Chiral Chromatographic Separation of Fifteen New Hexahydroquinoline Derivatives

Abstract

Hexahydroquinoline (HHQ) scaffold attracts great interest due to its diverse pharmacological activities. HHQ framework also includes 1,4-dihydropyridine (DHP) ring, the pharmacophore of the most popular group of drugs known as calcium channel blockers, which are frequently used in the treatment of cardiovascular conditions. In this work, we synthesized 15 HHQ-based potential calcium channel modulators (EM1–EM15) as racemic mixtures. The 15 chiral compounds were assayed on five high-efficiency liquid chromatography columns containing different small chiral selectors: derivatized β-cyclodextrin, called CDShell-RSP, WhelkoShell, and three macrocyclic glycopeptide selectors: vancomycin, VancoShell; teicoplanin, TeicoShell; and a modified macrocycle referred as NicoShell. These small chiral selectors were bonded to modern superficially porous 2.7-μm particles and packed in 10-cm columns. Small structural differences in the compounds affect their enantioselectivity. The NicoShell column was the most effective, fully separating the whole set in both the reversed-phase and normal-phase chromatographic modes. For seven compounds, the enantioresolution factor was higher than 7. The VancoShell and WhelkoShell columns could also separate the enantiomers of the entire set of chiral HHQs. The TeicoShell column was somewhat less effective, separating only 13 compounds, while the CDShell-RSP column was not as effective for these particular compounds. In the supercritical fluid chromatographic phase mode, the WhelkoShell column gave outstanding results, fully separating all 15 compounds. For nine compounds, the enantioresolution factors were higher than 5. The three macrocyclic-based chiral columns could fully separate 10 compounds. Preparative separations of these compounds will be possible using the chiral NicoShell column in reversed-phase liquid chromatography or the WhelkoShell column in supercritical fluid chromatography with minimal mobile-phase optimization.