Study on enantioselective recognition of metofoline enantiomers with cyclodextrins using capillary electrophoresis, nuclear magnetic resonance spectroscopy and molecular modeling techniques

• Separation of metofoline enantiomers in capillary electrophoresis and liquid chromatography • Assignment of absolute stereochemical configuration of metofoline enantiomers • Determination of structure of metofoline complexes with cyclodextrins in solution • Explanation of enantiomer affinity pattern based on molecular modeling calculations Compared to any other analytical technique, the main advantage of using capillary electrophoresis (CE) for studying enantioselective recognition mechanisms in intermolecular interaction is its higher sensitivity to detect weak noncovalent interactions. Furthermore, nuclear magnetic resonance (NMR) and molecular modeling proved to be very effective to complement CE for mechanistic purposes. On the other hand, multiple factors may impact selector-selectand geometries and binding energies affecting the overall enantiorecognition process. In this regard, the validation of computational tools to verify the reliability of proposed models is still a critical issue, and suitable experimental data sets are necessary for this purpose. In this study, we combined CE, NMR spectroscopy and molecular modeling with the aim of investigating the molecular bases of the enantioseparations of metofoline (MF) with β-cyclodextrin (CD), γ-CD, and heptakis (2,3-di- O -acetyl)-β-CD (HDA-β-CD). Based on this strategy and focusing on the reversal of migration order observed by using γ-CD [( R )-( S )] in place of β-CD [( S )-( R )], good agreement between experimental and theoretical data was obtained. The absolute configuration of MF enantiomers was assigned by comparison of experimental and computed chiroptical spectra.