Monobactams, synthesis

In an application to asymmetric monobactam synthesis. Overman and Osawa observe a high level of 1,4-diastereofacial selectivity in the reaction of (5)-cyanoamine (235) with the enolate of STABASE-protected glycine ester (234), affording diastereomeric 3-amino-2-azetidinones (236) and (237) in a 10 1 ratio, respectively, and in 65% yield (Scheme 49). Based on the (E)-enolate geometry of glycine ester (234), determined in trapping experiments with TMSCl, the authors postulate a chelated, chair-like transition state (238) that is consistent with the observed stereoselectivity. 

Fig. 1. Synthesis of C-3 side chain analogues of monobactams, where P is an amine protecting group and other terms are defined in text.

All of the naturally-occurring monobactams discovered as of this writing have exhibited poor antibacterial activity. However, as in the case of the penicillins and cephalosporins, alteration of the C-3 amide side chain led to many potent new compounds (12). Furthermore, the monobactam nucleus provides a unique opportunity to study the effect of stmctural modifications at the N-1 and C-4 positions of the a2etidinone ring on biological activity. In contrast to the bicycHc P-lactams, these positions on the monocyclic ring system are readily accessible by synthesis. 

A second, conceptually distinct chiral synthesis of monobactams was developed from P-hydroxy amino acids. As shown in Figure 2, cycli2ation of the acylsulfamate of an amino-protected 0-mesylserine derivative (14, R = H) leads directiy to the monobactam (15). This methodology was also appHed to the synthesis of 4a- (15, R = CH ) and 4P-methyl monobactams from L-threonine and aHothreonine, respectively (17). The... 

Although the activity of methoxylated monobactams could be improved by appropriate side-chain modifications, difficulty of synthesis and poor chemical stabihty focused attention on the nonmethoxylated analogues. Both high intrinsic activity and excellent P-lactamase stabiUty are exhibited by monobactams that combine C-3 arninothia2ole oxime side chains and 4-alkyl, 4-alkenyl, and 4-alkynyl groups (19). 

Fig. 2. Synthesis of clinically useful monobactams where R = H, CH P is an amino protecting group, and Mes = mesyl is methanesulfonyl.

Lactams Penicillins Cephalosporins Monobactams Carbapenems Vancomycin Bacitracin Cycloserin Fosfomycin Inhibition of synthesis of, or damage to, cell wall... 

Monocyclic azetidinones are useful building blocks in organic synthesis. Besides the wide use in the syntheses of monobactam antibiotics and nuclear analogues of natural bicyclic p-lactam antibiotics,1 2 3 new applications have appeared with the syntheses of unnatural a-amino acids, amino sugars4 and inhibitors of elastase.5 ... 

Beta-lactam antibiotics are a second great class of antibacterials penicillins, cephalosporins, carbapenems, and monobactams. They act by inhibiting bacterial cell wall synthesis. 

Pharmacology Aztreonam, a synthetic bactericidal antibiotic, is the first of a class identified as monobactams. The monobactams have a monocyclic -lactam nucleus. Aztreonam s bactericidal action results from the inhibition of bacterial cell wall synthesis because of a high affinity of aztreonam for penicillin-binding protein 3 (PBP3). 

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. 

Mechanism of Action A monobactam antibacterial that inhibits bacterial cell wall synthesis. Therapeutic Effect Bactericidal. 

Cell-wall synthesis inhibitors Penicillins Cephalosporins Monobactams Carbapenem Vancomycin Cycloserine... 

S. Hanessian, C. Couture, and H. Wyss, Design and reactivity of organic functional groups. Utility of imidazolylsulfonates in the synthesis of monobactams and 3-amino nocardicinic acid, Can. J. Chem. (55 3613 (1985). 

Jarrahpour et al. [135] have described the synthesis of novel mono- and bis-spiro-[S-lactams 231 and 233, respectively, from benzylisatin 229 (Scheme 52). The starting substrate, benzylisatin 229 was prepared by reaction of isatin 228 with benzyl bromide and calcium chloride in DMF. The benzylisatin substituted imines 230 and di-imines 232 were further subjected to Staudinger reaction with ketenes derived from methoxy, phenoxy, and phthaloglycyl chlorides to afford novel mono- and bis-spiro-p-lactams 231 and 233, respectively. The configuration of benzylisatin 229 and monocyclic spiro-p-lactams 231 was established by X-ray crystallographic studies. These spiro-p-lactams will be studied as precursors of modified p-amino acids, (3-peptides and monobactam analogues. 

The development of efficient routes to synthesize (3-lactams is an area of significant research interest [41 -5]. This has been driven, in large part, by the importance of these molecules as constituents of antibiotics, ranging from penicillin-based substrates to a number of more recently developed compounds (e.g., penems, cephems, monobactams, carbapenems, and trinems) [46-51]. (3-Lactams have also been demonstrated to be important synthons in organic synthesis (Fig. 1) [52,53] and to be monomers in the generation of polyamides [e.g., poly((3-peptides)] [54, 55]. 

The monobactams, of which aztreonam [az TREE oh nam] is the only commercially available example, are unique because the p-lac-tam ring is not fused to another ring (Figure 30.9). Monobactams also disrupt cell wall synthesis. The drug s narrow antimicrobial spectrum precludes its use alone in empiric therapy (p. 279). Aztreonam is resistant to the action of p-lactamases. 

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