Comparative molecular field analysis of quinine derivatives used as chiral selectors in liquid chromatography: 3D QSAR for the purposes of molecular design of chiral stationary phases

Abstract

A comparative molecular field analysis (CoMFA) was carried out on a set of aligned quinine-based stationary phase molecules used in enantioselective chromatography. The best QSAR derived has a cross-validated (predictive) r(2)(cv) = 0.671 and a normal r(2) = 0.998. For CoMFAs using both steric and electrostatic fields as descriptors, the steric field descriptors explained more than 91% of the variance while the electrostatic descriptors explained less than 9% of the variance. It is concluded that the long-range electrostatic potential surrounding the positively charged CSPs are not enantiodiscriminating, while the van der Waals and local electrostatic surface features of these CSPs are highly discriminating. Quantum mechanical calculations back up this claim by showing a relatively symmetric electrostatic iso-contour surface. From the QSAR derived here, a region around the carbamate moiety was located where placement of steric bulk is predicted to enhance chiral discrimination. A set of possible synthetic target molecules is presented.