Beta-Lactam antibiotics, including the penicillins, cephalosporins and monobactams, are very important in the treatment of bacterial infections. Pathogens can become resistant to these antibiotics when they produce beta-lactamases, enzymes that hydrolyze the reactive beta-lactam ring. Total and partial syntheses have provided derivatives with increased activity and resistance to hydrolytic enzymes. Because of its chemical reactivity, incorporation of the beta-lactam ring in these derivatives is a difficult synthetic step. In the biosynthesis of both penicillins and cephalosporins, a small, soluble enzyme is responsible for the oxidative cyclization of the tripeptide delta-(L-alpha-aminoadipyl)-L-cysteinyl-D-valine to isopenicillin N. Iron salts and molecular oxygen are required for activity. The available evidence on isopenicillin N synthetase can be used to formulate a mechanism for the oxidative cyclization reaction which involves a series of steps occurring within the coordination sphere of a high oxidation state iron complex. In this study, iron, ruthenium, and osmium complexes which model the chemical reactivity of isopenicillin-N-synthetase and related enzymes will be prepared. The use of soluble inorganic and organometallic complexes as model compounds will allow the use of NMR, IR and electronic spectroscopy to follow the course of reactions in solution and identify products. The specific goals of this research are: (1) to structurally and spectroscopically characterize oxometal cysteine and cysteinylvaline complexes in order to determine the preferred bonding mode, (2) to investigate the electronic and stearic requirements for beta-hydride elimination form coordinated cysteine to the metal, (3) to induce the formation of beta-lactams and beta-lactones at the metal center, and (4) to prepare oxo-iron alkyls and study chemical reactions resulting in Fe-C homolysis and reductive elimination. Results from this project should provide a better understanding of the action of isopenicillin N synthetase and other non-heme, iron-containing enzymes. Also, the development of transition metal catalysts for the stereoselective formation of beta-lactam rings could lead to the chemical synthesis of new antibiotics.
