EFFICIENT SYNTHESIS OF METHYLENEBIS(PHOSPHONATE) ANALOGS OF P-1,P-2-DISUBSTITUTED PYROPHOSPHATES OF BIOLOGICAL INTEREST - A NOVEL PLAUSIBLEMECHANISM

Synthesis of novel nucleoside bicyclic trisanhydrides 7 in the reactio n of nucleoside-5'-methylenebis-(phosphonate)s (4) with DCC is describ ed. They were obtained by P-1,P-3- and P-2,P-3-dehydration of initiall y formed P-1,P-2,P-3,P-4-bismethylenetetraphosphonate 6. Reaction of 7 (N = 2',3'-O-isopropylideneadenosin-5'-yl) with 2',3'-O-isopropyliden etiazofurin gave, after hydrolysis and deisopropylidenation, beta-meth ylene-TAD (10a), the known potent inhibitor of inosine monophosphate d ehydrogenase (IMPDH). Similar reaction of 7 with benzyl 2,3-O-isopropy lidene-beta-D-riboside followed by hydrolysis and deprotection afforde d a new methylenebis(phosphonate) analogue of ADP-ribose 10b. Upon rea ction of 7 with riboflavin, the corresponding beta-methylene-FAD (10c) was obtained. Bicyclic trisanhydride 7 prepared from e-N-4-acetylcyti din-5'yl)methylenebis(phosphonate) was used in the synthesis of the me thylenebis(phosphonate) analogues of CDP-ethanolamine 10d and CDP-dipa lmitoylglycerol 10e.