Antibiotics monobactam

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 ... 

Aztreonam lysine (29 Cayston ) Aztreonam (29) Monobactam antibiotic NP-deiived Microbial Antibacterial Inhibits bacterial cell wall synhiesis 312-318... 

D. Marini, F. Balestrieri, and A. Sacchini, Characterization and assay of a new monobactamic antibiotic aztreonam, Boll. Chim. Farm., 724 218 (1985). 

In some cases, the standard conditions for removing phthalimides can be applied to p-lactams as illustrated in Scheme 8,5.11 However, attempts to remove a phthalimide function from the monobactam antibiotic Nocardtcinic acid failed... 

R. B. Sykes and D. P. Bonner, "Monobactam Antibiotics History and Development," in J. D. Williams and P. Woods, Eds., Aztreonam, The Antibiotic Discovery for Gram-negative Infections, Royal Society Medicine International Congress Symposium Series No. 89, Royal Society Medicine, London, 1985, pp. 3-24. 

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. 

Aztreonam, a monobactam antibiotic (500 mg to 2 g IV or IM q. 8 to 12 honrs), is indicated in the treatment of nrinary tract, respiratory tract, intra-abdominal, gynecological, or skin infections or septicemia caused by Gram-negative bacteria (see Fignre 74). 

Aminations which afford 6-aminocarboxylates are of interest in relation to monobactam antibiotics. A secondary aminomethyl group can be introduced at the -position of carboxylic esters by reaction of hexahydro-1,3,5-triazines with ketene silyl acetals in the presence of a catalytic quantity of trifluoromethanesulphonic acid (Scheme 25). The triazine (10) is considered to be converted into an N-silylated methyleneiminium salt which undergoes addition of the ketene silylacetal (11). 

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. 

Frumin J, Gallagher JC. Allergic crosssensitivity between penicillin, carbapenem, and monobactam antibiotics what are the chances Ann Pharmacother 2009 43(2) 304-15. 

As stated in Section 3.1, the first members of this class were nocardicins produced by the strains of Noncardia and Streptomyces. Several monocydic P-lactams containing heteroatom substituents were investigated thereafter for antibacterial activity. Naturally occurring monobactams, however, had only weak antibacterial activity. The only currently available monobactam antibiotic is aztreonam. A monocyclic P-lactam tabtoxin (Figure 3.2), which is a dipeptide esrotoxin, is... 

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. 

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