Thiazolidine ring opening in penicillin derivatives. Part 1. Imine formation

Abstract

The rate of epimerisation of (3S,5R,6R)-benzylpenicilloic acid at C-5 shows three distinct dependencies upon pH in aqueous solution. Below pH 6 the rate shows a sigmoidal dependence upon pH, whereas it is pH-independent between pH 6 and 12, and above pH 12 the rate is hydroxide-ion dependent. These different regions of pH dependence are interpreted in terms of three mechanistic pathways all of which involve opening the thiazolidine ring by C–S bond fission and re-closure to generate the epimer. At low pH the reaction occurs by unimolecular ring opening of the S-conjugate acid which is kinetically equivalent to the N-conjugate acid of pK_a 5.14. The pH-independent pathway involves formation of a zwitterion by unimolecular opening of the neutral thiazolidine. At high pH the unprotonated imine intermediate is formed by concerted hydroxide-ion-catalysed ring opening. The mono- and di-methyl esters of benzylpenicilloate also epimerise at C-5. At low pH the rates are similar for all three compounds but above pH 6 the mono- and di-esters are, respectively, 21 and 1700 times less reactive than the dianion of the diacid.