ring is attached as a prefix ending in “o,” such as benzo, naphtho, and so on. When the name of a component in a fusion name contains locants (numerals or letters), these locants are placed in square brackets. In this case, the side of the heterocyclic ring is labeled by the letters “a,” “b,” “c,” etc., starting from the atom numbered 1. Therefore, side “a” refers to the bond between atoms 1 and 2, side “b” denotes the bond between atoms 2 and 3, and so on. For example, the structure (a) in Figure 1.9 is named as benzo[h] isoquinoline, but not pyrido[2,3-b]naphthalene. When two heterocyclic rings are fused, the molecule is named according to the ring with higher priority, as listed in Table 1.7. For example, when furan and thiophene are fused, the structure (b) in Figure 1.9 is named thieno[2,3-b]furan, instead of furo[2,3-b] thiophene, as oxygen has higher priority than sulfur. In this compound, the bond between atoms 2 and 3 in thiophene is fused with the side “b” in furan. When both cyclic rings contain the same heteroatom, then the component of the largest ring determines the base structure. For example, the structure (c) is named 2H-furo[3,2-b]pyran, but not 2H-pyrano[3,2-b]furan. If both fused components are of the same size and contain the same number and kind of heteroatoms, the cyclic component with the lower numbers for the hetero atoms before fusion will be the base structure, as shown by the structure (d) in Figure 1.9 that is pyrazino[2,3-d]pyridazine, indicating that the ring of pyridazine is the base structure, and its “d” bond is fused with the bond between atoms 2 and 3 in pyrazine. When more than one heteroatom of the same kind exists in the same heterocycle, the numbering preferably commences at the saturated heteroatom rather than the unsaturated one, such as structure (e) in Figure 1.9 for 1-methyl-1H-indazole. However, there are still some fused heterocyclic compounds that retain their common names, as shown in Figure 1.10.

FIGURE 1.9 Structures of fused heterocyclic compounds.

Heterocyclic Compounds

27

FIGURE 1.10 Representative fused heterocyclic compounds.

For heterocycles containing multiple identical rings that are not fused together but are joined with single bonds, their names are given by the prefixes of “bi-, ter-, quater-, penta-, hexa-, etc.,” to indicate the number of heterocyclic systems and the locants to show how these units are connected. The representa­ tives of this kind of heterocycles are 2,2’-bipyridine [49] and 4,4’-bipyridine [50] that are often applied as ligands in the formation of organometallic compounds

28

Amino Acids: Insights and Roles in Heterocyclic Chemistry, Volume 2

or coordination polymers, and terthiophenes (e.g., [2,2’:5’,2”-terthiophene]5-carbaldehyde) [51] and quaterthiophene (e.g., 2,2’:5’,2”:5”,2”’-quaterthio­ phene) [52] that are formed by joining three and four thiophene units with wide applications in material science, as shown in Figure 1.11.

FIGURE 1.11 Heterocyclic compounds of repeated units joined by single bonds.

The third method to name heterocyclic compounds is the replacement nomenclature, in which the name of the heterocyclic compound is composed of the carbocycle’s name and a prefix of “aza,” “oxa” or “thia” that denotes the heteroatom of nitrogen, oxygen or sulfur on the ring. In this case, the heterocyclic ring is numbered starting from the more prior heteroatom in a direction to assign other heteroatoms the lowest possible numbers. This nomenclature method is typically used for monocyclic heterocycles, spiro-heterocycles, and bridged heterocycles. The simple cases for monocyclic heterocycles with replacement nomenclature are represented by the azacyclobutane for azetidine, azacyclopentane for azolidine (pyrrolidine), oxacyclopropane for oxirane, oxacyclobutane for oxetane and N-ethylazacyclopentane for N-ethylpyrrolidine, as shown in Figure 1.12. Spiro-heterocycles are a type of spiro compound that have at least two rings sharing at only one common atom (the spiro atom that is often the tetravalent carbon atom), and have two rings fused at the spiro atom with at least one heteroatom on one of the rings. The spiro compounds are named by placing “spiro” prior to the square bracket which contains the number of atoms in the smaller ring, then the number of atoms in the larger ring, separated by a period, followed by the hydrocarbon name based on the total number of carbon atoms. As an example, spiro[3.5]nonane is demonstrated in Figure 1.11. Following the same trend, the name of spiro-heterocycle is given by the prefix of hetero­ atom followed by the square bracket to designate the size of the two rings and the name of hydrocarbon. Different from the regular spiro hydrocarbons, the position of the heteroatom on the ring in spiro-heterocycles should be clarified in the name so that the heteroatoms are indicated by their prefixes preceded by their positions. The numbering in the spiro-heterocycles proceeds first around the smaller ring (if the two rings are of unequal size) attached to the

Heterocyclic Compounds

29

spiro atom and then around the larger ring through the spiro atom. While the numbering is irrespective of whether the larger ring contains the heteroatom, the heteroatoms are assigned with the lowest possible number locants. If there is only one ring containing the heteroatom, the heterocyclic ring is preferred over the carbocyclic ring of the same size. However, if both rings of equal size are heterocyclic, preference in numbering is given to the ring with the hetero­ atom of higher preference. If the ring contains unsaturation(s), the numbering remains the same, but the direction around the ring is to give as low a number as possible for the location of a double or triple bond. Still, the heteroatom is preferred over the multiple bonds. The nomenclature rules on fused and bridged fused ring systems have been assembled in detail in a pure and applied chemistry publication [53], which also includes the bridged heterocyclic compounds. More references about the nomenclature of organic compounds and particularly the hetero­ cycles in general are easily available [54–60].

FIGURE 1.12 Examples of heterocycles with replacement nomenclature.

1.4 HETEROCYCLIC COMPOUNDS FROM Α-AMINO ACIDS α-Amino acids, as abundant natural products, have great potential in organic synthesis, due to their richness in functional groups (e.g., both the amino and carboxyl groups, as well as their side chain groups), and the naturally pure stereochemistry (i.e., all with L-configurations except for glycine). However, as of the opposite acidities between the amino group and carboxyl group, and the generally low solubility of amino acids in common organic solvents, it is challenging for the direct application of the α-amino acids in organic synthesis. Therefore, amino acids are often protected either at the carboxyl group (via

30

Amino Acids: Insights and Roles in Heterocyclic Chemistry, Volume 2

an ester functionality) or at the amino group (via an amido functionality, e.g., Fmoc or Boc group), so that the solubility of amino acid derivatives in organic solvents can be adjusted and the reactivity of the resulting amino acids can be manipulated and controlled accordingly. Nevertheless, amino acids have been widely applied in organic synthesis, either used as catalysts (e.g., L-proline) [61] or as substrates to make another kind of compounds, such as peptides [62] or alternative chiral molecules [63]. Besides these applications, α-amino acids have often been applied to make heterocyclic compounds involving both the carboxyl and amino group within the amino acids, or either the amino group or carboxyl group or the side chain functional group. Although α-amino acids are generally known to form peptides and proteins, this book will be focused on the transformations of α-amino acids into heterocyclic compounds. The heterocycles arising from α-amino acids will be classified into four categories. The first class of heterocycles are those, of which the corresponding heterocyclic scaffolds contain the heteroatoms or functional group from both the amino and carboxyl groups within the same amino acids; or the heterocycles that can be directly broken down to α-amino acids, as shown in Figure 1.13. This class of heterocycles includes hydantoins, thiohydantoins, 2,5-diketopiperazines (DKPs), sydnones, N-carobxyanhydrides (NCAs), azlactones, oxazolones [64], oxazolidines [65], oxazolidin-5-ones, pyrrolidine-2,4-diones [66], among others. The second groups of heterocycles are the compounds, of which the heterocy­ clic moieties are formed involving the side chain functional group and an additional group from either the amino group or carboxyl group (or hydroxyl reduced from the carboxyl group) of the same amino acids. These types of heterocycles are oxazolines [67], b-lactones [68], γ-lactams (from cyclization of glutamic acid), thietan-2-ones, etc. The third types of heterocycles include b-lactams (from cyclization of aspartic acid) [69], b-sultams, indolines [70], aziridines [71], etc., of which the heterocyclic moieties are formed from either the amino groups or the carboxyl groups, but not both. The last groups of heterocycles are those compounds, of which the heterocyclic moieties are solely formed from the side chain functional groups without the participation of either amino or carboxyl group, such as cyclization of methyl levulinate with aspartic acid’s amino group [72]. Among these four classes of molecules, group one heterocycles are the most common heterocycles, which have been identified with many biological activities. Likewise, b-lactams among group three heterocycles also have many biological activities, with especially important applications in the field of antibiotics. Many of these heterocycles have already demonstrated a

Heterocyclic Compounds

31

variety type of biological activities, and have been used as intermediates for organic synthesis as well.

FIGURE 1.13 Group one heterocycles arising from both amino and carboxyl groups of the α-amino acids.

As a part of a five-volume book series on amino acids, different from volume 1 on the introduction of α-amino acids and their protecting groups, books from volume 2 to volume 4 will introduce many of these heterocycles that are directly originated from α-amino acids in the following order: general introduction, natural existence and physical properties, characteriza­ tion methods, biological activities, medicinal, and pharmaceutical applica­ tions, traditional synthetic methods with detailed experimental procedures, mechanistic discussions, and new trends in synthesis. Volume 5 will be

Amino Acids: Insights and Roles in Heterocyclic Chemistry, Volume 2

32

solely devoted to b-lactams. However, depending on the available source of information, this order will not be exactly followed in each chapter. KEYWORDS • • • • • •

carbocycles cyclic compounds Hantzsch-Widman System heterocycle Hückel’s rule nomenclature

REFERENCES 1. Zanda, M., Bucci, R., Sloan, N. L., & Topping, L., (2020). Highly strained unsaturated carbocycles. European Journal of Organic Chemistry, (33), 5278–5291. doi: 10.1002/ ejoc.202000512. 2. Xie, X., Huang, W., Peng, C., & Han, B., (2018). Organocatalytic asymmetric synthesis of six-membered carbocycle-based spiro compounds. Advanced Synthesis & Catalysis, 360(2), 194–228. doi: 10.1002/adsc.201700927. 3. Barabe, F., Levesque, P., Sow, B., Bellavance, G., Betournay, G., & Barriault, L., (2013). Gold(I)-catalyzed formation of bridged and fused carbocycles. Pure and Applied Chemistry, 85(6), 1161–1173. doi: 10.1351/PAC-CON-13-01-02. 4. Wu, T., & Tang, W., (2021). Construction of bridged polycyclic skeletons via transitionmetal catalyzed carbon-carbon bond-forming reactions. Chemistry – A European Journal, 27(12), 3944–3956. doi: 10.1002/chem.202003863. 5. Liu, C., Ni, Y., Lu, X., Li, G., & Wu, J., (2019). Global aromaticity in macrocyclic polyradicaloids: Hückel’s rule or Baird’s rule? Accounts of Chemical Research, 52(8), 2309–2321. doi: 10.1021/acs.accounts.9b00257. 6. Butora, G., & Hudlicky, T., (1998). The story of morphine structure elucidation: One hundred years of deductive reasoning. Organic Synthesis: Theory and Applications, 4, 1–51. 7. Pavao, A. C., Soares, N. L. A., Ferreira, N. J., & Leao, M. B. C., (1995). Structure and activity of aflatoxins b and g. Journal of Molecular Structure: Theochem., 337(1), 57–60. doi: 10.1016/0166-1280(94)04104-Z. 8. Rix, U., Zheng, J., Rix, L. L. R., Greenwell, L., Yang, K., & Rohr, J., (2004). The dynamic structure of jadomycin b and the amino acid incorporation step of its biosynthesis. Journal of the American Chemical Society, 126(14), 4496, 4497. doi: 10.1021/ja031724o.

Heterocyclic Compounds

33

9. Zhang, M., Song, C., Yao, Z., & Ji, Q., (2012). Theoretical studies of the structure and properties of anticancer drug Taxol. Current Organic Chemistry, 16(19), 2321–2331. doi: 10.2174/138527212803520281. 10. Barton, D. H. R., Pradhan, S. K., Sternhell, S., & Templeton, J. F., (1961). Triterpenoids. XXV. Constitution of limonin and related bitter principles. Journal of the Chemical Society, 255–275. doi: 10.1039/jr9610000255. 11. Ronnest, M. H., Rebacz, B., Markworth, L., Terp, A. H., Larsen, T. O., Kramer, A., & Clausen, M. H., (2009). Synthesis and structure-activity relationship of griseofulvin analogues as inhibitors of centrosomal clustering in cancer cells. Journal of Medicinal Chemistry, 52(10), 3342–3347. doi: 10.1021/jm801517j. 12. Kleeman, A., Engel, J., Kutscher, B., & Reichert, D., (2009). Pharmaceutical Substances: Syntheses, Patents and Applications of the Most Relevant AIPs (5th edn.). Georg Thieme Verlag: Stuttgart, New York. 13. Turner, J. A., (2018). The Pesticide Manual (18th edn.). British Crop Production Council: Cambridge, U.K. 14. Lamberth, C., & Dinges, J., (2012). Chapter 1: The significance of heterocycles for pharmaceuticals and agrochemicals. In: Dinges, J., & Lamberth, C., (eds.), Bioactive Heterocyclic Compound Classes (Pharmaceuticals) (pp. 1–20). Wiley-VCH Verlag & Co.: Weinheim, Germany. 15. You, C., Hu, B., Wu, P., & Kong, D., (2012). Chemoinformatics analysis on pesticides. Nongyaoxue Xuebao, 14(5), 482–488. doi: 10.3969/j.issn.1008-7303.2012.05.03. 16. Brown, D. J., (2008). Cumulative index of heterocyclic systems. In: Taylor, E. C., & Wipf, P., (eds.), Chemistry of Heterocyclic Compounds: A Series of Monographs. John Wiley & Sons, Inc. 17. Quraishi, M. A., Chauhan, D. S., & Saji, V. S., (2020). Heterocyclic Organic Corrosion Inhibitors: Principles and Applications. Elsevier. 18. Shinde, R. S., & Haghi, A. K., (2020). Modern Green Chemistry and Heterocyclic Compounds: Molecular Design, Synthesis, and Biological Evaluation. Apple Academic Press. 19. Kaur, N., (2020). Metals and Non-metals: Five-Membered N-Heterocycle Synthesis. CRC Press. 20. Biju, A. T., (2019). N‐Heterocyclic Carbenes in Organocatalysis. Wiley‐VCH Verlag GmbH & Co. KGaA. 21. Huynh, H. V., (2017). The Organometallic Chemistry of N‐Heterocyclic Carbenes. John Wiley & Sons Ltd. 22. Wu, X. F., & Wang, Z., (2017). Transition Metal Catalyzed Pyrimidine, Pyrazine, Pyridazine and Triazine Synthesis, in Transition Metal-Catalyzed Heterocycle Synthesis Series. Elsevier. 23. Wu, X. F., (2016). Transition Metal-Catalyzed Pyridine Synthesis, in Transition MetalCatalyzed Heterocycle Synthesis Series. Elsevier: Amsterdam, Netherlands.

34

Amino Acids: Insights and Roles in Heterocyclic Chemistry, Volume 2

24. Wu, X. F., (2016). Transition Metal‐Catalyzed Heterocycle Synthesis via C-H Activation. Wiley‐VCH Verlag GmbH & Co. KGaA. 25. Nenajdenko, V., (2014). Fluorine in Heterocyclic Chemistry (Vol. 1: 5-membered heterocycles and macrocycles; Vol. 2: 6-membered heterocycles). Springer International Publishing. 26. Nikonov, G., & Finocchio, A. L., (2008). Ring index. In: Katritzky, A. R., Ramsden, C. A., Scriven, E. F. V., & Taylor, R. J. K., (eds.), Comprehensive Heterocyclic Chemistry III (Vol. 15) Elsevier. 27. Powell, W. H., (1983). Revision of the extended Hantzsch-Widman system of nomenclature for heteromonocycles. Recommendations 1982. Pure and Applied Chemistry, 55(2), 409–416. doi: 10.1351/pac198855020409. 28. Widman, O., (1888). Nomenclature of compounds containing nitrogenous nuclei. Journal für Praktische Chemie (Leipzig), 38(2), 185–201. 29. Hantzsch, A., & Weber, J. H., (1887). On compounds of thiazole (pyridine of the thiophene series). Berichte der Deutschen Chemischen Gesellschaft, 20(2), 3118–3132, 3336, 3337. doi: 10.1002/cber.188702002200. 30. Hantzsch, A., & Osswald, G., (1900). About the conversion of color bases into pseudoammonium hydrates, cyanides, and sulfonic acids. Berichte der Deutschen Chemischen Gesellschaft, 33(1), 278–317. doi: 10.1002/cber.19000330142. 31. Hantzsch, A., (1900). On the nomenclature of diazo compounds. Berichte der Deutschen Chemischen Gesellschaft, 33(2), 2556–2559. doi: 10.1002/cber.190003302196. 32. Hantzsch, A., (1902). About quinoid diazo substances and the so-called triazoles. Berichte der Deutschen Chemischen Gesellschaft, 35(1), 888–896. doi: 10.1002/ cber.190203501143. 33. Hantzsch, A., (1905). The nomenclature of compounds with changeable constitution. Berichte der Deutschen Chemischen Gesellschaft, 38, 998–1004. 34. Hantzsch, A., (1906). Relations between object color and constitution of acid, salts and esters. Berichte der Deutschen Chemischen Gesellschaft, 39, 3080–3102. 35. Hantzsch, A., (1891). Nomenclature of stereoisomeric nitrogen compounds and of rings containing nitrogen. Berichte der Deutschen Chemischen Gesellschaft, 24(2), 3479–3788. doi: 10.1002/cber.189102402210. 36. Widman, O., (1889). Nomenclature of compounds containing nitrogenous nuclei. Journal für Praktische Chemie (Leipzig), 45(2), 200–212. 37. Widman, O., (1909). About the constitution of the so-called halodiphenacyls. Berichte der Deutschen Chemischen Gesellschaft, 42(3), 3261–3270. doi: 10.1002/ cber.19090420355. 38. Meyer, V., & Riecke, E., (1888). The carbon-atom and valency. Reports of the German Chemical Society, 21(1), 946–956. 39. Hinsberg, O., (1887). Nomenclature of the quinoxaline series. Berichte der Deutschen Chemischen Gesellschaft, 20, 21–23.

Heterocyclic Compounds

35

40. Williams, S. W., (1889). The nomenclature and notation of alkaloidal salts. Journal of the American Chemical Society, 11(8), 130–138. 41. Graebe, C., (1894). Nomenclature of cyclic derivatives of naphthalene. Berichte der Deutschen Chemischen Gesellschaft, 27, 3066–3068. 42. Richter, M. M., (1896). A contribution to nomenclature. Berichte der Deutschen Chemischen Gesellschaft, 29, 586–608. 43. Jaubert, G. F., (1896). Nomenclature of phenazine dyes. Berichte der Deutschen Chemischen Gesellschaft, 29, 414–418. 44. Voswinkel, H., (1899). Ueber derivate des triazans. Berichte der Deutschen Chemischen Gesellschaft, 32(2), 2481–2492. 45. Stoermer, R., (1900). Nomenclature of coumarone derivatives. Berichte der Deutschen Chemischen Gesellschaft, 34, 1148–1150. 46. Willgerodt, C., (1900). Derivation and rational nomenclature of the quinopyridines. Chemiker-Zeitung, 24, 437–439. 47. Willgerodt, C., (1900). For the knowledge of the nomenclature and way of writing of thienopyridine and chinochinoline, to which the so-called “phenanthrolines” belong. Chemiker-Zeitung, 24, 311, 312. 48. Panico, R., Powell, W. H., & Richer, J. C., (1994). A Guide to IUPAC Nomenclature of Organic Compounds Recommendations 1993 (International Union of Pure and Applied Chemistry Organic Chemistry Division), (2nd edn., pp. 18–44). Blackwell Science. 49. Dun, L. N., Zhang, B. S., Wang, J. J., Wang, H., Chen, X., & Li, C. B., (2020). Crystal structure, synthesis and luminescence sensing of a Zn(II) coordination polymer with 2,5-dihydroxy-1,4-terephthalic acid and 2,2’-bipyridine as ligands. Crystals, 10(12), 1105/1–1105/13. doi: 10.3390/cryst10121105. 50. Mudsainiyan, R. K., Jassal, A. K., & Pandey, S. K., (2020). Structural diversity from co-crystal to 1D coordination polymers of 2,6-naphthalene dicarboxylic acid with 4,4’-bipyridine as coligand: Structural and computational approach. Journal of Coordination Chemistry, 73(24), 3363–3381. doi: 10.1080/00958972.2020.1853108. 51. Zhu, D., Wagner, P., & Xiao, P., (2021). Terthiophene derivative-based photoinitiating systems for free radical and cationic polymerization under blue LEDs. Industrial & Engineering Chemistry Research, 60(24), 8733–8742. doi: 10.1021/acs.iecr.1c00743. 52. Alencar, R. S., Aguiar, A. L., Ferreira, R. S., Chambard, R., Jousselme, B., Bantignies, J. L., Weigel, C., et al., (2021). Raman resonance tuning of quaterthiophene in filled carbon nanotubes at high pressures. Carbon, 173, 163–173. doi: 10.1016/j.carbon.2020.10.083. 53. Moss, G. P., (1998). Nomenclature of fused and bridged fused ring systems (IUPAC recommendations 1998). Pure and Applied Chemistry, 70(1), 143–216. doi: 10.1351/ pac199870010143. 54. Gupta, R. R., Kumar, M., & Gupta, V., (1998). Nomenclature of heterocycles. In: Heterocyclic Chemistry (pp. 3–38). Springer: Berlin, Heidelberg.

36

Amino Acids: Insights and Roles in Heterocyclic Chemistry, Volume 2

55. Verkade, P. E., (1960). Definitive rules for nomenclature of organic chemistry. Journal of the American Chemical Society, 82(21), 5545–5574. doi: 10.1021/ja01506a003. 56. Zinner, G., (1980). Are you familiar with dioxixan? Remarks on the revision of the expanded Hantzsch-Widman system for heterocycle nomenclature. Pharmazeutische Zeitung, 125(28), 1351, 1352. 57. Hellwich, K. H., Hartshorn, R. M., Yerin, A., Damhus, T., & Hutton, A. T., (2020). Brief guide to the nomenclature of organic chemistry (IUPAC technical report). Pure and Applied Chemistry, 92(3), 527–539. doi: 10.1515/pac-2019-0104. 58. Rasmussen, S. C., (2016). The nomenclature of fused-ring arenes and heterocycles: A guide to an increasingly important dialect of organic chemistry. ChemTexts, 2(4), 1–13. doi: 10.1007/s40828-016-0035-3. 59. Hepler-Smith, E., (2015). “Just as the structural formula does”: Names, diagrams, and the structure of organic chemistry at the 1892 Geneva nomenclature congress. Ambix, 62(1), 1–28. doi: 10.1179/1745823414y.0000000006. 60. Flynn, A. B., Caron, J., Laroche, J., Daviau-Duguay, M., Marcoux, C., & Richard, G., (2014). Nomenclature101.com: A free, student-driven organic chemistry nomenclature learning tool. Journal of Chemical Education, 91(11), 1855–1859. 61. Satyajit, B., (2020). Cross aldol condensation of d-glyceraldehyde with cyclohexanone in aqueous micellar media using l-proline as catalyst: A green approach. Research Journal of Chemistry and Environment, 24(9), 105–111. 62. Bockman, M. R., Miedema, C. J., & Brennan, B. B., (2012). A discovery-oriented approach to solid-phase peptide synthesis. Journal of Chemical Education, 89(11), 1470–1473. doi: 10.1021/ed2008813. 63. Das, A., Arefina, I. A., Danilov, D. V., Koroleva, A. V., Zhizhin, E. V., Parfenov, P. S., Kuznetsova, V. A., et al., (2021). Chiral carbon dots based on L/D-cysteine produced via room temperature surface modification and one-pot carbonization. Nanoscale, 13(17), 8058–8066. doi: 10.1039/d1nr01693h. 64. Teegardin, K. A., & Weaver, J. D., (2017). Polyfluoroarylation of oxazolones: Access to non-natural fluorinated amino acids. Chemical Communications (Cambridge, United Kingdom), 53(35), 4771–4774. doi: 10.1039/C7CC01606A. 65. Xia, P. J., Li, J., Qian, Y. L., Zhao, Q. L., Xiang, H. Y., Xiao, J. A., Chen, X. Q., & Yang, H., (2018). Solvent-minimized, chromatography-free, diastereoselective synthesis of oxazolidine-dispirooxindoles via oxa-1,3-dipolar cycloaddition of 3-oxindole. Journal of Organic Chemistry, 83(5), 2948–2953. doi: 10.1021/acs.joc.7b02865. 66. Lei, N., Lin, Y., & Chao, H., (2020). Synthesis of 2,4-pyrrolidinedione compounds. Guangzhou Huagong, 48(22), 41, 42. 67. Kovalenko, V., & Vasiutovich, K., (2019). Scalable synthesis of N-acetylated α-amino acid-derived oxazoline ligands. Journal of Heterocyclic Chemistry, 56(3), 909–914. doi: 10.1002/jhet.3468.

Heterocyclic Compounds

37

68. Gundogdu, O., Turhan, P., Kose, A., Altundas, R., & Kara, Y., (2017). Reaction of (S)-homoserine lactone with Grignard reagents: Synthesis of amino-keto-alcohols and β-amino acid derivatives. Tetrahedron: Asymmetry, 28(9), 1163–1168. doi: 10.1016/j. tetasy.2017.08.009. 69. Orellana, M. D., Knapp, M. R., Zhang, Z. L., Lloyd, S. E., & Wu, W. M., (2018). Convenient synthesis of N-substituted β-lactam-4-carboxylates. Tetrahedron Letters, 59(25), 2434, 2435. doi: 10.1016/j.tetlet.2018.05.025. 70. Zheng, Y., Song, W., Zhu, Y., Wei, B., & Xuan, L., (2018). Pd-catalyzed intramolecular C(sp2)-H amination of phenylalanine moieties in dipeptides: Synthesis of indoline2-carboxylate-containing dipeptides. Organic & Biomolecular Chemistry, 16(14), 2402–2405. doi: 10.1039/C8OB00207J. 71. Chaudhari, P., & Bari, S., (2015). Efficient synthesis of N-sulfonyl β-arylmethylalaninates from serine via ring-opening of N-sulfonyl aziridine-2-carboxylate. Synthetic Communications, 45(3), 401–412. doi: 10.1080/00397911.2014.965328. 72. Bernhard, Y., Pellegrini, S., Bousquet, T., Favrelle, A., Pelinski, L., Cazaux, F., Gaucher, V., et al., (2019). Reductive amination/cyclization of methyl levulinate with aspartic acid: Towards renewable polyesters with a pendant lactam unit. ChemSusChem, 12(14), 3370–3376. doi: 10.1002/cssc.201900745.

CHAPTER 2

Hydantoin

2.1 INTRODUCTION 2.1.1 STRUCTURE Hydantoin, also known as imidazolidin-2,4-dione, is a five-membered heterocycle, with a dense distribution of functional groups, such as carbonyl, amino, amido, urea, etc., as shown in Figure 2.1. Due to the partial conjuga­ tion between the amino groups and the carbonyl groups, this cyclic molecule should be flat in shape with N and C atoms that adopt an sp2 hybridization. Also, as of the electronic delocalization in the ring, bond lengths are interme­ diate between single and double bonds. In fact, even two bulky bromophenyl groups at position C5, the hydantoin ring of 5,5’-dibromophenyl-hydantoin is still planar as indicated by X-ray crystallography, with the bromophenyl rings perpendicular to each other [1]. To provide additional support for this statement, the structural characterization (bond length, bond angle, etc.), of hydantoin optimized at basis set of 6–311++G(3df,3pd) or aug-cc-pvqz in combination with either B3LYP or MP2 method using Gaussian 09 [2] on a supercomputer at the Research Computing Center of University of Houston are listed in Table 2.1. The calculation dihedral angles among the five ringatoms are all less than 5° in absolute values, indicating that the hydantoin ring is very close to planar.

FIGURE 2.1 The basic structure of hydantoin.

40

Amino Acids: Insights and Roles in Heterocyclic Chemistry, Volume 2

TABLE 2.1 Structural Characterization of Hydantoin Items

MP2 6–311++Ga

B3LYP cc-PVQZb

6–311++G cc-PVQZ

Average

Expt. Value [3]

Bond Length (Å) C2-N3

1.402

1.401

1.409

1.409

1.405 ± 0.003

1.393

C4-N3

1.371

1.368

1.375

1.375

1.372 ± 0.002

1.367

C4-C5

1.521

1.518

1.531

1.531

1.525 ± 0.005

1.46

C5-N1

1.440

1.437

1.448

1.447

1.443 ± 0.004

1.457

C2-N1

1.365

1.360

1.367

1.366

1.364 ± 0.002

1.371

C2-O2

1.206

1.206

1.205

1.205

1.206 ± 0.000

1.222

C4-O4

1.207

1.207

1.203

1.203

1.205 ± 0.001

1.225

N3-H3

1.006

1.005

1.008

1.006

1.006 ± 0.001

–

N1-H1

1.003

1.001

1.004

1.003

1.003 ± 0.001

–

C5-H5’

1.088

1.087

1.092

1.091

1.089 ± 0.002

–

C5-H5”

1.090

1.087

1.091

1.091

1.090 ± 0.001

N1-C2-N3

105.39

105.28

105.42

105.38

105.37 ± 0.04

107.4

C2-N3-C4

113.42

113.46

113.55

113.58

113.50 ± 0.05

111.67

N3-C4-C5

105.41

105.46

105.35

105.34

105.39 ± 0.04

106.8

C4-C5-N1

102.54

102.45

102.41

102.38

102.45 ± 0.04

104.7

C2-N1-C5

112.96

113.35

113.21

113.32

113.21 ± 0.10

109.4

O2-C2-N3

125.95

125.93

125.91

125.92

125.93 ± 0.01

124.4

O2-C2-N1

128.65

128.79

128.67

128.71

128.71 ± 0.04

128.2

O4-C4-C5

127.04

127.01

127.15

127.17

127.09 ± 0.06

127.9

N3-C4-O4

127.55

127.53

127.50

127.49

127.52 ± 0.02

125.3

C2-N3-H3

122.17

122.14

122.09

122.08

122.12 ± 0.03

–

C2-N1-H1

119.64

120.58

120.64

120.88

120.43 ± 0.32

–

C4-C5-H5’

109.03

109.21

109.43

109.54

109.30 ± 0.15

–

C4-C5-H5”

109.47

109.21

109.62

109.54

109.46 ± 0.10

–

N1-C5-H5’

113.29

113.31

113.32

113.31

113.31 ± 0.01

–

N1-C5-H5”

113.12

113.31

113.23

113.31

113.24 ± 0.05

–

0.00

–1.42

0.00

–1.09 ± 0.87

–

Bond Angle (°)

Dihedral Angle (°) N1-C2-N3-C4

–2.95

Hydantoin

41

TABLE 2.1 (Continued) Items

MP2

B3LYP

Average

Expt. Value [3]

0.00

–0.08 ± 0.09

–

–2.37

0.00

–1.93 ± 1.54

–

0.00

–5.60

0.00

–4.27 ± 3.42

–

–2.36

0.00

–1.07

0.00

–0.86 ± 0.69

–

–0.33

0.00

–0.18

0.00

–0.13 ± 0.10

–

O4-C4-C5-H5’ 62.76

59.60

60.82

59.48

60.67 ± 0.90

–

O4-C4-C5-H5” –56.54

–59.60

–58.20

–59.48

–58.46 ± 0.87

–

H1-N1-C5-H5’ –50.67

–62.48

–56.30

–62.13

–57.90 ± 3.53

–

H1-N1-C5-H5” 74.18

62.48

67.99

62.13

66.70 ± 3.51

–

6–311++Ga

cc-PVQZb

6–311++G cc-PVQZ

C2-N3-C4-C5

–0.31

0.00

–0.02

C4-C5-N1-C2

–5.36

0.00

O2-C2-N1-H1

–11.47

O2-C2-N3-H3 H3-N3-C4-O4

abasis bbasis

set of 6–311++G(3df,3pd). set of aug-cc-PVQZ.

As shown by its structure in Figure 2.1, the derivatives of hydantoin would carry substituents at positions 1, 3, or 5. The most important and common derivatives have functional groups at position 5, which can easily form from common α-amino acids. Alternatively, hydantoin derivatives exist as the oxidation products of bases, such as guanine, 8-oxo-7,8-dihydroguanine (OG) [4], thymidine, 2’-deoxycytidine, cytosine, and 5-methylcytosine [5, 6]. It is known that cellular respiration and the inflammatory response [4], as well as external ionizing radiation [5], generate reactive oxygen and nitrogen species (RONS), such as superoxide, hydrogen peroxide, peroxynitrite, hydroxyl radicals and hypochlorous acid. The reaction of RONS with OG leads to the formation of hydantoin lesions, guanidinohydantoin (Gh) and two diastereomers of spiroiminodihydantoin (Sp1 and Sp2); likewise, 2’-deoxythy­ midine decomposes to N1-(2-deoxy-β-D-erythro-pentofuranosyl)-5-hydroxy5-methylhydantoin (5R/S diastereomers). These structures are shown in Figure 2.2. The formation of these hydantoin derivatives within DNA leads to hydantoin lesion, which has been demonstrated to be highly mutagenic through both in vitro and in vivo studies. For example, in single-nucleotide insertion and primer extension experiments using E. coli Klenow fragment of DNA polymerase lacking the exonuclease activity, dAMP, and dGMP are inserted opposite the oxidized lesions [7], resulting in G→C and G→T transversion mutations [4]. Although the oxidized DNA bases are mitigated in part by base excision repair, primarily by means of DNA glycosylases,

42

Amino Acids: Insights and Roles in Heterocyclic Chemistry, Volume 2

hydantoin derivatives have been the important molecules due to the oxida­ tive damages of DNA. In base excision repairing, glycosylases search for aberrant bases in the genome and extrude the damaged nucleobases from the helix and catalyze N-glycosidic bond cleavage to release the modified bases [8–10].

FIGURE 2.2 The structures of OG and hydantoin derivatives from the oxidation of OG and thymidine.

2.2 MELTING POINTS OF α-AMINO ACID BASED HYDANTOINS α-Amino acid derivatives of hydantoins are very common and can be easily formed when α-amino acids, peptides or proteins are involved in reactions. For example, treatment of peptides or proteins in a slightly alkaline solu­ tion with potassium cyanate, the corresponding amino acid hydantoin is formed by subsequent acidification [11]. This method has been applied to the characterization of the N-terminal amino acid of peptide or protein. Most amino acid hydantoins are stable in solutions during storage over a period of 6 months [12]. As the importance of amino acid hydantoins, their melting points from various literature are summarized in Table 2.2. TABLE 2.2 Melting Points (°C) of Common Amino Acid Hydantoins Amino Acid Hydantoin

M.P. [12]

M.P.a

M.P. [11]

Ala-H

167–168

174–177

177

Asp-H

210–212

210–213

218

Cys-H

139–140

–

–

Glu-H

175–177

175–176

174

Gly-H

221–223

223–225

222

His-H

255 (decomp.)

235

50: 1) by rearrangement of its N-carboxamido (urea) derivatives (Scheme 2.14) [158]. Hydrolysis of the resulting hydantoins leads to enantiopure quaternary proline derivatives. Following the same pattern, metallonitriles with features of both enolates and organometallics, when treated with sec-BuLi in THF at –78°C for 1 hour, are transformed into iminohydantoins in good yields upon quenching with methanol (Scheme 2.15). In this procedure, the urea N-phenyl substituent has evidently migrated to the α-carbon of the metal­ lated nitrile, with cyclization of the resulting urea anion onto the nitrile, giving the heterocyclic product. In all cases, aryl migration was followed by cyclization, irrespective of the electronic properties of the migrating ring [159]. A reaction similar to this approach has been reported recently [160].

SCHEME 2.10 A fluorous reagent supported traceless synthesis of hydantoin.

70

Amino Acids: Insights and Roles in Heterocyclic Chemistry, Volume 2

SCHEME 2.11 Ring-switch transformation to form hydantoin.

SCHEME 2.12 EDCI promoted rearrangement leading to hydantoin formation.

SCHEME 2.13 Preparation of (S)-1,3,5-trimethyl-5-phenylimidazolidine-2,4-dione via rearrangement.

Hydantoin

71

SCHEME 2.14 Preparation of a bicyclic hydantoin.

SCHEME 2.15 Conversion of 1-(1-cyanoethyl)-1,3-dimethyl-3-arylurear into hydantoin.

Alternatively, treatment of glyoxal (i.e., oxalaldehyde) with N,N′dimethylurea followed by pinacol rearrangement leads to the formation of 1,3-dimethylhydantoin. Condensation of this compound with various aldehydes afforded the (E)-1,3-dimethyl-5-arylidenehydantoins as the final products, as shown in Scheme 2.16 [161]. Likewise, glyoxal, and urea condense in the presence of phosphoric acid in water at room temperature, also affording hydantoin [162]. However, the reaction between benzils and phenylureas under microwave irradiation in DMSO in the presence of base only affords benzhydryl-phenylurea, whereas phenylthiourea or benzylurea reacts normally with benzils to give the cyclized thiohydantoins or hydan­ toins [163]. Another preparation method of hydantoin involving group migration or rearrangement is shown in Scheme 2.17, in which carbodi­ imides and α,b-unsaturated carboxylic acids with an electron-withdrawing group at the α-position undergo a regiospecific domino condensation/azaMichael addition/N-O-acyl migration to afford a variety of 1,3,5-trisubsti­ tuted hydantoins [164]. For example, the reaction between carbodiimide and fumaric acid derivative bearing an electron-withdrawing group at the α position takes place under a very mild condition (20°C, CH2Cl2). In contrast, less activated substrates bearing only one electron-withdrawing group at the α position require more polar solvents (e.g., acetonitrile, DMF) and a base (e.g., 2,4,6-trimethylpyridine). Reactions with asym­ metric carbodiimides are generally of high chemo- and regioselectivity,

72

Amino Acids: Insights and Roles in Heterocyclic Chemistry, Volume 2

affording a single regio-isomeric hydantoin. This method is particularly convenient for the synthesis of trifluoromethyl-substituted hydantoins, and is very suitable for the solid-phase/combinatorial preparation of hydan­ toins. Besides the rearrangements mentioned above, imidazolones upon treatment with bromine and sodium acetate/acetic acid can be converted into α,b-unsaturated hydantoins, as shown in Scheme 2.18 [165]. Also, the reaction between 4-phenylurazole and fumaric esters in the presence of tetrabutylammonium bromide (TBAB), and 1,4-diaza-bicyclo[2,2,2] octane (DABCO) at 70°C leads to the formation of 5-alkylidene hydan­ toins under solvent-free conditions, as shown in Scheme 2.19 [166]. It is found that (hydroxylamino)barbituric acid (HABA) at pH 7.4 rearranges almost exclusively at 37°C to hydantoin with a half-life of 62 minutes (Scheme 2.20) [167].

SCHEME 2.16 Preparation of hydantoin from glyoxal.

SCHEME 2.17 Preparation of hydantoin from carbodiimide and substituted acrylic acid.

Hydantoin

73

SCHEME 2.18 Bromination of 1,3-dihydro-2H-imidazol-2-one into hydantoin.

SCHEME 2.19 Reaction of 4-phenyl-1,2,4-triazolidine-3,5-dione and dialkyl fumarate to afford hydantoin.

SCHEME 2.20 Isomerization of substituted 1,3-dimethylpyrimidine-2,4,6(1H,3H,5H)­ trione into hydantoin derivative.

A unique type of hydantoin preparation involves catalysis with a tran­ sition metal. For example, 5-benzylidene-1,3-disubstituted hydantoins have been synthesized by a formal intermolecular [2 + 2 + 1] cycloaddi­ tion reaction of one molecule of phenylacetylene with two equivalents of isocyanate, involving iron catalyst and carbodiimide [168], or ruthenium catalyst (affording the Z-isomer as the major product, although the Z/E ratio varies depending on the catalyst used) [169], or manganese complexes (MnBr(CO)5) and Re2(CO)4 or Fe(CO)5 [170]. Similarly, esters can be aminated at the α-position with di-tert-butyldiaziridinone as a nitrogen source and CuCl as the catalyst to form 1,3-di-tert-butyl substituted

74

Amino Acids: Insights and Roles in Heterocyclic Chemistry, Volume 2

hydantoins, as shown in Scheme 2.21 [171]. Also, a palladium-catalyzed one-pot synthesis of 5-, 3,5- and 1,3,5-substituted hydantoins, is based on the carbonylation of aldehydes in the presence of urea derivatives, in high yield with excellent chemo- and regioselectivity [172]. Recently, a Ni(COD)2/1,3bis(2,6-diisopropylphenyl)-imidazolidin-2-ylidene catalyzed preparation of 1,3,5-trisubstituted hydantoin from one molecule of acrylate and two equiva­ lents of isocyanate has been reported, as shown in Scheme 2.22 [173]. This procedure involves two sequential processes, i.e., regioselective formation of N-substituted fumaramate from acrylate and isocyanate and subsequent ring closure of the fumaramate with the incorporation of another molecule of isocyanate.

SCHEME 2.21 Transition metal catalyzed reaction of 1,2-di-tert-butyldiaziridin-3-one with ester to yield hydantoin.

SCHEME 2.22 Transition metal complex catalyzed reaction of acrylate and isocyante to afford hydantoin derivative.

In addition to the above-mentioned methods for the preparation of hydantoins, there have been several isolated methods that work under particular conditions. For example, an Ugi-Joullie reaction/cyclization sequence has been reported to form bicyclic hydantoins, as displayed in Scheme 2.23 [174]. Similarly, an Ugi five-component condensation

Hydantoin

75

procedure has recently been reported for one-pot synthesis of 5-hydroxyl hydantoins by means of microwave-assisted air oxidation of the Ugi prod­ ucts [175]. In 2012, dibutyl phosphate has been applied for the conversion of N-cyano α-amino acid ester in toluene to hydantoin derivatives, as shown in Scheme 2.24 [176]. A unique method has been reported to make 5-acyl hydantoin derivatives that are difficult to obtain by other methods [177]. In this method, 1,2-diaza-1,3-dienes react as Michael acceptors with primary amines to afford α-aminohydrazones that are in situ coupled with isocyanates. Subsequent intramolecular ring closure of asymmetric ureas leads to the formation of hydantoins with hydrazone moiety at the 5-position, which are then hydrolyzed as shown in Scheme 2.25. For spiro-hydantoins, they can be achieved by a phosphine-catalyzed [3 + 2]-cycloaddition of 5-methylenehydantoins with ylides derived from the addition of tributylphosphine to the 2-butynoic acid derivatives, as shown in Scheme 2.26 [178].

SCHEME 2.23 Synthesis of bicyclic hydantoins from nitrile and 1,2-diamine.

SCHEME 2.24 Conversion of N-cyano α-amino acid ester into hydantoin.

76

Amino Acids: Insights and Roles in Heterocyclic Chemistry, Volume 2

SCHEME 2.25 Synthesis of 5-acyl hydantoin derivative.

SCHEME 2.26 Synthesis of spiro-hydantoin via [3+2] cycloaddition.

Recently, a cascade approach has been developed to synthesize 5-(indol3-yl)hydantoin framework from the reaction of indole with glyoxylic acid/ pyruvic acid using (+)-tartaric acid-N,N’-dimethylurea as both reactant and eutectic solvent. N,N’-Dimethylurea forms a deep eutectic solution. Mecha­ nistic study indicates the formation of 5-hydroxyhydantoin intermediate from the reaction of N,N’-dimethylurea and glyoxylic acid, which then couples with indole to afford the final product (Scheme 2.27). This method has been extended to the total synthesis of an alkaloid, (±)-oxoaplysinopsin B, with an overall yield of 48% for the first time [179]. This approach has also been applied to make combretastatin A-4 analog of hydantoins [70].

SCHEME 2.27 Reaction of 2-oxoacetic acid and 1,3-dimethylurea to give 5-hydroxy-1,3dimethylhydantoin and subsequent coupling with indole.

A special case to form bicyclic or even tricyclic hydantoin derivatives has been described lately via an intramolecular nucleophilic aromatic

Hydantoin

77

substitution of metalated nitriles, e.g., 1-(2,3,4,5-tetrahydro-1H-benzo[b] azepine-1-carbonyl)pyrrolidine-2-carbonitrile tethered by a urea linkage to a series of electronically inactivated heterocyclic precursors, affording strained iminohydantoins. Hydrolysis of the iminohydantoins leads to the bicyclic hydantoin derivative, as shown in Scheme 2.28 [180].

SCHEME 2.28 Synthesis of bicyclic and tricyclic hydantoins.

An enzyme-catalyzed mild reaction has been reported recently, for the intramolecular cyclization of urea to give hydantoin derivative. For example, the reaction of (E)-3-(3,4-dihydroxyphenyl)acrylic acid with dicyclohex­ ylcarbodiimide (DCC) in acetonitrile in the presence of DIPEA led to the formation of urea (E)-N-cyclohexyl-N-(cyclohexylcarbamoyl)-3-(3,4­ dihydroxyphenyl)acrylamide. This intermediate was treated with Trametes versicolor laccase (TvL) in a biphasic solvent system (EtOAc/acetate buffer, pH 4.7) at room temperature to give (Z)-1,3-dicyclohexyl-5-(3,4-dihydroxy­ benzylidene)imidazolidine-2,4-dione, as shown in Scheme 2.29 [181]. This reaction is similar to the condition outlined in Scheme 2.17.

SCHEME 2.29 Synthesis of hydantoin derivative from DCC.

A Ugi four-component reaction involving amine, aldehyde, isonitrile, and propiolic acid has been applied to prepare a small hydantoin library in good yields. A representative reaction among aniline, benzaldehyde, propiolic acid and benzylisonitrile is provided in Scheme 2.30, where the intermediate of N-(2-(benzylamino)-2-oxo-1-phenylethyl)-N-phenylpropanolamine was

78

Amino Acids: Insights and Roles in Heterocyclic Chemistry, Volume 2

treated with K2CO3 in acetonitrile under microwave irradiation to give 75% of 3-benzyl-1,5-diphenylimidazolidine-2,4-dione. Each component in this reaction has been labeled with different color [182].

SCHEME 2.30 Synthesis of hydantoins from the Ugi four-component reaction.

Another combinatorial approach involving the amidation between the primary amine and 2,2,2-trifluoroethyl carbonochloridate or bis(2,2,2trifluoroethyl) carbonate to give substituted 2,2,2-trifluoroethyl carbamate intermediate, which is then react with α-amino ester to give hydantoin derivatives, as shown in Scheme 2.31 [183].

R1 NH2

CF3CH2OC(O)Cl i-Pr2NEt, 1,4-dioxane r.t., 1.5 hrs. (Method A) (CF3CH2O)2C(O) ° 2 hrs. CH3CN, 75 C, (Method B)

R3

O F 3C

O

N H

R1

R2

O OR

R1 N O O R4 ° 12 hrs. i-Pr2NEt, 100 C, N R2 (Method A) R4 R3 ° 4 hrs. DBU, 100 C, (Method B) NH

SCHEME 2.31 Combinatorial synthesis of hydantoin from carbamate and α-amino acid ester.

One straight method to form the hydantoin core is the cyclization of a molecule with an acetamido moiety by providing a source of carbonyl moiety, such as para-nitrophenol chloroformate, as represented in the conversion of methyl (S)-2-(1-(2-((4-fluorophenyl)amino)acetamido) ethyl)-1-methyl-1H-benzo[d]imidazole-6-carboxylate into methyl (S)-2-(1-(3-(4-fluorophenyl)-2,5-dioxoimidazolidin-1-yl)ethyl)-1methyl-1H-benzo[d]imidazole-6-carboxylate in THF in the presence of triethylamine, and then treated with 1 M TBAF in THF (Scheme 2.32).

Hydantoin

79

Alternatively, this conversion has been carried out in DMF in the presence of 60% NaH in one step at a temperature from 0°C to room temperature for certain substrates [184].

SCHEME 2.32 Conversion of substituted α-amino acetamide into hydantoin derivative.

A surprising reaction occurs when the mixture of 4-phenyl-1,2,4-triazoli­ dine-3,5-dione and dialkyl fumarate such as diethyl fumarate was treated with 1,4-diaza-bicyclo[2,2,2]octane (DABCO) in the presence of an organic salt (e.g., tetrabutylammonium bromide), that yields ethyl (Z)-2-(2,5-dioxo­ 1-phenylimidazolidin-4-ylidene)acetate (Scheme 2.33). Instead, the expected Michael addition product, such as tetraethyl 2,2’-(3,5-dioxo-4-phenyl-1,2,4triazolidine-1,2-diyl)disuccinate has not been obtained [166].

SCHEME 2.33 Formation of hydantoin derivative from 4-phenyl-1,2,4-triazolidine-3,5dione and diethyl fumarate.

It should be pointed out that hydantoins can also be obtained from the oxidation of their thio-analogs, i.e., thiohydantoins [185]. Other preparations of hydantoin derivatives include the reaction among N-acyl amino acid ester, ammonium carbonate, and KCN under ultrasound or microwave irradiation [186], the reductive amidation between aldehyde and glycinate in the presence of NaBH(OAc)3 followed by the treatment with isocyanate and base [50], the formation of water-soluble resin supported hydantoins [187], and the direct reaction between amino acid and urea in the presence of concentrated sulfuric acid [188], etc.

80

Amino Acids: Insights and Roles in Heterocyclic Chemistry, Volume 2

2.7.2 PRACTICAL PREPARATION OF HYDANTOINS 2.7.2.1  PREPARATION OF CYSTINEHYDANTOIN [140]

Two grams of cystine were suspended in 10 mL of boiling water and 1.5 g of potassium cyanate was added slowly. The solution was then acidified with 25 mL of 10% HCl and refluxed for 30 minutes. After the solution was cooled down to room temperature, 2.2 grams of cystinehydantoin, i.e., (5R,5’R)-5,5’-(disulfane-diylbis(methylene))bis(imidazolidine-2,4-dione), was separated in diamond-shaped plates, in a yield of 91%. 2.7.2.2  PREPARATION OF 3′,4′-DIHYDRO-6′-(N-HEXYL)SPIRO[IMIDAZOLIDINE-4,3′(4′H)-CHROMAN]-2,5-DIONE [126]

A mixture of 4.0 g 6-n-hexyl-3,4-dihydro-2H-1-benzopyran-3-one (i.e., 6-hexylchroman-3-one, 17.2 mmol), 1.2 g KCN (19 mmol), and 15.0 g (NH4)2CO3 (150 mmol) in 125 mL of 50% aqueous EtOH (volume ratio) was refluxed under stirring for 2 hours. After evapora­ tion of EtOH, the suspension was filtrated to provide 2.0 g of 3′,4′dihydro-6′-(n-hexyl)-spiro[imidazolidine-4,3′(4′H)-chroman]-2,5-dione, i.e., 6-hexylspiro[chromane-3,4’-imidazolidine]-2’,5’-dione, as a white solid, in a yield of 40%, m. p. >250°C. 2.7.2.3  PREPARATION OF 5-(O-CARBORAN-1-YLMETHYL)HYDANTOIN [139]

Hydantoin

81

A solution of 1.0 g of o-carboranylalanine (4.32 mmol) and 0.34 g of sodium cyanate (5.23 mmol) in 10 mL of water was refluxed with stirring until the components were completely dissolved (10–15 min). Then 3 mL of concentrated HCl was added, and the reaction mixture was refluxed for an additional 20–30 minutes under stirring, cooled to room temperature, and filtered. The solid was washed three times with 20 mL of water, dried under vacuum (0.2 mm) over anhydrous calcium sulfate, and purified by column chromatography (hexane/ethyl acetate, 1:1) to afford 685 mg of 5-(o-carboran-1-ylmethyl)hydantoin as a white powder, in a yield of 62%, m.p. 226°C, Rf = 0.07 (hexane/ethyl acetate, 5:3). 2.7.2.4 PREPARATION OF 3-CARBOXYMETHYLHYDANTOIN [63]

Anhydrous ammonia was bubbled through a suspension of 11.93 g ethyl glycinate hydrochloride (86 mmol) in 60 mL of CHCl3 (distilled from P2O5) for 30 minutes and the resulting precipitate of NH4Cl was filtered off. The solution was evaporated to dryness to remove excess ammonia, and the residue was taken up in 50 mL fresh CHCl3. This solu­ tion was cooled in an ice bath and a solution of 6.71 g di(1H-imidazol-2-yl) methanone (41 mmol) in CHCl3 was added dropwise over 30 minutes. The resulting solution was stirred at room temperature for an additional 20 hours, before being washed with 1 M HCl and water, dried over Na2SO4 and evaporated. The white solid was recrystallized from CHCl3 to yield 4.3 g of pure N,N’-bis(ethoxycarbonylmethyl)urea, also known as diethyl 2,2’-(carbonylbis(azanediyl))diacetate, in a yield of 51%, m.p. 143–145°C. N,N’-bis(ethoxycarbonylmethyl)urea (1.75 g, 7.5 mmol) was refluxed in a mixture of 25 mL 2 M HCl and 10 mL glacial acetic acid for 3 hours. The solution was then evaporated to dryness and the crude product was recrystallized from ethanol-ether to yield 0.62 g of 3-carboxymethylhy­ dantoin, i.e., 2-(2,5-dioxoimidazolidin-1-yl)acetic acid, in a yield of 52%, m.p. 190°C.

82

Amino Acids: Insights and Roles in Heterocyclic Chemistry, Volume 2

2.7.2.5  PREPARATION OF (S)-2-BUTYL-5-(4-NITROPHENYL)5,6,11,11A-TETRAHYDRO-1H-IMIDAZO[1’,5’:1,6]PYRIDO[3,4-B] INDOLE-1,3(2H)-DIONE [152]

To a solution of 0.2 g 3-(perfluorooctyl)-propan-1-ol (i.e., 4,4,5,5,6,6,7,7,8,8, 9,9,10,10,11,11,11-heptadecafluoroundecan-1-ol, 0.2 mmol) and 0.091 g N-Boc-tryptophan (0.3 mmol) in 5 mL of dichloro­ methane was added 0.103 g dicyclohexylcarbodiimide (DCC, 0.5 mmol) and 0.002 g of 4-dimethyl-aminopyridine (DMAP). The mixture was stirred at room temperature and monitored by TLC. After the reaction was completed (ca. 3 hours), dicyclohexyl urea (DCU) was filtered off and concentrated, and the residue was loaded onto a Fluoro Flash cartridge containing 10 g of fluorous silica gel. The cartridge was eluted with 20 mL of MeOH/H2O (4/1) followed by 20 mL of MeOH. The MeOH frac­ tion was concentrated to give N-Boc-tryptophan 3-(perfluorooctyl)-propyl ester, i.e., 4,4,5,5,6,6,7,7,8,8,9,9,10,10,11,11,11-heptadecafluoroundecyl (tert-butoxycarbonyl)-L-tryptophanate, which was subsequently treated with 30% TFA in dichloromethane at room temperature for three hours to remove the N-protecting group. After deprotection of the Boc group, 0.045 g of p-nitrobenzaldehyde (0.3 mmol) in 10 mL CHCl3 was added, and the solution was heated under microwave irradiation (CEM Discover) at 240 W for 15 min in an open vessel system. Upon completion of the reaction, a solution of 0.03 g of n-butyl isocyanate (0.3 mmol) and 0.051 mL of

Hydantoin

83

triethylamine (0.37 mmol) in 8 mL of dichloromethane was added to the above solution. After completion of the reaction (ca. 3 hours), the reaction mixture was directly loaded on a Fluoro Flash cartridge containing 10 g of fluorous silica gel. The cartridge was eluted with 20 mL of MeOH/H2O (4/1). The fractions were collected and concentrated to give analytical pure (S)-2-butyl-5-(4-nitrophenyl)-5,6,11,11a-tetrahydro-1H-imidazo-[1’,5’:1,6] pyrido[3,4-b]indole-1,3(2H)-dione. 2.7.2.6 PREPARATION OF [14C]SCH 900567 [61]

To 2.0 mL of anhydrous MeOH was added 0.40 mL of thionyl chloride (SOCl2, 5.49 mmol) dropwise under N2 at 0°C. The reaction was stirred at 0°C for 50 minutes and then 1.0 g of (S)-2-amino-2-(furo[3,2-c]pyridin­ 2-yl)-3-(6-methoxy-1-oxoisoindolin-2-yl)propanoic acid (2.72 mmol) were added. The reaction was stirred at 58°C for 24 hours and monitored for completion after 24 hours, then 4.0 mL of CH3OH and 0.6 mL of SOCl2 was added. The reaction was stirred at the same condition for an additional 24 hours. Then the reaction was stopped and the solvent was removed under vacuum. The crude product was purified by silica gel chromatography (330

84

Amino Acids: Insights and Roles in Heterocyclic Chemistry, Volume 2

g silica gel column, eluted with 1–10% CH3OH in CH2Cl2 to give 600 mg of methyl (S)-2-amino-2-(furo[3,2-c]pyridin-2-yl)-3-(6-methoxy-1­ oxoisoindolin-2-yl)propanoate, in a yield of 57.8%. Then 136 mg of this ester (0.356 mmol) and 28.2 mg of potassium [14C]cyanate (KO14CN, 17.5 mCi, 0.339 mmol) were dissolved in 2.5 mL of acetic acid in a reaction vial. The vial was flushed with N2, sealed, and stirred at room temperature for 2 hours, at which time ~ 63.4% of the ester was converted to methyl (S)-2-(furo[3,2-c]pyridin-2-yl)-3-(6-methoxy-1-oxoisoindolin-2-yl)-2­ (ureido-14C)propanoate by radio-HPLC. The conversion slightly changed (64.7%) after stirring for additional 2 hours. The reaction mixture was refluxed for 2 hours, all urea was converted to (S)-5-(furo[3,2-c]pyridin-2­ yl)-5-((6-methoxy-1-oxoisoindolin-2-yl)methyl)imidazo-lidin-2,4-dione2-14C ([14C]SCH 900567), in 68.4% RCP. The crude product was directly purified by RP-HPLC (Gemini C18, 10 Å~ 250 mm, 5 μ, 5 ml/min, eluted with 87:13 H2O (0.1% TFA)-CH3CN followed by CH3CN strip, 254 nm) to give the final product [14C]SCH 900567 (7.5 mCi, 42.8% yield from KO14CN). 2.7.2.7 PREPARATION OF 5-HEPTYL-5-PHENYLHYDANTOIN [108]

A mixture containing 1.5 g of 1-phenyloctan-1-one (7.5 mmol), 0.70 g of trimethylsilanecarbonitrile (TMSCN, 7.5 mmol), and 5–10 mg of ZnI2 was stirred at room temperature under a Nitrogen atmosphere, and monitored by the disappearance of the C=O stretching peak (1,670 cm–1) in the IR spectrum of the reaction mixture (ca. 2 hours), indicating complete conver­ sion to 2-phenyl-2-((trimethylsilyl)oxy)nonanenitrile. The TMS ether was hydrolyzed to 2-hydroxy-2-phenylnonanenitrile by adding 10 mL of ether and 10 mL of 15% HCl under vigorous stirring for 1 hour. The ether layer

Hydantoin

85

was separated, and the aqueous layer was washed with ether (3 × 20 mL). The combined extracts were evaporated to give 1.8 g of 2-hydroxy-2-phenylnon­ anenitrile, in a yield of 100%. Then 2-hydroxy-2-phenylnonanenitrile (9.0 mmol) and 3.6 g of (NH4)2CO3 (3.6 mmol) were dissolved in 30 mL of 50% ethanol while stirring under a Nitrogen atmosphere. The mixture was heated slowly between 40 and 60°C for 12 hours. The basic mixture was evaporated to one-half volume and cooled to room temperature. The precipitate was filtered and recrystallized from hot ethanol to give 0.50 g of 5-heptyl-5-phe­ nylimidazolidine-2,4-dione, i.e., 5-heptyl-5-phenyl-hydantoin, in a yield of 21%, m.p. 124–126°C. 2.7.2.8  PREPARATION OF (S)-2-(4-(3-GUANIDINOPROPYL)-2,5DIOXOIMIDAZOLIDIN-1-YL)ACETIC ACID [53]

At 0°C, 19.5 mL of N-ethylmorpholine (150 mmol) and 18.45 mL of ethyl 2-isocyanatoacetate (150 mmol) were added to a solution of 39.18 g arginine methyl ester dihydrochloride (150 mmol) in 450 mL of DMF. The mixture was stirred at 0°C for 1 hour and then at 22°C for additional 4 hours. The reaction was monitored by TLC with an eluent of n-butanol/water/ pyridine/glacial acetic acid (60:24:20:6). After the reaction was completed, the precipitate was filtered off and the filtrate was evaporated under reduced pressure to give 103.33 g of methyl ((2-ethoxy-2-oxoethyl)carbamoyl)-L­ argininate containing DMF. This oily mixture was refluxed in 1,000 mL 6 N HCl for 30 minutes. The solvent was removed under reduced pressure, and the remaining residue was adjusted to pH = 7 with saturated NaHCO3 solution. The product crystallized from the aqueous solution. The crystals were sucked, washed with water, and dried under reduced pressure to give 31.75 g of (S)-2-(4-(3-guanidinopropyl)-2,5-dioxoimidazolidin-1-yl)acetic acid, in a yield of 99%.

86

Amino Acids: Insights and Roles in Heterocyclic Chemistry, Volume 2

2.7.2.9  PREPARATION OF 4,6-DICHLORO-3-[(3-ISOPROPYL-2,4-DIOXO1-IMIDAZOLIDINYL)-METHYL]INDOLE-2-CARBOXYLIC ACID ETHYL ESTER [50]

To a suspension of 188.3 mg of methyl glycinate hydrochloride (1.5 mmol) in 20 mL of dichloromethane was added 0.25 mL of triethylamine (1.8 mmol), followed by 572 mg of ethyl 4,6-dichloro-3-formyl-1H-indole­ 2-carboxylate (2.0 mmol). After the mixture was stirred at room temperature for 20 minutes, 487.5 mg of sodium triacetoxyborohydride (NaBH(OAc)3), 2.3 mmol) was added, and the resulting mixture was stirred at room tempera­ ture for 24 hours. Then 170 mg of isopropyl isocyanate (2.0 mmol) was added, and after another 1 hour, 0.25 mL of triethylamine (1.8 mmol) was added again. Subsequently, the reaction mixture was refluxed for 12 hours. After EtOAc was added, the separated organic layer was washed with 5% HCl, saturated NaHCO3 solution, and water, dried over MgSO4, and concen­ trated under reduced pressure. Column chromatography (petroleum ether/ EtOAc = 2/1) afforded 386 mg of pure ethyl 4,6-dichloro-3-((3-isopropyl-1(2-methoxy-2-oxoethyl)ureido)methyl)-1H-indole-2-carboxylate, in a yield of 58%, m.p. 162°C. This urea intermediate was suspended in ethanol, and a freshly prepared solution of sodium ethoxide in ethanol was added. The reaction mixture was left at room temperature overnight. After acidification with 10% HCl and extraction with dichloromethane, the organic extracts were dried over MgSO4 and evaporated. The residue was recrystallized from dichloromethane, meth­ anol, and n-hexane to afford 79–83% of ethyl 4,6-dichloro-3-((3-isopropyl2,4-dioxo-imidazolidin-1-yl)methyl)-1H-indole-2-carboxylate, m.p. 196°C.

Hydantoin

87

2.7.2.10 PREPARATION OF E-BROMOAXINOHYDANTOIN AND Z-BROMOAXINOHYDANTOIN [165]

To a stirred solution of 65 mg 3-bromo-4-(2-oxo-2,3-dihydro-1H-imid­ azol-4-yl)-4,5,6,7-tetrahydropyrrolo[2,3-c]azepin-8(1H)-one (0.21 mmol) in 15 mL of acetic acid was added 172 mg of sodium acetate (2.1 mmol) and 32 µL of bromine (0.63 mmol) at room temperature. After 16 hours, the reaction mixture was concentrated and the resulting residue was purified by chroma­ tography (CH2Cl2/MeOH = 9: 1) to afford 38 mg of Z-bromoaxinohydantoin (i.e., (Z)-5-(2,3-dibromo-8-oxo-5,6,7,8-tetrahydropyrrolo[2,3-c]azepin4(1H)-ylidene)imidazo-lidine-2,4-dione, 45%) and 30 mg of E-bromoaxino­ hydantoin (i.e., (E)-5-(2,3-dibromo-8-oxo-5,6,7,8-tetrahydropyrrolo[2,3-c] azepin-4(1H)-ylidene)imidazo-lidine-2,4-dione, 35%) as colorless solids. 2.7.2.11  REARRANGEMENT OF AMINOBARBITURIC ACIDS TO HYDANTOINS [189]

• Conditions A: To 27 mL anhydrous ethanol was added 0.18 g of sodium (8 mmol) to form the solution of sodium ethoxide, then 2 mmol of aminobarbituric acid was added. The mixture was refluxed for 3 hours under an argon atmosphere and was evaporated to dryness. The residue was taken up with a small amount of water, and insoluble

88

Amino Acids: Insights and Roles in Heterocyclic Chemistry, Volume 2

•

•

•

•

material was removed by filtration. The filtrate was acidified with 1N cold HCl. The precipitate was filtered off and dried under reduced pressure. Conditions B: To 10 mL anhydrous ethanol was added 0.18 g of sodium (8 mmol) to form the solution of sodium ethoxide, then 2 mmol of aminobarbituric acid was added. The mixture was heated in a sealed tube at 120°C for 5 hours under an argon atmosphere. The solution was evaporated to dryness under reduced pressure, the residue was taken up with a small amount of water, and insoluble material was removed by filtration. The filtrate was acidified with 1 N cold HCl. The precipitate was filtered off and dried under reduced pressure. Conditions C: To 15 mL anhydrous butanol was added 0.28 g of sodium (12 mmol) to form the solution of sodium butoxide, then 3 mmol of aminobarbituric acid was added. The mixture was refluxed for 5 hours under an argon atmosphere. Afterward, most of the solvent was removed under reduced pressure. Water (10 mL) was added, the mixture was stirred for 2 minutes, kept at room temperature for 30 minutes, and then the organic layer was removed. The aqueous phase was washed with ethyl acetate (4 × 5 mL), acidified with 2 N HCl to pH 2, and cooled. The precipitate was filtered off and dried under reduced pressure. If no crystallization was observed, the solution was extracted with ethyl acetate (4 × 5 mL), and the combined organic layers were dried over Na2SO4 and evaporated to dryness. Conditions D: To a solution of 0.20 g of dry sodium hydride (95%, 8 mmol) in 26.7 mL anhydrous DMF was added 2 mmol of amino­ barbituric acid. The solution was heated at 78°C for 3 hours under an argon atmosphere. The mixture was poured into 100 mL cold 1 N HCl solution and cooled. The product was filtered off, washed with water, and dried under reduced pressure. Conditions E: To a solution of 0.20 g of dry sodium hydride (95%, 8 mmol) in 10 mL anhydrous DMF was added 2 mmol of aminobarbi­ turic acid. The solution was heated at 78°C for 5 hours under an argon atmosphere. The mixture was poured into 100 mL cold 1 N HCl solu­ tion. The product was isolated by extracting the aqueous phase with ethyl acetate (4 × 25 mL). The organic layers were combined, dried over Na2SO4, and evaporated to dryness. The crude oil was dissolved in diethyl ether. After the solution was cooled for at least 5 days, pure crystals were separated by suction filtration and dried.

Hydantoin

89

2.7.2.12  PREPARATION OF ETHYL 2-(1,3-DIISOPROPYL-2,5DIOXOIMIDAZOLIDIN-4-YL)-3,3,3-TRIFLUOROPROPANOATE [164]

To a stirred solution of 0.1 M diisopropyl carbodiimide (1 equiv.) in CH2Cl2 was added 1 equivalent of 2,4,6-trimethylpyridine (TMP, also known as sym-collidine) followed by a solution of 1 equivalent of (Z)-3-(ethoxycarbonyl)-4,4,4-trifluorobut-2-enoic acid in a minimum amount of CH2Cl2. The resulting solution was stirred overnight. The organic solvent was evaporated under reduced pressure, diluted with EtOAc, and extracted with 1 M HCl aqueous solution. The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under vacuum, and the residue was purified by flash chromatography to afford 70% of ethyl 2-(1,3-diisopropyl-2,5-dioxoimidazolidin-4-yl)-3,3,3-trifluoropropanoate (Note: No base TMP was added in the original procedure for this particular reaction, whereas base was normally added). 2.7.2.13  PREPARATION OF 5-ALLYL-5-PHENYL-HYDANTOIN [156]

To a flame-dried 50 mL round-bottom flask were added 150 mg of allyl 2-(3-(ethoxycarbonyl)thioureido)-2-phenylacetate (0.466 mmol) and 15 mL of anhydrous CH2Cl2. Then 0.2 mL of anhydrous triethylamine (1.4 mmol) was added, and the resulting mixture was cooled to 0°C. 1-Ethyl­ 3-(3-dimethyl-aminopropyl)-carbodiimide (EDCI, 197 mg, 1.02 mmol) was then added, and the mixture was stirred at 0°C under nitrogen for 1 hour and refluxed for 15 hours. After the first step was completed as indicated by TLC, the solution was cooled to 0°C, and a solution of 93 mg of NaH (2.33 mmol) in 5 mL of MeOH was added dropwise. The cloudy mixture was stirred at 0°C for 1 hour and then at room temperature for 2 hours. The mixture was

90

Amino Acids: Insights and Roles in Heterocyclic Chemistry, Volume 2

acidified with 5% HCl, and then the solvents were removed. The aqueous mixture was extracted with EtOAc (3 × 30 mL), and the combined organic layers were dried over anhydrous sodium sulfate and concentrated. The crude residue was purified by column chromatography (silica gel, EtOAc/ CH2Cl2 = 1:4) to afford 70 mg of 5-allyl-5-phenyl-hydantoin (i.e., 5-allyl5-phenylimidazolidine-2,4-dione) as a whitish solid, in a yield of 70%. 2.7.2.14  PREPARATION OF (4AS,8AS,9AR)-2-METHYL-9APHENYLOCTAHYDRO-1H-IMIDAZO-[1,5-A]INDOLE-1,3(2H)DIONE [158]

To an anhydrous solution of 56 mg LiCl (2.5 equiv.) and 166 mg of methyl (2S,3aS,7aS)-1-(methyl(phenyl)carbamoyl)octahydro-1H-indole­ 2-carboxylate (0.5 mmol) in 5.25 mL dry THF cooled to –78°C, was added 1.31 mL KHMDS solution (2.5 equiv.) dropwise. After being stirred at –78°C for 30 minutes, the reaction mixture was warmed to room tempera­ ture and stirred for 20 hours, and then quenched with NH4Cl and stirred for 15 minutes. The solution was extracted three times with EtOAc, dried over MgSO4, and concentrated under reduced pressure. The residue was purified by flash column chromatography (SiO2, 100: 0 to 70: 30 petroleum ether: EtOAc) to afford 123 mg of (4aS,8aS,9aR)-2-methyl-9a-phenyloctahydro­ 1H-imidazo[1,5-a]indole-1,3(2H)-dione as an oil, in a yield of 82%. 2.7.2.15  PREPARATION OF 1,3-DIMETHYLIMIDAZOLIDIN-2,4-DIONE [161]

Hydantoin

91

To a 1,000 mL round-bottom flask equipped with a stirrer, thermometer, and addition funnel, was added 290 g of 40 wt.% aqueous glyoxal solution (2.0 mol) and triethylamine (pH of the reaction mixture equals 9). While the temperature of the reaction mixture was maintained at 25−35°C, a solution of 176 g of 1,3-dimethylurea (2.0 mol) in 176 mL of water was gradually added to the mixture. After the addition was completed, the reaction mixture was stirred at the same temperature for additional 3 hours and monitored by TLC. After the completion of the reaction, the solvent was removed on a rotatory evaporator under reduced pressure to afford 297 g of crude 4,5-dihydroxy1,3-dimethylimidazolidin-2-one as a colorless oil, which was used directly without further purification for acidic rearrangement. To a 2,000 mL round-bottom flask equipped with a stirrer, thermometer, and reflux condenser was loaded with 297 g of crude 4,5-dihydroxy1,3-dimethylimidazolidin-2-one, 600 mL H2O, and 54 g of 98% sulfuric acid (0.54 mol). The resulting mixture was stirred at 95−100°C for 6 hours. After completion of the reaction, the reaction mixture was cooled on an ice bath, and 90 g of sodium bicarbonate was added slowly. The crude residue was diluted with EtOAc/H2O (500 mL/200 mL) and the aqueous layer was separated and extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with brine (200 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The crude residue was purified by column chro­ matography on silica gel with EtOAc/hexane (20/80 to 35/65) to give 161 g of 1,3-dimethylimidazolidine-2,4-dione (i.e., 1,3-dimethylhydantoin) as a colorless oil, in an overall yield of 63%. (Note: Product of this scale should be purified by vacuum distillation if possible, rather than column chromatography). 2.7.2.16 PREPARATION OF HYDANTOIN [188]

A mixture of 19.5 g of glycine (0.26 mol), 15.6 g of urea (0.26 mol) and 10 mL of concentrated H2SO4 was heated to reflux for 20 minutes in an oil bath at 120–130°C. After the formation of a white precipitate, acetic acid was added and heating was maintained for another 30 minutes. Normal workup afforded 70% of hydantoin, m.p. 220°C.

92

Amino Acids: Insights and Roles in Heterocyclic Chemistry, Volume 2

2.7.2.17  PREPARATION OF 1,3-DI-TERT-BUTYL-5PHENYLIMIDAZOLIDINE-2,4-DIONE [171]

To a 1.5 mL vial equipped with a stir bar was added 0.004 g of CuCl (0.04 mmol). The sealed vial was evacuated and filled with argon three times, then 0.05 mL of CHCl3 and 0.01 mL of tri-n-butylphosphine (0.04 mmol) were added. After the mixture was stirred at room temperature for 10 minutes, 0.120 g of methyl phenylacetate (0.80 mmol) was added. The reaction mixture was warmed to 65°C using an oil bath with stirring, and 0.272 g of di-t-butyldiaziridinone (1.60 mmol) was added by syringe pump over 8 hours. The reaction mixture was stirred at this temperature for an additional 4 hours and purified by flash chromatography (silica gel, petro­ leum ether: EtOAc: CHCl3 = 20: 1: 2) to give 0.182 g of 1,3-di-tert-butyl­ 5-phenylimidazolidine-2,4-dione, as a white solid, in a yield of 79%. (Note: the amount of CHCl3 sounds too small) 2.7.2.18  PREPARATION OF METHYL 2-(2,5-DIOXO-1,3-DI-PTOLYLIMIDAZOLIDIN-4-YL)-ACETATE [173]

In an N2-filled glove-box, 11.1 mg of Ni(cod)2 (40 μmol, 10 mol.%), 15.7 mg of SIPr (i.e., 1,3-bis(2,6-diisopropylphenyl)-4,5-dihydro-1H-imidazol3-ium, 40 μmol, 10 mol.%), and 2 mL of 1,4-dioxane were added into an oven-dried 4 mL vial equipped with a stir bar. The reaction mixture was stirred for 20 minutes, then 34.6 mg of methyl acrylate (0.40 mmol, 1.0 equiv.) and 151.3 μL of p-tolyl isocyanate (1.2 mmol, 3.0 equiv.) were added via syringe. The vial was capped with a Teflon film and the reaction mixture was taken outside the glove-box. After being heated at 90°C for 18 hours, the

Hydantoin

93

reaction mixture was cooled to room temperature and stirred for 30 minutes in the open air. The resulting mixture was passed through a pad of Florisil® and eluted with EtOAc. The filtrate was concentrated under reduced pressure, and the residue was purified by gel permeation chromatography (CHCl3), and then preparative TLC (hexane/EtOAc = 4:1) to give 112.2 mg of methyl 2-(2,5-dioxo-1,3-di-p-tolylimidazolidin-4-yl)acetate, in a yield of 79%. 2.7.2.19 PREPARATION OF 1-(P-TOLUENESULFONYL)-HYDANTOIN [185]

To a round-bottomed flask were added 1.352 g of 1-(p-toluenesulfonyl)2-thiohydantoin (i.e., 2-thioxo-1-tosylimidazolidin-4-one, 5 mmol) and 20 mL 50% (w/v) nitric acid. The mixture was heated under stirring on a boiling water bath for 30 minutes, and 10 mL of 60% (w/v) nitric acid was added again. Then, the reaction mixture was heated under stirring on a boiling water bath for 2 more hours. The resultant solution was then cooled, evaporated, and treated with ice-cooled water. The precipitates formed were filtered, washed successively with water, methanol, and dichloromethane and recrys­ tallized from ethanol/water to afford 75% of 1-tosylimidazolidine-2,4-dione, i.e., 1-(p-toluenesulfonyl)-hydantoin, m.p. 268°C. 2.8 REACTIONS The reactions of hydantoin primarily take place at position 1, 3, or 5. Adja­ cent to the carbonyl group, the methylene group of position 5 is intrinsically nucleophilic, as represented by the Aldol condensation between hydantoins and benzaldehydes to form benzylhydantoin alcohols [190] and benzylidene hydantoins (Scheme 2.34) [53, 161, 191, 192], or with other aldehydes, e.g., an optically enriched α–chloroaldehyde [193]. On the other hand, the 3-NH group, being adjacent to two carbonyl groups, is more acidic than the 1-NH, which can be deprotonated with K2CO3, and the resulting anion can undergo an SN2 reaction to form 3-alkylated hydantoin [1], or 3-arylated hydantoin

94

Amino Acids: Insights and Roles in Heterocyclic Chemistry, Volume 2

derivatives [56]. Even the 1-NH can be deprotonated with K2CO3 and the resulting nitrogen anion undergoes SN2 reaction with alkyl halides to form 1-substituted hydantoin derivatives [194, 195].

SCHEME 2.34 Formation of substituted 5-benzylidene hydantoin.

In addition, in the presence of Cs2CO3 or K3PO4, 1-NH of hydantoins reacts with propargylic bromides upon activation with a combination of a copper catalyst and a 2,2′-bipyridine derivative to form allenamides of oxazolidinones and hydantoins, via copper-catalyzed SN2′ reaction. This reaction is suitable for the preparation of mono-, di-, and trisubstituted alle­ namides under mild conditions (Scheme 2.35) [196].

SCHEME 2.35 Formation of allene-substituted hydantoin.

2.9 APPLICATIONS Besides the wide applications in biological fields due to their various biological activities, hydantoins have several other applications in industry. First of all, 5,5-dimethyl hydantoin has been applied as a complexing agent (i.e., ligand) in a cyanide-free gold electroplating environment to form a golden bright gold electrodeposit of a smooth and compact surface [197]. The latest report for gold electroplating indicates that 1-methylhydantoin and hydantoin outperform the gold plating solution of 5,5-dimethyl hydantoin. Particularly, the gold-hydantoin complex solution is stable at pH 5–9, and no change in pH or decomposition occurs even when hydrogen peroxide is added [198]. A recent report indicated that the presence of hydantoin leads the deposition potential of nickel to shift to more negative overpotentials without alternation of the nickel solution over a wide range of temperature

Hydantoin

95

and coordination environments around the nickel center, and hydantoin acts as an effective species in the nucleation and growth mechanisms of Ni deposition. As a result, a mirror-like and shiny nickel layer of relatively high brightness that is free of crystal grain has been achieved [199]. Based on molecular dynamic simulation on various hydantoin derivatives, 5,5-dimethyl hydantoin has been selected as a gold complexing agent due to its strong electron-donating abilities and high adsorption energies on the metal surfaces. Likewise, 5,5-dimethyl hydantoin has been added to the succinimide cyanide-free silver plating solution [200]. Computational study also reveals that 5,5-dimethyl hydantoin is a proper complexing agent in the cyanide-free silver electroplating process [201, 202]. More organometallic complexes with hydantoins and thiohydantoins as the ligands have been prepared, although with no additional biological activities reported, such as the copper (II) complexes with 1,3-diazaspiro[4.4] nonane-2,4-dione or spiro[fluorene-9,4’-imidazolidine]-2’,5’-dione as well as their thio-analogs [203]. A similar hydantoin derivative, i.e., 1,3-dihydroxymethyl-5,5-dimethyl hydantoin has been identified as a cosmetic preservative because it is effec­ tive against Gram-negative bacteria (e.g., Escherichia coli), Gram-positive bacteria (e.g., Staphylococcus aureus), mold, and yeast [204]. Similarly, monohydroxymethyl-5,5-dimethyl hydantoin has been explored as a precursor for the generation of a biocidal halamine structure on cellulose by exposure of the modified fabric to a laundering process involving a chlorine bleach rinse [205]. It is found that the linkage between the hydantoin ring and cellulose units is unaffected by repeated laundry and bleaching operations due to the outstanding stability of the hydantoin ring. The biocidal effect of the fabrics prepared with this monohydroxymethyl5,5-dimethyl hydantoin is controllable, generating rapid killing of Staphylococcus aureus and Escherichia coli on the surfaces of fabrics. In addition, 3-(2,3-dihydroxypropyl)-5,5-dimethylimidazolidine-2,4-dione as an antibacterial agent, has been bonded to cotton fabrics with crosslinking agent 1,2,3,4-butane tetracarboxylic acid (BTCA) using the pad-dry-cure process [206]. Also, a series of 3-triethoxysilylpropylhydantoin derivatives have been synthesized with the variation of alkyl substitution at position 5 of hydantoin moiety. These hydantoin derivatives have been coated onto cotton and converted into surface-bound N-halamines by exposure to household bleach to enhance the biocidal activities of cotton [207]. These N-halamine stabilizing oxidative halogens are highly effective disinfectants. Especially, N-halohydantoins are exceptionally stable over

96

Amino Acids: Insights and Roles in Heterocyclic Chemistry, Volume 2

the long term in dry storage, and efficiently inactivate a broad range of microorganisms including drug-resistant bacteria. Their biocidal activities can be regenerated after the loss of oxidative halogen simply by exposure to household bleach. Furthermore, hydantoinylacrylamide has been copolymerized with a sodium sulfonate monomer to render the copolymers soluble in waterbased latex paint formulations at 1.5 wt.% [208]. The treated dry paints are then chlorinated with dilute household bleach to have biocidal activities on the painted surface. Polyurethane coating made from castor oil and toluene diisocyanate has been transformed into an antimicrobial coating by covalently attaching monohydroxymethyl hydantoin for the same reason [209]. Even 5,5-dimethyl hydantoin has been used as biocidal polymer surface modifiers (PSMs) which can be converted into chloramide with dilute hypochlorite solution, resulting in oxidative biocidal surfaces [210]. It is found that polyurethane containing 5,5-dimethylhydantoin displays unusual wetting behavior, for which the hydrophilic dry coatings become hydrophobic when wet, indicating a “contraphilic” wetting behavior because it is opposite to an expected amphiphilic surface response. When the coating is dried at 50°C under vacuum, the initial hydrophilic state is restored [210]. Polystyrene often forms water-insoluble beads, hydantoin containing polystyrene beads, such as poly[1,3-dichloro-5-methyl-5-(4’-vinylphenyl)hydantoin] and poly[1,3-dibromo-5-methyl-5-(4’-vinylphenyl)hydantoin] and the monochlorinated derivative have been prepared as insoluble porous beads, and applied for disinfection of water [211, 212]. Owing to the reactivity of N-haloamine, 1,3-dibromo or 1,3-dichlorohydantoin can be used as halogenation reagent, just like N-bromosuccinimide to carry out the bromination reaction, 1,3-dibromohydantoin has been applied for the bromination of alkenes, and even alkynes and aromatics [213]. It is found that the presence of base would enhance the bromination rate. Likewise, 1,3-dichlorohydantoin can be used for chlorination. On the other hand, substitution at position 5 with phenyl group instead of methyl group weakens the N-Cl bond at position 1 of hydantoin ring in a series of N-halamine derivatives, leading to increased antimicrobial efficacy of the siloxane against Staphylococcus aureus and Escherichia coli O157:H7, but to decreased stabilities of these compounds in the presence of water and exposure to ultraviolet irradiation [214]. Water-soluble 5,5-dimethyl hydantoin poly(epoxide) (DMHP) has been well-distributed in the adhesive system that is commonly used to

Hydantoin

97

treat plywood, and the water-resistance of the adhesive/resultant plywood increases with an increased amount of DMHP added. This is because DMHP reacts with the active groups of proteins to form a dense crosslinking network to improve the crosslinking degree of the cured adhesive; in addition, the added DMHP decreases the adhesive viscosity, helping the adhesive penetrate into the wood surface and interlock with increased wettability. Also, the adhesive with DMHP creates a smooth surface with fewer holes and cracks to prevent moisture intrusion [215]. In addition, water-soluble hydantoin epoxy resin has been applied to modify the surface of ferroelectric BaTiO3 (BT) ceramics to prepare nanocomposites of high energy density [216]. BaTiO3 has a high dielectric constant and relatively low dielectric loss, and epoxy resin has features of high insulating property and low weight. The modification of BaTiO3 with water-soluble hydantoin epoxy resin renders a solvent-free process. Similarly, dimethyl hydantoin formaldehyde resin is soluble in water or in a mixed solvent of EtOH/H2O (7: 3), and can be used as a mounting medium due to its excellent adhesion to glass, low viscosity even in high percentage solutions, and hardness on drying [217]. Moreover, hydantoin has been applied for non-isotopic immunoassay termed carbonyl metallo immunoassay (CMIA), using metal carbonyl complexes as tracers and Fourier transform infrared spectroscopy (FT-IR) as the detection method, and hydantoin of biological activities is connected to the complex moiety [218]. Hydantoin, such as 3-(3,5-dichlorophenyl)-N-isopropyl-2,4-dioxoimid­ azolidine-1-carboxamide (i.e., iprodione) has been widely applied as a pesticide component [219], and over 3,000 literature can be easily located for “iprodione.” On the other hand, N-hydroxysuccinimide has been commonly used as acyl activating agent in peptide synthesis of high yield without racemization, 3-hydroxyhydantoin containing N-hydroxyimide moiety can also be used as an acyl activating reagent [220]. Apparently, since 3-hydroxyhydantoin has an asymmetric center at position 5, it is possible of asymmetrical selectivity when 3-hydroxyhydantoin ester of N-blocked α-amino acid reacts with racemic α-amino acid ester. However, the most useful application of hydantoin derivatives is to decompose the 5-substituted hydantoins into natural and non-natural amino acids, especially the L-amino acids by means of dynamic kinetic resolution of 5-monosubstituted hydantoins using tailor-made whole-cell biocatalysts coexpressing a L-carbamoylase, a hydantoin racemase, and a hydantoinase

98

Amino Acids: Insights and Roles in Heterocyclic Chemistry, Volume 2

[221]. Alternatively, R-, and S-5-monosubstituted hydantoin derivatives can be chemically or enzymatically racemized and enantiomerically pure 5-alkylhydantoins can be obtained by capillary gas chromatography, using octakis(2,6-di-O-methyl-3-O-pentyl)-γ-cyclodextrin as a chiral stationary phase. From the pure 5-alkylhydantoins, optically pure D- or L-amino acids can be obtained [222]. ACKNOWLEDGMENT The author acknowledges the use of the Maxwell/Opuntia Cluster and the advanced support from the Research Computing Data Core at the University of Houston to carry out the calculation of hydantoin structures presented in Table 2.1 of this chapter. KEYWORDS • • • • • •

anticancer antimicrobial agent Bucherer-Bergs reaction hydantoin protein inhibitors x-ray crystallography

REFERENCES 1.

Ooms, F., Wouters, J., Oscari, O., Happaerts, T., Bouchard, G., Carrupt, P. A., Testa, B., & Lambert, D. M., (2002). Exploration of the pharmacophore of 3-alkyl-5arylimidazolidinediones as New CB1 cannabinoid receptor ligands and potential antagonists: Synthesis, lipophilicity, affinity, and molecular modeling. Journal of Medicinal Chemistry, 45, 1748–1756. 2. Frisch, M. J., Trucks, G. W., Schlegel, H. B., Scuseria, G. E., Robb, M. A., Cheeseman, J. R., Scalmani, G., et al., (2013). Gaussian(R) 09 Program. Gaussian, Inc. 3. Yu, F. L., Schwalbe, C. H., & Watkin, D. J., (2004). Hydantoin and hydrogen-bonding patterns in hydantoin derivatives. Acta Crystallographica Section C, 60(10), o714–o717. 4. McKibbin, P. L., Fleming, A. M., Towheed, M. A., Van, H. B., Burrows, C. J., & David, S. S., (2013). Repair of hydantoin lesions and their amine adducts in DNA by base and nucleotide excision repair. J. Am. Chem. Soc., 135, 13851−13861.

Hydantoin

99

5. Ali, A., & Wagner, J. R., (2016). Isomerization of 5-hydroxy-5-methylhydantoin 2’-deoxynucleoside into α-furanose, β-furanose, α-pyranose, and β-pyranose anomers. Chem. Res. Toxicol., 29, 65–74. 6. Gasparutto, D., Ait-Abbas, M., Jaquinod, M., Boiteux, S., & Cadet, J., (2000). Repair and coding properties of 5-hydroxy-5-methylhydantoin nucleosides inserted into DNA oligomers. Chem. Res. Toxicol., 13, 575–584. 7. Krishnamurthy, N., Muller, J. G., Burrows, C. J., & David, S. S., (2007). Unusual structural features of hydantoin lesions translate into efficient recognition by Escherichia coli FPG. Biochemistry, 46(33), 9355–9365. 8. Fleming, A. M., Muller, J. G., Dlouhy, A. C., & Burrows, C. J., (2012). Structural context effects in the oxidation of 8-oxo-7,8-dihydro-2’-deoxyguanosine to hydantoin products: Electrostatics, base stacking, and base pairing. J. Am. Chem. Soc., 134, 15091−15102. 9. Zhao, X., Krishnamurthy, N., Burrows, C. J., & David, S. S., (2010). Mutation versus repair: NEIL1 removal of hydantoin lesions in single-stranded, bulge, bubble, and duplex DNA contexts. Biochemistry, 49(8), 1658–1666. 10. Krishnamurthy, N., Zhao, X., Burrows, C. J., & David, S. S., (2008). Superior removal of hydantoin lesions relative to other oxidized bases by the human DNA glycosylase hNEIL1. Biochemistry, 47(27), 7137–7146. 11. Suzuki, T., Komatsu, K., & Tuzimura, K., (1973). Thin-layer chromatography of amino acid hydantoins. Journal of Chromatography, 80, 199–204. 12. Huang, Z., & Ough, C. S., (1991). Determination of amino acid hydantoins by HPLC with diode array detection. J. Agric. Food Chem., 39(12), 2218–2222. 13. Paul, W. A. S., & Demoen, P. J. A., (1966). An infrared study of -CONCO- structures. Bull. Soc. Chim. Belges, 75, 524–538. 14. Sucharda-Sobczyk, A., Sedzik-Hibner, D., & Prelicz, D., (1984). Infrared carbonyl absorption of hydantoin derivatives. Polish Journal of Chemistry, 58, 1107–1114. 15. Kleinpeter, E., Klod, S., Perjéssy, A., Šamaliková, M., Synderlata, K., & Šusteková, Z., (2003). Correlation analysis of characteristic infrared spectral data of hydantoin derivatives: Evidence for vibrational coupling. Journal of Molecular Structure, 645, 17–27. 16. Katritzky, A. R., Perumal, S., Petrukhin, R., & Kleinpeter, E., (2001). CODESSA-based theoretical QSPR model for hydantoin HPLC-RT lipophilicities. Journal of Chemical Information and Computer Sciences, 41(3), 569–574. 17. Trišović, N., Valentić, N., & Ušćumlić, G., (2011). Solvent effects on the structureproperty relationship of anticonvulsant hydantoin derivatives: A solvatochromic analysis. Chemistry Central Journal, 5. doi: 10.1186/1752-153X-5-62. 18. Cachet, N., Genta-Jouve, G., Regalado, E. L., Mokrini, R., Amade, P., Culioli, G., & Thomas, O. P., (2009). Parazoanthines A-E, hydantoin alkaloids from the Mediterranean Sea anemone Parazoanthus axinellae. J. Nat. Prod., 72(9), 1612–1615. 19. Mio, S., Kumagawa, Y., & Sugai, S., (1991). Synthetic studies on (+)-hydantocidin(3): A new synthetic method for construction of the spiro-hydantoin ring at the anomeric position of D-ribofuranose. Tetrahedron, 47(12, 13), 2133–2144.

100

Amino Acids: Insights and Roles in Heterocyclic Chemistry, Volume 2

20. Youssef, D. T. A., Shaala, L. A., & Alshali, K. Z., (2015). Bioactive hydantoin alkaloids from the red sea marine sponge hemimycale arabica. Mar. Drugs, 13(11), 6609–6619. 21. Mudit, M., Khanfar, M., Muralidharan, A., Thomas, S., Shah, G. V., Van, S. R. W. M., & El Sayed, K. A., (2009). Discovery, design, and synthesis of anti-metastatic lead phenylmethylene hydantoins inspired by marine natural products. Bioorganic & Medicinal Chemistry, 17(4), 1731–1738. 22. Sallam, A. A., Mohyeldin, M. M., Foudah, A. I., Akl, M. R., Nazzal, S., Meyer, S. A., Liu, Y. Y., & El Sayed, K. A., (2014). Marine natural products-inspired phenylmethylene hydantoins with potent in vitro and in vivo antitumor activities via suppression of Brk and FAK signaling. Org. Biomol. Chem., 12, 5295–5303. 23. Spengler, G., Handzlik, J., Ocsovszki, I., Viveiros, M., Kieć-Kononowicz, K., Molnar, J., & Amaral, L., (2011). Modulation of multidrug efflux pump activity by new hydantoin derivatives on colon adenocarcinoma cells without inducing apoptosis. Anticancer Research, 31(10), 3285–3288. 24. Audoin, C., Cocandeau, V., Thomas, O. P., Bruschini, A., Holderith, S., & Genta-Jouve, G., (2014). Metabolome consistency: Additional parazoanthines from the Mediterranean zoanthid Parazoanthus axinellae. Metabolites, 4(2), 421–432. doi: 10.3390/ metabo4020421. 25. Vitale, R. M., Thellung, S., Tinto, F., Solari, A., Gatti, M., Nuzzo, G., Ioannou, E., et al., (2020). Identification of the hydantoin alkaloids parazoanthines as novel CXCR4 antagonists by computational and in vitro functional characterization. Bioorganic Chemistry, 105, 104337/1–104337/10. 26. Teli, M. K., Kumar, S., Yadav, D. K., & Kim, M. H., (2021). In silico identification of hydantoin derivatives:Anovel natural prolyl hydroxylase inhibitor. Journal of Biomolecular Structure and Dynamics, 39(2), 703–717. doi: 10.1080/07391102.2020.1714480. 27. Lee, T. H., Khan, Z., Kim, S. Y., & Lee, K. R., (2019). Thiohydantoin and hydantoin derivatives from the roots of Armoracia rusticana and their neurotrophic and anti­ neuroinflammatory activities. Journal of Natural Products, 82(11), 3020–3024. doi: 10.1021/acs.jnatprod.9b00527. 28. Pettit, G. R., Herald, C. L., Leet, J. E., Gupta, R., Schaufelberger, D. E., Bates, R. B., Clewlow, P. J., et al., (1990). Antineoplastic agents. 168. Isolation and structure of axinohydantoin. Canadian Journal of Chemistry, 68(9), 1621–1624. doi: 10.1139/ v90–250. 29. Guella, G., Mancini, I., Zibrowius, H., & Pietra, F., (1988). Novel aplysinopsin type alkaloids from scleractinian corals of the family dendrophylliidae of the Mediterranean and the Philippines. Configurational assignment criteria, stereospecific synthesis, and photoisomerization. Helvetica Chimica Acta, 71(4), 773–781. doi: 10.1002/ hlca.19880710412. 30. Al Tarabeen, M., Hassan, A. A., Perez, H. C. F., Rasheed, M., Wray, V., & Proksch, P., (2015). New nitrogenous compounds from a red sea sponge from the Gulf of Aqaba. Zeitschrift fuer Naturforschung, C: Journal of Biosciences, 70(3, 4), 75–78. doi: 10.1515/znc-2014-4197.

Hydantoin

101

31. Mancini, I., Guella, G., Zibrowius, H., & Pietra, F., (2003). On the origin of quasi-racemic aplysinopsin cycloadducts, (Bis)indole alkaloids isolated from scleractinian corals of the family dendrophylliidae. Involvement of enantiodefective diels-alderases or asymmetric induction in artifact processes involving adventitious catalysts? Tetrahedron, 59(44), 8757–8762. doi: 10.1016/j.tet.2003.09.038. 32. Meyer, M., Delberghe, F., Liron, F., Guillaume, M., Valentin, A., & Guyot, M., (2009). An Antiplasmodial new (Bis)indole alkaloid from the hard coral Tubastraea sp. Natural Product Research, 23(2), 178–182. doi: 10.1080/14786410801925134. 33. Geng, H. C., Yang, D. S., Chen, X. L., Wang, L. X., Zhou, M., & Mei, W. Q., (2018). Meyeniihydantoins A-C, three novel hydantoin derivatives from the roots of Lepidium meyenii walp. Phytochemistry Letters, 26, 208–211. doi: 10.1016/j.phytol.2018.06.010. 34. Gerona-Navarro, G., González-Muñiz, R., Fernández-Carvajal, A., González-Ros, J. M., Ferrer-Montiel, A., Carreño, C., Albericio, F., & Royo, M., (2011). Solid-phase synthesis of a library of amphipatic hydantoins. Discovery of new hits for TRPV1 blockade. ACS Comb. Sci., 13, 458–465. 35. Šmit, B. M., Pavlović, R. Z., Milenković, D. A., & Marković, Z. S., (2015). Mechanism, kinetics and selectivity of selenocyclization of 5-alkenylhydantoins: An experimental and computational study. Beilstein J. Org. Chem., 11, 1865–1875. 36. Lopez-Rodriguez, M. L., Rosado, M. L., Benhamu, B., Morcillo, M. J., Sanz, A. M., Orensanz, L., Beneitez, M. E., et al., (1996). Synthesis and structure-activity relationships of a new model of arylpiperazines. 1. 2-[[4-(o-methoxyphenyl)piperazin-1-yl]methyl]1,3-dioxoperhydroimidazo[1,5-a]pyridine: A selective 5-HT1A receptor agonist. Journal of Medicinal Chemistry, 39(22), 4439–4450. 37. Moas-Heloire, V., Renault, N., Batalha, V., Arias, A. R., Marchivie, M., Yous, S., Deguine, N., et al., (2015). Design and synthesis of fused tetrahydroisoquinolineiminoimidazolines. European Journal of Medicinal Chemistry, 106, 15–25. 38. Nique, F., Hebbe, S., Peixoto, C., Annoot, D., Lefrancois, J. M., Duval, E., Michoux, L., et al., (2012). Discovery of diarylhydantoins as new selective androgen receptor modulators. Journal of Medicinal Chemistry, 55(19), 8225–8235. 39. Payen, O., Top, S., Vessieres, A., Brule, E., Plamont, M. A., McGlinchey, M. J., MuellerBunz, H., & Jaouen, G., (2008). Synthesis and structure-activity relationships of the first ferrocenyl-aryl-hydantoin derivatives of the nonsteroidal antiandrogen nilutamide. Journal of Medicinal Chemistry, 51(6), 1791–1799. 40. Khanfar, M. A., Hill, R. A., Kaddoumi, A., & El Sayed, K. A., (2010). Discovery of novel GSK-3β inhibitors with potent in vitro and in vivo activities and excellent brain permeability using combined ligand- and structure-based virtual screening. Journal of Medicinal Chemistry, 53, 8534–8545. 41. Last-Barney, K., Davidson, W., Cardozo, M., Frye, L. L., Grygon, C. A., Hopkins, J. L., Jeanfavre, D. D., et al., (2001). Binding site elucidation of hydantoin-based antagonists of LFA-1 using multidisciplinary technologies: Evidence for the allosteric inhibition of a protein-protein interaction. J. Am. Chem. Soc., 123, 5643–5650.

102

Amino Acids: Insights and Roles in Heterocyclic Chemistry, Volume 2

42. Watterson, S. H., Xiao, Z., Dodd, D. S., Tortolani, D. R., Vaccaro, W., Potin, D., Launay, M., et al., (2010). Structure-activity relationships leading to the identification of 6-((5S,9R)-9-(4-cyanophenyl)-3-(3,5-dichlorophenyl)-1-methyl-2,4-dioxo-1,3,7­ triazaspiro[4.4]nonan-7-yl)nicotinic acid (BMS-688521). Journal of Medicinal Chemistry, 53(9), 3814–3830. 43. DelMonte, A. J., Fan, Y., Girard, K. P., Jones, G. S., Waltermire, R. E., Rosso, V., & Wang, X., (2011). Kilogram synthesis of a second-generation LFA-1/ICAM inhibitor. Organic Process Research & Development, 15, 64–72. 44. Kucwaj-Brysz, K., Warszycki, D., Podlewska, S., Witek, J., Witek, K., Gonzalez, I. A., Satala, G., et al., (2016). Rational design in search for 5-phenylhydantoin selective 5-HT7R antagonists. Molecular modeling, synthesis and biological evaluation. European Journal of Medicinal Chemistry, 112, 258–269. 45. Kucwaj-Brysz, K., Latacz, G., Podlewska, S., Zeslawska, E., Handzlik, J., Lubelska, A., Satala, G., et al., (2021). The relationship between stereochemical and both, pharmacological and ADME-tox, properties of the potent hydantoin 5-HT7R antagonist MF-8. Bioorganic Chemistry, 106, 104466/1–104466/13. doi: 10.1016/j. bioorg.2020.104466. 46. Latacz, G., Lubelska, A., Jastrzebska-Wiesek, M., Partyka, A., Sobilo, A., Olejarz, A., Kucwaj-Brysz, K., et al., (2017). In the search for a lead structure among series of potent and selective hydantoin 5-HT7R agents: The drug-likeness in vitro study. Chemical Biology & Drug Design, 90(6), 1295–1306. doi: 10.1111/cbdd.13106. 47. Lubelska, A., Latacz, G., Jastrzebska-Wiesek, M., Kotnska, M., Kurczab, R., Partyka, A., Marc, M. A., et al., (2019). Are the hydantoin-1,3,5-triazine 5-HT6R ligands a hope to a find new procognitive and anti-obesity drug considerations based on primary in vivo assays and ADME-tox profile in vitro. Molecules, 24(24), 4472/1–4472/24. doi: 10.3390/molecules24244472. 48. Bisht, N., & Singh, B. K., (2018). Structure based virtual screening, molecular docking studies and modification of hydantoin nucleus analogues as anticonvulsants. Indian Journal of Chemistry, Section B: Organic Chemistry Including Medicinal Chemistry, 57B(12), 1514–1525. 49. Bauman, A., Piel, M., Höhnemann, S., Krauss, A., Jansen, M., Solbach, C., Dannhardt, G., & Rösch, F., (2011). Synthesis, labelling and evaluation of hydantoin-substituted indole carboxylic acids as potential ligands for positron emission tomography imaging of the glycine binding site of the N‐methyl‐D‐aspartate receptor. J. Label Compd. Radiopharm., 54(10), 645–656. 50. Jansen, M., Potschka, H., Brandt, C., Löscher, W., & Dannhardt, G., (2003). Hydantoinsubstituted 4,6-dichloroindole-2-carboxylic acids as ligands with high affinity for the glycine binding site of the NMDA receptor. Journal of Medicinal Chemistry, 46, 64–73. 51. Zha, C., Brown, G. B., & Brouillette, W. J., (2004). Synthesis and structure-activity relationship studies for hydantoins and analogues as voltage-gated sodium channel ligands. Journal of Medicinal Chemistry, 47(26), 6519–6528.

Hydantoin

103

52. Wang, C., Zhao, Q., Vargas, M., Jones, J. O., White, K. L., Shackleford, D. M., Chen, G., et al., (2016). Revisiting the SAR of the antischistosomal aryl hydantoin (Ro 13-3978). Journal of Medicinal Chemistry, 59(23), 10705–10718. doi: 10.1021/acs. jmedchem.6b01410. 53. Stilz, H. U., Guba, W., Jablonka, B., Just, M., Klingler, O., Koenig, W., Wehner, V., & Zoller, G., (2001). Discovery of an orally active non-peptide fibrinogen receptor antagonist based on the hydantoin scaffold. Journal of Medicinal Chemistry, 44(8), 1158–1176. 54. Vázquez, J., García-Jareño, A., Mondragón, L., Rubio-Martinez, J., Pérez-Payá, E., & Albericio, F., (2008). Conformationally restricted hydantoin-based peptidomimetics as inhibitors of caspase-3 with basic groups allowed at the S3 enzyme subsite. ChemMedChem, 3, 979–985. 55. Rajic, Z., Zorc, B., Raic-Malic, S., Ester, K., Kralj, M., Pavelic, K., Balzarini, J., et al., (2006). Hydantoin derivatives of L- and D-amino acids: Synthesis and evaluation of their antiviral and antitumoral activity. Molecules, 11, 837–848. 56. Vachal, P., Miao, S., Pierce, J. M., Guiadeen, D., Colandrea, V. J., Wyvratt, M. J., Salowe, S. P., et al., (2012). 1,3,8-Triazaspiro [4.5]decane-2,4-diones as efficacious pan-inhibitors of hypoxia-inducible factor prolyl hydroxylase 1-3 (HIF PHD1-3) for the treatment of anemia. Journal of Medicinal Chemistry, 55(7), 2945–2959. 57. Mohamed, H. A., Girgis, N. M. R., Wilcken, R., Bauer, M. R., Tinsley, H. N., Gary, B. D., Piazza, G. A., et al., (2011). Synthesis and molecular modeling of novel tetrahydroβ-carboline derivatives with phosphodiesterase 5 inhibitory and anticancer properties. Journal of Medicinal Chemistry, 54(2), 495–509. 58. Emeigh, J., Gao, D. A., Goldberg, D. R., Kuzmich, D., Miao, C., Potocki, I., Qian, K. C., et al., (2004). Second-generation lymphocyte function-associated antigen-1 inhibitors: 1H-imidazo[1,2-α]imidazol-2-one derivatives. Journal of Medicinal Chemistry, 47(22), 5356–5366. 59. Sacconnay, L., Ryckewaert, L., Randazzo, G. M., Petit, C., Passos, C. D. S., Jachno, J., Michailoviene, V., et al., (2016). 5-Benzylidene-hydantoin is a new scaffold for SIRT inhibition: From virtual screening to activity assays. European Journal of Pharmaceutical Sciences, 85, 59–67. doi: 10.1016/j.ejps.2016.01.010. 60. Somsak, L., Kovacs, L., Toth, M., Osz, E., Szilagyi, L., Gyoergydeak, Z., Dinya, Z., et al., (2001). Synthesis of and a comparative study on the inhibition of muscle and liver glycogen phosphorylases by epimeric pairs of D-gluco- and D-xylopyranosylidene-spiro­ (thio)hydantoins and N-(D-glucopyranosyl) amides. Journal of Medicinal Chemistry, 44(17), 2843–2848. 61. Ren, S., Hesk, D., McNamara, P., Koharski, D., & Borges, S., (2014). Synthesis of [3H], [13C3, 15N], and [14C]SCH 900567: An inhibitor of TNF-α (tumor necrosis factor-alpha) converting enzyme (TACE). J. Label Compd. Radiopharm., 57, 632–636. 62. Teng, X., Degterev, A., Jagtap, P., Xing, X., Choi, S., Denu, R., Yuan, J., & Cuny, G. D., (2005). Structure-activity relationship study of novel necroptosis inhibitors. Bioorganic & Medicinal Chemistry Letters, 15, 5039–5044.

104

Amino Acids: Insights and Roles in Heterocyclic Chemistry, Volume 2

63. Buntain, I. G., Suckling, C. J., & Wood, H. C. S., (1988). Latent inhibitors. Part 4. Irreversible inhibition of dihydro-orotate dehydrogenase by hydantoins derived from amino acids. J. Chem. Soc., Perkin Trans I., 3175–3182. 64. Upadhyay, N., Tilekar, K., Loiodice, F., Anisimova, N. Y., Spirina, T. S., Sokolova, D. V., Smirnova, G. B., et al., (2021). Pharmacophore hybridization approach to discover novel pyrazoline-based hydantoin analogs with anti-tumor efficacy. Bioorganic Chemistry, 107, 104527. doi: 10.1016/j.bioorg.2020.104527. 65. Thirupathi, R. Y., Narsimha, R. P., Koduru, S., Damodaran, C., & Crooks, P. A., (2010). Aplysinopsin analogs: Synthesis and antiproliferative activity of substituted (Z)-5­ (N-benzylindol-3-ylmethylene)imidazolidine-2,4-diones. Bioorganic & Medicinal Chemistry, 18(10), 3570–3574. doi: 10.1016/j.bmc.2010.03.054. 66. Penthala, N. R., Yerramreddy, T. R., & Crooks, P. A., (2011). Synthesis and in vitro screening of novel N-benzyl aplysinopsin analogs as potential anticancer agents. Bioorganic & Medicinal Chemistry Letters, 21(5), 1411–1413. doi: 10.1016/j. bmcl.2011.01.020. 67. Hmuda, S., Trisovic, N., Rogan, J., Poleti, D., Vitnik, Z., Vitnik, V., Valentic, N., et al., (2014). New derivatives of hydantoin as potential antiproliferative agents: Biological and structural characterization in combination with quantum chemical calculations. Monatshefte fuer Chemie, 145(5), 821–833. doi: 10.1007/s00706-013-1149-6. 68. Alkahtani, H. M., Alanazi, M. M., Almehizia, A. A., Alanazi, M. G., El-Azab, A. S., Abdel-Aziz, A. A. M., Aleanizy, F. S., Alqahtani, F. Y., et al., (2019). Synthesis, anticancer, apoptosis-inducing activities and EGFR And VEGFR2 assay mechanistic studies of 5,5-diphenylimidazolidine-2,4-dione derivatives: Molecular docking studies. Saudi Pharmaceutical Journal: SPJ: The Official Publication of the Saudi Pharmaceutical Society, 27(5), 682–693. doi: 10.1016/j.jsps.2019.04.003. 69. Obradovic, A., Matic, M., Ognjanovic, B., Durdevic, P., Marinkovic, E., Uscumlic, G., Bozic, B., & Nedeljkovic, B. B., (2020). Antiproliferative and anti-migratory effects of 3-(4-substituted benzyl)-5-isopropyl-5-phenylhydantoin derivatives in human breast cancer cells. Saudi Pharmaceutical Journal, 28(3), 246–254. doi: 10.1016/j. jsps.2020.01.003. 70. Zhang, M., Liang, Y. R., Li, H., Liu, M. M., & Wang, Y., (2017). Design, synthesis, and biological evaluation of hydantoin bridged analogues of combretastatin A-4 as potential anticancer agents. Bioorganic & Medicinal Chemistry, 25(24), 6623–6634. doi: 10.1016/j.bmc.2017.10.045. 71. Liang, T., Hou, X., Zhou, Y., Yang, X., & Fang, H., (2019). Design, synthesis, and biological evaluation of 2,4-imidazolinedione derivatives as HDAC6 isoform-selective inhibitors. ACS Medicinal Chemistry Letters, 10(8), 1122–1127. doi: 10.1021/ acsmedchemlett.9b000. 72. Aboeldahab, A. M. A., Beshr, E. A. M., Shoman, M. E., Rabea, S. M., & Aly, O. M., (2018). Spirohydantoins and 1,2,4-triazole-3-carboxamide derivatives as inhibitors of histone deacetylase: Design, synthesis and biological evaluation. European Journal of Medicinal Chemistry, 146, 79–92. doi: 10.1016/j.ejmech.2018.01.021.

Hydantoin

105

73. Azizmohammadi, M., Khoobi, M., Ramazani, A., Emami, S., Zarrin, A., Firuzi, O., Miri, R., & Shafiee, A., (2013). 2H-Chromene derivatives bearing thiazolidine-2,4-dione, rhodanine or hydantoin moieties as potential anticancer agents. European Journal of Medicinal Chemistry, 59, 15–22. doi: 10.1016/j.ejmech.2012.10.044. 74. Ahmed, A. H., Ebead, A., Afifi, H., & Abdel-Rahman, A. A. H., (2019). Synthesis and antitumor evaluation of novel alkylated hydantoin and thiohydantoin derivatives. Russian Journal of General Chemistry, 89(2), 357–363. doi: 10.1134/S1070363219020294. 75. Marinova, P., Marinov, M., Kazakova, M., Feodorova, Y., Slavchev, A., Blazheva, D., Georgiev, D., et al., (2016). Study on the synthesis, characterization and bioactivities of 3-methyl-9’-fluorenespiro-5-hydantoin. Acta Chimica Slovenica, 63(1), 26–32. doi: 10.17344/acsi.2015.1591. 76. Bakalova, A. G., Buyukliev, R. T., & Cherneva, E. D., (2020). New Pt(II) complexes with 3’-methyl tetrahydro-4H-thiopyranspiro-5’-hydantoin: Synthesis, theoretical and cytotoxic investigation. Medicinal Chemistry Research, 29(12), 2218–2223. doi: 10.1007/s00044-020-02639-9. 77. Cherneva, E., Atanasova, M., Buyukliev, R., Tomovic, K., Smelcerovic, Z., Bakalova, A., & Smelcerovic, A., (2020). 3’-Methyl-4-thio-1H-tetrahydropyranspiro-5’-hydantoin platinum complex as a novel potent anticancer agent and xanthine oxidase inhibitor. Archiv der Pharmazie (Weinheim, Germany), 353(7), e2000039/1–e2000039/6. doi: 10.1002/ardp.202000039. 78. Vatannavaz, L., Sabounchei, S. J., Sedghi, A., Karamian, R., Farida, S. H. M., & Rahmani, N., (2020). New nickel, palladium and platinum complexes of hydantoin derivative: Synthesis, characterization, theoretical study and biological activity. Polyhedron, 181, 114478/1–114478/9. doi: 10.1016/j.poly.2020.114478. 79. Bakalova, A. G., Buyukliev, R. T., Nikolova, R. P., Shivachev, B. L., Mihaylova, R. A., & Konstantinov, S. M., (2019). Synthesis, spectroscopic properties, crystal structure and biological evaluation of new platinum complexes with 5-methyl-5-(2-thiomethyl)ethyl hydantoin. Anti-Cancer Agents in Medicinal Chemistry, 19(10), 1243–1252. doi: 10.217 4/1871520619666190214103345. 80. Zivanovie, M. N., Kosaric, J. V., Smit, B., Seklie, D. S., Pavlovie, R. Z., & Markoviel, S. D., (2017). Novel seleno-hydantoin palladium(II) complex – anti-migratory, cytotoxic and pro-oxidative potential on human colon HCT-116 and breast MDA-MB231 cancer cells. General Physiology and Biophysics, 36(2), 187–196. doi: 10.4149/ gpb_2016036. 81. Cherneva, E., Buyukliev, R., & Bakalova, A., (2017). Pt(II) complex with 3’-amino2-indanespiro-5’-hydantoin – synthesis, spectral investigation and quantum chemical study. Comptes Rendus de l’Academie Bulgare des Sciences, 70(7), 641–646. 82. Keivanloo, A., Lashkari, S., Sepehri, S., Bakherad, M., & Abbaspour, S., (2021). Synthesis of hydantoin alkynes through palladium-catalyzed reaction, antibacterial evaluation, and molecular docking studies. Journal of the Chinese Chemical Society (Weinheim, Germany). Ahead of Print. doi: 10.1002/jccs.202000475.

106

Amino Acids: Insights and Roles in Heterocyclic Chemistry, Volume 2

83. Mistry, P. P., & Desai, V. A., (2018). Synthesis, characterization and biological evolution of various novel heterocyclic compounds of hydantoin and piperazine. Heterocyclic Letters, 8(1), 145–154. 84. Handzlik, J., Szymanska, E., Chevalier, J., Otrebska, E., Kiec-Kononowicz, K., Pages, J. M., & Alibert, S., (2011). Amine-alkyl derivatives of hydantoin: New tool to combat resistant bacteria. European Journal of Medicinal Chemistry, 46(12), 5807–5816. doi: 10.1016/j.ejmech.2011.09.032. 85. Su, M., Xia, D., Teng, P., Nimmagadda, A., Zhang, C., Odom, T., Cao, A., Hu, Y., & Cai, J., (2017). Membrane-active hydantoin derivatives as antibiotic agents. Journal of Medicinal Chemistry, 60(20), 8456–8465. doi: 10.1021/acs.jmedchem.7b00847. 86. Otreebska-Machaj, E., Chevalier, J., Boyer, G., Bolla, J. M., Pages, J. M., Alibert, S., Handzlik, J., et al., (2016). Efflux pump blockers in gram-negative bacteria: The new generation of hydantoin based-modulators to improve antibiotic activity. Frontiers in Microbiology, 7, 622/1–622/8. doi: 10.3389/fmicb.2016.00622. 87. Rai, R. K., & Jayakrishnan, A., (2018). Synthesis and polymerization of a new hydantoin monomer with three halogen binding sites for developing highly antibacterial surfaces. New Journal of Chemistry, 42(14), 12152–12161. doi: 10.1039/C8NJ02743A. 88. Ravichandran, V., Rai, R. K., Kesavan, V., & Jayakrishnan, A., (2017). Tyrosine-derived novel antimicrobial hydantoin polymers: Synthesis and evaluation of antibacterial activities. Journal of Biomaterials Science, Polymer Edition, 28(18), 2131–2142. doi: 10.1080/09205063.2017.1377395. 89. Rai, R. K., & Jayakrishnan, A., (2019). Development of new hydantoin-based biocidal polymers with improved rechargeability and anti-microbial activity. New Journal of Chemistry, 43(9), 3778–3787. doi: 10.1039/c8nj06015k. 90. Orhan, M., Demirci, F., Kocer, H. B., & Nierstrasz, V., (2020). Supercritical carbon dioxide application using hydantoin acrylamide for biocidal functionalization of polyester. Journal of Supercritical Fluids, 165, 104986/1–104986/10. doi: 10.1016/j. supflu.2020.104986. 91. Farah, S., Aviv, O., Daif, M., Reddy, K. K., Laout, N., Ratner, S., Beyth, N., & Domb, A. J., (2016). N-Bromo-hydantoin grafted polystyrene beads: Synthesis and nano-micro beads characteristics for achieving controlled release of active oxidative bromine and extended microbial inactivation efficiency. Journal of Polymer Science, Part A: Polymer Chemistry, 54(5), 596–610. doi: 10.1002/pola.27894. 92. Chylinska, M., & Kaczmarek, H., (2020). N-Halamine hydantoin-containing chitosan: Synthesis, characterization, thermal and photolytic stability studies. Molecules, 25(16), 3728/1–3728/22. doi: 10.3390/molecules25163728. 93. Liu, T., Zeng, X., Fang, W., Lai, X., & Li, H., (2017). Synthesis of a novel hydantoincontaining silane and its effect on the tracking and bacteria resistance of additioncure liquid silicone rubber. Applied Surface Science, 423, 630–640. doi: 10.1016/j. apsusc.2017.06.117. 94. Chang, J., Yang, X., Ma, Y., Shao, J., Yang, X., & Chen, Z., (2016). Alkyl substituted hydantoin-based N-halamine: Preparation, characterization, and structure-antibacterial

Hydantoin

107

efficacy relationship. Industrial & Engineering Chemistry Research, 55(35), 9344–9351. doi: 10.1021/acs.iecr.6b01306. 95. Wang, F., Ren, F., Ma, D., Mu, P., Wei, H., Xiao, C., Zhu, Z., et al., (2018). Particle and nanofiber shaped conjugated microporous polymers bearing hydantoin-substitution with high antibacterial activity for water cleanness. Journal of Materials Chemistry A: Materials for Energy and Sustainability, 6(1), 266–274. doi: 10.1039/C7TA09405A. 96. Ghasempour, L., Asghari, S., Tajbakhsh, M., & Mohseni, M., (2020). One-pot synthesis of new hydantoin (thiohydantoin) derivatives and evaluation of their antibacterial and antioxidant activities. Journal of Heterocyclic Chemistry, 57(12), 4136–4148. doi: 10.1002/jhet.4120. 97. Guo, X., Wang, J., Su, C., Liu, C., Ma, X. Y., Yu, Z., Li, J., et al., (2019). A unique spiroβ-triazinedione-γ-hydantoin type alkaloid with antiviral activity against tobacco mosaic virus from Streptomyces gamaensis. Organic Chemistry Frontiers, 6(18), 3215–3219. doi: 10.1039/c9qo00742c. 98. Gerzon, K., Ryan, C. W., & De Long, D. C., (1974). Virus Suppression by Hydantoins. United State Patent, US 3790673 A. 99. Tijsma, A., Thibaut, H. J., Franco, D., Dallmeier, K., & Neyts, J., (2016). Hydantoin: The mechanism of its in vitro anti-enterovirus activity revisited. Antiviral Research, 133, 106–109. doi: 10.1016/j.antiviral.2016.07.023. 100. Nishinami, S., Ikeda, K., Nagao, T., Koyama, A. H., Arakawa, T., & Shiraki, K., (2021). Aromatic interaction of hydantoin compounds leads to virucidal activities. Biophysical Chemistry, 275, 106621. doi: 10.1016/j.bpc.2021.106621. 101. Desai, V. A., Mistry, P. P., & Sudani, B. R., (2016). Synthesis, spectroscopic, thermal and biological aspects of nickel(II) complexes with hydantoin. International Journal of Chemical and Pharmaceutical Analysis, 3(2), 940/1–940/5. 102. Abd, E. H., El Desoky, S., Al-Shareef, H. F., & El-mekawy, R., (2019). Synthesis, reactions, and applications of hydantoin and 2-thiohydantoin derivatives. Acta Poloniae Pharmaceutica, 76(6), 971–986. doi: 10.32383/appdr/112124. 103. Lopez-Lopez, L. I., De Loera-Carrera, D. A., De Rivera-Avalos, E. J., & Saenz-Galindo, A., (2018). Hydantoin and derivatives as framework in medicinal chemistry: Recent approaches. Afinidad, 75(584), 279–289. 104. Cho, S., Kim, S. H., & Shin, D., (2019). Recent applications of hydantoin and thiohydantoin in medicinal chemistry. European Journal of Medicinal Chemistry, 164, 517–545. doi: 10.1016/j.ejmech.2018.12.066. 105. Yamaguchi, J. I., Noguchi-Yachide, T., Sakaguchi, Y., Shibata, C., Kanuma, S., Yoshizaki, A., Takizawa, Y., & Hashimoto, Y., (2015). Synthesis of new hydantoins bearing glutarimide or succinimide moiety and their evaluation for cell differentiationinducing and anti-angiogenic activities. Heterocycles, 91(4), 764–781. 106. Yang, K., Tang, Y., & Iczkowski, K. A., (2010). Phenyl-methylene hydantoins alter CD44-specific ligand binding of benign and malignant prostate cells and suppress CD44 isoform expression. Am. J. Transl. Res., 2(1), 88–94.

108

Amino Acids: Insights and Roles in Heterocyclic Chemistry, Volume 2

107. Konnert, L., Dimassi, M., Gonnet, L., Lamaty, F., Martinez, J., & Colacino, E., (2016). Poly(ethylene) glycols and mechanochemistry for the preparation of bioactive 3,5-disubstituted hydantoins. RSC Advances, 6(43), 36978–36986. 108. Brown, M. L., Zha, C. C., Van, D. C. C., Brown, G. B., & Brouillette, W. J., (1999). Comparative molecular field analysis of hydantoin binding to the neuronal voltagedependent sodium channel. Journal of Medicinal Chemistry, 42(9), 1537–1545. 109. Putnam, T. J., & Jacobs, J., (1957). Spirodon (tetrantoin): A new anticonvulsant of the hydantoin group. Neurology, 7(11), 784–788. 110. Sutherland, J. J., & Weaver, D. F., (2003). Development of quantitative structureactivity relationships and classification models for anticonvulsant activity of hydantoin analogues. J. Chem. Inf. Comput. Sci., 43, 1028–1036. 111. Farah, S., Aviv, O., Laout, N., Ratner, S., & Domb, A. J., (2015). Antimicrobial N-brominated hydantoin and uracil grafted polystyrene beads. Journal of Controlled Release, 216, 18–29. 112. Chen, Y., Li, M., Xin, M., & Lin, Y., (2015). Synthesis and antibacterial research of hydantoin modified quaternary ammonium chitosan. Huagong Jinzhan, 34(1), 188–192, 233. 113. Djakovic, S. T. L., Smolinski, A., Trisovic, N. P., Uscumlic, G. S., & Bozic, B. D., (2015). Chemometric study of the antiproliferative activity of some new hydantoin derivatives: Assessment of activity and chromatographic lipophilicity data. Journal of the Brazilian Chemical Society, 26(7), 1379–1386. 114. Wen, H., Li, Y., Liu, X., Ye, W., Yao, X., & Che, Y., (2015). Fusagerins A–F, new alkaloids from the fungus Fusarium sp. Nat. Prod. Bioprospecting., 5, 195–203. 115. Spengler, G., Evaristo, M., Handzlik, J., Serly, J., Molnár, J., Viveiros, M., KiećKononowicz, K., & Amaral, L., (2010). Biological activity of hydantoin derivatives on P-glycoprotein (ABCB1) of mouse lymphoma cells. Anticancer Research, 30, 4867–4872. 116. De Queiroz, R. B., De Carvalho, F. L., Da Fonsêca, D. V., Barbosa-Filho, J. M., Salgado, P. R. R., Paulo, L. L., De Queiroz, A. B. M., et al., (2015). Antinociceptive effect of hydantoin 3-phenyl-5-(4-ethylphenyl)-imidazolidine-2,4-dione in mice. Molecules, 20, 974–986. 117. Keiser, J., Panic, G., Vargas, M., Wang, C., Dong, Y., Gautam, N., & Vennerstrom, J. L., (2015). Aryl hydantoin Ro 13-3978, a broad-spectrum antischistosomal. Journal of Antimicrobial Chemotherapy, 70(6), 1788–1797. 118. Zhang, Q. L., Song, L. J., & Wang, E. S., (2013). Synthesis and antitussive effect of new hydantoin compounds. Chemical Research in Chinese Universities, 29(1), 76–81. 119. Opačić, N., Barbarić, M., Zorc, B., Cetina, M., Nagl, A., Frković, D., Kralj, M., et al., (2005). The novel L- and D-amino acid derivatives of hydroxyurea and hydantoins: Synthesis, X-ray crystal structure study, and cytostatic and antiviral activity evaluations. Journal of Medicinal Chemistry, 48, 475–482. 120. Singh, R., Kumar, N., Arora, S., Bhandari, R., & Jain, A., (2012). Fetal hydantoin syndrome and its anaesthetic implications: A case report. Case Reports in Anesthesiology, 1, 2. doi: 10.1155/2012/370412.

Hydantoin

109

121. Hayden, M., (1978). The fetal hydantoin syndrome: A case report. South Africa Med. J., 53, 145, 146. 122. Gollop, T. R., & Salzo, I., (1999). A case of prenatal diagnosis of fetal hydantoin syndrome by ultrasound. Genetics and Molecular Biology, 22(2), 147–150. 123. Jogdand, A. R., Kathane, L. L., Kuhite, N. G., Padole, C. D., Amdare, M. D., & Mahapatra, D. K., (2017). Fabricating hydantoin/thiohydantoin hybrids from a natural product, cuminaldehyde: New players for anti-convulsant therapeutics. Scholars Academic Journal of Pharmacy, 6(7), 300–303. 124. Won, H., Lee, J. H., Seok, J. H., Jung, K., Yang, J. Y., Jeong, J., & Lee, J. K., (2021). Single- and repeated-dose 28-day oral toxicity study of MDM hydantoin in spragueDawley rats. Toxicological Research (Cham, Switzerland), 37(1), 59–69. doi: 10.1007/ s43188-020-00055-0. 125. Safari, J., & Javadian, L., (2013). A one-pot synthesis of 5,5-disubstituted hydantoin derivatives using magnetic Fe3O4 nanoparticles as a reusable heterogeneous catalyst. Comptes Rendus Chimie, 16(12), 1165–1171. 126. Wu, Y., Shang, G., Tang, Q., Zhang, B., & Wang, E., (2016). Synthesis and immunosuppressive activity of amino alcohol-containing coumarin and benzothiophene. Chem. Res. Chin. Univ., 32(3), 357–365. 127. Waser, M., Moher, E. D., Borders, S. S. K., Hansen, M. M., Hoard, D. W., Laurila, M. E., LeTourneau, M. E., et al., (2011). Process development for a key synthetic intermediate of LY2140023, a clinical candidate for the treatment of schizophrenia. Org. Process Res. Dev., 15, 1266–1274. 128. Tomohara, K., Ito, T., Hasegawa, N., Kato, A., & Adachi, I., (2016). Direct chemical derivatization of natural plant extract: Straightforward synthesis of natural plant-like hydantoin. Tetrahedron Letters, 57(8), 924–927. doi: 10.1016/j.tetlet.2016.01.054. 129. Pesquet, A., Daïch, A., & Hijfte, L. V., (2006). General and versatile entry to 4,5-fused polycyclic imidazolones systems. Use of the tandem transposition/π-cyclization of N-acyliminium species. J. Org. Chem., 71, 5303–5311. 130. Monteiro, J. L., Pieber, B., Correa, A. G., & Kappe, C. O., (2016). Continuous synthesis of hydantoins: Intensifying the Bucherer-Bergs reaction. Synlett, 27(1), 83–87. 131. Murray, R. G., Whitehead, D. M., Franck, L. S., & Conway, S. J., (2008). Facile one-pot synthesis of 5-substituted hydantoins. Org. Biomol. Chem., 6, 988–991. 132. Chubb, F. L., Edward, J. T., & Wong, S. C., (1980). Simplex optimization of yields in the Bucherer-Bergs reaction. J. Org. Chem., 45(12), 2315–2320. 133. Harrington, P. M., & Jung, M. E., (1994). Stereoselective bromination of β-ribofuranosyl amide. Enantioselective synthesis of (+)-hydantocidin. Tetrahedron Letters, 35(29), 5145–5148. 134. Sano, H., & Sugai, S., (1995). Synthesis of an optically active carbocyclic derivative of (+)-hydantocidin. Tetrahedron: Asymmetry, 6(5), 1143–1150. 135. Park, K. H., Olmstead, M. M., & Kurth, M. J., (1998). Diastereoselective synthesis of cyclopentanoids with hydantoin and isoxazoline substituents. J. Org. Chem., 63(1), 113–117.

110

Amino Acids: Insights and Roles in Heterocyclic Chemistry, Volume 2

136. Barve, I. J., Dalvi, P. B., Thikekar, T. U., Chanda, K., Liu, Y. L., Fang, C. P., Liu, C. C., & Sun, C. M., (2015). Design, synthesis and diversification of natural product-inspired hydantoin-fused tetrahydroazepino indoles. RSC Advances, 5(89), 73169–73179. 137. Blanco-Ania, D., Hermkens, P. H. H., Sliedregt, L. A. J. M., Scheeren, H. W., & Rutjes, F. P. J. T., (2009). Synthesis of hydantoins and thiohydantoins spiro-fused to pyrrolidines: Druglike molecules based on the 2-arylethyl amine scaffold. J. Comb. Chem., 11, 527–538. 138. Nefzi, A., Giulianotti, M., Truong, L., Rattan, S., Ostresh, J. M., & Houghten, R. A., (2002). Solid-phase synthesis of linear ureas tethered to hydantoins and thiohydantoins. J. Comb. Chem., 4, 175–178. 139. Wyzlic, I. M., Tjarks, W., Soloway, A. H., Perkins, D. J., Burgos, M., & O’Reilly, K. P., (1996). Synthesis of carboranyl amino acids, hydantoins, and barbiturates. Inorg. Chem., 35(16), 4541–4547. 140. Hess, W. C., (1934). Preparation of cystinehydantoin. J. Am. Chem. Soc., 56, 1421–1421. 141. Karabinos, J. V., & Szabo, J. L., (1944). Hydantoins of some sulfur containing amino acids. J. Am. Chem. Soc., 66, 649, 650. 142. Livak, J. E., Britton, E. C., Vander, W. J. C., & Murray, M. F., (1945). Synthesis of dl-methionine. J. Am. Chem. Soc., 67, 2218–2220. 143. Connors, T. A., Ross, W. C. J., & Wilson, J. G., (1960). Aryl-2-halogenoalkylamines. Part XIX. Some N,N-Di-2-chloroethylamino-phenyl- and -phenylalkyl-hydantoins and related amino-acids. J. Chem. Soc., 2994–3007. 144. Braña, M. F., Garrido, M., Hernando, J. L., López, R. M. L., & Morcillo, M. J., (1987). Reaction of 5-hydroxy-L-tryptophan with alkyl isocyanates. J. Heterocycl. Chem., 24, 1725–1727. 145. Gubitz, F. W., & McKeon, J. W. B., (1962). Mercury derivatives of allylhydantoins. Journal of Medicinal Chemistry, 5, 168–175. 146. Ware, E., (1950). The chemistry of the hydantoins. Chemical Reviews, 46, 403–470. 147. El Bakkari, M., & Vincent, J. M., (2004). Fluorous phase-switching of pyridyl-tagged substrates/products. Org. Lett., 6(16), 2765–2767. 148. Manku, S., & Curran, D. P., (2005). Fluorous mixture synthesis of fused-tricyclic hydantoins. Use of a redundant tagging strategy on fluorinated substrates. J. Org. Chem., 70(11), 4470–4473. 149. Zorc, B., Dzolic, Z. R., & Butula, I., (2012). Benzotriazole as a synthetic auxiliary. Croat Chem. Acta, 85(4), 595–602. 150. Coursindel, T., Martinez, J., & Parrot, I., (2010). Microwave-assisted hydantoins synthesis on solid support. Journal of Chemical Education, 87(6), 640–642. 151. Maiti, B., Chanda, K., & Sun, C. M., (2009). Traceless synthesis of hydantoin fused tetrahydro-β-carboline on ionic liquid support in green media. Org. Lett., 11(21), 4826–4829. 152. Lin, M. J., Zhang, W., & Sun, C. M., (2007). Fluorous and traceless synthesis of substituted indole alkaloids. J. Comb. Chem., 9, 951–958.

Hydantoin

111

153. Liu, S. I., Haung, J. Y., Barve, I. J., Huang, S. C., & Sun, C. M., (2019). Enantioselective synthesis of hydantoin and diketopiperazine-fused tetrahydroisoquinolines via Pictet-Spengler reaction. ACS Combinatorial Science, 21(4), 336–344. doi: 10.1021/ acscombsci.9b00005. 154. Huang, Y., Guo, Z., Song, H., Liu, Y., Wang, L., & Wang, Q., (2018). Design, synthesis, and biological activity of β-carboline analogues containing hydantoin, thiohydantoin, and urea moieties. Journal of Agricultural and Food Chemistry, 66(31), 8253–8261. doi: 10.1021/acs.jafc.8b03087. 155. Grošelj, U., & Svete, J., (2015). Recent advances in the synthesis of polysubstituted 3-pyrazolidinones. Archive, (i), 175–205. 156. Hupp, C. D., & Tepe, J. J., (2009). 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride-mediated oxazole rearrangement: Gaining access to a unique marine alkaloid scaffold. J. Org. Chem., 74(9), 3406–3413. 157. Atkinson, R. C., Fernández-Nieto, F., Rosellý, J. M., & Clayden, J., (2015). Pseudoephedrine-directed asymmetric α-arylation of α-amino acid derivatives. Angew. Chem. Int. Ed., 54, 8961–8965. 158. Maury, J., & Clayden, J., (2015). α-Quaternary proline derivatives by intramolecular diastereoselective arylation of N-carboxamido proline ester enolates. J. Org. Chem., 80, 10757–10768. 159. Atkinson, R. C., Leonard, D. J., Maury, J., Castagnolo, D., Volz, N., & Clayden, J., (2013). Intramolecular arylation of amino acid enolates. Chem. Commun., 49, 9734–9736. 160. Fesenko, A. A., & Shutalev, A. D., (2020). Different pathways in the reaction of N-(tosylmethyl)-substituted ureas, thioureas, and N’-cyanoguanidines with sodium cyanide. Synthesis of α-ureido nitriles, α-ureido amides, and hydantoin imino derivatives. Tetrahedron, 76(40), 131340. doi: 10.1016/j.tet.2020.131340. 161. Martínez-López, D., Yu, M. L., García-Iriepa, C., Campos, P. J., Frutos, L. M., Golen, J. A., Rasapalli, S., & Sampedro, D., (2015). Hydantoin-based molecular photoswitches. J. Org. Chem., 80(8), 3929–3939. 162. Borisa, A. C., Bhatt, H. G., Thakkar, D., & Trivedi, S., (2015). Iso-steric replacement of thiazolidiene Dione to imidazoline Dione (hydantoin) as a novel scaffold: Synthesis and pharmacological evaluation. World Journal of Pharmacy and Pharmaceutical Sciences, 4(4), 928–941. 163. Muccioli, G. G., Wouters, J., Poupaert, J. H., Norberg, B., Poppitz, W., Scriba, G. K. E., & Lambert, D. M., (2003). Versatile access to benzhydryl-phenylureas through an unexpected rearrangement during microwave-enhanced synthesis of hydantoins. Org. Lett., 5(20), 3599–3602. 164. Volonterio, A., De Arellano, C. R., & Zanda, M., (2005). Synthesis of 1,3,5-trisubstituted hydantoins by regiospecific domino condensation/Aza-Michael/O→N acyl migration of carbodiimides with activated α,β-unsaturated carboxylic acids. J. Org. Chem., 70, 2161–2170. 165. Sosa, A. C. B., Yakushijin, K., & Horne, D. A., (2002). Synthesis of axinohydantoins. J. Org. Chem., 67(13), 4498–4500.

112

Amino Acids: Insights and Roles in Heterocyclic Chemistry, Volume 2

166. Soltanzadeh, Z., Imanzadeh, G., Noroozi-Pesyan, N., Sahin, E., & Hooshmand, H., (2016). Unexpected formation of 5-alkylidene derivatives of hydantoin from the Michael addition of 4-phenylurazole to fumaric esters. Tetrahedron, 72(14), 1736–1741. doi: 10.1016/j.tet.2016.02.024. 167. Guthrie, D. A., Nourian, S., Takahashi, C. G., & Toscano, J. P., (2015). Curtailing the hydroxylaminobarbituric acid−hydantoin rearrangement to favor HNO generation. J. Org. Chem., 80, 1349−1356. 168. Ohshiro, Y., Kinugasa, K., Minami, T., & Agawa, T., (1970). Chemistry of a cumulated double-bond compound. X. Reactions of isocyanates and carbodiimide with acetylenic compounds. J. Org. Chem., 35(7), 2136–2140. 169. Suess-Fink, G., Schmidt, G. F., & Herrmann, G., (1987). Catalytic synthesis of 5-benzylidenehydantoins from alkyl isocyanates and phenylacetylene. Chemische Berichte, 120(8), 1451–1453. 170. Kuninobu, Y., Kikuchi, K., & Takai, K., (2008). Manganese-catalyzed synthesis of hydantoin derivatives from terminal alkynes and isocyanates. Chemistry Letters, 37(7), 740, 741. 171. Zhao, B., Du, H., & Shi, Y., (2008). A Cu(I)-catalyzed C-H α-amination of esters. Direct synthesis of hydantoins. J. Am. Chem. Soc., 130(23), 7220, 7221. 172. Beller, M., Eckert, M., Moradi, W. A., & Neumann, H., (1999). Palladium-catalyzed reactions for the synthesis of fine chemicals, part 10. Palladium-Catalyzed Synthesis of substituted hydantoins-a new carbonylation reaction for the synthesis of amino acid derivatives. Angew. Chem. Int. Ed., 38(10), 1454–1457. 173. Miura, T., Mikano, Y., & Murakami, M., (2011). Nickel-catalyzed synthesis of 1,3,5-trisubstituted hydantoins from acrylates and isocyanates. Org. Lett., 13(14), 3560–3563. 174. Firth, J. D., Zhang, R., Morgentin, R., Guilleux, R., Kalliokoski, T., Warriner, S., Foster, R., et al., (2015). Exploitation of the Ugi-Joullie reaction in the synthesis of libraries of drug-like bicyclic hydantoins. Synthesis, 47(16), 2391–2406. 175. Huang, A., Wo, K., Pierson, A., Lee, S. Y. C., Yang, E., & Johnson, C., (2016). 5-Hydroxyl hydantoins via one-pot microwave-assisted air oxidation of Ugi products. Journal of Heterocyclic Chemistry, 53(5), 1499–1504. 176. Agrawal, S. K., Sathe, M., Halve, A. K., & Kaushik, M. P., (2012). Dibutylphosphate (DBP) mediated synthesis of cyclic N,N’-disubstituted urea derivatives from amino esters: A comparative study. Tetrahedron Letters, 53, 5996–5999. 177. Attanasi, O. A., De Crescentini, L., Favi, G., Nicolini, S., Perrulli, F. R., & Santeusanio, S., (2011). 1,3,5-Trisubstituted and 5-Acyl-1,3-disubstituted hydantoin derivatives via novel sequential three-component reaction. Org. Lett., 13(3), 353–355. 178. Pham, T. Q., Pyne, S. G., Skelton, B. W., & White, A. H., (2005). Synthesis of carbocyclic hydantocidins via regioselective and diastereoselective phosphine-catalyzed [3 + 2]-cycloadditions to 5-methylenehydantoins. J. Org. Chem., 70(16), 6369–6377. 179. Sathieshkumar, P. P., Anand, S. M. D., & Nagarajan, R., (2021). A cascade approach for the synthesis of 5-(indol-3-yl)hydantoin: An application to the total synthesis of

Hydantoin

113

(±)-oxoaplysinopsin B. Journal of Organic Chemistry, 86(5), 3730–3740. doi: 10.1021/ acs.joc.0c02435. 180. Millward, M. J., Ellis, E., Ward, J. W., & Clayden, J., (2021). Hydantoin-bridged medium ring scaffolds by migratory insertion of urea-tethered nitrile anions into aromatic C-N bonds. Chemical Science, 12(6), 2091–2096. doi: 10.1039/d0sc06188c. 181. Bhusainahalli, V. M., Rescifina, A., Cardullo, N., Spatafora, C., & Tringali, C., (2018). Bio-activated intramolecular anti-Aza-Michael addition: Stereoselective synthesis of hydantoin derivatives. New Journal of Chemistry, 42(2), 18348–18357. doi: 10.1039/ c8nj02909a. 182. Xu, Z. G., Ding, Y., Meng, J. P., Tang, D. Y., Li, Y., Lei, J., Xu, C., & Chen, Z. Z., (2018). Facile construction of hydantoin scaffolds via a post-Ugi cascade reaction. Synlett, 29(16), 2199–2202. doi: 10.1055/s-0037-1610234. 183. Bogolubsky, A. V., Moroz, Y. S., Savych, O., Pipko, S., Konovets, A., Platonov, M. O., Vasylchenko, O. V., et al., (2018). An old story in the parallel synthesis world: An approach to hydantoin libraries. ACS Combinatorial Science, 20(1), 35–43. doi: 10.1021/ acscombsci.7b00163. 184. Teno, N., Gohda, K., Yamashita, Y., Otsubo, T., Yamaguchi, M., Wanaka, K., & Tsuda, Y., (2016). Plasmin inhibitors with hydrophobic amino acid-based linker between hydantoin moiety and benzimidazole scaffold enhance inhibitory activity. Bioorganic & Medicinal Chemistry Letters, 26(9), 2259–2261. doi: 10.1016/j.bmcl.2016.03.047. 185. Ahmad, R., Jabeen, R., Zia-ul-Haq, M., Nadeem, H., Duddeckb, H., & Verspohl, E. J., (2000). Chiral aryl sulfonyl hydantoins as hypoglycemic agents. Z. Naturforsch., 55b, 203–207. 186. Thennarasu, S., & Perumal, P. T., (2001). Synthesis of new hydantoins as intermediates for diamino acids. Indian J. Chem., 40B, 1174–1176. 187. Stroganov, V. F., Mukhametova, A. M., & Eselev, A. D., (2015). Water-soluble hydantoincontaining epoxy resins and polymers based on them. Polymer Science, Series D, 8(4), 34–38. 188. Goes, A. J. S., Alves De, L. M. C., Galdino, S. L., Pitta, I. R., & Luu-Duc, C., (1991). Synthesis and antimicrobial activity of fluorobenzyl(benzylidene)thiazolidinediones and substituted imidazolidinediones. Journal de Pharmacie de Belgique, 46(4), 236–240. 189. Meusel, M., Ambrozak, A., Hecker, T. K., & Gütschow, M., (2003). The aminobarbituric acid-hydantoin rearrangement. J. Org. Chem., 68, 4684–4692. 190. Hidayat, I. W., Bhadbhade, M., & Read, R. W., (2015). A study of the microwaveaccelerated condensation of substituted benzaldehydes with 3-substituted hydantoins and the unexpected interception of alcohol products. Procedia Chemistry, 17, 75–83. 191. Meanwell, N. A., Roth, H. R., Smith, E. C. R., Wedding, D. L., Wright, J. J. K., Fleming, J. S., & Gillespie, E., (1991). 1,3-Dihydro-2H-imidazo[4,5-b]quinolin-2-ones – inhibitors of blood platelet cAMP phosphodiesterase and induced aggregation. Journal of Medicinal Chemistry, 34(9), 2906–2916.

114

Amino Acids: Insights and Roles in Heterocyclic Chemistry, Volume 2

192. Potin, D., Launay, M., Monatlik, F., Malabre, P., Fabreguettes, M., Fouquet, A., Maillet, M., et al., (2006). Discovery and development of 5-[(5S,9R)-9-(4-cyanophenyl)-3­ (3,5-dichlorophenyl)-1-methyl-2,4-dioxo-1,3,7-triazaspiro[4.4]non-7-yl-methyl]-3thiophene carboxylic acid (BMS-587101)----a small molecule antagonist of leukocyte function-associated antigen-1. Journal of Medicinal Chemistry, 49(24), 6946–6949. 193. Dhand, V., Chang, S., & Britton, R., (2013). Total synthesis of the cytotoxic anhydrophytosphingosine pachastrissamine (jaspine B). J. Org. Chem., 78, 8208−8213. 194. Nique, F., Hebbe, S., Triballeau, N., Peixoto, C., Lefrancois, J. M., Jary, H., Alvey, L., et al., (2012). Identification of a 4-(hydroxymethyl)diarylhydantoin as a selective androgen receptor modulator. Journal of Medicinal Chemistry, 55(19), 8236–8247. 195. Dhara, K., Midya, G. C., & Dash, J., (2012). A diversity-oriented approach to spirocyclic and fused hydantoins via olefin metathesis. J. Org. Chem., 77, 8071−8082. 196. Demmer, C. S., Benoit, E., & Evano, G., (2016). Synthesis of allenamides by coppercatalyzed coupling of propargylic bromides and nitrogen nucleophiles. Organic Letters, 18, 1438–1441. 197. Ren, X., Song, Y., Liu, A., Zhang, J., Yang, P., Zhang, J., & An, M., (2015). Experimental and theoretical studies of DMH as a complexing agent for a cyanide-free gold electroplating electrolyte. RSC Advances, 5(80), 64997–65004. 198. Sasaki, H., (2020). Gold(I) complexes of hydantoin derivatives and their properties. Hyomen Gijutsu, 71(12), 828–832. doi: 10.4139/sfj.71.828. 199. Juma, J. A., Ismail, H. K., Karim, W. O., & Salih, S. J., (2021). High quality mirror finish fabrication of nickel electrodeposited using hydantoin from a mixture of choline chloride-ethylene glycol. Arabian Journal of Chemistry, 14(3), 102966. doi: 10.1016/j. arabjc.2020.102966. 200. Yang, C., & Liu, D., (2015). The impact of DMH on succinimide cyanide-free silver plating. Diandu Yu Jingshi, 37(3), 28–31. 201. Hajiahmadi, Z., & Tavangar, Z., (2021). Proposing a new complexing agent for cyanidefree silver electroplating through a comprehensive computational study of dimethyl hydantoin. Molecular Simulation, 47(8), 619–627. doi: 10.1080/08927022.2021.1895436. 202. Luo, G., Li, D. Y., Yuan, G. H., & Li, N., (2016). Applications of hydantoin compounds in cyanide-free electroplating. Diandu Yu Tushi, 35(5), 268–273. 203. Ahmedova, A., Marinova, P., Marinov, M., & Stoyanov, N., (2016). An integrated experimental and quantum chemical study on the complexation properties of (9’-fluorene)-spiro-5-hydantoin and its thioanalogue. Journal of Molecular Structure, 1108, 602–610. doi: 10.1016/j.molstruc.2015.12.018. 204. Schanno, R. J., Westlund, J. R., & Foelsch, D. H., (1980). Evaluation of 1,3-dimethylol5,5-dimethyl hydantoin as a cosmetic preservative. Journal of the Society of Cosmetic Chemists, 31, 85–96. 205. Sun, G., Xu, X., Bickett, J. R., & Williams, J. F., (2001). Durable and regenerable antibacterial finishing of fabrics with a new hydantoin derivative. Ind. Eng. Chem. Res., 40, 1016–1021.

Hydantoin

115

206. Li, R., Lv, B., Li, J., Chen, X., Yan, S., Shao, X., Ren, X., & Liang, J., (2015). Multifunctional properties of cotton fabrics treated with UV absorber and N-halamine. Fibers and Polymers, 16(9), 1876–1881. 207. Kocer, H. B., Akdag, A., Ren, X., Broughton, R. M., Worley, S. D., & Huang, T. S., (2008). Effect of alkyl derivatization on several properties of N-halamine antimicrobial siloxane coatings. Ind. Eng. Chem. Res., 47(20), 7558–7563. 208. Kocer, H. B., Cerkez, I., Worley, S. D., Broughton, R. M., & Huang, T. S., (2011). N-Halamine copolymers for use in antimicrobial paints. ACS Appl. Mater. Interfaces, 3, 3189–3194. 209. Wilfredo, B. J., & Sumera, F. C., (2011). Regenerable antimicrobial polyurethane coating based on N-hydroxymethylated hydantoin. Philippine Journal of Science, 140(2), 207–219. 210. Makal, U., Uslu, N., & Wynne, K. J., (2007). Water makes it hydrophobic: Contraphilic wetting for polyurethanes with soft blocks having semifluorinated and 5,5-dimethylhydantoin side chains. Langmuir, 23, 209–216. 211. Chen, Y., Worley, S. D., Kim, J., Wei, C. I., Chen, T. Y., Santiago, J. I., Williams, J. F., & Sun, G., (2003). Biocidal poly(styrenehydantoin) beads for disinfection of water. Ind. Eng. Chem. Res., 42, 280–284. 212. Chen, Y., Worley, S. D., Kim, J., Wei, C. I., Chen, T. Y., Suess, J., Kawai, H., & Williams, J. F., (2003). Biocidal polystyrenehydantoin beads. 2. Control of chlorine loading. Ind. Eng. Chem. Res., 42, 5715–5720. 213. Hernández-Torres, G., Tan, B., & Barbas, III. C. F., (2012). Organocatalysis is a safe practical method for the stereospecific dibromination of unsaturated compounds. Org. Lett., 14(7), 1858–1861. 214. Kocer, H. B., Worley, S. D., Broughton, R. M., Acevedo, O., & Huang, T. S., (2010). Effect of phenyl derivatization on the stabilities of antimicrobial N-chlorohydantoin derivatives. Ind. Eng. Chem. Res., 49(22), 11188–11194. 215. Luo, J., Li, C., Li, X., Luo, J., Gao, Q., & Li, J., (2015). A New soybean meal-based bioadhesive enhanced with 5,5-dimethyl hydantoin polyepoxide for the improved waterresistance of plywood. RSC Advances, 5(77), 62957–62965. 216. Luo, H., Zhang, D., Jiang, C., Yuan, X., Chen, C., & Zhou, K., (2015). Improved dielectric properties and energy storage density of poly(vinylidene fluoride-cohexafluoropropylene) nanocomposite with hydantoin epoxy resin coated BaTiO3. ACS Appl. Mater. Interfaces, 7, 8061–8069. 217. Steedman, H. F., (1958). Dimethyl hydantoin formaldehyde: A new water-soluble resin for use as a mounting medium. Quarterly Journal of Microscopical Science, 451–452. 218. Vessières, A., Kowalski, K., Zakrzewski, J., Stepien, A., Grabowski, M., & Jaouen, G., (1999). Synthesis of CpFe(CO)(L) complexes of hydantoin anions (Cp=η5-C5H5, L=CO, PPh3), and the use of the 5,5-diphenylhydantoin anion complexes as tracers in the nonisotopic immunoassay CMIA of this antiepileptic drug. Bioconjugate Chem., 10, 379–385.

116

Amino Acids: Insights and Roles in Heterocyclic Chemistry, Volume 2

219. Fioresi, V. S., Vieira, B. D. C. R., Salabert De, C. J. M., & Souza, T. D. S., (2020). Cytogenotoxic activity of the pesticides imidacloprid and iprodione on allium cepa root meristem. Environmental Science and Pollution Research, 27(22), 28066–28076. doi: 10.1007/s11356-020-09201-5. 220. Teramoto, T., Kurosaki, T., & Okawara, M., (1977). A new, versatile acyl activating reagent for peptide synthesis: Asymmetrically selective peptide synthesis by use of optically active 3-hydroxyhydantoin. Tetrahedron Letters, (18), 1523–1526. 221. May, O., Verseck, S., Bommarius, A., & Drauz, K., (2002). Development of dynamic kinetic resolution processes for biocatalytic production of natural and non-natural L-amino acids. Organic Process Research & Development, 6(4), 452–457. 222. Lickefett, H., Krohn, K., König, W. A., Gehreke, B., & Syldatk, C., (1993). Enantioseparation of 5-monosubstituted hydantoins by capillary gas chromatography – investigation of chemical and enzymatic racemization. Tetrahedron: Asymmetry, 4(6), 1129–1135.

CHAPTER 3

Thiohydantoins

3.1 INTRODUCTION 3.1.1 STRUCTURE Thiohydantoins are sulfur analogs of hydantoins with one or both carbonyl group(s) replaced by a thiocarbonyl group, including 2-thiohydantoins, 4-thiohydantoins, and 2,4-dithiohydantoins. It should be mentioned that there have been some confusions about the nomenclature of thiohydantoins in the literature due to different numbering systems used, concurring with the pattern used for hydantoins. For example, the positions of atoms on the rings of the hydantoin series had been numbered clockwise prior to 1907, whereas they have been numbered counterclockwise after 1907, and such a numbering system has been adopted by both Chemical Abstracts and IUPAC ever since. The new numbering system is consistent with the general requirement of the IUPAC nomenclature system to have the sum of heteroatoms on the ring being minimal, while still giving the smallest numbers for the locations of carbonyl and thiocarbonyl groups. Similarly, the numbering systems in thiohydantoins have been changed accordingly after 1907, as shown in Figure 3.1 [1]. Still, there have been the uses of the old numbering system after 1907 in a few cases, causing the confusion of nomenclature and structures. For example, 4-thiohydantoin was named as 5-thiohydantoin, and 2,4-dithiohydantoin was called 2,5-dithiohydantoin in one publication in 1912 [2]. Among these thiohydantoins, 2-thiohydantoins (also known as 2-thioxo­ imidazolidin-4-ones) are the most common ones due to their easy formation and wide applications. The 2-thiohydantoins can be easily prepared from the reaction between α-amino acid derivatives and alkyl (or aryl) isothiocyanates, as exemplified in the preparation section. On the other hand, 2-thiohydantoins have been applied as the intermediates in developing medicines, herbicides, and fungicides as well as standards for protein sequencing, etc. Particularly, 2-thiohydantoins containing both amido group and thioamido group in the

118

Amino Acids: Insights and Roles in Heterocyclic Chemistry, Volume 2

same molecule render equal numbers of the proton donor (D) and acceptor (A) in a D-A-D-A sequence [3]. Therefore, 2-thiohydantoins are expected to form intricate hydrogen bonding networks in crystals, due to this unique structural feature. For example, X-ray crystallographic data of seven 2-thio­ hydantoins synthesized from alkyl isothiocyanates and amino acid methyl esters indicated that four of the seven structures contain hydrogen-bonded dimeric units linked via N–H/S interactions and three crystals have N–H/O linked H-bonded chains [4]. Since crystals of different polymorphs have different physicochemical properties, such as melting point or solubility, it is important to control the crystal form of the targeted molecules [3].

FIGURE 3.1 The ring numbering system of thiohydantoins.

In addition, 2-thiohydantoins can be applied as ligands to form complexes with a metal cation, as represented by the metal complexes of 3-phenyl2-thiohydantoin with Hg(II) and Ag(I) prepared in neutral or basic media [5]. In these complexes, 2-thiohydantoins have been identified as monobasic or neutral monodentate S-coordinative ligands. Similar to hydantoin, thiohydantoins should be planar in geometry as well. Like the treatment of hydantoin in Chapter 3, in order to provide the basic structural characterization on thiohydantoins, the bond length, bond angle, and dihedral angle of thiohydantoins, including 2-thiohydantoin, 4-thiohydantoin, and 2,4-dithiohydantoin have been computed by both MP2 and B3LYP methods, based on 6–311++G** and aug-cc-pvqz basis sets. All these calculated results along with the relevant experimental data are summarized in Tables 3.1 to 3.3.

MP2

B3LYP

Averagec

Expt. Value [3]

Expt. Value [6]

1.388

1.387 ± 0.002

1.389 ± 0.004

1.393 ± 0.003

1.381

1.381

1.378 ± 0.004

1.368 ± 0.004

1.349 ± 0.003

1.518

1.530

1.530

1.524 ± 0.006

1.515 ± 0.004

1.508 ± 0.003

1.440

1.438

1.449

1.449

1.444 ± 0.006

1.458 ± 0.004

1.448 ± 0.003

C2-N1

1.350

1.348

1.353

1.353

1.351 ± 0.002

1.332 ± 0.004

1.322 ± 0.004

C2-S2

1.630

1.631

1.646

1.647

1.638 ± 0.009

1.664 ± 0.003

1.642 ± 0.003

C4-O4

1.206

1.205

1.202

1.202

1.204 ± 0.002

1.218 ± 0.004

1.225 ± 0.003

N3-H3

1.007

1.006

1.007

1.006

1.006 ± 0.001

–

0.83 ± 0.05

N1-H1

1.004

1.003

1.004

1.004

1.004 ± 0.001

–

0.92 ± 0.05

C5-H5’

1.089

1.087

1.092

1.091

1.090 ± 0.002

–

0.95 ± 0.04

C5-H5”

1.089

1.087

1.092

1.091

1.090 ± 0.002

–

0.94 ± 0.05

N1-C2-N3

105.56

105.61

105.79

105.79

105.68 ± 0.12

107.2 ± 0.3

106.3 ± 0.2

C2-N3-C4

113.72

113.71

113.81

113.83

113.77 ± 0.06

112.3 ± 0.3

112.6 ± 0.2

N3-C4-C5

105.02

105.00

104.90

104.88

104.95 ± 0.07

106.1 ± 0.3

106.5 ± 0.2

C4-C5-N1

102.09

102.10

101.97

101.96

102.03 ± 0.08

101.5 ± 0.2

101.1 ± 0.2

C2-N1-C5

113.62

113.58

113.54

113.55

113.57 ± 0.04

112.7 ± 0.3

113.4 ± 0.2

Items

6–311++Ga

cc-PVQZb

6–311++G

cc-PVQZ

C2-N3

1.386

1.384

1.389

C4-N3

1.375

1.374

C4-C5

1.520

C5-N1

Bond Length (Å)

Thiohydantoins

TABLE 3.1 The Structural Characteristics for 2-Thiohydantoin

Bond Angle (°)

119

MP2

120

TABLE 3.1 (Continued) B3LYP

Expt. Value [3]

Expt. Value [6]

125.96

125.97 ± 0.02

124.3 ± 0.2

124.3 ± 0.2

128.26

128.25

128.34 ± 0.10

128.5 ± 0.3

129.4 ± 0.2

127.66

127.85

127.88

127.75 ± 0.14

127.9 ± 0.3

127.5 ± 0.2

127.38

127.34

127.25

127.24

127.3 ± 0.07

126.0 ± 0.3

126.0 ± 0.2

C2-N3-H3

121.80

121.78

121.88

121.87

121.83 ± 0.05

–

131.4 ± 2.8

C2-N1-H1

120.28

120.27

120.69

120.69

120.48 ± 0.24

–

122.9 ± 3.0

C4-C5-H5’

109.62

109.59

109.95

109.95

109.78 ± 0.20

–

108.6 ± 2.5

C4-C5-H5”

109.62

109.59

109.95

109.95

109.78 ± 0.20

–

–

N1-C5-H5’

113.04

113.06

113.08

113.10

113.07 ± 0.02

–

115.4 ± 2.5

N1-C5-H5”

113.04

113.06

113.08

113.10

113.07 ± 0.02

–

–

S2-C2-N3-C4

180.0

180.0

180.0

180.0

180.0 ± 0.0

177.1 ± 0.2

–

S2-C2-N1-C5

–180.00

–180.00

–180.00

–180.00

0.0 ± 0.0

–179.1 ± 0.2

–

O4-C4-N3-C2

–180.00

–180.00

–180.0

–180.00

0.0 ± 0.0

–175.1 ± 0.3

–

O4-C4-C5-N1

180.0

180.00

180.0

180.0

180.0 ± 0.0

176.1 ± 0.3

–

N3-C2-N1-C5

0.0

0.0

0.0

0.0

0.0 ± 0.0

1.3 ± 0.3

–

N3-C4-C5-N1

0.0

0.0

0.0

0.0

0.0 ± 0.0

–2.7 ± 0.3

–

N1-C2-N3-C4

0.0

0.0

0.0

0.0

0.0 ± 0.0

–3.3 ± 0.4

–

6–311++Ga

cc-PVQZb

6–311++G

cc-PVQZ

S2-C2-N3

126.00

125.98

125.95

S2-C2-N1

128.44

128.41

O4-C4-C5

127.60

N3-C4-O4

Dihedral Angle (°)

Amino Acids: Insights and Roles in Heterocyclic Chemistry, Volume 2

Averagec

Items

B3LYP

Expt. Value [3]

Expt. Value [6]

0.0

0.0 ± 0.0

3.7 ± 0.3

–

0.0

0.0

0.0 ± 0.0

0.8 ± 0.3

–

59.89

59.78

59.77

59.84 ± 0.07

–

–

–59.91

–59.89

–59.78

–59.77

–59.84 ± 0.08

–

–

H1-N1-C5-H5’

–62.34

–62.35

–62.00

–61.99

–62.17 ± 0.20

–

–

H1-N1-C5-H5”

62.33

62.35

62.00

61.99

62.17 ± 0.20

–

–

6–311++Ga

cc-PVQZb

6–311++G

cc-PVQZ

C2-N3-C4-C5

0.0

0.0

0.0

C2-N1-C5-C4

0.0

0.0

O4-C4-C5-H5’

59.91

O4-C4-C5-H5”

Thiohydantoins

MP2

Averagec

Items

aThe

actual basis set is 6–311++G**. actual basis set is aug-cc-PVQZ. cCalculation at MP2/6-31G** can be found at reference [7]. bThe

121

122

Amino Acids: Insights and Roles in Heterocyclic Chemistry, Volume 2

TABLE 3.2 The Calculated Structural Characteristics for 4-Thiohydantoin Items

MP2

B3LYP

Average

6–311++Ga

cc-PVQZb

6–311++G

cc-PVQZ

C2-N3

1.410

1.409

1.417

1.417

1.413 ± 0.004

C4-N3

1.353

1.351

1.354

1.354

1.353 ± 0.002

C4-C5

1.515

1.512

1.522

1.522

1.518 ± 0.005

C5-N1

1.441

1.440

1.450

1.450

1.445 ± 0.006

C2-N1

1.359

1.357

1.363

1.362

1.360 ± 0.003

C2-O2

1.206

1.205

1.204

1.204

1.205 ± 0.001

C4-S4

1.620

1.621

1.634

1.635

1.627 ± 0.008

N3-H3

1.008

1.006

1.008

1.007

1.007 ± 0.001

N1-H1

1.003

1.001

1.004

1.003

1.003 ± 0.001

C5-H5’

1.089

1.087

1.091

1.091

1.089 ± 0.002

C5-H5”

1.089

1.087

1.091

1.091

1.089 ± 0.002

N1-C2-N3

104.65

104.63

104.70

104.70

104.67 ± 0.04

C2-N3-C4

114.25

114.24

114.38

114.37

114.31 ± 0.08

N3-C4-C5

105.20

105.24

105.20

105.21

105.21 ± 0.02

C4-C5-N1

102.83

102.80

102.79

102.78

102.8 ± 0.02

C2-N1-C5

113.08

113.09

112.92

112.94

113.01 ± 0.09

O2-C2-N3

125.58

125.59

125.59

125.58

125.59 ± 0.00

O2-C2-N1

129.76

129.78

129.70

129.72

129.74 ± 0.04

S4-C4-C5

126.77

126.77

126.95

126.93

126.86 ± 0.10

N3-C4-S4

128.03

127.98

127.84

127.85

127.93 ± 0.10

C2-N3-H3

121.90

121.91

121.76

121.76

121.83 ± 0.08

C2-N1-H1

120.91

120.88

121.27

121.27

121.08 ± 0.22

C4-C5-H5’

109.60

109.57

109.92

109.96

109.76 ± 0.21

C4-C5-H5”

109.60

109.57

109.92

109.96

109.76 ± 0.21

N1-C5-H5’

112.87

112.92

112.89

112.88

112.89 ± 0.02

N1-C5-H5”

112.87

112.92

112.89

112.88

112.89 ± 0.02

Bond Length (Å)

Bond Angle (°)

Thiohydantoins

123

TABLE 3.2 (Continued) MP2

Items

B3LYP

6–311++Ga

cc-PVQZb

6–311++G

cc-PVQZ

Average

Dihedral Angle (°) N1-C2-N3-C4

0.0

0.0

0.0

0.0

0.0 ± 0.0

C2-N3-C4-C5

0.0

0.0

0.0

0.0

0.0 ± 0.0

C4-C5-N1-C2

0.0

0.0

0.0

0.0

0.0 ± 0.0

O2-C2-N1-H1

0.0

0.0

0.0

0.0

0.0 ± 0.0

O2-C2-N3-H3

0.0

0.0

0.0

0.0

0.0 ± 0.0

H3-N3-C4-S4

0.0

0.0

0.0

0.0

0.0 ± 0.0

S4-C4-C5-H5’

59.72

59.69

59.57

59.56

59.64 ± 0.08

S4-C4-C5-H5”

–59.72

–59.69

–59.57

–59.56

–59.64 ± 0.08

H1-N1-C5-H5’

–62.00

–62.03

–61.63

–61.60

–61.81 ± 0.23

H1-N1-C5-H5”

62.00

62.03

61.63

61.60

61.81 ± 0.23

aThe bThe

actual basis set is 6–311++G**. actual basis set is aug-cc-PVQZ.

TABLE 3.3 The Calculated Structural Characteristics for 2,4-Dithiohydantoin Items

MP2 6–311++Ga

B3LYP cc-PVQZb

6–311++G

cc-PVQZ

Average

Bond Length (Å) C2-N3

1.392

1.390

1.395

1.394

1.393 ± 0.002

C4-N3

1.358

1.355

1.360

1.359

1.358 ± 0.002

C4-C5

1.513

1.510

1.520

1.520

1.516 ± 0.005

C5-N1

1.443

1.442

1.453

1.453

1.447 ± 0.006

C2-N1

1.348

1.345

1.350

1.349

1.348 ± 0.002

C2-S2

1.629

1.630

1.644

1.645

1.637 ± 0.009

C4-S4

1.620

1.620

1.632

1.633

1.626 ± 0.007

N3-H3

1.008

1.007

1.008

1.007

1.008 ± 0.001

N1-H1

1.004

1.003

1.004

1.004

1.004 ± 0.001

C5-H5’

1.090

1.087

1.091

1.091

1.090 ± 0.002

C5-H5”

1.090

1.087

1.091

1.091

1.090 ± 0.002

124

Amino Acids: Insights and Roles in Heterocyclic Chemistry, Volume 2

TABLE 3.3 (Continued) Items

MP2

B3LYP

Average

6–311++Ga

cc-PVQZb

6–311++G

cc-PVQZ

N1-C2-N3

104.93

104.97

105.13

105.13

105.04 ± 0.11

C2-N3-C4

114.55

114.52

114.66

114.66

114.60 ± 0.08

N3-C4-C5

104.84

104.88

104.81

104.82

104.84 ± 0.03

C4-C5-N1

102.38

102.38

102.30

102.27

102.33 ± 0.06

C2-N1-C5

113.30

113.25

113.10

113.11

113.19 ± 0.10

S2-C2-N3

125.64

125.60

125.61

125.60

125.61 ± 0.02

S2-C2-N1

129.43

129.43

129.26

129.27

129.35 ± 0.10

S4-C4-C5

127.41

127.41

127.61

127.60

127.51 ± 0.11

N3-C4-S4

127.74

127.71

127.58

127.58

127.65 ± 0.09

C2-N3-H3

121.54

121.54

121.52

121.50

121.53 ± 0.02

C2-N1-H1

120.64

120.64

121.14

121.15

120.89 ± 0.29

C4-C5-H5’

110.04

110.04

110.42

110.46

110.24 ± 0.23

C4-C5-H5”

110.04

110.04

110.42

110.46

110.24 ± 0.23

N1-C5-H5’

112.67

112.66

112.67

112.66

112.67 ± 0.00

N1-C5-H5”

112.67

112.66

112.67

112.66

112.67 ± 0.00

Bond Angle (°)

Dihedral Angle (°) N1-C2-N3-C4

0.00

0.00

0.00

0.00

0.0 ± 0.0

C2-N3-C4-C5

0.00

0.00

0.00

0.00

0.0 ± 0.0

C4-C5-N1-C2

0.00

0.00

0.00

0.00

0.0 ± 0.0

S2-C2-N1-H1

0.00

0.00

0.00

0.00

0.0 ± 0.0

S2-C2-N3-H3

0.00

0.00

0.00

0.00

0.0 ± 0.0

H3-N3-C4-S4

0.00

0.00

0.00

0.00

0.0 ± 0.0

S4-C4-C5-H5’

59.99

60.00

59.86

59.87

59.93 ± 0.07

S4-C4-C5-H5” –59.99

–60.00

–59.86

–59.87

–59.93 ± 0.07

H1-N1-C5-H5’ –61.85

–61.84

–61.44

–61.42

–61.64 ± 0.24

H1-N1-C5-H5” 61.85

61.84

61.44

61.41

61.64 ± 0.24

aThe

actual basis set is 6–311++G**. bThe actual basis set is aug-cc-PVQZ.

Thiohydantoins

125

Although two different methods (MP2 and B3LYP) are used in combina­ tion with two basis sets (6–311++G** and aug-cc-PVQZ), the results from these four calculations for all three thiohydantoins are very consistent, with the standard deviation of bond lengths less than 0.01 Å, and a larger deviation occurs between the two MP2 calculations rather than that between the two B3LYP calculations. Likewise, the largest deviation of bond angles is for the C2-N1-H1 angle, with a standard deviation of ±0.24° for 2-thiohydantoin, ±0.22° for 4-thiohydantoin, and ±0.29° for 2,4-dithiohydantoin. On the other hand, the MP2 calculation in general creates a larger standard deviation than the corresponding B3LYP calculation from different basis sets for these three thiohydantoins, indicating the strengths of B3LYP calculation (robustness, fast, smaller file size, etc.). 3.1.2 STABILITY Thiohydantoins containing both thioamido group and amido group, are perceived to be not so stable towards the treatment with acid or base, as well as oxidizing agent, because amides and thioamides can be hydrolyzed under acidic or basic condition [8], such as the digestion of protein with acid or base, and thousands of thioamides have been oxidized to amides [9–12]. However, thiohydantoin derivatives are generally stable under normal condi­ tions. Certain aspects relating to the stabilities of thiohydantoins have been demonstrated when these compounds are treated under basic or acidic condi­ tions, as well as oxidative conditions. For example, 2-thiohydantoins are stable under acidic conditions, with the treatment of acyl chloride, and POCl3/ pyridine under microwave irradiation to form 1,3,4-oxadiazole derivatives (Scheme 3.1) [13]. For comparison, 2-thiohydantoin derivatives have been demonstrated in several cases to withstand the treatment under harsh basic conditions. For instance, 2,4-dithiohydantoin is stable when treated with base such as NaOEt during deacetylation [14], 3-phenyl-4-thiohydantoin is stable under the treatment with Grignard reagent (e.g., ethylmagnesium bromide) for the Michael addition (Scheme 3.2) [15] and 5-methyl-3(substituted phenyl)-4-oxo-2-thioxoimidazolidines can tolerate very basic condition under which these thiohydantoins undergo Aldol condensation with substituted benzaldehydes to form solely 2-thiohydantoin-containing anti-derivatives with prior treatment with a strong base (i.e., LDA, Scheme 3.3) [16]. Also, 2,4-dithiohydantoin undergoes a Mannich reaction with formaldehyde and morpholine (Scheme 3.4) [14].

126

Amino Acids: Insights and Roles in Heterocyclic Chemistry, Volume 2

SCHEME 3.1 Conversion of 2-thiohydantoin’s side chain diacyl hydrazine moiety into 1,3,4-oxadiazole ring.

SCHEME 3.2 Michael addition to the α,β-unsaturated thiocarbonyl functionality.

SCHEME 3.3 Deprotonation of 2-thiohydantoin with LDA and subsequent reaction with benzaldehyde.

SCHEME 3.4 A Mannich reaction involving 2-thiohydantoin.

On the other hand, 2-thiohydantoin has been reported to undergo desul­ furization, as represented by the disappearance of the thiohydantoin signal in acylthiohydantoin when a peptidylthiohydantoin was exposed to air in 0.05 M NaHCO3 solution at room temperature, with a half-time of about 3 hours. Such desulfurization is assumed to be similar to the well-known desulfuriza­ tion of phenylthiocarbamylamino acids. As a result, exposure to both air and light should be minimized [17]. However, in the case of 2,4-dithiohydantoin, the 4-thioamido group is stable even under the oxidation with KMnO4, although the 2-thioamido group is often converted into amido group under oxidation conditions [14].

Thiohydantoins

127

3.1.3  MELTING POINTS OF Α-AMINO ACID BASED 2-THIOHYDANTOINS As there are many 2-thiohydantoin derivatives, it is impossible to collect all the melting points of these 2-thiohydantoins here. Therefore, only the 2-thiohydantoins directly prepared from α-amino acids without additional functional groups will be summarized and listed in Table 3.4. TABLE 3.4 The Melting Points of α-Amino Acids Based 2-Thiohydantoins Amino Acid

M.P. (°C) [17]

M.P. (°C)

Alanine

165–166

163–165 [18]

Arginine

148–150

–

Asparagine

252 (dec.)

246 [19]

Glutamic acid

115–116

–

Glutamine

189–191

190–191 [19]

Glycine

229–231

227 [19]

Histidine

220 (dec.)

–

Isoleucine

132–133

131–133 [18]

Leucine

177–178

174–176 [18]

Lysine

189–191

Methionine

147–149

149.5–151 [18]

Phenylalanine

178–180

184–184.5 [18]

Threonine

264

264 [19]

Tryptophan

190–192

190 [19]

Tyrosine

206–208

211 [19]

Valine

137–140

138–140 [18]

3.1.4  NMR AND MS DATA OF THIOHYDANTOINS Typically, the common signals for characterization of 2-thiohyantoins arising from α-amino acids with 1H NMR would be the chemical shifts for H-1, H-3 and H-5. The chemical shifts and splitting patterns for other hydrogen atoms on the side chains vary, depending on the source of amino acids to form the 2-thiohdyantoins. These side chains may interfere with H-5 as well. However, the characteristic chemical shifts for spiro-thiohydantoins would be those of H-1 and H-3, as there isn’t an H-5. The chemical shift of H-1 is generally found

128

Amino Acids: Insights and Roles in Heterocyclic Chemistry, Volume 2

between 8.9 and 10 ppm, the chemical shift for H-3 would be located between 10 and 12 ppm, and the one for H-5 will be between 4 and 5 ppm. For 13C NMR, the chemical shifts of carbonyl and thiocarbonyl are very close. As no hydrogen is bound to these carbon atoms, it is difficult to assign clearly a particular chemical shift to the carbonyl or thiocarbonyl group. This is the reason that the assignment of 13C signals to carbonyl and thiocarbonyl in thiohydantoins is contradicting. For example, in the spiro-5-(2-thiohydantoin)s, all carbonyl groups have been considered to be more deshielded than the corresponding thiocarbonyl groups, thus all thiocarbonyl groups have been assigned a smaller chemical shift than the carbonyl groups [7, 20]. In contrast, for a group of 5,5-disubstituted 2-thiohydantoins, all thiocarbonyl groups have been assigned with a larger chemical shift than the carbonyl groups [21]. Being with extensive experience in NMR, the author also strongly believes that the thiocarbonyl group should appear in an even lower field than that of the carbonyl group. This has been supported by the solid-state and theoretical treatment of carbon chemical shift tensor for both carbonyl and thiocarbonyl groups [22]. For 13C chemical shift of C-5, it would be found between 50 and 70 ppm. For comparison, the 1H NMR and 13C NMR data for representative thiohydantoins are listed in Table 3.5, with falsely assigned chemical shifts corrected. Regarding the mass spectra of thiohydantoins, a general trend is summarized based on 14 3-aryl-2-thiohydantoins prepared from glycine and aryl-isothiocy­ anates, which have several characteristic ions, like [M-72]+ and [M-SH]+ [25]. The abundance of [M-SH]+ ion depends mainly on the type and substitution mode of the substituent in the phenyl ring. In addition, the molecular ion may be fragmented in different ways. One of them is the loss of a hydrogen atom from the molecular ion, particularly distinct for the derivatives with unsubstituted aromatic ring and especially for 3-b-naphthyl-2-thiohydantoin. Another frag­ mentation is the loss of 29 mass units, arising from the simultaneous splitting of CO and the hydrogen atom, but not from the loss of CH2=NH fragment from the 2-thiohydantoin ring. The loss of 28 mass units from the molecular ion does not result from the loss of CO group from 2-thiohydantoin moiety; instead, the [M-28] ion is only the isotope ion of [M-29] ion. One more characteristic peak is the [M-57] ion, with a high abundance. Its composition and exact mass show that it corresponds with the RNCS fragment, which is stable and does not show further fragmentation. In contrast, the fragmentation pathways for the alkyl 2-thiohydantoins depend mainly on the number of carbon atoms in the substituent and the structure of the chain. An illustrative explanation for the mass peaks for 3-o-tolyl-2-thiohydantoin (also known as 2-thioxo-3-(o-tolyl) imidazolidin-4-one) is displayed in Figure 3.2 [25].

1H

Thiohydantoins

Solvent

H-1

H-3

H-5

C-2

C-4

C-5

Gly-2-thiohydantoin

DMSO-d6

9.80

11.61

4.03 (dd, J1 = 14.7, J2 = 6.5 Hz)

187.4

178.4

54.2 600 MHz [23]

Ala-2-thiohydantoin

DMSO-d6

9.05

10.56

4.01 (quart, J = 6.2 Hz)

186.0

181.2

51.2 600 MHz [23]

–

DMSO-d6

10.01

11.64

4.23 (dddd, J = 1.1, 7.1, 7.1, 7.1 Hz)

182.0

177.3

56.3 500 MHz [1]

Val-2-thiohydantoin

DMSO-d6

9.99

11.60

4.10 (d, J = 3.4 Hz)

186.9

180.0

69.7 600 MHz [23]

Leu-2-thiohydantoin

acetone-d6

9.14

10.63

4.34 (dd, J1 = 8.6, J2 = 5.2 Hz)

174.0

167.2

50.8 600 MHz [23]

Ile-2-thiohydantoin

acetone-d6

8.96

4.28 (d, J = 3.7 Hz), 4.34 (d, J = 3.2 Hz)

174.3, 174.6

166.2, 55.9, 600 MHz [23] 166.7 56.8

Met-2-thiohydantoin

DMSO-d6

4.30 (dd, J1 = 6.8, J2 = 6.1 Hz)

186.5

180.2

63.5 600 MHz [23]

Phe-2-thiohydantoin –

acetone-d6 DMSO-d6

9.10 10.07

10.47 11.44

4.63 (t, J = 4.8 Hz) 4.56 (t, J = 5.1 Hz)

174.2 182.3

166.1 175.8

53.4 600 MHz [23] 61.5 500 MHz [1]

Tyr-2-thiohydantoin

acetone-d6

9.10

10.23

4.63 (dd, J1 = 4.7, J2 = 1.6 Hz)

174.1

166.6

53.1 600 MHz [23]

Trp-2-thiohydantoin

acetone-d6

8.93

10.12

4.44–4.48 (m)

166.6

161.4

53.2 600 MHz [23]

Pro-2-thiohydantoin

acetone-d6

~

10.42

4.39 (dd, J1 = 10.1, J2 = 6.6 Hz)

177.3

165.7

57.7 600 MHz [23]

DMSO-d6

10.28

11.59

–

180.5

179.7

250.13 MHz [20]

DMSO-d6

10.46

11.54

–

180.9

179.0

250.13 MHz [20]

C5-spiro-5-(2­ thiohydantoin) C6-spiro-5-(2­ thiohydantoin)

10.55

Magnet Field

DMSO-d6

10.44

11.60

–

180.9

178.8

250.13 MHz [7]

DMSO-d6

10.38

11.55

–

180.6

180.1

250.13 MHz [20]

–

DMSO-d6

10.36

11.52

–

180.5

180.0

250.13 MHz [7]

C8-spiro-5-(2­ thiohydantoin)

DMSO-d6

10.32

11.53

–

180.6

179.5

250.13 MHz [20]

129

– C7-spiro-5-(2­ thiohydantoin)

Thiohydantoins

TABLE 3.5 Representative Chemical Shifts of Thiohydantoins

Magnet Field

H-1

H-3

H-5

C-2

C-4

–

DMSO-d6

10.30

11.54

–

180.6

179.3

250.13 MHz [7]

C12-spiro-5-(2­ thiohydantoin)

DMSO-d6

10.14

11.58

–

180.7

178.5

250.13 MHz [20]

–

DMSO-d6

10.12

11.57

–

180.7

178.5

250.13 MHz [7]

(9’-fluorene)-spiro-5DMSO-d6 (2-thiohydantoin)

10.59

12.33

–

183.5

174.7

250.13 MHz [20]

DMSO-d6

10.93

13.15

–

179.1

212.3

250.13 MHz [7]

DMSO-d6

9.04

11.08

–

180.0

212.7

250.13 MHz [7]

DMSO-d6

10.90

13.11

–

179.3

212.5

250.13 MHz [7]

DMSO-d6

11.07

13.06

–

180.0

211.8

250.13 MHz [7]

3-(4-Cl-C6H4)-5-Me­ 2-thiohydantoin

DMSO-d6

7.71

4.38 (q, J = 7.0 Hz)

–

–

–

400 MHz [24]

3-(4-Br-C6H4)-5-Me­ 2-thiohydantoin

DMSO-d6

7.77

4.38 (q, J = 7.2 Hz)

–

–

–

400 MHz [24]

DMSO-d6

10.13

4.29 (s)

–

–

–

400 MHz [24]

DMSO-d6

10.40

4.30 (s)

–

–

–

400 MHz [24]

DMSO-d6

7.31

4.26 (s)

–

–

–

400 MHz [24]

3-(4-Cl-C6H4)-2­ thiohydantoin 3-(4-Br-C6H4)-2­ thiohydantoin 3-(4-EtO-C6H4)-2­ thiohydantoin

Note: “C5-spiro-” means cyclopentanespiro-; “C8-spiro-” means cyclooctanespiro-, etc.

Amino Acids: Insights and Roles in Heterocyclic Chemistry, Volume 2

Solvent

C5-spiro-5-(4­ thiohydantoin) C6-spiro-5-(4­ thiohydantoin) C5-spiro-5-(2,4­ dithiohydantoin) C6-spiro-5-(2,4­ dithiohydantoin)

C-5

1H

Thiohydantoins

130

TABLE 3.5 (Continued)

Thiohydantoins

131

FIGURE 3.2 The mass fragmentation patterns of 3-o-tolyl-2-thiohydantoin.

3.1.5  POLARITY AND LIPOPHILICITY OF AMINO ACID-BASED 2-THIOHYDANTOINS Since the most common 2-thiohydantoins are the ones formed from α-amino acids and phenylisothiocyanate, i.e., 3-phenyl-2-thiohydantoins, which have often been used for the sequencing of peptides and proteins via the Edman degradation, the discussion on the polarity of thiohydantoins will be focused on these 2-thiohydantoins. Among these 2-thiohydantoins, the one to affect the polarity of the whole molecule would be the polarity and geometry of the side chains attaching to C-5. An effective way to measure the polarity of a molecule is by means of TLC in the normal phase, from which the larger the Rf value is for a particular 2-thiohydantoin, the lower polarity the 2-thiohy­ dantoin corresponds to. For comparison, two solvent systems have been used to gauge the relative polarity of these 2-thiohdyantoins, i.e., xylene-acetic acid-phthalate buffer at pH 6 (3:2:1) and s-butyl alcohol-phthalate buffer at pH 6 (7:1) [26]. In order to differentiate the overlapping of 2-thiohydantoins of similar Rf values, a Grote’s solution can be applied, due to the different color of the spots [26, 27]. The relative polarity of 2-thiohydantoins arising from α-amino acids under different solvent systems as well as individual colors with the Grote’s reagents are collected in Table 3.6. Due to the less intensity of UV absorption of the phenyl group in 3-phenyl-2-thiohydantoins of the corresponding amino acids, alternative aryl isothiocyanate has been developed to react with α-amino acids to afford similar 2-thiohydantoins but of intense UV or even visible absorption, for better detection of 2-thiohydantoins of lower quantity. For example, the colored Edman reagent of 4-N,N-dimethylaminoazobenzene-4’-isothiocya­ nate (DABITC), together with phenyl isothiocyanate has been applied for

132

Amino Acids: Insights and Roles in Heterocyclic Chemistry, Volume 2

micro-sequencing peptides and proteins, involving the initial coupling of a peptide with DABITC and subsequent coupling with phenyl isothiocyanate. After acidic cleavage and conversion reaction, only the colored DABthiohydantoin-amino acids are identified by TLC, avoiding the high coupling temperature (75°C) required by the single coupling with DABITC. Many images for individual polyamide TLC of DAB-thiohydantoin-amino acids have been provided, as well as the micro-sequencing results for short peptide sequences [28]. To provide a visual impression on the relative polarity of DAB-thiohydantoin-amino acids under different TLC conditions and high performance TLC conditions, the corresponding TLC and HPTLC are repro­ duced from the published results as shown in Figure 3.3 [29]. TABLE 3.6 The Rf Values of 3-Phenyl-2-Thiohydantoins and Corresponding Colors with the Grote’s Reagents [26] α-Amino Acid PTH sec-BuOH/Buffer

Xylene/Acetic Acid/ Color with Grote’s Buffer Reagent

Ala-PTH

0.78

0.08

Blue

Asp-PTH

0.13

0.03

Blue

Arg-PTH

0.44

0.00

Blue-violet

Cys-PTH

0.00

0.00

Bluish

Gly-PTH

0.78

0.30

Red

Glu-PTH

0.29

0.00

Blue

His-PTH

0.78

0.00

Yellow

Ile-PTH

0.92

0.47, 0.90

Blue

Leu-PTH

0.92

0.41, 0.90

Blue

Lys-PTH

0.92

0.49

Blue-violet

Met-PTH

0.92

0.23

Blue

Phe-PTH

0.92

0.30, 0.83, 0.90

Blue, yellow

Pro-PTH

0.92

0.45, 0.87

Blue, purple

Ser-PTH

0.92

0.81

Red

Thr-PTH

0.92

0.77

Blue

Tyr-PTH

0.92

0.10

Yellow

Try-PTH

0.92

0.50

Yellow

Val-PTH

0.92

0.30, 0.85

Blue

Note: Some α-amino acid-2-thiohydantoins display multiple spots, and the italic colors correspond to the spots of italic Rf values. It is questionable that 2-thiohydantoin derivative of cysteine with Rf of 0 for both solvent systems, and is quite different from that of serine and threonine.

Thiohydantoins

133

FIGURE 3.3 The TLC and HPTLC of DAB-thiohydantoin-amino acids. Solvent system I with CHCl3:EtOH = 92:2 (v/v), II with CHCl3:EtOH:MeOH = 88.2:1.8:10 (v/v/v), III with CHCl3:EtOAc = 90:10, and IV with CHCl3:i-PrOH = 90:10 (v/v). (O) for origin, and (f) for solvent front.

3.2 BIOLOGICAL ACTIVITIES Different from hydantoins that have been commonly distributed in natural products, thiohydantoins are not commonly identified in natural products. However, due to their structural similarity with hydantoins, thiohydantoins, especially 2-thiohydantoins have been identified with many biological activities that hydantoins bear, as well as some unique properties, specifi­ cally held by 2-thiohydantoins. For example, 2-thiohydantoins have been widely applied as anti-epileptic, anti-inflammatory agents, anti-ulcer, anticarcinogenic, anticonvulsant, antimicrobial (antifungal and antibacterial), antimicrobial, antimutagenic, antineoplastic, antithrombotic, antithyroidal, antitumor activities, antiviral (e.g., herpes simplex virus, human immu­ nodeficiency virus, tuberculosis), and hypolipidemic agents as well as fungicides, herbicides, and pesticides [23, 30–33]. These physicochemical and biological activities might be attributed to the unique structural feature of 2-thiohydantoin, which contains a thioamido group and an amido group, providing an equal number of hydrogen-bond proton donor (D) and acceptor (A) in the D-A-D-A sequence [34]. Specifically, the biological activities of 2-thiohydantoins can be classified into the following groups: protein ligands, enzyme inhibitors, antibacterial agents, antiviral agents, anti-parasite agents, anti-insects, and practically medical agents.

134

Amino Acids: Insights and Roles in Heterocyclic Chemistry, Volume 2

3.2.1 PROTEIN LIGANDS The first type of biological application of 2-thiohydantoins is to bind with proteins or receptors, either as a role of ligand (agonist) or inhibitor (antago­ nist). For example, cannabinoid receptors, as a part of the endocannabinoid system, are involved in a variety of physiological processes such as appetite, memory, mood, and pain sensation. Cannabinoid receptors, with seven transmembrane domains, belong to G protein-coupled receptors and consist of two subtypes: CB1 and CB2. CB1 is primarily expressed in the brain of the central nervous system, and also in the kidney, lung, and liver (e.g., in the cerebellum, the basal ganglia, the substantia nigra pars compacta, some regions of the globus pallidus, as well as in peripheral organs such as the adrenal glands, bone marrow, lungs, testis, and uterus) [21]. In contrast, CB2 is mainly expressed in the cells associated with the immune system and hematopoietic cells, like leukocytes, spleen, thymus, and tonsils. Recently, CB2 has been identified in some specific human cerebellum microglial cells as well. As the ligands for the CB1 receptor, 5,5’-bis-(4-iodophenyl)-3-butyl2-thioxoimidazolidin-4-one (1) and 3-allyl-5,5’-bis(4-bromophenyl)2-thioxoimidazolidin-4-one (2; Figure 3.4) possess the highest affinity described to date for the hydantoin and thiohydantoin series [21]. It has been reported that general diphenyl 2-thiohydantoins behave as inverse agonists for CB1 receptors with good selectivity between CB1 and CB2 [35]. On the other hand, somatostatin, also known as growth hormone-inhibiting hormone (GHIH), growth hormone release-inhibiting hormone (GHRIH), somatotropin release-inhibiting factor (SRIF), as well as somatotropin release-inhibiting hormone (SRIH), exerts its pharmacological action by binding to receptors that belong to the G-protein-coupled superfamily, i.e., the somatostatin receptors [36]. There are six different somatostatin genes that have been named SS1, SS2, SS3, SS4, SS5, and SS6 for vertebrates, but humans have only one somatostatin gene, i.e., SST. [37, 38] Somatostatin is produced in the brain by neuroendocrine neurons of the hypothalamus, in two active forms with 14 amino acids and 28 amino acids, known as SRIF-14 and SRIF-28, respectively. Somatostatin inhibits the release of (a) growth hormone from the anterior pituitary, (b) insulin and glucagon from the pancreas, and (c) gastrin from the gastrointestinal tract, with additional antiproliferative function and regulation of neurotransmission (either as a neurotransmitter or neuromodulator). A series of 2-thiohydantoins have been prepared and tested as the ligands for somatostatin subtype 4 (SST4) [36]. Another type of the G protein-coupled receptors are 5-HT receptors that bind to the endogenous neurotransmitter serotoin (5-hydroxytryptamine, 5-HT),

Thiohydantoins

135

among which the subtype 5-HT1A receptor is the most widespread 5-HT receptor, existing in the cerebral cortex, hippocampus, septum, amygdala, and raphe nucleus in high densities. 5-HT1A is coupled to Gi/G0 and mediates inhibitory neurotransmission. For this particular G protein-coupled receptor, it is found that bicyclothiohydantoin is one of the two most important ligand classes [32], and one representative example is 3-thioxohexahydro­ 1H-pyrrolo[1,2-c]imidazol-1-one (3) as shown in Figure 3.4. On the other hand, the androgen receptor (AR), as a DNA-binding transcription factor, regulates gene expression, and the androgen receptorregulated genes are critical for the development and maintenance of the male sexual phenotype. As a result, androgen receptor plays a fundamental role in the regulation of cell proliferation, cell cycle, apoptosis, angiogenesis, and differentiation in prostate cancer. This type of receptor can be activated by androgenic hormones, testosterone, or dihydrotestosterone in the cytoplasm, as well as other nonsteroidal AR antagonists such as bicalutamide, nilutamide, and flutamide. Therefore, the first line of treatment for prostate cancer is by means of androgen deprivation therapy (ADT) which impedes the interac­ tions between androgen and androgen receptors by castration or using AR antagonists as mentioned above [39]. 4-(3-(4-Cyano-3-(trifluoromethyl) phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)-2-fluoro-N-meth­ ylbenzamide, also known as enzalutamide or MDV3100 (4 in Figure 3.4), is a second-generation nonsteroidal antagonist for androgen receptor for the treatment of castration-resistant prostate cancer (CRPC) [40]. It has been reported that the analog of MDV3100, i.e., 4-(7-(4-cyano-3-(trifluoromethyl) phenyl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-5-yl)-2-fluoro-N-meth­ ylbenzamide, also known as RD162 (5; Figure 3.4), has similar activity as that of MDV3100 against CRPC, still with a superb pharmacokinetic profile [41]. Proxalutamide, i.e., 4-(4,4-dimethyl-3-(6-(3-(oxazol-2-yl)propyl) pyridin-3-yl)-5-oxo-2-thioxoimidazolidin-1-yl)-3-fluoro-2-(trifluoromethyl) benzonitrile, is a newly developed androgen receptor (AR) antagonist for the treatment of castration-resistant prostate cancer (PCa), and is currently at phase III trial [42]. Interestingly enough, this thiohydantoin has been identi­ fied as an effective agent in viral clearance in patients with mild to moderate COVID-19 based on a randomized, double-blinded, placebo-controlled trial [43], which will reduce the mortality rate in hospitalized COVID-19 patients depending on the duration of treatment [44]. Another androgen receptor inhibitor, apalutamide, i.e., 4-(7-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-8oxo-6-thioxo-5,7-diazaspiro[3.4]-octan-5-yl)-2-fluoro-N-methylbenzamide, has recently been shown to provide an added survival benefit in the treatment of metastatic castration-sensitive prostate cancer (mCSPC) [45]. Further

136

Amino Acids: Insights and Roles in Heterocyclic Chemistry, Volume 2

study indicates that the isomerization of the thiohydantoin core via S-arylation into 2-mercapto-3,5-dihydro-4H-imidazol-4-one moiety, as represented by (Z)-2-((4-chlorophenyl)thio)-5-(4-ethoxybenzylidene)-3,5-dihydro-4Himidazol-4-one and (Z)-5-(4-fluorobenzylidene)-2-((4-methoxy-phenyl) thio)-3,5-dihydro-4H-imidazol-4-one, potentially turns the resulting deriva­ tives into androgen receptor’s allosteric co-activator, instead of inhibitor [46]. Alzheimer’s disease (AD), sometimes known as Alzheimer’s, is a chronic and progressive neurodegenerative disorder, characterized by abundant senile plaques (SPs) composed of b-amyloid (Ab) peptides and numerous neurofibrillary tangles (NFTs) formed by filaments of highly phosphorylated tau proteins in the brain, both are toxic to neurons. It has been known that thiohydantoin has an activity to inhibit the aggregation of tau proteins and de-aggregate the preformed tau aggregates [47]. For example, a 125I isotopelabeled thiohydantoins derivative, i.e., (Z)-3-(2-(1H-imidazol-4-yl)ethyl)5-((5-(3-iodophenyl)furan-2-yl)methylene)-2-thioxoimidazolidin-4-one, known as [125I]TH2 (6; Figure 3.4), has displayed high specific binding to tau aggregates in the in vitro experiments with tau and b-amyloid aggregates. As [125I]TH2 intensely stains the neurofibrillary tangles in hippocampal sections obtained from AD patients, and also demonstrates a good uptake and a rapid washout from the brain, it obviously becomes a potential imaging agent for detecting the tau pathology [48].

FIGURE 3.4 2-Thiohydantoins that function as the protein ligands.

3.2.2 ENZYME INHIBITORS Different from various functions of proteins, enzymes primarily catalyze the biosynthesis and degradation of important biological molecules.

Thiohydantoins

137

2-Thiohydantoins, due to their high dense functional groups that include thioamido, amido, and thiouredio groups as well as additional functional­ ities on the side chains at positions 1, 3, and 5, have often been identified or applied as the inhibitors of enzymes, such as tyrosinase, indoleamine 2,3-dioxygenase, c-di-AMP synthase (DisA), cyclooxygenase, DNA topoi­ somerase I, fatty acid hydrolase, glycogen phosphorylases, glycosidase, HIV-1 integrase, isocitrate dehydrogenase, serine protease, and amylase, just to name a few. The first enzyme discussed here is tyrosinase located in melanocytes. Tyrosinase is an oxidase that is involved in the rate-limiting step for the hydroxylation of monophenol (the side chain of α-amino acid tyrosine and dopamine) to o-diphenol and subsequent conversion of the o-diphenol into the corresponding dopaquinone using oxygen as the oxidant. Dopaquinone undergoes several reactions to eventually form melanin, the substance that gives skin, hair, and eyes their color. This enzyme is a copper-containing enzyme found inside melanosomes synthesized in skin melanocytes, with the copper atom coordinating to three histidine residues. Tyrosinases from different species are not the same, but human tyrosinase is a single membranespanning transmembrane protein with about 13% of carbohydrate content and the catalytical domain residing within melanosomes. It is reported that the variations in skin color of human beings among different racial groups are due to the differences in the production and deposition of melanin in the skin. Cultured human melanocytes from different racial skin types demon­ strate an excellent correlation between the melanin content of melanocytes and the in situ activity of tyrosinase, where melanocytes derived from black skin have up to 10 times more activity of tyrosinase and produce up to 10 times more melanin than the melanocytes derived from white skin, although the number of tyrosinase molecules is almost the same in both melanocytes (white-skin and highly pigmented black skin) [49]. Obviously, the inhibitors of tyrosinase can be used to treat hyperpigmentation, melasma, freckles, and age spots, and used as skin whitening agents; whereas activators or agonists of tyrosinase that increase melanogenesis can protect the skin from UV damage. In addition, tyrosinase inhibitors can be applied to maintain the quality and nutritional value of agricultural products after harvest by means of preventing the formation of a quinone from tyrosinase catalyzed browning reaction. Also, tyrosinase inhibitors can be used to control insects and pests by inhibiting their developmental and defensive functions, including wound healing, sclerotization, melanin synthesis and parasite encapsulation. Popular tyrosinase inhibitors are coumarins [50], kojic acid

138

Amino Acids: Insights and Roles in Heterocyclic Chemistry, Volume 2

[51], tropolone [52], vanillic acid, vanillin [53], etc. Recently, substituted benzylidene derivatives of 2-thiohydantoin prepared from the condensation between benzaldehydes and 2-thiohydantoin have been synthesized in order to develop more potent, safer tyrosinase inhibitors capable of being utilized in the agricultural, food, cosmetics, and pharmaceutical industries. For example, (Z)-5-(2,4-dihydroxybenzylidene)-2-thiohydantoin (7; Figure 3.5) has 24 times the inhibitory effect of resveratrol and 18 times that of kojic acid against mushroom tyrosinase and has demonstrated its anti-melanogenesis activity through the inhibition of tyrosinase in B16 cells with no appreciable cytotoxicity [54]. The second type enzyme is the cyclic dinucleotide synthase (or synthe­ tase) which catalyzes the synthesis or degradation of bacterial cyclic dinucleotide. As cyclic dinucleotides regulate various cellular processes in different bacterial species, including virulence, formation of biofilms, and synthesis of the cell wall, they have emerged as new antibacterial targets. For example, cyclic di-adenosine monophosphate (cyclic di-AMP or c-di-AMP) has been well known to be a second messenger in signal transduction of bacteria [55], which regulates various processes in Gram-positive bacteria and mycobacteria, such as DNA damage sensing, fatty acid synthesis, potas­ sium ion transport, cell wall homeostasis and type I interferon response, etc. [56]. Therefore, the inhibitor of this type enzyme would affect bacterial growth and viability. For example, 5-(3,5-dibromo-2-hydroxylbenzylidene)2-thioxoimidazolidin-4-one (also known as bromophenol thiohydantoin or bromophenol-TH, 8 in Figure 3.5) is a specific inhibitor for c-di-AMP synthase (DisA), that does not inhibit other cyclic dinucleotide synthases, such as RocR (c-di-GMP PDE), YybT (c-di-AMP PDE) or WspR (c-di-GMP synthase) [56]. The third type of enzyme that can be inhibited by 2-thiohydantoin derivatives is the isocitrate dehydrogenase (IDH), which catalyzes the oxidative decarboxylation of isocitrate to generate α-ketoglutarate and CO2 by means of oxidation of isocitrate to oxalosuccinate and subsequent decarboxylation of oxalosuccinate [57]. The conversion of isocitrate to α-ketoglutarate corresponds to a large negative free energy change, resulting in favored reactions in the citric acid cycle. In humans, there are three isoforms of IDH, i.e., IDH1, IDH2 and IDH3 [58]. It is known that mutations of IDH1 and IDH2 lead to the production of D-2-hydroxy­ glutarate from α-ketoglutarate, and D-2-hydroxyglutarate of high concen­ tration can further inhibit the function of enzymes that are dependent on α-ketoglutarate, resulting in a hypermethylated state of DNA and histones

Thiohydantoins

139

and different gene expression that can activate oncogenes and inactivate tumor-suppressor genes [59]. Thus, IDH mutation is an early event in cancer initiation and development. Obviously, it is important and critical to regulate the activity of IDH, in order to avoid the depletion of isocitrate and accumulation of α-ketoglutarate. Regarding the inhibitor of IDH, it is reported that 3-benzyl-5-(3,4-dihydroxybenzylidene)-2-thiohydantoin (9; Figure 3.5) is an inhibitor of IDH1 (R132H) with a Ki value of 4.7 μM against the substrate α-ketoglutarate [60]. The fourth type of enzyme that could be inhibited by thiohydantoins is DNA topoisomerase I. Topoisomerases are isomerases that act on the topology of DNA, which regulate the overwinding or underwinding of DNA structure arising from the intertwined nature of the double-helix during DNA replication and transcription [61]. There are two groups of topoisomerases, i.e., type I topoisomerases and type II topoisomerases, which cut one and both DNA strands in one round of action, respectively [62]. Type I topoisomerases are not ATP dependent, which cut, relax, and re-anneal one of the two strands, and are further classified into type 1A topoisomerases and type 1B topoisomerases, where the former are metaldependent and change the linking number of a circular DNA strand by units of strictly 1 whereas the latter change the linking number by multiples of 1 (n). Likewise, type II topoisomerases cut both strands of DNA double helix and re-anneal the cut strands. Regarding DNA topoisomerase I, it has been reported that (E)-5-((5-(6-methoxypyridin-3-yl)thiophen-2-yl) methylene)-2-thioxoimidazolidin-4-one (10; Figure 3.5) exhibited potent inhibition of human Top1 (HTop1) through stabilization of Top1-DNA cleavage complexes, and showed selective anticancer activity against human cervical carcinoma (HeLa) and breast carcinoma (MCF-7) cell lines [63]. Another enzyme that can be interfered with is cyclooxygenase. Cyclooxygenase (COX), officially known as prostaglandin-endoperoxide synthase (PTGS), is involved along with lipoxygenases and epoxygenases in the metabolism of arachidonic acid to form prostaglandins and throm­ boxanes. There are two types of cyclooxygenases, i.e., COX-1 and COX-2. For example, COX-2 is responsible for the production of prostaglandin E2 (PGE2), and contributes to colorectal neoplasia development [64]. COX-1 and COX-2 are commonly used in medical terms, however, “PTGS” is officially used for this family of proteins because the root symbol “COX” has already been used for the family of cytochrome c oxidases. The main COX inhibitors are non-steroidal anti-inflammatory drugs (NSAIDs). It is

140

Amino Acids: Insights and Roles in Heterocyclic Chemistry, Volume 2

found that (±)-3,5-diaryl-2-thioxoimidazolidin-4-ones can be developed as inhibitors for cyclooxygenases [65]. Also, 2-thiohydantoin has been found to inhibit another important type of enzyme, the receptor-interacting protein kinase (RIPK), or receptorinteracting serine/threonine-protein kinase. In humans, there are five subtypes of RIPKs, i.e., RIPK1, RIPK2, RIPK3, RIPK4 and RIPK5. RIPK1 has functions in a variety of cellular pathways including the NF-κB pathway and programmed necrotic cell death (necroptosis) [66], RIPK2 has conserved domain architecture and important functions in apoptosis, necrosis, and innate immunity [67], RIPK3 has an essential function in necroptosis whose activity is controlled by phosphorylation [68]. Depending on the cellular context, tumor necrosis factor (TNF) induces RIPK1 and RIPK3 dependent necrotic cell death (regulated necrosis or necroptosis). 2-Thiohydantoin necrostatin-1 (Nec-1), i.e., 5-((1H-indol3-yl)methyl)-3-methyl-2-thiohydantoin (11; Figure 3.5), originally identi­ fied in a screen for chemical inhibitors of necrotic cell death in human U937 cells, has been identified as an allosteric inhibitor of RIPK1 [69]. As a result, it has been widely used in disease models to examine the contribution of RIPK1 in cell death and inflammation. In addition, it is also an inhibitor of the potent immunomodulatory enzyme indoleamine 2,3-dioxygenase (IDO) [70]. Besides those enzymes mentioned above, many other enzymes can also be inhibited by 2-thiohydantoins. For example, (E)-2-hydroxy-5­ (5-((5-oxo-2-thioxoimidazolidin-4-ylidene)methyl)furan-2-yl)benzoic acid (12; Figure 3.5) has been identified as the inhibitor for HIV-1 integrase [71], D-glucopyranosylidene-spiro-thiohydantoin (13; Figure 3.5) and D-xylopyranosylidene-spiro-thiohydantoin (14; Figure 3.5) have been reported as efficient inhibitors of muscle and liver glycogen phosphorylases [72, 73], 5,5-bis(2-pyridyl)-2-thiohydantoin (15; Figure 3.5) is the inhibitor for fatty acid hydrolase that has a slightly better activity than 5,5-diphenyl-2-thiohydantoin in lowering liver cholesterol values [74, 75], (6R,7S)-2-butyl-5,6,7-trihydroxy-3-thioxo-2,3,6,7­ tetrahydroimidazo[1,5-a]pyridin-1(5H)-one (16; Figure 3.5) and (6R,7S)­ 5,6,7-trihydroxy-2-octyl-3-thioxo-2,3,6,7-tetrahydroimidazo[1,5-a] pyridin-1(5H)-one (17; Figure 3.5), as the thiohydantoin-castanosper­ mine glycomimetics, have demonstrated the inhibitive activities against b-glucosidase/b-galactosidase from bovine liver and b-galactosidase from E. coli [76].

Thiohydantoins

141

FIGURE 3.5 Enzyme inhibiting 2-thiohydantoins.

3.2.3  ANTIBACTERIAL AGENTS, ANTIVIRAL AGENTS, AND ANTIPARASITE AGENTS Besides the direct interactions with proteins and enzymes as mentioned above, the biological activities of thiohydantoins have been demonstrated in their potential applications to interact with parasites and microbes, including bacteria and viruses. Some cases for the treatment of insects (e.g., moths) with thiohydantoins have also been reported. For example, it has been reported that (Z)-4-((2-hydroxyethyl)imino)-1,3-diazaspiro[4.4]nonane-2-thione, also known as 4-(2-hydroxyethylimino)-cyclopentanespiro-5-(2-thiohy­ dantoin) (HEICPSTH, 18; Figure 3.6) displayed an effective dose-response curve against potato tuber moth [77]. A series of 3-(3-alkyl-2,6-diarylpip­ erin-4-ylidene)-2-thioxoimidazolidin-4-ones (19; Figure 3.6) have been screened for their antimicrobial activities against a spectrum of clinically isolated microbial organisms such as Staphylococcus aureus, β-Hemolytic Streptococcus, Vibrio cholerae, Escherichia coli, Pseudomonas aeruginosa, Aspergillus flavus, Candida albicans at a minimum inhibitory concentration of 50–100 μg/mL [78]. Also, (E)-5-((5,5,8,8-tetramethyl-5,6,7,8-tetrahydro­ naphthalen-2-yl)methylene)-2-thioxoimidazolidin-4-one (20; Figure 3.6) has been evaluated for its in vitro antimicrobial activity against methicillin­ resistant Staphylococcus aureus (MRSA) (standard), methicillin-resistant

142

Amino Acids: Insights and Roles in Heterocyclic Chemistry, Volume 2

Staphylococcus aureus (isolated), Staphylococcus aureus, Escherichia coli, Bacillus subtilis, and Candida albicans, which displayed equal and/ or greater antimicrobial activity against MRSA and E. coli than ampicillin and sultamicillin [79]. On the other hand, 1-aryl-3-[3,5-dichlorobenzo[b] thien-2-yl)carbonyl]-2-thioxoimidazolidin-4-one (21; Figure 3.6) has been reported as a potential antimicrobial agent by agar diffusion method against E. coli [80]. Regarding the activity of anti-parasite, several hybrid molecules containing 2-thiohydantoin nucleus have been synthesized and tested for antileishmanial activity, such as (Z)-4-((5-(3-((5-oxo-2-thioxoimidazolidin-4-ylidene) methyl)-1H-indol-1-yl)pentyl)oxy)benzonitrile (22; Figure 3.6) with 95.1% inhibition for promastigote and 62.0% inhibition for intracellular amastigote measured at 10 µg/mL and 12.5 µg/mL, respectively; likewise, (Z)-5-((1­ (5-phenoxypentyl)-1H-indol-3-yl)methylene)-2-thiohydantoin (23; Figure 3.6), (Z)-4-(4-(3-((5-oxo-2-thioxoimidazolidin-4-ylidene)methyl)-1H-indol­ 1-yl)butoxy)benzonitrile (24; Figure 3.6), (Z)-4-((6-(3-((5-oxo-2-thiox­ oimidazolidin-4-ylidene)methyl)-1H-indol-1-yl)-hexyl)oxy)benzonitrile (25; Figure 3.6), and (Z)-5-((1-(5-(4-phenylpiperazin-1-yl)pentyl)-1H­ indol-3-yl)methylene)-2-thiohydantoin (26; Figure 3.6) have demonstrated 40.7%, 58.8%, 71.3% and 88.3% of inhibiting activity against promastigote, respectively, although without detected activity against the intracellular amastigote. However, (Z)-4-((5-(3-((5-oxo-2-thioxoimidazolidin-4-ylidene) methyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)pentyl)oxy)benzonitrile (27; Figure 3.6) demonstrated a 97% of inhibition measured at 10.0 µg/mL for the intra­ cellular amastigote [81]. 2-Thiohydantoins have also been detected of anti-fungus activity, as demonstrated in the more than 50% inhibition of mycelial growth against Aspergillus flavus with 3-benzyl-5-(3’-nitro)benzylidene-2-thiohydantoin (28; Figure 3.6) [82]. Several 2-thiohydantoin derivatives have demonstrated anti-bacterial activity as well. For examples homoveratryl based thiohydantoins, e.g., (Z)-1,3-bis(3,4-dimethoxyphenethyl)-2-thioxo-5-(3,4,5-trimethoxybenzyli­ dene)imidazole-din-4-one (29; Figure 3.6) has displayed activities for the inhibition of Escherichia coli, Staphylococcus aureus, Salmonella typhi, and Bacillus substilis [83], simple 5-heptyl-2-thiohydantoin has demonstrated activity against Mycobacterium tuberculosis [80, 84]. Several 2-thio­ hydantoins have activities against Staphylococcus aureus, β-Hemolytic Streptococcus, Vibrio cholera, Escherichia coli, Pseudomonas aeruginosa, Aspergillus flavus, Candida albicans, etc. [85]. It has also been reported that for the case of 3-arylidene substituted 2-thiohydantoin, the attachment of

Thiohydantoins

143

carboxyl group to thiohydantoin ring produces strong antimicrobial activity, and the presence of acetyl group with thiophene ring in 2-thiohydantoin derivative (i.e., (E)-1-acetyl-5-(thiophen-2-ylmethylene)-2-thioxo-3-((E)-2­ (p-tolyl)prop-1-en-1-yl)imidazolidin-4-one, 30; Figure 3.6) leads to a higher activity against bacteria [86].

FIGURE 3.6 2-Thiohydantoin derivatives with antibacterial, antiviral or anti-parasite activities.

Also, 2-thiohydantoins have shown anti-virus activities. Examples include a series of 5-arylidene-3-aryl-2-(2’,3’,4’,6’-tetra-O-acetyl-b-D­ glucopyranosyl)-2-thiohydantoins with activity in suppressing the replication of herpes simplex virus (HSV) [87]; specifically, the 5-(2-thienylmethylene)3-phenyl-2-(2,3,4,6-tetra-O-acetyl-b-D-glucopyranosyl)-2-thiohydantoin (31; Figure 3.6) and its 3-(4-chlorophenyl) analog, have demonstrated remarkable activity against both HSV-1 and HSV-2 [88]. In addition, a series of 2-thiohydantoins containing heterocyclic moieties such as 5-bromothie­ nylidene, 5-(2-carboxyphenylthio)-2-thienylidene and 4H-thieno-[2,3-b][1] benzothiopyran-4-one have been tested for their activity against HIV-1 virus. Closer inspection of the structures of non-nucleoside reverse tran­ scriptase inhibitors reveals a common feature of these compounds with a carboxamide or (thio)urea entity surrounded by two hydrophobic “wings,”

144

Amino Acids: Insights and Roles in Heterocyclic Chemistry, Volume 2

mostly aryl moieties – one of which is quite often substituted by a halogen, resembling a butterfly with a hydrophilic center (body) and two hydrophobic wings [89]. Apparently, it is not surprising that S-(2-phenyl-3’-indolal)2-thiohydantoin containing two structural moieties found in highly active anti-HIV agents has exhibited poor activity against HIV and a rather high cytotoxicity [90]. 3.2.4 PRACTICAL MEDICAL ACTIVITIES With so many activities in interaction with proteins, enzymes, and microbes, many 2-thiohydantoins have been identified with practical biological activities and have already been applied in actual medical treatments. These practical biological activities include anti-angiogenesis, anti-necroptosis, antiarrhythmic, anticonvulsant, antimutagenic, and/or anticarcinogenic, and antithyroid activities, just to name a few. Angiogenesis is a physiological process to grow new blood vessels from pre-existing vessels, which is distinct from vasculogenesis, the de novo formation of endothelial cells from mesoderm cell precursors [91]. After the first vessel forms through vasculogenesis in the developing embryo, angio­ genesis is the primary process for blood vessel growth during development and many pathogenic conditions [92], such as the development of atheroscle­ rosis, diabetic retinopathy, and tumor formation. These pathogenic conditions are characterized by persistent, unregulated angiogenesis. As a result, the application of anti-angiogenic therapy has been suggested to be a potential therapeutic strategy against cancer development and metastasis. It has been known that the antiepileptic drug phenytoin (i.e., 5,5-diphenylhydantoin) is capable of retarding the cell cycle in human vascular endothelial cells and the analogous 5,5-diphenyl-2-thiohydantoin can inhibit the proliferation of human umbilical venous endothelial cells (HUVEC) by increasing the level of p21 protein, which in turn inhibits the activities of cyclin-dependent kinase CDK2 and CDK4, and finally interrupts the cell cycle. Especially, the introduction of a side-chain containing an aromatic ring structure with the right spatial arrangement at the sulfur atom of 5,5-diphenyl-2-thiohydantoin enhances the anti-angiogenic activity in HUVEC [93], in particular the one with 2-methylnaphthalenyl at the 2-thio position of the parent DPTH, i.e., 2-((naphthalen-2-ylmethyl)thio)-5,5-diphenyl-1,5-dihydro-4H-imidazol4-one (32; Figure 3.7) demonstrates the strongest inhibition on the growth of HUVEC in culture [94].

Thiohydantoins

145

Besides the anti-angiogenesis, which has important application in thera­ peutic strategy against cancer development and metastasis, programed cell death provides another venue to treat cancer. Cell death can be apoptosis or necrosis, the former is an active, programmed process of autonomous cellular dismantling that avoids eliciting inflammation, whereas necrosis is a passive, accidental cell death resulting from environmental perturbations such as infection, toxins, or trauma with the uncontrolled release of inflammatory cellular contents [95]. For necrosis, its corresponding programed form or inflammatory cell death is known as necroptosis, which is very useful in targeting pathogens by the immune system. Necroptosis is a common viral defense mechanism, which allows the cell to undergo “cellular suicide” in a caspase-independent fashion in the presence of viral caspase inhibitors [96]. In comparison, apoptosis is a highly regulated and controlled process that confers advantages during an organism’s lifecycle. Apoptosis can be initiated in two ways, i.e., intrinsic pathway and extrinsic pathway [97], where the cell kills itself when it senses stress following the intrinsic pathway, while in the extrinsic pathway, the cell kills itself when it receives signals from other cells. Both pathways induce cell death by means of triggering the activity of essential proteases in the process of programed cell death, i.e., caspases [98], the acronym of cysteine-aspartic proteases, cysteine aspartases or cysteinedependent aspartate-directed proteases. There are more than 10 different caspases, and apoptosis can be initiated by caspase 2, caspase 8, caspase 9 and caspase 10. On the other hand, pyroptosis is a highly inflammatory form of programed cell death that occurs most frequently upon infection with intracellular pathogens and promotes the rapid clearance of various bacterial and viral infections by removing intracellular replication niches and enhancing the host’s defensive responses [99]. Pyroptosis also involves caspases, such as caspase 1, caspase 4, caspase 5, caspase 11 and caspase 12. Regarding necroptosis, its inhibitor is known as necrostatin. It has been reported that 5-(1H-indol-3-ylmethyl)-2-thiohydantoins and 5-(1H-indol-3­ ylmethyl)hydantoins are potent necrostatins, especially the one with smaller substituents (e.g., 33; Figure 3.7), such as methoxy or chloro at the 7-posi­ tion, which has demonstrated obviously higher activity than other derivatives [100]. As phenytoin has been used as an antiarrhythmic agent that suppresses abnormal rhythms of the heart (cardiac arrhythmias), which may include atrial fibrillation, atrial flutter, ventricular tachycardia, and ventricular fibrillation, the corresponding 2-thiohydantoin derivatives have been tested for such application as well. It is found that a series of

146

Amino Acids: Insights and Roles in Heterocyclic Chemistry, Volume 2

3-dialkylaminopropyl-5-monosubstituted-2-thiohydantoins are potential antiarrhythmic agents [101], with pharmacological activity comparable to that of quinidine [80]. Besides the anti-angiogenesis and antiarrhythmic agents, 2-thiohydan­ toins can be applied as anticonvulsants, a diverse group of pharmacological agents used for the treatment of epileptic seizures, thus also known as antiepileptic drugs and antiseizure drugs [102]. The term “seizure” is often used interchangeably with “convulsion” to describe a status of physical findings or changes in behavior that occur after an episode of abnormal electrical activity in the brain, leading to rapid and uncontrollable body shakes. During convulsions, the person’s muscles contract and relax repeatedly. There are six types of seizures, including “Grand Mal” or generalized tonicclonic, absence, myoclonic, clonic, tonic, and atonic seizures. [103, 104] Anticonvulsants suppress the rapid and excessive firing of neurons during seizures and also prevent the spread of the seizure within the brain. As many anticonvulsants seem to act as mood stabilizers, the anticonvulsants are increasingly being used in the treatment of the bipolar disorder, borderline personality disorder and neuropathic pain. The way anticonvulsants work is to block sodium or calcium channels to reduce the release of excitatory glutamate, as the release of glutamate is considered to be elevated during epilepsy. This class of pharmacological agents has been the fifth bestselling medicine in the US in 2007, which include a variety of organic molecules, such as aromatic allylic alcohols, barbiturates, benzodiazepines, carbamates, carboxamides, GABA analogs, hydantoins, oxazolidinediones, pyrimidinediones, pyrrolidines, triazines, ureas, and valproylamides (amide derivatives of valproate). Regarding the application of 2-thiohydantoin as the anticonvulsant, it is found that change of the alkyl group at 5-position of 3-allyl-2-thiohydantoin nucleus might affect the potency of the 2-thiohydan­ toin principally in metrazol seizure threshold test, whereas short-chain vari­ ants at the 3-position of 5-isobutyl-2-thiohydantoin had a greater influence on potency in the maximal electroshock seizure pattern test [80]. 2-Thiohydantoins can be applied as a hypolipidemic agent as well. Hypo­ lipidemic agents, also known as antihyperlipidemic agents, are a diverse group of pharmacological agents for the treatment of abnormally elevated levels of any or all fats (lipids) and/or lipoproteins in the blood, a syndrome known as hyperlipidemia, hyperlipoproteinemia, or hyperlipidemia. Hyper­ lipidemia is the most common form of dyslipidemia. Therefore, the drugs used to lower blood fats are called lipid-lowering drugs or hypolipidemic agents. There are several classes of hypolipidemic drugs, differing in both

Thiohydantoins

147

their impact on the cholesterol profile and adverse effects, such as statins, fibrates, niacin, bile acid sequestrants, ezetimibe, lomitapide, phytosterols, and orlistat. 5,5-Diphenyl-2-thiohydantoin (DPTH) has been known as a hypolipidemic agent, other 5,5-diaryl-2-thiohydantoins and 5,5-diaryl­ substituted-2-thiohydantoins related to 5,5-diphenyl-2-thiohydantoin have been investigated as potential hypolipidemic agents in order to increase potency over DPTH itself, such as 5,5-bis(2-pyridyl)-2-thiohydantoin (34; Figure 3.7), with slightly better activity than DPTH in lowering liver choles­ terol values [74]. In addition to the above medical usages of 2-thiohydantoins, the more important and attractive medical applications of thiohydantoins explore 2-thiohydantoins’ anticarcinogenic and/or antimutagenic activity. Cancer has become one of the major killing factors in the USA, and roughly about 1,600 people die of cancer each day. The terms of tumor and cancer are sometimes used interchangeably, but the tumor is a non-specific term for a neoplasm, the new abnormal growth of cells, and tumor can be benign or malignant. The malignant tumor or malignant neoplasm is cancer, which is a disease in which abnormal cells divide without control and can invade the nearby tissues. Cancer cells can also spread to other parts of the body through the blood and lymph systems. It is generally known that the muta­ tion of a gene can cause cancer, and a mutagen is a physical or chemical agent to change the genetic material and increases the frequency of muta­ tions above the natural background level. On the other hand, a carcinogen is an agent directly involved in cancer development, including radiation. Thus, a mutagen is likely to be a carcinogen, but not always necessarily so. There­ fore, the substance that interferes with the mutagenicity of other molecules is called antimutagen, including desmutagens and bioantimutagens. While desmutagens inactivate the chemical interactions before the mutagen attacks the gene, bioantimutagens stop the mutation process after the genes are damaged by mutagens. Likewise, an anticarcinogen or a carcinopreventive agent is a substance that counteracts the effects of a carcinogen or inhibits the development of cancer. An antitumor agent is a substance used in the treatment of cancer. According to the mechanism of its action, antitumor agents are classified into angiogenesis inhibitors, DNA intercalators/cross-linkers, DNA synthesis inhibitors, DNA-RNA transcription regulators, enzyme inhibitors, gene regulation agents, microtubule inhibitors, and other antitumor agents. So far, several 2-thiohydantoin derivatives have been identified as antitumor agents [41, 105]. For example, the introduction of certain functional groups to N-3 of

148

Amino Acids: Insights and Roles in Heterocyclic Chemistry, Volume 2

2-thiohydantoins has resulted in a concentration-dependent cytotoxic effect, especially for the p-methylphenyl, benzyl, and cyclohexyl groups; [106] also, the anti-isomer of Aldol product of 5-methyl-3-(substituted phenyl)-2-thio­ hydantoin displayed the inhibition of growth of PC-3 and LNCaP prostate cancer cells. Especially, (R)-5-((S)-(4-bromophenyl)(hydroxy)methyl)-3­ (4-chlorophenyl)-5-methyl-2-thiohydantoin (35; Figure 3.7) demonstrates cytotoxicity which is better than that of doxorubicin and flutamide on PC-3 and LNCaP cells, respectively [16]. One carbohydrate-containing 2-thio­ hydantoin, i.e., 5-(5-bromo-2-thienylmethylene)-3-morpholinomethyl­ 1-(2,3,4,6-tetra-O-acetyl-D-glucopyranosyl)thiohydantoin, also known as (2R,3R,4S,5R,6R)-2-(acetoxymethyl)-6-((Z)-5-((5-bromothiophen-2-yl) methylene)-3-(morpholinomethyl)-4-oxo-2-thioxoimidazolidin-1-yl) tetrahydro-2H-pyran-3,4,5-triyl triacetate (36; Figure 3.7), possesses a broad spectrum of antitumor activity against a wide range of different human cell lines (ca. nine tumor subpanels) causing both cytostatic and cytotoxic effects [80]. Moreover, (Z)-5-((5-bromothiophen-2-yl)methylene)­ 3-(piperidin-1-ylmethyl)-2-thioxoimidazolidin-4-one (37; Figure 3.7) or (Z)-5-((5-bromothiophen-2-yl)methylene)-3-(morpholinomethyl)­ 2-thioxoimidazolidin-4-one (38; Figure 3.7) and its S-glucosylated analog ((2R,3R,4S,5R,6S)-2-(acetoxymethyl)-6-(((Z)-4-((5-bromothiophen-2-yl) methylene)-1-(morpholinomethyl)-5-oxo-4,5-dihydro-1H-imidazol-2-yl) thio)tetrahydro-2H-pyran-3,4,5-triyl triacetate) are potential broad-spectrum antitumor agents based on the antitumor drug discovery screen from the National Cancer Institute [107]. Likewise, (E)-5-((2-phenyl-1H-indol-3-yl) methylene)-2-thioxoimidazolidin-4-one (39; Figure 3.7) has been evaluated as an anti-cancer compound for several cancer cell lines, including leukemia, melanoma, and cancer of lung, colon, kidney, ovary, breast, prostate, and central nervous system by the National Cancer Institute [108]. For a particular case, it has been shown that 7,12-dimethylbenz[a] anthracene (DMBA) can induce buccal pouch carcinogenesis as shown in the experiment that all the Syrian male hamsters painted with DMBA on their buccal pouches developed squamous cell carcinoma after 14 weeks. However, administration of 3-[2,6-bis(4-fluorophenyl)-3-methylpiperidin4-ylideneamino]-2-thiohydantoin (40; Figure 3.7) effectively suppressed the oral carcinogenesis as revealed by a reduced incidence of neoplasms [109]. For simple 2-thiohydantoin deriving from tryptophan, i.e., methylthiohydantoin-tryptophan (MTH-trp) or (S)-5-((1H-indol-3-yl)methyl)­ 3-methyl-2-thiohydantoin (41; Figure 3.7), it has been demonstrated to retard the growth of MMTV-neu/HER2 tumors and elicit regressions in

Thiohydantoins

149

combination with paclitaxel, without increased side-effects [110]. Although MTH-trp is more soluble in aqueous solution than 1-methyl-thiohydantoin (1-MT), it is more rapidly cleared from serum and shows approximately 20-fold more potency than 1-MT in a cell-based assay [111]. However, some 2-thiohydantoin derivatives have shown weak anticancer activity [112], such as 5,5-diphenyl-2-thiohydantoin and 1,3-diethyl-5,5-diphenyl-2-thiohydan­ toin, which displayed relatively low cytotoxic activity against brine shrimp lethality bioassay [113]. For the S9 mix-mediated metabolic activation of the mutagen 2-amino-3-methylimidazo[4,5-f]quinoline (IQ) on Salmonella typhimurium TA 98, it has been found that the IQ mutagenicity has been inhibited by the 3,5-disubstituted 2-thiohydantoins prepared by the reaction of allyl isothiocyanate (AITC) or 4-(methylthio)-3-butenyl isothiocyanate (MTBI) with various amino acids, in a dose-dependent manner with 23% to 86% inhibition [114].

FIGURE 3.7 2-Thiohydantoin derivatives of potential medical applications.

Another important medical application of 2-thiohydantoins is their antithyroid activity. The thyroid gland, or simply the thyroid is an endo­ crine gland, which secretes thyroid hormones to influence the metabolic

150

Amino Acids: Insights and Roles in Heterocyclic Chemistry, Volume 2

rate, protein synthesis as well as a wide range of other effects. The thyroid hormones T3 and T4 are synthesized from iodine and tyrosine. Hormonal output from the thyroid is regulated by thyroid-stimulating hormone (TSH) secreted from the anterior pituitary. Two abnormal statuses for thyroid are hyperthyroidism and hypothyroidism. Hyperthyroidism occurs when the thyroid gland produces excessive amounts of thyroid hormones due to an autoimmune disorder, whereas hypothyroidism is a state of insufficient thyroid hormone production, primarily due to iodine deficiency. An antithy­ roid agent is a hormone antagonist acting upon thyroid hormones. It has been found that 2-thiohydantoin and its derivatives containing 5-alkyl group from 5-methyl to 5-sec-butyl group bear a considerable antithyroid activity at a dose of 0.05 mmol/kg by mouth [115], however, the presence of polar groups at the 5-substituent leads to a reduction or complete loss of antithy­ roid activity [116]. Finally, 2-thiohydantoin derivatives have some other medical applica­ tions, such as inhibitors of platelet aggregation [80]. It should be pointed out that even though 2-thiohydantoins have been known of many biological activities and some practical medical applications, they have a reputation for being unselective compounds that appear as “frequent hitters” in screening campaigns. This behavior has been the subject of controversial debate in the medicinal chemistry community [117, 118]. 3.3 PREPARATIVE METHODS 3.3.1 PREPARATION OF 2-THIOHYDANTOINS Although there are three kinds of thiohydantoins, i.e., 2-thiohydantoin, 4-thiohydantoin and 2,4-dithiohydantoin, the most commonly studied thio­ hydantoins are actually the 2-thiohydantoins, due to their easy preparations. In fact, there have been many synthetic methods developed for making 2-thiohydantoins, whereas only a limited number of methods for the prepara­ tion of either 4-thiohydantoins or 2,4-dithiohydantoins. As indicated in the core structure, 2-thiohydantoins contain one amido, one thioamido as well as one thioureido functional group, thus all synthetic methods for 2-thiohydantoins always involve an amino-bearing component and a sulfur-containing moiety. In general, the reaction of an α-amino acid with ammonium thiocyanate under acetic anhydride activation, and the coupling of an isothiocyanate with an α-amino acid have been the most popular conditions applied to synthesize 2-thiohydantoins.

Thiohydantoins

151

Regarding the formation of 2-thiohydantoins by means of the activation of the reaction with acetic anhydride, the mixture of α-amino acid and ammo­ nium thiocyanate (NH4SCN) is heated in acetic anhydride (b.p. 139.8°C) at 100°C for half an hour [119]. This reaction can also be heated in acetic anhydride in the presence of 10% of acetic acid [18, 84, 120], or heated under other conditions, such as under microwave irradiation [121], or starting from N-acyl α-amino acid [122]. A typical reaction is displayed in Scheme 3.5. For this reaction, the acetyl group would be acetylated at either N-1 or N-3 position, forming either 1-acetyl or 3-acetyl-2-thiohydantoin. However, it is difficult to form 3-acetyl 2-thiohydantoin, because the 3-NH is more acidic than the 1-NH, as indicated by the NMR chemical shift mentioned previ­ ously. In fact, methyl glycinate when treated with acetyl isothiocyanate in CH2Cl2/Et3N led to the formation of methyl (acetylcarbamothioyl)glycinate, which when treated with a suitable base (K2CO3, MeOH, 25°C, 1 h) failed to cyclize to afford the corresponding 2-thiohydantoin. It is expected that the 1-acyl-2-thiohydantoin would tend to lose the 1-acyl group to even weak nucleophiles; in other words, this compound would not be particularly stable in the presence of nucleophiles, resulting in the expected 2-thiohydantoin [1]. Besides NH4SCN, KSCN is another source of thiocarbonyl group in the preparation of 2-thiohydantion, as represented in the reaction between α-amino acid ester and KSCN [123], and similar reaction in ethanol [124].

SCHEME 3.5 Preparation of 1-acetyl-2-thiohydantoins from α-amino acids and ammonium thiocyanate.

Probably, the more common method to form 2-thiohydantoin is by means of the reaction between alkyl (aryl) isothiocyanate and α-amino acid derivative (α-amino acid, α-amino acid ester or N-acyl α-amino acid) under basic condition. For example, the reaction between α-amino acid ester and substituted isothiocyanate in CH2Cl2 or DMF in the presence of a base (e.g., KOBut/THF) leads to a combinatorial library of 64 2-thiohydantoins, with yields ranging from 65 to 100% (89% average) and purities from 67 to 100% (93% average) [125]. The same procedure has been extended to tetra­ hydroisoquinolines and tetrahydro-β-carbolines containing the 2-arylethyl

152

Amino Acids: Insights and Roles in Heterocyclic Chemistry, Volume 2

amine scaffold, affording a library of 32-membered thiohydantoins with purities from 73 to 100% (94% average), as shown in Scheme 3.6 [126]. However, the author has some concerns about one particular preparation of 2-thiohydantoin involving α-amino esters and isothiocyanates in the aqueous medium (DMF/H2O = 3:1) under microwave irradiation as the reaction mixture was heated to a temperature as high as 400°C [127].

SCHEME 3.6 Combinatorial synthesis of 2-thiohydantoins from alkyl or aryl-isothiocyanate.

In several preparations of this kind, triethylamine has been applied as the base, as shown in the reaction of amino acid esters with [128] or without perfluoroalkyl (Rfh)-tag [129], and the reaction between α-amino acid and isothiocyanate in 1,4-dioxane/H2O [13]. Besides triethylamine, NaOH in EtOH [130] and alkaline Al2O3 [131] have been applied as the base, as exem­ plified in the reaction of α-amino acid with cinnamoyl isothiocyanate. This preparation can even be carried out in the solid phase by means of pressing the mixture of aryl isothiocyanate, NaOH, and amino acid in mortar while heating followed by the addition of NaHSO4 [33]. Meanwhile, this proce­ dure can be carried out in two consecutive steps, with thiourea derivatives formed as the intermediates. In this case, treatment of the reaction mixture at the thiourea stage with KOH and subsequent acidification with H2SO4 in acetone affords 2-thiohydantoin derivatives [60]. In another example, the thiourea derivatives prepared from the reaction between α-amino acids and isothiocyanate in the presence of NaOH under microwave irradiation were further treated with NaHSO4 under microwave irradiation to afford 2-thiohydantoins. For this particular preparation, it was found that the reaction is faster for the substrates with electron-withdrawing groups, but no relationship exists between the yield and the electron-withdrawing and electron-donating groups in the substrates [24]. In addition, N-substituted amino acids prepared from reductive amination of glyoxylic acid and amines

Thiohydantoins

153

or natural amino acids with aldehydes can react with isothiocyanate to form thiourea intermediates, which are then treated with triethylamine to give 2-thiohydantoins [132]. It should be pointed out that α-amino acid ester could be further alkyl­ ated by means of the formation of imine derivatives with aldehydes that are then reduced by sodium triacetoxyborohydride (NaBH(OAc)3). Then, an isothiocyanate is added to the solution of N-alkylated amino acid ester together with a stoichiometric amount of triethylamine, leading to the 2-thiohydantoin product in high yield and purity after an extractive aqueous workup. This practice has been applied to generate a combinatorial library of over 600 discrete thiohydantoins on a 0.1 mmol scale, with purities of 52–98% by HPLC analysis [133]. A similar strategy has been applied for the base-promoted solid-phase synthesis of substituted thiohydantoins where sodium cyanoborohydride (NaBH3CN) is used as the reducing reagent, in the presence of 1% acetic acid [134]. Besides α-amino acid and α-amino acid ester, even less reactive α-amino amide can react with isothiocyanate to afford 2-thiohydantoin, as indicated in a series reaction of 2-(1-alkyl (or aryl)-2,5-dioxopyrrolidin-3-yl)hydrazine-1-carboxamides with alkyl or aryl isothiocyanates. A particular one is the conversion of 2-(1-methyl2,5-dioxopyrrolidin-3-yl)hydrazine-1-carboxamide into 2-(1-ethyl-5-oxo-2thioxo-3-ureidoimidazolidin-4-yl)-N-methylacetamide with ethyl isothio­ cyanate [135]. On the other hand, α-amino acid ester can be generated in situ from α-azido ester through catalytic hydrogenation that is then treated with alkyl isothiocyanate (e.g., BuNCS) to afford the corresponding 2-thiohydantoins [76]. Similarly, 1,5-substituted tetrazole-thiohydantoins have been prepared by means of TMSN3-Ugi multicomponent reaction involving amine, alde­ hyde, isonitrile, and TMSN3 to form the intermediate of tetrazole-substituted amino ester that is then treated with an excess amount of isothiocyanate [136]. This similar preparation with isothiocyanate has been modified to a fluo­ rous synthesis of 2-thiohydantoin. Fluorous synthesis uses perfluoroalkyl chains (Rfh) as the phase tag for easy separation, and the scope of fluorous reactions is similar to the conventional solution-phase synthesis. The separa­ tion of reaction mixtures containing light fluorous molecules can be achieved by fluorous silica gel-based solid-phase extraction. For this practice, two perfluoroalkyl-tagged α-amino esters, prepared by means of coupling Fmoc- or Boc-protected amino acids (e.g., L-leucine, and L-phenylalanine) with fluorous alcohol containing a C8F17 chain with a propylene spacer to

154

Amino Acids: Insights and Roles in Heterocyclic Chemistry, Volume 2

minimize the electronic effect of the fluorous tag and hydroxyl group and subsequent deprotection of the Fmoc or Boc group [128], each reacts with six aromatic aldehydes under reductive amination conditions to afford 12 amino esters then each reacts with 10 isothiocyanates in parallel in the presence of Et3N. The purifications of intermediate and final products are performed with solid-phase extraction (SPE) over FluoroFlashTM cartridges without chromatography. With standard instruments and a straightforward SPE tech­ nique, one can generate a 120-member library in less than five working days, including the syntheses of starting materials and analyzes of products [137]. This convenient preparation of 2-thiohydantoins is illustrated in Scheme 3.7.

SCHEME 3.7 Fluorous synthesis of 2-thiohydantoin.

A similar strategy has been applied to the preparation of 2-thiohydantoins with solid support. For example, Fmoc-protected amino acids were mounted to polyethylene glycol-6000 (PEG-6000) with dicyclohexyl carbodiimide (DCC) in the presence of DMAP, and upon deprotection of the amino group, the PEG-supported amino acids were treated with isothiocyanate and 2-thio­ hydantoins were released by base cleavage. In this practice, polymer support was removed from the homogeneous solution to provide the corresponding products in 88–99% yield based on the initial loading to the support, with 81–99% purity as assessed by HPLC [138]. The same procedure can be carried out under microwave irradiation, and it is reported that the polymersupported intermediates and the polymer support themselves remain stable under microwave exposure [139]. Similarly, isoxazole-containing thiohydan­ toins have been prepared by means of solid-phase synthesis, involving the

Thiohydantoins

155

mounting of 2-((tert-butoxycarbonyl)amino)pent-4-ynoic acid to hydroxy­ propyloxymethylpolystryene resin with DIC and DMAP and subsequent treatment with (nitromethyl)benzene/phenyl isothiocyanate and cleavage of polymer support with isothiocyanate by forming the 2-thiohydantoin ring, as shown in Scheme 3.8 [140].

SCHEME 3.8 Polymer-supported synthesis of 2-thiohydantoins.

For the particular organic base promoted reaction of α-amino esters with (E)-2-nitrovinyl aromatics and aryl-isothiocyanates, among those tested organic bases such as Et3N, quinine, and DABCO, Et3N is the best one, whereas other two bases lead to the formation of thiohydantoins of lower diastereoselectivity and enantioselectivity (1% ee). Similarly, among the tested solvents, including toluene, acetonitrile, dichloromethane, chlo­ roform, and ethyl acetate, acetonitrile is the best solvent, whereas other solvents result in the corresponding products of slightly lower diastereose­ lectivity. However, when the reaction was carried out in the absence of a base, a complex mixture was obtained without the desired product. The reaction starting with the hydrochloride salt of the α-amino ester using 1.1 equivalent of Et3N leads to a result similar to the one from a neutral amino ester. However, the α-amino esters containing aromatic substituents afford thiohydantoins of better yield than those with aliphatic substituents at the α-position, although with slightly lower diastereoselectivity. Regarding the aryl-isothiocyanate, the ones with electron-withdrawing substituents result in the corresponding thiohydantoins of better yields but poorer diastereose­ lectivities in comparison with phenyl isothiocyanate; however, this reaction does not work with bulky isothiocyanates [117]. A typical reaction is illus­ trated in Scheme 3.9.

156

Amino Acids: Insights and Roles in Heterocyclic Chemistry, Volume 2

SCHEME 3.9 Generation of 2-thiohydantoin from aryl isothiocyanate and amino ester and subsequent addition to nitro-alkene.

Besides the solid support and fluorous support, the reaction with isothiocyanate has been supported on functionalized ionic liquid for a traceless synthesis of 3,5-disubstituted 2-thiohydantoins. For this practice, benzylamine functionalized ionic liquid support was dissolved in CH3CN and coupled with Boc-protected amino acids under DIC activation at room temperature for 8 hours. The mixture was filtered and the solution was concentrated. The ionic liquid-supported Boc-amino acid was precipitated out by treatment of the residue with ether, and then treated with 55% trifluo­ roacetic acid in dichloromethane to remove the Boc protecting group. After that, the ionic liquid-supported amino acid reacted with isothiocyanate to afford ionic liquid-supported thiourea which underwent intramolecular cyclization and in situ cleavage reaction with 25% TFA in dichloromethane to afford the 3,5-disubstituted 2-thiohydantoin in good yield and purity. It should be pointed out that the efficiency of this ionic liquid-phase strategy facilitated the isolation of intermediates and removal of excess reagents and by-products during the reaction process [141]. It should be pointed out that for the reaction between α-amino acid and isothiocyanate in an alkaline solution, the phenylthiocarbamyl (PTC) intermediate undergoes partial desulfurization if the total amount of alkali required was added at the beginning of the reaction and if the temperature was too high. In order to avoid undesired desulfurization, it is suggested to add the alkali in small portions continuously while still keeping the reaction temperature below 40°C. The crude PTC-derivatives are not necessarily puri­ fied and can be transferred directly into phenyl thiohydantoins by refluxing in acid. For the particular amino acid of L-Lysine, the phenylthiocarbamyl group will remain at the ε-amino group of Lysine even if the amino acid has been converted into the corresponding 2-thiohydantoin [142]. Also, the 2-thiohydantoins are formed via a condensation reaction in which the amino acids undergo nucleophilic addition to the isothiocyanate moiety followed by ring closure so that the asymmetric center of the amino acid is

Thiohydantoins

157

not involved in the reaction. Therefore, the configuration of the chiral center will not change even after the reaction under microwave irradiation [24]. This very convenient preparation of 2-thiohydantoin has been modified using Woodward’s reagent K (3-(2-ethylisoxazol-2-ium-5-yl)benzenesul­ fonate also known as 2-ethyl-5-phenylisoxazolium-3’-sulfonate), α-amino acid (or α-amino acid ester) and trimethylsilyl isothiocyanate, as shown in Scheme 3.10. This especially mild condition provides an improved synthetic route for 2-thiohydantoins, especially for the amino acids bearing sensitive side-chain groups, such as arginine and threonine. The 2-thiohydantoin derivatives of these amino acids can be obtained in reasonable quantities without side-chain modifications [143].

SCHEME 3.10 Synthesis of 2-thiohydantoin using Woodward’s reagent K.

Interestingly, for the preparation of 2-thiohydantoin from substituted isothiocyanate, different products, i.e., 1,3,5-trisubstituted 2-thiohydan­ toins or 2-iminothiazolidin-4-ones bearing a valuable point of diversity at the 5-position of the heterocyclic rings, could be obtained from the one-pot three-component reaction among 1,2-diaza-1,3-dienes, primary amines, and isothiocyanates simply by means of varying the order for the addition of these three reagents. Explicitly, the mixing of 1,2-diaza-1,3-diene with the primary amines in chloroform at room temperature followed by the addition of substituted isothiocyanates leads to the formation of 2-thiohydantoin derivatives; whereas the reaction between the primary amines and substituted isothiocyanate followed by the addition of the 1,2-diaza-1,3-dienes results in the formation of 5-hydrazinoethylidene-2-iminothiazolidin-4-ones as

158

Amino Acids: Insights and Roles in Heterocyclic Chemistry, Volume 2

shown in Scheme 3.11. The mechanism for the generation of 2-thiohy­ dantoin in the first reaction sequence is illustrated in Scheme 3.12. It is suggested that the formation of 2-iminothiazolidin-4-one nucleus involves the initial regioselective S-Michael addition of the thiourea intermediate (arising from the primary amine and isothiocyanate) to the 1,2-diaza-1,3diene, followed by the intramolecular attack of the NH of the resulting Michael addition product at the ester function on C4 of the hydrazone chain with a loss of an alcohol moiety, as shown in Scheme 3.13 [144].

SCHEME 3.11 One-pot three-component synthesis of 2-thiohydantoins.

SCHEME 3.12 Proposed mechanism for the one-pot three-component synthesis of 2-thiohydantoin.

Thiohydantoins

159

SCHEME 3.13 Proposed mechanism for the second one-pot three-component synthesis outlined in Scheme 3.11.

Besides the above common methods for syntheses of 2-thiohydan­ toin derivatives, a very common method for 2-thiohydantoin without substituent at position 5, i.e., 5-unsubstituted 2-thiohydantoins starts from α-chloroacetic acid or α-chloroacetate, the resulting 2-thiohydantoins are often used for further condensation with aldehydes to generate 5-arylidene2-thiohydantoins. For example, ethyl α-chloroacetate has been subjected to a one-pot three-component synthesis with isothiocyanates and amines under solvent-free conditions, affording 2-thiohydantoins in high yields, as displayed in Scheme 3.14 [145]. This reaction has been claimed to have features of reasonable reaction times, solvent-free condition, high yields, simple work-up procedure, and no further purification of products. It has been found that aliphatic amines lead to 2-thiohydantoins of good yields, while aromatic amines although still working in this condition yield fewer 2-thiohydantoins than those from the aliphatic amines. Regarding the aromatic amines, the ones with electron-donating group afford thio­ hydantoins in good yields, and aromatic amines of electron-withdrawing group yield much less thiohydantoins, especially for the one with strong electron-withdrawing group such as CF3. After the reaction, the ammonium

160

Amino Acids: Insights and Roles in Heterocyclic Chemistry, Volume 2

chloride can be washed off with water and the unreacted starting material can be removed by ethyl acetate/petroleum ether (1/10), and the purity of the product often exceeds 95%. It must be pointed out that slight alternation of the reaction condition may change this electronic demand. For example, the reaction between ethyl 2-isothiocyanatoacetate and (2-chlorophenyl) methanamine (or (2-bromophenyl)methanamine) in water in the presence of pyridine gives the corresponding 2-thiohydantoin, i.e., 3-(2-chlorobenzyl)2-thioxoimidazolidin-4-one (or 3-(2-bromobenzyl)-2-thioxoimidazolidin4-one). In contrast, the same reaction of ethyl 2-isothiocyanatoacetate with benzylamine or ((3-chlorophenyl)-methanamine, (4-chlorophenyl)metha­ namine, (3-bromophenyl)methanamine or (4-bromophenyl)methanamine) under this condition only gives ethyl (benzyl-carbamothioyl)glycinate or the corresponding halo-substituted ethyl (benzyl-carbamothioyl)glycinate. These thiourea derivatives can be converted into arylidene thiohydantoin when they are treated with base (KOH) in the presence of an aromatic aldehyde [146].

SCHEME 3.14 One-pot three-component synthesis of 5-unsubstituted 2-thiohydantoin.

While most of the above reactions involving isothiocyanate have α-amino acids or α-amino esters as the initial substrates for the preparation of 2-thio­ hydantoins, the reverse order reaction also exist, in which the α-amino acid ester has been converted into α-isothiocyanato ester by treatment of the α-amino acid ester with thiophosgene in methylene chloride in the presence of triethylamine. The α-isothiocyanato ester is then treated with an amine in CH2Cl2 to form 2-thiohydantoin along with the formation of tert-butyl (S)-2-((((S)-4-benzyl-5-oxo-4,5-dihydrothiazol-2-yl)amino)methyl)pyrro­ lidine-1-carboxylate, as shown in Scheme 3.15 [147]. The same principle has been applied to make 2-thiohydantoin spironucleosides by means of the intermediates of methyl 2-deoxy-2-isothiocyanatohex-2-ulofura(pyra) nosonates, which spontaneously cyclized to 2-thiohydantoins in reacting with amines in high yields [148].

Thiohydantoins

161

SCHEME 3.15 Generation of 2-thiohydantoin from α-isothiocyanato ester and an amine.

As the reaction between amine and isothiocyanate affords thiourea deriva­ tive, thiourea can be directly subjected to react with α-chloroacetic acid, as indicated in the reaction between thiosemicarbazide and α-chloroacetic acid, in which cyclododecanone (CDD) was used as protecting group for the primary amino group in thiosemicarbazide to avoid the unwanted side product, as illustrated in Scheme 3.16 [149]. Among those solvents tested that include acetic acid, methanol, ethanol, and isopropanol, THF, DCM, DMF, and DMSO, acetic acid is the best solvent, leading to the product of good yield, whereas no product is formed in other tested aprotic solvents. In this reaction, solid cyclododecanone easily reacts with the free amino group to form stable ketimine in the presence of an acid catalyst. Meanwhile, aromatic aldehydes can be added to the reaction mixture at the same time in a one-pot manner, and the orientation of benzaldehydes has limited influence on this reaction. In addition, a wide range of functional groups such as fluoro, chloro, nitro, and hydroxy remain intact in this reaction condition. This reaction has been extended to chloroacetic acid ester rather than chloroacetic acid, as shown in the reaction between (E)-2-(2-hydroxybenzylidene)hydrazine1-carbothioamide and ethyl 2-chloroacetate in methanol in the presence of sodium acetate, that affords (E)-3-((2-hydroxybenzylidene)amino)-2-thioxo­ imidazolidin-4-one [150]. A similar reaction has been carried out using isatin as the protecting group of the primary amino group in thiosemicarbazide in pyridine, however, the refluxing in EtOH in the presence of sodium acetate leads to the formation of 3-[(1,3-thiazolidin-4-one-2-yl)hydrazido]-indole2-one [151]. On the other hand, α-amino acid ester can be converted into alkyl 2-isothiocyanatocarboxylate that then reacts with hydrazine in alcohol to generate alkoxycarbonyl thiosemicarbazide, which undergoes cyclization to afford 3-amino-5-substituted 2-thiohydantoin [152]. One phenomenal practice has adopted two preparative methods of 2-thiohydantoin to make

162

Amino Acids: Insights and Roles in Heterocyclic Chemistry, Volume 2

multi-cyclic molecules of two thiohydantoin moieties. One involves the formation of hydrazone between 2-oxo-carboxylate and thiosemicarbazide (also known as hydrazinecarbothioamide), leading to the formation of the first thiohydantoin ring. The resulting product was then hydrolyzed with LiOH and subsequently treated with phosphoryl triisothiocyanate PO(NCS)3 to afford benzyl (4S,6’S)-5,5”-dioxo-2,2”-dithioxotetrahydrodispiro[imidaz olidine-4,1’-cyclopenta[c]pyrrole-6’,4”-imidazolidine]-2’(3’H)-carboxylate, after generation of the second thiohydantoin ring, as shown in Scheme 3.17 [153].

SCHEME 3.16 Formation of 2-thiohydantoin from the reaction of thiosemicarbazide and 2-chloroacetic acid.

SCHEME 3.17 Formation of 2-thiohydantoin from the reaction of thiosemicarbazide and α-keto ester.

Another example is the reaction of N-aryl-N’-(3-chloro-2-benzo[b] thenoyl)-thioureas (prepared from the 3-chloro-2-benzo[b]thenoyl chloride, different arylamines and ammonium thiocyanate) and α-chloroacetic acid

Thiohydantoins

163

to form the N3-acyl-2-thiohydantoin. However, in the presence of sodium acetate, 2-arylimino-3-(3-chloro-2-benzo[b]thenoyl)-4-thiazolidinones are formed instead of the expected 2-thiohydantoins, as shown in Scheme 3.18 [154].

SCHEME 3.18 Synthesis of 2-thiohydantoin from thiourea and 2-chloroacetic acid.

Similar preparations of 2-thiohydantoins from α-chloroacetic acid or α-chloroacetate include the reaction between p-methyl acetophenone thiosemicarbazone and ethyl α-chloroacetate in the presence of fused sodium acetate [86], the reaction between (E)-2-benzylidenehydrazine1-carbothioamide and ethyl α-chloroacetate in the presence of fused sodium acetate in absolute methanol under refluxing [30], cyclization of 3-bromo4-methoxy benzaldehyde thiosemicarbazone with ethyl α-chloroacetate to afford 3-[(3-bromo-4-methoxy benzylidine) amino]-2-thiohydantion [155], cyclization of thiosemicarbazones ethyl α-chloroacetate [156], and the reac­ tion between amine and potassium thiocyanate (KSCN) in xylene and the subsequent reaction with α-chloroacetic acid in pyridine [83]. Another relatively popular method for the preparation of 2-thiohydantoins uses 1,1-thiocarbonyldiimidazole (CSIm2) as the source of thiocarbonyl moiety in 2-thiohydantoin. In this method, either amino acid or peptide is treated with 5 equivalent of CSIm2 in CH2Cl2 [157] or THF [158], to afford 2-thiohydantoins of purity greater than 80% [159]. Similarly, 1-(methyldi­ thiocarbonyl)imidazole has been applied as the transfer reagent of thiocar­ bonyl group and used in the reaction with an amine, α-amino acid ester in the presence of a base in a one-pot three-component manner of synthesis to form 3,5- or 1,3,5-substituted-2-thiohydantoins, as shown in Scheme 3.19 [160]. Similarly, ethyl acetyl- or benzoyldithiocarbamate reacts smoothly

164

Amino Acids: Insights and Roles in Heterocyclic Chemistry, Volume 2

with glycocoll or its ethyl ester to afford the acylated 2-thiohydantoin with the evolution of ethyl mercaptan. The acyl thiohydantoins upon treatment with HCl are converted into 2-thiohydantoins [123]. The alkyldithiocarba­ mate also reacts with the amino acid to form a 2-thiohydantoin derivative, as demonstrated in the consecutive reaction of Nα-acetyllysine with CS2 in water/NaOH and then with valine (oil bath at 110°C) to afford (S)-2-acet­ amido-6-((S)-4-isopropyl-5-oxo-2-thioxoimidazolidin-1-yl)hexanoic acid, as shown in Scheme 3.20 [161]. In addition, thiophosgene (CSCl2) has been used as a thiocarbonyl source, as shown in the preparation of 5-chlo­ romethylene thiohydantoins by chlorination of dehydroalanine followed by condensation with thiophosgene; alternatively, the same compound has been prepared by the treatment of 2-aminoacrylamide with LiHTMDS/THF and then thiophosgene [162].

SCHEME 3.19 Application of 1-(methyldithiocarbonyl)imidazole as the source of thiocarbonyl group for 2-thiohydantoin.

SCHEME 3.20 Synthesis of 2-thiohydantoin from the reaction of alkyldithiocarbamate and amino acid.

Thiohydantoins

165

As mentioned previously, thiourea is the intermediate for the reaction between isothiocyanate and an α-amino acid that cyclizes to give 2-thiohy­ dantoin. Therefore, it is not surprising that thiourea can be applied directly for the preparation of 2-thiohydantoin. In fact, we have tested the reaction without solvent by heating the mixture of α-amino acid and thiourea (1:3) at about 170°C, and obtained 2-thiohydantoin derivatives in half-hour. This process is fast and easy to perform, and often affords 2-thiohydantoins in high yields from α-amino acids of non-polar side chains. Using this method, N-substituted 2-thiohydantoins can also be formed, which can be isolated from regular 2-thiohydantoin by column chromatography [23]. A typical reaction is shown in Scheme 3.21. This method has been success­ fully applied in other similar preparations [34]. Following our procedure, the solvent-free reaction between α-amino acid and 2 equivalents of thio­ urea has been performed by means of simple grinding in a mortar with 2 equivalents of NaOH. This reaction is said to be simple, rapid, and efficient with additional features of good yield, low cost, simple workup, and easy purification [163]. Even the reaction between thiourea and α-chloroacetic acid in ethanol in the presence of pyridine would afford the simple 2-thiohydantoin [89]. Following this trend, N-substituted thioureas have been applied in reaction with α-chloro-acetyl chloride in the presence of base for the preparation of 1-substituted 2-thiohydantoins. It is found that this particular reaction would be well performed in polar solvents such as PEG, CH3OH and DMF, not in the solvents of lower polarity such as toluene, THF, and dioxane. Among the PEG solvents, including PEG-200, PEG-400, PEG-600 and PEG-800, PEG-400 works the best, possibly as the molecular weight of PEGs increases, viscosity increases that retards the reaction to occur. On the other hand, among the tested bases, such as K2CO3, Na2CO3, NaOH, KOH, K3PO4 and NaOAc, K2CO3 is the best base catalyst. The amount of catalyst should be somewhere about 5–15 mol%. Due to the nature of the reaction (nucleophilic substitution for the cyclization), monosubstituted thioureas with electron-donating groups afford 2-thiohydantoins in good yields, whereas thioureas with a strong electron-withdrawing group such as nitro give 2-thiohydantoins in very low yield [164]. Also, thiourea, N-alkyl, and N-arylthioureas, and various N,N’-disubstituted thioureas react with N-(2-aryl-1-chloro-2-oxoethyl) carboxamides under mild conditions to selectively form 2,5-diamino1,3-thiazole derivatives which when heated with HCl in ethanol undergo cyclization and subsequent hydrolysis to give substituted 2-thiohydantoins [165].

166

Amino Acids: Insights and Roles in Heterocyclic Chemistry, Volume 2

SCHEME 3.21 Simple preparation of 2-thiohydantoin from the reaction of amino acid and thiourea.

More examples of the reaction of thiourea to form 2-thiohydantoins are the ones between thiourea and benzil in the presence of 10% NaOH under microwave irradiation (Scheme 3.22) [31, 166], the one between thiourea and benzil in ethanol under heating [74], the ones between thiourea or substituted thiourea (e.g., monomethylthiourea, dimethylthiourea, dieth­ ylthiourea) and benzil in ethanol under refluxing [113], and the reaction between thiourea and benzil in DMSO/KOH under ultrasound irradiation [21,167]. However, for the aryl-substituted urea, when it is treated with benzil under similar conditions, benzhydryl-phenylurea is formed, whereas in the reaction between aryl-substituted thiourea and benzil, thiohydantoins derivative is formed, although the mechanism is still uncertain for the forma­ tion of benzhydryl-phenylurea [168]. Besides the benzil, adjacent dicarbonyl compounds, such as 2-oxo-2-phenylacetaldehyde, also reacts with thiourea supported on acidic alumina under solvent-free microwave irradiation to form 2-thiohydantoin derivatives [169]. This is because these compounds undergo benzilic rearrangement in reaction with thiourea, or its derivatives under basic conditions. It should be pointed out that this reaction could even be carried out at room temperature in the absence of solvent. To do so, the mixture of benzil, NaOH, and thiourea is ground with a pestle and mortar. After a while, the reaction mixture started to become sticky, and the stickiness reached its maximum in different amounts of time depending on the starting materials used, at which point further grinding is difficult. The reaction mixture was then dissolved in water and filtered, and the resulting filtrate was acidified with concentrated HCl to obtain 2-thiohydantoins in excellent yields. For this reaction, monosubstituted thiourea derivatives always furnished 3-N substituted 2-thiohydantoins. However, phenyl

Thiohydantoins

167

derivatives of thiourea containing an electron-withdrawing group at the para position on the phenyl moiety did not furnish the expected products due to electronic factors, also N,N’-disubstituted thiourea did not proceed for this reaction because of the increasing steric effects [170].

SCHEME 3.22 Generation of 2-thiohydantoin from the reaction of thiourea and benzil.

Another method for the formation of 2-thiohydantoin with isothiocyanate starts with α-amino nitrile [40] (also known as α-cyanoamine [41]) under conditions of acidic hydrolysis (HCl/MeOH). Such preparation of 2-thio­ hydantoin is quite understandable, as the cyano group has been applied as a latent carboxyl group in many organic syntheses already. Thus, no further example for this preparation is provided here. Finally, 2-thiohydantoins can be prepared from the selective desulfuriza­ tion of 2,4-dithiohydantoins, where the 2,4-dithiohydantoins can be easily formed from the sulfurization of the corresponding hydantoins. For example, treatment of cyclopentanespiro-5-hydantoin in xylene with P4S10 led to the formation of cyclopentanespiro-5-(2,4-dithiohydantoin), which was then treated with 2-aminoethanol to give 4-(2-hydroxyethylimino)-cyclo­ pentanespiro-5-(2-thiohydantoin). Further refluxing of this intermediate in 20% HCl yielded cyclopentanespiro-5-(2-thiohydantoin) [77]. Other similar treatments include the treatment of the corresponding 2,4-dithiohydantoin in 50% aqueous solution of 2-aminoethanol [7], treatment of spirodithiohy­ dantoins with barium hydroxide [20]. Particularly, treatment of a series of cycloalkanespiro-5-(2,4-dithiohydantoins) with barium hydroxide at normal pressure in the presence of ethanol at 100°C leads to the formation of the relevant cycloalkanespiro-5-(2-thiohydantoins) as the only products. At higher temperatures such as 160°C, besides the main product of cyclopentane­ spiro-5-(2-thiohydantoin) from cyclopentanespiro-5-(2,4-dithiohydantoin), 1-aminocyclopentanecarboxylic acid, 1-aminocyclopentane-carbothioic acid and 1-aminocyclopentanecarbodithioic acid have also been observed [171].

168

Amino Acids: Insights and Roles in Heterocyclic Chemistry, Volume 2

It is worthy to bring up an unusual method for the preparation of 2-thiohy­ dantoin that involves the reaction of methyl Nα-cyano-Nα-alkyl (or Nα-aryl) carboxylate with diethyl thiophosphate, as shown in Scheme 3.23. This preparation involves the reaction of amines with cyanogen bromide to give monoalkyl/aryl cyanamides, which then react with methyl bromoacetate in the presence of sodium hydride to afford various methyl Nα-cyano-Nα-alkyl (or Nα-aryl) carboxylate derivatives. The final reaction step with diethyl thiophosphate takes place at 60°C in good to excellent yields under solventfree conditions [32].

SCHEME 3.23 Generation of 2-thiohydantoin from the reaction of N-cyano amino ester and diethyl thiophosphate.

3.3.2 PREPARATION OF 4-THIOHYDANTOINS Different from so many methods for the preparation of 2-thiohydantoins, there are only a few practices for the preparations of 4-thiohydantoins. This might be the reason that 4-thiohydantoin derivatives have not gained popularity in comparison to 2-thiohydantoins yet. One such practice is to reflux 3-phenyl hydantoin in dioxane with phosphorous pentasulfide followed by the treat­ ment with metal zinc to afford 3-phenyl-4-thiohydantoin in good yield [15]. However, it might be difficult to control this reaction as 2,4-dithiohydantoin can also be formed as mentioned previously. Similar to the conversion of 2,4-dithiohydantoins into 2-thiohydantoins with 2-aminoethanol, 2,4-dithio­ hydantoins can also be transformed into 4-thiohydantoins when they are treated with 8% NaOH and dimethylsulfate (Me2SO4) and subsequently with 20% HCl for hydrolysis, as shown in Scheme 3.24 for the conversion of 1,3-diazaspiro[4.5]decane-2,4-dithione into 4-thioxo-1,3-diazaspiro[4.5]

Thiohydantoins

169

decan-2-one [7]. An alternative method for making 4-thiohydantoin involves α-amino acetonitrile that is initially acylated at the amino group and then treated with hydrogen sulfide to form thioamide. Subsequent cyclization leads to the formation of 4-thiohydantoin [2]. One example of these preparations is the conversion of carbethoxyaminoacetonitrile (i.e., ethyl (cyanomethyl) carbamate) into ethyl (2-amino-2-thioxoethyl)carbamate (i.e., carbethoxy­ aminoacetothioamide) by the addition of hydrogen sulfide, and the latter is then condensed to 4-thiohydantoin by the action of a stoichiometric amount of 5–10% NaOH, as shown in Scheme 3.25.

SCHEME 3.24 Conversion of 2,4-dithiohydantoins into 4-thiohydantoins.

SCHEME 3.25 Synthesis of 4-thiohydantoin from α-amino-acetonitrile.

3.3.3 PREPARATION OF 2,4-DITHIOHYDANTOINS In theory, 2,4-dithiohydantoins can be prepared from the corresponding hydantoins by means of full sulfurization of the carbonyl group within the hydantoin ring. For example, 5,5-disubstituted hydantoins have been treated with phosphorus trisulfide (P2S6) in tetralin at 225–230°C to give the

170

Amino Acids: Insights and Roles in Heterocyclic Chemistry, Volume 2

respective 2,4-dithiohydantoins [172]. Ketones are converted into 5,5-disub­ stituted 2,4-dithiohydantoins in reaction with carbon disulfide (CS2) and ammonium cyanide (NH4CN) in an aqueous methanol solution [173]. Also, hydantoin can be treated with P4S10 or P2S5 to afford 2,4-dithiohydantoins

as mentioned early. It should be pointed out that the popular sulfurization reagent, e.g., Lawesson’s reagent, can be used to convert the hydantoins into 2,4-dithiohydantoins in toluene [7]. Besides these direct and common methods, α-amino acetonitrile can be converted into 2,4-dithiohydantoins involving the formylation of the amino group and subsequent conversion of the formamide group into the isocyano group, such as the preparation of ethyl 2-cyano-2-formamidopropanoate and its transformation into ethyl 2-cyano-2-isocyanopropanoate, and further transformation into carbodiimide chloride moiety with chlorine in CH2Cl2/ CCl4 to form α-cyano-α-(dihalogenomethyleneamino) derivative (e.g., ethyl 2-cyano-2-((dichloromethylene)amino)propanoate), that is then treated with two equivalents of KHS in acetone to afford 5,5-disubstituted 2,4-dithio­ hydantoin (e.g., ethyl 4-methyl-2,5-dithioxoimidazolidine-4-carboxylate) [174], as shown in Scheme 3.26. Likewise, α-amino acetonitrile (e.g., 2-amino-2-phenylacetonitrile) when treated with CS2 affords 4-substituted 5-amino-thiazole-2-thiol (e.g., 5-amino-4-phenylthiazole-2-thiol) that upon treatment with base and subsequently with acid leads to the formation of 5-substituted 2,4-dithiohydantion (e.g., 5-phenylimidazolidine-2,4-dithione), as shown in Scheme 3.27.

SCHEME 3.26 Preparation of 5,5-disubstituted 2,4-dithiohydantoin.

Thiohydantoins

171

SCHEME 3.27 Preparation of 2,4-dithiohydantoin using CS2 as the sulfur source.

3.3.4 PRACTICAL PREPARATIONS OF THIOHYDANTOINS 3.3.4.1 PREPARATION OF 2-THIOHYDANTOINS 3.3.4.1.1  Preparation of (S)-5-Benzyl-2-Thiohydantoin with NH4SCN/Ac2O [119]

• Step A: Formation of N-acetyl-2-thiohydantoin: To a round-bottomed flask with a magnetic stir bar, were added 2.0 g of L-phenylalanine (12.1 mmol), 0.921 g of NH4SCN (12.1 mmol), and 6.86 mL of acetic anhydride (72.6 mmol, d = 1.08 g/mL). The mixture was stirred at 100°C for 30 minutes, by which time all solids dissolved. The reaction mixture was then quenched with ice and water (30 mL), and the aqueous layer was extracted with EtOAc (3 × 20 mL). The combined organic layers were dried over MgSO4, concentrated in vacuo and purified by silica gel column chromatography to give (S)-1-acetyl-5-benzyl-2-thioxoimidazolidin-4-one. • Step B: N-Deacetylation: (S)-1-Acetyl-5-benzyl-2-thioxoimid­ azolidin-4-one (0.248 g, 1 mmol) was dissolved in 10 mL of anhy­ drous methanol (dried over 3 Å molecular sieves) under argon. The solution was cooled in an ice-salt bath, then sodium metal was added at 0°C until the pH value reached 9–10. The resulting solution was

172

Amino Acids: Insights and Roles in Heterocyclic Chemistry, Volume 2

stirred for 2 hours at room temperature, then quenched with Amberlite IR 120 H+ until neutral pH, after which the solution was concentrated in vacuo. The crude product was purified on silica gel column chro­ matography to afford (S)-5-benzyl-2-thiohydantoin. The overall yield of the two consecutive steps was 76%. 3.3.4.1.2  Preparation of (S)-5-Methyl-2-thiohydantoin with NH4SCN/Ac2O under Microwave Irradiation [121]

• Step A: To a microwave reaction tube, were added 0.891 g of L-alanine (10.0 mmol), 1.218 g of NH4SCN (16.0 mmol), 9 mL of acetic anhydride and 1 mL of acetic acid. The sealed microwave reaction tube was irradiated at 100°C in Mars 5 microwave reactor for 2 minutes. Then the reaction mixture while still warm was poured into 30 mL ice/water under stirring. The precipitate was filtered, washed with water, and dried under a vacuum. The crude solid was further purified by recrystallization from 95% EtOH to afford (S)-1-acetyl-5-methyl-2-thioxoimidazolidin-4-one as a light yellow crystal, in a yield of 88.1%, m.p. 164–165°C. For comparison, about 74.0% yield of (S)-1-acetyl-5-methyl-2-thioxoimidazolidin-4-one was obtained with the conventional method without microwave irradiation. • Step B: To a 50 mL round-bottomed flask, were added 1.722 g of (S)-1-acetyl-5-methyl-2-thioxoimidazolidin-4-one and 20 mL of 6 M HCl. The mixture was refluxed under stirring for 30 minutes and then cooled to room temperature. The precipitate was filtered, washed with water, and dried under a vacuum. The solid was further purified by recrystallization from 95% EtOH to afford (S)-5-methyl­ 2-thiohydantoin as a white crystal, m.p. 161–162°C.

Thiohydantoins

173

3.3.4.1.3  Preparation of 1,5-Diphenyl-2-Thiohydantoin with KNCS/ Et3N [119]

Methyl α-(phenylamino)-α-phenylacetate (1.20 g, 4.98 mmol) was dissolved in 10 mL of ethanol under heating. Then 0.87 g of potassium thio­ cyanate (8.95 mmol) in 5.0 mL of water and 1.74 mL of triethylamine (1.26 g, density 0.726 g/mL, 9.04 mmol) were added. The reaction mixture was refluxed until the reaction was complete. The reaction was then concentrated and acidified. The resulting solid was washed with ice water and purified by recrystallization from aqueous ethanol. Unfortunately, the yield was only 5%. When the same reaction was irradiated under the microwave (490 W) and worked up under the same condition, the yield was 7%. Rf = 0.27 (MeOH/CH2Cl2 = 10/1), m.p. 140–142°C. 3.3.4.1.4  Preparation of 2-Thiohydantoin from α-Amino Acid Ester and Alkyl Isothiocyanate, Formation of (5R,9S)-9(3,5-Dimethoxyphenyl)-3-Ethyl-7-Methyl-2-Thioxo-1,3,7Triazaspiro[4.4]Nonan-4-One [125]

. To a 1.5 mLsolution of methyl (3R,4S)-3-amino-4-(3,5-dimethoxyphenyl)­ 1-methylpyrrolidine-3-carboxylate in DMF (0.1 mmol) was added 0.1 mmol

174

Amino Acids: Insights and Roles in Heterocyclic Chemistry, Volume 2

of ethyl isothiocyanate from a 0.3 M stock solution in DMF. The resulting reaction mixture was stirred at 40°C for 40 hours. After that, the solvent was evaporated. The crude mixture of compounds was added with 2 mL of diethyl ether and the mixture was shaken until a white precipitate was formed. The sample was centrifuged, and the solvent was carefully eliminated with a pipet, to afford 89% of (5R,9S)-9-(3,5-dimethoxyphenyl)-3-ethyl-7-methyl­ 2-thioxo-1,3,7-triazaspiro[4.4]nonan-4-one, in 94% of purity. 3.3.4.1.5  Preparation of 5-Methyl-3-Phenyl-2-Thiohydantoin [13]

To a solution of 936.3 mg of phenyl isothiocyanate (7.0 mmol, 1.0 equiv.) in 15 mL of 1,4-dioxane/H2O (1:1, v/v) at 0°C was added 623.6 mg of DL-alanine (7.0 mmol, 1.0 equiv.). Then 1.42 g of Et3N (14.0 mmol, 2.0 equiv.) was added slowly to the reaction mixture and the solution was stirred for 1 hour at room temperature, followed by the addition of 2.13 mL of concentrated HCl (21.0 mmol, 3.0 equiv.) at 0°C until the pH reached ~ 2. The reaction mixture was transferred into a 20 mL sealed reactor vessel and irradiated with microwave under stirring at 160°C for 2 min. After being cooled to room temperature, the reaction mixture was neutralized with satu­ rated NaHCO3 until the pH became ~ 6. The precipitate formed was filtered and dried to yield 1.34 g of 5-methyl-3-phenyl-2-thiohydantoin as a white solid, with a yield of 93%. 3.3.4.1.6  Preparation of 3-(5-Chloro-2-Methylphenyl)-1-Ethyl-2Thiohydantoin [132]

Thiohydantoins

175

• Step A: Preparation of N-ethylglycine: To a solution of 92.05 g of glyoxylic acid monohydrate (1 mol) in 700 mL water was added 101 mL of 70% ethylamine in water (1.25 mol) slowly under stirring. The mixture was stirred at 35–40°C for 1 hour and then transferred to a pressure hydrogenation bottle containing 10% palladium on carbon (20 g) in 200 mL of water. The mixture was hydrogenated at 50 psi for 18 hours. The catalyst was removed by filtration, and the filtrate was concentrated to the half volume under reduced pressure ( 2,000) and PDE6 (IC50 ratio = 1,000) but is less selective over PDE11 (IC50 ratio = 5) [24]. This compound has been developed based on a hydantoin lead molecule [338] and is currently the only clinically approved drug with the DKP scaffold [339]. 4.4 PREPARATIVE METHODS

Chemically, the preparation of DKP involves the formation of peptide bonds during the initial generation of dipeptide and cyclization of the resulting dipeptide to form DKP. Many synthetic practices have been undertaken for the DKPs, either for the purpose of creating a DKP library in order to screen for a particular biological activity, or challenging the complexity that many DKP-containing natural products of biological importance bear as mentioned previously. In this section, the formation of the DKP core will be the focus. The known synthetic methods for DKPs can be classified into several groups, including the cyclization of dipeptide, direct generation of DKP from the amino acid, solid-phase synthesis of DKP, Ugi multiple component reaction, enzyme-catalyzed formation of DKP, preparation of DKP under microwave irradiation, synthesis of arylidene-DKPs, etc. 4.4.1 CYCLIZATION OF DIPEPTIDE This method includes the formation of dipeptide and subsequent cycliza­ tion of such dipeptide, both involving the formation of a peptide bond. As mentioned in Chapter 2, the formation of a particular dipeptide requires the protection of both amino and carboxyl groups and the activation of remaining groups, as well as the application of peptide condensation reagent. Many of these condensation reagents are actually very expensive. During these preparations, the amino group is often protected by Boc, and the carboxyl group is converted into an ester group. For example, an optically pure Boc­ dipeptide methyl ester generated from the condensation between an N-Boc protected amino acid and a methyl ester of amino acid in the presence of

290

Amino Acids: Insights and Roles in Heterocyclic Chemistry, Volume 2

dicyclohexylcarbodiimide (DCC), undergoes cyclization under heating upon the removal of the Boc protecting group under acidic condition (treatment with formic acid) [340]. In another example, the amino group in (S)-2-amino­ 5-methoxy-5-oxopentanoic acid is first protected with Boc, and the resulting amino acid is activated with N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquino­ line (EEDQ), a highly specific reagent for the coupling of N-acylamino acids with amino acid esters in high yield without racemization, followed by the treatment with ethyl glycinate to afford methyl (S)-4-((tert-butoxycarbonyl) amino)-5-((2-ethoxy-2-oxoethyl)amino)-5-oxopentanoate. Upon deprotec­ tion of the Boc with acid, the corresponding dipeptide cyclizes to yield methyl (S)-3-(3,6-dioxopiperazin-2-yl)propanoate (Scheme 4.1) [341]. In order to prepare a 1,2,3,4-tetrahydro-β-carboline based peptidomimetic scaffold capable of forming an unusual α-turn conformation, benzyl L-alaninate was treated with ethyl bromoacetate, followed by 9-fluorenylmethoxycarbonyl chloride. After that, the benzyl group was removed under hydrogenation, and the resulting carboxyl group was activated into carboxyl chloride, which then condenses with methyl (1S,3S)-1-((((benzyloxy)carbonyl)amino) methyl)-2,3,4,9-tetrahydro-1H-pyrido-[3,4-b]indole-3-carboxylate. Upon removal of the Fmoc protection group with piperidine, the corresponding DKP, i.e., ethyl 2-((3S,6S,12aS)-6-(benzyloxycarbonylaminomethyl)-3methyl-1,4-dioxo-3,4,12,12a-tetrahydro-pyrazino-[1’,2’:1,6]pyrido[3,4-b] indol-2(1H,6H,7H)-yl)acetate was formed [342]. The synthetic route of this DKP is displayed in Scheme 4.2. Generally, the formed 2,5-DKPs are insoluble in reaction solvents and precipitate as they are formed. Therefore, stereochemically pure 2,5-DKPs can be easily obtained by a simple work­ up, such as filtration and recrystallization of the crude products [1].

SCHEME 4.1 Preparation of DKP starting from (S)-2-amino-5-methoxy-5-oxopentanoic acid.

It is generally accepted that when the carboxyl group is converted into the corresponding ester group, the formation of amide between the resulting

2,5-Diketopiperazine

291

ester and free amino group is more readily achieved. For example, a range of non-natural dipeptides of the general formula D-(-)-phenylglycyl-L-X, where X is a natural α-amino acid, prepared from D-(-)-phenylglycine amide and the corresponding amino acids by penicillin acylase-catalyzed synthesis in an aqueous medium, once transformed into the corresponding dipeptide esters, spontaneously cyclize to the stereochemically pure diketopiperazines [343], as displayed in Scheme 4.3.

SCHEME 4.2 Cyclization of dipeptide derivative to form a fused DKP.

SCHEME 4.3 Cyclization of dipeptide ester into stereochemically pure DKP.

292

Amino Acids: Insights and Roles in Heterocyclic Chemistry, Volume 2

Particularly, when dipeptides or even longer peptides are heated, the corresponding DKPs are readily formed. For example, the DKP of hexahydrodipyrrolo[1,2-a:1,2-d]pyrazine-3,5,10(10aH)-trione has been identified by ESI-MS/MS and extensive NMR analysis after the pyrolysis of Pro-Glu, as well as in the pyrolysates of dipeptide Pro-Gln, tripeptide ProGlu-Leu, collagen, and bovine serum albumin (BSA) [11]. The dipeptide esters would more readily cyclize to DKPs under heating, especially under microwave irradiation. For example, N-Boc-dipeptide ester dissolved or suspended in water, once heated at 250°C and 150 psi using a monomode CEM Discover microwave apparatus at 250 W for 10 minutes, DKP can be obtained by filtration of the resulting suspension through a Hirsch funnel and washed with water without further purification. This methodology has been extended to the syntheses of dimeric structures based on intermolecular DKP formation by activation of C-terminal glycine monomer, solvent-free synthesis of DKPs in one-pot deprotection-cyclization of N-Boc-dipeptidyl ethyl and methyl esters, and the DKPs formation using dipeptide methyl ester hydrochlorides in water in two or three steps [9]. Similarly, dipeptide methyl esters have been heated in water under microwave irradiation to form DKPs, and a total of 11 structurally different DKPs have been obtained. Along with water, a range of common laboratory solvents have been tested as well as different reaction times and temperatures, and water has been identified as the best media for the formation of DKP under microwave irradiation [344]. Especially, unstable peptides easily form diketopiperazine structures. It is observed that N-methylation of the peptide amide bond closest to the N-terminal leads to unstable derivatives that in PBS cyclize to their corresponding 2,5-diketopiperazine derivatives [18]. A lysine based 1,3,6-trisubstituted-2,5-diketopiperazine scaffold has been prepared upon removal of the Fmoc protecting group on the dipeptide of lysine prepared from sequential Fukuyama-Mitsunobu alkylation, and dipeptide coupling. This DKP bears up to three ‘clickable’ sites for further introduction of func­ tional groups for inhibition of Ab40 fibril formation, by means of oxime bond or alkyne-azide cycloaddition ligations [345]. For glycine-containing DKPs, they can also be prepared from other amino acids and α-halo acetic acid derivatives, particularly the cheap α-chloro-acetic acid. In this case, the resulting α-chloro-dipeptide undergoes cyclization to form the glycine-containing DKPs, as chloro is a reason­ ably good leaving group [346]. Following this route, a similar strategy for substitution of the α-halo group has been developed to make 1,3,4,6-tetra­ substituted DKPs in a one-pot fashion. By doing so, L-amino acid-derived

2,5-Diketopiperazine

293

(αRS)-α-bromo tertiary acetamides are treated with primary aliphatic amine to substitute the α-bromo group, and the resulting intermediates cyclize to form the respective DKPs [347]. 4.4.2 ENZYME-CATALYZED SYNTHESIS OF DKPS In general, there are several advantages associated with the enzymecatalyzed chemical reactions, including the mild reaction conditions (room temperature, neutral pH, etc.), simple or readily available substrate, and high reaction efficiency (e.g., high reaction rate, high reaction selectivity and regioselectivity, and high turnover rate). In contrast, chemical reaction sometimes requires harsh reaction conditions (e.g., high reaction tempera­ ture, unstable substrate, extremely acidic or basic condition), and expensive reagents. The enzyme-catalyzed synthesis of DKPs is not much different from many other enzyme-catalyzed reactions. From the biosynthetic point of view, proteins are generally synthesized on the ribosomes. Besides the ribosomal enzymes, there are non-ribosomal enzymes, such as nonribosomal peptide synthetases (NRPSs). These multimodular enzymes act as molecular assembly lines to catalyze the formation of peptide bonds between amino acid substrates and modifications to these residues [48]. In addition, these synthetases also catalyze the generation of DKP-containing natural products, as in the case of cyclo(D-Phe-L-Pro), either by means of a dedicated pathway or cyclization of the prematurely released peptidyl intermediates [50]. Recently, another type of enzyme that catalyzes the pathway exclusively dedicated to the formation of DKP has been identi­ fied, i.e., the first cyclodipeptide synthase (CDPS) AlbC, which is secreted on the albonoursin biosynthetic gene cluster in Streptomyces noursei [348, 349]. These enzymes catalyze the formation of two successive peptide bonds in an ATP-independent fashion by hijacking aminoacyl-tRNAs (aa-tRNAs) from the ribosomal machinery and the corresponding DKPs directly using the formed dipeptides as substrates [50]. After that, more than 50 putative CDPS encoding genes clusters have been found through the use of iterative positionspecific iterative basic local alignment search tool (PSIBLAST) searches in many prokaryotic and a few eukaryotic species. Often, more than one putative DKP-modifying enzymes can be found in the direct surroundings of all puta­ tive prokaryotic CDPS genes, including seven distinct types of cytochrome P450s, five different types of non-heme FeII/α-ketoglutarate-dependent oxygenases, three distinct flavin-containing monooxygenases, and different

294

Amino Acids: Insights and Roles in Heterocyclic Chemistry, Volume 2

kinds of transferases among others [47]. These CDPS are responsible for the generation of antibiotic albonoursin (Table 4.10), the siderochrome pulcher­ rimininic acid and the nocazine family (Nocardipsis spp.) of antibiotics. A general reaction pathway is demonstrated in Scheme 4.4.

SCHEME 4.4 Enzyme-catalyzed synthesis of DKPs.

In an example of the enzyme-catalyzed synthesis of DKP, the expression of two nonribosomal peptide synthetases larger than 100 kDa resulted in the production of cyclo(D-Phe-L-Pro) at levels higher than the previously reported cell-based recombinant expression, approximately at 12 mg/L. This occurs in the biosynthesis of Gramicidin S in Brevibacillus brevis. By turning through the assembly line pathway two times, cyclo(D-Phe-L-Pro) is produced [195]. In another example of enzyme-catalyzed DKP synthesis, the immobi­ lized Escherichia coli penicillin acylase with high selectivity for L-amino acids catalyzes the efficient acylation of L-phenylglycine by D-phenyl­ glycine amide at pH 9.7 to give D-phenylglycyl-L-phenylglycine in 69% yield, without further formation of isomers or tripeptides. Due to the low enantiospecificity of this enzyme for the acyl donor, the corresponding L,L­ dipeptide of L-phenylglycyl-L-phenylglycine methyl ester is formed from L-phenylglycine methyl ester as both the donor and acceptor at pH 7.5, in a yield of 63% [343, 350]. These dipeptide esters of phenylglycine easily cyclize to diketopiperazines in aqueous methanol. Also, it has been reported that among Bacillus species, both CDPS synthesis of the YvmC of Bacillus licheniformis and non-ribosomal synthesis of Tyrocidine A and Gramicidin S synthesis are accompanied by the secre­ tion of cyclo(Phe-Pro) in Bacillus brevis. The genome of the erythromycinproducing bacterium Saccharopolyspora erythraea contains many orphan

2,5-Diketopiperazine

295

secondary metabolite gene clusters, including two non-ribosomal peptide synthetases (NRPS3 and NRPS5) which are responsible for the biosynthesis of nonribosomal peptide-based siderophores, i.e., erythrochelin with a tetrapeptide backbone of (α-N-acetyl-δ-N-acetyl-δ-N-hydroxyornithine­ serine-δ-N-hydroxyornithine-δ-N-acetyl-δ-N-hydroxyornithine), even under iron-sufficient conditions. Deletion of the nonribosomal peptide synthetase gene ercD within the NRPS5 cluster abolished the production of erythro­ chelin [351]. 4.4.3 DIRECT SYNTHESIS OF DKPS FROM α-AMINO ACIDS During the condensation of α-amino acids to form peptides, water is gener­ ated as a byproduct. Therefore, the presence of a dehydration reagent would benefit the formation of dipeptides directly from amino acids and subsequent cyclization of dipeptides to DKPs. In addition, the condensation of α-amino acid can be favored when the reaction is carried out at a high temperature, as the removal of water under this condition would shift the equilibrium towards the formation of DKP. One example of this synthetic method is the treatment of L-proline with PCl5 in methylene chloride to form (5aS,10aS)-octahydro-5H,10H­ dipyrrolo[1,2-a:1’,2’-d]pyrazine-5,10-dione at room temperature while the system is purged with nitrogen to remove the released gas (HCl) (Scheme 4.5) [352]. A general method has been developed for the formation of DKPs of phenylalanine, alanine, leucine, valine, and threonine, starting from the corresponding N-Boc protected amino acid and amino acid methyl ester in the presence of a condensation reagent, such as N,N-dicyclohexylcarbodiimide (DCC) to initially generate an optically pure Boc-dipeptide methyl ester, which upon deprotection of the Boc group under acidic condition and heating, lead to the formation of relevant DKP accordingly, as shown in Scheme 4.6 [353]. However, this method is not applicable to make the corresponding DKP of L-cysteine, due to the formation of a potential disulfide linkage. In order to make such cyclic dipeptide, the sulfhydryl group should be protected prior to the condensation step. For this particular DKP, L-cysteine is converted into (R)-thiazole-4-carboxylic acid, which cyclizes into (5aR,10aR)-tetrahydro-3H,5H,8H,10H-dithiazolo[3,4-a:3’,4’-d]pyrazine5,10-dione in the presence of O-benzotriazol-1-yl-tetramethyluronium (HBTU) and diisopropylethylamine (DIEPA) [340]. The sulfhydryl group can be released under acidic conditions (Scheme 4.7).

296

Amino Acids: Insights and Roles in Heterocyclic Chemistry, Volume 2

SCHEME 4.5 Direct dimerization of proline to DKP.

SCHEME 4.6 Thermal cyclization of dipeptides to DKPs.

SCHEME 4.7 Direct conversion of amino acid into DKP in the presence of a dehydration agent.

Besides PCl5 and HBTU, zirconates, such as Zr(O-i-Pr)4, being the water absorbents, also effect the dimerization of amino acids (e.g., glycine, alanine) to the corresponding DKPs. Likewise, the corresponding titanium reagent has a similar effect on the preparation of DKP [354]. Other suitable dehydrating agents, such as polyphosphoric acid also facilitate the forma­ tion of DKPs. When an excess amount of polyphosphoric acid is employed, α-amino acids including glycine, alanine, leucine, isoleucine, and phenyl­ alanine, are converted into the corresponding diketopiperazines with the yields varying at different temperatures. For example, the maximal yield of cyclo(Gly-Gly) appears at the temperature ranging from 85–95°C, whilst the yield of cyclo(Ala-Ala) peaks at temperatures from 80–90°C. The optimal temperature ranges for leucine, isoleucine, and phenylalanine are 70–75, 95–100, and 90–95°C, respectively [355]. The amino acids of non-polar side

2,5-Diketopiperazine

297

chains also dimerize under the “gas-solid-phase” reaction condition in which the particular amino acid is sublimed in the presence of macro-porous silica at a temperature ranging from 160 to 220°C at reduced pressure [356]. When amino acids (alanine, valine, norvaline, leucine, and 2-aminoisobutyric acid) are subjected to repeated sublimation in the presence of silica at a tempera­ ture of 220–240°C for 5 to 9 times, the corresponding diketopiperazines are formed as the major products, in yields of 27–89%. In addition, further dehydration proceeds to form bicyclic and tricyclic amidine derivatives of DKPs, as illustrated by the reaction of alanine in Scheme 4.8, which affords (2S,5S,8S)-2,5,8-trimethyl-7,8-dihydroimidazo[1,2-a]pyrazine-3,6(2H,5H)­ dione and (2S,5S,7S,10S)-2,5,7,10-tetramethyl-2,5,7,10-tetrahydro-3H,8H­ diimidazo[1,2-a:1’,2’-d]pyrazine-3,8-dione, in addition to cyclo(Ala-Ala) [357].

SCHEME 4.8 Formation of DKP and bicyclic and tricyclic amidine derivatives from L-alanine.

The corresponding DKP of L-threonine, i.e., 3,6-bis(α-hydroxyethyl)-2,5­ diketopiperazine, has been prepared in two ways, by means of dimerization of carbobenzoxy-L-threonine in the presence of DCC followed by catalytic hydrogenation, or thermal condensation of crystalline L-threonine methyl ester at 75°C [358]. It is reported that D-aspartic acid does not cyclize when it is heated under reflux in toluene and/or benzyl alcohol. When D-aspartic acid is heated at 150–200°C or reacted with peptide coupling reagents, such as DCC, 1-(((3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)oxy)(pyrrolidin-1-yl)meth­ ylene)pyrrolidin-1-ium hexafluorophosphate (HAPyU), etc., many complex linear compounds are generated. In comparison, when D-aspartic acid was converted into D-aspartic acid benzyl ester and left at room temperature over two weeks, a small amount of nice crystalline could form from the oil, which was determined to be meso-3,6-disubstituted piperazine-2,5-diones. When dibenzyl D-aspartate was heated under refluxing in toluene and benzyl alcohol for about 24 hours, and then cooled to room temperature, a higher yield of the corresponding DKP was obtained, as shown in Scheme 4.9 [359].

298

Amino Acids: Insights and Roles in Heterocyclic Chemistry, Volume 2

SCHEME 4.9 Thermal dimerization of dibenzyl D-aspartate.

It should be pointed out that ethylene glycol is a good solvent for the direct formation of DKP. For example, when L-leucine was heated in dry ethylene glycol at 180°C for 10 hours, the corresponding 3,6-diisobutyl2,5-diketopiperazine was recrystallized from hot ethanol/water (5:1) [360]. Similarly, when D/L-phenylalanine is refluxed in ethylene glycol, the corre­ sponding DKP forms [361]. For the case of isoleucine, three isomers are formed in good yields when refluxed in ethylene glycol [362]. Finally, amino acid once converted into the corresponding N-carboxy­ anhydride (NCA), is very reactive that can condense with another amino acid ester to generate dipeptide, which spontaneously cyclizes to give the corresponding DKP, as represented in the reaction between (S)-4-isopro­ pyloxazolidine-2,5-dione and ethyl glycinate hydrochloride as shown in Scheme 4.10 [363].

SCHEME 4.10 Direct formation of DKP from L-valine NCA and ethyl glycinate.

Besides ethylene glycol, amino acids in an aqueous solution under extreme conditions also dimerize to form DKPs. For example, amino acid dimers and the corresponding DKPs have been identified after the nearly saturated aqueous solution of lysine, norvaline, aminobutyric acid, proline, or phenylalanine sealed in stainless steel capsules was shocked by ballistic impact with a steel projectile plate accelerated along a 12 meters long gun barrel to velocities of 0.5–1.9 km/sec. According to 1D hydrodynamical simulations, the maximum conditions experienced by the solutions lasted 0.85 to 2.7 seconds with the corresponding pressure and temperature ranging from 5.1 to 21 GPa and 412 to 870 K, respectively. Under this condition,

2,5-Diketopiperazine

299

phenylalanine appeared to be the most reactive amino acid, whereas amino­ butyric acid was the least reactive amino acid [13]. Similarly, the direct formation of DKP under simulated hydrothermal conditions was studied by injecting glycine solution into water close to sub- and supercritical states, at 250, 300, 350, 374, and 400°C and pressures of 22.2 and 40.0 MPa. At 350°C, 2,5-diketopiperazine, diglycine, and a trace amount of triglycine as well as an unidentified product with a high molecular mass of 433 Daltons were found under a pressure of 15.0–40.0 MPa [14]. In another practice, an in situ cyclization of iminodiacetic acid in lanthanide-based coordination polymers, namely, [Ln2(oxalate)2L(H2O)2]n (Ln = Dy, Ho, Er, Yb; L=2,5-diketopiperazine-1,4-diacetate), was observed, for which oxalic acid plays a key role in the formation of the 2,5-dike­ topiperazine-1,4-diacetate ligand. The block crystals were obtained by hydrothermal reactions of Ln2O3 (Ln = Dy, Ho, Er, Yb), iminodiacetic acid, oxalic acid, HNO3 and water in a molar ratio of 1: 4: 2: 6: 550 at 180°C for 100 hours, resulting in the in situ transformation of iminodiacetic acid into 2,5-diketopiperazine-1,4-diacetic acid through intermolecular dehydration coupling [364]. 4.4.4 UGI MULTI-COMPONENT REACTION As DKP is a cyclic dipeptide that can be readily formed from the cyclization of a linear dipeptide, any synthetic method for the construction of the linear dipeptide or similar structure would be very useful in the preparation of DKPs. Ugi multicomponent reaction is one of such reactions, which involves four components (i.e., a ketone or aldehyde, an amine, an isocyanide and a carboxylic acid) to form a bis-amide, as demonstrated in Scheme 4.11. This reaction is named after Ivar Karl Ugi, who initially reported this reaction in 1959 [365]. Due to the nature of this reaction, it is also termed as “Ugi four-component reaction” and “Ugi four-component condensation,” and is often abbreviated as Ugi-4CR or U-4CC [366].

SCHEME 4.11 General Ugi four-component reaction to afford dipeptide derivatives.

300

Amino Acids: Insights and Roles in Heterocyclic Chemistry, Volume 2

This reaction is believed to start with the formation of an imine between ketone (or aldehyde) and the primary amine, which is then protonated by the carboxylic acid. Due to the nucleophilic nature of the isonitrile, the terminal carbon atom will add to the in situ generated iminium to afford nitrilium ion, which is highly electrophilic and subsequently attacked by the carboxylate. Internal rearrangement leads to the formation of the final product of the Ugi reaction, as shown in Scheme 4.12.

SCHEME 4.12 The mechanism of the Ugi four-component reaction to yield dipeptide derivatives.

The Ugi reaction is an efficient reaction to form bis-amide, particularly with the component of non-natural amino acid, resulting in the diversity and versatility of the final product when different starting materials are used. For example, the acid component may be HN3, HNCO, HNCS, HNCSe, H2S2O3 or H2Se, thiocarboxylic acid, phenol or water, whilst the amino group might be a part of hydrazine, hydrazides, urea, semicarbazide, mono­ hydrazones, sulfonamides, hydroxylamine, etc. [366]. Particularly, when one of the components is bound to a resin, a solid-phase synthesis version of the Ugi reaction is established, which shares many common advantages of the solid-phase peptide synthesis. For the Ugi reaction, often the component of isonitrile is linked to a resin, such as the universal Rink isocyanide resin, the safety-catch linker isocyanide resin, the cyclohexenyl isocyanide resin and the carbonate convertible isocyanide resin.

2,5-Diketopiperazine

301

SCHEME 4.13 The Ugi four-component reaction to give DKP derivative.

The resulting bis-amide can be easily converted into DKP if the initial carboxylic acid with a good leaving group at its α-position is used, such as chloroacetic acid. In this case, the terminal amide can attack the carbon atom with the chloro group, resulting in the cyclization and formation of the corresponding DKP [366]. Alternatively, when the Ugi reaction involves a component of α,b-unsaturated carboxylic acid, the cascade Michael reaction of the terminal amide to the unsaturated double bond would afford highly substituted DKP, in a one-pot synthesis manner, as shown in Scheme 4.13 [367]. However, the outcome of the Ugi reaction under this condition is vari­ able depending on the structures of the four substrates. For example, the reac­ tion among (E)-4-ethoxy-4-oxobut-2-enoic acid, 4-methoxybenzylamine, an aldehyde and an isonitrile under microwave irradiation in a protic solvent yields the normal DKP product, whilst the reaction among (E)-4-ethoxy-4­ oxobut-2-enoic acid, 4-hydroxybenzylamine, an aldehyde and an isonitrile under the same condition generates 2-azaspiro[4.5]deca-6,9-diene-3,8-dione derivative, (aminomethyl)phenol; particularly, the reaction among (E)-4­ ethoxy-4-oxobut-2-enoic acid, 4-methoxybenzylamine, 2-thienylaldehyde, and an isonitrile under microwave irradiation but in an aprotic solvent, a tricyclic lactam predominates in the reaction cascade involving a subsequent Diels-Alder cycloaddition of the Ugi product, as shown in Scheme 4.14 [368]. In addition, if the component of the carboxylic acid is an α-keto­ carboxylic acid, a cascade Ugi/Pictet-Spengler two-step procedure can be carried out to form the highly substituted DKP, as represented in the reaction among 2-oxopropanoic acid, ortho-nitrobenzaldehyde, n-butylamine, and homoveratryl isonitrile as shown in Scheme 4.15 [369]. When a dipeptide is applied, only isonitirle and aldehyde are needed, as demonstrated by the experiment of slow addition of isonitrile solution in trifluoroethanol to a

302

Amino Acids: Insights and Roles in Heterocyclic Chemistry, Volume 2

mixture of aldehyde and dipeptide under a nitrogen atmosphere to yield a DKP [370]. However, it should be pointed out that the main disadvantage of using the Ugi reaction in the formation of DKP is the great difficulty in the cyclization of the dipeptide as a C-terminal amide is generated, which is not very much nucleophilic [24].

SCHEME 4.14 Products of the Ugi four-component reaction in different solvents under microwave irradiation.

On the other hand, many factors can affect the overall outcome of the Ugi reaction, including the diversity of the components, reaction temperature, concentration, pressure, solvent, the presence of electrolytes, etc. According to the mechanism in Scheme 4.12, the primary amine of high nucleophi­ licity is preferred, in order to form the imine intermediate. It is found that if scarcely nucleophilic amines are employed, often the Ugi reaction ends up with a low yield or even failure. For the same reason, the electrophilicity of the carbonyl compound is also much needed, thus the Ugi reaction takes

2,5-Diketopiperazine

303

place easily with aliphatic or aromatic aldehydes [366]. With highly reactive aldehydes such as formaldehyde in an aqueous solution, water behaves as the acid component. As expected, aryl ketones are the least reactive carbonyl compounds. Likewise, the acid component of high acidity more likely protonates the imine intermediate, leading to a shorter reaction time as well as higher chemical yield.

SCHEME 4.15 A cascade Ugi/Pictet-Spengler reaction to give highly substituted DKPs.

Although four components react together in the Ugi reaction, it does not mean that these components can be mixed in random order. According to the mechanism, the initial step is the formation of imine, thus the pre-formation of the imine has a beneficial effect on the reaction. For this reason, the amine and the carbonyl compound are usually mixed before other reagents are added. Also, due to the nucleophilicity of the terminal carbon atom within the isonitrile, the isonitrile has low stability in an acidic medium, thus addi­ tion of isonitrile to the acid (or vice versa) prior to the addition of amine should be avoided. Regarding the solvent effect, polar solvent is beneficial to the Ugi reac­ tion as amide is formed in this reaction. For this reason, the Ugi reaction is usually performed in MeOH, which experimentally gives the best condi­ tions of polarity, the solubility of the reagents and low solubility of the products, leading to the highest yields and simplest workup of the reaction. In addition, other polar solvents, such as ethanol, trifluoroethanol, THF, DMSO, or even mixed solvent systems such as CHCl3/MeOH, CH2Cl2/ MeOH, THF/MeOH, DMSO/ethanol have once been used for this reaction [366].

304

Amino Acids: Insights and Roles in Heterocyclic Chemistry, Volume 2

On the other hand, high concentrations of reactants (0.5–2 M) favor the reaction. In many cases, one or more components are neatly employed. As of high concentration, it is often necessary to add additional solvent for effective agitation. Due to the high reactivity of isonitrile, the Ugi reaction is often carried out at room temperature, although several cases of the reac­ tion in boiling methanol have been reported [366]. In addition, it is reported that high pressure is of help to this reaction due to the negative activation volume, as four components condense to the final product of bis-amide and water side product. Finally, the microwave accelerates this reaction just like its effects in many other reactions. When amino acid or dipeptide is used for the Ugi reaction, as both the amino group and carboxyl group are rendered in the same reacting compo­ nent, only isonitrile and aldehyde are additionally needed. The reaction is then known as Ugi four-center three-component reaction. Examples of such reactions are the reactions among benzaldehyde, t-butyl isonitrile and a dipeptide of Gly-L-Leu, L-Ala-L-Ala or L-Ala-L-Pro at temperatures ranging from –40°C to room temperature in α,α,α-trifluoroethanol, in yield of 83, 87, and 56%, respectively [370]. When optically pure α-amino acid is applied for the Ugi reaction, the existing chiral center functions as the chiral auxiliary group in helping the formation of stereospecific trisubstituted DKP, as shown in the reaction among methyl leucinate hydrochloride, benzaldehyde, tert-butyl isonitrile, and (R)-2-((tert-butoxycarbonyl)amino)-2-(2,3-dihydro-1H-inden-2-yl) acetic acid in methanol in the presence of trimethylamine, where methyl leucinate hydrochloride and benzaldehyde are allowed to react for 18 hours to ensure the formation of the imine prior to the addition of tert-butyl isonitrile and the second amino acid. In this reaction, the two amino acids form the DKP ring, whilst benzaldehyde and tert-butyl isonitrile become the pendant group attaching to the nitrogen atom of the DKP ring (Scheme 4.16) [371]. In a microwave promoted one-pot reaction setup, tryptophan reacts with formaldehyde (or isobutyraldehyde, cyclohexylaldehyde), another amino acid (e.g., glycine, isoleucine, leucine, and phenylalanine), and one isoni­ trile (cyclohexyl isonitrile, tert-butyl isonitrile, benzyl isonitrile) to afford tryptophan-derived diketopiperazines with variable side chains. Similarly, the second amino acid constitutes the DKP ring along with the tryptophan, with the other two components (isonitrile and aldehyde) as a part of the side chains [372]. Due to the similarity between this reaction and the one illustrated in Scheme 4.16, the reaction scheme is not provided here.

2,5-Diketopiperazine

305

SCHEME 4.16 Stereospecific synthesis of trisubstituted DKPs from an optically pure amino acid.

In order to avoid the notorious isonitriles of typically offensive odors, 2-isocyanophenyl 4-methylbenzoate, a promising convertible isocyanide, has been applied to substitute for the isonitriles in reacting with N-Boc protected amino acid, aldehyde, and amine to afford trisubstituted DKPs, in which the convertible isocyanide provides the source of one carbonyl group within the DKP scaffold from its isonitrile group and the rest moiety has been cleaved at the end of the reaction [373]. Likewise, the isonitrile has been modified to resin-bound isonitrile as the convertible isonitrile, including cyclohexenyl isonitrile resin, safety-catch linker isonitrile resin and universal Rink-isonitrile resin [374]. In general, convertible isonitriles provide a method of transforming the secondary amide of the Ugi products into a carboxylic acid, ester, or thioester that is suitable for further elaboration. In a typical practice, 4,4-dimethyl-2-oxazo­ line was treated with n-BuLi in THF at –78°C for 1 hour to generate lithium 2-isocyano-2-methylpropan-1-olate, which was transferred via a cannula into the freshly prepared resin-bound chloroformate from hydroxymethyl polystyrene resin and 20% phosgene/toluene solution. Such resin-bound isonitrile then reacts with 2-chlorobenzylamine, 2-phenylpropionaldehyde, N-Boc-alanine, trimethylorthoformate in trifluoroethanol and methylene chloride at room temperature for 3 days. The Ugi reaction product was cleaved from the carbonate resin with KOBut to form N-acyloxazolidone intermediate which upon the treatment with sodium methoxide led to the formation of ester intermediate and the subsequent cyclization to afford the final DKP product, as shown in Scheme 4.17. The resin can be prepared cost-effectively in three steps on a 200-g scale, and 80 different DKP

306

Amino Acids: Insights and Roles in Heterocyclic Chemistry, Volume 2

molecules have been made in parallel with an average mass recovery of 83%, by using different aldehydes, amines, and amino acids [374].

SCHEME 4.17 Synthesis of DKP from resin-bound isonitrile.

4.4.5 SOLID PHASE-BASED SYNTHESIS OF DKPS DKPs are cyclic dipeptides that are often formed from the cyclization of linear dipeptide derivatives. Thus, the well-developed solid-phase peptide synthesis is still applicable for the generation of DKPs. The peptide synthesis requires specific protection of the amino group of one amino acid and the carboxyl group of the other amino acid and the activation of the remaining carboxyl group to facilitate the formation of the peptide bond, in order to afford the dipeptide of the expected amino acid sequence. In addition, due to the zwitterion characteristic of amino acid, i.e., forming inner salt, the amino acid is usually not much soluble in common organic solvent (see details in Chapter 2). On the other hand, many amino acids of non-polar side chains are not much soluble in water either. Such solubility difference naturally makes the synthesis starting from amino acid a difficult task. Therefore, the protection of the amino group and carboxyl

2,5-Diketopiperazine

307

group can alter the polarity of the whole amino acid and adjust its solubility in the organic solvent, so that the solution-phase synthesis of peptide becomes possible. However, as the size of peptide increases, the polarity of the peptide also increases, then the difficulty in dealing with amino acid and peptide is getting worse as the size of the peptide increases. In addition, every step of peptide formation is not guaranteed in completion, which causes challenges in the isolation and purification of the synthesized peptides. Solid-phase peptide synthesis (SPPS) was initially developed by Robert Bruce Merrifield in 1963 for him to overcome the many difficulties and challenges naturally associated with the solution-phase peptide synthesis, as briefed above. The initial peptide synthesized by Merrifield through SPPS is L-leucyl-L-alanylglycyl-L-valine, which was identical to a tetrapeptide prepared by the standard p-nitrophenyl ester procedure [375]. The principle of SPPS is to specifically attach the C-terminal amino acid to the surface of solid support by means of its carboxyl group while the amino group is protected, then the amino protecting group is removed to expose the free amino group for coupling with the second amino acid. The solid support mounted amino acid can react with the subsequent amino acid also with its amino group protected directly in the presence of peptide condensation reagent, or react with the said amino acid of the carboxyl group being activated. For the second case, the peptide condensation reagent is not necessary. Theoretically, this process can be repeated again and again until the whole peptide sequence is completed, and then the target peptide is cleaved from the solid support. The mostly used protecting groups for the amino group in the peptide synthesis are 9-fluorenylmethyloxycarbonyl group (Fmoc) and t-butyloxycarbonyl (Boc). These two protecting groups are orthogonal, where the Fmoc group is removed from the amino terminus with a base while the Boc group is removed with acid. However, the Fmoc approach has been approved as the most versatile practice of SPPS [376]. This principle is illustrated in Scheme 4.18. Compared to the solution phase peptide synthesis, SPPS has several obvious advantages, including high reaction yield and product purity, solvent compatibility, automation, etc. As amino acid is mounted to the surface of solid support, which naturally does not dissolve in any solvent (either organic or inorganic), any unreacted reagents and amino acids can be removed by simple wash, leaving pure peptide products on the solid phase. For the same reason, an excess amount of reagent and individual amino acid substrate can be applied for each step of peptide synthesis, in order to push the reaction to complete without worry about side products. Thus, it is possible to achieve a very high chemical yield for each step of peptide formation. Moreover, the solid phase supported amino acid is simply immersed in the liquid phase, solvent

308

Amino Acids: Insights and Roles in Heterocyclic Chemistry, Volume 2

compatibility is not an issue. What is more, the cycle of peptide synthesis, including peptide coupling, washing, drying, reactivation, etc., can be auto­ matically programmed according to the amino acid sequence of the target peptide. Due to the so many features of SPPS, Merrifield won the Nobel Prize in Chemistry in 1984. Currently, three primary types of solid supports have been developed, i.e., gel-type supports, surface-type supports, and composites. The gel-type supports are the most common supports with equal distribution of functional groups, including the highly solvated polymers of polystyrene (PS), polyacrylamide, polyethylene glycol (PEG), and the block copolymers of PEG-PS, PEG-polypropylene glycol, etc. The surface-type supports include controlled pore glass, cellulose fibers, and highly cross-linked polystyrene, whereas composites are gel-type polymers supported by rigid matrices.

SCHEME 4.18 Principle of the solid-phase peptide synthesis.

So far, several types of peptide condensation reagents have been developed, which are carbodiimides, benzotriazoles, uranium salts of a non-nucleophilic anion (e.g., BF4–, PF6–), and phosphonium salts of non-nucleophilic anion. The representative carbodiimides are dicyclohexylcarbodiimide (DCC), diisopro­ pylcarbodiimide (DIC), and 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide

2,5-Diketopiperazine

309

(EDC)). Typical benzotriazoles include 1-hydroxy-benzotiazole (HOBt), 1-hydroxy-7-aza-benzotriazole (HOAt), (benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (BOP), (benzotriazol-1-yloxy) tripyrrolidinophosphonium hexafluorophosphate (PyBOP), (7-azabenzotri­ azol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (PyAOP), O-(benzotriazol-1-yl)-N,N,N’,N’-tetramethyluronium hexafluoro-phosphate (HBTU), O-(benzotriazol-1-yl)-N,N,N’,N’-tetramethyluronium tetra-fluorob­ orate (TBTU), O-(7-azabenzotriazol-1-yl)-N,N,N’,N’-tetramethyluronium hexafluorophosphate (HATU), O-(7-azabenzotriazol-1-yl)-N,N,N’,N’-tetramethyluronium tetrafluoroborate (TATU), N,N,N’,N’-tetramethyl-O(3,4-dihydro-4-oxo-1,2,3-benzotriazin-3-yl)uronium tetrafluoroborate (TDBTU) and O-(6-chlorobenzotriazol-1-yl)-N,N,N’,N’-tetramethyluronium hexafluorophosphate (HCTU). The uronium salts are modified N,N,N’,N’tetramethylurea derivatives, including some benzotriazole derivatives mentioned above and 1-[(1-(cyano-2-ethoxy-2-oxoethylideneaminooxy) dimethylaminomorpholino)]uronium hexafluoro-phosphate (COMU), O-(Nsuccinimidyl)-1,1,3,3-tetramethyl-uronium tetrafluoro-borate (TSTU), O-(5-norbornene-2,3-dicarboximido)-N,N,N’,N’-tetramethyl-uronium tetrafluoroborate (TNTU), O-(1,2-dihydro-2-oxo-1-pyridyl-N,N,N’,N’tetramethyluronium tetrafluoroborate (TPTU), etc. The representative phos­ phonium salts are bis(2-oxooxazolidin-3-yl)phosphinic chloride (BOP-Cl), bromotri(pyrrolidin-1-yl)phosphonium hexafluorophosphate (PyBrOP), among others [377]. These common reagents are shown in Figure 4.9. N,N-Dimethylformamide (DMF), N-methyl-2-pyrrolidone, and dichloro­ methane (DCM) are the most widely used solvents for Fmoc based solid-phase peptide synthesis, which are normally used in large amounts for washing (multiple cycles), deprotection, and coupling steps. Therefore, a whole green practice of SPPS is to use 2-methyltetrahydrofuran (2-Me-THF) for removal of Fmoc, washing, and coupling, with additional washing by EtOAc, in combina­ tion with PEG resin [378]. Recently, using a microwave as an energy source, Rink Amide Tentagel as solid support, and N-ethyl-N′-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDC hydrochloride) in combination with N-hydroxy-5-norbornene-2,3-dicarboxylic acid imide (HONB) as the peptide coupling agent, an aqueous-based peptide synthesis has been developed [379]. In addition, an optimized process that allows for a complete cycle time of approximately 4 minutes along with a significant reduction (approximately 90%) in total chemical waste for SPPS has been developed, which uses micro­ wave irradiation for both deprotection and coupling, DIC in combination with HOBt or ethyl 2-cyano-2-(hydroxyimino)acetate (Oxyma) as the condensation agent, and optimized washing with NMP and DMF [380].

310

Amino Acids: Insights and Roles in Heterocyclic Chemistry, Volume 2

FIGURE 4.9 The common peptide condensation reagents.

2,5-Diketopiperazine

311

Regarding the solid-phase synthesis of peptides, it has been well known that peptides on a solid support can be cyclized, with a variety of cyclization reagent combinations such as HBTU/HOBt/DIEPA, PyBop/DIEPA, and (6-chlorobenzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophos­ phate (PyClock)/DIEPA. Particularly, when the Fmoc approach is used in peptide synthesis, once the Backbone Amide Linker (BAL) anchored dipep­ tides (through backbone nitrogen instead of the C-terminal carboxyl group) are formed, base promoted removal of Fmoc, even at the dipeptidyl stage, might lead to the quantitative formation of diketopiperazines, as illustrated in Scheme 4.19 [381]. In another solid-phase synthesis of DKP, hydroxymethyl benzoic acid was used as the linker for solid support (POEPOP1500), which is then bound with two consecutive leucine and the terminal amino group is further connected to 4-oxobutryic acid with its aldehyde group protected, by means of 3-(3-(tert-butoxycarbonyl)-1,3-oxazinan-2-yl)propanoic acid. Once two amino groups are methylated in order to avoid the further reaction between them and the aldehyde group, the latent aldehyde group is unpro­ tected, and additional amino acids are then mounted to the solid phase by means of reductive amination. The two-terminal amino acids cyclize to form DKP on the solid support [382]. This protocol is shown in Scheme 4.20.

SCHEME 4.19 Formation of DKP from BAL-anchored dipeptides.

A solid-supported synthesis of spiro-2,5-diketopiperazine has been developed, by means of loading α-nitro-acetic acid to polymer support in the presence of DIC and HOBt, which is then treated with PhCH=NHPh to

312

Amino Acids: Insights and Roles in Heterocyclic Chemistry, Volume 2

introduce a conjugated double bond. With both electron-withdrawing groups of α-nitro and ester group, the dienophile undergoes a Diels-Alder reaction with a diene to afford the first ring of the spiro-DKP. Upon reduction of the nitro group into an amino group, another amino acid is mounted to the solid support, and the corresponding spiro-DKP is generated at the cleavage stage [383].

SCHEME 4.20 Solid-phase synthesis of DKP using hydroxymethyl benzoic acid as the linker.

Overall, the rate of cyclic cleavage of dipeptides from the polymer supports is highly dependent on their ability to achieve a cis-amide bond. This conformation is favored when glycine, proline, or N-alkyl group is present. For this reason, the majority of solid-phase DKP syntheses integrate a central tertiary amide bond [309]. 4.4.6 PREPARATION OF ALKYLIDENE- AND ARYLIDENE-DKPS As indicated in the structures of natural products containing DKP moieties, many natural DKP-containing molecules have an α,b-unsaturated

2,5-Diketopiperazine

313

functionality, which directly connects to either an alkyl or an aryl group, corresponding to the so-called alkylidene-DKPs or arylidene-DKPs, respectively. This type of DKPs are also known as dehydro-DKPs [309, 384], or monodehydro-DKPs [385] if containing only one α,b-unsaturated functionality. In general, three general methods have been developed for the construction of these DKPs, which are Aldol condensation between a DKP and aldehyde, Wittig reaction between a phosphorus ylide and 2,3,6-pipera­ zinetrione, and Horner–Emmons reaction between a phosphinyl glycine ester and an aldehyde followed by cyclization to create the DKP ring. The Aldol condensation strategy explores the acidity of α-methylene within the DKP ring. In fact, the hydrogen atom at the α-methylene group on the DKP ring should be acidic due to the fact that the carbonyl group is an electron-withdrawing group, although an amino group of electron-donating character is also attached to the methylene moiety. Therefore, this α-hydrogen can be removed in the presence of a strong base, and the resulting carbanion or enolate becomes nucleophilic and will add to an aldehyde to afford the Aldol product. Removal of water results in the α,b-unsaturated DKP, either alkylidene-DKP or arylidene-DKP, depending on the nature of the aldehyde. Particularly, when the amino group within the DKP is acylated, such as being acetylated, then its electron-donating ability would be greatly reduced, then the acidity of the α-hydrogen is increased. Under this condition, even a weak base such as cesium carbonate (Cs2CO3) is able to deprotonate such α-hydrogen to complete the expected Aldol condensation with the aldehyde [4, 226, 312]. This method has been optimized to occur in a manner of one-pot reaction, in which 1,4-diacetyl-2,5-DKP was initially treated with Cs2CO3, allyl bromide, and benzaldehyde, each at 2.5 equivalents at –10°C until the completion of the first Aldol condensation and the alkylation of the allyl bromide on the nitrogen atom, then the reaction mixture was heated at 95°C in DMF to afford DKP derivative of two α,b-unsaturated functional­ ities. Under this optimized condition, the two α,b-unsaturated functionalities are in Z-configurations. In addition, two different aldehydes can be applied to this reaction in order to form DKP of two different α,b-unsaturated functionalities. In doing so, the same 1,4-diacetyl-2,5-DKP is treated with 2.5 equivalents of allyl bromide and Cs2CO3 but 1.0 equivalent of the first aldehyde in order to avoid the excessive Aldol condensation. When the first Aldol condensation is completed, the second aldehyde is added to the reaction system, in an amount variable to achieve the highest yield of the target product, with an optimal amount of 2.0 equivalents for the model reaction among 1,4-diacetyl-2,5-DKP, benzaldehyde, allyl bromide,

314

Amino Acids: Insights and Roles in Heterocyclic Chemistry, Volume 2

Cs2CO3 and 3-bromobenzaldehyde (2.5 equiv.) [312], as shown in Scheme 4.21. 1,4-Diacetyl-2,5-DKP can be formed by refluxing 2,5-DKP in acetic anhydride overnight [226].

SCHEME 4.21 Aldol condensation of DKP with benzaldehydes.

The synthetic method involving the Wittig reaction starts with 5-substi­ tuted-2,3,6-piperazinetriones which are prepared by treatment of amino acid ester with ammonia to form amino amide and subsequent deproton­ ation with sodium methoxide prior to the addition of dialkyl oxalate. This 2,3,6-piperazinetrione is then condensed with stabilized phosphorus ylide to afford 3-alkylidene-6-substituted-2,5-DKP in a good yield [386], as shown in Scheme 4.22.

SCHEME 4.22 Preparation of alkylidene DKPs from α-amino amide and dialkyl oxalate and subsequent Wittig reaction.

Besides the Wittig reaction, the α,b-unsaturated functionality can also be constructed by the well-known reaction between a ketone and secondary amine, for which an enamine is formed. Following this strategy, the cycli­ zation of terminal substituted amine to α-keto-peptide would afford the α,b-unsaturated DKP. Often, during the base-catalyzed cyclization of the corresponding dipeptide units, racemization at the α-position of α-amino acids is observed. Also, the racemization occurs during the base-catalyzed introduction of the dehydro-moiety onto the DKP ring with a chiral side chain at the opposite apposition. In order to minimize such unfavorable racemiza­ tion, α-ketocarboxylic acid is condensed with α-amino amide in the presence of EDC/HOBt. The resulting molecule is refluxed in toluene in the presence of

2,5-Diketopiperazine

315

3–5 mol.% p-TsOH to afford the monodehydro-DKP, with a Z-configuration. A representative reaction is shown in Scheme 4.23. In order to apply this methodology to synthesize (-)-tert-butyl-oxa-phenylahistin, a tubulin depo­ lymerization agent, tert-butyl-P,P-dimethylphosphonoacetate was diazotized with tosyl azide (TsN3) in the presence of NaH, and then the diazo compound was refluxed with Boc–NH2 in the presence of Rh2(OAc)4 catalyst in toluene to give N-tert-butoxycarbonyl-α-dimethylphosphonoglycine tert-butyl ester. This compound is then converted into tert-butyl-1-(tert-butoxycarbonyl)-2­ (5-tert-butyloxazol-4-yl)vinylcarbamate by means of Horner–Emmons reac­ tion with 5-tert-butyl-4-oxazolecarboxaldehyde. Upon treatment with 4 M HCl in dioxane, (Z)-3-(5-(tert-butyl)oxazol-4-yl)-2-hydroxyacrylic acid is resolved, which is then condensed with phenylalanine amide in the presence of EDC/HOBt to yield (S,Z)-N-(1-amino-1-oxo-3-phenylpropan-2-yl)-3-(5­ (tert-butyl)oxazol-4-yl)-2-hydroxyacrylamide and its unfavored tautomer, i.e., (S)-N-(1-amino-1-oxo-3-phenylpropan-2-yl)-3-(5-(tert-butyl)oxazol4-yl)-2-oxopropanamide. In the presence of catalytic amount of p-TsOH, the (-)-tert-butyl-oxa-phenylahistin is prepared [385], as shown in Scheme 4.24.

SCHEME 4.23 Preparation of alkylidene-DKP from the condensation of α-ketoacid and α-amino amide.

Likewise, using the Horner–Emmons reaction, methyl 2-((S)-2-((tert­ butoxycarbonyl)amino)-3-phenylpropanamido)-2-(dimethoxyphosphoryl) acetate that is prepared from methyl 2-amino-2-(dimethoxyphosphoryl) acetate and (tert-butoxycarbonyl)-L-phenylalanine in the presence of EDC/HOBt, reacts with 5-(2-methylbut-3-en-2-yl)-1H-imidazole4-carbaldehyde to form methyl (S,Z)-2-(2-((tert-butoxycarbonyl)amino)­ 3-phenylpropanamido)-3-(5-(2-methylbut-3-en-2-yl)-1H-imidazol-4-yl)

316

Amino Acids: Insights and Roles in Heterocyclic Chemistry, Volume 2

acrylate. Upon the deprotonation of the tert-butyl group with trifluoroacetic acid, (-)-phenylahistine is formed by means of the cyclization of dipeptide [384], as shown in Scheme 4.25. This method has been improved to mount the Schmidt’s phosphonate to polymer support, to prepare a small library of dehydro-2,5-diketopiperazines, combining several natural amino acids with diverse heterocycles including thiazole, pyridine, indole, and imidazole [387].

SCHEME 4.24 Synthesis piperazine-2,5-dione.

of

(S,Z)-3-benzyl-6-((5-(tert-butyl)oxazo-4-yl)methylene)

Besides the above outlined methods for the synthesis of DKPs, an inter­ esting method has been reported to form DKP for which the source of amino acid is not so obvious. In this method, N-acyl transformation was initially carried out between 2,5-dioxopyrrolidin-1-yl (2E,4E)-hexa-2,4-dienoate and L-proline to afford ((2E,4E)-hexa-2,4-dienoyl)-L-proline, which was then condensed with N-hydroxysuccinimide in the presence of DCC to give 2,5-dioxopyrrolidin-1-yl ((2E,4E)-hexa-2,4-dienoyl)-L-prolinate. After that, the N-hydroxysuccinimide moiety was substituted by hydroxylamine. The resulting (S)-1-((2E,4E)-hexa-2,4-dienoyl)-N-hydroxypyrrolidine-2-carbox­ amide was oxidized with tetraethyl-ammonium periodate in the presence of cyclopentadiene to trap the in situ formed nitroso group in order to avoid the substitution of the nitroso group. The subsequent Diels-Alder cycloaddition between the diene moiety in s-cis conformation and the nitroso group leads to

2,5-Diketopiperazine

317

the formation of (2R,4aR,9aS)-2-methyl-2,4a,7,8,9,9a-hexahydro-5H,10H­ pyrrolo[1’,2’:4,5]pyrazino[1,2-b][1,2]oxazine-5,10-dione, containing a DKP moiety [388], as shown in Scheme 4.26.

SCHEME 4.25 Synthesis of (-)-phenylahistine.

SCHEME 4.26 Formation of the DKP ring via Diels-Alder cycloaddition.

Finally, starting from trans-4-hydroxy-L-proline, ((2S,4R)-4-((((9Hfluoren-9-yl)methoxy)carbonyl)amino)-1-(tert-butoxycarbonyl)-4­ (methoxycarbonyl)-pyrrolidine-2-carboxylic acid and (2R,4S)-4-((((9H-

318

Amino Acids: Insights and Roles in Heterocyclic Chemistry, Volume 2

fluoren-9-yl)methoxy)-carbonyl)amino)-1-(tert-butoxycarbonyl)-4­ (methoxycarbonyl)pyrrolidine-2-carboxylic acid are synthesized after multistep transformations, which are used to make oligomers by means of solid supported peptide synthesis, and subsequent internal cyclization leads to the formation of spiro-DKP oligomers [389]. 4.4.7 PRACTICAL PREPARATIONS OF DKPS 4.4.7.1  SYNTHESIS OF (3S,6S)-3,6-BIS(HYDROXYMETHYL)PIPERAZINE2,5-DIONE [390]

• Step A: Synthesis of Methyl O-Benzyl-N-((benzyloxy)carbonyl)L-seryl-L-serinate: To a 500 mL dry three-necked round bottom flask, were added 6.01 g of O-benzyl-N-((benzyloxy)carbonyl)L-serine (18.2 mmol, 1 equiv.), 3.69 g of 1-hydroxybenztriazole (HOBt) (27.3 mmol, 1.5 equiv.) and 18.0 mL of DMF under nitrogen. Then 3.76 g of dicyclohexylcarbodiimide (DCC) (18.2 mmol, 1 equiv.) and 100 mL of dry ethyl acetate were added to the above solution. The reaction mixture was stirred under nitrogen for ~1 hour. In another dry flask, were added 3.69 g of L-serine methyl ester hydrochloride (23.7 mmol, 1.3 equiv.), 18 mL of DMF and then 3.30 mL of dry triethylamine (23.7 mmol, 1.3 equiv.) and 100 mL of EtOAc. The resulting solution of L-serine methyl ester was cannulated into the three-necked flask, and the reaction mixture was stirred overnight under nitrogen. After that, the reaction mixture was filtered and then washed 4 times with saturated sodium bicarbonate solution (100 mL), followed by 3% hydrochloric acid solution (twice) and brine. The organic layer was dried over sodium sulfate and then concentrated in vacuo. The resulting white solid (6.89 g, 88% crude yield) contained a slight impurity of dicyclohexylurea. The product was used without further purification. The melting point was 108–110°C.

2,5-Diketopiperazine

319

• Step B: Synthesis of (3S,6S)-3,6-Bis(hydroxymethyl)piperazine2,5-dione: To a thick wall hydrogenator flask, were added 3.0 g of methyl O-benzyl-N-((benzyloxy)carbonyl)-L-seryl-L-serinate (6.97 mmol, 1 equiv.), 150 mL of methanol, 2.96 g of activated 5% palla­ dium on carbon (Degussa type E101 NO/W) (0.2 equiv.). The flask was then placed in a Parr Shaker apparatus, pressurized to 45 psi of hydrogen and shaken for 24 hours. Then the reaction solution was filtered through a Celite bed and a fine filter paper. The methanol solution was concentrated under the boiling condition to 100 mL. The solution was then capped until crystal formation (~ 10 hours). The crystals were collected (742 mg, 61% yield). M.p. > 260°C. 4.4.7.2 SYNTHESIS OF (S)-3-ISOPROPYLPIPERAZINE-2,5-DIONE [391]

•

Step A: Synthesis of L-valine-N-carboxyanhydride: To a stirred suspension of 351 g L-valine (3.0 mol) in 3,000 mL of THF was passed a stream of phosgene vigorously (~ 3.5–4 mol). Note: to conserve phosgene and avoid unnecessary loss of this hazardous gas, a second flask with 5% of the total required L-valine in THF can be set up in line after the first flask. This second flask was crucial in reactions where more than 1 equivalent of phosgene was employed. In addition, a third flask containing concentrated NaOH solution (~ 10 N) cooled to 0°C should follow last in line as a trap for any excess phosgene. The reaction mixture was maintained at 40°C with a water bath. After 5 hours, the reaction mixture became homogeneous and the addition of phosgene was terminated. The solution(s) in the first two flasks were purged with nitrogen for 2 hours, and the combined solution was concentrated in vacuo on a rotatory evaporator in the hood, and the residue was flash evapo­ rated with THF (3 × 800 mL) on a rotatory evaporator under vacuum until a white solid formed. This provided a nearly quantitative yield of L-valine-N-carboxyanhydride (428 g, 99.7%), which was stored in the refrigerator overnight under a nitrogen atmosphere and used

320

Amino Acids: Insights and Roles in Heterocyclic Chemistry, Volume 2

immediately the next day without further purification due to the unstable nature of this anhydride. • Step B: Synthesis of (S)-3-isopropylpiperazine-2,5-dione: To a 3 L three-necked flask, were added 49.4 g of ethyl glycinate hydrochlo­ ride (0.354 mol), 80.6 g of freshly distilled triethylamine (0.80 mol), and 500 mL of dry chloroform. Then the flask was cooled to –70°C. To this cooled solution under vigorously stirring, a solution of 50.6 g of L-valine-N-carboxyanhydride (0.354 mol) in 400 mL of THF was added dropwise. After that, the solution was stirred at –70°C for 3 hours and then at room temperature for 2 hours, and then filtered to remove the precipitated triethylamine hydrochloride. The filtrate was concentrated under reduced pressure at a temperature < 40°C. To the residue was added 1,700 mL of toluene, and the resulting solution was refluxed for 12 hours and then cooled to 0°C. The (S)-3-isopropylpi­ perazine-2,5-dione was recovered by vacuum filtration, washed with ether (4 × 200 mL), and dried under vacuum at 100°C, in an amount of 40.0 g (73% yield), m.p. 235–238°C. 4.4.7.3  SYNTHESIS OF (S)-3-METHYL-1,4-BIS((S)-1-PHENYLETHYL) PIPERAZINE-2,5-DIONE AND (R)-3-METHYL-1,4-BIS((S)-1PHENYLETHYL)PIPERAZINE-2,5-DIONE [392]

• Step A: Preparation of (S)-2-chloro-N-(1-phenylethyl)acetamide: To a solution of 23 mL (S)-1-phenylethylamine (0.180 mol) and 27 g Na2CO3⋅10H2O in 200 mL of water/acetone (1:1) at 0°C, was slowly added a solution of 14.5 mL chloroacetyl chloride (0.180 mol) in 50 mL of acetone dropwise. After 1 hour, the solvent was removed under

2,5-Diketopiperazine

321

reduced pressure, the residue was acidified with 6 N HCl and extracted with ethyl acetate. Upon removal of the solvent, 32 g of (S)-2-chloro­ N-(1-phenylethyl)acetamide was obtained as a solid (90% yield), which can be crystallized from ethyl acetate/ether (m.p. 94°C). • Step B: Preparation of N-((S)-1-phenylethyl)-2-(((S)-1-phenylethyl) amino)-acetamide: To a solution of 22.85 g of (S)-2-chloro-N­ (1-phenylethyl)acetamide (0.116 mol) and 15 mL of (S)-1-phenyle­ thylamine (0.116 mol) in 100 mL of absolute ethanol was added 8.24 g of K2CO3 (0.06 mol), and the resulting mixture was refluxed for 8 hours. After removal of the solvent under vacuum, water was added, and the mixture was extracted with ethyl acetate and dried. Upon removal of solvent, the residue was recrystallized from ether to afford 87% of the product, m.p. 70°C. • Step C: Preparation of (S)-2-chloro-N-(2-oxo-2-(((S)-1-phenylethyl) amino)ethyl)-N-((S)-1-phenylethyl)propanamide and (R)-2-chloro­ N-(2-oxo-2-(((S)-1-phenylethyl)amino)ethyl)-N-((S)-1-phenylethyl) propenamide: To a solution of 36.66 g N-((S)-1-phenylethyl)-2-(((S)­ 1-phenylethyl)amino)-acetamide (0.130 mol) in 200 mL of wateracetone (1:1) at 0°C was added 20.0 g of Na2CO3⋅10H2O (0.07 mol). Then 13 mL of (R,S)-2-chloropropionyl chloride (0.130 mol) in 50 mL of acetone at 0°C was added dropwise. After 1 hour, the solvent was removed under reduced pressure, and the residue was acidi­ fied with 6 N HCl. After extraction with ethyl acetate and removal of the solvent, 43.4 g of product was obtained (90% yield), which was separated by silica gel chromatography with 85:15 cyclohexane/ EtOAc to yield (S)-2-chloro-N-(2-oxo-2-(((S)-1-phenylethyl)amino) ethyl)-N-((S)-1-phenylethyl)propenamide (Rf = 0.46, cyclohexane/ EtOAc = 1:1, white solid, m.p. 112°C) and (R)-2-chloro-N-(2-oxo-2­ (((S)-1-phenylethyl)amino)ethyl)-N-((S)-1-phenylethyl)propenamide (Rf = 0.26, cyclohexane/EtOAc = 1:1, white solid, m.p. 134°C). • Step D: Preparation of (S)-3-Methyl-1,4-bis((S)-1-phenylethyl) piperazine-2,5-dione: To a solution of 21.2 g of (R)-2-chloro-N­ (2-oxo-2-(((S)-1-phenylethyl)amino)ethyl)-N-((S)-1-phenylethyl) propanamide (57 mmol) in 200 mL of dry THF at 0°C, was added 23 mL of 2.5 M n-BuLi in hexane (57.5 mmol) under an inert atmosphere. After 2 hours, the cooling bath was removed, 2 N HCl was added, and the mixture was extracted with ethyl acetate and dried. After removal of the solvent, the residue was purified by silica gel chromatography (hexane/EtOAc = 4:1) to give 17.6 g of

322

Amino Acids: Insights and Roles in Heterocyclic Chemistry, Volume 2

(S)-3-methyl-1,4-bis((S)-1-phenylethyl)piperazine-2,5-dione, in a yield of 92%, m.p. 110°C. 4.4.7.4  SYNTHESIS OF (3S)-1,4-DIBENZYL-3-METHYL-6PHENYLPIPERAZINE-2,5-DIONE [347]

To a solution of 0.389 g of methyl N-benzyl-N-(2-bromo-2-phenylacetyl)­ L-alaninate (1.0 mmol) in 10 mL dry CH3CN (≈ 0.1 M of substrate) at room temperature, was added 0.128 g of benzylamine (1.2 mmol), 0.37 g of tetrabutylammonium iodide (TBAI, 1.0 mmol) and 0.13 g of diisopropyle­ thylamine (DIPEA, 1.0 mmol). The resulting reaction mixture was stirred at room temperature for 48 hours before the solvent was evaporated in vacuo. The resulting residue was purified by column chromatography on silica gel to give 0.338 g of (3S,6S)-1,4-dibenzyl-3-methyl-6-phenylpiperazine2,5-dione as a colorless oil, in a yield of 88%. 4.4.7.5  SYNTHESIS OF 2,5-DIKETOPIPERAZINE-1,4-DIACETATE IN LANTHANIDE-BASED COORDINATION POLYMERS [364]

A mixture of 0.27 g iminodiacetic acid (2.0 mmol), 0.12 g oxalic acid (2.0 mmol), 0.187 g Dy2O3 (0.5 mmol) and 0.25 mL HNO3 (3 mmol) in 10.0 mL of water was stirred at room temperature first and then transferred to a 25 mL Teflon-lined stainless steel container. After being sealed, the container was heated to 180°C and held at that temperature for 100 hours. Then, the container was cooled to 100°C at a rate of 3°C per hour and held for 16 hours to afford 170 mg of complex, in a yield of 45% (based on Dy2O3).

2,5-Diketopiperazine

323

4.4.7.6  SYNTHESIS OF 1-ALLYL-6-((Z)-BENZYLIDENE)-3-((Z)-3,4DICHLOROBENZYLIDENE)-PIPERAZINE-2,5-DIONE [226]

• Step A: Synthesis of 1,4-diacetylpiperazine-2,5-dione: The mixture of 500 mg glycine anhydride (2.5 mmol) and 20 mL acetic anhydride was refluxed overnight, and the excess acetic anhydride was removed under reduced pressure. The residue was purified by silica gel chromatography to afford 97% of 1,4-diacetylpiperazine-2,5-dione. • Step B: Synthesis of 1-acetyl-3-benzylidenepiperazine-2,5-dione: To a mixture of 3.0 g 1,4-diacetylpiperazine-2,5-dione (15 mmol) and 1.06 g benzaldehyde (10 mmol) in 20 mL of dry DMF, was added 4.9 g of Cs2CO3 (15 mmol), and the mixture was stirred at room temperature for about 5 hours. After the reaction was completed, the mixture was poured into crushed ice and the solid was filtered, washed three times with water and dried to give 87% of 1-acetyl-3-benzylidenepiperazine-2,5-dione. • Step C: Synthesis of 1-acetyl-4-allyl-3-benzylidenepiperazine2,5-dione: To a mixture of 1.22 g of 1-acetyl-3-benzylidenepiperazine2,5-dione (5.0 mmol) and 0.5 mL of allyl bromide (6.0 mmol) in 20 mL of dry DMF, was added 1.38 g of K2CO3 (10.0 mmol), and the mixture was stirred at room temperature overnight. After the reaction was completed, the mixture was poured into crashed ice and the solid was filtered, washed with water three times and dried to afford 45% of 1-acetyl-4-allyl-3-benzylidenepiperazine-2,5-dione. • Step D: Synthesis of 1-Allyl-6-benzylidene-3-(3,4-dichlorobenzylidene)-piperazine-2,5-dione: To a mixture of 50.0 mg 1-acetyl-4-allyl-3-benzylidenepiperazine-2,5-dione (0.18 mmol) and 36.8 mg of 3,4-dichlorobenzaldehyde (0.21 mmol) in 1.5 mL of dry DMF, was added 82.9 mg of Cs2CO3 (0.26 mmol). The mixture

324

Amino Acids: Insights and Roles in Heterocyclic Chemistry, Volume 2

was stirred at room temperature for about 5 hours. After the reac­ tion was completed, the mixture was slowly poured into water and extracted three times with EtOAc. The combined organic layer was dried, filtered, and purified with a silica gel column to afford 46.3% of 1-allyl-6-benzylidene-3-(3,4-dichlorobenzylidene)-piperazine-2,5dione as a yellow solid, m.p. 155–157°C. 4.4.7.7  SYNTHESIS OF (3R,6R)-3,6-BIS(4-(DODECYLOXY)PHENYL) PIPERAZINE-2,5-DIONE

• Step A: Synthesis of Methyl (R)-2-((tert-Butoxycarbonyl)amino)-2­ (4-(dodecyloxy)phenyl)acetate [44]: To a mixture of 11.6 g N-tert­ butoxycarbonyl-D-p-hydroxyphenylglycine methyl ester (41.2 mmol) and 5.67 g of K2CO3 (41.0 mmol) in distilled DMF, was added 9.8 mL of dodecyl bromide (40.9 mmol) through a dropping funnel at room temperature under nitrogen atmosphere. The resulting mixture was heated to be transparent (ca. 60°C) and maintained at this temperature for 21 hours under stirring. The precipitate formed was filtered off and the filtrate was concentrated in vacuo. The residue was purified by column chromatography with EtOAc to afford pure (R)-2-((tert­ butoxycarbonyl)amino)-2-(4-(dodecyloxy)phenyl)acetic acid methyl ester as a viscous liquid, in a yield of 76%. • Step B: Synthesis of (3R,6R)-3,6-Bis(4-(dodecyloxy)phenyl) piperazine-2,5-dione: To a solution of 14.1 g of methyl (R)-2-((tert­ butoxycarbonyl)amino)-2-(4-(dodecyloxy)phenyl)acetate (31.4 mmol) in 300 mL of CH2Cl2, was added 12.0 mL of trifluoroacetic acid (162 mmol) at 0°C through a dropping funnel, and the resulting mixture was stirred at room temperature overnight. After CH2Cl2 and TFA were distilled off in vacuo, 0.2 mL of triethylamine (1.44 mmol) was added to a solution containing 446 mg of the residual mass (1.0 mmol) in 1 mL of toluene, and the reaction mixture was heated to 80°C for 5 days. After being cooled to room temperature,

2,5-Diketopiperazine

325

the precipitate was separated by filtration to afford (3R,6R)-3,6­ bis(4-(dodecyloxy)phenyl)piperazine-2,5-dione as a colorless solid, in a yield of 41%.

4.4.7.8  SYNTHESIS OF (3S,6S)-3,6-BIS(2-METHOXYBENZYL) PIPERAZINE-2,5-DIONE, (3R,6R)-3,6-BIS(2-METHOXYBENZYL) PIPERAZINE-2,5-DIONE AND (3R,6S)-3,6-BIS(2METHOXYBENZYL)PIPERAZINE-2,5-DIONE [393]

Methyl (S)-2-amino-3-(2-methoxyphenyl)propanoate (3.1 g, 15 mmol) was heated neat in an oil bath at 100–110°C for 24 hours while being monitored by TLC using a mixture of 20% acetonitrile, 0.1% trifluoroacetic acid and water as eluent, where Rf = 0.28 for (±)-DKP, Rf = 0.56 for mesoDKP. The residue was dissolved in 10 mL ethanol and two compounds were obtained by fractional crystallization. The (±)-DKP crystallized first (0.2 g, 8% after repeated recrystallizations), m.p. 190–192°C. The mesoDKP crystallized second (0.3 g, 12% after repeated crystallizations), m.p. 186–188°C. 4.4.7.9  SYNTHESIS OF (R)-2-((3R,6R)-3-(2,3-DIHYDRO-1H-INDEN-2YL)-6-ISOBUTYL-2,5-DIOXOPIPERAZIN-1-YL)-N-ISOPROPYL2-PHENYLACETAMIDE AND (S)-2-((3R,6R)-3-(2,3-DIHYDRO-

326

Amino Acids: Insights and Roles in Heterocyclic Chemistry, Volume 2

1H-INDEN-2-YL)-6-ISOBUTYL-2,5-DIOXOPIPERAZIN-1-YL)-NISOPROPYL-2-PHENYLACETAMIDE [394]

To a solution of 182 mg of D-leucine methyl ester hydrochloride (1.0 mmol) in 3 mL methanol was added 140 µL of triethylamine (1.0 mmol) and 102 µL of benzaldehyde (1.0 mmol). The mixture was stirred for 2.5 hours before 291 mg of (R)-2-((tert-butoxycarbonyl)amino)-2-(2,3-dihydro­ 1H-inden-2-yl)acetic acid (1.0 mmol) and 150 µL of isopropylisonitrile (1.6 mmol) were added sequentially. After the mixture was stirred for 16 hours, the solvent was removed in vacuo and the residue was dissolved in 20 mL dichloromethane (20 mL). This solution was then washed with a saturated aqueous sodium hydrogen carbonate solution (× 2), dried over magnesium sulfate, and evaporated in vacuo. The residue was mixed with 3 mL of dichlo­ romethane and 4 mL of trifluoroacetic acid, and the mixture was stirred for 3 hours at ambient temperature. After that, the solvent was removed in vacuo and the residue was re-evaporated from dichloromethane (10 mL × 2). The residue was mixed with 10 mL 5% triethylamine in dioxane and stirred over­ night. Then, dioxane was removed in vacuo, and the residue was dissolved in 50 mL dichloromethane. The solution was washed with 0.1 N HCl (10 mL × 2), and the organic phase was separated using a hydrophobic frit and evapo­ rated in vacuo to give a yellow gum. This crude material was purified by

2,5-Diketopiperazine

327

preparative plate chromatography, eluting with 2.5% 2-propanol in dichloro­ methane (× 3) to give 17.6% of (R)-2-((3R,6R)-3-(2,3-dihydro-1H-inden-2­ yl)-6-isobutyl-2,5-dioxopiperazin-1-yl)-N-isopropyl-2-phenylacetamide as a colorless solid and 35.2% of (S)-2-((3R,6R)-3-(2,3-dihydro-1H-inden-2­ yl)-6-isobutyl-2,5-dioxopiperazin-1-yl)-N-isopropyl-2-phenylacetamide as a colorless solid. 4.4.7.10  SYNTHESIS OF (5AS,10AS)-TETRAHYDRO-3H,5HDIPYRROLO[1,2-A:1’,2’-D]PYRAZINE-3,5,8,10(2H,5AH)TETRAONE (PYROGLUTAMIC DIKETOPIPERAZINE) [286]

To a 1,000 mL round-bottomed flask attaching to a refluxing condenser, were added 345 mL of acetic anhydride, 64 mL of pyridine, and a magnetic stirring bar. The flask was lowered into an oil bath preheated to 110°C. Then 77.4 g of S-pyroglutamic acid was added to the solvent mixture when the temperature reached 110°C. Pyroglutamic diketopiperazine began to precipitate from the solution as a white solid after 5 min. Heating was continued for an additional 15 minutes. The reaction mixture was cooled in an ice bath, and the product was collected by vacuum filtration and washed with cold methanol. The product was transferred to an Erlenmeyer flask, covered with methanol, and collected by filtration. This was repeated with distilled water to afford 39.7 g of (5aS,10aS)-tetrahydro-3H,5H­ dipyrrolo[1,2-a:1’,2’-d]pyrazine-3,5,8,10(2H,5aH)-tetraone, in a yield of 60%, m.p. 290°C (dec.).

328

Amino Acids: Insights and Roles in Heterocyclic Chemistry, Volume 2

4.4.7.11  SYNTHESIS OF (2R,4AR,9AS)-2-METHYL-2,4A,7,8,9,9AHEXAHYDRO-5H,10H-PYRROLO[1’,2’:4,5]PYRAZINO[1,2-B][1,2] OXAZINE-5,10-DIONE [388]

• Step A: Synthesis of (S)-1-((2E,4E)-hexa-2,4-dienoyl)-N-hydroxy­ pyrrolidine-2-carboxamide: To 50 mL of anhydrous ethanol was added 1.61 g of sodium (70 mmol). To this basic solution was added 5.1 g of hydroxylamine hydrochloride (70 mmol) and the mixture was stirred until all the reagent was dissolved. This solution of hydroxylamine was filtered and added drop-wise to a solution of 21.4 g 2,5-dioxo­ pyrrolidin-1-yl ((2E,4E)-hexa-2,4-dienoyl)-L-prolinate (70 mmol) in 50 mL methanol. The mixture was stirred for 48 hours at room temperature and evaporated to afford a brown oil. This oil was chro­ matographed first using chloroform/EtOAc (3:1) to elute impurities, and then methanol to collect the desired product. Evaporation of the proper fraction gave a yellow oil. This can be chromatographed again using methanol/chloroform (1:1) to give 15.7 g of (S)-1-((2E,4E)­ hexa-2,4-dienoyl)-N-hydroxypyrrolidine-2-carboxamide as a light yellow solid (64 mmol), in a yield of 92%, m.p. 97°C. • Step B: Synthesis of (2E,4E)-1-((S)-2-((1R,4S)-2-oxa-3-azabi­ cyclo[2.2.1]hept-5-ene-3-carbonyl)pyrrolidin-1-yl)hexa-2,4-dien­ 1-one: A stirred solution of 3.9 g of tetraethylammonium periodate (10.5 mmol) and 1.74 g of cyclopentadiene (21 mmol, 2 equivalents) in 80 ml of dichloromethane was cooled in an ice bath. A solution of 2.36 g of (S)-1-((2E,4E)-hexa-2,4-dienoyl)-N-hydroxypyrrolidine­ 2-carboxamide (10.5 mmol) in 80 mL of dichloromethane was added slowly over 15 minutes in a darkened hood. The mixture was stirred at 0°C for an additional 15 minutes and then for 45 minutes at room

2,5-Diketopiperazine

329

temperature. The reaction mixture was mixed with 230 mL of EtOAc and the brown turbid solution was rinsed consecutively with a 1 M solution of sodium carbonate containing 5% sodium thiosulfate or sodium sulfite, and then several times with brine. Evaporation of the solvent gave a brown oil. This oil was purified by column chro­ matography with EtOAc/CHCl3 (1:1) to afford 1.84 g of (2E,4E)­ 1-((S)-2-((1R,4S)-2-oxa-3-azabicyclo[2.2.1]hept-5-ene-3-carbonyl) pyrrolidin-1-yl)hexa-2,4-dien-1-one, as a yellow oil, in a yield of 61%. • Step C: Synthesis of (2R,4aR,9aS)-2-methyl-2,4a,7,8,9,9a-hexahydro­ 5H,10H-pyrrolo[1’,2’:4,5]pyrazino[1,2-b][1,2]oxazine-5,10-dione: A solution of 2.5 g (2E,4E)-1-((S)-2-((1R,4S)-2-oxa-3-azabicyclo[2.2.1] hept-5-ene-3-carbonyl)pyrrolidin-1-yl)hexa-2,4-dien-1-one (8.7 mmol) in 200 mL of toluene was refluxed for 5 hours. The solution was filtered hot from the small amount of precipitate formed and evaporated to give a brown solid, which was purified by column chromatography using a EtOAc/CHCl3 (2:1) solution and further recrystallized from chloro­ form and petroleum ether to yield 0.77 g of (2R,4aR,9aS)-2-methyl­ 2,4a,7,8,9,9a-hexahydro-5H,10H-pyrrolo-[1’,2’:4,5]-pyrazino[1,2-b] [1,2]oxazine-5,10-dione, in a yield of 40%, m.p. 76°C.

4.4.7.12  SYNTHESIS OF (S,Z)-3-BENZYL-6-((5-(TERT-BUTYL)OXAZOL-4YL)METHYLENE)-PIPERAZINE-2,5-DIONE [385]

A solution of 50 mg of (S,Z)-N-(1-amino-1-oxo-3-phenylpropan-2-yl)­ 3-(5-(tert-butyl)oxazol-4-yl)-2-hydroxyacrylamide (0.14 mmol) in 5 mL of toluene was refluxed in the presence of 1.3 mg of p-TsOH (0.007 mmol) for 6 hours in a small flask connecting to a Dean-Stark trap filled with molecular sieves 3 Å in the trap part. Upon removal of the solvent, the residue was purified by HPLC to obtain 8.1 mg of (S,Z)-3-benzyl-6-((5-(tert-butyl) oxazol-4-yl)methylene)piperazine-2,5-dione as a white powder, in a yield of 20%, m.p. 52–56°C.

330

Amino Acids: Insights and Roles in Heterocyclic Chemistry, Volume 2

4.5 REACTIONS OF DKPS Within the structure of 2,5-diketopiperazine, the two amino groups at posi­ tions 1 and 4 can be further acylated. As these two amino groups are a part of the amido functional group, the hydrogen on the amino group is relatively acidic and can be removed by a base, and the resulting nitrogen anion is nucleophilic and will undergo nucleophilic substitution. On the other hand, the methylene groups at positions 3 and 6 are essentially nucleophilic, due to the electron-withdrawing characteristic of the carbonyl groups. Thus, several reactions relating to the α-carbon of carbonyl compounds are also applicable to these two methylene groups within the DKP, such as alkylation, Aldol condensation, Dickman condensation, etc. Moreover, the hydrogen on the α-carbon can be removed to form acylimium intermediate, which under­ goes nucleophilic addition and other reactions relating to iminium species. Particularly, the DKP can be converted into the Schöllkopf compound, which is a very important intermediate in the enantioselective synthesis of novel amino acids. Furthermore, the carbonyl groups within the DKP can be reduced and dehydrated to form pyrazine or piperazine. Finally, epoxidation can take place on the double bond of alkylidene- or arylidene-DKPs. These possible reactions are summarized in Scheme 4.27.

SCHEME 4.27 Potential reactivities of DKPs.

2,5-Diketopiperazine

331

4.5.1 REACTIONS AT 1,4-POSITIONS The reactions occurring on the nitrogen atoms within DKPs often involve acylation and alkylation. The DKPs can be easily acylated when they are treated with reactive acyl compounds, such as acyl halide and carboxylic anhydrides, as exemplified in refluxing of simple DKP in acetic anhydride (Section 4.4.7.6). On the other hand, due to the high stability of DKP under basic conditions (even being treated with sodium hydride), the amide group once deprotonated, can react with active alkyl halide so that an additional alkyl group can be mounted to the nitrogen atoms. The examples of N-alkyl­ ation include the conversion of N,N’-(((2S,5S)-3,6-dioxopiperazine-2,5-diyl) bis(propane-3,1-diyl))bis(N-(benzyloxy)acetamide) into N,N’-(((2S,5S)­ 1,4-dimethyl-3,6-dioxopiperazine-2,5-diyl)bis(propane-3,1-diyl))bis(N­ (benzyloxy)acetamide) with sodium hydride and methyl iodide in DMF at 0°C (Scheme 4.28) [395], syntheses of 1,4-diallylpiperazine-2,5-dione and 1,4-di(but-3-en-1-yl)piperazine-2,5-dione from 2,5-diketopiperazine by means of the treatment with the corresponding bromide in the presence of sodium hydride, and tetrabutylammonium iodide in DMF (Scheme 4.29) [396]. It is found that when DKP is treated with a strong base like NaH, racemization occurs, whereas when the same DKP is treated with a mild base such as AgO, no racemization has been observed, as demonstrated in the methylation of cyclo(L-Leu-L-Leu) (Scheme 4.30). In this reaction, N-methylation of (3S,6S)-3,6-diisobutylpiperazine-2,5-dione with methyl iodide and silver oxide afforded only 10% of dimethylated DKP, whereas the N-methylation with NaH and MeI yielded 80% of cis and trans-diketopi­ perazines in an approximate ratio of 1:2, which were separated by fractional crystallization [397, 398]. In another N-alkylation practice, while the use of sodium hydride was unsuccessful, the DKP was treated with 2-tert­ butylimino-2-diethylamino-1,3-dimethylperhydro-1,3,2-diazaphosphorine (BEMP) and the corresponding alkylation reagents (propargyl bromide, allyl bromide, n-pentyl bromide, benzyl bromide, 2-phthalimidoethyl bromide) to yield 52–94% of the target products (Scheme 4.31), either in CH2Cl2 at room temperature, or in DMF under microwave irradiation [399]. Further­ more, the N-alkylation, particularly the N-allylation has been observed to occur concurrently with Aldol condensation under various conditions in one-pot synthesis of arylidene-DKPs, by means of the treatment with NaOH, Cs2CO3, K2CO3, and DBU [312].

332

Amino Acids: Insights and Roles in Heterocyclic Chemistry, Volume 2

SCHEME 4.28 N-methylation of DKP.

SCHEME 4.29 General N-alkylation of DKPs.

SCHEME 4.30 Potential racemization of N-alkylation of DKPs.

SCHEME 4.31 General N-alkylation of DKP in the presence of BEMP.

2,5-Diketopiperazine

333

4.5.1.1  REPRESENTATIVE EXAMPLES FOR THE REACTIONS AT 1,4-POSITIONS OF DKPS 4.5.1.1.1  Preparation of 1-Allyl-3,6-di((Z)-Benzylidene)Piperazine2,5-Dione [312]

To a 25 mL two-necked flask filled with nitrogen, were added 50 mg of 1,4-diacetyl-2,5-diketopiperazine (0.25 mmol, 1.0 equiv), 64 µL of benz­ aldehyde (0.63 mmol, 2.5 equiv), 54 µL of allyl bromide (0.63 mmol, 2.5 equiv), 205 mg of Cs2CO3 (0.63 mmol, 2.5 equiv), 200 mg of 4 Å molecular sieves and 2 mL of dry DMF. The reaction mixture was firstly stirred at –10°C until the completion of the first Aldol condensation and the allylation and then heated at 95°C for about 4 hours (monitored with TLC analysis). The solvent was removed under the reduced pressure, and water (50 mL) and EtOAc (20 mL) were added. The mixture was extracted with EtOAc (20 mL × 3). The combined organic layer was dried over Na2SO4, filtered, and evaporated. The residues were purified by silica gel flash column chromatog­ raphy to afford 55% of 1-allyl-3,6-di((Z)-benzylidene)piperazine-2,5-dione as a slightly yellow oil which changed into solid after about one week, m.p. 106–108°C. 4.5.1.1.2  Preparation of 1,4-Diallyl-2,5-Diketopiperazine [396]

To a suspension of 2.28 g 2,5-diketopiperazine (20 mmol) and 1.48 g tetrabutylammonium iodide (TBAI, 4 mmol) in 40 mL of DMF were slowly added 2.4 g of sodium hydride (60% dispersion in mineral oil, 60 mmol) at room temperature. After 15 minutes, 5.2 mL of allyl bromide (60 mmol) was

334

Amino Acids: Insights and Roles in Heterocyclic Chemistry, Volume 2

added and the resulting mixture was stirred for 20 hours at room tempera­ ture. The reaction mixture was then poured into 60 mL cold water and the aqueous phase was washed three times with 60 mL heptanes to remove the mineral oils. The aqueous phase was concentrated under reduced pressure and the resulting solid was extracted two times with diethyl ether and once with dichloromethane. The combined organic phase was evaporated and the resulting yellow oil was placed in a sublimation apparatus and vaporized at 100°C and 0.003 mbar. The solid was further purified via column chro­ matography over silica gel with acetone/heptanes (1:1) to afford 2.18 g of 1,4-diallyl-2,5-diketopiperazine as a colorless solid, in a yield of 56%. 4.5.2 REACTIONS AT 2,5-POSITIONS As the functional groups at positions 2 and 5 of DKPs are the carbonyls, the reactions at these two positions involve the transformation of carbonyls into other functional groups, including the conversion of the carbonyl group into vinyl ether (e.g., Schöllkopf’s bis-lactim ether), vinyl halide, alkenyl, and reduction of carbonyl into methylene group, etc. The most famous derivative arising from DKP is the Schöllkopf bislactim ether, Schöllkopf chiral auxiliaries [1], or Schöllkopf reagent [400], which was initially reported by Schöllkopf in 1983 [401]. This bis-lactim ether can be easily prepared from DKP with Meerwein’s salt (R3O+BF4–), which once treated with a strong base (e.g., BuLi) to form carbanion, can be alkylated and decomposed to yield unnatural amino acid in high optical purity, as demonstrated in Scheme 4.32. It should be pointed out that the lithiated Schöllkopf’s bis-lactim ether not only reacts with an alkylating agent but also reacts with carbonyl compounds (e.g., Aldol reaction) and thiocarbonyl compounds, to give b,γ-unsaturated α-amino acid methyl esters after acidic decomposition. In addition, being a carbanion, such lithi­ ated Schöllkopf’s bis-lactim ether undergoes Michael addition, such as the reaction with methyl acrylate; and adds to α-halo-acetophenone to generate b-epoxy α-amino acid derivatives. The diastereoselectivity is caused by the existing chiral auxiliary originating from another constituting amino acid, and such diastereoselectivity can be further enhanced when the lithium cation is replaced with a bulky transition metal complex, such as tris(dimethylamino) titanium [401]. This bis-lactim ether has been alkylated with ortho-bromo­ or ortho-iodobenzyl halide, and the resulting product once being treated with trimethylsilyl iodide is converted into ortho-halobenzyl substituted DKP. In

2,5-Diketopiperazine

335

the presence of CuI and CsOAc, intramolecular amidation of the aromatic moiety with the amino group inside the DKP ring leads to an indoline fused DKP derivative, as shown in Scheme 4.33 [400]. In a practical preparation of unnatural α-amino acid, (S)-3,6-diethoxy-2-(2-((4-methoxyphenyl)thio) propan-2-yl)-2,5-dihydropyrazine was alkylated with propargyl bromide in toluene, then decomposed with trifluoroacetic acid in acetonitrile/water to afford ethyl (S)-2-aminopent-4-ynoate. The optical purity of this compound can be estimated by means of converting this acid into its Mosher’s ester with either R(-)-α-methoxy-α-(trifluoromethyl)phenylacetyl chloride (also known as (R)-3,3,3-trifluoro-2-methoxy-2-phenylpropanoyl chloride in IUPAC name) or S(+)-α-methoxy-α-(trifluoromethyl)phenylacetyl chloride (also known as (S)-3,3,3-trifluoro-2-methoxy-2-phenylpropanoyl chloride in IUPAC name) in chloroform in the presence of trimethylamine [402]. This method has been applied to prepare substituted aromatic amino acids. For example, (S)-2-isopropyl-3,6-diethoxy-2,5-dihydropyrazine was deprotonated with n-butyl lithium, followed by alkylation with a series of alkylating agent, including (3-bromoprop-1-yn-1-yl)trimethylsilane, diethyl (3-(trimethylsilyl)prop-2-yn-1-yl) phosphate, diphenyl (3-(trimeth­ ylsilyl)prop-2-yn-1-yl) phosphate, 3-(trimethylsilyl)prop-2-yn-1-yl 4-methylbenzenesulfonate, 3-(trimethylsilyl)prop-2-yn-1-yl 4-methoxy­ benzene-sulfonate, or 3-(trimethylsilyl)prop-2-yn-1-yl methanesulfonate to afford (2S,5R)-3,6-diethoxy-2-isopropyl-5-(3-(trimethylsilyl)prop-2-yn-1­ yl)-2,5-dihydropyra-zine [391]. This compound then couples with ortho­ iodo aniline (i.e., 2-iodoaniline) or structurally similar aromatic amines to generate aromatic ring fused pyrrole scaffolds connecting to 2,5-dihydro­ pyrazine. Upon acidic decomposition of the 2,5-dihydropyrazine, unusual aromatic amino acids can be obtained, as illustrated in Scheme 4.34 for a representative preparation [403]. Furthermore, when the Schöllkopf’s bislactim ether was treated with N-chlorosuccinimide (NCS)/CCl4, the corre­ sponding chloropyrazine is formed. Upon the treatment with alkyl lithium, the alkyl-substituted Schöllkopf’s bis-lactim ether is resolved, which can be hydrolyzed to afford substituted amino acid [404]. Besides the most popular method to make 3,6-dialkoxy-2,5-dihydropyr­ azine by means of the Meerwein’s salt, trimethylsilyl trifluoromethanesul­ fonate (TMSOTf) has also been applied to the conversion of the carbonyl group within the DKP into vinyl ether functionality, which is explicated in the reactions of DKPs arising from glycine, leucine, valine, phenylalanine, etc., with 1,4-phenylenebis(methylene) bis(2,2,2-trichloroacetimidate) to form 2,5-dihydropyrazine-containing polymer [405], as displayed in Scheme

336

Amino Acids: Insights and Roles in Heterocyclic Chemistry, Volume 2

4.35. Similarly, (S)-1-acetyl-3-(2,5-dimethoxybenzyl)piperazine-2,5-dione when treated with TMSOTf in the presence of diisopropylethylamine, the corresponding trimethylsilyl lactim ether, i.e., (S)-1-acetyl-3-(2,5­ dimethoxybenzyl)-5-((trimethylsilyl)oxy)-3,6-dihydropyrazin-2(1H)-one was formed, which further underwent the Aldol condensation with acetal­ dehyde dimethyl acetal to afford (3S)-1-acetyl-3-(2,5-dimethoxybenzyl)4-(1-methoxyethyl)piperazine-2,5-dione. Refluxing with formic acid, (6R,11aS)-2-acetyl-7,10-dimethoxy-6-methyl-2,3,11,11a-tetrahydro-4Hpyrazino[1,2-b]isoquinoline-1,4(6H)-dione was resolved, as demonstrated in Scheme 4.36 [406–408]. Besides acetaldehyde acetal, other active aldehydes such as formaldehyde in the form of paraformaldehyde, and benzaldehyde also react with 1-acetyl-3-aryl-5-((trimethylsilyl)oxy)-3,6-dihydropyr­ azin-2(1H)-one under similar conditions, in which the aryl groups include benzyl, 3-methoxybenzyl, 2,4,5-trimethoxybeznyl, 3-methyl-2,4,5-trime­ thoxybenzyl, and 3-thienyl, etc. [408]. When paraformaldehyde is used in the reaction with (S)-1-acetyl-3-(2,4,5-trimethoxybenzyl)piperazine-2,5-dione under a similar condition, i.e., treatment of the DKP with trimethylsilyl chloride instead of TMSOTf, in the presence of triethylamine to form the corresponding trimetylsilyl lactim ether, following the subsequent reaction with paraformaldehyde in the presence of BF3, the oxygen atom of the methoxy group on the aryl moiety becomes the nucleophile that affords (S)-2-acetyl-9,10-dimethoxy-2,3,12,12a-tetrahydro-6H-benzo[f]pyrazino[1,2-c][1,3]oxazepine-1,4-dione [408]. It should be pointed out that similar transformation is not applicable to arylidene-DKP as the enamine moiety is not stable enough under such conditions.

SCHEME 4.32 Synthesis of α,α-disubstituted a-amino ester from DKP.

2,5-Diketopiperazine

337

SCHEME 4.33 Synthesis of fused DKP from Schöllkopf bis-lactim ether.

SCHEME 4.34 Synthesis of ethyl (R)-2-amino-3-(1H-pyrrolo[2,3-c]pyridin-3-yl) propanoate from Schöllkopf bis-lactim ether.

In addition to the treatment of DKP with TMSOTf, the carbonyl group can be converted into vinyl acetate when the DKP is treated with acetyl chloride, as exemplified by the treatment of (8S,8aS,Z)-8-methyl-3-((2-(2­ methylbut-3-en-2-yl)-1H-indol-3-yl)methylene)hexahydropyrrolo[1,2-a] pyrazine-1,4-dione with acetyl chloride to generate (1S,5aR,12aR,13aS)­ 1 , 1 2 , 1 2 - t r i m e t h y l - 2 , 3 , 11 , 1 2 , 1 2 a , 1 3 - h e x a h y d r o - 1 H , 5 H , 6 H ­ 5a,13a-(epiminomethano)indolizino[7,6-b]carbazole-5,14-dione, (1S,5aR,12aS,13aS)-1,12,12-trimethyl-2,3,11,12,12a,13-hexahydro­

338

Amino Acids: Insights and Roles in Heterocyclic Chemistry, Volume 2

1H,5H,6H-5a,13a-(epiminomethano)indolizino[7,6-b]carbazole5,14-dione and other isomers via intramolecular Diels-Alder cycloaddition, as shown in Scheme 4.37. In another transformation, the lactim ether is not generated directly from DKP, instead it is formed from azido functional group and ester moiety, and the resulting lactim ether undergoes the DielsAlder cycloaddition to form aromatically fused lactam, as shown in Scheme 4.38. In this synthesis, the azido group in methyl (2-azidoacetyl)-L-prolinate couples with the intramolecular ester group to form (S)-1-methoxy­ 6,7,8,8a-tetrahydropyrrolo[1,2-a]pyrazin-4(3H)-one, which undergoes Aldol condensation with 2-ethynylbenzaldehyde. Subsequently, (S,Z)­ 3-(2-ethynylbenzylidene)-1-methoxy-6,7,8,8a-tetrahydropyrrolo[1,2-a] pyrazin-4(3H)-one undertakes intramolecular Diels-Alder reaction to yield (5aS,11aS)-12-methoxy-2,3-dihydro-1H,5H,6H-5a,11a-(azenometheno) indeno-[2,1-f]indolizin-5-one [409]. In a more complex preparation, (±)-saframycin B was prepared by initial reduction of the carbonyl group of isopropyl (Z)-4-benzyl2,5-dioxo-6-(2,4,5-trimethoxy-3-methylbenzyl)-3-(2,4,5-trime­ thoxy-3-methylbenzylidene)piperazine-1-carboxylate, prepared from (Z)-1-acetyl-6-(2,4,5-trimethoxy-3-methylbenzyl)-3-(2,4,5trimethoxy-3-methylbenzylidene)piperazine-2,5-dione, by a mild reducing agent of lithium tri-tert-butoxide aluminum hydride (LiAlH(OBut)3) to form isopropyl (Z)-4-benzyl-2-hydroxy-5-oxo-6-(2,4,5-trimethoxy3-methylbenzyl)-3-(2,4,5-trimethoxy-3-methylbenzylidene)piperazine1-carboxylate, which was then deoxygenated in formic acid. After several steps of further transformations based on the formed intermediate of (Z)-4-benzyl-1-(isopropoxycarbonyl)-3-oxo-2-(2,4,5-trimethoxy-3methylbenzyl)-5-(2,4,5-trimethoxy-3-methylbenzylidene)-2,3,4,5-tetrahy­ dropyrazin-1-ium, (±)-saframycin B was yielded, as displayed in Scheme 4.39 [410–412]. A similar transformation can be found in the preparation of isopropyl (1R,2S,5S)-8,10-dihydroxy-9-methoxy-2,3-dimethyl-4­ oxo-1,2,3,4,5,6-hexahydro-1,5-epiminobenzo[d]azocine-11-carboxylate and isopropyl (1R,2R,5S)-8,10-dihydroxy-9-methoxy-2,3-dimethyl-4­ oxo-1,2,3,4,5,6-hexahydro-1,5-epiminobenzo[d]azocine-11-carboxylate from (S,Z)-1,6-dimethyl-3-(2,3,4,5-tetramethoxybenzylidene)piperazine2,5-dione, also using LiAlH(OBut)3 as the reducing agent [413], and the preparation of (±)-quinocarcin from 3-((Z)-3-((hexyldimethylsilyl)oxy) benzylidene)-6-(3-(phenylthio)allyl)piperazine-2,5-dione using sodium borohydride as the reducing agent [414].

2,5-Diketopiperazine

339

SCHEME 4.35 Conversion of DKP into Schöllkopf bis-lactim ether with TMSOTf.

SCHEME 4.36 Synthesis of (6R,11aS)-2-acetyl-7,10-dimethoxy-6-methyl-2,3,11,11a­ tetrahydro-4H-pyrazino[1,2-b]isoquinoline-1,4(6H)-dione from DKP precursor.

SCHEME 4.37 Intramolecular [4+2]-cycloaddition of (S)-8-methyl-3-((2-(2-methylbut-3­ en-2-yl)-1H-indol-3-yl)methyl)-4-oxo-4,6,7,8-tetrahydropyrrolo[1,2-a]pyrazin-1-yl acetate to give fused DKP derivatives.

340

Amino Acids: Insights and Roles in Heterocyclic Chemistry, Volume 2

SCHEME 4.38 Preparation of 3-(2-ethynylbenzyl)-1-methoxy-7,8-dihydropyrrolo[1,2-a] pyrazin-4(6H)-one and its intramolecular [4+2]-cycloaddition.

SCHEME 4.39 Synthesis of (±)-saframycin B.

2,5-Diketopiperazine

341

When DKP is connected to a p-nucleophile, one of the carbonyl groups is activated by N-methoxycarbonylation and then chemoselectively reduced with sodium borohydride in methanol. Upon the formation of acyliminium ion, intramolecular addition of the p-nucleophile to the acyliminium leads to the formation of 2,6-bridged piperazine-3-one [415]. Similarly, when methyl (S)-4-benzyl-3,6-dioxo-2-(prop-2-yn-1-yl)piperazine-1-carbox­ ylate was reduced with sodium borohydride in methanol and subsequently treated with formic acid at high temperature, 3,5-bridged 2-oxopiperazine, i.e., methyl (1S,5R)-3-benzyl-2,7-dioxo-3,9-diazabicyclo[3.3.1]nonane9-carboxylate was obtained. Even the benzyl group and indole ring can nucleophilically add to the generated acyliminium intermediate to form the 2-oxopiperazine with the aromatic ring bridged at the 3,5-positions [416]. Also, the carbonyl groups at positions 2 and 5 of the DKP can be removed and converted into vinyl halide functional groups when the corresponding DKP is treated with phosphorus oxychloride (POCl3) or a mixture of POCl3 and phosphorus pentachloride (PCl5). For example, when (3S,6S)­ 3,6-dibenzylpiperazine-2,5-dione was treated with POCl3 in the presence of diethyl aniline at 95°C, the corresponding (2S,5S)-2,5-dibenzyl-3,6-di­ chloro-2,5-dihydropyrazine was formed [405]. In contrast, when the same DKP was treated with POCl3 and a catalytic amount of PCl5 at 110°C, both 2,5-dibenzyl-3-chloropyrazine and 2,5-dibenzyl-3,6-dichloropyrazine were produced with a full aromatic ring [361], as shown in Scheme 4.40. Besides the POCl3 and PCl5, the carbonyl group can also be converted into vinyl chloride when the DKP is treated with phosgene, diphosgene or triphosgene, as illustrated in Scheme 4.41, where (3R,8aS)-3-((1H-indol-3-yl)methyl) hexahydropyrrolo[1,2-a]pyrazine-1,4-dione was treated with phosgene generated in situ from the decomposition of diphosgene or triphosgene to form (3R,8aS)-3-((1H-indol-3-yl)methyl)-1-chloro-4-oxo-3,4,6,7,8,8a­ hexahydropyrrolo[1,2-a]pyrazin-2-ium intermediate, in which the indole ring undergoes nucleophilic addition to the iminium cation moiety to yield (6R,13S,13aS)-13-chloro-1,2,3,6,7,12,13,13a-octahydro-5H-6,13-epimino­ pyrrolo-[1’,2’:1,2]azocino[4,5-b]indol-5-one. Then the chloro group was substituted with a variety of nucleophile, including water, methanol, allyl alcohol, phenol, aniline, allylamine, benzyl alcohol, benzylamine to form 13-substituted (6R,13S,13aS)-1,2,3,6,7,12,13,13a-octahydro-5H-6,13­ epiminopyrrolo[1’,2’:1,2]azocino[4,5-b]-indol-5-one [288]. Furthermore, the carbonyl group of the DKP can be deoxygenated in various ways. The DKP can be converted into N-acyliminium ion with rich chemistry. When the DKP is N-acylated or N-alkoxycarbonated to the corresponding

342

Amino Acids: Insights and Roles in Heterocyclic Chemistry, Volume 2

imide or carbamate derivative, selective reduction of the adjacent carbonyl group in the DKP system by addition of a hydride affords α-oxylactam. Carbamate derivatives are more suitable for this transformation than the imide analogs because the carbamates are less reactive than the imide moieties [417]. The most common reducing agent is NaBH4 in methanol. Similarly, due to the relatively high stability of N-alkoxycarbonated DKP, the addition of organolithium or Grignard reagent to the adjacent carbonyl group results in the formation of tertiary hemiaminal. Acidic dehydration of hemiaminal leads to the formation of acyliminium ion [418], that can undergo nucleophilic addition or hydrogenation to yield amine. Particularly, when the original DKP moiety is close to an aromatic ring, such DKP may fuse to the aromatic ring to form much complicated DKP derivatives as seen in many natural products mentioned previously. These transformations are displayed in Scheme 4.42.

SCHEME 4.40 Synthesis of 2,5-pyrazine and 2,5-dihydropyrazine derivatives from phenylalanine DKP.

SCHEME 4.41 Treatment of DKP with diphosgene or triphosgene

2,5-Diketopiperazine

343

SCHEME 4.42 Conversion of DKP into acyliminium ion.

Finally, the carbonyl group can be completely deoxygenated and converted into a methylene group. To do so, the DKP can be reduced with sodium borohydride in the presence of titanium tetrachloride [340], or reduced at lead and copper amalgamated cathodes using 3% alcoholic sulfuric acid as catholyte to form piperazine, which upon zinc dust distillation, affords piperazine. Also, the DKP can be reduced at the lead and copper amalgam­ ated cathodes with 2 N HCl as catholyte [419]. It is reported that the boraneTHF complex also reduces the DKP into piperazine, as demonstrated in the synthesis of Dragmacidin B from sarcosine anhydride by means of radical bromination with NBS (AIBN initiation), halide elimination, and subsequent trapping with 6-bromo-indole [420]. 4.5.2.1 REPRESENTATIVE EXAMPLES OF REACTIONS AT 2,5-POSITIONS 4.5.2.1.1  Preparation of (3R)-3,6-Dihydro-2,5-Diethoxy-3Isopropyl-Pyrazine [421]

In a typical experiment, a mixture of 4.5 g (R)-3-isopropylpiperazine2,5-dione (28.8 mmol) and 18.5 g of Et3O+BF4– (97 mmol) in 150 mL of dichloromethane was stirred at room temperature for 5 days. Then the

344

Amino Acids: Insights and Roles in Heterocyclic Chemistry, Volume 2

reaction mixture was added in portions to a vigorously stirred mixture of 150 mL saturated NaHCO3 and 150 mL dichloromethane at 5°C, while the pH was adjusted to 8–9 by the addition of 3 M NaOH (60 mL). The phases were separated and the aqueous phase was extracted with dichloromethane (2 × 100 mL). The combined organic phases were washed with 150 mL brine, dried with MgSO4 and concentrated under a vacuum. The residual yellow oil was purified by flash column chromatography using hexane/EtOAc (9:1) as eluent to afford 5.6 g of (R)-3,6-diethoxy-2-isopropyl-2,5-dihydropyrazine as a colorless oil, in yield of 92%. A similar procedure for the preparation of 3,6-dihydro-2,5-dialkoxypyrazine on a large scale has been reported in Organic Process Research and Development [422]. 4.5.2.1.2  Preparation of 3-(((2S,5R)-3,6-Diethoxy-5-Isopropyl2,5-Dihydropyrazin-2-yl)Methyl)-2-(Trimethylsilyl)-1HIndole [391]

• Step A: Preparation of (2R,5S)-3,6-diethoxy-2-isopropyl-5-(3­ (trimethylsilyl)prop-2-yn-1-yl)-2,5-dihydropyrazine: To a solution of 0.827 g of (R)-3,6-diethoxy-2-isopropyl-2,5-dihydropyrazine (3.9 mmol) in 25 mL dry THF under nitrogen was added 1.72 mL 2.5 M n-BuLi (4.3 mmol) dropwise at –78°C via syringe. The mixture was stirred at –78°C for 30 minutes. Then, a solution of 1.4 g diphenyl (3-(trimethylsilyl)prop-2-yn-1-yl) phosphate (39 mmol) in 20 mL of dry THF was added slowly. After being stirred at –78°C for 6 hours, the reaction mixture was slowly warmed to room temperature. The

2,5-Diketopiperazine

345

solution was then quenched with 2 mL of water. THF was removed under reduced pressure, and the residue was partitioned between water (20 mL) and diethyl ether (60 mL). The organic layer was separated, and the aqueous layer was extracted with ether (3 × 30 mL). The combined organic layers were washed with brine and dried over MgSO4. After removal of solvent under reduced pressure, the residue was purified by silica gel column chromatography (hexane/ EtOAc = 98:2) to afford 1.0 g of (2R,5S)-3,6-diethoxy-2-isopropyl-5­ (3-(trimethylsilyl)prop-2-yn-1-yl)-2,5-dihydropyrazine, in a yield of 80%. • Step B: Preparation of 3-(((2S,5R)-3,6-diethoxy-5-isopropyl-2,5-di­ hydropyrazin-2-yl)methyl)-2-(trimethylsilyl)-1H-indole: To a 100 mL round-bottomed flask equipped with a stirring bar, were added 200 mg 2-iodoaniline (0.91 mmol), 322 mg of (2R,5S)-3,6-diethoxy­ 2-isopropyl-5-(3-(trimethylsilyl)prop-2-yn-1-yl)-2,5-dihydropyr­ azine (1 mmol), 8 mg palladium(II) acetate (0.036 mmol), 39 mg of lithium chloride (0.91 mmol), 193 mg of sodium carbonate (1.8 mmol), and 12 mL of DMF. The reaction mixture was degassed and then heated at 100°C under argon until the disappearance of iodo­ aniline as monitored by TLC (30 hours). DMF was removed under reduced pressure, and the residue was taken up in 50 mL of CH2Cl2. The resulting suspension was passed through a Celite pad to remove insoluble solids, and the solution was concentrated under a vacuum. The residue was purified by flash chromatography (silica gel, hexane/EtOAc = 98:2) to afford 301 mg of 3-(((2S,5R)-3,6-diethoxy5-isopropyl-2,5-dihydropyrazin-2-yl)methyl)-2-(trimethylsilyl)-1H­ indole as an oil, in a yield of 81%. 4.5.2.1.3  Preparation of (6R,13S,13aS)-13-Chloro1,2,3,6,7,12,13,13a-Octahydro-5H-6,13Epiminopyrrolo[1’,2’:1,2]Azocino[4,5-b]Indol-5-One [288]

346

Amino Acids: Insights and Roles in Heterocyclic Chemistry, Volume 2

To a suspension of 2.83 g of (3R,8aS)-3-((1H-indol-3-yl)methyl) hexahydropyrrolo[1,2-a]pyrazine-1,4-dione (10 mmol) in dry CH2Cl2 cooled to 0°C with an ice bath under a nitrogen atmosphere was added 5.93 g of diphosgene (30 mmol) in dry CH2Cl2 dropwise. The mixture was refluxed until the completion of the reaction. Then, the reaction mixture was washed with saturated NaHCO3 and then with water. The organic phase was dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by chromatography to afford 1.51 g of (6R,13S,13aS)-13-chloro-1,2,3,6,7,12,13,13a-octahydro-5H-6,13­ epiminopyrrolo[1’,2’:1,2]azocino[4,5-b]indol-5-one as a white crystal, in a yield of 50%, Rf = 0.25 (EtOAc/petroleum ether (6:4) + 4% Et3N); m.p. 248–250°C. 4.5.3 REACTIONS AT 3,6-POSITIONS The α-hydrogens at positions 3 and 6 of DKPare acidic and can be deprotonated with a strong base, and the resulting carbanion undergoes Aldol condensation to form alkylidene- or arylidene-DKP, as mentioned previously. In addition, the chiral group introduced to the nitrogen atom, such as the 1-phenylethyl group in 1,4-bis((S)-1-phenylethyl)piperazine-2,5-dione, greatly impacts the stereochemistry at positions 3 and 6 of DKP when such DKP is lithiated with a strong base and then alkylated with an alkylating agent. Decomposition of this stereochemically alkylated DKP leads to a chiral unnatural α-amino acid [423]. When asymmetric DKP is used, even though the protecting group on the nitrogen atom is achiral, e.g., para-methoxybenzyl, the existing chiral group from one amino acid component also directs the stereochemistry of the other methylene group during alkylation. As illustrated by N-para­ methoxybenzyl protected (R)-3-isopropylpiperazine-2,5-dione, once lithi­ ated to enolate, a hydroxyl group was introduced to position 3 in a 2:1 ratio for trans- and cis-diastereomers by oxygen oxidation. In contrast, the reduc­ tion of (R)-6-isopropyl-1,4-bis(4-methoxybenzyl)piperazine-2,3,5-trione by diisobutylaluminum hydride generated the same diastereomer pair but in a ratio of 1:4. When this DKP is lithiated, the alkylation of the resulting lithium enolate with allyl bromide afforded the allylated DKP in 94% diastereomeric selectivity [424]. On the other hand, nucleophiles can be introduced to positions 3 and 6 of DKP by means of bromination (NBS) and subsequent nucleophilic substitution; or by means of bromination and subsequent elimination

2,5-Diketopiperazine

347

to generate acylinimium intermediate, and the subsequent addition of a nucleophile to the resulting acylinimium, as demonstrated in the synthesis of (±)- and (+)-bicyclomycin, a clinically useful antibiotic, shown in Scheme 4.43. In this total synthesis, 1,4-bis(4-methoxybenzyl)piperazine2,5-dione was brominated with NBS, and the bromo was subsequently substituted with sodium pyridine-2-thiolate, the resulting (3R,6R)-1,4-bis(4­ methoxybenzyl)-3,6-bis(pyridin-2-ylthio)piperazine-2,5-dione was treated with silver trifluoromethylsulfonate to afford the acylinimium intermediate of (R)-1,4-bis(4-methoxybenzyl)-2,5-dioxo-3-(pyridin-2-ylthio)-2,3,4,5tetrahydropyrazin-1-ium. Nucleophilic addition of 4,5-dihydrofuran-2-yl trimethylsilyl ether to this acylinimium intermediate yielded (3R,6R)-1,4­ bis(4-methoxybenzyl)-3-((S)-2-oxotetrahydrofuran-3-yl)-6-(pyridin-2ylthio)piperazine-2,5-dione. The lactone functional group was reduced with LiAlH4, and the remaining pyridine-2-ylthio group was removed in a similar manner to generate another acylinimium intermediate, which was then intra­ molecularly attacked by the nucleophilic hydroxyl group. After additional transformations, (+)-bicyclomycin was obtained [425, 426]. In another similar transformation, 1,4-dimethyl-piperazine-2,5-dione was brominated and subsequently eliminated to generate the acylinimium intermediate, then the nucleophilic addition of 6-bromo-indole to the acylinimium afforded 3,6-bis(6-bromo-1H-indol-3-yl)-1,4-dimethylpiperazine-2,5-dione. Reduc­ tion of the carbonyl group in DKP with BH3·THF led to the final product of Dragmacidin B [420].

SCHEME 4.43 Application of DKP in the synthesis of (+)-Bicyclomycin.

348

Amino Acids: Insights and Roles in Heterocyclic Chemistry, Volume 2

4.5.3.1  PREPARATION OF (2R,5S)-5-ISOPROPYL-1,4-BIS((4METHOXYBENZYL)OXY)-3,6-DIOXOPIPERAZIN-2-YL ACETATE AND (2S,5S)-5-ISOPROPYL-1,4-BIS((4-METHOXYBENZYL)OXY)3,6-DIOXOPIPERAZIN-2-YL ACETATE [424]

To a solution of 5.4 g (S)-3-isopropyl-1,4-bis((4-methoxybenzyl)oxy)piperazine-2,5-dione (12.6 mmol) in 100 mL of dry THF at –78°C was added 13.9 mL 1.0 M lithium hexamethyldisilazide solution in THF (13.9 mmol). After being stirred at –78°C for 1 hour, the reaction mixture was treated with 1.75 mL chlorotrimethylsilane (13.9 mmol) and the mixture was stirred at –78°C for 30 minutes before 4.47 g of (diacetoxyiodo)benzene (13.9 mmol) was added. The resulting mixture was stirred at –78°C for 2 hours, then 2.0 g of sodium acetate (33.4 mmol) was added and the mixture was stirred at –78°C for 3 hours, and warmed to room temperature over 12 hours. After mixing with 50 mL saturated NH4Cl and 500 mL water, the mixture was extracted with ether. The combined organic layers were dried over MgSO4, and evaporated to afford a 2: 1 mixture of (2R,5S)-5-isopropyl-1,4-bis((4­ methoxybenzyl)oxy)-3,6-dioxopiperazin-2-yl acetate and (2S,5S)-5-iso­ propyl-1,4-bis((4-methoxybenzyl)oxy)-3,6-dioxo-piperazin-2-yl acetate. The residue was purified by silica gel column chromatography (ether/hexane = 1:1) to afford 0.96 g of (2S,5S)-5-isopropyl-1,4-bis((4-methoxybenzyl) oxy)-3,6-dioxopiperazin-2-yl acetate (17%) as a colorless oil, 2.85 g of the mixture of cis- and trans-diastereomers (50%) and 0.51 g of (2R,5S)­ 5-isopropyl-1,4-bis((4-methoxybenzyl)oxy)-3,6-dioxopiperazin-2-yl acetate (9%) as a colorless solid. 4.5.4  REACTIONS AT Α,Β-UNSATURATED Π-BOND OF ALKYLIDENEAND ARYLIDENE-DKPS The α,b-unsaturated p-bond in alkylidene- and arylidene-DKPs is conju­ gated to the carbonyl group, so that the potential reactions involving the alkylidene- or arylidene-DKPs are the Michael addition with a nucleophile, and the reactions solely occurring on the p-bond, such as cyclopropanation, epoxidation, halogenation, hydration, etc.

2,5-Diketopiperazine

349

In a series of preparations, the exocyclic p-bond of the alkylidene-DKPs undergoes the addition of chlorine or bromine to give vicinal dihalogenated DKPs. Subsequent treatment of these adducts with water, MeOH or thiol leads to the easy substitution of the halogen α to nitrogen by OH, MeO, or RS group through acyliminium intermediates [427]. When a series of 1,4-dimethyl-arylidene-DKPs are treated with NBS and water in acetonitrile or 1,4-dioxane, hydroxybromination occurs at the p-bond. Subsequent intramolecular nucleophilic substitution yields diastereomeric epoxy DKPs (SSSS and SSSR configuration), as shown in Scheme 4.44 [4]. However, it is unclear for the relationship between the diastereoselectivity and the aryl group.

SCHEME 4.44 Epoxidation of the arylidene-DKPs.

In comparison, the bromination of (Z)-3-arylidenepiperazine-2,5-dione in methanol yields 3-(bromo(aryl)methyl)-3-methoxypiperazine-2,5-dione. Upon the treatment with base, 6-methoxy-7-aryl-1,4-diazabicyclo[4.1.0] heptane-2,5-dione is formed. The addition of a nucleophile to the amide bond of the DKP opens the lactam, leading to the formation of an aziridinecontaining dipeptide [428], as shown in Scheme 4.45.

SCHEME 4.45 Conversion of arylidene-DKP into an aziridine-containing dipeptide.

350

Amino Acids: Insights and Roles in Heterocyclic Chemistry, Volume 2

Also, the double bond in alkylidene- or arylidene-DKP undergoes regular cyclopropanation, as demonstrated in the reaction between (S,Z)-1-acetyl­ 3-benzylidene-6-isopropylpiperazine-2,5-dione and diazomethane to afford (1S,3S,6S)-7-acetyl-6-isopropyl-1-phenyl-4,7-diazaspiro[2.5]octane-5,8dione, which upon being transformed into the corresponding Schöllkopf’s bis-lactim ether, and subsequent acidic hydrolysis, was converted into methyl (1S,2S)-1-amino-2-phenylcyclopropane-1-carboxylate [363]. 4.5.4.1  PREPARATION OF (2S,3S,6S,8S)-4,9-DIMETHYL-2,8-DIPHENYL1,7-DIOXA-4,9-DIAZADISPIRO[2.2.26.23]DECANE-5,10-DIONE AND (2R,3S,6S,8S)-4,9-DIMETHYL-2,8-DIPHENYL-1,7-DIOXA4,9-DIAZADISPIRO[2.2.26.23]DECANE-5,10-DIONE [4]

To a suspension of 64 mg 3,6-di((Z)-benzylidene)-1,4-dimethylpi­ perazine-2,5-dione (0.20 mmol) in 2.2 mL H2O/CH3CN (1:10) cooled on an ice bath was added 78 mg of NBS (0.44 mmol) under stirring. The resulting mixture was then warmed to 25°C and stirred for 18 hours at the same temperature. EtOAc (4.0 mL) was added to the reaction mixture, and the resulting solution was dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was dissolved in 2.0 mL EtOAc, and 0.20 mL Et3N (1.4 mmol) was added to the resulting mixture at 25°C under a nitrogen atmosphere. After being stirred for 23 hours at 25°C, the reaction mixture was filtered to remove the insoluble salts. The filtrate was concentrated under reduced pressure, and the crude residue was purified by flash chromatography (10–40% EtOAc in hexanes) on silica gel to afford 25 mg of (2S,3S,6S,8S)-4,9-dimethyl-2,8-diphenyl­ 1,7-dioxa-4,9-diazadispiro[2.2.26.23]decane-5,10-dione as a white solid (36% yield, m.p. 140–142°C, Rf = 0.29 for 30% EtOAc in hexanes) and 42 mg of (2R,3S,6S,8S)-4,9-dimethyl-2,8-diphenyl-1,7-dioxa-4,9-diaza­ dispiro[2.2.26.23]decane-5,10-dione as a colorless crystalline (60% yield), m.p. 179–181°C, Rf = 0.20 (30% EtOAc in hexanes).

2,5-Diketopiperazine

351

4.6 APPLICATIONS Besides the various biological applications of DKPs as mentioned above, DKP has been found to catalyze chemical reactions. For example, (3S,6S)­ 3-((1H-imidazol-5-yl)methyl)-6-benzylpiperazine-2,5-dione catalyzes the asymmetric addition of hydrogen cyanide to benzaldehydes in toluene to afford (R)-mandelonitrile in high yield with an enantiomeric excess greater than 95%. For the addition of hydrogen cyanide to other aldehydes in the presence of this DKP, such as para-methoxybenzaldehyde, meta-methoxy­ benzaldehyde, ortho-methoxybenzaldehyde, meta-phenoxybenzaldehyde, para-methylbenzaldehyde,para-nitrobenzaldehyde,meta-nitrobenzaldehyde, para-cyanobenzaldehyde, 2-naphthaldehyde, 6-methoxy-2-naphthaldehyde, furfural, nicotin-3-aldehyde, cyclohexanecarbaldehyde, isobutyraldehyde, isovaleraldehyde, hexanal, and pivalaldehyde, the conversion yields vary from 40% to 100%, and the enantioselectivity of aromatic aldehyde is usually higher than that of aliphatic aldehydes, except for meta-nitrobenzaldehyde (Scheme 4.46) [429]. The resulting (R)-mandelonitrile has been converted into various chiral synthons including mandelic acid, methyl mandelate and 2-amino-1-phenylethanol without noticeable racemization. In addition, the reaction between 3-phenoxybenzaldehyde and HCN in the presence of (3S,6S)­ 3-((1H-imidazol-5-yl)methyl)-6-benzylpiperazine-2,5-dione demonstrates an enantioselective autocatalysis, i.e., (S)-3-phenoxymandelonitrile further reacts with (3S,6S)-3-((1H-imidazol-5-yl)methyl)-6-benzylpiperazine-2,5-dione to form a new, more enantioselective catalytic species. Upon addition of a small quantity of (S)-mandelonitrile or (S)-3-phenoxymandelonitrile (8 mol.%) to the reaction mixtures, the enantioselectivity of the resulting cyanohydrin was improved by as much as 20% ee [430]. Based on this seminal work, another DKP, i.e., 1-(2-((2S,5S)-5-benzyl-3,6-dioxopiperazin-2-yl)ethyl)guanidine has been identified to catalyze the enantiomeric addition of hydrogen cyanide to imines. For this reaction, the imines arising from aromatic amines have higher enantioselectivity than other imines containing the aliphatic amine component. Similarly, the imines from aromatic aldehydes also afford α-amino nitriles of higher chemical yields and enantioselectivities than the corresponding imines arising from the aliphatic aldehydes (Scheme 4.47) [431]. When another DKP, i.e., cyclo(L-Tyr-L-His), is attached to chlorometh­ ylated polystyrene or polysiloxane polymers via spacer groups coupled to the tyrosine phenolic residue, these polymer-attached dipeptides have become efficient catalysts for the conversion of aromatic aldehydes to cyanohydrins although the enantioselectivities are low [432].

352

Amino Acids: Insights and Roles in Heterocyclic Chemistry, Volume 2

SCHEME 4.46 DKP catalyzed asymmetric cyanohydration of aldehydes.

SCHEME 4.47 DKP catalyzed asymmetric addition of HCN to imine.

In addition, 1,4-dihydroxymethyl-2,5-diketopiperazine had been claimed as one of the emulsion hardeners, which was synthesized by adding form­ aldehyde to the active imino groups of DKP. The hardening action of this compound is proposed to be the presence of hydroxymethyl groups, as diketopiperazine itself does not show any hardening property. As a result, 1,4-dihydroxymethyl-2,5-diketopiperazine has a tendency to give fog and decrease emulsion sensitivity after keeping, possibly due to the reverse reac­ tion of losing the hydroxymethyl group [433]. KEYWORDS • • • • •

biological activity diketopiperazine peptide condensation reagent Schöllkopf reagent Ugi multi-component reaction

2,5-Diketopiperazine

353

REFERENCES 1. Sano, S., & Nakao, M., (2015). Chemistry of 2,5-diketopiperazine and Its bis-lactim ether: A brief review. Heterocycles, 91(7), 1349–1375. 2. Cornacchia, C., Cacciatore, I., Baldassarre, L., Mollica, A., Felician, F., & Pinnen, F., (2012). 2,5-Diketopiperazines as neuroprotective agents. Mini-Reviews in Medicinal Chemistry, 12(1), 2–12. 3. Yamamoto, K., Hayashi, M., Murakami, Y., Araki, Y., Otsuka, Y., Kashiwagi, T., Shimamura, T., & Ukeda, H., (2016). Development of LC-MS/MS analysis of cyclic dipeptides and its application to tea extract. Bioscience, Biotechnology, and Biochemistry, 80(1), 172–177. 4. Ando, S., Grote, A. L., & Koide, K., (2011). Diastereoselective synthesis of diketopiperazine bis-α,β-epoxides. Journal of Organic Chemistry, 76(4), 1155–1158. 5. Egusa, S., Takagi, J., Sisido, M., & Imanishi, Y., (1986). Synthesis and conformation of aromatic cyclic dipeptides. Cyclo(phenylalanyl)2, cyclo(1-naphthylalanyl)2, and cyclo(2-naphthylalanyl)2. Bull. Chem. Soc. Jpn., 59, 2195–2201. 6. Gdaniec, M., (1988). Structure of cyclo(-L-phenylalanyl-N-methyl-L-α-aminobutyryl-). Acta Crystallographica, Section C: Crystal Structure Communications, C44(6), 1042–1044. 7. Benedetti, E., Corradini, P., & Pedone, C., (1969). Crystal and molecular structure of L-Cis-3,6-dimethyl-2,5-piperazinedione (L-Alanyl-L-alanyl-2,5-diketopiperazine). Biopolymers, 7(5), 751–764. 8. Degeilh, R., & Marsh, R. E., (1959). A refinement of the crystal structure of diketopiperazine (2,5-piperazinedione). Acta Crystallographica, 12, 1007–1014. 9. Pérez-Picaso, L., Escalante, J., Olivo, H. F., & Rios, M. Y., (2009). Efficient microwave assisted syntheses of 2,5-diketopiperazines in aqueous media. Molecules, 14, 2836–2849. 10. Ciarkowski, J., Gdaniec, M., Kolodziejczyk, A., Liberek, B., Borremans, F. A. M., & Anteunis, M. J. O., (1990). Conformation of cyclo-(D-phenylalanyl-trans-4-fluoro-D­ prolyl). International Journal of Peptide & Protein Research, 36(3), 285–291. 11. Fabbri, D., Adamiano, A., Falini, G., De Marco, R., & Mancini, I., (2012). Analytical pyrolysis of dipeptides containing proline and amino acids with polar side chains. Novel 2,5-diketopiperazine markers in the pyrolysates of proteins. Journal of Analytical and Applied Pyrolysis, 95, 145–155. 12. Laville, R., Nguyen, T. B., Moriou, C., Petek, S., Debitus, C., & Al-Mourabit, A., (2015). Marine natural occurring 2,5-diketopiperazines: Isolation, synthesis and optical properties. Heterocycles, 90(2), 1351–1366. 13. Blank, J. G., Miller, G. H., Ahrens, M. J., & Winans, R. E., (2001). Experimental shock chemistry of aqueous amino acid solutions and the cometary delivery of prebiotic compounds. Origins of Life and Evolution of the Biosphere, 31, 15–51. 14. Alargov, D. K., Deguchi, S., Tsujii, K., & Horikoshi, K., (2002). Reaction behaviors of glycine under super- and subcritical water conditions. Origins of Life and Evolution of the Biosphere, 32, 1–12.

354

Amino Acids: Insights and Roles in Heterocyclic Chemistry, Volume 2

15. Marshall-Bowman, K., Ohara, S., Sverjensky, D. A., Hazen, R. M., & Cleaves, H. J., (2010). Catalytic peptide hydrolysis by mineral surface: Implications for prebiotic chemistry. Geochimica et Cosmochimica Acta, 74, 5852–5861. 16. Ryan, L. A. M., Dal, B. F., Arendt, E. K., & Koehler, P., (2009). Detection and quantitation of 2,5-diketopiperazines in wheat sourdough and bread. Journal of Agricultural and Food Chemistry, 57(20), 9563–9568. 17. Chen, Y. H., Liou, S. E., & Chen, C. C., (2004). Two-step mass spectrometric approach for the identification of diketopiperazines in chicken essence. European Food Research and Technology, 218, 589–597. 18. Pedersen, B. T., Østergaard, J., Larsen, S. W., Cornett, C., Ankersen, M., & Larsen, C., (2011). Physicochemical characteristics and in vitro release from oil-based vehicles of peptidomimetics: Parenteral depots for intra-articular administration. Drug Development and Industrial Pharmacy, 37(1), 62–71. 19. Buckley, S. A., Stott, A. W., & Evershed, R. P., (1999). Studies of organic residues from ancient Egyptian mummies using high temperature-gas chromatography-mass spectrometry and sequential thermal desorption-gas chromatography-mass spectrometry and pyrolysis-gas chromatography-mass spectrometry. The Analyst, 124, 443–452. 20. Gupta, M. K., & Gupta, V. D., (1978). Vibrational analysis of 2:5-diketopiperazine in relation to its conformation. Indian Journal of Biochemistry & Biophysics, 15(5), 407–412. 21. Kaya, K., & Nagakuru, S., (1972). Electronic absorption spectra of the 2,5-diketopiperazine single crystal and evaporated film. Journal of Molecular Spectroscopy, 44(2), 279–285. 22. Corey, R. B., (1938). Crystal structure of diketopiperazine. Journal of the American Chemical Society, 60, 1598–1604. 23. Mendham, A. P., Dines, T. J., Snowden, M. J., Chowdhry, B. Z., & Withnall, R., (2009). Vibrational spectroscopy and DFT calculations of di-amino acid cyclic peptides. Part I: Cyclo(gly-gly), cyclo(L-ala-L-ala) and cyclo(L-ala-gly) in the solid state and in aqueous solution. Journal of Raman Spectroscopy, 40(11), 1478–1497. 24. Borthwick, A. D., (2012). 2,5-Diketopiperazines: Synthesis, reactions, medicinal chemistry, and bioactive natural products. Chemical Reviews, 112, 3641–3716. 25. Bettens, F. L., Bettens, R. P. A., Brown, R. D., & Godfrey, P. D., (2000). The microwave spectrum, structure, and ring-puckering of the cyclic dipeptide diketopiperazine. Journal of the American Chemical Society, 122(24), 5856–5860. 26. Hirst, J. D., & Persson, B. J., (1998). Ab initio calculations of the vibrational and electronic spectra of diketopiperazine. Journal of Physical Chemistry A, 102(38), 7519–7524. 27. Benedetti, E., Corradini, P., & Pedone, C., (1969). Crystal and molecular structure of trans-3,6-dimethyl-2,5-piperazinedione (L-alanyl-D-alanine 2,5-diketopiperazine). Journal of Physical Chemistry, 73(9), 2891–2895. 28. Fava, G. G., Belicchi, M. F., Marchelli, R., & Dossena, A., (1981). Synthesis, crystal structure and conformation of the cyclic dipeptide cyclo(-L-seryl-L-seryl-). Acta Crystallographica, Section B: Structural Crystallography and Crystal Chemistry, B37(3), 625–629.

2,5-Diketopiperazine

355

29. MacDonald, J. C., & Whitesides, G. M., (1994). Solid-state structures of hydrogenbonded tapes based on cyclic secondary diamides. Chemical Reviews, 94(8), 2383–2420. 30. Barfield, M., Al-Obeidi, F. A., Hruby, V. J., & Walter, S. R., (1982). Interproton coupling over five bonds 5J(H-Cα-C(O)-N-Cα-H) in the peptide moiety: The importance of specific association effects. Journal of the American Chemical Society, 104(12), 3302–3306. 31. Sletten, E., (1970). Conformation of cyclic dipeptides. The crystal and molecular structures of cyclo-D-alanyl-L-alanyl and Cyclo-L-alanyl-L-alanyl (3,6-dimethylpiperazine-2,5dione). Journal of the American Chemical Society, 92(1), 172–177. 32. Mendham, A. P., Spencer, J., Chowdhry, B. Z., Dines, T. J., Mujahid, M., Palmer, R. A., Tizzard, G. J., & Coles, S. J., (2011). X-Ray crystallographic structure and absolute configuration of the cyclic di-amino acid peptide: Cyclo(L-homoCySH-L-Homocysh). Journal of Chemical Crystallography, 41(9), 1328–1334. 33. Mendham, A. P., Potter, B. S., Palmer, R. A., Dines, T. J., Mitchell, J. C., Withnall, R., & Chowdhry, B. Z., (2010). Vibrational spectra and crystal structure of the di-amino Acid Peptide Cyclo(L-Met-L-Met): Comparison of experimental data and DFT calculations. Journal of Raman Spectroscopy, 41(2), 148–159. 34. Jeziorna, A., Stopczyk, K., Skorupska, E., Luberda-Durnas, K., Oszajca, M., Lasocha, W., Marcin, G. M., et al., (2015). Cyclic dipeptides as building units of nano- and microdevices: Synthesis, properties, and structural studies. Crystal Growth and Design, 15, 5138–5148. 35. Goldberg, I., Stein, Z., Lin, L. T. W., & Hart, H., (1985). Structure of N,N’-ditrityl2,5-diketopiperazine and its 1:1 Inclusion complex with methylene chloride. Acta Crystallographica, Section C: Crystal Structure Communications, C41(10), 1539–1543. 36. Du, Y., Creighton, C. J., Tounge, B. A., & Reitz, A. B., (2004). Noncovalent self-assembly of bicyclo[4.2.2]diketopiperazines: Influence of saturation in the bridging carbacyclic ring. Organic Letters, 6(3), 309–312. 37. Terada, K., Masuda, T., & Sanda, F., (2009). Synthesis and secondary structure of polyacetylenes carrying diketopiperazine moieties. The first example of helical polymers stabilized by S-cis-amide-based hydrogen bonding. Macromolecules, 42, 913–920. 38. Togashi, T., Umetsu, M., Tsuchizaki, H., Ohara, S., Naka, T., & Adschiri, T., (2006). Simultaneous synthesis and self-assembly of cyclic diphenylalanine at hydrothermal condition. Chemistry Letters, 35(6), 636, 637. 39. Benedetti, E., Bavoso, A., Di Blasio, B., Pavone, V., Pedone, C., Paolillo, L., D’Alagni, M., (1988). Structural studies of cyclopeptides. Solid state and solution conformation of cyclo(L-histidyl-D-histidyl). International Journal of Peptide & Protein Research, 31(2), 220–224. 40. Brienne, M. J., Gabard, J., Leclercq, M., Lehn, J. M., Cesario, M., Pascard, C., Cheve, M., & Dutruc-Rosset, G., (1994). Chirality directed self-assembly. Resolution of 2,5-diazabicyclo[2.2.2]octane-3,6-dione and crystal structures of its racemic and (-) enantiomeric forms. Tetrahedron Letters, 35(44), 8157–8160. 41. Lyssenko, K. A., Lenev, D. A., & Kostyanovsky, R. G., (2002). Self-assembly of cage structures. 12. The synthesis and crystal structures of 2,5-diazabicyclo[2.2.2]

356

Amino Acids: Insights and Roles in Heterocyclic Chemistry, Volume 2

octane-3,6-dione-1,4-dicarboxylic acids and their diesters. Tetrahedron, 58(42), 8525–8537. 42. Palacin, S., Chin, D. N., Simanek, E. E., MacDonald, J. C., Whitesides, G. M., McBride, M. T., & Palmore, G. T. R., (1997). Hydrogen-bonded tapes based on symmetrically substituted diketopiperazines: A robust structural motif for the engineering of molecular solids. Journal of the American Chemical Society, 119(49), 11807–11816. 43. Palmore, G. T. R., Luo, T. J. M., McBride-Wieser, M. T., Picciotto, E. A., & Reynoso-Paz, C. M., (1999). Engineering crystalline architecture with diketopiperazines: An investigation of the strength of hydrogen-bonded tapes based on the cyclic dipeptide of (S)-aspartic acid. Chem. Mater., 11, 3315–3328. 44. Ohta, Y., Terada, K., Masuda, T., & Sanda, F., (2009). Diketopiperazine supramolecule derived from hydroxyphenylglycine. Heterocycles, 78(6), 1477–1483. 45. Vanbever, R., (2005). Performance-driven, pulmonary delivery of systemically acting drugs. Drug Discovery Today: Technologies, 2(1), 39–46. 46. Levins, C. G., & Schafmeister, C. E., (2005). The synthesis of curved and linear structures from a minimal set of monomers. Journal of Organic Chemistry, 70, 9002–9008. 47. Giessen, T. W., & Marahiel, M. A., (2015). Rational and combinatorial tailoring of bioactive cyclic dipeptides. Frontiers in Microbiology, 6, 785. 48. James, E. D., Knuckley, B., Alqahtani, N., Porwal, S., Ban, J., Karty, J. A., Viswanathan, R., & Lane, A. L., (2016). Two distinct cyclodipeptide synthases from a marine actinomycete catalyze biosynthesis of the same diketopiperazine natural product. ACS Synthetic Biology, 5, 547−553. 49. Ochoa, J. L., Bray, W. M., Lokey, R. S., & Linington, R. G., (2015). Phenotype-guided natural products discovery using cytological profiling. Journal of Natural Products, 78, 2242−2248. 50. Giessen, T. W., Von, T. A. M., & Marahiel, M. A., (2013). A tRNA-dependent two-enzyme pathway for the generation of singly and doubly methylated ditryptophan 2,5-diketopiperazines. Biochemistry, 52(24), 4274–4283. 51. Kim, J., Ashenhurst, J. A., & Movassaghi, M., (2009). Total synthesis of (+)-11,11’-dideoxyverticillin A. Science, 324, 238–241. 52. Zhang, M., Wang, W. L., Fang, Y. C., Zhu, T. J., Gu, Q. Q., & Zhu, W. M., (2008). Cytotoxic alkaloids and antibiotic nordammarane triterpenoids from the marine-derived fungus Aspergillus sydowi. Journal of Natural Products, 71(6), 985–989. 53. Olsen, E. K., Hansen, E., Moodie, L. W. K., Isaksson, J., Sepčić, K., Cergolj, M., Svenson, J., & Andersen, J. H., (2016). Marine AChE inhibitors isolated from Geodia barretti: Natural compounds and their synthetic analogs. Organic & Biomolecular Chemistry, 14, 1629–1640. 54. Sjoegren, M., Goeransson, U., Johnson, A. L., Dahlstroem, M., Andersson, R., Bergman, J., Jonsson, P. R., & Bohlin, L., (2004). Antifouling activity of brominated cyclopeptides from the marine sponge Geodia barretti. Journal of Natural Products, 67(3), 368–372. 55. Maiya, S., Grundmann, A., Li, S. M., & Turner, G., (2006). The fumitremorgin gene cluster of Aspergillus fumigatus: Identification of a gene encoding brevianamide F synthetase. ChemBioChem, 7(7), 1062–1069.

2,5-Diketopiperazine

357

56. Mehdi, R. B. A., Shaaban, K. A., Rebai, I. K., Smaoui, S., Bejar, S., & Mellouli, L., (2009). Five naturally bioactive molecules including two rhamnopyranoside derivatives isolated from the Streptomyces sp. strain TN58. Natural Product Research, 23, 1095–1107. 57. Wang, B., Park, E. M., King, J. B., Mattes, A. O., Nimmo, S. L., Clendinen, C., Edison, A. S., et al., (2015). Transferring fungi to a deuterium-enriched medium results in assorted, conditional changes in secondary metabolite production. Journal of Natural Products, 78, 1415–1421. 58. Kimura, Y., Sawada, A., Kuramata, M., Kusano, M., Fujioka, S., Kawano, T., & Shimada, A., (2005). Brevicompanine C, cyclo-(D-Ile-L-Trp), and cyclo-(D-Leu-L-Trp), plant growth regulators from Penicillium brevicompactum. Journal of Natural Products, 68(2), 237–239. 59. Kimura, Y., Tani, K., Kojima, A., Sotoma, G., Okada, K., & Shimada, A., (1996). Cyclo-(L-tryptophyl-L-phenylalanyl), a plant growth regulator produced by the fungus Penicillium sp. Phytochemistry, 41(3), 665–669. 60. Shiono, Y., Akiyama, K., & Hayashi, H., (1999). New Okaramine Congeners, Okaramines J, K, L, M and related compounds, from Penicillium simplicissimum ATCC 90288. Bioscience, Biotechnology, and Biochemistry, 63(11), 1910–1920. 61. Lee, K. H., Kim, G. W., & Rhee, K. H., (2010). Identification of Streptomyces sp. KH29, which produces an antibiotic substance processing an inhibitory activity against multidrug-resistant Acinetobacter baumannii. Journal of Microbiology and Biotechnology, 20(12), 1672–1676. 62. Soledade, M., Pedras, C., Smith, K. C., & Taylor, J. L., (1998). Production of 2,5-dioxopiperazine by a new isolate type of the blackleg fungus Phoma. Phytochemistry, 49(6), 1575–1577. 63. Kanokmedhakul, S., Kanokmedhakul, K., Phonkerd, N., Soytong, K., Kongsaeree, P., & Suksamrarn, A., (2002). Antimycobacterial anthraquinone-chromanone compound and diketopiperazine alkaloid from the fungus Chaetomium globosum KMITL-N0802. Planta Medica, 68(9), 834–836. 64. Kozlovsky, A. G., Vinokurova, N. G., Adanin, V. M., Burkhardt, G., Dahse, H. M., & Graefe, U., (2000). New diketopiperazine alkaloids from Penicillium fellutanum. Journal of Natural Products, 63(5), 698–700. 65. Byun, H. G., Zhang, H., Mochizuki, M., Adachi, K., Shizuri, Y., Lee, W. J., & Kim, S. K., (2003). Novel antifungal diketopiperazine from marine fungus. Journal of Antibiotics, 56(2), 102–106. 66. Soledade, M., Pedras, C., & Biesenthal, C. J., (2001). Isolation, structure determination, and phytotoxicity of unusual dioxopiperazines from the phytopathogenic fungus Phoma lingam. Phytochemistry, 58(6), 905–909. 67. Yang, S. W., Chan, T. M., Terracciano, J., Loebenberg, D., Chen, G., Patel, M., Gullo, V., et al., (2004). Structure elucidation of a new diketopiperazine Sch 725418 from Micromonospora sp. Journal of Antibiotics, 57(5), 345–347. 68. Fujimoto, H., Fujimaki, T., Okuyama, E., & Yamazaki, M., (1999). Immunomodulatory constituents from an ascomycete, Microascus tardifaciens. Chemical & Pharmaceutical Bulletin, 47(10), 1426–1432.

358

Amino Acids: Insights and Roles in Heterocyclic Chemistry, Volume 2

69. King, R. R., & Calhoun, L. A., (2009). The thaxtomin phytotoxins: Sources, synthesis, biosynthesis, biotransformation and biological activity. Phytochemistry, 70(7), 833–841. 70. Cui, C. B., Kakeya, H., Okada, G., Onose, R., & Osada, H., (1996). Novel mammalian cell cycle inhibitors, tryprostatins A, B and other diketopiperazines produced by Aspergillus fumigatus. I. Taxonomy, fermentation, isolation and biological properties. Journal of Antibiotics, 49(6), 527–533. 71. Woehlecke, H., Osada, H., Herrmann, A., & Lage, H., (2003). Reversal of breast cancer resistance protein–mediated drug resistance by tryprostatin A. International Journal of Cancer, 107(5), 721–728. 72. Zhao, S., Smith, K. S., Deveau, A. M., Dieckhaus, C. M., Johnson, M. A., Macdonald, T. L., & Cook, J. M., (2002). Biological Activity of the tryprostatins and their diastereomers on human carcinoma cell lines. Journal of Medicinal Chemistry, 45(8), 1559–1562. 73. Matsunaga, K., Shizuri, Y., Yamamura, S., Kawai, K., & Furukawa, H., (1991). Isolation and structure of citreoindole, a new metabolite of hybrid strain KO 0052 derived from Penicillium citreo-viride B. IFO 6200 and 4692. Tetrahedron Letters, 32(47), 6883–6884. 74. Larsen, T. O., Petersen, B. O., & Duus, J. O., (2001). Lumpidin, a novel biomarker of some ochratoxin a producing penicillia. Journal of Agricultural and Food Chemistry, 49(10), 5081–5084. 75. Balkbindseil, W., Helmke, E., Weyland, H., & Laatsch, H., (1995). Marine bacteria. Part 8. Maremycin A (Ia) and B (Ib), new diketopiperazine from a marine Streptomyces sp. Liebigs Annalen der Chemie, 7, 1291–1294. 76. Ueda, T., Inada, M., Okamoto, I., Morita, N., & Tamura, O., (2008). Synthesis of maremycins A and D1 via cycloaddition of a nitrone with (E)-3-ethylidene-1­ methylindolin-2-one. Organic Letters, 10(10), 2043–2046. 77. Tang, Y. Q., Sattler, I., Thiericke, R., Grabley, S., & Feng, X. Z., (2001). Maremycins C and D, new diketopiperazines, and maremycins E and F, novel polycyclic spiro-indole metabolites isolated from Streptomyces sp. European Journal of Organic Chemistry, (2), 261–267. 78. Grubbs, A. W., Artman, III. G. D., Tsukamoto, S., & Williams, R. M., (2007). A concise total synthesis of the notoamides C and D. Angewandte Chemie International Edition, 46(13), 2257–2261. 79. Kato, H., Yoshida, T., Tokue, T., Nojiri, Y., Hirota, H., Ohta, T., Williams, R. M., & Tsukamoto, S., (2007). Notoamides A–D: Prenylated indole alkaloids isolated from a marine-derived fungus, Aspergillus sp. Angewandte Chemie International Edition, 46(13), 2254–2256. 80. Finefield, J. M., & Williams, R. M., (2010). Synthesis of notoamide J: A potentially pivotal intermediate in the biosynthesis of several prenylated indole alkaloids. Journal of Organic Chemistry, 75(9), 2785–2789. 81. Stipanovic, R. D., & Schroeder, H. W., (1976). Preechinulin, a metabolite of Aspergillus chevalieri. Transactions of the British Mycological Society, 66(Pt. 1), 178, 179.

2,5-Diketopiperazine

359

82. Du, F. Y., Li, X., Li, X. M., Zhu, L. W., & Wang, B. G., (2017). Indole diketopiperazine alkaloids from Eurotium cristatum EN-220, an endophytic fungus isolated from the marine alga Sargassum thunbergii. Marine Drugs, 15(2), 24/1–24/10. 83. Chen, L., & Gu, Q., (2010). Study on the antitumor metabolites of a sponge-derived fungus, Aspergillus repens. Zhongguo Haiyang Daxue Xuebao, Ziran Kexueban (Periodical of Ocean University of China), 40(5), 69–71. 84. Zin, W. W. M., Buttachon, S., Dethoup, T., Pereira, J. A., Gales, L., Inacio, A., Costa, P. M., et al., (2017). Antibacterial and antibiofilm activities of the metabolites isolated from the culture of the mangrove-derived endophytic fungus Eurotium chevalieri KUFA 0006. Phytochemistry (Elsevier), 141, 86–97. 85. Cui, C. B., Kakeya, H., & Osada, H., (1996). Spirotryprostatin B, a novel mammalian cell cycle inhibitor produced by Aspergillus fumigatus. Journal of Antibiotics, 49(8), 832–835. 86. Cui, C. B., Kakeya, H., & Osada, H., (1996). Novel mammalian cell cycle inhibitors, spirotryprostatins A and B, produced by Aspergillus fumigatus, which inhibit mammalian cell cycle at G2/M phase. Tetrahedron, 52(39), 12651–12666. 87. Osada, H., (1998). Bioprobes for investigating mammalian cell cycle control. Journal of Antibiotics, 51(11), 973–982. 88. Wang, F. Z., Fang, Y. C., Zhu, T. J., Zhang, M., Lin, A. Q., Gu, Q. Q., & Zhu, W. M., (2008). Seven new prenylated indole diketopiperazine alkaloids from holothurianderived fungus Aspergillus Fumigatus. Tetrahedron, 64(34), 7986–7991. 89. Yang, X., Du, L., Tang, X., Jung, S. Y., Zheng, B., Soh, B. Y., Kim, S. Y., et al., (2009). Brevicompanine E reduces lipopolysaccharide-induced production of proinflammatory cytokines and enzymes in microglia by inhibiting activation of activator protein-1 and nuclear factor-κB. Journal of Neuroimmunology, 216(1, 2), 32–38. 90. Takase, S., Kawai, Y., Uchida, I., Tanaka, H., & Aoki, H., (1985). Structure of amauromine, a new hypotensive vasodilator produced by Amauroascus sp. Tetrahedron, 41(15), 3037, 3048. 91. Matsumura, K., & Kitahara, T., (2001). Synthesis of brevicompanines, plant growth regulators. Heterocycles, 54(2), 727–733. 92. Sprogoe, K., Manniche, S., Larsen, T. O., & Christophersen, C., (2005). Janoxepin and brevicompanine B: Antiplasmodial metabolites from the fungus Aspergillus janus. Tetrahedron, 61(36), 8718–8721. 93. Kimura, Y., Sawada, A., Kuramata, M., Kusano, M., Fujioka, S., Kawano, T., & Shimada, A., (2005). Brevicompanine C, Cyclo-(D-Ile-L-Trp), and Cyclo-(D-Leu-L-Trp), plant growth regulators from Penicillium brevicompactum. Journal of Natural Products, 68(2), 237–239. 94. Cui, C. B., Kakeya, H., & Osada, H., (1997). Novel mammalian cell cycle inhibitors, cyclotryprostatins A-D, produced by Aspergillus Fumigatus, which inhibit mammalian cell cycle at G2/M phase. Tetrahedron, 53(1), 59–72. 95. De Guzman, F. S., & Glober, J. B., (1992). New diketopiperazine metabolites from the sclerotia of Aspergillus ochraceus. Journal of Natural Products, 55(7), 931–939.

360

Amino Acids: Insights and Roles in Heterocyclic Chemistry, Volume 2

96. Arai, K., Kimura, K., Mushiroda, T., & Yamamoto, Y., (1989). Structures of fructigenines A and B, new alkaloids isolated from Penicillium fructigenum. Chemical & Pharmaceutical Bulletin, 37(11), 2937–2939. 97. Chang, J. H., & Moon, H. S., (2004). Synthesis and anti-inflammatory activity of fructigenine a derivatives. Biotechnology and Bioprocess Engineering, 9(1), 59–61. 98. Hino, T., & Nakagawa, M., (1997). Total synthesis of fumitremorgins and verruculogens. Heterocycles, 46, 673–704. 99. Rabindran, S. K., Ross, D. D., Doyle, L. A., Yang, W., & Greenberger, L. M., (2000). Fumitremorgin C reverses multidrug resistance in cells transfected with the breast cancer resistance protein. Cancer Research, 60(1), 47–50. 100. Nuber, B., & Hansske, F., (1994). Gypsetin, a new inhibitor of acyl-CoA: Cholesterol acyltransferase produced by Nannizzia gypsea var. Incurvata IFO 9228. II. Structure determination. Journal of Antibiotics, 47(2), 168–172. 101. Taechowisan, T., Wanbanjob, A., Tuntiwachwuttikul, P., & Liu, J., (2009). Antiinflammatory activity of lansais from endophytic Streptomyces sp. SUC1 in LPS-induced RAW 264.7 cells. Food and Agricultural Immunology, 20(1), 67–77. 102. Tuntiwachwuttikul, P., Taechowisan, T., Wanbanjob, A., Thadaniti, S., & Taylor, W. C., (2008). Lansai A-D, secondary metabolites from Streptomyces sp. SUC1. Tetrahedron, 64(32), 7583–7586. 103. Alqahtani, N., Porwal, S. K., James, E. D., Bis, D. M., Karty, J. A., Lane, A. L., & Viswanathan, R., (2015). Synergism between genome sequencing, tandem mass spectrometry and bio-inspired synthesis reveals insights into nocardioazine B biogenesis. Organic & Biomolecular Chemistry, 13, 7177–7192. 104. Raju, R., Piggott, A. M., Huang, X. C., & Capon, R. J., (2011). Nocardioazines: A novel bridged diketopiperazine scaffold from a marine-derived bacterium inhibits P-glycoprotein. Organic Letters, 13(10), 2770–2773. 105. Ishikawa, K., Hosoe, T., Itabashi, T., Wakana, D., Takizawa, K., Yaguchi, T., & Kawai, K. I., (2000). Novoamauromine and ent-cycloechinulin: Two new diketopiperazine derivatives from Aspergillus novofumigatus. Chemical & Pharmaceutical Bulletin, 58(5), 717–719. 106. Steyn, P. S., (1973). Structure of five dioxopiperazines from Aspergillus ustus. Tetrahedron, 29(1), 107–120. 107. Ravikanth, V., Niranjan, R. V. L., Ramesh, P., Prabhakar, R. T., Diwan, P. V., Khar, A., & Venkateswarlu, Y., (2001). An immunosuppressive tryptophan-derived alkaloid from Lepidagathis cristata. Phytochemistry, 58(8), 1263–1266. 108. Rahman, K. M., Hossain, M. D., Sohrab, M. H., Drake, A. F., Bui, T. T., Husby, J., Gunaratnam, M., et al., (2012). The prenylated dioxopiperazine alkaloid cristatin a has selective telomeric DNA G-quadruplex stabilizing properties. Chemical Communications (Cambridge, United Kingdom), 48(70), 8760–8762. 109. Du, F. Y., Li, X. M., Li, C. S., Shang, Z., & Wang, B. G., (2012). Cristatumins A-D, new indole alkaloids from the marine-derived endophytic fungus Eurotium cristatum EN-220. Bioorganic & Medicinal Chemistry Letters, 22(14), 4650–4653.

2,5-Diketopiperazine

361

110. Baran, P. S., & Corey, E. J., (2002). A short synthetic route to (+)-austamide, (+)-deoxyisoaustamide, and (+)-hydratoaustamide from a common precursor by a novel palladium-mediated indole → dihydroindoloazocine cyclization. Journal of the American Chemical Society, 124(27), 7904, 7905. 111. Sorensen, D., Larsen, T. O., Christophersen, C., Nielsen, P. H., & Anthoni, U., (1999). Dipodazine, a diketopiperazine from Penicillium dipodomyis. Phytochemistry, 51(8), 1181–1183. 112. Yagi, R., & Doi, M., (1999). Isolation of an antioxidative substance produced by Aspergillus repens. Bioscience, Biotechnology, and Biochemistry, 63(5), 932–933. 113. Li, Y., Li, X., Kim, S. K., Kang, J. S., Choi, H. D., Rho, J. R., & Son, B. W., (2004). Golmaenone, a new diketopiperazine alkaloid from the marine-derived fungus Aspergillus sp. Chemical & Pharmaceutical Bulletin, 52(3), 375, 376. 114. Maruyama, K., Ohuchi, T., Yoshida, K., Shibata, Y., Sugawara, F., & Arai, T., (2004). Protective properties of neoechinulin A against SIN-1-induced neuronal cell death. Journal of Biochemistry, 136(1), 81–87. 115. Marchelli, R., Dossena, A., Pochini, A., & Dradi, E., (1977). The structures of five new didehydropeptides related to neoechinulin, isolated from Aspergillus amstelodami. Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry, (7), 713–717. 116. Chen, X., Si, L., Liu, D., Proksch, P., Zhang, L., Zhou, D., & Lin, W., (2015). Neoechinulin B and its analogues as potential entry inhibitors of influenza viruses, targeting viral hemagglutinin. European Journal of Medicinal Chemistry, 93, 182–195. 117. Kozlovsky, A., Vinokurova, N. G., Adanin, V. M., & Grafe, U., (2000). Piscarinines, new polycyclic diketopiperazine alkaloids from Penicillium piscarium VKM F-691. Natural Product Letters, 14(5), 333–340. 118. Zhelifonova, V. P., Maier, A., & Kozlovskii, A. G., (2008). Effect of various factors on the biosynthesis of piscarinines, secondary metabolites of the fungus Penicillium piscarium westling. Prikladnaia Biokhimiia i Mikrobiologiia, 44(6), 671–675. 119. Aninat, C., Hayashi, Y., Andre, F., & Delaforge, M., (2001). Molecular requirements for inhibition of cytochrome P450 activities by roquefortine. Chemical Research in Toxicology, 14(9), 1259–1265. 120. Kopp-Holtwiesche, B., & Rehm, H. J., (1990). Antimicrobial action of roquefortine. Journal of Environmental Pathology, Toxicology and Oncology: Official Organ of the International Society for Environmental Toxicology and Cancer, 10(1, 2), 41–44. 121. Clark, B., Capon, R. J., Lacey, E., Tennant, S., & Gill, J. H., (2005). Roquefortine E, A diketopiperazine from an Australian isolate of Gymnoascus reessii. Journal of Natural Products, 68(11), 1661–1664. 122. Meng, L. H., Du, F. Y., Li, X. M., Pedpradab, P., Xu, G. M., & Wang, B. G., (2015). Rubrumazines A-C, indolediketopiperazines of the isoechinulin class from Eurotium rubrum ma-150, a fungus obtained from marine mangrove-derived rhizospheric soil. Journal of Natural Products, 78(4), 909–913.

362

Amino Acids: Insights and Roles in Heterocyclic Chemistry, Volume 2

123. Chu, Y. S., Niu, X. M., Wang, Y. L., Guo, J. P., Pan, W. Z., Huang, X. W., & Zhang, K. Q., (2010). Isolation of putative biosynthetic intermediates of prenylated indole alkaloids from a thermophilic fungus Talaromyces thermophilus. Organic Letters, 12(19), 4356–4359. 124. Komagata, D., Sawa, R., Kinoshita, N., Imada, C., Hamada, M., Okami, Y., & Takeuchi, T., (1992). Isolation of glutathione-S-transferase inhibitors. Journal of Antibiotics, 45(10), 1681–1683. 125. Kakinuma, K., & Rinehart, K. L. Jr., (1974). Tryptophan-dehydrobutyrine diketopiperazine, A metabolite of Streptomyces spectabilis. Journal of Antibiotics, 27(10), 733–737. 126. Gomes, N. M., Dethoup, T., Singburaudom, N., Gales, L., Silva, A. M. S., & Kijjoa, A., (2012). Eurocristatine, a new diketopiperazine dimer from the marine sponge-associated fungus Eurotium cristatum. Phytochemistry Letters, 5(4), 717–720. 127. Yan, H. J., Li, X. M., Li, C. S., & Wang, B. G., (2012). Alkaloid and anthraquinone derivatives produced by the marine-derived endophytic fungus Eurotium rubrum. Helvetica Chimica Acta, 95(1), 163–168. 128. Wang, W. L., Lu, Z. Y., Tao, H. W., Zhu, T. J., Fang, Y. C., Gu, Q. Q., & Zhu, W. M., (2007). Isoechinulin-type alkaloids, variecolorins A-L, from halotolerant Aspergillus variecolor. Journal of Natural Products, 70(10), 1558–1564. 129. Zhou, L. N., Zhu, T. J., Cai, S. X., Gu, Q. Q., & Li, D. H., (2010). Three new indolecontaining diketopiperazine alkaloids from A deep ocean sediment-derived fungus, Penicillium griseofulvum. Helvetica Chimica Acta, 93(9), 1758–1763. 130. Bringmann, G., Lang, G., Steffens, S., & Schaumann, K., (2004). Petrosifungins A and B, novel cyclodepsipeptides from a sponge-derived strain of Penicillium brevicompactum. Journal of Natural Products, 67(3), 311–315. 131. Paterson, R. R. M., Simmonds, M. J. S., Kemmelmeier, C., & Blaney, W. M., (1990). Effects of brevianamide A, its photolysis product brevianamide D, and ochratoxin A from two penicillium strains on the insect pests Spodoptera frugiperda and Heliothis virescens. Mycological Research, 94(4), 538–542. 132. Rand, T. G., Giles, S., Flemming, J., Miller, J. D., & Puniani, E., (2005). Inflammatory and cytotoxic responses in mouse lungs exposed to purified toxins from building isolated Penicillium brevicompactum dierckx and P. chrysogenum Thom. Toxicological Sciences, 87(1), 213–222. 133. Birch, A. J., & Russell, R. A., (1972). Biosynthesis. XLIV. Structural elucidations of brevianamides-B, -C, -D, and -F. Tetrahedron, 28(11), 2999–3008. 134. Williams, R. M., & Glinka, T., (1986). Promising cyclization reactions to construct the ring systems of brevianamides A and B. Tetrahedron Letters, 27(31), 3581–3584. 135. Stocking, E. M., Sanz-Cervera, J. F., Unkefer, C. J., & Williams, R. M., (2001). Studies on the biosynthesis of paraherquamide. Construction of the amino acid framework. Tetrahedron, 57, 5303–5320. 136. Savall, B. M., McWhorter, W. W., & Walker, E. A., (1996). Synthesis of 6,7-dihydroxyoxindole (a subunit of paraherquamide a). Journal of Organic Chemistry, 61(24), 8696–8697.

2,5-Diketopiperazine

363

137. Liesch, J. M., & Wichmann, C. F., (1990). Novel antinematodal and antiparasitic agents from Penicillium charlesii. II. Structure determination of paraherquamides B, C, D, E, F, and G. Journal of Antibiotics, 43(11), 1380–1386. 138. Lopez-Gresa, M. P., Gonzalez, M. C., Ciavatta, L., Ayala, I., Moya, P., & Primo, J., (2006). Insecticidal activity of paraherquamides, paraherquamides, including paraherquamide H and paraherquamide I, two new alkaloids isolated from Penicillium cluniae. Journal of Agricultural and Food Chemistry, 54(8), 2921–2925. 139. Baran, P. S., Hafensteiner, B. D., Ambhaikar, N. B., Guerrero, C. A., & Gallagher, J. D., (2006). Enantioselective total synthesis of avrainvillamide and the stephacidins. Journal of the American Chemical Society, 128(26), 8678–8693. 140. Kato, H., Nakahara, T., Sugimoto, K., Matsuo, K., Kagiyama, I., Frisvad, J. C., Sherman, D. H., et al., (2015). Isolation of notoamide s and enantiomeric 6-epi-stephacidin A from the fungus Aspergillus amoenus: Biogenetic implications. Organic Letters, 17(3), 700–703. 141. Mikkola, R., Andersson, M. A., Hautaniemi, M., & Salkinoja-Salonen, M. S., (2015). Toxic Indole alkaloids avrainvillamide and stephacidin b produced by a biocide tolerant indoor mold Aspergillus westerdijkiae. Toxicon, 99, 58–67. 142. Baran, P. S., Guerrero, C. A., Hafensteiner, B. D., & Ambhaikar, N. B., (2005). Total synthesis of avrainvillamide (CJ-17,665) and stephacidin B. Angewandte Chemie International Edition, 44(25), 3892–3895. 143. Sugie, Y., Hirai, H., Inagaki, T., Ishiguro, M., Kim, Y. J., Kojima, Y., Sakakibara, T., et al., (2001). A new antibiotic CJ-17,665 from Aspergillus ochraceus. Journal of Antibiotics, 54(11), 911–916. 144. Miller, K. A., Welch, T. R., Greshock, T. J., Ding, Y., Sherman, D. H., & Williams, R. M., (2008). Biomimetic total synthesis of malbrancheamide and malbrancheamide B. Journal of Organic Chemistry, 73(8), 3116–3119. 145. Whyte, A. C., Gloer, J. B., Wicklow, D. T., & Dowd, P. F., (1996). Sclerotiamide: A new member of the paraherquamide class with potent antiinsectan activity from the sclerotia of Aspergillus sclerotiorum. Journal of Natural Products, 59(11), 1093–1095. 146. Tsukamoto, S., Kato, H., Samizo, M., Nojiri, Y., Onuki, H., Hirota, H., & Ohta, T., (2008). Notoamides F-K, prenylated indole alkaloids isolated from a marine-derived Aspergillus sp. Journal of Natural Products, 71(12), 2064–2067. 147. Kito, K., Ookura, R., Kusumi, T., Namikoshi, M., & Ooi, T., (2009). X-ray structures of two stephacidins, heptacyclic alkaloids from the marine-derived fungus Aspergillus ostianus. Heterocycles, 78(8), 2101–2106. 148. Chen, M., Shao, C., Zheng, J., & Wang, C., (2013). Indole alkaloids from a gorgonianDerived fungus Aspergillus sp. Zhongguo Keji Lunwen, 8(3), 239–243. 149. Kagiyama, I., Kato, H., Nehira, T., Frisvad, J. C., Sherman, D. H., Williams, R. M., & Tsukamoto, S., (2016). Taichunamides: Prenylated indole alkaloids from Aspergillus taichungensis (IBT 19404). Angewandte Chemie, International Edition, 55(3), 1128–1132.

364

Amino Acids: Insights and Roles in Heterocyclic Chemistry, Volume 2

150. Gardiner, D. M., Waring, P., & Howlett, B. J., (2005). The epipolythiodioxopiperazine (ETP) class of fungal toxins: Distribution, mode of action, functions and biosynthesis. Microbiology (Reading, United Kingdom), 151(4), 1021–1032. 151. Kishi, Y., Fukuyama, T., & Nakatsuka, S., (1973). New method for the synthesis of epidithiodiketopiperazines. Journal of the American Chemical Society, 95(19), 6490–6492. 152. Williams, R. M., & Rastetter, W. H., (1980). Syntheses of the fungal metabolites (±)-gliovictin and (±)-hyalodendrin. Journal of Organic Chemistry, 45(13), 2625–2631. 153. Fukuyama, T., Nakatsuka, S., & Kishi, Y., (1981). Total synthesis of gliotoxin, dehydrogliotoxin and hyalodendrin. Tetrahedron, 37(11), 2045–2078. 154. Wu, Z., Williams, L. J., & Danishefsky, S. J., (2000). A three-step entry to the aspirochlorine family of antifungal agents. Angewandte Chemie, International Edition, 39(21), 3866–3868. 155. Chen, Y., Miao, Z. H., Zhao, W. M., & Ding, J., (2005). The P53 pathway is synergized by P38 MAPK signaling to mediate 11,11’-dideoxyverticillin-induced G2/M arrest. FEBS Letters, 579(17), 3683–3690. 156. Zhang, Y. X., Chen, Y., Guo, X. N., Zhang, X. W., Zhao, W. M., Zhong, L., Zhou, J., et al., (2005). 11,11’-Dideoxy-verticillin: A natural compound possessing growth factor receptor tyrosine kinase-inhibitory effect with anti-tumor activity. Anti-Cancer Drugs, 16(5), 515–524. 157. Chen, Y., Zhang, Y. X., Li, M. H., Zhao, W. M., Shi, Y. H., Miao, Z. H., Zhang, X. W., et al., (2005). Antiangiogenic activity of 11,11’-dideoxyverticillin, a natural product isolated from the fungus Shiraia bambusicola. Biochemical and Biophysical Research Communications, 329(4), 1334–1342. 158. Greiner, D., Bonaldi, T., Eskeland, R., Roemer, E., & Imhof, A., (2005). Identification of a specific inhibitor of the histone methyltransferase SU(VAR)3-9. Nature Chemical Biology, 1(3), 143–145. 159. Iwasa, E., Hamashima, Y., Fujishiro, S., Higuchi, E., Ito, A., Yoshida, M., & Sodeoka, M., (2010). Total synthesis of (+)-chaetocin and its analogues: Their histone methyltransferase G9a inhibitory activity. Journal of the American Chemical Society, 132(12), 4078–4079. 160. Li, G. H., Zhang, K. Q., Xu, J. P., Dong, J. Y., & Liu, Y. J., (2007). Nematicidal substances from fungi. Recent Patents on Biotechnology, 1(3), 212–233. 161. Minato, H., Matsumoto, M., & Katayama, T., (1973). Metabolites of verticillium species. Structures of verticillins A, B, and C. Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry, (17), 1819–1825. 162. Dong, J. Y., He, H. P., Shen, Y. M., & Zhang, K. Q., (2005). Nematicidal epipolysulfanyldioxopiperazines from Gliocladium roseum. Journal of Natural Products, 68(10), 1510–1513. 163. Zheng, C. J., Kim, C. J., Bae, K. S., Kim, Y. H., & Kim, W. G., (2006). Bionectins A-C, epidithiodioxopiperazines with anti-MRSA activity, from Bionectra byssicola F120. Journal of Natural Products, 69(12), 1816–1819.

2,5-Diketopiperazine

365

164. Xu, G. B., He, G., Bai, H. H., Yang, T., Zhang, G. L., Wu, L. W., & Li, G. Y., (2015). Indole alkaloids from Chaetomium globosum. Journal of Natural Products, 78, 1479–1485. 165. Sekita, S., Yoshihira, K., Natori, S., Udagawa, S., Muroi, T., Sugiyama, Y., Kurata, H., & Umeda, M., (1981). Mycotoxin production by Chaetomium species and related fungi. Canadian Journal of Microbiology, 27(8), 766–772. 166. Fujimoto, H., Sumino, M., Okuyama, E., & Ishibashi, M., (2004). Immunomodulatory constituents from an ascomycete, Chaetomium seminudum. Journal of Natural Products, 67(1), 98–102. 167. McInnes, A. G., Taylor, A., & Walter, J. A., (1976). The structure of chetomin. Journal of the American Chemical Society, 98(21), 6741–6741. 168. Kung, A. L., Zabludoff, S. D., France, D. S., Freedman, S. J., Tanner, E. A., Vieira, A., Cornell-Kennon, S., et al., (2004). Small molecule blockade of transcriptional coactivation of the hypoxia-inducible factor pathway. Cancer Cell, 6(1), 33–43. 169. Saito, T., Koyama, K., Natori, S., & Litaka, Y., (1985). Chetracin A, A new epipolythiodioxopiperazine having a tetrasulfide bridge from Chaetomium abuense and C. retardatum. Tetrahedron Letters, 26(39), 4731–4734. 170. Saito, T., Suzuki, Y., Koyama, K., Natori, S., Litaka, Y., & Kinoshita, T., (1988). Chetracin A and Chetocins B and C, three new epipolythiodioxopiperazines from Chaetomium spp. Chemical & Pharmaceutical Bulletin, 36(6), 1942–1956. 171. Li, L., Li, D., Luan, Y., Gu, Q., & Zhu, T., (2012). Cytotoxic metabolites from the antarctic psychrophilic fungus Oidiodendron truncatum. Journal of Natural Products, 75(5), 920–927. 172. Takahashi, C., Numata, A., Ito, Y., Matsumura, E., Araki, H., Iwaki, H., & Kushida, K., (1994). Leptosins, antitumor metabolites of a fungus isolated from a marine alga. Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry, (13), 1859–1864. 173. Yanagihara, M., Sasaki-Takahashi, N., Sugahara, T., Yamamoto, S., Shinomi, M., Yamashita, I., Hayashida, M., et al., (2005). Leptosins isolated from marine fungus Leptoshaeria species inhibit DNA topoisomerases I and/or II and induce apoptosis by inactivation of Akt/protein kinase B. Cancer Science, 96(11), 816–824. 174. Takahashi, C., Minoura, K., Yamada, T., Numata, A., Kushida, K., Shingu, T., Hagishita, S., et al., (1995). Potent cytotoxic metabolites from a Leptosphaeria species. Structure determination and conformational analysis. Tetrahedron, 51(12), 3483–3498. 175. Yamada, T., Iwamoto, C., Yamagaki, N., Yamanouchi, T., Minoura, K., Yamori, T., Uehara, Y., et al., (2002). Leptosins M-N1, cytotoxic metabolites from a Leptosphaeria Species separated from a marine alga. Structure determination and biological activities. Tetrahedron, 58(3), 479–487. 176. Joshi, B. K., Gloer, J. B., & Wicklow, D. T., (1999). New verticillin and glisoprenin analogs from Gliocladium catenulatum, a mycoparasite of Aspergillus flavus sclerotia. Journal of Natural Products, 62(5), 730–733. 177. Ebrahim, W., Kjer, J., El Amrani, M., Wray, V., Lin, W., Ebel, R., Lai, D., & Proksch, P., (2012). Pullularins E and F, two new peptides from the endophytic fungus Bionectria

366

Amino Acids: Insights and Roles in Heterocyclic Chemistry, Volume 2

ochroleuca isolated from the mangrove plant. Sonneratia caseolaris. Marine Drugs, 10, 1081–1091. 178. Zheng, C. J., Park, S. H., Koshino, H., Kim, Y. H., & Kim, W. G., (2007). Verticillin G, A new antibacterial compound from Bionectria byssicola. Journal of Antibiotics, 61(1), 61–64. 179. Rank, C., Klejnstrup, M. L., Petersen, L. M., Kildgaard, S., Frisvad, J. C., Gotfredsen, C. H., & Larsen, T. O., (2012). Comparative chemistry of Aspergillus oryzae (RIB40) and A. flavus (NRRL 3357). Metabolites, 2(1), 39–56. 180. Saruwatari, T., Yagishita, F., Mino, T., Noguchi, H., Hotta, K., & Watanabe, K., (2014). Cytochrome P450 as dimerization catalyst in diketopiperazine alkaloid biosynthesis. ChemBioChem, 15(5), 656–659. 181. Varoglu, M., Corbett, T. H., Valeriote, F. A., & Crews, P., (1997). Asperazine, a selective cytotoxic alkaloid from a sponge-derived culture of Aspergillus Niger. Journal of Organic Chemistry, 62(21), 7078, 7079. 182. Varoglu, M., & Crews, P., (2000). Biosynthetically diverse compounds from a saltwater culture of sponge-derived Aspergillus Niger. Journal of Natural Products, 63(1), 41–43. 183. Ding, G., Jiang, L., Guo, L., Chen, X., Zhang, H., & Che, Y., (2008). Pestalazines and pestalamides, bioactive metabolites from the plant pathogenic fungus Pestalotiopsis theae. Journal of Natural Products, 71(11), 1861–1865. 184. Ovenden, S. P. B., Sberna, G., Tait, R. M., Wildman, H. G., Patel, R., Li, B., Steffy, K., et al., (2004). A diketopiperazine dimer from a marine-derived isolate of Aspergillus Niger. Journal of Natural Products, 67(12), 2093–2095. 185. Perez-Balado, C., Rodriguez-Grana, P., & De Lera, A. R., (2009). Stereo controlled and versatile total synthesis of bispyrrolidinoindoline diketopiperazine alkaloids: Structural revision of the fungal isolate (+)-asperdimin. Chemistry – A European Journal, 15(38), 9928–9937, S9928/1–S9928/74. 186. Ruiz-Sanchis, P., Savina, S. A., Albericio, F., & Alvarez, M., (2011). Structure, bioactivity and synthesis of natural products with hexahydropyrrolo[2,3-b]indole. Chemistry – A European Journal, 17(5), 1388–1408. 187. Li, Y., Sun, K. L., Wang, Y., Fu, P., Liu, P. P., Wang, C., & Zhu, W. M., (2013). A cytotoxic pyrrolidinoindoline diketopiperazine dimer from the algal fungus Eurotium herbariorum HT-2. Chinese Chemical Letters, 24(12), 1049–1052. 188. Raju, R., Piggott, A. M., Conte, M., Aalbersberg, W. G. L., Feussner, K., & Capon, R. J., (2009). Naseseazines A and B: A new dimeric diketopiperazine framework from a marine-derived actinomycete, Streptomyces sp. Organic Letters, 11(17), 3862–3865. 189. Xiong, Z. Q., Liu, Q. X., Pan, Z. L., Zhao, N., Feng, Z. X., & Wang, Y., (2015). Diversity and bioprospecting of culturable actinomycetes from marine sediment of the yellow sea, China. Archives of Microbiology, 197(2), 299–309. 190. Barrow, C. J., Cai, P., Snyder, J. K., Sedlock, D. M., Sun, H. H., & Cooper, R., (1993). WIN 64821, a new competitive antagonist to substance P, isolated from An Aspergillus species: Structure determination and solution conformation. Journal of Organic Chemistry, 58(22), 6016–6021.

2,5-Diketopiperazine

367

191. Cai, S., Kong, X., Wang, W., Zhou, H., Zhu, T., Li, D., & Gu, Q., (2012). Aspergilazine A, A diketopiperazine dimer with a rare N-1 to C-6 linkage, from a marine-derived fungus Aspergillus taichungensis. Tetrahedron Letters, 53(21), 2615–2617. 192. Yamada, T., Iwamoto, C., Yamagaki, N., Yamanouchi, T., Minoura, K., Hagishita, S., & Numata, A., (2004). Leptosins O-S, cytotoxic metabolites of a strain of Leptosphaeria sp. isolated from a marine alga. Heterocycles, 63(3), 641–653. 193. Cho, J. Y., Kang, J. Y., Hong, Y. K., Baek, H. H., Shin, H. W., & Kim, M. S., (2012). Isolation and structural determination of the antifouling diketopiperazines from marinederived Streptomyces praecox 291-11. Bioscience, Biotechnology, and Biochemistry, 76(6), 1116–1121. 194. Ou, Y. X., Huang, J. F., Li, X. M., Kang, Q. J., & Pan, Y. T., (2016). Three new 2,5-diketopiperazines from the fish intestinal Streptomyces sp. MNU FJ-36. Natural Product Research, 30(15), 1771–1775. 195. Goering, A. W., Li, J., McClure, R. A., Thomson, R. J., Jewett, M. C., & Kelleher, N. L., (2017). In vitro reconstruction of nonribosomal peptide biosynthesis directly from DNA using cell-free protein synthesis. ACS Synthetic Biology, 6(1), 39–44. 196. Kumar, N., Mohandas, C., Nambisan, B., Kumar, D. R. S., & Lankalapalli, R. S., (2013). Isolation of proline-based cyclic dipeptides from Bacillus Sp. N strain associated with rhabitid entomopathogenic nematode and its antimicrobial properties. World Journal of Microbiology & Biotechnology, 15(2), 203–208. 197. Klausmeyer, P., Howard, O. M. Z., Shipley, S. M., & McCloud, T. G., (2009). An inhibitor of CCL2-induced chemotaxis from the fungus Leptoxyphium sp. Journal of Natural Products, 72(8), 1369–1372. 198. McCleland, K., Milne, P. J., Lucieto, F. R., Frost, C., Brauns, S. C., Van De, V. M., Du Plessis, J., & Dyason, K., (2004). An investigation into the biological activity of the selected histidine-containing diketopiperazines cyclo(His-Phe) and cyclo(His-Tyr). Journal of Pharmacy and Pharmacology, 56(9), 1143–1153. 199. Jiang, L., Wen, H., Shao, Y., Yu, R., Liu, Z., Wang, S., Wang, Q., et al., (2015). Novel diketopiperazine dihydroorotate dehydrogenase inhibitors purified from traditional Tibetan animal medicine osteon myospalacem baileyi. Chemical Biology & Drug Design, 86(4), 626–636. 200. Stark, T., Bareuther, S., & Hofmann, T., (2006). Molecular definition of the taste of roasted cocoa nibs (Theobroma cacao) by means of quantitative studies and sensory experiments. Journal of Agricultural and Food Chemistry, 54(15), 5530–5539. 201. Bofinger, M. R., De Sousa, L. S., Fontes, J. E. N., & Marsaioli, A. J., (2017). Diketopiperazines as cross-communication quorum-sensing signals between Cronobacter sakazakii and Bacillus cereus. ACS Omega, 2(3), 1003–1008. 202. Lee, M. S., Wang, S. W., Wang, G. J., Pang, K. L., Lee, C. K., Kuo, Y. H., Cha, H. J., Lin, R. K., & Lee, T. H., (2016). Angiogenesis inhibitors and anti-inflammatory agents from Phoma sp. NTOU4195. Journal of Natural Products, 79(12), 2983–2990.

368

Amino Acids: Insights and Roles in Heterocyclic Chemistry, Volume 2

203. Zhu, S., Wu, H., Zeng, M., Liu, Z., & Wang, Y., (2015). The involvement of bacterial quorum sensing in the spoilage of refrigerated Litopenaeus vannamei. International Journal of Food Microbiology, 192, 26–33. 204. Xu, W., Ding, Z. G., Li, M. G., Wen, M. L., & Zhao, J. Y., (2014). Study on secondary metabolites of Nocardiopsis sp. YIM 90087. Tianran Chanwu Yanjiu Yu Kaifa (Natural Product Research and Development), 26(8), 1198–1201, 1211. 205. Liu, B., Wang, S. M., Wang, B. L., Xu, Y. T., Yan, E. L., Hu, X. G., & Liang, S. W., (2015). Anticoagulant activity of cyclic dipeptides from Sparganii rhizome. Zhongchengyao, 37(1), 34–39. 206. Huang, Z., Yang, J., She, Z., & Lin, Y., (2012). A new isoflavone from the mangrove endophytic fungus Fusarium sp. (ZZF60). Natural Product Research, 26(1), 11–15. 207. Kilian, G., Jamie, H., Brauns, S. C. A., Dyason, K., & Milne, P. J., (2005). Biological activity of selected tyrosine-containing 2,5-diketopiperazines. Pharmazie, 60(4), 305–309. 208. Li, S. Q., Yang, Y. B., Yang, X. Q., Jiang, Y., Li, Z. J., Li, X. Z., Chen, X., et al., (2016). Two new cyclic tetrapeptides of Streptomyces rutgersensis T009 isolated from elaphodus davidianus excrement. Helvetica Chimica Acta, 99(3), 210–214. 209. Dourtoglou, E. G., Marinea, M., Filandra, K., Bratakos, S., & Dourtoglou, V. G., (2012). Diketopiperazines in wine. Bulletin de L’O.I.V., 85(980, 981, 982), 459–467. 210. Liu, H. B., Gao, H., Wang, N. L., Lin, H. P., Hong, K., & Yao, X. S., (2007). Cyclic dipeptide constituents from the mangrove fungus Penicillium oxalicum. Shenyang Yaoke Daxue Xuebao, 24(8), 474–478. 211. Bobylev, M. M., Bobyleva, L. I., Cutler, H. G., Cutler, S. J., & Strobel, G. A., (1999). Growth regulating activity of maculosin analogs in the etiolated wheat coleoptile bioassay (Triticum aestivum L. Cv. wakeland). PGRSA Quarterly, 27(4), 105–118. 212. Qi, S., Qian, P., & Zhang, S., (2009). Antibacterial metabolites from marine bacterium Pseudomonas sp. Tianran Chanwu Yanjiu Yu Kaifa, 21(3), 420–423. 213. Alvarez, M. E., Houck, D. R., White, C. B., Brownell, J. E., Bobko, M. A., Rodger, C. A., Stawicki, M. B., et al., (1994). Isolation and structure elucidation of two new calpain inhibitors from Streptomyces griseus. The Journal of Antibiotics, 47(11), 1195–1201. 214. Donkor, I. O., & Sanders, M. L., (2001). Synthesis of a reported calpain inhibitor isolated from Streptomyces griseus. Bioorganic & Medicinal Chemistry Letters, 11(19), 2647–2649. 215. Arnone, A., Capelli, S., Nasini, G., Valdo, M. S., & Vajna De, P. O., (1996). Secondary mold metabolites. Part 52. Structure elucidation of diatretol. A new diketopiperazine metabolite from the fungus Clitocybe Diatreta. Liebigs Annalen, (11), 1875–1877. 216. Chen, X. L., Wu, M., Ti, H. H., Wei, X. Y., & Li, T. H., (2011). Three new 3,6-dioxygenated diketopiperazines from the basidiomycete Lepista sordida. Helvetica Chimica Acta, 94(8), 1426–1430. 217. Li, X. J., Gao, J. M., Chen, H., Zhang, A. L., & Tang, M., (2012). Toxins from a symbiotic fungus, Leptographium qinlingensis associated with Dendroctonus armandi and their in vitro toxicities to Pinus armandi seedlings. European Journal of Plant Pathology, 134(2), 239–247.

2,5-Diketopiperazine

369

218. Cochrane, J. R., White, J. M., Wille, U., & Hutton, C. A., (2012). Total synthesis of mycocyclosin. Organic Letters, 14(9), 2402–2405. 219. Brooks, T. D., Wang, S. W., Bruenner, N., & Charlton, P. A., (2004). XR5967, a novel modulator of plasminogen activator inhibitor-1 activity, suppresses tumor cell invasion and angiogenesis in vitro. Anti-Cancer Drugs, 15(1), 37–44. 220. Wang, S., Golec, J., Miller, W., Milutinovic, S., Folkes, A., Williams, S., Brooks, T., et al., (2002). Novel inhibitors of plasminogen activator inhibitor-1: Development of new templates from diketopiperazines. Bioorganic & Medicinal Chemistry Letters, 12(17), 2367–2370. 221. Folkes, A., Roe, M. B., Sohal, S., Golec, J., Faint, R., Brooks, T., & Charlton, P., (2001). Synthesis and in vitro evaluation of a series of diketopiperazine inhibitors of plasminogen activator inhibitor-1. Bioorganic & Medicinal Chemistry Letters, 11(19), 2589–2592. 222. Li, Y., Lai, Y. M., Lu, Y., Yang, Y. L., & Chen, S., (2014). Analysis of the biosynthesis of antibacterial cyclic dipeptides in Nocardiopsis alba. Archives of Microbiology, 196(11), 765–774. 223. Gondry, M., Lautru, S., Fusai, G., Meunier, G., Menez, A., & Genet, R., (2001). Cyclic dipeptide oxidase from streptomyces noursei: Isolation, purification and partial characterization of a novel, amino acyl α,β-dehydrogenase. European Journal of Biochemistry, 268(6), 1712–1721. 224. Kanoh, K., Kohno, S., Katada, J., Hayashi, Y., Muramatsu, M., & Uno, I., (1999). Antitumor activity of phenylahistin in vitro and in vivo. Bioscience, Biotechnology, and Biochemistry, 63(6), 1130–1133. 225. Yamazaki, Y., Kohno, K., Yasui, H., Kiso, Y., Neuteboom, S., Barral, A. M., Potts, B., et al., (2009). Synthesis of biotin-tagged diketopiperazine-based anti-microtubule agents and tubulin photoaffinity labeling. Advances in Experimental Medicine and Biology, 611(Peptides for Youth), 527–528. 226. Liao, S., Qin, X., Li, D., Tu, Z., Li, J., Zhou, X., Wang, J., et al., (2014). Design and synthesis of novel soluble 2,5-diketopiperazine derivatives as potential anticancer agents. European Journal of Medicinal Chemistry, 83, 236–244. 227. Harinantenaina, R. L., Rasolomampianina, R., Park, H. Y., Li, J., Slebodnik, C., Brodie, P. J., Blasiak, L. C., et al., (2015). Antiproliferative and antiplasmodial compounds from selected Streptomyces species. Bioorganic & Medicinal Chemistry Letters, 25(23), 5646–5649. 228. Ogasawara, M., Hasegawa, M., Hamagishi, Y., Kamel, H., & Oki, T., (1992). Potentiation of vincristine cytotoxicity by rubiginone B1 and piperafizine a in human Moser and K562 cells – mode of action. Journal of Antibiotics, 45(1), 129–132. 229. Kamei, H., Oka, M., Hamagishi, Y., Tomita, K., Konishi, M., & Oki, T., (1990). Piperafizines A and B, potentiators of cytotoxicity of vincristine. Journal of Antibiotics, 43(8), 1018–1020. 230. Kanzaki, H., Yanagisawa, S., Kanoh, K., & Nitoda, T., (2002). A novel potent cell cycle inhibitor dehydrophenylahistin: Enzymatic synthesis and inhibitory activity toward sea urchin embryo. Journal of Antibiotics, 55(12), 1042–1047.

370

Amino Acids: Insights and Roles in Heterocyclic Chemistry, Volume 2

231. Meng, L. H., Wang, C. Y., Mándi, A., Li, X. M., Hu, X. Y., Kassack, M. U., Kurtán, T., & Wang, B. G., (2016). Three diketopiperazine alkaloids with spirocyclic skeletons and one bisthiodiketopiperazine derivative from the mangrove-derived endophytic fungus Penicillium brocae MA-231. Organic Letters, 18, 5304–5307. 232. Charlton, P. A., Faint, R. W., Bent, F., Bryans, J., Chicarelli-Robinson, I., Mackie, I., Machin, S., & Bevan, P., (1996). Evaluation of a low molecular weight modulator of human plasminogen activator inhibitor-1 activity. Thrombosis and Haemostasis, 75(5), 808–815. 233. Gils, A., Stassen, J. M., Nar, H., Kley, J. T., Wienen, W., Ries, U. J., & Declerck, P. J., (2002). Characterization and comparative evaluation of a novel PAI-1 inhibitor. Thrombosis and Haemostasis, 88(1), 137–143. 234. Sun, M., Chen, X., Li, W., Lu, C., & Shen, Y., (2017). New diketopiperazine derivatives with cytotoxicity from Nocardiopsis sp. YIM M13066. Journal of Antibiotics, 70(6), 795–797. 235. Bryans, J., Charlton, P., Chicarelli-Robinson, I., Collins, M., Faint, R., Latham, C., Shaw, I., & Trew, S., (1996). Inhibition of plasminogen activator inhibitor-1 activity by two diketopiperazines, XR330 and XR334 produced by Streptomyces sp. Journal of Antibiotics, 49(10), 1014–1021. 236. Mistry, P., Plumb, J., Eccles, S., Watson, S., Dale, I., Ryder, H., Box, G., et al., (1999). In vivo efficacy of XR9051, a potent modulator of P-glycoprotein mediated multidrug resistance. British Journal of Cancer, 79 (11/12), 1672–1678. 237. Nicolaou, K. C., Lu, M., Totokotsopoulos, S., Heretsch, P., Giguere, D., Sun, Y. P., Sarlah, D., et al., (2012). Synthesis and biological evaluation of epidithio-, epitetrathio-, and bis-(methylthio)diketopiperazines: Synthetic methodology, enantioselective total synthesis of epicoccin G, 8,8’-epi-ent-Rostratin B, gliotoxin, gliotoxin G, emethallicin E, and haematocin and discovery of new antiviral and antimalarial agents. Journal of the American Chemical Society, 134(41), 17320–17332. 238. Neuss, N., Boeck, L. D., Brannon, D. R., Cline, J. C., DeLong, D. C., Gorman, M., Huckstep, L. L., et al., (1968). Aranotin and related metabolites from Arachniotus aureus (Eidam) schroeter. IV. Fermentation, isolation, structure elucidation, biosynthesis, and antiviral properties. Antimicrobial Agents and Chemotherapy, 8, 213–219. 239. DeLong, D. C., Nelson, J. D., Cline, J. C., Neuss, N., & Ho, P. P. K., (1970). Mode of antiviral action of aranotin and related metabolites. Progr. Antimicrob. Anticancer Chemother., Proc. Int. Congr. Chemother., 2, 53–56. 240. Chankhamjon, P., Boettger-Schmidt, D., Scherlach, K., Urbansky, B., Lackner, G., Kalb, D., Dahse, H. M., et al., (2014). Biosynthesis of the halogenated mycotoxin aspirochlorine in koji mold involves a cryptic amino acid conversion. Angewandte Chemie, International Edition, 53(49), 13409–13413. 241. Klausmeyer, P., McCloud, T. G., Tucker, K. D., Cardellina, J. H. II., & Shoemaker, R. H., (2005). Aspirochlorine class compounds from Aspergillus flavus inhibit azole-resistant candida albicans. Journal of Natural Products, 68(8), 1300–1302.

2,5-Diketopiperazine

371

242. Monti, F., Ripamonti, F., Hawser, S. P., & Islam, K., (1999). Aspirochlorine: a highly selective and potent inhibitor of fungal protein synthesis. Journal of Antibiotics, 52(3), 311–318. 243. Meng, L. H., Li, X. M., Lv, C. T., Huang, C. G., & Wang, B. G., (2014). Brocazines A-F, cytotoxic bisthiodiketopiperazine derivatives from Penicillium brocae MA-231, an endophytic fungus derived from the marine mangrove plant Avicennia marina. Journal of Natural Products, 77(8), 1921–1927. 244. Choi, E. J., Park, J. S., Kim, Y. J., Jung, J. H., Lee, J. K., Kwon, H. C., & Yang, H. O., (2011). Apoptosis-inducing effect of diketopiperazine disulfides produced by Aspergillus sp. KMD 901 isolated from marine sediment on HCT116 colon cancer cell lines. Journal of Applied Microbiology, 110(1), 304–313. 245. Nazawa, K., Seya, H., Nakajima, S., Kawai, K., Norizuki, K., Udagawa, S., & Yamazaki, M., (1986). Antifungal epidithiodioxopiperazine derivative, emestrin, and its related compounds from Emericella spp. Tennen Yuki Kagobutsu Toronkai Koen Yoshishu, (28), 41–48. 246. Kawai, K., & Nozawa, K., (1989). Novel biologically active compounds from Emericella species. Bioactive Molecules, 10(Mycotoxins Phycotoxins’ 88), 205–212. 247. Kawahara, N., Nozawa, K., Yamazaki, M., Nakajima, S., & Kawai, K., (1990). Studies on fungal products. Part 32. Novel epidithiodioxopiperazines, emethallicins E and F, from Emericella heterothallica. Heterocycles, 30 (1, Spec. Issue), 507–515. 248. Wang, J. M., Ding, G. Z., Fang, L., Dai, J. G., Yu, S. S., Wang, Y. H., Chen, X. G., et al., (2010). Thiodiketopiperazines produced by the endophytic fungus Epicoccum nigrum. Journal of Natural Products, 73(7), 1240–1249. 249. Chunyu, W. X., Ding, Z. G., Zhao, J. Y., Wang, Y. X., Han, X. L., Li, M. G., & Wen, M. L., (2017). Two new diketopiperazines from the tin mine tailings-derived fungus Schizophyllum commune YIM DT 10058. Natural Product Research, 31(13), 1566–1572. 250. Herath, K., Jayasuriya, H., Zink, D. L., Sigmund, J., Vicente, F., De La Cruz, M., Basilio, A., et al., (2012). Isolation, structure elucidation, and antibacterial activity of methiosetin, a tetramic acid from a tropical sooty mold (Capnodium sp.). Journal of Natural Products, 75(3), 420–424. 251. Baute, R., Deffieux, G., Baute, M. A., Filleau, M. J., & Neveu, A., (1976). A new fungal metabolite of the 3,6-epidithio-2,5-dioxopiperazine group: Epicorazine A, isolated from the trunk of Epicoccum nigrum link (adelomycetes). Tetrahedron Letters, (44), 3943, 3944. 252. Brown, A. E., Finlay, R., & Ward, J. S., (1987). Antifungal compounds produced by epicoccum purpurascens against soil-borne plant pathogenic fungi. Soil Biology & Biochemistry, 19(6), 657–664. 253. Kleinwachter, P., Dahse, H. M., Luhmann, U., Schlegel, B., & Dornberger, K., (2001). Epicorazine C, an antimicrobial metabolite from Stereum hirsutum HKI 0195. Journal of Antibiotics, 54(6), 521–525. 254. Kim, Y. J., Park, H. B., Yoo, J. H., Kwon, H. C., Kim, J., & Yang, H. O., (2014). Glionitrin A, a new diketopiperazine disulfide, activates ATM-ATR-Chk1/2 via 53BP1

372

Amino Acids: Insights and Roles in Heterocyclic Chemistry, Volume 2

phosphorylation in DU145 cells and shows antitumor effect in xenograft model. Biological & Pharmaceutical Bulletin, 37(3), 378–386. 255. Zhang, H., Liu, R., Yang, J., Li, H., & Zhou, F., (2017). Bioactive alkaloids of Aspergillus fumigatus, an endophytic fungus from Astragalus membranaceus. Chemistry of Natural Compounds, 53(4), 802–805. 256. Scharf, D. H., Brakhage, A. A., & Mukherjee, P. K., (2016). Gliotoxin – bane or boon? Environmental Microbiology, 18(4), 1096–1109. 257. Schlam, D., Canton, J., Carreno, M., Kopinski, H., Freeman, S. A., Grinstein, S., & Fairn, G. D., (2016). Gliotoxin suppresses macrophage immune function by subverting phosphatidylinositol 3,4,5-trisphosphate homeostasis. mBio, 7(2), e02242-15/–e02242-15/15. 258. Luo, X., Zhou, X., Lin, X., Qin, X., Zhang, T., Wang, J., Tu, Z., et al., (2017). Antituberculosis compounds from A deep-sea-derived fungus Aspergillus sp. SCSIO Ind09F01. Natural Product Research, 31(16), 1958–1962. 259. Kirby, G. W., Rao, G. V., Robins, D. J., & Stark, W. M., (1986). Partial synthesis of gliotoxin G, an epitetrathiodioxopiperazine. Tetrahedron Letters, 27(45), 5539–5540. 260. Waring, P., Eichner, R. D., Palni, U. T., & Mullbacher, A., (1986). The isolation and identification of a new metabolite from Aspergillus fumigatus related to gliotoxin. Tetrahedron Letters, 27(6), 735–738. 261. Sun, Y., Takada, K., Takemoto, Y., Yoshida, M., Nogi, Y., Okada, S., & Matsunaga, S., (2012). Gliotoxin analogs from a marine-derived fungus, Penicillium sp., and their cytotoxic and histone methyltransferase inhibitory activities. Journal of Natural Products, 75(1), 111–114. 262. Onodera, H., Hasegawa, A., Tsumagari, N., Nakai, R., Ogawa, T., & Kanda, Y., (2004). MPC1001 and its analogs: New antitumor agents from the fungus Cladorrhinum sp. Organic Letters, 6(22), 4101–4104. 263. Ando, S., Burrows, J., & Koide, K., (2017). Synthesis of violaceic acid and related compounds through aryl triazene. Organic Letters, 19(5), 1116–1119. 264. Dong, S., Indukuri, K., Clive, D. L. J., & Gao, J. M., (2016). Synthesis of models of the BC ring systems of MPC1001 and MPC1001F. Chemical Communications (Cambridge, United Kingdom), 52(53), 8271–8274. 265. Wang, L., & Clive, D. L. J., (2012). Synthetic studies related to MPC1001: Formation of a model epidithiodiketopiperazine. Tetrahedron Letters, 53(12), 1504–1506. 266. Kong, F., Wang, Y., Liu, P., Dong, T., & Zhu, W., (2014). Thiodiketopiperazines from the marine-derived fungus Phoma sp. OUCMDZ-1847. Journal of Natural Products, 77(1), 132–137. 267. Tan, R. X., Jensen, P. R., Williams, P. G., & Fenical, W., (2004). Isolation and structure assignments of rostratins A-D, cytotoxic disulfides produced by the marine-derived fungus Exserohilum rostratum. Journal of Natural Products, 67(8), 1374–1382. 268. Ernst-Russell, M. A., Chai, C. L. L., Hurne, A. M., Waring, P., Hockless, D. C. R., & Elix, J. A., (1999). Structure revision and cytotoxic activity of the scabrosin esters,

2,5-Diketopiperazine

373

epidithiopiperazinediones from the lichen Xanthoparmelia scabrosa. Australian Journal of Chemistry, 52(4), 279–283. 269. Moerman, K. L., Chai, C. L. L., & Waring, P., (2003). Evidence that the lichen-derived scabrosin esters target mitochondrial ATP synthase in P388D1 cells. Toxicology and Applied Pharmacology, 190(3), 232–240. 270. Hegde, V. R., Dai, P., Patel, M., Das, P. R., & Puar, M. S., (1997). Novel thiodiketopiperazine fungal metabolites as epidermal growth factor receptor antagonists. Tetrahedron Letters, 38(6), 911–914. 271. Narita, K., Atsumi, S., & Katoh, T., (2013). Synthetic studies on vertihemiptellide A, a potential antituberculosis agent: synthesis of bis-sulfenylated diketopiperazine derivative. Journal of Tohoku Pharmaceutical University, 60, 55–63. 272. Isaka, M., Palasarn, S., Rachtawee, P., Vimuttipong, S., & Kongsaeree, P., (2005). Unique diketopiperazine dimers from the insect pathogenic fungus verticillium hemipterigenum body centered cubic 1449. Organic Letters, 7(11), 2257–2260. 273. Owens, R. A., O’Keeffe, G., Smith, E. B., Dolan, S. K., Hammel, S., Sheridan, K. J., Fitzpatrick, D. A., et al., (2015). Interplay between gliotoxin resistance, secretion, and the methyl/methionine cycle in Aspergillus fumigatus. Eukaryotic Cell, 14(9), 941–957. 274. Duell, E. R., Glaser, M., Le Chapelain, C., Antes, I., Groll, M., & Huber, E. M., (2016). Sequential inactivation of gliotoxin by the S-methyltransferase TmtA. ACS Chemical Biology, 11(4), 1082–1089. 275. Vidal-Garcia, M., Domingo, M. P., De Rueda, B., Roc, L., Delgado, M. P., Revillo, M. J., Pardo, J., et al., (2016). Clinical validity of bis(methylthio)gliotoxin for the diagnosis of invasive aspergillosis. Applied Microbiology and Biotechnology, 100(5), 2327–2334. 276. Rodrigues, B. S. F., Sahm, B. D. B., Jimenez, P. C., Pinto, F. C. L., Mafezoli, J., Mattos, M. C., Rodrigues-Filho, E., et al., (2015). Bioprospection of cytotoxic compounds in fungal strains recovered from sediments of the Brazilian coast. Chemistry & Biodiversity, 12(3), 432–442. 277. Gu, B., He, S., Chen, J., Zhang, J., Zhang, Y., Dong, J., Ding, L., et al., (2015). Preparative separation of sulfur-containing diketopiperazines from marine fungus Cladosporium sp. Using high-speed counter-current chromatography in stepwise elution mode. Marine Drugs, 13(1), 354–365. 278. Hoepfner, D., McNamara, C. W., Lim, C. S., Studer, C., Riedl, R., Aust, T., McCormack, S. L., et al., (2012). Selective and specific inhibition of the plasmodium falciparum Lysyl-tRNA synthetase by the fungal secondary metabolite cladosporin. Cell Host & Microbe, 11(6), 654–663. 279. Nicolaou, K. C., Totokotsopoulos, S., Giguere, D., Sun, Y. P., & Sarlah, D., (2011). Total synthesis of epicoccin G. Journal of the American Chemical Society, 133(21), 8150–8153. 280. Sugawara, K., Sugawara, F., Strobel, G. A., Fu, Y., He, C. H., & Clardy, J., (1985). Exserohilone: a novel phytotoxin produced by Exserohilum holmii. Journal of Organic Chemistry, 50(26), 5631–5633.

374

Amino Acids: Insights and Roles in Heterocyclic Chemistry, Volume 2

281. Suzuki, Y., Takahashi, H., Esumi, Y., Arie, T., Morita, T., Koshino, H., Uzawa, J., Uramoto, M., & Yamaguchi, I., (2000). Haematocin, a new antifungal diketopiperazine produced by Nectria haematococca berk. et Br. (880701a-1) causing Nectria blight disease on ornamental plants. Journal of Antibiotics, 53(1), 45–49. 282. Brack, C., Mikolasch, A., & Schauer, F., (2014). 2,5-Diketopiperazines produced by Bacillus pumilus during bacteriolysis of Arthrobacter citreus. Marine Biotechnology, 16, 385–395. 283. Puopolo, G., Cimmino, A., Palmieri, M. C., Giovannini, O., Evidente, A., & Pertot, I., (2014). Lysobacter capsici AZ78 produces cyclo(L-Pro-L-Tyr), a 2,5-diketopiperazine with toxic activity against sporangia of Phytophthora infestans and Plasmopara viticola. Journal of Applied Microbiology, 117(4), 1168–1180. 284. Martins, M. B., & Carvalho, I., (2007). Diketopiperazines: biological activity and synthesis. Tetrahedron, 63, 9923–9932. 285. Zhang, T. D., Shi, Y. Z., Ye, Z. W., Guo, L. Q., & Lin, J. F., (2013). Isolation and characterization of an antimicrobial compound produced by Lactobacillus casei C7-2. Journal of Pure & Applied Microbiology, 7(4), 3037–3042. 286. Parrish, D. A., & Mathias, L. J., (2002). Five- and six-membered ring opening of pyroglutamic diketopiperazine. Journal of Organic Chemistry, 67(6), 1820–1826. 287. Wang, Y. C., Zhang, Y. W., Zheng, L. H., Bao, Y. L., Wu, Y., Yu, C. L., Sun, L. G., et al., (2013). A new compound from liquid fermentation broth of Armillaria mellea and the determination of its absolute configuration. Journal of Asian Natural Products Research, 15(2), 203–208. 288. Wauters, I., Goossens, H., Delbeke, E., Muylaert, K., Roman, B. I., Van, H. K., Van, S. V., & Stevens, C. V., (2015). Beyond the diketopiperazine family with alternatively bridged brevianamide F analogues. Journal of Organic Chemistry, 80, 8046–8054. 289. Sugimoto, K., Sadahiro, Y., Kagiyama, I., Kato, H., Sherman, D. H., Williams, R. M., & Tsukamoto, S., (2017). Isolation of amoenamide a and five antipodal prenylated alkaloids from Aspergillus amoenus NRRL 35600. Tetrahedron Letters, 58(29), 2797–2800. 290. Kawai, K., Nozawa, K., Seya, H., Kawahara, N., Udagawa, S., & Nakajima, S., (1987). Studies on fungal products. XII. Structure of aurantioemestrin from Emericella striata. Heterocycles, 26(2), 475–479. 291. Kawahara, N., Nozawa, K., Nakajima, S., & Kawai, K., (1986). Aurantioemestrin from Emericella striata and silvathione from Aspergillus silvaticus, possible key intermediates from epidithiodioxopiperazines to trioxopiperazines. Journal of the Chemical Society, Chemical Communications, (19), 1495–1496. 292. Seya, H., Nozawa, K., Udagawa, S., Nakajima, S., & Kawai, K., (1986). Studies on fungal products. IX. Dethiosecoemestrin, a new metabolite related to emestrin, from Emericella striata. Chemical & Pharmaceutical Bulletin, 34(6), 2411–2416. 293. Kawahara, N., Nozawa, K., Nakajima, S., & Kawai, K., (1987). Studies on fungal products. Part 13. Isolation and structures of dithiosilvatin and silvatione, novel dioxopiperazine derivatives from Aspergillus silvaticus. Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry, (9), 2099–2101.

2,5-Diketopiperazine

375

294. Kawahara, N., Nozawa, K., Nakajima, S., Yamazaki, M., & Kawai, K., (1989). Studies on fungal products. Part 28. Sulfur-containing dioxopiperazine derivatives from Emericella heterothallica. Heterocycles, 29(2), 397–402. 295. Schmeda-Hirschmann, G., Hormazabal, E., Astudillo, L., Rodriguez, J., & Theoduloz, C., (2005). Secondary metabolites from endophytic fungi isolated from the Chilean gymnosperm Prumnopitys andina (Lleuque). World Journal of Microbiology & Biotechnology, 21(1), 27–32. 296. Shin, J., & Fenical, W., (1987). Isolation of gliovictin from the marine deuteromycete Asteromyces cruciatus. Phytochemistry, 26(12), 3347. 297. Dorn, F., & Arigoni, D., (1974). Gliovictin, a new metabolite of helminthosporium victoriae. Experientia, 30(2), 134, 135. 298. Stillwell, M. A., Magasi, L. P., & Strunz, G. M., (1974). Production, isolation, and antimicrobial activity of hyalodendrin, a new antibiotic produced by a species of hyalodendron. Canadian Journal of Microbiology, 20(5), 759–764. 299. Gulder, T. A. M., Hong, H., Correa, J., Egereva, E., Wiese, J., Imhoff, J. F., & Gross, H., (2012). Isolation, structure elucidation and total synthesis of lajollamide a from the marine fungus Asteromyces cruciatus. Marine Drugs, 10(12), 2912–2935. 300. Wang, F. Q., Tong, Q. Y., Ma, H. R., Xu, H. F., Hu, S., Ma, W., Xue, Y. B., et al., (2015). Indole diketopiperazines from endophytic Chaetomium sp 88194 induce breast cancer cell apoptotic death. Scientific Reports, 5, 9294/1–9294/9. 301. Guo, C. J., Yeh, H. H., Chiang, Y. M., Sanchez, J. F., Chang, S. L., Bruno, K. S., & Wang, C. C. C., (2013). Biosynthetic pathway for the epipolythiodioxopiperazine acetylaranotin in Aspergillus terreus revealed by genome-based deletion analysis. Journal of the American Chemical Society, 135(19), 7205–7213. 302. Curtis, P. J., Greatbanks, D., Hesp, B., Forbes, C. A., & Freer, A. A., (1977). Sirodesmins A, B, C, and G, antiviral epipolythiopiperazine-2,5-diones of fungal origin: X-ray analysis of sirodesmin a diacetate. Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry, (2), 180–189. 303. Mitrovic, P. M., Orcic, D. Z., Sakac, Z. O., Marjanovic-Jeromela, A. M., Grahovac, N. L., Milosevic, D. M., & Marisavljevic, D. P., (2012). Characterization of sirodesmins isolated from the phytopathogenic fungus Leptosphaeria Maculans. Journal of the Serbian Chemical Society, 77(10), 1363–1379. 304. Borthwick, A. D., & Liddle, J., (2011). The design of orally bioavailable 2, 5-diketopiperazine oxytocin antagonists: From concept to clinical candidate for premature labor. Medicinal Research Reviews, 31(4), 576–604. 305. Avendaño, C., & De La Cuesta, E., (2013). Application of N-acyliminium ions to the synthesis of pyrazino[2,1-b]quinazoline-3,6-dione derivatives. Advances in Organic Synthesis, 5, 309–354. 306. Wyatt, P. G., Allen, M. J., Borthwick, A. D., Davies, D. E., Exall, A. M., Hatley, R. J. D., Irving, W. R., et al., (2005). 2,5-Diketopiperazines as potent and selective oxytocin antagonists 1: Identification, stereochemistry and initial SAR. Bioorganic & Medicinal Chemistry Letters, 15(10), 2579–2582.

376

Amino Acids: Insights and Roles in Heterocyclic Chemistry, Volume 2

307. Santagada, V., Fiorino, F., Perissutti, E., Severino, B., Terracciano, S., Cirino, G., & Caliendo, G., (2003). A convenient strategy of dimerization by microwave heating and using 2,5-diketopiperazine as scaffold. Tetrahedron Letters, 44(6), 1145–1148. 308. Perzborn, M., Syldatk, C., & Rudat, J., (2013). Enzymatical and microbial degradation of cyclic dipeptides (diketopiperazines). AMB Express, 3, 51/1–51/12. 309. O’Neill, J. C., & Blackwell, H. E., (2007). Solid-phase and microwave-assisted syntheses of 2,5-diketopiperazines: Small molecules with great potential. Combinatorial Chemistry & High Throughput Screening, 10, 857–876. 310. Francavilla, C., Turtle, E. D., Kim, B., O’Mahony, D. J. R., Shiau, T. P., Low, E., Alvarez, N. J., et al., (2011). Novel N-chloroheterocyclic antimicrobials. Bioorganic & Medicinal Chemistry Letters, 21(10), 3029–3033. 311. Zeng, Y., Li, Q., Hanzlik, R. P., & Aubé, J., (2005). Synthesis of a small library of diketopiperazines as potential inhibitors of calpain. Bioorganic & Medicinal Chemistry Letters, 15, 3034–3038. 312. Liao, S. R., Du, L. J., Qin, X. C., Xu, L., Wang, J. F., Zhou, X. F., Tu, Z. C., et al., (2016). Site selective synthesis of cytotoxic 1,3,6-trisubstituted 3,6-diunsaturated (3Z,6Z)-2,5-diketopiperazines via a one-pot multicomponent method. Tetrahedron, 72(8), 1051–1057. 313. Fani, N., Bordbar, A. K., Ghayeb, Y., & Sepehri, S., (2015). Integrating docking and molecular dynamics approaches for a series of proline-based 2,5-diketopiperazines as novel αβ-tubulin inhibitors. Journal of Biomolecular Structure and Dynamics, 33(10), 2285–2295. 314. Sun, D., Sun, L., Luo, M., & Gou, Z., (2011). One-pot preparation of 3-hydroxymethyl 2,5-diketopiperazine for total synthesis of pepticinnamin E. Asian Journal of Chemistry, 23(11), 5169–5170. 315. Caflisch, A., Schramm, H. J., & Karplus, M., (2000). Design of dimerization inhibitors of HIV-1 aspartic proteinase: A computer-based combinatorial approach. Journal of Computer-Aided Molecular Design, 14, 161–179. 316. Naini, S. R., Lalancette, R. A., Gorlova, O., Ramakrishna, K. V. S., Yadav, J. S., & Ranganathan, S., (2014). Sulfate encapsulation in supramolecular structures from L-asparagine-derived 2,5-diketopiperazine scaffolds: Anion binding. European Journal of Organic Chemistry, (31), 7015–7022. 317. De Guzman, F. S., Glober, J. B., Wicklow, D. T., & Dowd, P. F., (1992). New diketopiperazine metabolites from the sclerotia of Aspergillus ochraceus. Journal of Natural Products, 55(7), 931–939. 318. Liao, S. R., Qin, X. C., Wang, Z., Li, D., Xu, L., Li, J. S., Tu, Z. C., & Liu, Y., (2016). Design, synthesis and cytotoxic activities of novel 2,5-diketopiperazine derivatives. European Journal of Medicinal Chemistry, 121, 500–509. 319. Monga, V., Meena, C. L., Kaur, N., & Jain, R., (2008). Chemistry and biology of thyrotropin-releasing hormone (TRH) and its analogs. Current Medicinal Chemistry, 15, 2718–2733.

2,5-Diketopiperazine

377

320. Prakash, K. R., Tang, Y., Kozikowski, A. P., Flippen-Anderson, J. L., Knoblach, S. M., & Faden, A. I., (2002). Synthesis and biological activity of novel neuroprotective diketopiperazines. Bioorganic Medicinal Chemistry, 10, 3043–3048. 321. Guan, J., Mathai, S., Harris, P., Wen, J. Y., Zhang, R., Brimble, M., & Gluckman, P., (2007). Peripheral administration of a novel diketopiperazine, NNZ 2591, prevents brain injury and improves somatosensory-motor function following hypoxia-ischemia in adult rats. Neuropharmacology, 53, 749–762. 322. Mieczkowski, A., Koźmiński, W., & Jurczak, J., (2010). A traceless, solid-supported synthesis of b-turn mimetics based on the hexahydropyrazino[1,2-a]pyrazine-1,2-dione scaffold. Synthesis, (2), 221–232. 323. Feng, D. Z., Song, Y. L., Jiang, X. H., Chen, L., & Long, Y. Q., (2007). Forward- and reverse-synthesis of piperazinopiperidine amide analogs: A general access to structurally diverse 4-piperazinopiperidine-based CCR5 antagonists. Organic & Biomolecular Chemistry, 5, 2690–2697. 324. Maeda, K., Nakata, H., Koh, Y., Miyakawa, T., Ogata, H., Takaoka, Y., Shibayama, S., et al., (2004). Spirodiketopiperazine-based CCR5 inhibitor which preserves CC-chemokine/ CCR5 interactions and exerts potent activity against R5 human immunodeficiency virus type 1 in vitro. Journal of Virology, 78(16), 8654–8662. 325. Brooks, T. D., Wang, S. W., Brünner, N., & Charlton, P. A., (2004). XR5967, a novel modulator of plasminogen activator inhibitor-1 activity, suppresses tumor cell invasion and angiogenesis in vitro. Anti-Cancer Drugs, 15(1), 37–44. 326. Kanoh, K., Kohno, S., Katada, J., Takahashi, J., & Uno, I., (1999). (-)-Phenylahistin arrests cells in mitosis by inhibiting tubulin polymerization. The Journal of Antibiotics, 52, 134–141. 327. Nicholson, B., Lloyd, G. K., Miller, B. R., Palladino, M. A., Kiso, Y., Hayashi, Y., & Neuteboom, S. T. C., (2006). NPI-2358 is a tubulin-depolymerizing agent: in-vitro evidence for activity as a tumor vascular-disrupting agent. Anti-Cancer Drugs, 17(1), 25–31. 328. Carbonell, T., Masip, I., Sánchez-Baeza, F., Delgado, M., Araya, E., Llorens, O., Corcho, F., et al., (2000). Identification of selective inhibitors of acetylcholinesterase from a combinatorial library of 2,5-piperazinediones. Molecular Diversity, 5(3), 131–143. 329. Tsuruoka, N., Beppu, Y., Koda, H., Doe, N., Watanabe, H., & Abe, K., (2012). A DKP cyclo(L-Phe-L-Phe) found in chicken essence is a dual inhibitor of the serotonin transporter and acetylcholinesterase. PLoS One, 7, e50824. 330. Konstantinopoulos, P. A., Karamouzis, M. V., & Papavassiliou, A. G., (2007). Posttranslational modifications and regulation of the RAS superfamily of GTPases as anticancer targets. Nature Reviews Drug Discovery, 6(7), 541–555. 331. Vigushin, D. M., Mirsaidi, N., Brooke, G., Sun, C., Pace, P., Inman, L., Moody, C. J., & Coombes, R. C., (2004). Gliotoxin is a dual inhibitor of farnesyltransferase and geranylgeranyltransferase I with antitumor activity against breast cancer in vivo. Medical Oncology, 21(1), 21–30.

378

Amino Acids: Insights and Roles in Heterocyclic Chemistry, Volume 2

332. Weber, I. T., Zhang, Y., & Tözsér, J., (2009). HIV-1 Protease and AIDS Therapy/Viral Proteases and Antiviral Protease Inhibitor Therapy (Vol. 8, pp. 25–45.). Springer Netherlands. 333. Evans, D. R., & Guy, H. I., (2004). Mammalian pyrimidine biosynthesis: Fresh insights into an ancient pathway. Journal of Biological Chemistry, 279(32), 33035–33038. 334. Baumann, P., Mandl-Weber, S., Voelkl, A., Adam, C., Bumeder, I., Oduncu, F., & Schmidmaier, R., (2009). Dihydroorotate dehydrogenase inhibitor A771726 (Leflunomide) induces apoptosis and diminishes proliferation of multiple myeloma cells. Molecular Cancer Therapeutics, 8(2), 366–375. 335. Chen, S. F., Ruben, R. L., & Dexter, D. L., (1986). Mechanism of action of the novel anticancer agent 6-fluoro-2-(2’-fluoro-1,1’-biphenyl-4-yl)-3-methyl-4quinolinecarboxylic acid sodium salt (NSC 368390): Inhibition of de novo pyrimidine nucleotide biosynthesis. Cancer Research, 46(10), 5014–4019. 336. Herrmann, M. L., Schleyerbach, R., & Kirschbaum, B. J., (2000). Leflunomide: an immunomodulatory drug for the treatment of rheumatoid arthritis and other autoimmune diseases. Immunopharmacology, 47(2, 3), 273–289. 337. Merrill, J. E., Hanak, S., Pu, S. F., Liang, J., Dang, C., Iglesias-Bregna, D., Harvey, B., et al., (2009). Teriflunomide reduces behavioral, electrophysiological, and histopathological deficits in the dark agouti rat model of experimental autoimmune encephalomyelitis. Journal of Neurology, 256(1), 89–103. 338. Daugan, A., Grondin, P., Ruault, C., Le Monnier De, G. A. C., Coste, H., Linget, J. M., Kirilovsky, J., et al., (2003). The discovery of tadalafil: a novel and highly selective PDE5 inhibitor. 2: 2,3,6,7,12,12a-hexahydropyrazino[1’,2’:1,6]pyrido[3,4-b]indole-1,4dione analogues. Journal of Medicinal Chemistry, 46(21), 4533–4542. 339. Ivanovich, R. A., Vincent-Rocan, J. F. O., Elkaeed, E. B., & Beauchemin, A. M., (2015). One-pot synthesis of aza-diketopiperazines enabled by controlled reactivity of N-isocyanate precursors. Organic Letters, 17, 4898–4901. 340. Warner, D. S., Limberg, C., & Mebs, S., (2013). Synthesis of a chiral, polydentate ligand system setting out from L-cysteine and first nickel complexes thereof. Zeitschrift fuer Anorganische und Allgemeine Chemie, 639(8, 9), 1577–1583. 341. Jerumanis, S., & Lefebvre, J., (1994). Synthese de L’acide 3-(3,6-dioxopiperazin-2-yl) propanoique. Bull. Soc. Chim. Belg., 103(3), 127–130. 342. Airaghi, F., Fiorati, A., Lesma, G., Musolino, M., Sacchetti, A., & Silvani, A., (2013). The diketopiperazine-fused tetrahydro-β-carboline scaffold as a model peptidomimetic with an unusual α-turn secondary structure. Beilstein J. Org. Chem., 9, 147–154. 343. Khimiuk, A. Y., Korennykh, A. V., Van, L. L. M., Van, R. F., Sheldon, R. A., & Švedas, V. K., (2003). Penicillin acylase-catalyzed peptide synthesis in aqueous medium: A chemoenzymatic route to stereoisomerically pure diketopiperazines. Tetrahedron: Asymmetry, 14, 3123–3128. 344. Tullberg, M., Grøtli, M., & Luthman, K., (2006). Efficient synthesis of 2,5-diketopiperazines using microwave assisted heating. Tetrahedron, 62, 7484–7491.

2,5-Diketopiperazine

379

345. Dufour, E., Moni, L., Bonnat, L., Chierici, S., & Garcia, J., (2014). ‘Clickable’ 2,5-diketopiperazines as scaffolds for ligation of biomolecules: Their use in Aβ inhibitor assembly. Organic & Biomolecular Chemistry, 12(27), 4964–4974. 346. Fryszkowska, A., & Ostaszewski, R., (2008). Studies towards the synthesis of bicyclomycin precursors: Synthesis of N,N’-disubstituted 2,5-diketopiperazines in solution and on solid phase. J. Heterocyclic Chem., 45, 765–772. 347. Lee, M. S., Baek, J., Youk, E., Kim, Y., & Park, Y. S., (2016). Convenient asymmetric synthesis of 1,3,4,6-tetrasubstituted 2,5-diketopiperazines. ARKIVOC, (iv), 100–113. 348. Gondry, M., Sauguet, L., Belin, P., Thai, R., Amouroux, R., Tellier, C., Tuphile, K., et al., (2009). Cyclodipeptide synthases are a family of tRNA-dependent peptide bond-forming enzymes. Nature Chemical Biology, 5, 414–420. 349. Lautru, S., Gondry, M., Genet, R., & Pernodet, J. L., (2002). The albonoursin gene cluster of S. Noursei biosynthesis of diketopiperazine metabolites independent of nonribosomal peptide synthetases. Chemistry & Biology, 9, 1355–1364. 350. Van, L. L. M., Van, R. F., Švedas, V. K., & Sheldon, R. A., (2000). Penicillin acylase-catalyzed peptide synthesis: A chemo-enzymatic route to stereoisomers of 3,6-diphenylpiperazine-2,5-dione. Tetrahedron: Asymmetry, 11, 1077–1083. 351. Lazos, O., Tosin, M., Slusarczyk, A. L., Boakes, S., Cortes, J., Sidebottom, P. J., & Leadlay, P. F., (2010). Biosynthesis of the putative siderophore erythrochelin requires unprecedented crosstalk between separate nonribosomal peptide gene clusters. Chemistry & Biology, 17(2), 160–173. 352. Bortoluzzi, M., Marchetti, F., Murrali, M. G., & Pampaloni, G., (2015). Revisitation of the PCl5-chlorination reaction of α-amino acids: Spectroscopic and DFT insights, and synthesis of the l-proline-derived 2,5-diketopiperazine. Inorganica Chimica Acta, 427, 150–154. 353. Nitecki, D. E., Halpern, B., & Westley, J. W., (1968). Simple route to sterically pure diketopiperazines. Journal of Organic Chemistry, 33(2), 864–866. 354. Gundersen, L. L., Rise, F., & Undheim, K., (2001). Zirconium tetraisopropoxide. e-EROS Encyclopedia of Reagents for Organic Synthesis, 2001, 1–4. 355. Galinsky, A. M., Gearien, J. E., & Smissman, E. E., (1957). A synthesis of diketopiperazines using polyphosophoric acid. Journal of the American Pharmaceutical Association, 46(7), 391–393. 356. Basiuk, V. A., Gromovoy, T. Y., Chuiko, A. A., Soloshonok, V. A., & Kukhar, V. P., (1992). A novel approach to the synthesis of symmetric optically active 2,5-dioxopiperazines. Synthesis, 449–451. 357. Basiuk, V. A., (1992). Condensation of vaporous amino acids in the presence of silica. Formation of Bi- and tricyclic amidines. Origins of Life and Evolution of the Biosphere, 22(6), 333–348. 358. Fujii, T., & Okawa, K., (1966). The synthesis of 3,6-bis(α-hydroxyethyl)-2,5diketopiperazine. Bulletin of the Chemical Society of Japan, 39(7), 1598–1599. 359. Li, Y. C., Pang, S. P., & Yu, Y. Z., (2007). Studies on the cyclization reaction of D-aspartic acid. Chinese Chemical Letters, 18, 516–518.

380

Amino Acids: Insights and Roles in Heterocyclic Chemistry, Volume 2

360. Rafiemanzelat, F., Zonouz, A. F., & Emtiazi, G., (2012). Synthesis and characterization of poly(ether-urethane)s derived from 3,6-diisobutyl-2,5-diketopiperazine and PTMG and study of their degradability in environment. Polymer Degradation and Stability, 97(1), 72–80. 361. Ohta, A., Kojima, A., & Aoyagi, Y., (1990). Emeheterone: synthesis and structural revision. Heterocycles, 31(9), 1655–1662. 362. Cook, B., Hill, R. R., & Jeffs, G. E., (1992). Efficient one-step synthesis of diastereoisomeric cyclic dipeptides from amino acids: Three diastereoisomers of cycloL-isoleucyl-L-isoleucine. Journal of the Chemical Society, Perkin Transactions I, (10), 1199–1201. 363. Campbell, M. M., Horwell, D. C., Mahon, M. F., Pritchard, M. C., & Walford, S. P., (1993). Diastereoselective synthesis of cyclopropyl phenylalanines and their incorporation into dipeptides. Bioorganic & Medicinal Chemistry Letters, 3(4), 667–670. 364. Kong, X. J., Zhuang, G. L., Ren, Y. P., Long, L. S., Huang, R. B., & Zheng, L. S., (2009). In situ cyclodehydration of iminodiacetic acid into 2,5-diketopiperazine-1,4-diacetate in lanthanide-based coordination polymers. Dalton Transactions, (10), 1707–1709. 365. Ugi, I., Meyr, R., Fetzer, U., & Steinbrückner, C., (1959). Versuche mit isonitrilen. Angew. Chem., 71(11), 386–386. 366. Marcaccini, S., & Torroba, T., (2007). The use of the Ugi four-component condensation. Nature Protocols, 2(3), 632–639. 367. Hartung, A., Seufert, F., Berges, C., Gessner, V. H., & Holzgrabe, U., (2012). One-pot Ugi/aza-Michael synthesis of highly substituted 2,5-diketopiperazines with antiproliferative properties. Molecules, 17, 14685–14699. 368. Santra, S., & Andreana, P. R., (2007). A one-pot, microwave-influenced synthesis of diverse small molecules by multicomponent reaction cascades. Organic Letters, 9(24), 5035–5038. 369. El Kaim, L., Gageat, M., Gaultier, L., & Grimaud, L., (2007). New Ugi/Pictet-Spengler multicomponent formation of polycyclic diketopiperazines from isocyanides and α-keto acids. Synlett, (3), 500–502. 370. Cho, S., Keum, G., Kang, S. B., Han, S. Y., & Kim, Y., (2003). An efficient synthesis of 2,5-diketopiperazine derivatives by the Ugi four-center three-component reaction. Molecular Diversity, 6(3, 4), 283–286. 371. Sollis, S. L., (2005). Short and novel stereospecific synthesis of trisubstituted 2,5-diketopiperazines. Journal of Organic Chemistry, 70(12), 4735–4740. 372. Rhoden, C. R. B., Westermann, B., & Wessjohann, L. A., (2008). One-pot multicomponent synthesis of N-substituted tryptophan-derived diketopiperazines. Synthesis, 2077–2082. 373. Ji, F., Yi, W. B., & Cai, C., (2014). Synthesis of 2,5-diketopiperazine derivatives using 2-isocyanophenyl 4-methylbenzoate as a fragrant convertible isocyanide. Journal of Heterocyclic Chemistry, 51(5), 1287–1292. 374. Kennedy, A. L., Fryer, A. M., & Josey, J. A., (2002). A new resin-bound universal isonitrile for the Ugi 4CC reaction: Preparation and applications to the synthesis of 2,5-diketopiperazines and 1,4-benzodiazepine-2,5-diones. Organic Letters, 4(7), 1167–1170.

2,5-Diketopiperazine

381

375. Merrifield, R. B., (1963). Solid phase peptide synthesis. I. The synthesis of a tetrapeptide. Journal of American Chemical Society, 85, 2149–2154. 376. Bockman, M. R., Miedema, C. J., & Brennan, B. B., (2012). A discovery-oriented approach to solid-phase peptide synthesis. Journal of Chemical Education, 89, 1470–1473. 377. Albeiicio, F., Chinchilla, R., Dodsworth, D. J., & Nájera, C., (2001). New trends in peptide coupling reagents. Organic Preparations and Procedures International: The New Journal for Organic Synthesis, 33(3), 203–303. 378. Jad, Y. E., Acosta, G. A., Govender, T., Kruger, H. G., El-Faham, A., De La Torre, B. G., & Albericio, F., (2016). Green solid-phase peptide synthesis 2. 2-methyltetrahydrofuran and ethyl acetate for solid-phase peptide synthesis under green conditions. ACS Sustainable Chemistry & Engineering, 4, 6809–6814. 379. Galanis, A. S., Albericio, F., & Grøtli, M., (2009). Solid-phase peptide synthesis in water using microwave-assisted heating. Organic Letters, 11(20), 4488–4491. 380. Collins, J. M., Porter, K. A., Singh, S. K., & Vanier, G. S., (2014). High-efficiency solid phase peptide synthesis (HE-SPPS). Organic Letters, 16, 940–943. 381. Del, F. M., Alsina, J., Royo, M., Barany, G., & Albericio, F., (1998). Solid-phase synthesis of diketopiperazines, useful scaffolds for combinatorial chemistry. Tetrahedron Letters, 39(17), 2639–2642. 382. Groth, T., & Meldal, M., (2001). N-Terminal peptide aldehydes as electrophiles in combinatorial solid phase synthesis of novel peptide isosteres. Journal of Combinatorial Chemistry, 3(1), 45–63. 383. Kuster, G. J. T., van Berkom, L. W. A., Kalmoua, M., van Loevezijn, A., Sliedregt, L. A. J. M., van Steen, B. J., Kruse, C. G., Rugjes, F. P. J. T., & Scheeren, H. W., et al., (2006). Synthesis of spirohydantoins and spiro-2,5-diketopiperazines via resin-bound cyclic α,α-disubstituted α-amino esters. Journal of Combinatorial Chemistry, 8, 85–94. 384. Couladouros, E. A., & Magos, A. D., (2005). Total asymmetric synthesis of (–)-phenylhistine, (–)-aurantiamine and related compounds. Part I. Molecular Diversity, 9, 99–109. 385. Yamazaki, Y., Mori, Y., Oda, A., Okuno, Y., Kiso, Y., & Hayashi, Y., (2009). Acid catalyzed monodehydro-2,5-diketopiperazine formation from n-α-ketoacyl amino acid amides. Tetrahedron, 65(18), 3688–3694. 386. Person, D., & Le Corre, M., (1989). Nouvelle voie d’accès aux alkylidène-3 pipérazinediones-2,5. Bulletin de la Societe Chimique de France, 673–676. 387. Couladouros, E. A., & Magos, A. D., (2005). Solid-phase total synthesis of (-)-phenylhistine and (-)-aurantiamine. Synthesis of a diverse dehydro-2,5-diketopiperazine library. Part II. Molecular Diversity, 9, 111–121. 388. Sheradsky, T., & Silcoff, E. R., (1998). Synthesis of (2R,5R)-2-amino-5-hydroxyhexanoic acid by intramolecular cycloaddition. Molecules, 3, 80–87. 389. Levins, C. G., Brown, Z. Z., & Schafmeister, C. E., (2006). Maximizing the stereochemical diversity of spiro-ladder oligomers. Organic Letters, 8(13), 2807–2810.

382

Amino Acids: Insights and Roles in Heterocyclic Chemistry, Volume 2

390. Sorrells, J. L., & Menger, F. M., (2008). Hydrogen-bond-induced hysteresis in the compression/relaxation of monolayer films. Journal of American Chemical Society, 130, 10072, 10073. 391. Ma, C., Liu, X., Li, X., Flippen-Anderson, J., Yu, S., & Cook, J. M., (2001). Efficient asymmetric synthesis of biologically important tryptophan analogues via a palladiummediated heteroannulation reaction. Journal of Organic Chemistry, 4525–4542. 392. Orena, M., Porzi, G., & Sandri, S., (1992). Diastereoselective alkylation of (3S)- and (3R)-3-methylpiperazine-2,5-dione derivatives. A convenient approach to both (S)- and (R)-alanine. Journal of Organic Chemistry, 57, 6532–6536. 393. Danthi, S. N., & Hill, R. A., (1997). Synthesis of chirally pure 2,5-disubstituted diketopiperazines derived from trisubstittued phenylalanines. J. Heterocyclic Chem., 34, 835–844. 394. Borthwick, A. D., Davies, D. E., Exall, A. M., Livermore, D. G., Sollis, S. L., Nerozzi, F., Allen, M. J., et al., (2005). 2,5-Diketopiperazines as potent, selective, and orally bioavailable oxytocin antagonists. 2. Synthesis, chirality, and pharmacokinetics. Journal of Medicinal Chemistry, 48, 6956–6969. 395. Nakao, M., Fukayama, S., Kitaike, S., & Sano, S., (2015). Synthesis of rhodotorulic acid and its 1,4-dimethylated derivative. Heterocycles, 90(2), 1309–1316. 396. Fuehrer, F. N., & Schlaad, H., (2014). ADMET polymerization of amino-acid-based diene. Macromolecular Chemistry and Physics, 215(22), 2268–2273. 397. Yoshimura, J., Nakamura, H., & Matsunari, K., (1975). A new synthesis of 3,6-dialkyl1,4-dimethyl-3,6-epithio- and -3,6-eidithio-2,5-piperazinediones. Bulletin of the Chemical Society of Japan, 48(2), 605–609. 398. Durow, A. C., Long, G. C., O’Connell, S. J., & Willis, C. L., (2006). Total synthesis of the chlorinated marine natural product dysamide B. Organic Letters, 8(23), 5401–5404. 399. Tullberg, M., Grøtli, M., & Luthman, K., (2007). Synthesis of functionalized, unsymmetrical 1,3,4,6-tetrasubstituted 2,5-diketopiperazines. Journal of Organic Chemistry, 72(1), 195–199. 400. Lim, H. J., Gallucci, J. C., & RajanBabu, T. V., (2010). Annulated diketopiperazines from dipeptides or schöllkopf reagents via tandem cyclization-intramolecular N-arylation. Organic Letters, 12(9), 2162–2165. 401. Schöllkopf, U., (1983). Asymmetric syntheses of amino acids via metalated bis-lactim ethers of 2,5-diketopiperazines. Pure & Applied Chemistry, 55(11), 1799–1806. 402. Richter, L. S., & Gadek, T. R., (1996). Penicillamine: an extractable chiral auxiliary providing excellent stereocontrol. Tetrahedron: Asymmetry, 7(2), 427–434. 403. Li, X., Yin, W., Sarma, P. V. V. S., Zhou, H., Ma, J., & Cook, J. M., (2004). Synthesis of optically active ring-a substituted tryptophans as IDO inhibitors. Tetrahedron Letters, 45, 8569–8573. 404. Groth, U., Huhn, T., Porsch, B., Schmeck, C., & Schöllkopf, U., (1993). Synthesis of tert-leucine and related amino acids. Liebigs Annalen der Chemie, 7, 715–719.

2,5-Diketopiperazine

383

405. Kunisaki, T., Kawai, K., Hirohata, K., Minami, K., & Kondo, K., (2001). Synthesis of polyethers containing cyclodipeptide moiety in the main chain. Journal of Polymer Science: Part A: Polymer Chemistry, 39, 927–933. 406. Murata, S., Suzuki, M., & Noyori, R., (1988). Trimethylsilyl triflate catalyzed aldoltype reaction of enol silyl ethers and acetals or related compounds. Tetrahedron, 44(13), 4259–4275. 407. Hernandez, F., Lumetzberger, A., Avendano, C., & Sollhuber, M., (2001). Regioselective N-acylation of 3-arylmethylpiperazine-2,5-diones: short synthesis of (-)-glyantrypine and (-)-fumiquinazoline F. Synlett, (9), 1387–1390. 408. Gonzalez, J. F., De La Cuesta, E., & Avendano, C., (2004). Pictet-Spengler-type reactions in 3-arylmethylpiperazine-2,5-diones. Synthesis of pyrazinotetrahydroisoquinolines. Tetrahedron, 60(30), 6319–6326. 409. Margrey, K. A., Hazzard, A. D., & Scheerer, J. R., (2014). Synthesis of 2-pyridones by cycloreversion of [2.2.2]- bicycloalkene diketopiperazines. Organic Letters, 16, 904–907. 410. Kubo, A., Saito, N., Yamato, H., Masubuchi, K., & Nakamura, M., (1988). Stereoselective total synthesis of (±)-saframycin B. Journal of Organic Chemistry, 53(18), 4295–4310. 411. Kubo, A., Saito, N., Nakamura, M., Ogata, K., & Sakai, S., (1987). A promising cyclization of the 3-arylidene-6-arylmethyl-2,5-piperazinedione to construct tricyclic lactam as an intermediate to saframycin synthesis. Heterocycles, 26(7), 1765–1770. 412. Saito, N., Tachi, M., Seki, R. I., Kamayachi, H., & Kubo, A., (2000). A practical synthesis of the ABC ring model of ecteinascidins. Chemical & Pharmaceutical Bulletin, 48(10), 1549–1557. 413. Saito, N., Tanitsu, M. A., Betsui, T., Suzuki, R., & Kubo, A., (1997). Synthesis of novel octahydro-1,5-imino-3-benzazocin-4,7,10-trione derivatives having a methyl group at the C-2 position as ABC ring models of saframycins. Chemical & Pharmaceutical Bulletin, 45(7), 1120–1129. 414. Fukuyama, T., & Nunes, J. J., (1988). Stereocontrolled total synthesis of (±)-quinocarcin. Journal of the American Chemical Society, 110(15), 5196–5198. 415. Veerman, J. J. N., Bon, R. S., Hue, B. T. B., Girones, D., Rutjes, F. P. J. T., Van, M. J. H., & Hiemstra, H., (2003). Synthesis of 2,6-bridged piperazine-3-ones by N-acyliminium ion chemistry. Journal of Organic Chemistry, 68(11), 4486–4494. 416. Gonzalez, J. F., Salazar, L., De La Cuesta, E., & Avendano, C., (2005). Synthesis of phthalascidin analogs. Tetrahedron, 61(31), 7447–7455. 417. Lee, B. H., & Clothier, M. F., (1999). Selective reduction of secondary amides to amines in the presence of tertiary amides. Tetrahedron Letters, 40(4), 643–644. 418. Avendaño, C., & De La Cuesta, E., (2009). Synthetic chemistry with N-acyliminium ions derived from piperazine-2,5-diones and related compounds. Current Organic Synthesis, 6, 143–168. 419. Krishnan, V., Muthukumaran, A., & Udupa, H. V. K., (1975). Synthesis of piperazine & its salts. Indian Journal of Technology, 13, 126–129.

384

Amino Acids: Insights and Roles in Heterocyclic Chemistry, Volume 2

420. Whitlock, C. R., & Cava, M. P., (1994). A total synthesis of dragmacidin B. Tetrahedron Letters, 35(3), 371–374. 421. Carlsson, A. C., Jam, F., Tullberg, M., Pilotti, Å., Ioannidis, P., Luthman, K., & Grøtli, M., (2006). Microwave-assisted synthesis of the Schöllkopf chiral auxiliaries: (3S)and (3R)-3,6-dihydro-2,5-diethoxy-3-isopropyl-pyrazine. Tetrahedron Letters, 47, 5199–5201. 422. Chen, J., Corbin, S. P., & Holman, N. J., (2005). An improved large scale synthesis of the Schöllkopf chiral auxiliaries: (2R)- and (2S)-2,5-dihydro-3,6-dimethoxy-2­ isopropylpyrazine. Organic Process Research & Development, 9, 185–187. 423. Balducci, D., Lazzari, I., Monari, M., Piccinelli, F., & Porzi, G., (2010). (S)-α-Methyl, α-amino acids: a new stereocontrolled synthesis. Amino Acids, 38(3), 829–837. 424. Bull, S. D., Davies, S. G., Garner, A. C., O’Shea, M. D., Savory, E. D., & Snow, E. J., (2002). Chiral glycine cation equivalents: N-acyliminium species derived from diketopiperazines. Journal of the Chemical Society, Perkin Transaction I, 2442–2448. 425. Williams, R. M., Armstrong, R. W., Maruyama, L. K., Dung, J. S., & Anderson, O. P., (1985). Divergent, generalized synthesis of unsymmetrically substituted 2,5-piperazinediones. Journal of the American Chemical Society, 107(11), 3246–3253. 426. Williams, R. M., Armstrong, R. W., & Dung, J. S., (1984). Stereo controlled total synthesis of (±)- and (+)-bicyclomycin: new carbon-carbon bond-forming reactions on electrophilic glycine anhydride derivatives. Journal of the American Chemical Society, 106(19), 5748–5750. 427. Yoshimura, J., Sugiyama, Y., & Nakamura, H., (1973). Synthesis and substitution of 1,3,4,6-tetra-substituted-3,6-dihalo-2,5-piperazinediones. Bulletin of the Chemical Society of Japan, 46(9), 2850–2853. 428. Huck, L., González, J. F., De La Cuesta, E., & Menéndez, J. C., (2016). Three-component synthesis of highly functionalized aziridines containing a peptide side chain and their one-Step transformation into β-functionalized α-ketoamides. Beilstein J. Org. Chem., 12, 1772–1777. 429. Tanaka, K., Mori, A., & Inoue, S., (1990). The cyclic dipeptide cyclo[(S)-phenylalanyl­ (S)-histidyla] as a catalyst for asymmetric addition of hydrogen cyanide to aldehydes. Journal of Organic Chemistry, 55(1), 181–185. 430. Kogut, E. F., Thoen, J. C., & Lipton, M. A., (1998). Examination and enhancement of enantioselective autoinduction in cyanohydrin formation by cyclo[(R)-His-(R)-Phe]. Journal of Organic Chemistry, 63, 4604–4610. 431. Iyer, M. S., Gigstad, K. M., Namdev, N. D., & Lipton, M., (1996). Asymmetric catalysis of the Strecker amino acid synthesis by a cyclic dipeptide. Journal of American Chemical Society, 118(20), 4910, 4911. 432. Kim, H. J., & Jackson, W. R., (1992). Polymer attached cyclic dipeptides as catalysts for enantioselective cyanohydrin formation. Tetrahedron: Asymmetry, 3(11), 1421–1430. 433. Tejima, H., Murofushi, K., & Ashikawa, E., (1956). On the new emulsion hardeners containing hydroxymethyl groups. Bulletin of the Society of Scientific Photography of Japan, 6, 22–32.

Index

1

1-(2-(3,5-diphenyl-4,5-dihydro-1H-pyrazol1-yl)-2-oxoethyl)imidazolidine-2,4-dione, 53

1-(hydroxymethyl)-5,5­ dimethylimidazolidine-2,4-dione, 58, 63 1-(methyldithiocarbonyl)imidazole, 163, 164 1,1-carbonyldiimidazole (CDI), 65 1,1-thiocarbonyldiimidazole (CSIm2), 163

1,2,3,4-butane tetracarboxylic acid (BTCA),

95

1,2-diaza-1,3-diene, 75, 157 1,2-dibromoethane, 59

1,3,5-trisubstituted hydantoin, 66, 71, 74

1,3,6-thiadiazine, 22 1,3-diethyl-5,5-diphenyl-2-thiohydantoin, 149

1,3-dimethylhydantoin, 71, 91

1,3-dimethylimidazolidine-2,4-dione, 59, 91 1,3-di-tert-butyl-5-phenylimidazolidine-2,4dione, 92

1,4-diaza-bicyclo[2,2,2]octane (DABCO), 72, 79, 155

1,4-dihydroxymethyl-2,5-diketopiperazine, 352

1,4-dimethyl-piperazine-2,5-dione, 347 1,4-phenylenebis(methylene) bis(2,2,2­ trichloroacetimidate), 335

1,5-dibromopentane, 59

1-aminocyclopentanecarboxylic acid, 167

1D hydrodynamical simulations, 298

1-ethyl-3-(3-dimethylaminopropyl)­ carbodiimide, 308

hydrochloride (EDCI), 68, 70, 89

1-hydroxy

7-aza-benzotriazole (HOAt), 309 benzotiazole (HOBt), 309, 311, 314, 315,

318

1-methyl

1H-indole-3-carbaldehyde, 195

hydantoin, 60, 94

thiohydantoin (1-MT), 149

1-substituted 2-thiohydantoins, 165

1-ureido-2-thiohydantoin derivative, 193

2

2-(1-ethyl-5-oxo-2-thioxo-3­ ureidoimidazolidin-4-yl)-N­ methylacetamide, 153

2-(3-methoxybenzyl)tetrahydro-1H­ pyrrolo[1,2-c] imidazole-1,3(2H)-dione,

48

2-(4-(chloromethyl)benzyl)isoindoline-1,3dione, 179

2,2,2-trifluoroethyl carbonochloridate, 78 2,2,6,6-tetramethylpiperidine, 188

2,4,6-trimethylpyridine (TMP), 71, 89 2,4-dithiohydantoin, 117, 118, 125, 126,

150, 167–171, 199

2,5-diketopiperazine, 30, 221–223, 225–230, 248, 279, 292, 298, 299, 311,

316, 330, 331, 333, 334, 352

1,4-diacetic acid, 299

ring, 223, 225, 226

2,5-dioxopiperazine, 221 2,5-dioxopyrrolidin-1-yl (2E,4E)-hexa-2,4­ dienoate, 316

2,5-dithiohydantoin, 117

2,5-piperazinedione, 221, 224, 225 2-arylimino-3-(3-chloro-2-benzo[b] thenoyl)-4-thiazolidinones, 163 2-azaspiro[4.5]deca-6,9-diene-3,8-dione

derivative, 301

2-chlorobenzylamine, 305 2H-1,5,2-dithiazine, 22 2H-chromone-containing hydantoins, 54

2H-pyran, 26, 148

2-hydroxy

2-phenylnonanenitrile, 84, 85

ethyl methacrylate, 58

2-isocyanophenyl 4-methylbenzoate, 305 2-methyltetrahydrofuran (2-Me-THF), 309 2-naphthaldehyde, 351

386

Index

2-oxo-2-phenylacetaldehyde, 166

2-phenethyltetrahydro-1H-pyrrolo[1,2-c]

imidazole-1,3(2H)-dione, 47

2-phenyl-2-((trimethylsilyl)oxy)

nonanenitrile, 84

2-pyrrolidone, 47, 309

2-tert-butylimino-2-diethylamino­ 1,3-dimethylperhydro-1,3,2­ diazaphosphorine, 331, 332 2-thioamido group, 126

2-thiohyantoins, 127

2-thiohydantoin, 93, 117–119, 125–128,

131–134, 136–168, 171–175, 177–185,

187–193, 195–202

derivatives, 125, 127, 138, 142, 145, 147,

149, 150, 152, 157, 159, 165, 166, 190,

199, 200

2-thioxoimidazolidin-4-one, 134, 136,

138–142, 148, 160, 161, 171, 172, 178

3

3-(3-(4-benzhydrylpiperazin-1-yl)-2hydroxypropyl)-5-(4-fluorophenyl)-5methylimidazolidine-2,4-dione, 50 3-(3-(tert-butoxycarbonyl)-1,3-oxazinan2-yl)propanoic acid, 311

3-(3,5-dichlorophenyl)-N-isopropyl-2,4­ dioxoimidazolidine-1-carboxamide, 97 3-(5-chloro-2-methylphenyl)-1-ethyl-2­ thiohydantoin, 174

3-(bromo(aryl)methyl)-3­ methoxypiperazine-2,5-dione, 349 3,3-(ethane-1,2-diyl)bis(5,5­ dimethylimidazolidine-2,4-dione), 59 3,5-disubstituted hydantoins, 65

3,6-bis(6-bromo-1H-indol-3-yl)-1,4­ dimethylpiperazine-2,5-dione, 347 3,6-di((Z)-benzylidene)-1,4dimethylpiperazine-2,5-dione, 350 3,6-dihydro-2,5-dialkoxypyrazine, 344 3-benzyl 5-arylidene-2-thiohydantoin, 196

oxyhydantoin, 61

3-ethyl-5-phenylimidazolidine-2,4-dione, 61 3-hydroxyhydantoin, 97

3-N-phenyl-2-thiohydantoins, 199

3-N-substituted 2-thiohydantoins, 166

3-o-tolyl-2-thiohydantoin, 128, 131

3-phenoxybenzaldehyde, 351 3-phenyl

2-thiohydantoin, 118

4-thiohydantoin, 125, 168, 186, 194

5-(4-ethylphenyl)-imidazolidine-2,4dione, 61

3-substituted 1-methyl-2-thiohydantoins, 188

3-triethoxysilylpropylhydantoin derivatives,

95

4

4-(2-(2,5-dioxoimidazolidin-4-yl) acetamido)phenyl methacrylate, 58

4-(2-hydroxyethylimino)-cyclopentanespiro­ 5-(2-thiohydantoin) (HEICPSTH), 141 4-(methylthio)-3-butenyl isothiocyanate (MTBI), 149 4,5-dihydrofuran-2-yl trimethylsilyl ether, 347 4-dimethyl amino-1-naphthyl isothiocyanate (DNITC), 200 aminopyridine (DMAP), 82, 154, 155,

176, 177

4-N,N-dimethylaminoazobenzene-4isothiocyanate (DABITC), 131, 132, 199 4-oxobutryic acid, 311

4-phenyl-1,2,4-triazolidine-3,5-dione, 73, 79 4-thiohydantoin, 186

5

5-((1H-indol-3-yl)methylene)-1,3­ dimethylimidazolidine-2,4-dione, 48 5-((6-bromo-1H-indol-3-yl)methylene)-1,3­ dimethylimidazolidine-2,4-dione, 48 5-(o-carboran-1-ylmethyl)hydantoin, 81

5,5-dibromophenyl-hydantoin, 39

5,5-bis(2-pyridyl)-2-thiohydantoin, 140, 147

5,5-dimethyl

3-(2-(trifluoromethyl)pyridin-4-yl) imidazoli-dine- 2,4-dione, 51 hydantoin, 58, 59, 96

poly(epoxide) (DMHP), 96, 97 5,5-diphenyl

2-thiohydantoin, 140, 144, 147, 149, 190,

193, 198

3-((4-methylpiperazin-1-yl)methyl) imidazolidine-2,4-dione, 57 thiohydantoin, 192

Index

387

5,5-dipyridylhydantoin, 61

5,5-disubstituted hydantoins, 169

5-alkylidene hydantoins, 72

5-arylfuran-2-carbaldehyde, 188 5-benzylidene-1,3-disubstituted hydantoins,

73

5-ethyl-1-methyl-5-phenylimidazolidine2,4-dione, 61

5-heptyl-5-phenylimidazolidine-2,4-dione, 85

5-hydroxyhydantoin, 76

5-methyl

3-(substituted phenyl)-4-oxo-2­ thioxoimidazolidines, 125 5-(2-thiomethyl)ethyl hydantoin), 55

5-phenylhydantoin, 46

5-phenyl-3-benzyl-hydantoins, 54 5-substituted hydantoins, 65, 74, 97

5-tert-butyl-4-oxazolecarboxaldehyde, 315 5-thiohydantoin, 117

6

6-bromo-indole, 343, 347

6-methoxynicotinaldehyde, 195

6-methoxyspirotryprostatin B, 245

7

7,9-diazabicyclo[4.2.2]decane-8,10-dione, 226, 227, 229

7a-hydroxy-2-(3-methoxybenzyl)tetrahydro1H-pyrrolo[1,2-c]imidazole-1,3(2H)­ dione, 48

8

8-oxo-7,8-dihydroguanine (OG), 41, 42

9

9-fluorenylmethyloxycarbonyl group (Fmoc), 30, 154, 176, 290, 292, 307, 309,

311

A Absorption distribution metabolism elimination toxicity (ADMET), 50 Acaricidal, 191

Acetamido moiety, 78

Acetic anhydride, 150, 151, 171, 172, 188,

193, 200, 201, 314, 323, 327, 331

Acetonitrile, 71, 77, 78, 155, 169, 170, 179,

180, 188, 195, 325, 335, 349

Acetylcholine, 284, 285

Acetyl-glyceryl-ether-phosphorylcholine,

280

Acidic decomposition, 334, 335

Actinobacteria, 231

Addition-cure liquid silicone rubber

(ALSR), 59

Adenocarcinoma cells, 55

Aflatoxin B1, 2 Agonist, 134

Agrochemical, 2, 4

Alanine, 69, 172, 174, 228, 231, 295–297,

305

Albonoursin, 266, 293, 294

Aldol condensation, 93, 125, 313, 314, 330,

331, 333, 336, 338, 346

Aldose reductase, 52

Aliphatic substituents, 155

Alkaloid, 48, 76, 232, 284

Alkaloidal salts, 19

Alkyl

(aryl) isothiocyanate, 151

isothiocyanate (AITC), 118, 149, 153 orthoformates, 190 Alkylating, 189, 190, 202, 313, 330, 331,

335, 346

agent, 189, 190, 193, 334, 335, 346

reagents, 331

Alkyldithiocarbamate, 164

Allyl

bromide, 313, 323, 331, 333, 346

isothiocyanate, 149

Alzheimers disease (AD), 136, 280 Amauromine, 240

Amino

acid

hydantoins, 42–46

methyl ester, 118, 295, 334

acyl-tRNAs (aatRNAs), 231, 293

barbituric acid, 87, 88

butyric acid, 222, 285, 298, 299

groups, 30, 39, 311, 330

Ammina-(3-amino-2-indanespiro-5­ hydantoin)-dichloridoplatinum (II), 56

388

Ammonium carbonate, 63, 64, 79, 185 cyanide, 170 Amnesia, 280 Amoenamide A, 276 Amylase, 137 Amyotrophic lateral sclerosis (ALS), 280 Anandamine, 285 Anaphylaxis, 280 Androgen deprivation therapy (ADT), 135 hormones, 135 receptor (AR), 50, 51, 135, 136 Angiogenesis, 60, 135, 144–147, 253, 284 Anhydrous ammonia, 81 calcium sulfate, 81 sodium sulfate, 90 Aniline, 77, 191, 194, 198, 335, 341 Animal xenograft model, 53 Anthranaphtopiazin, 19 Antiamnesic agents, 280 Anti-angiogenic therapy, 144 Anti-apoptotic protein, 53 Antiarrhythmic, 144–146, 279 Antibacterial properties, 191 test, 58 Antibiotic, 266, 270, 279, 294, 347 Anticancer, 49, 53–57, 98, 139, 149, 238, 239, 253, 279, 284 activities, 53, 55, 56 agents, 49, 53 cisplatin, 55 Anticarcinogenic, 133, 144, 147 Anticonvulsant, 46, 61, 133, 144, 146 agent, 61 drug, 46 Antidepressant, 50, 61 Antiepileptic drugs, 146 Anti-HIV, 61, 144, 282 Antihypertensive, 61, 279 Antimicrobial, 49, 57, 58, 60, 61, 96, 98, 133, 141–143, 268, 275, 279 Anti-microtubule agents, 280 Anti-migratory potential, 56 Antimutagenic, 133, 144, 147 Antineoplastic pyrrologuanidines, 47

Index

Anti-neuroinflammatory activities, 47 Antinociceptive, 61 Anti-parasite agents, 133 Antiplasmodial activity, 48 Antiproliferative activities, 53, 54, 61 effect, 288 Antischistosomal hydantoin, 51 Antiseizure drugs, 146 Antithyroidal, 133 Antituberculosis, 61, 272 Antitumor, 6, 46, 61, 133, 147, 148, 263, 266, 279, 287 activity,, 263 Antiviral protease inhibitors, 287 Anxiolytic agents, 280 Apalutamide, 135 Aplaviroc, 282 Apoptosis, 51, 54, 135, 140, 145, 269, 283, 288 Aranotin, 268 Archaeon, 231 Arginine, 85, 157, 222 Armillaria mellea, 275 Armoracia rusticana, 47 Aromatic, 7 aldehyde, 154, 160, 161, 187, 188, 192, 193, 303, 351 amines, 159, 194, 335, 351 compounds, 1 Arthrobacter citreus, 274 Aryl isothiocyanate, 128, 131, 152, 153, 155, 156 methyl groups, 225 piperazine-substituted 5-(4-fluorophenyl)5-methylhydantoins, 50

substituted hydantoins, 50

sulfonyl chloride, 188, 189 Aspartic acid, 30, 297 Aspergamide A, 250 Aspergamide B, 250 Aspergilazine A, 261 Aspergillus, 141, 142, 231, 239, 240, 246, 248–250, 252, 258–261, 266, 268–270, 272, 276, 278, 279 flavus, 141, 142, 258, 272 Aspirochlorine, 268

Index

389

Atherosclerosis, 144, 283

Atonic seizures, 146 Attenuated total reflectance fourier transform infrared spectroscopy (ATR-FTIR), 224 Aug-cc-PVQZ, 39, 41, 118, 123–125 Aurantioemestrin, 276

Austamide, 245

Autoimmune disorder, 150

Autonomic system, 285

Autotaxin, 288

Avrainvillamide, 250

Awamori, 230

Axinella, 47

Axinohydantoin, 48

Azacyclobutane, 28 Azacyclopentane, 28 Azepine, 77 Azetidine, 28 Azimilide, 61 Azine, 335 Aziridine, 349 Azocine, 21, 338 Azolidine, 28 Azosine, 19

B Bacillus brevis, 294

licheniformis, 294

pumilus, 274

species, 294

subtilis, 58, 142, 254, 274, 275

Backbone amide linker (BAL), 311

Barbiturates, 146

Barettin, 245, 285

Barium hydroxide, 167, 185

Basic condition, 125, 151, 166, 293, 331

Bavistin, 274

Benzaldehyde, 77, 126, 163, 176, 178, 192,

193, 304, 313, 323, 326, 336

Benzhydryl-phenylurea, 71, 166 Benzil, 166, 167, 184 Benzo, 5, 26, 50, 52, 55, 77, 78, 162, 336 diazepines, 146 triazole, 9, 66, 309 Benzyl alcohol, 65, 66, 297, 341

hydantoin alcohols, 93

idene hydantoins, 93

isonitrile, 77

L-alaninate, 290

Bicalutamide, 135

Bioantimutagens, 147

Bioavailability, 3, 53, 279

Biocidal activities, 95, 96

Biofouling, 280 Biological

activities, 49, 133, 253, 279, 289, 352

agonists-antagonists (protein

receptors), 50

antibacterial agents antiviral agents

anti-parasite agents, 141

anticancer agents, 53

antimicrobial agents, 56

enzyme inhibitors, 136 hydantoins (medical applications), 60

practical medical activities, 144

protein inhibitors, 51

protein ligands, 134

quorum-sensing molecules, 280

Bionectin A, 253

Bionectin B, 254

Bis(2-oxooxazolidin-3-yl)phosphinic chloride (BOP-Cl), 309

Blood

brain barrier, 46

lymph systems, 147

Boat conformation, 224–226 Botryodiplodia theobromae, 275

Bovine serum albumin (BSA), 292

Breast

cancer, 53–55, 61, 287

carcinoma, 139

Brevianamide A, 275, 249

Brevianamide F, 275

Brevibacillus brevis., 294

Brevicompanines A-C, 240

Bridged

cyclic compound, 1

structural scaffolds, 2 Bridgehead, 5, 13

Brocazine A, 268 Brocazine F, 268 Brocazine G, 268 Bromination, 73, 96, 343, 346, 349

390

Index

Bromophenol thiohydantoin, 138

Bromophenyl

groups, 39

rings, 39

Bromotri(pyrrolidin-1-yl)phosphonium

hexafluorophosphate (PyBrOP), 309 Bucherer-Bergs reaction, 63–65, 98

Butyrine, 69

Butyrylcholine, 284, 285

Butyrylcholinesterase, 279, 285

C Calcite, 222

Calcium

channel, 146, 264, 279

mobilization, 280 Calpains, 281

Cancer development, 144, 145, 147

Candida albicans, 58, 141, 142, 270

Cannabinoid receptor, 134

Capillary gas chromatography, 98

Carbamate derivative, 342

Carbanion, 313

Carbazole, 12, 48, 337, 338 Carbethoxyaminoacetonitrile, 169

Carbocycles, 1, 2, 28, 32

molecules, 2

ring, 29

Carbohydrate, 7, 9, 137, 148

Carboline, 52, 290

Carbon

compounds, 1

disulfide, 170 heteroatom bond, 3

Carbonyl

group, 39, 43, 45, 93, 117, 128, 169, 223,

305, 313, 330, 334, 335, 337, 338,

341–343, 347, 348

metallo immunoassay (CMIA), 97

Carboxamides, 146, 153, 165

Carboxyl

chloride, 290

group, 29–31, 143, 167, 289, 290, 304,

306, 307, 311

Carboxylic acid, 71, 228, 230, 295,

299–301, 305, 317, 318

Carcinogen, 147

Carcinopreventive agent, 147

Caspase-independent fashion, 145 Castration-resistant prostate cancer (CRPC),

135

Cataract, 281

C-C chemokine receptor type 5 (CCR5),

279, 281, 282

C-di-AMP synthase, 137, 138

Celite pad, 345

Cell

proliferation, 135, 283, 288 typespecific functions, 281 Central

nervous system, 134, 148, 275, 280

Tuber Crops Research Institute farm, 274 Chaetocochin J, 254

Chaetomin, 254

Chalcogen, 20

Characterization methods, 31 Chemical

messengers, 284, 285

synapse, 285

Chemokine, 279, 281, 282

Chemotherapeutic agents, 284

Chetomin, 254

Chetoseminudin A, 254

Chetracin A, 254

Chetracin B, 254

Chinochinolines, 19

Chinopyridine, 19

Chiral

auxiliary group, 68, 304

stationary phase, 98

Chloramide, 96

Chlorination, 59, 96, 164

Chloroacetyl chloride, 320

Chloroform, 45, 155, 157, 175, 320, 328,

329, 335

Chlorosulfonyl isocyanide (ClSO2NCO), 64

Chlorotrimethylsilane, 348

Cholinesterase, 284, 285

Chroman, 80

Cialis, 289

Cinnamoyl isothiocyanate, 152

Cis-amido functional group, 229 Cis-cyclo(L-Leu-L- Pro), 222

Citreoindole, 238

Cladosporin A, 273

Cladosporin B, 273

Clodantoin, 62

Index

Clostridium (Zymobacterium) oroticum, 52

Cocaine, 285

Cognitiveenhancing properties, 280

Colon

adenocarcinoma cells, 51

cancer, 53, 61, 269, 272

Column chromatography, 81, 90, 91, 165,

171, 172, 176, 178, 183, 184, 196, 199,

322, 324, 329, 333, 334, 344, 345, 348

Combinatorial library, 151, 153

Combretastatin, 54, 76

Compendium, 4, 5

Comprehensive descriptors for structural statistical analysis (CODESSA), 46

Configuration, 157, 188, 315, 349 Conjugation, 39, 190

Controlled pore glass (CPG), 200, 308

Conventional solution-phase synthesis, 153

Coordination polymer, 28, 322

Copper amalgamated cathodes, 343

Coumarone, 19

Coxsackievirus-A21 (CVA21), 60 Craniofacial anomalies, 62 Cristatin A, 245

Cristatumin A, 245

Cristatumin C, 261

Cristatumin E, 259

Cross-linked polystyrene, 308

Crude oil, 88

Crystalline precipitate, 198

C-terminal glycine monomer, 292

Cultured human melanocytes, 137

Cuminaldehyde, 63

Cuminum cyminum, 63

C-X-C chemokine receptor 4 fusion protein (CXCR4), 47

Cyanide

dye, 13

free silver electroplating process, 95 Cyanohydrin, 65, 351

Cyclic

compounds, 1, 32

di-adenosine monophosphate, 138

dinucleotide synthase, 138

dipeptide, 221, 222, 295, 299, 306

molecule, 1, 2, 20, 39, 68, 162

nucleotide, 288

phosphodiesterase, 288

reaction, 180

391

Cyclo(3,5-di-tertbutyl-tyrosine-Pro), 280

Cyclo(Leu-Gly) related DKPs, 280

Cyclo(L-Pro-L- Met), 274

Cyclo(L-Tyr-L-Ala), 226, 228

Cycloaddition, 16, 73, 75, 76, 292, 338–340

Cyclobutane, 1

Cyclodipeptide, 231, 293

synthase (CDPS), 231, 293, 294

Cyclododecanone (CDD), 161, 182

Cycloechinuline, 245

Cyclohexanecarbaldehyde, 351

Cyclohexenyl isonitrile resin, 305

Cyclooxygenase (COX), 137, 139

Cyclopentadiene, 199, 316, 328

Cyclopropane, 1, 280

Cysteine

aspartic proteases, 145

dependent aspartate-directed proteases, 145

hydantoin, 80

Cytosine, 41

Cytotoxicity, 53–55, 138, 144, 148, 238,

245, 249, 254, 266, 277

D D-(-)-phenylglycine, 291

D-2-hydroxyglutarate, 138

DAB-thiohydantoin-amino acids, 132, 133

Dehydro

DKP, 313

moiety, 314

Dementia, 285, 289

Dendrophyllidae, 48

Density functional theory (DFT), 224, 225 calculation, 225

Desulfurization, 126, 156, 167 Dethiosecoemestrin, 276

D-glucopyranosylidene-spiro-thiohydantoin,

140

Di(1H-imidazol-2-yl)methanone, 81 Diastereoselective, 69, 155, 178, 334, 349

migration, 68

Diatretol, 265

Diazine, 19 Diaziridine, 15 Diazoxine, 19 Dichloromethane (DCM), 82, 83, 86, 93,

155, 156, 161, 181, 199, 309, 326–328,

334, 343, 344

392

Dickman condensation, 330 Dicyclohexylcarbodiimide (DCC), 65, 77, 82, 154, 290, 295, 297, 308, 316, 318 Dicyclohexylurea (DCU), 65, 82, 318 Diels-Alder cycloaddition, 191, 301, 316, 317, 338 reaction, 190, 191, 312, 338 Diethyl ether, 88, 174, 195, 334, 345 fumarate, 79 Differential scanning calorimetry (DSC), 224 Diglycine, 222, 299 Dihedral angle (thiohydantoins), 118 Dihydroflavin mononucleotide (FMNH2), 288 Dihydroorotate dehydrogenase (DHODH), 275, 287, 288 Dihydrotestosterone, 135 Diisopropylcarbodiimide (DIC), 155, 156, 176, 177, 180, 308, 309, 311 Diisopropylethylamine (DIEPA), 64, 77, 180, 295, 311, 322, 336 Diketopiperazine (DKPs), 30, 221–223, 225–233, 238–241, 245, 248, 253, 258, 261, 262, 265, 268, 272, 274–276, 279–282, 284, 285, 287–299, 303–306, 311, 313, 314, 316, 330–332, 334, 335, 348, 349, 351, 352 containing natural products, 231, 289, 293 Dimethyl amino-1-naphthyl isothiocyanate, 200 hydantoin formaldehyde resin, 97 sulfate, 168, 186 Dipeptides, 221, 222, 291–293, 295, 296, 311, 312, 351 Dipheniazin, 19 Diphenyl-phosphoroisothiocyanatidate, 201 Diphosgene, 341, 342, 346 Dipodazine, 246 Di-tert-butyldiaziridinone, 73, 92 Dithiohydantoin, 117, 125, 167, 202 Dithiosilvatin, 276 DNA, 139, 288 replication, 139 topoisomerase I, 137, 139 Docetaxel, 284 Dopamine, 137, 285 Dopaquinone, 137 D-p-dodecyloxyphenylglycine, 229

Index

D-phenylglycine amide, 294 Dragmacidin B, 343, 347 Drug delivery agents, 280 discovery, 49, 148 Dynamic kinetic resolution, 97 Dyslipidemia, 146

E Escherichia coli, 41, 57–59, 61, 95, 96, 140–142, 245, 259, 267, 273, 275, 294 Edman agent, 199 degradation, 131, 199 Electric eel acetylcholinesterase, 279 Electron-donating abilities, 95 groups, 152, 165 Electronic activation, 191 circular dichroism (ECD), 224 properties, 69 Electron, 1 rich aromatic rings, 69 withdrawing group, 71, 152, 159, 165, 167, 191, 312, 313 Emestrin, 269 Emestrin B, 269 Emethacin A, 276 Emethacin B, 276 Emethallicin E, 269 Enantiopure quaternary proline derivatives, 69 Enantioselective, 155, 351 arylation, 69 autocatalysis, 351 catalytic species, 351 synthesis, 330 Enantiospecificity, 294 Endocannabinoid system, 134 Endogenous neurotransmitter serotoin, 134 Enolization, 68 Enterobacter aerogenes, 57, 58, 259 Entomopathogenic nematodes (EPN), 274 Environmental perturbations, 145 Enzalutamide, 135 Enzyme catalyzed, 77, 230, 289, 293, 294 chemical reactions, 293

reactions, 293

Index

393

inhibitor, 202

Eosinophils, 282

Epiamauromine, 240

Epicoccin G, 273

Epicoccin T, 269 Epicoccin U, 269

Epicorazine A, 270 Epicorazine C, 270 Epidithiodiketopiperazine alkaloids, 253 Epilepsy, 61, 146

Epinephrine, 285

Epipolythiodioxopiperazine (ETP), 287 Epoxygenases, 139

Erlenmeyer flask, 327 Erythrochelin, 295

Erythrocyte cholinesterase, 285

Erythromycinproducing bacterium, 294

Ethotoin, 50, 61

Ethyl

2-amino-2-thioxoethyl-carbamate, 169, 186

2-cyano-2-formamidopropanoate, 170 2-isothiocyanatoacetate and

(2-chlorophenyl) methanamine, 160

2-(1,3-diisopropyl-2,5-dioxoimidazolidin4-yl)-3,3,3-trifluoropropanoate, 89 4,6-dichloro-3-((3-isopropyl-2,4-dioxo­ imidazolidin-1-yl)methyl)-1H-indole2-carboxylate, 86

4,6-dichloro-3-formyl-1H-indole-

2-carboxylate, 86

acetate-petroleum ether, 160, 181

glycinate hydrochloride, 81, 298, 320

Ethylene glycol, 196, 298

Exo-selective, 191

Exserohilone, 273

F Farnesol, 286

Farnesyl

group, 286

protein transferase (FPTase), 279 transferase, 286, 287 inhibitors, 286

Fatty acid hydrolase, 137, 140

Fetal hydantoin syndrome, 62

Fibrin, 283

Fibrinolysis, 283

Fibronectin, 283

Firmicutes, 231

Flash chromatography, 89, 92, 181, 345, 350

Flattened-chair conformation, 224, 226 Flavin mononucleotide (FMN), 288

Fluoro flash cartridge, 82, 83 Fluorous copper(II)-carboxylate complex, 65

Flutamide, 135, 148

Foodstuff, 222 Formaldehyde, 125, 191, 202, 303, 304,

336, 352

Fosphenytoin, 50, 61

Fourier transform infrared spectroscopy

(FT-IR), 97 Fractional crystallization, 325, 331 Fragmentation pathways, 128

Fukuyama-Mitsunobu alkylation, 292

Fumaramate, 74

Fumaric acid, 71

Fumitremorgin A, 240

Fumitremorgin C, 240, 275

Fungicides, 62, 117, 133, 191, 274

Furan, 22, 26, 61, 136, 140, 183, 275

2-ylmethanamine, 183

Furfural, 351 Fusarium oxysporum, 57, 274

Fused cyclic molecule, 1

G G protein, 134, 135, 282

Gabriel primary amine synthesis, 187

Gas chromatography

mass spectrometry (GC/MS), 274 negative ion chemical ionization-mass

spectrometry (GC-NICI-MS), 200

Gasotransmitters, 285

Gastric cancer, 281

Gastrodia elata, 275

Gel

permeation chromatography, 93

type

polymers, 308

supports, 308

Genetic disorders, 281

Geranyl, 286

pyrophosphate, 286

transferase, 286, 287 Glacial acetic acid, 81, 85, 185

Glaucoma, 285

394

Index

Gliocladine A, 255

Gliocladine B, 255

Gliocladine C, 255

Gliocladine D, 255

Gliocladine E, 255

Glionitrin A, 270

Gliotoxin, 270, 272, 286

Gliotoxin G, 270

Gliovictin, 277

Globus pallidus, 134

Glucopyranosylidene-spirohydantoin, 52

Glycine anhydride, 221, 323

Glycogen phosphorylase, 137, 140

Glycosidase, 137

Glycosylases, 41, 42

Glycosylation moieties, 283

Glyoxal, 71, 72, 91

G-protein-coupled superfamily, 134 Gramicidin S, 294

Gram

negative bacteria, 57, 58, 95

positive bacteria, 57, 58, 95, 138, 247

Graphenes, 1

Grignard reagent, 125, 194, 342

Griseofulvin, 2 Grote reagent, 202

Growth hormone

inhibiting hormone (GHIH), 134 release-inhibiting hormone (GHRIH), 134 Guanidine, 46, 48, 351

Guanidinohydantoin (Gh), 41

Guanine, 41

Gypsetin, 240

H Hageman factor, 283 Halamine, 95 Halimide, 266 Halogen, 20, 58, 144, 349 Haloterrigena hispanica, 231

Hantzsch-Widman nomenclature, 18, 21

system, 18, 19, 32

Helicoverpa zea, 252, 280

Hematopoietic cells, 134 Hemimycale arabica, 46

Hemimycalins A, 46, 61 Herbicides, 62, 117, 133

Heroin, 285 Herpes simplex virus, 60, 133, 143 Heteroatom, 3, 5, 6, 8, 18–21, 26, 28, 29 Heterocycle, 2–4, 6, 12, 17–20, 22, 24–32,

39, 279, 316

compounds, 2–4, 6, 9, 17–22, 25–30

moieties, 2, 30, 143

molecules, 2

product, 69

ring, 2–5, 26, 28, 29, 157

scaffolds, 30 structures, 4, 17

systems, 27

Heterodimer, 258 Heteromonocyclic compounds, 19, 20, 23, 26 Hexafluorophosphate, 297, 309, 311 Hexahydropyrrolo[2,3-b]indole, 258

Hexanal, 351 Hirsch funnel, 292 Histamine, 269, 285 Histone deacetylase 6 (HDAC6), 54

HIV-1 integrase, 137, 140

PR aspartic proteinase, 279

Homeostasis, 138 Homocysteine, 225 Homodimer, 258, 287 Horner–Emmons reaction, 313, 315 Hückels rule, 1, 32 Human cerebellum microglial cells, 134

cervical carcinoma, 139

dihydroorotate dehydrogenase

(HDHODH), 279 immunodeficiency virus, 133 Top1, 139 tumor cell lines, 53, 55, 56

umbilical venous endothelial cells

(HUVEC), 144 Hyalodendrin, 277 Hydantoin, 30, 39, 41–79, 85, 90, 91,

93–98, 117, 118, 133, 134, 145, 146,

167–170, 185, 187, 190, 194, 289

derivatives, 49, 51

lesion, 41

moiety, 49, 95

ring, 39, 46, 95, 96, 169

Hydantoins

Index

395

Hydantoinylacrylamide, 96 Hydrazides, 300 Hydrazone, 75, 158, 162 Hydrogen peroxide, 41, 94

sulfide, 169, 186, 285 Hydrogenation, 20, 153, 175, 290, 297, 342 Hydrothermal reactions, 299 Hydroxylamine hydrochloride, 328 Hydroxylase, 47, 52 Hydroxymethyl benzoic acid, 311, 312 group, 352

Hydroxypropyloxymethylpolystryene resin, 155, 177

Hymeniacidon, 47

Hyperactivation, 281 calpains, 281

Hyperlipidemia, 146 Hyperlipoproteinemia, 146 Hyperpigmentation, 137 Hyperthyroidism, 150 Hypochlorous acid, 41 Hypolipidemic agents, 133, 146, 147 Hypothyroidism, 150

I

Imidazole, 12, 19, 47, 48, 56, 78, 142, 183,

188, 315, 316

Imidazolidin-2,4-dione, 39, 61 Imidazolones, 72 Iminohydantoins, 69, 77

Immunoassay, 97

In situ cyclization, 299 In vitro vascularization, 54 In vivo efficacy, 284 Indazole, 26 Indole, 12, 14, 48, 52, 53, 67, 76, 82, 83,

86, 90, 161, 232, 238–240, 290, 316, 341,

344, 345

amine 2,3-dioxygenase (IDO), 137, 140

moiety, 53, 232, 238, 239

Indoline, 239, 335

Inflammation, 140, 145, 280 Inhibitory neurotransmission, 135

Intermolecular dehydration coupling, 299

International Union of Pure Applied Chemistry (IUPAC), 17, 18, 117, 335

nomenclature system, 117

Intracellular

amastigote, 142

localization, 281 replication niches, 145

transport, 284

Intramolecular cyclization, 77, 156 Ion channel blocker, 49, 52

Ionic liquid

bound tryptophan, 66

phase strategy, 156

supported amino acid, 156, 180

Irine, 20, 21

Irreversible tissue damage, 281

Isatin, 161

Isobutyraldehyde, 304, 351

Isocitrate dehydrogenase (IDH), 137–139 Isocyanate, 65, 73, 74, 79, 82, 86, 92, 177,

193

Isocyanocyclohexane, 198

Isoform-selectivity, 54 Isoleucine, 184, 231, 296, 298, 304

Isomeric imidazo-[2,1-b]thiazole derivatives, 190

Isonitrile, 77, 153, 300, 301, 303–306

Isoquinoline, 26, 67, 336, 339

Isosteric replacement, 2

Isothiocyanate, 117, 150–161, 165, 167,

174, 175, 178, 181, 199

Isoxazole, 154, 178 Isoxazolothiohydantoin, 178

J Jadomycin B, 2

K Kallikrein, 283

Kamlet-Taft solvatochromic equation, 46 Ketimine, 161

Klebsiella pneumoniae, 57

Kojic acid, 137, 138

L L,L- dipeptide of L-phenylglycyl-L­ phenylglycine methyl ester, 294

Lactobacillus

casei, 275

396

Index

plantarum, 274

Laminin, 283

Lansai A, 240

Lanthanide coordination polymers, 299

Layer-type structure, 228

Lepidium meyenii Walp, 48

Lepistamide A, 265

Leptopsammia pruvoti, 48

Leptosin C, 256

Leptosin F, 256

Leptosin K, 256

Leptosin M, 256

Leptosin O, 261

Leucine, 69, 153, 231, 232, 295–298, 304,

311, 326, 335

Leucocyte

elastase, 52

functions, 280 Lewis acid, 63, 188

Ligand, 50, 51, 55, 94, 134, 135, 299

Limonin, 2

Linear tape orientation, 228

Linguistic monstrosities, 18

Lipid, 3, 146, 286

lowering drugs, 146

Lipophilicity, 2, 44, 46, 131

Lipoxygenases, 139

Liquid chromatography-mass spectrometry

(LC-MS), 274

Lithium

2-isocyano-2-methylpropan-1-olate, 305

tri-tert-butoxide aluminum hydride, 338

L-leucyl-L-alanylglycyl-L-valine, 307

L-phenylglycine, 294

L-pyroglutamyl-L-histidyl-L-prolineamide,

280

Lumpidin, 238

Lysine, 69, 127, 156, 222, 253, 292, 298

Lysobacter capsici AZ78, 274, 275

M Macrophages, 282

Macro-porous silica, 297

Maculosin-1, 265

Maculosin-2, 264

Magnesium sulfate, 326, 346 Malbrancheamide B, 250

Male sexual phenotype, 135

Malignant neoplasm, 147

Mannich reaction, 125, 126, 187, 191, 202

Maraviroc, 282

Maremycin A, 238

Maremycin B, 238

Maremycin C1, 238

Maremycin C2, 238

Maximal electroshock seizure (MES), 63, 146 Medical applications, 49, 60, 62, 147, 149, 150

Medicinal chemistry community, 150

Melanin, 137

Melanogenesis, 137, 138

Melanosomes, 137

Melinacidin IV, 256 Membranespanning transmembrane protein,

137

Mephenythoin, 50, 61

Mesoderm cell precursors, 144

Metabolic rates, 279, 280

Metabolite, 2, 246–248, 284, 295

Metal nanoparticles, 189

Metallated nitrile, 69

Metallonitriles, 69

Meta-nitrobenzaldehyde, 351 Metastatic castration-sensitive prostate

cancer (mCSPC), 135

Metathesis, 9

Methacryloyl chloride, 58

Methetoin, 61

Methicillin-resistant Staphylococcus

aureus (MRSA), 57, 141, 142, 253, 254

epidermidis (MRSE), 57

Methionine, 69, 232

Methyl

(1S,2S)-1-amino-2-phenylcyclopropane­ 1-carboxylate, 350

(R)-2-((tert-butoxycarbonyl)amino)-2-(4­ (dodecyloxy)phenyl)acetate, 324

(S)-3-(3,6-dioxopiperazin-2-yl) propanoate, 290

bromoacetate, 168

glycinate hydrochloride, 86

leucinate hydrochloride, 304

levulinate, 30

L-isoleucinate, 181

O-benzyl-N-((benzyloxy)carbonyl)-L­ seryl-L-serinate, 318, 319

phenylacetate, 92

thiohydantoin-tryptophan (MTH-trp), 148, 149

Index

397

transferase, 270 Micrococcus luteus, 57, 274

Microplate assay, 274

Micro-sequencing, 132

Microwave

assisted air oxidation, 75

irradiation, 67, 71, 78, 79, 82, 125, 151,

152, 154, 157, 166, 172, 184, 187, 188,

289, 292, 301, 302, 309, 331

pulses, 185

Minimum inhibitory concentration (MIC),

57, 258, 141

Mitosis, 284

Mivacurium, 285

Mold, 95, 268, 270

Molecular

dynamic simulation, 95

fragments, 3 mass, 222, 299

modeling, 6, 229

Monoclinic system, 226

Monocyclic compound, 1, 20–22, 25

Monograph, 9, 11

Monolithic nanoporous foam, 59 Montmorillonite, 222

Morphine, 2

Morpholine, 125

Multi-component reaction, 7, 153, 188,

191–193, 299, 352

Multidomain enzyme complexe, 231 Multidrug efflux pump activity, 51 resistance (MDR), 57

Multimodular enzymes, 293 Mummy

horemkenesi, 223

khnum nakht, 223

Mutagen, 147, 149

Mutation, 139, 147, 282

Mycobacterium tuberculosis, 142, 280

Mycocyclosin, 265

Myoblasts, 281

Myoclonic, 146

N N,N-dimethylurea, 76

N,N-dimethylformamide (DMF), 71, 79,

85, 88, 151, 152, 161, 165, 173, 174,

176–179, 190, 198, 228, 309, 313, 318,

323, 324, 331, 333, 345

N-alkylation, 189, 190, 331, 332

Naphthalene, 19, 26, 47, 58, 61, 199

Naphtho, 26, 192

Natural abundance, 230

other important DKPS, 275

phenylalanine tyrosine-containing DKPS,

261

phenylalanine annulated DKPS, 272

phenylalanine-tyrosine-containing

DKPS, 265, 268

simple phenylalanine-tyrosine­ containing DKPS, 261

proline-containing DKPS, 274

tryptophan DKPS, 232

annulated tryptophan, 240

homodimers-heterodimers (tryptophan­ containing DKPS), 258

modified tryptophan, 238 simple tryptophan-containing DKPS, 232

spiro-linked tryptophan, 239

tryptophan-containing DKPS, 245,

248, 253

N-Boc

dipeptide ester, 292

protected amino acid, 289, 295, 305

N-carboxyanhydride (NCA), 30, 298, 319,

320

N-chlorosuccinimide (NCS), 162, 335

Necroptosis, 140, 144, 145

Necrosis, 52, 140, 145, 281

Necrostatin, 140, 145

Neoechinulin A, 246

Neoechinulin B, 246

Neoechinulin C, 246

Neoplasm, 147

N-ethoxycarbonyl-2-ethoxy-1,2­ dihydroquinoline (EEDQ), 290 N-ethylglycine, 175

Neurodegenerative

diseases, 280

disorder, 136

Neuroendocrine neurons, 134

Neurokinin-1 receptors, 279

Neuromodulatory, 280

Neuron, 285

Neuroprotective

398

action, 280

nootropic agents, 280

Neurotransmitter, 134, 284, 285

Neutral monodentate S-coordinative

ligands, 118

N-halamine, 58, 59, 61, 95, 96

hydantoin-containing chitosan, 58

N-halohydantoins, 95

N-hydroxy-5-norbornene-2,3-dicarboxylic

acid imide (HONB), 309 Nigrifortine, 240 Nilutamide, 50, 51, 135

Nirvanol, 46

Nitrofurantoin, 57, 61 Nitrogen atoms, 221, 331

N-methoxycarbonylation, 341

N-methylation, 223, 292, 331, 332

Nocardipsis spp., 294

Nomenclature, 4, 17–20, 22, 25, 26, 28, 29,

32, 117

heterocycles, 18

nitrogencontaining molecules, 18

Non-cumulated double bonds, 20

Non-lysosomal cysteine protease family, 281 Non-nucleoside reverse transcriptase

inhibitors, 143

Non-ribosomal peptide synthetases

(NRPSs), 231, 293, 295

Non-steroidal anti-inflammatory drugs (NSAIDs), 139

Nootropic activities, 280

Norantoin, 61

Norepinephrine, 285

Norgeamide A, 238

Norgeamide B, 239

Norvaline, 222, 297, 298

Notoamide B, 250

Notoamide C, 239

Notoamide F, 250

Notoamide J, 239

Novel spirocyclic alkaloid, 59

N-paramethoxybenzyl protected (R)-3­ isopropylpiperazine-2,5-dione, 346 N-propylglycine, 69

N-substituted amino acids, 152

N-terminal amino acid, 42, 200, 201

Nuclear magnetic resonance (NMR), 43,

127, 128, 151, 224, 225, 229, 292

Index

Nucleic acid, 2

Nucleobases, 42

Nucleophilic, 76, 93, 151, 156, 165, 190,

300, 302, 303, 308, 313, 330, 341, 342,

346, 347, 349

nature, 300

substitution, 165, 330, 346, 349

Numerous neurofibrillary tangles (NFTs), 136

O O-(1,2-dihydro-2-oxo-1-pyridyl-N,N,N,N­ tetramethyluronium tetrafluoroborate

(TPTU), 309 O-(5-norbornene-2,3-dicarboximido)­ N,N,N,’N’-tetramethyl-uronium

tetrafluoroborate (TNTU), 309 O-(6-chlorobenzotriazol-1-yl)-N,N,N,’N’tetramethyluronium hexafluorophosphate

(HCTU), 309 O-(7-azabenzotriazol-1-yl)-N,N,N,’N’tetramethyluronium hexafluorophosphate (HATU), 309 tetrafluoroborate (TATU), 309 O-(benzotriazol-1-yl)-N,N,N,N­ tetramethyluronium

hexafluoro-phosphate, 309 tetra-fluoroborate (TBTU), 309 O-(N-succinimidyl)-1,1,3,3-tetramethyl­ uronium tetrafluoro-borate (TSTU), 309 O-benzotriazol-1-yl-tetramethyluronium

(HBTU), 295, 296, 309, 311 O-diphenol, 137

Oidioperazine A, 277 Oidioperazine B, 277 Oidioperazine C, 277 Oidioperazine D, 277 Oidioperazine E, 278 One-pot synthesis, 75, 178, 180, 187, 301,

331

Opioid, 279, 285

Organic

molecules, 1, 2, 4, 146

process research development, 344

synthesis, 29–31

Organometallic, 69

complexes, 95

compounds, 27

Ortho-methoxybenzaldehyde, 351

Index

399

Ortho-nitrobenzaldehyde, 301 Osteon myospalacem baileyi, 264, 275, 288

Osteosarcoma cells, 60

Oxacyclobutane, 28

Oxacyclopropane, 28

Oxadiazole, 125, 126 Oxalaldehyde, 71

Oxalosuccinate, 138

Oxazine, 317, 328, 329 Oxazole,, 19 Oxazolidinones, 94 Oxazolines, 30, 305 Oxidative

damages, 42

halogen, 95, 96

Oxidoreductases, 231

Oxytocin, 279

P Parazoanthus axinellae, 46, 47

Palladium-catalyzed one-pot synthesis, 74 Paraherquamide E, 251

Paraherquamide F, 251

Paraherquamide G, 251

Para-methoxybenzaldehyde, 351 Para-methoxybenzyl, 346 Para-nitrobenzaldehyde, 351 Parasite encapsulation, 137

Parazoanthines A-E (1–5), 46 Parkinsons disease (PD), 280

Parr Shaker apparatus, 319

Pathogen, 275

Penicillium, 231, 238, 246–249, 251–253,

267, 268, 273, 274, 277

expansum, 274

Pentafluorophenyl isothiocyanate, 200 Peptide

condensation reagent, 289, 307, 352

microtubes (PMT), 228 nanotubes (PNT), 228 Peptidomimetic, 290

Peptidylthiohydantoin, 126

Perfluoroalkyl chains, 153 Peripheral-central nervous systems, 285

Peroxynitrite, 41

Peruvian ginseng, 48

Pharmaceutical

applications, 31

molecules, 2

substances, 3

Pharmacokinetic data, 46

Pharmacological

agents, 146

properties, 288

Phenazine, 19 Phenethylamine, 285

Phenisoiazol, 18 Phenyl

hypochloroselenoite, 56

isothiocyanate (PhNCS), 131, 132, 155,

174, 178, 181, 199, 200

Phenylahistin, 266, 284, 315

Phenylalanine, 153, 171, 222, 228, 231,

232, 261, 265, 268, 272, 275, 295, 296,

298, 299, 304, 315, 335, 342

containing DKPs, 232

Phenylisothiocyanate, 131, 177, 178, 180

Phenylmagnesium bromide, 194

Phenylmethylene hydantoins, 46, 60

Phenylthiocarbamyl, 156

amino acids, 126

group, 156

Phenylureas, 71

Phenytoin, 46, 50, 61–63, 144, 145

Phomazine C, 271 Phophorylase, 52

Phosgene, 65, 305, 319, 341

Phosphate-buffered saline (PBS), 223, 292 Phosphodiesterase (PDE), 138, 279, 287, 288

type 5 (PDE5), 52, 279, 287–289

Phospholipase, 288

Phosphorous

oxychloride (POCl3), 125, 341

pentachloride (PCl5), 295, 296, 341

pentasulfide, 168 Physalospora piricola, 57

Phytophthora infestans, 275, 280

Phytotoxic, 264, 279

Pictet-Spengler reaction, 66, 67, 303

Pinacol rearrangement, 71

Piperafizine A, 266 Piperafizine B, 266 Piperazine, 57, 221, 223, 226, 279, 283,

284, 297, 316, 319, 321–325, 329–331,

333, 335, 336, 338, 341, 343, 346–348

400

2,5-dione, 221, 226, 283, 284, 297, 316,

320–325, 329, 331, 333, 335, 336, 338,

346–348

natural products, 279

Piperidine, 188, 195, 290

Piscarinine A, 246

Piscarinine B, 246

Pivalaldehyde, 351

Plasmin, 283

Plasminogen, 267, 279, 282, 283

activator, 267, 282, 283

inhibitor-1 (PAI-1), 265–267, 279,

282–284

inhibitor-2 (PAI-2), 283

Plasmopara viticola, 275, 280

Platelet aggregation degranulation, 280

Plinabulin, 266, 284

P-nitrobenzaldehyde, 82 Polarity, 2, 44–46, 131, 132, 165, 189, 303,

307

Poliovirus, 60

Poly[1,3-dichloro-5-methyl-5-(4­ vinylphenyl)-hydantoin], 96

Polycyclic compound, 1

Polyethylene glycol (PEG), 154, 165, 189,

196, 308, 309

polypropylene glycol, 308

stabilized nickel nanoparticles, 189 supported amino acids, 154

Polymer surface modifiers, 96 Polymethine, 7

Polyphosphoric acid, 296

Polystyrene (PS), 58, 61, 96, 305, 308, 351

Polyurethane, 96

Position

emission tomography, 51

specific iterative basic local alignment

search tool (PSIBLAST), 293 Post natal growth deficiencies, 62 translational proteolytic cleavages, 201

Potassium

cyanate, 42, 65, 80

thiocyanate (KSCN), 151, 163, 173, 188

Potential disulfide linkage, 295 Powder X-ray diffraction (PXRD), 224 Prearanotin A, 278

Preechinulin, 239

Index

Prenyl groups, 286

Prenylated proline, 248

Prenyltransferase, 231, 286 group, 286

Preparative

methods, 63, 150, 289

cyclization (dipeptide), 289 direct synthesis of DKPS (α-amino

acids), 295

enzyme-catalyzed synthesis (DKPS), 293

general description, 63

practical preparation, 80, 171, 318

2,4-dithiohydantoins, 169

2-thiohydantoins, 150, 171

4-thiohydantoins, 168, 185

alkylidene-arylidene-DKPS, 312

solid phase synthesis (DKPS), 306

UGI multi-component reaction, 299

plate chromatography, 327

Procaine, 285

Proline, 30, 69, 222, 223, 226, 231, 232,

248, 274, 275, 280, 281, 295, 296, 298,

312, 316, 317

containing DKP natural products, 275

Promastigote, 142

Prostaglandin, 139

endoperoxide synthase, 139

Prostaglandin E2 (PGE2), 139

Prostate cancer, 46, 47, 60, 61, 135, 148,

246, 270

Protein

inhibitor, 49, 52, 98

sequence, 117, 199, 201, 202

Proteobacteria, 231

Proton donor, 118, 133

Protozoal infection, 289 Pseudoephedrine, 68

Pseudomonas aeruginosa, 57, 58, 141, 142

P-toluene sulfonic acid, 192 Pu-erh tea, 222

Pulmonary arterial hypertension, 289

Putative prokaryotic CDPS genes, 293

Pyricularia oryzae, 273, 280

Pyridazine, 12, 17, 26 Pyridyl-tagged amino acid, 65

Pyrimidine, 17, 288

Pyrite, 222

Pyroglutamic diketopiperazine, 327

Index

401

Pyroptosis, 145

Pyrrole, 16, 162, 335

Pyrrolidine, 28, 30, 77, 160, 181, 230, 317, 318

2,4-dione, 30

Q Quantitative structure activity relationship

(QSAR), 6 Quaterthiophene, 28 Quinoline, 149 Quinopyridines, 19 Quinoxaline, 19

R Rab geranylgeranyltransferase, 286 Racemization, 97, 290, 314, 331, 332, 351 Radical copolymerization, 58 Raman spectroscopy, 225

Reactions, 93, 187, 343

DKPS, 330, 348, 350

alkylidene-arylidene-DKPS, 348

reactions at 1,4-positions, 331

reactions at 2,5-positions, 334

reactions at 3,6-positions, 346

representative examples for reactions

(1,4-positions of DKPS), 333 reaction (2-thiohydantoins), 187

alkylation, 189

diels-alder reaction, 190

formation of 5-arylidene-2thiohydantoins, 187

mannich reaction, 191

multi-component reaction, 191

reduction, 193

reaction of 4-thiohydantoins, 193 representative reactions (thiohydantoins),

194

general procedure (diels-alder

reaction), 198

mannich reaction (2-thiohydantoin),

197

PEG supported NI nanoparticle

promoted N-alkylation, 196

preparation of (2-pyridinone-3-yl) methylene-2-thiohydantoin, 195

preparation of (e)-4-((5-oxo-2thioxoimidazolidin- 4-ylidene)

methyl)phenyl benzenesulfonate, 195

preparation of (e)-5-((1-methyl1h-indol-3-yl) methylene)-2­ thiohydantoin, 194

preparation of 2-(methylthio)3,5-dihydro-4h-imidazol-4-one derivative, 197

preparation of dimethyl 7-(cyclohexylimino)-3,5,6,7tetrahydro-3-oxo-2,2-diphenyl­ 2h-imidazo[2,1-b] [1,3] thiazine-5,6-dicarboxylate, 198 Reactive oxygen

nitrogen species (RONS), 41

species (ROS), 54, 288

Receptor-interacting protein kinase (RIPK),

140

Recyclable auxiliary, 69

Red blood cell membranes, 285

Refluxing condenser, 198, 199, 327 Regioselectivity, 71, 74, 293

Replacement nomenclature, 18, 25, 28, 29

Resin-bound chloroformate, 305 Restriction endonuclease, 288

Retroviral aspartyl protease, 287

Reverse transcriptase, 287

Rhizoctonia solani, 274

Ribosomal translation, 231

Ring switching, 68

Rink

amide tentagel, 309

isonitrile resin, 305

Roasted malt, 230

Roquefortine C, 247 Roquefortine E, 247 Rostratin A, 271

Rostratin B, 268, 271

Rostratin C, 271

Rostratin D, 271

Rubrumazine A, 247

S Saccharomyces cerevisiae, 275

Saccharopolyspora erythraea, 294

S-alkylation, 189, 190, 194

Salmonella, 58, 142, 149, 275

enterica, 58

typhi, 142, 149

402

typhimurium TA 98, 149 Sarcosine, 343

S-butyl alcohol-phthalate buffer, 131 Scabrosin ester, 271

Scanning electron microscopy (SEM), 224

Schizophrenia, 289 Schöllkopf chiral auxiliaries, 334

compound, 330

reagent, 334, 352

Sclerotiamide, 252

Seesaw conformation, 55 Seizure, 146 Selenium, 24, 25, 56

Semicarbazide, 300 Senile plaques (SPs), 136

Sensory compounds, 223

Serine protease, 137, 283

Serotoninergic 5-HT1A, 279 Sesquiterpenoids, 286

Siderochrome pulcherrimininic acid, 294

Siderophoric activities, 279

Signal transduction, 138, 281

Silica gel chromatography, 83, 321, 323

Silvathione, 278

Simple monoclinic unit, 224

Single-nucleotide insertion, 41

Sirodesmin A, 278

Sirodesmin B, 278

Sirodesmin C, 278

Sodium

bicarbonate, 91, 318

borohydride, 338, 341, 343

cyanate, 65, 81

cyanoborohydride, 153

hydroxide, 201, 202

pyridine-2-thiolate, 347

triacetoxyborohydride (NaBH(OAc)3),

79, 86, 153, 176

Solid

phase

extraction (SPE), 153, 154

peptide synthesis (SPPS), 300,

306–309

synthesis, 153, 154, 289, 300, 311

state NMR (SS-NMR), 224

Solubility, 2, 3, 29, 30, 118, 303, 306, 307

Solution phase

peptide synthesis, 307

Index

synthesis, 307

Solvent-cyclopentadiene, 199

Somatostatin, 134, 285

receptors, 134

subtype 4 (SST4), 134 Somatotropin release-inhibiting factor (SRIF), 134 hormone (SRIH), 134 Sonogashira-Hagihara cross-coupling

reaction, 59

Sphingomyelin, 288

phosphodiesterase, 288

Spirobrocazine A, 273 Spirobrocazine B, 274 Spirobrocazine C, 267 Spiro-carbocycle, 1

Spirocyclic hydantoins, 50

Spirodithiohydantoins, 167

Spiro-DKP oligomers, 318

Spirodon, 61

Spirogamaenzine A, 59 Spiro-heterocycle, 28

Spirohydantoin, 62, 75

Spiroiminodihydantoin, 41

Spirotryprostatin A, 239, 240, 275

Spirotryprostatin B, 247

Sporangia, 274

Sprague-Dawley rats, 63

S-pyroglutamic acid, 327

Squamous cell carcinoma, 148

Stability, 125

Standard deviation, 125

Staphylococcus aureus, 57–59, 61, 95, 96,

141, 142, 253, 254, 258, 268, 274, 275

Stereoselectivity, 69

Steric interaction, 191

Straightforward liquid-liquid phaseswitching process, 65

Streptomyces

gamaensis, 59

NEAU-Gz11, 59 griseus, 264, 281

noursei, 266, 293

thioluteus, 284

Structural

complexity, 232

properties, 288

Subgenomic replication, 60

Index

403

Sublimation apparatus, 334 Succinylcholine, 285 Suction filtration, 88 Sulfonamides, 300 Sulfur-catenated DKPs, 232 Supercritical condition, 222 Superoxide, 41 Supramolecular chemistry, 7 structure, 227, 229, 230 Surface-type supports, 308 Systematic nomenclature system, 22 Systemic circulation, 283

T Tadalafil, 289 Taichunamide A, 252 Taichunamide D, 252 Talathermophilin A, 247 Talathermophilin B, 247 Tau protein, 136 Taxol, 2, 284 T-butyl isonitrile, 304 T-butyloxycarbonyl (Boc), 30, 82, 153, 154, 156, 180, 289, 290, 292, 295, 305, 307, 315 dipeptide methyl ester, 295 Teflon-lined stainless steel container, 322 Terpene, 286 Terrespirodione A, 278 Terrespirodione B, 279 Tert-butyl (S)-2-(aminomethyl)pyrrolidine-1­ carboxylate, 181 hypochlorite, 45 isonitrile, 304 Terthiophene, 28 Tesetaxel, 284 Tetrabutylammonium bromide (TBAB), 72, 79 iodide (TBAI), 322, 331, 333 Tetrahydro-2H-pyran, 148 Tetrahydrofuran, 22 Tetrantoin, 61 Theoretical molecular descriptors, 46 Thermometer, 91 Thiazole, 12, 14, 18, 19, 165, 170, 295, 316 Thietan-2-one, 30

Thin-layer chromatography (TLC), 44, 45, 82, 85, 89, 91, 93, 131–133, 181–184, 196, 325, 333, 345 Thioalkyl group, 190 Thioamide derivative, 186 Thioamido group, 117, 125, 126, 133 Thiocarbonyl compounds, 334 group, 117, 128, 151, 163, 164, 187, 194 Thiohydantoin, 30, 47, 71, 79, 95, 117, 118, 125, 127, 128, 131, 133, 134, 136,

139, 141–143, 147, 150, 152–156, 159,

163–169, 187, 188, 190, 191, 193, 194,

199, 201, 202

amino acid derivatives, 201

castanospermine glycomimetics, 140

Thionyl chloride, 66, 83 Thiophene, 12, 15, 24, 26, 28, 143 Thiophosgene, 160, 164, 181 Thiosemicarbazide, 161, 162, 182 Thiourea derivatives, 152, 160, 166 Thioxohydantocidin, 62 Thrombosis, 283 Thrombospondin, 283 Thromboxanes, 139 Thymidine, 41, 42 Thyroid releasing hormone (TRH), 275, 280 stimulating hormone (TSH), 150 Thyrotropin-releasing hormone, 280 Tick-borne encephalitis, 282 Tissue plasminogen activator (tPA), 283 Tobacco mosaic virus, 59 Tolupiazin, 19 Traceless synthesis, 67, 69, 156 Traditional synthetic methods, 31 Trametes versicolor laccase (TvL), 77 Trans-cis-diastereomers, 346 Transferase, 231, 248, 286, 294 Traumatic injury, 280 Trialkyl phosphite, 192 Triazane, 19 Triazole, 52 Tributylphosphine, 75 Tributylsilyl isothiocyanate (TBuS-ITC), 201 Tricholomataceae, 275 Triclinic unit cell, 224 Tricyclic

404

Index

amidine derivatives, 297

hydantoin derivative, 69, 76

Triethylamine, 78, 83, 86, 89, 91, 152, 153,

160, 173, 175, 178, 181, 188, 318, 320,

324, 326, 336

Trifluoroacetic acid, 156, 199, 228, 316,

324, 326, 335

Trifluoroethanol, 301, 303–305 Triglycine, 222, 299 Trimethyl amine, 304, 335

orthoformate (TMOF), 178, 305 silanecarbonitrile (TMSCN), 84 silyl trifluoromethanesulfonate

(TMSOTf), 335–337, 339 Tri-n-butylphosphine, 92

Triphosgene, 341, 342 Tris(dimethylamino) titanium, 334 Trisubstituted allenamides, 94 Tropolone, 138 Tryprostatin A, 275 Tryptamine, 285 Tryptophan (Trp), 43–45, 82, 148, 232,

238–240, 248, 261, 275, 304

Tubastraea sp., 48

Tubulin, 54, 279, 284, 315 dynamics, 284

polymerization, 54, 284 Tumor, 52, 53, 55, 139, 140, 144, 147, 148,

253, 254, 259, 281, 284

necrosis factor (TNF), 52, 140 Twist-boat conformation, 225 Two-dimensional quantitative structure-

activity relationship (2D-QSAR), 47 Type 1A topoisomerases, 139 Type 1B topoisomerases, 139 Type I topoisomerases, 139 Type II topoisomerases, 139 Tyramine, 285 Tyrocidine A, 294 Tyrosinase, 137, 138 inhibitors, 137, 138

Tyrosine hydantoin, 58

U Ugi four-component condensation, 299

reaction, 300–305 Ultra-high pressure liquid chromatography (UHPLC), 47 Unit cell, 224, 228

Universal rink isocyanide resin, 300

Unsaturation, 4, 20–22, 29, 226, 229, 245

Urokinase plasminogen activator (uPA), 283

receptor (uPAR), 283

US FDA-approved small molecular drugs,

279

UV-vis spectroscopic measurements, 229

V

Vacuum filtration, 184, 320, 327 ultraviolet microspectrophotometer, 223

Valproylamides, 146 Vancomycin-resistant Enterococcus faecalis

(VREF), 57 Vanillic acid, 138 Vanillin, 138 Variecolorin J, 248 Variecolorin M, 248 Vascular disease, 283

disrupting agents, 280

endothelial growth factor (VEGF), 60 Vasculogenesis, 144 Ventricular fibrillation, 145 tachycardia, 145

Verticillin D, 257 Verticillin G, 258 Vertihemiptellide A, 272 Vertihemiptellide B, 272 Vibrational frequencies, 43 Vibrio

anguillarum, 275

cholera, 141, 142

Vicriviroc, 282 Vinblastine, 284 Vincristine, 266, 284 Virion, 287 Viscosity, 97, 165 Von Willebrand factor, 283

W

Index

405

Water latex paint formulations, 96 soluble hydantoin epoxy resin, 97

West Nile virus, 282

Whey protein, 230

X

X-ray

crystal structure, 229

crystallographic, 39, 98

data, 118

Xylene-acetic acid-phthalate buffer, 131

Y Yeast, 95

Z Z-bromoaxinohydantoin, 87

Zwitterion characteristic, 306

intermediates, 191

Zymogen, 283