Chiral analysis using the kinetic method with optimized fixed ligands: applications to some antibiotics.

Abstract

A new version of the kinetic method for chiral analysis, which employs a fixed (nondissociating) ligand as well as the usual analyte and chiral reference ligands, is introduced to simplify the kinetics of this experiment. Singly charged clusters containing the divalent transition metal ion MnII, a peptide which serves as a fixed ligand, an amino acid chiral reference, and the analyte 4-benzyl-2-oxazolidinone were generated by electrospray ionization (ESI). The cluster ion of interest was mass-selected, and the kinetics of its competitive unimolecular dissociations was investigated in an ion trap mass spectrometer. The chiral selectivity (R(fixed)chiral), the ratio of the two fragment ion abundances when the cluster contains one pure enantiomer of the analyte expressed relative to that for the other enantiomer, varies with increasing size of the fixed peptide ligands. The metal-ligand and the ligand-ligand interactions that produce chiral discrimination are optimized in the tetrapeptide fixed ligand Gly-Gly-Ala-Gly, as shown by data for 15 fixed ligands. The difference in the free energies of activation for the two competitive reactions is estimated to be approximately 7 kJ/mol for this particular fixed ligand. The sensitive nature of the methodology and the linear relationship between the logarithm of the fragment ion abundance ratio and the optical purity (intrinsic to the kinetic method) allows mixtures to be analyzed for as little as 1% enantiomeric excess (ee), by simply recording the ratios of fragment ion abundances in a tandem mass spectrum. These features are demonstrated in the case of the pharmacologically important 4-benzyl-2-oxazolidinones and in the case of penicillamine.