Cephamycins synthesis

A second major approach to semi-synthetic cephamycin synthesis utilises carbanion formation a to the P-lactam carbonyl. Reaction with electrophiles then provides substrates suitable for the introduction of the methoxy group. Several papers have described how the anion generated from the SchifPs base (220 =60 ) reacts readily with methyl methan-... 

Cefmetazole (78) is a cephamycin-inspired cephalosporin differing from the mainstream compounds in having an aliphatic amide moiety attached to C-7. Its antibacterial spectrum is similar to the second generation agent cefoxitin. The synthesis starts with 7-aminocephalosporan-... 

As a result of research on cephamycins a new synthetic analogue. Cefoxitin, has appeared from the total synthesis developed by Ratcliffe and Christensen [212-214]. 

Cephalosporins and cephamycins inhibit bacterial cell wall synthesis in a manner similar to that of penicillin. 

Several groups have shown that azetidine-2,3-diones are useful synthetic targets for the construction of p-lactams with the cephamycin [48], aspareno-mycin [49] and nocardicin [50] type side chains. Azetidine-2,3-diones like 93, have been utilized by us (Scheme 14), for the preparation of appropriately substituted P-lactam intermediates in carbapenem synthesis. 

Kem BA, Henditn D, Inamine E. l-Lysine C aminotransferase involved in cephamycin C synthesis in Strepcomyces loctamdurans. Antimicrob Agents Chemother 1980 17 676 85. 

Recent work with penicillins and their analogues has included the synthesis of thiazolidine-azetidinone (117) from L-cysteine and the structure determination of cephamycins A (118a) and B (118b). 

The foregoing transacylation method was later employed in the synthesis of other highly bioactive cephamycin derivatives including CS1170 (Nakao et al., 1976 Shimizu et al., 1976). N-BOC-protected esters (425) were diacylated (426) with chloroacetyl chloride (or faster with bromo-acetyl bromide) and bis(trimethylsilyl)trifluoroacetamide in methylene chloride (40°C). Trifluoroacetic acid treatment afforded the transacylated acid (427). Nucleophilic substitution of 427 by a variety of heterocyclic mercapto compounds in the presence of 2 equiv of sodium hydroxide gave a series of semisynthetic cephamycins for which antibacterial data were given vide infra). 

Shimizu and co-workers (1976) also utilized direct C-3 displacements on A -cephamycins to prepare a series of new antibiotics. N-BOC-ce-phamycin C (508) reacted with l-methyl-5-mercaptotetrazole (95°C, 30 min) in phosphate buffer (pH 7.0) to produce derivative 509, a key compound in the synthesis of CS1170. 

As is readily evident, there exists a wide variety of semisynthetic cephamycin derivatives. In general, the choice of synthetic route for any particular cephamycin depends upon a number of factors including accessibility from cephamycin C, stability of the desired side-chain acid chloride, and feasibility of synthesis from 7-aminocephalosporanic acid (derivatives). In principle, a semisynthetic cephamycin possessing a relatively inert side chain and a C-3 substituent could readily be prepared... 

These early studies opened the way for synthesis of large numbers of broad-spectrum p-lactamase-stable, semisynthetic cephamycins. The following account will focus only on those being considered as clinical antimicrobial agents, or where an understanding of a structure-activity relationship is evident. 

It is speculated that lactams are formed rather than lactones owing to the lowered pjSTa of the amide function. The first example of the synthesis of p-lactams having cephamycin-type substituents has appeared. Derivatives of hippuric acid may be converted into the compounds (71) by reaction with Schiff s bases. 

---