Synthesis of some novel glucosyl triazoles from 2,3,4,6-tetra-O-pivaloyl-D- glucopyranosyl azide

Article abstract of DOI:10.1080/07328303.2010.487231

In the present study, we have synthesized a series of novel glucosyl triazoles for the first time. The glucosyl triazoles 4a-e were synthesized by reaction of some azidoglycosides with various terminal alkynes via a copper-catalyzed [3+2] cycloaddition ("

Full text of DOI:10.1080/07328303.2010.487231

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Synthesis of Some Novel Glucosyl
Triazoles from 2,3,4,6-Tetra-O-pivaloyl-
D-glucopyranosyl Azide
Chao Shen a b , Hui Zheng b , Pengfei Zhang b & Xinzhi Chen b
a Department of Chemical and Biological Engineering , Zhejiang
University , Hangzhou, 310027, China
b College of Material, Chemistry and Chemical Engineering ,
Hangzhou Normal University , Hangzhou, 310036, China
Published online: 26 Aug 2010.
To cite this article: Chao Shen , Hui Zheng , Pengfei Zhang & Xinzhi Chen (2010) Synthesis of
Some Novel Glucosyl Triazoles from 2,3,4,6-Tetra-O-pivaloyl-D-glucopyranosyl Azide, Journal of
Carbohydrate Chemistry, 29:4, 155-163, DOI: 10.1080/07328303.2010.487231
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Journal of Carbohydrate Chemistry, 29:155–163, 2010
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Copyright Taylor & Francis Group, LLC
ISSN: 0732-8303 print / 1532-2327 online
DOI: 10.1080/07328303.2010.487231
Synthesis of Some Novel
Glucosyl Triazoles from
2,3,4,6-Tetra-O-pivaloyl-D-
glucopyranosyl Azide
Chao Shen,1,2 Hui Zheng,2 Pengfei Zhang,2 and Xinzhi Chen2
1Department of Chemical and Biological Engineering, Zhejiang University
Hangzhou 310027, China
2College of Material, Chemistry and Chemical Engineering, Hangzhou Normal
University, Hangzhou 310036, China
In the present study, we have synthesized a series of novel glucosyl triazoles for the
first time. The glucosyl triazoles 4a–e were synthesized by reaction of some azidoglyco-
sides with various terminal alkynes via a copper-catalyzed [3+2] cycloaddition (“click
chemistry”) and were deprotected to afford the corresponding glucosyl triazoles 5a–e in
good yields. The structures of the new compounds were determined by IR, NMR spec-
troscopy, and mass spectrometry. The antitumor (human cervical cancer cell) activity
was evaluated for the target compounds.
Keywords Click chemistry; Glucosyl triazoles; Azidoglycosides
INTRODUCTION
Organic compounds bearing triazoles of different pharmacodynamic nuclei
were found to possess various biological activity. Glucosyl triazoles and their
derivatives also have received considerable attention because of their bioac-
tivity and many applications in organic and medicinal chemistry.[1] For exam-
ple, Poulsen’s group has reported that a series of glucosyl triazole benzene
sulfonamide derivatives are a novel class of carbonic anhydrase inhibitors.[2]
The classical method for the preparation of 1,2,3-triazoles is the Huisgen reac-
tion.[3] This powerful and reliable Cu-catalyzed 1,3-dipolar cycloaddition has
Received January 7, 2010; accepted April 17, 2010.
Address correspondence to Pengfei Zhang, College of Material, Chemistry and Chem-
ical Engineering, Hangzhou Normal University, Hangzhou 310036, China. E-mail:
zpf100@163.com
155

C. Shen et al.
156
found widespread applications in combinatorial chemistry for drug discov-
ery,[4] material science,[5] and bioconjugation.[6] Since that time triazole-linked
glycoconjugates have become increasingly useful and important in glycobi-
ology.[7] Glycoconjugates exert important effects on many complex biological
processes,[8] including the cellular recognition in the processes of immune re-
sponse,[9] inflammation,[10] tumor metastasis,[11] and viral infections. In addi-
tion, glycosylation of proteins and lipids are key factors in modulating their
structures and functions. Therefore, the preparation of these compounds has
become increasingly important. Herein, we report a convenient method for the
synthesis of novel glucosyl triazole derivatives from D-glucose by means of
a three-step sequence involving stereospecific displacement with azide anion,
copper-catalyzed [3+2] cycloaddition, and deprotection of the pivaloyl group.
RESULTS AND DISCUSSION
During our previous research,[12] we developed a novel route for the synthesis
of thiazol-2(3H)-imine-linked glycoconjugates, which were screened for their
antitumor activities against Hela, HCT-8, and Bel-7402. Some of the com-
pounds showed moderate cytotoxicity against HCT-8. That study forms part
of our research program to evolve new methodologies for the construction of
novel glycoconjugates and to discover new lead molecules with antitumor ac-
tivities. Further synthesis and biological investigation of new glucosyl triazoles
containing different active sugar moieties for antitumor activity are reported
here.
The glucosyl triazole 4a was used as a model to study the rate of tri-
azole formation.[13] Using a procedure adapted from the literature,[14,15] the
2,3,4,6-tetra-O-pivaloyl-D-glucopyranosyl azide 2 is available from compound
1 by means of stereospecific displacement with azide anion. Then reaction of
phenylacetylene with the azide 2 in the presence of a CuSO4/ascorbate mixture
affords exclusively the glucosyl triazole 4a with complete retention of anomeric
stereochemistry and in high yield. The effects of various solvents were studied
for the preparation of 4a and comparative results are presented in Table 1.
As a result, the reaction of azide 2 proceeded smoothly in tert-butanol within
a short period at room temperature to afford the desired products in very
high yield (Table 1, entry 8). In other cases, the yields varied 75% to 91%.
These results encouraged further studies with various other alkynes such as
2-ethynylpyridine, 4-bromophenylacetylene, 4-fluorophenyla-cetylene, and 4-
methylphenylacetylene. These alkynes readily reacted with glucosyl azides
under identical conditions to produce triazole-linked glycosides in high yields
(Table 2, entries 2–4). The structure of all new compounds was confirmed by 1H
NMR, 13C NMR, IR, and elemental analysis. The O-pivaloyl group of glucosyl
triazoles 4a–e was subsequently removed to obtain the fully deprotected sugar
analog 5a–e in quantitative or near-quantitative yields (Scheme 1).

Synthesis of Some Novel Glucosyl Triazoles
157
Table 1: Study of formation of glucosyl triazole 4aa
OPiv
OPiv
N
O
O
PivO
PivO
N
PivO
PivO
+
N
N3
OPiv
OPiv
2
4a
Entry
Solvent
Temp (◦C)
Time (h)
Yield (%)b
1
2
3
4
5
6
7
8
CH3CN
40
40
40
40
40
40
40
25
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.5
83
80
75
78
88
91
95
95
CH2Cl2
Toluene
THF
Methanol
Isopropanol
tert-Butanol
tert-Butanol
aAll reactions were carried out using 2 (0.5 M), phenylacetylene (0.5 M), 20 mol% CuSO4, 40
mol% sodium ascorbate (relative to substrate).
bIsolated yield after chromatography.
Next, some of the newly synthesized glucosyl triazoles 5a–e were screened
for their antitumor activity against Hela (cervical carcinoma), HCT-8 (colon
carcinoma), and Bel-7402 (liver carcinoma). The cytotoxicity was evaluated
by MTT assay.[16] However, all the compounds showed very weak cytotoxicity
against Bel-7402, Hela, and HCT-8.
In conclusion, we have synthesized a series of triazole derivatives bearing
sugar moieties, providing a convenient method for constructing such gluco-
syl triazole derivatives under very mild conditions. The preliminary biological
Table 2: Synthesis of different D-glucose-derived 1,2,3-triazolesa
Entry
Ar
Product
Time (h)
Yield (%)b
Mp (◦C)
1
2
3
3
4
Ph
4a
4b
4c
4d
4e
2.5
2.5
2.5
2.5
2.5
92
88
92
95
96
230–231
218–220
208–210
215–217
214–216
p-Br-C6H4
p-F-C6H4
p-CH3-C6H4
C5H4N
aAll reactions were carried out using 2 (0.5 M), alkynes (0.5 M), 20 mol% CuSO4, 40 mol% sodium
ascorbate (relative to substrate).
bIsolated yield after chromatography.

C. Shen et al.
158
R
X
OPiv
PivO
Me3SiN3/SnCl4
OPiv
3a-e
O
O
PivO
PivO
PivO
PivO
N3
cat.Cu(I)
OPiv
OPiv
a
: X=C, R=H
1
2
b: X=N, R=H
c
: X=C, R=Br
d: X=C, R=F
e: X=C, R=CH3
OPiv
OH
N
N
NaOCH3/CH3OH
O
O
PivO
PivO
N
N
HO
HO
N
N
OPiv
4a-e
OH
X
X
5a-e
R
R
Scheme 1: A general glucosyl triazoles synthesis.
evaluation of compounds 5a–e showed no antitumor activities. Further syn-
theses and biological studies of new triazoles containing different active sugar
moieties for biological activity are continued by our group.
EXPERIMENTAL
General Methods
1,2,3,4,6-Penta-O-pivaloyl-D-glucopyranose (1) was prepared according to
our previous reports.[12] Other chemicals and solvents were either purchased
or purified by standard techniques. Analytical TLC was performed on a Merck
precoated TLC (silica gel 60 F254) plate. Melting points were recorded on an
X4-Data microscopic melting point apparatus and are uncorrected. IR spec-
tra were recorded on a Nicolet 380 FT-IR spectrophotometer using KBr discs.
Optical rotation values were measured on a Perkin Elmer P241 polarimeter.
1
ESI-MS were acquired on a Bruker Esquire 3000 plus spectrometer. H and
13C NMR spectra of samples in CDCl3 or CD3OD were recorded on a Bruker
Avance 400 spectrometer using TMS as internal standard. Elemental analyses
were performed on Carlo-Erba 1106.

Synthesis of Some Novel Glucosyl Triazoles
159
General procedure for the synthesis of glucosyl triazoles via click
chemistry
To
a mixture of the corresponding 2,3,4,6-tetra-O-pivaloyl-D-gluco
pyranosyl azide 2 (541 mg, 1.0 mmol) and alkyne (1.0 mmol) in tert-butyl al-
cohol (1 mL), 0.5 mL of an aqueous solution of CuSO4 (50 mg, 0.2 mmol) and
0.5 mL of an aqueous solution of sodium ascorbate (79.2 mg, 0.4 mmol) were
added. The reaction mixture was stirred vigorously for 24 h. The suspended
product was filtered and washed with water. The crude product was purified by
column chromatography on silica gel, eluting with hexane/ethyl acetate mix-
tures of increasing polarity to afford the triazole products.
4-Phenyl-1-(2,3,4,6-tetra-O-pivaloyl-1-D-glucopyranosyl)-1,2,3-
triazole (4a)
Yellow solid; yield: 92%; mp 216–220◦C; [α]D20 = −18.0 (c 0.1, CH3OH); 1H
NMR (400 MHz, DCCl3): δ 8.05 (s, 1H), 7.85 (d, J = 8.6 Hz, 2H), 7.46 (t, 2H),
7.38 (t,1H), 5.87 (d, J = 8.0 Hz, 1H), 5.65 (t, J = 9.6 Hz, 2H), 5.60 (d, J = 3.8 Hz,
1H), 5.36 (d, J = 3.3 Hz, 1H), 4.74 (m, 1H), 4.31 (m, 1H), 4.04 (m, 1H), 0.92–1.25
(m, 36H, Piv-CH3); 13C NMR (100 MHz, DCCl3): δ 177.78, 176.52, 147.43,
144.60, 129.00, 127.95, 127.58, 125.01, 85.12, 74.64, 71.14, 69.15, 66.18, 60.42,
37.76, 25.79–26.12; IR (KBr, cm−1) υ: 2970, 2077, 1744, 1637, 1481, 1400, 1368,
1280, 1140, 1037.
4-Pyridyl-1-(2,3,4,6-tetra-O-pivaloyl-1-D-glucopyranosyl)-1,2,3-
triazole (4b)
Yellow solid; yield: 95%; mp 179–181◦C; [α]D20 = −43.2 (c 0.1, CH3OH); 1H
NMR (400 MHz, DCCl3): δ 8.60 (s, 1H), 8.37 (d, J = 3.6 Hz, 1H), 8.11 (t, 1H),
7.78 (t, 1H), 7.76 (d, J = 12.2 Hz, 1H), 5.97 (d, J = 9.2 Hz, 1H), 5.55 (m, 2H),
5.32 (m, 1H), 4.21 (m, 2H), 4.05 (d, J = 2.4 Hz, 1H), 1.89 (m, 1H), 0.94–1.21 (m,
36H, Piv-CH3); 13C NMR (100 MHz, DCCl3): δ 177.71, 177.12, 177.10, 155.3,
149.20, 137.21, 131.41, 129.52, 123.64, 97.62, 78.21, 73.69, 69.15, 69.82, 62.42,
36.76, 25.79–26.12; IR (KBr, cm−1) υ: 3431, 2974, 1742, 1601, 1479, 1400, 1281,
1141, 1034. Anal. Calcd for C33H48N4O9: C, 61.55; H, 7.82; N, 8.78. Found: C,
61.58; H, 7.80; N, 8.75.
4-(4-Bromophenyl)-1-(2,3,4,6-tetra-O-pivaloyl-1-D-
glucopyranosyl)-1,2,3-triazole (4c)
Yellow solid; yield: 88.1%; mp 220–222◦C; [α]D20 = −38.2 (c 0.1, CH3OH); 1H
NMR (400 MHz, DCCl3): δ 7.97 (s, 1H), 7.70 (d, J = 5.6 Hz, 2H), 7.56 (t, 2H),
5.99 (d, J = 9.6 Hz, 1H), 5.55 (m, 2H), 5.36 (d, J = 4.2 Hz, 1H), 4.21 (m,
2H), 4.06 (m, 1H), 0.92–1.25 (m, 36H, Piv-CH3); 13C NMR (100 MHz, DCCl3): δ

C. Shen et al.
160
177.71, 176.74,131.9, 129.72, 127.24, 122.36, 85.94, 77.18, 71.84, 69.96, 66.94,
61.14, 38.76, 25.53–26.92; IR (KBr, cm−1) υ: 3422, 2974, 1742, 1637, 1481, 1403,
1368, 1140, 1040. Anal. Calcd for C34H48BrN3O9: C, 56.62; H, 6.73; N, 5.93.
Found: C, 56.65; H, 6.70; N, 5.91.
4-(4-Fluorophenyl)-1-(2,3,4,6-tetra-O-pivaloyl-1-D-
glucopyranosyl)-1,2,3-triazole (4d)
White solid; yield: 89.1%; mp 190–192◦C; [α]D20 = −21.6 (c 0.1, CH3OH); 1H
NMR (400 MHz, DCCl3): δ 8.02 (s, 1H), 7.82 (d, 2H), 7.82 (t, 2H), 5.96 (d, J = 9.6
Hz, 1H), 5.58 (m, 2H), 5.38 (d, J = 2.4 Hz, 1H), 4.20 (m, 2H), 4.11 (d, J = 12.4
Hz, 1H), 0.95–1.26 (m, 36H, Piv-CH3); 13C NMR (100 MHz, DCCl3): δ 178.71,
176.99, 132.1, 128.72, 127.24, 122.36, 85.94, 77.20, 71.86, 69.98, 66.90, 61.20,
38.73, 25.53–26.92; IR (KBr, cm−1) υ: 3436, 2976, 1740, 1641, 1485, 1406, 1360,
1141, 1039. Anal. Calcd for C34H48FN3O9: C, 61.76; H, 7.22; N, 6.43. Found: C,
61.73; H, 7.20; N, 6.45.
4-(4-Methylphenyl)-1-(2,3,4,6-tetra-O-pivaloyl-1-D-
glucopyranosyl)-1,2,3-triazole (4e)
White solid; yield: 92.6%; mp 208–210◦C; [α]D20 = +3.2 (c 0.1, CH3OH); 1H
NMR (400 MHz, DCCl3): δ 8.00 (s, 1H), 7.74 (d, J = 5.6 Hz, 2H), 7.25 (t, 2H),
5.86 (d, J = 11.6 Hz, 1H), 5.55 (d, J = 4.2 Hz, 1H), 5.34 (m, 1H), 4.71 (m, 2H),
4.45 (d, J = 2.2 Hz, 1H), 4.30 (d, J = 6.2 Hz, 1H), 2.39 (s, 1H), 0.92–1.25 (m,
36H, Piv-CH3); 13C NMR (100 MHz, DCCl3): δ 177.46, 8176.18, 176.18, 144.29,
137.99, 129.11, 126.46, 126.24, 115.86, 86.16, 76.82, 76.19, 66.02, 65.94, 60.03,
38.38, 29.19–26.47; IR (KBr, cm−1) υ: 3443, 2352, 2118, 1746, 1649, 1540, 1398,
1280, 1146. Anal. Calcd for C35H51N3O9: C, 63.86; H, 7.74; N, 6.50; Found: C,
63.86; H, 7.74; N, 6.50.
Representative procedure for the depivaloylation of glucosyl
triazoles
The corresponding glucosyl triazole (1 mmol) was dissolved in 10 mL of
methanol. Freshly prepared sodium methoxide was then added portion-wise
and the reaction was monitored by TLC. Upon completion, Amberlite resin
(H+ form) was added until the solution was at neutral pH, and the solution
was filtered and concentrated in vacuo. The crude product was taken up in
hot water and treated with activated charcoal. The product was recrystallized
from water to give a white solid. 4-Phenyl-1-D-glucopyranosyl-1,2,3-triazole
(5a) was reported by Basu et al.[16]

Synthesis of Some Novel Glucosyl Triazoles
161
4-Pyridyl-1-D-glucopyranosyl-1,2,3-triazole (5b)
Yellow solid; yield: 97%; mp 198–200◦C; [α]D20 = −11.2 (c 0.055, CH3OH); 1H
NMR (400 MHz, CD3OD): δ 8.53 (s, 1H), 8.37 (d, J = 10.2 Hz, 1H), 8.13 (t, 1H),
7.81 (t, 1H), 7.73 (d, J = 6.4 Hz, 1H), 5.72 (d, J = 9.6 Hz, 1H), 4.26 (t, 1H),
4.03 (d, J = 8.2 Hz, 1H), 3.78–3.71 (m, 4H); 13C NMR (100 MHz, CD3OD): δ
177.69, 177.10, 177.08, 155.30, 149.20, 137.21, 131.43, 129.49, 123.64, 95.62,
76.09, 71.26, 69.15, 62.42; Anal. Calcd for C13H16N4O5: C, 50.68; H, 5.96; N,
18.02. Found: C, 50.70; H, 5.93; N, 18.16.
4-(4-Bromophenyl)-1-D-glucopyranosyl-1,2,3-triazole (5c)
Yellow solid; yield: 96%; mp 215–217◦C; [α]D20 = −7.8 (c 0.062, CHCl3); 1H
NMR (400 MHz, CD3OD): δ 8.01 (s, 1H), 7.81 (d, J = 11.2 Hz, 2H), 7.72 (d,
J = 4.6 Hz, 2H), 5.81 (d, J = 9.2 Hz, 1H), 4.41 (t, 1H), 4.21 (d, J = 8.2 Hz,
1H), 3.65–3.70 (m, 4H); 13C NMR (100 MHz, CD3OD): δ 177.66, 176.45, 131.9,
129.72, 127.24, 122.36, 85.94, 77.08, 71.76, 69.77, 66.80, 61.19; Anal. Calcd for
C14H16BrN3O5: C, 43.89; H, 4.02; N, 10.56. Found: C, 43.86; H, 4.10; N, 10.52.
4-(4-Fluorophenyl) -1-D-glucopyranosyl -1,2,3-triazole (5d)
White solid; yield: 95%; mp 182–185◦C; [α]D20 = −15.8 (c 0.068, CHCl3); 1H
NMR (400 MHz, CD3OD): δ 8.12 (s, 1H), 7.86 (d, J = 6.2 Hz, 2H), 7.73 (d, J =
3.2 Hz, 2H), 5.79 (d, J = 9.8 Hz, 1H), 4.66 (t, 1H), 4.21 (d, J = 3.6 Hz, 1H),
13
3.69–3.72 (m, 4H);
C NMR (100 MHz, CD3OD): δ 177.53, 176.31, 131.09,
129.14, 127.12, 122.28, 85.44, 77.11, 72.03, 69.66, 66.52, 61.28; Anal. Calcd for
C14H16FN3O5: C, 51.56; H, 4.81; N, 12.23. Found: C, 51.52; H, 4.78; N, 12.19.
4-(4-Methylphenyl)-1-D-glucopyranosyl -1,2,3-triazole (5e)
White solid; yield: 95%; mp 216–219◦C; [α]D20 = −22.1 (c 0.075, CHCl3); 1H
NMR (400 MHz, CD3OD): δ 8.03 (s, 1H), 7.56 (d, J = 5.6 Hz, 2H), 7.31 (d,
J = 5.6 Hz, 2H), 5.66 (d, J = 9.4Hz, 1H), 4.70 (t, 1H), 4.18 (d, J = 2.6 Hz,
1H), 3.68–3.72 (m, 4H), 2.35 (s, 3H); 13C NMR (100 MHz, CD3OD): δ 177.21,
176.22, 175.58, 144.28, 138.20, 128.02, 126.24, 126.11, 115.75, 86.25, 76.74,
76.09, 66.12, 65.34, 60.23, 38.14. Anal. Calcd for C15H19N3O5: C, 56.26; H, 5.82;
N, 13.11. Found: C, 56.30; H, 5.81; N, 13.14.
Biological activity assays
Cell culture
Three different human carcinoma cell lines were used for cytotoxicity de-
termination: Hela (cervical carcinoma), HCT-8 (colon carcinoma), and Bel-7402

C. Shen et al.
162
(liver carcinoma). They were obtained from the American Type Culture Collec-
tion (ATCC) and cultured in RPMI-1640 medium supplemented with 10% FBS,
100 units/mL of penicillin, and 100 µg/mL of streptomycin. Cells were main-
tained at 37◦C in a humidified atmosphere of 5% CO2 in air.
Cytotoxicity Analysis
Briefly, cells were plated in 96-well culture plates (104 cells per well) and
incubated overnight at 37◦C in a 5% CO2 incubator. Then, compounds were
added to the wells to achieve final concentrations ranging from 10−7 to 10−4 M.
Control wells were prepared by addition of culture medium. Wells containing
culture medium without cells were used as blanks. The plates were incubated
at 37◦C in a 5% CO2 incubator for 44 h. Upon completion of the incubation,
MTT dye solution (20 µL, 5 mg/mL) was added to each well. After 4 h of in-
cubation, 2-propanol (100 µL) was added to solubilize the MTT formazan. The
OD was measured at a wavelength of 570 nm by a microplate spectrophotome-
ter. The IC50 value was determined from plots of% viability against the dose of
complexes added.
ACKNOWLEDGEMENT
This work was supported by the National Science and Technology Ministry of
China (No. 2007BAI34B05) and Zhejiang Provincial Natural Science Founda-
tion of China (No. Y4090052).
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