Theoretical study of thiolysis in penicillins and cephalosporins

Abstract

[eng] Semiempirical calculations were used to conduct a comprehensive study of the thiolysis of the fundamental core of penicillins and cephalosporins. The significance of the intramolecular protonation of the β-lactam nitrogen in the formation and cleavage of the tetrahedral intermediate (T in Scheme 1) was examined in two thiols bearing substituents of different basicity in β with respect to the thiol group in the attacking nucleophile, namely 2-mercaptoethanol (6) and 2-mercaptoethylamine (7). Based on the results, the rate-determining step in the reaction of penicillins is the cleavage of the tetrahedral intermediate, consistent with an intramolecular acid catalysis process in their thiolysis by 2-mercaptoethylamine. On the other hand, the rate-determining step in the reaction of cephalosporins, which possess an appropriate leaving group at position 3 , is the formation of the tetrahedral intermediate, so the desolvation energy of the nucleophile is a major contributor to the overall energy of the process. This differential behavior between the two types of β-lactam bicycles arises from the presence of the acetate group at 3 and the delocalization of π electrons over the N5<br>C4<br>C3 system in cephalosporins; this favors the formation of a thiolate with the 5-ethoxymethylene-1,3-thiazine group in the cleavage of the tetrahedral intermediate, which is stabilized by an intramolecular hydrogen bond between N5 and the alcohol or amine group in β of the attacking thiol. The theoretical results are consistent with previous experimental data showing that, unlike penicillins, cephalosporins undergo no intramolecular acid catalysis in their thiolysis