Synthesis of Methylenebis(phosphonate) Analogs of Dinucleotide Pyrophosphates

Abstract

A facile method is described for preparation of nonsymmetrical P1,P2-methylenebis(phosphonate) diesters based on the 31P-NMR-controlled reaction of methylenebis(phosphonate) monoesters with diisopropylcarbodiimide, resulting in the formation of the intermediate P1,P4-disubstituted bicyclic trisanhydride. This intermediate, after treatment with an another nucleoside, carbohydrate, or alcohol followed by hydrolysis, is converted into the corresponding methylenebis(phosphonate) diester. An analog of a natural dinucleotide pyrophosphate can be obtained when a nucleoside 5'-methylenebis(phosphonate) is coupled with another nucleoside. This method is suitable for preparation of metabolically stable (resistant to phosphodiesterase cleavage) analogs of NAD, FAD, and related natural pyrophosphates. The resulting compounds are useful for mechanistic studies of enzymes that use the natural pyrophosphates as cofactors or substrates, and in development of inhibitors that have potential applications as therapeutic agents.