Total Synthesis of (−)-Enigmazole A by the Macrocyclization/Transannular Pyran Cyclization Strategy: Application to Structure–Activity Relationship Investigations

An 18-step total synthesis of (-)-enigmazole A was achieved by means of our macrocyclization/transannular pyran cyclization strategy. Specifically, the 18-membered macrolactone skeleton of (-)-enigmazole A was constructed from three readily available building blocks through a Horner-Wadsworth-Emmons olefination, a Yamaguchi esterification, a macrocyclic ring-closing metathesis, and a transannular oxa-Michael addition as key transformations. Furthermore, late-stage diversification of the 18-membered macrolactone skeleton enabled access to a series of synthetic analogues that were useful for investigating the structure-activity relationship of (-)-enigmazole A.