Enantioselective [2π + 2σ] cycloaddition of bicyclobutanes with imines: An efficient approach to chiral 2-aza-bicyclo[2.1.1]hexanes

Abstract

The efficient construction of bicyclo[2.1.1]hexanes (BCHs) has gained significant attention due to their potential use as bioisostere of arenes in drugs. While the synthesis of racemic BCHs has been extensively explored, strategy enabling the enantioselective assembly of such motifs remains rare. Herein, we present an efficient approach to chiral 2-azabicyclo[2.1.1]hexanes through a copper-catalyzed asymmetric [2π + 2σ] cycloaddition of bicyclobutanes with imines. With the aid of a bifunctional chiral quinolinyl oxazoline ligand, we achieved high yields and excellent ee. Density functional theory (DFT) calculations and independent gradient model based on the Hirschfeld partition (IGMH) analysis showed the π-π stacking interactions between the quinoline ring of the ligand and the phenyl ring of imine are the key to increasing both the reactivity and enantioselectivity of the reaction.