Methodology Based on Chiral Silanes in the Synthesis of Polypropionate‐Derived Natural Products − Total Synthesis of Epothilone A

Abstract

Epothilones A and B (1 and 2) are natural products with potent antitumor activity. These compounds have a TaxolTM-like mechanism of action against tumor cells. A total synthesis of epothilone A (1) is reported, which is based on the synthesis and union of two advanced fragments: C3-C11 fragment 4 and C12-C21 fragment 5. Bond construction methodology based on chiral silanes was utilized to introduce the key C6 and C7 stereocenters of fragment 4. A lipase-mediated kinetic resolution established the C15 stereocenter of fragment 5. The 16-membered lactone was constructed using a three-step sequence: an intermolecular B-alkyl Suzuki coupling of 4 and 5, an aldol condensation, and a Yamaguchi-type macrolactonization reaction.