Zhang Xiaolong, Song Qingmin, Liu Shaopeng, Sivaguru Paramasivam, Liu Zhaohong, Yang Yong, Ning Yongyue, Anderson Edward A, de Ruiter Graham, Bi Xihe
Department of Chemistry, Northeast Normal University, Changchun, China.
Chemistry Research Laboratory, Department of Chemistry, University of Oxford, Oxford, UK.
Nat Chem. 2025 Feb;17(2):215-225. doi: 10.1038/s41557-024-01680-0. Epub 2024 Nov 28.
Heterocycle skeletal editing has recently emerged as a powerful tactic for achieving heterocycle-to-heterocycle transmutation without the need for multistep de novo heterocycle synthesis. However, the enantioselective skeletal editing of heteroarenes through single-atom logic remains challenging. Here we report the enantiodivergent dearomative skeletal editing of indoles and pyrroles via an asymmetric carbon-atom insertion, using trifluoromethyl N-triftosylhydrazones as carbene precursors. This strategy provides a straightforward methodology to access enantiomerically enriched six-membered N-heterocycles containing a trifluoromethylated quaternary stereocentre from planar N-heteroarenes. The synthetic utility of this enantiodivergent methodology was demonstrated by a broad evaluation of reaction scope, product derivatization and concise syntheses of drug analogues. Mechanistic studies reveal that the excellent asymmetric induction arises from the initial cyclopropanation step. The asymmetric single-atom insertion strategy is expected to have a broad impact on the field of single-atom skeletal editing and catalytic asymmetric dearomatization of aromatic compounds.
杂环骨架编辑最近已成为一种强大的策略，可实现无需多步从头合成杂环的杂环到杂环转化。然而，通过单原子逻辑对杂芳烃进行对映选择性骨架编辑仍然具有挑战性。在此，我们报告了通过不对称碳原子插入，使用三氟甲基 N-三氟甲磺酰腙作为卡宾前体，对吲哚和吡咯进行对映发散性去芳构化骨架编辑。该策略提供了一种直接的方法，可从平面 N-杂芳烃获得富含对映体的六元 N-杂环，其中含有三氟甲基化的季立体中心。通过对反应范围、产物衍生化和药物类似物的简洁合成进行广泛评估，证明了这种对映发散方法的合成效用。机理研究表明，优异的不对称诱导源于初始环丙烷化步骤。不对称单原子插入策略有望对单原子骨架编辑和芳香族化合物的催化不对称去芳构化领域产生广泛影响。
