Kato Shota, Mizukami Daichi, Sugai Tomoya, Tsuda Masashi, Fuwa Haruhiko
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.
Chem Sci. 2020 Nov 20;12(3):872-879. doi: 10.1039/d0sc06021f.
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.
海葵二素-2是一种线性聚酮化合物代谢产物，对某些人类癌细胞系表现出强大且具有选择性的细胞毒性活性。我们在此披露海葵二素-2的首次全合成及其绝对构型的确定。我们的合成方法大量使用了钴催化的γ-羟基烯烃的 Mukaiyama 型环化反应，用于立体选择性地形成天然产物中所有的四氢呋喃环，以及后期的 Stille 型偶联反应，用于整个碳骨架的汇聚式组装。以统一、汇聚的方式合成了海葵二素-2的四种候选非对映异构体，并将它们的光谱/色谱性质与真实材料的性质进行了比较。本研究最终重新确定了C5/C7的相对构型，确定了C12/C18的相对构型，并确定了海葵二素-2的绝对构型。
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