Digitalising the Development of Chemoenzymatic Cascades

Chemoenzymatic cascades combine the versatile reactivity of chemocatalysis and the high selectivity of biocatalysis, offering advantages such as reducing the number of separate steps, energy consumption and waste. Despite this, the development of chemoenzymatic cascades remains limited, owing to the incompatibility of chemical and biocatalysts and thus the requirement for divergent reaction conditions.

In addition, cross-reactivity and inhibition between catalysts, substrates and intermediates can result in the formation of undesired by-products and deactivation respectively. Multistep continuous flow systems enable catalysts to be spatially separated in different reactors, mimicking the compartmentalisation approach adopted by nature for chemical transformations inside the cell.

Nevertheless, solvent compatibility remains a significant challenge, as most enzymes exhibit optimal activity in aqueous environments, where substrate solubility is low, and many chemical catalysts are sensitive to deactivation. Furthermore, catalytic reactions represent challenging multi-reagent optimisation problems, due to many possible combinations of continuous (e.g., reaction time, temperature, stoichiometry) and categorical (e.g., catalyst, ligand, base) variables.

In this project, the application of alternative bio-based solvents as mutually compatible reaction media will be explored to develop new chemoenzymatic cascades in continuous flow. Our existing automated reactor platforms and machine learning algorithms will be advanced to provide a digital technology capable of rapidly optimising these multistep processes.