DECOMPOSITION OF N-PHOSPHORYLATED NITROGEN MUSTARDS - A MECHANISTIC INVESTIGATION

Lithium methyl N-(2-chloroethyl)phosphoramidate (2b) and lithium methy l N,N-bis(2-chloroethyl)phosphoramidate (2c) were prepared as models o f N-phosphorylated mustards used in cancer chemotherapy. The decomposi tion of those substrates in D2O and in D2O-pyridine-d(5) was studied t o elucidate the mechanism of their alkylating reactivity. The products of the decomposition and the variation of the proportions of the prod ucts with time were determined, and the results led to the following c onclusions. Decomposition of substrates of the type 2 can follow three independent pathways: (i) 1,5-cyclization to a 1,3,2-oxazaphospholidi ne derivative, followed by fast ring opening via the pH-dependent P-O or P-N bond cleavage; (ii) 1,3-cyclization to a N-phosphorylated aziri dinium derivative, followed by the nucleophilic opening of the aziridi ne ring; (iii) fragmentation to metaphosphate and aziridine species, f ollowed by rapid reactions of those intermediates with nucleophiles. T he first pathway deactivates the substrate with respect to the alkylat ing reactivity. Relative contributions of individual pathways to the d ecomposition are highly sensitive to the detailed structure of the sub strate and to the nucleophilic composition of the reaction medium.