Carbapenam derivatives

Interest in the development of new carbapenam analogues of the potent ft-lactam antibiotics initiated major efforts toward the aza analogues of carbapenam derivatives. Taylor and Davies attempted to synthesize azacarbepe-nams 205 by intramolecular aldol condensation reaction of 204 using LDA as a deprotonating agent, as shown in Scheme 29 <1986JOC1530>. However, an unexpected bicyclic compound 208 was isolated in addition to imida-... 

The carbapenam (276) is formed with high diastereoselectivity and the regioselectivity of the cyclization can be controlled either by varying the initial concentration of the bromide (275) or by varying the cyclization conditions (thermal or photochemical). An alternative approach to the carbapenam derivative (279) has been described by Dumas et al. which utilizes an efficient base-catalysed intramolecular N-alkylation of the iodide (278).150 Interestingly, attempted cyclization of the epimeric (at C-3) iodide was unsuccessful. 

It was reported also that Mitsunobu alkylation of 105 with carbapenam derivative 106 could be effected (Equation 9) <1999BML673>. 

Thienothienylglycyl)cephalosporin (85JMC1896, 86USP4581352) and 2-(thie-nothienylphenyl)carbapenam derivatives (93USP5143914) possess antibacterial properties. 

The conversion of the amide group in 34 into the carboxy group via 35 seems to be a promising way to solve the "cunide problem" of B-lactam syntheses by 4CC (refs. 2,21). The conversion of B-lactam amides into the carboxylic acids via the esters was very successful in the hands of Hofheinz and Isenring (ref. 22) who worked with the N-benzhydryl amides of nocardicin derivatives. The stereoselective and regiose-lective 1,3-dipolar cycloaddition of chiral nitrones to benzyl crotonate is a key step in our approach to thienamy-cine (ref. 23) and related carbapenam derivatives. Besides chiral 2-phenylethyl hydroxylamine (ref. 24) the 1-hydro-xylamino derivative of 2,3-5,6-diacetone mannose (ref. 25) is a promising source of chiral nitrones for such enantiose-lective cycloadditions. 

Since we were unable to obtain the succinaldehyde derivatives, e.g. 38 (ref. 26) that are needed for the above carbapenam derivatives, we confined ourselves to model experiments with malonaldehyde dimethyl acetal (ref. 23). In the meantime, we have found a convenient synthesis for succinal-dehyde diethyl acetal 38 (Scheme 8). Thus we now are able to continue our carbapenem syntheses via the cycloadducts 40. 

Schane 3.34 Synthesis of a carbapenam derivative via Suzuki-Miyaura cross-coupling. 

Efforts to realize an intramolecular version of the above reactions met with limited success when monocyclic 4-thio-substituted (3-lactams were used. Cu(acac)2-catalyzed decomposition of diazoketone 358 produced the epimeric carbapenams 359 a, b together with the oxapenam derivative 360 341 these compounds correspond to the C4/S insertion products obtained in intermolecular reactions. Oxapenams were obtained exclusively when the acrylate residue in 359 was replaced by an aryl or heteroaryl substituent 275 342). The different reaction mode of diazoketones 290a, b, which furnish mainly or exclusively carbonyl ylide rather than sulfur ylide derived products, has already been mentioned (Sect. 5.2). 

However, carbacepham derivatives 179 and 180 could be generated from 178 by Jones oxidation to furnish a mixture (10 90) of keto-enol isomers 179 and 180, which can be methylated using diazomethane to give 181 in 63% yield (Scheme 24). Evaluation of various carbacepham analogues as well as carbapenam analogues indicated that some are promising potent antibiotics. 

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... 

A method for the enantioselective synthesis of the ftmctionalised carbapenam core 38 from D-serine-derived pyrrolidines has been reported <03JOC187>. Disubstituted pyrrolidines, obtained from the retro Dieckmann reaction of azabicyclo[2.2.1]heptan-2-one-1-carboxylic acid methyl esters, have been used as starting materials to develop concise syntheses of all four stereoisomers of carbapenam-3-carboxylic acid methyl esters <03JOC2889>. The synthesis of 1-methylcarbapenams 39 by intramolecular attack of lactam nitrogen on a 77 -propargylpalladium complex has been reported <03JOC8068>. 

A series of carbapenams have been generated using the sulfide-contraction reaction to construct the constituent -amino acid segment. The thiopyroglutamate derivative (143) was condensed with ethyl 2-bromoacetoacetate in the presence of sodium bicarbonate to afford the a-acyl vinylogous carbamate (144 Scheme 31). The use of sodium bicarbonate in the sulfide contraction was critical in this particular... 

In the chemistry of (3-lactam antibiotics, isolations of carboxylic acid derivatives are successfully achieved by formation of amidinium salts [56]. Lewis acid catalysed reaction of 4-substituted 1-trimethylsilyloxyfurans with 4-acetoxyazetidinone chiron leads to highly enantioselective construction of tricyclic carbapenam and penems, in which DBU (1) and Eshenmoser amidine (4) were used for the introduction of the exo double bond on the (3-lactam skeleton by demesylation (A route) and the isolation of carboxylic acids as... 

NitroaUcenes derived from -lactam aldehydes may be converted into diverse bicyclic -lactams via intramolecular Michael addition and ozonolysis (eq 8). The method is appropriate for penam, carbapenam, carbacephem, and oxapenam arrays. In some cases, (benzyloxy)nitromethane is a superior reagent. This Michael addition-oxidation strategy is also useful for the... 

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