Synthesis and biological properties of C-2 triazolylinosine derivatives

Article abstract of DOI:10.1021/jo300628y

O⁶-(Benzotriazol-1H-yl)guanosine and its 2′-deoxy analogue are readily converted to the O⁶-allyl derivatives that upon diazotization with t-BuONO and TMS-N₃ yield the C-2 azido derivatives. We have previously analyzed the solvent-dependent azide-tetrazole equilibrium of C-6 azidopurine nucleosides, and in contrast to these, the O ⁶-allyl C-2 azido nucleosides appear to exist predominantly in the azido form, relatively independent of solvent polarity. In the presently described cases, the tetrazole appears to be very minor. Consistent with the presence of the azido functionality, each neat C-2 azide displayed a prominent IR band at 2126-2130 cm^-1. A screen of conditions for the ligation of the azido nucleosides with alkynes showed that CuCl in t-BuOH/H₂O is optimal, yielding C-2 1,2,3-triazolyl nucleosides in 70-82% yields. Removal of the silyl groups with Et₃N-3HF followed by deallylation with PhSO₂Na/Pd(PPh₃)₄ gave the C-2 triazolylinosine nucleosides. In a continued demonstration of the versatility of O ⁶-(benzotriazol-1H-yl)purine nucleosides, one C-2 triazolylinosine derivative was converted to two adenosine analogues via these intermediates, under mild conditions. Products were desilylated for biological assays. The two C-2 triazolyl adenosine analogues demonstrated pronounced antiproliferative activity in human ovarian and colorectal carcinoma cell cultures. When evaluated for antiviral activity against a broad spectrum of DNA and RNA viruses, some of the C-2 triazolylinosine derivatives showed modest inhibitory activity against cytomegalovirus.

Full text of DOI:10.1021/jo300628y

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Synthesis and Biological Properties of C-2 Triazolylinosine
Derivatives
Mahesh K. Lakshman,*,† Amit Kumar,† Raghavan Balachandran,‡ Billy W. Day,‡,§ Graciela Andrei,∥
Robert Snoeck,∥ and Jan Balzarini∥
†Department of Chemistry, The City College and The City University of New York, 160 Convent Avenue, New York, New York
10031, United States
‡Department of Pharmaceutical Sciences, and §Department of Chemistry, University of Pittsburgh, Pennsylvania 15213, United States
∥Laboratory of Virology and Chemotherapy, Rega Institute for Medical Research, Minderbroedersstraat 10, B 3000 Leuven, Belgium
S
* Supporting Information
ABSTRACT: O6-(Benzotriazol-1H-yl)guanosine and its 2′-deoxy analogue are readily converted to the O6-allyl derivatives that
upon diazotization with t-BuONO and TMS-N3 yield the C-2 azido derivatives. We have previously analyzed the solvent-
dependent azide·tetrazole equilibrium of C-6 azidopurine nucleosides, and in contrast to these, the O6-allyl C-2 azido nucleosides
appear to exist predominantly in the azido form, relatively independent of solvent polarity. In the presently described cases, the
tetrazole appears to be very minor. Consistent with the presence of the azido functionality, each neat C-2 azide displayed a
prominent IR band at 2126−2130 cm−1. A screen of conditions for the ligation of the azido nucleosides with alkynes showed that
CuCl in t-BuOH/H2O is optimal, yielding C-2 1,2,3-triazolyl nucleosides in 70−82% yields. Removal of the silyl groups with
Et3N·3HF followed by deallylation with PhSO2Na/Pd(PPh3)4 gave the C-2 triazolylinosine nucleosides. In a continued
demonstration of the versatility of O6-(benzotriazol-1H-yl)purine nucleosides, one C-2 triazolylinosine derivative was converted
to two adenosine analogues via these intermediates, under mild conditions. Products were desilylated for biological assays. The
two C-2 triazolyl adenosine analogues demonstrated pronounced antiproliferative activity in human ovarian and colorectal
carcinoma cell cultures. When evaluated for antiviral activity against a broad spectrum of DNA and RNA viruses, some of the C-2
triazolylinosine derivatives showed modest inhibitory activity against cytomegalovirus.
the other hand, CuAAC chemistry involving C-2 azidopurine
nucleosides has been reported in the context of adenosine A3
receptor research14 as well as in the development of
antituberculosis agents,15 and both describe reactions of 2-
azidoadenosine analogues. In general, there are three methods
for the synthesis of 2-azidoadenosine derivatives. The first
involves treatment of 6-amino-2-hydrazino ribofuranosylpurine
with nitrous acid,16 the second is a Cu-catalyzed azidation of tri-
O-silyl 6-amino-2-iodo ribofuranosylpurine,17 and the third
involves diazotization/azidation of tri-O-acetyl 2-amino-6-
chlororibofuranosylpurine with isoamylONO/azidotrimethylsi-
lane (TMS-N3), followed by replacement of the chloride with
an amino group.18
INTRODUCTION
■
The Cu-catalyzed version1,2 of the classic Huisgen azide−
alkyne cycloaddition3−9 is a highly atom-economical reaction,
often requiring mild conditions. Both factors render Cu-
catalyzed azide−alkyne cycloaddition (CuAAC) highly attrac-
tive for the modification of complex and sensitive molecules
such as nucleosides. We have recently reported a facile and
general synthesis of C-6 azidopurine nucleosides and their use
in CuAAC reactions, where some of these new compounds
showed low cytostatic activity against ovarian carcinoma cell
lines.10 In general, azide−alkyne cycloaddition reactions have
been a highly important transformation in the chemistry of
nucleosides and DNA.11−13
To our knowledge, our previous report on the CuAAC
reactions of 6-azidopurine nucleosides was the first to describe
such reactions at the C-6 position of purine nucleosides.10 On
Received: March 26, 2012
© XXXX American Chemical Society
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Scheme 1. Synthesis of Protected O6-Allyl-2-azidoinosine and O6-Allyl-2-azido-2′-deoxyinosine
a
Table 1. Optimization of Azide−alkyne Ligation Conditions Using Trisilyl O6-Allyl-2-azidoinosine 2a and Phenylacetylene
b
entry
catalytic system
solvent (1:1)
time (h)
% yield of 3
1
2
3
4
20 mol % CuSO4/40 mol % Na ascorbate
20 mol % CuSO4/40 mol % Na ascorbate
20 mol % Cu(I) thiophene-2-carboxylate
20 mol % CuCl
CH2Cl2/H2O
t-BuOH/H2O
t-BuOH/H2O
t-BuOH/H2O
24
36
48
36
30 (60% of 2a recovered)
54
68
82
a
b
Conditions: 0.1 M 2a in the solvents indicated, room temperature (reactions were monitored for completion by TLC analysis). Yield of isolated
and purified product.
For the current study, we were interested in the CuAAC
reactions of 2-azidoinosine and its 2′-deoxy analogue. Syntheses
of 2-azidoinosine derivatives are less well developed in
comparison to the adenosine analogues. Reaction of 2-
chloroinosinic acid with NaN3 has been shown to yield 2-
azidoinosine-5′-monophosphate, which was subsequently con-
verted to 2-azidoinosine by reaction with acid phosphatase.19
Similarly, 2-fluoro-2′-deoxyinosine, which requires relatively
nontrivial synthesis,20 has been converted to the 2-azido
derivative within the context of a DNA oligomer.21 For our
purposes, we needed a simple, general access to 2-azidoinosine
and 2-azido-2′-deoxyinosine. In this paper we report the
synthesis of suitable O6-protected 2-azidoinosine derivatives
and their applicability toward CuAAC reactions. We have
evaluated the anticancer and antiviral properties of C-2 (1,2,3-
triazol-1H-yl)inosine and 2′-deoxyinosine analogues after
appropriate deprotection protocols. We also report method-
ology for conversion of C-2 triazolylinosine derivatives to
adenosine analogues via their O6-(benzotriazol-1H-yl) deriva-
tives, as well as the development of doubly reactive 2-azido-O6-
(benzotriazol-1H-yl)purine ribonucleoside.
RESULTS AND DISCUSSION
■
Synthesis of C-2 Triazolylinosine and 2′-Deoxyinosine
Derivatives. We have recently reported that O6-(benzotriazol-
1H-yl)inosine and -guanosine derivatives, as well as the
corresponding 2′-deoxy analogues, are exceptionally effective
reagents for the introduction of substituents at the C-6 position
of these purine nucleosides.22−26 On the basis of these results,
we reasoned that O6-allylguanosine and 2′-deoxyguanosine
would be excellent precursors for the present work.25 We have
previously developed the synthesis of 2-chloro-3′,5′-di-O-(tert-
butyldimethylsilyl)-2′-deoxyinosine from an O6-allyl-2′-deoxy-
guanosine precursor,27 and as reported for 2-chloroinosinic
acid,19 this can potentially be used to generate the 2-
azidoinosine derivative. Despite this, as shown in Scheme 1,
it is more expeditious to directly install the azido group at the
C-2 position by diazotization of the amino group in the
presence of TMS-N3.18
Silyl-protected O6-allyl-2-azidoinosine 2a(A) and the 2′-
deoxyinosine analogue 2b(A) could be synthesized via this
procedure in ca. 60% yield. C-2 azido derivatives of purines28,29
and purine nucleosides16,30−33 can exist in equilibrium with two
possible tetrazolyl isomers. Similarly, 2a,b can exist as two
B
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a
Table 2. Azide−alkyne Ligation Reactions of Nucleosides 2a and 2b
a
Conditions: 0.5 M 2a or 2b in 1:1 t-BuOH/H2O, 20 mol % of CuCl, room temperature (reactions were monitored for completion by TLC
b
analysis). Yields are of isolated and purified products.
tautomers termed 2a,b(T1) and 2a,b(T3), depending upon the
nitrogen atom of the purine that is involved. Among the two
azide derivatives, synthesis of 2b from the C-2 triflate has been
reported in 26% yield, and this compound was reported not to
display any tetrazole tautomer.34 In our case, assessment by 1H
NMR indicated that both 2a and 2b exist predominantly as the
azide 2a(A) and 2b(A) (≥90% in CDCl3, acetone-d6, and
DMSO-d6). Consistent with this, IR spectra of 2a and 2b
showed absorptions at 2126 and 2130 cm−1, respectively. By
comparison, 2-azidoadenosine derivatives demonstrated 17−
55% of the tetrazolyl isomer.14,15,30,31,33 Apart from factors such
as temperature and solvent polarity,31,33 the electronic nature of
substituents also influences the azide/tetrazole ratio of purinyl
derivatives.33 Whereas electron-donating substituents favor the
ring-closed tetrazolyl form, the azide form is preferred with
electron-withdrawing groups.33 The significantly greater
proportion of the azido rather than the tetrazolyl forms of 2-
azidoinosine derivatives 2a,b as compared to the 2-
azidoadenosines is possibly linked to this substituent effect.
Between the two tetrazolyl forms, the T1 form is generally
invoked for nucleosides.14,15,32,33
With the synthesis of the C-2 azido derivatives 2a,b
completed, conditions for effectuating their ligation reactions
with alkynes were evaluated (Table 1). In previous work with 6-
azidopurine nucleosides, we had observed that reduction of the
azide to the amine was a competing process and that biphasic
conditions were essential in order to obtain satisfactory azide−
alkyne ligation.10 Interestingly, application of those conditions
here resulted in an unsatisfactory outcome (entry 1). Switching
the solvent to 1:1 t-BuOH/H2O gave an improved result (entry
2). Cu(I) thiophene-2-carboxylate as the catalyst gave a modest
improvement (entry 3), whereas CuCl proved to be the best
under the conditions tested, affording a product yield of 82%
(entry 4). Therefore, the generality of azide−alkyne ligation
C
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Scheme 2. Deprotection of O6-Allyl C-2 Triazolylinosine and 2′-Deoxyinosine Analogues
Scheme 3. Synthesis of C-2 Triazolyladenosine Analogues via O6-Benzotriazolyl Derivatives
chemistry was next investigated using both the ribose derivative
2a as well as the 2′-deoxy analogue 2b. Results from these
experiments are summarized in Table 2.
atom, we considered methodology for facile synthesis of C-2
triazolyladenosine analogues (derivatives of 2,6-diaminopurine
nucleosides). For this purpose, our previously described
methodology for activation of the amide linkage, via the O6-
(benzotriazol-1H-yl) derivative, appeared to be a reasonable
approach.22,25,26
As shown in Scheme 3, deallylation of 3 followed by
exposure of the resulting silyl-protected C-2 triazolylinosine
derivative to 1H-benzotriazol-1-yloxytris(dimethylamino)-
phosphonium hexafluorophosphate (BOP) and i-Pr2NEt in
THF at room temperature led to the formation of the
corresponding O6-(benzotriazolyl) derivative 31 in 55% yield.
Reactions of 31 with morpholine and benzyl amine were
conducted in 1,2-dimethoxyethane (DME) to yield the
adenosine derivatives 32 and 33 in 77% and 90% yields,
respectively. The products were then desilylated to yield the C-
2 triazolyl adenosine analogues 34 and 35.
Synthesis of a Doubly Reactive Purine Nucleoside
Derivative. The foregoing experiments clearly showed that
azide−alkyne ligation could be effectively utilized to synthesize
C-2 triazolyl nucleoside analogues. This in combination with
chemistry leading to O6-(benzotriazol-1H-yl)purine nucleosides
produces a powerful new approach to difunctionalization at C-2
and C-6 of the purine scaffold. At this point, we considered
whether an appropriately functionalized, doubly reactive purine
nucleoside derivative could be obtained.
With a series of O6-protected C-2 triazolylinosine and 2′-
deoxyinosine derivatives available, deprotection of the products
became the focus. Two possible sequences could be envisioned;
either deprotection of the O6-allyl group followed by
desilylation or vice versa. Desilylation by Et3N·HF followed
by deallylation was the preferred order. This is because we have
noted that nucleoside desilylations with amine·HF complexes
can leave a fluoride contaminant in some instances, which can
be difficult to eliminate. Hence, our chosen deprotection
sequence offers the possibility to chromatographically purify the
products of desilylation prior to deallylation. We also generally
recommend checking products of desilylation by 19F NMR.
Several conditions were tested for this purpose: Pd2(dba)3/
( )-BINAP with morpholine in THF, Pd2(dba)3/( )-BINAP
+
−
with Et2NH2 HCO3 , in CH2Cl2, and Pd(PPh3)4 with sodium
benzenesulfinate (PhSO2Na) in THF. The first two sets of
conditions were not very successful, but use of Pd(PPh3)4/
PhSO2Na proved optimal. Scheme 2 shows the products
prepared by deprotection.
Synthesis of C-2 Triazolyladenosine Derivatives.
Having synthesized a series of C-2 triazolylinosine and 2′-
deoxyinosine analogues, which can also be considered as
modified guanine nucleosides by virtue of the C-2 nitrogen
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Scheme 4. Synthesis of Difunctionalizable Purine Nucleoside Derivative
Therefore, the synthesis of a 2-azido-O6-(benzotriazol-1H-
yl)purine nucleoside derivative was investigated. This would
not only allow us to evaluate the stability of the benzotriazolyl
moiety to the diazotization/azidation conditions but also
provide a route to novel reactive nucleosides that can be
difunctionalized at the C-2 and the C-6 positions of the purine.
In this context, hydroxyl-protected O6-(benzotriazolyl)-
guanosine derivatives have been converted to the C-2 halo
(F, Cl, and I) purine nucleosides.35 We chose to diazotize O6-
(benzotriazol-1H-yl)-2′,3,5′-tri-O-(tert-butyldimethylsilyl)-
guanosine (37)25 with t-BuONO/TMS-N3 (Scheme 4), along
the lines of previously published methods.18,31 This reaction
gave a 49% unoptimized yield of 38 indicating the general
stability of the O6-(benzotriazol-1H-yl) group to the reaction
conditions.
Table 3. Anti-CMV Activity of the Test Compounds in HEL
Cell Cultures
a
anti-CMV activity EC50
(μM)
HEL cell effects (μM)
AD-169
strain
Davis
strain
cell morphology
cell growth
c
b
compd
(MDC)
(IC50)
d
17
18
19
20
21
22
23
24
25
26
27
28
29
30
34
35
>50
118
>50
151
240
>240
>230
>270
>200
≥190
≥260
>230
>250
>240
>290
>210
>200
>270
≥40
nd
≥240
>230
nd
≥230
>270
≥200
120
≥230
>270
>200
123
d
>200
123
>250
nd
73
39
d
>230
≥250
>240
>290
>210
≥200
>270
>40
>230
158
188
nd
1
The H and 13C NMR spectra of 38 in CDCl3 showed the
d
d
d
>240
>290
>210
≥200
>270
>40
presence of three isomers, presumably the azide and the two
nd
tetrazolyl forms (T1 and T3). For example, three singlets are
nd
1
observed in the H NMR spectrum (δ 8.63, 8.58, and 8.55
>200
nd
d
d
d
ppm) corresponding to the purinyl resonances. Although only
two resonances are observed for H-1′ (δ 6.16 and 6.05 ppm),
the HMQC spectrum clearly shows three C-1′ resonances (δ
89.61, 89.06, 88.99 ppm). The three H-2′ resonances at δ 4.58
(22%), 4.54 (42%), and 4.47 ppm (36%) ppm were used to
determine the isomer ratio. At this time, no attempts have been
made to assign structures to these isomers. The IR spectrum of
38 showed an absorption at 2128 cm−1. Doubly reactive
compounds, such as 38, with two preinstalled reactive entities
can potentially be functionalized at the C-2 and the C-6 by
CuAAC and SNAr chemistry, respectively. Further work along
these lines is forthcoming.
Biological Activities of the New Compounds. The
compounds were evaluated for their antiviral activity against a
broad variety of DNA and RNA viruses. Several compounds
(i.e., 18, 22, and 25, see Table 3) showed marginal activity
against cytomegalovirus (CMV), whereas the anti-CMV activity
of 23 was somewhat more pronounced. Indeed, the inosine
derivative 23 showed activity against CMV in human
embryonic lung (HEL) cells at an EC50 of 39−73 μM. None
of the compounds showed antiviral activity against other viruses
at subtoxic concentrations except the inosine derivative 17 that
was endowed with moderate antivesicular stomatitis virus
(VSV) activity (27 2.4 μM) in human cervix carcinoma HeLa
cell cultures. This activity could not be confirmed in human
embryonic lung (HEL) fibroblast cell cultures against the same
virus, making the moderate activity rather cell-type specific. Yet,
in the HeLa and HEL cell cultures toxicity of 17 was observed
at 100−240 μM. This may also mean that the anti-VSV activity
noticed for 17 in the VSV/HeLa cell assay can be due to
underlying toxicity to the host cells, rather than to a specific
nd
>40
>40
200
nd
a
Effective concentration required to reduce virus plaque formation by
b
50%. Virus input was 100 plaque-forming units (PFU). Minimum
cytotoxic concentration that caused a microscopically detectable
c
alteration of cell morphology. Concentration required to reduce cell
d
growth by 50%. Not determined.
antiviral activity of the compound. From the antiviral assay
systems performed, compound 34 had the highest impact on
mammalian cell morphology, but this highly depended on the
nature of the cell line used as the virus host [minimum
detectable morphology-altering (cytotoxic) concentration
(MCC): 8.3 μM against canine kidney MDCK, 42 μM against
HeLa, 83 μM against feline kidney CRFK, 210 μM against
green monkey kidney Vero, and ≥40 μM against HeLa cells].
The inosine derivatives 17−24 and 2′-deoxyinosine deriva-
tives 25−30 were also evaluated for their cytostatic activity
against murine leukemia L1210, human lymphocyte CEM, and
HeLa cells. Modest cytostatic activity was noticed for several
compounds. In particular, the HeLa cells were usually
somewhat more sensitive to the inhibitory potential of these
compounds than the other cell lines. Also, the ribose derivatives
were consistently more cytostatic than their corresponding 2′-
deoxyribose derivatives. Among all compounds tested, 17
proved most cytostatic, irrespective the nature of the tumor cell
line (IC50: 34−124 μM). Both adenosine derivatives 34 and 35
were poorly cytostatic (IC50 for 34 98−185 μM, for 35 90−120
μM).
E
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All of the newly synthesized C-2 triazolyl nucleoside
analogues were also tested for their antiproliferative activity
using human ovarian cancer 1A9 cells and their paclitaxel-
resistant clones, 1A9-PTX10 and 1A9-PTX22, and colorectal
carcinoma HCT116 cells and their clones (Table 4). Several
to the O6-(benzotriazol-1H-yl) derivatives. SNAr substitution of
the benzotriazolyloxy group with amines then furnished C-2
triazolyl adenosine analogues. In addition, we have converted
silyl-protected O6-(benzotriazol-1H-yl)guanosine to a doubly
reactive 2-azido-O6-(benzotriazol-1H-yl)purine nucleoside de-
rivative. Interestingly, based upon the NMR results, this
compound appears to exist as the azide and two tetrazolyl
isomers. This nucleoside derivative, which can react at the C-2
via CuAAC and at the C-6 via SNAr, should find broad utility in
greatly diversifying the purine nucleoside scaffold via generally
simple operational procedures.
Table 4. GI50 (μM) of the Test Compounds against Ovarian
(1A9), Two Paclitaxel-Resistant (PTX10 and PTX22)
Ovarian, Colorectal (HCT116), and p53KO HCT116
Cancer Cell Lines
compd
1A9
PTX10
PTX22 HCT116
p53KO
17
18
19
20
21
22
23
24
25
26
27
28
29
30
34
35
22.8
38.0
29.5
20.4
6.32
29.7
37.0
34.0
31.0
37.2
49.4
49.6
41.6
46.1
0.18
5.0
>50
>50
>50
>50
>50
>50
>50
>50
>50
>50
>50
>50
>50
>50
11.73
>50
79
4.76
13.4
>50
>50
>50
>50
>50
>50
>50
>50
>50
>50
>50
>50
>50
>50
>50
>50
>50
42.6
>50
>50
>50
>50
>50
>50
>50
>50
>50
>50
10.4
>50
8.58
EXPERIMENTAL SECTION
■
General Experimental Considerations. Thin-layer chromatog-
raphy was performed on 250 μm silica plates, and column
chromatographic purifications were performed on 200−300 mesh
silica gel. CH2Cl2 was distilled over CaCl2, and THF and 1,2-DME
were distilled over LiAlH4 and then over Na prior to use. All other
reagents were obtained from commercial sources and were used as
received. 1H NMR spectra were recorded at 500 MHz, in the solvents
indicated, and are referenced to residual protonated solvent resonance.
13C NMR data were recorded at 125 MHz in the solvents indicated
and are referenced to the solvent resonance. In all cases, for HRMS
analyses ESI ionization and a TOF analyzer were used. Although 1a
and 1b are reported in the literature,25 larger scale syntheses are
described below.
8.56
3.53
14.1
12.9
28.1
31.0
14.8
15.7
32.9
32.2
18.0
26.9
O6-Allyl-2′,3′,5′-tri-O-(tert-butyldimethylsilyl)guanosine
(1a).25 In a clean, dry 100 mL round-bottomed flask equipped with a
stirring bar were placed O6-(benzotriazol-1H-yl)-2′,3′,5′-tri-O-(tert-
butyldimethylsilyl)guanosine25 (5.0 g, 6.7 mmol), allyl alcohol (50
mL), and Cs2CO3 (4.74 g, 14.1 mmol). The reaction mixture was
flushed with nitrogen gas and stirred at room temperature for 2 h after
which the mixture was evaporated to dryness. Chromatographic
purification of the crude material on a silica gel column using 20%
EtOAc in hexanes afforded 3.60 g (81% yield) of 1a as a white foam. Rf
0.95
3.7
24.5
68
43.61
6.85
paclitaxel (nM)
1.51
compounds were modestly active against 1A9 and 1A9-PTX22,
but all were inactive against 1A9-PTX10. Adenosine derivatives
34 and 35 showed the best activity against 1A9, and among the
two, 34 bearing a morpholinyl group at C-6 was most active
(0.18 μM). Inosine derivative 21 with a phthalimido triazolyl
substituent also showed activity at <10 μM. Against HCT116,
only 34 showed notable activity (3.7 μM), and this compound
was also active against HCT116 p53 knockout cells, albeit at a
higher concentration (10.4 μM). In the series, adenosine
derivative 34 emerged as the most interesting cytostatic
candidate showing activity against 1A9, 1A9-PTX22,
HCT116, and HCT116 p53 knockout cells.
1
(SiO2/20% EtOAc in hexanes) = 0.52. H NMR (CDCl3): δ 7.96 (s,
1H, Ar-H), 6.16−6.08 (m, 1H, CH), 5.92 (d, 1H, H-1′, J = 5.3 Hz),
5.41 (dd, 1H, CHtrans, J = 1.4, 17.2 Hz), 5.25 (dd, 1H, CHcis, J =
1.4, 10.2 Hz), 5.05 (s, 1H, NH2), 4.98 (d, 2H, OCH2, J = 5.7 Hz), 4.48
(t, 1H, H-2′, J = 4.6 Hz), 4.27 (t, 1H, H-3′, J = 3.4 Hz), 4.09 (app q,
1H, H-4′, Japp ≈ 3.2 Hz), 3.96 (dd, 1H, H-5′, J = 3.6, 11.4 Hz), 3.77
(dd, 1H, H-5′, J = 2.5, 11.4 Hz), 0.96, 0.95, and 0.82 (3s, 27H, t-Bu),
0.15, 0.14, 0.13, 0.12, −0.02, and −0.16 (6s, 18H, SiCH3). 13C NMR
(CDCl3): δ 160.7, 159.1, 153.8, 137.7, 132.7, 118.0, 115.6, 87.5, 85.2,
76.2, 72.0, 67.2, 62.6, 26.0, 25.8, 25.6, 18.5, 18.0, 17.9, −4.3, −4.7,
−5.0, −5.4. HRMS: calcd for C31H60N5O5Si3 [M + H]+ 666.3897,
found 666.3909.
CONCLUSIONS
■
In this paper, we describe syntheses of O6-allyl-2-azidoinosine
and 2′-deoxyinosine derivatives and their use in CuAAC
reactions. In contrast to the C-6 azidopurine nucleosides,
these C-2 azides do not exhibit significant azide·tetrazole
equilibrium, and the azido form appears to predominate. In
comparison, C-2 azidoadenosine analogues show a greater
proportion of the tetrazolyl form. This is possibly linked to the
greater electron-withdrawing allyloxy group at the C-6 position
in the present cases. The products from the CuAAC reactions
were desilylated and evaluated for their potential antiviral
activity. Unfortunately, none of the compounds proved
antivirally active at subtoxic concentrations with the exception
of compound 17 that was endowed with a moderate inhibitory
activity against vesicular stomatitis virus and compound 23,
which showed activity against cytomegalovirus. It is, however,
currently unclear whether the anti-VSV activity is a specific
antiviral effect or due to underlying compound toxicity.
O6-Allyl-3′,5′-di-O-(tert-butyldimethylsilyl)-2′-deoxyguano-
sine (1b).25 As described for the synthesis of 1a, this compound was
prepared by a reaction of O6-(benzotriazol-1H-yl)-3′,5′-di-O-(tert-
butyldimethylsilyl)-2′-deoxyguanosine25 (5.0 g, 8.16 mmol), allyl
alcohol (50 mL), and Cs2CO3 (5.64 g, 17.1 mmol). Chromatographic
purification of the crude material on a silica gel column using 30%
EtOAc in hexanes) afforded 3.71 g (87% yield) of 1b as a white foam.
1
Rf (SiO2/40% EtOAc in hexanes) = 0.60. H NMR (CDCl3): δ 7.93
(s, 1H, Ar-H), 6.34 (t, 1H, H-1′, J = 6.5 Hz), 6.17−6.09 (m, 1H, 
CH), 5.43 (dd, 1H, CHtrans, J = 1.4, 17.2 Hz), 5.27 (dd, 1H, 
CHcis, J = 1.4, 10.4 Hz), 5.01 (d, 2H, OCH2, J = 5.7 Hz), 4.94 (s, 1H,
NH2), 4.66−4.58 (m, 1H, H-3′), 3.99 (app q, 1H, H-4′, Japp ≈ 3.5 Hz),
3.83 (dd, 1H, H-5′, J = 4.4, 11.2 Hz), 3.77 (dd, 1H, H-5′, J = 3.4, 11.2
Hz), 2.57 (app quint, 1H, H-2′, Japp ≈ 6.5 Hz), 2.37 (ddd, 1H, H-2′, J =
4.0, 6.0, 13.0 Hz), 0.92 (s, 18H, t-Bu), 0.11 and 0.09 (2s, 12H, SiCH3).
13C NMR (CDCl3): δ 160.0, 159.2, 153.5, 137.8, 132.8, 118.4, 116.0,
87.8, 88.8, 72.1, 67.5, 63.0, 41.1, 26.1, 25.9, 18.6, 18.1, −4.4, −4.6,
−5.2, −5.3. HRMS: calcd for C25H46N5O4Si2 [M + H]+ 536.3083,
found 536.3093.
O6-Allyl-2-azido-2′,3′,5′-tri-O-(tert-butyldimethylsilyl)-
inosine (2a). To a solution of 1a (3.0 g, 4.5 mmol) in dry CH2Cl2 (40
The C-2 triazolylinosine nucleosides, which can be
considered as modified guanine analogues, were also converted
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mL) at −20 °C was added TMS-N3 (5.92 mL, 45.1 mmol) dropwise,
followed by the addition of t-BuONO (5.67 mL, 45.1 mmol). The
reaction mixture was stirred at −20 °C for 1 h and then brought to
room temperature and allowed to stir for 24 h. The reaction mixture
was diluted with MeOH/H2O (1:1), allowed to stir for 1 h, and then
extracted with CH2Cl2 (3 × 25 mL). The organic layer was washed
with water and brine. Evaporation of the solvent followed by
chromatographic purification on a silica gel column using 15% acetone
in hexanes afforded 1.83 g (59% yield) of 2a as a thick, pale-yellow oil.
Rf (SiO2/20% EtOAc in hexanes) = 0.60. IR (neat): 2958, 2927, 2857,
followed by brine. The organic layer was dried over Na2SO4 and
concentrated under reduced pressure. Chromatographic purification
on a silica gel column using 20% EtOAc in hexanes afforded 461.0 mg
(82% yield) of 3 as an off-white foam. Rf (SiO2/20% EtOAc in
hexanes) = 0.57. 1H NMR (CDCl3): δ 8.74 (s, 1H, Ar-H), 8.50 (s, 1H,
Ar-H), 7.96 (d, 2H, Ar-H, J = 7.8 Hz), 7.48 (t, 2H, Ar-H, J = 7.3 Hz),
7.39 (t, 1H, Ar-H, J = 7.3 Hz), 6.23−6.19 (m, 1H, CH), 6.17 (d,
1H, H-1′, J = 4.4 Hz), 5.57 (dd, 1H, CHtrans, J = 1.0, 17.2 Hz), 5.37
(d, 1H, CHcis, J = 10.3 Hz), 5.26 (d, 2H, OCH2, J = 6.3 Hz), 4.55 (t,
1H, H-2′, J = 4.4 Hz), 4.35 (t, 1H, H-3′, J = 4.2 Hz), 4.18 (br s, 1H, H-
4′), 4.10 (dd, 1H, H-5′, J = 3.4, 11.7 Hz), 3.84 (dd, 1H, H-5′, J = 2.0,
11.7 Hz), 0.97, 0.94, and 0.83 (3s, 27H, t-Bu), 0.18, 0.16, 0.11, 0.10,
−0.02, and −0.07 (6s, 18H, SiCH3). 13C NMR (CDCl3): δ 160.4,
151.8, 147.8, 147.0, 141.5, 131.1, 129.6, 128.2, 127.8, 125.3, 120.6,
119.6, 117.8, 88.1, 84.6, 75.8, 70.8, 68.2, 61.6, 25.5, 25.2, 25.0, 17.9,
17.5, 17.2, −4.9, −5.2, −5.3, −5.9. HRMS: calcd for C39H64N7O5Si3
[M + H]+ 794.4271, found 794.4281.
1
2929, 2856, 2126, 1597 cm−1. H NMR (CDCl3): δ 8.26 (s, 1H, Ar-
H), 6.23−6.12 (m, 1H, CH), 6.03 (d, 1H, H-1′, J = 4.8 Hz), 5.49
(dd, 1H, CHtrans, J = 1.2, 17.1 Hz), 5.34 (dd, 1H, CHcis, J = 1.2,
10.3 Hz), 5.11 (d, 2H, OCH2, J = 5.9 Hz), 4.51 (t, 1H, H-2′, J = 4.4
Hz), 4.32 (t, 1H, H-3′, J = 4.4 Hz), 4.13 (app q, 1H, H-4′, Japp ≈ 4.0
Hz), 4.03 (dd, 1H, H-5′, J = 3.9, 11.7 Hz), 3.77 (dd, 1H, H-5′, J = 2.5,
11.7 Hz), 0.95, 0.94, and 0.84 (3s, 27H, t-Bu), 0.17, 0.16, 0.12, 0.11,
−0.02, and −0.14 (6s, 18H, SiCH3). Resonances of the tetrazolyl form
(<10%): δ 8.29 (s, 1H, Ar-H), 4.60 (t, 1H, H-2′, J = 4.4 Hz), 4.34 (t,
1H, H-3′ J = 4.4 Hz), 4.06 (d, 1H, H-5′, J = 4.2 Hz). 13C NMR
(CDCl3): δ 160.9, 155.8, 153.0, 140.8, 131.9, 119.1, 119.0, 88.3, 85.1,
76.0, 71.5, 68.1, 62.2, 26.1, 25.8, 25.6, 18.5, 18.0, 17.8, −4.4, −4.6,
O6-Allyl-2-[4-(4-methylphenyl)-1,2,3-triazol-1H-yl]-2′,3′,5′-
tri-O-(tert-butyldimethylsilyl)inosine (4). Synthesized from 2a
(413.0 mg, 0.597 mmol) and 4-ethynyltoluene (138 μL, 1.19 mmol).
Chromatography of the crude reaction mixture on a silica gel column
using 15% EtOAc in hexanes yielded 380.1 mg (79% yield) of 4 as a
white, foamy solid. Rf (SiO2/20% EtOAc in hexanes) = 0.60. 1H NMR
(CDCl3): δ 8.70 (s, 1H, Ar-H), 8.50 (s, 1H, Ar-H), 7.85 (d, 2H, Ar-H,
J = 7.8 Hz), 7.30 (d, 2H, Ar-H, J = 7.8 Hz), 6.25−6.17 (m, 1H, 
CH), 6.16 (d, 1H, H-1′, J = 4.4 Hz), 5.56 (dd, 1H, CHtrans, J = 1.0,
17.1 Hz), 5.37 (dd, 1H, CHcis, J = 1.0, 10.1 Hz), 5.26 (d, 2H, OCH2,
J = 6.3 Hz), 4.52 (t, 1H, H-2′, J = 4.4 Hz), 4.35 (t, 1H, H-3′, J = 4.2
Hz), 4.18 (q, 1H, H-4′, J = 3.0 Hz), 4.10 (dd, 1H, H-5′, J = 3.4, 11.2
Hz), 3.84 (dd, 1H, H-5′, J = 2.4, 11.2 Hz), 2.41 (s, 3H, CH3), 0.97,
0.94, and 0.83, (3s, 27H, t-Bu), 0.18, 0.16, 0.11, 0.09, −0.02, and −0.06
(6s, 18H, SiCH3). 13C NMR (CDCl3): δ 161.0, 152.5, 148.6, 147.8,
142.2, 138.5, 131.9, 129.7, 129.1, 126.0, 121.2, 119.8, 118.2, 88.8, 85.3,
76.6, 71.5, 68.9, 62.3, 26.3, 26.0, 25.8, 21.4, 18.7, 18.2, 18.0, −4.1, −4.5,
−4.6, −5.1. HRMS: calcd for C40H66N7O5Si3 [M + H]+ 808.4428,
found 808.4435.
1
−4.8, −5.3. H NMR (DMSO-d6): δ 8.53 (s, 1H, Ar-H), 6.17−6. 09
(m, 1H, CH), 5.92 (d, 1H, H-1′, J = 5.8 Hz), 5.46 (d, 1H, CHtrans
,
J = 17.2 Hz), 5.33 (d, 1H, CHcis, J = 10.7 Hz), 5.06 (d, 2H, OCH2, J
= 5.4 Hz), 4.82 (t, 1H, H-2′, J = 4.9 Hz), 4.32 (t, 1H, H-3′, J = 3.0 Hz),
4.00−3.98 (m, 1H, H-4′), 3.95 (dd, 1H, H-5′, J = 4.6, 11.2 Hz), 3.74
(dd, 1H, H-5′, J = 3.7, 11.2 Hz), 0.91, 0.90, and 0.74 (3s, 27H, t-Bu),
0.13, 0.11, 0.10, 0.08, −0.07, and −0.30 (6s, 18H, SiCH3). Resonances
of the tetrazolyl form (<10%): δ 8.63 (s, 1H, Ar-H), 4.89 (t, 1H, H-2′ J
= 5.0 Hz), 4.38 (q, 1H, H-3′ J = 3.0 Hz). HRMS: calcd for
C31H58N7O5Si3 [M + H]+ 692.3802, found 692.3808.
O6-Allyl-2-azido-3′,5′-di-O-(tert-butyldimethylsilyl)-2′-deox-
yinosine (2b).34 As described for the synthesis of 2a, this compound
was prepared by a reaction 1b (3.0 g, 5.6 mmol) with TMS-N3 (10
molar equiv) and t-BuONO (10 molar equiv). Chromatographic
purification of the crude material on a silica gel column using 20%
EtOAc in hexanes afforded 1.98 g (63% yield) of 2b as a viscous,
yellow oil. Rf (SiO2/30% EtOAc in hexanes) = 0.63. IR (neat): 2956,
O6-Allyl-2-[4-(4-methoxyphenyl)-1,2,3-triazol-1H-yl]-2′,3′,5′-
tri-O-(tert-butyldimethylsilyl)inosine (5). Synthesized from 2a
(403.0 mg, 0.582 mmol) and 4-ethynylanisole (154 μL, 1.16 mmol).
Chromatography of the crude reaction mixture on a silica gel column
using 20% EtOAc in hexanes yielded 373.3 mg (78% yield) of 5 as a
white, foamy solid. Rf (SiO2/20% EtOAc in hexanes) = 0.46. 1H NMR
(CDCl3): δ 8.66 (s, 1H, Ar-H), 8.55 (s, 1H, Ar-H), 7.88 (d, 2H, Ar-H,
J = 8.3 Hz), 7.00 (d, 2H, Ar-H, J = 8.3 Hz), 6.22 (m, 1H, CH), 6.16
(d, 1H, H-1′, J = 3.9 Hz), 5.56 (d, 1H, CHtrans, J = 17.1 Hz), 5.36 (d,
1H, CHcis, J = 10.3 Hz), 5.25 (d, 2H, OCH2, J = 5.7 Hz), 4.47 (br t,
1H, H-2′, J = 3.9 Hz), 4.33 (t, 1H, H-3′, J = 3.9 Hz), 4.18 (br s, 1H, H-
4′), 4.10 (dd, 1H, H-5′, J = 2.9, 11.7 Hz), 3.86 (s, 3H, OCH3), 3.83 (br
d, 1H, H-5′, J = 11.7 Hz), 0.96, 0.91, and 0.82 (3s, 27H, t-Bu), 0.18,
0.15, 0.09, 0.079, −0.00, and −0.07 (6s, 18H, SiCH3). 13C NMR
(CDCl3): δ 161.2, 160.0, 152.6, 148.6, 147.6, 142.2, 131.9, 127.4,
123.01, 121.3, 119.8, 117.7, 114.5, 88.7, 85.3, 76.6, 71.6, 68.9, 62.3,
55.5, 26.3, 26.0, 25.8, 18.7, 18.2, 18.0, −4.1, −4.9, −4.5, −4.6, −5.1,
−5.2. HRMS: calcd for C40H66N7O6Si3 [M + H]+ 824.4377, found
824.4380.
1
2930, 2857, 2130, 1600 cm−1. H NMR (CDCl3): δ 8.18 (s, 1H, Ar-
H), 6.42 (t, 1H, H-1′, J = 6.4 Hz), 6.18−6.11 (m, 1H, CH), 5.49
(dd, 1H, CHtrans, J = 1.4, 17.2 Hz), 5.33 (dd, 1H, CHcis, J = 1.4,
10.2 Hz), 5.11 (d, 2H, OCH2, J = 5.8 Hz), 4.61−4.59 (m, 1H, H-3′),
4.01 (app q, 1H, H-4′, Japp ≈ 3.4 Hz), 3.88 (dd, 1H, H-5′, J = 4.0, 10.2
Hz), 3.79 (dd, 1H, H-5′, J = 3.0, 10.2 Hz), 2.56 (app quint, 1H, H-2′,
Japp ≈ 6.5 Hz), 2.43 (ddd, 1H, H-2′, J = 3.9, 5.9, 10.3 Hz), 0.93 and
0.92 (2s, 18H, t-Bu), 0.11 (s, 12H, SiCH3). Resonances of the
tetrazolyl form (<5%): δ 8.25 (s, 1H, Ar-H), 4.64−4.63 (m, 1H, H-3′),
2.64−2.62 (m, 1H, H-2′). 13C NMR (CDCl3): δ 161.0, 155.8, 153.0,
140.6, 132.1, 119.3, 88.1, 84.5, 71.9, 68.6, 68.2, 62.9, 41.6, 26.1, 25.9,
18.5, 18.1, −4.4, −4.6, −5.3. 1H NMR (DMSO-d6): δ 8.47 (s, 1H, Ar-
H), 6.32 (t, 1H, H-1′, J = 6.4 Hz), 6.16−6.09 (m, 1H, CH), 5.46 (d,
1H, CHtrans, J = 18.0 Hz), 5.33 (d, 1H, CHcis, J = 10.7 Hz), 5.07
(d, 2H, OCH2, J = 5.4 Hz), 4.62 (m, 1H, H-3′), 3.58 (d, 1H, H-4′, J =
4.0 Hz), 3.78 (dd, 1H, H-5′, J = 5.9, 11.2 Hz), 3.67 (dd, 1H, H-5′, J =
4.4, 11.2 Hz), 2.90 (app quint, 1H, H-2′, Japp ≈ 6.5 Hz), 2.34 (dd, 1H,
H-2′, J = 5.2, 11.2 Hz), 0.93 and 0.83 (2s, 18H, t-Bu), 0.12, 0.01, and
−0.0.1 (3s, 12H, SiCH3). Resonances of the tetrazolyl form (<10%): δ
8.57 (s, 1H, Ar-H), 4.70 (m, 1H, H-3′), 0.81 (s, 18H, t-Bu), 0.13, 0.04,
and −0.03 (3s, 12H, SiCH3). HRMS: calcd for C25H43N7O4Si2Na [M
+ Na]+ 584.2807 found: 584.2818.
O6-Allyl-2-[4-(hydroxymethyl)-1,2,3-triazol-1H-yl]-2′,3′,5′-
tri-O-(tert-butyldimethylsilyl)inosine (6). Synthesized from 2a
(368.0 mg, 0.532 mmol) and propargyl alcohol (61 μL, 1.06 mmol).
Chromatography of the crude reaction mixture on a silica gel column
using 40% EtOAc in hexanes yielded 311.3 mg (79% yield) of 6 as a
white, foamy solid. Rf (SiO2/40% EtOAc in hexanes) = 0.48. 1H NMR
(CDCl3): δ 8.54 (s, 1H, Ar-H), 8.49 (s, 1H, Ar-H), 6.25−6.18 (m, 1H,
CH), 6.16 (d, 1H, H-1′, J = 4.3 Hz), 5.56 (dd, 1H, CHtrans, J =
1.5, 17.2 Hz), 5.38 (dd, 1H, CHcis, J = 1.5, 10.3 Hz), 5.24 (d, 2H,
OCH2, J = 5.6 Hz), 4.97 (s, 2H, CH2), 4.58 (t, 1H, H-2′ J = 4.2 Hz),
4.35 (t, 1H, H-3′, J = 4.2 Hz), 4.19 (q, 1H, H-4′, J = 3.6 Hz), 4.09 (dd,
1H, H-5′, J = 3.6, 11.6 Hz), 3.85 (dd, 1H, H-5′, J = 2.0, 11.6 Hz), 0.99,
0.96, and 0.83 (3s, 27H, t-Bu), 0.20, 0.18, 0.13, 0.12, 0.02, and −0.11
(6s, 18H, SiCH3). 13C NMR (CDCl3): δ 161.1, 152.5, 148.5, 147.9,
142.4, 131.8, 121.9, 121.1, 119.7, 88.8, 85.5, 76.5, 71.7, 68.9, 62.4, 56.6,
Typical Procedure for the Ligation Reactions of 2a. O6-Allyl-
2-(4-phenyl-1,2,3-triazol-1H-yl)-2′,3′,5′-tri-O-(tert-
butyldimethylsilyl)inosine (3). Azide 2a (492.0 mg, 0.711 mmol)
and CuCl (14.0 mg. 0.2 mol %) were suspended in 8 mL of t-BuOH/
H2O (1:1), and the reaction mixture was flushed with nitrogen gas.
Phenylacetylene (155 μL, 1.42 mmol) was added, and the
heterogeneous mixture was stirred at room temperature until TLC
revealed no starting material (see Table 2 for reaction times). The
reaction mixture was diluted with CH2Cl2 and washed with water
G
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Featured Article
26.2, 25.9, 25.7, 18.6, 18.2, 17.9, −4.1, −4.5, −4.6, −4.7, −5.2. HRMS:
calcd for C34H62N7O6Si3 [M + H]+ 748.4064, found 748.4064.
O6-Allyl-2-[4-(N-phthalimidomethyl)-1,2,3-triazol-1H-yl]-
2′,3′,5′-tri-O-(tert-butyldimethylsilyl)inosine (7). Synthesized
from 2a (418 mg, 0.604 mmol) and N-propargylphthalimide (223.0
mg, 1.20 mmol). Chromatography of the crude reaction mixture on a
silica gel column using 20% EtOAc in hexanes yielded 435.3 mg (82%
yield) of 7 as an off-white, foamy solid. Rf (SiO2/20% EtOAc in
hexanes) = 0.44. 1H NMR (CDCl3): δ 8.53 (s, 1H, Ar-H), 8.49 (s, 1H,
Ar-8), 7.89 (dd, 2H, Ar-H, J = 3.2, 5.4 Hz), 7.74 (dd, 2H, Ar-H, J =
3.2, 5.4 Hz), 6.22−6.14 (m, 1H, CH), 6.10 (d, 1H, H-1′, J = 4.1
Hz), 5.56 (dd, 1H, CHtrans, J = 1.2, 17.2 Hz), 5.35 (br d, 1H, 
CHcis, J = 10.4 Hz), 5.22 (d, 2H, OCH2, J = 5.9 Hz), 5.12 (s, 2H,
NCH2), 4.51 (t, 1H, H-2′, J = 4.0 Hz), 4.34 (t, 1H, H-3′, J = 4.0 Hz),
4.17 (app q, 1H, H-4′, Japp ≈ 4.0 Hz), 4.10 (dd, 1H, H-5′, J = 3.5, 11.6
Hz), 3.82 (dd, 1H, H−5′, J = 2.6, 11.6 Hz), 0.96, 0.93, and 0.81 (3s,
27H, t-Bu), 0.17, 0.15, 0.11, 0.08, 0.00, and −0.10 (6s, 18H, SiCH3).
13C NMR (CDCl3): δ 167.6, 161.1, 152.4, 148.4, 143.0, 142.3, 142.3,
134.2, 132.2, 123.6, 122.1, 121.2, 119.8, 88.9, 85.2, 76.5, 71.4, 68.9,
62.2, 33.2, 26.2, 25.9, 25.7, 18.6, 18.2, 17.9, −4.1, −4.6, −5.1, −5.2.
HRMS: calcd for C42H65N8O7Si3 [M + H]+ 877.4279, found 877.4293.
O6-Allyl-2-(4-ferrocenyl-1,2,3-triazol-1H-yl)-2′,3′,5′-tri-O-
(tert-butyldimethylsilyl)inosine (8). Synthesized from 2a (482.0
mg, 0.697 mmol) and ethynylferrocene (292.0 mg, 1.39 mmol).
Chromatography of the crude reaction mixture on a silica gel column
using 10% EtOAc in hexanes yielded 492.8 mg (78% yield) of 8 as a
brown, foamy solid. Rf (SiO2/20% EtOAc in hexanes) = 0.62. 1H
NMR (CDCl3): δ 8.53 (s, 1H, Ar-H), 8.43 (s, 1H, Ar-H), 6.26−6.19
(m, 1H, CH), 6.18 (d, 1H, H-1′, J = 3.9 Hz), 5.58 (br d, 1H, 
CHtrans, J = 17.1 Hz), 5.38 (br d, 1H, CHcis, J = 10.4 Hz), 5.27 (d,
2H, OCH2, J = 5.8 Hz), 4.84 (app q, 1H, ferrocenyl-H, Japp ≈ 1.9 Hz),
4.82 (app q, 1H, ferrocenyl-H, Japp ≈ 1.9 Hz), 4.52 (t, 1H, H-2′ J = 4.3
Hz), 4.35 (d, 2H, ferrocenyl-H, J = 1.9 Hz), 4.34 (t, 1H, H-3′, J = 3.9
Hz), 4.18 (br s, 1H, H-4′), 4.12 (s, 5H, ferrocenyl-H), 4.09 (dd, 1H,
H-5′, J = 3.5, 11.5 Hz), 3.84 (dd, 1H, H-5′, J = 2.3, 11.5 Hz), 1.00, 0.96,
and 0.87 (3s, 27H, t-Bu), 0.21, 0.19, 0.14, 0.12, 0.05, and −0.03 (6s,
18H, SiCH3). 13C NMR (CDCl3): δ 161.0, 152.4, 148.3, 146.9, 141.8,
131.8, 120.9, 119.7, 117.2, 88.5, 85.1, 76.6, 74.7, 71.3, 69.5, 68.8, 68.7,
66.8, 62.1, 26.1, 25.8, 25.6, 18.5, 18.0, 17.8, −4.3, −4.6, −4.7, −4.8,
−5.3, −5.4. HRMS: calcd for C43H68FeN7O5Si3 [M + H]+ 902.3934,
found 902.3936.
1H, CHtrans, J = 1.0, 17.2 Hz), 5.39 (dd, 1H, CHcis, J = 1.0, 10.4
Hz), 5.29 (d, 2H, OCH2, J = 5.9 Hz), 4.57 (t, 1H, H-2′, J = 4.2 Hz),
4.37 (t, 1H, H-3′, J = 4.2 Hz), 4.20 (br s, 1H, H-4′), 4.11 (dd, 1H, H-5′,
J = 3.6, 11.6 Hz), 3.82 (dd, 1H, H-5′, J = 2.1, 11.6 Hz), 0.99, 0.96, and
0.85 (3s, 27H, t-Bu), 0.20, 0.18, 0.13, 0.12, 0.04, and −0.06 (6s, 18H,
1
SiCH3). 13C NMR (CDCl3): δ 164.1 and 162.1 (d, J = 246.8 Hz),
3
161.2, 152.6, 148.5, 146.9, 142.4, 131.9, 128.0 and 127.9 (d, J = 8.2
2
Hz), 126.6, 121.4, 119.8, 118.2, 116.2 and 116.0 (d, J = 21.8 Hz),
88.8, 85.5, 76.7, 71.6, 69.0, 62.4, 26.3, 26.0, 25.8, 18.7, 18.3, 18.0, −4.1,
−4.4, −4.5, −4.6, −5.1. HRMS: calcd for C39H62FN7O5Si3Na [M +
Na]+ 834.3996, found 834.3993.
O6-Allyl-2-(4-phenyl-1,2,3-triazol-1H-yl)-3′,5′-di-O-(tert-bu-
tyldimethylsilyl)-2′-deoxyinosine (11). Synthesized from 2b
(320.0 mg, 0.569 mmol) and phenylacetylene (125 μL, 1.13 mmol).
Chromatography of the crude reaction mixture on a silica gel column
using 30% EtOAc in hexanes yielded 281.2 mg (74% yield) of 11 as an
1
off-white, foamy solid. Rf (SiO2/20% EtOAc in hexanes) = 0.50. H
NMR (CDCl3): δ 8.76 (s, 1H, Ar-H), 8.41 (s, 1H, Ar-H), 7.99 (d, 2H,
Ar-H, J = 8.0 Hz), 7.49 (t, 2H, Ar-H, J = 7.5 Hz), 7.40 (t, 1H, Ar-H, J
= 7.5 Hz), 6.64 (t, 1H, H-1′, J = 6.2 Hz), 6.26−6.19 (m, 1H, CH),
5.58 (d, 1H, CHtrans, J = 17.2 Hz), 5.39 (d, 1H, CHcis, J = 10.4
Hz), 5.27 (d, 2H, OCH2, J = 5.3 Hz), 4.68 (br s, 1H, H-3′), 4.07 (m,
1H, H-4′), 3.95 (br d, 1H, H-5′, J = 11.3 Hz), 3.79 (br d, 1H, H-5′, J =
11.3 Hz), 2.62 (app quint, 1H, H-2′, Japp ≈ 6.5 Hz), 2.58−2.54 (m, 1H,
H-2′), 0.95 (s, 18H, t-Bu), 0.14 (s, 12H, SiCH3). 13C NMR (CDCl3):
δ 161.1, 152.5, 148.5, 147.9, 142.0, 131.9, 130.3, 129.0, 128.7, 126.2,
121.1, 119.8, 118.8, 88.3, 84.7, 71.9, 69.0, 62.9, 42.2, 26.2, 25.9, 18.6,
18.2, −4.3, −4.5, −5.1, −5.2. HRMS: calcd for C33H49N7O4Si2Na [M
+ Na]+ 686.3277, found 686.3285.
O6-Allyl-2-[4-(4-methoxyphenyl)-1,2,3-triazol-1H-yl]-3′,5′-di-
O-(tert-butyldimethylsilyl)-2′-deoxyinosine (12). Synthesized
from 2b (352.0 mg, 0.626 mmol) and 4-ethynylanisole (165 μL,
1.25 mmol). Chromatography of the crude reaction mixture on a silica
gel column using 40% EtOAc in hexanes yielded 302.3 mg (78% yield)
of 12 as an off-white, foamy solid. Rf (SiO2/30% EtOAc in hexanes) =
1
0.54. H NMR (CDCl3): δ 8.67 (s, 1H, Ar-H), 8.42 (s, 1H, Ar-H),
7.91 (d, 2H, Ar-H, J = 8.0 Hz), 7.02 (d, 2H, Ar-H, J = 8.0 Hz), 6.64 (br
s, 1H, H-1′), 6.17 (br m, 1H, CH), 5.58 (d, 1H, CHtrans, J = 17.0
Hz), 5.38 (d, 1H, CHcis, J = 10.3 Hz), 5.26 (br d, 2H, OCH2, J = 4.6
Hz), 4.68 (br s, 1H, H-3′), 4.06 (br s, 1H, H-4′), 3.94 (br d, 1H, H-5′, J
= 11.2 Hz), 3.88 (s, 3H, OCH3), 3.83 (br d, 1H, H-5′, J = 11.2 Hz),
2.64−2.54 (br m, 2H, H-2′), 0.94 (s, 18H, t-Bu), 0.14 (s, 12H, SiCH3).
13C NMR (CDCl3): 161.1, 160.0, 152.5, 148.6, 147.7, 142.1, 132.0,
127.5, 123.0, 121.2, 119.7, 117.9, 114.5, 88.3, 84.7, 71.9, 68.9, 62.9,
55.5, 42.1, 26.1, 25.9, 18.6, 18.2, −4.3, −4.5, −4.9, −5.3. HRMS: calcd
for C34H51N7O5Si2Na [M + Na]+ 716.3382, found 716.3395.
O6-Allyl-2-(4-n-butyl-1,2,3-triazol-1H-yl)-2′,3′,5′-tri-O-(tert-
butyldimethylsilyl)inosine (9). Synthesized from 2a (595.0 mg,
0.860 mmol) and propargyl alcohol (197 μL, 1.72 mmol).
Chromatography of the crude reaction mixture on a silica gel column
using 15% EtOAc in hexanes yielded 501.3 mg (75% yield) of 9 as a
white, foamy solid. Rf (SiO2/20% EtOAc in hexanes) = 0.48. 1H NMR
(CDCl3): δ 8.48 (s, 1H, Ar-H), 8.26 (s, 1H, Ar-H), 6.25−6.17 (m, 1H,
CH), 6.16 (d, 1H, H-1′, J = 4.3 Hz), 5.56 (dd, 1H, CHtrans, J =
1.4, 17.2 Hz), 5.38 (dd, 1H, CHcis, J = 1.4, 10.5 Hz), 5.25 (d, 2H,
OCH2, J = 5.9 Hz), 4.54 (t, 1H, H-2′, J = 4.2 Hz), 4.35 (t, 1H, H-3′, J =
4.3 Hz), 4.18 (app q, 1H, H-4′, Japp ≈ 3.5 Hz), 4.09 (dd, 1H, H-5′, J =
3.5, 11.5 Hz), 3.84 (dd, 1H, H-5′, J = 2.2, 11.5 Hz), 2.84 (t, 2H, butyl-
CH2, J = 7.6 Hz), 1.75 (quint, 2H, butyl-CH2, J = 7.6 Hz), 1.46 (sextet,
2H, butyl-CH2, J = 7.5 Hz), 0.99 (t, 3H, butyl-CH3, J = 7.5 Hz), 0.98,
0.95, and 0.83 (3s, 27H, t-Bu), 0.19, 0.17, 0.12, 0.11, −0.02, and −0.09
(6s, 18H, SiCH3). 13C NMR (CDCl3): δ 161.3, 152.6, 148.8, 148.6,
142.2, 132.0, 121.2, 120.1, 119.8, 88.9, 85.4, 76.7, 71.7, 69.0, 62.5, 31.6,
26.4, 26.1, 25.9, 25.5, 22.5, 18.8, 18.3, 18.1, 14.0, −4.1, −4.4, −4.5,
−4.6, −5.1. HRMS: calcd for C37H68N7O5Si3 [M + H]+ 774.4584,
found 774.4582.
O6-Allyl-2-[4-(hydroxymethyl)-1,2,3-triazol-1H-yl]-3′,5′-di-O-
(tert-butyldimethylsilyl)-2′-deoxyinosine (13). Synthesized from
2b (350.0 mg, 0.622 mmol) and propargyl alcohol (272 μL, 1.24
mmol). Chromatography of the crude reaction mixture on a silica gel
column using 50% EtOAc in hexanes yielded 272.1 mg (70% yield) of
13 as a white, foamy solid. Rf (SiO2/40% EtOAc in hexanes) = 0.21.
1H NMR (CDCl3): δ 8.55 (s, 1H, Ar-H), 8.40 (s, 1H, Ar-H), 6.59 (t,
1H, H−1′, J = 6.3 Hz), 6.20−6.15 (m, 1H, CH), 5.52 (d, 1H, 
CHtrans, J = 17.2 Hz), 5.34 (d, 1H, CHcis, J = 10.4 Hz), 5.20 (d, 2H,
OCH2, J = 5.9 Hz), 4.93 (d, 2H, CH2, J = 5.9 Hz), 4.65 (app q, 1H, H-
3′, Japp ≈ 4.5 Hz), 4.02 (br d, 1H, H-4′ J = 3.2 Hz), 3.91 (dd, 1H, H-5′,
J = 3.5, 11.5 Hz), 3.80 (dd, 1H, H−5′, J = 2.7, 11.3 Hz), 3.01 (t, 1H,
OH, J = 5.9 Hz), 2.60 (app quint, 1H, H-2′, Japp ≈ 6.5 Hz), 2.56−2.52
(ddd, 1H, H-2′ J = 4.5, 6.0, 10.6 Hz), 0.92 (s, 18H, t-Bu), 0.11 (s, 12H,
SiCH3). 13C NMR (CDCl3): δ 161.1, 152.4, 148.4, 148.0, 142.2, 131.9,
121.4, 121.2, 119.7, 88.3, 84.7, 71.8, 68.9, 62.9, 56.8, 42.1, 26.1, 25.9,
18.6, 18.2, −4.4, −4.5, −5.1, −5.2. HRMS: calcd for C28H47N7O5Si2Na
[M + Na]+ 640.3069, found 640.3077.
O6-Allyl-2-[4-(4-fluorophenyl)-1,2,3-triazol-1H-yl]-2′,3′,5′-tri-
O-(tert-butyldimethylsilyl)inosine (10). Synthesized from 2a
(600.0 mg, 0.867 mmol) and 4-ethynylfluorobenzene (200 μL, 1.73
mmol). Chromatography of the crude reaction mixture on a silica gel
column using 15% EtOAc in hexanes yielded 500.1 mg (71% yield) of
10 as an off-white, foamy solid. Rf (SiO2/20% EtOAc in hexanes) =
O6-Allyl-2-[4-(N-phthalimidomethyl)-1,2,3-triazol-1H-yl]-
3′,5′-di-O-(tert-butyldimethylsilyl)-2′-deoxyinosine (14). Syn-
thesized from 2b (365.0 mg, 0.649 mmol) and N-propargylphthali-
mide (240 μL, 1.29 mmol). Chromatography of the crude reaction
mixture on a silica gel column using 35% EtOAc in hexanes yielded
351.8 mg (73% yield) of 14 as a white, foamy solid. Rf (SiO2/20%
1
0.61. H NMR (CDCl3): δ 8.70 (s, 1H, Ar-H), 8.52 (s, 1H, Ar-H),
7.95 (dd, 2H, Ar-H, J = 5.3, 8.6 Hz), 7.19 (t, 2H, Ar-H, J = 8.6 Hz),
6.27−6.19 (m, 1H, CH), 6.08 (d, 1H, H-1′, J = 4.3 Hz), 5.57 (dd,
H
dx.doi.org/10.1021/jo300628y | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Featured Article
1
EtOAc in hexanes) = 0.28. H NMR (CDCl3): δ 8.56 (s, 1H, Ar-H),
H-4′, Japp ≈ 3.6 Hz), 3.71 (ddd, 1H, H-5′, J = 2.8, 7.2, 11.2 Hz), 3.63
(ddd, 1H, H-5′, J = 5.0, 7.2, 11.2 Hz).
8.39 (s, 1H, Ar-H), 7.88 (dd, 2H, Ar-H, J = 3.0, 5.5 Hz), 7.74 (dd, 2H,
Ar-H, J = 3.0, 5.5 Hz), 6.57 (t, 1H, H-1′, J = 6.3 Hz), 6.21−6.13 (m,
1H, CH), 5.53 (dd, 1H, CHtrans, J = 1.4, 17.2 Hz), 5.34 (dd, 1H,
CHcis, J = 1.4, 10.4 Hz), 5.20 (d, 2H, OCH2, J = 5.9 Hz), 5.12 (s,
2H, NCH2), 4.64 (app q, 1H, H-3′, Japp ≈ 4.0), 4.02 (app q, 1H, H-4′,
Japp ≈ 3.3 Hz), 3.92 (dd, 1H, H-5′, J = 3.5, 11.3 Hz), 3.80 (dd, 1H, H-
5′, J = 2.9, 11.3 Hz), 2.57 (app quint, 1H, H-2′, Japp ≈ 6.5 Hz), 2.50
(ddd, 1H, H-2′, J = 4.5, 6.3, 10.6 Hz), 0.92 and 0.90 (2s, 18H, t-Bu),
0.12 and 0.10 (2s, 12H, SiCH3). 13C NMR (CDCl3): δ 167.5, 160.9,
152.1, 148.1, 142.8, 141.8, 134.1, 132.0, 131.7, 123.4, 122.2, 119.5,
88.1, 84.5, 71.6, 68.7, 62.6, 58.1, 41.9, 33.0, 25.9, 25.7, 18.4, 18.0, −4.6,
−4.8, −5.3, −5.5. HRMS: calcd for C36H50N8O6Si2Na [M + Na]+
769.3284, found 769.3290.
Step 2: Deallylation. A solution of PhSO2Na (14.5 mg, 0.088
mmol) in MeOH (1.0 mL) was added to a suspension of the
desilylated product obtained in step 1 (40.0 mg, 0.088 mmol) and
Pd(PPh3)4 (5.1 mg, 5 mol %) in dry THF (2.0 mL), at room
temperature. The reaction mixture was stirred at room temperature for
2 h, at which time TLC revealed no starting material. The reaction
mixture was concentrated under reduced pressure and triturated with
EtOAc to give 26.4 mg (72% yield) of 17 as a white solid. Rf (SiO2/
1
MeOH) = 0.54. H NMR (DMSO-d6): δ 9.07 (s, 1H, Ar-H), 8.01 (s,
1H, Ar-H), 7.98 (d, 2H, Ar-H, J = 7.8 Hz), 7.48 (t, 2H, Ar-H, J = 7.3
Hz), 7.36 (t, 1H, Ar-H, J = 7.3 Hz), 5.86 (d, 1H, H-1′, J = 6.3 Hz),
5.46 (d, 1H, OH, J = 6.3 Hz), 5.20 (d, 1H, OH, J = 4.6 Hz), 5.08 (t,
1H, OH, J = 6.0 Hz), 4.66 (app q, 1H, H-2′, Japp ≈ 5.9 Hz), 4.19 (app
q, 1H, H-3′, Japp ≈ 4.0 Hz), 3.95 (q, 1H, H-4′, J = 3.4 Hz), 3.71−3.66
(m, 1H, H-5′), 3.59−3.54 (m, 1H, H-5′). 13C NMR (DMSO-d6): δ
167.8, 151.5, 150.6, 147.4, 137.8, 131.9, 129.6, 128.8, 126.0, 125.5,
120.6, 87.9, 86.2, 73.9, 71.4, 62.5. HRMS: calcd for C18H17N7O5Na [M
+ Na]+ 434.1183, found 434.1200.
O6-Allyl-2-(4-ferrocenyl-1,2,3-triazol-1H-yl)-3′,5′-di-O-(tert-
butyldimethylsilyl)-2′-deoxyinosine (15). Synthesized from 2b
(595.0 mg, 1.05 mmol) and ethynylferrocene (444 μL, 2.11 mmol).
Chromatography of the crude reaction mixture on a silica gel column
using 20% EtOAc in hexanes yielded 620.2 mg (72% yield) of 15 as a
reddish-brown, foamy solid. Rf (SiO2/30% EtOAc in hexanes) = 0.30.
1H NMR (CDCl3): δ 8.40 (s, 1H, Ar-H), 8.35 (s, 1H, Ar-H), 6.64 (br
s, 1H, H-1′), 6.23 (br m, 1H, CH), 5.57 (d, 1H, CHtrans, J = 17.0
Hz), 5.40 (d, 1H, CHcis, J = 10.0 Hz), 5.26 (br s, 2H, OCH2), 5.04
(br s, 2H, ferrocenyl-H), 4.66 (br s, 1H, H-3′), 4.54(br s, 2H,
ferrocenyl-H), 4.28 (br s, 5H, ferrocenyl-H), 4.06 (br s, 1H, H-4′),
3.93 (dd, 1H, H-5′, J = 3.0, 11.2 Hz), 3.82 (dd, 1H, H-5′, J = 2.0, 11.2
Hz), 2.59−2.57 (br m, 2H, H-2′), 0.95 and 0.94 (2s, 18H, t-Bu), 0.14
and 0.13 (2s, 12H, SiCH3). 13C NMR (CDCl3) δ 161.2, 152.6, 148.7,
147.3, 142.0, 132.1, 121.1, 119.8, 117.7, 88.4, 84.6, 72.0, 69.8, 69.1,
69.0, 67.2, 67.1, 63.0, 42.3, 26.2, 26.0, 18.7, 18.3, −4.4, −4.6, −5.1,
−5.3. HRMS: calcd for C37H54FeN7O4Si2 [M + H]+ 772.3120, found
772.3126.
2-[4-(4-Methylphenyl)-1,2,3-triazol-1H-yl]inosine (18). Step
1: Desilylation. Using the procedure described for 17, this compound
was synthesized from 4 (300.0 mg, 0.371 mmol) and Et3N·3HF (300
μL, 1.85 mmol). Chromatography of the crude reaction mixture on a
silica gel column using 10% MeOH in EtOAc yielded 130.8 mg (76%
yield) of the O6-allyl-protected nucleoside as a white, foamy solid. Rf
1
(SiO2/10% MeOH in EtOAc) = 0.27. H NMR (DMSO-d6): δ 9.37
(s, 1H, Ar-H), 8.74 (s, 1H, Ar-H), 7.95 (d, 2H, Ar-H, J = 7.9 Hz), 7.32
(d, 2H, Ar-H, J = 7.9 Hz), 6.26−6.18 (m, 1H, CH), 6.08 (d, 1H, H-
1′, J = 5.8 Hz), 5.57 (d, 1H, OH, J = 5.4 Hz), 5.56 (br s, 1H, 
CHtrans), 5.38 (d, 1H, CHcis, J = 10.5 Hz), 5.31 (d, 1H, OH, J = 5.6
Hz), 5.28 (d, 2H, OCH2, J = 5.7 Hz), 5.04 (t, 1H, OH, J = 5.5 Hz),
4.66 (app q, 1H, H-2′, Japp ≈ 5.5 Hz), 4.22 (app q, 1H, H-3′, Japp ≈ 4.0
Hz), 4.00 (br d, 1H, H-4′, J = 3.5 Hz), 3.74−3.69 (m, 1H, H-5′), 3.63−
3.59 (m, 1H, H-5′), 2.36 (s, 3H, CH3).
O6-Allyl-2-(4-n-butyl-1,2,3-triazol-1H-yl)-3′,5′-di-O-(tert-bu-
tyldimethylsilyl)-2′-deoxyinosine (16). Synthesized from 2b
(393.0 mg, 0.699 mmol) and 1-hexyne (160 μL, 1.39 mmol).
Chromatography of the crude reaction mixture on a silica gel column
using 20% EtOAc in hexanes yielded 320.1 mg (71% yield) of 16 as a
white, foamy solid. Rf (SiO2/20% EtOAc in hexanes) = 0.40. 1H NMR
(CDCl3): δ 8.41 (s, 1H, Ar-H), 8.28 (s, 1H, Ar-H), 6.62 (t, 1H, H-1′, J
= 6.3 Hz), 6.23−6.15 (m, 1H, CH), 5.53 (dd, 1H, CHtrans, J = 1.4,
17.2 Hz), 5.36 (dd, 1H, CHcis, J = 1.4, 10.4 Hz), 5.22 (d, 2H, OCH2,
J = 5.9 Hz), 4.64 (m, 1H, H-3′), 4.02 (app q, 1H, H-4′, Japp ≈ 3.5 Hz),
3.92 (dd, 1H, H-5′, J = 3.4, 11.3 Hz), 3.81 (dd, 1H, H-5′, J = 2.7, 11.3
Hz), 2.83 (t, 2H, butyl-CH2, J = 7.7 Hz), 2.57 (app quint, 1H, H-2′,
Japp ≈ 6.5 Hz), 2.52 (ddd, 1H, H-2′, J = 4.3, 6.3, 11.0 Hz), 1.74 (quint,
2H, butyl-CH2, J = 7.5 Hz), 1.44 (sextet, 2H, butyl-CH2, J = 7.5 Hz),
0.96 (t, 3H, butyl-CH3, J = 7.5 Hz), 0.93 and 0.92 (2s, 18H, t-Bu), 0.12
and 0.11 (2s, 12H, SiCH3). 13C NMR (CDCl3): δ 160.9, 152.3, 148.6,
148.5, 141.9, 131.8, 120.9, 120.0, 119.5, 88.1, 84.5, 71.7, 68.7, 62.8,
41.9, 31.5, 26.0, 25.8, 25.3, 22.3, 18.5, 18.0, 13.8, −4.5, −4.7, −5.3,
−5.4. HRMS: calcd for C31H54N7O4Si2 [M + H]+ 644.3770, found
644.3777.
Typical Procedure for Disilylation and Deallylation Reac-
tions of the Triazolyl Nucleosides. 2-(4-Phenyl-1,2,3-triazol-
1H-yl)inosine (17). Step 1: Desilylation. Et3N·3HF (389 μL, 2.39
mmol) was added to a solution of 3 (380.0 mg, 0.47 mmol) in dry
THF (5.0 mL), and the reaction mixture was stirred at room
temperature for 24 h. The mixture was evaporated under a stream of
nitrogen gas using a polypropylene pipet. The crude product was
purified by chromatography on silica gel column using 10% MeOH in
EtOAc to give 171.2 mg (80% yield) of the O6-allyl-protected
nucleoside as colorless, amorphous solid. Rf (SiO2/10% MeOH in
Step 2: Deallylation. The desilylated product (80.0 mg, 0.172
mmol) obtained in step 1 was deallylated as described for 17 using
Pd(PPh3)4 (5.1 mg, 5 mol %) and PhSO2Na (26.9 mg, 0.172 mmol)
to yield 52.2 mg (71% yield) of 18 as a pale yellow solid. Rf (SiO2/
1
MeOH) = 0.64. H NMR (DMSO-d6): δ 8.95 (s, 1H, Ar-H), 7.95 (s,
1H, Ar-H), 7.87 (d, 2H, Ar-H, J = 8.0 Hz), 7.28 (d, 2H, Ar-H, J = 8.0),
5.82 (d, 1H, H-1′, J = 6.3 Hz), 5.41 (d, 1H, OH, J = 6.3 Hz), 5.12 (d,
1H, OH, J = 4.6 Hz), 5.04 (t, 1H, OH, J = 5.6 Hz), 4.65 (app q, 1H,
H-2′, Japp ≈ 6.0 Hz), 4.15 (app q, 1H, H-3′, Japp ≈ 4.5 Hz), 4.00 (app q,
1H, H-4′, Japp ≈ 3.7 Hz), 3.69−3.64 (m, 1H, H-5′), 3.57−3.52 (m, 1H,
H-5′), 2.34 (s, 3H, CH3). 13C NMR (DMSO-d6): δ 167.4, 150.9,
150.1, 146.2, 137.6, 137.4, 129.8, 128.2, 125.7, 123.9, 119.5, 87.6, 85.9,
73.6, 71.1, 61.2, 21.3. HRMS: calcd for C19H19N7O5Na [M + Na]+
448.1340, found 448.1342.
2-[4-(4-Methoxyphenyl)-1,2,3-triazol-1H-yl]inosine (19). Step
1: Desilylation. Using the procedure described for 17, this compound
was synthesized from 5 (290.0 mg, 0.351 mmol) and Et3N·3HF (285
μL, 1.75 mmol). Chromatography of the crude reaction mixture on a
silica gel column using 10% MeOH in EtOAc yielded 135.0 mg (80%
yield) of the O6-allyl-protected nucleoside as a white, foamy solid. Rf
(SiO2/5% MeOH in EtOAc) = 0.19. 1H NMR (DMSO-d6): δ 9.32 (s,
1H, Ar-H), 8.75 (s, 1H, Ar-H), 7.95 (d, 2H, Ar-H, J = 8.6 Hz), 7.00 (d,
2H, Ar-H, J = 8.6 Hz), 6.26−6.18 (m, 1H, CH), 6.07 (d, 1H, H-1′, J
= 5.7 Hz), 5.56 (dd, 1H, CHtrans, J = 1.1, 17.2 Hz), 5.37 (dd, 1H, 
CHcis, J = 1.1, 10.4 Hz), 5.28 (d, 2H, OCH2, J = 5.5 Hz), 4.63 (t, 1H,
H-2′, J = 5.2 Hz), 4.23 (app t, 1H, H-3′, Japp ≈ 4.2 Hz), 4.17 (app q,
1H, H-4′, Japp ≈ 3.8), 3.82 (s, 3H, OCH3), 3.70 (dd, 1H, H-5′, J = 4.2,
12.0 Hz), 3.60 (dd, 1H, H-5′, J = 4.0, 12.0 Hz).
1
EtOAc) = 0.31. H NMR (DMSO-d6): δ 9.42 (s, 1H, Ar-H), 8.74 (s,
Step 2: Deallylation. The desilylated product (94.0 mg, 0.195
mmol) obtained in step 1 was deallylated as described for 17 using
Pd(PPh3)4 (11.2 mg, 5 mol %) and PhSO2Na (31.9 mg, 0.195 mmol)
to yield 72.1 mg (84% yield) of 19 as a white solid. Rf (SiO2/MeOH)
1H, Ar-H), 8.00 (d, 2H, Ar-H, J = 8.3 Hz), 7.52 (t, 2H, Ar-H, J = 7.5
Hz), 7.43 (t, 1H, Ar-H, J = 7.5 Hz), 6.26−6.15 (m, 1H, CH), 6.08
(d, 1H, H-1′, J = 5.8 Hz), 5.64 (br s, 1H, OH), 5.56 (dd, 1H, 
CHtrans, J = 1.6, 17.2 Hz), 5.39 (br d, 1H, CHcis, J = 17.2 Hz), 5.37
(br s, 1H, OH), 5.28 (d, 2H, OCH2, J = 5.8 Hz), 5.11 (t, 1H, OH, J =
5.3 Hz), 4.66 (br s, 1H, H-2′), 4.23 (br s, 1H, H-3′), 4.01 (app q, 1H,
1
= 0.73. H NMR (DMSO-d6): δ 8.94 (s, 1H, Ar-H), 8.01 (s, 1H, Ar-
H), 7.99 (d, 2H, Ar-H, J = 8.7 Hz), 7.04 (d, 2H, Ar-H, J = 8.7 Hz),
5.85 (d, 1H, H-1′, J = 6.3 Hz), 5.46 (d, 1H, OH, J = 6.3 Hz), 5.19 (d,
I
dx.doi.org/10.1021/jo300628y | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Featured Article
1H, OH, J = 4.6 Hz), 5.11 (t, 1H, OH, J = 6.3 Hz), 4.64 (app q, 1H,
H-2′, Japp ≈ 5.8 Hz), 4.17 (app q, 1H, H-3′, Japp ≈ 4.1 Hz), 3.94 (app q,
1H, H-4′, Japp ≈ 3.5 Hz), 3.80 (s, 3H, OCH3), 3.71−3.65 (m, 1H, H-
5′), 3.59−3.53 (m, 1H, H-5′). 13C NMR (DMSO-d6): δ 167.1, 159.7,
150.4, 146.2, 137.4, 127.4, 124.9, 124.0, 119.3, 115.0, 94.7, 87.9, 86.2,
73.9, 71.4, 62.5, 55.8. HRMS: calcd for C19H19N7O6Na [M + Na]+
464.1289, found 464.1299.
Ar-H), 8.69 (s, 1H, Ar-H), 6.21−6.13 (m, 1H, CH), 6.02 (d, 1H, H-
1′, J = 5.7 Hz), 5.53 (br s, 1H, OH), 5.52 (br d, 1H, CHtrans, J = 17.0
Hz), 5.33 (d, 1H, CHcis, J = 10.3 Hz), 5.27 (s, 1H, OH), 5.23 (d,
2H, OCH2, J = 5.6 Hz), 5.00 (t, 1H, OH, J = 4.3 Hz), 4.88 (s, 2H,
ferrocenyl-H), 4.60 (br t, 1H, H-2′, J = 4.5 Hz), 4.33 (s, 2H,
ferrocenyl-H), 4.10 (br s, 1H, H-3′), 4.04 (s, 5H, ferrocenyl-H), 3.95
(br s, 1H, H-4′), 3.67−3.65 (m, 1H, H-5′), 3.57−3.55 (m, 1H, H-5′).
Step 2: Deallylation. The desilylated product (95.0 mg, 0.156
mmol) obtained in step 1 was deallylated as described for 17 using
Pd(PPh3)4 (9.0 mg, 5 mol %) and PhSO2Na (25.6 mg, 0.156 mmol)
to yield 70.1 mg (86% yield) of 22 as a brown red solid. Rf (SiO2/
2-[4-(Hydroxymethyl)-1,2,3-triazol-1H-yl]inosine (20). Step 1:
Desilylation. Using the procedure described for 17, this compound
was synthesized from 6 (210.0 mg, 0.280 mmol) and Et3N·3HF (228
μL, 1.40 mmol). Chromatography of the crude reaction mixture on a
silica gel column using 10% MeOH in EtOAc yielded 95.0 mg (83%
yield) of the O6-allyl-protected nucleoside as a white, foamy solid. Rf
1
MeOH) = 0.71. H NMR (DMSO-d6): δ 8.66 (s, 1H, Ar-H), 7.99 (s,
1H, Ar-H), 5.84 (d, 1H, H-1′, J = 6.3 Hz), 5.46 (br s, 1H, OH), 5.20
(br s, 1H, OH), 5.09 (t, 1H, OH, J = 5.3 Hz), 4.86 (s, 2H, ferrocenyl-
H), 4.63 (br s, 1H, H-2′), 4.33 (s, 2H, ferrocenyl-H), 4.17 (br s, 1H,
H-3′), 4.07 (s, 5H, ferrocenyl-H), 3.94 (br s, 1H, H-4′), 3.69−3.66 (m,
1H, H-5′), 3.57−3.54 (m, 1H, H-5′). 13C NMR (DMSO-d6): δ 166.9,
150.8, 150.2, 145.2, 137.1, 124.5, 118.9, 87.5, 85.9, 79.6, 76.2, 73.7,
71.2, 69.7, 68.7, 66.8, 62.2. HRMS: calcd for C22H22FeN7O5 [M + H]+
520.1026, found 520.1006.
1
(SiO2/10% MeOH in EtOAc) = 0.46. H NMR (DMSO-d6): δ 8.77
(s, 1H, Ar-H), 8.74 (s, 1H, Ar-H), 6.24−6.16 (m, 1H, CH), 6.05 (d,
1H, H-1′, J = 5.7 Hz), 5.58 (d, 1H, OH, J = 5.9 Hz), 5.53 (br d, 1H, 
CHtrans, J = 17.2 Hz), 5.39 (d, 1H, OH, J = 6.2 Hz), 5.36 (br d, 1H, 
CHcis, J = 10.3 Hz), 5.30 (d, 1H, OH, J = 4.9 Hz), 5.24 (d, 2H, OCH2,
J = 5.9 Hz), 5.04 (t, 1H, OH, J = 5.3 Hz), 4.66−4.63 (m, 3H, CH2 and
H-2′), 4.22 (app q, 1H, H-3′, Japp ≈ 4.5 Hz), 3.99 (app q, 1H, H-4′, Japp
≈ 4.0 Hz), 3.73−3.68 (m, 1H, H-5′), 3.62−3.58 (m, 1H, H-5′).
Step 2: Deallylation. The desilylated product (35.2 mg, 0.085
mmol) obtained in step 1 was deallylated as described for 17 using
Pd(PPh3)4 (4.9 mg, 5 mol %) and PhSO2Na (14.0 mg, 0. 085 mmol)
to yield 20.4 mg (64% yield) of 20 as a white solid. Rf (SiO2/MeOH)
2-(4-n-Butyl-1,2,3-triazol-1H-yl)inosine (23). Step 1: Desilyla-
tion. Using the procedure described for 17, this compound was
synthesized from 9 (172.0 mg, 0.222 mmol) and Et3N·3HF (180 μL,
1.10 mmol). Chromatography of the crude reaction mixture on a silica
gel column using 10% MeOH in EtOAc yielded 70.1 mg (73% yield)
of the O6-allyl-protected nucleoside as a white, foamy solid. Rf (SiO2/
1
= 0.54. H NMR (DMSO-d6): δ 8.43 (s, 1H, Ar-H), 7.97 (s, 1H, Ar-
1
10% MeOH in EtOAc) = 0.57. H NMR (DMSO-d6): δ 8.73 (s, 1H,
H), 5.83 (d, 1H, H-1′, J = 5.8 Hz), 5.42 (d, 1H, OH, J = 6.2 Hz), 5.23
(t, 1H, OH, J = 5.8 Hz), 5.15 (d, 1H, OH, J = 4.8 Hz), 5.06 (t, 1H,
OH, J = 5.8 Hz), 4.63 (q, 1H, H-2′, J = 5.9 Hz), 4.58 (d, 2H, CH2, J =
5.4 Hz), 4.15 (m, 1H, H-3′), 3.92 (m, 1H, H-4′), 3.67−3.62 (dt, 1H,
H-5′, J = 4.4, 11.7 Hz), 3.56−3.51 (ddd, 1H, H-5′, J = 4.4, 6.3, 11.2
Hz). 13C NMR (DMSO-d6): δ 166.9, 150.9, 150.1, 147.8, 137.0, 124.5,
121.4, 87.6, 85.8, 73.6, 71.1, 62.2, 55.4. HRMS: calcd for
C13H15N7O6Na [M + Na]+ 388.0976, found 388.0982.
Ar-H), 8.69 (s, 1H, Ar-H), 6.23−6.16 (m, 1H, CH), 6.05 (d, 1H, H-
1′, J = 5.7 Hz), 5.65 (s, 1H, OH), 5.53 (dd, 1H, CHtrans, J = 1.2, 17.2
Hz), 5.36 (dd, 1H, CHcis, J = 1.2, 10.2 Hz), 5.24 (d, 2H, OCH2, J =
5.7 Hz), 5.07 (s, 1H, OH), 4.64 (t, 1H, H-2′, J = 5.0 Hz), 4.23 (t, 1H,
H-3′, J = 3.8 Hz), 4.00 (app q, 1H, H-4′, Japp ≈ 4.0 Hz), 3.70 (br d, 1H,
H-5′, J = 10.2 Hz), 3.60 (br d, 1H, H-5′, J = 10.2 Hz), 2.74 (t, 2H,
butyl-CH2, J = 7.6 Hz), 1.68 (quint, 2H, butyl-CH2, J = 7.6 Hz), 1.37
(sextet, 2H, butyl-CH2, J = 7.3 Hz), 0.93 (t, 3H, butyl-CH3, J = 7.3
Hz). 13C NMR (DMSO-d6): δ 160.7, 153.2, 148.1, 143.7, 132.8, 121.3,
120.6, 119.5, 87.9, 86.2, 74.2, 70.7, 68.4, 61.6, 31.3, 24.3, 24.8, 22.0,
14.0.
2-[4-(N-Phthalimidomethyl)-1,2,3-triazol-1H-yl]inosine (21).
Step 1: Desilylation. Using the procedure described for 17, this
compound was synthesized from 7 (350.0 mg, 0.428 mmol) and
Et3N·3HF (348 μL, 2.14 mmol). Chromatography of the crude
reaction mixture on a silica gel column using 10% MeOH in EtOAc
yielded 165.0 mg (72% yield) of the O6-allyl-protected nucleoside as a
white, foamy solid. Rf (SiO2/EtOAc) = 0.23. 1H NMR (DMSO-d6): δ
8.90 (s, 1H, Ar-H), 8.73 (s, 1H, Ar-H), 7.93 (dd, 2H, Ar-H, J = 3.2, 5.4
Hz), 7.74 (dd, 2H, Ar-H, J = 3.2, 5.4 Hz), 6.22−6.14 (m, 1H, CH),
6.03 (d, 1H, H-1′, J = 5.8 Hz), 5.56 (d, 1H, OH, J = 6.2 Hz), 5.53 (br
d, 1H, CHtrans, J = 17.5 Hz), 5.35 (d, 1H, CHcis, J = 10.5 Hz), 5.28
(d, 1H, OH, J = 5.0 Hz), 5.22 (d, 2H, OCH2, J = 5.6 Hz), 5.02 (t, 1H,
OH, J = 5.4 Hz), 4.97 (s, 2H, NCH2), 4.62 (app q, 1H, H-2′ Japp ≈ 5.5
Hz), 4.20 (app q, 1H, H-3′, Japp ≈ 4.5 Hz), 3.98 (app q, 1H, H-4′, Japp
≈ 4.1 Hz), 3.71−3.66 (m, 1H, H-5′), 3.60−3.56 (m, 1H, H-5′).
Step 2: Deallylation. The desilylated product (150.0 mg, 0.280
mmol) obtained in step 1 was deallylated as described for 17 using
Pd(PPh3)4 (16.2 mg, 5 mol %) and PhSO2Na (45.9 mg, 0.128 mmol)
to yield 110.0 mg (79% yield) of 21 as a white solid. Rf (SiO2/MeOH)
Step 2: Deallylation. The desilylated product (30.0 mg, 0.069
mmol) obtained in step 1 was deallylated as described for 17 using
Pd(PPh3)4 (4.0 mg, 5 mol %) and PhSO2Na (11.4 mg, 0. 069 mmol)
to yield 19.4 mg (70% yield) of 23 as a white solid. Rf (SiO2/MeOH)
1
= 0.51. H NMR (DMSO-d6): δ 8.32 (s, 1H, Ar-H), 7.96 (s, 1H, Ar-
H), 5.82 (d, 1H, H-1′, J = 6.3 Hz), 5.43 (d, 1H, OH, J = 6.2 Hz), 5.16
(d, 1H, OH, J = 3.9 Hz), 5.07 (t, 1H, OH, J = 5.8 Hz), 4.63 (app q,
1H, H-2′, Japp ≈ 5.9 Hz), 4.15 (app q, 1H, H-3′, Japp ≈ 4.3 Hz), 3.92
(app q, 1H, H-4′, Japp ≈ 3.4 Hz), 3.67−3.63 (m, 1H, H-5′), 3.56−3.51
(m, 1H, H-5′), 2.69 (t, 2H, butyl-CH2, J = 7.6 Hz), 1.64 (quint, 2H,
butyl-CH2, J = 7.5 Hz), 1.36 (sextet, 2H, butyl-CH2, J = 7.5 Hz), 0.92
(t, 3H, butyl-CH3, J = 7.3 Hz). 13C NMR (DMSO-d6): δ 166.9, 150.9,
150.2, 146.8, 137.1, 124.4, 120.6, 87.6, 85.9, 73.7, 71.1, 62.2, 31.4, 25.0,
22.0, 14.1. HRMS: calcd for C16H21N7O5Na [M + Na]+ 414.1496,
found 414.1499.
1
= 0.70. H NMR (DMSO-d6): δ 8.53 (s, 1H, Ar-H), 7.97 (s, 1H, Ar-
2-[4-(4-Fluorophenyl)-1,2,3-triazol-1H-yl]inosine (24). Step 1:
Desilylation. Using the procedure described for 17, this compound
was synthesized from 10 (310.0 mg, 0.381 mmol) and Et3N·3HF (310
μL, 1.90 mmol). Chromatography of the crude reaction mixture on a
silica gel column using 10% MeOH in EtOAc yielded 143.8 mg (80%
yield) of the O6-allyl-protected nucleoside as a white, foamy solid. Rf
H), 7.92 (dd, 2H, Ar-H, J = 3.2, 5.4 Hz), 7.864 (dd, 2H, Ar-H, J = 3.2,
5.4 Hz), 5.80 (d, 1H, H-1′, J = 6.3 Hz), 5.40 (d, 1H, OH, J = 6.3 Hz),
5.13 (d, 1H, OH, J = 4.6 Hz), 5.03 (t, 1H, OH, J = 5.9 Hz), 4.91 (s,
2H, NCH2), 4.60 (app q, 1H, H-2′, Japp ≈ 5.6 Hz), 4.13 (app q, 1H, H-
3′, Japp ≈ 4.7 Hz), 3.90 (app q, 1H, H-4′, Japp ≈ 3.4 Hz), 3.65−3.10 (m,
1H, H-5′), 3.53−3.48 (m, 1H, H-5′). 13C NMR (DMSO-d6): δ 167.8,
166.3, 150.4, 150.0, 142.2, 137.2, 134.9, 132.1, 124.5, 123.6, 122.1,
87.6, 85.9, 73.7, 71.1, 62.2, 33.3. HRMS: calcd for C21H19N8O7 [M +
H]+ 495.1371, found 495.1379.
1
(SiO2/10% MeOH in EtOAc) = 0.48. H NMR (DMSO-d6): δ 9.45
(s, 1H, Ar-H), 8.77 (s, 1H, Ar-H), 8.11 (dd, 2H, Ar-H, J = 5.3, 8.6 Hz),
7.36 (t, 2H, Ar-H, J = 8.6 Hz), 6.26−6.20 (m, 1H, CH), 6.18 (d,
1H, H-1′, J = 5.8 Hz), 5.66 (br s, 1H, OH), 5.57 (dd, 1H, CHtrans, J
= 1.5, 17.2 Hz), 5.43 (br s, 1H, OH), 5.39 (dd, 1H, CHcis, J = 1.2,
10.4 Hz), 5.29 (d, 2H, OCH2, J = 5.9 Hz), 5.08 (t, 1H, OH, J = 4.0
Hz), 4.68 (t, 1H, H-2′, J = 5.2 Hz), 4.24 (t, 1H, H-3′, J = 3.9 Hz), 4.01
(app q, 1H, H-4′, Japp ≈ 4.0 Hz), 3.74 (dd, 1H, H-5′, J = 4.2, 11.8 Hz),
3.62 (dd, 1H, H-5′, J = 3.4, 11.8 Hz).
2-(4-Ferrocenyl-1,2,3-triazol-1H-yl)inosine (22). Step 1: Desi-
lylation. Using the procedure described for 17, this compound was
synthesized from 8 (400.0 mg, 0.442 mmol) and Et3N·3HF (359 μL,
2.21 mmol). Chromatography of the crude reaction mixture on a silica
gel column using 10% MeOH in EtOAc yielded 175.0 mg (65% yield)
of the O6-allyl-protected nucleoside as a brown, foamy solid. Rf (SiO2/
Step 2: Deallylation. The desilylated product (24.0 mg, 0.048
mmol) obtained in step 1 was deallylated as described for 17 using
1
5% MeOH in EtOAc) = 0.20. H NMR (DMSO-d6): δ 8.94 (s, 1H,
J
dx.doi.org/10.1021/jo300628y | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Featured Article
Pd(PPh3)4 (2.8 mg, 5 mol %) and PhSO2Na (8.0 mg, 0. 048 mmol) to
yield 15.0 mg (72% yield) of 24 as a white solid. Rf (SiO2/MeOH) =
0.42. 1H NMR (DMSO-d6): δ 9.12 (s, 1H, Ar-H), 8.05 (s, 1H, Ar-H),
8.03 (br t, 2H, Ar-H, Japp ≈ 6.8 Hz), 7.31 (t, 2H, Ar-H, J = 8.5 Hz),
5.87 (d, 1H, H-1′, J = 6.2 Hz), 5.54 (br d, 1H, OH, J = 4.6 Hz), 5.28
(br s, 1H, OH), 5.10 (t, 1H, OH, J = 5.5 Hz), 4.66 (br d, 1H, H-2′, J =
4.5 Hz), 4.18 (br s, 1H, H-3′), 3.94 (br s, 1H, H-4′), 3.69−3.66 (m,
1H, H-5′), 3.57−3.54 (m, 1H, H-5′). 13C NMR (DMSO-d6): δ 167.1,
HRMS: calcd for C19H19N7O5Na [M + Na]+ 448.1340, found
448.1346.
2-[4-(Hydroxymethyl)-1,2,3-triazol-1H-yl]-2′-deoxyinosine
(27). Step 1: Desilylation. Using the procedure described for 17, this
compound was synthesized from 13 (211.0 mg, 0.341 mmol) and
Et3N·3HF (183 μL, 1.13 mmol). Chromatography of the crude
reaction mixture on a silica gel column using 15% MeOH in EtOAc
yielded 103.5 mg (78% yield) of the O6-allyl-protected nucleoside as a
white, foamy solid. Rf (SiO2/10% MeOH in EtOAc) = 0.33. 1H NMR
(DMSO-d6): δ 8.77 (s, 1H, Ar-H), 8.70 (s, 1H, Ar-H), 6.48 (t, 1H, H-
1′, J = 6.8 Hz), 6.23−6.15 (m, 1H, CH), 5.53 (br d, 1H, CHtrans, J
= 17.3 Hz), 5.38 (d, 1H, OH, J = 4.2 Hz), 5.35 (br d, 1H, CHcis, J =
10.6 Hz), 5.36 (t, 1H, OH, J = 5.6 Hz), 5.22 (d, 2H, OCH2, J = 5.9
Hz), 4.92 (t, 1H, OH, J = 5.6 Hz), 4.64 (d, 2H, CH2, J = 5.6 Hz), 4.46
(m, 1H, H-3′), 3.91 (app q, 1H, H-4′, Japp ≈ 3.2 Hz), 3.65−3.61 (m,
1
163.2 and 161.3 (d, J = 244.6 Hz), 150.8, 150.2, 145.2, 137.4, 127.9
and 127.8 (d, 3J = 8.2 Hz), 127.6, 124.5, 120.0, 116.3 and 116.1 (d, 2J
= 21.5 Hz), 87.6, 86.0, 73.7, 71.1, 62.2. HRMS: calcd for
C18H16FN7O5Na [M + Na]+ 452.1089, found 452.1090.
2-(4-Phenyl-1,2,3-triazol-1H-yl)-2′-deoxyinosine (25). Step 1:
Desilylation. Using the procedure described for 17, this compound
was synthesized from 11 (230.0 mg, 0.346 mmol) and Et3N·3HF (187
μL, 1.15 mmol). Chromatography of the crude reaction mixture on a
silica gel column using 8% MeOH in EtOAc yielded 120.1 mg (76%
yield) of the O6-allyl-protected nucleoside as a white, foamy solid. Rf
1H, H-5′), 3.57−3.52 (m, 1H, H-5′), 2.78 (app sextet, 1H, H-2′, Japp
6.5 Hz), 2.40 (ddd, 1H, H-2′, J = 3.7, 6.3, 10.0 Hz).
≈
Step 2: Deallylation. The desilylated product (82.0 mg, 0.210
mmol) obtained in step 1 was deallylated as described for 17 using
Pd(PPh3)4 (12.1 mg, 5 mol %) and PhSO2Na (34.4 mg, 0. 210 mmol)
to yield 65.0 mg (88% yield) of 27 as a pale yellow solid. Rf (SiO2/
1
(SiO2/10% MeOH in EtOAc) = 0.50. H NMR (DMSO-d6): δ 9.44
(s, 1H, Ar-H), 8.72 (s, 1H, Ar-H), 8.07 (d, 2H, Ar-H, J = 7.8 Hz), 7.51
(t, 2H, Ar-H, J = 7.5 Hz), 7.41 (t, 1H, Ar-H, J = 7.5 Hz), 6.51 (t, 1H,
H-1′, J = 6.4 Hz), 6.26−6.18 (m, 1H, CH), 5.56 (br d, 1H, 
CHtrans, J = 17.2 Hz), 5.38 (br d, 1H, CHcis, J = 10.4 Hz), 5.28 (d,
2H, OCH2, J = 5.9 Hz), 4.49 (br s, 1H, H-3′), 3.91 (br d, 1H, H-4′, J =
2.5 Hz), 3.67 (dd, 1H, H-5′, J = 4.5, 11.8 Hz), 3.57 (dd, 1H, H-5′, J =
4.3, 11.8 Hz), 2.79 (app quint, 1H, H-2′, Japp ≈ 6.5 Hz), 2.39 (ddd, 1H,
H-2′, J = 2.5, 6.0, 9.5 Hz). 13C NMR (DMSO-d6): 160.7, 152.9, 147.9,
147.2, 143.8, 132.9, 130.3, 129.4, 128.9, 126.0, 120.8, 120.7, 119.7,
88.6, 84.2, 71.1, 68.6, 61.9, 40.2.
1
MeOH) = 0.50. H NMR (DMSO-d6): δ 8.44 (s, 1H, Ar-H), 7.98 (s,
1H, Ar-H), 6.28 (t, 1H, H-1′, J = 6.4 Hz), 5.30 (d, 1H, OH, J = 3.4
Hz), 5.24 (t, 1H, OH, J = 5.7 Hz), 4.96 (t, 1H, OH, J = 5.4 Hz), 4.58
(d, 2H, CH2, J = 5.0 Hz), 4.40 (br s, 1H, H-3′), 3.84 (br s, 1H, H-4′),
3.61−3.58 (m, 1H, H-5′), 3.52−3.50 (m, 1H, H-5′), 2.70 (app quint,
1H, H-2′, Japp ≈ 5.5 Hz), 2.22 (br dd, 1H, H-2′, J = 3.0, 12.7 Hz). 13
C
NMR (DMSO-d6): δ 166.5, 150.6, 149.9, 147.8, 136.8, 124.3, 121.5,
88.1, 83.5, 71.4, 62.4, 55.4, 40.1. HRMS: calcd for C13H15N7O5Na [M
+ Na]+ 372.1027, found 372.1029.
Step 2: Deallylation. The desilylated product (95.0 mg, 0.218
mmol) obtained in step 1 was deallylated as described for 17 using
Pd(PPh3)4 (12.6 mg, 5 mol %) and PhSO2Na (35.7 mg, 0. 218 mmol)
to yield 64.3 mg (75% yield) of 25 as a white solid. Rf (SiO2/MeOH)
2-[4-(N-Phthalimidomethyl)-1,2,3-triazol-1H-yl]-2′-deoxyi-
nosine (28). Step 1: Desilylation. Using the procedure described for
17, this compound was synthesized from 14 (289.0 mg, 0.387 mmol)
and Et3N·3HF (201 μL, 1.29 mmol). Chromatography of the crude
reaction mixture on a silica gel column using 10% MeOH in EtOAc
yielded 159.3 mg (79% yield) of the O6-allyl-protected nucleoside as a
yellow, foamy solid. Rf (SiO2/10% MeOH in EtOAc) = 0.56. 1H NMR
(DMSO-d6): δ 8.91 (s, 1H, Ar-H), 8.70 (s, 1H, Ar-H), 7.93 (br d, 2H,
Ar-H, J = 3.6 Hz), 7.88 (br d, 2H, Ar-H, J = 3.6 Hz), 6.46 (t, 1H, H-1′,
J = 6.7 Hz), 6.21−6.13 (m, 1H, CH), 5.52 (d, 1H, CHtrans, J =
16.5 Hz), 5.38 (d, 1H, OH, J = 4.0 Hz), 5.34 (d, 1H, CHcis, J = 10.6
Hz), 5.20 (d, 2H, OCH2, J = 5.6 Hz), 4.97 (s, 2H, NCH2), 4.92 (t, 1H,
OH, J = 5.4 Hz), 4.45 (br s, 1H, H-3′), 3.89 (br d, 1H, H-4′, J = 2.8
Hz), 3.64−3.60 (m, 1H, H-5′), 3.56−3.52 (m, 1H, H-5′), 2.80 (app
quint, 1H, H-2′, Japp ≈ 6.5 Hz), 2.36 (ddd, 1H, H-2′, J = 3.4, 6.0, 9.6
Hz).
1
= 0.54. H NMR (DMSO-d6): δ 9.06 (s, 1H, Ar-H), 8.00 (s, 1H, Ar-
H), 7.98 (d, 2H, Ar-H, J = 7.6 Hz), 7.46 (t, 2H, Ar-H, J = 7.5 Hz), 7.36
(t, 1H, Ar-H, J = 7.1 Hz), 6.31 (t, 1H, H-1′, J = 6.7 Hz), 5.30 (br s, 1H,
OH), 4.97 (br s, 1H, OH), 4.42 (br s, 1H, H-3′), 3.85 (br s, 1H, H-4′),
3.63−3.60 (m, 1H, H-5′), 3.55−3.50 (m, 1H, H-5′), 2.72 (app quint,
1H, H-2′, Japp ≈ 6.6 Hz), 2.24 (br dd, 1H, H-2′, J = 3.0, 11.3 Hz). 13
C
NMR (DMSO-d6): δ 166.8, 150.8, 149.9, 146.0, 136.7, 131.1, 129.3,
128.3, 125.8, 121.5, 120.0, 88.1, 83.6, 71.5, 62.4, 40.1. HRMS: calcd for
C18H17N7O4Na [M + Na]+ 418.1234, found 418.1240.
2-[4-(4-Methoxyphenyl)-1,2,3-triazol-1H-yl]-2′-deoxyinosine
(26). Step 1: Desilylation. Using the procedure described for 17, this
compound was synthesized from 12 (171.0 mg, 0.24 mmol) and
Et3N·3HF (133 μL, 0.821 mmol). Chromatography of the crude
reaction mixture on a silica gel column using 10% MeOH in EtOAc
yielded 104.1 mg (93% yield) of the O6-allyl-protected nucleoside as a
white, foamy solid. Rf (SiO2/10% MeOH in EtOAc) = 0.38. 1H NMR
(DMSO-d6): δ 9.33 (s, 1H, Ar-H) 8.72 (s, 1H, Ar-H), 7.99 (d, 2H, Ar-
H, J = 8.6 Hz), 7.07 (d, 2H, Ar-H, J = 8.6 Hz), 6.48 (t, 1H, H-1′, J =
6.7 Hz), 6.26−6.18 (m, 1H, CH), 5.56 (d, 1H, CHtrans, J = 17.4
Hz), 5.42 (d, 1H, OH, J = 4.0 Hz), 5.38 (d, 1H, CHcis, J = 10.5 Hz),
5.28 (d, 2H, OCH2, J = 5.6 Hz), 4.96 (t, 1H, OH, J = 5.4 Hz), 4.49 (br
s, 1H, H-3′), 3.92 (br d, 1H, H-4′, J = 2.9 Hz), 3.82 (s, 3H, OCH3),
3.68−3.64 (m, 1H, H-5′), 3.60−3.55 (m, 1H, H-5′), 2.80 (app quint,
1H, H-2′, Japp ≈ 7.0 Hz), 2.40 (ddd, 1H, H-2′, J = 3.0, 6.5, 10.5 Hz).
Step 2: Deallylation. The desilylated product (100.0 mg, 0.214
mmol) obtained in step 1 was deallylated as described for 17 using
Pd(PPh3)4 (12.4 mg, 5 mol %) and PhSO2Na (35.1 mg, 0. 048 mmol)
to yield 78.1 mg (80% yield) of 26 as a pale yellow solid. Rf (SiO2/
Step 2: Deallylation. The desilylated product (144.0 mg, 0.277
mmol) obtained in step 1 was deallylated as described for 17 using
Pd(PPh3)4 (16.0 mg, 5 mol %) and PhSO2Na (45.4 mg, 0. 277 mmol)
to yield 98.9 mg (75% yield) of 28 as a pale yellow solid. Rf (SiO2/
1
MeOH) = 0.49. H NMR (DMSO-d6): δ 8.54 (s, 1H, Ar-H), 7.97 (s,
1H, Ar-H), 7.92 (dd, 2H, Ar-H, J = 3.0, 5.4 Hz), 7.86 (dd, 2H, Ar-H, J
= 3.0, 5.4 Hz), 6.26 (t, 1H, H-1′, J = 6.2 Hz), 5.32 (d, 1H, OH, J = 4.0
Hz), 4.94 (t, 1H, OH, J = 5.7 Hz), 4.81 (s, 2H, NCH2), 4.38 (br s, 1H,
H-3′), 3.85 (app q, 1H, H-4′, Japp ≈ 4.5 Hz), 3.60−3.57 (m, 1H, H-5′),
3.56−3.48 (m, 1H, H-5′), 2.70 (app quint, 1H, H-2′, Japp ≈ 5.5 Hz),
2.38 (ddd, 1H, H-2′, J = 2.5, 5.2, 11.0 Hz). 13C NMR (DMSO-d6): δ
167.8, 166.6, 150.6, 149.8, 142.2, 136.7, 134.9, 132.1, 124.4, 123.6,
122.1, 88.1, 83.5, 71.4, 62.4, 40.2, 33.3. HRMS: calcd for
C21H18N8O6Na [M + Na]+ 501.1242, found 501.1241.
2-(4-Ferrocenyl-1,2,3-triazol-1H-yl)-2′-deoxyinosine (29).
Step 1: Desilylation. Using the procedure described for 17, this
compound was synthesized from 15 (394.0 mg, 0.480 mmol) and
Et3N·3HF (257 μL, 1.60 mmol). Chromatography of the crude
reaction mixture on a silica gel column using 10% MeOH in EtOAc
yielded 240.8 mg (84% yield) of the O6-allyl-protected nucleoside as a
brown, foamy solid. Rf (SiO2/10% MeOH in EtOAc) = 0.58. 1H NMR
(DMSO-d6): δ 9.00 (s, 1H, A-H) 8.71 (s, 1H, Ar-H), 6.51 (t, 1H, H-1′,
J = 6.7 Hz), 6.26−6.18 (m, 1H, CH), 5.57 (dd, 1H, CHtrans, J =
1.5, 17.2 Hz), 5.42 (d, 1H, OH, J = 4.0 Hz), 5.34 (br d, 1H, CHcis, J
1
MeOH) = 0.46. H NMR (DMSO-d6): δ 8.97 (s, 1H, Ar-H), 8.02 (s,
1H, Ar-H), 7.91 (d, 2H, Ar-H, J = 8.1 Hz), 7.03 (d, 2H, Ar-H, J = 8.1
Hz), 6.32 (t, 1H, H-1′, J = 6.6 Hz), 5.30 (br s, 1H, OH), 4.99 (br s,
1H, OH), 4.43 (br s, 1H, H-3′), 3.86 (br s, 1H, H-4′), 3.80 (s, 3H,
OCH3), 3.63−3.61 (m, 1H, H-5′), 3.54−3.52 (m, 1H, H-5′), 2.73 (app
quint, 1H, H-2′, Japp ≈ 6.6 Hz), 2.25 (br dd, 1H, H-2′, J = 5.5, 11.5
Hz). 13C NMR (DMSO-d6): δ 166.9, 159.4, 150.9, 149.9, 145.9, 139.6,
127.1, 124.4, 123.7, 119.0, 114.7, 88.1, 83.5, 71.5, 62.4, 55.6, 40.1.
K
dx.doi.org/10.1021/jo300628y | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Featured Article
= 11.2 Hz), 5.28 (d, 2H, OCH2, J = 5.6 Hz), 4.96 (t, 1H, OH, J = 5.5
Hz), 4.94 (s, 2H, ferrocenyl-H), 4.49 (br s, 1H, H-3′), 4.39 (s, 2H,
ferrocenyl-H), 4.10 (s, 5H, ferrocenyl-H), 3.92 (br d, 1H, H-4′, J = 3.0
Hz), 3.68−3.64 (m, 1H, H-5′), 3.60−3.56 (m, 1H, H-5′), 2.78 (app
quint, 1H, H-2′, Japp ≈ 6.5 Hz), 2.40 (ddd, 1H, H-2′, J = 3.5, 6.5, 9.5
Hz).
temperature for 24 h, at which time TLC indicated complete reaction.
The mixture was diluted with EtOAc and washed with water
containing a small amount of NaCl, and the aqueous layer was
separated and reextracted with EtOAc. The combined organic layer
was dried over Na2SO4 and evaporated to dryness. Chromatographic
purification of the crude material on a silica gel column using 20%
EtOAc in hexanes provided 101.4 mg (55% yield) of 31 as a white
Step 2: Deallylation. The desilylated product (189.0 mg, 0.319
mmol) obtained in step 1 was deallylated as described for 17 using
Pd(PPh3)4 (18.4 mg, 5 mol %) and PhSO2Na (52.3 mg, 0. 319 mmol)
to yield 135.1 mg (84% yield) of 29 as a brownish red solid. Rf (SiO2/
1
foam. Rf (SiO2/20% EtOAc in hexanes) = 0.57. H NMR (CDCl3): δ
8.75 (s, 1H, Ar-H), 8.21 (d, 1H, Ar-H, J = 8.4 Hz), 7.87 (s, 1H, Ar-H),
7.74 (d, 2H, Ar-H, J = 7.3 Hz), 7.59−7.49 (m, 3H, Ar-H), 7.40 (t, 2H,
Ar-H, J = 7.4 Hz), 7.33 (t, 1H, Ar-H, J = 7.4 Hz), 6.21 (d, 1H, H-1′, J =
3.7 Hz), 4.61 (t, 1H, H-2′, J = 3.9 Hz), 4.37 (t, 1H, H-3′, J = 4.6 Hz),
4.22 (app q, 1H, H-4′, Japp ≈ 3.6 Hz), 4.14 (dd, 1H, H-5′, J = 3.6, 11.6
Hz), 3.85 (dd, 1H, H-5′, J = 2.5, 11.6 Hz), 0.98, 0.93, and 0.85 (3s,
1
MeOH) = 0.53. H NMR (DMSO-d6): δ 8.65 (s, 1H, Ar-H), 7.98 (s,
1H, Ar-H), 6.51 (t, 1H, H-1′, J = 6.2 Hz), 5.32 (d, 1H, OH, J = 3.9
Hz), 4.98 (t, 1H, OH, J = 5.7 Hz), 4.86 (s, 2H, ferrocenyl-H), 4.42 (br
s, 1H, H-3′), 4.34 (s, 2H, ferrocenyl-H), 4.07 (s, 5H, ferrocenyl-H),
3.86 (br d, 1H, H-4′, J = 2.3 Hz), 3.64−3.60 (m, 1H, H-5′), 3.56−3.51
(m, 1H, H-5′), 2.71 (app quint, 1H, H-2′, Japp ≈ 6.6 Hz), 2.24 (ddd,
1H, H-2′, J = 2.0, 6.0. 10.9 Hz). 13C NMR (DMSO-d6): δ 166.6, 150.7,
149.9, 145.2, 136.5, 131.9, 129.1, 118.9, 88.1, 83.5, 76.2, 71.5, 69.6,
68.7, 66.8, 62.4, 40.2. HRMS: calcd for C22H21FeN7O4Na [M + Na]+
526.0897, found 526.0890.
27H, t-Bu), 0.19, 0.17, 0.12, 0.09, 0.06, and 0.02 (6s, 18H, SiCH3). 13
C
NMR (CDCl3): δ 159.7, 155.1, 147.9, 147.8, 145.4, 143.6, 129.8,
129.4, 129.2, 129.0, 128.8, 126.1, 125.3, 120.9, 119.4, 118.5, 108.8,
89.7, 85.4, 76.6, 71.2, 62.1, 26.3, 26.0, 25.9, 18.8, 18.3, 18.1, −4.1, −4.6,
−5.1, −5.2. HRMS: calcd for C42H63N10O5Si3 [M + H]+ 871.4285,
found 871.4298.
2-(4-n-Butyl-1,2,3-triazol-1H-yl)-2′-deoxyinosine (30). Step 1:
Desilylation. Using the procedure described for 17, this compound
was synthesized from 16 (275.1 mg, 0.427 mmol) and Et3N·3HF (231
μL, 1.42 mmol). Chromatography of the crude reaction mixture on a
silica gel column using 8% MeOH in EtOAc yielded 152.3 mg (86%
yield) of the O6-allyl-protected nucleoside as a brown, foamy solid. Rf
6-(Morpholin-4-yl)-2-(4-phenyl-1,2,3-triazol-1H-yl)-9-
[2′,3′,5′-tri-O-(tert-butyldimethylsilyl)-β-D-ribofuranosyl]-
purine (32). In a clean, dry reaction vial equipped with a stirring bar
was placed 31 (50.0 mg, 0.057 mmol) in dry DME (2 mL).
Morpholine (20.0 μL, 0.229 mmol) was added, the reaction mixture
was flushed with nitrogen gas and allowed to stir at room temperature
for 1 h. The reaction mixture was evaporated, the residue was
dissolved in EtOAc and washed with water containing a small amount
of NaCl. The aqueous layer was separated and reextracted with EtOAc.
The combined organic layer was dried over Na2SO4 and evaporated to
dryness. Chromatographic purification of the crude material on a silica
gel column using 20% EtOAc in hexanes afforded 36.1 mg (77% yield)
1
(SiO2/10% MeOH in EtOAc) = 0.50. H NMR (DMSO-d6): δ 8.70
(s, 2H, Ar-H), 6.48 (t, 1H, H-1′, J = 6.6 Hz), 6.24−6.16 (m, 1H, 
CH), 5.54 (d, 1H, CHtrans, J = 17.2 Hz), 5.39 (br s, 1H, OH), 5.36
(d, 1H, CHcis, J = 10.6 Hz), 5.22 (d, 2H, OCH2, J = 5.4 Hz), 4.93
(br s, 1H, OH), 4.48 (br s, 1H, H-3′), 3.91 (br d, 1H, H-4′, J = 2.7 Hz),
3.65 (br d, 1H, H-5′, J = 10.5 Hz), 3.57 (br d, 1H, H-5′, J = 10.5 Hz),
2.80−2.73 (m, 3H, butyl-CH2, and H-2′) 2.38 (br dd, 1H, H-2′, J = 3.4,
7.5 Hz), 1.69 (quint, 2H, butyl-CH2, J = 7.5 Hz), 1.39 (sextet, 2H,
butyl-CH2, J = 7.5 Hz), 0.94 (t, 3H, butyl-CH3, J = 7.3 Hz).
1
of 32 as a white foam. Rf (SiO2/30% EtOAc in hexanes) = 0.70. H
NMR (CDCl3): δ 8.69 (s, 1H, Ar-H), 8.20 (s, 1H, Ar-H), 7.95 (d, 2H,
Ar-H, J = 7.2 Hz), 7.46 (t, 2H, Ar-H, J = 7.5 Hz), 7.36 (t, 1H, Ar-H, J
= 7.5 Hz), 6.11 (d, 1H, H-1′, J = 4.5 Hz), 4.60 (t, 1H, H-2′, J = 4.5
Hz), 4.48−4.35 (br m, 4H, 2CH2), 4.34 (t, 1H, H-3′, J = 4.3 Hz), 4.15
(app q, 1H, H-4′, Japp ≈ 3.6 Hz), 4.08 (dd, 1H, H-5′, J = 3.7, 11.4 Hz),
3.88 (t, 4H, 2CH2, J = 4.8 Hz), 3.82 (dd, 1H, H-5′, J = 2.8, 11.4 Hz),
0.96, 0.94, and 0.88 (3s, 27H, t-Bu), 0.16, 0.14, 0.12, 0.10, 0.01, and
−0.06 (6s, 18H, SiCH3). 13C NMR (CDCl3): δ 153.8, 151.3, 149.0,
147.2, 138.3, 130.4, 128.8, 128.2, 125.9, 119.5, 118.4, 88.3, 85.0, 75.9,
71.5, 66.9, 62.3, 45.8 (br s), 26.1, 25.8, 25.6, 18.5, 18.0, 17.8, −4.3,
−4.7, −5.3. HRMS: calcd for C40H67N8O5Si3 [M + H]+ 823.4537,
found 823.4550.
6-N-Benzyl-2-(4-phenyl-1,2,3-triazol-1H-yl)-2′,3′,5′-tri-O-
(tert-butyldimethylsilyl)adenosine (33). As described for the
synthesis of 32, this compound was prepared by a reaction between
31 (50.0 mg, 0.057 mmol) and benzylamine (25.0 μL, 0.228 mmol) in
dry DME (2.0 mL) at room temperature over 10 h. Workup as
described for 32 and chromatographic purification of the crude
material on a silica gel column using 20% EtOAc in hexanes afforded
43.1 mg (90% yield) of 33 as a white foam. Rf (30% EtOAc in
hexanes) = 0.55. 1H NMR (CDCl3): δ 8.68 (s, 1H, Ar-H), 8.41 (br s,
1H, Ar-H), 7.95 (d, 2H, Ar-H, J = 7.8 Hz), 7.48−7.45 (m, 4H, Ar-H
Hz), 7.38−7.34 (m, 3H, Ar-H), 7.28 (app t, 1H, Ar-H, J = 7.3 Hz),
6.90 (br s, 1H, NH), 6.10 (d, 1H, H-1′, J = 3.8 Hz), 4.93 (br s, 2H,
CH2), 4.58 (t, 1H, H-2′, J = 3.9 Hz), 4.34 (t, 1H, H-3′, J = 4.6 Hz),
4.17 (br s, 1H, H-4′), 4.12 (br d, 1H, H-5′, J = 11.0 Hz), 3.83 (dd, 1H,
H-5′, J = 2.0, 11.0 Hz), 0.97, 0.92, and 0.86 (3s, 27H, t-Bu), 0.17, 0.15,
0.11, 0.09, 0.05, and 0.02 (6s, 18H, SiCH3). 13C NMR (CDCl3): δ
154.3, 150.3, 148.8, 147.4, 138.5, 137.7, 130.4, 128.9, 128.8, 128.4,
128.1, 127.8, 126.0, 118.7, 89.3, 84.3, 76.2, 70.6, 61.8, 60.4, 45.2, 26.2,
25.9, 25.8, 18.6, 18.1, 18.0, −4.1, −4.4, −4.7, −5.1, −5.3. HRMS: calcd
for C43H67N8O4Si3 [M + H]+ 843.4588, found 843.4596.
Step 2: Deallylation. The desilylated product (144.0 mg, 0.346
mmol) obtained in step 1 was deallylated as described for 17 using
Pd(PPh3)4 (20.0 mg, 5 mol %) and PhSO2Na (56.7 mg, 0. 346 mmol)
to yield 89.3 mg (69% yield) of 30 as a white solid. Rf (SiO2/MeOH)
1
= 0.55. H NMR (DMSO-d6): δ 8.35 (s, 1H, Ar-H), 8.00 (s, 1H, Ar-
H), 6.28 (t, 1H, H-1′, J = 6.3 Hz), 5.32 (br s, 1H, OH), 4.98 (br s, 1H,
OH), 4.41 (br s, 1H, H-3′), 3.85 (br s, 1H, H-4′), 3.61−3.59 (m, 1H,
H-5′), 3.52−3.50 (m, 1H, H-5′), 2.73−2.65 (m, 3H, butyl-CH2, and H-
2′), 2.38 (ddd, 1H, H-2′, J = 3.5, 8.5, 11.0 Hz), 1.63 (quint, 2H, butyl-
CH2, J = 7.4 Hz), 1.35 (sextet, 2H, butyl-CH2, J = 7.4 Hz), 0.91 (t, 3H,
butyl-CH3, J = 7.3 Hz). 13C NMR (DMSO-d6): δ 166.9, 150.8, 149.9,
146.8, 136.7, 124.2, 120.6, 88.1, 83.5, 71.5, 62.4, 40.1, 31.4, 25.0, 22.1,
14.1. HRMS: calcd for C16H21N7O4Na [M + Na]+ 398.1547, found
398.1553.
O6-(1-Benzotriazol-1H-yl)-2-(4-phenyl-1,2,3-triazol-1H-yl)-
2′,3′,5′-tri-O-(tert-butyldimethylsilyl)inosine (31). Step 1: Deal-
lylation. Following the procedure described for the preparation of 17,
compound 3 (170 mg, 0.214 mmol) was deallylated using Pd(PPh3)4
(12.3 mg, 5 mol %) and PhSO2Na (35.1 mg, 0.214 mmol).
Chromatographic purification of the crude material on a silica gel
column using 10% MeOH in EtOAc afforded 146.3 mg (91% yield) of
the deallylated compound as a clear gum. Rf (SiO2/10% MeOH in
1
EtOAc) = 0.46. H NMR (DMSO-d6): δ 8.96 (s, 1H, Ar-H), 8.05 (s,
1H, Ar-H), 7.95 (d, 2H, Ar-H, J = 7.6 Hz), 7.47 (t, 2H, Ar-H, J = 7.2
Hz), 7.36 (t, 1H, Ar-H, J = 7.2 Hz), 5.85 (d, 1H, H-1′, J = 6.4 Hz),
5.12 (t, 1H, H-2′, J = 5.0 Hz), 4.30 (br s, 1H, H-3′), 4.08 (dd, 1H, H-5′,
J = 6.9, 10.8 Hz), 3.97 (br s, 1H, H-4′), 3.72 (dd, 1H, H-5′, J = 3.5,
10.8 Hz), 0.92, 0.86, and 0.72 (3s, 27H, t-Bu), 0.14, 0.12, 0.07, 0.05,
−0.10, and −0.31 (6s, 18H, SiCH3).
Step 2: Introduction of the O6-Benzotriazolyl Group. In a clean,
dry round-bottomed flask equipped with a stirring bar were placed the
2-(4-phenyl-1,2,3-triazol-1H-yl)-2′,3′-5′-tri-O-(tert-butyldimethylsilyl)-
inosine derivative 3 (160.0 mg, 0.212 mmol), BOP (187.7 mg, 0.424
mmol), and i-Pr2NEt (45 μL, 0.318 mmol) in dry THF (4.0 mL). The
reaction mixture was flushed with nitrogen gas, and stirred at room
6-(Morpholin-4-yl)-2-(4-phenyl-1,2,3-triazol-1H-yl)-9-(β-D-
ribofuranosyl)purine (34). Using the procedure described for 17,
this compound was synthesized from 32 (30.0 mg, 0.036 mmol) and
Et3N·3HF (29.0 μL, 0.18 mmol). Chromatography of the crude
reaction mixture on a silica gel column using 10% MeOH in EtOAc
L
dx.doi.org/10.1021/jo300628y | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Featured Article
yielded 13.9 mg (80% yield) of 34 as a white, foamy solid. Rf (SiO2/
30% MeOH in EtOAc) = 0.57. H NMR (DMSO-d6): δ 9.34 (s, 1H,
The antiviral assays (except antihuman immunodeficiency virus
(HIV) assays) were based on inhibition of virus-induced cytopathicity
in HEL [herpes simplex virus type 1 (HSV-1), HSV-2 (G), vaccinia
virus, and vesicular stomatitis virus, cytomegalovirus, and varicella-
zoster virus], Vero (parainfluenza-3, reovirus-1, Coxsackie B4, and
Punta Toro virus), HeLa (vesicular stomatitis virus, Coxsackie virus
B4, and respiratory syncytial virus), MDCK (influenza A (H1N1;
H3N2) and B virus) and CrFK (feline corona virus (FIPV) and feline
herpes virus) cell cultures. Confluent cell cultures in microtiter 96-well
plates were inoculated with 100 cell culture inhibitory dose-50
(CCID50) of virus (1 CCID50 being the virus dose to infect 50% of the
cell cultures) in the presence of varying concentrations (100, 20, 4, 0.8
μg/mL) of the test compounds. Viral cytopathicity was recorded as
soon as it reached completion in the control virus-infected cell cultures
that were not treated with the test compounds.
The methodology of the anti-HIV assays was as follows: human
CEM (∼3 × 105 cells/mL) cells were infected with 100 CCID50 of
HIV(IIIB) or HIV-2(ROD)/mL and seeded in 200 μL wells of a
microtiter plate containing appropriate dilutions of the test
compounds. After 4 days of incubation at 37 °C, HIV-induced CEM
giant cell formation was examined microscopically. The 50% effective
concentration (EC50) was defined as the compound concentration
required to inhibit syncytia formation by 50%. The 50% cytostatic
concentration (CC50) was defined as the compound concentration
required to inhibit CEM cell proliferation by 50% in comparison to
mock-infected cell cultures.
Determination of GI50s using ovarian cancer and colon carcinoma
cell lines were essentially as described.10,36−38 A 10 mM stock solution
of paclitaxel (PTX), obtained from the Drug Synthesis Branch of the
National Cancer Institute, was prepared in DMSO. Control samples
contained 1% (v/v) DMSO vehicle, a level equivalent to that in the
drug-treated cultures. Ovarian cancer cells were cultured in RPMI
1640 medium without phenol red containing 10% fetal bovine serum
at 37 °C in a humidified 5% carbon dioxide incubator. 1A9/PTX10
and 1A9/PTX22 cells were maintained in the presence of 15 ng/mL of
PTX and 5 μg/mL of verapamil. This medium was replaced with
regular medium 2−3 days before plating the cells in 96-well plates.
HCT116 and p53KO−/− cell lines were maintained in McCoy medium
with 10% fetal bovine serum.
Cells were plated in 96-well tissue culture plates for 48 h and the
compounds (prepared in 100% DMSO as a stock solution) were
added in quadruplicate. At least five different concentrations were
tested for each compound. In each experiment, one plate consisted
entirely of cells and medium used for time zero cell number
determination, at the time/day of addition of compounds. After four
days, 20 μL of Promega Cell Titer reagent was added into each well
and plates were incubated in the tissue culture incubator.
Approximately 2 h later, the plates were read using a plate reader at
490 nm minus 630 nm absorbance wavelengths. The data was then
analyzed using an Excel Spreadsheet grid. Resulting average values
ranging from <50 or >50 cell culture expansion for two or more
concentrations were used to calculate the GI50.
1
Ar-H), 8.55 (s, 1H, Ar-H), 8.05 (d, 2H, Ar-H, J = 7.8 Hz), 7.50 (t, 2H,
Ar-H, J = 7.5 Hz), 7.39 (t, 1H, Ar-H, J = 7.5 Hz), 6.03 (d, 1H, H-1′, J =
5.8 Hz), 5.53 (d, 1H, OH, J = 6.0 Hz), 5.27 (d, 1H, OH, J = 4.9 Hz),
5.01 (t, 1H, OH, J = 5.6 Hz), 4.64 (app quint, 1H, H-2′, Japp ≈ 5.8 Hz),
4.48−4.35 (br m, 4H, 2CH2), 4.22 (app q, 1H, H-3′, Japp ≈ 4.8 Hz),
3.98 (app q, 1H, H-4′, J = 3.8 Hz), 3.80 (t, 4H, 2CH2, J = 4.8 Hz),
3.79−3.70 (m, 1H, H-5′), 3.62−3.58 (m, 1H, H-5′). 13C NMR
(DMSO-d6): δ 153.7, 151.8, 148.8, 146.9, 140.2, 130.5, 129.3, 128.3,
126.0, 120.5, 119.2, 87.7, 86.2, 74.2, 70.8, 66.6, 61.8, 46.0 (br s).
HRMS: calcd for C22H24N8O5Na [M + Na]+ 503.1762, found
503.1765.
6-N-Benzyl-2-(4-phenyl-1,2,3-triazol-1H-yl)adenosine (35).
Using the procedure described for 17, this compound was synthesized
from 33 (35.0 mg, 0.041 mmol) and Et3N·3HF (34.0 μL, 0.207
mmol). Chromatography of the crude reaction mixture on a silica gel
column using 10% MeOH in EtOAc yielded 16.8 mg (82% yield) of
35 as a white, foamy solid. Rf (SiO2/30% MeOH in EtOAc) = 0.44. 1H
NMR (DMSO-d6): δ 9.22 (s, 1H, Ar-H), 9.04 (br s, 1H, NH), 8.51 (s,
1H, Ar-H), 8.02 (d, 2H, Ar-H, J = 7.6 Hz), 7.50 (m, 4H, Ar-H), 7.39
(t, 1H, Ar-H, J = 7.3 Hz), 7.33 (t, 2H, Ar-H, J = 7.5 Hz), 7.23 (t, 1H,
Ar-H, J = 7.3 Hz), 6.00 (d, 1H, H-1′, J = 6.0 Hz), 5.51 (d, 1H, OH, J =
5.6 Hz), 5.25 (d, 1H, OH, J = 3.9 Hz), 5.00 (t, 1H, OH, J = 5.8 Hz),
4.81−4.90 (m, 2H, CH2), 4.69−4.62 (m, 1H, H-2′), 4.28−4.24 (m,
1H, H-3′), 4.17 (m, 1H, H-4′), 3.72−3.70 (m, 1H, H-5′), 3.62−3.58
(m, 1H, H-5′). 13C NMR (DMSO-d6): δ 155.1, 151.3, 149.8, 149.3,
146.8, 141.1, 140.0, 130.5, 129.3, 128.7, 128.1, 127.3, 126.0, 120.3,
119.4, 87.6, 86.2, 74.1, 70.9, 61.9, 43.8. HRMS: calcd for
C25H24N8O4Na [M + Na]+ 523.1813, found 523.1822.
2-Azido-O6-(benzotriazol-1H-yl)-2′,3′,5′-tri-O-(tert-
butyldimethylsilyl)inosine (38). A solution of 3725 (50.0 mg, 0.067
mmol) in CH2Cl2 (3 mL) was cooled to −78 °C. To this stirred
solution TMS-N3 (0.088 mL, 0.67 mmol) was added followed by
dropwise addition of t-BuONO (0.08 mL, 0.67 mmol). The reaction
mixture was allowed to warm to rt and stirred for 9 h. To the reaction
mixture were added 1:1 H2O/MeOH (1 mL), and the stirring was
continued for 1 h. The mixture was then extracted with CH2Cl2. After
layer separation, the organic layer was removed, washed with water,
dried over Na2SO4, and evaporated to dryness. The crude product was
purified on silica gel column using 10% EtOAc/hexanes to afford 25.5
mg (49% yield) of 38 as white, foamy solid. Rf (SiO2/30% EtOAc in
hexanes) = 0.66. IR (neat): 2955, 2930, 2857, 2128, 1618, 1570 cm−1.
1
The following H and 13C NMR data list all discernible signals of the
1
isomer mixture. H NMR (500 MHz, CDCl3): δ 8.63, 8.58, and 8.55
(3s, 1H, Ar-H), 8.13 (m, 1H, Ar-H), 7.57−7.43 (m, 3H, Ar-H), 6.16
and 6.05 (2d, 1H, H-1′, J = 4.9, 3.9 Hz, respectively), 4.58, 4.54, and
4.47 (3t, 1H, H-2′, J = 4.4, 4.2, 4.2 Hz, respectively), 4.35−4.31 (m,
1H, H-3′), 4.19−4.15 (m, 1H, H-4′), 4.08−4.02 (m, 1H, H-5′), 3.83−
3.79 (m, 1H, H-5′), 0.972, 0.969, 0.96, 0.93, 0.925, 0.85, 0.84, and 0.81
(8s, 27H, t-Bu), 0.17, 0.16, 0.15, 0.10, 0.09, 0.02, 0.01, −0.008, −0.12,
and −0.17 (10s, 18H, SiCH3). 13C NMR (125 MHz, CDCl3): δ
159.81, 159.22, 155.97, 155.60, 155.10, 154.06, 152.81, 151.63, 144.62,
144.09, 143.72, 143.64, 143.57, 129.21, 129.12, 129.03, 128.94, 128.91,
125.14, 125.06, 125.03, 120.84, 120.10, 119.22, 117.19, 108.86, 108.77,
108.72, 89.61, 89.06, 88.99, 85.70, 85.56, 85.39, 76.66, 76.61, 76.46,
71.76, 71.47, 71.42, 62.45, 62.28, 62.19, 26.33, 26.31, 26.02, 25.86,
18.78, 18.75, 18.27, 18.09, 18.07, −4.09, −4.12, −4.15, −4.45, −4.49,
−4.53, −4.57, −4.59, −4.72, −5.11, −5.19, −5.23. HRMS: calcd for
C34H57N10O5Si3 [M + H]+ 769.3816, found 769.3839.
Biological Assays. The cytostatic effects of the test compounds on
murine leukemia cells (L1210), human T-lymphocyte cells (CEM),
and human cervix carcinoma cells (HeLa) were evaluated as follows:
an appropriate number of cells suspended in growth medium were
allowed to proliferate in 200 μL wells of 96-well microtiter plates in
the presence of variable amounts of test compounds at 37 °C in a
humidified CO2-controlled atmosphere. After 48 h (L1210), 72 h
(CEM), or 96 h (HeLa), the number of cells was counted in a Coulter
counter. The IC50 value is defined as the concentration required to
inhibit cell proliferation by 50%.
ASSOCIATED CONTENT
■
S
* Supporting Information
Copies of 1H and 13C NMR spectra of 1a,b, 2a,b, and 3−35, IR
spectra of 2a, 2b, and 38, 1H NMR spectra of O6-allyl
intermediates obtained by desilylation of 3−16 and the
deallylation product of 3, 13C NMR spectra of O6-allyl
1
intermediates obtained by desilylation 9 and 11, H NMR
1
spectrum of product obtained by the deallylation of 3, H−1H
COSY spectra of 1b, 3, 11, 19, 29, and 38, and HMQC spectra
of 10 and 38. This material is available free of charge via the
Internet at http://pubs.acs.org
M
dx.doi.org/10.1021/jo300628y | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Featured Article
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AUTHOR INFORMATION
Corresponding Author
*Tel: (212) 650-7835. Fax: (212) 650-6107. E-mail:
lakshman@sci.ccny.cuny.edu.
■
ACKNOWLEDGMENTS
■
This research was supported in part by NIH Grant No. 1R21
AI094545-01 to M.K.L. and with financial support of the K. U.
Leuven to J.B., G.A., and R.S. (GOA 10/014). 1A9, 1A9/
PTX10, and 1A9/PTX22 cell lines were obtained from Dr.
Paraskevi Giannakakou (Cornell University), and HCT-116/
p53KO−/− cells were obtained from Dr. Lin Zhang (UPCI
University of Pittsburgh) and Prof. Bert Vogelstein (Johns
Hopkins University). Infrastructural support at CCNY via NIH
Grant Numbers 2G12RR03060-26A1 from the National Center
for Research Resources and 8G12MD007603-27 from the
National Institute on Minority Health and Health Disparities is
gratefully acknowledged. We thank Dr. Padmanava Pradhan
(CCNY) for assistance with NMR experiments, Dr. Raghu
Chamala for assistance with the synthesis and characterization
of compound 38, and Leen Ingels, Lizette van Berckelaer, Lies
Van den Heurck, Anita Camps, Leentje Persoons, Frieda De
Meyer and Steven Carmans for assistance with the antiviral/
cytostatic assays.
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