Continuous-Flow Chemoenzymatic Enantioselective Synthesis of Chiral α-Mono- and Difluoromethyl Amines
Chen Huang, Yunting Liu, Weixi Kong, Guanhua Liu, Liya Zhou, Ying He, Jing Gao, Yanjun Jiang
Abstract
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.