A universal multistage cascade CSTR has been developed that is suitable for a wide range of continuous-flow processes. Coined by our group the “Freactor” (free-to-access reactor), the new reactor integrates the efficiency of pipe-flow processing with the advanced mixing of a CSTR, delivering a general “plug-and-play” reactor platform which is well-suited to multiphasic continuous-flow chemistry. Importantly, the reactor geometry is easily customized to accommodate reactions requiring long residence times (≥3 h tested).

We describe the implementation of a system of immobilised enzymes for H-driven NADH recycling coupled to a selective biotransformation to enable H-driven biocatalysis in flow. This approach represents a platform that can be optimised for a wide range of hydrogenation steps and is shown here for enantioselective ketone reduction and reductive amination.

The high selectivity of biocatalysis offers a valuable method for greener, more efficient production of enantiopure molecules. Operating immobilised enzymes in flow reactors can improve the productivity and handling of biocatalysts, and using H2 gas to drive redox enzymes bridges the gap to more traditional metal‐catalysed hydrogenation chemistry. Herein, we describe examples of H2‐driven heterogeneous biocatalysis in flow employing enzymes immobilised on a carbon nanotube column, achieving near‐quantitative conversion in <5 min residence time. Cofactor recycling is carried out in‐situ using H2 gas as a clean reductant, in a completely atom‐efficient process. The flow system is demonstrated for cofactor conversion, reductive amination and ketone reduction, and then extended to biocatalytic deuteration for the selective production of isotopically labelled chemicals.

In this study a batch reactor process is compared to a flow chemistry approach for lipase catalysed resolution of the cyclopropyl ester (±)-3. (1R, 2R)-3 is a precursor of the amine (1R, 2S)-2 which is a key building block of the API ticagrelor. For both flow and batch operation, the biocatalyst could be recycled several times, whereas in the case of the flow process the reaction time was significantly reduced.2