Lipase-catalyzed two-step transesterification of diols: Estimation of selectivities

Reactions for the lipase-catalyzed kinetic resolution of chiral diols or the desymmetrization of achiral meso-diols involve two alternative routes, each of which contains two steps. During such reactions, up to four different nucleophiles compete to attack the acyl-enzyme intermediate of the catalytic cycle. The selectivities of the lipase for these different nucleophiles determines the success of the desymmetrization or resolution process and are important parameters for time-based mathematical models of these processes. Current methods for estimating these selectivities are not sufficiently accurate. In the current work, we develop a new approach to determining selectivities in lipase-catalyzed desymmetrization or resolution reactions with diols. The method is based on a model in which the only parameters are selectivities. We demonstrate the application of the method using literature data for three case studies of increasing complexity: (i) the two-step acetylation of phlorizin; (ii) the kinetic resolution of racemic 1,3-butanediol and (iii) the two-step desymmetrization of a meso-diol to produce a monoacetylated diol that is a key intermediate in the synthesis of biotin. We demonstrate the advantages of our estimation method over previously proposed estimation methods. The selectivities estimated by our method will be important parameters in models describing the desymmetrization and resolution of diols.

Automated summary

The lipase-catalyzed kinetic resolution of chiral diols or the desymmetrization of achiral meso-diols involves two alternative routes, each consisting of two steps. The selectivities of the lipase for different nucleophiles competing to attack the acyl-enzyme intermediate during these reactions are critical for the success of the resolution process and for the mathematical models describing these processes. Current methods for estimating these selectivities are not accurate enough. In this study, a new approach based on a model using selectivities as the only parameters is developed to determine selectivities in lipase-catalyzed desymmetrization or resolution reactions with diols. The advantages of this method over previously proposed methods are demonstrated using literature data from three case studies of increasing complexity.