Nicolaou K C, Kim David W, Baati Rachid, O'Brate Aurora, Giannakakou Paraskevi
Department of Chemistry and The Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
Chemistry. 2003 Dec 15;9(24):6177-91. doi: 10.1002/chem.200305230.
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.
