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Access to fluorinated chiral building blocks by employing two enantiocomplementary HHDHs

Halohydrin dehalogenases (HHDHs) are synthetically highly versatile biocatalysts. In this sense, they can be applied for the enantioselective and regioselective syntheses of a wide range of 1, 2-difunctionalised chiral compounds. Enzyme-catalysed ring-opening reaction of epoxides represents an attractive alternative to metal-catalysed reactions, since they take place at ambient temperature in aqueous media at neutral pH and atmospheric pressure. Over the last years, we and others have demonstrated that HHDHs efficiently catalyses kinetic resolution of aliphatic, aromatic and functionalised epoxides, affording enantiomerically pure or highly enantioenriched products. Because of its high enantioselectivity and wide nucleophile tolerance, HheC from Agrobacterium radiobacter has been particularly used for exploring synthetic applicability. In this study, we are focused on the HHDH- catalysed transformation of epoxides bearing fluoroaryl groups. Fluoroaromatic compounds are widely used as starting materials for chemical syntheses, especially pharmaceuticals and agrochemicals. Introduction of fluorine atoms into the molecule usually increases target effectiveness, biological half-life, bioabsorption etc. Such fluorinated organics can be modified in an enantioselective fashion leading to optically active building blocks, for example alcohols, amines and epoxides. While 1, 2-azido alcohols are precursors for aziridines, tetrazoles and 1, 2-amino alcohols, epoxides are highly reactive intermediates that can be modified with many different nucleophiles via ring-opening reactions. An alternative to these methods is the kinetic resolution of epoxides which involves the use of HHDHs and sodium azide as a nucleophile. Synthesis of both chiral epoxide and b-substituted azido alcohol can be achieved this way. In this context, two HHDHs showing opposite stereopreference, HheC (R-selective wild-type enzyme) and HheA-N178A (S-selective mutant), were investigated for the azidolysis of fluorine-substituted styrene-oxide derivatives. In general, kinetic resolutions experiments were performed at analytical scale in order to determine enantioselectivity and regioselectivity of both enzymes. The origin of enantioselectivity is studied using in silico approach. These results lead to further understanding of biocatalytic properties of HHDHs and guide their application to the synthesis of chiral fluoroaryl substituted azido alcohols and epoxides.

halohydrin dehalogenase ; fluorinated epoxides ; biocatalysis

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