JS-Lactams

The last comprehensive review of the chemistry of oxazolones covered the literature through 1954. Most of the studies up to that time stemmed from either interest in the role of azlactones as precursors of a-amino acids and peptides or the monumental studies on penicillin, which, for a time, was thought to possess an oxazolone ring, rather than the correct jS-lactam moiety. 

The Lewis acid induced reaction of silyl enol ethers and silyl ketene (thio)acetals with 4-acetoxyazetidinones is often used for introduction of a carbon substituent in the 4-position of the jS-lactam ring. Numerous examples are known, both with and without substituents at nitrogen, some of which are shown. 

Many peptide antibiotics have novel structural motifs, such as cyclic structures and are often further modified, (such as in jS-lactamic antibiotics) and conjugated with sugars, lipids, and other molecules. 

Photolysis of a-diazo-amides to produce cw-/ -lactams has provided a route to the synthesis of new types of jS-lactam antibacterial agents<39) ... 

Kinetic studies of the unnatural 6-a -epimer of ampicillin, fi-ept-ampicillin (154), have revealed an intramolecular process not undergone by ampicillin (or other natural /3-substituted penicillins) At pH 6-9, intramolecular attack of the jS-lactam carbonyl group by the side-chain amino group of (154) yields a stable piperazine-2,5-dione derivative (155). Theoretical calculations show that the intramolecular aminolysis of 6-epi-ampicillin nucleophilic attack occurs from the a-face of the -lactam ring with an activation energy of 14.4kcalmor In other respects, the hydrolysis of the b-a-epimer is unexceptional. 

The reduction of (2,3)-q - and (2,3)-jS-methylenepenam j6-sulfoxides to the corresponding sulfides using potassium iodide and trifluoroacetic anhydride (TFAA) is found to be much faster than for bicyclic jS-lactam jS-sulfoxides.- In the proposed mechanism, initial attack of the sulfoxide oxygen on TFAA is followed by rate-limiting, nucleophilic displacement of trifluoroacetate by iodide ion nucleophilic attack of iodide on the iodine atom then yields the sulfide and iodine. The rate enhancement is accounted for by the stabilization of the transition state in the rate-limiting step by interaction of the p-like orbital of sulfur and the cyclopropane a orbital. 

Condensation with imines to afford jS-lactams. These latter ones can also be obtained by cycloaddition of the same imines with the keten stemming from fluoroacetyl chloride. ... 

Conversion of /3-lactam-N-sulfonyl chlorides to the free lactams may also be accomplished by means of reducing agents,3 and for jS-lactam-N-sulfonyl chlorides which are hydrolytically more... 

I. Panfil, C. Belzecki, and M. Chmielewski, An entry to the optically pure jS-lactam skeleton based on 1,3-dipolar cycloaddition of nitrones to 4,6-di-0-acetyl-2,3-dideoxy-D-t/ireo-hex-2-enono-l,5-lactone, J. Carbohydr. Chem., 6 (1987) 463 170. 

Another indolizidinedione, the 2,3-isomer 236, synthesized by a standard Dieckmann procedure, was converted by periodate into the jS-lactam 237, which has been patented as an intermediate in penicillin or cephalosporin syntheses.273,274... 

General procedure for the reduction of N-chlorosulphonyl [3-lactams with sodium sulphite. A solution of IV-chlorosulphonyl jS-lactam dissolved in ether is added slowly to a stirred mixture of about two parts of 25 per cent aqueous sodium sulphite and one part of ether. The aqueous phase is kept slightly basic by addition of 10 per cent potassium hydroxide solution as the reduction proceeds. The reaction course could easily be followed by t.l.c. in which the product has a considerably smaller RF value than the starting material. At the end of the reaction (usually less than 15 minutes) the ether layer is separated and dried and evaporated. The products are of greater than 95 per cent purity as determined by p.m.r. spectroscopy. The reaction may be carried out at 25 °C or at 0°C. 

The formation of the azetidin-one ring is by a [2 + 2] imine-acid chloride cycloaddition via the insitu formation of methoxy ketene. Other jS-lactams have been prepared using this route (1) as illustrated in Eq. 1. Spiro[3.5] jS-lactams have also been prepared in this manner and are discussed (2). 

Cefazolin is the best-studied antibiotic and is thus the drug of choice. For hip fracture repairs and joint replacements, it should be administered for 24 hours. Vancomycin is not recommended unless a patient has a history of jS-lactam hypersensitivity or the propensity for MRSA infection at the institution necessitates its use. 

Carbodiimides are exceedingly useful compounds in organic synthesis. Of particular significance is their use as dehydrating agents in the synthesis of jS-lactam antibiotics. 

S-Hydroxy-l-azetidinones. A biomimetic synthesis of the y3-lactam 4 from BOC-L-serine (1) has been reported. The protected serine derivative is converted into the hydroxamic acid 2 by condensation with O-benzylhydroxylamine mediated by the water-soluble l-ethyl-3(3 -dimethylaminopropyl)carbodiimide (1, 371). The product is cyclized directly in high yield to the / -lactam 3 by treatment with diethyl azodicarboxylate and triphenylphosphine. No racemization is observed. Deprotection by catalytic hydrogenation gives the N-hydroxy-jS-lactam 4. Previous biomimetic syntheses of 2-azetidinones have involved cyclization ot /3-cMoroamides with sodium hydride (e.g., 7, 335). 

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