A kinetic and thermodynamic study of the lipase-catalyzed remote resolution of a chiral tertiary alcohol

► Novozym 435 catalyzed remote asymmetric alcoholysis of a tertiary alcohol. ► The chiral discrimination was achieved four bonds away from the center. ► A kinetic model based on the reversible ping-pong bi-bi mechanism was proposed. ► The product inhibition and substrate inhibition were also considered. ► The kinetic and thermodynamic analysis were investigated using kinetic parameters. The kinetics and thermodynamics of Candida antarctica lipase B-catalyzed remote asymmetric alcoholysis of the citalopram intermediate 3-[(acetyloxy)methyl]-4-[4-(dimethylamino)-1-(4-fluorophenyl)-1-hydroxybutyl]-benzonitrile (diol monoacetate) have been studied. A kinetic model based on the reversible ping-pong bi-bi mechanism with competitive enantiomer substrates was proposed. The product inhibition by each diol enantiomer and the substrate inhibition by isobutyl alcohol were also considered. The diffusion limitation was proven to be negligible. By reducing the degree of freedom in parameter estimation by model discrimination and Haldane equations, 14 free parameters were successfully identified. The model parameters were simulated by the Matlab program using time–concentration curves of different diol monoacetate concentrations; the simulated values fit the experimental values well, with an average relative error of 9.6%. The reaction activity and enantioselectivity of C. antarctica lipase B toward the tertiary alcohol were investigated by kinetic and thermodynamic analysis using simulated kinetic parameters.