Total Synthesis of Bafilomycin A1

摘要

Bafilomycin A1 (1; Scheme 1) was first isolated in 1983 from a culture of Streptomyces griseus sp. sulphurus and classified as a member of the plecomacrolide family of natural products. In addition to its broad antibacterial and antifungal activity, the ability of bafilomycin A1 to selectively inhibit V-type ATPases has attracted the most attention, leading to SAR studies and evaluation of its potential for the treatment of diseases, such as osteoporosis. The continued interest in this class of molecules and the need for biologically active analogues demand new synthetic approaches. Moreover, a compex structure such as bafilomycin A1 provides a forum to examine new methods and consequently implement novel tactics. Herein, we disclose an efficient synthesis that showcases the convergent coupling of complex fragments 4 and 5 (Scheme 1) through a zinc-mediated acetylide addition reaction, and stereoselective reduction of the ensuing enyne moiety by a sequence consisting of a ruthenium-catalyzed trans-hydrosilylation and subsequent protodesilylation.