A biocatalytic approach towards a range of 4‐aryloxazolidinones is developed using a halohydrin dehalogenase from Ilumatobacter coccineus (HheG) as biocatalyst. The method is based on the HheG‐catalyzed α‐position regioselective ring‐opening of styrene oxide derivatives with cyanate as a nucleophile, producing the corresponding 4‐aryloxazolidinones in moderate to good yields. Synthesis of enantiopure 4‐aryloxazolidinones is also achievable using chiral epoxide materials.magnified image

Halohydrin dehalogenases are usually recognized as strict b-position regioselective enzymes in the nucleophile-mediated ring-opening of epoxides. Here we found the HheG from Ilumatobacter coccineus exhibited excellent a-position regioselectivity in the azide-mediated ring-opening of styrene oxide derivatives 1a-1k, producing the corresponding 2-azido-2-aryl-1-ols 2a-2k with the yields up to 96%.Scheme 1 HHDH-catalyzed a-position and b-position regioselective ring-opening of epoxides with azide.

It is significant to expand enzymatic catalysis in order to develop efficient strategies for the synthesis of valued molecules. Herein, an efficient enzymatic process involving the catalytic kinetic resolution of bulky spiro-epoxyoxindoles has been developed via halohydrin dehalogenase-catalyzed enantio- and regioselective azidolysis. The enzymatic reaction provides a range of chiral spiro-epoxyoxindoles and 3-(azidomethyl)-3-hydroxyoxindoles in good yields (up to 48% isolated yield) and optical purity (up to >99% ee), both of which are useful compounds in medicinal and synthetic chemistry. In addition, the substrate scope has been expanded to sterically hindered spiro-epoxyoxindoles by directed evolution of the enzyme. Moreover, gram-scale reaction and further transformations were also performed to demonstrate the synthetic utility and scalability of the enzymatic kinetic resolution strategy.

We report the discovery of an unusual halohydrin dehalogenase, HHDHamb, that can work under relatively low acidic conditions and extremely low temperatures for the bio-nitration of epoxides using nitrite as a nitrating agent. The bio-nitration strategy exhibits high chemo-, regio-, and enantioselectivity, catalyzing the kinetic resolution of various epoxides to enantiopure β-nitroalcohols with nitro-bearing stereocenters in up to 41 % isolated yield and > 99 % enantiomeric excess (ee). Additionally, the bio-nitration method displays a high reaction efficiency and can be performed on a gram scale. We also solved the crystal structure of HHDHamb to understand the possible structural determinants of chemoselectivity control in the bio-nitration reaction.