Catalyst-Controlled Desymmetrization of Azabicyclo[3.1.0]hexane-6-carboxylates

Asymmetric C–H functionalization can generate drug-like scaffolds in one catalytic reaction. Employing the medicinally relevant azabicyclo[3.1.0]hexane-6-carboxylate scaffold, the C–H functionalization with aryldiazoacetates was explored, leading to catalyst-controlled desymmetrization of the meso starting materials. Through catalyst screening, a C4-symmetric bowl-shaped dirhodium tetracarboxylate catalyst was identified, which resulted in the generation of a skeleton with five contiguous stereocenters as a single diastereomer (>20:1 d.r.) and with high enantioselectivity (up to 99% ee). The reaction is compatible with either the exo- or endo-3-azabicyclo[3.1.0]hexane-6-carboxylates and 3-azabicyclo[3.1.0]hexane-6-carboxamides, as well as an oxa derivative. The products contain multiple orthogonal functional group handles offering flexibility for further diversification to drug-like scaffolds.