Synthesis of novel N-glycoside derivatives via CuSCN-catalyzed reactions and their SGLT2 inhibition activities

Article abstract of DOI:10.1016/j.tet.2015.05.108

A convenient approach to the synthesis of novel triazole-N-glycoside derivatives was developed via CuSCN-catalyzed click reaction and Ullmann-type coupling reaction for the first time. The SGLT2 inhibitory activities of these synthetic N-glycosides were evaluated, and some compounds showed moderate SGLT2 inhibition activities at 100 nM. The results could benefit the discovery of new SGLT2 inhibitors for the treatment of diabetes.

Full text of DOI:10.1016/j.tet.2015.05.108

Tetrahedron 71 (2015) 4909e4919
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Synthesis of novel N-glycoside derivatives via CuSCN-catalyzed
reactions and their SGLT2 inhibition activities
,
,
,
a,b,
*
Shao-Tao Bai a y, De-Cai Xiong a y, Youhong Niu a, Yan-Fen Wu a , Xin-Shan Ye
*
a State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Xue Yuan Road No. 38, Beijing 100191,
China
b National Engineering Research Center for Carbohydrate Synthesis, Jiangxi Normal University, Nanchang 330022, Jiangxi, China
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 17 April 2015
Received in revised form 24 May 2015
Accepted 28 May 2015
Available online 4 June 2015
A convenient approach to the synthesis of novel triazole-N-glycoside derivatives was developed via
CuSCN-catalyzed click reaction and Ullmann-type coupling reaction for the first time. The SGLT2 in-
hibitory activities of these synthetic N-glycosides were evaluated, and some compounds showed mod-
erate SGLT2 inhibition activities at 100 nM. The results could benefit the discovery of new SGLT2
inhibitors for the treatment of diabetes.
Ó 2015 Elsevier Ltd. All rights reserved.
Keywords:
N-Glycoside
Heterocycle
Coupling reaction
SGLT2 inhibitor
Carbohydrate
1. Introduction
carbohydrate analogues with biological importance. On the other
hand, heterocyclic components such as triazoles, which can interact
Carbohydrate-based drug discovery has become a subject of an
increasing interest. As a result, considerable efforts have been ex-
panded in design and synthesis of carbohydrate-processing en-
zyme inhibitors or mimics of carbohydrate-protein interactions.
Since O-glycosides are usually hydrolytically unstable, many car-
bohydrate analogues such as C-glycosides1 and S-glycosides2 have
been synthesized as useful tools or therapeutic agents. In contrast,
N-glycosides are less described in literature.3 Actually, a N-glyco-
side known as acarbose carrying nitrogen atom between sugar and
pseudosugar is currently used for the oral treatment of diabetes.4
Some indole-N-glycosides (Fig. 1b) have also revealed inhibitory
activities5 against the sodium-glucose co-transporter 2 (SGLT2) at
the luminal surface of cells lining the first segment of the proximal
tubules responsible for more than 90% renal glucose reabsorption.6
Moreover, to the best of our knowledge, SGLT2 inhibitors currently
used as drugs or drug candidates for clinical trials are C-glycosides
and O-glycosides (Fig. 1a), which generate some drawbacks such as
carcinogenesis, while N-glycosides, which might solve these
problems, have not gained as much attention especially SAR studies
as their counterparts.5,7 Thus, N-glycosides represent a new type of
with histamine H4 receptor,8 are very useful scaffolds in drug dis-
covery and related fields.8,9 Therefore, we want to prepare a series
of new N-glycosides combining carbohydrates with triazoles. Due
to the structural similarity to indole-N-glycosides, we will also test
the SGLT2 inhibition activities of the synthetic compounds. For this
purpose, we plan to synthesize these novel N-glycoside derivatives
by using various carbohydrate azides and alkyne compounds via
copper-catalyzed click or Ullmann chemistry under mild conditions
(Fig. 1c).
Copper-catalyzed coupling reactions have gained rapid de-
velopment in recent years and have played an important role in the
fields of organic synthesis, medicinal chemistry, and material sci-
ence.10 Cai and co-workers developed a CuAAC/Ullmann CeC cou-
pling tandem reaction to construct heterocycles,11 and the similar
results were also achieved by using CuI and strong base.12,13 Shi and
co-workers disclosed the synthesis of [1,2,3]triazole[5,1-a]iso-
quinoline derivatives using the copper-catalyzed cascade re-
action,14 whereas Lautens and co-workers synthesized 1,2,3-
triazole-fused heterocycles via the Pd-catalyzed cyclization of 5-
iodotriazole.15 In spite of these advances, these copper (or other
metal) catalyzed coupling reactions have not yet been applied to
carbohydrate substrates for the synthesis of N-glycoside de-
rivatives, and the approaches to prepare N-glycosides are limited.
Based on the previous work, herein we report a convenient strategy
* Corresponding authors. Fax: þ86 10 82805736; e-mail addresses: wuyanfen@
pku.edu.cn (Y.-F. Wu), xinshan@bjmu.edu.cn (X.-S. Ye).
y
These authors contributed equally to this work.
http://dx.doi.org/10.1016/j.tet.2015.05.108
0040-4020/Ó 2015 Elsevier Ltd. All rights reserved.

4910
S.-T. Bai et al. / Tetrahedron 71 (2015) 4909e4919
Fig. 1. a. Representative C-glycosides and O-glycosides as SGLT2 inhibitors in clinical trials or used as drugs; b. N-glycosides as SGLT2 inhibitors; c. the design of new triazole-N-
glycosides.
to synthesize triazole-N-glycoside derivatives and evaluate their
SGLT2 inhibition activities.
As shown in Table 1, based on the previous studies,10b,12,14,15,17
after screening various inorganic bases ranging from mild bases
to strong bases, it was found that Cs2CO3 is the best base with DMF
as the solvent. The yield of 3a was increased to 47% when Cs2CO3
was used (entry 2). To our surprise, silver salts such as Ag2O had the
ability to activate the CeI bond to some extent, but they did not
have sound effects for the formation of product 3a (entry 3). DMF
seems to be the best solvent among all kinds of solvents both polar
and nonpolar solvents checked (entries 2, 4e7). Interestingly, the
use of CuSCN significantly improved the yield of product 3a (76%)
and enhanced the ratio of 3a/4a (4.1/1), while other copper salts
such as CuTC,10b,18 CuOAc, CuCl,19 CuBr,13,20 CuCN, and Cu2O did not
give good results (entries 8e12, 14e15). When the amount of cat-
alyst was increased to 150% mmol and the co-solvent (DMF/HMPA)
was used, the ratio of 3a/4a was further increased to 7.2/1 (entry
2. Results and discussion
Initially, according to our design, using glucose azide 1a16 and
alkyne compound 2a12 as the starting materials, we tried to per-
form the key copper-catalyzed click reaction followed by Ullmann-
type coupling reaction. Under the conditions11 of CuI as catalyst,
DMSO as solvent, and K2CO3 as base at 70 ꢀC, the coupling reaction
of 1a and 2a afforded the target N-glycoside 3a in less than 10%
yield accompanied by 4a as the major product (Table 1, entry 1). In
order to improve the yield of 3a, various reaction parameters such
as base, solvent, and catalyst were screened (Table 1).
Table 1
Optimization of the reaction conditions for the synthesis of N-glycoside 3aa
Entry
Base
T (ꢀC)
Solvent
Catalyst
Ratio of 3a/4a, total yield (%)e
1
2
3
4
5
6
7
8
K2CO3
Cs2CO3
Ag2O
70
70
70
70
70
70
70
70
70
70
70
70
70
70
70
DMSO
DMF
DMF
dioxane
MeCN
toluene
DMSO
DMF
DMF
DMF
DMF
DMF
CuIb
1/9, 98
CuIb
1.1/1, 89
1/11.8, 98
1/8.6, 99
d, 97f
CuIb
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
CuIb
CuIb
CuIb
d, 95f
CuIb
1/1.3, 83
1.1/1, 100
no reaction
1.6/1, 99
1.0/1, 87
4.1/1, 95
7.2/1, 92
1/1.9, 99
1/2.7, 89
CuTCc
CuOAcc
CuClc
CuBrc
CuSCNc
CuSCNd
CuCNc
Cu2Oc
9
10
11
12
13
14
15
DMF/HMPA(3/1)
DMF
DMF
a
Reaction conditions: 1a (0.050 mmol), 2a (0.075 mmol), base (0.150 mmol), solvent (2 mL).
Catalyst used (20%).
Catalyst used (100%).
Catalyst used (150%), reaction for 10 h.
Isolated yield.
b
c
d
e
f
Trace amount of 3a.

S.-T. Bai et al. / Tetrahedron 71 (2015) 4909e4919
4911
13). In addition, we also tried various additives and other methods
such as click reaction followed by Heck reaction15,17b,17c to enhance
the yield and reduce the amount of catalyst used, but unfortunately,
all of these trials failed to achieve better results.
Under the optimized reaction conditions, the substrate scope of
this coupling reaction was examined. As displayed in Table 2, for
carbohydrate azides, glucosyl azide 1a, galactosyl azide 1b,21 and
aminoglucosyl azide 1e (see Electronic Supplementary data) per-
formed the reaction smoothly to generate the fully fused-triazole-
N-glycosides with high selectivity (entries 1, 2, 5), while mannosyl
azide 1c22 and lactosyl azide 1f16 just showed moderate selectivity
(entries 3 and 7). The fully fused-triazole-N-riboside 3d was also
obtained from ribosyl azide 1d23 in this way (entry 4). After the
successful construction of [6,6]ring-fused triazole-N-glycosides, the
preparation of [6,7] or [6,8]ring-fused triazole-N-glycosides via this
protocol was also tried. When using both glucosyl azide 1a and
galactosyl azide 1b to react with alkyne 2b,12 the desired [6,7]ring-
fused N-glycosides were obtained, but the ratio of 3g (3h)/4g (4h)
was not as good as their [6,6]ring-fused counterparts (entries 8 and
9). In addition, when alkyne 2c12 was coupled with azides 1g and
1h,16 the [6,8]ring-fused triazole-N-glycosides were not afforded,
and only uncyclized products 4i and 4j were gained instead (entries
10 and 11). Thus, a small library of triazole-N-glycoside derivatives
was generated.
With these N-glycoside derivatives in hand, we next tried to get
target compounds by deprotection operations (Table 3). Taking
Table 2
Synthesis of triazole-N-glycoside derivativesa.
aReaction conditions: substrate 1 (0.050 mmol), substrate 2 (0.075 mmol), Cs2CO3 (0.150 mmol),
CuSCN (0.075 mmol), solvent (DMF/HMPA 3/1), reaction time (10 h). bIsolated yield.
cTemperature (65 oC). dTemperature (80 oC), reaction time (2 h). eTemperature (80 oC).
fTemperature (90 oC), solvent (DMF), catalyst (1 eq. of CuI), without base.

4912
S.-T. Bai et al. / Tetrahedron 71 (2015) 4909e4919
Table 3
Deprotection of triazole-N-glycoside derivatives.
aDeprotection conditions: BCl3, CH2Cl2, -73 oC to 0 oC, 36 h. bConditions: Pd(OH)2/C, H2, r.t., 18
h. cConditions: 1,2-diaminoethane, 80 oC, overnight; then pyridine, Ac2O, overnight; then
NaOMe/MeOH, r.t.. dConditions: NaOMe/CH2Cl2/MeOH, r.t., 1.5 h. eIsolated yield.
triazole-N-glycoside 3b as the model reaction, Pd/C- or Pd(OH)2/C-
found that both N-glucoside derivatives 5a, 6a, 5g, 6g, 6i and N-
galactoside derivatives 5b, 6b, 5h, 6h, 6j display inhibition effects
with inhibition rates ranging from 10% to 32%. It was also found that
compound series 6 have better SGLT2 inhibition activities than
catalyzed hydrogenolysis was tried to remove the benzyl groups,
but it failed to complete the reaction. Fortunately, the deprotection
was carried out smoothly in the presence of BCl3 in CH2Cl2 at
ꢁ73 ꢀC to 0 ꢀC for 36 h, affording compound 5b in excellent yield.
Through this protocol, the benzyl-containing N-glycosides were
deprotected to provide target compounds in high to moderate
yields (entries 1e6, 8, 11e16). For the substrates in lower yields
such as 3f, 4f, 4g and 4h, it was found that the partial de-
composition occurred during the BCl3-mediated debenzylation
process. Regarding N-glycoside 3d, it totally decomposed in BCl3
deprotection conditions, but was subjected to hydrogenolysis over
Pd(OH)2/C in THF, successfully providing 5d in quantitative yield.
Compound 3e was successively treated with 1,2-diaminoethane,
acetic anhydride/pyridine, and sodium methoxide, yielding N-gly-
coside 5e. Finally, the acetyl-containing N-glycosides were directly
treated with sodium methoxide to obtain the corresponding target
compounds.
To test the glucose transportation inhibition activities of these
compounds, a cell-based assay was employed.24 According to the
results of cell-based assay (Fig. 2), most triazole-N-glycosides show
some inhibition activities at the concentration of 100 nM when
compared with Dapagliflozin, a SGLT2 inhibitor for the treatment of
type 2 diabetes mellitus in clinical. Among these compounds, it was
Fig. 2. Inhibitory rates of methyl-a
-D-[Ue14C]glucopyranoside transportation on
NIH3T3-hSGLT2 cell: each compound was tested at concentration of 100 nM. Values
are mean values ꢂSEM.

S.-T. Bai et al. / Tetrahedron 71 (2015) 4909e4919
4913
compound series 5. More importantly, our results firstly showed
that N-galactosides and N-ribosides have the potential to be used as
SGLT2 inhibitors other than the currently used glucoside de-
rivatives and xyloside derivatives.5a,25
purified by column chromatography on silica gel to give the de-
sired product.
4.2.2. General procedure of click reaction catalyzed via CuI (B). A
round flask was charged with carbohydrate azide (0.050 mmol),
alkyne compound (0.075 mmol) and CuI (0.050 mmol), evacuated
and backfilled with argon. DMF (2.0 mL) was added via syringe
under argon. The reaction mixture was heated at 70 ꢀC for 10 h. The
reaction was completed (detected by TLC, petroleum ether/
EtOAc¼1:1). After adding NH3$H2O (2 mL) and EtOAc (5 mL) into
the reaction mixture, the organic phase was separated and the
aqueous phase was extracted with EtOAc (5 mLꢃ3). The combined
organic phase was washed with brine, dried over Na2SO4, filtered
and concentrated under reduced pressure. The residue was purified
by column chromatography on silica gel to give the desired product.
3. Conclusion
Herein, we firstly disclosed a convenient approach to synthe-
size various triazole-N-glycoside derivatives via the CuSCN-
catalyzed coupling reaction. In this way, a small library of tri-
azole-N-glycosides was constructed. The SGLT2 inhibitory activi-
ties of synthetic compounds were evaluated. The biological assay
results showed that triazole-N-glycoside derivatives such as N-
glucosides, N-galactosides, and N-ribosides might be served as
SGLT2 inhibitors for the treatment of diabetes. Moreover, the
generated triazole-N-glycoside derivatives may have other phar-
maceutical applications.
4.2.3. General procedure of debenzylation reaction catalyzed via BCl3
(C). A round flask was charged with triazole-N-glycoside
(0.040 mmol), evacuated and backfilled with argon. Anhydrous
dichloromethane (3.0 mL) was added under argon. The flask was
placed in an alcohol-dry ice bath, followed by the addition of boron
trichloride (0.30 mmol, 1 M solution in heptane). The reaction
mixture was stirred at ꢁ78 ꢀC for 2 h, then maintained at 0 ꢀC for
36 h. Methanol was added to the mixture at ꢁ78 ꢀC to quench the
reaction. The resulting solution was concentrated and the residue
was purified by column chromatography on silica gel or C-18
reversed-phase silica gel to give the pure product.
4. Experimental
4.1. General information
All chemicals were purchased as reagent grade and used with-
out further purification, unless otherwise noted. Dichloromethane
(CH2Cl2), pyridine, and acetonitrile were distilled over calcium
hydride (CaH2). Methanol was distilled from magnesium. DMF and
1,4-dioxane were stirred with calcium hydride (CaH2) and distilled
under reduced pressure. All reactions were carried out under an-
hydrous conditions with freshly distilled solvents, unless otherwise
noted. Reactions were monitored by analytical thin-layer chroma-
tography on silica gel 60-F254 precoated on aluminium plates (E.
Merck.). Spots were detected under UV (254 nm) and/or by staining
with acidic ceric ammonium molybdate. Solvents were evaporated
under reduced pressure and below 40 ꢀC (bath). Column chroma-
tography was performed on silica gel (200e300 mesh, TsingDao
Ocean or 230e400 mesh, Merck), reversed phase column chro-
4.2.4. General procedure of debenzylation reaction catalyzed via
Pd(OH)2/C (D). A mixture of triazole-N-glycoside (0.035 mmol) and
catalytic amount of Pd(OH)2/C in THF (4 mL) was stirred under
4 atm H2 at ambient temperature for 36 h. The reaction was com-
pleted (detected by TLC, CH2Cl2/MeOH¼9:2). The reaction mixture
was filtered and the filtrate was concentrated under reduced
pressure, followed by purification through column chromatogra-
phy on silica gel to give the desired product.
matography was performed on LiChroprep RP-18 (40e63
mm,
4.2.5. General procedure of dephthaloylation and detrimethylsilyla-
tion followed by N-acetylation reaction (E). The reaction mixture of
triazole-N-gycoside (0.030 mmol) and ethylenediamine (3.0 mL)
was stirred under argon at 80 ꢀC overnight. The reaction was
completed (detected by TLC, CH2Cl2/MeOH¼9:2). The reaction
mixture was concentrated under reduced pressure, followed by
adding Ac2O (1.5 mL) and pyridine (3.0 mL). The mixture was
allowed to stir at ambient temperature overnight and monitored by
TLC. After completion, the reaction mixture was concentrated un-
der reduced pressure, followed by adding MeOH (3.0 mL), CH2Cl2
(1.0 mL), and NaOMe (20.0 mg). After stirring at ambient temper-
ature for 1.5 h, the reaction mixture was concentrated under re-
duced pressure and then purified by column chromatography on
silica gel to give the desired product.
Merck). 1H NMR spectra were recorded on a Bruker 400M or 600M
spectrometers at 25 ꢀC. Chemical shifts (in ppm) were referenced to
tetramethylsilane (
d
¼0 ppm) or CHCl3 ( ¼7.26 ppm) in deuterated
d
chloroform. 13C NMR spectra were obtained by using the same
NMR spectrometers and were calibrated with CDCl3
(
d
¼77.00 ppm). Mass spectra were recorded using a Bruker APEX IV
FT-MS (7.0 T) spectrometer. Analytical HPLC was performed on an
Agilent 1200 series system equipped with an Eclipse XDB-C18 re-
verse phase column (250*4.6 mm, 5 mm). Optical rotations were
recorded on an Autopol III Rudolph research automatic
polarimeter.
4.2. Preparation procedures
4.2.1. General procedure of click reaction followed by Ullmann-type
reaction catalyzed via CuSCN (A). After drying the glassware with
flame under reduced pressure, a round flask was charged with-
4.2.6. General procedure of deacetylation reaction (F). A reaction
mixture of triazole-N-gycoside (0.030 mmol), NaOMe (20.0 mg) in
MeOH/CH2Cl2 (3/1, 4.0 mL) was stirred under argon at ambient
temperature for 1.5 h and monitored by TLC. After completion, the
mixture was concentrated under reduced pressure and then puri-
fied by column chromatography on silica gel to give the desired
product.
carbohydrate
azide
(0.050
mmol),
alkyne
compound
(0.075 mmol), Cs2CO3 (0.150 mmol) and CuSCN (0.075 mmol),
evacuated and backfilled with argon three times. Anhydrous DMF
(2.0 mL) and anhydrous HMPA (0.7 mL) were added via syringe
under argon. The reaction mixture was heated at 70 ꢀC for 10 h.
The reaction was completed (detected by TLC, petroleum ether/
EtOAc¼2:1). After adding NH3$H2O (2 mL) and EtOAc (5 mL) into
the reaction mixture, the organic phase was separated and the
aqueous phase was extracted with EtOAc (5 mLꢃ3). The combined
organic phase was washed with brine, dried over Na2SO4, filtered
and concentrated under reduced pressure. The residue was
4.3. 1-(2,3,4,6-Tetra-O-benzyl-b-D-glucopyranosyl)-4H-benzo-
pyrano[3,4-d]-1H-1,2,3-triazole (3a)
The title compound was synthesized from 1a and 2a according
to procedure A. Yield 80%, yellow oil: [
NMR (400 MHz, CDCl3)
a
]
21 ꢁ3.0 (c 0.70, CHCl3); 1H
D
d
7.82 (d, J¼7.4 Hz, 1H), 7.35e7.13 (m, 19H),

4914
S.-T. Bai et al. / Tetrahedron 71 (2015) 4909e4919
7.00 (dd, J¼0.9, 8.2 Hz, 1H), 6.94e6.91 (m, 2H), 6.71 (td, J¼7.7,
0.7 Hz, 1H), 5.87 (d, J¼9.2 Hz, 1H), 5.44 (d, J¼13.2 Hz, 1H), 5.33 (d,
J¼13.2 Hz, 1H), 4.93 (d, J¼10.8 Hz, 1H), 4.89 (d, J¼1.1 Hz, 2H), 4.68
(d, J¼10.8 Hz, 1H), 4.55 (d, J¼11.6 Hz, 1H), 4.48 (d, J¼11.6 Hz, 1H),
4.40 (d, J¼10.5 Hz, 1H), 4.25 (t, J¼9.1 Hz, 1H), 4.14 (d, J¼10.5 Hz, 1H),
4.00 (t, J¼9.2 Hz,1H), 3.91e3.81 (m, 4H); 13C NMR (100 MHz, CDCl3)
4.7. 1-(2,3,4,6-Tetra-O-benzyl-b-D-mannopyranosyl)-4H-ben-
zopyrano[3,4-d]-1H-1,2,3-triazole (3c)
The title compound was synthesized from 1c and 2a according
to procedure A. Yield 68%, yellow oil: [
NMR (400 MHz, CDCl3)
a
]
21 ꢁ37.0 (c 0.95, CHCl3); 1H
D
d
8.33 (dd, J¼8.0, 1.1, 1H), 7.33e7.23 (m,
d
154.02, 140.45, 138.14, 138.02, 137.96, 137.12, 130.80, 128.95,
15H), 7.13e7.05 (m, 4H), 6.90 (d, J¼7.8 Hz, 1H), 6.86e6.84 (m, 2H),
6.57 (t, J¼7.8 Hz, 1H), 6.04 (s, 1H), 5.33 (d, J¼1.4, 2H), 4.98 (d,
J¼10.7 Hz, 1H), 4.71 (s, 2H), 4.68 (d, J¼10.7 Hz, 1H), 4.59 (d,
J¼12.1 Hz, 1H), 4.51 (d, J¼6.6, 1H), 4.49 (d, J¼7.4, 1H), 4.35e4.29 (m,
3H), 3.85 (dt, J¼11.2, 4.0 Hz, 2H), 3.78e3.71 (m, 2H); 13C NMR
128.66, 128.65, 128.54,128.39, 128.27, 128.10, 128.07,128.04,128.02,
128.00, 127.91, 122.76, 117.94, 114.00, 87.88, 85.94, 78.59, 78.08,
77.07, 76.19, 75.43, 74.90, 73.75, 68.44, 64.21, 29.84; HRMS (ESI):
Calcd for C43H41N3O6Na [MþNa]þ, 718.2893; Found, 718.2893.
(100 MHz, CDCl3)
d 154.01, 138.23, 138.05, 137.86, 136.99, 130.36,
129.05, 128.69, 128.59, 128.54, 128.15, 128.10, 128.06, 127.99, 127.91,
127.81, 127.77, 127.71, 122.03, 116.87, 114.61, 88.71, 82.83, 78.69,
76.27, 75.63, 74.89, 73.96, 73.68, 72.78, 68.65, 63.97, 29.84; HRMS
4.4. 4-[(2-Iodophenoxy)methyl]-1-(2,3,4,6-tetra-O-benzyl-
b-
D-glucopyranosyl)-1H-1,2,3-triazole (4a)
(ESI): Calcd for
718.2889.
C
43H41N3O6Na [MþNa]þ, 718.2893; Found,
The title compound was synthesized from 1a and 2a according
to procedure A. Yield 11%, yellow oil: [
NMR (400 MHz, CDCl3)
a
]
21 ꢁ5.0 (c 0.39, CHCl3); 1H
D
d
7.85 (s, 1H), 7.74 (dd, J¼7.8, 1.6 Hz, 1H),
4.8. 4-[(2-Iodophenoxy)methyl]-1-(2,3,4,6-tetra-O-benzyl-
b-
7.33e7.16 (m, 19H), 6.97 (dd, J¼8.3, 1.2 Hz, 1H), 6.95e6.92 (m, 2H),
6.69 (td, J¼7.6, 1.3 Hz, 1H), 5.60 (d, J¼9.1 Hz, 1H), 5.29 (s, 2H),
4.94e4.90 (m, 2H), 4.86 (d, J¼10.8 Hz, 1H), 4.61 (d, J¼10.7 Hz, 1H),
4.56 (d, J¼12.1 Hz, 1H), 4.49 (d, J¼12.1 Hz, 1H), 4.43 (d, J¼10.5 Hz,
D-mannopyranosyl)-1H-1,2,3-triazole (4c)
The title compound was synthesized from 1c and 2a according
21 ꢁ14.0 (c 0.83, CHCl3); 1H
1H), 4.05e3.98 (m, 2H), 3.86e3.79 (m, 2H), 3.77e3.69 (m, 3H); 13
C
to procedure A. Yield 20%, yellow oil: [
a
]
D
NMR (400 MHz, CDCl3)
d
8.07 (s, 1H), 7.74 (d, J¼7.2 Hz, 1H),
NMR (100 MHz, CDCl3)
d 156.68, 139.56, 138.14, 137.82, 137.75,
7.32e7.21 (m, 19H), 7.12e7.11 (m, 2H), 6.99 (d, J¼8.1 Hz, 1H), 6.71 (t,
J¼7.4 Hz, 1H), 5.87 (s, 1H), 5.24 (s, 2H), 4.91 (d, J¼10.7 Hz, 1H),
4.70e4.60 (m, 5H), 4.53 (d, J¼12.0 Hz, 1H), 4.22e4.19 (m, 2H), 4.11
136.91, 129.64, 128.55, 128.49, 128.45, 128.33, 128.06, 128.01, 127.87,
127.83, 127.79, 123.27, 122.44, 112.79, 87.69, 86.73, 85.37, 81.00,
78.17, 77.26, 75.86, 75.27, 75.08, 73.62, 68.41, 63.37, 29.78; HRMS
(ESI): Calcd for C43H43IN3O6 [MþH]þ, 824.2197; Found, 824.2195.
(t, J¼9.4 Hz, 1H), 3.85e3.76 (m, 3H), 3.69 (dd, J¼9.6, 3.8 Hz, 1H); 13
C
NMR (100 MHz, CDCl3)
d 157.09, 139.67, 138.22, 138.09, 137.80,
137.47, 129.64, 128.71, 128.57, 128.52, 128.26, 128.23, 128.11, 127.97,
127.94, 127.82, 127.79, 123.26, 112.94, 86.97, 86.69, 82.67, 78.97,
76.84, 75.99, 75.53, 74.94, 74.03, 73.83, 72.72, 69.00, 63.61, 29.85;
HRMS (ESI): Calcd for C43H43IN3O6 [MþH]þ, 824.2197; Found,
824.2196.
4.5. 1-(2,3,4,6-Tetra-O-benzyl-b-D-galactopyranosyl)-4H-ben-
zopyrano[3,4-d]-1H-1,2,3-triazole (3b)
The title compound was synthesized from 1b and 2a according
21
to procedure A. Yield 77%, yellow oil. [
NMR (400 MHz, CDCl3)
a
]
D
ꢁ17 (c 2.78, CHCl3); 1H
d
7.89 (d, J¼7.7 Hz, 1H), 7.36e7.25 (m, 15H),
4.9. 1-(2,3,5-Tri-O-benzyl-b-D-ribofuranosyl)-4H-benzopyr-
7.14e7.08 (m, 3H), 7.02 (dt, J¼7.8, 1.3 Hz, 1H), 6.90e6.88 (m, 3H),
6.06 (t, J¼7.2 Hz, 1H), 5.89 (d, J¼9.4 Hz, 1H), 5.44 (d, J¼13.2 Hz, 1H),
5.27 (d, J¼13.2 Hz, 1H), 5.04 (d, J¼10.6 Hz, 1H), 4.81 (d, J¼11.7 Hz,
1H), 4.77 (d, J¼11.7 Hz, 1H), 4.64 (d, J¼10.6 Hz, 1H), 4.64e4.50 (m,
3H), 4.38 (d, J¼10.8 Hz, 1H), 4.15 (d, J¼2.2 Hz, 1H), 4.05 (d,
J¼10.8 Hz, 1H), 3.94 (t, J¼10.6 Hz, 1H), 3.81e3.76 (m, 2H), 3.68 (dd,
ano[3,4-d]-1H-1,2,3-triazole (3d)
The title compound was synthesized from 1d and 2a according
to procedure A. Yield 53%, yellow oil: [
a
]
21 ꢁ14.0 (c 0.62, CHCl3); 1H
D
NMR (400 MHz, CDCl3)
d
7.64 (d, J¼7.6 Hz, 1H), 7.36e7.23 (m, 14H),
7.14e7.13 (m, 2H), 7.04e7.01 (m, 2H), 6.08 (d, J¼2.0 Hz, 1H), 5.48 (d,
J¼13.2 Hz, 1H), 5.28e5.25 (m, 2H), 4.73e4.60 (m, 4H), 4.52 (s, 2H),
4.38 (s, 2H), 3.58e3.56 (m, 1H), 3.47e3.46 (m, 1H); 13C NMR
J¼9.2, 5.6 Hz, 1H); 13C NMR (100 MHz, CDCl3)
d 153.69, 140.14,
138.50, 138.02, 137.67, 137.08, 130.46, 128.70, 128.65, 128.58, 128.48,
128.41, 128.26, 128.13, 128.06, 128.01, 127.95, 127.76, 126.49, 122.37,
117.33, 113.68, 89.04, 83.44, 76.63, 75.60, 75.02, 74.89, 74.00, 73.86,
73.15, 68.10, 64.10, 29.90; HRMS (ESI): Calcd for C43H41N3O6Na
[MþNa]þ, 718.2893; Found, 718.2899.
(100 MHz, CDCl3)
d 153.81, 139.60, 138.00, 137.68, 137.36, 130.96,
129.13, 128.60, 128.38, 128.31, 128.17, 128.14, 127.63, 127.57, 123.98,
122.58, 117.81, 113.89, 89.61, 83.15, 79.13, 78.09, 73.47, 73.30, 73.05,
69.77, 64.34, 29.87; HRMS (ESI): Calcd for C35H34N3O5 [MþH]þ,
576.2498; Found, 576.2494.
4.6. 4-[(2-Iodophenoxy)methyl]-1-(2,3,4,6-tetra-O-benzyl-
b-
D-galactopyranosyl)-1H-1,2,3etriazole (4b)
4.10. 4-[(2-Iodophenoxy)methyl]-1-(2,3,5-tri-O-benzyl-
b-D-ri-
bofuranosyl)-1H-1,2,3-triazole (4d)
The title compound was synthesized from 1b and 2a according
to procedure A. Yield 14%, yellow oil. [
NMR (400 MHz, CDCl3)
a
]
21 ꢁ13.0 (c 1.47, CHCl3); 1H
The title compound was synthesized from 1d and 2a according
D
d
7.83 (s, 1H), 7.73 (d, J¼7.4 Hz, 1H),
to procedure A. Yield 38%, yellow oil: [
NMR (400 MHz, CDCl3)
a
]
21 ꢁ5.0 (c 2.31, CHCl3); 1H
D
7.35e7.17 (m, 19H), 6.97e6.95 (m, 3H), 6.67 (t, J¼7.5 Hz,1H), 5.60 (d,
J¼9.0 Hz, 1H), 5.25 (s, 2H), 5.00 (d, J¼11.4 Hz, 1H), 4.77 (d, J¼11.8 Hz,
1H), 4.73 (d, J¼11.8 Hz, 1H), 4.64 (d, J¼11.5 Hz, 1H), 4.53 (d,
J¼10.5 Hz, 1H), 4.46 (d, J¼11.8 Hz, 1H), 4.40 (d, J¼11.8 Hz, 1H), 4.34
(t, J¼9.2 Hz, 1H), 4.06e4.04 (m, 2H), 3.80 (t, J¼6.4 Hz, 1H), 3.74 (dd,
J¼9.5, 2.2 Hz, 1H), 3.63e3.56 (m, 2H); 13C NMR (100 MHz, CDCl3)
d
7.96 (s, 1H), 7.76 (dd, J¼7.8, 1.3 Hz, 1H),
7.34e7.20 (m,16H), 6.96 (d, J¼7.7 Hz,1H), 6.73 (dt, J¼7.7, 0.9 Hz,1H),
6.20 (d, J¼2.1 Hz,1H), 5.12 (d, J¼12.3 Hz,1H), 5.07 (d, J¼12.3 Hz,1H),
4.68 (d, J¼12.0 Hz, 1H), 4.63 (d, J¼12.0 Hz, 1H), 4.59 (d, J¼11.8 Hz,
1H), 4.51 (d, J¼11.7 Hz, 1H), 4.47e4.41 (m, 4H), 4.19 (t, J¼5.8 Hz,1H),
3.77 (dd, J¼10.9, 2.7 Hz, 1H), 3.57 (dd, J¼10.9, 3.1 Hz, 1H); 13C NMR
d
156.89,144.41,139.62,138.57,138.01,137.69,137.27,129.67,128.64,
(100 MHz, CDCl3) d 157.05, 143.82, 139.65, 137.64, 137.48, 137.04,
128.59, 128.48, 128.43, 128.09, 128.05, 127.98, 127.92, 127.83, 127.72,
123.26, 122.01, 112.96, 88.11, 86.85, 83.07, 77.96, 76.50, 75.33, 74.84,
73.74, 73.40, 72.95, 68.30, 63.58; HRMS (ESI): Calcd for C43H43IN3O6
[MþH]þ, 824.2197; Found, 824.2195.
129.67, 128.68, 128.63, 128.32, 128.30, 128.18, 128.06, 128.01, 127.99,
123.24,122.24,113.07, 91.53, 86.88, 82.44, 80.72, 76.20, 73.66, 72.82,
72.71, 68.86, 63.35; HRMS (ESI): Calcd for C35H35IN3O5 [MþH]þ,
704.1621; Found, 704.1621.

S.-T. Bai et al. / Tetrahedron 71 (2015) 4909e4919
4915
4.11. 1-(3,4,6-Tri-O-trimethylsilyl-2-deoxy-2-phthalimido-
-glucopyranosyl)-4H-benzopyrano[3,4-d]-1H-1,2,3-triazole
(3e)
b
-
J¼11.4 Hz, 1H), 4.85 (d, J¼11.2 Hz, 1H), 4.77e4.68 (m, 4H), 4.57 (d,
J¼2.8 Hz, 1H), 4.54 (d, J¼1.3 Hz, 1H), 4.49e4.45 (m, 2H), 4.37 (d,
J¼12.0 Hz, 1H), 4.33 (d, J¼12.0 Hz, 1H), 4.26 (d, J¼11.9 Hz, 1H),
4.14 (t, J¼9.3 Hz, 1H), 4.03 (d, J¼10.6 Hz, 1H), 3.93e3.70 (m, 5H),
D
The title compound was synthesized from 1e and 2a according
3.64 (d, J¼10.9 Hz, 1H), 3.55e3.50 (m, 2H), 3.44e3.38 (m, 3H); 13
C
21
to procedure A. Yield 72%, white solid: [
a]
ꢁ20.0 (c 0.62, CHCl3);
NMR (100 MHz, CDCl3) d 156.80, 144.47, 139.64, 139.12, 138.80,
D
1H NMR (400 MHz, CDCl3)
d
8.04 (d, J¼7.6 Hz, 1H), 7.76e7.65 (m,
138.57, 138.26, 138.11, 137.27, 129.68, 128.54, 128.51, 128.46,
128.44, 128.40, 128.30, 128.19, 128.05, 127.90, 127.83, 127.76,
127.71, 127.56, 127.51, 127.44, 123.29, 121.86, 112.83, 102.82, 87.75,
86.81, 83.78, 82.67, 80.35, 80.08, 78.43, 75.85, 75.69, 75.56, 75.24,
74.85, 73.72, 73.56, 73.37, 72.74, 68.23, 67.76, 63.57, 29.83; HRMS
4H), 7.32 (t, J¼7.4 Hz, 1H), 7.11 (t, J¼7.5 Hz, 1H), 7.06 (d, J¼8.2 Hz,
1H), 6.72 (d, J¼10.0 Hz, 1H), 5.33 (d, J¼13.1 Hz, 1H), 5.21 (d,
J¼13.2 Hz, 1H), 4.81 (t, J¼10.0 Hz, 1H), 4.69 (t, J¼8.0 Hz, 1H), 4.04 (t,
J¼9.1 Hz,1H), 3.92 (s, 2H), 3.79 (d, J¼9.5 Hz,1H), 0.25 (s, 9H), 0.08 (s,
9H), ꢁ0.13 (s, 9H); 13C NMR (100 MHz, CDCl3)
d
168.66, 166.49,
(ESI): Calcd for
1256.4231.
C
70H71IN3O11 [MþH]þ, 1256.4133; Found,
154.15, 140.22, 134.38, 131.60, 131.26, 130.99, 129.00, 125.73, 123.86,
123.50, 122.64, 117.88, 114.26, 83.95, 79.82, 73.82, 72.03, 64.00,
61.10, 54.99, 0.96, 0.84, ꢁ0.32; HRMS (ESI): Calcd for C32H44N4O7
-
4.15. 1-(2,3,4,6-Tetra-O-benzyl-b-D-glucopyranosyl)-4,5-
dihydrobenzoxepino[4,5-d]-1H-1,2,3-triazole (3g)
Si3Na [MþNa]þ, 703.2415; Found, 703.2416.
4.12. 4-[(2-Iodophenoxy)methyl]-1-(2-acetylamino-2-deoxy-
The title compound was synthesized from 1a and 2b according
-glucopyranosyl)-1H-1,2,3-triazole (4e0)
21
to procedure A. Yield 29%, yellow oil: [
a
]
¼0 (c 2.12, CHCl3); 1H
3,4,6-tri-O-acetyl-
b-
D
D
NMR (400 MHz, CDCl3)
d
7.79 (d, J¼7.7 Hz, 1H), 7.34e7.27 (m, 14H),
The title compound was synthesized from 3,4,6-tri-O-acetyl-2-
7.21e7.15 (m, 6H), 7.06 (t, J¼7.6 Hz, 1H), 6.89e6.82 (m, 2H), 5.43 (d,
J¼9.0 Hz, 1H), 4.92e4.85 (m, 3H), 4.77 (m, 1H), 4.67e4.49 (m, 6H),
4.10 (dt, J¼11.6, 3.9 Hz, 1H), 3.87e3.73 (m, 5H), 3.53e3.45 (m, 1H),
deoxy-2- acetylamino-
according to procedure B. Yield 84%, white solid: [
pyridine); 1H NMR (400 MHz, DMSO-d6)
b-D
-glucopyranosyl azide (1e0)26 and 2a
a]
21 ꢁ27.0 (c 2.08,
D
3.29 (dt, J¼17.0, 3.6 Hz, 1H); 13C NMR (100 MHz, CDCl3)
d 159.93,
d
8.39 (s, 1H), 8.09 (d,
J¼9.3 Hz, 1H), 7.77 (dd, J¼7.8, 1.6 Hz, 1H), 7.36 (dt, J¼8.4, 1.6 Hz, 1H),
7.19 (dd, J¼8.3, 1.1 Hz, 1H), 6.77 (dt, J¼7.5, 1.2 Hz, 1H), 6.15 (d,
J¼10.0 Hz, 1H), 5.35 (t, J¼9.8 Hz, 1H), 5.22 (s, 2H), 5.11 (t, J¼9.8 Hz,
1H), 4.66e4.59 (m, 1H), 4.28e4.24 (m, 1H), 4.16 (dd, J¼12.5, 5.1 Hz,
1H), 4.07 (dd, J¼12.5, 2.2 Hz, 1H), 2.02 (s, 3H), 2.00 (s, 3H), 1.95 (s,
143.15, 138.36, 138.11, 137.92, 137.75, 132.40, 130.39, 128.64, 128.62,
128.52, 128.40, 128.13, 128.09, 128.06, 127.88, 127.82, 124.54, 122.43,
119.55, 86.55, 86.05, 79.63, 77.91, 77.69, 75.95, 75.35, 73.76, 72.02,
69.06, 28.47; HRMS (ESI): Calcd for C44H43N3O6Na [MþNa]þ,
732.3050; Found, 732.3048.
3H), 1.58 (s, 3H); 1C NMR (100 MHz, DMSO-d6)
d 170.04, 169.61,
169.38, 169.35,156.57, 142.63, 139.09, 129.73, 129.36, 123.52, 123.07,
115.21, 113.27, 86.61, 84.70, 73.41, 72.40, 67.96, 62.09, 61.73, 51.95,
22.34, 20.55, 20.43, 20.29; HRMS (ESI): Calcd for C23H27IN4O9Na
[MþNa]þ, 653.0720; Found, 653.0735.
4.16. 4-[2-(2-Iodophenoxy)ethyl]-1-(2,3,4,6-tetra-O-benzyl-
-glucopyranosyl)-1H-1,2,3-triazole (4g)
b-
D
The title compound was synthesized from 1a and 2b according
to procedure A. Yield 57%, yellow oil: [
a
]
21 ꢁ3.0 (c 0.97, CHCl3); 1H
4.13. 1-(2,3,6-20,30,40,60-Hepta-O-benzyl-
zopyrano[3,4-d]-1H-1,2,3-triazole (3f)
b-D-lactosyl)-4H-ben-
D
NMR (400 MHz, CDCl3)
d
7.94 (s, 1H), 7.73 (dd, J¼7.8, 1.4 Hz, 1H),
7.35e7.23 (m, 14H), 7.18e7.09 (m, 5H), 6.88 (d, J¼6.8 Hz, 2H), 6.76
(d, J¼7.5 Hz, 1H), 6.69 (dt, J¼7.7, 1.0 Hz, 1H), 5.60 (d, J¼9.2 Hz, 1H),
4.93e4.84 (m, 3H), 4.60 (d, J¼10.8 Hz, 1H), 4.56 (d, J¼12.2 Hz, 1H),
4.48 (d, J¼12.2 Hz,1H), 4.44 (d, J¼10.7 Hz,1H), 4.22 (t, J¼6.0 Hz, 2H),
4.06e4.00 (m, 2H), 3.86e3.79 (m, 2H), 3.76e3.69 (m, 3H) 3.30 (t,
The title compound was synthesized from 1f and 2a according
to procedure A. Yield 69%, yellow oil: [
NMR (400 MHz, CDCl3)
a
]
21 ꢁ24.0 (c 2.87, CHCl3); 1H
D
d
7.73 (d, J¼7.5 Hz, 1H), 7.36e7.10 (m, 34H),
6.98 (d, J¼8.3 Hz, 1H), 6.93e6.92 (m, 2H), 6.67 (t, J¼7.3 Hz, 1H),
5.81 (d, J¼9.2 Hz, 1H), 5.42 (d, J¼13.2 Hz, 1H), 5.31 (d, J¼13.2 Hz,
1H), 5.14 (d, J¼10.2 Hz, 1H), 5.00 (d, J¼11.4 Hz, 1H), 4.90 (d,
J¼11.3 Hz, 1H), 4.80 (d, J¼11.9 Hz, 1H), 4.73 (t, J¼7.9 Hz, 3H), 4.56 (t,
J¼11.9 Hz, 2H), 4.47 (t, J¼6.3 Hz, 2H), 4.37 (t, J¼10.2 Hz, 2H), 4.28
(d, J¼11.9 Hz, 2H), 4.23 (d, J¼8.7 Hz, 1H), 4.17 (d, J¼11.3 Hz, 1H),
3.97e3.94 (m, 2H), 3.83 (t, J¼8.3 Hz, 1H), 3.77 (t, J¼8.9 Hz, 1H), 3.70
(d, J¼10.8 Hz, 1H), 3.62 (d, J¼9.8 Hz, 1H), 3.56 (d, J¼10.5 Hz, 1H),
J¼5.80 Hz, 2H); 13C NMR (100 MHz, CDCl3)
d 157.27, 144.81, 139.61,
138.32, 138.00, 137.94, 137.24, 129.68, 128.61, 128.54, 128.38, 128.14,
128.11, 128.05, 127.94, 127.84, 122.88, 122.42, 112.16, 87.75, 86.52,
85.55, 81.36, 78.23, 75.93, 75.34, 75.10, 73.72, 68.60, 68.01, 26.33;
HRMS (ESI): Calcd for C44H45IN3O6 [MþH]þ, 838.2353; Found,
838.2328.
3.47e3.42 (m, 3H); 13C NMR (100 MHz, CDCl3)
d
153.88, 140.33,
4.17. 1-(2,3,4,6-Tetra-O-benzyl-b-D-galactopyranosyl)-4,5-
139.10, 138.85, 138.54, 138.15, 137.36, 130.67, 128.79, 128.55, 128.52,
128.44, 128.42, 128.32, 128.21, 128.09, 127.91, 127.88, 127.85, 127.73,
127.67, 127.57, 127.53, 127.49, 125.18, 122.80, 117.82, 113.94, 102.95,
87.78, 84.18, 82.72, 80.18, 78.24, 77.84, 75.94, 75.74, 75.67, 75.06,
74.89, 73.65, 73.60, 73.36, 73.22, 72.70, 68.22, 67.80, 64.17, 29.88;
HRMS (ESI): Calcd for C70H69N3O11Na [MþNa]þ, 1150.4830; Found,
1150.4896.
dihydro-benzoxepino [4,5-d]-1H-1,2,3-triazole (3h)
The title compound was synthesized from 1b and 2b according
to procedure A. Yield 28%, yellow oil: [
NMR (400 MHz, CDCl3)
a
]
21 ꢁ34.0 (c 0.07, CHCl3); 1H
D
d
7.83 (d, J¼7.7 Hz, 1H), 7.38e7.21 (m, 16H),
7.18e7.15 (m, 3H), 7.12 (d, J¼7.2 Hz, 1H), 6.89 (dd, J¼7.2, 3.6 Hz, 3H),
5.43 (d, J¼8.0 Hz, 1H), 5.09 (s, 1H), 5.04 (d, J¼11.5 Hz, 1H), 4.77e4.67
(m, 4H), 4.60 (s, 1H), 4.53 (d, J¼11.5 Hz, 1H), 4.43 (d, J¼11.6 Hz, 2H),
4.15e4.13 (m, 1H), 4.02 (d, J¼2.2 Hz, 1H), 3.86 (t, J¼5.9 Hz, 1H), 3.76
(dd, J¼9.6, 6.3 Hz, 1H), 3.68e3.63 (m, 2H), 3.51e3.43 (m, 1H), 3.30
4.14. 4-[(2-Iodophenoxy)methyl]-1-(2,3,6-20,30,40,60-hepta-O-
benzyl-b-D-lactosyl)-1H-1,2,3-triazole (4f)
(dt, J¼17.0, 4.0 Hz, 1H); 13C NMR (100 MHz, CDCl3)
d 159.75, 143.14,
The title compound was synthesized from 1f and 2a according
138.57, 138.09, 137.97, 137.88, 132.15, 130.16, 128.65, 128.58, 128.47,
128.38, 128.33, 128.16, 128.01, 127.98, 127.87, 127.76, 127.75, 124.51,
122.24, 119.62, 84.01, 76.66, 76.42, 75.52, 74.76, 73.82, 73.58, 73.02,
71.98, 69.20, 29.84, 28.50; HRMS (ESI): Calcd for C44H43N3O6Na
[MþNa]þ, 732.3050; Found, 732.3052.
21
to procedure A. Yield 20%, yellow oil: [
1H NMR (400 MHz, CDCl3)
a
]
ꢁ13.0 (c 1.86, CHCl3);
D
d
7.76 (s, 1H), 7.73 (d, J¼7.8 Hz, 1H),
7.35e7.12 (m, 34H), 6.96e6.92 (m, 3H), 6.68 (t, J¼7.5 Hz, 1H), 5.59
(d, J¼9.1 Hz, 1H), 5.26 (s, 2H), 5.14 (d, J¼10.5 Hz, 1H), 4.98 (d,

4916
S.-T. Bai et al. / Tetrahedron 71 (2015) 4909e4919
4.18. 4-[2-(2-Iodophenoxy)ethyl]-1-(2,3,4,6-tetra-O-benzyl-
b-
115.12, 89.24, 81.17, 78.61, 72.32, 70.79, 64.77, 62.28; HRMS (ESI):
D-galactopyranosy-l)-1H-1,2,3-triazole (4h)
Calcd for C15H17N3O6Na [MþNa]þ, 358.1015; Found, 358.1025.
The title compound was synthesized from 1b and 2b according
4.22. 4-[(2-Iodophenoxy)methyl]-1-(
1,2,3-triazole (6a)
b-D-glucopyranosyl)-1H-
to procedure A. Yield 52%, yellow oil: [
NMR (400 MHz, CDCl3)
a
]
21 ꢁ10.0 (c 1.28, CHCl3); 1H
D
d
7.97 (s, 1H), 7.70 (dd, J¼7.8, 1.4 Hz, 1H),
7.36e7.21 (m, 16H), 7.15e7.09 (m, 3H), 6.88 (dd, J¼6.0, 1.8 Hz, 2H),
6.73 (d, J¼8.3 Hz, 1H), 6.67 (dt, J¼7.7, 1.0 Hz, 1H), 5.61 (d, J¼9.1 Hz,
1H), 5.00 (d, J¼11.4 Hz, 1H), 4.77 (d, J¼12.0 Hz, 1H), 4.74 (d,
J¼12.2 Hz, 1H), 4.63 (d, J¼11.5 Hz, 1H), 4.52 (d, J¼10.7 Hz, 1H), 4.46
(d, J¼11.7 Hz, 1H), 4.40 (d, J¼11.8 Hz, 1H), 4.36 (t, J¼9.4 Hz, 1H),
4.20e4.16 (m, 2H), 4.07e4.04 (m, 2H), 3.81 (t, J¼6.4 Hz, 1H), 3.74
The title compound was synthesized from 4a according to
21
procedure C. Yield 95%, white solid: [
NMR (400 MHz, CD3OD)
a
]
ꢁ4.0 (c 1.56, MeOH); 1H
D
d
8.30 (s, 1H), 7.77 (dd, J¼1.6, 7.8 Hz, 1H),
7.35 (dt, J¼1.6, 7.8 Hz, 1H), 7.13 (dd, J¼1.1, 8.3 Hz, 1H), 6.75 (dt, J¼1.3,
7.6 Hz, 1H), 5.64 (d, J¼9.2 Hz, 1H), 5.25 (s, 2H), 3.93 (t, J¼9.0 Hz, 1H),
3.89 (dd, J¼2.0, 12.3 Hz, 1H), 3.72 (dd, J¼5.5, 12.2 Hz, 1H), 3.61e3.48
(dd, J¼9.6, 2.6 Hz, 1H), 3.66e3.56 (m, 2H), 3.26 (t, J¼6.0 Hz, 2H); 13
C
(m, 3H); 13C NMR (100 MHz, CD3OD)
d 158.51, 144.73, 140.75,
NMR (100 MHz, CDCl3)
d
157.26, 144.68, 139.60, 138.70, 138.14,
130.75, 124.93, 124.21, 114.08, 89.64, 87.02, 81.20, 78.51, 73.98,
70.88, 63.59, 62.38; HRMS (ESI): Calcd for C15H18IN3O6Na [MþNa]þ,
486.0138; Found, 486.0135.
137.75, 137.52, 129.60, 128.63, 128.60, 128.51, 128.28, 128.13, 128.10,
128.05, 127.94, 127.80, 127.73, 127.70, 122.75, 122.04, 112.07, 88.08,
86.40, 83.10, 78.33, 76.33, 75.33, 74.90, 73.76, 73.60, 72.94, 68.31,
67.93, 26.27; HRMS (ESI): Calcd for C44H45IN3O6 [MþH]þ, 838.2353;
Found, 838.2348.
4.23. 1-(b-D-Galactopyranosyl)-4H-benzopyrano[3,4-d]-1H-
1,2,3-triazole (5b)
The title compound was synthesized from 3b according to
4.19. 4-[3-(2-Iodophenoxy)propyl]-1-(2,3,4,6-tetra-O-acetyl-
procedure C. Yield 99%, white solid: [
NMR (400 MHz, CD3OD)
a
]
21 ꢁ13.0 (c 0.89, MeOH); 1H
D
b-D
-glucopyranosyl)-1H-1,2,3-triazole (4i)
d
8.18 (d, J¼7.8 Hz, 1H), 7.30 (dt, J¼8.0,
1.5 Hz, 1H), 7.07 (dt, J¼7.7, 1.1 Hz, 1H), 7.03 (d, J¼8.2 Hz, 1H), 5.79 (d,
J¼9.3 Hz,1H), 5.42 (d, J¼13.3 Hz,1H), 5.33 (d, J¼13.3 Hz, 1H), 4.47 (t,
J¼9.4 Hz,1H), 4.06 (d, J¼3.0 Hz,1H), 3.97 (t, J¼5.8 Hz 1H), 3.90e3.80
(m, 2H), 3.75 (dd, J¼9.4, 3.2 Hz, 1H); 13C NMR (100 MHz, CD3OD)
The title compound was synthesized from 2,3,4,6-tetra-O-ace-
tyl-
Yield 77%, yellow oil: [
CDCl3)
b-D-glucopyranosyl azide 1g and 2c according to procedure B.
a
]
D
21 ꢁ18 (c 1.21, CHCl3); 1H NMR (400 MHz,
d
7.78 (dd, J¼7.7, 1.2 Hz, 1H), 7.61 (s, 1H), 7.30e7.26 (m, 1H),
d
155.32, 131.90, 130.09, 127.44, 123.59, 118.47, 115.20, 90.66, 80.19,
6.81 (d, J¼7.9 Hz, 1H), 6.71 (t, J¼7.6 Hz, 1H), 5.89e5.84 (m, 1H),
5.45e5.39 (m, 2H), 5.26e5.22 (m, 1H), 4.30 (dd, J¼12.6, 4.9 Hz, 1H),
4.16e4.08 (m, 1H), 4.06e3.99 (m, 3H), 3.02 (t, J¼7.3 Hz, 2H),
2.27e2.21 (m, 2H), 2.08 (s, 3H), 2.07 (s, 3H), 2.03 (s, 3H),1.85 (s, 3H);
75.51, 70.33, 69.37, 64.73, 62.65; HRMS (ESI): Calcd for
C
15H17N3O6Na [MþNa]þ, 358.1015; Found, 358.1009.
13C NMR (100 MHz, CDCl3)
d 170.55, 169.95, 169.42, 168.92, 157.35,
4.24. 4-[(2-Iodophenoxy)methyl]-1-(b-D-galactopyranosyl)-
1H-1,2,3-triazole (6b)
147.91, 139.43, 129.50, 122.57, 119.49, 112.20, 86.73, 85.71, 75.07,
72.71, 70.31, 67.76, 67.72, 61.61, 60.44, 28.51, 22.21, 20.77, 20.61,
20.59, 20.21; HRMS (ESI): Calcd for
660.1054; Found, 660.1064.
C
25H31IN3O10 [MþH]þ,
The title compound was synthesized from 4b according to
21
procedure C. Yield 93%, white solid: [
NMR (400 MHz, CD3OD)
a
]
D
þ4.0 (c 1.59, MeOH); 1H
d
8.37 (s, 1H), 7.78 (dd, J¼7.8, 1.3 Hz, 1H),
7.35 (dt, J¼8.4, 1.3 Hz, 1H), 7.13 (d, J¼7.9 Hz, 1H), 6.76 (t, J¼7.4 Hz,
1H), 5.61 (d, J¼9.2 Hz,1H), 5.26 (s, 2H), 4.17 (t, J¼9.4 Hz,1H), 3.98 (d,
J¼3.0 Hz, 1H), 3.87e3.69 (m, 4H); 13C NMR (100 MHz, CD3OD)
4.20. 4-[3-(2-Iodophenoxy)propyl]-1-(2,3,4,6-tetra-O-acetyl-
-galactopyranosyl)-1H-1,2,3-triazole (4j)
b-D
d
158.47, 140.74, 130.75, 124.20, 114.01, 90.38, 87.00, 80.07, 75.30,
The title compound was synthesized from 2,3,4,6-tetra-O-ace-
71.42, 70.40, 63.58, 62.45, 28.27; HRMS (ESI): Calcd for
tyl-
B. Yield 97%, yellow oil: [
(400 MHz, CDCl3)
b-D-galactopyra- nosyl azide 1h and 2c according to procedure
C
15H18IN3O6Na [MþNa]þ, 486.0138; Found, 486.0133.
21
a
]
D
ꢁ1.0 (c 2.06, CHCl3); 1H NMR
d
7.77 (dd, J¼7.7, 1.2 Hz, 1H), 7.66 (s, 1H),
4.25. 1-(b-D-Mannopyranosyl)-4H-benzopyrano[3,4-d]-1H-
1,2,3-triazole (5c)
7.30e7.26 (m, 1H), 6.81 (d, J¼8.1 Hz, 1H), 6.71 (d, J¼7.6 Hz, 1H), 5.82
(d, J¼9.3 Hz, 1H), 5.56e5.51 (m, 2H), 5.24 (dd, J¼10.3, 3.2 Hz, 1H),
4.23e4.11 (m, 3H), 4.09e4.01 (m, 2H), 3.03 (t, J¼7.1 Hz, 2H), 2.26
(dd, J¼13.4, 6.9 Hz, 2H), 2.22 (s, 3H), 2.05 (s, 3H), 2.01 (s, 3H),1.87 (s,
The title compound was synthesized from 3c according to pro-
21
cedure C. Yield 96%, white solid: [
NMR (400 MHz, DMSO-d6)
a
]
D
ꢁ32.0 (c 0.84, pyridine); 1H
3H); 13C NMR (100 MHz, CDCl3)
d 170.45, 170.09, 169.93, 169.16,
d
8.27 (dd, J¼8.6, 1.5 Hz, 1H), 7.26 (dt,
157.41, 147.93, 139.48, 129.54, 122.60, 119.64, 112.21, 86.75, 86.30,
74.04, 70.91, 67.92, 67.80, 66.97, 61.32, 28.60, 22.30, 20.80, 20.78,
J¼7.9, 1.5 Hz, 1H), 6.99 (t, J¼7.8 Hz, 2H), 6.16 (s, 1H), 5.41 (d,
J¼13.3 Hz, 1H), 5.34 (d, J¼13.3 Hz, 1H), 5.12 (d, J¼4.4 Hz, 1H),
5.08e5.01 (m, 1H), 4.66 (t, J¼4.8 Hz, 1H), 4.10 (s, 1H), 3.80 (dd,
J¼10.8, 4.9 Hz, 1H), 3.67e3.43 (m, 5H); 13C NMR (100 MHz, DMSO-
20.63, 20.37; HRMS (ESI): Calcd for
660.1054; Found, 660.1054.
C
25H31IN3O10 [MþH]þ,
d6)
d 153.37, 139.04, 130.18, 129.08, 128.41, 121.67, 116.61, 114.49,
4.21. 1-(
1,2,3-triazole (5a)
b
-
D
-Glucopyranosyl)-4H-benzopyrano[3,4-d]-1H-
87.58, 80.67, 72.97, 71.26, 66.18, 63.31, 60.87; HRMS (ESI): Calcd for
C
15H17N3O6Na [MþNa]þ, 358.1015; Found, 358.1021.
The title compound was synthesized from 3a according to
4.26. 4-[(2-Iodophenoxy)methyl]-1-(b-D-mannopyranosyl)-
1H-1,2,3-triazole (6c)
procedure C. Yield 100%, white solid: [
NMR (400 MHz, CD3OD)
1.5 Hz, 1H), 7.12 (dt, J¼7.6, 1.1 Hz, 1H), 7.05 (dd, J¼8.2, 0.9 Hz, 1H),
5.80 (d, J¼9.2 Hz, 1H), 5.37 (dd, J¼15.6, 13.4 Hz, 2H), 4.25 (t,
J¼8.9 Hz, 1H), 3.95 (dd, J¼12.2, 2.0 Hz, 1H), 3.81 (dd, J¼12.2, 5.5 Hz,
1H), 3.75e3.71 (m, 1H), 3.66e3.60 (m, 2H); 13C NMR (100 MHz,
a
]
21 ꢁ48.0 (c 1.14, MeOH); 1H
D
d
7.84 (dd, J¼7.8, 1.4 Hz, 1H), 7.33 (dt, J¼8.1,
The title compound was synthesized from 4c according to pro-
21
cedure C. Yield 100%, white solid: [
NMR (400 MHz, CD3OD)
a
]
D
ꢁ12.0 (c 1.05, MeOH); 1H
d
8.40 (s, 1H), 7.77 (dd, J¼7.8, 1.5 Hz, 1H),
7.34 (dt, J¼8.3, 1.6 Hz, 1H), 7.13 (dd, J¼8.3, 1.2 Hz, 1H), 6.75 (dt, J¼7.6,
1.2 Hz, 1H), 6.05 (d, J¼1.1 Hz, 1H), 5.25 (s, 2H), 4.14 (m, 1H), 3.94 (dd,
CD3OD)
d 155.40, 141.12, 132.08, 130.38, 125.97, 123.67, 118.81,

S.-T. Bai et al. / Tetrahedron 71 (2015) 4909e4919
4917
J¼12.1, 2.1 Hz, 1H), 3.80e3.71 (m, 3H), 3.57e3.53 (m, 1H); 13C NMR
4.31. 1-(
triazole (5f)
b-D-lactosyl)-4H-benzopyrano[3,4-d]-1H-1,2,3-
(100 MHz, CD3OD)
d 158.55, 144.09, 140.75, 130.74, 125.36, 124.19,
114.14, 88.34, 87.06, 81.62, 75.01, 72.21, 67.83, 63.70, 62.65; HRMS
(ESI): Calcd for
486.0127.
C
15H18IN3O6Na [MþNa]þ, 486.0138; Found,
The title compound was synthesized from 3f according to pro-
21
cedure C. Yield 59%, white solid: [
NMR (400 MHz, DMSO-d6)
a
]
ꢁ19.0 (c 1.32, pyridine); 1H
D
d
7.86 (d, J¼7.7 Hz, 1H), 7.35 (t, J¼7.9 Hz,
1H), 7.13e7.08 (m, 2H), 5.89 (d, J¼9.2 Hz, 1H), 5.61 (d, J¼5.9 Hz, 1H),
5.45 (d, J¼13.4 Hz,1H), 5.37 (d, J¼13.4 Hz,1H), 5.16 (d, J¼4.4 Hz,1H),
4.94 (s, 1H), 4.86 (d, J¼5.2 Hz, 1H), 4.78 (t, J¼5.6 Hz, 1H), 4.70 (d,
J¼5.0 Hz, 1H), 4.58 (d, J¼4.5 Hz, 1H), 4.32 (d, J¼7.1 Hz, 1H),
4.01e4.00 (m, 1H), 3.89e3.81 (m, 2H), 3.76e3.52 (m, 8H), 3.38 (t,
4.27. 1-(b-D-Ribofuranosyl)-4H-benzopyrano[3,4-d]-1H-1,2,3-
triazole (5d)
The title compound was synthesized from 3d according to
procedure D. Yield 100%, white solid: [
NMR (400 MHz, CD3OD)
a
]
21 ꢁ72.0 (c 0.86, MeOH); 1H
D
J¼9.5 Hz 1H); 13C NMR (100 MHz, DMSO-d6)
d 153.41, 139.62,
d
7.79 (dd, J¼7.8, 1.4 Hz,1H), 7.32 (dt, J¼8.2,
130.77, 127.84, 125.05, 122.59, 117.57, 113.85, 103.82, 86.96, 79.73,
77.70, 75.59, 75.21, 73.32, 70.62, 70.29, 68.19, 63.52, 60.48, 59.83;
HRMS (ESI): Calcd for C21H27N3O11Na [MþNa]þ, 520.1543; Found,
520.1537.
1.5 Hz, 1H), 7.11 (dt, J¼7.7, 1.0 Hz, 1H), 7.05 (dd, J¼8.2, 0.8 Hz, 1H),
6.15 (d, J¼3.4 Hz,1H), 5.44 (d, J¼13.4 Hz,1H), 5.32 (d, J¼13.2 Hz,1H),
5.15 (dd, J¼4.8, 3.4 Hz, 1H), 4.51 (t, J¼5.3 Hz, 1H), 4.22 (dt, J¼5.3,
3.8 Hz, 1H), 3.74 (dd, J¼12.2, 3.6 Hz, 1H), 3.59 (dd, J¼12.2, 5.2 Hz,
1H); 13C NMR (100 MHz, CD3OD)
d 155.25, 140.69, 132.14, 130.41,
4.32. 4-[(2-Iodophenoxy)methyl]-1-(b-D-lactosyl)-1H-1,2,3-
124.94, 123.60, 118.80, 114.95, 92.57, 87.50, 74.93, 72.35, 64.84,
63.22; HRMS (ESI): Calcd for C14H15N3O5Na [MþNa]þ, 328.0909;
Found, 328.0910.
triazole (6f)
The title compound was synthesized from compound 4f
according to procedure C. Yield 55%, white solid: [
a
]
21 ꢁ6.0 (c 1.06,
D
4.28. 4-[(2-Iodophenoxy)methyl]-1-(
1,2,3-triazole (6d)
b
-D
-ribofuranosyl)-1H-
MeOH); 1H NMR (400 MHz, CD3OD)
d
8.33 (s, 1H), 7.77 (d, J¼7.8 Hz,
1H), 7.35 (t, J¼7.4 Hz, 1H), 7.14 (d, J¼8.2 Hz, 1H), 6.76 (t, J¼7.5 Hz,
1H), 5.69 (d, J¼9.1 Hz,1H), 5.25 (s, 2H), 4.42 (d, J¼7.6 Hz,1H), 4.02 (t,
J¼9.1 Hz,1H), 3.91 (s, 2H), 3.83e3.70 (m, 6H), 3.62 (dd, J¼7.5, 4.5 Hz,
1H), 3.57 (d, J¼7.7 Hz, 1H), 3.51 (dd, J¼9.6, 3.0 Hz, 1H); 13C NMR
The title compound was synthesized from 4d according to
procedure C. Yield 77%, white solid: [
NMR (400 MHz, CD3OD)
a
]
21 ꢁ31.0 (c 1.54, MeOH); 1H
D
d
8.44 (s, 1H), 7.77 (dd, J¼7.8, 1.6 Hz, 1H),
(100 MHz, CD3OD) d 158.51, 144.78, 140.75, 130.76, 124.91, 124.21,
7.35 (dt, J¼8.2, 1.5 Hz, 1H), 7.12 (dd, J¼8.0, 1.0 Hz, 1H), 6.75 (dt, J¼7.7,
1.1 Hz, 1H), 6.08 (d, J¼3.8 Hz, 1H), 5.24 (s, 2H), 4.52 (t, J¼4.5 Hz, 1H),
4.32 (t, J¼5.1 Hz, 1H), 4.15 (dd, J¼7.9, 4.2 Hz, 1H), 3.82 (dd, J¼12.2,
3.2 Hz, 1H), 3.70 (dd, J¼12.2, 4.2 Hz, 1H); 13C NMR (100 MHz,
114.04, 105.08, 89.37, 87.00, 79.61, 79.54, 77.15, 76.87, 74.80, 73.62,
72.53, 70.31, 63.56, 62.53, 61.45; HRMS (ESI): Calcd for
C
21H28IN3O11Na [MþNa]þ, 648.0666; Found, 648.0662.
CD3OD)
d
158.52, 140.73, 130.74, 124.29, 114.30, 94.67, 87.24, 77.19,
4.33. 1-(b-D-Glucopyranosyl)-4,5-dihydro-benzoxepino[4,5-
d]-1H-1,2,3-triazole (5g)
71.91, 63.73, 62.81; HRMS (ESI): Calcd for C14H17IN3O5 [MþH]þ,
434.0213; Found, 434.0208.
The title compound was synthesized from compound 3g
according to procedure C. Yield 96%, white solid: [
a
]
21 ꢁ48.0 (c 1.03,
D
4.29. 1-(2-Acetylamino-2-deoxy-b-D-glucopyranosyl)-4H-ben-
zopyrano[3,4-d]-1H-1,2,3-triazole (5e)
MeOH); 1H NMR (400 MHz, CD3OD)
d
7.89 (dd, J¼7.8, 1.3 Hz, 1H),
7.42 (dt, J¼7.8, 1.4 Hz, 1H), 7.32 (dt, J¼7.6, 1.1 Hz, 1H), 7.19 (dd, J¼8.0,
0.9 Hz, 1H), 5.37 (d, J¼9.0 Hz, 1H), 4.70e4.65 (m, 1H), 4.56e4.52 (m,
1H), 4.08e3.99 (m, 2H), 3.76e3.72 (m, 1H), 3.66e3.62 (m, 1H),
3.53e3.39 (m, 3H), 3.25e3.21 (m, 1H); 13C NMR (100 MHz, CD3OD)
The title compound was synthesized from compound 3e
according to procedure E. Yield 68%, white solid: [
a
]
21 ꢁ19.0 (c 0.58,
D
MeOH); 1H NMR (400 MHz, DMSO-d6)
d
7.98 (d, J¼7.3 Hz, 1H), 7.86
d
161.48, 131.72, 129.76, 125.71, 123.27, 120.23, 87.77, 81.17, 78.99,
(d, J¼8.6 Hz, 1H), 7.32 (dt, J¼8.0, 1.4 Hz, 1H), 7.09 (dt, J¼7.7, 1.0 Hz,
1H), 7.05 (dd, J¼8.2, 0.8 Hz, 1H), 6.01 (d, J¼9.9 Hz, 1H), 5.42 (d,
J¼13.3 Hz, 1H), 5.35e5.29 (m, 3H), 4.79 (t, J¼5.4 Hz, 1H), 4.18e4.09
(m, 1H), 3.77 (dd, J¼10.5, 5.8 Hz, 1H), 3.70e3.55 (m, 3H), 3.50e3.44
72.79, 72.59, 71.24, 62.75, 29.12; HRMS (ESI): Calcd for
C
16H19N3O6Na [MþNa]þ, 372.1172; Found, 372.1174.
4.34. 4-[2-(2-Iodophenoxy)ethyl]-1-(
1,2,3-triazole (6g)
b-D-glucopyranosyl)-1H-
(m,1H),1.56 (s, 3H); 13C NMR (100 MHz, DMSO-d6)
d 168.94,153.40,
139.44, 130.45, 128.03, 125.49, 122.32, 117.40, 114.24, 86.34, 80.16,
73.77, 69.58, 63.34, 60.34, 53.38, 22.58; HRMS (ESI): Calcd for
The title compound was synthesized from compound 4g
according to procedure C. Yield 67%, white solid: [
C
17H20N4O6Na [MþNa]þ, 399.1281; Found, 399.1264.
a
]
21 þ2.0 (c 0.80,
D
MeOH); 1H NMR (400 MHz, CD3OD)
d
8.23 (s, 1H), 7.75 (dd, J¼7.8,
4.30. 4-[(2-Iodophenoxy)methyl]-1-(2-acetylamino-2-deoxy-
-glucopyranosyl)-1H-1,2,3-triazole (6e)
1.5 Hz, 1H), 7.32 (dt, J¼8.5, 1.5 Hz, 1H), 6.95 (dd, J¼8.3, 0.9 Hz, 1H),
6.72 (dt, J¼7.7, 1.1 Hz, 1H), 5.59 (d, J¼9.2 Hz, 1H), 4.28e4.25 (m, 2H),
3.92e3.86 (m, 2H), 3.70 (dd, J¼12.1, 5.6 Hz, 1H), 3.60e3.54 (m, 2H),
3.48 (t, J¼9.4 Hz, 1H), 3.25 (t, J¼6.3 Hz, 2H); 13C NMR (100 MHz,
b-D
The title compound was synthesized from 4e0 according to
procedure F. Yield 66%, white solid: [
NMR (400 MHz, DMSO-d6)
a
]
21 ꢁ6.0 (c 0.90, pyridine); 1H
CD3OD) d 158.74, 140.58, 130.74, 124.11, 123.83, 113.50, 89.55, 86.96,
D
d
8.26 (s, 1H), 7.91 (d, J¼9.2 Hz, 1H), 7.77
81.09, 78.47, 74.09, 70.91, 69.00, 62.41, 26.83; HRMS (ESI): Calcd for
(dd, J¼7.7, 1.5 Hz, 1H), 7.36 (dt, J¼8.2, 1.5 Hz, 1H), 7.20 (dd, J¼8.3,
1.0 Hz, 1H), 6.77 (dt, J¼7.6, 1.2 Hz, 1H), 5.74 (d, J¼10.0 Hz, 1H), 5.30
(t, J¼5.7 Hz, 2H), 5.20 (s, 2H), 4.70 (t, J¼5.6 Hz, 1H), 4.14e4.06 (m,
1H), 3.71 (dd, J¼10.7, 5.9 Hz, 1H), 3.59e3.43 (m, 3H), 3.32e3.26 (m,
C
16H20IN3O6Na [MþNa]þ, 500.0294; Found, 500.0288.
4.35. 1-(b-D-Galactopyranosyl)-4,5-dihydro-benzoxepino[4,5-
d]-1H-1,2,3-triazole (5h)
1H), 1.61 (s, 3H); 13C NMR (100 MHz, DMSO-d6)
d 169.13, 156.61,
149.60, 142.12, 139.06, 129.72, 123.24, 122.99, 113.22, 86.60, 86.07,
80.18, 74.00, 69.95, 62.11, 60.60, 54.33, 22.71; HRMS (ESI): Calcd for
C
The title compound was synthesized from compound 3h
according to procedure C. Yield 88%, white solid: [
a]
21 ꢁ37.0 (c 0.81,
D
17H21IN4O6Na [MþNa]þ, 527.0403; Found, 527.0399.
MeOH); 1H NMR (400 MHz, CD3OD)
d
7.97 (dd, J¼7.8, 1.3 Hz, 1H),

4918
S.-T. Bai et al. / Tetrahedron 71 (2015) 4909e4919
7.41 (dt, J¼7.8, 1.4 Hz, 1H), 7.31 (dt, J¼7.7, 1.1 Hz, 1H), 7.18 (dd, J¼8.0,
1.0 Hz, 1H), 5.32 (d, J¼9.1 Hz, 1H), 4.86 (t, J¼9.2 Hz, 1H), 4.61e4.69
(m, 1H), 4.06 (dt, J¼11.3, 4.1 Hz, 1H), 4.00 (d, J¼3.2 Hz, 1H),
3.88e3.94 (m, 2H), 3.78e3.83 (m, 1H), 3.63 (dd, J¼9.5, 3.3 Hz, 1H),
3.39e3.47 (m, 1H), 3.23 (td, J¼17.0, 3.6 Hz, 1H); 13C NMR (100 MHz,
100
pounds in 60
8.3 Ci/mL methyl-
1/6 Mm methyl-
well plate and incubated at 37 ꢀC for 1 h. Then cells were washed
three times with 100 L of wash buffer (137 mM NaCl, 2.7 mM KCl,
10 mM Na2HPO4$12H2O, 2 mM KH2PO4), followed by solubilizing
with 50 L of 1& Triton-X 100 for 10 min. Their radioactivity was
m
L of sodium or sodium-free buffer for 30 min. Tested com-
L each of sodium or sodium-free buffer containing
-[Ue14C]glucopyranoside (Perkinelmer) and
- glucopyranoside was added per well of the 96-
m
m
a-D
a-D
CD3OD)
d
161.44, 131.62, 129.94, 125.73, 123.18, 120.29, 88.41, 80.13,
m
75.83, 72.78, 70.53, 69.79, 62.80, 29.15; HRMS (ESI): Calcd for
C
16H19N3O6Na [MþNa]þ, 372.1172; Found, 372.1166.
m
measured with a liquid scintillation counter by adding 150 mL of
scintillation solution (PerkineElmer 1450-023).
4.36. 4-[2-(2-Iodophenoxy)ethyl]-1-(b-D-galactopyranosyl)-
1H-1,2,3-triazole (6h)
Acknowledgements
The title compound was synthesized from compound 4h
according to procedure C. Yield 52%, white solid: [
a
]
21 þ4.0 (c 1.94,
D
This work was financially supported by the grants
(2012CB822100, 2013CB910700, 2012ZX09502001-001) from the
Ministry of Science and Technology of the People’s Republic of
China, and the National Natural Science Foundation of China
(21232002, 91213301).
MeOH); 1H NMR (400 MHz, CD3OD)
d
8.26 (s, 1H), 7.75 (dd, J¼7.8,
1.5 Hz, 1H), 7.32 (dt, J¼8.5, 1.5 Hz, 1H), 6.96 (dd, J¼8.2, 0.8 Hz, 1H),
6.72 (dt, J¼7.7, 1.1 Hz, 1H), 5.56 (d, J¼9.1 Hz, 1H), 4.28 (t, J¼6.3 Hz,
2H), 4.17 (t, J¼9.4 Hz, 1H), 3.98 (d, J¼3.0 Hz, 1H), 3.84e3.68 (m, 4H),
3.26 (t, J¼6.3 Hz, 2H); 13C NMR (100 MHz, CD3OD)
d 158.78, 140.58,
130.72, 123.85, 113.59, 90.30, 87.07, 79.89, 75.34, 71.44, 70.35, 69.01,
62.45, 26.85; HRMS (ESI): Calcd for C16H21IN3O6 [MþH]þ, 478.0475;
Found, 478.0474.
Supplementary data
Supplementary data related to this article can be found at http://
dx.doi.org/10.1016/j.tet.2015.05.108.
4.37. 4-[3-(2-Iodophenoxy)propyl]-1-(b-D-glucopyranosyl)-
1H-1,2,3-triazole (6i)
References and notes
The title compound was synthesized from compound 4i
according to procedure F. Yield 94%, white solid: [
a
]
21 ꢁ6.0 (c 1.27,
1. (a) Bouchie, A. Nat. Biotechnol. 2013, 31, 469e470; (b) Chemistry of C-glycosides;
Levy, W., Chang, D., Eds.; Elsevier: Cambridge, UK, 1995.
D
MeOH); 1H NMR (400 MHz, CD3OD)
d
8.01 (s, 1H), 7.74 (dd, J¼7.8,
2. Moreau, V.; Driguez, H. J. Chem. Soc., Perkin Trans. 1 1995, 525e527.
3. (a) Randell, K. D.; Johnston, B. D.; Pinto, B. M. Carbohydr. Res. 2000, 326,
145e150; (b) Renaudet, O.; Dumy, P. Tetrahedron 2002, 58, 2127e2135; (c) Peri,
1.3 Hz, 1H), 7.30 (dt, J¼8.4, 1.2 Hz, 1H), 6.91 (d, J¼7.8 Hz, 1H), 6.71
(dt, J¼7.4, 0.7 Hz, 1H), 5.58 (d, J¼9.2 Hz, 1H), 4.07 (t, J¼5.9 Hz, 2H),
3.91e3.86 (m, 2H), 3.71 (dd, J¼12.1, 5.1 Hz, 1H), 3.59e3.47 (m, 3H),
3.01 (t, J¼7.4 Hz, 2H), 2.22e2.15 (m, 2H); 13C NMR (100 MHz,
ꢀ
ꢁ
F.; Jimenez-Barbero, J.; García-Aparicio, V.; Tvaroska, I.; Nicotra, F. Chem.dEur. J.
2004, 10, 1433e1444; (d) Peri, F.; Marinzi, C.; Barath, M.; Granucci, F.; Urbano,
M.; Nicotra, F. Bioorg. Med. Chem. 2006, 14, 190e199.
4. (a) Lee, S.-B.; Park, K.-H.; Robyt, J. F. Carbohydr. Res. 2001, 331, 13e18; (b) Jacob,
G. S. Curr. Opin. Struct. Biol. 1995, 5, 605e611.
CD3OD)
d 158.83, 140.43, 130.70, 123.56, 113.41, 89.48, 87.04, 81.03,
78.44, 73.94, 70.83, 68.98, 62.34, 29.92, 23.05; HRMS (ESI): Calcd
5. (a) Yao, C. H.; Song, J. S.; Chen, C. T.; Yeh, T. K.; Hung, M. S.; Chang, C. C.; Liu, Y.
W.; Yuan, M. C.; Hsieh, C. J.; Huang, C. Y.; Wang, M. H.; Chiu, C. H.; Hsieh, T. C.;
Wu, S. H.; Hsiao, W. C.; Chu, K. F.; Tsai, C. H.; Chao, Y. S.; Lee, J. C. J. Med. Chem.
2011, 54, 166e178; (b) Nomura, S.; Yamamoto, Y.; Matsumura, Y.; Ohba, K.;
Sakamaki, S.; Kimata, H.; Nakayama, K.; Kuriyama, C.; Matsushita, Y.; Ueta, K.;
Tsuda-Tsukimoto, M. ACS Med. Chem. Lett. 2014, 5, 51e55.
for C17H23IN3O6 [MþH]þ, 492.0632; Found, 492.0628.
4.38. 4-[3-(2-Iodophenoxy)propyl]-1-(b-D-galactopyranosyl)-
1H-1,2,3-triazole (6j)
6. Bailey, C. J. Trends Pharmacol. Sci. 2011, 32, 63e71; (b) Mohler, M. L.; He, Y.; Wu,
Z.; Hwang, D. J.; Miller, D. D. Med. Res. Rev. 2009, 29, 125e195.
7. (a) Washburn, W. N. J. Med. Chem. 2009, 52, 1785e1794; (b) Ghosh, R. K.; Ghosh,
S. M.; Chawla, S.; Jasdanwala, S. A. J. Clin. Pharmacol. 2012, 52, 457e463; (c)
Jones, D. Nat. Rev. Drug Discov. 2011, 10, 645e646; (d) Kanwal, A. K.; Banerjee, S.
K. Pharm. Pat. Anal. 2013, 2, 77e91 and references cited therein.
8. Wijtmans, M.; de Graaf, C.; de Kloe, G.; Istyastono, E. P.; Smit, J.; Lim, H.;
Boonnak, R.; Nijmeijer, S.; Smits, R. A.; Jongejan, A.; Zuiderveld, O.; de Esch, I. J.;
Leurs, R. J. Med. Chem. 2011, 54, 1693e1703.
9. (a) Hooyberghs, G.; De Coster, H.; Vachhani, D. D.; Ermolat’ev, D. S.; Van der
Eycken, E. V. Tetrahedron 2013, 69, 4331e4337; (b) Li, Y.; Geng, J.; Liu, Y.; Yu, S.;
Zhao, G. ChemMedChem. 2013, 8, 27e41.
10. (a) Rostovtsev, V. V.; Green, L. G.; Fokin, V. V.; Sharpless, K. B. Angew. Chem., Int.
Ed. 2002, 41, 2596e2599; (b) Beletskaya, I. P.; Cheprakov, A. V. Coord. Chem. Rev.
2004, 248, 2337e2364.
The title compound was synthesized from compound 4j
according to procedure F. Yield 53%, white solid: [
a
]
21 þ9.0 (c 1.13,
D
MeOH); 1H NMR (400 MHz, CD3OD)
d
8.11 (s, 1H), 7.76 (dd, J¼7.8,
1.4 Hz, 1H), 7.31 (dt, J¼8.4, 1.5 Hz, 1H), 6.92 (d, J¼8.2 Hz, 1H), 6.71
(dt, J¼7.6, 1.1 Hz, 1H), 5.56 (d, J¼9.2 Hz, 1H), 4.14 (t, J¼9.5 Hz, 1H),
4.09 (t, J¼6.0 Hz, 2H), 3.98 (d, J¼3.1 Hz, 1H), 3.85e3.68 (m, 4H), 3.03
(t, J¼7.4 Hz, 2H), 2.24e2.17 (m, 2H); 13C NMR (100 MHz, CD3OD)
d
158.85, 140.45, 130.72, 123.58, 113.42, 90.34, 87.04, 79.94, 75.24,
71.42, 70.36, 68.95, 62.41, 29.88, 22.99; HRMS (ESI): Calcd for
C
17H22IN3O6Na [MþNa]þ, 514.0451; Found, 514.0453.
11. Cai, Q.; Yan, J.; Ding, K. Org. Lett. 2012, 14, 3332e3335.
4.39. Determination of SGLT2 inhibition rates of compounds
on cell based assay
12. Nagarjuna Reddy, M.; Kumara Swamy, K. C. Eur. J. Org. Chem. 2012, 2013e2022.
13. Ackermann, L.; Potukuchi, H. K. Org. Biomol. Chem. 2010, 8, 4503e4513.
14. Chen, Y.; Zhou, S.; Ma, S.; Liu, W.; Pan, Z.; Shi, X. Org. Biomol. Chem. 2013, 11,
8171e8174.
15. Schulman, J. M.; Friedman, A. A.; Panteleev, J.; Lautens, M. Chem. Commun. 2012,
55e57.
SGLT2 expressed NIH3T3 cells (2.5ꢃ105 cells per well in 100
mL
of medium) were seeded on 96-well ScintiPlates (PerkinElmer) in
high glucose DMEM containing 10% FBS and incubated at 37 ꢀC
under 5% CO2. After three days, the medium was replaced with
2 mM sodium butyrate. For the uptake assay, cells were washed
16. Salunke, S. B.; Babu, N. S.; Chen, C.-T. Chem. Commun. 2011, 10440e10442.
17. (a) Jeyachandran, R.; Potukuchi, H. K.; Ackermann, L. Beilstein J. Org. Chem. 2012,
ꢀ
8, 1771e1777; (b) Ackermann, L.; Jeyachandran, R.; Potukuchi, H. K.; Novak, P.;
€
Buttner, L. Org. Lett. 2010, 12, 2056e2059; (c) Ackermann, L.; Potukuchi, H. K.;
Landsberg, D.; Vicente, R. Org. Lett. 2008, 10, 3081e3084.
18. Hein, J. E.; Fokin, V. V. Chem. Soc. Rev. 2010, 39, 1302e1315.
19. Hiroki, H.; Ogata, K.; Fukuzawa, S.-i Synlett 2013, 843e846.
20. Gogoi, A.; Guin, S.; Rout, S. K.; Patel, B. K. Org. Lett. 2013, 15, 1802e1805.
21. Mizuno, M.; Shioiri, T.; Mizuno, M. Chem. Commun. 1997, 2165e2166.
22. Suzuki, T.; Suzuki, S. T.; Yamada, I.; Koashi, Y.; Yamada, K.; Chida, N. J. Org. Chem.
2002, 67, 2874e2880.
three times with 100 mL of either sodium buffer (137 mM NaCl,
5.4 mM KCl, 2.8 mM CaCl2, 1.2 mM MgCl2, 10 mM tris(hydrox-
ymethyl)-aminomethane/N-2-hydroxyethylpiperazine-N0- ethane
sulfonic acid [Tris/Hepes], pH 7.2) or sodium-free buffer (137 mM
NaCl N-methyl-glucamine, 5.4 mM KCl, 2.8 mM CaCl2, 1.2 mM
MgCl2, 10 mM Tris/Hepes, pH 7.2), followed by incubating with
23. Hachi2ya, I.; Kobayashi, S. Tetrahedron Lett. 1994, 35, 3319e3320.

S.-T. Bai et al. / Tetrahedron 71 (2015) 4909e4919
4919
24. (a) Wu, J. S.; Peng, Y. H.; Wu, J. M.; Hsieh, C. J.; Wu, S. H.; Coumar, M. S.; Song, J.
S.; Lee, J. C.; Tsai, C. H.; Chen, C. T.; Liu, Y. W.; Chao, Y. S.; Wu, S. Y. J. Med. Chem.
2010, 53, 8770e8774; (b) Xu, B.; Feng, Y.; Lv, B.; Xu, G.; Zhang, L.; Du, J.; Peng,
K.; Xu, M.; Dong, J.; Zhang, W.; Zhang, T.; Zhu, L.; Ding, H.; Sheng, Z.; Welihinda,
A.; Seed, B.; Chen, Y. Bioorg. Med. Chem. 2010, 18, 4422e4432; (c) Kakinuma, H.;
Oi, T.; Hashimoto-Tsuchiya, Y.; Arai, M.; Kawakita, Y.; Fukasawa, Y.; Iida, I.;
Hagima, N.; Takeuchi, H.; Chino, Y.; Asami, J.; Okumura-Kitajima, L.; Io, F.; Ya-
mamoto, D.; Miyata, N.; Takahashi, T.; Uchida, S.; Yamamoto, K. J. Med. Chem.
2010, 53, 3247e3261; (d) Lv, B.; Xu, B.; Feng, Y.; Peng, K.; Xu, G.; Du, J.; Zhang,
L.; Zhang, W.; Zhang, T.; Zhu, L.; Ding, H.; Sheng, Z.; Welihinda, A.; Seed, B.;
Chen, Y. Bioorg. Med. Chem. Lett. 2009, 19, 6877e6881.
25. Goodwin, N. C.; Mabon, R.; Harrison, B. A.; Shadoan, M. K.; Almstead, Z. Y.; Xie,
Y.; Healy, J.; Buhring, L. M.; DaCosta, C. M.; Bardenhagen, J.; Mseeh, F.; Liu, Q.;
Nouraldeen, A.; Wilson, A. G.; Kimball, S. D.; Powell, D. R.; Rawlins, D. B. J. Med.
Chem. 2009, 52, 6201e6204.
26. Bianchi, A.; Bernardi, A. J. Org. Chem. 2006, 71, 4565e4577.