Partial Synthesis of Cephalosporins and Penicillins

The search for novel p-lactam antibiotics has been severely restricted by the relative inaccessibility of these ring systems by stereospecific total syntheses. Because of the availability of both the penicillin and, more recently, cephalosporin nuclei from fermentation processes, partial synthesis of new ring systems from these starting materials has been extensively investigated. The penicillin-cephalosporin interconversions continue to be studied while new degradative procedures have permitted the synthesis of useful snythons by complete removal of the thiazoline ring of penicillin. 

The first general method of transforming a penicillin into a cephalosporin, the acid-catalysed rearrangement of penicillin sulphoxides, continues to receive attention. That this rearrangement proceeds via a sulphenic acid derivative has been further confirmed by isolation of the crystalline sulphenic acid (74 f, y) from the thermal rearrangement of the penicillin sulphoxide (27 f, y). This intermediate slowly reverts to the penicillin at 38 0, and, on treatment with methanesulphonic acid in dimethylacetamide, cyclizes to cephalosporin (75 f, y). Trapping of (74) by oxidation to the sulphinyl chloride (76 f, y) has been reported cyclization to a cephalosporin sulphoxide was accomplished under base catalysis/ Treatment of penicillin sulphoxides with azo-compounds also effects rearrangement to 

Derivatives of sulphenic acids have been utilized in cephalo-sporin-penicillin interconversions. The sulphenyl chloride (88 f, y), obtained by chlorinolysis of penicillin, cyclized to the penicillin (89 f, y) and 

Numata, Y. Imashiro, I. Minamida, and M. Yamaoka, Tetrahedron Letters, 1972, 5097. M. Yoshimoto, S. Ishihara, E. Nakayama, E, Shoji, and H. Kuwano, Tetrahedron Letters, 1972, 4387. 

The sulphenic acids produced on thermal rearrangement of penicillin sulphoxides have been trapped by a variety of reagents, including thiols and acetylene and olefin derivatives such as norbomadiene, keten dimer, vinyl ethers, keten acetals, and acetylenedicarboxylates. Removal of the nitrogen substituent of the resulting 2-azetidinones, e.g. (98 c,v), was achieved by addition of diazomethane to the olefin followed by base treatment or reduction of the intermediate pyrazoline (99).  

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