Enantio- and diastereoselective NHC/Cu-catalyzed intermolecular dearomative cyclopropanation of indoles with diazo esters

Abstract

We report a highly enantioselective N-heterocyclic carbene (NHC)/copper-catalyzed intermolecular dearomative cyclopropanation of indoles with diazo esters. This protocol enables the efficient construction of cyclopropane-fused indolines featuring quaternary stereogenic centers under mild conditions. A broad range of substituted indoles and diazo esters is tolerated, delivering the corresponding products in high yields with enantioselectivities of up to 90% ee. Notably, the employment of a bulky chiral NHC ligand is crucial for achieving effective stereocontrol over the challenging quasi-linear copper–carbenoid intermediate. Furthermore, gram-scale reactions and downstream transformations demonstrate the synthetic utility of this methodology. Mechanistic investigations, including kinetic isotope effect and Hammett studies, support a reaction pathway involving nucleophilic attack of the indole on a copper–carbenoid species. This earth-abundant copper catalytic system serves as a sustainable alternative to traditional noble-metal-based asymmetric carbene-transfer reactions.

Keywords

Asymmetric cyclopropanation / chiral NHC ligand / copper catalysis / dearomatization / indole

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