Quantitative measurements of chirality and the synthesis of heterocycles in the mass spectrometer

Weiguo Tao, Purdue University

Abstract

A novel mass spectrometric method for rapid, accurate chiral recognition and enantiomeric determination is presented. The technique uses electrospray ionization on a commercial ion trap mass spectrometer to form transition metal ion-bound cluster ions that promote enantiospecific interactions. Collision induced dissociation (CID) of the cluster ions yields data that is treated by the kinetic method, a sensitive linear free energy method of treating mass spectrometric results and converting them to thermochemical data. Chiral recognition and enantiomeric measurements of amino acids, peptides, α-hydroxy acids, carbohydrates, and some model chiral drugs, including β-blockers, DOPA, and antiviral nucleoside agents, are demonstrated. Two quantitative methods, the single ratio (SR) and quotient ratio (QR) methods, are being developed for enantiomeric determination. A two-point calibration curve based on the SR method, allows rapid quantitation of enantiomeric excess of drug mixtures, while a single-point calibration curve can be established using the QR method. The chiral sensitivity of both quantitative methods is such as to allow determination of mixtures with a few percent enantiomeric contamination with accuracy less than 1%ee. The underlying kinetics, thermochemistry and intrinsic chiral interactions that are responsible for chiral distinction are investigated by tandem mass spectrometry and ab initio calculations. The method is extended to the distinction and quantitative analysis of isomeric mixtures. The analysis of isomeric dipeptides differing in amino acid sequences or residues with the same mass (i.e., a leucine/isoleucine substitution) is demonstrated. The generality of Eberlin reaction is explored using ambiphilic ions including phosphonium, borinium, silylium, and sulfenium cations. Heterocyclic ions are synthesized by a highly exothermic channel, which proceeds via initial cationic binding to a heteroatom followed by a consecutive ring opening and ring reclosing process.

Degree

Ph.D.

Advisors

Cooks, Purdue University.

Subject Area

Analytical chemistry|Organic chemistry

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