Continuous-flow chemoenzymatic enantioselective synthesis of chiral β-nitroalcohols

• A continuous-flow chemoenzymatic system was developed for the enantioselective synthesis of chiral β-nitroalcohols. • High activity and reusability were achieved using Co(II)@DON in the Henry reaction between benzaldehydes and nitroalkanes for the production of racemic β-nitroalcohols. • Immobilised lipase (BCL@DON) was used for the KR of β-nitroalcohols with high enantioselectivity . The synthesis of enantiopure β-nitroalcohols is of great meaningful, but remains highly challenging especially for commercial applications. Herein, we developed a continuous-flow chemoenzymatic system for the enantioselective synthesis of chiral β-nitroalcohols by combing metal-catalyzed non-enantioselective Henry reaction and enzymatic enantioselective kinetic resolution (KR) reaction. A Lewis acidic metal catalyst (Co(II)@DON) for Henry reaction was prepared by immobilizing cobalt ions on dendrimeric organosilica nanoparticle (DON), which exhibited high activity and reusability for production of racemic β-nitroalcohols. A biocatalyst (BCL@DON) for KR reaction with high activity and high enantioselectivity was prepared by immobilizing the lipase from Burkholderia cepacia (BCL) on DON . The integration of these two catalysts in continuous-flow systems produced enantiopure chiral β-nitroalcohols in 37-49% yields and 99% ee, and achieved a 26-fold improvement in space-time yield (STY) compared to the batch system. We developed a continuous-flow chemoenzymatic system for the enantioselective synthesis of chiral β-nitroalcohols by combing metal-catalyzed non-enantioselective Henry reaction and enzymatic enantioselective kinetic resolution (KR) reaction. Metal catalysts (Co(II)@DON) was used in the Henry reaction for the production of racemic β-nitroalcohols, and biocatalysts (BCL@DON) was used in the KR reaction of in situ formed β-nitroalcohols. The two catalysts were finally integrated in continuous-flow systems to produce enantiopure chiral β-nitroalcohols and their acetylated derivatives in high enantioselectivity (99% ee).