Synthesis of bitriazolyl nucleosides and unexpectedly different reactivity of azidotriazole nucleoside isomers in the Huisgen reaction

Article abstract of DOI:10.1039/b703420b

Novel bitriazolyl nucleosides were synthesized via the Huisgen reaction, starting with 3-azidotriazole nucleoside (1). Surprisingly, its isomer, 5-azidotriazole nucleoside (1′) did not yield the corresponding Huisgen reaction products efficiently because it was rapidly reduced to amine in the presence of Cu(ii)-ascorbate. The significant differences between the reactivity of these two isomers in Cu(ii)-ascorbate mediated reactions are mainly due to differences in their electronic properties and steric congestion as a result of different relative positions of the azido and the ribosyl moieties. This journal is The Royal Society of Chemistry.

Full text of DOI:10.1039/b703420b

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PAPER
www.rsc.org/obc | Organic & Biomolecular Chemistry
Synthesis of bitriazolyl nucleosides and unexpectedly different reactivity of
azidotriazole nucleoside isomers in the Huisgen reaction
Yi Xia,a,b Wei Li, Fanqi Qu, Zhijin Fan, Xiufeng Liu, Charles Berro, Evelyne Rauzy and Ling Peng*
a
a
c
c
b
b
a,b
Received 6th March 2007, Accepted 23rd March 2007
First published as an Advance Article on the web 25th April 2007
DOI: 10.1039/b703420b
Novel bitriazolyl nucleosides were synthesized via the Huisgen reaction, starting with 3-azidotriazole
ꢀ
nucleoside (1). Surprisingly, its isomer, 5-azidotriazole nucleoside (1 ) did not yield the corresponding
Huisgen reaction products efficiently because it was rapidly reduced to amine in the presence of
Cu(II)–ascorbate. The significant differences between the reactivity of these two isomers in
Cu(II)–ascorbate mediated reactions are mainly due to differences in their electronic properties and
steric congestion as a result of different relative positions of the azido and the ribosyl moieties.
Introduction
we report on the synthesis and characterization of these novel
bitriazolyl ribonucleosides using the Huisgen reaction with 3-
Triazole units are heterocyclic structural motifs with considerable
medicinal and agrochemical potential. Ribavirin (Scheme 1),
a triazole nucleoside, which was the first synthetic nucleoside
azidotriazole nucleoside 1, and describe the unexpected reduction
of 5-azidotriazole nucleoside 1 occurring in the mild Cu(II)–
ascorbate system.
ꢀ
1
found to show antiviral activity, is the only small-molecule
drug currently available for treating patients infected with the
2
Results and discussion
hepatitis C virus. Fluconazole (Scheme 1), which has two 1,2,4-
3
triazole residues, is a powerful antifungal agent. We recently
1. Synthesis of bitriazolyl nucleosides
discovered bitriazolyl compounds (Scheme 1) which showed
4,5
ꢀ
promising activity against the tobacco mosaic virus (TMV). In
our ongoing research on novel triazole compounds with medicinal
3-Azidotriazole nucleoside 1 and 5-azidotriazole nucleoside 1 , the
precursors of the photolabeling probes of ribavirin, which were
previously developed at our laboratories, were used as starting
4–6
7
and agrochemical potentials, we are interested in developing
bitriazolyl ribonucleosides (Scheme 1) because nucleoside deriva-
tives provide useful means of combating various viruses. Here
materials to synthesize the bitriazolyl nucleosides via the Huisgen
8
reaction (Scheme 2).
Scheme 2 Synthesis of the bitriazolyl nucleosides via Cu(I)-catalyzed
Huisgen reaction.
Scheme 1 Ribavirin, fluconazole, bitriazolyles and bitriazolyl nucleoside.
4,5
In line with previous findings, bitriazolyl nucleoside 2 was
obtained in good to excellent yields from 1 under copper(I)-
catalyzed Huisgen reaction conditions (Table 1), regardless of
whether the substituents in the alkynes were aliphatic (entries
a
College of Chemistry and Molecular Sciences, Wuhan University, Wuhan,
4
30072, P. R. China
b
CNRS UMR 6114, D e´ partement de chimie, 163, avenue de Luminy, 13288,
Marseille, France. E-mail: ling.peng@ univmed.fr; Fax: 00 33 4 91 82 93
3
–6 in Table 1), aromatic (entries 7–11 in Table 1), or electron-
withdrawing groups (entries 1, 2 in Table 1). The reactions were
conveniently carried out by simply stirring 1 and the corresponding
0
1; Tel: 00 33 4 91 82 91 54
c
State Key Laboratory of Elemento-Organic Chemistry, Nankai University,
Tianjin, 300071, P. R. China
terminal alkynes in the presence of CuSO
4
and sodium ascorbate
This journal is © The Royal Society of Chemistry 2007
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Table 1 Bitriazolyl nucleosides (2) synthesized via copper(I)-catalyzed
Huisgen reaction using 1
a
b
Entry
1
R
Product
Yield (%)
81.4
Yield (%)
2a
78.5
2
3
4
5
2b
2c
2d
2e
77.6
87.7
81.1
98.4
72.7
79.7
74.0
75.5
Fig. 1 X-Ray structures of 2a (A and B) and 2i (C and D) (ORTEP
probability 50%).
6
7
8
9
2f
2g
2h
2i
70.1
98.1
85.9
81.9
73.2
89.1
85.0
77.5
83.9
66.3
70.2
71.4
bitriazolyl unit may therefore be an interesting motif for mimicking
conjugated or enlarged nucleobases.
In addition, the Huisgen reaction between 1 and various alkynes
occurred readily even at room temperature, although this gave
slightly lower yields (Table 1). We know from our previous
work that the azidotriazole without a ribosyl substituent was
not able to undergo the Huisgen reaction at room temperature
4,5
to give the corresponding bitriazolyl compounds. Therefore,
the introduction of the ribosyl group at N-1 of the triazole ring
promotes the reactivity of 1 in the Huisgen reaction.
1
1
0
1
2j
2k
However, the Huisgen reaction was not straightforward in the
ꢀ
case of 5-azidotriazole nucleoside (1 ). The reaction led to nu-
ꢀ
a
◦
b
◦
merous products, while 1 was almost completely consumed. This
At 80 C. At 25 C.
isomer did not yield the corresponding Huisgen product efficiently
either under conventional heating or by microwave irradiation
in the presence or absence of catalysts such as Cu(II)–ascorbate,
◦
at 80 C in a THF–H
2
O solvent system for 1 h. Only the 1,4-
Cu(0)–Cu(II), CuI–NEt , CuBr and CuCl (data not shown). We
3
disubstituted 1,2,3-triazoles were obtained, which is in agreement
with the proposed reaction mechanism that the copper(I) acetylide
intermediate formed may undergo stepwise addition with the
first thought that this might be simply due to the steric congestion
occurring between the azido group and the ribosyl moiety in
1 . When phenylacetylene was used, two completely unexpected
ꢀ
9
azide, resulting in the regioselective product. The structures of 1,4-
products were isolated: the amine 3 (38%) and the amide 4 (40%)
disubstituted 1,2,3-triazoles were further confirmed by performing
X-ray structural analysis on the two products 2a and 2i (Fig. 1).
Although the X-ray crystallographic analysis only established the
relative, not the absolute stereochemistry, it is worth noting that
the bitriazolyl units in both 2a and 2i approach co-planarity, as
(Scheme 3). To our great surprise, the 5-azidotriazole nucleoside
1 was reduced to 5-aminotriazole nucleoside 3 under mild Cu(II)–
ꢀ
ascorbate reaction conditions, although amide formation was
reported to occur via a hydrative reaction between terminal
alkynes, sulfonyl azides and water in the presence of a copper
5
10
previously observed in the case of bitriazolyl compounds. The
catalyst. Although alkyne homocoupling might possibly be a side
ꢀ
Scheme 3 Cu(I)-catalyzed Huisgen reaction of 5-azidotriazole nucleoside 1 with phenylacetylene.
1
696 | Org. Biomol. Chem., 2007, 5, 1695–1701
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8e,9b,11
reaction of the copper(I)-catalyzed Huisgen reaction,
we were
3 occurred readily even at room temperature, although a much
not able to isolate or identify any alkyne homocoupling products.
longer reaction time was required (entry 3 in Table 2). Without
the Cu catalyst, the azide 1 could also be reduced to the amine 3
ꢀ
by ascorbate, although at a much slower rate (entries 5 and 6 in
Table 2). Yields of 50% and 80% were obtained when 0.5 eq and
2.
Reduction of azide by the Cu (II)–ascorbate system
1
.0 eq sodium ascorbate was used, respectively. However, in the
The copper(I)-catalyzed Huisgen reaction, which is a reliable
and efficient method to generate triazole, has resulted in various
elegant and important contributions in the field of organic
synthesis and in the medicinal and material sciences. To our
knowledge, however, the azide reduction found here to occur under
mild Cu(II)–ascorbate Huisgen reaction conditions has never been
ꢀ
absence of sodium ascorbate (entry 4 in Table 2), azide 1 could not
be reduced to the corresponding amine in the presence of CuSO
or other Cu(I) catalysts such as CuI or CuBr.
4
Our expanded studies on other azides revealed that electron-
deficient aryl azides (entries 12–14 in Table 2) could be reduced
to amine in the Cu(II)–ascorbate system, while aryl azides with
electron-donating substituents and alkyl azides did not undergo
reduction (entries 8 and 11 in Table 2). This finding suggests
that the electronic properties of azides contribute significantly
to their reduction to amines. Similar findings were previously
reported by Knowles et al. as regards the reduction of azides
by propane-1,3-dithiol and recently by Wong et al. as regards the
regioselective reduction of azides by the Staudinger reaction using
ꢀ
reported so far. The reduction of 1 occurring in the Cu(II)–
ascorbate system prompted us to wonder whether these mild
Huisgen reaction conditions might reduce other azides, which
would seriously limit the general applicability of the Huisgen
reaction. We therefore treated several azides with the Cu(II)–
ascorbate system in the absence of any alkynes (Table 2). The
12
3
-azidotriazole nucleoside 1 (entry 1 in Table 2) was found to
be extremely stable in the Cu(II)–ascorbate system and could be
recovered with a yield of more than 80% even after being refluxed
13
trimethylphosphine.
◦
ꢀ
for 25 h at 80 C; whereas the 5-azidotriazole nucleoside 1 (entry
in Table 2) underwent rapid reduction and gave an almost
3
.
Different reactivity of azidotriazole nucleoside isomers
2
quantitative yield of the corresponding product, 5-aminotriazole
nucleoside 3, within 30 minutes. Reduction of azide 1 to amine
We were curious about the tremendous difference in reactivity
observed between azidotriazole nucleoside isomers 1 and 1 . In
ꢀ
ꢀ
Table 2 Reduction of various azido compounds under Cu-catalyzed Huisgen conditions
◦
a
Entry
Azide
CuSO
4
Sodium ascorbate
Temp./ C
Time/h
Yield (%)
b
1
2
3
4
5
6
7
8
1
0.16 eq
0.16 eq
0.16 eqc
0.16 eq
No
No
No
0.5 eq
0.5 eq
0.5 eq
No
0.5 eq
1.0 eq
No
80
80
25
80
80
80
80
80
25
—
97
ꢀ
ꢀ
1
0.5
8.5
23
21.5
6.5
8.0
10.5
1
74 (21)
ꢀ
ꢀ
ꢀ
ꢀ
b
1
—
1
50 (41)
80
1
b
1
—
—
b
0.16 eq
0.5 eq
b
9
0.16 eq
0.16 eq
0.16 eq
0.16 eq
0.16 eq
0.5 eq
0.5 eq
0.5 eq
0.5 eq
0.5 eq
80
80
80
80
10
8
—
b
1
1
1
1
0
1
2
3
—
b
10
9
—
31 (48)
d
e
70
16
25 (24)
d
1
4
0.16 eq
0.5 eq
70
22
68 (21)
a
b
The yields stand for the isolated amine product. In some cases, the yield of starting material recovery is indicated in parentheses. No reduction product
c
d
◦
◦
4
could be detected and isolated. CuSO , CuI and CuBr were tested respectively. The reaction was carried out at 70 C, not at 80 C because the starting
e
◦
material was not stable and partially decomposed at 80 C. Part of the ester product was further hydrolyzed to the corresponding acid during the
reaction.
This journal is © The Royal Society of Chemistry 2007
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order to explain this difference, theoretical calculations were
carried out on these two isomers. The results show that the
will be engaged in the Huisgen reaction. In the reduction reaction,
azide is going to receive the electrons in order to be reduced to the
corresponding amine. Therefore, the unoccupied LUMO of azide
will be engaged. Calculations showed that 1, on one hand, has the
14
azido-connecting carbon at the 3-position of 1 has a negative
ꢀ
charge of −0.036, while the carbon at the 5-position of 1 has a
ꢀ
positive charge of +0.065 (Scheme 4), indicating that the carbon
HOMO orbital with higher energy than 1 (Fig. 2), suggesting that
ꢀ
at the 3-position of 1 is electron-rich, while that at the 5-position
1 is more favorable to undergo Huisgen reaction than 1 . The steric
ꢀ
ꢀ
of 1 is electron-deficient. The azide group of 1 can be therefore
crowding around the azido group in 1 may also be an additional
taken to be attached to the electron-rich substituent, while that
of 1 is connected to the electron-deficient substituent. It was
factor to the problematic Huisgen cycloaddition. On the other
hand, the higher energy LUMO orbital as well as the practically
null LUMO orbital coefficient at the nitrogen atom to be reduced
makes it difficult for the reduction of 1 to the corresponding
amine. Contrary to 1, the lower energy LUMO orbital and higher
orbital coefficient at the nitrogen concerned make the reduction
ꢀ
recently reported that the use of highly electron-deficient azides
15
in the Huisgen reaction might be problematic. Since electron-
rich azides are favorable for the Huisgen reaction and electron-
deficient azides are suitable for reduction, this readily explains
ꢀ
ꢀ
the differences in reactivity observed for 1 and 1 under Huisgen
of 1 favorable. Taken together, results from both calculation and
reaction conditions.
experiments are in good agreement and demonstrate the significant
difference in the reaction activity between 1 and 1 .
ꢀ
4
. Biological evaluation
The synthesized bitriazolyl nucleosides 2a–k were evaluated for
their antiviral activity against the tobacco mosaic virus (TMV), a
basic model in the search for antiviral agents capable of combating
the agricultural plant virus. The antiviral activity of 2 was assessed
with the fresh leaves of tobacco plants using the conventional
16
half-leaf juice rubbing method as we have employed for the
5
Scheme 4 Charge distribution on the triazole ring of 1 and 1ꢀ.
non-nucleosidic bitriazolyl compounds. The results are listed in
Table 3, together with that of ribavirin, the control reference.
Compounds 2g and 2h showed similar level of antiviral activity to
that of ribavirin (Table 3). These results together with our previous
results have demonstrated the potential of bitriazolyl compounds
as antiviral candidates.
ꢀ
We further studied the frontier orbitals of 1 and 1 (Fig. 2) in
order to better understand their different chemical reactivity. It is
well known that the energy and the population of frontier orbitals
are important factors to chemical reactivity. During the reaction,
the electrons are transferred from the highest occupied molecular
orbital (HOMO) of the donor to the lowest unoccupied molecular
orbital (LUMO) of the acceptor. The interaction of HOMO–
LUMO is stronger if the energy difference between the HOMO
and LUMO is smaller or if the spatial overlap between the orbitals
involved is more efficient. Therefore, the reaction proceeds faster
when the HOMO energy is raised or the LUMO energy decreased
or the spatial overlap of orbitals is more favorable. Based on the
proposed mechanism for the copper(I) mediated Huisgen reaction,
the azide will undergo nucleophilic addition to the copper(I)
acetylide intermediate, indicating that the HOMO orbital of azide
5
Conclusions
In conclusion, we have accomplished the convenient synthesis of
a series of novel bitriazolyl nucleosides via the Huisgen reaction.
During the synthesis, we have discovered the surprisingly different
reactivity of 3-azidotriazole nucleoside (1) and 5-azidotriazole
ꢀ
nucleoside (1 ) in a Cu(II)–ascorbate mediated reaction: 1 under-
ꢀ
went efficient Cu(I)-catalyzed Huisgen reaction, whereas 1 was
rapidly reduced to the corresponding amine. A calculation has
been used to interpret this different reactivity, which is mainly
due to their different electronic properties: 1 is an electron-rich
ꢀ
azide which is favorable for the Huisgen reaction, while 1 is
Table 3 Antiviral activity of the synthesized triazole nucleosides against
tobacco mosaic virus
Compound
Ribavirin
Antiviral activity (%)
49 ± 8
11 ± 9
12 ± 8
21 ± 7
17 ± 3
25 ± 5
8 ± 5
2
2
2
2
2
2
2
2
2
2
2
a
b
c
d
e
f
g
h
i
40 ± 3
42 ± 8
8 ± 5
j
k
18 ± 10
28 ± 6
Fig. 2 The energy and the shape of the HOMO and LUMO orbitals of 1
ꢀ
and 1 , respectively.
1
698 | Org. Biomol. Chem., 2007, 5, 1695–1701
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electron-deficient azide which is favorable for reduction. Ad-
ditionally, the steric crowding of 1 may also be responsible
to the CCDC, 12 Union Road, Cambridge CB2 1EZ UK (email:
deposit@ccdc.cam.ac.uk).†
ꢀ
for the problematic Huisgen reaction. The different reactivity
between 1 and 1 may be further exploited for synthesizing
structurally different triazole compounds with various biological
activities. Studies in this direction are currently under way in our
laboratories.
3
-[4-(Ethoxycarbonyl)-1H -1,2,3-triazol-1-yl]-1-(2,3,5-tri-O-
acetyl-b-D-ribofuranosyl)-1,2,4-triazole-5-carboxylic acid methyl
ester (2b). Colorless oil (95.5 mg, 77.6%). R 0.28 (petroleum
): d 8.82 (s, 1H,
ꢀ
f
1
ether–EtOAc, 1 : 1); H NMR (300 MHz, CDCl
3
ꢀ
H-triazole), 7.00 (d, J = 3.0 Hz, 1H, H-1 ), 5.87 (dd, J = 3.0,
ꢀ
ꢀ
5
.1 Hz, 1H, H-2 ), 5.64–5.68 (m, 1H, H-3 ), 4.42–4.49 (m, 4H,
ꢀ
ꢀ
ꢀ
H-4 + H-5 + –CH
2
–), 4.22 (dd, J = 4.8, 12.0 Hz, 1H, H-5 ), 4.07
Experimental
(
1
1
s, 3H, –OCH
3
), 2.14 (s, 6H, –C(O)CH
3
), 2.08 (s, 3H, –C(O)CH
3
),
): d
70.6, 169.5, 169.4, 159.9, 156.9, 153.9, 145.8, 140.6, 126.7, 90.0,
1
3
.43 (t, 3H, J = 7.1 Hz, –CH
3
); C NMR (150 MHz, CDCl
3
General method
1
13
The H NMR and C NMR spectra were recorded at 300 MHz
and 150 MHz, respectively, on Varian Mercury-VX300 and Varian
Inova-600 spectrometers. The chemical shifts were recorded in
parts per million (ppm) with TMS as the internal reference. FAB
and ESI MS were determined using ZAB-HF-3F or Finnigan LCQ
Advantage mass spectrometer. High resolution mass spectra were
obtained by Matrix-assisted laser desorption/ionization mass
spectrometry (MALDI-MS) using an IonSpec 4.7 Tesla fourier
transform mass spectrometer. All compounds were purified by
performing flash chromatography on silica gel (200–300 mesh).
81.2, 74.3, 70.7, 62.6, 61.7, 54.0, 20.7, 20.51, 20.48, 14.3; ESI-
MS: m/z 524.8 [M + H] , 546.9 [M + Na] , 1070.5 [2M + Na] ,
calcd for C H N O 524; HRMS: calcd. for C H N O Na
+
+
+
+
2
0
24
6
11
20
24
6
11
547.1401. Found 547.1393.
-[4-(Acetoxymethyl)-1H -1,2,3-triazol-1-yl]-1-(2,3,5-tri-O-
acetyl-b-D-ribofuranosyl)-1,2,4-triazole-5-carboxylic acid methyl
ester (2c). Colorless oil (107.9 mg, 87.7%). R 0.30 (petroleum
): d 8.37 (s, 1H, H-
3
f
1
ether–EtOAc, 1 : 1); H NMR (300 MHz, CDCl
3
ꢀ
triazole), 7.01 (d, J = 3.0 Hz, 1H, H-1 ), 5.88 (dd, J = 3.0, 5.1 Hz,
ꢀ
ꢀ
1
2
H, H-2 ), 5.67–5.70 (m, 1H, H-3 ), 5.30 (s, 2H, –CH –O–C(O)–
ꢀ
ꢀ
CH
3
), 4.44–4.49 (m, 2H, H-4 + H-5 ), 4.23 (dd, J = 5.7, 12.3 Hz,
General procedure for the synthesis of the bitriazolyl derivatives
ꢀ
1
3
H, H-5 ), 4.06 (s, 3H, –OCH
3
3
), 2.13 (s, 6H, –C(O)CH ), 2.10 (s,
), 2.06 (s, 3H, –C(O)CH ); C NMR (150 MHz,
3
7
2
through a copper(I)-catalyzed Huisgen reaction. The azide 1
13
H, –C(O)CH
): d 170.9, 170.8, 169.7, 169.6, 157.2, 154.5, 145.8, 143.7,
23.1, 90.1, 81.3, 74.4, 71.0, 63.0, 57.4, 54.1, 21.0, 20.9, 20.7; ESI-
3
(
100 mg, 0.23 mmol) and alkynes (0.28 mmol) were dissolved in a
CDCl
3
mixed solvent system (THF–H O, 1 : 2, 9 mL). A freshly prepared
2
1
aqueous solution of sodium ascorbate (0.12 mmol, 0.2 mL)
was added, followed by a freshly prepared aqueous solution of
+
+
MS: m/z 525.0 [M + H] , 1048.8 [2M] , calcd for C20
HRMS: calcd. for C20
H
24
N O11 524;
6
+
H
24
N
6
O
11Na 547.1401. Found 547.1378.
CuSO
4
·5H
2
O (0.04 mmol, 0.2 mL). The yellowish reaction mixture
◦
◦
3-[4-(1-Hydroxycyclopentyl)-1H-1,2,3-triazol-1-yl]-1-(2,3,5-tri-
O-acetyl-b-D-ribofuranosyl)-1,2,4-triazole-5-carboxylic acid methyl
ester (2d). Colorless oil (102.1 mg, 81.1%). R
was stirred at 80 C or at 25 C, until complete consumption of 1.
The solvent was evaporated under reduced pressure and the crude
material was purified by column chromatography (petroleum
ether–EtOAc, 1 : 1). The residue was dried in vacuo to afford 2.
f
0.28 (petroleum
): d 8.23 (s, 1H, H-
1
ether–EtOAc, 1 : 1); H NMR (300 MHz, CDCl
3
ꢀ
triazole), 7.01 (d, J = 3.0 Hz, 1H, H-1 ), 5.89 (dd, J = 2.7, 5.1 Hz,
ꢀ
ꢀ
ꢀ
1
5
2
2
H, H-2 ), 5.67–5.71 (m, 1H, H-3 ), 4.45–4.50 (m, 2H, H-4 + H-
3
-[4-(Methoxycarbonyl)-1H-1,2,3-triazol-1-yl]-1-(2,3,5-tri-O-
acetyl-b-D-ribofuranosyl)-1,2,4-triazole-5-carboxylic acid methyl
ester (2a). White crystal (97.5 mg, 81.4%). R 0.25 (petroleum
): d 8.85 (s, 1H, H-
ꢀ
ꢀ
), 4.23 (dd, J = 5.7, 13.2 Hz, 1H, H-5 ), 4.07 (s, 3H, –OCH
3
),
–),
.27 (br s, 1H, –OH), 2.15–2.22 (m, 8H, –C(O)CH
3
+ –CH
2
f
1
3
.09 (s, 3H, –C(O)CH
): d 170.9, 169.8, 169.6, 157.3, 155.1, 154.7,
45.7, 119.4, 90.0, 81.2, 79.0, 74.5, 71.0, 63.1, 54.1, 41.4, 23.8,
3
2
), 1.86–2.05 (m, 6H, –CH –). C NMR
1
ether–EtOAc, 1 : 1); H NMR (300 MHz, CDCl
3
(
150 MHz, CDCl
3
ꢀ
triazole), 7.02 (d, J = 2.4 Hz, 1H, H-1 ), 5.88 (dd, J = 2.7, 5.1 Hz,
1
2
ꢀ
ꢀ
ꢀ
1
5
H, H-2 ), 5.66–5.69 (m, 1H, H-3 ), 4.45–4.50 (m, 2H, H-4 + H-
+
+
0.9, 20.7; ESI-MS: m/z 558.8 [M + Na] , 1096.5 [2M + Na] ,
calcd for C22
59.1765. Found 559.1749.
ꢀ
ꢀ
), 4.24 (dd, J = 5.1, 12.3 Hz, 1H, H-5 ), 4.09 (s, 3H, –OCH
3
), 4.01
);
+
H
28
N
6
O
10 536; HRMS: calcd. for C22
H
28
N O10Na
6
(
s, 3H, –OCH
3
), 2.16 (s, 6H, –C(O)CH
3
), 2.09 (s, 3H, –C(O)CH
3
5
1
3
C NMR (150 MHz, CDCl ): d 166.1, 165.0, 164.9, 155.8, 152.4,
3
1
1
49.4, 141.3, 135.8, 122.2, 85.5, 76.6, 69.7, 66.2, 58.1, 49.5, 48.1,
3-[4-(1-Hydroxycyclohexyl)-1H-1,2,3-triazol-1-yl]-1-(2,3,5-tri-
O-acetyl-b-D-ribofuranosyl)-1,2,4-triazole-5-carboxylic acid methyl
ester (2e). Colorless oil (127.1 mg, 98.4%). R 0.28 (petroleum
): d 8.22 (s, 1H,
+
+
6.2, 16.0; ESI-MS: m/z 510.9 [M + H] , 532.9 [M + Na] , 1042.6
+
[2M + Na] , calcd for C19
H
22
N
6
O11 510. Crystallographic data of
f
1
2
4
9
a: C19
H
22
N
6
O
11 (Mr 510.43), monoclinic space group c 2, Z =
ether–EtOAc, 1 : 1); H NMR (300 MHz, CDCl
3
ꢀ
˚
H-triazole), 7.01 (d, J = 2.7 Hz, 1H, H-1 ), 5.89 (dd, J = 3.2,
, a = 11.8185 (4), b = 11.0156 (4), c = 18.8659 (8) A, a =
3
ꢀ
ꢀ
˚
5.3 Hz, 1H, H-2 ), 5.67–5.71 (m, 1H, H-3 ), 4.44–4.51 (m, 2H,
0.00, b = 95.528 (3), c = 90.00, V = 2444.69 (16) A , MoK
a
◦
◦
ꢀ
ꢀ
ꢀ
˚
H-4 + H-5 ), 4.22 (dd, J = 5.7, 13.2 Hz, 1H, H-5 ), 4.07 (s, 3H, –
OCH ), 2.37 (br s, 1H, –OH), 2.13 (s, 6H, –C(O)CH ), 2.07 (s, 3H,
–C(O)CH –); C NMR (150 MHz,
CDCl ): d 170.9, 169.8, 169.6, 157.3, 156.3, 154.8, 145.7, 119.3,
90.0, 81.3, 74.5, 71.1, 69.8, 63.0, 54.2, 38.1, 25.5, 22.1, 21.0, 20.74,
radiation, k = 0.71073 A, 3.86 < h < 26.00 , 2366 reflections,
T = 293 K on a Brucker-Nonius Kappa CCD. The structure
was solved using direct methods (SHELXS 97) and refined with
3
3
1
3
3
), 1.30–2.04 (m, 10H, –CH
2
2
2
SHELXL97 to final R (F > 2rF ) = 0.0425 and wR = 0.119 [w =
3
2
2
2
2
2
1
/[r (Fo ) + (0.0889P) + 0.6416P], where P = (Fo + 2Fc )/3].
The X-ray structure data has been deposited in the Cambridge
Crystallographic Data Center with deposition no. CCDC 639564.
Copy of the data can be obtained, free of charge, on application
†
CCDC reference numbers 639564 and 639565. For crystallographic data
in CIF or other electronic format see DOI: 10.1039/b703420b
This journal is © The Royal Society of Chemistry 2007
Org. Biomol. Chem., 2007, 5, 1695–1701 | 1699

View Article Online
+
2
0.70; ESI-MS: m/z 573.0 [M + Na] , calcd for C23
H
30
N
6
O
10 550;
90.1, 81.3, 74.5, 71.1, 63.0, 55.6, 54.2, 21.0, 20.74, 20.71; FAB-MS:
+
+
HRMS: calcd. for C23
H
30
N
6
O
10Na 573.1921. Found 573.1896.
m/z 559.0 [M + H] , calcd for C24
H
26
6
N O10 558. Crystallographic
data of 2i: C24
H
26
N
6
O
10 (Mr 558.51), monoclinic space group p 21
3
-(4-Cyclohexenyl-1H-1,2,3-triazol-1-yl)-1-(2,3,5-tri-O-acetyl-
b-D-ribofuranosyl)-1,2,4-triazole-5-carboxylic acid methyl ester
2f). Colorless oil (87.5 mg, 70.1%). R 0.45 (petroleum ether–
): d 8.13 (s, 1H, H-
˚
2
1 21, Z = 4, a = 7.5396 (10), b = 7.9351 (2), c = 43.1982 (6) A,
3
˚
a = 90.00, b = 90.00 (3), c = 90.00, V = 2584.44 (8) A , MoK
a
(
f
◦
◦
˚
radiation, k = 0.71073 A, 0.47 < h < 28.24 , 2946 reflections,
T = 293 K on a Brucker-Nonius Kappa CCD. The structure
was solved using direct methods (SHELXS 97) and refined with
1
EtOAc, 1 : 1); H NMR (600 MHz, CDCl
3
ꢀ
triazole), 7.02 (d, J = 1.8 Hz, 1H, H-1 ), 6.73 (br, 1H, –CH=C–),
ꢀ
ꢀ
5
.91 (br, 1H, H-2 ), 5.71–5.73 (m, 1H, H-3 ), 4.48–4.50 (m, 2H,
2
2
SHELXL97 to final R (F > 2sF ) = 0.0613 and wR = 0.1449 [w =
ꢀ
ꢀ
ꢀ
H-4 + H-5 ), 4.23 (dd, J = 4.8, 12.0 Hz, 1H, H-5 ), 4.08 (s, 3H,
2
2
2
2
2
1
/[r (Fo ) + (0.1151P) + 0.0000P], where P = (Fo + 2Fc )/3].
–
OCH
3
), 2.41 (br, 2H, –CH
2
–), 2.24 (m, 2H, –CH
), 1.79–1.80 (m, 2H, –CH
–); C NMR (150 MHz, CDCl ): d
70.8, 169.7, 169.6, 157.3, 154.8, 150.0, 145.6, 127.1, 126.4, 117.2,
0.0, 81.3, 74.5, 71.0, 62.9, 54.1, 26.5, 25.5, 22.5, 22.3, 20.9, 20.7,
2
–), 2.15 (s, 6H,
The X-ray structure data has been deposited in the Cambridge
Crystallographic Data Center with deposition no. CCDC 639565.
Copy of the data can be obtained, free of charge, on application
to the CCDC, 12 Union Road, Cambridge CB2 1EZ UK (email:
deposit@ccdc.cam.ac.uk).†
–
)
C(O)CH
3
), 2.07 (s, 3H, –C(O)CH
3
2
–
1
3
, 1.69–1.71 (m, 2H, –CH
2
3
1
9
2
+
+
0.6; ESI-MS: m/z 533.2 [M + H] , 1065.6 [2M + H] , calcd
for C23
Found 555.1825.
+
H
28
N
6
O
9
532; HRMS: calcd. for C23
H
28
N
6
O Na 555.1815.
9
3
-[4-(4-Fluorophenyl)-1H -1,2,3-triazol-1-yl]-1-(2,3,5-tri-O-
acetyl-b-D-ribofuranosyl)-1,2,4-triazole-5-carboxylic acid methyl
ester (2j). White solid (93.8 mg, 73.2%). R 0.48 (petroleum
ether–EtOAc, 1 : 1); H NMR (300 MHz, CDCl ): d 8.52 (s, 1H,
H-triazole), 7.90 (dd, JHF = 5.4 Hz, JHH = 9.0 Hz, 2H, ArH), 7.17
(dd, JHF = 8.4 Hz, JHH = 9.0 Hz, 2H, ArH), 7.04 (d, J = 3.0 Hz,
3
-(4-Phenyl-1H-1,2,3-triazol-1-yl)-1-(2,3,5-tri-O-acetyl-b-D-
ribofuranosyl)-1,2,4-triazole-5-carboxylic acid methyl ester (2g).
White solid (121.6 mg, 98.1%). R 0.55 (petroleum ether–EtOAc, 1
): d 8.56 (s, 1H, H-triazole), 7.93
f
1
3
4
3
f
1
3
3
:
1); H NMR (300 MHz, CDCl
3
ꢀ
ꢀ
(
3
(
1
2
1
1
d, J = 7.5 Hz, 2H, ArH), 7.39–7.50 (m, 3H, ArH), 7.04 (d, J =
1H, H-1 ), 5.92 (dd, J = 3.0, 5.4 Hz, 1H, H-2 ), 5.71–5.75 (m, 1H,
ꢀ ꢀ ꢀ
ꢀ
ꢀ
.0 Hz, 1H, H-1 ), 5.93 (dd, J = 3.0, 5.7 Hz, 1H, H-2 ), 5.72–5.76
H-3 ), 4.47–4.53 (m, 2H, H-4 + H-5 ), 4.26 (dd, J = 6.0, 13.2 Hz,
ꢀ
ꢀ
ꢀ
ꢀ
m, 1H, H-3 ), 4.47–4.53 (m, 2H, H-4 + H-5 ), 4.26 (dd, J = 6.0,
1H, H-5 ), 4.09 (s, 3H, –OCH
3
3
), 2.15 (s, 6H, –C(O)CH ), 2.09 (s,
ꢀ
13
3.2 Hz, 1H, H-5 ), 4.09 (s, 3H, –OCH
3
), 2.15 (s, 6H, –C(O)CH
); C NMR (150 MHz, CDCl
3
),
3H, –C(O)CH
169.6, 163.2 (d, 1C, JCF = 248.3 Hz), 157.3, 154.7, 147.6, 145.8,
128.1 (d, 2C, JCF = 6.3 Hz), 125.9, 118.5, 116.2 (d, 2C, JCF
21.3 Hz), 90.2, 81.3, 74.6, 71.1, 63.0, 54.1, 20.9, 20.7; FAB-MS:
m/z 547.0 [M + H] , 569.0 [M + Na] , calcd for C23
HRMS: calcd. for C23
3
); C NMR (150 MHz, CDCl ): d 170.8, 169.8,
3
1
3
1
.09 (s, 3H, –C(O)CH
69.8, 169.6, 157.3, 154.7, 148.4, 145.8, 129.6, 129.2, 129.0, 126.3,
18.7, 90.1, 81.3, 74.5, 71.0, 63.0, 54.2, 21.0, 20.73, 20.71; ESI-
MS: m/z 528.9 [M + H] , 551.1 [M + Na] , 1056.8 [2M] , calcd
for C23
3
3
): d 170.9,
3
2
=
+
+
+
+
+
H
23FN
6
O 546;
9
+
+
H
24
N
6
O
9
528; HRMS: calcd. for C23
H
24
N
6
O
9
Na 551.1502.
H
23FN
6
O
9
Na 569.1408. Found 569.1420.
Found 551.1478.
3
-[4-(4-Pentylphenyl)-1H -1,2,3-triazol-1-yl]-1-(2,3,5-tri-O-
acetyl-b-D-ribofuranosyl)-1,2,4-triazole-5-carboxylic acid methyl
ester (2k). Colorless oil (125.1 mg, 89.1%). R 0.45 (petroleum
): d 8.52 (s, 1H,
3
-(4-p-Tolyl-1H-1,2,3-triazol-1-yl)-1-(2,3,5-tri-O-acetyl-b-D-
ribofuranosyl)-1,2,4-triazole-5-carboxylic acid methyl ester (2h).
White solid (109.3 mg, 85.9%). R 0.50 (petroleum ether–EtOAc,
: 1); H NMR (300 MHz, CDCl ): d 8.50 (s, 1H, H-triazole),
f
f
1
ether–EtOAc, 1 : 1); H NMR (600 MHz, CDCl
3
1
1
7
7
3
H-triazole), 7.83 (d, J = 7.8 Hz, 2H, ArH), 7.28 (d, J = 7.8 Hz, 2H,
.81 (d, J = 8.1 Hz, 2H, ArH), 7.27 (d, J = 7.2 Hz, 2H, ArH),
ꢀ
ArH), 7.04 (d, J = 3.0 Hz, 1H, H-1 ), 5.93 (dd, J = 3.0, 5.4 Hz, 1H,
ꢀ
.03 (d, J = 2.7 Hz, 1H, H-1 ), 5.93 (dd, J = 3.0, 5.1 Hz, 1H,
ꢀ
ꢀ
ꢀ
ꢀ
H-2 ), 5.73–5.75 (m, 1H, H-3 ), 4.49–4.52 (m, 2H, H-4 + H-5 ),
ꢀ
ꢀ
ꢀ
ꢀ
H-2 ), 5.71–5.75 (m, 1H, H-3 ), 4.46–4.51 (m, 2H, H-4 + H-5 ),
ꢀ
4
2
1
.24–4.27 (m, 1H, H-5 ), 4.09 (s, 3H, –OCH
3
), 2.65 (t, J = 7.5 Hz,
), 2.09 (s, 3H, –C(O)CH ),
–), 1.33–1.37 (m, 4H, –CH –), 0.90 (t,
): d 170.8,
69.7, 169.6, 157.3, 154.7, 148.5, 145.7, 144.0, 129.2, 127.0, 126.2,
18.3, 90.1, 81.3, 74.5, 71.0, 63.0, 54.1, 35.9, 31.6, 31.2, 22.7, 20.9,
ꢀ
4
.25 (dd, J = 5.7, 12.3 Hz, 1H, H-5 ), 4.08 (s, 3H, –OCH
3
), 2.40
), 2.08 (s, 3H, –C(O)CH );
): d 170.9, 169.8, 169.6, 157.3, 154.8,
H, –CH
2
–), 2.16 (s, 6H, –C(O)CH
3
3
(
s, 3H, –CH
3
), 2.14 (s, 6H, –C(O)CH
3
3
.64–1.68 (m, 2H, –CH
2
2
1
3
C NMR (150 MHz, CDCl
48.5, 145.7, 139.0, 129.9, 126.8, 126.2, 118.3, 90.1, 81.3, 74.5,
1.0, 63.0, 54.2, 21.6, 21.0, 20.73, 20.70; ESI-MS: m/z 542.8 [M
H] , 565.0 [M + Na] , 1084.6 [2M] , 1106.6 [2M + Na] , calcd.
for C24
Found 565.1663.
3
1
3
J = 6.9 Hz, 3H, –CH
3
); C NMR (150 MHz, CDCl
3
1
1
1
2
1
7
+
+
+
+
+
+
+
0.68, 20.66, 14.2; ESI-MS: m/z 599.1 [M + H] , 1196.9 [2M] ,
198.1 [2M + H] , calcd. for C28
+
H
26
N
6
O
9
542; HRMS: calcd. for C24
H
26
N
6
O Na 565.1659.
9
+
H
34
N
6
O 598; HRMS: calcd. for
9
+
C
28
H
34
N
6
O
9
Na 621.2285. Found 621.2295.
3
-[4-(4-Methoxyphenyl)-1H-1,2,3-triazol-1-yl]-1-(2,3,5-tri-O-
acetyl-b-D-ribofuranosyl)-1,2,4-triazole-5-carboxylic acid methyl
ester (2i). White crystal (107.3 mg, 81.9%). R 0.50 (petroleum
ether–EtOAc, 1 : 1); mp: 163.4–163.5 C; H NMR (300 MHz,
Procedure for Cu(I)-catalyzed Huisgen reaction of 5-azidotriazole
nucleoside 1 with phenylacetylene. The azide 1 (30 mg,
0.07 mmol) and phenylacetylene (9.3 lL, 0.08 mmol) were
ꢀ
ꢀ7
f
◦
1
CDCl
3
): d 8.46 (s, 1H, H-triazole), 7.85 (d, J = 8.7 Hz, 2H, ArH),
dissolved in a mixed solvent system (THF–H O, 1 : 2, 3.0 mL). A
freshly prepared aqueous solution of sodium (6.9 mg, 0.035 mmol,
0.2 mL) was added, followed by a freshly prepared aqueous
2
ꢀ
7
.03 (d, J = 2.7 Hz, 1H, H-1 ), 7.00 (d, J = 8.7 Hz, 2H, ArH), 5.93
ꢀ
ꢀ
(
dd, J = 3.0, 5.1 Hz, 1H, H-2 ), 5.71–5.75 (m, 1H, H-3 ), 4.46–4.51
m, 2H, H-4 + H-5 ), 4.25 (dd, J = 5.7, 12.9 Hz, 1H, H-5 ), 4.08 (s,
H, –OCH ), 3.86 (s, 3H, –OCH ), 2.15 (s, 6H, –C(O)CH ), 2.08
s, 3H, –C(O)CH ); C NMR (150 MHz, CDCl ): d 170.9, 169.8,
69.6, 160.3, 157.3, 154.8, 148.3, 145.7, 127.6, 122.3, 117.8, 114.6,
ꢀ
ꢀ
ꢀ
(
3
(
1
solution of CuSO
4
·5H
2
O (2.5 mg, 0.01 mmol, 0.2 mL). The
◦
3
3
3
yellowish reaction mixture was stirred at 80 C, until complete
consumption of the azide. The solvent was evaporated under
reduced pressure and the crude material was purified by column
1
3
3
3
1
700 | Org. Biomol. Chem., 2007, 5, 1695–1701
This journal is © The Royal Society of Chemistry 2007

View Article Online
chromatography. The residue was dried in vacuo to afford the title
compound 3 (10.9 mg, 38.7%) and 4 (14.7 mg, 40.4%).
Acknowledgements
We are grateful to Dr Michel Giorgi for X-ray analysis. Financial
support from the Ministry of Science and Technology of China
5
-Amino-1-(2,3,5-tri-O-acetyl-b-D-ribofuranosyl)-1,2,4-triazole-
-carboxylic acid methyl ester (3). White solid. R 0.35
): d 5.87
3
f
(
No 2003CB114403, 2003CB514102, 2003AA2Z3506), National
Natural Science Foundation of China (No 20372055, 20572081,
0672062), Wuhan University and CNRS is gratefully acknowl-
1
(
CH
2
Cl
2
–CH
3
OH, 20 : 1); H NMR (300 MHz, CDCl
3
ꢀ
ꢀ
(
2
d, J = 4.5 Hz, 1H, H-1 ), 5.75–5.78 (m, 1H, H-2 ), 5.68 (br s,
2
ꢀ
ꢀ
H, –NH
H-5 ), 3.90 (s, 3H, –OCH
150 MHz, CDCl
2
), 5.48–5.51 (m, 1H, H-3 ), 4.31–4.39 (m, 3H, H-4 +
edged. We thank Curt Wentrup, Michele Bertrand, Michel Rajz-
mann, Gilles Qu e´ l e´ ver and Weiming Wu for helpful discussions
and careful reading.
ꢀ
13
3
), 2.09 (s, 9H, –C(O)CH
): d 170.7, 169.7, 160.5, 156.3, 151.6, 88.6, 81.0,
3.0, 70.6, 63.0, 52.7, 20.8, 20.7, 20.6; FAB-MS: m/z 401.0 [M +
3
); C NMR
(
3
7
+
+
H] , 423.0 [M + Na] , calcd for C15
H
20
N
4
O 400; HRMS: calcd.
9
+
for C15
H
20
N
4
O
9
Na 423.1128. Found 423.1117.
References
5
-(2-Phenylacetamido)-1-(2,3,5-tri-O-acetyl-b-D-ribofuranosyl)-
1
R. W. Sidwell, J. H. Huffman, G. P. Khare, L. B. Allen, J. T. Witkowski
1
R
,2,4-triazole-3-carboxylic acid methyl ester (4). Yellowish solid.
and R. K. Robins, Science, 1972, 177, 705.
1
2 E. De Clercq, Nat. Rev. Drug Discovery, 2002, 1, 13.
f
0.4 (CH
2
Cl
2
–CH
3
OH, 20 : 1); H NMR (300 MHz, CDCl
3
):
3
Y. A. Al-Soud, M. N. Al-Dweri and N. A. Al-Masoudi, Il Farmaco,
d 10.12 (brs, 1H, –NH), 7.22–7.26 (m, 5H, ArH), 6.06 (brs, 1H,
2
004, 59, 775.
ꢀ
ꢀ
H-1 ), 5.89–5.90 (m, 1H, H-2 ), 5.70 (dd, J = 5.9, 11.7 Hz, 1H,
4
Y. Xia, F. Q. Qu, W. Li, Q. Y. Wu and L. Peng, Heterocycles, 2005, 65,
ꢀ
ꢀ
ꢀ
H-3 ), 4.39–4.47 (m, 2H, H-4 + H-5 ), 4.19 (dd, J = 5.1, 11.7 Hz,
345.
ꢀ
5 Y. Xia, Z. J. Fan, J. H. Yao, Q. Liao, W. Li, F. Q. Qu and L. Peng,
Bioorg. Med. Chem. Lett., 2006, 16, 2693.
(a) J. Q. Wan, R. Z. Zhu, Y. Xia, F. Q. Qu, Q. Y. Wu, G. F. Yang, J.
Neyts and L. Peng, Tetrahedron Lett., 2006, 47, 6727; (b) R. Z. Zhu,
F. Q. Qu, G. Qu e´ l e´ ver and L. Peng, Tetrahedron Lett., 2007, 48, 2389.
7 Q. Y. Wu, F. Q. Qu, J. Q. Wan, X. Zhu, Y. Xia and L. Peng, Helv. Chim.
Acta, 2004, 87, 811.
(a) R. Huisgen, Angew. Chem., Int. Ed. Engl., 1963, 2, 565; (b) R.
Huisgen, Angew. Chem., Int. Ed. Engl., 1963, 2, 633; (c) H. C. Kolb,
M. G. Finn and K. B. Sharpless, Angew. Chem., Int. Ed., 2001, 40, 2004;
(d) H. C. Kolb and K. B. Sharpless, Drug Discovery Today, 2003, 8,
1
H, H-5 ), 3.94 (s, 3H, –OCH
3
2
), 3.83 (s, 2H, –CH ), 2.12 (s, 3H,
1
3
–
C(O)CH
3
), 2.09 (s, 3H, –C(O)CH
): 170.8, 170.6, 169.4, 169.1, 159.5, 152.3,
48.4, 133.2, 129.4, 129.0, 127.7, 89.9, 80.6, 74.4, 70.5, 63.1, 52.7,
3
3
), 2.05 (s, 3H, –C(O)CH ); C
6
NMR (150 MHz, CDCl
3
1
4
1
+
+
3.1, 20.6, 20.5; ESI-MS: m/z 519.0 [M + H] , 541.1 [M + Na] ,
+
+
036.7 [2M] , 1058.9 [2M + Na] , calcd. for C23
H
26
N O10 518;
4
8
+
HRMS: calcd. for C23
H
26
N
4
O
10Na 541.1547. Found 541.1544.
General procedure for the reduction of various azides under
1
128; (e) V. D. Bock, H. Hiemstra and J. H. van Maarseveen, Eur. J. Org.
copper(I)-catalyzed Huisgen conditions. The azide was dissolved
in a mixed solvent system (THF–H
aqueous solution of sodium ascorbate was added, followed by a
freshly prepared aqueous solution of CuSO
reaction mixture was stirred at 80 C, until complete consumption
of the azide. The solvent was evaporated under reduced pressure
and the crude material was purified by column chromatography.
The residue was dried in vacuo to afford the corresponding amine.
Chem., 2006, 51.
2
O, 1 : 2). A freshly prepared
9
(a) V. V. Rostovtsev, L. G. Green, V. V. Fokin and K. B. Sharpless,
Angew. Chem., Int. Ed., 2002, 41, 2596; (b) C. W. Tornøe, C. Christensen
and M. Meldal, J. Org. Chem., 2002, 67, 3057.
4
·5H
2
O. The yellowish
◦
10 S. H. Cho, E. J. Yoo, I. Bae and S. Chang, J. Am. Chem. Soc., 2005,
27, 16046.
1 E.-H. Ryu and Y. Zhao, Org. Lett., 2005, 7, 1035.
1
1
12 H. Bayley, D. N. Standring and J. R. Knowles, Tetrahedron Lett., 1978,
19, 3633.
1
1
3 P. T. Nyffeler, C.-H. Liang, K. M. Koeller and C.-H. Wong, J. Am.
Chem. Soc., 2002, 124, 10773.
Procedure for calculation. Calculations were performed using
4 Calculations were performed using the AMPAC version 8.50.9 com-
putational modeling program with the semi-empirical method AM1.
AMPAC 8, Semichem, Inc, PO Box 1649, Shaunee, KS 66222.
5 Y. M. Wu, J. Deng, X. Fang and Q. Y. Chen, J. Fluorine Chem., 2004,
the AMPAC version 8.50.9 computational modeling program with
the semi-empirical method AM1.
14
1
1
Antiviral evaluation against tobacco mosaic virus. Antiviral
1
25, 1415.
activity of the synthesized bitriazolyl nucleosides against TMV
was performed by the conventional half-leaf method.
6 T. Y. An, R. Q. Huang, Z. Yang, D. K. Zhang, G. R. Li, Y. C. Yao and
16
J. Gao, Phytochemistry, 2001, 58, 1267.
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