Total Synthesis and Biological Evaluation of (−)Apicularen A and Analogues Thereof

Abstract

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 equivalent to its proposed biosynthesis and entails a reiterative two‐step procedure featuring allylation and ozonolytic cleavage to grow the molecule's chain by one acetate unit at a time. The developed synthetic technology was applied to the construction of a series of apicularen A analogues whose biological evaluation established a set of structure–activity relationships in this new area of potential importance in cancer chemotherapy.