Mi. Page et al., REACTIVITY OF BETA-LACTAMS AND PHOSPHONAMIDATES AND REACTIONS WITH BETA-LACTAMASE, Pure and applied chemistry, 67(5), 1995, pp. 711-717
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).