Determination of the absolute configuration of the enantiomers of dihydroquinolines, isolated by chiral chromatography, by non empirical analysis of circular dichroism spectra and X-ray analysis

Abstract The enantiomers of racemic 3,4-dihydroquinolines with an acetal or thioacetal spiro ring and a quaternary stereogenic carbon have been isolated through semipreparative chiral chromatography using a polysaccharide-derived chiral stationary phase (Chiralpak AD) and n -hexane/ethanol as a mobile phase. The absolute configurations of the enantiomers of four compounds have been determined by a comparison of density functional theory (DFT) calculations of their electronic circular dichroism (ECD) spectra with the experimental ECD data. A detailed conformer population search to achieve a conformational average of these compounds was crucial, due to the flexibility of these molecules. The conformer distribution was evaluated by spartan 02 and the structure of each of the conformers found within 4 kcal/mol energy range was optimized with DFT. The final calculated ECD spectrum obtained after Boltzmann averaging was compared with the ECD spectrum of the less well retained enantiomer and the correlation ( R )/(−) was established for all compounds. The monocrystals of both enantiomers of one compound were obtained from the HPLC eluates. Their absolute configurations were determined by X-ray crystallographic analysis and confirmed by ECD analysis. In all cases, the second-eluted enantiomer in chiral HPLC exhibits an ( R )-configuration.