P-Lactams, monocyclic

Monocyclic, Bicyclic and Tricyclic P-Lactams An Overview 2.1 Monocyclic P-Lactams... 

Several monocyclic p-lactams variously substituted have also been reported to have antibacterial activity against different strains of bacteria and with different mechanisms of action. 

The synthesis of monocyclic p-lactams via the ester-enolate imine condensation route has been reported to be carried out utilizing triazene esters (Scheme 54), [141], Esters were attached to benzylamine resin by a triazene linker employing the respective diazonium salts. Immobilized ester-enolates were reacted with various imines to give polymer-bound p-lactams in different substitution patterns. Traceless cleavage from the triazene linker yielded the desired p-lactams. 

Scheme 54 Solid phase synthesis of monocyclic P-lactam derivatives...

The Staudinger reaction has been extensively studied for the synthesis of monocyclic p-lactams (Scheme 4, e.g., 19 and 20) [37]. An imine 18, a tertiary base (triethylamine), and acid chloride 17 (or equivalent) are required for this reaction. 

The ability to produce synthetic P-lactam antibiotics that have not come from fermentation is of considerable advantage industrially because microbiological spores are not present, negating the use of a dedicated contained plant. Evans and colleagues have described the synthesis of 1-carbacephalosporins (89), which are useful intermediates in the production of monocyclic P-lactam antibiotics.83 A significant step during this procedure is the conversion of an acylaminoazetidinone 90 to a P-keto ester 91 by ozonolysis (Scheme 11.24). 

A recent paper explored the 1,2-functionalization of the allene moiety in monocyclic P-lactam allenynol derivatives under palladium-catalyzed reaction conditions <02CEJ1719>. Remarkably, a novel domino process, namely allene cyclization/intramolecular Heck reaction... 

The synthesis of dansyl amino penicillanic acid (DNS-APA, I) was carried out according to the procedure outlined in Ref. (8). The e-dansyl monocyclic p-lactam of lysine (II) prepared essentially as described for another monocyclic p-lactam (9). 

Table 4. Identification of PBPs and MGPS in Fraction I L Isolated from the Sequential F/S DNS-Monocyclic p-Lactam (II) and Treated E. coU Log Phase Cells. Parenthesis indicate possible but not confirmed by one or more peptides unique to the parenthetic protein.

S. Hanessian, S. P. Sahoo, C. Couture, and H. Wyss, Novel synthetic approaches to monocyclic p-lactam antibiotics. Bull Soc. Chim. Belg. 93 571 (1984). 

Exposure of an azirine to carbon monoxide in the presence of a catalytic amount of [Pd(PPh3)4] gives the bicyclic P-lactam (23) in reasonable yield. Attempts to synthesize monocyclic P-lactams from azirines has so far failed, but aziridines can be carbonylated to -lactams. )epending on the organome-tallic reagent used two different products can be obtained (Scheme 26). Using catalytic quantities of [Rh2(CO)4Ch] carbon monoxide inserts selectively into the more-substituted C—N bond, whereas using a stoichiometric amount of [Ni(CO)4] it is the less-substituted C—N bond that is carbonylated. ... 

Acylamino-2-oxoazetidine-l-sulfonates, or monobactams (96), are monocyclic p-lactam antibiotics which are active against Gram-negative bacteria.7 Monobactams (96) may be prepared by either sulfonation of an azetidinone (97) with a sulfur trioxide complex or by cydisation of an acylsulfamate (98) (Figure 6). 

Baldwin, J.E., Adhngton, R.M., Russell, A.T., and Smith, M.L., Carbon based nucleophilic ring opening of activated monocyclic P-lactams. Synthesis and stereochemical assignment of the ACE inhibitor WE-10129. Tetrahedron, 51, 4733, 1995. 

Li, L., Mao, S., Zhao, K. and Tian, A. (2001) Semi-empirical quantum chemical study on structure-activity relationship in monocyclic-p-lactam antibiotics. /. Mol. Struct. (Theochem), 545, 1-5. 

Aztreonam (Azactam) is a monocyclic p-lactam compound (a monobactam) isolated from Chromobacterium violaceum. 

The monocyclic p-lactam nocardicin, from Nocardia uniforms, was discovered using high phosphate media [98]. This antibiotic was the first compound of this chemical class to be discovered. Similar methods of high phosphate fermentation yielded the immunostimulant FK-156 from Streptomyces olivaceogriseus and S. violaceus [99], This antibiotic showed protection against bacterial infection, enhancement of humoral antibody formation, and anticancer activity in experimental animals. 

Further, the discovery of 7-a-methoxycephalosporins [5] from Streptomyces in 1971, carbapenems [6], thienamycin [7], clavulanic acid [8], sulbactum [9] as well as the totally synthetic oxapenems [10], oxacephams [11], and other bicyclic p-lactams stimulated the search for novel antibiotics. More recent dedicated efforts to find new active molecules and modify the penicillin and cephalosporin structure have resulted in the discovery of simple monocyclic p-lactams such as norcardicins and monobactams [12, 13]. Yet another dimension has been added to the p-lactam research with the recent discovery of tricyclic p-lactam antibiotics called trinems [14]. Thus, p-lactam antibiotics in general can be classified into several groups based on their structures (Fig. 1). 

The discovery of the norcardicins and monobactams demonstrated for the first time that a conformationally constrained bicyclic structure was not necessary for antibacterial activity of p-lactams [12, 13]. In recent years, various natural and unnatural monocyclic-p-lactams have been shown to exhibit high biological activity, suggesting that the biological activity of the particular ring is influenced by the type of substitution attached to the azetidin-2-one ring (Fig. 2). 

Burnett et al. [16] have reported monocyclic p-lactam I as a potent cholesterol absorption inhibitor in vivo, and this can inhibit the absorption of dietary... 

In 2003, Cainelli and coworkers have shown that monocyclic p-lactams substituted at the C-3, the C-4, and the N-1 positions are the most active in inhibiting LE and gelatinases MMP-2 and MMP-9 [340]. They have also reported that C-4 unsaturation on the p-lactam ring raised the inhibitory activity towards these proteases, with selectivity over LE by 3-[l-(ferf-butyldimethylsilyloxy)ethyl] derivatives, and over the gelatinase MMP-2 by C-3-unsubstituted 4-[l-ethoxycarbonyl]... 

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