Carbacephems

Fig. 5.5 A, clavulanic acid B, latamoxef C, 1-carbapenems D, olivanic acid (general structure) E, thienamycin F, meropenem G, 1-carbacephems H, loracarbef.

In the 1-carbacephems (Fig. 5.5G), the sulphur in the six-membered dihydrothiazine ring ofthe cephalosporins (based on the cephem structure, see Fig. 5.4) is replaced by carbon. Loracarbef (Fig. 5.5U) is a new oral carbacephem which is highly active against Gram-positive bacteria, including staphylococci. 

In their synthesis of the 1-carbacephem derivatives, Hatanaka and Ishimaru observed that the 3-lactam (132) cyclized to the desired carbacephem skeleton (133) with 3 equiv. of lithium hexamethyldisilazane (Scheme 42), but cyclized through the amine nitrogen to give (134) with I equiv.Presumably deprotonation of the amine occurs with the flrst equivalent of base. 

Intramolecular cyclization of 2-phenysulfonylmethyl lactam 3 took place upon reaction with lithium hexamethyldisilazan via generating its a-sulfonyl carbanion to give a cyclized postulated intermediate that can be quenched with trimethylchlorosilane to afford the stable silyl ketal 4. The later ketal was desulfonylated by Raney-Ni and desilylated through treatment with tetrabutyl ammonium fluoride (BU4NF) to afford the carbacephem 5 (94M71) (Scheme 1). 

The exceptional mildness of Nugent s and RajanBabu s system was demonstrated by Grande et al. in a synthesis of polyfunctionalized carbacephems as shown in Scheme 21. The sensitive -lactam and the other functional groups are readily tolerated by Cp2TiCl [ 100]. 

Treatment of the azetidinone 139 with zinc chloride generates the highly unstable azetinone 140, which is trapped as the carbacephem 142 in the presence of the diene... 

The carbacephem was converted into the carbapenam-2-one system ( )-143 by a multistep sequence (equation 78)68. 

Pharmacology Cephalosporins are structurally and pharmacologically related to penicillins. Cefoxitin and cefotetan (cephamycins) and loracarbef (a carbacephem) are included because of their similarity. 

A number of antibiotics produced by fungi of the genus Cephalosporium have been identified. These antibiotics called cephalosporins contain, in common with the penicillins, a p-lactam ring. In addition to the numerous penicillins and cephalosporins in use, three other classes of p-lactam antibiotics are available for clinical use. These are the carbapenems, the carbacephems, and the monobactams. All 3-lactam antibiotics have the same bactericidal mechanism of action. They block a critical step in bacterial cell wall synthesis. 

The newest classes of (3-lactam antibiotics are the car-bapenems and carbacephems. Their mechanism of action is the same as those of the other (3-lactam antibiotics. 

Loracarbef Lorabid) is a synthetic p-lactam antibiotic of the carbacephem class. The chemical structure of loracarbef is similar to that of cefaclor. Selected pharmacokinetic information appears in Table 45.2. Lora-carbef s spectrum of antibacterial activity resembles those of the second-generation cephalosporins. Comparative clinical trials reveal similar outcomes in patients treated with cefaclor, cefprozil, and loracarbef. 

Brand Name(s) Lorabid, Lorabid Pulvules Chemical Class Carbacephem derivative... 

Carbacephem 69 is obtained in excellent yield by ring-closure of the 1,4-diallyl-P-lactam 68 by a metathesis reaction in the presence of a ruthenium catalyst <99JCS(P1)1695>. Annulated carbacephams 71 is obtained by cyclization of the piperidine 70 in the presence of a 2-chloro-l-methylpyridinium salt <98JOC8170>. 

Carbacephem skeleton 86a can be constructed using enyne metathesis. Synthesis of carbapenem 86b has been reported, although the yield is moderate due possibly to high strain in the product (Scheme 35). ... 

The key sequence in a somewhat involved stereospecihc total synthesis of a carbacephem starts by preparation of a chiral auxiliary. It is interesting to note that nitrogen is the only atom from this molecule retained in the hnal product. Constmction of this moiety starts with the formation of the carbethoxy derivative (37-2) from L(- -)-phenylglycine (37-1). Selective reduction of the free carboxyl group with borane. THF leads to the hydroxycarbamate (37-3). In a one-pot sequence, this is first cyclized to the corresponding oxazolidinone (37-4) by means of sodium hydride and then alkylated with ethyl bromoacetate (37-5). Saponification of the side chain then affords the chiral acetic acid (37-6). The carboxyl group is then activated by conversion to its acid chloride (37-7). 

This research group further carried out an asymmetric version of the solid-phase Staudinger reaction using a chiral auxiliary at C-3 for the generation of active carbacephems and other multicyclic (3-lactam. Thus, the homochiral (,S )-4... 

Scheme 17 Asymmetric solid-phase synthesis of carbacephems...

Asymmetric synthesis on solid support is crucial for the generation of combinatorial libraries of novel optically active carbacephems and other polycyclic p-lactam derivatives [44]. Solid-phase Staudinger reaction of the homochiral... 

Scheme 25 Synthesis of novel optically active carbacephems...

Carbacephems aOO 1 loracarbef ° N v Acl co2h improved chemical stability, longer half-life, better oral bioavailability compared to cefaclor... 

---