Water-soluble calix[4]resorcinarenes with hydroxyproline groups as chiral NMR solvating agents

Water-soluble calix4]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 calix4]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 calix4]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 calix4]resorcinarenes with trans-4-hydroxyproline and trans-3-hydroxyproline moieties generally produce the largest nonequivalence in the 1H NMR spectra of the substrates.