Total synthesis and biological evaluation of (+)-gambieric acid A and its analogues

Kazuya Ishigai, Haruhiko Fuwa, Keisuke Hashizume, Ryo Fukazawa, Yuko Cho, Mari Yotsu-Yamashita, Makoto Sasaki

    Research output: Contribution to journalArticlepeer-review

    31 Citations (Scopus)

    Abstract

    In this study, we report the first total synthesis and complete stereostructure of gambieric acid A, a potent antifungal polycyclic ether metabolite, in detail. The A/B-ring exocyclic enol ether 32 was prepared through a Suzuki-Miyaura coupling of the B-ring vinyl iodide 18 and the alkylborate 33 and subsequent closure of the A-ring by using diastereoselective bromoetherification as the key transformation. Suzuki-Miyaura coupling of 32 with acetate-derived enol phosphate 49, followed by ring-closing metathesis of the derived diene, produced the D-ring. Subsequent closure of the C-ring through a mixed thioacetalization completed the synthesis of the A/BCD-ring fragment 8. The A/BCD- and F′GHIJ-ring fragments (i.e., 8 and 9) were assembled through Suzuki-Miyaura coupling. The C25 stereogenic center was elaborated by exploiting the intrinsic conformational property of the seven-membered F′-ring. After the oxidative cleavage of the F′-ring, the E-ring was formed as a cyclic mixed thioacetal (i.e., 70) and then stereoselectively allylated by using glycosylation chemistry. Ring-closing metathesis of the diene 3 thus obtained closed the F-ring and completed the polycyclic ether skeleton. Finally, the J-ring side chain was introduced by using a Julia-Kocienski olefination in the presence of CeCl3 to complete the total synthesis of gambieric acid A (1), thereby unambiguously establishing its complete stereostructure. The present total synthesis enabled us to evaluate the antifungal and antiproliferative activities of 1 and several synthetic analogues.

    Original languageEnglish
    Pages (from-to)5276-5288
    Number of pages13
    JournalChemistry - A European Journal
    Volume19
    Issue number17
    DOIs
    Publication statusPublished - 2013 Apr 22

    Keywords

    • Suzuki-Miyaura coupling
    • natural products
    • polycyclic ethers
    • structure-activity relationships
    • total synthesis

    ASJC Scopus subject areas

    • Catalysis
    • Organic Chemistry

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