Classics in Total Synthesis

Classics in Total Synthesis

K. C. Nicolaou and E. J. Sorensen

Targets, Strategies, Methods

With a Foreword by E. J. Corey

VCH

Weinheim New York Basel Cambridge Tokyo

Table of Contents

Chapter 1

Introduction: Constructing Molecules ofNature 1.1 1.2 1.3 1.4 1.5 1.6 1.7 1.8 1.9 1.10

the

Synthetic Chemistry and Total Synthesis The Scope of Organic Synthetis A Brief History of Organic Synthesis The Practice of Total Synthesis Target Molecules Natural Products as Synthetic Targets Designed Molecules as Synthetic Targets Synthetic Strategy Retrosynthetic Analysis Classics in Total Synthesis

2 3 5 7 8 9 12 13 14 17

Chapter 2

Strychnine R.B. Woodward (1954) 2.1 2.2 2.3 2.4

Introduction Retrosynthetic Analysis and Strategy Total Synthesis Conclusion

21 22 27 40

Chapter 3

Penicillin V J. C. Sheehan (1957) 3.1 3.2 3.3 3.4

Introduction Retrosynthetic Analysis and Strategy Total Synthesis Conclusion

i

41 44 45 50

XIV

Table of Contents

Chapter 4

Res erpine

(

R. B. Woodward (1958) 4.1 4.2 4.3 4.4

Introduction Retrosynthetic Analysis and Strategy Total Synthesis Conclusion

55 56 57 63

Chapter 5

Prostaglandin F2a {PGF20) and Prostaglandin E2 (PGE2) E. J. Corey (1969) 5.1 5.2 5.3 5.4

Introduction Retrosynthetic Analysis and Strategy Total Synthesis Conclusion

65 67 71 81

Chapter 6

Progesterone W. S. Johnson (1971) 6.1 6.2 6.3 6.4

Introduction Retrosynthetic Analysis and Strategy Total Synthesis Conclusion

83 85 88 92

Chapter 7

Carpanone O. L. Chapman (1971) 7.1 7.2 7.3 7.4

Introduction Retrosynthetic Analysis and Strategy Total Synthesis Conclusion

95 95 96 97

Table of Contents Chapter 8

Vitamin B12 R. B. Woodward and A. Eschenmoser 8.1 8.2 8.3 8.3.1 8.3.2 8.3.3 8.3.4 8.3.5 8.3.6 8.3.7 8.3.8 8.3.9 8.4

(1973)

Introduction Retrosynthetic Analysis and Strategy Total Synthesis The Woodward Synthesis of Cyanobromide 6 The Eschenmoser Synthesis of B-Ring Intermediate 8 . The Woodward Synthesis of C-Ring Intermediate 9 . . . The Eschenmoser Synthesis of C-Ring Intermediate 9 . The Eschenmoser Synthesis of Thiodextrolin (7) The Woodward-Eschenmoser Macrocyclization Strategy The Eschenmoser Synthesis of A-Ring Intermediate 24 and D-Ring Intermediate 25 The Eschenmoser Cyclization Strategy Completion of the Woodward-Eschenmoser Total Synthesis of Cobyric Acid and Vitamin B12 Conclusion

99 100 105 105 113 115 115 117 121 123 126 130 134

Chapter 9

Prostaglandin A2 (PGA2) and Prostaglandin F20. (PGF2a) G. Stork (1976, 1978) 9.1 9.2 9.3 9.4 9.5 9.6

Introduction Retrosynthetic Analysis and Strategy for PGA 2 Total Synthesis of PGA 2 Retrosynthetic Analysis and Strategy for PGF 2 a Total Synthesis of PGF 2 a Conclusion

137 138 140 144 146 151

Chapter 10

Estrone K.P.C. Vollhardt (1977) 10.1 10.2 10.3 10.4

Introduction Retrosynthetic Analysis and Strategy Total Synthesis Conclusion

V

153 160 162 165

XVI

Table of Contents Chapter 11

Erythronolide B E. J. Corey (1978) 11.1 11.2 11.3 11.4

Introduction Retrosynthetic Analysis and Strategy Total Synthesis Conclusion

167 169 172 183

Chapter 12

Monensin Y. Kishi (1979) 12.1 12.2 12.3 12.4

Introduction Retrosynthetic Analysis and Strategy Total Synthesis Conclusion

185 187 194 207

Chapter 13

Periplanone B W. C. Still (1979) 13.1 13.2 13.3 13.4

Introduction Retrosynthetic Analysis and Strategy Total Synthesis Conclusion

211 212 215 219

Chapter 14

Isocomene M. C. Pirrung (1979) 14.1 14.2 14.3 14.4

Introduction Retrosynthetic Analysis and Strategy Total Synthesis Conclusion

221 221 223 225

Table of Contents Chapter 15

Monensin W. C. Still (1980) 15.1 15.2 15.3 15.4

Introduction Retrosynthetic Analysis and Strategy Total Synthesis Conclusion

227 230 235 246

Chapter 16

Thienamycin Merck (1980) 16.1 16.2 16.3 16.4

Introduction Retrosynthetic Analysis and Strategy Total Synthesis Conclusion

249 250 251 262

Chapter 17

Endiandric Acids

A-D

K. C. Nicolaou (1982) 17.1 17.2 17.3 17.3.1

Introduction Retrosynthetic Analysis and Strategy Total Synthesis Stepwise, Stereocontrolled Total Synthesis of Endiandric Acids A-D (and E-G) 17.3.2 "Biomimetic", One-Step Total Synthesis of Endiandric Acids A-D (and E-G) 17.4 Conclusion

265 267 270 270 275 283

Chapter 18

Biotin Hoffmann-La Roche (1982) 18.1 18.2 18.3 18.4

Introduction Retrosynthetic Analysis and Strategy Total Synthesis Conclusion

285 286 288 291

XVII

Table of Contents Chapter 19

L-Hexoses S. Masamune and K. B. Sharpless (1983) 19.1 19.2 19.3 19.4

Introduction Retrosynthetic Analysis and Strategy Total Synthesis Conclusion

293 298 310 313

Chapter 20

Asteltoxin S.L. Schreiber (1983) 20.1 20.2 20.3 20.4

Introduction Retrosynthetic Analysis and Strategy Total Synthesis Conclusion

317 322 324 331

Chapter 21

Periplanone B S. L. Schreiber (1984) 21.1 21.2 21.3 21.4

Introduction Retrosynthetic Analysis and Strategy Total Synthesis Conclusion

333 336 337 340

Chapter 22

Menthol Takasago (1984) 22.1 22.2 22.3 22.4 22.5

Introduction Retrosynthetic Analysis and Strategy Total Synthesis Conclusion Appendix: Catalytic Asymmetrie Reactions, an Overview

343 354 355 357 358

Table of Contents Chapter 23

Hirsutene and A9(12)-Capnellene D. P. Curran (1986) 23.1 23.2 23.3 23.4

Introduction Retrosynthetic Analysis and Strategy Total Synthesis Conclusion

381 409 410 416

Chapter 24

Amphoteronolide B and Amphotericin B K. C. Nicolaou (1987) 24.1 24.1.1 24.2 24.3 24.3.1 24.3.2

Introduction Degradation Studies Retrosynthetic Analysis and Strategy Total Synthesis Construction of Building Blocks 16 and 19 Construction of Building Blocks 17 and 18: The Carbohydrate Approach 24.3.3 Construction of Building Blocks 17 and 18: The Sharpless Asymmetrie Epoxidation Approach 24.3.4 Completion of the Synthesis of Amphoteronolide B 24.3.5 Completion of the Synthesis of Amphotericin B 24.4 Conclusion

421 421 425 429 429 432 . . . 434 438 444 448

Chapter 25

Ginkgolide B E.J. 25.1 25.2 25.3 25.4

Corey(1988) Introduction Retrosynthetic Analysis and Strategy Total Synthesis Conclusion

451 452 456 463

XIX

Table of Contents Chapter 26

Methyl Homosecodaphniphyllate C. H. Heathcock 26.1 26.2 26.3 26.4

(1988)

Introduction Retrosynthetic Analysis and Strategy Total Synthesis Conclusion

465 465 467 469

Chapter 27

Indolizomycin S. J. Danishefsky 27.1 27.2 27.3 27.4

(1990)

Introduction Retrosynthetic Analysis and Strategy Total Synthesis Conclusion

471 472 475 483

Chapter 28

Cytovaricin D.A. Evans (1990) 28.1 28.2 28.3 28.3.1 28.3.2 28.3.3 28.4

Introduction Retrosynthetic Analysis and Strategy Total Synthesis Synthesis of Spiroketal Subunit 6 Synthesis of Polyol Glycoside Subunit 7 Synthesis of Seco Acid 4 and Completion of the Total Synthesis of Cytovaricin Conclusion

485 487 491 491 497 503 506

Table of Contents

Chapter 29

Gilvocarcin M and Gilvocarcin V K. Suzuki (1992, 1994) 29.1 29.2 29.3 29.4

Introduction Retrosynthetic Analysis and Strategy Total Synthesis Conclusion

509 510 512 519

Chapter 30

Calicheamicin yj K. C. Nicolaou (1992) 30.1 30.2 30.3 30.3.1 30.3.2 30.3.3 30.4

Introduction 523 Retrosynthetic Analysis and Strategy 525 Total Synthesis 535 Synthesis of Oligosaccharide 8 535 Synthesis of Aglycon 5 548 Coupling of Intermediates 8 and 9 and Completion of the Total Synthesis of Calicheamicin y] 556 Conclusion 562

Chapter 31

Rapamycin K. C. Nicolaou (1993) 31.1 31.1.1 31.1.2 31.1.3 31.1.4 31.1.5 31.2 31.3 31.3.1 31.3.2 31.3.3 31.4

Introduction 565 The Heck Reaction 566 Palladium-Catalyzed Cycloisomerizations 578 The Stephens-Castro and the Sonogashira Couplings . . 582 The Suzuki Coupling 586 The Stille Coupling 591 Retrosynthetic Analysis and Strategy 599 Total Synthesis 607 Synthesis of Intermediates 147 and 158-160 607 Coupling of Key Intermediates 147 and 158-160 620 Final Stages and Cyclization to Rapamycin 624 Conclusion 626

XXI

XXII

Table of Contents Chapter 32

Paeoniflorigenin Paeoniflorin E.J. 32.1 32.3 32.3 32.4

and

Corey(1993) Introduction Retrosynthetic Analysis and Strategy Total Synthesis Conclusion

633 633 636 640

Chapter 33

Strychnine L.E. Overman (1993) 33.1 33.2 33.3 33.4

Introduction Retrosynthetic Analysis and Strategy Total Synthesis Conclusion

641 643 646 652

Chapter 34

Taxol K. C. Nicolaou (1994) 34.1 34.2 34.3 34.4

Introduction Retrosynthetic Analysis and Strategy Total Synthesis Conclusion

655 656 660 671

Chapter 35

Zaragozic Acid A/ Squalestatin Sl K. C. Nicolaou (1994) 35.1 35.1.1 35.2 35.3 35.3.1 35.3.2 35.3.3

Introduction The Asymmetrie Dihydroxylation Retrosynthetic Analysis and Strategy Total Synthesis Degradation and Reconstitution Chemistry Synthesis of Key Intermediate Aldehyde 68 Model Studies

673 675 691 694 694 695 699

Table of Contents

35.3.4 Synthesis of the Side Chains 702 35.3.5 Coupling of Key Intermediates and Completion of the Total Synthesis ofZaragozic Acid A/Squalestatin Sl . 704 35.4 Conclusion 707 Chapter 36

Palytoxin Y. Kishi (1994) 36.1 36.1.1 36.2 36.3 36.4

Introduction The NiCl2/CrCl2 Coupling Reaction Retrosynthetic Analysis and Strategy Total Synthesis Conclusion

711 712 717 719 729

Chapter 37

Brevetoxin B K. C. Nicolaou (1995) 37.1 Introduction 37.1.1 The Invention and Development of New Synthetic Methods a. Tetrahydropyran Systems b. Didehydrooxocane c. Oxepane Systems 37.2 Retrosynthetic Analysis and Strategy 37.2.1 The Triply Convergent Approach: The First-Generation Strategy 37.2.2 Stepwise Bis(oxepane) Synthesis Approach: The Second-Generation Strategy 37.2.3 The Doubly Convergent Approach with Stepwise Formation of the Bis(oxepane) System: The Third-Generation Strategy 37.3 Total Synthesis 37.3.1 Synthesis of IJK Framework 86 37.3.2 Synthesis of ABCDEFG Framework 87 37.3.3 Final Stages and Completion of the Total Synthesis of Brevetoxin B 37.4 Conclusion

731 733 733 735 737 748 750 752 755 762 762 768 781 784

Author Index

787

Subject Index

789