Copper-catalysed dynamic kinetic (4+1) cyclization of 1,3-enynes for atroposelective arylpyrrole synthesis.

Abstract

Axially chiral arylpyrroles are a promising class of compounds with broad applications in catalysis, medicinal chemistry, and materials science. Herein, we report a copper-catalysed dynamic kinetic asymmetric (4 + 1) cyclization for the atroposelective synthesis of arylpyrroles bearing a single stereogenic axis or 1,2-diaxes from 1,3-enynes and amines. This dynamic kinetic asymmetric transformation employs a chiral Cu/Pybox complex, with air as the oxidant and DABCO serving as both a base and a proton shuttle. A key feature is the reversibility of the aza-Michael addition, which enables the dynamic formation/cleavage of distal C-N bonds. The 5-endo-dig cyclization serves as both the rate-determining and stereodetermining step, ensuring precise stereocontrol of the proximal stereocenters by the catalyst. This strategy overcomes long-standing challenges in the stereocontrol of distal C-N bond formation and enables the synthesis of atropisomeric DMAP catalysts with two stereogenic axes. DFT calculations provide insights into the mechanism of stereocontrol.