title: Total Synthesis of Potent Antitumor Macrolide, (-)-Zampanolide: An Oxidative Intramolecular Cyclization-Based Strategy.
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 promotedN-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.
authors.affiliation: Department of Chemistry and Department of Medicinal Chemistry, Purdue University 560 Oval Drive, West Lafayette, IN 47907 (USA).
authors.forename: Arun K
authors.initials: AK
authors.lastname: Ghosh
authors.forename: Xu
authors.initials: X
authors.lastname: Cheng
authors.forename: Ruoli
authors.initials: R
authors.lastname: Bai
authors.forename: Ernest
authors.initials: E
authors.lastname: Hamel
keywords: C-H bond activation; Metathesis; Natural product; Stereoselective catalysis; Total Synthesis