Robert R. Chauvette

Cephalosporin Antibiotics Prepared by Modifications at the C-3 Position

Publisher Summary This chapter reviews the preparations of 3-methylenecephams that led to direct heteroatom substitutions at C-3. The chemistry of 3-hydroxy-3-cephems pertains to syntheses of 3-halo- and 3-methoxy-3-cephems. The chapter discusses both the chemistry and biology of important members of these series. It presents a retrospective view of other cephalosporins modified at C-3. With the discovery of cephalosporin C and its structure determination, scientists faced the prospect of altering this natural product at several sites on the molecule to achieve optimal biological effects. Hence, following the availability of the cephalosporin nucleus, also known as 7-ACA, synthesis of a large number of cephalosporin derivatives proceeded first by acylation of the 7-amino function of 7-ACA. The concomitant efforts to displace the acetoxyl group at C-10 with heterocyclic tertiary bases and then later with sulfur nucleophiles also led to useful antimicrobials. 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.