Penicillin thiazolidine ring opening

Fig. 1. The penicillin thiazolidine ring (a) open conformation (b) closed conformation.

A. M. Davis, N. J. Layland, M. I. Page, F. Martin, R. M. O Ferrall, Thiazolidine ring opening in penicillin derivatives. Part 2 Enamine Formation , J. Chem. Soc., Perkin Trans. 2 1991, 1225-1229. 

Oxidation reactions on the sulfur atom of penicillins remain the most important reactivity of S-1 encountered in the literature. Penam sulfoxides and sulfones are indeed important compounds as they confer to the skeleton an ease of thiazolidine ring opening by weakening the C(5)-S(l) and S(l)-C(2) bonds (see Section 2.03.5.9) <2004CHE816>. In particular, the former constitute key intermediates in ring-expansion transformations from penams to cephems (see Section 2.03.5.9), while the latter have a special biological interest as /3-lactamase inhibitors (e.g., sulbactam, tazobactam see Sections 2.03.1, 2.03.5.2, and 2.03.12.4). Since CHEC-II(1996) covers all the aspects of these oxidation reactions on the S-1 atom of penicillins, this section focuses on the most relevant recent papers. As there is no particular change in the subject, only a few articles have been released since 1995. 

Sodium carbonate Thiazolidine ring opening of the penicillin ring skeleton via sulfonium salts... 

The sulfonium ylide derived chemistry of penicillins continues to meet the interest of several research groups. It is well known that intermolecular carbenoid attack at the sulfur atom generates a sulfonium ylide which undergoes spontaneous opening of the thiazolidine ring to furnish a l,2-sm>-penicillin 326). Novel examples of this reaction type were found upon Rb2(0Ac)4-catalyzed decomposition of diazomalonic esters in the presence of various penicillins this transformation constituted the opening step of a synthetic sequence directed towards 2-alkoxycarbonyl-cephems 345 a) or modified penicillins 345 b). Similar to its reaction with 4-thio-2-azetidinone... 

Fig. 2 Hapten/peptide and p-i concept of T cell stimulations by drugs, (a) Haptens haptens are chemically reactive compounds. Drugs like penicillin are haptens they bind to lysine amino acids in proteins or by the SH-group formed by opening the thiazolidine ring. This covalent binding can modify soluble or cell bound molecules. They can even bind directly to the immunogenic major histocompatibiliy complex (MHC)/peptide complex on antigen presenting cells (ARC), either to the embedded peptide or to the MHC molecule itself. Thus, the chemical reactivity of haptens can lead to...

Around neutral pH a-penici)loyl esters [68] epimerise at C(5) faster than the ester function is hydrolysed (Davis and Page, 1985). If this occurs with penicilloyl enzymes from penicillins and the serine hydroxyl at the active site of the enzyme, the ring-opening of the thiazolidine generates electrophilic sites capable of irreversibly inactivating the enzyme. 

The fundamental reason for both the commercial and research importance of penicillin sulfoxides is that the thiazolidine (5-membered ring) can be quantitatively opened under relatively mild conditions with-... 

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