1-Carbacephem synthesis

This penam synthesis was improved by the use of R = All and R = All or CH2C02Et. In these recent 3-lactam syntheses the Ugi reaction was executed in trifluoroethanol, a magic solvent for such conversions. In a recent carbacephem synthesis ethylene glycol/glycerol gave very good results as the sol-... 

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]. 

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). ... 

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). 

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...

The synthesis of carbacephems 183 and 186 involving C(4)-N(5) bond formation has been described. Carbacephem 183 has been prepared through aza-Achmatowicz rearrangement of 4-(2-furyl) azetidinones (Scheme 32) <1996CC881, 1998SL105>. Azetidinone 175 was obtained by the formal cycloaddition of suitable ketenes with iV-/>-anisyl-2-furylimines. 

Oxidative methanolysis of azetidinone 176 followed by hydrogenolysis of compound 177 afforded /3-lactam 178, which was protected to obtain the protected amine 179. The best conditions for rearrangement of 179 were found using TFA. Conversion of compound 180 to carbacephem 183 was accomplished by ketone reduction, alcohol protection, and elimination of methanol. Synthesis of carbacephem derivative 186 has been performed by rhodium(n)-catalyzed cycliza-tion of iodonium ylide 185 <1997TL6981> (Scheme 33). The iodonium ylide 185 was easily prepared from the corresponding /3-keto ester 184 and [(diacetoxy)iodo]benzene in good yield. 

The synthesis of Az-carbacephems has been accomplished by ring-closing metathesis reaction of monocyclic diene- and enyne-/3-lactams <1998JOC7893, 1999J(PI) 1695>. The enyne metathesis of compounds 190 afforded bicycles 191 in good yields (Equation 13). 

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>. 

In 1973, it was demonstrated that 1,2-epoxystannanes, produced from vinylstannanes and MCPBA, could be isolated and characterized, in comparison widi 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-epoxy stannanes have been reported, including the internal alkyne ketone conversion, in the caibapenem and carbacephem 0-lactam antibiotic) skeletons. Ketone (10) should be of value in the construction of the biologically interesting l-carbapen-2-ene ring system. Synthesis 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... 

In order to study possible side reactions which may reduce the yield in the Woodward method of annulation of azetidin-2-ones (Scheme 31) similar reactions of ylides (214), which do not contain groups capable of conversion to carbonyl by DMSO-acetic anhydride treatment, have been investigated. 30 A range of products, e.g. (215) and (216), were obtained. A mild, four-carbon homologation of the 4-formyl-substituted azetidinone (217) involving reaction with the phosphonium ylide (218) has been used to synthesize (219), a useful intermediate in the synthesis of carbacephem antibiotics. 3 ... 

Doecke, C.W. Staszak, M. A. Luke,W. D., A Mild, Efficient Methodology for the Synthesis of Carbacephem Intermediates via Phase Transfer Catalysis. Synthesis 1991,985. 

Ogasa, T., Saito, H., Hashimoto, Y., Sato, K., and Hirata, T., Synthesis and biological evaluation of optically active 3-/7-l-carbacephem compounds, Chem. Pharm. Bull., 37, 315, 1989. 

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. 

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... 

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