Regioselective and enantioselective propargylic hydroxylations catalyzed by P450tol monooxygenases

TL;DR

Scientists developed a green and efficient method to create chiral propargylic alcohols using P450tol enzymes, which could be useful in drug production.

Contribution

A green and scalable biohydroxylation method using P450tol for enantioselective propargylic hydroxylation is introduced.

Findings

Optically active propargylic alcohols were synthesized with up to 99% ee using P450tol under mild conditions.

The C≡C bonds remained unreacted during the hydroxylation process.

The method was scaled up to produce a key antifungal drug intermediate with 96% ee.

Abstract

Regioselective and enantioselective hydroxylation of propargylic C-H bonds are useful reactions but often lack appropriate catalysts. Here a green and efficient asymmetric hydroxylation of primary and secondary C–H bonds at propargylic positions has been established. A series of optically active propargylic alcohols were prepared with high regio- and enantioselectivity (up to 99% ee) under mild reaction conditions by using P450tol, while the C≡C bonds in the molecule remained unreacted. This protocol provides a green and practical method for constructing enantiomerically chiral propargylic alcohols. In addition, we also demonstrated that the biohydroxylation strategy was able to scaled up to 2.25 mmol scale with the production of chiral propargyl alcohol 2a at a yield of 196 mg with 96% ee, which’s an important synthetic intermediate of antifungal drug Ravuconazole.

The online version contains supplementary material available at 10.1186/s40643-024-00771-7.

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