Cephalothin, synthesis

The answer is c. (Hardman, pp 1143-1144.) Bacitracin, cycloserine, cephalothin, and vancomycin inhibit cell-wall synthesis and produce bacteria that are susceptible to environmental conditions. Polymyxins disrupt the structural integrity of the cytoplasmic membranes by acting as cationic detergents. On contact with the drug, the permeability of the membrane changes. Polymyxin is often applied in a mixture with bacitracin and/or neomycin for synergistic effects. 

This intermediate, like 6-APA, incorporates a primary amine that can be coupled with a host of side chains. The presence of an additional reactive function, the allylic acetate at the 3 position, provides an additional center that can be modified. The observation that both types of modifications provided unproved antibiotics has resulted in the synthesis of hundreds of analogues. The very few examples discussed below barely scratch the surface in this field. One of the earliest examples of a doubly derivatized 7-ACA derivative, cephalothin (19-1), is stUl widely used as an antibiotic. Acylation of (18-4) with 2-thiophenylacetyl chloride gives the corresponding amide (19-2). Heating that product with pyridine leads to the displacement of the allyl acetate by the basic nitrogen. The resulting product, cephalothin (19-3), is isolated as the internal betaine [23]. 

Formation of p-Lactams, Peptides and Oligonucleotides. The intramolecular cyclization technology to form /8-lactams using DCC in the condensation reaction was used by Sheehan and Henery-Logan in the total synthesis of penicilline in 1957. They also found that N-trityl penicilloates are cyclized with diisopropylcarbodiimides. Other p-lactames, such as cephalothin lactone and (—)-thienamicin are similarly constructed. The latter synthesis proceeds in a stereospecific manner and DCC is used in combination with triethylamine to give a 93 % yield of the /3-lactam 661. 

The Sheehan carbodiimide method was also used in the synthesis of other /8-lactam antibiotics. Examples include the total synthesis of cephalothin lactone,the total synthesis of cefotaxin and the stereospecific construction of thienamycin. ... 

Although cephalosporin C is divisable into a-aminoadipic acid, cysteine, and valine, the actual mechanism whereby Cephalosporium sp. incorporates the three amino acids into cephalosporin C has not been established, Arnstein and Morris isolated 8 (a-aminoadipyl) cysteinyl valine from mycelia of Penicillium chrysogenum and suggested that the tripeptide is a precursor in all penicillin biosynthesis.. This same tripeptide also appears to be found in the intracellular pool of Cephalosporium sp.- The final postulated step in the biosynthesis of penicillin is an acyl transfer reaction, or the production of 6-aminopeni-cillanic acid if precursor is not added. Cephalosporium sp. apparently do not produce sidechain amidases or acyl transferases, and no 7-ACA has been reported found in the fermentation. Thus, to obtain clinically useful antibiotics, chemical manipulation of cephalosporin C is necessary. Synthesis of many 7-acyl derivatives was possible once a practical cleavage reaction made available large amounts of 7-ACA from cephalosporin C. of these derivatives, sodium cephalothin was the first... 

The crowning intellectual achievement of the year was Woodward s S brilliant total synthesis of cephalothin (X) and cephalosporin C (XIII) via a key intermediate presumably useful for the synthesis of unique variants of both cephalosporins and penicillins. 

Semisynthetic Cephalosporins. Once the structure of cephalosporin C became known (98), attempts were made to find chemically modified analogs having superior biological properties. This was successfully achieved with the synthesis of cephalothin, cephaloridine, cephalogly-cine, and cephalexin (Figure 20). In the first two, in vitro potency was enhanced as much as 10,000 fold (99), in the latter two oral absorption... 

This method was successfully applied to the synthesis of imidazolidinones 251 bearing C-6 (P) side-chains related to penicillin G (a), penicillin V (b), methicillin (c), cephalothin (d), ampicillin (e) or cefotaxime (f) [131]. Compound 251a has been further functionalised using conventional reactions [131] (structures 252 to 256). 

These first attempts were very soon followed by total and partial syntheses of true nuclear oxa-analogues of cephalosporins. The Merck group reported the total synthesis of the 1-oxaoctam analogue (51b) of cephalothin (51a) ( ) 1-... 

Ratcliffe, R. W., and B. G. Christensen Total Synthesis of p-Lactam Antibiotics II. ( )-Cephalothin. Tetrahedron Letters 1973, 4649. 

A carbon analogue of penicillin V (Ic) was resistant to Bacillus cer-eus B l ctamase and moderately active against gram-positive organisms.6 ) Several 2-acetoxymethyl penicillins (2ja,y6 and 2-spirocyclopropyl cephalosporins (3 )65 vere prepared. Various chemical procedures were developed for the 7(6)a-methoxylation of B-lactam antibiotics.66-72 Conversion of penicillins to cephalosporins was achieved by new synthetic routes.73-76 Some [2,3]-fused tricyclic cephem derivatives (4a-c) were synthesized.77,78 Compound displayed significant antibiotic activity.78 Racemic cephalothin, 7-methoxycephalothin, and cefoxitin were obtained by total synthesis of a novel type.79-81 nuclear analogue of a 7-methylcephalosporin (5), prepared by total synthesis, lacked antibiotic activity,82... 

The meteibolic fate of radioactive cephalothin and ceph-aloridine was determined in the rat. 58 a greatly improved synthesis of cephaloridine and analogs was reported 59 Two excellent reviews on the cephalosporins % ere published. 50 61... 

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