Oxidation of P-lactams

Reaction of these antibiotics with chlorine mostly generated chlorinated and OH-substituted by-products [86, 87]. Unlike fluroquinolones, whose quinolone ring is left mostly intact, disinfection with CIO2 may diminish the antibiotic capacity of tetracyclines because it leads to cleavage of the tetracyclines ring system [86,88]. On the other hand, oxidation of p-lactam antibiotics such as penicillin, amoxicillin, and cefadroxil with CIO2 leads to the formation of hydroquinone and a wide range of substituted phenols [89]. 

Aerobic oxidation of P-lactams can be performed highly efficiently in the presence of acetaldehyde, an acid, and sodium acetate [119]. Typically, the RuCls-catalyzed oxidation of P-lactam 54 with molecular oxygen (1 atm) in the presence of acetaldehyde and sodium carboxylate gave the corresponding 4-acyloxy p-lactam 55 in 91% yields (de >99%) (Eq. (7.72)). This aerobic oxidation shows similar reactivity to the ruthenium-catalyzed oxidation with peracetic acid. 

Ring opening of p-lactams at C2-C3 with application in peptide synthesis was first reported on a-keto p-lactams 126 ([116] for applications of a-keto p-lactams, see [117]), Scheme 42. These p-lactams, readily available via oxidation of 3-hydroxy p-lactams 125, undergoes a Baeyer-Villiger reaction upon exposure to m-CPBA and affords /V-carboxy a-amino acid anhydrides (NCAs) 127 [118]. Shortly after, it was discovered that a more direct, one pot route to these NCAs is feasible by treatment of 3-hydroxy p-lactams with a solution of commercial bleach... 

The method is useful for synthesis of five-, six- and seven-membered lactams, but not of P-lactams or macrolactams. The bridged lactam 2 was obtained from 1 in 77% yield by reaction with di-n-butyltin oxide. 

Moreover, intracellular accumulation and cytochrome P450 catalyzed bioactivation of p-lactams such as cephaloridine overwhelms of the GSH redox cycle by inhibiting glutathione reductase activity [35, 56], depletion of GSH and accumulation of GSSG [35, 42, 49,56]. Most of GSSG formed is subsequently reduced by glutathione reductase and GSH is regenerated with concomitant oxidation (consumption) of NADPH to NADP+ [104]. 

It has been shown that the renal bioactivation of xenobiotics such as the herbicides paraquat and diquat [10, 111, 112], and of p-lactams such as cephaloridine and cefsulodin [10, 40, 41] or the antitumor agent adriamycin [113, 114] can induce the generation of reactive oxygen species (oxidative stress) which can be involved in alterations of the structure and functions of cell membranes, cytoskeletal injury, mutagenicity, carcinogenicity, and cell necrosis [115-117]. 

Although the mechanism(s) of p-lactam-induced nephrotoxicity is not fully elucidated, there is growing evidence that for some of the p-lactams, oxidative stress plays a pivotal role in the chain of events leading to nephrotoxicity and cell death [10, 34, 40]. 

Kawabata T, Minami T, Hiyama T (1992) Stereoselective synthesis of P-lactams by oxidative coupling of dianions of acyclic tertiary amides. J Org Chem 57 1864-1873... 

The asymmetric synthesis of c -3,4-disubstituted P-sultams 65, based on the oxidation of 1,2-aminothiols with H2O2 and ammonium heptamolybdate has been achieved <05S1807>. Different transition-state structures for the reactions of P-lactams and their sulfonyl analogues P-sultams with serine P-lactamases have been reported <05JA17556>. It has been discovered that the 3-oxo-P-sultam 66 is unusual in that it inhibits elastase by acylation resulting from substitution at the carbonyl center, C-N fission, and expulsion of the sulfonamide <05JA8946>. 

There are only a few reports in the literature on the use of isothermal microcalorimetry for the stability testing of pharmaceuticals (although in other fields, such as explosives, there are many more references testifying to a good degree of success). These include the degradation of P-lactam antibiotics (7), the oxidation of lovastatin (8), the hydrolysis of meclofenoxate hydrochloride (9), and the oxidation of d,l-a-tocopherol (10). 

Bose and coworkers have reported that the condensation of ethyl biomoacetate with a variety of imines can be completed in a few hours at room temperature by means of ultrasound activation. Oxidative removal of a N-(p-methoxyphenyl) group gave )V-unsubstituted P-lactams, which are useful intermediates in the preparation of p-lactam antibiotics (Scheme 18). 

Radical cations of triaiylamines are known to be single electron transfer oxidizing agents. Very recently, these substances have been used as efficient mediators for gcm-difluorodesulfurization as shown in Scheme 56. ° Furthermore, triarylamines have recently been shown to be highly effective mediators for monofluorodesulfurization of P-lactams. Severe passivation of the anode takes place during anodic fluorination of P-phenylthio- P-lactams, which is quite different from the case of a-phenylthio-P-lactams 60. However, selective anodic fluorodesulfurization proceeds efficiently without passivation when tris(2,4-dibromophenyl)amine is employed as a mediator as shown in Scheme 57. ... 

The methods based on the selective oxidation were reported for penam and cephem analogs containing phenolic substitutes at C6 and C7, respectively. These methods permitted also selective determination of (3-lactam analogs in the presence of excipaents being in their pharmaceutical preparations. The application of oxidation properties of iron ions was used in analysis of a huge number of P-lactam analogs ... 

The reduction of oxidized quercetin by cephem analogs was used in development of visible spectrophotmetric method for determination of P-lactam analogs. Quercetin is a flavonol (3,5,7,3, 4 - pentahydroxyflavone) which is oxidized by N-bromosuccinimide giving reddish green colour (Xmax = 510 nm). As the result of reduction of oxidized form of quercetin by cephem analog fade colour was observed (Fig. 9). This colour is the result of formation of o-quinone derivative of quercetin under the mild oxidants [34],... 

For determination of phenolic derivative of P-lactam analog (cefadroxil) measurement of absorption of formed product in the reaction between it and 4-aminoantipyrine in the presence of alkaline potassium hexacyanoferrate(III) at 510 nm was also proposed (Fig. 16). Potassium hexacyanoferrate(III), being oxidant in this reaction, yielding N-substituted quinine imines and in the result was responsible for formation of red-colored antipyrine dye. Additionally, a sequential injection analysis (SIA) spectrophotometric procedure for the determination was reported [52]. 

The synthesis of p-lactams unsubstituted on nitrogen also cannot be accomplished directly due to the instability of most imines derived from ammonia. However, imines derived from 4-methoxyaniline and 4-ethoxyaniline readily afford A/-aryl p-lactams cleavage of the A-aryl bond is accomplished by oxidation with ceric ammonium nitrate. A-Trimethylsilyl imines have also been used to provide NH P-lactams. ... 

Concurrent with the above, a group at the Squibb Institute (Gordon et al., 1977, 1980) independently reported a different approach to 7(6)-a-methoxylation of p-lactams, which also relied upon sulfenimines as key intermediates. These workers found that reaction of amine esters with 3 equiv of toluenesulfenyl chloride or methylsulfenyl chloride in methylene chloride containing propylene oxide-molecular sieves to act as an acid scavenger, afforded sulfenimines 230-232 in about 80% yield. This reaction presumably proceeds by successive sulfenylation of amine... 

Interest in the monobactams has prompted the publication" of a new synthesis of p-lactams. Ganem and co-workers have developed methodology which leads efficiently to four-membered lactams under kinetic control. Thus, the oxidative cyclization of Pyunsaturated amidosulphamoyl esters (69) (and related structures) affords A -sulphonylhalo-P-lactams (70) which are readily dehaJogenated. 

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