Journal
CHEMISTRY-A EUROPEAN JOURNAL
Volume 17, Issue 9, Pages 2678-2688Publisher
WILEY-V C H VERLAG GMBH
DOI: 10.1002/chem.201003135
Keywords
antiproliferative activity; macrolides; natural products; olefin metathesis; total synthesis
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Funding
- Ministry of Education, Culture, Sports, Science and Technology (MEXT), Japan [22106504]
- Grants-in-Aid for Scientific Research [22106504, 22240092] Funding Source: KAKEN
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We describe herein an enantioselective total synthesis of (-)-exiguolide, the natural enantiomer. The methylene bis(tetrahydropyran) substructure was efficiently synthesized by exploiting olefin cross-metathesis for the assembly of readily available acyclic segments and intramolecular oxa-conjugate cyclization and reductive etherification for the formation of the tetrahydropyran rings. The 20-membered macrocyclic framework was constructed in an efficient manner by means of Julia-Kocienski coupling and Yamaguchi macrolactonization. Finally, the (E,Z,E)-triene side chain was introduced stereoselectively via Suzuki-Miyaura coupling to complete the total synthesis. Assessment of the growth inhibitory activity of synthetic (-)-exiguolide against a panel of human cancer cell lines elucidated for the first time that this natural product is an effective antiproliferative agent against the NCI-H460 human lung large cell carcinoma and the A549 human lung adenocarcinoma cell lines. Moreover, we have investigated structure-activity relationships of (-)-exiguolide, which elucidated that the C5-methoxycarbonylmethylidene group and the length of the side chain are important for the potent activity.
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