Abstract

Phosphonate analogues of nucleoside polyphosphates

Highlights

  • They found that organic salts of pyrophosphoric acid and its halomethylenebisphosphonate analogues react with an excess of 1,1‫׳‬-carbonyldiimidazole (CDI) to give stable, isolable diimidazolidates 77, and that these diimidazolidates react with nucleoside 5 ́-monophosphates or monothiophosphate to give the corresponding nucleotide analogues conveniently and in high yield (Scheme 31)

  • The usefulness of the Ludwig-Eckstein approach in the development of a convenient synthetic route to β, -methylene modified nucleotides was demonstrated by Wang and co-workers who reported the synthesis of AZT 5 ́-triphosphate mimics 123.108 reaction of AZT with 2-chloro-4H-1,3,2-benzodioxaphosphorin-4one, followed by treatment of the phosphite intermediate 121 with a bisphosphonate salt, yielded the cyclic triphosphate analogues 122, which were subjected to boronation and subsequent hydrolysis to give AZT 5 ́-αP-borano-β, -bridge-modified triphosphates 123 in moderate to good yields (Scheme 49)

  • Synthesis of α,β;β, -bis-CH2 ATP via anhydride of bismethylenetriphosphonic acid. Another approach to methylene-modified nucleoside polyphosphates via ring-opening reactions is based on the reactions of a P1,P3-cyclic nucleoside trimetaphosph(on)ates which can be prepared by treatment of the corresponding nucleoside triphosph(on)ate analogues with carbodiimides or phosphitylation of the 5 ́hydroxy group of 2 ́,3 ́-protected nucleosides, followed by double substitution of salicylate with bisphosphonates and oxidation of the resulting cyclic phosphite

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Summary

Introduction

Compared to the conventional phosphoromorpholidate method, this approach afforded products in shorter reaction time and higher isolated yields.[75] A one-pot method for DCI-promoted synthesis of symmetrical NppCX2ppN bisphosphonate analogues from nucleoside 5 ́-phosphoropiperidates without using nucleoside phosphonates has been described.[76] A very effective synthetic procedure for the preparation of a series of dinucleoside tetraphosphate analogues via activated bisphosphonates and nucleoside monophosphates was developed by Yanachkov et al.[77] They found that organic salts of pyrophosphoric acid and its halomethylenebisphosphonate analogues react with an excess of 1,1‫׳‬-carbonyldiimidazole (CDI) to give stable, isolable diimidazolidates 77, and that these diimidazolidates react with nucleoside 5 ́-monophosphates or monothiophosphate to give the corresponding nucleotide analogues conveniently and in high yield (Scheme 31).

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