J. Frau et al., THEORETICAL CALCULATIONS OF BETA-LACTAM ANTIBIOTICS .6. AM1 CALCULATIONS OF ALKALINE-HYDROLYSIS OF CLAVULANIC ACID, Helvetica Chimica Acta, 77(6), 1994, pp. 1557-1569
The gas-phase basic hydrolysis of clavulanic acid (a) was studied by u
sing the AM1 semi-empirical method. The results obtained show that the
hydroxyethylidene side chain at C(2) is pivotal to the stability of t
he different reaction products involved. The products with an open oxa
zolidine ring are more stable than those with a closed ring fused to t
he beta-lactam ring. This behaviour differs from that of penicillins a
nd cephalosporins where the most stable degradation products are those
with an intact thiazolidine or dihydrothiazine ring, respectively, fu
sed to the beta-lactam ring. The different chemical reacivity of clavu
lanic acid relative to penicillins and cephalosporins could explain th
e disparate behaviour of the latter two types of compound towards beta
-lactamases. Once the acyl-enzyme intermediate of clavulanic acid has
been formed, it can evolve with cleavage of the oxazolidine ring to fo
rm a difficult to deacylate compound.