Monocyclic 2-azetidinones

Lactam antibiotics are bicyclic or monocyclic azetidinone ring-containing compounds (Fig. 1). They kill bacteria by preventing the assembly of (4-3) peptidoglycans. These covalently closed net-like polymers form the matrix of the cell wall by which the bacteria can divide and multiply, despite their high internal osmotic pressure. 

In monocyclic -lactams (termed monobactams) the activation is achieved solely by electronic effects. X-ray crystallographic data indicate that there is no steric activation since the azetidinone ring is planar with the sulfonate residue lying within the plane. Electron withdrawal by the sulfonate group is... 

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 ... 

I.I.I.3.3.2.2. Alkylation of Monocyclic Lactams Monocyclic /1-Lactams (2-Azetidinones)... 

The synthesis of bicyclic 2-azetidinones 154 has been accomplished by ringclosing metathesis reaction of monocyclic diene- and enyne-(3-lactams. The enyne metathesis of compounds 153 afforded bicycles 154 in good yields (Scheme 52) [92]. 

They have also reported a direct route to optically pure, fused, or bridged tricyclic (3-lactams (III and IV, Fig. 18) as further advances in the intramolecular nitrone-alkene cycloaddition reactions of monocyclic 2-azetidinone-tethered alkenyl-aldehydes [289]. 

Enamine 107 and monocyclic lactam 222 were formed by the cleavage of C(3)—C(4) and N(l)—C(4) bonds of hydroxy azetidinone derivative 652, respectively. An increase of solvent polarity alters the relative ratio of the C(3)—C(4) to N(l)—C(4) bond cleavage. Hydroxy azetidinone derivative 652 was formed from azetidinyl cation 647 by nucleophilic attack by water. 

The intramolecular nitrone-alkene cycloaddition reaction of monocyclic 2-azetidinone-tethered alkenyl(alkynyl) aldehydes 211, 214, and 216 with Ar-aIkylhydroxylamincs has been developed as an efficient route to prepare carbacepham derivatives 212, 215, and 217, respectively (Scheme 40). Bridged cycloadducts 212 were further transformed into l-amino-3-hydroxy carbacephams 213 by treatment with Zn in aqueous acetic acid at 75 °C. The aziridine carbaldehyde 217 may arise from thermal sigmatropic rearrangement. However, formation of compound 215 should be explained as the result of a formal reverse-Cope elimination reaction of the intermediate ct-hydroxy-hydroxylamine C1999TL5391, 2000TL1647, 2005EJ01680>. 

Cyclization of bromoarenes 34 gave the benzocarbapenems 35 and benzocarbacephems 36, which were obtained as single stereoisomers. The process is remarkably independent of the nature of the substituent at C-3 of the azetidinone ring and measurements of in the carbapenem showed that the relative stereochemistry present in the monocyclic azetidinone is retained in the cyclized product (also see Chapter 2.01). Nuclear Overhauser effect (NOE) experiments showed that the ethyl group in the carbapenem at C-l had a ry -configuration with H-5 so that H-l must have the //-configuration <1996TA2203>. 

Opening of the fused ring of a bicyclic azetidinone has sometimes been used as a method of obtaining a monocyclic /3-lactam of known stereochemistry. Ozonolysis of the unsaturated a-D-glucopyranosylamine 149 yielded a /3-lactam ISO, which was useful in the synthesis of carbapenems and carbacephems <2000PJC1243>. 

An efficient use of triphosgene, as an acid activator, for the synthesis of substituted 2-azetidinones via ketene-imine cycloaddition reaction using various acids and imines has been achieved <02T2215>. Novel routes to monocyclic (3-lactams 13 and 14 through the photochemical decomposition of oxime oxalate amides <02CC2086> and a-oxoamides <02OL1443> have also been described. 

The importance of j -lactams in the penicillins , cephalosporins , thienamycin and the recent discovery of antibiotic activity among monocyclic j -lactams such as norcardicins or the )5-lactamase inhibitor clavulanic acid have recently intensified research toward the synthesis of this system . Among the different procedures that have been developed for incorporating a 2-azetidinone unit , the ring expansion of cyclopropanol amines provides a simple and convenient route to these attractive small ring compounds. 

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). 

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 structural modifications at the N-l and C-4 positions of the azetidinone ring on biological activity. In contrast to the bicydic p-lactams, these positions on the monocyclic ring system are readily accessible by synthesis. 

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