Skip to main content
SpringerLink
Log in

Total Synthesis of Epothilones A-F

  • Chapter
The Epothilones: An Outstanding Family of Anti-Tumor Agents

Abstract

Although epothilones A-F are available from fermentation, their potential for broad refunctionalization and structural modification is rather limited. Therefore, from early on, the demand of more detailed SAR studies and the search of more specific and higher activity epothilone derivatives have stimulated very intensive synthetic investigations world wide, all the more so as the epothilones possess a far simpler overal chemical structure than, for instance, the taxanes.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 129.00
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 169.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Altmann KH, Pfeiffer B, Arseniyadis S, Pratt BA, Nicolaou KC (2007) The Chemistry and Biology of Epothilones — the Wheel Keeps Turning. Chem Med Chem 2: 396

    CAS  Google Scholar 

  2. Watkins EB, Chittiboyina AG, Avery MA (2006) Recent Developments in the Syntheses of the Epothilones and Related Analogues. Eur J Org Chem 18: 4071

    Article  Google Scholar 

  3. Altmann KH, Cachoux F, Caravatti G, Isarno T, Wartmann M (2006) Recent Developments in the Chemistry and Biology of Epothilones. ARKIVOC 8: 131

    Google Scholar 

  4. Luduvico I, Le Hyaric M, De Almeida MV, Da Silva AD (2006) Synthetic Methodologies for the Preparation of Epothilones and Analogs. Mini-Rev Org Chem 3: 49

    Article  CAS  Google Scholar 

  5. Watkins EB, Chittiboyina AG, Jung J-C, Avery MA (2005) The Epothilones and Related Analogues — A Review of Their Syntheses and Anti-Cancer Activities. Curr Pharm Design 11: 1615

    Article  CAS  Google Scholar 

  6. Altmann KH (2004) The Merger of Natural Product Synthesis and Medicinal Chemistry: On the Chemistry and Chemical Biology of Epothilones. Org Biomol Chem 2: 2137

    Article  CAS  Google Scholar 

  7. Altmann KH, Flörsheimer A, O’Reilly T, Wartmann M (2004) The Natural Products Epothilones A and B as Lead Structures for Anticancer Drug Discovery: Chemistry, Biology, and SAR Studies. Prog Med Chem 42: 171

    Article  CAS  Google Scholar 

  8. Zhang R, Liu Z (2004) Recent Progress in the Synthesis of Epothilones. Curr Org Chem 8: 267

    Article  CAS  Google Scholar 

  9. Mulzer J, Martin HJ (2004) Lessons Learned from Macrolide Synthesis. Chem Record 3: 258

    Article  CAS  Google Scholar 

  10. Altmann KH (2003) Epothilone B and its Analogs — a New Family of Anticancer Agents. Mini-Rev Med Chem 3: 149

    Article  CAS  Google Scholar 

  11. Nicolaou KC, Snyder SA (2003) Classics in Total Synthesis II, p. 161. Wiley VCH, Weinheim

    Google Scholar 

  12. Wartmann M, Altmann KH (2002) The Biology and Medicinal Chemistry of Epothilones. Curr Med Chem Anti-Cancer Agents 2: 123

    Article  CAS  Google Scholar 

  13. Stachel SJ, Biswas K, Danishefsky SJ (2001) The Epothilones, Eleutherobins, and Related Types of Molecules. Curr Pharm Design 7: 1277

    Article  CAS  Google Scholar 

  14. Nicolaou KC, Ritzen A, Namoto K (2001) Recent Developments in the Chemistry, Biology and Medicine of the Epothilones. Chem Commun: 1523

    Google Scholar 

  15. Harris CR, Kuduk SD, Danishefsky SJ (2001) Chemical Synthesis and Biological Studies of the Epothilones — Microtubule Stabilizing Agents with Enhanced Activity Against Multidrug-Resistant Cell Lines and Tumors. Chemistry for the 21st Century: 8

    Google Scholar 

  16. Florsheimer A, Altmann KH (2001) Epothilones and Their Analogues — a New Class of Promising Microtubule Inhibitors. Expert Opinion on Therapeutic Patents 11: 951

    Article  CAS  Google Scholar 

  17. Wessjohann LA, Scheid G (2000) Synthetic Access to Epothilones — Natural Products with Extraordinary Anticancer Activity. In: Schmalz HG (ed.) Organic Synthesis Highlights IV, p. 251. Wiley VCH, Weinheim

    Chapter  Google Scholar 

  18. Mulzer J (2000) Epothilone B and its Derivatives as Novel Antitumor Drugs: Total and Partial Synthesis and Biological Evaluation. Monatsh Chem 131: 205

    Article  CAS  Google Scholar 

  19. a) Harris CR, Balog A, Savin K, Danishefsky SJ, Chou TC, Zhang X-G (1999) Epothilones: Microtubule Stabilizing Agents with Enhanced Activity Against Multidrug-Resistant Cell Lines and Tumors. Act Chim Therap 25: 187; b) Harris CR, Danishefsky SJ (1999) Complex Target-Oriented Synthesis in the Drug Discovery Process: A Case History in the dEpoB Series. J Org Chem 64: 8434

    CAS  Google Scholar 

  20. Jiang J (1999) Advances in Research on Novel Natural Anticancer Compounds: Epothilones. Tianran Chanwu Yanjiu Yu Kaifa 11: 77

    CAS  Google Scholar 

  21. Nicolaou KC, Roschangar F, Vourloumis D (1998) Chemical Biology of Epothilones. Angew Chem Int Ed 37: 2014

    Article  CAS  Google Scholar 

  22. Chou TC, Zhang XC, Balog A, Su DS, Meng D, Savin K, Bertino JR, Danishefsky SJ (1998) Desoxyepothilone B: An Efficacious Microtubule-Targeted Antitumor Agent with a Promising in Vivo Profile Relative to Epothilone B. Proc Natl Acad Sci USA 95: 9642

    Article  CAS  Google Scholar 

  23. Appendino G, Casiraghi G (1998) The Synthesis of Epothilones: Highlights from a Year’s Race. Chemtracts 11: 678

    CAS  Google Scholar 

  24. Buck SB, Victory SF, Himes RH, Georg GI (1998) Epothilones, a New Class of Microtubule-Stabilizing Agents with a Taxol-Like Mechanism of Action. Chemtracts 11: 671

    CAS  Google Scholar 

  25. Nakamura S, Hashimoto S (1997) Total Synthesis of Antitumor Antibiotic Epothilone Having Same Action Mechanism with Taxol. Kagaku (Kyoto) 52: 70

    CAS  Google Scholar 

  26. Marshall A, Castellino A (1997) Total Synthesis of Epothilone. Nature Biotechnol 15: 205

    Article  Google Scholar 

  27. Inanaga J, Hirata K, Saeki H, Katsuki T, Yamaguchi M (1979) A Rapid Esterification by Means of Mixed Anhydride and Its Application to Large-Ring Lactonization. Bull Chem Soc Jpn 52: 1989

    Article  CAS  Google Scholar 

  28. Schinzer D (2004) The Aldol Reaction in Natural Product Synthesis. The Epothilone Story. Modern Aldol Reactions 1: 311

    Article  CAS  Google Scholar 

  29. Harris CR, Kuduk SD, Balog A, Savin K, Glunz PW, Danishefsky SJ (1999) New Chemical Synthesis of the Promising Cancer Chemotherapeutic Agent 12, 13-Desoxyepothilone B: Discovery of a Surprising Long-Range Effect on the Diastereoselectivity of an Aldol Condensation. J Am Chem Soc 121: 7050

    Article  CAS  Google Scholar 

  30. Lee CB, Wu Z, Zhang F, Chappell MD, Stachel SJ, Chou T-C, Guan Y, Danishefsky SJ (2001) Insights into Long-Range Structural Effects on the Stereochemistry of Aldol Condensations: A Practical Total Synthesis of Desoxyepothilone F. J Am Chem Soc 123: 5249

    Article  CAS  Google Scholar 

  31. Bertinato P, Sorensen EJ, Meng D, Danishefsky SJ (1996) Syntheis of Epothilone A: Stereocontrolled Assembly of the Acyl Region and Models for Macrocyclization. J Org Chem 61: 8000

    Article  CAS  Google Scholar 

  32. Meng D, Sorensen EJ, Bertinato P, Danishefsky SJ (1996) Studies Toward a Synthesis of Epothilone A: Use of Hydropyran Templates for the Management of Acyclic Stereochemical Relationships. J Org Chem 61: 7998

    Article  CAS  Google Scholar 

  33. Balog A, Meng D, Kamenecka T, Bertinato P, Su D-S, Sorensen EJ, Danishefsky SJ (1997) Total Synthesis of (−)-Epothilone A. Angew Chem Int Ed 35: 2801

    Google Scholar 

  34. Meng D, Bertinato P, Balog A, Su D-S, Kamenecka T, Sorensen EJ, Danishefsky SJ (1997) Total Syntheses of Epothilones A and B. J Am Chem Soc 119: 10073

    Article  CAS  Google Scholar 

  35. Balog A, Harris CR, Savin K, Zhang X-G, Chou T-C, Danishefsky SJ (1998) A Novel Aldol Condensation with 2-Methyl-4-Pentenal and its Application to an Improved Total Synthesis of Epothilone B. Angew Chem Int Ed 37: 2675

    Article  CAS  Google Scholar 

  36. a) Harris CR, Kuduk SD, Savin K, Balog A, Danishefsky SJ (1999) Dianion Equivalents Corresponding to the Polypropionate Domain of Epothilone B. Tetrahedron Lett 40: 2263; b) Su D-S, Meng D, Bertinato P, Balog A, Sorensen EJ, Danishefsky SJ, Zheng H, Chou T-C, He L, Horwitz SB (1997) Total Synthesis of (−)-Epothilone B: An Extension of the Suzuki Coupling Method and Insights into Structure-Activity Relationships of the Epothilones. Angew Chem Int Ed 36: 757

    Article  CAS  Google Scholar 

  37. Stachel SJ, Danishefsky SJ (2001) Chemo-and Stereoselective Epoxidation of 12, 13-Desoxyepothilone B Using 2,2′-Dimethyldioxirane. Tetrahedron Lett 42: 6785

    Article  CAS  Google Scholar 

  38. Meng D, Su D-S, Balog A, Bertinato P, Sorensen EJ, Danishefsky SJ, Zheng H, Chou, TC, He L, Horwitz SB (1997) Remote Effects in Macrolide Formation Through Ring-Forming Olefin Metathesis: An Application to the Synthesis of Fully Active Epothilone Congeners. J Am Chem Soc 119: 2733

    Article  CAS  Google Scholar 

  39. Rivkin A, Cho YS, Gabarda AE, Yoshimura F, Danishefsky SJ (2004) Application of Ring-Closing Metathesis Reactions in the Synthesis of Epothilones. J Nat Prod 67: 139

    Article  CAS  Google Scholar 

  40. Chappell MD, Stachel SJ, Lee CB, Danishefsky SJ (2000) En Route to a Plant Scale Synthesis of the Promising Antitumor Agent 12,13-Desoxyepothilone B. Org Lett 2: 1633: b) Rivkin A, Njardarson JT, Biswas K, Chou T-C, Danishefsky SJ (2002) Total Syntheses of [17]-and [18]-Dehydrodesoxyepothilones B via a Concise Ring-Closing Metathesis-Based Strategy: Correlation of Ring Size with Biological Activity in the Epothilone Series. J Org Chem 67: 7737

    Article  CAS  Google Scholar 

  41. Biswas K, Lin H, Njardarson JT, Chappell MD, Chou T-C, Chao G, Yongbiao T, William P, He L, Horwitz SB, Danishefsky SJ (2002) Highly Concise Routes to Epothilones: The Total Synthesis and Evaluation of Epothilone 490. J Am Chem Soc 124: 9825

    Article  CAS  Google Scholar 

  42. Rivkin A, Yoshimura F, Gabarda AE, Chou T-C, Dong H, Tong WP, Danishefsky SJ (2003) Complex Target-Oriented Total Synthesis in the Drug Discovery Process: The Discovery of a Highly Promising Family of Second Generation Epothilones. J Am Chem Soc 125: 2899

    Article  CAS  Google Scholar 

  43. Nicolaou KC, He Y, Vourloumis D, Vallberg H, Yang Z (1996) An Approach to Epothilones Based on Olefin Metathesis. Angew Chem Int Ed 35: 2399

    Article  CAS  Google Scholar 

  44. Nicolaou KC, He Y, Vourloumis D, Vallberg H, Roschangar F, Sarabia F, Ninkovic S, Yang Z, Trujillo JI (1997) The Olefin Metathesis Approach to Epothilone A and Its Analogs. J Am Chem Soc 119: 7960

    Article  Google Scholar 

  45. Nicolaou KC, King NP, He Y (1998) Ring-Closing Metathesis in the Synthesis of Epothilones and Polyether Natural Products. Top Organomet Chem 1 (Alkene Metathesis in Organic Synthesis): 73

    Article  CAS  Google Scholar 

  46. Nicolaou KC, Sarabia F, Ninkovic S, Yang Z (1997) Total Synthesis of Epothilone A: The Macrolactonization Approach. Angew Chem Int Ed 36: 525

    Article  CAS  Google Scholar 

  47. Nicolaou KC, Ninkovic S, Sarabia F, Vourloumis D, He Y, Vallberg H, Finlay MRV, Yang Z (1997) Total Syntheses of Epothilones A and B via a Macrolactonization-Based Strategy. J Am Chem Soc 119: 7974

    Article  CAS  Google Scholar 

  48. Nicolaou KC, Winssinger N, Pastor J, Ninkovic S, Sarabia F, He Y, Vourloumis D, Yang Z, Li T, Giannakakou P, Hamel E (1997) Synthesis of Epothilones A and B in Solid and Solution Phase. Nature 387: 268; Erratum: Nature 390: 100

    Article  CAS  Google Scholar 

  49. Nicolaou KC, Hepworth D, Finlay MRV, King NP, Werschkun B, Bigot A (1999) Synthesis of 16-Desmethyl Epothilone B: Improved Methodology for the Rapid, Highly Selective and Convergent Construction of Epothilone B and Analogs. Chem Commun: 519

    Google Scholar 

  50. Schinzer D, Limberg A, Boehm OM (1996) Studies Towards the Total Synthesis of Epothilones: Asymmetric Synthesis of the Key Fragments. Chemistry Eur J 2: 1477

    Article  CAS  Google Scholar 

  51. Schinzer D, Limberg A, Bauer A, Boehm OM, Cordes M (1997) Total Synthesis of (−)-Epothilone A. Angew Chem Int Ed 36: 523

    Article  CAS  Google Scholar 

  52. Schinzer D, Bauer A, Boehm OM, Limberg A, Cordes M (1999) Total Synthesis of (−)-Epothilone A. Chemistry Eur J 5: 2483

    Article  CAS  Google Scholar 

  53. Schinzer D, Bauer A, Schieber J (1998) Synthesis of Epothilones. Stereoselective Routes to Epothilone B. Synlett: 861

    Google Scholar 

  54. Schinzer D, Bauer A, Schieber J (1999) Syntheses of (−)-Epothilone B. Chemistry Eur J 5: 2492

    Article  CAS  Google Scholar 

  55. Sinha SC, Barbas CF III, Lerner LA (1998) The Antibody Catalysis Route to the Total Synthesis of Epothilones. Proc Natl Acad Sci USA 95: 14603

    Article  CAS  Google Scholar 

  56. Sinha SC, Sun J, Miller G, Barbas CF III, Lerner RA (1999) Sets of Aldolase Antibodies with Antipodal Reactivities. Formal Synthesis of Epothilone E by Large-Scale Antibody-Catalyzed Resolution of Thiazole Aldol. Org Lett 1: 1623

    Article  CAS  Google Scholar 

  57. Sinha SC, Sun J, Miller GP, Wartmann M, Lerner RA (2001) Catalytic Antibody Route to the Naturally Occurring Epothilones: Total Synthesis of Epothilones A-F. Chem Eur J 7: 1691

    Article  CAS  Google Scholar 

  58. Sun J, Sinha SC (2002) Stereoselective Total Synthesis of Epothilones by the Metathesis Approach Involving C9−C10 Bond Formation. Angew Chem Int Ed 41: 1381

    Article  CAS  Google Scholar 

  59. Taylor RE, Haley JD (1997) Towards the Synthesis of Epothilone A: Enantioselective Preparation of the Thiazole Sidechain and Macrocyclic Ring Closure. Tetrahedron Lett 38: 2061

    Article  CAS  Google Scholar 

  60. Bode JW, Carreira EM (2001) Stereoselective Syntheses of Epothilones A and B via Nitrile Oxide Cycloadditions and Related Studies. J Org Chem 66: 6410

    Article  CAS  Google Scholar 

  61. Bode JW, Carreira EM (2001) Stereoselective Syntheses of Epothilones A and B via Directed Nitrile Oxide Cycloaddition. J Am Chem Soc 123: 3611

    Article  CAS  Google Scholar 

  62. Review of the Nitrile Oxide Approach: Blackman B, Georg GI (2003) Stereoselective Syntheses of Epothilones A and B via Nitrile Oxide Cycloadditions. Chemtracts 16: 97

    CAS  Google Scholar 

  63. Shibasaki M, Kanai M (2001) Multifunctional Asymmetric Catalysis. Chem Pharm Bull 49: 511

    Article  CAS  Google Scholar 

  64. Sawada D, Shibasaki M (2000) Enantioselective Total Synthesis of Epothilone A Using Multifunctional Asymmetric Catalyses. Angew Chem Int Ed 39: 209

    Article  CAS  Google Scholar 

  65. Hamashima Y, Sawada D, Nogami H, Kanai M, Shibasaki M (2001) Highly Enantioselective Cyanosilylation of Aldehydes Catalyzed by a Lewis Acid-Lewis Base Bifunctional Catalyst. Tetrahedron 57: 805

    Article  CAS  Google Scholar 

  66. Sawada D, Kanai M, Shibasaki M (2000) Enantioselective Total Synthesis of Epothilones A and B Using Multifunctional Asymmetric Catalysis. J Am Chem Soc 122: 10521

    Article  CAS  Google Scholar 

  67. Fürstner A, Mathes C, Grela K (2001) Concise Total Syntheses of Epothilone A and C Based on Alkyne Metathesis. Chem Commun: 1057

    Google Scholar 

  68. Fürstner A, Mathes C, Lehmann CW (2001) Alkyne Metathesis: Development of a Novel Molybdenum-Based Catalyst System and its Application to the Total Synthesis of Epothilone A and C. Chem Eur J 7: 5299

    Article  Google Scholar 

  69. Liu Z-Y, Yu C-Z, Wang R-F, Li G (1998) Epoxide Opening with Acetylide for Synthesis of Epothilone A C7-21 Segment. Tetrahedron Lett 39: 5261

    Article  CAS  Google Scholar 

  70. Liu Z-Y, Chen Z-C, Yu C-Z, Wang R-F, Zhang R-Z, Huang C-S, Yan Z, Cao D-R, Sun J-B, Li G (2002) Total Synthesis of Epothilone A Through Stereospecific Epoxidation of the p-Methoxybenzyl Ether of Epothilone C. Chem Eur J 8: 3747

    Article  CAS  Google Scholar 

  71. Tokunaga M, Larrow JF, Kakiuchi F, Jacobsen EN (1997) Asymmetric Catalysis with Water: Efficient Kinetic Resolution of Terminal Epoxides by Means of Catalytic Hydrolysis. Science 277: 936

    Article  CAS  Google Scholar 

  72. Hinterding K, Jacobsen EN (1999) Regioselective Carbomethoxylation of Chiral Epoxides: A New Route to Enantiomerically Pure β-Hydroxy Esters. J Org Chem 64: 2164

    Article  CAS  Google Scholar 

  73. Zhu B, Panek JS (2000) Enzymatic Resolution of Thiazole-Containing Vinyl Carbinols. Synthesis of the C12−C21 Fragment of the Epothilones. Tetrahedron Lett 41: 1863

    Article  CAS  Google Scholar 

  74. Zhu B, Panek JS (2000) Total Synthesis of Epothilone A. Org Lett 2: 2575

    Article  CAS  Google Scholar 

  75. Zhu B, Panek JS (2001) Methodology Based on Chiral Silanes in the Synthesis of Polypropionate-Derived Natural Products — Total Synthesis of Epothilone A. Eur J Org Chem: 1701

    Google Scholar 

  76. Machajewski TD, Wong C-H (1999) Chemoenzymic Synthesis of Key Epothilone Fragments. Synthesis: 1469

    Google Scholar 

  77. Liu J, Wong C-H (2002) Aldolase-Catalyzed Asymmetric Synthesis of Novel Pyranose Synthons as a New Entry to Heterocycles and Epothilones. Angew Chem Int Ed 41: 1404

    Article  CAS  Google Scholar 

  78. Storer RJ, Takemoto T, Jackson PS, Ley SV (2003) A Total Synthesis of Epothilones Using Solid-Supported Reagents and Scavengers. Angew Chem Int Ed 42: 2521

    Article  CAS  Google Scholar 

  79. Storer RJ, Takemoto T, Jackson PS, Brown DS, Baxendale IR, Ley SV (2004) Multi-Step Application of Immobilized Reagents and Scavengers: A Total Synthesis of Epothilone C. Chem Eur J 10: 2529

    Article  CAS  Google Scholar 

  80. Mulzer J, Mantoulidis A (1996) Synthesis of the C(1)−C(9) Segment of the Cytotoxic Macrolides Epothilone A and B. Tetrahedron Lett 37: 9179

    Article  CAS  Google Scholar 

  81. Mulzer J, Mantoulidis A, Öhler E (1997) Synthesis of the C(11)−C(20) Segment of the Cytotoxic Macrolide Epothilone B. Tetrahedron Lett 38: 7725

    Article  CAS  Google Scholar 

  82. Mulzer J, Mantoulidis A, Öhler E (1998) Easy Access to the Epothilone Family-Synthesis of Epothilone B. Tetrahedron Lett 39: 8633

    Article  CAS  Google Scholar 

  83. Mulzer J, Mantoulidis A, Öhler E (2000) Total Syntheses of Epothilones B and D. J Org Chem 65: 7456

    Article  CAS  Google Scholar 

  84. Gaich T, Mulzer J (2005) Synthesis of Epothilones via a Silicon-Tethered RCM Reaction. Org Lett 7: 1311

    Article  CAS  Google Scholar 

  85. Gaich T, Karig G, Martin HJ, Mulzer J (2006) New Solutions to the C-12, 13 Stereoproblem of Epothilones B and D; Synthesis of a 12,13-Diol-Acetonide Epothilone B Analog. Eur J Org Chem: 3372

    Google Scholar 

  86. Martin HJ, Drescher M, Mulzer J (2000) How Stable are Epoxides? A Novel Synthesis of Epothilone B. Angew Chem Int Ed 39: 581

    Article  CAS  Google Scholar 

  87. Martin HJ, Pojarliev P, Kahlig H, Mulzer J (2001) The 12, 13-Diol Cyclization Approach for a Truly Stereocontrolled Total Synthesis of Epothilone B and the Synthesis of a Conformationally Restrained Analog. Chem Eur J 7: 2261

    Article  CAS  Google Scholar 

  88. May SA, Grieco PA (1998) Total Synthesis of (−)-Epothilone B. Chem Commun: 1597

    Google Scholar 

  89. White JD, Carter RG, Sundermann KF (1999) A Highly Stereoselective Synthesis of Epothilone B. J Org Chem 64: 684

    Article  CAS  Google Scholar 

  90. White JD, Sundermann KF, Carter RG (1999) Improved Synthesis of Epothilone B Employing Alkylation of an Alkyne for Assembly of Subunits. Org Lett 1: 1431

    Article  CAS  Google Scholar 

  91. White JD, Sundermann KF, Wartmann M (2002) Synthesis, Conformational Analysis, and Bioassay of 9,10-Didehydroepothilone D. Org Lett 4: 995

    Article  CAS  Google Scholar 

  92. a) White JD, Carter RG, Sundermann KF, Wartmann M (2001) Total Synthesis of Epothilone B, Epothilone D, and cis-and trans-9, 10-Dehydroepothilone D. J Am Chem Soc 123: 5407; b) White JD, Carter RG, Sundermann KF, Wartmann M (2003) Erratum: J Am Chem Soc 125: 3190

    Article  CAS  Google Scholar 

  93. Ermolenko MS, Potier P (2002) Synthesis of Epothilone A and B from D-Glucose. Tetrahedron Lett 43: 2895

    Article  CAS  Google Scholar 

  94. Martin N, Thomas EJ (2001) Total Syntheses of Epothilones B and D: Applications of Allylstannanes in Organic Synthesis. Tetrahedron Lett 42: 8373

    Article  CAS  Google Scholar 

  95. Bijoy P, Avery MA (1998) Synthetic Studies Directed Towards Epothilone A: Enantioselective Synthesis of a C7−C15 Carboxaldehyde Segment. Tetrahedron Lett 39: 209

    Article  CAS  Google Scholar 

  96. Panicker B, Karle JM, Avery MA (2000) An Unusual Reversal of Stereoselectivity in a Boron Mediated Aldol Reaction: Enantioselective Synthesis of the C1−C6 Segment of the Epothilones. Tetrahedron 56: 7859

    Article  CAS  Google Scholar 

  97. Valluri M, Hindupur RM, Bijoy P, Labadie G, Jung J-C, Avery MA (2001) Total Synthesis of Epothilone B. Org Lett 3: 3607

    Article  CAS  Google Scholar 

  98. Hindupur RM, Panicker B, Valluri M, Avery MA (2001) Total Synthesis of Epothilone A. Tetrahedron Lett 42: 7341

    Article  CAS  Google Scholar 

  99. Jung J-C, Kache R, Vines KK, Zheng Y-S, Panicker B, Valluri M, Avery MA (2004) Total Syntheses of Epothilones B and D. J Org Chem 69: 9269

    Article  CAS  Google Scholar 

  100. Taylor RE, Haley JD (1997) Towards the Synthesis of Epothilone A: Enantioselective Preparation of the Thiazole Sidechain and Macrocyclic Ring Closure. Tetrahedron Lett 38: 2061

    Article  CAS  Google Scholar 

  101. Taylor RE, Galvin GM, Hilfiker KA, Chen Y (1998) A Formal Total Synthesis of Epothilone A: Enantioselective Preparation of the C1−C6 and C7−C12 Fragments. J Org Chem 63: 9580

    Article  CAS  Google Scholar 

  102. Taylor RE, Chen Y (2001) Total Synthesis of Epothilones B and D. Org Lett 3: 2221

    Article  CAS  Google Scholar 

  103. Claus E, Pahl A, Jones PG, Meyer HM, Kalesse M (1997) Synthesis of the C1−C9 Segment of Epothilones. Tetrahedron Lett 38: 1359

    Article  CAS  Google Scholar 

  104. Gerlach K, Quitschalle M, Kalesse M (1998) Synthesis of the C((7)−C(17) Segment of Epothilones by a 10-Membered Ring Closing Metathesis Reaction. Synlett: 1108

    Google Scholar 

  105. Kalesse M, Quitschalle M, Claus E, Gerlach K, Pahl A, Meyer HH (1999) The Formal Total Synthesis of Epothilone A. Eur J Org Chem: 2817

    Google Scholar 

  106. Quitschalle M, Kalesse M (1999) Improved Synthesis of the Northern Hemisphere of Epothilone A by a Sharpless Asymmetric Dihydroxylation. Tetrahedron Lett 40: 7765

    Article  CAS  Google Scholar 

  107. Gerlach K, Quitschalle M, Kalesse M (1999) Synthesis of the Northern Hemisphere of Epothilone A by a Ten-Membered Ring Closing Metathesis Reaction. Tetrahedron Lett 40: 3553

    Article  CAS  Google Scholar 

  108. Chandrasekhar S, Reddy CR (2002) Towards a Synthesis of Epothilone A: Asymmetric Synthesis of C(1)−C(6) and C(7)−C(15) Fragments. Tetrahedron Asym 13: 261

    Article  CAS  Google Scholar 

  109. Ramachandran PV, Prabhudas B, Pratihar D, Chandra JS, Reddy MVR (2003) Stereoselective Synthesis of the C7−C21 Segment of Epothilone A via Asymmetric Alkoxyallyl-and Crotylboration. Tetrahedron Lett 44: 3745

    Article  CAS  Google Scholar 

  110. Ramachandran PV, Prabhudas B, Chandra JS, Reddy MVR, Brown HC (2004) Preparative-scale Synthesis of Both Antipodes of B-γ,γ-Dimethylallydiisopinocampheylborane: Application for the Synthesis of C1−C6 Subunit of Epothilone. Tetrahedron Lett 45: 1011

    Article  CAS  Google Scholar 

  111. a) De Brabander J, Rosset S, Bernardinelli G (1997) Towards a Synthesis of Epothilone A. Rapid Assembly of the C(1)−C(6) and C(7)−C(12) Fragments. Synlett: 824 b) De Brabander J, Rosset S, Bernardinelli G (1998) Towards a Synthesis of Epothilone A. Rapid Assembly of the C1−C6 and C7−C12 Fragments [Erratum to document cited in CA127:234203]. Synlett: 32

    Google Scholar 

  112. Scheid G, Ruijter E, Konarzycka-Bessler M, Bornscheuer UT, Wessjohann LA (2004) Synthesis and Resolution of a Key Building Block for Epothilones: A Comparison of Asymmetric Synthesis, Chemical and Enzymatic Resolution. Tetrahedron Asym 15: 2861

    Article  CAS  Google Scholar 

  113. Bekish AV, Isakov VE, Kulinkovich OG (2005) A cyclopropanol Approach to the Synthesis of the C13−C21 Fragment of Epothilones from Diethyl (S)-Malate. Tetrahedron Lett 46: 6979

    Article  CAS  Google Scholar 

  114. Reiff EA, Nair SK, Reddy BSN, Inagaki J, Henri JT, Greiner JF, Georg GI (2004) Practical Syntheses of the C12−C21 Epothilone Subunit via Catalytic Asymmetric Reductions: Itsuno-Corey Oxazaborolidine Reduction and Asymmetric Noyori Hydrogenation. Tetrahedron Lett 45: 5845

    Article  CAS  Google Scholar 

  115. Shioji K, Kawaoka H, Miura A, Okuma K (2001) Synthesis of C1−C6 Fragment for Epothilone A via Lipase-Catalyzed Optical Resolution. Synthetic Comm 31: 3569

    Article  CAS  Google Scholar 

  116. Tanimori S, Tanimoto K, Kirihata M (1998) Simple Synthesis of Both Enantiomers of the C7−C12 Segment of Epothilones. Biosci, Biotech BioCh 62: 2428

    Article  CAS  Google Scholar 

  117. Dong SD, Sundermann K, Smith KMJ, Petryka J, Liu F, Myles DC (2004) Rapid Access to Epothilone Analogs via Semisynthetic Degradation and Reconstruction of Epothilone D. Tetrahedron Lett 45: 1945

    Article  CAS  Google Scholar 

  118. Höfle G, Glaser N, Leibold T, Karama U, Sasse F, Steinmetz H (2003) Semisynthesis and Degradation of the Tubulin Inhibitors Epothilone and Tubulysin. Pure Appl Chem 75: 167

    Article  Google Scholar 

  119. Chakraborty TK, Dutta S (1998) Radical-Induced Opening of Trisubstituted Epoxides: Application in the Synthesis of C1−C12 Segment of Epothilones. Tetrahedron Lett 39: 101

    Article  CAS  Google Scholar 

  120. Lee HW, Hong YD, Lee I-YC (1999) Synthesis Toward Epothilone A: Coupling Reaction Between the Sulfone of C1−C10 and the Allylic Bromide of C11−C21. Bull Kor Chem Soc 20: 403

    CAS  Google Scholar 

  121. Lee HW, Lee I-YC, Hong YD (2000) Synthesis of the C11−C21 and C13−C21 Fragments of Epothilones from D-Glucose. Bull Kor Chem Soc 21: 1177

    CAS  Google Scholar 

  122. Lalic G, Galonic D, Matovic R, Saicic RN (2202) A Model Study of Epothilone Synthesis: An Alternative Synthetic Approach to the C1−C7 Fragment. J Serb Chem Soc 67: 221

    Article  Google Scholar 

  123. Guzman A, Alfaro R, Diaz E, Quintero A, Solano J (2002) Synthesis and Cytotoxic Evaluation of Some Structural Fragments of Epothilone A. Revista de la Sociedad Quimica de Mexico 46: 235

    CAS  Google Scholar 

  124. a)Zhang HS, Zhong CF, Bao XP (2003) Studies on the Total Synthesis of Epothilone B and D: A Facile Synthesis of C7−C14 and C15−C21 Fragments. Chin Chem Lett 14: 115; b) Hong YD, Lee HW, Lee IYC, Jung J-K (2007) Synthesis of the C11−C21 Fragments of Epothilones A and B Using Ring-Closing Metathesis. Bull Kor Chem Soc 28: 367

    CAS  Google Scholar 

  125. Broadrup RL, Sundar HM, Swindell CS (2005) Total Synthesis of 12, 13-Desoxyepothilone B (Epothilone D). Bioorg Chem 33: 116

    Article  CAS  Google Scholar 

  126. Nicolaou KC, Hepworth D, King NP, Finlay MRV, Scarpelli R, Pereira MMA, Bollbuck B, Bigot A, Werschkun B, Winssinger N (2000) Total Synthesis of 16-Desmethylepothilone B, Epothilone B10, Epothilone F, and Related Side Chain Modified Epothilone B Analogues. Chem Eur J 6: 2783

    Article  CAS  Google Scholar 

  127. Nicolaou KC, Pratt BA, Arseniyadis S, Wartmann M, O’Brate A, Giannakakou P (2006) Molecular Design and Chemical Synthesis of a Highly Potent Epothilone. Chem Med Chem 1: 41

    CAS  Google Scholar 

  128. Sinha SC, Sun J, Miller GP, Wartmann M, Lerner RA (2001) Catalytic Antibody Route to the Naturally Occurring Epothilones: Total Synthesis of Epothilones A-F. Chem Eur J 7: 1691

    Article  CAS  Google Scholar 

  129. Nicolaou KC, Sasmal PK, Rassias G, Reddy MV, Altmann K-H, Wartmann M, O’Brate A, Giannakakou P (2003) Design, Synthesis, and Biological Properties of Highly Potent Epothilone B Analogues. Angew Chem Int Ed 42: 3515

    Article  CAS  Google Scholar 

  130. Nicolaou KC, Ritzen A, Namoto K, Buey RM, Diaz JF, Andreu JM, Wartmann M, Altmann K-H, O’Brate A, Giannakakou P (2002) Chemical Synthesis and Biological Evaluation of Novel Epothilone B and trans-12, 13-Cyclopropyl Epothilone B Analogues. Tetrahedron 58: 6413

    Article  CAS  Google Scholar 

  131. Nicolaou KC, Namoto K, Li J, Ritzen A, Ulven T, Shoji M, Zaharevitz D, Gussio R, Sackett DL, Ward RD, Hensler A, Fojo T, Giannakakou P (2001) Synthesis and Biological Evaluation of 12,13-Cyclopropyl and 12,13-Cyclobutyl Epothilones. Chem BioChem 2: 69

    CAS  Google Scholar 

  132. Nicolaou KC, Scarpelli R, Bollbuck B, Werschkun B, Pereira MMA, Wartmann M, Altmann K-H, Zaharevitz D, Gussio R, Giannakakou P (2000) Chemical Synthesis and Biological Properties of Pyridine Epothilones. Chem Bio 7: 593

    Article  CAS  Google Scholar 

  133. Nicolaou KC, Namoto K, Ritzen A, Ulven T, Shoji M, Li J, D’Amico G, Liotta D, French CT, Wartmann M, Altmann K-H, Giannakakou P (2001) Chemical Synthesis and Biological Evaluation of cis-and trans-12,13-Cyclopropyl and 12,13-Cyclobutyl Epothilones and Related Pyridine Side Chain Analogues. J Am Chem Soc 123: 9313

    Article  CAS  Google Scholar 

  134. Klar U, Buchmann B, Schwede W, Skuballa W, Hoffmann J, Lichtner RB (2006) Total Synthesis and Antitumor Activity of ZK-EPO: The First Fully Synthetic Epothilone in Clinical Development. Angew Chem Int Ed 45: 7942

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Institut für Organische Chemie, Fakultät für Chemie der Universität Wien, Währingerstr. 38, 1090, Wien, Austria

    Prof. Dr. Johann Mulzer & Mag. Kathrin Prantz

Authors
  1. Prof. Dr. Johann Mulzer
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Mag. Kathrin Prantz
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

Copyright information

© 2009 Springer-Verlag/Wien

About this chapter

Cite this chapter

Mulzer, J., Prantz, K. (2009). Total Synthesis of Epothilones A-F. In: The Epothilones: An Outstanding Family of Anti-Tumor Agents. Fortschritte der Chemie organischer Naturstoffe / Progress in the Chemistry of Organic Natural Products, vol 90. Springer, Vienna. https://doi.org/10.1007/978-3-211-78207-1_3

Download citation

Publish with us

Policies and ethics

Search

Navigation