Efficient synthesis of methylenebis(phosphonate) analogues of P¹,P²-disubstituted pyrophosphates of biological interest. A novel plausible mechanism

Synthesis of novel nucleoside bicyclic trisanhydrides 7 in the reaction of nucleoside-5'-methylenebis(phosphonate)s (4) with DCC is described. They were obtained by P¹,P³- and P²,P⁴-dehydration of initially formed P¹,P²,P³,P⁴-bismethylenetetraphosphonate 6. Reaction of 7 (N = 2',3'-O-isopropylideneadenosin-5'-yl) with 2',3'O-isopropylidenetiazofurin gave, after hydrolysis and deisopropylidenation, β-methylene-TAD (10a), the known potent inhibitor of inosine monophosphate dehydrogenase (IMPDH). Similar reaction of 7 with benzyl 2,3-O-isopropylidene-β-D-riboside followed by hydrolysis and deprotection afforded a new methylenebis(phosphonate) analogue of ADP-ribose 10b. Upon reaction of 7 with riboflavin, the corresponding β-methylene-FAD (10c) was obtained. Bicyclic trisanhydride 7 prepared from (2',3'-O-isopropylidene-N⁴-acetylcytidin-5'-yl)methylenebis(phosphona te) was used in the synthesis of the methylenebis(phosphonate) analogues of CDP-ethanolamine 10d and CDP-dipalmitoylglycerol 10e.