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. An enantioselective synthesis of (–)‐zampanolide has been achieved. This rare marine natural product shows microtubule‐stabilizing properties. It also displays potent activity against taxol‐resistant cells. This synthesis will provide a convenient access to analogues for important structure–activity relationship studies and less complex anticancer agents related to zampanolide.