Theoretical prediction of selectivity in kinetic resolution of secondary alcohols catalyzed by chiral DMAP derivatives.

The mechanism of esterification of the secondary alcohol 1-(1-naphthyl)ethanol 9 by isobutyric anhydride catalyzed by 4-pyrrolidinopyridine (PPY, 11) and a series of single enantiomer atropisomeric 4-dialkylaminopyridines 8a-g has been studied computationally at the B3LYP/6-311+G(d,p)//B3LYP/6-31G(d) level. Comparison of the levels of enantioselectivity predicted computationally with the results obtained experimentally allowed the method to be validated. The value of the approach is demonstrated by the successful prediction that a structural modification of an aryl group within the catalyst from phenyl to 3,5-dimethylphenyl would lead to improved levels of selectivity in this type of kinetic resolution (KR) reaction, as was subsequently verified following synthesis and evaluation of this catalyst (8d). Experimentally, the selectivity of this type of KR is found to exhibit a significant deuterium isotope effect (for 9 vs d(1)-9).