Total synthesis and complete configurational assignment of amphirionin-2 |
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| Authors: | Shota Kato Daichi Mizukami Tomoya Sugai Masashi Tsuda Haruhiko Fuwa |
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| Institution: | Department of Applied Chemistry, Faculty of Science and Engineering, Chuo University, 1-13-27 Kasuga, Bunkyo-ku, Tokyo 112-8551 Japan.; Center for Advanced Marine Core Research and Department of Agriculture and Marine Science, Kochi University, Nankoku, Kochi 783-8502 Japan |
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| Abstract: | Amphirionin-2 is a linear polyketide metabolite that exhibits potent and selective cytotoxic activity against certain human cancer cell lines. We disclose herein the first total synthesis of amphirionin-2 and determination of its absolute configuration. Our synthesis featured an extensive use of cobalt-catalyzed Mukaiyama-type cyclization of γ-hydroxy olefins for stereoselective formation of all the tetrahydrofuran rings found in the natural product, and a late-stage Stille-type coupling for convergent assembly of the entire carbon backbone. Four candidate diastereomers of amphirionin-2 were synthesized in a unified, convergent manner, and their spectroscopic/chromatographic properties were compared with those of the authentic material. The present study culminated in the reassignment of the C5/C7 relative configuration, assignment of the C12/C18 relative configuration, and determination of the absolute configuration of amphirionin-2.An extensive application of cobalt-catalyzed Mukaiyama-type cyclization of γ-hydroxy olefins and a late-stage Stille-type reaction enabled syntheses of four diastereomers of amphirionin-2 to establish its absolute configuration. |
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