Total Synthesis of Potent Antitumor Macrolide (-)-Zampanolide: An Oxidative Intramolecular Cyclization-Based Strategy.

A detailed account of the enantioselective total synthesis of (-)-zampanolide, a macrolide marine natural product with high anticancer activity, is described. For the synthesis of the 4-methylenetetrahydropyran unit of (-)-zampanolide, we initially relied upon an oxidative C-H activation of an alkenyl ether and intramolecular cyclization to provide the substituted tetrahydropyran ring. However, this strategy was unsuccessful. Subsequently, we found that a cinnamyl ether is critical for the successful oxidative intramolecular cyclization reaction. The synthesis also features a cross-metathesis reaction for the construction of a trisubstituted olefin, a ring-closing metathesis to form a highly functionalized macrolactone, and a chiral phosphoric acid promoted formation of an N-acyl aminal to furnish (-)-zampanolide stereoselectively and in good yield. The synthetic (-)-zampanolide had effects on cultured cells and on tubulin assembly consistent with the properties reported for the natural product. [ABSTRACT FROM AUTHOR]