THEORETICAL CALCULATIONS OF BETA-LACTAM ANTIBIOTICS .6. AM1 CALCULATIONS OF ALKALINE-HYDROLYSIS OF CLAVULANIC ACID

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.