Water-Soluble Calix[4]resorcinarenes with Hydroxyproline Groups as Chiral NMR Solvating Agents

Abstract

Water-soluble calix[4]resorcinarenes containing 3- and 4-hydroxyproline, d-nipecotic acid, (S)-2-(methoxymethyl)pyrrolidine, (S)-2-pyrrolidine methanol, and (S,S)-(+)-2,4-bis(methoxymethyl)pyrrolidine substituents are synthesized and evaluated as chiral NMR solvating agents. The derivatives with the hydroxyproline groups are especially effective at causing enantiomeric discrimination in the spectra of water-soluble cationic and anionic compounds with pyridyl, phenyl, and bicyclic aromatic rings. Binding studies show that mono- and ortho-substituted phenyl rings associate within the cavity of the calix[4]resorcinarenes, as do naphthyl rings with mono-, 2,3-, and 1,8-substitution patterns. Anthracene derivatives with an amino or sulfonyl group at the 1-position bind within the cavity, as well. Aromatic resonances of the substrates exhibit substantial upfield shifts because of shielding from the aromatic rings of the calix[4]resorcinarene. The effectiveness of the reagents at producing chiral recognition in 1H NMR spectra is demonstrated with sodium mandelate, the sodium salt of tryptophan, and doxylamine succinate. While no one reagent is consistently the most effective, the calix[4]resorcinarenes with trans-4-hydroxyproline and trans-3-hydroxyproline moieties generally produce the largest nonequivalence in the 1H NMR spectra of the substrates.

Water‐soluble calix[4]resorcinarenes as chiral NMR solvating agents for bicyclic aromatic compounds

“…Bicyclic rings, being more hydrophobic than phenyl rings, will have a greater energetic stabilization when involved in host-guest complexes with the calixresorcinarenes in water. Shifts of the aromatic resonances of 5-12 with 2-4 are usually larger than those for phenylcontaining compounds at the same concentration ratios, 53,55,56 indicating the stronger association with bicyclic substrates. Shifts in the 1 H-NMR spectra of 5-12 with the calixresorcinarenes reported herein are frequently at much lower resorcinarene-substrate ratios than in prior reports with phenyl-containing substrates.…”

“…[53][54][55] The stronger association is most likely because of the relative hydrophobicities of phenyl and bicyclic rings. Bicyclic rings, being more hydrophobic than phenyl rings, will have a greater energetic stabilization when involved in host-guest complexes with the calixresorcinarenes in water.…”

“…52,55 Substrates were purchased as hydrochloride salts when available. For those substrates only available in neutral form, hydrochloride salts were obtained in solution by adding a stoichiometric equivalent of hydrochloric acid in deuterium oxide.…”

“…[52][53][54][55][56] Compounds similar to 1 that contain optically pure hydroxyprolinylmethyl substituents including cis-4-hydroxy-L-proline (2), trans-4-hydroxy-Lproline (3), and trans-3-hydroxy-L-proline (4) have since been studied and often function more effectively as chiral NMR solvating agents than 1 for phenyl-containing compounds. 55,56 Compounds 1-4 adopt a cone configuration in solution or are in rapid exchange among a variety of possible configurations (see Fig. 1).…”

NMR enantiodifferentiation of quaternary ammonium salts of Tröger base

“…[32][33][34] Although efficient NMR enantiodifferentiation is regularly achieved among ions in ''low polarity'' halogenated solvents, it is not the case in high polarity solvents as a result of weaker electrostatic interactions. 35,36 Cations and anions, and small organic ones in particular, tend to behave as dissociated ion pairs in such solvents and hence a sharp decrease in NMR enantiodifferentiation. 37 It was thus debatable whether an effective NMR discrimination of quaternary ammonium organic cations could be achieved in polar solvent medium.…”