Polymer-Supported Chiral Heterogeneous Copper Catalyst for Asymmetric Conjugate Addition of Ketones and Imines under Batch and Flow

Enantioselective conjugate addition reactions are powerful methods in synthesizing optically active molecules. Procedures that employ chiral homogeneous catalysts have been developed extensively, but ones that use chiral heterogeneous catalysts are less explored and remain a challenge. Here we report a polymer-supported chiral heterogeneous copper catalyst that demonstrated high reactivity and enantioselectivity in asymmetric conjugate addition reactions of both ketones and imines. It was found that reduced steric hindrance inside the micro catalytic environment and a 1:1 ligand to metal ratio was crucial for the high efficiency and reusability of the chiral heterogeneous catalyst. Various α,β-unsaturated carbonyl substrates, including pharmaceutical intermediates and natural products, could be transformed in high yields with high enantioselectivities. Successful application of this methodology in a continuous flow fashion further broadened its usage in dealing with sensitive organozinc reagents. In addition, production was successfully scaled up under the flow condition.