Theoretical aspects of cephalosporin isomerism

Abstract

The A3 double bond of cephalosporins isomerks to the A2 position, resulting in biological inactivation of these antibiotics. This phenomenon occurs slowly in the case of cephalosporanic acids, but is rapid when the rlcarboxylate moiety is esterified or otherwise derivatized, leading to an equilibrium between the A2 and A' forms. A theoretical study of this isomerintion is demibed in the framework of two semiempirical all-valence electron molecular orbital (MO) approximations, namely MNDO and AM 1. Specifically, the methyl ester and Free ciuboxylate derivatives of both the A' and A2 isomers of 7-phenylacetamidocephalosporin were studied. The results obtained indicated that the A' derivatives were thermodynamically more stable than were the A 2 isomers both in the case of the free acids and methyl esters. These data are consistent with experimental findings and suggest that the more rapid isomerization demonstrated in the case of the esters is due primarily to kinetic rather than to thermodynamic factors.Examination of the calculated molecular structures lend support to various theories that correlate the inactivity of the A 2 isomers with spatial considerations and the degree of j3-lactam amide resonance.

Syntheses and biological evaluation of new cephalosporin-oxazolidinone conjugates

“…Reaction of the activated carbonate 11 with 3a in the presence of pyridine and DMAP was attempted. Desired coupling product 12 was generated; however, as often during reactions of cephalosporins, partial isomerization of the cephem nucleus occurred, 10 to give a nonseparable mixture of the Δ 3 and Δ 2 double bond isomers ( 12 and 12b , Fig. 3).…”

“…3). Cephalosporin Δ 2 isomers 12b are not effective antibiotics 10c,11 and also are not substrates for the planned β-lactamase induced prodrug process depicted earlier in Scheme 1. Further studies of the coupling reaction revealed that without any basic additives, reaction between 11 and 3a still took place and provided the desired protected conjugate 12 in 40% yield.…”