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

Abstract

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.

Highly enantioselective synthesis of both tetrahydroquinoxalines and dihydroquinoxalinonesviaRh–thiourea catalyzed asymmetric hydrogenation

“…Recently, flow chemistry received remarkable attention in asymmetric hydrogenation because of advantages such as short residence time, high surface area-to-volume ratio, excellent reproducibility, easy scale-up, etc. 21 More importantly, this technology can reduce the hazards associated with the use of hydrogen gas which is highly flammable and forms an explosive mixture in air. 22 Therefore, this new Rh-catalysed asymmetric hydrogenation system was also applied to the continuous flow conditions ( Scheme 2 ).…”

Copper-catalyzed asymmetric allylic alkylation of racemic inert cyclic allylic ethers under batch and flow conditions

“…A mixture of 1,1-and Although satisfactory results were achieved in batch, an intractable question worth thinking about is Grignard reagents are too reactive to scale up. [37][38][39] The recent emerging continuous flow technology demonstrated many advantages, including higher safety and efficiency, accurate control, better heat and mass transfer, easier amplification and better sustainability. [40][41][42][43] Thus we also explored the application of this protocol under continuous flow conditions.…”

Copper-catalyzed asymmetric allylic substitution of racemic/meso substrates

“…94 Utilizing CuBr$SMe 2 and phosphoramidite ligand L7 facilitated convenient access to optically pure cycloalkene derivatives. Furthermore, the catalytic enantioselective allylic alkylation processes have been successfully adapted to continuous ow techniques, [95][96][97][98][99][100] but only with 33% e.e. The difference in the contact mode between batch and ow reactions primarily led to a decrease in enantioselectivities.…”