Lactam ring opening

The anticancer activity of complex natural products having a cyclodecenediyne system [for a review see <96MI93>] has prompted the synthesis of 54 (X = CH2 and OCH2) <96CC749> and 55 (R = a-OH and p-OH) <95AG(E)2393> on the basis that such compounds are expected to develop anticancer activity as the P-lactam ring opens. This is because cycloaromatization can only occur in the monocyclic enediyne and the diradical intermediate in the cyclization is thought to be the cytotoxic species. 

Scheme 2.76. MeLi-induced p-lactam ring-opening/intramolecular cyclization leading to anatoxin-a (2-326).

Cephalosporins such as cefixime (5.40) and cefotaxime (5.41) undergo epimerization at C(7) under alkaline conditions without preliminary /3-lactam ring opening. The epimerization is believed to begin with the removal of the acidic H-atom at C(7). The acidity of this proton derives from the resonance effect of the neighboring carbonyl group (Fig. 5.13) enhanced by the presence of electron-withdrawing substituents at C(3 ) [113][114],... 

Imipenem (5.46) has not completely fulfilled such expectations [122], Indeed, this compound is unstable in both acidic and alkaline media. In weakly acidic solutions, imipenem undergoes complex oligomerization, a reaction initiated by the intermolecular attack of the carboxy group on the /3-lactam Fig. 5.17) and yields, finally, a diketopiperazine compound. In weakly alkaline solution, an intermolecular reaction between the /3-lactam and (iminome-thyl)amino group was observed Fig. 5.18). This reaction proceeds via an unstable dimer that breaks down to thienamycin (5.45) and a /3-lactam ring-opened compound bearing a Ai-formyl group [123],... 

The first carbapenem released for clinical use was imipenem (5.46), a compound with relatively high resistance to microbial /3-lactamases. The addition of the (iminomethyl)amino side chain renders imipenem chemically more stable than thienamycin. But, like thienamycin, imipenem is also easily hydrolyzed by renal dehydropeptidase I, producing a mixture of /3-lactam ring-opened 1-pyrrolidine epimers at C(3) [161], The renal metabolism of imipenem can be minimized by co-administration of cilastatin (5.53), a competitive inhibitor of DHP-I [15 6] [162],... 

Hydrolytic cleavage of a seven-membered ring occurs in the metabolism of chlordiazepoxide (5.82, Fig. 5.22,a) and other benzodiazepines (see also Sect. 11.9). The lactam ring opened metabolite 5.83 was detected in humans and dogs and is believed to be generated by hydrolysis of the intermediate lactam [181][182], However, the diazepine ring can be split by other mech-... 

Y. Okamoto, K. Kiriyama, Y. Namiki, J. Matsushita, M. Fujioka, T. Yasuda, Degradation Kinetics and Isomerization of Cefdinir, a New Oral Cephalosporin, in Aqueous Solution. 2. Hydrolytic Degradation Pathway and Mechanism for beta-Lactam Ring Opened Lactones , J. Pharm. Sci. 1996, 85, 984-989. 

All penicillins are susceptible to attack in acidic solution via intramolecular attack of the amide carbonyl oxygen on the (3-lactam carbonyl, leading to the complete destruction of the (3-lactam ring, and thus the antibacterial activity. Similarly, penicillins are unstable in basic solution because of (3-lactam ring opening by free basic nucleophiles. Thus, for the antibacterial activity, the stability of the (3-lactam functional group in penicillins is of paramount importance. 

S-Lactam Ring Opening A Useful Entry to Amino Acids... 

Although no conclusive evidence has been found yet for this assumption, it is postulated that the p-lactam opening reactions promoted by CN- or N3 -containing additives proceed via an acyl azide or an acyl cyanide intermediate. The mode of action of some p-lactamases and the fact that no p-lactam ring opening usually takes place in the absence of such additives support this hypothesis. 

Scheme 31 Access to phytosphingosines through P-lactam ring opening by lithiated sulfones...

Scheme 36 (3-lactam ring opening with Li-enolates of esters. An access to the hydroxy (keto) ethylene dipeptide isostere... 

Scheme 39 Synthesis of anatoxin-a precursor 118 via MeLi mediated [3-lactam ring opening...

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