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

Davis, Andrew M., Jones, Mark and Page, Michael I. (1991) Thiazolidine ring opening in penicillin derivatives. Part 1. Imine formation. Journal of the Chemical Society, Perkin Transactions 2 (8). pp. 1219-1223. ISSN 1472-779X

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 pKa 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

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