Renewable Resources for Enantiodiscrimination: Chiral Solvating Agents for NMR Spectroscopy from Isomannide and Isosorbide

Abstract

A new family of chiral selectors was synthesized in a single synthetic step with yields up to 84% starting from isomannide and isosorbide. Mono- or disubstituted carbamate derivatives were obtained by reacting the isohexides with electron-donating arylisocyanate (3,5-dimethylphenyl- or 3,5-dimethoxyphenyl-) and electron-withdrawing arylisocyanate (3,5-bis(trifluoromethyl)phenyl-) groups to test opposite electronic effects on enantiodifferentiation. Deeper chiral pockets and derivatives with more acidic protons were obtained by derivatization with 1-naphthylisocyanate and p -toluenesulfonylisocyanate, respectively. All compounds were tested as chiral solvating agents (CSAs) in 1 H NMR experiments with rac - N -3,5-dinitrobenzoylphenylglycine methyl ester in order to determine the influence of different structural features on the enantiodiscrimination capabilities. Some selected compounds were tested with other racemic analytes, still leading to enantiodiscrimination. The enantiodiscrimination conditions were then optimized for the best CSA/analyte couple. Finally, a 2D- and 1D-NMR study was performed employing the best performing CSA with the two enantiomers of the selected analyte, aiming to determine the enantiodiscrimination mechanism, the stoichiometry of interaction, and the complexation constant.

A Traceless Chiral Shift Reagent Based on Nonbonding Interactions with Single‐Handed Helical Poly(quinoxaline‐2,3‐diyl)

“…Those cavity‐based CSRs are highly attractive in that they allow the quantification of unfunctionalized molecules but often meet with difficulties associated with the limited size of the cavities. To overcome the difficulties, noncavity‐based CSRs that have tweezer‐like structures have been reported [7j] . The rigid structure compensates for the loss of entropy for CSR‐analyte interaction in comparison to the cavity‐based CSRs, and the anisotropic shielding effect could enhance the shift of chemical shift in the NMR spectra (Figure 1b).…”

A Simple Chiral 1H NMR Method for the Discrimination of (R)- and (S)-Cannabichromene in Complex Natural Mixtures and Their Effects on TRPA1 Activity

“…Consequently, the enantiomeric composition of the chiral compound can be readily deduced from an 1 H NMR spectrum. 23 To investigate the chirality of cannabichromene, we developed a fast and robust chiral NMR experiment with the use of Pirkle's alcohol as the CSA and the use of (S)-ibuprofen as a CDA. Chiral NMR with the use of CSAs is a straightforward experiment, which can determine the enantiomeric composition within a few minutes without the need of time-consuming preparation steps.…”

“…To investigate the chirality of cannabichromene, we developed a fast and robust chiral NMR experiment with the use of Pirkle’s alcohol as the CSA and the use of ( S )-ibuprofen as a CDA. Chiral NMR with the use of CSAs is a straightforward experiment, which can determine the enantiomeric composition within a few minutes without the need of time-consuming preparation steps . Moreover, these experiments can be run by any NMR instrument.…”

“…Chiral NMR with the use of CSAs is a straightforward experiment, which can determine the enantiomeric composition within a few minutes without the need of time-consuming preparation steps. 23 Moreover, these experiments can be run by any NMR instrument. The chemically synthesized racemic cannabichromene, along with its two enantiomers isolated using semipreparative chiral HPLC, were tested on transient receptor ankyrin 1 (TRPA1) channels, a recognized and well-studied pharmacological target of cannabichromene.…”

“…Chiral NMR spectroscopy is an emerging analytical method that provides both qualitative and quantitative results. The primary methods for assessing the enantiomeric composition through NMR involve employing chiral derivatizing agents (CDAs), chiral solvating agents (CSAs), chiral lanthanide shift reagents (CLSRs), or chiral liquid crystals (CLCs). − Notably, CSAs stand out as useful substances due to their straightforward addition to an analyte solution, eliminating the necessity for laborious derivatization procedures. Consequently, the enantiomeric composition of the chiral compound can be readily deduced from an 1 H NMR spectrum …”