K.C.NICOLAOU, E. J. SORENSEN CLASSICS IN TOTAL SYNTHESISClassics in Total Synthesis K.C. Nicolaou and E.J. SorensenOther successful books in organic chemistry from VCH IM. Lehn Supramolecular Che Concepts and Perspectives 1995, X, 271 pages with 51 figures. Hardcover. ISBN 3-527-29312-4. Softcover. ISBN 3-527-29311-6. J. Fuhthop, G. Penzl Organic Synthesis - Concepts, Methods, Starting Materials Second, Revised and Enlarged Edition With a Foreword by E.J. Corey 1994. XVI, 432 pages with 16 figures and 37 tables. Hardcover. ISBN 3-527-29086-9 Softcover. ISBN 3-527-29074-5. M. Nogradi Stereoselective Synthesis — A Practical Approach Second, Thoroughly Revised and Updated Edition With a Foreword by A.I. Meyers 1994. XVI, 452 pages with 171 figures and 23 tables. Hardcover. ISBN 3-527-29242-X. Softcover. ISBN 3-527-29243-8, D.P. Curran, N.A. Porter, B. Giese Stereochemistry of Radical Reactions — Concepts, Gt and Synthetic Applications 1995, XII, 280 pages with 31 figures and 2 tables. Hardcover. ISBN 3-527-29372-8. H. Waldmann (Ed.) Organic Synthesis Highlights II 1995. XIII, 407 pages with 318 figures and 3 tables. Hardcover. ISBN 3-527-29200-4, © VCH Verlagsgesellschalt mbH, D-60451 Weinheim (Federal Republic of Germany), 1996 oat 1 Distribution: VCH, P.O. Box 101161, D-6945) Weinheim, Federal Republic of Germany Switzerland: VCH, P.O. Box, CH-8020 Basel, Switzerland | United Kingdom and Kreland: VCH, 8 Wellington Court, Cambridge CBI 1HZ, United Kingdom USA and Canada: VCH, 220 Bast 25rd Street, New York, NY 10010-4606, USA. Japan: VCH, Eikow Building, 10-9 Hongo l-chome, Bunkyo-ku, Tokyo 113, Japan ISBN 3-527-29284-5 ISBN 3-527-20231-4Classics in Tota Synthesis Targets, Strategies, Methods With a Foreword by E.J. Corey (iL VCH"! K.C. Nicolaou and E.J. Sorensen Weinheim New York Basel Cambridge TokyoK.C, Nicolaou, Ph. D. Erik J, Sorensen, Ph. D. Department of Chemistry ‘and Department of Chemistry and Biochemistry The Scripps Research Institute University of California, San Diego 10666 North Torrey Pines Road 9500 Gilman Drive La Jolla, CA 92037 La Jolla, CA. 92093, USA USA ‘This book was carefully produced. Nevertheless, authors and publisher do not warrant the information contained therein to be free if errors. Readers are advised to Keep in mind that statements, data, illustrations, procedural details or other items may inadver tently be inaccurate Published jointly by VCH Verlagsgeselischaft mbH, Weinheim (Federal Republic of Germany) ‘CH Publishers, In., New York, NY (USA) Copy Editor: Dr. Rachel Schmidt-Radde Production Manager: Dipl.-Ing. (FH) Hans Jorg Maier Front cover: A red-tide incident that occurred on 8th May 1976, off Matsushima Istand, in Hyogo Prefecture, Japan, The structure ‘shown is that of brevetoxin B, a neurotoxin produced by algae that proliferate during red-tide incidents. Brevetoxin B is believed to have been responsible for massive fish killings and poisoning of humans who ate affected seafood. The total synthesis of brevetoxia Bis described in Chapter 37 of this book, Back cover: Structure of vitamin By. Library of Congress Card No. applied for ‘A catalogue record for this book is available from the British Library. Deutsche Bibliothek Cataloguing-in-Publication Data: Nicolaou, K.C. Classics in total synthesis / K.C. Nicolaou and Erik J. Sorensen, - Weinheim ; New York ; Basel ; Cambridge ; Tokyo VCH, 1996 ISBN 3-527-29284-5 Pp. ISBN 3-527-29231-4 brosch. NB: Sorensen, Erik J: © VCH Veriagsgeselschaft mbH, D-69451 Weinheim (Federal Republic of Germany), 1996 Printed on acid-free and chlorine-ree paper All rights reserved (including those of translation in other languages). No part of this book may be reproduced in any form ~ by photo. printing, microfilm, or any other means - nor transmitted or translated into machine language without writen permission from the Publishers. Registered names, trademarks, etc. used in this book, even when not specifically marked as such, are not to be considered “unprotected by law. Composition: Fa, Hagedornsatz GmbH, D.68519 Viemheim, Printing: Zechnersche Buchdruckerci, D-67346 Speyer. Bookbinding: Wilhelm Osswald & Co, D-67433 Neustadt. Printed in the Federal Republic of Germany.Foreword Ifa definitive history of twentieth century science is ever written, one of the highlights may well be a chapter on the chemical synthesis of complex molecules, especially the total synthesis of naturally occur- ring substances. I state this, while trying to be as objective as possible, because it is not easy to find an area of scientific work that encom- asses so many interesting elements. I shall name just a few: great com- plexity and variety; challenge verging on impossibility; demand for both mental and manipulative rigor, and for dedication, persistence, and hard work; never-ending frontiers for discovery and never-ending advances in sophistication; unlimited opportunities for intellectual excitement and satisfaction; strong coupling not only with all areas of chemistry, but also with biology and medicine: relevance, at a very fun- damental level to human well-being, health, and education As I read a prepublication draft of “Classics in Total Synthesis”, all of these general characteristics of synthetic research assumed a reality and sharpness that I had not expected, partly because 1 was already familiar with each of the thirty-seven classics in this collec- tion. It was a sheer delight to revisit each of these triumphs guided by the wise insights and analyses found throughout this book. There is a nice balance between the underlying historical material and the design and execution aspects of each synthesis. In addition, the broad perspectives on synthesis, supplemented in each section by detailed explanations of the key features of each synthesis, lead toa presentation that is both clear and stimulating. The pedagogy is effective As mentioned by the authors in their preface, the achievements in total synthesis have been so numerous and so important that it is Clearly impossible to include them all in a single volume. My hope is that “Classics in Total Synthesis” will be successful and that it will be followed by a continuing series. Such a colléction will add to our reading pleasure and further encourage and inspire new generations of chemists to dare the impossible (or even the unfashionable). There is much still to be leamed and to be discovered. Humanity will be enriched beyond measure if the twenty-first century is a period of continued vigorous development of synthetic chemistry. I would like to congratulate Professor Nicolaou and Dr, Sorensen on this fine addition to the literature of synthetic chemistry and to wish them well in their further work as scientists and as authors. May the joumey in total synthesis follow the Ithaca model (page 16) E.J. Corey Harvard University 30 October 1995Abbreviations Ac acetyl cae acetylacetonyl AD asymmetric dihydroxylation AIBN 2,2-azobisisobutyronitrile BBEDA N,N'-bis(benzylidene)ethylenediamine 9-BBN 9-borabicyclo[3.3.1}nonane BINAL-H 2,2-dihydroxy-1,1’-binaphthylaluminum. BINAP Bn benzyl BOC (-BOC)’ tert-butoxycarbonyl BOM benzyloxymethyl BTMSA bis(trimethylsilylacetylene Bz benzoyl 18-C-6 18-crown-6 Cbz benzyloxycarbonyl CHD coronary heart disease CoA cop Cp CSA Cy (Cy-Hex) DAIB DAST dba DBN DBs DBU DCBI pec D_Q de DEAD DEIPS DET DHP DHQ DHQD DIAD Dibal-H DIOP DiPAMP DIPT DMA 4-DMAP. (DMAP) DME DMF DMs DMSO DNA 1-DOPA, DPC DTBMS. EDC (EDCH e ee EE Et-DuPHOS Fmoe FPP coenzyme A 1,5-cyclooctadiene cyclopentadieny! 10-camphorsulfonic acid ceyclohexy? 3-ex0-(dimethylamino)isoborneo! diethylaminosulfur trifluoride trans, trans-dibenzy 1,5-diazabicyclo[4.3.0)non-5-ene S-dibenzosuberyl 1,8-diazabicyclo[5.4.0]undec-7-ene NN'-dicyclohexyl-O-benzylisourea 1,3-dicyclohexylcarbodiimide 2/3-dichloro-5,6-dicyano-1,4-benzoquinone diastereomeric excess diethyl azodicarboxylate diethylisopropylsily! diethy! tartrate 3.4-dihydro-2H-pyran dihydroquinine dibydroquinidine diisopropyl azodicarboxylate diisobutylaluminum hydride 2,3-O-isopropylidene-2,3-dihydroxy-1,4- bis(diphenylphosphino)butane 1,2-bis(o-anisylphenylphosphino)ethane diisopropy! tartrate N,N-dimethylacetamide 4-dimethylaminopyridine ethylene glycol dimethyl ether N.N-dimethylformamide dimethy! sulfide dimethyl sulfoxide deoxyribonucleic acid 3-(3,4-dihydroxyphenyl: dipyridine chromium(vi) oxide di(fert-buty!)methylsily! 1-(3-dimethylaminopropyl)-3-ethylearbodii- hydrochloride electron enantiomeric excess 1-ethoxyethy! 1,2-bis(2',5'-diethylphospholanoyethane 9-fluorenylmethoxycarbonyl farnesyl pyrophosphate Gc HETE hfe HMPA HMG HPLC HWE Im (imid.) IND Ipe KHMDS LDA LHMDS mCPBA MEM MOM Ms NaHMDS NB pNB NBS NCS NIS NMM NMO NMP PNNP PPTS psi pyr. (pyr, Py) PYR Ra-Ni Red-Al SAE SEM Sia TBAF TBAL TBS TEOC gas chromatography hydroxyeicosatetraenoic 3-{hepiafluoropropylhydroxymiethylene |v camphorato hexamethylphosphoramide hydroxymethylelutaryl high-pressure liquid chromatography Homer-Wadsworth-Emmons imidazole indoline isopinocamphey! potassium bis(trimethylsilylamide lithium diisopropylamide lithium bis(trimethylsilylamide 3-chloroperoxybenzoic acid 2-methoxyethoxymethyl methoxymethyl methanesulfanyl sodium bis(trimethylsily!)amide 2-nitrobenzy! 4-nitrobenzyl N-bromosuccinimide N-chlorosuccinimide N-iodosuccinimide 4-methylmorpholine 4-methylmorphotine N-oxide I-methyl-2-pyrrolidinone nnclear magnetic resonance nucleophile pyridinium chlorochromate pyridinium dichromate prostaglandin pheny! phthalazine phthalimido pivaloy! 4-methoxybenzy! N,N’-bis(1-phenylethy)-N,N’-bis-(diphe- nylphosphino)ethylenediamine pyridinium 4-toluenesulfonate ‘pounds per square inch pyridine diphenyipyrimidine Raney nickel sodium bis(2-methoxyethoxy)aluminum hydride Sharpless Asymmetric Epoxidation 2-(trimethylsilyethoxymethy! siamyl tetra-n-butylammonium fluoride tetra-n-butylammonium iodide tert-butyldimethylsily! 2-(trimethylsilyethoxycarbonyl triethylsily! trifluoromethanesulfonyl trifluoroacetic acid trifluoroacetic anhydride tetrahydrofuran tetrahydropyranyl * triisopropylsilyl N.N.N’,N'-tetramethylethylenediamine trimethylsilyl tetra-n-propylammoniuim perruthenate tert-butyldiphenylsilyl triphenylmethy! 4-toluenesulfonylPreface This book is intended to be an historical record of some of the greatest total syntheses of all time. We also hope that it will serve as a teaching and learning tool for teachers, students, and practi- tioners of organic synthesis. In Chapter 1, the reader will find a dis- cussion on the philosophy, purpose, and use of total synthesi each of the remaining 36 chapters, we describe the total synthesis of a natural product. Through the examples chosen, an effort was made to trace the evolution of the science of total synthesis to its present state and to demonstrate the utility of important chemical reactions in the construction of target organic molecules. Despite the diversity of structures, each total synthesis is presented in a uni- fying pedagogical format, which hopefully distinguishes this book from any other. In the Introduction section of each chapter, the background and biological action of the target molecule is discussed, and the impor- tant synthetic reactions involved in the synthesis are presented. Following the introduction is the Retrosynthetic Analysis and Strategy section, in which the target molecule is analyzed retro- synthetically to show and explain the evolution of the synthetic strategy. In the Total Synthesis section, the execution of the syn- thesis is discussed, with special emphasis placed on tactics, effi- ciency, selectivity, stereochemistry, and synthetic maneuvering. The Conclusion section summarizes in a concise manner the main find- ings and impact of the total synthesis Throughout each chapter, clear structures, schemes, and figures accompany the text. Mechanism, reactivity, selectivity, and stereo- chemistry are especially addressed. Special emphasis is also placed on introducing both the logic of total synthesis and the rationale for the invention and use of important synthetic methods. In particular, we amplify the most important developments in asymmetric synthe- sis, catalysis, cyclization reactions, and organometallic chemistry. This volume is based partly on the lecture notes of K.C.N. that were used for teaching courses at the University of Pennsylvania, the University of California, San Diego, and The Scripps Research Institute. We apologize sincerely to those whose brilliant works have been left out owing to the inevitable closing of the curtain and hope that in the event of a second volume we can rectify these omissions. We also apologize in advance for the inevitable errors that a volume of this size may contain, and welcome constructive comments from our readers in order to correct such errors in future editions, It is our hope that this book will find its way into the hands of every student of organic synthesis and that it will serve both to edu-vill Preface cate and inspire. If we can excite and stimulate a new generation of chemists in the direction of organic synthesis, then we will be satis fied that a major part of our goal has been reached. We wish to thank Janise L. Petrey for her tenacity, skill, and patience in processing the many and fragmentary versions of this, book. We would also like to thank Alan Nadin for his thoughtful comments and useful suggestions on various aspects of the manu- script. We are grateful to Chris F. Claiborne, Otto Griither, R. Kip Guy, John |. Trujillo, and Eddy W. Yue for their assistance and for checking the references. We thank Professors Charlie L. Perrin, Jay S. Siegel, and Emmanuel A. Theodorakis for useful discussions and suggestions, and Vicky Nielsen for her managerial skills in keeping us all together, We owe our many thanks to Georgette, Colette, Alex, Chris, and P.J. Nicolaou and Karla Sorensen for their support and patience during this odyssey, and we offer our apologies for not being there when we should have been .. Our sincere appreciation goes to all the members of the K.C.N. group whose dedication, brilliance, and diverse ethnic background have made this group's contributions both possible and enjoyable, Finally, we would like to dedicate this book to Professor E.J. Corey, whose teachings and research have helped shape the science of organic synthesis and the art of total synthesis as we know it today. La Jolla K.C. Nicolaou October 1995 E.J. SorensenAbout the Authors K.C. Nicolaou was born in 1946 in Cyprus. He studied chemistry at the University of London (B. Sc.. 1969; Ph. D., 1972), Columbia University (postdoctoral research) and Harvard University (postdoc- toral research). Between 1976 and 1989 he was a faculty member at the University of Pennsylvania. He currently holds joint appointments at The Scripps Research Institute, where he is the Darlene Shiley Professor of Chemistry and Chairman of the Department of Chemistry, and at the Univer- sity of California, San Diego, where he is Professor of Chem- istry. His research interests, span the areas of synthetic. organic chemistry, bioorganic chemistry, molecular design, and the chemistry and biology of natural produets.x About the Authors Erik J. Sorensen was born in 1966 in Oneida, New York. He graduated from Syracuse Uni- versity with a B.A. in chernis- try, He received his Ph.D. degree in chemistry from the University of California, Diego in 1995 working under the guidance of Professor K.C. Nicolaou. His research interests are in the areas of total syn~ thesis and reaction engineeringContents Overview . Introduction: Constructing the Molecules of Nature 2. Strychnine (R. B. Woodward) (1954) 3. Penicillin V (J.C. Sheehan) (1957) 4, Reserpine (R. B. Woodward) (1958) 5, Prostaglandin Faq (PGF2q) and (E.J. Corey) (1969) Prostaglandin E> (PGE2) 6. Progesterone (W.S. Johnson) (1971) 7. Carpanone (O.L. Chapman) (971) 8. Vitamin B12 (R.B. Woodward and (1973) A. Eschenmoser) 9. Prostaglandin A> (PGA2) and (G. Stork) (1976, 1978) Prostaglandin Faq (PGF2a) 10, Estrone (K. P.C. Vollhardt) (1977) 11. Erythronolide B (E. J. Corey) (1978) 12. Monensin (¥. Kishi) (1979) 13. Periplanone B (W.C. Still) (1979) 14, Isocomene (M.C. Pirrung) (1979) 15. Monensin (W.C. Still) (1980) 16, Thienamycin (Merck) (1980) 17. Endiandric Acids (K.C. Nicolaou) (1982) 18. Biotin (Hoffmann-La Roche) (1982) 19. -Hexoses (S. Masamune and (1983) K.B. Sharpless) 20. Asteltoxin’ (S.L. Schreiber) (1983) 21. Periplanone B (S.L. Schreiber) (1984) 22. Menthol (Takasago) (1984) 23. Hirsutene and A%'2)-Capnellene (D. P. Curran) (1986) 24, Amphoteronolide B and (K.C. Nicolaou) (1987) Amphotericin B 25. Ginkgolide B (E.J. Corey) (1988) 26. Methyl Homosecodaphniphyllate —_ (C. H. Heathcock) (1988) 27. Indolizomycin (S.J. Danishefsky) (1990) 28. Cytovaricin (D.A. Evans) (1990) 29, Gilvocarcin M and Gilvocarcin V—_(K. Suzuki) (1992, 1994) 30. Calicheamicin y} (K.C. Nicolaou) (1992) 31, Rapamycin (K.C. Nicolaou) (1993) 32. Paconiflorigenin and Paeoniflorin (E.J. Corey) * (1993) 33. Strychnine (L.E. Overman) (1993) 34. Taxol (K.C. Nicolaou) (1994) 35, Zaragozic Acid A/Squalestatin $1 (K. C. Nicolaou) (1994) 36. Palytoxin (¥. Kishi) (1994) 37. Brevetoxin B (K.C. Nicolaou) (1995)Table of Contents Chapter 1 Introduction: Constructing the Molecules of Nature 1.1 Synthetic Chemistry and Total Synthesis .. . . 1.2 The Scope of Organic Synthetis.. 1.3. A Brief History of Organic Synthesis 1.4 The Practice of Total Synthesis 1.5. Target Molecules . : : 1.6 Natural Products as Synthetic Targets . 1.7 Designed Molecules as Synthetic Targets, 1.8 Synthetic Strategy gosneoeo 1.9 Retrosynthetic Analysis 1.10 Classics in Total Synthesis . .. Chapter 2 Strychnine R.B. Woodward (1954) 2.1. Introduction 22. Retrosynthetic Analysis and Strategy 2.3 Total Synthesis bees 24 Conclusion ....... Chapter 3 Penicillin V J.C. Sheehan (1957) Introduction . Retrosynthetic Analysis and Strategy... Total Synthesis . . Conclusion ... 21 22 21 40 4 44 45 50XIV Table of Contents Chapter 4 Reserpine R.B. Woodward (1958) 44 42 43 44 Introduction *Retrosynthetic Analysis ‘and Suey : Total Synthesis. Conclusion... . Chapter 5 Prostaglandin F2q (PGF2q) and Prostaglandin Ez (PGE2) E. J. Corey (1969) 5.1 Introduction... .. . 5.2 Retrosynthetic ‘Analysis ‘and I Sateey 5.3 Total Synthesis... 54 Conclusion Chapter 6 Progesterone W.S. Johnson (1971) 6.1 Introduction ..... 6.2 Retrosynthetic Anas ‘and Seategy 6.3 Total Synthesis 64 Conclusion Chapter 7 Carpanone O.L. Chapman (1971) 7.1 Introduction... . . 72 Rewrosynthetic Analysis and. a Sitegy 7.3 Total Synthesis. 74 Conclusion 65 67 a 81 83 85 88 92