GREENE’S PROTECTIVE GROUPS IN ORGANIC SYNTHESIS

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GREENE’S PROTECTIVE

GROUPS IN ORGANIC

SYNTHESIS

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GREENE’S PROTECTIVE GROUPS IN ORGANIC

SYNTHESIS

Fifth Edition

PETER G. M. WUTS Kalamazoo, Michigan, USA

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Published by John Wiley & Sons, Inc., Hoboken, New Jersey Published simultaneously in Canada

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Library of Congress Cataloging-in-Publication Data:

Wuts, Peter G. M.

Greene’s protective groups in organic synthesis. – Fifth edition / Peter G.M. Wuts.

pages cm Includes index.

ISBN 978-1-118-05748-3 (cloth)

1. Organic compounds–Synthesis. 2. Protective groups (Chemistry) I. Greene, Theodora W.

(Theodora Whatmough), 1931-2005. II. Greene, Theodora W. (Theodora Whatmough), 1931-2005.

Protective groups in organic synthesis. III. Title. IV. Title: Protective groups in organic synthesis.

QD262.G665 2014 547.2–dc23

2014011451 Printed in the United States of America

oBook ISBN: 9781118905074 ePDF ISBN: 9781118905098 ePub ISBN: 9781118905128 10 9 8 7 6 5 4 3 2 1

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Reactivity Chart 1. Protection for Hydroxyl Group: Ethers, 1269 Reactivity Chart 2. Protection for Hydroxyl Group: Esters, 1274 Reactivity Chart 3. Protection for 1,2- and 1,3-Diols, 1278 Reactivity Chart 4. Protection for Phenols and Catechols, 1282 Reactivity Chart 5. Protection for the Carbonyl Group, 1286 Reactivity Chart 6. Protection for the Carboxyl Group, 1290 Reactivity Chart 7. Protection for the Thiol Group, 1294

Reactivity Chart 8. Protection for the Amino Group: Carbamates, 1298 Reactivity Chart 9. Protection for the Amino Group: Amides, 1302

Reactivity Chart 10. Protection for the Amino Group: Special–NH Protective Groups, 1306

Reactivity Chart 11. Selective Deprotection of Silyl Ethers, 1311

Index 1333

CONTENTS ix

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PREFACE TO THE FIFTH EDITION

Thefifth edition continues in the tradition of the previous volumes. The literature search is complete to the middle of 2013, and was done using a hand search where I looked at the individual papers tofind appropriate material and by using the search engines provided by the various publishers. SciFinder was also used to complement my search, by looking for specific information rather than a general search of protective group chemistry as this results in too many hits to examine. Given the ever-expanding literature, it is becoming increasingly more time consuming to maintain the comprehensive tradition of the last four editions. If I have passed over a favorite method or even a new protective group, it was not done intentionally.

During the preparation of this edition, I processed over 4100 new references. Not all have been included because in many cases the examples did not offer anything new. However, approximately 2800 new references have been included in this edition. Overall, I have tried to be as all-inclusive as possible because this book is about giving the user all the available options for protection and deprotection.

Protective group chemistry is largely driven by natural product synthesis, and over the years since the last edition, the emphasis on highly hydroxylated natural products has given way to more alkaloid natural products that tend not to use protective groups as heavily. In fact, there are many syntheses that have avoided the use of protective groups altogether. There are, however, many classes of molecules where our chemical technology is still not adequate to completely avoid the use of protective groups, such as in polypropionate macrolide synthesis, peptide synthesis, and oligonucleotide synthesis.

Again, I have tried to emphasize examples that provide selectivity information. In many of the methodology papers, this issue is barely addressed because the reported examples are largely on rather simple substrates and thus these methods must still be xi

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tested on more complex systems. How protective groups affect reactivity is an area that is only lightly covered. It turns out to be a book in itself based on the piles of literature that I have collected.

In conclusion, I would like to thank my editor Jonathan Rose, who gave me complete access to the Wiley collection of books and journals for a year, which greatly facilitated obtaining papers from journals that in some cases I had no other access to.

Many thanks go to Jed Fisher, who gave me a copy of his database from which I was able to obtain numerous useful references, and to the Chemistry Department at Western Michigan University, for giving me an Adjunct Professorship, which gave me access to their library. I would also like to thank José L. Giner and Nathalie Stransky-Heilkron for pointing out a couple of errors in the previous edition, which have been corrected. Andﬁnally my greatest thanks must go to my wife, Lizzie, who has encouraged me to undertake this edition and then helped with various aspects of its preparation, such as printing out papers and proofreading. She also put up with me while I was glued to my computer night after night and many a long weekend.

However, when it was time to call it quits for the night, she would graciously bring me a glass of wine.

PETERG. M. WUTS January 2014

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PREFACE TO THE FOURTH EDITION

After completing the mammoth third edition, I never imagined that a fourth edition would eventuate because of the sheer volume of literature that must be examined to cover the subject comprehensively. Nonetheless, I took on the task with the encouragement and help of my wife, Lizzie, who agreed to assist me with this one, since Theo was not able to. As with the last edition, the searches were primarily done by hand because databases such as SciFinder fail to be selective and have such a prodigious output that no one can be expected tofilter all that material in a reasonable amount of time. Nevertheless, SciFinder was used to locate material in journals that were not readily accessible. In recent years, in both corporate and academic America, there has also been a trend to do away with physical libraries, which makes doing a literature search extremely difficult, especially if you like reading the literature at home in a comfortable chair. Reading journals on a computer screen may be easy for Spock, but Ifind it difficult and stressful. With limited access to hard copies of some of the literature, I may have missed some things. For this I apologize and will not be offended if the author sends me the material for inclusion in a possible future edition.

The literature search is complete through the end of 2005.

With that said, the fourth edition contains over 3100 new references compared to the 2349 new citations in the third edition. In keeping with the tradition of the past, I tried to include material covering new methods for existing protective groups along with new groups that have been developed. When the authors disclosed the information, I also provided the rationale for the choice of a given protective group.

In that synthetic chemistry is still not sufﬁciently developed to do away with protective groups altogether, I have included many examples that highlight selective protection and deprotection, especially when the selectivity might not be totally obvious or expected. Issues of unexpected reactivity are also included, since these xiii

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cases should help in choosing a group during the development of a synthetic plan. On the whole, this is a book of options for the synthetic chemist, since no one method is suitable for all occasions. Also, many of the published methods have not been tested in complex situations; thus, it is impossible to determine which method of a particular set might be the best, and, as such, no attempt was made to try and order the various methods that appear in a section. The issue of functional group compatibility is often not addressed in papers describing new methods, and this further complicates the evaluation process. Comparative studies for either protection or deprotection are rarely done, and as a result, trial and error and chemical intuition must be used to deﬁne the most suitable method in a given situation.

All sections of the book have seen some expansion, especially the chapters on alcohol and amine protection. I had considered adding a section that covered areas such as diene protection as metal complexes and Diels–Alder adducts, but the use of these is rather limited. The Reactivity Charts of Chapter 10 have not been altered, but a new chart covering selectivity in silyl group deprotection has been added. The overall format of the book has been retained, and in some of the larger sections, similar methods have been grouped together. A new area has emerged since the last edition, and this is the use ofﬂuorous protective groups. These have been included and placed in the appropriate sections rather than having collected them together.

The completion of this project was aided by a number of people. First of all, this work would not have been started without the encouragement and dedication of my wife, Lizzie, who looked up and downloaded many of the references and then typed every new reference into an Endnote^TMdatabase. She double-checked the entire set in order to prevent errors. She also read through the entire manuscript to check it for punctuation, grammar, and consistency. She has a degree in Near Eastern Medieval History; thus, I take full responsibility for any chemical errors. I must also thank her for not complaining about becoming a book widow while I spent countless hours on this project over a period of∼3 years. A special note of thanks must be extended to Peter Green, the Pﬁzer Michigan site head, who approved giving Lizzie access to the company library system even though she was not an employee. I would also like to thank Jake Szmuszkovicz, Raymond Conrow, and Martin Lang for providing me with references to be included in the fourth edition, and ﬁnally I wish to thank Joseph Muchowski for bringing an error in the third edition, now corrected, to my attention.

PETERG. M. WUTS January 2006

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PREFACE TO THE THIRD EDITION

Organic synthesis has not yet matured to the point where protective groups are not needed for the synthesis of natural and unnatural products; thus, the development of new methods for functional group protection and deprotection continues. The new methods added to this edition come from both electronic searches and a manual examination of all the primary journals through the end of 1997. We have found that electronic searches of Chemical Abstracts fail toﬁnd many new methods that are developed during the course of a synthesis, and issues of selectivity are often not addressed. As with the second edition, we have attempted to highlight unusual and potentially useful examples of selectivity for both protection and deprotection. In some areas, the methods listed may seem rather redundant, such as the numerous methods for THP protection and deprotection, but we have included them in an effort to be exhaustive in coverage. For comparison, theﬁrst edition of this book contains about 1500 references and 500 protective groups, the second edition introduces an additional 1500 references and 206 new protective groups, and the third edition includes 2349 new citations and 348 new protective groups.

Two new sections on the protection of phosphates and the alkyne-CH are included.

All other sections of the book have been expanded, some more than others. The section on the protection of alcohols has increased substantially, reﬂecting the trend of the 1990s to synthesize acetate- and propionate-derived natural products. An effort was made to include many more enzymatic methods of protection and deprotection.

Most of these are associated with the protection of alcohols as esters and the protection of carboxylic acids. Here we have not attempted to be exhaustive, but hopefully a sufﬁcient number of cases are provided that illustrate the true power of this technology, so that the reader will examine some of the excellent monographs and review articles cited in the references. The Reactivity Charts in Chapter 10 are xv

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identical to those in thefirst edition. The chart number appears beside the name of each protective group when it isfirst introduced. No attempt was made to update these charts, not only because of the sheer magnitude of the task, but also because it is nearly impossible in a two-dimensional table to adequately address the effect that electronic and steric controlling elements have on a particular instance of protection or deprotection. The concept of fuzzy sets as outlined by Lotfi Zadeh would be ideally suited for such a task.

The completion of this project was aided by the contributions of a number of people. I am grateful to Rein Virkhaus and Gary Callen, who for many years forwarded me references when they found them, to Jed Fisher for the information he contributed on phosphate protection, and to Todd Nelson for providing me a preprint of his excellent review article on the deprotection of silyl ethers. I heartily thank Theo Greene for checking and rechecking the manuscript—all 15 cm of it—for spelling and consistency and for the arduous task of checking all the references for accuracy. I thank Fred Greene for reading the manuscript, for his contribution to Chapter 1 on the use of protective groups in the synthesis of himastatin, and for his contribution to the introduction to Chapter 9, on phosphates. I thank my wife, Lizzie, for encouraging me to undertake the third edition, for the hours she spent in the library looking up and photocopying hundreds of references, and for her understanding while I sat in front of the computer night after night and numerous weekends over a two-year period. She is the greatest!

PETERG. M. WUTS Kalamazoo, Michigan

June 1998

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PREFACE TO THE SECOND EDITION

Since publication of theﬁrst edition of this book in 1981, many new protective groups and many new methods of introduction or removal of known protective groups have been developed: 206 new groups and approximately 1500 new references have been added. Most of the information from theﬁrst edition has been retained. To conserve space, generic structures used to describe Formation/Cleavage reactions have been replaced by a single line of conditions, sometimes with explanatory comments, especially about selectivity. Some of the new information has been obtained from online searches of Chemical Abstracts, which have limitations. For example, Chemi- cal Abstracts indexes a review article about protective groups only if that word appears in the title of the article. References are complete through 1989. Some references, from more widely circulating journals, are included for 1990.

Two new sections on the protection for indoles, imidazoles, and pyrroles and the protection for the amide –NH are included. They are separated from the regular amines because their chemical properties are sufficiently different to affect the chemistry of protection and deprotection. The Reactivity Charts in Chapter 8 are identical with those in thefirst edition. The chart number appears beside the name of each protective group when it isfirst discussed.

A number of people must be thanked for their contributions and help in completing this project. I am grateful to Gordon Bundy, who loaned me his card ﬁle, which provided many references that the computer failed to ﬁnd, and to Bob Williams, Spencer Knapp, and Tohru Fukuyama for many references on amine and amide protection. I thank Theo Greene who checked and rechecked the manuscript for spelling and consistency and for the herculean task of checking all the references to make sure my 3’s and 8’s and 7’s and 9’s were not interchanged, all without a single complaint. I thank Fred Greene who read the manuscript and provided valuable xvii

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suggestions for its improvement. My wife Lizzie was a major contributor to getting this projectﬁnished, by looking up and photocopying references, by turning on the computer in an evening ritual, and by typing many sections of the original book, which made the changes and additions much easier. Without her understanding and encouragement, the volume probably would never have been completed.

PETERG. M. WUTS Kalamazoo, Michigan

May 1990

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PREFACE TO THE FIRST EDITION

The selection of a protective group is an important step in synthetic methodology, and reports of new protective groups appear regularly. This book presents information on the synthetically useful protective groups (∼500) for ﬁve major functional groups:-OH, -NH, -SH, -COOH, and >CO. References through 1979, the best method(s) of formation and cleavage, and some information on the scope and limitations of each protective group are given. The protective groups that are used most frequently and that should be considered ﬁrst are listed in Reactivity Charts, which give an indication of the reactivity of a protected functionality to 108 prototype reagents.

The first chapter discusses some aspects of protective group chemistry: the properties of a protective group, the development of new protective groups, how to select a protective group from those described in this book, and an illustrative example of the use of protective groups in a synthesis of brefeldin. The book is organized by functional group to be protected. At the beginning of each chapter are listed the possible protective groups. Within each chapter protective groups are arranged in order of increasing complexity of structure (e.g., methyl, ethyl, t-butyl, . . . , benzyl). The most efficient methods of formation or cleavage are described first. Emphasis has been placed on providing recent references, since the original method may have been improved. Consequently, the original reference may not be cited; my apologies to those whose contributions are not acknowledged.

Chapter 8 explains the relationship between reactivities, reagents, and the Reactivity Charts that have been prepared for each class of protective groups.

This work has been carried out in association with Professor Elias J. Corey, who suggested the study of protective groups for use in computer-assisted synthetic analysis. I appreciate his continued help and encouragement. I am xix

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grateful to Dr. J. F. W. McOmie (Ed.,Protective Groups in Organic Chemistry, Plenum Press, New York and London, 1973) for his interest in the project and for several exchanges of correspondence, and to Mrs. Mary Fieser, Professor Frederick D. Greene, and Professor James A. Moore for reading the manuscript.

Special thanks are also due to Halina and Piotr Starewicz for drawing the structures, and to Kim Chen, Ruth Emery, Janice Smith, and Ann Wicker for typing the manuscript.

THEODORAW. GREENE Harvard University

September 1980

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ABBREVIATIONS

PROTECTIVE GROUPS

In some cases, several abbreviations are used for the same protective group. We have listed the abbreviations as used by an author in his original paper, including capital and lowercase letters. Occasionally, the same abbreviation has been used for two different protective groups. This information is also included.

AAM anthranilamide

ABn 4-azidobenzyl

ABO 2,7,8-trioxabicyclo[3.2.1]octyl

Ac acetyl

ACBZ 4-azidobenzyloxycarbonyl

ACE O-bis(2-acetoxyethoxy)methyl

1-chloroethylcarbonyl

AcHmb 2-acetoxy-4-methoxybenzyl

Acm acetamidomethyl

Ad 1-adamantyl

ADMB 4-acetoxy-2,2-dimethylbutanoate

Adoc 1-adamantyloxycarbonyl

Adpoc 1-(1-adamantyl)-1-methylethoxycarbonyl Alloc or AOC allyloxycarbonyl

Allocam allyloxycarbonylaminomethyl

Als allylsulfonyl

AMB 2-(acetoxymethyl)benzoyl

Amoc acridin-9-ylmethyl

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AMPA (2-azidomethyl)phenylacetate AN(An) 4-methoxyphenyl or anisyl Anpe 2-(4-acetyl-2-nitrophenyl)ethyl

Ans anisylsulfonyl

AOC or Alloc allyloxycarbonyl

p-AOM p-anisyloxymethyl or (4-methoxyphenoxy)methyl

APAC 2-allyloxyphenylacetate

APOE (2-acetoxyphenoxy)ethyl

Aqmoc anthraquinone-2-ylmethoxycarbonyl

Az azulen-1-yl-oxo-acetyl

Azb p-azidobenzyl

AZBn 4-[(2-azidomethyl)benzoyloxy]benzyl AzDMB 2,2-dimethyl-4-azidobutanoate

Azm azidomethyl

AZMB 2-(azidomethyl)benzoate

Azoc azidomethylcarbonyl

Bam benzamidomethyl

BBA butane-2,3-bisacetal

Bbc but-2-ynylbisoxycarbonyl

BCMACM {7-[bis(carboxymethyl)amino]coumarin-4-yl}

methyl

BDIPS biphenyldiisopropylsilyl

BDMS biphenyldimethylsilyl

benzyldimethylsilyl

Bdt 1,3-benzodithiolan-2-yl

BEC bromoethylcarbonyl

Betsyl or Bts benzothiazole-2-sulfonyl Bhcmoc 6-bromo-7-hydroxycoumarin-4-

ylmethoxycarbonyl

6-bromo-7-hydroxycoumarin-4-ylmethyl BHQ 8-bromo-7-hydroxyquinoline-2-ylmethyl BHT 2,6-di-t-butyl-4-methylphenyl

BIBS di-t-butylisobutylsilyl

Bic 5-benzisoxazolylmethoxycarbonyl

Bim 5-benzisoazolylmethylene

Bimoc benz[f]inden-3-ylmethoxycarbonyl BIPSOP N-2,5-bis(triisopropylsiloxy)pyrrolyl

BMB o-(benzoyloxymethyl)benzoyl

Bmcmoc 6-bromo-7-methoxycoumarin-4-ylmethylcarbonyl Bmpc 2,4-dimethylthiophenoxycarbonyl

Bmpm bis(4-methoxyphenyl)-10-pyrenylmethyl

Bn benzyl

Bnf ﬂuorousbenzyl

Bnpeoc 2,2-bis(40-nitrophenyl)ethoxycarbonyl

Bns benzylsulfonate

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BOB benzyloxybutyrate

BOC t-butoxycarbonyl

Bocdene 2-(t-butylcarbonyl)ethylidene

BOM benzyloxymethyl

Beer of the month

Bpf bisﬂuorous chain propanyl

Bpoc 1-methyl-1-(4-biphenyl)ethoxycarbonyl

Bs benzenesulfonyl

BSB benzostabase

Bsmoc 1,1-dioxobenzo[b]thiophene-2-ylmethoxycarbonyl BTB 2,6-bis(triﬂuoromethyl)benzyl

BTM t-butylthiomethyl

Bts or Betsyl benzothiazole-2-sulfonyl B^tSE 2-t-butylsulfonylethyl

Bts-Fmoc 2,7-bis(trimethylsilyl)ﬂuorenylmethoxycarbonyl

Bum t-butoxymethyl

t-Bumeoc 1-(3,5-di-t-butylphenyl)-1-methylethoxycarbonyl

Bus t-butylsulfonyl

Bz benzoyl

CAEB 2-[(2-chloroacetoxy)ethyl]benzoyl

Cam carboxamidomethyl

CAMB 2-(chloroacetoxymethyl)benzoyl

Cbz or Z benzyloxycarbonyl

CDA cyclohexane-1,2-diacetal

CDM 2-cyano-1,1-dimethylethyl

CE or Cne 2-cyanoethyl

Cee 1-(2-chloroethoxy)ethyl

CEE 1-(2-cyanoethoxy)ethyl

CEM 2-cyanoethoxymethyl

Ceof cyclic ethyl orthoformate

cHex cyclohexyl

Chx cyclohexyl

Cin cinnamyl

ClAzab 4-azido-3-chlorobenzyl

Climoc 2-chloro-3-indenylmethoxycarbonyl

Cms carboxymethylsulfenyl

CNAP 2-naphthylmethoxycarbonyl

Cne or CE 2-cyanoethyl

Coc cinnamyloxycarbonyl

CPC p-chlorophenylcarbonyl

CPDMS (3-cyanopropyl)dimethylsilyl Cpeoc 2-(cyano-1-phenyl)ethoxycarbonyl

Cpep 1-(4-chlorophenyl)-4-methoxypiperidin-4-yl CPTr 4,40,400-tris(4,5-dichlorophthalimido)triphenylmethyl CTFB 4-triﬂuoromethylbenzyloxycarbonyl

ABBREVIATIONS xxiii

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CTMP 1-[(2-chloro-4-methyl)phenyl]-4- methoxypiperidin-4-yl Cyclo-SEM 5-trimethylsilyl-1,3-dioxane

Cys cysteine

DAM di-p-anisylmethyl or bis(4-methoxyphenyl)methyl 20-O-{[2,2-dimethyl-2-(2-nitrophenyl)acetyl]oxy}

methyl

DAN dansyl

DATE 1,1-di-p-anisyl-2,2,2-trichloroethyl DB-t-BOC 1,1-dimethyl-2,2-dibromoethoxycarbonyl DBD-Tmoc 2,7-di-t-butyl[9-(10,10-dioxo-10,10,10,10-

tetrahydrothioxanthyl)]methoxycarbonyl

dbf N-(N0,N0-dibutylaminomethylene)

DBS dibenzosuberyl

DCP dichlorophthalimide

Dcpm dicyclopropylmethyl

DCV dichlorovinyl

Dde 2-(4,4-dimethyl-2,6-dioxocyclohexylidene)ethyl Ddm or Dmbh bis(4-methoxyphenyl)methyl

(2,6-dichloro-4-alkoxyphenyl)(2,4-dichlorophenyl) methyl

(2,6-dichloro-4-methoxyphenyl)(2,4- dichlorophenyl)methyl

Ddz 1-methyl-1-(3,5-dimethoxyphenyl)ethoxycarbonyl DEACE 1-(7-(N,N-diethylamino)-coumarin-4-yl)-1-ethyl DECDO 4,5-bis(ethoxycarbonyl)-[1,3]-dioxolan-2-yl

DEIPS diethylisopropylsilyl

DEM diethoxymethyl

Desyl 2-oxo-1,2-diphenylethyl

DG diglycoloyl

DIFA N-(N0,N0-diisopropylaminomethylene)

Dim 1,3-dithianyl-2-methyl

Dios 2-(1,3-dioxan-2-yl)ethylsulfonyl

Dmab 4-{N-[1-(4,4-dimethyl-2,6-dioxocyclohexylidene)- 3-methylbutyl]amino}benzyl

8-DMAQ 8-(N,N-dimethylamino)quinolone-2-ylmethyl DMATr 3-dimethylaminophenyldiphenylmethyl

Dmb 2,4-dimethoxybenzyl

DMB 30,50-dimethoxybenzoin

DMBM [(3,4-dimethoxybenzyl)oxy]methyl

DMIPS dimethylisopropylsilyl

DMN 2,3-dimethylmaleimide

Dmoc dithianylmethoxycarbonyl

Dmp 2,4-dimethyl-3-pentyl

dimethylphosphinyl

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DMP dimethoxyphenyl dimethylphenacyl dimethylphosphinothioyl 2,4-dimethyl-3-pentyl

DMPM 3,4-dimethoxybenzyl

DMT or DMTr di(p-methoxyphenyl)phenylmethyl or dimethoxytrityl

DMTC dimethylthiocarbamate

DMTM 2,2-dimethyltrimethylene phosphate DMTr or DMT di(p-methoxyphenyl)phenylmethyl

or dimethoxytrityl

DNAP 2-(dimethylamino)-5-nitrophenyl

DNB p,p0-dinitrobenzhydryl

DNMBS 4-(40,80-dimethoxynaphthylmethyl) benzenesulfonyl

DNP 2,4-dinitrophenyl

Dnpe 2-(2,4-dinitrophenyl)ethyl

Dnpeoc 2-(2,4-dinitrophenyl)ethoxycarbonyl

DNs 2,4-dinitrobenzenesulfonyl

DNse 2-(2,4-dinitrophenylsulfonyl)ethoxycarbonyl

Dnseoc 2-dansylethoxycarbonyl

Dobz p-(dihydroxyboryl)benzyloxycarbonyl

Doc 2,4-dimethylpent-3-yloxycarbonyl

Dod bis(4-methoxyphenyl)methyl

DOD bis(trimethylsiloxy)cyclododecyloxysilyl DOPS dimethyl[1,1-dimethyl-3-(tetrahydro-2H-pyran-

2-yloxy)propyl]silyl

DPA diphenylacetyl

DPE diphenylphosphinoylethyl

DPIPS diphenylisopropylsilyl

DPM or Dpm diphenylmethyl

N-2,3-diphenylmaleimide

DPMS diphenylmethylsilyl

Dpp diphenylphosphinyl

Dppe 2-(diphenylphosphino)ethyl

Dppm (diphenyl-4-pyridyl)methyl

DPSE 2-(methyldiphenylsilyl)ethyl DPSide diphenylsilyldiethylene

Dpt diphenylphosphinothioyl

DPTBOS t-butoxydiphenylsilyl DPTBS diphenyl-t-butoxysilyl

diphenyl-t-butylsilyl

Dtb-Fmoc 2,6-di-t-butyl-9-ﬂuorenylmethoxycarbonyl DTBMS di-t-butylmethylsilyl

DTBS di-t-butylsilylene

ABBREVIATIONS xxv

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DTE 2-(hydroxyethyl)dithioethyl or dithiodiethanol

DTPM N-(1,3-dimethyl-2,4,6-(1H,3H,5H)- trioxopyrimidine-5-ylidene)methyl

Dts dithiasuccinimidyl

E-DMT 1,2-ethylene-3,3-bis(40400-dimethoxytrityl)

EE 1-ethoxyethyl

EOM ethoxymethyl

FBOC ﬂuorous BOC

FCbz ﬂuorous benzyloxycarbonyl

Fcm ferrocenylmethyl

Flu ﬂuorenyl

Fm 9-ﬂuorenylmethyl

Fmoc 9-ﬂuorenylmethoxycarbonyl

Fms (9H-ﬂuoren-9-yl)methanesulfonyl

Fnam N-[2,3,5,6-tetraﬂuoro-4-(N0-piperidino)phenyl]- N-allyloxycarbonylaminomethyl

Fpmp 1-(2-ﬂuorophenyl)-4-methoxypiperidiny-4-yl Froc 2-bromo-3,3,4,4,5,5,6,6,7,7,8,8,9,9,10,10,10-

heptadecaﬂuoro-1-decylcarbonyl Fsec 2-[(4-ﬂuorophenyl)sulfonyl]ethyl

GUM guaiacolmethyl

HAPE 1-[2-(2-hydroxyalkyl)phenyl]ethanone

HBn 2-hydroxybenzyl

Hdoc hexadienyloxycarbonyl

HFB hexaﬂuoro-2-butyl

HIP 1,1,1,3,3,3-hexaﬂuoro-2-phenylisopropyl

Hoc cyclohexyloxycarbonyl

HPsc [2-[(4,4,5,5,6,6,7,7,8,8,9,9,10,10,11,11,11- heptadecaﬂuoroundecyl)sulfonyl]ethyl Hqm S-[[[2-[8-[[(1,1-dimethylethyl)dimethylsilyl]oxy]

octahydro-1(2H)-quinolinyl]acetyl]amino]

methyl]

HSDIS (hydroxystyryl)diisopropylsilyl HSDMS (hydroxystyryl)dimethylsilyl hZ or homo Z homobenzyloxycarbonyl IDTr 3-(imidazol-1-ylmethyl)-40,400-

dimethoxytriphenylmethyl

IETr 4,40-dimethoxy-300-[N-(imidazolylethyl)carba- moyl]trityl

iMds 2,6-dimethoxy-4-methylbenzenesulfonyl Ipaoc 1-isopropylallyloxycarbonyl

Ipc isopinocampheyl

IPDMS isopropyldimethylsilyl

Lev levulinoyl

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LevS 4,4-(ethylenedithio)pentanoyl levulinoyldithioacetal ester

LMMo(p)NBz 6-(levulinyloxymethyl)-3-methoxy-2-nitrobenzoate MAB 2-{{[(4-methoxytrityl)thio]methylamino}methyl}

benzoate

MAQ 2-(9,10-anthraquinonyl)methyl or 2-methyleneanthraquinone

MBE 1-methyl-1-benzyloxyethyl

MBF 2,3,3a,4,5,6,7,7a-octahydro-7,8,8-trimethyl-4,7- methanobenzofuran-2-yl

Mbh bis(4-methylphenyl)methyl

N-bis(4-methylphenyl)methyl

MBOM N-4-methoxybenzyloxymethyl

MBS or Mbs p-methoxybenzenesulfonyl MCPM 1-methyl-10-cyclopropylmethyl

MDPM [1-(6-nitro-1,3-benzodioxol-5-yl)ethoxy]methyl MDPS methylene-bis(diisopropylsilanoxanylidene) Mds 2,6-dimethyl-4-methoxybenzenesulfonyl

Me methyl

ME methoxyethyl

MEC α-methylcinnamyl

MEDAM N-bis(3,5-dimethyl-4-methoxyphenyl)methyl

Mee methoxyethoxyethyl

MEM 2-methoxyethoxymethyl

Menpoc α-methylnitropiperonyloxycarbonyl

MeOAc methoxyacetyl

MeOZ or Moz p-methoxybenzyloxycarbonyl Mes mesityl or 2,4,6-trimethylphenyl

MIDA N-methyliminodiacetic acid

MIP methoxyisopropyl or 1-methyl-1-methoxyethyl

MIS 1,2-dimethylindole-3-sulfonyl

MM menthoxymethyl

MMPPOC 2-(3,4-methylenedioxy-6-nitrophenyl) propyloxycarbonyl

MMT or MMTr p-methoxyphenyldiphenylmethyl MMTr or MMT p-methoxyphenyldiphenylmethyl

MMTrS 4-monomethoxytritylsulfenyl

MOB 2-{[(4-methoxytritylthio)oxy]methyl}benzoate Mocdene 2-(methoxycarbonyl)ethylidene

MoEt 2-N-(morpholino)ethyl

MOM methoxymethyl

MOMO methoxymethoxy

MOTES ( )-(R)- and ()-(S)-(1-methoxy-2,2,2- triphenylethyl)dimethylsilyl

Mov or MocVinyl N-1-(carboxymethyl)ethen-2-yl

ABBREVIATIONS xxvii

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Moz or MeOZ p-methoxybenzyloxycarbonyl

MP p-methoxyphenyl

MPDMB 2,2-dimethyl-4-(4-methoxyphenoxy)butanoate

Mpe 3-methyl-3-pentyl

MPM or PMB p-methoxyphenylmethyl or p-methoxybenzyl MPMP 1-(4-methoxyphenyl)-2-methylpropane-1,2-diol

MPoc (1-ethyl)cyclopropylcarbonyl

Mps p-methoxyphenylsulfonyl

Mpt dimethylphosphinothioyl

Mptc 4-methylthiophenylcarbonyl

Ms methanesulfonyl or mesyl

Msc 2-(methylsulfonyl)ethylcarbonyl

MSE 2-(methylsulfonyl)ethyl

Msem methylsulfonylethoxymethyl

Msib 4-(methylsulﬁnyl)benzyl

Mspoc 2-methylsulfonyl-3-phenyl-1-prop-2-enyloxy

Msz 4-methylsulﬁnylbenzyloxycarbonyl

MTAD 4-methyl-1,2,4-triazoline-3,5-dione

Mtb 2,4,6-trimethoxybenzenesulfonyl

Mte 2,3,5,6-tetramethyl-4-methoxybenzenesulfonyl MTFOC cis-[4-[[(-methoxytrityl)sulfenyl]oxy]tetraydro-

furan-3-yl]oxycarbonyl

MTHP 4-methoxytetrahydropyranyl

MTM methylthiomethyl

MTMB 4-(methylthiomethoxy)butyryl

MTMEC 2-(methylthiomethoxy)ethoxycarbonyl MTMT 2-(methylthiomethoxymethyl)benzoyl

Mtpc 4-(methylthio)phenoxycarbonyl

Mtr 2,3,6-trimethyl-4-methoxybenzenesulfonyl Mts 2,4,6-trimethylbenzenesulfonyl or

mesitylenesulfonyl

Mtt 4-methoxytrityl

4-methyltrityl

Nap 2-naphthylmethyl

NBM nitrobenzyloxymethyl

NBOM nitrobenzyloxymethyl

NDBF N-3-[[1-(3-nitro-2-dibenzofuranyl)ethoxy]methyl]

NDMS 2-norbornyldimethylsilyl

Ne 2-nitroethyl

NNM 3-nitro-2-naphthylmethyl

Noc 4-nitrocinnamyloxycarbonyl

Nosyl or Ns 2- or 4-nitrobenzenesulfonyl Nox naphtho[2,3-d]oxazole-2-ylmethyl

NPAc (2-nitrophenyl)acetate

NPB 4-nitrophthalimidobutyryl

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Npe or npe 2-(nitrophenyl)ethyl

Npeoc 2-(4-nitrophenyl)ethoxycarbonyl Npeom [1-(2-nitrophenyl)ethoxy]methyl Npes 2-[(4-nitrophenyl)ethyl]sulfonyl

NPOM [1-(6-nitro-1,3-benzodioxol-5-yl)ethoxy]methyl N-6-nitropiperonyloxymethyl

NPPOC 2-(2-nitrophenyl)propyloxycarbonyl NPS or Nps 2-nitrophenylsulfenyl

NpSSPeoc 2-[(2-nitrophenyl)dithio]-1-phenylethoxycarbonyl

Npys 3-nitro-2-pyridinesulfenyl

Ns or Nosyl 2- or 4-nitrobenzenesulfonyl

Nse 2-(4-nitrophenylsulfonyl)ethoxycarbonyl NVOC or Nvoc 3,4-dimethoxy-6-nitrobenzyloxycarbonyl

or 6-nitroveratryloxycarbonyl OBO 2,6,7-trioxabicyclo[2.2.2]octyl O-DMT 3,30-oxybis(dimethoxytrityl)

ONB o-nitrobenzyl

PAB p-acylaminobenzyl

acetoxybenzyl

PAC_H 2-[2-(benzyloxy)ethyl]benzoyl

PAC_M 2-[2-(4-methoxybenzyloxy)ethyl]benzoyl

Paloc 3-(3-pyridyl)allyloxycarbonyl or 3-(3-pyridyl)prop- 2-enyloxycarbonyl

Pbf 2,2,4,6,7-pentamethyldihydrobenzofuran-5- sulfonyl

Pbfm 2,2,4,6,7-pentamethyl-2,3-dihydrobenzofuran- 5-methyl

PeNB pentadienylnitrobenzyl

PeNP pentadienylnitropiperonyl

Peoc 2-phosphonioethoxycarbonyl

2-(triphenylphosphonio)ethoxycarbonyl

Pet 2-(20-pyridyl)ethyl

Pf 9-phenylﬂuorenyl

Pfp pentaﬂuorophenyl

PhAc 4-phenylacetoxybenzyloxycarbonyl

Phamc phenylacetamidomethyl

Phedec phenyldithioethylcarbonyl

Phenoc 4-methoxyphenacyloxycarbonyl

Pic picolinate

PIDA N-pinenyliminodiacetic acid

Pim phthalimidomethyl

Pixyl or Px 9-(9-phenyl)xanthenyl

PMB or MPM p-methoxybenzyl or p-methoxyphenylmethyl

PMBM p-methoxybenzyloxymethyl

Pmc 2,2,5,7,8-pentamethylchroman-6-sulfonyl

ABBREVIATIONS xxix

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Pme pentamethylbenzenesulfonyl

PMP p-methoxyphenyl

Pms 2-[phenyl(methyl)sulfonio]ethoxycarbonyl

PMS p-methylbenzylsulfonyl

PNB p-nitrobenzyl

p-nitrobenzoate

pNBZ p-nitrobenzoate

PNP p-nitrophenyl

PNPE 2-(4-nitrophenyl)ethyl

PNZ p-nitrobenzylcarbonyl

POC propargyloxycarbonyl

Pocam S-N-methylphenacyloxycarbamidomethyl

POM 4-pentenyloxymethyl

pivaloyloxymethyl

[(p-phenylphenyl)oxy]methyl

POMB 2-(prenyloxy)methylbenzoate

Pop diphenylphosphoryl

Pp 2-phenyl-2-propyl

Ppoc 2-triphenylphosphonioisopropoxycarbonyl

Ppt diphenylthiophosphinyl

PPTS pyridinium tosylate

Pre prenyl

Preoc prenyloxycarbonyl

Proc or Poc propargyloxycarbonyl

PSB p-siletanylbenzyl

PSE 2-(phenylsulfonyl)ethyl

Psec 2-(phenylsulfonyl)ethoxycarbonyl Psoc (2-phenyl-2-trimethylsilyl)ethoxycarbonyl

PTE 2-(4-nitrophenyl)thioethyl

PTM phenylthiomethyl

PTMSE (2-phenyl-2-trimethylsilyl)ethyl

Pv pivaloyl

Px or pixyl 9-(9-phenyl)xanthenyl Pydec pyridyldithioethylcarbonyl

Pyet 1-(α-pyridyl)ethyl

Pym 1-pyrenylmethyl

pymisyl pyrimidine-2-sulfonyl

Pyoc 2-(20- or 40-pyridyl)ethoxycarbonyl

pza 2-pyrazol-5-ylaniline

Qm 2-quinolinylmethyl

Qn 2-quinolinylmethyl

QUI 4-quinolinylmethyl

SATE S-acetylthioethyl

Scm S-carboxymethylsulfenyl

SEE 1-[2-(trimethylsilyl)ethoxy]ethyl

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SEM 2-(trimethylsilyl)ethoxymethyl SES 2-(trimethylsilyl)ethanesulfonyl SIBA 1,1,4,4-tetraphenyl-1,4-disilanylidene SiOMB 2-[(t-butyldiphenylsiloxy)methyl]benzoyl Sisyl tris(trimethylsilyl)silyl

SMOM (phenyldimethylsilyl)methoxymethyl Snm S-(N0-methyl-N0-phenylcarbamoyl)sulfenyl

SOB 4-trialkylsilyloxybutyrate

S-Px or S-Pixyl 9-phenylthioxanthyl

STABASE 1,1,4,4-tetramethyldisilylazacyclopentane

sTr tris(4-t-butylphenyl)methyl

TAB 2-{[(methyl(tritylthio)amino]methyl}benzoate

Tacm trimethylacetamidomethyl

TBAB tetrabutylammonium bromide

TBDMS or TBS t-butyldimethylsilyl

TBDPS t-butyldiphenylsilyl

TBDPSE t-butyldiphenylsilylethyl

TBDS tetra-t-butoxydisiloxane-1,3-diylidene Tbeoc 2-(t-butyldisulfanyl)ethyl

Tbf-DMTr 4-(17-tetrabenzo[a,c,g,i]ﬂuorenylmethyl)-40,400- dimethoxytrityl

Tbfmoc 17-tetrabenzo[a,c,g,i]ﬂuorenylmethoxycarbonyl

TBMPS t-butylmethoxyphenylsilyl

TBS or TBDMS t-butyldimethylsilyl

TBTr 4,40,400-tris(benzyloxy)triphenylmethyl TCB 2,2,2-trichloro-1,1-dimethylethyl

TCBOC 1,1-dimethyl-2,2,2-trichloroethoxycarbonyl

Tces trichloroethoxysulfonyl

TCP N-tetrachlorophthalimido

Tcroc 2-(triﬂuoromethyl)-6-

chromonylmethyleneoxycarbonyl Tcrom 2-(triﬂuoromethyl)-6-chromonylmethylene TDE (2,2,2-triﬂuoro-1,1-diphenyl)ethyl

TDG thiodiglycoloyl

TDS thexyldimethylsilyl

tris(2,6-diphenylbenzyl)silyl

TEM 2-(4-tolylsulfonyl)ethoxymethyl

Teoc 2-(trimethylsilyl)ethoxycarbonyl

TES triethylsilyl

Tf triﬂuoromethanesulfonyl

TFA triﬂuoroacetyl

Tfav 4,4,4-triﬂuoro-3-oxo-1-butenyl

Thexyl 2,3-dimethyl-2-butyl

THF tetrahydrofuranyl

THP tetrahydropyranyl

ABBREVIATIONS xxxi

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TIBS triisobutylsilyl

TIPDS 1,3-(1,1,3,3-tetraisopropyldisiloxanylidene)

TIPS triisopropylsilyl

TIX trimethylsilylxylyl

TLTr 4,40,400-tris(levulinoyloxy)triphenylmethyl

Tmb 2,4,6-trimethylbenzyl

TMBPP 3-(20-benzoyloxy-40,60-dimethylphenyl)-3,3- dimethylpropanyl

Tmob trimethoxybenzyl

TMPM trimethoxyphenylmethyl

Tms (2-methyl-2-trimethylsilyl)ethyl

TMS trimethylsilyl

TMSBz 2-(trimethylsilyl)benzoyl TMSE or TSE 2-(trimethylsilyl)ethyl

TMSEC 2-(trimethylsilyl)ethoxycarbonyl TMSP 2-trimethylsilylprop-2-enyl

TMTr tris(p-methoxyphenyl)methyl

TOB 2-{[(tritylthio)oxy]methyl}benzoate

Tom triisopropylsilyloxymethyl

Tos or Ts p-toluenesulfonyl

m-TPh 2,6-diphenylphenyl

TPS triphenylsilyl

2,4,6-triisopropylbenzenesulfonyl TPTE 2-(4-triphenylmethylthio)ethyl

Tr triphenylmethyl or trityl

Tritylone 9-(9-phenyl-10-oxo)anthryl Troc 2,2,2-trichloroethoxycarbonyl

TrtF7 2,3,4,40,400,5,6-heptaﬂuorotriphenylmethyl Ts or Tos p-toluenesulfonyl

Tsc 2-(4-triﬂuoromethylphenylsulfonyl)ethoxycarbonyl Tse 2-(p-toluenesulfonyl)ethyl

TSE or TMSE 2-(trimethylsilyl)ethyl

Tsoc triisopropylsiloxycarbonyl

Tsv p-toluenesulfonylvinyl

Voc vinyloxycarbonyl

Xan xanthenyl

Z or Cbz benzyloxycarbonyl

REAGENTS

9-BBN 9-borabicyclo[3.3.1]nonane

bipy 2,20-bipyridine

BOP reagent benzotriazol-1-yloxytris(dimethylamino) phosphonium hexaﬂuorophosphate

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BOP-Cl bis(2-oxo-3-oxazolidinyl)phosphinic chloride

BroP bromotris(dimethylamino)phosphonium

hexaﬂuorophosphate

Bt benzotriazol-1-yl or 1-benzotriazolyl

BTEAC benzyltriethylammonium chloride

CAL Candida antarctica lipase

CAN ceric ammonium nitrate

CBTFB 3,5-bis-(triﬂuoromethyl)benzylcarbonyl

CMPI 2-chloro-1-methylpyridinium iodide

CNAP 2-naphthylmethylcarbonyl

cod cyclooctadiene

cot cyclooctatetraene

CSA camphorsulfonic acid

CTFB 4-triﬂuoromethylbenzylcarbonyl

DABCO 1,4-diazabicyclo[2.2.2]octane

DBAD di-t-butyl azodicarboxylate

DBN 1,5-diazabicyclo[4.3.0]non-5-ene

DBU 1,8-diazabicyclo[5.4.0]undec-7-ene

DCC dicyclohexylcarbodiimide

DDQ 2,3-dichloro-5,6-dicyano-1,4-benzoquinone

DEAD diethyl azodicarboxylate

DIAD diisopropyl azodicarboxylate

DIBAL-H diisobutylaluminum hydride

DIPEA diisopropylethylamine

DMAC N,N-dimethylacetamide

DMAP 4-N,N-dimethylaminopyridine

DMB 2,4-dimethoxybenzyl

DMDO 2,2-dimethyldioxirane

DME 1,2-dimethoxyethane

DMF N,N-dimethylformamide

DMPU 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)- pyrimidinone

DMS dimethyl sulﬁde

DMSO dimethyl sulfoxide

dppb 1,4-bis(diphenylphosphino)butane

dppe 1,2-bis(diphenylphosphino)ethane

DTE dithioerythritol

DTT dithiothreitol

EDC or EDCI 1-ethyl-3-(3-dimethylaminopropyl)- carbodiimide (or 1-[3-(dimethylamino)- propyl]-3-ethylcarbodimide

hydrochloride)

EDCI or EDC 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide

EDTA ethylenediaminetetraacetic acid

ABBREVIATIONS xxxiii

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HATU N-[(dimethylamino)(3H-1,2,3-triazolo[4,5-b]

pyridin-3-yloxy)methylene]-N-methylme- thanaminium hexaﬂuorophosphate, previ- ously known as O-(7-azabenzotriazol- 1-yl)-1,1,3,3-tetramethyluronium hexaﬂuorophosphate

HMDS 1,1,1,3,3,3-hexamethyldisilazane

HMPA hexamethylphosphoramide

HMPT hexamethylphosphorous triamide

HOAt 7-aza-1-hydroxybenzotriazole

HOBt 1-hydroxybenzotriazole

Im imidazol-1-yl or 1-imidazolyl

IPA isopropyl alcohol

IPCF (IPCC) isopropenyl chloroformate (isopropenyl chlorocarbonate)

KHMDS potassium hexamethyldisilazide

LAH lithium aluminum hydride

LDBB lithium 4,40-di-t-butylbiphenylide

MAD methylaluminum bis(2,6-di-t-butyl-4-

methylphenoxide)

MCPBA m-chloroperoxybenzoic acid

MoOPH oxodiperoxymolybdenum(pyridine)

hexamethylphosphoramide

MS molecular sieves

MSA methanesulfonic acid

Msz 4-methylsulﬁnylbenzylcarbonyl

MTB methylthiobenzene

MTBE t-butyl methyl ether

NBS N-bromosuccinimide

Ni(acac)2 nickel acetylacetonate

NMM N-methylmorpholine

NMO N-methylmorpholine N-oxide

NMP N-methylpyrrolidinone

P polymer support

Pc phthalocyanine

PCC pyridinium chlorochromate

PdCl₂(tpp)₂ dichlorobis[tris(2-methylphenyl)phosphine]

palladium

Pd₂(dba)₃ tris(dibenzylideneacetone)dipalladium

PG protective group

PhAcOZ 4-phenylacetoxybenzylcarbonyl

PhI(OH)OTs [hydroxy(tosyloxy)iodo]benzene

PMS 2-[phenyl(methyl)sulfonio]ethoxycarbonyl

PPL porcine pancreatic lipase

PPTS pyridiniump-toluenesulfonate

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proton sponge 1,8-bis(dimethylamino)naphthalene

Pyr pyridine

Rh₂(pfb)₄ rhodium perﬂuorobutyrate

ScmCl methoxycarbonylsulfenyl chloride

SMEAH sodium bis(2-methoxyethoxy)aluminum

hydride

Su succinimidyl

TAS-F tris(dimethylamino)sulfonium

diﬂuorotrimethylsilicate

TBAF tetrabutylammoniumﬂuoride

TEA triethylamine

TEBA or TEBAC triethylbenzylammonium chloride TEBAC or TEBA triethylbenzylammonium chloride

TESH triethylsilane

Tf triﬂuoromethanesulfonyl

TFA triﬂuoroacetic acid

TFAA triﬂuoroacetic anhydride

TFMSA or TfOH triﬂuoromethanesulfonic acid TfOH or TFMSA triﬂuoromethanesulfonic acid

THF tetrahydrofuran

THP tetrahydropyran

TMEDA N,N,N00,N00-tetramethylethylenediamine

TMOF trimethyl orthoformate

TPAP tetrapropylammonium perruthenate

TPP tetraphenylporphyrin

TPPTS sulfonated triphenylphosphine

TPS triisopropylbenzenesulfonyl chloride

TrBF4 or Ph3CBF4 triphenylcarbenium tetraﬂuoroborate

TrS Bu4N tetrabutylammonium

triphenylmethanethiolate

ABBREVIATIONS xxxv

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1

THE ROLE OF PROTECTIVE GROUPS IN ORGANIC SYNTHESIS

PROPERTIES OF A PROTECTIVE GROUP

When a chemical reaction is to be carried out selectively at one reactive site in a multifunctional compound, other reactive sites must be temporarily blocked. Many protective groups have been, and are being, developed for this purpose. A protective group must fulfill a number of requirements. It must react selectively in good yield to give a protected substrate that is stable to the projected reactions. The protective group must be selectively removed in good yield by readily available, preferably nontoxic reagents that do not attack the regenerated functional group. The protective group should form a derivative (without the generation of new stereogenic centers) that can easily be separated from side products associated with its formation or cleavage. The protective group should have a minimum of additional functionality to avoid further sites of reaction. All things considered, no protective group is the best protective group. Currently, the science and art of organic synthesis, contrary to the opinions of some, has a long way to go before we can call it afinished and well-defined discipline, as amply illustrated by the extensive use of protective groups during the synthesis of multifunctional molecules. A greater number of protective group-free syntheses have been accomplished since the last edition of this book, but in some cases this is the result of a suitable target choice rather than a fundamental advance in organic chemistry. Greater control over the chemistry used in the building of Nature’s architecturally beautiful and diverse molecular frameworks, as well as unnatural structures, is needed when one considers the number of protection and deprotection

1 Greene’s Protective Groups in Organic Synthesis, Fifth Edition. Peter G. M. Wuts.

 2014 John Wiley & Sons, Inc. Published 2014 by John Wiley & Sons, Inc.

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steps often used to synthesize a molecule. Peptides, carbohydrates, and polyketides are among the classes of compounds that still require extensive use of protective groups, whereas the synthesis of alkaloids appears to be less dependent upon protective group use.

HISTORICAL DEVELOPMENT

Since a few protective groups cannot satisfy all these criteria for elaborate substrates, a large number of mutually complementary protective groups are needed and, indeed, are available. In early syntheses, the chemist chose a standard derivative known to be stable to the subsequent reactions. In a synthesis of callistephin chloride, the phenolic –OH group in 1 was selectively protected as an acetate.¹In the presence of silver ion, the aliphatic hydroxyl group in2 displaced the bromide ion in a bromoglucoside. In a ﬁnal step, the acetate group was removed by basic hydrolysis.

HO O

OH

NaOH CH3COCl

AcO O

OH 2

1

Other classical methods of cleavage include acidic hydrolysis (eq. 1), reduction (eq. 2), and oxidation (eq. 3):

(1) ArO-R ! ArOH (2) RO-CH2Ph! ROH

(3) RNH-CHO ! RNHCOOH ! RNH3

Some of the original work in the carbohydrate area in particular reveals extensive protection of carbonyl and hydroxyl groups. For example, a cyclic diacetonide of glucose was selectively cleaved to the monoacetonide.²A summary³describes the selective protection of primary and secondary hydroxyl groups in a synthesis of gentiobiose, carried out in the 1870s, as triphenylmethyl ethers.

DEVELOPMENT OF NEW PROTECTIVE GROUPS

As chemists proceeded to synthesize more complicated structures, they developed more satisfactory protective groups and more effective methods for the formation and cleavage of protected compounds. Atﬁrst, a tetrahydropyranyl acetal was prepared,⁴ by an acid-catalyzed reaction with dihydropyran, to protect a hydroxyl group. The acetal is readily cleaved by mild acid hydrolysis, but formation of this acetal introduces a new stereogenic center. Formation of the 4-methoxytetrahydropyranyl ketal⁵eliminates this problem.

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Catalytic hydrogenolysis of an O-benzyl protective group is a mild, selec- tive method introduced by Bergmann and Zervas⁶ to cleave a benzyl carbamate (>NCO–OCH2C₆H₅® >NH) prepared to protect an amino group during peptide syntheses. The method has also been used to cleave alkyl benzyl ethers, stable compounds prepared to protect alkyl alcohols; benzyl esters are cleaved by catalytic hydrogenolysis under neutral conditions.

Three selective methods to remove protective groups have received attention:

“assisted,” electrolytic, and photolytic removal. Four examples illustrate “assisted removal” of a protective group. A stable allyl group can be converted to a labile vinyl ether group (eq. 4)⁷; aβ-haloethoxy (eq. 5)⁸or aβ-silylethoxy (eq. 6)⁹derivative is cleaved by attack at theβ-substituent; and a stable o-nitrophenyl derivative can be reduced to the o-amino compound, which undergoes cleavage by nucleophilic displacement (eq. 7)¹⁰:

(4) ROCH₂CHCH2−−−−®^t-BuO ROCHCHCH3 −−−−®^H³^O ROH (5) RO-CH2-CCl3 Zn ! RO CH2CCl2

(6) RO-CH2-CH2-SiMe3−−−−®^F RO CH2CH2 FSiMe3

R alkyl; aryl; R^´CO-; or R^´NHCO-

(7) NH

N N

+ N O

H

O NH2

NO2

O

The design of new protective groups that are cleaved by“assisted removal” is a challenging and rewarding undertaking.

Removal of a protective group by electrolytic oxidation or reduction is useful in some cases. An advantage is that the use and subsequent removal of chemical oxidants or reductants (e.g., Cr or Pb salts; Pt–C or Pd–C) are eliminated. Reductive cleavages have been carried out in high yield at 1 to 3 V (vs. SCE) depending on the group; oxidative cleavages in good yield have been realized at 1.5–2 V (vs. SCE).

For systems possessing two or more electrochemically labile protective groups, selective cleavage is possible when the half-wave potentials, E1/2, are sufﬁciently different; excellent selectivity can be obtained with potential differences on the order of 0.25 V. Protective groups that have been removed by electrolytic oxidation or reduction are described at the appropriate places in this book; a review article by Mairanovsky¹¹ discusses electrochemical removal of protective groups.¹²

Photolytic cleavage reactions (e.g., ofo-nitrobenzyl, phenacyl, and nitrophenylsulfenyl derivatives) take place in high yield on irradiation of the protected compound for a few hours at 254–350 nm. For example, the o-nitrobenzyl group, used to protect alcohols,¹³ amines,¹⁴ and carboxylic acids,¹⁵ has been removed by irradiation.

DEVELOPMENT OF NEW PROTECTIVE GROUPS 3

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Protective groups that have been removed by photolysis are described at the appropriate places in this book; in addition, the reader may consult ﬁve review articles.^16–20

One widely used method involving protected compounds is solid-phase synthesis^21–24 (polymer-supported reagents). This method has the advantage of simple workup by ﬁltration and automated syntheses, especially of polypeptides, oligonucleotides, and oligosaccharides.

Internal protection, used by van Tamelen in a synthesis of colchicine, may be appropriate²⁵:

1. DCC 2. CH₂N₂

CO₂Me

O

O CH3O

CH₃O CH₃O OH

CO₂H CO2H CH₃O

CH₃O CH₃O

SELECTION OF A PROTECTIVE GROUP FROM THIS BOOK

To select a speciﬁc protective group, the chemist must consider in detail all the reactants, reaction conditions, and functionalities involved in the proposed synthetic scheme. First, he or she must evaluate all functional groups in the reactant to determine those that will be unstable to the desired reaction conditions and require protection. The chemist should then examine reactivities of possible protective groups, listed in the Reactivity Charts, to determine compatibility of protective group and reaction conditions. A guide to these considerations is provided in Chapter 10. (The protective groups listed in the Reactivity Charts in that chapter were the most widely used groups at the time the charts were prepared in 1979 in a collaborative effort with other members of Professor Corey’s research group.) Much new technology has been developed since the creation of those tables and thus the user should be aware of that. He or she should consult the complete list of protective groups in the relevant chapter and consider their properties. It will frequently be advisable to examine the use of one protective group for several functional groups (i.e., a 2,2,2-trichloroethyl group to protect a hydroxyl group as an ether, a carboxylic acid as an ester, and an amino group as a carbamate). When several protective groups are to be removed simultaneously, it may be advantageous to use the same protective group to protect different functional groups (e.g., a benzyl group, removed by hydrogenolysis, to protect an alcohol and a carboxylic acid). When selective removal is required, different classes of protection must be used (e.g., a benzyl ether, cleaved by hydrogenolysis but stable to basic hydrolysis, to protect an alcohol, and an alkyl ester, cleaved by basic hydrolysis but stable to hydrogenolysis, to protect a carboxylic acid). One often overlooked issue in choosing a protective group is that the electronic and steric environments of a given functional group will greatly inﬂuence the rates of

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formation and cleavage. For an obvious example, a tertiary acetate is much more difﬁcult to form or cleave than a primary acetate.

If a satisfactory protective group has not been located, the chemist has a number of alternatives: rearrange the order of some of the steps in the synthetic scheme so that a functional group no longer requires protection or a protective group that was reactive in the original scheme is now stable; redesign the synthesis, possibly making use of latent functionality²⁶(i.e., a functional group in a precursor form; e.g., anisole as a precursor of cyclohexanone). Or, it may be necessary to include the synthesis of a new protective group in the overall plan or, better yet, design new chemistry that avoids the use of a protective group.

Several books and chapters are associated with protective group chemistry. Some of these cover the area^27,28; others deal with more limited aspects. Protective groups continue to be of great importance in the synthesis of three major classes of naturally occurring substances—peptides,²² carbohydrates,²⁴ and oligonucleotides²³—and signiﬁcant advances have been made in solid-phase synthesis,²²^–24including automated procedures. The use of enzymes in the protection and deprotection of functional groups has been reviewed.²⁹Special attention is also called to a review on selective deprotection of silyl ethers.³⁰

SYNTHESIS OF COMPLEX SUBSTANCES: TWO EXAMPLES (AS USED IN THE SYNTHESIS OF HIMASTATIN AND PALYTOXIN) OF THE SELECTION, INTRODUCTION, AND REMOVAL OF

PROTECTIVE GROUPS Synthesis of Himastatin

Himastatin, isolated from an actinomycete strain (ATCC) from the Himachal Pradesh State in India and active against Gram-positive microorganisms and a variety of tumor probe systems, is a C72H104N14O20compound,1.³¹It has a novel bisindolyl structure in which the two halves of the molecule are identical. Each half contains a cyclic peptidal ester containing an L-tryptophanyl unit, D-threonine, L-leucine, D-[(R)-5- hydroxy]piperazic acid, (S)-2-hydroxyisovaleric acid, and ^D-valine. Its synthesis³² illustrates several important aspects of protective group usage.

Synthesis of himastatin involved the preparation of the pyrroloindoline moietyA, its conversion to the bisindolyl unitA^´₂, synthesis of the peptidal ester moietyB, the subsequent joining of these units (A^´₂ and twoB units), and cyclization leading to himastatin. The following brief account focuses on the protective group aspects of the synthesis.

Unit A (Scheme 1)

Theﬁrst objective was the conversion of^L-tryptophan into a derivative that could be converted to pyrroloindoline3, possessing a cis ring fusion and a syn relationship of the carboxyl and hydroxyl groups. This was achieved by the conversions shown in Scheme 1. A critical step was e. Of many variants tried, the use of the

SYNTHESIS OF COMPLEX SUBSTANCES 5

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trityl group on the NH₂of tryptophan and thet-butyl group on the carboxyl resulted in stereospeciﬁc oxidative cyclization to afford 3 of the desired cis–syn stereo- chemistry in good yield.

NH NH

CO2t-Bu HO

NH

NH O O

TBSO C

N HN

OTBS O

O O Troc N

H

NH N

CO₂-Allyl N O

HN Allyl-O2C O

H

H TES

TES

HO O NH

N

HO N O

NH NH O OOO NH

N

OO OH

OH HN

N N OH O

HN HN

OOO O NN H

OO HO

OH

A'2

H

two B units Himastatin

H

1 Himastatin 1

A

B

•

Bisindolyl Unit A^´₂(Schemes 2 and 3)

The conversion of3 to 8 is summarized in Scheme 2. The trityl group (too large and too acid sensitive for the ensuing steps) was removed from N and both N’s were protected by Cbz (benzyloxycarbonyl) groups. Protection of the tertiary OH speciﬁ- cally as the robust TBS (t-butyldimethylsilyl) group was found to be necessary for the sequence involving the electrophilic aromatic substitution step,5 to 6, and the Stille coupling steps (6 + 7 ® 8).

The TBS group then had to be replaced (two steps, Scheme 3: a and b) by the more easily removable TES (triethylsilyl) group to permit deblocking at the last step in the synthesis of himastatin. Before combination of the bisindolyl unit with the peptidal ester unit, several additional changes in the state of protection at the two