A General Strategy for the Synthesis of Jerangolids Enabled by π-allyl Stille Coupling

Abstract

Jerangolids are polyketide natural products with potent antifungal activity and low mammalian toxicity, originally isolated from Sorangium cellulosum So ce 307. Their structure, consisting of a δ-lactone and a pyran unit connected by a chiral skipped 1,4-diene, presents a significant synthetic challenge. Herein, we describe a general, modular strategy that enables the synthesis of all naturally occurring jerangolids and their stereoisomers, including the still elusive jerangolid H. The lactone fragment was built through a vinylogous Mukaiyama aldol reaction, with the hydroxymethyl group at C2 introduced in one step by Stille coupling with a novel p-methoxybenzyloxymethyl (PMBM) stannatrane. The stereocenter at both C14 and C15 was generated via deoxygenation of a tertiary alcohol involving a [1,2]-H-shift. Using a highly modular approach recently developed by our group, the jerangolid framework was assembled in a single step through enantioselective π-allyl Stille coupling of the two key fragments. Synthesis and comparison of both C14 epimers allowed us to unambiguously establish the total configuration of jerangolid H.