Enzyme-Catalyzed Intramolecular Enantioselective Hydroalkoxylation

Hydroalkoxylation is a powerful and efficient method of forming C–O bonds and cyclic ethers in synthetic chemistry. In studying the biosynthesis of the fungal natural product herque­inone, we identified an enzyme that can perform an intra­molecular enantio­selective hydro­alkoxyl­ation reaction. PhnH catalyzes the addition of a phenol to the terminal olefin of a reverse prenyl group to give a dihydro­benzo­furan product. The enzyme accelerates the reaction by 3 × 105-fold compared to the uncatalyzed reaction. PhnH belongs to a super­family of proteins with a domain of unknown function (DUF3237), of which no member has a previously verified function. The discovery of PhnH demonstrates that enzymes can be used to promote the enantio­selective hydro­alkoxyl­ation reaction and form cyclic ethers.