Thiazolidine-P-lactams

Finally, a large number of -lactams and fused thiazolidine-P-lactams were studied intensively. The former category of compounds did not display a band near 1770 cm , but all the latter were found... 

Arnstein, H. R. V., and J. C. Crawhill The Biosynthesis of Penicillin. 6. A Study of the Mechanism of the Formation of the Thiazolidine-p-Lactam Rings Using Tritium-Labelled Cystine. Biochem. J. 67, 180 (1957). 

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 cyclic ketenes were generated from /V-acy 1-1,3-thiazolidine-2-carboxylic acids by means of Mukaiyama s reagent. The same reaction generated enantio-merically pure 1,3-thiazolidine-derived spiro-p-lactams, using optically active /V-A rt-butoxycarbonyl-1,3-thiazolidine-2-carboxylic acid derivatives as precursors of the asymmetrical chiral cyclic ketenes (7< r/-butoxy carbonyl Boc) [101]. 

Isopenicillin N synthase (IPNS, Table 1) or ACV cyclase (Fig. 1) catalyzes the oxidative cyclization of ACV by the removal of four hydrogens from the tripeptide with the consumption of one molecule of oxygen [22], The newly formed C—N and C—S bonds of the respective p-lactam and thiazolidine rings are putatively made in a stepwise manner while the intermediates are enzyme bound [22]. IPNS from C. acremonium was purified [23a,23b] and its N-terminal sequence reported [24] in the early 1980s. Samson et al. [25] utilized the sequence data to clone the IPNS gene pcbC [5], IPNS has been extensively characterized with respect to its enzymology [23,26,27], substrate specificity, and catalytic mechanism [28-30],... 

The synthesis of various heterocyclic systems via 1,3-dipolar cycloaddition reactions of 1,3-oxazolium-5-oxides (32) with different dipolarophiles was reported. The cycloaddition reactions of mesoionic 5H,7H-thiazolo[3,4-c]oxazolium-l-oxides (32), which were prepared from in situ N-acyl-(/J)-thiazolidine-4-carboxyIic acids and N,N -dicyclohexylcarbodiimide, with imines, such as N-(phenylmethylene)aniline and N-(phenylmethylene)benzenesulfonamide, gave 7-thia-2,5-diazaspiro[3,4]octan-l-one derivatives (33) and lH,3H-imidazo[ 1,5-cJthiazole derivative (35). The nature of substituents on imines and on mesoionic compounds influenced the reaction. A spirocyclic p-lactam (33) may be derived from a two-step addition reaction. Alternatively, an imidazothiazole (35) may be obtained from a typical 1,3-dipolar cycloaddition via a tricyclic adduct (34) which loses carbon dioxide and benzenesulfinic acid. [95T9385]... 

Carbapenems are synthetic p-lactam antibiotics that differ from the penicillins in that the sulfur atom of the thiazolidine ring (Figure 30.9) has been externalized and replaced by a carbon atom. Imipenem [i mi PEN em] is the only drug of this group currently available. 

All penicillins contain a common nucleus composed of a thiazolidine ring and a p-lactam ring connected to a side chain. An intact P-lactam ring is necessary for biologic activity, but the side chain primarily determines the antibacterial spectrum, susceptibility to destruction by gastric acid and P-lactamase enzymes, and pharmacokinetic properties. 

Penicillin was the hrst P-lactam and the hrst broad-spectrum antibiotic discovered that started the Golden age (1940-1962) of antibiotics. The stmcture of penicillin contains a thiazolidine ring that is fused to a P-lactam ring. The existence and stability of the P-lactam ring was highly controversial at the time despite the availability of a single crystal X-ray structure of one of the penicillins. Penicillin G (8) was the first penicillin that was clinically used. Penicillin G was converted easily by either chemical or biochemical means to 6-amino-penicillanic acid (9),... 

The penicillins, from the fungus Penicillium chryso-genum, are the oldest and most widely used antibiotics. They are formed through stepwise build-up from a tripeptide (ACV) derived from a-Amino adipic acid, cysteine, and valine. Successive oxidation steps form the p-lactam and close the thiazolidine ring to form isopenicillin N. Action of an acyltransferase then yields penicillin G (Fig. 47). Alternatively, hydrolysis of isopenicillin N (or penicillin G) yields 6-aminopenicillanic acid, a key precursor for the wide range of semisynthetic pencillins used therapeutically. 

The effect is compounded by the geometry of the fused bicyclic ring system. The P-lactam and thiazolidine rings of penicillin do not lie in the same plane (in fact, they lie almost perpendicular to each other), so resonance effects within the cyclic amide are prevented, which leaves the carbonyl carbon atom much more 5+ than expected and hence more liable... 

The P-lactam ring in the lactam-thiazolidine structure of penicillin (I) is much more sensitive to nucleophilic attack than simple P-lactams. The dibasic penicilloic acid (III) is the product formed under mild hydrolysis conditions in neutral and alkaline solutions. For penicillin G at constant temperature the reaction is first order with respect to penicillin and hydroxide ion concentrations. The mechanism in neutral... 

Penicillin contains a highly unstable-looking bicyclic system consisting of a four-membered p-lactam ring fused to a five-membered thiazolidine ring. The skeleton of the molecule suggests that it is derived from the amino acids cysteine and valine (Fig. 10.19), and this has been established. 

The structure of the penicillins (3.1) was established in the days before spectroscopic methods were routinely applied to structure determination. The degradative evidence for the structure of the penicillins is best understood if it is realized that the central carbon (C-5) of the thiazolidine ring in the core of the structure is a masked aldehyde and, secondly, that the p-lactam is a strained four-membered ring in which the lactam does not behave as a typical amide. The shape of the ring precludes the normal amide resonance and hence hydrolysis of the lactam takes place more easily than would be expected for an amide. This hydrolysis then places a carboxylic acid in the p-position to the masked aldehyde so that decarboxylation of a p-keto acid can occur. 

To overcome these problems, chemists have produced semisynthetic penicillins by modifying the core structure. The core of penicillins is 6-aminopenicillanic add, which consists of a thiazolidine ring fused to a p-lactam ring. In addition, there is an R group bonded via an amide bond to the core structure. 

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