Preparation of gem-difluorinated retrohydroxamic-fosmidomycin

Jean-Noël Volle,David Virieux,Camille Midriera,Klaus Haaf,Ralf Braun,Lothar Willms,Jean-Luc Pirata,Vincent Blanchard,Bert Maes

doi:10.3998/ark.5550190.p008.846

Abstract

From several decades, some organophosphorus compounds specifically designed to alter biological systems were introduced on market as agr ochemicals (ie glyphosate and glufosinate as herbicides). Nevertheless, it becomes necessary to find new compounds in order to counter plant resistances already observed with glyphosate. Fosmi domicyn and its N-acetyl analogues FR900098 were perceived as starting points for elabor ation of new herbicide candidates, targeting the second enzyme of the non-mevalonate pathway in plants, the 1-deoxy-D-xylulose 5phosphate reductoisomerase (DOXP reductoisomerase or DXR). It is expected that the enhancement of bioactivity compared to the parent c ompounds, might be reached by insertion of two fluorine atoms close to the phosphonate functio n. Indeed, the presence of both fluorine atoms could improve the lipophilicity, affect the p Ka 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.

Highlights

The world population is increasing and different estimations from United Nations planned for 2050 a population ranging from 8 to 10.5 billion people
The mevalonate-independent pathway of isoprenoid biosynthesis is widely found in many microorganisms[1,2,3,4] as well as in higher plants,[5,6] but it is missing in human, which uses mevalonate pathway for isoprenoid biosynthesis
The fosmidomycin 1a isolated from Streptomyces lavendulae in the seventies, has been referenced as an inhibitor of the D-xylulose 5-phosphate reductoisomerase (DXR) enzyme,[5,7] as well as N-acetyl homologue FR900098 1b,8,9 fosmidomycin and FR900098 retrohydroxamic acids 1c-d10,11 and phosphate analogues, namely fosfoxacin 1e12 or acetyl analogue 1f12 (Figure 1)

Summary

Introduction

The world population is increasing and different estimations from United Nations planned for 2050 a population ranging from 8 to 10.5 billion people. The preparation of N-phosphonohydroxamate ester 12 was accomplished through an ozonolysis of the alkene 5 applying the Chambers’s procedure.[26] Due to its low stability, aldehyde 9 had to be promptly used for the step, and its transformation by a reductive amination, using sodium cyanoborohydride in acidic conditions,[27] afforded the Obenzylhydroxylamino phosphonate 10 in 68% yield. The hydrolysis of the phosphonate ester using trimethylsilyl bromide,[28,29] followed by methanolysis at room temperature, did not afford pure phosphonic acid 3. The final step of the synthesis was the deprotection of the corresponding phosphonate into phosphonic acid 4 (75% yield), using 10 equivalents of trimethylsilyl bromide followed by a methanolysis at room temperature (Scheme 4).

Results

Conclusion