Organic Chemistry

Synthesis of 1,2,3-Triazole-Containing Furanosyl Nucleoside Analogs and Their Phosphate, Phosphoramidate or Phoshonate Derivatives as Potential Sugar Diphosphate or Nucleotide Mimetics



The synthesis of a variety of novel, rather stable and potentially bioactive nucleoside analogs and nucleotide mimetics based on xylofuranose scaffolds and comprising a 1,2,3-triazole moiety as a surrogate for a nucleobase or a phosphate group is reported. Isonucleosides embodying a 3-O-(benzyltriazolyl)methyl moiety at C-3 were accessed by using the Cu(I)-catalyzed “click” 1,3-dipolar cycloaddition between 3-O-propargyl-1,2-O-isopropylidene-α-D-xylofuranose and benzyl azide as the key step. Related isonucleotides comprising a phosphate or a phosphoramidate moiety at C-5 were obtained via 5-O-phosphorylation of acetonide-protected 3-O-propargyl xylofuranose followed by “click” cycloaddition or by Staudinger reaction of a 5ʹ-azido N-benzyltriazole isonucleoside with triethyl phosphite, respectively. Hydroxy, amino- or bromomethyl triazole 5ʹ-isonucleosides were synthesized through thermal cycloaddition between 5-azido 3-O-benzyl/dodecyl-1,2-O-isopropylidene-α-D-xylofuranoses and propargyl alcohol, propargylamine or propargyl bromide, respectively. The regiochemical outcome of the cycloaddition reactions was influenced by nature of the alkyne hetero substituent (alkyne CH2X substituent). The 5´-isonucleosides were converted into their [(xylofuranos-5-yl)triazolyl]methyl phosphate, phosphoramidate and phosphonate derivatives as prospective sugar diphosphate mimetics by an appropriate method involving treatment with diethyl phosphorochloridate or a Michaelis-Arbuzov reaction. 4-Phosphonomethyl-1-xylofuranos-5ʹ-yl triazoles were converted into 1,2-O-acetyl glycosyl donors and subsequently subjected to nucleosidation with uracil leading to the corresponding uracil nucleoside 5ʹ-(triazolyl)methyl phosphonates, whose structure potentially mimics that of a nucleoside diphosphate.


Thumbnail image of Manuscript.pdf

Supplementary material

Thumbnail image of Supporting Information.pdf
Supporting Information
Thumbnail image of checkcif_compound 12a.pdf
checkcif compound 12a
Thumbnail image of checkcif_compound 20.pdf
checkcif compound 20
Thumbnail image of checkcif_compound 35.pdf
checkcif compound 35