Asymmetric dearomative single-atom skeletal editing of indoles and pyrroles

Abstract

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.