Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, United States.
J Am Chem Soc. 2022 May 25;144(20):9126-9131. doi: 10.1021/jacs.2c03057. Epub 2022 May 11.
We describe the first total synthesis of complex aspidosperma alkaloids (-)-voacinol and (-)-voacandimine C via a late-stage C7-methylenation strategy inspired by a biogenetic hypothesis. We envisioned rapid access to these natural alkaloids from a common, symmetrical precursor assembled by methylenation of a D-ring-oxidized variant of the structurally related natural product (-)-deoxoapodine. Chemoselective N9-oxidation of a pentacyclic deoxoapodine precursor enabled the synthesis of the corresponding hexacyclic C8-aminonitrile. Stereocontrolled methylenation of a C8-enamine derivative of deoxoapodine, accessed by ionization of the C8-aminonitrile, afforded a symmetrical dodecacyclic bisaminonitrile as a versatile precursor to these bisindole alkaloids. The final-stage, biosynthesis-inspired, controlled reductive opening of the oxolane substructures of this dodecacyclic intermediate provided a unified approach to (-)-voacinol and (-)-voacandimine C, while direct reduction of the same intermediate afforded the structurally related (-)-methylenebisdeoxoapodine.
我们通过受生物合成假说启发的晚期 C7-亚甲基化策略，首次全合成了复杂的阿皮斯多培玛生物碱（-）-沃辛诺和（-）-沃坎定 C。我们设想从一个共同的、对称的前体快速获得这些天然生物碱，该前体是通过结构相关天然产物（-）-去氧阿波定的 D 环氧化变体的亚甲基化组装而成。五环去氧阿波定前体的选择性 N9-氧化使相应的六环 C8-氨腈得以合成。通过 C8-氨腈的离子化，立体控制的去氧阿波定 C8-烯胺衍生物的亚甲基化提供了一种对称的十二环双氨腈，作为这些双吲哚生物碱的多功能前体。最后阶段，受生物合成启发的对这个十二环中间体中环氧化物亚结构的受控还原开环提供了一种统一的方法来获得（-）-沃辛诺和（-）-沃坎定 C，而相同中间体的直接还原则得到结构相关的（-）-亚甲基双去氧阿波定。
