Chiral morphing and enantiomeric quantification in mixtures by mass spectrometry

A novel mass spectrometric method is introduced for rapid and accurate chiral quantification by examining a tetracoordinated transition metal complex into which a reference and a fixed ligand are incorporated simultaneously with the analyte. Chiral analysis is performed by measuring the dissociation kinetics of these trimeric cluster ions [(M(II) + L(fixed) - H)(ref)(An)]+ (M(II) = a transition metal ion, L(fixed) = chiral peptide fixed ligand, ref = chiral reference ligand, and An = chiral analyte) in an ion trap mass spectrometer. The ratio of the product ion branching ratios measured when a pair of pure chiral fixed ligands and chiral reference ligands (/ref(D) and /ref(L); or /ref(L) and /ref(D)) are employed in separate experiments is related, via the kinetic method formalism, to the enantiomeric composition of the chiral mixture. This fixed-ligand quotient ratio (QR(fixed)) is logarithmically proportional to enantiomeric purity allowing construction of a calibration curve for chiral analysis when the analyte is only available in one form of known optical purity. There are reciprocal relationships when switching the chirality of the fixed/reference ligands. Improved quantification accuracy (due to simplified dissociation kinetics) and ready construction of two or more single-point calibration curves allow data to be cross-checked and represent an advantage of this approach. These features and the matrix tolerance of the kinetic method are demonstrated using the QR(fixed) method for determinations of enantiomeric excess of the drug DOPA in the presence of the co-drug compound L-carbidopa. The chiral selectivity of DOPA was found to vary from 0.0581 to 0.337 using this method, depending on the choices of fixed-ligand and reference chirality. The average relative errors are less than 1.2%. The potential of chiral morphing (changing chiral centers in the ligands) to further refine the chiral interactions and hence to maximize chiral recognition is shown.