Asymmetric Heterogeneously Catalyzed Continuous-Flow Henry Reaction Towards an Antifungal Intermediate

An asymmetric heterogeneous catalytic flow system was successfully applied to the synthesis of an important antifungal intermediate. After preliminary batch studies, the ideal conditions for the Henry reaction were determined, including the use of a bulky ethertype solvent and a silica-supported cupreine catalyst. Under these optimized conditions, the desired β-nitroalcohol was obtained in a continuous-flow process with 64% conversion and a moderate enantiomeric excess (ee) of 72%. Furthermore, the unreacted starting material was separated from the product using centrifugal partition chromatography (CPC), enabling its recovery and reuse. The developed flow system demonstrates potential benefits for pharmaceutical scale-up, offering reproducibility, catalyst efficiency, and compatibility with continuous purification.