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.