Nucleosides difluoromethylenated

Fluoro and 3, 3-difluoromethylene nucleosides have been prepared as inhibitors of ribonucleotide diphosphate reductase (cf. Chapter 7). ... 

The mixture SmI2/HMPA has been applied to the conversion of vicinal bis (sulfonyl) derivatives into the corresponding alkenes.100 An application of this reaction to the synthesis of a difluoromethylene nucleoside, where conventional difluoromethylation strategies (e.g., Wadsworth-Emmons and Wittig reactions) failed, is shown in Eq. 132.234... 

Deoxy-3 -difluoromethyleneuridine (128), the first example of a 3 -difluoro-methylene nucleoside, has been made by use of the Wittig-type reagent derived from CFaBra, HMPT and zinc metal. The 2 -difluoromethylene isomer could be similarly prepared an earlier approach to 2 -difluoromethylene nucleosides (Vol. 26, p. 240) was not successful when applied to a 3 -keto-compound. 5 -0-Dmtr-3 -0-phosphoramidites of these difluoromethylene compounds were also made for assembly into oligonucleotides. ... 

Deoxy-2 -difluoromethylene nucleosides, also of interest in connection with the inhibition of ribonucleotide diphosphate reductase, have been made by a modified Julia synthesis as outlined in Scheme 13 the cytosine analogue was also reported. 0 OEt... 

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. 

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. 

Trifluoromethyl substituted nucleoside 118 was synthesized from a-trifluoromethyl-a,p-unsaturated ester 117 <02JOC1016> in eight steps involving the usual Pummerer rearrangement. Compound 119 was synthesized from L-xylose via 2-deoxy-2-C-difluoromethylene-4-thiosugar... 

A review on the synthesis of gew-difluoromethylene compounds has described carbohydrate (including nucleoside) examples. The synthesis of acetylated glycosyl fluorides directly from the unprotected methyl glycosides has been effected as the first step of a GLC analytical method. First the glycoside is treated with HF followed by the addition of acetic anhydride. Full details (cf. Vol. 25, p.l05) on the preparation of glycosyl fluorides by reaction of aryl 1-thioglycosides with 4-difluoroiodotoluene have been described. ... 

A route to 2, 3 -dideoxy-2 -trifluoromethylpyrimidine nucleosides involves the synthesis of the lactone 99, and its separable cis-isomer, from isopropylidene-D-glyceraldehyde, which provides C-3 to C-5. Reduction of 99 and glycosylation gave, with moderate stereoselectivity, the nucleosides 100 (B = Ura, Thy, Cyt), and the cis-isomer of 99 could also be converted to r,2 -tru 5-nucleosides. An alternative route to 100 (B = Ura) proceeds through the difluoromethylene... 

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. ... 

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