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Total Synthesis of Potent Antitumor Macrolide (–)‐Zampanolide: An Oxidative Intramolecular Cyclization‐Based Strategy
Author(s) -
Ghosh Arun K.,
Cheng Xu,
Bai Ruoli,
Hamel Ernest
Publication year - 2012
Publication title -
european journal of organic chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.825
H-Index - 155
eISSN - 1099-0690
pISSN - 1434-193X
DOI - 10.1002/ejoc.201200286
Subject(s) - chemistry , total synthesis , enantioselective synthesis , metathesis , natural product , intramolecular force , tetrahydropyran , stereochemistry , ring closing metathesis , ether , intramolecular reaction , combinatorial chemistry , semisynthesis , yield (engineering) , oxidative phosphorylation , ring (chemistry) , organic chemistry , catalysis , biochemistry , polymer , materials science , metallurgy , polymerization
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.