Synthesis of 5'-methylene-phosphonate furanonucleoside prodrugs: application to D-2'-deoxy-2'-α-fluoro-2'-β-C-methyl nucleosides

Org Lett. 2012 Sep 7;14(17):4426-9. doi: 10.1021/ol301937v. Epub 2012 Aug 23.

Abstract

A new and facile synthetic pathway to metabolically stable 5'-methylene-bis(pivaloyloxymethyl)(POM)phosphonate furanonucleoside prodrugs is reported. The key step involves a Horner-Wadsworth-Emmons reaction of a tetra(pivaloyloxymethyl) bisphosphonate salt with appropriately protected 5'-aldehydic nucleosides. This efficient approach was applied for the synthesis HCV related 2'-deoxy-2'-α-fluoro-2'-β-C-methyl nucleosides.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Amides / chemistry
  • Amides / pharmacology
  • Antiviral Agents / chemical synthesis
  • Hepacivirus / drug effects*
  • Methane / analogs & derivatives
  • Molecular Structure
  • Nucleosides / chemical synthesis*
  • Nucleosides / chemistry
  • Nucleosides / pharmacology
  • Phosphoric Acids / chemistry
  • Phosphoric Acids / pharmacology
  • Prodrugs / chemical synthesis*
  • Prodrugs / chemistry
  • Prodrugs / pharmacology

Substances

  • Amides
  • Antiviral Agents
  • Nucleosides
  • Phosphoric Acids
  • Prodrugs
  • carbene
  • phosphoramidic acid
  • Methane