Study On The Chiral Recognition Mechanism Of α-Cyclohexylmandelic Acid And Methyl α-Cyclohexylmandelate On Hydroxypropyl-β-Cyclodextrin

In this thesis, the deeper studies on the chiral recognition mechanism ofα-cyclohexylmandelic acid (CHMA) and methyl α-cyclohexylmandelate (MCHMA)enatiomers on hydroxypropyl-β-cyclodextrin (HP-β-CD) chiral selector were carried outby experimental and theoretical methods. High performance liquid chromatography(HPLC) and molecular modeling method were adopted. The nature of chiral recognitionwas illustrated at the molecular level in order to understand the forces of chiralrecognition on HP-β-CD and the structure of complexs.CHMA and MCHMA enatiomers were successfully separated on an achiral column(ODS3) with HP-β-CD as a mobile phase additive by high performance liquidchromatography. The influence of chromatographic conditions on the retention behaviorof (R/S)-CHMA and (R/S)-MCHMA were studied in detail, such as the species andconcentration of cyclodextrins, content of methanol, pH, along with the influence of thecolumn temperature. Meanwhile, the thermodynamics parameters of enantioseparationsfor CHMA and MCHMA were determined to discuss driven power and chiraldiscrimination mechanism of the enantioseparation process. The results indicated thatthe separation of CHMA and MCHMA enantiomers were enthalpy-driven process.Additionally, the inclusion complexation of HP-β-CD with each enantiomer for(R/S)-CHMA and (R/S)-MCHMA was simulated by autodock molecular docking tounderstand the chiral recognition mechanism of (R/S)-CHMA and (R/S)-MCHMA onHP-β-CD. The modelling results showed that the chiral recognition of (R/S)-CHMA andHP-β-CD was stronger than the interaction between (R/S)-MCHMA and HP-β-CD. So the results of autodock were consistent with the experimental results.ONIOM (B3LYP/6-31G+(d):B3LYP/6-31G) method was further adopted to studyof the most stable (R/S)-CHMA–HP-β-CD complexes obtained by autodock method.The result shows the interaction between (S)-CHMA and HP-β-CD was stronger. Andthe chiral recognition mechanism was closely related to the chiral environment providedwith C(2) and C(3) in the glucose unit of HP-β-CD, and the interaction of distancebetween the guest and host. Also,in contrast with the monomer molecule， theconformation of guest and host of complexs were obviously changed. Additionally, inorder to save the cost of calculation, the algorithm of low level was set to PM3, DFTmethod with different basis set were adopted to optimize (R/S)-MCHMA–HP-β-CDcomplexs. The results shows that the conformations of complexs tend to be more stablewith the calculation accuracy increased. The conformation of complexs obtained bycalculation level as B3LYP/6-31G:PM3or B3LYP/6-31G+:PM3was consistent. Provedthe ONIOM method that can save time and ensure the accuracy of simulation isfeasible.Finally, in order to have a better estimation of the chiral recognition between(R/S)-CHMA and HP-β-CD or between (R/S)-MCHMA and HP-β-CD, the interactionbetween host and guest was further studied by NBO analysis. The result show thathydrogen bonding interaction, hydrophobic force and charge-transfer function all playkey roles in the chiral recognition of (R/S)-CHMA and (R/S)-MCHMA on HP-β-CD.