Resolution, determination of enantiomeric purity and chiral recognition mechanism of new xanthone derivatives on (S,S)‐whelk‐O1 stationary phase

Abstract

The enantioresolution and determination of the enantiomeric purity of 32 new xanthone derivatives, synthesized in enantiomerically pure form, were investigated on (S,S)-Whelk-O1 chiral stationary phase (CSP). Enantioselectivity and resolution (α and R ) with values ranging from 1.41-6.25 and from 1.29-17.20, respectively, were achieved. The elution was in polar organic mode with acetonitrile/methanol (50:50 v/v) as mobile phase and, generally, the (R)-enantiomer was the first to elute. The enantiomeric excess (ee) for all synthesized xanthone derivatives was higher than 99%. All the enantiomeric pairs were enantioseparated, even those without an aromatic moiety linked to the stereogenic center. Computational studies for molecular docking were carried out to perform a qualitative analysis of the enantioresolution and to explore the chiral recognition mechanisms. The in silico results were consistent with the chromatographic parameters and elution orders. The interactions between the CSP and the xanthone derivatives involved in the chromatographic enantioseparation were elucidated.

Enantiomeric Resolution and Docking Studies of Chiral Xanthonic Derivatives on Chirobiotic Columns

“…However, poor enantioresolution were obtained, which prompted us to pursue our investigation increasing the library of compounds and the variables of the mobile phase to better understand the behavior of these chiral columns towards the target analytes. In this work, a library of thirty-one chiral xanthonic analytes ( Figure 2 ) was used for the systematic study of enantioresolution, including the previous seven enantiomeric pairs [ 21 ] and more twenty-four [ 22 ], applying the chiral columns based on these four macrocyclic glycopeptide selectors.…”

“…Chiral xanthonic analytes were obtained in enantiomeric pure form (enantiomeric excess between 98% and 99%) [ 21 , 22 , 24 ], by coupling carboxyxanthones with both enantiomers of commercially available chiral building blocks, using O -(benzotriazol-1-yl)- N , N , N ′, N ′-tetramethyluronium tetrafluoroborate (TBTU) as coupling reagent ( Scheme 1 ), according to procedures described elsewhere [ 17 , 18 ].…”

“…One of the most frequently applied techniques is LC with chiral columns [ 20 ]. Consequently, systematic studies of enantioresolution using different types of LC chiral columns, i.e., macrocyclic glycopeptide-based [ 21 ], Pirkle-type [ 22 , 23 ] and polysaccharide-based [ 24 ], and further determination of the enantiomeric purity of the synthesized xanthonic compounds, were described. By comparison, of the overall chromatographic results for the same small library of xanthonic derivatives considering the different types of chiral columns, in general, macrocyclic glycopeptide-based showed enantioselectivity but low resolution [ 25 ].…”

Synthetic Chiral Derivatives of Xanthones: Biological Activities and Enantioselectivity Studies

“…LC using different types of CSPs, namely polysaccharide-based [149], macrocyclic antibiotics [155,156], and Pirkle-type [157,158] was used for enantioresolution studies and determination of the enantiomeric purity of the synthesized CDXs. The enantioselective LC method using polysaccharide-based CSPs under multimodal elution conditions afforded very high resolutions with short chromatographic runs.…”

Carboxyxanthones: Bioactive Agents and Molecular Scaffold for Synthesis of Analogues and Derivatives

“…It is important to emphasize that, in our group, carboxyxanthone derivative 169 has been used as a suitable building block for the synthesis of several chiral derivatives [167,169] with high enantiomeric purity [170,171,172]. Some chiral derivatives showed interesting growth inhibitory activity on A375-C5, MCF-7 and NCI-H460 human tumor cell lines [167], ability to block sciatic nerve transmission [169] and inhibit cyclooxygenases 1 and 2 enzymes [173].…”