Journal of Organic Chemistry 2012-12-07

Dephosphorylation reactions of mono-, di-, and triesters of 2,4-dinitrophenyl phosphate with deferoxamine and benzohydroxamic acid.

Michelle Medeiros, Elisa S Orth, Alex M Manfredi, Paulina Pavez, Gustavo A Micke, Anthony J Kirby, Faruk Nome

Index: J. Org. Chem. 77(23) , 10907-13, (2012)

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Abstract

This work presents a detailed kinetic and mechanistic study of biologically interesting dephosphorylation reactions involving the exceptionally reactive nucleophilic group, hydroxamate. We compare results for hydroxamate groups anchored on the simple molecular backbone of benzohydroxamate (BHA) and on the more complex structure of the widely used drug, deferoxamine (DFO). BHA shows extraordinary reactivity toward the triester diethyl 2,4-dinitrophenyl phosphate (DEDNPP) and the diester ethyl 2,4-dinitrophenyl phosphate (EDNPP) but reacts very slowly with the monoester 2,4-dinitrophenyl phosphate (DNPP). Nucleophilic attack on phosphorus is confirmed by the detection of the phosphorylated intermediates formed. These undergo Lossen-type rearrangements, resulting in the decomposition of the nucleophile. DFO, which is used therapeutically for the treatment of acute iron intoxication, carries three hydroxamate groups and shows correspondingly high nucleophilic activity toward both triester DEDNPP and diester EDNPP. This result suggests a potential use for DFO in cases of acute poisoning with phosphorus pesticides.