Synthesis of phosphonate and phosphinate analogs of 2-oxo acids for site-specific inhibition of thiamine-diphosphate-dependent dehydrogenases of 2-oxo acids in vivo.

In this work, we describe the synthesis of the phosphonate and phosphinate analogs of pyruvate, as well as phosphonate analogs of 2-oxoglutarate and its homologs 2-oxoadipate and 2-oxopimelate. Arbuzov reaction and condensation of triethyl orthoacetate with the hypophosphorous acid or methyl dichlorophosphine is presented as efficient methods for preparation of 2-oxo organophosphorus esters. Subsequent transformations of the esters to free acids are achieved by treatment with trimethylbromosilane, or sodium iodide, or hydrogenation of the corresponding benzyl esters. The site-specific inhibition of thiamine-diphosphate-dependent dehydrogenases of 2-oxo acids by the phosphonate and phosphinate analogs of pyruvate and 2-oxodicarboxylic acids provides efficient tool to model their dysfunction under pathological conditions and to study the metabolic and signaling roles of these important enzymes in different organisms and cells.