Continuous‐Flow Modular Reactor with a Chiral Microenvironment Enhances the Biocatalytic Synthesis of Norepinephrine

Abstract

Abstract Chirality lies at the core of pharmaceutical molecular design. Multi‐enzyme cascade catalysis offers high stereoselectivity for constructing such molecules. Here, we present a continuous‐flow modular reactor engineered with a chiral microenvironment for the biocatalytic synthesis of norepinephrine. This system incorporates two functional modules: a chiral catalytic reactor, designed to enhance the C β stereoselectivity of L‐threonine aldolase (L‐TA), and a decarboxylation reactor to balance catalytic rates. Modifying the microenvironment surrounding L‐TA significantly enhanced its stereoselectivity, with 4.1 times increased the de value (from 18.4% to 75.01%). Seen from molecular dynamics simulations, these modifications reshaped the spatial conformation of the enzyme's active site. Moreover, at an optimal column height ratio of 3:5 between the chiral and decarboxylation modules, norepinephrine yield reached 3.07 g/L. This modular reactor strategy, enhanced by a tailored chiral microenvironment, offers substantial promise for the stereoselective synthesis of pharmaceutical intermediates.