Synthesis of Triazole‐Containing Furanosyl Nucleoside Analogues and Their Phosphate, Phosphoramidate or Phoshonate Derivatives as Potential Sugar Diphosphate or Nucleotide Mimetics

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.

Synthesis and Exploitation of the Biological Profile of Novel Guanidino Xylofuranose Derivatives

“…The treatment of 5-6 with diphenylphosphoryl azide in the presence of 1,8-diazabicyclo [5.4.0]undec-7-ene (DBU) proved also not to be feasible for the access to the corresponding 5-azido derivatives, leading solely to the xylofuranosyl phosphates 9 and 10 [47] that did not evolve towards the desired azides even after long reaction times (16-24 h), heating (40 ºC) and addition of sodium azide. Hence, the 3-O-allyl-5-azido furanose derivative 12 was synthesized by 3-O-allylation of known 5-azido-1,2-O-isopropylidene xylofuranose (11) [50] with allyl bromide in the presence of sodium hydride in 87% yield, similarly as for the 3-Opropargylated counterpart 13 which was obtained via O-propargylation of 11 as previously reported [47]. Scheme 1.…”

“…soln. ), r. t., 2.5-4 h; (b) NaBH4, EtOH/H2O (2/1), r. t., 1 h, 58 (5), 57% (6) [47], 64% (7) [48], 82% (8) [49], 2 steps; (c) TsCl, CH2Cl2/pyridine (1:1, from 7), pyridine (from 8), r. t., 16 h; (d) NaN3, DMF, 80 °C, 16 h, 77 % (14) [48], 80% (15) [47], 2 steps; (d) DPPA, DBU, toluene, r. t., 16 h (from 5), 24 h, then 40°C, 16 h (from 6), 98% (9), 68 % (10) [47]; (e) RBr, NaH, DMF, r. t., 16 h (for R = C3H5), 5 min. (for R = C3H3), 87% (12), 95 % (13) [47].…”

“…Hence, to avoid the reduction of the allyl and eventually of the propargyl moiety, an alternative method consisting of the selective reduction of the azide group by the Staudinger reaction with triphenylphosphane in tetrahydrofuran (THF)/water, followed by guanidinylation, was employed. [47].…”

“…A 5-guanidino sugar containing a 3-O-substituent combining a benzyl moiety with a triazole motif was also synthesized (Scheme 3). Hence, the previously reported 5-azido-3-O-(benzyltriazolyl)methyl xylofuranose derivative 23, accessed from 13 via 1,3-dipolar cycloaddition with benzyl azide and further azidation [47], was subjected to Staudinger reduction followed by guanidinylation leading to the 5-guanidino 3′-O-methyl-branched N-benzyltriazole isonucleoside 24 in 84% yield. Alternatively, 24 could be obtained through "click" cycloaddition between 18 with benzyl azide in the presence of copper iodide/Amberlyste A-21 [53] in 38% yield with the 5-iodotriazole 25 being also formed as secondary product in 10% yield.…”

Synthesis and Exploitation of the Biological Profile of Novel Guanidino Xylofuranose Derivatives

“…The synthesis of 3-O-substituted 5-guanidino xylofuranose derivatives involved the access to 5-azido precursors, which could be achieved by different pathways depending on the 3-O-substituent (Scheme 1). One pathway involved the oxidative cleavage of 3-Oallyl, -propargyl [47], -dodecyl [48] and -benzyl [49] 1,2-O-isopropylidene glucofuranose derivatives (1-4) with sodium metaperiodate, followed by reduction with sodium borohydride to afford the corresponding xylofuranose derivatives 5-8 for further installation of the azide functionality. This was firstly attempted by a sequence of tosylation (tosyl chloride/pyridine) and further nucleophilic replacement with sodium azide, by which the 3-O-dodecyl and 3-O-benzyl 1,2-O-isopropylidene xylofuranoses 7-8 were converted into 14-15 as previously reported [47,48].…”