REACTIVITY OF BETA-LACTAMS AND PHOSPHONAMIDATES AND REACTIONS WITH BETA-LACTAMASE

Thermodynamically strained four membered cyclic beta-lactams do not sh ow a corresponding kinetic effect in the rates of their ring opening r eactions. Contrary to expectations, breaking the C-N bond in these str ained ring structures appears to be a relatively difficult process. A four membered cyclic phosphonamidate, on the other hand, undergoes rap id hydrolysis in water with exclusive endocyclic P-N fission with a ra te difference, compared with an acyclic analogue, of greater than 5 x 10(8). Two diastereoisomers of a phosphonamidate completely and irreve rsibly inactivate the class C beta-lactamase (P99) from Enterobacter c loacae in a time dependent manner. There is diastereoselectivity shown by the two inactivators and the mom active one has proline displaced by the enzyme. Protonation of the phosphonamidate nitrogen is almost c ertainly required to expel neutral proline. Effective enzyme catalysed phosphonylation is surprising in view of the presumed different geome tries for the reaction (trigonal bipyramidal) compared with that for a cylation (tetrahedral).