Reactivity of p-lactams and phosphonamidates and reactions with P-lactamase

Themodynamicplly stnincd four membered cyclic 8-lactams do not show a corrcspondimg kinetic effect in the rates of their ring openhg reactions. Contrary to expectations. breaking the C-N bond in these mined ring seuc~ures appears to be a relatively difficult process. A four membend cyclic phosphonamidate. on the other hand, undergoes rapid hydrolysis in water with exclusive endocyclic P-N fision with a rrrc difference, compared with an acyclic d o m e , of grater than 5 x 10'. no diastercoisomea of a phosphonamidate wmpletely pnd irreversibly inactivate the class C 8-lacramasc 0) from Enrcrobaaner cloacuc in a time dependent manner. There is diastereoselectivity shown by the two inactivators and the more active one has proline displaced by the enzyme. htonatba of the phosphonamidatc nitrogen is almost certainly required to expel neuaal proline. Effective enzyme catalysed phosphonylation is surprising in view of the presumed different geometries for the reaction (trigonal bipynmidal) compared with that for acylation (tetrphedral). Chemical Reactivitv of B-Lactams Four membered D-lactams occur relatively rarely in nature, therefore it is not surprising that the biological activity of these compounds should be attributed to the chemical reactivity of the B-lactam ring. Shortly after the introduction of penicillin to the medical world it was suggested that the antibiotic's activity was due to the inherent strain of the four-membered ring or to reduced amide resonance. The non-planar butterfly shape of the penicillin molecule (1) could reduce amide resonance and thus increase the susceptibility of the carbonyl group to nucleophilic attack, compared with planar amides. However, the evidence to support an unusually strained or an amide-resonance inhibited D-lactam in penicillin is ambiguow2 It is estimated that resonance stabilises amides by about 19 kcal mol-'. If delocalisation is completely inhibited in an amide then the rate of nucleophilic attack could occur up to 1013-fold faster than in the analogous resonance-stabilised system. The strain energy of a four-membered ring is 26-29 kcal mol-' and a reaction involving opening of the D-lactam ring could therefore take place faster than the analogous bond fission process in a strain-free amide by a factor of up to 1e0 , although the total strain energy of four-membered rings is probably not released until there is significant bond extension. If strain or resonance inhibition is even slightly significant in penicillins and cephalosporins their effects should therefore be easily observable. The rates of alkaline hydrolysis of 8-lactams exhibit a first-order dependence on hydroxide ion concentration and show a Bronsted B value of -0.44 (Figure 1) which is indicative of rate-limiting formation of the tetrahedral intermedfate. It is only D-lactams of weakly basic amines which show enhanced reactivity. The rate enhancement of D-lactams compared with acyclic amides thus depends upon the basicity of the leaving group amine. B-Lactams of weakly basic amines @Ka of conjugate acid less than 4) are ca. 500-fold more reactive than an acyclic amide of the same amme. 13-lactams of basic amines show very similar reactivity to that of analogous non-cyclic amides. Fusing the B-lactam ring to a five-membered ring to make l-aza-bicyclo-[3.2.0]heptan-2-ones increases the reactivity by ca. 100-fold but does not significantly change the Bronsted 8 value, which is -0.55 for the bicyclic system. Although the rate enhancement is substantial, it is harhy of the magnitude expected from the release of strain energy in opening a four-membered ring, or from a system in which amide resonance is significantly inhibited. It is worth noting that monocyclic Dlactams of weakly basic amines can be as chemically reactive as penicillins and cephalosporins. It is not necessary to make the D-lactam part of a bicyclic system to have a reactive amide.