Carbapenem/carbacephem

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.

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. 

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). ... 

Opening of the fused ring of a bicyclic azetidinone has sometimes been used as a method of obtaining a monocyclic /3-lactam of known stereochemistry. Ozonolysis of the unsaturated a-D-glucopyranosylamine 149 yielded a /3-lactam ISO, which was useful in the synthesis of carbapenems and carbacephems <2000PJC1243>. 

Enzymatic inactivation or modification of antibiotics has been discussed by many authors [179-182, 186-188], As described earlier, /(-lactams may be susceptible to /(-lactamases. During the past 30-odd years, several -lactams have been synthesized that are less susceptible to these enzymes. Such drugs include (i) newer types of /(-lactam structures, e.g. carbapenems (37), cephamycins (40) and carbacephems (53), and (ii) modifications of the side-chains of existing penams (38) or cephems (39) [317]. Nevertheless, the wide diversity of /(-lactamases [180,181,318] means that organisms producing enzymes with broad-spectrum activity may be able to resist some members of the /(-lactam group, /(-lactamase inhibitors such as clavulanic acid (36), and the penicillanic acid sulphone (54) derivatives, tazobactam (55) and sulbactam (56) have been combined with, and protect, appropriate /(-lactamase-susceptible penicillins, with useful clinical results. Most extended-spectrum /(-lactamases are susceptible to these inhibitors, but newer -lactamase inhibitors may still be needed. 

In 1973, it was demonstrated that 1,2-epoxystannanes, produced from vinylstannanes and MCPBA, could be isolated and characterized,in comparison with 2,3-epoxystannanes (from allylstannanes), which are extremely reactive and have not been isolated (see Section 4.2.2.3). Subsequently, useful applications of 1,2-epoxystannanes have been reported, including the internal alkyne - ketone conversion, in the carbapenem and carbacephem ( -lactam antibiotic) skeletons. Ketone (10) should be of value in the construction of the biologically interesting l-caibapoi-2-ene ring system. Syndiesis of ketoacetates of potential use in the carbacephem system (e.g. 11 and 12) was also achieved by similar sequences shown in Scheme 11. ... 

The synthesis of the carbapenam-3-carboxylic acid 36 <03JA15746> as well as a study on carbapenem biosynthesis have been documented <03JA8486>. The cephalosporin derivative 37 has been prepared and its use as a novel fluorogenic substrate for imaging P-lactamase gene expression demonstrated <03JA11146>. The nucleus of the carbacephem antibiotic loracarbef has been synthesized in a highly efficient and enantioselective fashion from 25,3iS-2-amino-3-hydroxy-6-heptenoic acid, which was derived from enzyme-catalyzed... 

Cephalosporins and cephamycins Carbacephems and carbapenems Monocyclic beta-lactams... 

The large family of p-lactams comprises penicillins, cephalosporins, cephamycins, mono-bactams, carbacephems and carbapenems and are so named since they all containing the p-lactam moiety. 

NH insertions were already known at the time of the exclusive use of copper catalysts for metal-carbene transformations, but, like CH insertions, they became important in synthesis only at the time of growing interest in rhodium catalysts. A breakthrough was the intramolecular carbenoid insertion into the NH bond of azetidin-2-one, catalyzed by [Rh2(OCOCH3)4] (8.127), as it was first described for the synthesis of thienamycin (8.140) by the group of Salzmann (1980) in the Merck laboratories. This synthesis (8-60) opened the way for many related pharmaceutical products of the carbapenem and the carbacephem type (see Maas, 1987, Table 21, p. 201). At an early date, the NH insertion of the parent compound 8.141 was studied... 

Glucosamine-derived imines 58 were used for the synthesis of carbapenem and carbacephem antibiotics. [2 + 2] Cycloaddition with methoxyacetyl chloride provided diastereomeric S-lactams with low asymmetric induction [56]. Radical cyclization and oxidation reactions of diastereoisomer 59 led to car-bapenems 60 and 61 (Scheme 16) [57]. The same research group continued the transformation of S-lactams derived from o-glucosamine. In particular, a tandem ehmination-conjugate addition performed on 62 provided the second ring of the carbacephem, for example 63 (Scheme 17) [58]. 

The copper-promoted oxidative addition process reported by Merck [183] on the vinylic bromides 321 gave rise, unexpectedly, to rearranged isopenem products, whose correct structures were independently determined at Sankyo s [184] and Schering s [117]. The S-C4 cleavage promoted by the reaction conditions was not the sole cause of insuccess, since carbacephems, but not carbapenems, could be synthesized by this route [185]. Similarly, intramolecular vinylic substitution of enol mesylate or phosphate 322a, b by the azetidinone nitrogen could not be achieved [84b]. 

P-Lactams are extremely important compounds that range from simple monocyclic P-lactams to more complex bicy-clic p-lactams and are integral to the structure of penicillin, cephalosporin, carbapenem and carbacephem antibiotics, as well as structurally related classes of biologically interesting... 

Carbacephem 22a and carbapenem 22b were synthesized, respectively, from ene-ynes 21a and 21b, which were prepared from 4-acetoxy-azetidinone 20. The yield in compound 22b (29%) is lower compared to that in 22a (80%) because of the highly strained, fused 4,5-membered ring system (Scheme 6.6) [9]. 

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