Development of chemoenzymatic continuous flow processes for the preparation of biologically active compounds

Flow reactor technology represents one of the new strategies introduced in recent years to advance the sustainability of organic synthesis and shows many advantages compared with the classical batch methods, such as increased safety, high control of reaction parameters, possibility of automation, reduced manual handling, in-line purifications, reaction telescoping and increased contact surface between phases in biphasic or triphasic systems.1 Over the last few years, one of our research lines has been focused on devising efficient continuous-flow synthetic procedures to generate chemical complexity and produce pharmaceutically and nutraceutically relevant compounds, exploiting the use of immobilized reagents, scavengers and catalysts in flow reactors (Scheme 1). This strategy led to the obtainment of a small library of variously decorated thiazoles and imidazoles,2 to the multi-step synthesis of N-Boc-3,4-dehydro-L-proline methyl ester, the precursor of a number of non-natural amino acids active on the glutamatergic system,3 and to the obtainment of a series of bicyclic-Δ2-isoxazolines, intermediates in the synthesis of novel DNA methyltransferase 1 inhibitors.4 Recently, we also explored the innovative combination of biocatalysis with the flow chemistry facilities, using both immobilized enzymes (e.g. Novozyme 435) and whole cells.5,6 The application of whole cells in a flow reactor combines the advantages of an easy to produce biocatalyst, that can be employed even without immobilization, with a process-intensification technology, that can dramatically improve the performances of biotransformations, in particular in terms of productivity. At present, we are studying multi-phase enzymatic reactions in presence of immiscible liquids or gases (unpublished results).