MINDO/3 Study of N-Substituted Monocyclic β-Lactam Structures

Abstract

Molecular orbital computer experiments are used to determine the conformational preferences of N-R-3-aminoazetidin-2-ones. where R is methyl or vinyl. These structures, which model both monocyclic and bicyclic antibacterial agents, are found to be most stable when the R substituent is coplanar with the four-membered ring. Only 1-2 kcal/mole and 5-7 kcal/mole are required to twist the model structures into conformations with the CC-NCR dihedral angle around the &lactam C-N bond equal to that in A3-cephalosporins and penicillins, respectively. Twisting is shown to weaken the C-N bond and to make the carbonyl more susceptible to nucleophilic attack. Implications of the results to understanding structure-activity relationships of p-lactam antibiotics are discussed. The MIND0/3 method predicts the inversion barrier of NH3 satisfactorily at about 6 kcal/mole.