A Novel Aldol Condensation with 2-Methyl-4-pentenal and Its Application to an Improved Total Synthesis of Epothilone B

Aaron Balog; Christina Harris; Kenneth Savin; Xiu-Guo Zhang; Ting-Chao Chou; Samuel J Danishefsky

doi:10.1002/(SICI)1521-3773(19981016)37:19<2675::AID-ANIE2675>3.0.CO;2-O

A Novel Aldol Condensation with 2-Methyl-4-pentenal and Its Application to an Improved Total Synthesis of Epothilone B

Angew Chem Int Ed Engl. 1998 Oct 16;37(19):2675-2678. doi: 10.1002/(SICI)1521-3773(19981016)37:19<2675::AID-ANIE2675>3.0.CO;2-O.

Authors

Aaron Balog¹, Christina Harris¹, Kenneth Savin¹, Xiu-Guo Zhang², Ting-Chao Chou², Samuel J Danishefsky³

Affiliations

¹ Laboratory for Bioorganic Chemistry, Sloan-Kettering Institute for Cancer Research, 1275 York Avenue, Box 106, New York, NY 10021 (USA).
² Laboratory for Molecular Pharmacology and Therapeutics Program, Sloan-Kettering Institute for Cancer Research.
³ [+] Further address: Havemeyer Hall, Department of Chemistry, Columbia University, New York, NY 10027 (USA).

Abstract

The stabilization of the transition state through a favorable interaction between the double bond of 1 and the carbonyl group of 2 appears to be responsible for the high diastereoface selectivity of the aldol reaction. This key step in the highly concise total synthesis of epothilone B is followed by a Suzuki coupling to introduce the thiazole domain, a Noyori reduction to control the stereochemistry at C3, and a final macrolactonization (see reaction scheme). X=protecting group.

Keywords: Aldol reactions; Epothilones; Natural products; Suzuki coupling; Total synthesis.