STUDIES ON CLAVULANIC ACID .3. CATALYSIS OF HYDROLYSIS AND AMINOLYSIS OF CLAVULANIC ACID BY METAL-CHELATES

The Zn11-tris(hydroxymethyl)aminomethane (Tris) system has a large catalytic effect on the hydrolysis and aminolysis of the clavulanate ion, (Z)-(2R,5R)-3-(2-hydroxyethylidene)-7-oxo-4-oxa-1-azabicyclo[3.2.0] heptane-2-carboxylate. In order to ascertain the mechanism of this catalysis we have analysed the effects of other metal ions (Cd11, Co11, Cu11, Ni11, and Mn11), of amines structurally related to Tris, and of blocking the carboxylate group of the clavulanate ion. From these studies, we conclude that only the Cd11-Tris and Co 11-Tris systems have any substantial catalytic effect, although this is not as important as that of Zn11-Tris. Studies with methyl clavulanate indicate that co-ordination of the metal ion by the carboxylate group is necessary. We suggest that catalysis takes place via a ternary complex in which the metal ion plays a double role by (a) placing the clavulanate ion and the amino alcohol in the right position for the reaction and (b) lowering the pKa of the hydroxide group of Tris, which is co-ordinated with the metal ion generating a strong nucleophile.