Thiazolidine penicillin

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

Application of the Curtius reaction to the 3-carboxyl of a penicillin has provided intermediates which have been used for the construction of cephem derivatives. As can be seen in Scheme 23, this route allows the selective cleavage of the C(3)—N(4) bond of the thiazolidine ring, thereby allowing a reconstruction of that ring in a different form (72HCA388 and the following three papers). The preparation of a related intermediate is shown in Scheme 24 (76HCA2298). 

By virtue of their fused /3-lactam-thiazolidine ring structure, the penicillins behave as acylating agents of a reactivity comparable to carboxylic acid anhydrides (see Section 5.11.2.1). This reactivity is responsible for many of the properties of the penicillins, e.g. difficult isolation due to hydrolytic instability (B-49MI51102), antibacterial activity due to irreversible transpeptidase inhibition (Section 5.11.5.1), and antigen formation via reaction with protein molecules. 

In contrast to the preceding synthetic routes, the sequence shown in Scheme 62 forms the /3-lactam ring before closing the thiazolidine ring (80JCS(P1)2228 and refs, therein). The product (83) had been previously reported and converted to the corresponding penicillin derivative (see Scheme 61) (77MI51102). 

The clavams differ from penicillins (based on the penam structure) in two respects, namely the replacement of S in the penicillin thiazolidine ring (Fig. 5.1) with oxygen in the clavam oxazolidine ring (Fig. 5.5 A) and the absence of the side-chain at position... 

The /3-lactam bond is broken (instead of the equivalent peptide bond joining the alanine residues) but the remaining ring system in the /3-lactam (a thiazolidine in penicillins) is not released (Fig. 8.3). Instead, the transpeptidase remains linked to the hydrolysed antibiotic with a half hfe of 10-15 minutes. Whilst bound to the / -lactam, the transpeptidase cannot participate in further rounds of peptidoglycan... 

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... 

Electron-withdrawing substituents at C(7) in cephalosporins decrease the rate of acid hydrolysis just as substituents at C(6) in penicillins do. However, in terms of acid-catalyzed hydrolysis cephalosporins are much less reactive than penicillins, even when the substituents on the side chains are similar [76], because cephalosporins do not show neighboring-group participation. The absence of neighboring-group participation in cephalosporins can be explained by the lower basicity of the N-atom of the dihydrothiazine ring compared to that of the thiazolidine ring of penicillins. 

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. 

In this context, it should be pointed out that the correlation between aromatic solvent-induced shifts (ASIS) and the axial or equatorial orientation of protons in cyclic sulfoxides and sulfites is quite distinct (211-213) and may be utilized in the assignment of configurations. For instance, the absolute configuration at sulfur was assigned to the penicillin sulfoxide 202 based on analysis of the effect of aromatic solvents on the chemical shifts of protons of the thiazolidine ring (214,215). 

Penicillins are the most widely used of the clinical antibiotics. They contain in their structures an unusual fused ring system in which a four-membered P-lactam ring is fused onto a five-membered thiazolidine. Both rings are heterocyclic, and one of the ring fusion atoms is nitrogen. These heteroatoms do not alter our understanding of molecular shape, since we can consider that they also have an essentially tetrahedral array of bonds or lone pair electrons (see Section 2.6.3). 

Penicillin and cephalosporin antibiotics are usually classed as P-lactam antibiotics, since their common feature is a lactam function in a four-membered ring, typically fused to another ring system. This second ring takes in the P-lactam nitrogen atom and also contains sulfur. In the case of penicillins, e.g. benzylpenicillin, the second ring is a thiazolidine, and in the cephalosporins, e.g. cephalosporin C, this ring is a dihydrothiazine. What is not readily apparent from these structures is that they are both modified tripeptides and their biosyntheses share a common tripeptide precursor. 

The penicillins are a large group of bactericidal compounds. They can be subdivided and classified by their chemical structure and spectrum of activity. The structure common to all penicillins is a (3-lactam ring fused with a thiazolidine nucleus (Fig. 45.1).The antimicrobial activity of penicillin resides in the (3-lactam ring. Splitting of the (3-lactam ring by either acid hydrolysis or (3-lactamases results in the formation of penicilloic acid, a product without antibiotic activity. Addition of various side chains (R) to the basic penicillin molecule... 

Bacitracin is a mixture of polypeptide antibiotics produced by Bacillus subtilis. As with penicillin, it contains a thiazolidine nucleus attached through L-leucine to a peptide composed of both d- and L-amino acids. However, it does not contain a (3-lactam ring. Bacitracin prevents cell wall synthesis by binding to a lipid pyrophosphate carrier that transports cell wall precursors to the growing cell wall. 

Beta lactam antibiotics having a (3-lactam ring, which includes penicillin, in which a thiazolidine ring is attached to a betalactam ring that carries a secondary amino group. Other similar compounds are cephalosporins, monobactams and carbapenems. 

Penicillin was originally extracted from the mould Penicillium notatum but now it is extracted from its related mould Penicillium chrysogenum due to its high yield. Penicillin consists of thiazolidine ring fused with a beta lactam ring which is essential for its antibacterial activity. These two rings forms a nucleus named as 6-aminopenicillanic acid. 

---