13- Lactam reactivity

Fig. 2. Cephalosporin P-lactam reactivity where Nu is a nucleophile and X is a leaving group (a) path followed for nucleophiles (b) when Nu is the serine OH of an enzyme (ie, Nu = Enz Ser OH) deacylation may precede expulsion of the leaving group and both pathways (a) and (b) may be observed.

Boyd DB, Herron DK, Lunn WHW, Spitzer WA. Parabolic relationships between antibacterial activity of cephalosporins and beta-lactam reactivity predicted from molecular orbital calculations. / Am Chem Soc 1980 102 1812-14. 

In most cases, transformations at the C-7 position involve the /3-lactam ring opening due to the geometric strain it represents and its limited amide resonance . Except from a biological point of view, where the /3-lactam reactivity finds its interest (see Sections 2.03.5.2 and 2.03.12), it is mainly the nucleophilic attack that leads to opened carboxylic derivatives, as in the aminolysis shown in Scheme 16 <2006TL1737>. 

Parabolic Relationships Between Antibacterial Activity of Cephalosporins and P-Lactam Reactivity Predicted from Molecular Orbital Calculations. 

Bundgaard H (1974) Spectrophotometric determination of ampicillin sodium in the presence of its degradation and polymerization products. J Pharm Pharmacol 26 385 Bundgaard H (1975) Chemical studies related to cephalosporin allergy. I. Kinetics of aminolysis of cephalosporins and effect of C-3 substituents on beta-lactam reactivity. Arch Pharm 3 94... 

D. B. Boyd, D. K. Herron, W. H. W. Lunn, and W. A. Spitzer, /. Am. Chem. Soc., 102, 1812 (1980). Parabolic Relationships between Antibaaerial Activity of Cephalosporins and Beta-Lactam Reactivity Predicted from Molecular Orbital Calculations. 

Fig. 8). As expected, 6-acetylpenicillin V methyl ester was most susceptible to ring opening by hydroxide. Clearly, other factors besides p-lactam reactivity play a considerable role in determining the ultimate biological activity of any p-lactam antibiotic, since the free acid of 276 is poorly active. 

Another method for deallylation of ally esters is the transfer of the allyl group to reactive nucleophiles. Amines such as morpholine are used[415-417], Potassium salts of higher carboxylic acids are used as an accepter of the allyl group[418]. The method is applied to the protection and deprotection of the acid function in rather unstable /f-lactam 664[419,420]. 

The Q and e values of VP are 0.088 and —1.62, respectively (125). This indicates resonance interaction of the double bond of the vinyl group with the electrons of the lactam nitrogen, whence the electronegative nature. With high e+ monomers such as maleic anhydride, VP forms alternating copolymers, much as expected (126). With other monomers between these Q and e extremes a wide variety of possibiHties exist. Table 14 Hsts reactivity ratios for important comonomers. 

The antibacterial effectiveness of penicillins cephalospotins and other P-lactam antibiotics depends upon selective acylation and consequentiy, iaactivation, of transpeptidases involved ia bacterial ceU wall synthesis. This acylating ability is a result of the reactivity of the P-lactam ring (1). Bacteria that are resistant to P-lactam antibiotics often produce enzymes called P-lactamases that inactivate the antibiotics by cataly2ing the hydrolytic opening of the P-lactam ring to give products (2) devoid of antibacterial activity. 

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