Combining molecular modeling approaches to establish the chromatographic enantiomer elution order in the absence of pure enantiomeric standards: A study case with two tetracyclic quinolines

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Abstract
In this study, the stereoisomers of two tetracyclic quinolines previously discovered as Pregnane X Receptor ligands were stereodiscriminated with a Chiralcel OD‐H column under normal‐phase conditions. The two compounds are characterized by a C/D cis ring junction and the co‐existence of four diastereoisomers for the presence of a further chiral center at the ring C. A mobile phase made‐up of n ‐hexane/2‐PrOH – 99:1 (v/v) allowed to obtain the four peaks of each stereoisomer fully resolved with enantioseparation and enantioresolution factor values up to 2.98 and 11.16, respectively. Due to the lack of pure enantiomeric standards of known stereochemistry, an indirect protocol was successfully applied to define the enantiomeric elution order (EEO) under the identified optimal eluent conditions. This was possible by comparing experimental and theoretical Time‐Dependent Density Functional Theory (TD‐DFT) electronic circular dichroism spectra. In order to confirm the EEOs established through the ab initio calculations, molecular docking simulations were successfully performed with a nonameric model structure of the chiral selector. The results from the docking simulations were in perfect accordance with the results from the TD‐DFT study, thereby confirming the importance of performing multiple methods in the case of indirect attribution of the absolute configuration.

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