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

(S)-Arylpropionic acids are the pharmacologically active enantiomers of profen drugs that are challenging to synthesize chemically. Here, we report a chemoenzymatic synthesis of (S)-profens from alkenes involving styrene oxide isomerase (SOI)-catalyzed enantioretentive Meinwald-type isomerization of epoxides to aldehydes. This success relies on the engineering of SOI to accept larger substrates with enhanced activity for the rate-limiting isomerization step using a multi-Harmony analysis to guide directed evolution, which represents the first successful rational-based evolution of a membrane-associated enzyme without structural information. The engineered SOI-F35A/A131Y demonstrated 10.5-fold improvement in catalytic efficiency compared to wild-type SOI and was successfully combined in a cascade with aldehyde dehydrogenase to produce four (S)-profens from chemically derived (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 SOI can be useful to produce other types of chiral molecules.