End-to-End Continuous-Flow Biocatalytic Synthesis of High-Enantiopurity Chiral γ-Decalactone

Abstract

Enzymatic asymmetric reduction of keto esters provides high stereoselectivity, mild reaction conditions, and environmental benignity for the synthesis of chiral lactones. However, challenges including difficult reaction scale-up, inefficient enzyme recovery, and cumbersome downstream purification still hinder its industrial application. Here, we report an integrated end-to-end continuous-flow platform for the efficient synthesis of optically pure γ-decalactone, which integrates key unit processes: enzymatic reaction, enzyme recycling, intramolecular cyclization, and downstream extraction and purification. A poly(vinylidene fluoride) (PVDF) membrane and ethyl acetate were employed to construct an online membrane extraction process. By using a microfluidic chip with three-dimensional microchannels, ≥99% extraction efficiency was achieved while maintaining enzyme activity. Tangential flow filtration was integrated to enable rapid enzyme recycling, achieving a 20-fold concentration within 1 h at the pilot scale. Aqueous-phase cyclization exhibited excellent performance, reaching a 92% yield in <0.5 min. After process optimization, both free enzyme and immobilized enzyme continuous-flow systems maintained a stable γ-decalactone yield of over 85% after a 24 h continuous operation. Compared with the batch processes, the continuous-flow system shortened the reaction time from 3 h to 26 s, the total process time from 12 h to 10 min, and lactonization time from 6 h to 30 s—markedly improving efficiency and enhancing sustainability. By addressing the critical challenges of difficult scale-up, reaction-separation decouple, and high energy consumption in batch biocatalysis, this work establishes a scalable platform for the green and efficient continuous-flow synthesis of chiral lactones and other high-value chiral compounds, laying a foundation for their industrial application.