Thermodynamically strained four membered cyclic β -lactams do not show a corresponding kinetic effect in the rates of their ring opening reactions. Contrary to expectations, breaking the C-N bond in these strained ring structures appears to be a relatively difficult process. A four membered cyclic phosphonamidate, on the other hand, undergoes rapid hydrolysis in water with exclusive endocyclic P-N fission with a rate difference, compared with an acyclic analogue, of greater than 5x108. Two diastereoisomers of a phosphonamidate completely and irreversibly inactivate the class C β -lactamase (P99) from Enterobacter cloacae in a time dependent manner. There is diastereoselectivity shown by the two inactivators and the more active one has proline displaced by the enzyme. Protonation of the phosphonamidate nitrogen is almost certainly required to expel neutral proline. Effective enzyme catalysed phosphonylation is surprising in view of the presumed different geometries for the reaction (trigonal bipyramidal) compared with that for acylation (tetrahedral).