Synthesis of Triazole‐Containing Furanosyl Nucleoside Analogues and Their Phosphate, Phosphoramidate or Phoshonate Derivatives as Potential Sugar Diphosphate or Nucleotide Mimetics. Issue 8 (5th August 2020)

• Record Type: Journal Article
• Authors: Fortuna, Andreia; Costa, Paulo J.; Piedade, M. Fátima M.; Conceição Oliveira, M.; Xavier, Nuno M.
• Is Part Of: ChemPlusChem. Volume 85:Issue 8(2020)
• Page Start: 1676
• Page End: 1691
• Publication Date: 2020-08-05
• Subjects: cycloaddition reactions -- N-glycosylation -- nucleoside/nucleotide analogues -- phosphate bioisosteres -- triazoles; Chemistry -- Periodicals; 540.5
• DOI: 10.1002/cplu.202000424
• Languages: English
• ISSNs: 2192-6506

Abstract

Abstract: The synthesis of stable and potentially bioactive xylofuranosyl nucleoside analogues and potential sugar diphosphate or nucleotide mimetics comprising a 1, 2, 3‐triazole moiety is reported. 3′‐ O ‐Methyl‐branched N ‐benzyltriazole isonucleosides were accessed in 5–7 steps and 42–54 % overall yields using a Cu(I)‐catalyzed cycloaddition of 3‐ O ‐propargyl‐1, 2‐ O ‐isopropylidene‐α‐D‐xylofuranose with benzyl azide as key step. Related isonucleotides were obtained by 5‐ O ‐phosphorylation of acetonide‐protected 3‐ O ‐propargyl xylofuranose and further "click" cycloaddition or by Staudinger‐phosphite reaction of a 5‐azido N ‐benzyltriazole isonucleoside. Hydroxy‐, amino‐ or bromomethyl triazole 5′‐isonucleosides were synthesized by thermal cycloaddition of 5‐azido 3‐ O ‐benzyl/dodecyl xylofuranoses with propargyl alcohol, propargylamine or propargyl bromide. Better yields (82–85 %) were obtained when using propargyl alcohol and a high 1, 4‐regioselectivity was attained with propargyl bromide. Further O / N ‐phosphorylation or Arbuzov reaction led to (triazolyl)methyl phosphates, phosphoramidates or phosphonates. The latter were converted into uracil nucleoside 5′‐(triazolyl)methyl phosphonates as prospective nucleoside diphosphate mimetics. Abstract : Sweet nucleos(t)ides : The synthesis of novel 3′/5′‐isonucleosides and related prospective nucleotide or sugar diphosphate mimetics containg a triazole unit as a nucleobase surrogate or as a potential phosphate group bioisostere is described. The synthetic methodologies employed 3‐ O ‐propargyl or 5‐azido xylofuranoses as precursors and included the azide‐alkyne cycloaddition, N / O ‐phosphorylation, the Staudinger reaction, the Arbuzov reaction or N ‐glycosylation as key steps.