Theoretical Study of Amine-Assisted Aminolysis of Penicillins − The Kinetic Role of the Carboxylate Group

Abstract

The β‐lactam ring opening of 3α‐carboxypenam through a methylamine aminolysis reaction catalyzed by another methylamine molecule is studied at the B3LYP/6−31+G* level of theory. Two different neutral mechanisms have been found: a concerted one and a stepwise route through two neutral tetrahedral intermediates. In the gas‐phase the most favorable mechanism is stepwise, in which the carboxylate group of 3α‐carboxypenam participates directly in the reaction coordinate as a proton shuttle. In aqueous solution the concerted mechanism is the most favored route in which the electrostatic effect of the carboxylate group plays an important role by enhancement of the solute‐solvent interaction. The structure and molecular properties of the concerted transition state correlate well with the experimentally reported Brønsted β value and with the greater catalytic advantage of amines compared with water in the aminolysis of penicillins. These effects of the carboxylate group may be of some relevance, not only to understand the aminolysis of β‐lactam antibiotics, but also to understand their hydrolysis in aqueous or enzymatic environments.

Site of Nucleophilic Attack and Ring Opening of Five-Membered Heterocyclic 2,3-Diones: A Density Functional Theory Study

“…As expected from previous work, ,,17a,b,,,,22b,− catalysis by an ancillary water molecule of the various hydration and ring opening steps generally greatly reduces the corresponding activation energies (up to >20 kcal mol -1 , Table ).In contrast to the uncatalyzed 1,2-additions to the carbonyl groups (TS1, TS2) which involve unfavorable four-membered transition states, the 1,4-addition to C 5 and the heteroatom of the exocyclic double bond (TS5) is characterized by a six-membered TS. Catalysis by an ancillary water molecule requires in this latter reaction formation of an eight-membered cyclic TS with a concomitant less pronounced stabilizing effect as found for catalysis of 1,2-additions.…”

“…Consequently, numerous experimental studies, e.g., hydration of heterocumulenes and carbonyl groups, hydrolysis of esters (lactones) and amides, combined experimental/computational, − as well as purely computational studies, e.g., hydrolysis or formation of simple amides (peptides), , esters, , anhydrides, addition to aldehydes and ketones, 1,2- vs 1,4-addition to α,β-unsaturated carbonyl compounds, and models of enzymatic reactions have been published. Ring opening of lactams with special emphasis on models of β-lactam antibiotics also has attracted a wealth of theoretical studies. − The unique feature of the heterocyclic 2,3-diones investigated in this paper is to allow comparison of different types of carbonyl reactions (hydration of a keto group, concerted and/or stepwise ester (amide) hydrolysis, and conjugate addition of the nucleophile to an α,β-unsaturated carbonyl moiety) within one single molecule.

2 Possible Sites of Nucleophilic Attack at Pyrrole-2,3-diones

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Computational Study of the Aminolysis of 2-Benzoxazolinone

“…For a common acyl-transfer reaction X - + RCOY ↔ RCOX + Y - , Kim et al predicted a stepwise mechanism in the gas and solution phases. Model systems for the reaction of amines with esters have been investigated by Zipse and others. , Neutral and catalyzed aminolysis of β -lactams have been studied theoretically in a series of papers of Sordo and co-workers. − Adalstensson and Bruice 8 have compared experimental and theoretical results for the aminolysis of substituted phenyl esters of quinoline-6- and -8-carboxylic acids. The authors proposed a stepwise mechanism involving zwitterionic intermediates.…”

A Theoretical Study of the Aminolysis Reaction of Lysine 199 of Human Serum Albumin with Benzylpenicillin: Consequences for Immunochemistry of Penicillins

“…The QM region of the different structures as optimized with the PM3/AMBER method are shown in Figure , including the CM2 charges of selected functional groups. We note that the structure and properties of the TSs for the aminolysis reaction of model systems have been thoroughly discussed in previous work. −

3 Ribbon model of the PM3/AMBER minimized structure of the prereactive complex for the aminolysis reaction of BP and Lys199 in the IIA binding site of HSA. Benzylpenicillin, the catalytic water molecule, and the side chains of Lys199, Lys195, and Glu292 are shown as ball-and-stick structures.

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“…In previous work, − we performed a series of quantum chemical studies on the aminolysis of β-lactam compounds in order to obtain a sequence of models based on more detailed descriptions of this process. A B3LYP/6-31+G* study predicted that the most favored mechanism in aqueous solution for the water-assisted aminolysis of a penicillin model compound, 3α-carboxypenam (CP), is a concerted route, while a stepwise mechanism passing through a tetrahedral intermediate would be the most favored in the gas phase or in a low-polarity environment (see Scheme ) .…”