Difluoromethylene triphosphate

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. ... 

The concept of hydrolytically resistant phosphorus-based compounds emerged early in the 1960s. In this craitext, different nrai-hydrolysable ATP analogues or modified nucleotide triphosphates where the oxygen atoms of the triphosphate unit 250 were replaced by methylene groups 251 or difluoromethylene groups 252 were developed (Fig. 30). 

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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