Continuous-Flow Chemoenzymatic Enantioselective Synthesis of Chiral α-Mono- and Difluoromethyl Amines

The enantioselective synthesis of chiral fluorinated amines is of great importance but highly challenging in synthetic chemistry and the pharmaceutical industry. Herein, we established a chemoenzymatic cascade for enantioselective synthesis of chiral α-mono- and difluoromethyl amines from easily available β-keto-acid esters in water–oil–solid multiphasic systems via two catalytic modules, i.e., organo-enzymatic decarboxylative fluorination and bienzymatic reductive amination. An efficient continuous synthesis system was constructed by stepwise enzyme immobilization, biphasic system construction, and continuous-flow operation to achieve process intensification. The flow system achieved a high space-time yield of up to 19.7 g L–1 h–1, which was a 35-fold enhancement compared to the batch system using free enzymes, and also demonstrated high operational stability, maintaining 87% of the production activity after 96 h with a half-life of 443.9 h.