Ab initio molecular orbital calculations on the neutral hydrolysis and methanolysis of azetidinones, including catalysis by water. Relationship to the mechanism of action of β-lactam antibiotics

Abstract

The docking of penicillins to a computer model of the active site of the penicillin-binding protein of Streptornyces R61 produces structures that exhibit a four-centred interaction between the 0 -H of a serine residue and the (0)C-N of the p-lactam ring. If such a structure is a stationary point on the reaction coordinate for the acylation of the serine OH by the p-lactam carbonyl group, the acylation mechanism would appear to consist of 0-C and H-N bond formation, concerted with the cleavage of the C-N bond. The existence of this "N-protonation" mechanism, and the energetics of this mechanism in comparison to the usual "0-protonation" pathway in which proton transfer to oxygen and addition to the carbonyl group precede C-N bond fission, have been examined by ab initio M O calculations on the neutral hydrolysis and methanolysis of N-methylazetidinone, penam, and penam-3a-carboxylate. The geometries of reactants and transition structures have been optimized fully at the 3-21G or 3-21G* levels, the existence of transition structures has been confirmed by vibrational analysis, thermochemical data have been computed, and the one-point energies of all structures have been determined at the MP216-31G* level. The N-protonation mechanism is found to exist with all substrates, and to be preferred over the 0-protonation mechanism by over 5 kcallmol. The activation energies are 5 kcallmol lower in the bicyclic penam than in the monocyclic N-methylazetidinone, and attack from the convex face is preferred over attack from the concave face. The introduction of a 3a-carboxylate group, as in penicillin itself, results in an additional 5 kcallmol decrease in activation energy. The origins of these trends are discussed. Since the active sites of some penicillin-recognizing enzymes contain at least one water molecule, catalysis of the foregoing reactions by one water molecule has also been examined. The catalysis amounts to over 10 kcaVmol in both the N-and 0-protonation mechanisms, and the preference for the N-protonation mechanism is maintained. It is concluded that penicillin complexes to its receptor in such a manner as to allow acylation of the active site serine residue to proceed via the energetically most favourable mechanism. SAUL WOLFE, CHAN-KYUNG KIM et KIYULL YANG. Can. J. Chem. 72, 1033Chem. 72, (1994. L'ammage de pCnicillines au modble sur ordinateur du site actif de la protCine de liaison de la pCnicilline du Streptomyces R61 foumit des structures qui prCsentent une interaction 21 quatre centres entre le 0 -H de la sCrine et le (0)C-N du noyau p-lactame. Si une telle structure est un point stationnaire sur les coordonnCes rtactionnelles de l'acylation du OH de la sCrine par le groupe carbonyle du p-lactame, il semblerait que le mtcanisme d'acylation cornporterait la formation de liaisons 0-C et H-N concertCe avec un clivage de la liaison C-N. L'existence de ce mCcanisme de ccN-protonation, et les tnergies impliquCes dans ce mCcanisme, par comparaison avec la voie usuelle de ccO-protonation,, dans laquelle le trans...

Interactive design and synthesis of a novel antibacterial agent

“…This arrangement of the reacting groups suggests that the "reactivity" step of Scheme 1, which produces the acyl-enzyme, involves C=O bond formation and proton transfer to nitrogen, concerted with the $fission of the p-1ac:am bon:. As we report elsewhere (8), ab initio MP216-3 1 G 1/3-21 G calculations (9) of the neutral hydrolysis and alcoholysis of N-methylazetidinone (4) and penam (5) confirm that a concerted mechanism, with proton transfer to nitrogen, exists, and is 5-10 kcaY mol energetically more favorable than addition to the carbonyl group, with proton transfer to oxygen. In addition, attack on 5 from the convex face is more favourable than attack from the concave face.…”

“…The methanolysis of 4 exhibits significant catalysis by one water molecule (8). In this case, based on 3-21G calculations, the reaction proceeds via a ternary complex (Fig.…”

“…Although the reaction conditions are rather special, this is a general reaction, which usually proceeds in 70-80% yield. 8 The silylated ketol 29 (R = t-BDMS) was converted to the thiol 28 (R = t-BDMS), following activation as the mesylate and, as the lithium salt, 28 reacted with D-and L-18 to produce the 2S and 2R isomers of 27 (R' = t-BDMS, R2 = t-Boc) in over 80% yield.…”

Alkaline and acidic hydrolysis of the β‐lactam ring

“…A large number of kinetic studies regarding penicillin and cephalosporin degradation in acidic medium are found in the literature [17][18][19]; however, at present, there are still important doubts concerning the reaction pathway [20][21][22].…”

A semiempirical molecular orbital study of the methanolysis of complex azetidinones. A combined MM and QM analysis of the interaction of Δ2- and Δ3-cephems with the penicillin receptor

“…Examination of the geometry of the interaction between the serine 0 -H and the p-lactam N-C(0) in these complexes led to the suggestion that Step 2 may involve protonation of the p-lactam nitrogen concerted with C7-0 bond formation. Support has now been obtained for the existence and, indeed, energetic preference for this mechanism (8) in the gas phase, and also in the presence of a catalytic water molecule (9).…”