Of carbapenam

Aspects of the natural occurrence, biosynthetic pathways, and preparation by biosynthesis of carbapenams, carbape-nems, oxapenams, trinems, and related compounds have been reviewed <1997MI281, 1999MI335, 2004RMC69>. References to earlier reviews are given in CHEC-II(1996) <1996CHEC-II(1B)659>. 

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-... 

This reaction has been applied to the synthesis of carbapenam skeletons [69] (Eq. 52). 

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... 

Because of the extraordinary interest of carbapenam antibiotics several other approaches have been described for their formal or total synthesis. For example, appropriately substituted 3-[(/ )-l-hydroxyethyl)] P-lactams have been synthesized from a 1,3-dipolar cycloaddition of nitrones with crotonates [103]. Formation of P-amino-8-lactones 261 (Fig. 8), and their transformation into carbapenems 259 have also been reported [104]. 

Diastereoselective Cyclization Important intermediate for preparation of carbapenam antibiotics was synthesized by electrochemical intramolecular carbon-carbon bond forming reaction (Scheme 8) [9]. In this cyclization, (l )-phenylethyl group works as a good chiral auxiliary. 

An intramo leculdf Michael type reacdon of a nitrogen nucleophile to nitro ilkene, as shown n Eq 4 31, provides a useful raethod fci the ptepa ancn of 3,3-dimethyl-l-carbapenam ... 

An intramolecular Michael type reaction of a nitrogen nucleophile to nitroalkene, as shown in Eq. 4.31, provides a useful method for the preparation of 2,2-dimethyl-l-carbapenam.37... 

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). 

Penicillins replacement of thiazoline S-atom with CH2 (carbapenam) C-S-C Angle smaller, C-S bond length longer => more ring strain, but leaving group is more basic Increased ca. 3-fold... 

The interception of suitably substituted Dewar pyridinones (IV-alkyl-3-oxo-2-azabicyclo[2.2.0]hex-5-enes) is increasingly being exploited as a route to novel /3-lactams (Scheme 223) (81JCS(P1)2620). In another approach, 4-methoxypyridin-2-one has been used as a source of substituted azetidin-2-one (306) which is a precursor of potential carbapenam antibiotics (Scheme 224) (82H(19)89). 

Carbapenams (V, Fig. 6) have been produced by warming a solution of (3-lactams having a propargyl carbonate moiety linked at the C-4 position [253]. 

When the propargyl phosphate 225 was heated in the presence of Pd2(DBA)3-CHCl3 and sodium acetate in THF, the central sp carbon atom of the (j-allenylpalladium complex, formed from the propargyl alcohol ester and Pd(0), was attacked by the lactam nitrogen atom to yield the carbapenam 226 with an exocyclic methylene group <2001TL4869>. 

Intramolecular aldol condensation reaction of 272, brought about by the action of lithium hexamethyldisilazene on the acidic methylene group, produced the carbapenam 273 where Wra t-isomerization of the /3-lactam component has occurred <1996JOC7125>. 

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... 

By the Fp-assisted cyclization of y,<5-unsaturated imines, substituted carbapenams were prepared, with overall low yield and low diastereoselectivity34,35. 

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