DFT calculation-aided optimisation of a chiral phosphoric acid catalyst: case study of kinetic resolution of racemic secondary alcohols through lactonisation†

Abstract

Chiral phosphoric acids (CPAs) with a pseudo C₂ symmetric structure are privileged chiral Brønsted acid catalysts that have been used to accomplish challenging organic transformations in an enantioselective manner. However, it is sometimes difficult to improve enantioselectivity by exploring CPA catalysts experimentally. In order to demonstrate a case study to overcome this issue, we attempted to screen chiral backbones and substituents of CPAs by quantum chemical calculations for the kinetic resolution of racemic γ-hydroxy esters with a stereogenic centre at the γ-position through a lactonisation reaction. In constructing the theoretical prediction model, representative reaction pathways based on the two-step reaction mechanism of lactonisation were considered, and CPA candidates were screened rationally and efficiently without having to perform an exhaustive search for plausible reaction pathways by DFT (density functional theory) calculations. As a result, the selectivity factor (s-factor) was increased by using the predicted CPA with reduced computational load and experimental effort. This prediction model has a downside to be considered because some energetically unfavourable reaction pathways were ignored to simplify the model. However, the prediction model constructed on the basis of representative reaction pathways offers an efficient way to rapidly screen for catalysts and has been employed for rational catalyst optimisation while saving time and effort.