Concise Total Synthesis of Enigmazole A

Abstract

An efficient entry into the phosphorylated marine macrolide enigmazole A is described. Enigmazole A interferes with c-Kit signaling by an as yet unknown mode of action and is therefore a potential lead in the quest for novel anticancer agents. Key to success is a gold-catalyzed cascade comprising a [3,3]-sigmatropic rearrangement of a propargyl acetate along the periphery of a macrocyclic scaffold, followed by a transannular hydroalkoxylation of the resulting transient allenyl acetate. This transformation mandated the use of a chiral gold catalyst to ensure a matching double-asymmetric setting. Other noteworthy steps are the preparation of the oxazole building block by a palladium-catalyzed C-H activation, as well as the smooth ring-closing alkyne metathesis of a diyne substrate bearing a propargylic leaving group, which has only little precedent.

Keywords: alkynes; gold; metathesis; natural products; transannular reactions.