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

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

Ugo Pradere  1 , Franck Amblard, Steven J Coats, Raymond F Schinazi
Affiliations

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

Ugo Pradere et al. Org Lett. .

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.

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Figures

Figure 1
Figure 1
Biologically active phosphonate and phosphoramidate nucleosides
Figure 2
Figure 2
Retrosynthetic analysis
Scheme 1
Scheme 1
Synthesis of tetra(POM)-bisphosphonate (TPBP) 5
Scheme 2
Scheme 2
Introduction of 3′-TBS group and oxidation suitability
Scheme 3
Scheme 3
Synthesis of protected nucleosides 11, 14, 19 and 20.
See this image and copyright information in PMC

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