Total Synthesis and Biological Assessment of (−)-Exiguolide and Analogues

Authors

  • Prof. Dr. Haruhiko Fuwa,

    Corresponding author
    1. Graduate School of Life Sciences, Tohoku University, 2-1-1 Katahira, Aoba-ku, Sendai 980-8577 (Japan), Fax: (+81) 22-217-6214
    • Graduate School of Life Sciences, Tohoku University, 2-1-1 Katahira, Aoba-ku, Sendai 980-8577 (Japan), Fax: (+81) 22-217-6214
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  • Dr. Takaya Suzuki,

    1. Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai 980-8575 (Japan)
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  • Prof. Dr. Hiroshi Kubo,

    1. Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai 980-8575 (Japan)
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  • Dr. Takao Yamori,

    1. Division of Molecular Pharmacology, Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, 3-8-31 Ariake, Koto-ku, Tokyo 135-8550 (Japan)
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  • Prof. Dr. Makoto Sasaki

    1. Graduate School of Life Sciences, Tohoku University, 2-1-1 Katahira, Aoba-ku, Sendai 980-8577 (Japan), Fax: (+81) 22-217-6214
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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.

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