Enantioseparation and Chiral Recognition of α-Cyclohexylmandelic Acid and Methyl α-Cyclohexylmandelate on Hydroxypropyl-β-Cyclodextrin as Chiral Selector: HPLC and Molecular Modeling

Enantioseparations of (R/S)-alpha-cyclohexylmandelic acid [(R/S)-CHMA] and methyl (R/S)-alpha-cyclohexylmandelate [(R/S)-MCHMA] were performed on an achiral column (ODS) with 2-hydroxypropyl-beta-cyclodextrin (HP-beta-CD) as a chiral mobile phase additive. The influences of chromatographic conditions on the retention behavior of (R/S)-CHMA and (R/S)-MCHMA were studied in detail. Meanwhile, the thermodynamics parameters of enantioseparations for (R/S)-CHMA and (R/S)-MCHMA were determined to discuss driven power in the enantioseparation process. The inclusion complexation of HP-beta-CD with each enantiomer for (R/S)-CHMA and (R/S)-MCHMA was simulated by molecular docking to understand the chiral recognition mechanism of (R/S)-CHMA and (R/S)-MCHMA on HP-beta-CD. The results showed that the chiral recognition ability of enantiometers of (R/S)-CHMA and (R/S)-MCHMA on HP-beta-CD is better than alpha-CD, beta-CD, gamma-CD and DM-beta-CD. Under the selected chromatographic conditions, baseline separations of enantiomers of (R/S)-CHMA and (R/S)-MCHMA were achieved. It is proved that the stoichiometry for (R/S)-CHMA HP-beta-CD and (R/S)-MCHMA-HP-beta-CD complexes is 1:1. However, the results of thermodynamics parameters analysis and molecular modeling show that the enantioseparations of CHMA and MCHMA on HP-beta-CD are enthalpy-driven processes and the primary driving forces responsible for chiral recognition are hydrophobic forces, dipole-dipole interaction, charge-transfer and hydrophobic interaction.