Engineering of Styrene Oxide Isomerase for Enhanced Production of 2-Arylpropionaldehydes: Chemoenzymatic Synthesis of (S)-Profens

(S)-Arylpropionic acids are the pharmacologicallyactive enantiomers of profen drugs that are challenging to synthesizechemically. Here, we report a chemoenzymatic synthesis of (S)-profens from alkenes involving styrene oxide isomerase(SOI)-catalyzed enantioretentive Meinwald-type isomerization of epoxidesto aldehydes. This success relies on the engineering of SOI to acceptlarger substrates with enhanced activity for the rate-limiting isomerizationstep using a multi-Harmony analysis to guide directed evolution, whichrepresents the first successful rational-based evolution of a membrane-associatedenzyme without structural information. The engineered SOI-F35A/A131Ydemonstrated 10.5-fold improvement in catalytic efficiency comparedto wild-type SOI and was successfully combined in a cascade with aldehydedehydrogenase to produce four (S)-profens from chemicallyderived (S)-epoxides in 83-89% yield and 90-94% ee. This work represents a simple and cleaner route to synthesize(S)-profens from alkenes, and the engineered SOIcan be useful to produce other types of chiral molecules.