Chiral recognition of (18-crown-6)-tetracarboxylic acid as a chiral selector determined by NMR spectroscopy

Abstract

It is shown that the chiral selector (+)-(18-crown-6)-2,3,11,12-tetracarboxylic acid (18-C-6-TA) employed for resolution of α-amino acids in capillary electrophoresis and in chiral HPLC can be used for resolution of α-amino acids and ester derivatives in NMR experiments. In a quest for the origin of chiral recognition of α-amino acids in the presence of 18-C-6-TA as a chiral selector, these interactions responsible for the differential affinities shown toward enantiomers are investigated by NMR spectroscopy. Chemical-shift differences of the corresponding ¹H and ¹³C resonances of D- and L-phenylglycine (PG) or phenylglycine methyl ester (PG-ME) show that most chemical shifts in the presence of 18-C-6-TA moved in the same direction (i.e., upfield or downfield) as compared with those of the free state. Significant reduction of the T₁-values is observed for the host–guest complex molecules, indicating that the mobility of the isomers is significantly reduced due to tight binding with 18-C-6-TA. NMR line broadening of the analyte upon complexation further supports this finding. The observed intermolecular NOEs of the α-proton and ortho phenyl protons of PG or PG-ME in the presence of 18-C-6-TA are used for generating structures for 18-C-6-TA/enantiomer complexes. Molecular dynamics calculations based on NOEs illustrate the essential features of the chiral recognition mechanism: 1) three ⁺NH⋯O hydrogen bonds in a tripod arrangement between polyether oxygens of 18-C-6-TA and the ammonium moiety of the enantiomer; 2) a hydrophobic interaction between the polyether ring of 18-C-6-TA and the phenyl moiety of the enantiomer; 3) hydrogen bonding between the carboxylic acid of 18-C-6-TA and the carbonyl oxygen of the D-enantiomer.