Two‐Step Synthesis of a Chiral Fluorinated Alcohol With Silica‐Supported Enzyme <i>Rr</i> ADH in Batch and Continuous Flow Mode

The growing demand for sustainable and efficient methods for synthesizing fine chemicals has increased interest in innovative approaches for accessing high-quality chiral building blocks, particularly fluoroalcohols, which are relevant for the production of active pharmaceutical ingredients (APIs). This study presents the complete integration of a two-step process in a continuous flow reactor system for the synthesis of (R)-2-fluoro-1-phenylethanol as a reference molecule. To this end, the individual reaction steps and technologies for the decarboxylative fluorination of 3-oxo-3-phenylpropanoic acid in aqueous media, followed by an enantioselective biocatalytic reduction of the prochiral intermediate phenacyl fluoride, were adapted and implemented in a compact laboratory system for performance demonstration. Alcohol dehydrogenase (ADH) from Rhodococcus ruber (RrADH) produced in a plant-derived BY2 cell-free expression system was used as the biocatalyst, which was immobilized via an imine bond on glutaraldehyde-modified silica supraparticles. The immobilized enzymes were used in batch mode for comprehensive kinetic studies of the enantioselective reduction, including evaluations of their operational and storage stability. Excellent enantiomeric excess (> 99.9%) and overall yields of up to 91% were achieved for both synthesis steps. These results are a prerequisite for the targeted and stable use of the enzyme in a continuously operated two-step process, which was achieved by using a serial micro batch reactor (SMBR) setup with a capillary reactor for precise temperature control. This study demonstrates the advantages of combining immobilized biocatalysts with continuous-flow operation for achieving high efficiency and selectivity in the synthesis of chiral fluoroalcohols. The integrated process provides a sustainable and versatile basis for future developments in the green synthesis of fluorinated building blocks relevant to pharmaceutical applications.