Total Synthesis and Structure Revision of the Marine Metabolite Palmerolide A

Abstract

We describe a highly convergent and flexible synthesis of the novel antarctic marine metabolite palmerolide A an effort leading to a reformulation of palmerolide A as ent- 24, the enantiomer of the C19,C20-bis-epimer of the original proposed structure 1 . Our total synthesis features a highly stereoselective vinylogous Mukaiyama aldol reaction to introduce the C19,C20-stereodiad, an efficient Suzuki cross-coupling to install the endocyclic diene unit, and an intramolecular Horner−Wadsworth−Emmons olefination to close the macrocycle. Starting from fragments 2, 3 ( ent - 3 ), and 13 (prepared in five to eight steps each, 38−70% overall yield) the synthesis of the proposed structure 1 and the enantiomer of palmerolide A ( 24 ) was completed in an additional 14 steps (22 steps longest linear sequence).