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.

α,α-Difluorophosphonohydroxamic Acid Derivatives among the Best Antibacterial Fosmidomycin Analogues

“…Deprotection of the phosphonate group 16 using 10 equivalents of bromotrimethylsilane in DCM following by hydrolysis at room temperature led 9b as a mixture of conformers. In these conditions, 9a could not be obtained but led to a deformylated by-product as previously observed [ 21 ].…”

“…The key precursor 12 has been prepared by a copper(I) catalyzed coupling reaction of [(diethoxyphosphinyl)difluoromethyl]zinc, formed in situ from the commercially available diethyl bromodifluorophosphonate 11 and Zn dust, with allyl bromide. The synthesis of the diethyl α,α-difluorophosphonate 14 was achieved by previously reported methods [ 21 ]. Formylation with the mixed acetyl/formyl anhydride generated in situ from a formic acid and acetic anhydride mixture led to the N -formylated compound 15a , which was obtained as a mixture of conformers due to the restricted rotation around the C-N bond [ 9 , 24 , 25 , 26 ] and the large dipole moment of the C-F bond [ 27 ].…”

“…Formylation with the mixed acetyl/formyl anhydride generated in situ from a formic acid and acetic anhydride mixture led to the N -formylated compound 15a , which was obtained as a mixture of conformers due to the restricted rotation around the C-N bond [ 9 , 24 , 25 , 26 ] and the large dipole moment of the C-F bond [ 27 ]. Acetylation with a mixture of acetic anhydride and pyridine gave the N -acetylated analogue 15b as previously described [ 21 ].…”

“…After purification by flash chromatography, the primary alcohol 17 was oxidized into the carboxylic acid 18 with 2,2,6,6-tetramethyl-1-piperidinyloxyl (TEMPO) in catalytic proportion in presence of [bis(acetoxy)iodo]benzene [ 28 ]. Treatment of the carboxylic acid with O -benzylhydroxylamine hydrochloride in the presence of 1-(3-dimethyl-aminopropyl)-3-ethylcarbodiimide and 1-hydroxybenzotriazole hydrochloride in DCM gave the hydroxamic acid derivative 19a [ 21 ] as a mixture of conformers. The methyl group was introduced by reaction of 19a with K 2 CO 3 in acetone under reflux followed by addition of methyl iodide to give 19b as a single conformer.…”

“…Moreover, the presence of two fluorine atoms might increase the lipophilic properties of the compounds allowing a better cellular uptake [ 20 ]. In this context, the synthesis of the protected gem-difluoro FR-900098 derivative 16b and N-H phosphonohydroxamic acid 10a ( Scheme 2 ) have been recently reported for a herbicide application [ 21 ].…”