A Photo-Enzymatic Cascade to Access Dihydrocoumarins from Incompatibility to Compatibility

ABSTRACT The extensive use of dihydrocoumarins across several fields has spurred the need to develop innovative and efficient synthetic strategies for their synthesis. In this work, we present a novel chemo-enzymatic cascade system for the synthesis of dihydrocoumarin derivatives from biomass-derived cinnamic acid and its derivatives. The key features of this approach include the photochemical E → Z isomerization/photocyclization of cinnamic acid derivatives and the enzymatic (OYE1) reduction of the intermediate coumarins to the target dihydrocoumarin derivatives. Remarkably, the utilization of microreactors in the photochemical process facilitated a complete photocyclization transformation within 1 hour under continuous flow conditions. In contrast, the batch reaction achieved a 97 % conversion but took 6 hours to accomplish. Furthermore, deep eutectic solvents (DESs) were introduced to effectively overcome the incompatibility issues between the catalysts and solvents in chemo-enzymatic cascade reactions. Our platform showcases a promising model for rationalizing incompatibilities in other such reactions, setting the stage for the development of more efficient chemo-biocatalytic synthesis strategies.