7- methoxycephalosporins

The penicillins, discovered in 1929 by Fleming together with the cephalosporins, found in 1953 are named as the classic fi-h. a. With the exception of the cephamycins (7-methoxycephalosporin ) discovered in 1971, they are formed by fungi. Thousands of semisynthetic derivatives of the classical P-h. a. have been examined in order to improve the pharmacokinetic properties and to increase the resistance against the action of /3-lactamases (bacterial enzymes that cleave the lactam ring of /3-L. a. and thus inactivate... 

The discovery of cephamycins in streptomycetes fermentation broth and the announcement of their close structural relationship to cephalosporin C spurred efforts in many laboratories to develop chemical methods for methoxylating C-6 penicillins and C-7 cephalosporins. This chemistry engendered yet other methods for introducing a wide variety of substituents at this position. A number of 7-methoxycephalosporins possess interesting and useful biological activity. On the other hand, sporadic attempts to modify cephalosporins at C-2 proved more difficult and have not provided many biologically active compounds. 

A second unique feature of these new cephem compounds is the occurrence of a 7a-methoxyl function in their structures. Antibiotics containing this moiety are known as cephamycins. Many of their features are described in the chapter (3) on 7-methoxycephalosporins in Volume 1. This functionality imparts to the 3-lactam antibiotic great resistance toward 3-lactamases. The nature of these enzymes is detailed in Volume 3, Chapter 3. 

Some ten years after the structure of cephalosporin C had been established, the isolation of two naturally occurring cephalosporins possessing a 7(a)-methoxy group was reported (149). These were identified as 7-methoxycephalosporin C (202) and the C(3)-carbamate (203). Further examples of this type of natural product have been reported and are listed in Table 7. All possess the a-aminoadipic acid side chain, but vary in the substitution pattern at C(3). Collectively they are known as the cepha-mycins (174). A major point of interest with the cephamycin type of antibiotic is their intrinsically higher resistance to hydrolysis by 3-... 

Lunn, W. H. W., R. W. Burchfield, T. K. Elzey, and E. V. Mason Cleavage of 7-Methoxycephalosporin C Derivatives with Phosphorus Pentachloride. Tetrahedron Letters 1974, 1307. 

SuGiMURA, Y., K. Iino, Y. Iwano, T. Saito, and T. Hiraoka A Novel Synthesis of 7-Methoxycephalosporins and 6-Methoxypenicillins. Tetrahedron Letters 1976, 1310. Saito, T., Y. Sugimura, Y. Iwano, K. Iino, and T. Hiraoka A New Synthetic Route to 7a-Methoxycephalosporins. J. C. S. Chem. Commun. 1976, 516. 

The only natural derivatives of a-hydroxy-a-amino acids found to date are the 7-methoxycephalosporins (1) (cephamycins) (271), an important class of therapeutically valuable antibiotics. 

The most important a-alkoxy-a-amino acid compounds are the cephamycins (7-methoxycephalosporins) (1) (5, 271), which are of considerable therapeutic significance by virtue of their activity against Gram negative bacteria. Several methods have been developed for the conversion of penicillins and cephalosporins into their 6-(7-)methoxy derivative (44). 

Modification at C-6(7).—The discovery of 7-methoxycephalosporins as potent antibacterials, coupled with an early prediction that alkylation at C-6 should enhance the biological activity of penicillin, generated considerable interest in the functionalization a to the p-lactam carbonyl group. Use of an aryl Schiif base to increase the acidity of the C-6 proton permitted the generation of anion (IQ by sodium hydride or other strong bases. Alkylation of (16) by methyl iodide occurred preferentially from the less hindered a face, affording (17) as the major isomer. Similarly, stereoselective methylation of the cephalosporin anions (18 X = H) - and (18 X = OAc) yielded o-methylated products (19 X = H or OAc). 

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