Total Synthesis of Talatisamine
Total Synthesis of Talatisamine
复制标题
DOI：
10.1002/anie.201912737
复制
发表时间：
2019-11-19
影响因子：
16.6
通讯作者：
Inoue, Masayuki
中科院分区：
文献类型：
--
作者：
Kamakura, Daiki;Todoroki, Hidenori;Inoue, Masayuki
塔拉蒂胺(1)是C-19-二萜生物碱家族的一员，具有K+通道抑制和抗心律失常活性。1的巨大合成挑战是由于其高度氧化和错综复杂地融合的六环6/7/5/6/6/5元环结构(ABCDEF环)，具有12个连续的立体中心。本文报道了通过两个结构简单的片段，手性6/6元AE环7和芳香族6元D环6组装成1的有效路线。AE环7是由2-环己酮(8)通过双Mannich反应融合N-乙基哌啶环而成的。在6和7偶联后，氧化脱芳构化/Diels-Alder反应序列生成融合的五环4b，新形成的6/6元环系通过Wagner-Meerwein重排立体定向重组为7/5元BC环3。最后，Hg(OAc)(2)诱导2的氧化氮杂Prins环化，从而锻造剩余的5元F环。因此，1的总合成是通过优化和编排8的33个转换来完成的。
Talatisamine (1) is a member of the C-19-diterpenoid alkaloid family, and exhibits K+ channel inhibitory and antiarrhythmic activities. The formidable synthetic challenge that 1 presents is due to its highly oxidized and intricately fused hexacyclic 6/7/5/6/6/5-membered-ring structure (ABCDEF-ring) with 12 contiguous stereocenters. Here we report an efficient synthetic route to 1 by the assembly of two structurally simple fragments, chiral 6/6-membered AE-ring 7 and aromatic 6-membered D-ring 6. AE-ring 7 was constructed from 2-cyclohexenone (8) through fusing an N-ethylpiperidine ring by a double Mannich reaction. After coupling 6 with 7, an oxidative dearomatization/Diels-Alder reaction sequence generated fused pentacycle 4 b. The newly formed 6/6-membered ring system was then stereospecifically reorganized into the 7/5-membered BC-ring of 3 via a Wagner-Meerwein rearrangement. Finally, Hg(OAc)(2) induced an oxidative aza-Prins cyclization of 2, thereby forging the remaining 5-membered F-ring. The total synthesis of 1 was thus accomplished by optimizing and orchestrating 33 transformations from 8.