Difluoromethylene phosphonate

Saccharidic Difluorophosphonates Difluoromethylene phospho-nates have been the focus of numerous works. Indeed, these compounds are able to mimic the phosphate bond in the synthesis of enzyme inhibitors. This interest is obvious for the furanose series in this case, they are non scissible analogues of 5-phosphate nucleosides (cf. Chapter 7). Difluoromethylene phosphonates can be prepared via a radical path starting from compounds that have the difluoromethylene moiety in the pseudo-anomeric position. Nevertheless, methods based on metal derivatives of difluorophosphonates are generally easier and broadly applicable. 

In another series of experiments, addition of phosphonyl radicals to carbohydrate gem-difluoroenol ethers was investigated as a route to new anomeric carbohydrate difluoromethylene phosphonates 261,262 Phosphonyl radicals could be produced from either diethyl phosphite in the presence of di-ferf-butyl peroxide in refluxing octane, or diethyl(phenylselenyl)phosphonate, on treatment with n-Bu3SnH (plus AIBN) added slowly to a benzene solution under reflux. With the first method,... 

Inject 0.5 mL of the 1.5 M tris(tetra-r7-butylammonium) pyrophosphate solution in acetonitrile (0.5 mL) and stir at room temperature (this can be modified to use instead, the methylene or difluoromethylene phosphonates). 

A facile preparation of novel allenic (a,a-difluoromethylene)phosphonates (233) has been achieved by CuBr-promoted reaction of zinc reagent (234) with readily available propargylic substrates. ... 

Burton, D.J., Takei, R., and Shin-Ya, S., Preparation, stability, reactivity and synthetic utility of a cadmium stabilized complex of difluoromethylene phosphonic acid ester, J. Eluorine Chem., 18, 197, 1981. 

Herpin, T.E, Motherwell, W.B., Roberts, B.P., Roland, S., and Weibel, J.-M., Free radical chain reactions for the preparation of novel anomeric carbohydrate difluoromethylene -phosphonates and -phosphonothioates, Tetrahedmn, 53, 15085, 1997. 

The nucleotide analogue (38) has been prepared from the difluoromethylene phosphonate precursor (39). The presence of orthogonal protecting groups at positions 2 and 3 allows the synthesis of the difluoromethylene phosphonates of both ribonucleosides and deoxyribonucleosides. The difluoromethylene phosphonate (40) of the anti-HIV agent FTC has been prepared by glycosylation of Z>w(trimethylsilyl)-5-fluorocytosine with (41) in the presence of tin (IV)chloride. ... 

Some difluoromethylene phosphonates have been prepared by phosphonyl radical addition to difluoroenol ethers, e.g. 11 gave 12. Treatment of unsaturated 1,6-anhydro sugar 13 with DAST has afforded 14, and the epoxide 15 was opened (KHF2, ethylene glycol) to give deoxyfluoro sugar 16. 

JMC5309). Phosphate function is known to be advantageously replaced by a phosphonate, and a-fluoromethylene- or a,a -difluoromethylene-phosphonates are considered as better bioisosteres of the phosphate group. Replacement of one or two hydrogens of a methylene group is classically used to modulate metabolism or off-target activity. 

The method has the added advantage in that it provides a route not only to nucleoside diphosphates (upon reaction with pyrophosphate) but also allows the preparation of phosphonate analogues by the use of methylene or difluoromethylene bisphosphonates.10 The latter analogues are both stable to hydrolysis. 

Another approach employs the electrophilic fluorination of a preformed monofluorinated phosphonate. Diethyl 1-(ethoxycarbonyl)-1,1-difluoromethylphosphonate has been prepared in 60% yield from the commercially available monofluorinated derivative using Selectfluor and NaH in THF at room temperature. However, only partial fluorination of sodium tefraisopropyl fluoro-methylenediphosphonate occurs with AcOF in CFCI3 at -78 C, and the desired difluoromethylene-diphosphonate is isolated in 40% yield. ... 

Kawamoto, A.M., and Campbell, M.M., A new method for the synthesis of a phosphonic acid analogue of phosphoserine via a novel 1,1-difluorophosphonate intermediate, J. Fluorine Chem.. 81, 181, 1997. Burton, D.J., Naae. D.G., Flynn, R.M., Smart, B.E., and Brittelli, D.R.. Phosphine- and phosphite-mediated difluorocarbene exchange reactions of (bromodifluoromethyl)phosphonium salts. Evidence for facile dissociation of (difluoromethylene)triphenylphosphorane. J. Org. Chem.. 48. 3616, 1983. Li, A.-R., and Chen. Q.-Y., Diethyl iododifluoromethylphosphonate. A new synthetic method and its reaction with alkynes. Synthesis, 606, 1996. 

Evidence has been presented which appears to support an earlier hypothesis regarding the reaction between sodium dialkyl phosphites and polyhalogeno - methanes according to this, the phosphite salt and bromotrifluoromethane yield (difluoromethylene)bisphosphonic tetraesters through the abstraction of the bromonium cation by the phosphite anion, and this is followed by phosphorylation of the subsequent carbanion. The present evidence is based on the treatment of diethyl (dichlorofluoromethyl)phosphonate with sodium diethyl... 

McKenna reported the efiicient synthesis of the alpha, P-difluoromethylene deoxynucleoside 5 -triphosphate of adenosine and cytosine (89a,b), obtained enzymatically from catalytic ATP, phosphoenol pyruvate, nucleoside diphosphate kinase and pyruvate kinase using the nucleoside difluor-omethylene bisphosphonates as substrate for the kinase. The bispho-sphonate was prepared by nucleophilic displacement of the 5 -0-tosyl nucleoside precursor with tris(tetrabutylammonium) difluoromethylenebi-sphosphonate. Finally Mackman synthesised the diphosphate esters of two cyclopentyl based nucleoside phosphonates (90a,b). While (90b) was unstable following reduction of (90a) and therefore unsuitable for biological evaluation, (90a) exhibited potent inhibition against HIV reverse transcriptase. ... 

Propylthio)-5 -adenylic acid monoanhydride with (difluoromethylene)-bis[phosphonic acid], P-99 2-Propylthio-p,y-difluoromethylene ATP, P-99 Prosurugatoxin, N-28 Protomin, G-530 Protoquercitol, Q-6 Protostib, A-214 Protuberic acid, P-100 pRpp, R-141 Prumycin, P-101 Pmnose I, S-92 Prunose II, S-92 Prunose III, S-92 PS60, G-218 Pseudaminic acid, D-485 Pseudo-p-D-allopyranose, H-158 Pseudocytidine, C-200 Pseudo-6-deoxy-p-D-altropyranose, M-238 Pseudo-6-deoxy-p-L-altropyranose, M-238 Pseudofructose, P-108 Pseudo-a-L-fucopyranose, M-238 Pseudo-a-DL-fucopyranose, M-238... 

Various triphosphate analogues have been reported. Eckstein s group has prepared the 1,3-dithiotriphosphate of AZT, the first example of this modification, and also the 1,1-dithioderivative of TTP.226 xhc same workers have also made the 2 epimers of 1,2-dithio-GDP, and converted them to the four diastereomers of l,2-dithio-GTP.227 jhe a,p-methylene, fluoromethylene and difluoromethylene analogues of dATP and TTP have been synthesized,22S as has the p.y-difluoromethylene analogue of AZT triphosphate, the phosphonate proving to be some 30 times less inhibitory towards HIV reverse transcriptase than the triphosphate.229... 

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