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Kinetic characterization of C-type halohydrin dehalogenase in the synthesis of enantiopure fluoroaromatic compounds

Synthesis of fluorinated aromatic compounds is of increasing interest in the pharmaceutical and agrochemicals industry. More environmentally friendly biocatalytic modification of simpler molecules that contain a C-F bond is an attractive alternative to the often expensive and toxic metal-catalyzed fluorination of molecules, especially when optically active substances are obtained through the employment of enantioselective enzymes. Halohydrin dehalogenases (HHDHs) are industrially relevant enantioselective enzymes that catalyse the reversible conversion of vicinal halohydrins to epoxides. HHDH enzymes have been widely used in cascade reaction systems, whereby the most famous example is the joint action with nitrilase for the commercialized multi-ton-scale synthesis of ethyl (R)-4-cyano-3- hydroxybutyrate, chiral key precursor for statin side chains. In this work, reactions of fluorine- substituted aryl oxyranes with sodium azide catalyzed by C type HHDH (HheC) were studied. Obtained enantiopure fluoroaromatic vicinal azidoalcohols and epoxides are valuable chiral building blocks with a wide range of applications in the design and development of new drugs. The application of mathematical modelling approach can be of great importance since it can greatly accelerate the development of a new process where time is a key parameter. Therefore, in this work, kinetic characterization of HheC enzymes in the presence of individual epoxides was performed to find the system with the maximum potential for high yield enantioselective conversion. Based on kinetic constants, a system for further characterization and development of a complete kinetic model was selected. Due to the low solubility of epoxides and the influence of chemical hydrolysis in aqueous medium, the application of aqueous-organic systems has been investigated. Their applicability was examined by monitoring the activity of enzyme in the presence of different concentrations of selected organic solvents.

halohydrin dehalogenase ; fluorinated chiral building blocks ; kinetic mathematical modelling

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