Electroenzymatic Synthesis of Chiral Hydroxy Esters via COF-Immobilized Alcohol Dehydrogenase

Abstract Chiral hydroxy esters are critical pharmaceutical intermediates, but their traditional synthesis relies on expensive chiral metal catalysts, harsh conditions, and stoichiometric cofactors causing severe environmental pollution. Herein, we report a green electroenzymatic platform integrating covalent organic framework (COF)-immobilized alcohol dehydrogenase (ADH@Tp-Tt) with an 1,1′-diethyl-4,4′-bipyridinium dibromide/dihydrolipoyl dehydrogenase (EV/DH)-mediated NADH regeneration system for the efficient synthesis of chiral hydroxy esters. The flexible mesoporous Tp-Tt COF provides a confined microenvironment to stabilize ADH, enhancing substrate affinity and operational stability. The EV/DH cascade enables 32-fold higher NADH yield than that mediated by single EV, achieving 98.8% conversion of ethyl acetoacetate to (R)-ethyl 3-hydroxybutyrate with 99% enantiomeric excess (ee) under mild conditions. The system is extended to various chiral hydroxy esters with >99.9% conversion and 83–99% ee within 24 h, and ADH@Tp-Tt retains 71.7% activity after four cycles. This work presents a sustainable and metal-free strategy for chiral pharmaceutical intermediate synthesis, reducing costly cofactors and toxic reagents, and advancing green biomanufacturing.