Total synthesis and biological assessment of (-)-Exiguolide and analogues

Haruhiko Fuwa, Takaya Suzuki, Hiroshi Kubo, Takao Yamori, Makoto Sasaki

Research output: Contribution to journalArticlepeer-review

61 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)2678-2688
Number of pages11
JournalChemistry - A European Journal
Volume17
Issue number9
DOIs
Publication statusPublished - 2011 Feb 25

Keywords

  • antiproliferative activity
  • macrolides
  • natural products
  • olefin metathesis
  • total synthesis

ASJC Scopus subject areas

  • Catalysis
  • Organic Chemistry

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