Monobactam antibiotics synthesis

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 ... 

An in situ method for the preparation of N-methyleneamines has been devised by Overman and Osawa for use in condensation reactions with enolates and organometallic reagents. These species, with the exception of very hindered N-methyleneamines, cannot be isolated in the condensed phase because they rapidly trimerize to hexahydro-l,3,5-triazines. In this in situ method, A -methyleneamines (230) are generated from N-(cyanomethyl)amines (228) by deprotonation with an equivalent of enolate to give an intermediate amide (229) which loses LiCN (equation 22). When two equivalents of enolate are present, addition to the N-methyleneamine occurs and 3-lactams (233) are obtained in 60-70% yield upon warming the reaction mixture to 25 C (Scheme 48 Table 26). Uncyclized 3-amino esters can be isolated if the reaction is quenched at lower temperature a possible cycloaddition mechanism is thus ruled out. It is not clear to what extent, if any, the reaction is limited to a,a-disubstituted enolates. N-Methyleneamines, like oxime ethers, are useful for the synthesis of 4-unsubstituted 3-lactams and should also have important applications in the synthesis of monobactam antibiotics. 

The asymmetric synthesis of P-hydroxy-a-amino acids by various methods has been demonstrated [104-106] because of their utility as starting materials for the total synthesis of monobactam antibiotics. 

Another application of the Hantzsch process is found in the synthesis of a monobactam antibiotic, Tigemonam. The monobactams are follow-ups to the penicilMns, both families being unique as derivatives of azetidinones (beta-lactams). Tigemonam also possesses a thiazole ling, which component is synthesized as in Scheme 9.20 from thiourea (shown in the -SH tautomeric form) and the chloroketone 9.26. 

P-Hydroxy-amino acids (Figure 10.7) are multifunctional compoimds with valuable interest as intermediates for the synthesis of statine derivatives (106) [166-168], protease inhibitors [169], antivirals [170, 171], peptide mimetics [172], idulonic acid mimetics, for example, 3R,5R-dihydroxy-L-homoproline (111) [173], immimosup-pressive lipid mycestericin d (112) [174], 3,4-dihydroxyprolines (113) [175], (2S,3R)-2-amino-3-hydroxybutyrolactone, precursor of monobactam antibiotics [176], or L-ffereo-3-[4-(me ylthio)phenylserine] precursor of thiamphenicol (114), florfenicol (115) [177], sialyl Lewis x mimetics (117) [178], p-hydroxyomithine (109), a relevant building block for the p-lactamase inhibitor, clavulanic acid, and the antibiotic and anticancer acivicin [179], surveyed in previous reviews [41,57]. 

B. stearothermophilus LeuDH, yeast FDH, and NAD(H) [79]. Hanson et al. utilized a similar system consisting of B. sphaericus LeuDH, FDH, and NADH for the production of L-3-hydroxyvaline, which is a key intermediate needed for the synthesis of tigemonam, an orally active monobactam antibiotic [80]. The LeuDH catalyzes the reductive amination of 2-oxo-4-hydroxyisovalerate with a 41% of relative activity compared with the best substrate, i.e., 2-oxoisovalerate. 

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. 

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]. 

Synthesis in this field in recent times includes the synthesis of 4-alkylated monobactams123, of 101, a precursor of the antibiotic carumonam124, of monobactams... 

TBS-Protected D-lactaldehyde 961 is used as the chiral source for the synthesis of jS-lactam 969, a key intermediate in the synthesis of the antibiotic monobactam Aztreonam [254] (Scheme 131). The cmcial step in the synthesis, the reaction of A/-trimethylsilylimine 962 with the lithium enolate of STABASE (963), affords ra 5-j5-lactam 964 with 98% diaster-eoselectivity. Desilylation, Jones oxidation, and Baeyer—Villiger oxidation provides acetoxy jS-lactam 968, which in itself is a useful intermediate for the preparation of j5-lactam anti-... 

The f)-lactam class (penicillins, cephalosporins, monobactams, and carbapenems), exert their activity via inhibition of membrane-bound enzymes, resulting in interference with bacterial cell wall peptidoglycan synthesis. These enzymes are termed penicillin-binding proteins (PBPs) because of their ability to covalently bind f)-lactam antibiotics. ... 

Potent antibiotics [1] have been developed by systematic modifications of RS and X substituents of the naturally-occurring penicillins 1 and cephalosporins 2. Concomitantly, the intensive search for new microbial P-lactams has led to the discovery [1] of active compounds such as thienamycin 3, clavulanic acid 4 and monobactams 5 (Scheme 1). The non-classical structure of these compounds led to a re-evaluation of the structural requirements for biological activity, and to the synthesis of new classes of P-lactam antibiotics such as penems 6 [5], oxacephems 7 [6] and oxamazins 8 [7]. 

Further examination of the products of the organoiron reaction showed that the route was generally applicable to the synthesis of a range of pharmaceutically important P-lactam antibiotics which included thienemycin [273] (Scheme 130) and the monocyclic P-lactam systems of the nocardicins [274] (Scheme 131) and monobactams. 

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