Regioselective and enantioselective propargylic hydroxylations catalyzed by P450tol monooxygenases

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.

Keywords

Biocatalysis / Hydroxylation / P450 monooxygenase / Propargylic alcohols / Enantioselectivity

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Funding

the National Natural Science Foundation of China(32271537)

Guizhou Provincial Science and Technology Department(QKHRCPTGCC-2023-003)

the Science and Technology Department of Zunyi(ZSKRPT-2020-5)

Zunyi Medical University (QKH-2018-5772-014)