Unsubstituted Cephems

The synthesis of 3-unsubstituted cephalosporins demonstrated a gratifying application which accrued from research technology developed for the total synthesis of cephalosporin C. Having at hand a suitable intermediate and a know-how in constructing the cephem system, the Woodward group in Basel decided to prepare cephalocillin. This new substance is, in fact, a hybrid of the cephalosporin and penicillin structures, devoid of a substituent at the 3-position. 

While the alkylation of compound 207 with diazoalkanes clearly indicates its enol character, some other reactions reveal that it can also behave as a typical (3-ketoester. For example, reduction with sodium borohydride in aqueous methanol yielded the saturated alcohol (208) which after chromatography was isolated as a crystalline substance in 30% yield. Acetylation with acetic anhydride in pyridine gave 3-acetox-ycepham (209) from which the acetic acid was eliminated upon treatment with triethylamine in methylene chloride, affording the 3-H cephalosporin (210). 

Subsequently Peter and Bickel (1974) found that the 3-formyl-3-cephem (206) is readily decarbonylated on treatment with tris(triphenyl-phosphine)rhodium chloride in toluene, yielding acid 205. 

Biological tests of cephalosporins shown in Table XIX indicate that these compounds display a broad-spectrum antibacterial activity. In addition, it seems that compound 205a is almost equally as potent as ce- 

Another preparation of 3-unsubstituted 3-cephem esters and their corresponding acids was disclosed in Shionogi patents (W. Ger. Patent 2,651,509 U.S. Patent 4,081,595). The 3-halo- and 3-sulphonyloxy-3-ce-phems (211) are reduced with zinc and acetic acid in the presence of DMF, and the 3-unsubstituted 3-cephems (212) isolated in good yield. 

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Removal of the ester group afforded the cephalosporin acid (205). 7-Amino- and 7-acylaminocephalosporin esters directly substituted at position 3 with a secondary acyclic amino group or a cyclic secondary amino group were reduced in dry solvents with diborane to yield 3-unsubstituted 3-cephems. The same 3-aminocephalosporins were reacted with an alkyl or aryl Grignard reagent to afford the corresponding 3-alkyl- or 3-aryl-3-cephem esters (U.S. Patent 4,065,618). 

The addition of a p-hydroxyl substituent to a phenylglycine cephalosporin had little effect on the in vitro activity. In some cases no changes in activity were noted, whereas in other cases slight decreases in activity were seen (Webber and Ott, 1977). Studies by Preston and Wick (1974) and Dunn et al., (1976) suggested, however, that as in the case of amoxicillin, addition of a p-hydroxyl substituent increased oral absorption in mice relative to unsubstituted phenylglycine cephalosporins. The addition of a m-hydroxyl substitutent has been reported (Dunn et al., 1976) to have a negligible effect on the oral absorption of some cephem antibiotics in mice. 

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