7-a-Methoxycephalosporins

Further, the discovery of 7-a-methoxycephalosporins [5] from Streptomyces in 1971, carbapenems [6], thienamycin [7], clavulanic acid [8], sulbactum [9] as well as the totally synthetic oxapenems [10], oxacephams [11], and other bicyclic p-lactams stimulated the search for novel antibiotics. More recent dedicated efforts to find new active molecules and modify the penicillin and cephalosporin structure have resulted in the discovery of simple monocyclic p-lactams such as norcardicins and monobactams [12, 13]. Yet another dimension has been added to the p-lactam research with the recent discovery of tricyclic p-lactam antibiotics called trinems [14]. Thus, p-lactam antibiotics in general can be classified into several groups based on their structures (Fig. 1). 

Liersch, M., j. Nuesch, and H. J. Treichler Final Steps in the Biosynthesis of Cephalosporin C. In Second International Symposium on the Genetics of Industrial Micro-organisms (K. D. Macdonald, ed.), p. 179. London Academic Press. 1976. Stevens, C. M., E. P. Abraham, F.-C. Huang, and C. J. Sih Incorporation of Molecular Oxygen at C-17 of Cephalosporin C During its Biosynthesis. Fed. Proc. 34, 625 (1975). O Sullivan, J., R. T. Aplin, C. M. Stevens, and E. P. Abraham Biosynthesis of a 7-a-Methoxycephalosporin. Incorporation of Molecular Oxygen. Biochem. J. 179,47 (1979). Fujisawa, Y., M. Kikuchi, andT. Kanzaki Deacetylcephalosporin C Synthesis by Cell-Free Extracts of Cephalosporium acremonium. J. Antibiotics 30, 775 (1977). 

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-... 

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. 

Table XV presents in vitro and in vivo data for a series of 3-meth-oxycephalosporins with the 7-glycylamino-type side chains. These compounds displayed good antibacterial activity against certain gram-positive and gram-negative bacteria. The 3-methoxycephalosporin, known as compound CGP 9000, has somewhat better in vitro antibacterial activity...

In a synthesis of C-3 acetoxycephamycin analog 476, Ratcliffe and Christensen (1972) used excess BOC-a-trichloroethyl-o-a-aminodipoyl chloride (474) to acylate 7-amino-7a-methoxycephalosporin benzhydryl ester (475) (pyridine-methylene chloride, 0°C). A 48% yield of the desired acylated product (476) was obtained, contaminated with about 14% isomer. Lunn and Mason (1974) employed similar conditions to acylate 475, whereas Sankyo researchers (Nakao et al., 1976) acylated 477 with unstable (cyanomethylthio)acetyl chloride and N,N -dimethylaniline (1,2-dichloroethane) to obtain CS1170 (478). The use of dicyclohexyl car-bodiimide has also been employed by DeMartinis and co-workers (1976) in condensing trifluoromethylthioacetic acid to a variety of 7a-methoxy-amine esters. 

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. 

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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