Cephalosporin 3-substituents, electronic effects

We begin the discussion with one of the major sites of structural variation, namely at C(6) in penicillins and at C(7) in cephalosporins (Table 5.4,A). Electron-withdrawing substituents at C(6) in penicillins and at C(7) in cephalosporins increase the rate of base-catalyzed hydrolysis [76]. The same substituent effect has been observed for monobactams [93] [94],... 

Another important site of structural variation in cephalosporins is C(3) (Table 5.4.J). Electron-withdrawing substituents at C(3) such as a Cl-atom or a MeO group increase base-catalyzed hydrolysis of cephalosporins by both resonance and inductive effects [92], For cephalosporins carrying 3-methylene-linked substituents with leaving group ability (e.g., acetate, thiol, or pyridine), it has been postulated that a concerted expulsion of the substituent facilitates the nucleophilic attack on the /3-lactam carbonyl group [104][105]. However, there are also arguments for a stepwise process in which the ex-... 

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],... 

Figure 6 Examples of simplifying molecular structures for the purpose of speeding calculations on the models. The extraneous side chains in cephalosporins and gemcita-bine are replaced by smaller groups (not all hydrogens are shown explicitly). The point is to retain only those parts of the compounds that deal directly with the electronic questions being studied. Side chains do affect the chemical and biological properties of a compound, but would produce a more or less constant effect on the electronic structure of the model structure retained. In the cephalosporins, the 7-acylamido and 4-carboxylate substituents can be replaced by NH2 and H, respectively. Substituents at the 3 position of cephalosporins include H, CH3, Cl, acetoxymethyl, arylthiomethyl, etc.

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