Copper-Catalyzed Asymmetric Reductions of 2 H -Azirines

A highly enantioselective reduction of prochiral 2H-azirines has been achieved, mediated by chiral copper-hydride complexes. Both alkylated and arylated mono- and trisubstituted 2H-azirines are reduced to afford N–H aziridines in high yields (up to 96%) and enantioselectivities (up to 96% ee). Such aziridines are building blocks of wide synthetic utility, and to demonstrate this, we executed a gram-scale synthesis of the aziridine precursor (96% ee) of a neuro-peptide Y Y5 receptor antagonist. DFT calculations reveal distinct origins of enantioselectivity depending on the substrate: attractive dispersion interactions between aryl groups govern stereocontrol in monosubstituted azirines, whereas geometric distortion of the copper hydride dictates selectivity in the sterically demanding trisubstituted azirines.