P-lactams, cleavage

In addition to variable chemical stabiUty the carbapenems are susceptible to P-lactam cleavage by a dehydropeptidase en2yme (DHP-I) located on the bmsh borders of the kidney (53). Clinically, MK 0787 (18) is used with an inhibitor of this en2yme, cil a sta tin [78852-98-9] (MK 0791) (34), 16 26 2 5 dramatic effect not only on the urinary recovery of the drug, but also reduces any nephrotoxic potential (52) (see Enzyme... 

Solvolysis in MeOH/H20 at 21°C. This method was developed for a series of penicillin derivatives where conventional cleavage methods resulted in partial P-lactam cleavage. ... 

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. ... 

The stepwise process for P-lactam cleavage prior to loss of the C(3) leaving group generates the enamine [36] before the conjugated imine [37]. 

Oxidative cleavage of P-aminoacyl complexes can yield P-amino acid derivatives (320,321). The rhodium(I)-catalyzed carbonylation of substituted aziridines leads to P-lactams, presumably also via a P-aminoacyl—metal acycHc compound as intermediate. The substituent in the aziridine must have 7T or electrons for coordination with the rhodium (322,323). 

Benzyl- and Phenoxymethylpenicillins, Ampidllin, Carbenicillin Cephalosporin C Cephaloglycine, Cephaloridine, Cephalothin Hydrolysis Corresponding p-lactam ring cleavage products Escherichia coli Streptomyces aibus Pseudomonas aeruginosa Enterobacter cloacae Streptomyces sp. 

Studies using PM3 calculations of the alkaline hydrolysis of bicyclic P-lactam structures 82 (X = NNHCHO, 0, S) have shown that cleavage of the X-CO bond is the energetically favoured pathway both in the gas and solution phase <99MI287>. 

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]. 

The alcohol 177 was converted to starting substrates oxazolidinone 178 by acylation followed by reduction of the azide function along with cyclization. Oxazolidinone 178 was protected with f-butylpyrocarbonate-4-(dimethylamino) pyridine (DMAP) and triethylamine, which was further subjected to reductive cleavage of the benzyl ester unit to afford carboxylic acid 179. The treatment of 179 with solution of l-chloro-/V./V,2-trimethyl-1-propenv I airline resulted in the easy formation of the corresponding acid chloride which on reaction with imine in the presence of triethylamine provided the stereoselective formation of spiro-p-lactam 180. 

A multistep solid phase synthesis of (3-lactams with imines of benzaldehyde coming out from commercially available fluorinated a-amino acids has been reported in 2003 [77]. Using the Merrifield resin-bound imine [78, 79] in dichlor-omethane, the cycloaddition was carried out between -78°C and rt by addition of benzyloxyacetyl chloride in the presence of triethylamine. The resin cleavage using sodium methylate resulted in the two cis p-lactam derivatives (Scheme 20). 

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. 

In 2008, a very mild reductive N-O bond cleavage of fluorinated isoxazolidines was reported to provide a novel and general entry to p-lactams and ester of p-amino acids containing a trifluoromethyl group (Scheme 94), [210]. 

Scheme 114 Five-bond-cleavage rearrangement of O-propargyl oximes to P-lactams...

Scheme 5 Synthesis and subsequent cleavage of azetidin-2-one ring of bis-P-lactams...

Scheme 9 Enzymatic and chemical ring opening of P-lactams via N1-C2 bond cleavage...

Scheme 12 KCN-promoted cleavage of P-lactams leading to a,a-cyclic disubstituted P-mino esters 29...

Scheme 41 Cleavage of P-lactams ring with NaBELt...

Other strategies for the ring opening of p-lactams via Nx-C4 bond cleavage have seldom appeared in literature. Ahn [150] has reported the LDA-promoted ring enlargement of /V-benzyl p-lactams 194 to the corresponding /V-H y-lactams, Scheme 59. The reaction proceeds diastereoselectively to provide exclusively the ira ,v-4,5-disubstituted y-lactams 195. 

McMurray [151] has described the acid-assisted cleavage of the N]-C4 bond in trans 4-hydroxyphenyl p-lactams. The ring opening reaction may proceed with concomitant reduction or formation of carbon-carbon coupling products, as a function of the reagent employed. For instance, Scheme 60, treatment of 196 with 4 equivalents of triethylsilane in neat trifluoroacetic acid led to compound 197. On the contrary, treatment with anisole in trifluoroacetic acid led to compound 198. Unfortunately, no data are provided by authors regarding process yield or final diastereomeric ratio. 

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