Decomposition of N-Phosphorylated Nitrogen Mustards: A Mechanistic Investigation

Article abstract of DOI:10.1021/jo00117a039

Lithium methyl N-(2-chloroethyl)phosphoramidate (2b) and lithium methyl N,N-bis(2-chloroethyl)phosphoramidate (2c) were prepared as models of N-phosphorylated mustards used in cancer chemotherapy.The decomposition of those substrates in D2O and in D2O-pyridine-d5 was studied to elucidate the mechanism of their alkylating reactivity.The products of the decomposition and the variation of the proportions of the products with time were determined, and the results led to the following conclusions.Decomposition of substrates of the type 2 can follow three independent pathways: (i) 1,5-cyclization to a 1,3,2-oxazaphospholidine 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 aziridinium derivative, followed by the nucleophilic opening of the aziridine ring; (iii) fragmentation to metaphosphate and aziridine species, followed by rapid reactions of those intermediates with nucleophiles.The first pathway deactivates the substrate with respect to the alkylating reactivity.Relative contributions of individual pathways to the decomposition are highly sensitive to the detailed structure of the substrate and to the nucleophilic composition of the reaction medium.