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Communication

Highly Convergent Three Component Benzyne Coupling: The Total Synthesis of ent-Clavilactone B

Supporting Info

Igor Larrosa,^† Marianne I. Da Silva,^† Patricio M. Gómez,^† Peter Hannen,^† Eunjung Ko,^† Steven R. Lenger,^‡ Simon R. Linke,^‡ Andrew J. P. White,^† Donna Wilton,^† and Anthony G. M. Barrett*^†

Department of Chemistry, Imperial College London, London SW7 2AZ, England, and AstraZeneca, Process Research and Development, Avlon Works, Severn Road, Hallen, Bristol BS10 7ZE, England

J. Am. Chem. Soc., 2006, 128 (43), pp 14042–14043

DOI: 10.1021/ja0662671

Publication Date (Web): October 11, 2006

†

Imperial College London.

‡

AstraZeneca.

In papers with more than one author, the asterisk indicates the name of the author to whom inquiries about the paper should be addressed.

, agmb@imperial.ac.uk

Abstract

The first total synthesis of (+)-clavilactone B, a potent antifungal agent and novel tyrosine kinase inhibitor, is described. The absolute configuration of clavilactones has been unambiguously established by using Sharpless asymmetric epoxidation to generate the enantiomerically pure substrate. The strategy highlights the use of a powerful and convergent three-component benzyne coupling with a methylallyl Grignard and a chiral epoxy-aldehyde to generate two C−C bonds and install the carbon skeleton of clavilactone. Oxidative lactonization, ten-membered ring construction by ring closing metathesis, and oxidation gave clavilactone B.

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