Abstract Apicularen A (1) and related benzolactone acylenamines belong to a growing class of novel natural products possessing highly cytotoxic properties. The challenging structure of 1 includes a 10-membered macrolactone ring, a tetrahydropyran system, an o, m-substituted phenol and a doubly unsaturated acyl group attached on the side chain enamine functionality. The total synthesis of apicularen A described herein involves a strategy ...