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

Krzysztof W. Pankiewicz, Krystyna Lesiak, Kyoichi A. Watanabe

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31 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)3691-3695
Number of pages5
JournalJournal of the American Chemical Society
Volume119
Issue number16
DOIs
StatePublished - Apr 23 1997

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