Isoprenoid biosynthesis via the MEP pathway. Synthesis of (3R,4S)-3,4-dihydroxy-5-oxohexylphosphonic acid, an isosteric analogue of 1-deoxy-d-xylulose 5-phosphate, the substrate of the 1-deoxy-d-xylulose 5-phosphate reducto-isomerase

Abstract

(3,4)-3,4-Dihydroxy-5-oxohexylphosphonic acid, an isosteric analogue of 1-deoxy-D-xylulose 5-phosphate (DXP), was obtained in enantiomerically pure form from (+)-2,3--benzylidene--threitol by a seven-step sequence. This phosphonate did not affect the growth of. It did not inhibit the 1-deoxy-D-xylulose 5-phosphate reductoisomerase (DXR), but was converted by this enzyme into (3,4)-3,4,5-trihydroxy-3-methylpentylphosphonic acid, an isosteric analogue of 2-C-methyl-D-erythritol 4-phosphate. The enzyme was, however, less efficient with the methylene phosphonate analogue than with the natural substrate.

Synthesis and Evaluation of l-Rhamnose 1C-Phosphonates as Nucleotidylyltransferase Inhibitors

“…The presence of the fluorine atoms at the C1 position renders the possibility of in situ elimination of the ester moiety unlikely, given that there are no methylene protons available for abstraction. The oxalyl ester hydrolysis product (14)w a s detected by 31 Pa n d 19 F NMR spectroscopy in a minor amount (<3%) relative to the major product (16)a f t e rp u r i fication, indicating sensitivity of these esters to hydrolysis. Subsequent radical deoxygenation using azobisisobutyl nitrile and tributyl tin hydride in toluene, at 105°C, afforded the difluoro phosphonate 17 in an excellent yield (85%), with a minor side product (<5%) as detected by 19 F NMR spectroscopy.…”

“…An alternative method of ketosephosphonate deoxygenation 27 starting from the monofluoro ketosephosphonate 12a and using Et 3 SiH and trimethylsilyl trifluoromethanesulfonate (TMSOTf) was explored but resulted in complete breakdown of the starting material, as was determined via TLC analysis. Attempts to perform hydrogenation on the mixture of olefin products and ketosephosphonates resulted in the production of the desired compound 21 (∼40%) as well as significant amounts of the defluorinated material 22 (∼20%) and the monofluoro ketosephosphonate 23 (∼40%) as determined by 31 P NMR spectroscopy. Conceivably, demethylation of the resultant mixture of phosphonates (21−23)a n ds u b s e q u e n t inhibition studies on the mixture could be performed and qualitatively compared to inhibitors 9, 11,a n d13.…”

“…The intermediate oxalyl esters were always visible as the less polar species by thin layer chromatography (TLC) analysis. Olefins 10a and 10b were single Z stereoisomers as determined by 31 Pand, 1 H NMR spectroscopy, and by 1D nuclear Overhauser effect spectroscopy (NOESY) NMR experiments ( Figure 3). Irradiation of the olefin proton H1 of compound 10a produced an NOE at the equatorial H3 proton, suggesting a Z orientation about the double bond.…”

“…28,29 The selectively deprotected sugar was then oxidized using Albright−Goldman 30 conditions, in a dimethyl sulfoxide (DMSO) and acetic anhydride solvent mixture, to afford the starting material 7. Lactone 7 was transformed into the dimethyl or dibenzyl ketosephosphonate species 8a (88% yield) and 8b (76% yield), using lithiated salts of dimethyl methylphosphonate and dibenzyl methylphosphonate, 31 respectively, in tetrahydrofuran (THF) at −78°C. Both compounds were isolated as the single axial hydroxyl isomer as determined using 31 Pa n d 1 H NMR spectroscopy.…”

“…Lactone 7 was transformed into the dimethyl or dibenzyl ketosephosphonate species 8a (88% yield) and 8b (76% yield), using lithiated salts of dimethyl methylphosphonate and dibenzyl methylphosphonate, 31 respectively, in tetrahydrofuran (THF) at −78°C. Both compounds were isolated as the single axial hydroxyl isomer as determined using 31 Pa n d 1 H NMR spectroscopy. Olefins 10a and 10b were produced from the in situ formation, and subsequent elimination, of the oxalyl esters formed when ketosephosphonates 8a and 8b were treated with methyl oxalyl chloride (MeOXCl) in a 7:2 CH 2 Cl 2 :pyridine solvent mixture.…”