Total Synthesis of Biselyngbyolide B and Its C21-C22 Z-Isomer.
Total Synthesis of Biselyngbyolide B and Its C21-C22 Z-Isomer.
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Biselngbyolide B及其C21-C22 Z异构体的全合成
DOI：
10.1021/acs.joc.8b00298
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发表时间：
2018
期刊：
影响因子：
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通讯作者：
M. E. Maier
中科院分区：
文献类型：
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作者：
L. Kämmler;M. E. Maier
描述了从 C1–C13 和 C14–C23 片段合成 18 元大环内酯 biselngbyolide B (2) 的研究。作为 C1-C13 片段合成中的关键反应，我们使用了手性乙烯基烯酮甲硅烷基 N,O-缩醛 12 的不对称炔丙基化。最初尝试通过吡喃模板的还原断裂来获得具有跳过二烯和敏感烯丙醇功能的 C14-C23 片段。然而，碘化物 32 与丁基锂的开环导致形成具有 21Z 双键的二烯醇 33 。在3-OH处带有甲硅烷基保护基团，通过分子内Stille偶联进行大内酯化，得到biselngbyolide B(47)的21Z-异构体。为了制备具有 21E 构型的 C14-C23 片段，乙烯基锡烷 48 与 4-溴巴豆酸酯 (49) 的交叉偶联设定了两个双键的构型。然后通过分子内 Heck 偶联获得 Biselngbyolide B (2)。在初步的生物细胞毒性测定中，2 被证明具有活性，而 21Z-异构体 47 的活性要低得多。 3-OMEM类似物40缺乏活性。这些结果支持这样的观点：具有正确构型的侧链与 Ca2+-ATP酶的结合和生物活性相关。
Investigations toward the synthesis of the 18-membered macrolactone biselyngbyolide B (2) from a C1–C13 and a C14–C23 fragment are described. As a key reaction in the synthesis of the C1–C13 fragment, we used an asymmetric propargylation of chiral vinylketene silylN,O-acetal12. Access to a C14–C23 fragment featuring a skipped diene and a sensitive allyl alcohol function was initially attempted via reductive fragmentation of a pyran template. However, this ring opening on iodide32witht-BuLi led to dienynol33with a 21Zdouble bond. With a silyl protecting group at 3-OH and by implementing an intramolecular Stille coupling for macrolactonization, the 21Z-isomer of biselyngbyolide B (47) was obtained. For preparation of a C14–C23 fragment with the 21E-configuration, a cross-coupling of vinylstannane48with 4-bromocrotonate (49) set the configuration of the two double bonds. Biselyngbyolide B (2) was then accessed by an intramolecular Heck coupling. In preliminary biological cytotoxicity assays,2turned out to be active, whereas the 21Z-isomer47was much less active. The 3-OMEM analogue40was devoid of activity. These results support the notion that the side chain with the correct configuration is relevant for binding to the Ca2+-ATPase and the biological activity.