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

preprint
submitted on 20.05.2020, 19:45 and posted on 21.05.2020, 11:39 by Andreia Fortuna, Paulo J. Costa, Fátima Piedade, M. Conceição Oliveira, Nuno Manuel Xavier

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.

Funding

IF/01488/2013/CP1159/CT0006

IF/00069/2014/CP1216/CT0006

UIDB/00100/2020

UIDP/00100/2020

UID/MULTI/04046/2019

UIDB/04046/2020

UIDP/04046/2020

UID/MULTI/00612/2013

UID/MULTI/00612/2019

LISBOA-01-0145-FEDER-028455

PTDC/QUI-QFI/28455/2017

History

Email Address of Submitting Author

nmxavier@fc.ul.pt

Institution

Centro de Química Estrutural, Faculdade de Ciências, Universidade de Lisboa

Country

Portugal

ORCID For Submitting Author

0000-0001-8739-8768

Declaration of Conflict of Interest

No conflict of interest

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