Author(s): Ghosh AK, Cheng X, Bai R, Hamel E
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Abstract A detailed account of the enantioselective total synthesis of (-)-zampanolide, a macrolide marine natural product with high anti-cancer activity is described. For synthesis of the 4-methylene tetrahydropyran unit of (-)-zampanolide, initially, we 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 to construct a tri-substituted olefin, a ring-closing metathesis to form a highly functionalized macrolactone and a chiral phosphoric acid promoted N-acyl aminal formation to furnish (-)-zampanolide stereoselectively and in good yield. The synthetic (-)-zampanolide had effects on cultured cells and on tubulin assembly consistent with properties reported for the natural product.
This article was published in European J Org Chem
and referenced in Journal of Bioequivalence & Bioavailability