Journal
EUROPEAN JOURNAL OF ORGANIC CHEMISTRY
Volume 2012, Issue 22, Pages 4130-4139Publisher
WILEY-V C H VERLAG GMBH
DOI: 10.1002/ejoc.201200286
Keywords
Natural products; Total synthesis; C-H activation; Metathesis; Stereoselective catalysis
Categories
Funding
- National Institutes of Health
- Purdue University
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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 CH 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.
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