Carbapenem carboxylic acids

ANTIBIOTICS 0-LACTAMS. In the period up to 1970 most 0 lactam research was concerned with the penicillin and cephalosporin group of antibiotics. Since that time, however, a wide variety of new mono- and bicyclic 0-lactam structures have been described. The carbapenems, characterized by the presence of the bicyclic ring system (I. X =( H0 originated from natural sources the penem ring (1. X =S) and its derivatives are the products of the chemical synthetic approach to new antibiotics. The chemical names are 7-oxo-(R)-l-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid. C7H7NO3, and 7-oxo-(7J)-4-t Ilia-1 -azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid, 0,H5NO ,S. respectively. 

Analysis of energy-minimized conformations generated using a 1000-step Monte Carlo conformational search with the AMBER force field by use of a MacroModel (version 3.5) demonstrates that both the benzothiazole ring and the carboxylic acid moieties of carbapenem 7 could be overlapped with those of 3-benzothiazolethiocephem <1997BMC601>. 

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... 

Carbapenem SQ 27860 (5i )-7-oxo-l-aza-bicyclo[3.2.0]hept-2-ene-2-carboxylic acid, 5 was the first carbapenem antibiotic produced by bacteria. It shows a wide antibacterial spectrum and it is unstable, but it can be characterized as its p-nitrobenzyl ester. (-l-)-Thienamycin (6), 8-ep/-thienamycin (7), olivanic acids " and (- -)-PS-5... 

Through this approach formation of chiral P-hydroxy carboxylic acids with appropriate carbon frameworks is the key step of the method. Evans [92] reported an asymmetric synthesis of the carbapenem PS-5 in which the two stereocenters of the P-lactam ring were efficiently established via an asymmetric aldol addition reaction (Scheme 34). In this approach, the boron enolate 214 was... 

It is worth mentioning that the pyrrolidine intermediate 43, through tautomeriza-tion followed by ring closure and driven by the hydrolysis of the thioester bond, would yield carbapen-2-em-3-carboxylic acid, the simplest carbapenem 53 [75]. 

Alternatively, the acidity of the aldehyde-derived CH or CH2 group can be enhanced by converting the isocyanide derived amide into an ester. According to this principle, tandem Ugi-Dieckmann was exploited in the context of carbapenem synthesis, where the first 4-membered ring was built through an intramolecular Ugi reaction of p-amino acid 66. Then, after a three-step manipulation of the carboxylic appendages, a Dieckmann cyclization afforded, stereoselectively, the desired carbapenem skeleton 67 [79]. 

A stereoselective synthesis of 6-amino acid derivatives by an aldol-type condensation of tin(II) carboxylic thioester enolates with imines has been reported (Scheme 90) the method was used to synthesize an intermediate of the carbapenem antibiotic... 

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