Preparation of gem-difluorinated retrohydroxamic-fosmidomycin

Abstract

From several decades, some organophosphorus compounds specifically designed to alter biological systems were introduced on market as agrochemicals (ie glyphosate and glufosinate as herbicides). Nevertheless, it becomes necessary to find new compounds in order to counter plant resistances already observed with glyphosate. Fosmidomicyn and its N-acetyl analogues FR-900098 were perceived as starting points for elaboration of new herbicide candidates, targeting the second enzyme of the non-mevalonate pathway in plants, the 1-deoxy-D-xylulose 5-phosphate reductoisomerase (DOXP reductoisomerase or DXR). It is expected that the enhancement of bioactivity compared to the parent compounds, might be reached by insertion of two fluorine atoms close to the phosphonate function. Indeed, the presence of both fluorine atoms could improve the lipophilicity, affect the pKa of the phosphonic acid function and then induce better activities. Herein, the synthesis of gem-difluorinated analogues of retrohydroxamic fosmidomycin and FR-900098-ester is reported using a radical addition mediated by a cobaloxime complex.