Theoretical study of the water-assisted aminolysis of beta-lactams: Implications for the reaction between human serum albumin and penicillins

The ring opening of 2-azetidinone via a neutral H2O-assisted aminolysis pro cess is studied using different quantum chemical methods (MP2/6-31G**, B3LY P/6-31G**, and G2(MP2,SVP) levels of theory) as a further step to the theor etical investigation of the aminolysis reaction of beta-lactam antibiotics (Diaz, N.; Suarez, D.; Sordo, T. L. Chem Eur. J. 1999, 5, 1045-1054; Diaz, N.; Suarez, D.; Sordo, T. L. J. Org. Chem.. 1999, 64, 9144-9152). The calcu lated pathways are analogous to those previously described for the amine-as sisted aminolysis reaction, a syn stepwise mechanism being the most favored one both in the gas phase and in solution with an energy barrier of around 39.7 kcal/mol (Delta G(solution)). For this process the strong catalytic a ction of one water molecule amounts to 23.0 (G2(MP2,SVP) electronic energy) , 12.6 (Delta G(gas-phase)), and 9.1 kcal/mol (Delta G(solution)). The wate r-assisted reaction between methylamine and the 3 alpha-carboxypenam anion was also studied at the B3LYP/6-31+G* level of theory to model the specific role of water in the aminolysis of bicyclic beta-lactam antibiotics. For t his system the most favorable attack of CH3NH2 to the carbonylic group in a low polar media can occur through simultaneous H-transfer to the carboxyla te group assisted by the ancillary water molecule with a Delta G(gas phase) barrier of 31.0 kcal/mol with respect to separate reactants. A concerted r oute becomes the most favored mechanism for the aminolysis of penicillins a ssisted by an ancillary water molecule in aqueous solution. The structure o f the concerted transition stare is in agreement with the experimentally re ported Bronsted beta-values close to unity. Interestingly, according to the experimental structure of the Lys(199) active center of Human Serum Albumi n, the mechanism for the aminblysis reaction of beta-lactams in a protein e nvironment may be similar to the stepwise route found in the gas phase for 3 alpha-carboxypenam.