Recent advances in the synthesis of 5'-deoxynucleoside phosphonate analogs

: The present review focuses on the synthesis of cyclic 5-deoxynucleoside phosphonate analogs. The formation of various phosphonate alkyl moieties is accomplished through (i) Wittig (or HWE) type condensation to the nucleoside aldehyde moiety; (ii) nucleophilic displacement reaction using phosphonate anion or Lewis acid; (iii) Arbuzov reaction; (iv) olefin cross-metathesis between vinyl phosphonates and vinylated nucleosides; and (v) radical reaction and Pd catalyzed alkyne. For the coupling of nucleobases with cyclic moieties, the Mitsunobu reaction, and Sonogashira-type cross-coupling are usually applied. For the coupling of furanose moieties with nucleobases, Vorbrüggen-type condensation is generally applied. Addition reactions mediated by selenium ions are mainly applied for the coupling of carbocyclic moieties. Their biological activity results are summarized.

1,2,3-Triazoles as leaving groups in SNAr–Arbuzov reactions: synthesis of C6-phosphonated purine derivatives

A new method for C–N bond transformations into C–P bonds was developed using 1,2,3-triazoles as leaving groups in SNAr–Arbuzov reactions. A series of C6-phosphonated 2-triazolylpurine derivatives was synthesized for the first time, with the isolated yields reaching up to 82% in the C–P-bond-forming event. The SNAr–Arbuzov reaction of 2,6-bistriazolylpurines follows the general regioselectivity pattern of the C6-position being more reactive towards substitution, which was unambiguously proved by X-ray analysis of diethyl (9-heptyl-2-(4-phenyl-1H-1,2,3-triazol-1-yl)-9H-purin-6-yl)phosphonate.

Chemical Synthesis of Acyclic Nucleoside Phosphonate Analogs Linked with Cyclic Systems between the Phosphonate and the Base Moieties

The syntheses of acyclic nucleoside phosphonate (ANP) analogs linked with cyclic systems are described in the present review. The purpose of the review is to report the methodology of ANP analogs and to give an idea on the synthesis of a therapeutic structural feature of such analogs. The cyclopropane systems were mainly prepared by diazomethane cyclopropanation catalyzed by Pd(OAc)2, intramolecular alkylation, Kulinkovich cyclopropanation, and use of difluorocyclopropane, and so forth. The preparation of methylenecyclopropane system was made by diazoacetate cyclopropanation catalyzed by Rhodium followed by addition-elimination reactions. For the preparation of a variety of tethered 1,2,3-triazole systems, 1,3-dipolar cycloaddition between azidealkylphosphonates and propargylated nucleobases was mainly applied. The formation of various phosphonate moieties was achieved via phosphonylation of alkoxide, cross-coupling between BrZnCF2P (O)(OEt)2 with iodoalkens catalyzed by CuBr, Michaelis-Arbuzov reaction with phosphite, and Rh(II)-catalyzed O-H insertion, and so forth.

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

<p>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-<i>O</i>-(benzyltriazolyl)methyl moiety at C-3 were accessed by using the Cu(I)-catalyzed “click” 1,3-dipolar cycloaddition between 3-<i>O</i>-propargyl-1,2-<i>O</i>-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-<i>O</i>-phosphorylation of acetonide-protected 3-<i>O</i>-propargyl xylofuranose followed by “click” cycloaddition or by Staudinger reaction of a 5ʹ-azido <i>N</i>-benzyltriazole isonucleoside with triethyl phosphite, respectively. Hydroxy, amino- or bromomethyl triazole 5ʹ-isonucleosides were synthesized through thermal cycloaddition between 5-azido 3-<i>O</i>-benzyl/dodecyl-1,2-<i>O</i>-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-<i>O</i>-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. </p> <p><b> </b></p>

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

<p>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-<i>O</i>-(benzyltriazolyl)methyl moiety at C-3 were accessed by using the Cu(I)-catalyzed “click” 1,3-dipolar cycloaddition between 3-<i>O</i>-propargyl-1,2-<i>O</i>-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-<i>O</i>-phosphorylation of acetonide-protected 3-<i>O</i>-propargyl xylofuranose followed by “click” cycloaddition or by Staudinger reaction of a 5ʹ-azido <i>N</i>-benzyltriazole isonucleoside with triethyl phosphite, respectively. Hydroxy, amino- or bromomethyl triazole 5ʹ-isonucleosides were synthesized through thermal cycloaddition between 5-azido 3-<i>O</i>-benzyl/dodecyl-1,2-<i>O</i>-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-<i>O</i>-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. </p> <p><b> </b></p>