Synthesis of 2′-([1,2,3]triazol-1-yl)-2′-deoxyadenosines

Article abstract of DOI:10.1080/15257770802086880

A reliable and efficient protocol for the synthesis of 2′-([1,2,3] triazol-1-yl)-2′-deoxyadenosine derivatives from vidarabine is presented. Vidarabine was converted to 2′-azido-2′-deoxy-3′,5-O- (tetraisopropyldisiloxane-1,3-diyl)-adenosine. This azide was used as the starting material for the CuI-catalyzed parallel synthesis of 1,2,3-triazoles using a variety of alkynes. The reactions proceeded in good yield and gave almost exclusively the 1,4-disubstituted 1,2,3-triazoles. Copyright Taylor & Francis Group, LLC.

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Synthesis of 2′-([1,2,3]Triazol-1-yl)-2′-
deoxyadenosines
Gavin O′Mahony a , Sara Svensson a , Andreas Sundgren a & Morten
Gr⊘tli a
a Department of Chemistry, Medicinal Chemistry , Göteborg
University , Göteborg, Sweden
Published online: 19 Jun 2008.
To cite this article: Gavin O′Mahony , Sara Svensson , Andreas Sundgren & Morten Gr⊘tli (2008)
Synthesis of 2′-([1,2,3]Triazol-1-yl)-2′-deoxyadenosines, Nucleosides, Nucleotides and Nucleic Acids,
27:5, 449-459, DOI: 10.1080/15257770802086880
To link to this article: http://dx.doi.org/10.1080/15257770802086880
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Nucleosides, Nucleotides and Nucleic Acids, 27:449–459, 2008
Copyright ꢀC Taylor & Francis Group, LLC
ISSN: 1525-7770 print / 1532-2335 online
DOI: 10.1080/15257770802086880
SYNTHESIS OF 2ꢀ-([1,2,3]TRIAZOL-1-YL)-2ꢀ-DEOXYADENOSINES
Gavin OꢁMahony, Sara Svensson, Andreas Sundgren, and Morten Grøtli
Department of Chemistry, Medicinal Chemistry, Go¨teborg University, Go¨teborg, Sweden
A reliable and efficient protocol for the synthesis of 2 ꢁ-([1,2,3]triazol-1-yl)-2 ꢁ-deoxyadenosine
2
derivatives from vidarabine is presented. Vidarabine was converted to 2ꢁ-azido-2ꢁ-deoxy-3ꢁ,5-O-
(tetraisopropyldisiloxane-1,3-diyl)-adenosine. This azide was used as the starting material for the
CuI-catalyzed parallel synthesis of 1,2,3-triazoles using a variety of alkynes. The reactions proceeded
in good yield and gave almost exclusively the 1,4-disubstituted 1,2,3-triazoles.
Keywords Nucleoside analogues; [3+2] cycloaddition
INTRODUCTION
Adenosine derivatives are of great importance in medicinal and biolog-
ical chemistry, due to the abundance of adenosine-based species in living
systems, such as the biologically crucial molecules RNA, ATP, cAMP, and
NAD. It was recognized at an early stage that introducing diversity into the
Received 13 September 2007; accepted 22 February 2008.
We thank the Knut and Alice Wallenberg Foundation and Go¨teborg University for financial
assistance.
Address correspondence to Morten Grøtli, Department of Chemistry—Medicinal Chemistry,
Go¨teborg UniversitySE-412 96, Go¨teborg, Sweden. E-mail: grotli@chem.gu.se
449

450
G. OꢁMahony et al.
carbohydrate or base subunits of adenosine represent promising strate-
gies to identify specific receptor ligands, enzyme inhibitors, or nucleo-
side function modifiers. Several naturally-occurring adenosine analogues
demonstrate biological activities, such as protein synthesis inhibitors
(puromycin)[1] and methyl transferase inhibitors (sinefungin).[2] Some
synthetic analogues of nucleosides are prominent antiviral drugs owing to
their ability to inhibit viral DNA polymerases and reverse transcriptases.[3]
Many nucleoside analogues exhibit antiproliferative,[4] and antifungal
properties.[5] Furthermore, a considerable number of nucleoside-based
selective agonists and antagonists of adenosine receptors have been de-
veloped for potential therapeutic applications, including cardiovascular,
inflammatory, and neurodegenerative diseases.[6]
We have for some time been interested in designing enzyme in-
hibitors based on purine nucleosides, principally adenosine. For ex-
ample, we have reported the synthesis of several enzymatically non-
hydrolysable 5ꢁ-O-[N-(aminoacyl)-sulfamoyl]adenosine analogues of 5ꢁ-O-
aminoacylphosphates that have been used in structural studies on a number
of tRNA synthetases.[7] Recently, we have reported the preparation of
2ꢁ-aminoacylamino-2ꢁ-deoxyadenosine derivatives.[8] These compounds are
nonhydrolysable isosteres of 2ꢁ-aminoacyladenosines and are of use in x-ray
crystallographic studies of the elucidation of the editing mechanism of
various tRNA synthetases.[9] Members of this class of adenosine derivatives
have also been identified as potent inhibitors of trypanosomal glycosomal
glyceraldehyde-3-phosphate dehydrogenase (GAPDH).[10]
Given the ubiquitous nature of the peptide linkage in biological
molecules, replacement of the amide bond with isosteres in potential drug
candidates has been a continual goal of many laboratories. Many surrogates
have been introduced already,[11] yet the synthesis of many of these isosteres
in a combinatorial way is difficult and requires several steps. Thus, the im-
proved synthesis of peptide bond surrogates is an important endeavor that
may open new opportunities for the study of amide-containing molecules
and the development of compounds with novel physicochemical properties.
In this article, we present the synthesis of 2ꢁ-([1,2,3]triazol-1-yl)-2ꢁ-
deoxyadenosines as analogues of 2ꢁ-amino-2ꢁ-deoxyadenosines, with a 1,2,3-
triazole ring used as a bioisostere of the amide bond. We have used a
popular “click chemistry” reaction, the copper(I)-catalyzed azide-alkyne
[3+2] cycloaddition[12] as a straightforward method for the preparation of
2ꢁ-([1,2,3]triazol-1-yl)-2ꢁ-deoxyadenosine derivatives.
2. RESULTS AND DISCUSSION
Azide 1 is available from vidarabine, according to a literature
procedure.[13] 3ꢁ,5ꢁ-Diprotection of vidarabine with a tetraisopropyldisiloxy

2ꢁ-([1,2,3]Triazol-1-yl)-2ꢁ-deoxyadenosines
451
SCHEME 1 Synthesis of 2ꢁ-([1,2,3]triazol-1-yl)-2ꢁ-deoxyadenosine derivatives. i) TIPDS-Cl2, pyridine,
room temperature, 4 hours; ii) CF3SO2Cl, DMAP, DCM, 0◦C, 1 hour; iii) NaN3, DMF, room temperature,
5 hours; iv) 0.1 eq sodium ascorbate and 0.01 eq CuSO4, 50% aqueous t-BuOH, room temperature, 12
hours; v) NH4F, MeOH, room temperature, overnight.
group followed by 2ꢁ-O-triflation and subsequent nucleophilic displacement
with sodium azide (with inversion of configuration) afforded azide 1
(Scheme 1). With the desired 2ꢁ-azido starting material 1 in hand, we were
able to investigate the regioselective synthesis of the 1,2,3-triazole ring.
We previously have reported intra- and intermolecular 1,2,3-triazole ring
formation at the 2ꢁ-position of adenosine to produce fluorescent nucleoside
derivatives.[14] Using the same conditions as we have previously reported,
the copper(I)-catalyzed [3+2]-cycloaddition reaction between azide 1 and
various alkynes was carried out overnight at room temperature in a t-
BuOH/H2O solution, using catalytic amounts of sodium ascorbate and
.
CuSO4 5H2O. Other reported methods of producing copper(I) (e.g., by

452
G. OꢁMahony et al.
the use of copper(0) wire and microwave irradiation)[12a] for this reaction
failed to produce any of the desired products. The products were observed
to precipitate from the reaction mixtures, but isolation by filtration led to
low product recovery and thus a standard aqueous work-up procedure was
used. However, omission of the aqueous workup prior to chromatographic
purification led to no reduction in recovered yield or purity.
Good isolated yields were obtained for a variety of alkynes, including
those with an aromatic moiety (2a), an alkane chain (2g), a ketone (2b),
various esters (2d, 2h, 2i) in addition to both protected and unprotected
heterofunctionalities (2e and 2f, respectively). The 1,4-disubstituted 1,2,3-
triazole was produced exclusively in most cases. However, when 2 metyl-1-
buten-3-yne (entry 3) was used as the alkyne component, small amounts
(<15% by 1H NMR spectroscopy) of the 1,5-disubstituted 1,2,3-triazole was
formed and 61% triazole 2c was isolated by column chromatography. The
3ꢁ,5ꢁ-O-TIPDS group of compounds 2a–g was removed using ammonium
fluoride (10 equivalents) in methanol at room temperature.[15] Direct
purification by flash chromatography afforded compounds 3a–i in good
yields.
Compounds 3a–i can be regarded as non-hydrolysable isosteres of 2ꢁ-
aminoacyladenosines that are intermediates in the enzymatic reaction of
tRNA synthetases.[9] Work currently is underway to evaluate their potential
use in X-ray crystallographic studies for the elucidation of the editing
mechanism of various tRNA synthetases, and as potential tRNA synthetase
inhibitors.
3. CONCLUSION
We have developed a reliable and efficient protocol for the synthesis
of 2ꢁ-([1,2,3]triazol-1-yl-2ꢁ-deoxyadenosine derivatives from vidarabine. The
method reported leads to the simple and high-yielding conversion of 2ꢁ-
azidoadenosine 1 into 2ꢁ-([1,2,3]triazol-1-yl)-2ꢁ-deoxyadenosines.
4. EXPERIMENTAL
4. General Experimental Methods
All reactions were performed under a nitrogen atmosphere, except
those not susceptible to moisture or air. Solvents were dried using standard
1
procedures. H NMR spectra were recorded at 400 MHz and 13C NMR
spectra recorded at 100 MHz using a JEOL Eclipse spectrometer, in the
solvents specified. Spectra were referenced to residual nondeuterated sol-
vent (1H NMR: CDCl3 7.26 ppm, d6-DMSO 2.55 ppm and 13C NMR: CDCl3
77.2 ppm, d6-DMSO 39.5 ppm). Coupling constant (J ) values are quoted

2ꢁ-([1,2,3]Triazol-1-yl)-2ꢁ-deoxyadenosines
453
in Hertz. Elemental analyses were performed by MikroKemi AB, Uppsala,
Sweden. Mass spectra and high-resolution mass spectra were performed
by Stenhagen Analyslab AB, Mo¨lndal, Sweden, using a magnetic sector
(VG7070) instrument with FAB ionization (Xe gun operating at 10 kV).
The matrix used was 3-nitrobenzyl alcohol or glycerol. Acceleration voltage
was 6 kV and scan time 5 seconds. Optical rotations were measured using
a Perkin-Elmer 341 LC polarimeter and [α]D values are given in 10−1deg
cm2 g−1. IR spectra were recorded as KBr plates using a Perkin-Elmer 16
PC FTIR spectrometer. Flash chromatography was performed using Merck
Geduran Si 60 (0.063–0.200 mm) silica gel. Thin layer chromatography
(TLC) was performed using Merck Silica Gel 60 F254 aluminum-backed
plates and visualized using UV light (254 and/or 366 nm). The solvents
used to determine Rf values are the same as used for chromatographic
purification, unless otherwise stated.
General Procedure for Synthesis of the Triazoles (2a–2j)
The alkyne (1 eq) and 2ꢁ-azido-2ꢁ-deoxy-3ꢁ,5-O-(tetraisopropyldisiloxane-
1,3-diyl)-adenosine (1) (200 mg, 0.37 mmol) were suspended in 50%
aqueous t-BuOH (3 mL). Sodium ascorbate (7.3 mg, 0.037 mmol) was
added, followed by copper(II) sulfate pentahydrate (0.9 mg, 0.0037 mmol).
The mixture was stirred at room temperature until TLC analysis (90:10
DCM/MeOH) indicated complete conversion. The solvents were removed
under reduced pressure. The solid residue was dissolved in DCM (10
mL) and washed with water (3 × 10 mL) and dried over magnesium
sulfate. Concentration and purification by flash chromatography (90:10
DCM/MeOH) afforded the final product.
2ꢁ-(4-Phenyl-[1,2,3]triazol-1-yl)-2ꢁ-deoxy-3ꢁ,5ꢁ-O-(tetraisopropyldisiloxane-1,3-
diyl)-adenosine (2a). Phenylacetylene (24.5 µl, 0.37 mmol) was reacted
with 2ꢁ-azido-2ꢁ-deoxy-3ꢁ,5-O-(tetraisopropyldisiloxane-1,3-diyl)-adenosine
1
(1) according to the procedure above. H NMR (CDCl3): δ 8.32 (1H, s),
8.01 (1H, s), 7.9 (1H, s), 7.8–7.86 (2H, m), 7.34–7.49 (3H, m, 3), 6.85 (1H,
d, J = 2.6 Hz), 5.88–5.94 (1H, m), 5.67 (2H, br s), 5.47 (1H, t, J = 7.7
Hz), 4.35–4.43 (1H, m), 4.19 (1H, dd, J = 12.8, 2.9 Hz), 4.07 (1H, dd, J
= 12.8, 2.9 Hz), 1.30–0.78 (28H, m). 13C NMR (CDCl3): δ 156.0, 153.4,
149.3, 147.8, 140.5, 140.03, 130.5, 129.0, 128.4, 125.9, 121.8, 120.6, 86.8,
83.0, 70.3, 65.6, 61.3, 17.5, 17.49, 17.47, 17.40, 17.3, 16.93, 16.88, 13.4, 13.1,
12.9, 12.8. [α]D = -128.6 (c = 0.0075, CHCl3). HRMS [C30H44N8O4Si2]:
calcd. 637.551; found: 637.310. Elemental analysis: calcd. C, 56.52; H, 6.96;
N, 17.58, Found C, 56.50; H, 6.86; N, 17.67.
2ꢁ-(4-Carbomethyl-[1,2,3]triazol-1-yl)-2ꢁ-deoxy-3ꢁ,5ꢁ-O-(tetraisopropyldisilo-
xane-1,3-diyl)-adenosine (2b). 3-Butyn-2-one (28.9 µl, 0.37 mmol) was
reacted with 2ꢁ-azido-2ꢁ-deoxy-3ꢁ,5-O-(tetraisopropyldisiloxane-1,3-diyl)-
adenosine (1) according to the procedure above. 1H NMR (CDCl3): δ 8.30

454
G. OꢁMahony et al.
(1H, s), 8.20 (1H, s), 7.99 (1H, s), 6.77 (1H, d, J = 2.6 Hz), 5.89–5.94 (1H,
m), 5.61 (2H, s), 5.46 (1H, t, J = 7.9 Hz), 4.29–4.36 (1H, m), 4.17 (1H, dd,
J = 12.8, 4.0 Hz), 4.05 (1H, dd, J = 13.0, 3.1 Hz), 1.65 (3H, s), 1.15–0.79
(28H, m). 13C NMR (CDCl3): δ 192.8, 155.5, 153.1, 148.8, 147.5, 139.4,
127.4, 120.1, 86.4, 82.8, 69.7, 65.8, 60.8, 27.1, 17.2, 17.2, 17.1, 17.1, 17.0,
16.9, 16.6, 16.5, 13.1, 12.8, 12.6, 12.5. [α]D = -85.5 (c = 0.014, CHCl3).
HRMS [C26H42N8O5Si2]: calcd. 603.508; found 603.293.
2ꢁ-(4-Isopropenyl-[1,2,3]triazol-1-yl)-2ꢁ-deoxy-3ꢁ,5ꢁ-O-(tetraisopropyldisiloxane-
1,3-diyl)-adenosine (2c). 2-Methyl-1-buten-3-yne (35 µl, 0.37 mmol) was
reacted with 2ꢁ-azido-2ꢁ-deoxy-3ꢁ,5-O-(tetraisopropyldisiloxane-1,3-diyl)-
adenosine (1) according to the procedure above. 1H NMR (CDCl3): δ 8.25
(1H, s), 8.0 (1H, s), 7.62 (1H, s), 6.80 (1H, d, J = 1.8 Hz), 6.40 (2H, br
s), 5.88–5.81 (1H, m), 5.69 (1H, s), 5.41 (1H, t, J = 7.7 Hz), 5.08 (1H, s),
4.34–4.25 (1H, m), 4.13 (1H, dd, J = 12.6, 6.4 Hz), 4.02 (1H, J = 12.7, 2.7
Hz), 2.09 (3H, s), 1.12–0.74 (28H, m). 13C NMR (CDCl3): δ 155.7, 153.3,
149.4, 148.7, 140.0, 133.3, 121.6, 120.6, 112.9, 86.7, 82.9, 70.3, 65.4, 61.3,
20.8, 17.5, 17.4, 17.4, 17.3, 17.2, 16.9, 16.8, 13.4, 13.1, 12.8, 12.7. HRMS
[C27H45N8O4Si2]: calcd. 601.310; found 601.310. Elemental analysis: calcd.
C, 53.97; H, 7.38; N, 18.95, Found C, 53.92; H, 7.31; N, 18.89.
2ꢁ-(4-Hydroxymethyl-[1,2,3]triazol-1-yl)-2ꢁ-deoxy-3ꢁ,5ꢁ-O-(tetraisopropyldisilo-
xane-1,3-diyl)-adenosine propionate (2d). Propargyl propionate (43 µl, 0.37
mmol) was reacted with 2ꢁ-azido-2ꢁ-deoxy-3ꢁ,5-O-(tetraisopropyldisiloxane-
1,3-diyl)-adenosine (1) according to the procedure above. 1H NMR
(CDCl3): δ 8.30 (1H, s), 7.98 (1H, s), 7.74 (1H, s), 6.80 (1H, d, J = 2.6
Hz), 5.85 (1H, dd, J = 7.1, 2.4 Hz), 5.60 (2H, br s), 5.44 (1H, t, J = 7.9
Hz), 5.25 (2H, s), 4.28–4.35 (1H, m), 4.17 (1H, dd, J = 12.8, 4.0 Hz), 4.04
(1H, dd, J = 12.8, 2.9 Hz), 2.34 (2H, dd, J = 7.5, 15.2 Hz), 1.16–0.76 (31H,
m). 13C NMR (CDCl3): δ 174.3, 156.0, 153.2, 149.2, 142.9, 139.9, 125.9,
120.5, 86.6, 82.8, 70.1, 65.5, 61.2, 57.5, 27.4, 17.4, 17.4, 17.3, 17.3, 17.1, 16.8,
16.8, 13.3, 13.0, 12.7, 12.7, 9.0. [α]D = −74.4 (c = 0.01, CHCl3). HRMS
[C28H46N8O6Si2]: calcd. 646.886; found 647.3159.
2ꢁ-(4-[N-Cbz-aminomethyl]-[1,2,3]triazol-1-yl)-2ꢁ-deoxy-3ꢁ,5ꢁ-O-(tetraisopropyl-
disiloxane-1,3-diyl)-adenosine (2e). Cbz-propargyl amine (65 mg, 0.37
mmol) was reacted with 2ꢁ-azido-2ꢁ-deoxy-3ꢁ,5-O-(tetraisopropyldisiloxane-
1,3-diyl)-adenosine (1) according to the procedure above. 1H NMR
(CDCl3): δ 8.32 (1H, s), 8.01 (1H, s), 7.70 (1H, s), 7.40–7.30 (5H, m),
6.80–6.74 (1H, m), 5.88–5.80 (1H, m), 5.46–5.34 (1H, m), 5.10 (2H, s),
4.56–4.46 (1H, m), 4.36–4.26 (1H, m), 4.16 (1H, dd, J = 12.6, 3.7 Hz), 4.03
(1H, dd, J = 12.6, 2.8 Hz), 1.14–0.78 (28H, m). 13C NMR (CDCl3): δ 156.6,
156.0, 153.3, 149.1, 145.1, 140.2, 136.5, 128.6, 128.3, 128.2, 124.4, 120.4,
86.8, 82.9, 77.4, 70.4, 67.0, 65.6, 61.4, 36.3, 17.5, 17.44, 17.41, 17.36, 17.2,
16.9, 16.8, 13.3, 13.1, 12.8, 12.7. [α]D = −27.2 (c = 0.0035, CHCl3). HRMS

2ꢁ-([1,2,3]Triazol-1-yl)-2ꢁ-deoxyadenosines
455
[C25H41N8O5Si2]: calcd. 724.342; found 724.343. Elemental analysis: calcd.
C, 41.45; H, 5.72; N, 15.47, found C, 41.49; H, 5.69; N, 15.51.
2ꢁ-(4-Hydroxymethyl-[1,2,3]triazol-1-yl)-2ꢁ-deoxy-3ꢁ,5ꢁ-O-(tetraisopropyldisilo-
xane-1,3-diyl)-adenosine (2f). Propargyl alcohol (21.5 µl, 0.37 mmol) was
reacted with 2ꢁ-azido-2ꢁ-deoxy-3ꢁ,5-O-(tetraisopropyldisiloxane-1,3-diyl)-
adenosine (1) according to the procedure above.1H NMR (CDCl3): δ 8.28
(1H, s), 8.00 (1H, s), 7.68 (1H, s), 6.78 (1H, d, J = 2.6 Hz), 5.83 (1H, dd,
J = 7.3, 2.2 Hz), 5.80 (2H, br s), 5.42 (1H, t, J = 7.7 Hz), 4.84 (2H, s),
4.37–4.30 (1H, m), 4.17 (1H, J = 12.8, 4.0 Hz), 4.05 (1H, J = 12.8, 2.9
Hz), 1.50–0.79 (28H, m). 13C NMR (CD3OD): δ 157.3, 153.9, 150.0, 148.8,
141.8, 125.8, 120.8, 88.2, 84.5, 72.4, 66.9, 63.4, 56.4, 17.9, 17.8, 17.8, 17.7,
17.6, 17.5, 17.2, 17.2, 14.3, 14.1, 14.0, 13.7. [α]D = -84.6 (c = 0.01, CHCl3).
HRMS [C25H41N8O5Si2]: calcd. 590.497; found 591.2899.
2ꢁ-(4-Butyl-[1,2,3]triazol-1-yl)-2ꢁ-deoxy-3ꢁ,5ꢁ-O-(tetraisopropyldisiloxane-1,3-
diyl)-adenosine (2g). 1-Hexyne (42.5 µl, 0.37 mmol) was reacted with
2ꢁ-azido-2ꢁ-deoxy-3ꢁ,5-O-(tetraisopropyldisiloxane-1,3-diyl)-adenosine
(1)
1
according to the procedure above. H NMR (CDCl3): δ 8.23 (1H, s), 7.98
(1H, s), 7.39 (1H, s), 6.78 (1H, d, J = 2.2 Hz), 6.54–6.36 (2H, br s),
5.82–5.76 (1H, m), 5.38 (1H, t, J = 7.7 Hz), 4.34–4.24 (1H, m), 4.12 (1H,
dd, J = 12.8, 4.0 Hz), 4.0 (1H, dd, J = 12.8, 2.9 Hz), 2.62–2.27 (2H, m), 1.60
(2H, quintet, J = 7.5 Hz), 1.33 (2H, sextet, J = 7.4 Hz), 1.10–0.74 (31H,
m). 13C NMR (CDCl3): δ 156.1, 153.2, 149.2, 148.2, 140.0, 120.5, 122.7,
86.7, 82.9, 70.2, 65.3, 61.3, 31.7, 25.3, 22.3, 17.5, 17.42, 17.39, 17.3, 17.2,
16.8, 13.9, 13.3, 13.1, 12.8, 12.7. [α]D = -75.5 (c = 0.007, CHCl3). HRMS
[C28H48N8O4Si2]: calcd. 617.530; found 617.3433. Elemental analysis:
calcd. C, 54.46; H, 7.83; N, 18.15, found C, 54.38; H, 7.85; N, 18.08.
2ꢁ-(4-Carboethoxy-[1,2,3]triazol-1-yl)-2ꢁ-deoxy-3ꢁ,5ꢁ-O-(tetraisopropyldisilo-
xane-1,3-diyl)-adenosine (2h). Ethyl propiolate (37.5 µl, 0.37 mmol) was
reacted with 2ꢁ-azido-2ꢁ-deoxy-3ꢁ,5-O-(tetraisopropyldisiloxane-1,3-diyl)-
adenosine (1) according to the procedure above.1H NMR (CDCl3): 8.29
(1H, s), 8.23 (1H, s), 8.00 (1H, s), 6.79 (1H, d, J = 2.6 Hz), 5.94 (1H, dd,
J = 7.3, 2.2 Hz), 5.71 (2H, br s), 5.46 (1H, t, J = 7.7 Hz), 4.44 (2H, q, J
7.1 Hz), 4.33–4.27 (1H, m), 4.17 (1H, dd, J = 12.8, 4.0 Hz), 4.05 (1H, dd,
J = 12.8, 2.9 Hz), 1.41 (3H, t, J = 7.1 Hz), 1.14–0.79 (28H, m). 13C NMR
(CDCl3): δ 160.6, 155.9, 155.9, 153.1, 149.0, 139.9, 129.5, 120.1, 86.5, 82.8,
70.1, 65.9, 61.4, 61.2, 17.4, 17.3, 17.3, 17.2, 17.2, 17.0, 16.7, 16.7, 14.3, 13.2,
13.0, 12.7, 12.6. [α]D = -105.8 (c = 0.008, CHCl3). HRMS [C27H44N8O6Si2]:
calcd. 633.518; found 633.3014.
2ꢁ-(4-Carbomethoxy-[1,2,3]triazol-1-yl)-2ꢁ-deoxy-3ꢁ,5ꢁ-O-(tetraisopropyldisilo-
xane-1,3-diyl)-adenosine (2i). Methyl propiolate (33 µl, 0.37 mmol) was
reacted with 2ꢁ-azido-2ꢁ-deoxy-3ꢁ,5-O-(tetraisopropyldisiloxane-1,3-diyl)-
adenosine (1) according to the procedure above. 1H NMR (CDCl3): δ 8.26
(1H, s), 8.21 (1H, s), 8.06 (1H, s), 6.79 (1H, s), 6.36 (2H, br s), 5.95 (1H,
d, J = 7.0 Hz), 5.43 (1H, t, J = 7.9 Hz), 4.31–4.25 (1H, m), 4.15 (1H, dd,

456
G. OꢁMahony et al.
J = 12.8, 3.7 Hz), 4.02 (1H, dd, J = 12.8, 2.9 Hz), 3.91 (3H, s), 1.10–0.77
(28H, m). 13C NMR (CDCl3): δ 161.0, 155.9, 153.1, 149.0, 139.9, 139.5,
129.6, 120.4, 86.6, 82.8, 70.0, 65.9, 61.1, 52.3, 17.41, 17.35, 17.31, 17.26,
17.2, 17.1, 16.8, 16.7, 13.2, 13.0, 12.8, 12.5, 12.4. [α]D = -71.9 (c = 0.015,
CHCl3). HRMS [C26H42N8O6Si2]: calcd. 619.507; found 619.283. Elemental
analysis: calcd. C, 50.40; H, 6.85; N, 18.09, found C, 50.38; H, 6.86; N, 18.01.
General Procedure for the Synthesis of Compounds 3a–i
The 3ꢁ,5-O-(tetraisopropyldisiloxane-1,3-diyl)-protected compound 2 (1
eq) was suspended in methanol (10 mL). Ammonium fluoride (8.5 eq) was
added and the mixture was stirred at room temperature until TLC analysis
(90:10 DCM/MeOH) indicated that there was no starting material left,
usually requiring overnight. Concentration under reduced pressure and
purification by column chromatography (90:10 DCM/MeOH) afforded to
product 3 as a white solid.
2ꢁ-(4-Phenyl-[1,2,3]triazol-1-yl)- 2ꢁ-deoxy-adenosine (3a). Compound 2
(149 mg, 0.38 mmol) was treated with ammonium fluoride (119 mg, 3.21
mmol) according to the procedure above. 1H NMR (CD3OD) δ 8.57 (1H, s),
8.34 (1H, s), 8.18 (1H, s), 7.83–7.78 (2H, m), 7.45–7.30 (3H, m), 6.90 (1H,
d, J = 8.1 Hz), 6.06 (1H, dd, J = .7, 5.5 Hz), 4.80 (1H, dd, J = 5.5, 2.2 Hz),
4.44–4.38 (1H, m), 3.99 (1H, dd, J = 12.8, 2.6 Hz), 3.86 (1H, dd, J = 12.7,
2.7 Hz). 13C NMR (DMSO-d6): δ 156.2, 152.7, 148.9, 146.1, 139.9, 130.5,
128.9, 127.9, 125.1, 122.2, 119.3, 86.9, 85.2, 70.3, 64.3, 61.4. [α]D = -291.2
(c = 0.0055, MeOH). HRMS [C18H18N8O3]: calcd. 394.371; found 395.159.
Elemental analysis: calcd. C, 54.82; H, 4.60; N, 28.41, found C, 54.73; H,
4.65; N, 28.33.
2ꢁ-(4-Carbomethyl-[1,2,3]triazol-1-yl)- 2ꢁ-deoxy-adenosine (3b). Compound
2 (123 mg, 0.34 mmol) was treated with ammonium fluoride (107 mg, 2.89
mmol) according to the procedure above.1H NMR (CD3OD): δ 8.77 (1H,
s), 8.32 (1H, s), 8.18 (1H, s), 6.86 (1H, d, J = 7.7 Hz), 6.10 (1H, dd, J =
7.3, 5.5 Hz), 4.78 (1H, dd, J = 5.5, 2.2 Hz), 4.41–4.36 (1H, m), 3.98 (1H,
dd, J = 12.8, 2.6 Hz), 3.84 (1H, dd, J = 12.6, 2.7 Hz), 2.59 (3H, s). 13C
NMR (DMSO-d6): δ 191.6, 156.2, 152.7, 148.8, 146.8, 139.9, 128.1, 119.3,
86.8, 85.2, 70.2, 64.4, 61.4, 27.1. [α]D = -166.9 (c = 0.007, MeOH). HRMS
[C14H16N8O4]: calcd. 360.306; found 361.138. Elemental analysis. Calcd: C,
46.66; H, 4.48; N, 31.10, Found: C, 46.57; H, 4.50; N 31.07.
2ꢁ-(4-isopropenyl-[1,2,3]triazol-1-yl)- 2ꢁ-deoxy-adenosine (3c). Compound 2
(80 mg, 0.23 mmol) was treated with ammonium fluoride (73 mg, 1.97
mmol) according to the procedure above.1H NMR: (CD3OD) δ 8.32 (1H, s),
8.31 (1H, s), 8.27 (1H, s), 6.84 (1H, d, J = 8.1 Hz), 6.00 (1H, dd, J = 7.7, 5.5
Hz), 5.66 (1H, s), 5.10 (1H, s), 4.75 (1H, dd, J = 5.5, 2.2 Hz), 4.40–4.36 (1H,
m), 3.97 (1H, dd, J = 12.8, 2.6 Hz), 3.84 (1H, dd, J = 12.6, 2.7 Hz), 2.01
(3H, s). 13C NMR (DMSO-d6): 156.2, 152.6, 148.9, 147.2, 139.9, 133.5, 128.1,

2ꢁ-([1,2,3]Triazol-1-yl)-2ꢁ-deoxyadenosines
457
122.1, 119.3, 111.7, 86.9, 85.2, 70.3, 64.1, 61.4, 48.6, 20.3. [α]D = -118.3 (c =
0.005, MeOH).
2ꢁ-(4-Hydroxymethyl-[1,2,3]triazol-1-yl)-2ꢁ-deoxy-adenosine propionate (3d).
Compound 2 (190 mg, 0.47 mmol) was treated with ammonium fluoride
(148 mg, 3.99 mmol) according to the procedure above.1H NMR (CD3OD):
δ 8.31 (1H, s), 8.26 (1H, s), 8.17 (1H, s), 6.82 (1H, d, J = 7.7 Hz), 6.01 (1H,
dd, J = 7.7, 5.5 Hz), 5.17 (2H, s), 4.74 (1H, dd, J = 5.3, 2.4 Hz), 4.39–4.34
(1H, m), 3.96 (1H, dd, J = 12.4, 2.6 Hz), 3.83 (1H, dd, J = 2.7, 12.6 Hz), 2.33
(2H, q, J = 7.6 Hz), 1.08 (3H, t, J = 7.5 Hz). 13C NMR (DMSO-d6): δ 173.3,
156.2, 152.7, 148.9, 141.7, 139.8, 125.5, 119.2, 86.9, 85.1, 70.2, 64.2, 61.4,
57.0, 26.6, 8.9. [α]D = -116.3 (c = 0.006, MeOH). HRMS [C16H20N8O5]:
calcd. 404.354; found 405.162. Elemental analysis: calcd. C, 47.53; H, 4.99;
N, 27.71, found C, 47.58; H, 5.06; N, 27.63.
2ꢁ-(4-Carboethoxy-[1,2,3]triazol-1-yl)-2ꢁ-deoxy-adenosine (3e). Compound
2 (95 mg, 0.20 mmol) was treated with ammonium fluoride (63 mg, 1.70
mmol) according to the procedure above. 1H NMR (DMSO-d6): δ 8.39 (1H,
s), 8.14 (1H, s), 8.09 (1H, s), 7.42–7.27 (5H, m), 6.74 (1H, d, J = 7.3), 6.06
(1H, dd, J = 7.4, 5.9 Hz), 5.99 (1H, d, J = 5.1 Hz), 5.50 (1H, dd, J = 6.6, 5.1
Hz), 5.03 (2H, s), 4.64–4.61 (1H, m), 4.25–4.11 (3H, m), 3.82–3.77 (1H, m),
3.68–3.63 (1H, m). 13C NMR (DMSO-d6): δ 156.8, 153.3, 149.5, 145.6, 140.4,
137.6, 128.9, 128.3, 124.1, 119.8, 87.5, 85.7, 70.9, 66.0, 64.6, 62.0, 36.6. [α]D
= -99.4 (c = 0.004, MeOH). HRMS [C21H24N9O5]: calcd. 482.190; found
482.191. Elemental analysis. Calcd: C, 52.27; H, 5.03; N, 26.13, Found: C,
52.31; H, 5.05; N 26.17.
2ꢁ-(4-Hydroxymethyl-[1,2,3]triazol-1-yl)-2ꢁ-deoxy-adenosine
(3f). Comp-
ound 2 (156 mg, 0.45 mmol) was treated with ammonium fluoride (142
mg, 3.83 mmol) according to the procedure above.1H NMR (CD3OD): δ
8.31 (1H, s), 8.19 (1H, s), 8.11 (1H, s), 6.80 (1H, d, J = 8.0 Hz), 6.04 (1H,
dd, J = 7.9, 5.3 Hz), 4.74 (1H, dd, J = 5.5, 2.2 Hz), 4.66 (2H, s), 4.39–4.36
(1H, m), 3.97 (1H, dd, J = 12.8, 2.6 Hz), 3.84 (1H, dd, J = 12.8, 2.6 Hz).
13C NMR (DMSO-d6): δ 156.8, 153.3, 149.5, 148.3, 140.5, 124.0, 119.8,
87.6, 85.7, 70.9, 64.5, 62.0, 55.5. [α]D = -176.9 (c = 0.006, MeOH). HRMS
[C13H16N8O4]: calcd.- 349.137; found 349.136.
2ꢁ-(4-Butyl-[1,2,3]triazol-1-yl)-2ꢁ-deoxy-adenosine (3g). Compound 2 (142
mg, 0.41 mmol) was treated with ammonium fluoride (129 mg, 3.48 mmol)
according to the procedure above. 1H NMR (CD3OD): δ 8.31 (1H, s), 8.16
(1H, s), 7.98 (1H, s), 6.80 (1H, d, J = 7.7 Hz), 5.98–5.92 (1H, m), 4.72 (1H,
dd, J = 5.5, 2.2 Hz), 4.39–4.35 (1H, m), 3.96 (1H, dd, J = 12.5, 2.6 Hz),
3.83 (1H, dd, J = 12.6, 2.8 Hz,), 2.7 (2H, t, J = 7.5 Hz), 1.62 (2H, quintet, J
= 7.6 Hz), 1.35 (2H, sextet, J = 7.5 Hz), 0.92 (3H, t, J = 7.5 Hz). 13C NMR
(DMSO-d6) δ 156.2 152.6, 148.9, 146.6, 139.7, 122.5, 119.2, 87.0, 85.1, 70.4,
64.1, 61.5, 30.9, 24.6, 21.6, 13.7. [α]D = -206.0 (c = 0.007, MeOH). HRMS
[C13H16N8O4]: calcd. 348.370; found 348.377.

458
G. OꢁMahony et al.
2ꢁ-(4-Carboethoxy-[1,2,3]triazol-1-yl)-2ꢁ-deoxy-adenosine (3h). Compound
2 (145 mg, 0.38 mmol) was treated with ammonium fluoride (119 mg, 3.21
1
mmol) according to the procedure above. H NMR (CD3OD): δ 8.79 (1H,
s), 8.33 (1H, s), 8.18 (1H, s), 6.85 (1H, d, J = 7.7 Hz), 6.12–6.08 (1H, m),
4.81–4.76 (1H, m), 4.42–4.42 (3H, m), 1.37 (3H, t, J = 7.1 Hz). 13C NMR
(DMSO-d6) δ 160.1, 156.2, 152.6, 148.8, 139.9, 138.7, 129.9, 119.3, 86.8,
85.2, 70.2, 64.5, 61.4, 60.6, 14.2. [α]D = -27.1 (c = 0.005, MeOH). HRMS
[C15H18N8O5]: calcd. 390.327; found 391.146. Elemental analysis: calcd. C,
46.15; H, 4.65; N, 28.71, found: C, 46.06; H, 4.58; N, 28.59.
2ꢁ-(4-Carbomethoxy-[1,2,3]triazol-1-yl)-2ꢁ-deoxy-adenosine (3i). Compound
2 (149 mg, 0.40 mmol) was treated with ammonium fluoride (126 mg, 3.40
1
mmol) according to the procedure above. H NMR: (CD3OD) δ 8.8 (1H,
s), 8.30 (1H, s), 8.18 (1H, s), 6.85 (1H, d, J = 7.3 Hz), 6.12–6.06 (1H, m),
4.77 (1H, dd, J = 5.5, 2.6 Hz), 4.40–4.35 (1H, m), 3.97 (1H, dd, J = 18.8,
2.6 Hz), 3.91 (3H, s), 3.84 (1H, dd, J = 12.6, 2.7 Hz). 13C NMR (DMSO-d6):
δ 160.6, 156.2, 125.6, 148.8, 139.9, 138.4, 130.0, 119.3, 86.8, 85.2, 70.2, 64.5,
61.4, 51.8 [α]D = -225.2 (c = 0.005, MeOH). HRMS [C14H16N8O5]: calcd.
377.300; found: 377.134. Elemental analysis. Calcd: C, 44.69; H, 4.29; N,
29.78, Found: C, 44.56; H, 4.34; N 29.62.
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