P-Lactam antibiotics synthesis

Martin JF (1998). New aspects of genes and enzymes for P-lactam antibiotic synthesis. Appl. Microbiol. Biotechnol. 50 1-15. 

P-lactam antibiotics, exert thek antibacterial effect by interfering with the synthesis of the bacterial cell wall. These antibiotics tend to be "kreversible" inhibitors of cell wall biosynthesis and they are usually bactericidal at concentrations close to thek bacteriostatic levels. Cephalospotins are widely used for treating bacterial infections. They are highly effective antibiotics and have low toxicity. 

The P-lactam antibiotics ate produced by secondary metaboHc reactions that differ from those responsible for the growth and reproduction of the microorganism. In order to enhance antibiotic synthesis, nutrients must be diverted from the primary pathways to the antibiotic biosynthetic sequences. Although most media for the production of penicillins and cephalosporins are similar, they ate individually designed for the specific requkements of the high yielding strains and the fermentation equipment used. 

The antibacterial effectiveness of penicillins cephalospotins and other P-lactam antibiotics depends upon selective acylation and consequentiy, iaactivation, of transpeptidases involved ia bacterial ceU wall synthesis. This acylating ability is a result of the reactivity of the P-lactam ring (1). Bacteria that are resistant to P-lactam antibiotics often produce enzymes called P-lactamases that inactivate the antibiotics by cataly2ing the hydrolytic opening of the P-lactam ring to give products (2) devoid of antibacterial activity. 

Oxygen activation is a central theme in biochemistry and is performed by a wide range of different iron and copper enzymes. In addition to our studies of the dinuclear non-heme iron enzymes MMO and RNR, we also studied oxygen activation in the mononuclear non-heme iron enzyme isopenicillin N synthase (IPNS). This enzyme uses O2 to transform its substrate ACV to the penicillin precursor isopenicillin N [53], a key step in the synthesis of the important P-lactam antibiotics penicillins and cephalosporins [54, 55],... 

Ratcliffe, R.W. and Reuther, W., Total synthesis of P-lactam antibiotics. I. a-Thioformamidodiethylphosphonoacetates, Tetrahedron Lett., 4645, 1973. 

Synthesis of p-lactam antibiotics from sugars (either as chiral auxiliary or chiron), describing the general methodology developed in 1990s by Chmielewski and based on [2 + 2] cycloaddition of isothiocyanides to sugar olefins, was also comprehensively reviewed.5... 

An interesting preparation of alkyl carboxylates in high yield (Table 3.14) from the sodium salt of the carboxylic acids under mild phase-transfer catalytic conditions involves their reaction with alkyl chlorosulphate [50] and has been used with success in the preparation of alkyl esters derived from p-lactam antibiotics. The procedure is also excellent for the production of chloromethyl esters, particularly where the carboxylic acids will not withstand the classical Lewis acid-catalysed procedure using an acid chloride and formaldehyde, or where the use of iodochloromethane [51] results in the formation of the bis(acyloxy)methane. The procedure has been applied with some success to the synthesis of chloromethyl A-protected a-amino carboxylates [52],... 

Monocyclic azetidinones are useful building blocks in organic synthesis. Besides the wide use in the syntheses of monobactam antibiotics and nuclear analogues of natural bicyclic p-lactam antibiotics,1 2 3 new applications have appeared with the syntheses of unnatural a-amino acids, amino sugars4 and inhibitors of elastase.5 ... 

Holden, K. G., Total Synthesis of Penicillins, Cephalosporins and Their Nuclear Analogs in Chemistry and Biology of p-Lactam Antibiotics, Morin, R. B. Gorman, M., Eds. Academic Press New York, 1982 Vol. 2, pp. 99-164. 

P-Lactam antibiotics inhibit bacterial cell wall synthesis... 

B. Overproduction (A) of PABA is one of the resistance mechanisms of sulfonamides. Changes in the synthesis of DNA gyrases (B) is a well-described mechanism for quinolone resistance. Plasmid-mediated resistance (C) does not occur with quinolones. An active efflux system for transport of drug out of the cell has been described for quinolone resistance, but it is not plasmid mediated. Inhibition of structural blocks (D) in bacterial cell wall synthesis is a basic mechanism of action of p-lactam antibiotics. Inhibition of folic acid synthesis (E) by blocking different steps is the basic mechanism of action of sulfonamides. 

A number of antibiotics produced by fungi of the genus Cephalosporium have been identified. These antibiotics called cephalosporins contain, in common with the penicillins, a p-lactam ring. In addition to the numerous penicillins and cephalosporins in use, three other classes of p-lactam antibiotics are available for clinical use. These are the carbapenems, the carbacephems, and the monobactams. All 3-lactam antibiotics have the same bactericidal mechanism of action. They block a critical step in bacterial cell wall synthesis. 

During the biosynthesis of the cell wall, the muropeptide is formed from acetylmuramyl-pentapeptide, which terminates in a D-alanyl-D-alanine. The synthesis of this precursor is inhibited by the antibiotic cycloserine (9.36), a compound produced by many Streptomyces fungi but which is not used clinically. During the crosslinking of the pen-tapeptide precursor, the terminal fifth alanine must be split off by a transpeptidase enzyme. This last reaction in cell wall synthesis is inhibited by the p-lactam antibiotics. 

The enzymatic synthesis of P-lactam antibiotics from P-lactam nuclei 6-aminope-nicillanic acid (APA) and 7-aminodeacetoxycephalosporanic acid (ADCA) and appropriate side chain donors has been largely studied [75, 76]. 

Examples of enzyme inhibitors that can be used as drugs Enzyme inhibitors can be used as drugs, inhibiting either intracellular or extracellular reactions. For example, the p-lactam antibiotics, such as penicillin and amoxicillin, act by inhibiting one or more of the enzymes of bacterial cell wall synthesis. 

Bruggink A (2001) Synthesis of P-lactam antibiotics. Kluver, Dordecht (The Netherlands)... 

Gallop et al. [80] reported the preparation of p-lactams via a [2+2] cycloaddition reaction of ketenes with resin-bound imines derived from amino acids (Scheme 9). This is another solid-phase adaptation of the Staudinger reaction, which could lead to the synthesis of structurally diverse 3,4-bis-substituted 2-azetidinones [81]. In addition, a novel approach to the synthesis of A-unsubstituted-p-lactams, important building blocks for the preparation of p-lactam antibiotics, and useful precursors of chiral p-amino acids was described [82]. 

The biosynthesis of the p-lactam antibiotic penicillin (Fig. 65), and also of cephalosporin, involves incorporation of L-valine and the question arises as to which of the two diastereotopic terminal methyl groups of the valine occupies which position in the penicillin. (In the case of cephalosporin, the question is as to which methyl group is incorporated into the six-membered ring and which becomes the methylene group of the carbinyl acetate.) The problem has been solved by two groups 65d,141) by synthesis of specifically 13C methyl labeled valine (cf. Fig. 42, and p. 35) which was then biosynthetically incorporated in the antibiotics. The position of the 13C in the resulting antibiotic molecules was determined by 13C NMR spectroscopy. 

Here again are fairly good prospects for the industrial use of this method in the area of the area of fine chemicals. For example, Torii et al. (Otsuka Patents 90 92>) have used electrochemical allyl halogenation for the synthesis of intermediates for P-lactam antibiotics. 

Radical methods have found limited use in the preparation of four-membered heterocycles. Intramolecular cyclization of a-bromoeneamide (5) has been examined for the synthesis of p-lactams. The reaction proceeds cleanly through a 4-exo-trig pathway to furnish 6. As had been previously established, this regioselectivity is dependent on the nature of the substituent on the olefin. This methodology has been applied in the synthesis of p-lactam antibiotics ( )-PS-5 (7) and (+)-thienamycin [95JOC1276] [95SL912],... 

The ability to produce synthetic P-lactam antibiotics that have not come from fermentation is of considerable advantage industrially because microbiological spores are not present, negating the use of a dedicated contained plant. Evans and colleagues have described the synthesis of 1-carbacephalosporins (89), which are useful intermediates in the production of monocyclic P-lactam antibiotics.83 A significant step during this procedure is the conversion of an acylaminoazetidinone 90 to a P-keto ester 91 by ozonolysis (Scheme 11.24). 

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