Studies on clavulanic acid part 3. Catalysis of hydrolysis and aminolysis of clavulanic acid by metal chelates

Abstract

The Zn^II–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 (Cd^II, Co^II, Cu^II, Ni^II, and Mn^II), of amines structurally related to Tris, and of blocking the carboxylate group of the clavulanate ion. From these studies, we conclude that only the Cd^II-Tris and Co^II-Tris systems have any substantial catalytic effect, although this is not as important as that of Zn^II-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 pK_a of the hydroxide group of Tris, which is co-ordinated with the metal ion generating a strong nucleophile.