Continuous-flow enzymatic synthesis of chiral lactones in a three-dimensional microfluidic reactor

A new continuous-flow process for the enzymatic synthesis of optically pure γ-lactones, which are used as flavors and fragrances in the food and cosmetic industries, was developed in a three-dimensional microfluidic reactor. The microchannels (175 mm in length, 0.9 mm in depth, and 1.72 mL in volume) were carved precisely inside a single borosilicate glass (90 mm × 75 mm × 12 mm) with ultrafast femtosecond laser micromachining. The flow field analysis and reaction simulation showed that the mixing of substrates and enzymes was enhanced, allowing the adjustment of residence time in a wide window. SmCR_V4, a carbonyl reductase with excellent catalytic activity and enantioselectivity toward γ/δ-keto acids, was employed for the asymmetric synthesis of various chiral lactones. 30 mmol/L (R)-γ-decalactone (3g) can be obtained in 26 s with a space-time yield (STY) up to 16,877 g L⁻¹ d⁻¹, which is 14.4 times higher than the highest STY of batch reaction reported previously. This continuous-flow process was applied to the synthesis of 6 chiral lactones. In addition, the scaled-up synthesis of 3g was carried out in 6 cascade microreactors continuously for 6 h, demonstrating the feasibility and stability of the 3D continuous-flow process in enzymatic synthesis of optically pure compounds.