Synthesis of Glycosyl Azides and Their Applications Using CuAAC Click Chemistry to Generate Bis- and Tris(triazolyl)glycosyl Derivatives

Article abstract of DOI:10.1055/s-0036-1589090

2,3-Unsaturated C -(triazolyl)glycosyl acetates have been synthesized from 3,4,6-tri- O -acetyl- d -glucal using C -glycosylation and click chemistry and were then used in a palladium-catalyzed Tsuji-Trost type allylic azidation reaction to afford the cor

Full text of DOI:10.1055/s-0036-1589090

SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
2017, 49, A–N
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A. Shamim et al.
Paper
Synthesis
Synthesis of Glycosyl Azides and Their Applications Using CuAAC
Click Chemistry to Generate Bis- and Tris(triazolyl)glycosyl Deriva-
tives
Anwar Shamima
Stanley N. S. Vasconcelosb
Isadora Maria de Oliveiraa
Joel S. Reisb
Daniel C. Pimentac
Julio Zukerman-Schpectord
Hélio A. Stefani*b
a Instituto de Química, Av. Prof. Lineu Prestes, 748,
05508-000, Universidade de São Paulo, São Paulo – SP,
Brasil
b Faculdade de Ciências Farmacêuticas, Av. Prof. Lineu
Prestes, 580, 05508-00, Universidade de São Paulo,
São Paulo – SP, Brasil
hstefani@usp.br
c Instituto Butantã, São Paulo – SP, Brasil
d Departamento de Química, Universidade Federal de São
Carlos, São Carlos –SP, Brasil
Received: 24.05.2017
Accepted after revision: 11.07.2017
Published online: 10.08.2017
a triazole ring, is well known and has been investigated by
many research groups.7 This process of linking two species
via CuAAC reaction has been used extensively for the syn-
thesis of important drugs, bioactive compounds, and vari-
ous other industrially and photophysically important com-
pounds.8 Being a type of click chemistry reaction, the
CuAAC reaction is fast, efficient, mild, and an easy process
to connect an azide-containing moiety with a terminal
alkyne in the presence of a copper catalyst to generate a
1,4-substituted 1,2,3-triazole compound. The bioisosteric
potential of the triazole ring makes it a key moiety for po-
tential exploration as a drug, as a linker of a drug with an-
other biocompatible moiety, or to enhance the effect of a
drug.9 The applications of triazole ring compounds in poly-
mer chemistry and nanochemistry are also numerous and
are continuing to gain importance.10
DOI: 10.1055/s-0036-1589090; Art ID: ss-2017-m0353-op
Abstract 2,3-Unsaturated C-(triazolyl)glycosyl acetates have been
synthesized from 3,4,6-tri-O-acetyl-D-glucal using C-glycosylation and
click chemistry and were then used in a palladium-catalyzed Tsuji–Trost
type allylic azidation reaction to afford the corresponding regioisomeric
glucal-azide derivatives. Copper-catalyzed azide-alkyne cycloaddition
(CuAAC) reactions with these glucal-based allylic azides using CuI as the
catalyst, led to the corresponding glucal-based bis(triazole) derivatives.
Performing further functional group modification and another click
(CuAAC) reaction with each of these bis(triazolyl) glycosyl derivatives
afforded tris(triazolyl)glycosyl derivatives. Two libraries of regioisomeric
bis(triazole) derivatives and a small library of regioisomeric tris(triazole)
derivatives of glucal were then synthesized using different alkynes.
Key words D-glucal, azide, click chemistry, bis(triazole), tris(triazole)
Based on these potential applications and the inspiring
properties of triazoles and especially glycosyl triazole de-
rivatives, we report herein various methods to synthesize
libraries of bis- and tris(triazolyl)glycosyl derivatives start-
ing from 3,4,6-tri-O-acetyl-D-glucal (1). We look forward to
investigating and reporting the biological properties of
these libraries of glycosyl triazoles in future work.
In connection with our recently reported work on the
synthesis of glucal-based triazoles, 2-alkynyl D-glucal de-
rivatives and other glycosyl derivatives,11 here we first syn-
thesized bis(triazole) derivatives of D-glucal starting from
3,4,6-tri-O-acetyl-D-glucal (1). This was followed by the
synthesis of tris(triazolyl)glycoside derivatives using func-
tional group modifications and the click (CuAAC) reaction.
The synthesis of the glucal-based bis(triazole) derivatives
involved a Ferrier rearrangement to obtain glucal alkynes 2,
Glucal-derived triazoles are important in carbohydrate-
based biochemistry and organic synthesis. They have been
found to have antibacterial,1 anticancer2 and antidiabetic3
properties. A few examples of biologically important glucal
derived triazoles include an α-glucosidase inhibitor (com-
pound A),4a an antibacterial (compound B),4b and two anti-
inflammatory compounds (compounds C and D)4c,d (Figure
1). Due to the biological importance of glucal-derived tri-
azoles, many research groups have designed syntheses of
glucal-derived triazoles using different glucal precursors
and applying the azide-alkyne cyclization reaction5 (click
reaction), as well as other syntheses.6
The remarkable property of the copper-catalyzed azide-
alkyne cycloaddition (CuAAC), the main ‘click’ reaction to
link a wide variety of potential compounds via formation of
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–N

B
A. Shamim et al.
Paper
Synthesis
Bn
NH
O
O
O
Bn
OH
O
N
OAc
N
O
N
N
HO
HO
O
N
O
O
AcO
AcO
N
NH
O
OAc
A
B
antibacterial
α-glucosidase inhibitor
AcO
AcO
OAc
O
N
N
O
N
N
N
S
O
N
N
O
AcO
AcO
O
N
OAc
O
D
C
anti-inflammatory activities
Figure 1 Selected biologically active glucal-based triazole compounds
and a click reaction to obtain the glycosyl-triazoles 3, as
previously reported.12 These glycosyl triazoles 3, bearing al-
lylic acetate functionality, were then subjected to palladi-
um-catalyzed Tsuji–Trost type allylic azidation to obtain re-
gioisomeric glucal-based allylic azides 4a and 4b (Scheme
1).
Three C-(triazolyl)glycosyl derivatives 3a–c were syn-
thesized using the reaction conditions summarized in Table
1. To optimize the amount of catalyst (CuI), some experi-
ments were performed using different amounts of CuI (Ta-
ble 1, entries 1–3). It was observed that the use of 7 mol% of
CuI resulted in higher yields, rather than less than 7 mol%,
which resulted in lower yields; however, using higher con-
centrations of CuI did not increase in the yields (entry 3).
Thus, 7 mol% of CuI was used in the rest of CuAAC reactions
in this work.
Use of flash column chromatography to separate the
two regioisomeric azides 4a and 4b was unsuccessful; fur-
thermore, the use of gas chromatography to determine the
regioisomeric ratio of the two regioisomeric azides 4a and
4b was also unsuccessful. Therefore, both of the regioiso-
meric azides were used in the next synthetic step, that is,
the copper-catalyzed azide-alkyne cycloaddition reaction.
The resultant pair of regioisomeric bis(triazolyl)glycosyl
derivatives were, however, separable via flash column chro-
matography. Thus, a library of bis(triazolyl)glycosyl deriva-
tives was synthesized; the products were purified using
flash column chromatography and were analyzed using
NMR, IR, and HRMS data (Table 2). A range of terminal
alkynes including alkyl, cycloalkyl, and aryl alkynes were
used with different substituted glycosyl azides in the pres-
TMS
BF3K (1.2 equiv)
O
TMS
TMS
AcO
AcO
BF3•OEt2 (1.2 equiv)
O
O
AcO
AcO
AcO
AcO
+
MeCN, 0 °C, 30 min
OAc
2:98
1
2
RN3 (1.2 equiv)
CuI ( 7 mol%)
TBAF ( 1.2 equiv)
DMF, 80 °C, 2 h
R
R
N
N
R
N
N
Pd(PPh3) (5 mol%)
O
O
N
N
N
AcO
AcO
+
N
O
N
NaN3 (1.2 equiv)
THF/H2O (7:3)
50 °C
AcO
AcO
N3
N3
4b
4a
3
Scheme 1 Synthesis of glucal-based allylic azide regioisomers from 3,4,6-tri-O-acetyl-D-glucal
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ence of CuI in DMF at 60 °C with the reaction time ranging
from 2 to 4 hours to obtain a library of glycosyl bis(triazole)
derivatives (Table 2).
The stereoselectivity of the palladium-catalyzed allylic
substitution reaction has been discussed in the literature
and it has been found to be influenced by the palladium
catalyst used, the solvent system, substituents on the allylic
system, the nature of the leaving group (LG), the nature and
concentration of nucleophile (Nu), and temperature.12 Un-
der normal reaction conditions, the commonly observed
Table 1 Synthesis of C-Glycosyl Triazole Derivatives 3a–c Using CuAAC Reaction
R
RN3 (1.2 equiv)
CuI
TMS
N
TBAF (1.2 equiv)
O
N
O
AcO
AcO
N
AcO
AcO
DMF, 80 °C
3a–c
Entry
CuI (mol%)
Azide (R–N3)
Product
Time (h)
Yield (%)a
N
N3
1
5
3
90
N
N
O
O
O
AcO
AcO
3a
N
2
7
2
95
N3
N
N
AcO
AcO
3a
N
3
10
2
95
N3
N
N
AcO
AcO
3a
O
N
4
7
2
91
O
N3
N
N
O
AcO
AcO
3b
N
N
S
S
N
5
7
3
89
N
N
O
N3
AcO
AcO
3c
a Isolated yields.
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product is the allylic regioisomer that has the new nucleo-
phile added to the same position from where the leaving
group departed. In most cases in this work, we also ob-
served retention of configuration at C-4 in the bis(tri-
azolyl)glycosyl products (Table 2, entries 1–6). However, in
one case (entry 8) where higher temperatures and larger
amounts of sodium azide (2.5 equiv) were used, it was ob-
served that the products also included a regioisomer with
inversion of configuration at C-4, as confirmed by single-
crystal X-ray diffraction (Figure 2). It is important to men-
tion here that as we could not isolate the azide products, so
our observations for the stereochemistry of the Tsuji–Trost
azidation reaction are based on the bis(triazolyl) products.
Table 2 Synthesis of Bis(triazole) Glycosyl Derivatives via Click Reaction with Glucal Azides
R
R
N
N
OAc
OAc
N
N
N
O
O
N
N
R
N
N3
N
OAc
N
N
4a
N
R
R
O
Pd(PPh3)4
(5 mol%)
N
+
R' (1.2 equiv)
CuI (7 mol%)
N
R'
N
OAc
OAc
N
N
N
5a
O
+
O
N
N
N
NaN3 (1.3 equiv)
THF/H2O (3:1)
50 °C, 2–4 h
DMF, 60 °C, 2–5 h
R
5c
N3
AcO
R'
N
OAc
R
4b
+
3
N
N
O
OAc
N3
N
N
O
N
N
N
R'
N
4c
5b
Entry Glucal azide (R)
1
Alkyne
Product
a:b:c
Yield
(%)a
79
N
N
O
N
N
AcO
N
N
O
N
AcO
N
N
N
N
N
5b-1
5a-1
60:40
2
77
N
N
N
O
N
N
O
AcO
N
N
AcO
N
N
N
N
N
5b-2
5a-2
60:40
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Table 2 (continued)
Entry Glucal azide (R)
Alkyne
Product
a:b:c
Yield
(%)a
3
81
O
O
N
N
O
N
N
AcO
F
N
O
N
N
AcO
O
N
F
N
F
F
N
N
N
F
5b-3
F
5a-3
69:31
4
78
O
O
N
N
N
O
N
AcO
N
O
O
N
AcO
N
N
N
N
N
N
5b-4
5a-4
58:42
5
76
N
N
S
N
N
S
O
N
N
AcO
N
N
N
S
O
N
AcO
N
N
N
N
N
5b-5
5a-5
70:30
6b
75
O
O
N
AcO
AcO
N
OAc
OAc
N
O
N
O
O
O
OAc
OAc
N
N
AcO
TMS
O
O
AcO
N
N
N
N
N
N
5a-6
5b-6
68:32
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Table 2 (continued)
Entry Glucal azide (R)
Alkyne
Product
a:b:c
Yield
(%)a
7
82
N
N
OAc
N
N
O
O
N
N
AcO
N
N
N
N
N
N
5b-7
5a-7
61:39
8
80c
N
N
N
N
N
N
O
O
N
N
N
AcO
N
AcO
O
AcO
N
N
N
N
N
N
N
N
5b-8
5a-8
5c-8
24:42:34
a Isolated combined yield (for the two steps) of the regioisomers.
b Tetrabutylammonium fluoride (TBAF, 1.3 equiv) was used in the cycloaddition step to remove the trimethylsilyl group.
c Reflux conditions (in the azidation step) and a larger amount (2 to 2.5 equiv) of NaN3 were used.
this feature of the reactions could be used as an opportuni-
ty to make the epimers of such compounds by varying the
temperature and/or concentration.
Based on the isolated yields of the bis(triazolyl)glycosyl
products, the ratio of regioisomer a to b was roughly 3:2
and was in accordance with literature precedent.13 As we
were interested in both of the regioisomers of the bis(tri-
azolyl)glycosyl compound, we did not explore other palla-
dium catalysts or attempted to use ligands to improve the
regioselectivity as reported by several groups.14 The struc-
ture of each bis(triazolyl)glycoside was confirmed by the
COSY NMR analysis of both or one of the regioisomers of
each pair (SI) and with the XRD analysis of 5c-8, and in
some cases with the coupling constants.
Figure 2 The crystal structure of compound 5c-8
The synthetic scope of these bis(triazolyl)glycosyl deriv-
atives was explored using 5a-1 and 5b-1 as representative
compounds to synthesize tris(triazolyl)glycosyl compounds
9. This process consisted of functional group modification
including base-catalyzed transesterification, mesylation,
and nucleophilic azidation. In the first step, methoxide-cat-
alyzed transesterification of the acetate group of 5a-1 and
5b-1 was used to synthesize the corresponding hydroxyl
derivatives 6a and 6b respectively. Mesylation of the hy-
droxy group of each of the two products 6a and 6b was
then performed, generating the corresponding mesylate de-
The compound 5c-8 (Table 2, entry 8) is an epimer of
5a-8 with the opposite (inversion of) configuration at C-4 of
the glycosyl ring. The changed reaction conditions sup-
pressed the formation of the epimer 5a-8. To avoid this
complication, the temperature was kept at 50 °C in the azi-
dation reaction and 60 °C in the CuAAC reaction, compara-
tively lesser quantities of sodium azide (1.2 equiv) were
used, and the reaction was quenched as soon as the starting
material disappeared (TLC monitoring). On the other hand,
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N
N
N
N
N
N
OAc
O
OH
O
OMs
N3
N
N
N
N
N
N
O
O
NaN3 (3 equiv)
N
K2CO3 (10 mol%)
N
MsCl (1.2 equiv)
N
N
N
N
DMF, 80 °C, 4 h
N
MeOH, r.t., 2 h
CH2Cl2, Et3N, 0 °C, 1 h
N
N
N
N
N
(95%)
(92%)
(90%)
5b-1
6b
7b
8b
Note: The same steps were performed for compound 5a-1 to obtain the corresponding products 6a, 7a and 8a respectively.
Scheme 2 Synthesis of glycosyl azides from the corresponding glucal acetates via functional group transformations
rivatives 7a and 7b, respectively, followed by azidation of
the mesyl group in each case to afford the azide products 8a
and 8b (Scheme 2). For simplicity, in Scheme 2 these steps
have been represented with only the 5b-1 but the same was
performed for 5a-1. The yields of these reactions were ex-
cellent and the products in most of the cases did not need
purification via flash column chromatography.
same above-mentioned reaction conditions but with differ-
ent alkynes to synthesize a small library of tris(tri-
azolyl)glycosyl derivatives 9a–d. It appeared that the pres-
ence of triazole rings in compounds 8a and 8b did not in-
hibit the catalysis by CuI in the CuAAC reaction as indicated
by the yields of the tris(triazolyl)glycoside products 9a–d
(Table 3).
Once the two glycosyl azides 8a and 8b were synthe-
sized, they were used in another CuAAC reaction using the
Table 3 Synthesis of Tris(triazolyl)glycosyl Derivatives Using CuAAC Reactionsa
R''
R''
N
N
N
N
R'' (1.2 equiv)
N
N
N
N
N
N
N
N3
N
N3
N
N
CuI (7 mol%)
PMDETA (1.3 equiv)
N
N
N
N
O
O
O
O
N
N
N
N
or
or
N
N
N
N
N
N
DMF, 80 °C, 3 h
N
N
8a
8b
9a–d
Entry
Azide
Alkyne
Product
Yield (%)b
N
N
N
N
N
N
O
N
1
8b
85
N
N
9a
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Table 3 (continued)
Entry
Azide
Alkyne
Product
Yield (%)b
N
N
N
N
N
N
O
N
2
8b
94
92
89
N
N
9b
OAc
AcO
O
N
N
OAc
N
N
N
N
8bc
O
3
O
N
AcO
TMS
N
N
9c
N
N
N
N
N
O
N
4
8a
N
N
N
9d
a PMDETA:
Pentamethyldiethylenetriamine.
b Isolated yield.
c TBAF (1.2 equiv) was used to deprotect the TMS group.
In conclusion, libraries of regioisomeric bis(tri-
azolyl)glycosyl derivatives have been synthesized starting
from 3,4,6-tri-O-acetyl-D-glucal and using a click (CuAAC)
reaction, Tsuji–Trost type azidation, and functional group
transformations. The reactions tolerated the presence of
aryl, hetero-aryl, alkyl, and cycloalkyl groups. Further syn-
thetic evaluations of these bis(triazolyl)glycosyl derivatives
were done by performing functional groups transforma-
tions and another click (CuAAC) reaction to obtain a small
library of tris(triazolyl)glycosyl derivatives in very good to
excellent yields. It was also observed that in some products
more glucal units can be installed to generate polymeric
structures that may have applications in future studies.
Proton nuclear magnetic resonance spectra (1H NMR) were obtained
at 300 MHz. Spectra were recorded in chloroform-d solutions, some
of them in DMSO-d6. Chemical shifts are reported in ppm, referenced
to the solvent peak of chloroform-d or tetramethylsilane (TMS) as the
external reference. Data are reported as follows: chemical shift (δ),
multiplicity, coupling constant (J) in Hertz and integrated intensity.
Carbon-13 nuclear magnetic resonance spectra (13C NMR) were ob-
tained at 75 MHz. Spectra were recorded in chloroform-d solutions,
some of them in DMSO-d6. Chemical shifts are reported in ppm, ref-
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Synthesis
erenced to the solvent peak of chloroform-d or DMSO-d6. Abbrevia-
tions to denote the multiplicity of a particular signal are s (singlet), d
(doublet), t (triplet), q (quartet), quint (quintet), sex (sextet) and m
(multiplet). Column chromatography was performed using silica gel
(230–400 mesh). High resolution mass spectra were obtained using a
high-resolution ESI-TOF mass spectrometer Shimadzu LCMS-IT-TOF
using methanol as solvent, analysis was done in ESI+ and ESI–, with
50% solution of acetonitrile\H2O and 0.1% formic acid. Thin layer chro-
matography (TLC) was performed using silica gel UV254, 0.20 mm
thickness. For visualization, TLC plates were either placed under ul-
traviolet light, or stained with iodine or acidic vanillin solution. Tetra-
hydrofuran was dried from sodium with a benzophenone indicator
and purified by distillation. All other solvents were ACS or HPLC grade
unless otherwise noted. Air- and moisture-sensitive reactions were
conducted in flame-dried or oven-dried glassware equipped with
tightly fitted rubber septa and under a positive atmosphere of dry ni-
trogen. Reagents and solvents were handled using standard syringe
techniques.
HRMS (ESI): m/z calcd for C24H23N6O3 [M + H]+: 443.1832; found:
443.1795.
[(2S,5R,6S)-5-(4-Phenyl-1H-1,2,3-triazol-1-yl)-6-(1-phenyl-1H-
1,2,3-triazol-4-yl)-5,6-dihydro-2H-pyran-2-yl]methyl Acetate (5b-1)
Yield: 70 mg (32%); yellow solid; mp 63–65 °C.
IR (film): 1737, 1601, 1505, 1439, 1367, 1231, 1078, 1046, 909, 728,
703, 693 cm–1
.
1H NMR (300 MHz, CDCl3): δ = 8.12 (s, 1 H), 8.08 (s, 1 H), 7.81 (d, J =
7.8 Hz, 2 H), 7.71 (d, J = 8.7 Hz, 2 H), 7.55–7.27 (m, 6 H), 6.32 (d, J =
10.5 Hz, 1 H), 6.15 (d, J = 10.4 Hz, 1 H), 5.98 (s, 1 H), 5.46 (d, J = 4.1 Hz,
1 H), 4.59 (dd, J = 11.8, 5.8 Hz, 1 H), 4.49 (dd, J = 5.7, 2.9 Hz, 1 H), 4.22
(dd, J = 11.8, 3.2 Hz, 1 H), 2.11 (s, 3 H).
13C NMR (75 MHz, CDCl3): δ = 170.70, 147.59, 143.98, 136.71, 130.55,
130.35, 129.80 (2 C), 129.06, 128.81 (2 C), 128.17, 125.71 (2 C),
124.75, 121.74, 120.59 (2 C), 119.93, 69.74 (2 C), 64.41, 55.22, 20.94.
HRMS (ESI): m/z calcd for C24H23N6O3 [M + H]+: 443.1832; found:
443.1792.
The glycosyl-triazoles 3 were prepared as previously reported.12
Bis- and Tris(triazolyl)glycosyl Derivatives 5a, 5b, and 9a–d; Gen-
eral Procedure
[(2S,3S,6S)-3-(4-Butyl-1H-1,2,3-triazol-1-yl)-6-(1-phenyl-1H-1,2,3-
triazol-4-yl)-3,6-dihydro-2H-pyran-2-yl]methyl Acetate (5a-2)
A single-necked round-bottom flask equipped with a magnetic stirrer
bar and a reflux condenser was charged with Pd(PPh3)4 (5 mol%) and
allylic acetate 3 (0.5 mmol), THF/H2O (7:3), and NaN3 (1.1 equiv). The
reaction mixture was then heated at 50 °C for 1–2 h with magnetical-
ly mediated stirring. The color of the mixture changed from yellow to
brown as the reaction progressed to completion and TLC was used to
monitor the reaction. When the reaction was complete, sat. aq NH4Cl
(25 mL) was added followed by extraction with EtOAc (3 × 20 mL). The
organic phases were combined, dried (MgSO4), filtered, and the sol-
vent was removed by rotary evaporation. The mixture of the two
products was passed through a flash chromatographic column (hex-
ane/EtOAc 1:1) to remove any residual ligands and side products. A
two-necked round-bottom flask equipped with a magnetic stirrer bar
and a reflux condenser was charged with the mixture of azides 4, the
terminal alkyne (1.2 equiv), CuI (7 mol%), and DMF (5 mL). For the
preparation of 9, PMDETA (1.3 equiv) was added. The reaction mix-
ture was then heated at 60 °C for 2–5 h (80 °C for 3 h for 9) with mag-
netically mediated stirring. When the reaction was complete, sat. aq
NH4Cl (25 mL) was added followed by extraction with EtOAc (3 × 20
mL). The organic phases were combined, dried (MgSO4), filtered, and
the solvent was removed by rotary evaporation. The products were
purified by flash column chromatography using hexane and EtOAc as
eluents (50–80% EtOAc/hexane) (Tables 2, 3).
Yield: 98 mg (47%); colorless oil.
IR (film): 3134, 3077, 2933, 2959, 1739, 1601, 1506, 1374, 1235,
1048, 763, 735 cm–1
.
1H NMR (300 MHz, CDCl3): δ = 8.11 (s, 1 H), 7.76 (d, J = 8.1 Hz, 2 H),
7.59–7.45 (m, 4 H), 6.46 (dt, J = 10.2, 2.8 Hz, 1 H), 6.10 (dt, J = 10.2, 2.5
Hz, 1 H), 5.71 (d, J = 2.7 Hz, 1 H), 5.36 (dt, J = 7.8, 2.5 Hz, 1 H), 4.24 (dt,
J = 8.0, 4.2 Hz, 1 H), 4.15 (d, J = 5.4 Hz, 2 H), 2.71 (t, J = 7.8 Hz, 3 H),
2.06 (s, 3 H), 1.65 (pent, J = 7.6 Hz, 3 H), 1.38 (hept, J = 7.3 Hz, 3 H),
0.92 (t, J = 7.3 Hz, 4 H).
13C NMR (75 MHz, CDCl3): δ = 170.57, 148.91, 146.21, 136.83, 130.42,
129.89 (2 C), 129.10, 124.41, 120.92, 120.60 (2 C), 119.90, 71.13,
67.18, 62.82, 54.39, 31.51, 25.42, 22.36, 20.77, 13.80.
HRMS (ESI): m/z calcd for C24H23N6O3 [M + H]+: 423.2145; found:
423.2105.
[(2S,5R,6S)-5-(4-Butyl-1H-1,2,3-triazol-1-yl)-6-(1-phenyl-1H-
1,2,3-triazol-4-yl)-5,6-dihydro-2H-pyran-2-yl]methyl Acetate (5b-
2)
Yield: 65 mg (31%); light yellow oil.
IR (film): 3146, 2952, 2935, 2874, 1737, 1601, 1506, 1378, 1235,
1086, 1046, 763, 735, 694 cm–1
.
1H NMR (300 MHz, CDCl3): δ = 8.04 (s, 1 H), 7.72 (d, J = 7.8 Hz, 2 H),
7.60–7.41 (m, 4 H), 6.28 (dd, J = 8.5, 1.7 Hz, 1 H), 6.12 (d, J = 10.4 Hz, 1
H), 5.86 (s, 1 H), 5.37 (d, J = 4.2 Hz, 1 H), 4.57 (dd, J = 11.6, 6.0 Hz, 1 H),
4.49 (s, 1 H), 4.20 (dd, J = 11.7, 2.8 Hz, 1 H), 2.69 (t, J = 7.6 Hz, 2 H),
2.12 (s, 3 H), 1.63 (pent, J = 7.6 Hz, 2 H), 1.34 (hept, J = 7.2 Hz, 3 H),
0.90 (t, J = 7.4 Hz, 4 H).
[(2S,3S,6S)-3-(4-Phenyl-1H-1,2,3-triazol-1-yl)-6-(1-phenyl-1H-
1,2,3-triazol-4-yl)-3,6-dihydro-2H-pyran-2-yl]methyl Acetate (5a-
1)
Yield: 105 mg (47%); white solid; mp 59–61 °C.
IR (film): 1737, 1600, 1505, 1367, 1229, 1045, 910, 761, 728, 693 cm–1
.
13C NMR (75 MHz, CDCl3): δ = 170.68, 148.21, 144.14, 136.74, 129.91,
129.82 (2 C), 129.08, 125.05, 121.59, 120.77, 120.60 (2 C), 69.84,
69.68, 64.41, 55.12, 31.52, 25.42, 22.29, 20.90, 13.78.
HRMS (ESI): m/z calcd for C24H23N6O3 [M + H]+: 423.2145; found:
423.2098.
1H NMR (300 MHz, CDCl3): δ = 8.16 (s, 1 H), 8.11 (s, 1 H), 7.83 (d, J =
8.8 Hz, 2 H), 7.75 (d, J = 9.1 Hz, 2 H), 7.53 (t, J = 7.5 Hz, 2 H), 7.48–7.37
(m, 3 H), 7.31 (t, J = 7.5 Hz, 1 H), 6.50 (d, J = 10.2 Hz, 1 H), 6.15 (d, J =
10.3 Hz, 1 H), 5.73 (s, 1 H), 5.45 (d, J = 7.6 Hz, 1 H), 4.32 (dt, J = 7.8, 4.4
Hz, 1 H), 4.21 (d, J = 4.4 Hz, 2 H), 2.04 (s, 3 H).
13C NMR (75 MHz, CDCl3): δ = 170.53, 148.08, 146.11, 136.78, 130.92,
130.32, 129.88, 129.86, 129.08, 128.84 (2 C), 128.27, 125.73 (2 C),
124.00, 121.06, 120.59, 120.54, 119.15, 71.27, 67.09, 62.80, 54.67.
20.74.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–N

J
A. Shamim et al.
Paper
Synthesis
{(2S,3S,6S)-3-[4-(2,4-Difluorophenyl)-1H-1,2,3-triazol-1-yl]-6-[1-
(4-methoxyphenyl)-1H-1,2,3-triazol-4-yl]-3,6-dihydro-2H-pyran-
2-yl}methyl Acetate (5a-3)
IR (film): 3138, 3088, 2941, 1739, 1520, 1441, 1253, 1229, 1082,
1039, 836, 728 cm–1
.
1H NMR (300 MHz, CDCl3): δ = 7.94 (s, 1 H), 7.57 (d, J = 9.0 Hz, 2 H),
7.42 (s, 1 H), 6.96 (d, J = 9.0 Hz, 2 H), 6.44–6.29 (m, 1 H), 5.99 (dd, J =
10.2, 2.2 Hz, 1 H), 5.60 (d, J = 2.3 Hz, 1 H), 5.25 (dd, J = 7.7, 2.4 Hz, 1 H),
4.17–4.10 (m, 1 H), 4.10–4.02 (m, 2 H), 3.80 (s, 3 H), 1.97 (s, 3 H),
1.92–1.76 (m, 1 H), 0.92–0.81 (m, 2 H), 0.84–0.61 (m, 2 H).
13C NMR (75 MHz, CDCl3): δ = 170.50, 160.07, 145.97, 132.09, 130.53,
130.25, 124.27, 122.23, 121.04, 114.90, 71.05, 67.18, 62.85, 55.65,
54.46, 20.71, 7.76, 7.72, 6.73.
Yield: 142 mg (56%); pale yellow oil.
IR (film): 3153, 3082, 2963, 1743, 1628, 1601, 1521, 1493, 1257,
1235, 1041, 808, 737 cm–1
.
1H NMR (300 MHz, CDCl3): δ = 8.16 (dd, J = 15.2, 8.4 Hz, 1 H), 7.90 (d,
J = 3.5 Hz, 1 H), 7.39 (d, J = 8.8 Hz, 2 H), 7.16 (s, 1 H), 7.07–6.80 (m, 4
H), 6.49–6.36 (m, 1 H), 6.32 (d, J = 10.3 Hz, 1 H), 5.71 (s, 1 H), 5.56 (s, 1
H), 4.91 (d, J = 2.9 Hz, 1 H), 4.54 (dd, J = 12.0, 7.1 Hz, 1 H), 4.30 (dd, J =
12.1, 3.2 Hz, 1 H), 3.81 (s, 3 H), 2.12 (s, 3 H).
HRMS (ESI): m/z calcd for C22H25N6O4 [M + H]+: 437.1937; found:
13C NMR (75 MHz, CDCl3): δ = 171.35, 170.72, 159.86, 131.12, 130.19,
128.81, 124.38, 122.32, 120.14, 114.64, 112.14, 112.07, 111.84,
111.80, 104.43, 104.08, 103.75, 72.43, 68.55, 63.57, 55.72, 55.58,
20.88.
437.1693.
{(2S,3S,6S)-6-[1-(Benzo[d]thiazol-7-yl)-1H-1,2,3-triazol-4-yl]-3-(4-
phenyl-1H-1,2,3-triazol-1-yl)-3,6-dihydro-2H-pyran-2-yl}methyl
Acetate (5a-5)
HRMS (ESI): m/z calcd for C25H23F2N6O4 [M + H]+: 509.1749; found:
Yield: 133 mg (53%); white solid; mp 189–191 °C.
509.1697.
IR (film): 3136, 3080, 2954, 1739, 1609, 1486, 1369, 1233, 1046, 816,
{(2S,5R,6S)-5-[4-(2,4-Difluorophenyl)-1H-1,2,3-triazol-1-yl]-6-[1-
(4-methoxyphenyl)-1H-1,2,3-triazol-4-yl]-5,6-dihydro-2H-pyran-
2-yl}methyl Acetate (5b-3)
698 cm–1
.
1H NMR (300 MHz, CDCl3): δ = 9.08 (s, 1 H), 8.36 (s, 1 H), 8.23 (dd, J =
16.4, 8.8 Hz, 2 H), 8.09 (s, 1 H), 7.89–7.76 (m, 3 H), 7.42–7.28 (m, 3 H),
6.40–6.27 (m, 1 H), 6.21–6.11 (m, 1 H), 5.99 (s, 1 H), 5.49 (d, J = 4.1 Hz,
1 H), 4.61 (dd, J = 11.7, 5.9 Hz, 1 H), 4.53 (s, 1 H), 4.23 (d, J = 11.1 Hz, 1
H), 2.10 (s, 3 H).
Yield: 64 mg (25%); light brown oil.
IR (film): 3144, 2956, 1739, 1601, 1562, 1520, 1493, 1229, 1039, 834,
734 cm–1
.
13C NMR (75 MHz, CDCl3): δ = 175.37, 161.30, 157.88, 152.11, 149.02,
139.82, 139.04, 135.60, 135.34, 133.60 (3 C), 132.93, 130.39 (2 C),
129.20, 129.07, 127.26, 124.78, 124.03, 119.01, 74.70, 74.26, 69.26,
60.08, 25.66.
1H NMR (300 MHz, CDCl3): δ = 8.36–8.18 (m, 1 H), 8.12 (s, 1 H), 8.02
(s, 1 H), 7.65 (d, J = 8.6 Hz, 2 H), 7.04 (d, J = 7.7 Hz, 3 H), 6.89 (t, J = 9.0
Hz, 1 H), 6.52 (d, J = 9.9 Hz, 1 H), 6.16 (d, J = 10.2 Hz, 1 H), 5.74 (s, 1 H),
5.45 (dd, J = 4.8, 2.2 Hz, 1 H), 4.32 (d, J = 4.1 Hz, 1 H), 4.22 (d, J = 3.6 Hz,
2 H), 3.88 (s, 3 H), 2.07 (s, 3 H).
HRMS (ESI): m/z calcd for C25H22N7O3S [M + H]+: 500.1505; found:
13C NMR (75 MHz, CDCl3): δ = 170.52, 160.06, 145.94, 140.87, 132.69,
131.25, 130.27, 128.83, 123.66, 122.99, 122.29, 121.71, 121.55,
120.89, 120.71, 114.90, 114.86, 112.19, 112.15, 111.91, 111.86,
104.48, 104.14, 103.80, 71.31, 67.29, 62.73, 55.66, 54.71, 20.73.
500.1453.
{(2S,5R,6S)-6-[1-(Benzo[d]thiazol-7-yl)-1H-1,2,3-triazol-4-yl]-5-
(4-phenyl-1H-1,2,3-triazol-1-yl)-5,6-dihydro-2H-pyran-2-yl}ethyl
Acetate (5b-5)
HRMS (ESI): m/z calcd for C25H23F2N6O4 [M + H]+: 509,1749; found:
Yield: 57 mg (23%); pale yellow gummy solid.
509.1708.
IR (film): 3136, 3069, 2965, 1739, 1480, 1439, 1372, 1233, 1046, 767,
{(2S,3S,6S)-3-(4-Cyclopropyl-1H-1,2,3-triazol-1-yl)-6-[1-(4-meth-
oxyphenyl)-1H-1,2,3-triazol-4-yl]-3,6-dihydro-2H-pyran-2-
yl}methyl Acetate (5a-4)
698 cm–1
.
1H NMR (300 MHz, CDCl3): δ = 8.37 (s, 1 H), 8.20 (d, J = 8.8 Hz, 1 H),
8.09 (s, 1 H), 7.91 (s, 1 H), 7.80 (dd, J = 11.5, 4.3 Hz, 3 H), 7.41–7.17 (m,
4 H), 6.62 (dd, J = 10.0, 3.1 Hz, 1 H), 6.36–6.21 (m, 1 H), 5.79 (s, 1 H),
5.29 (d, J = 3.6 Hz, 1 H), 4.59 (dd, J = 11.7, 5.9 Hz, 1 H), 4.50 (s, 1 H),
4.22 (dd, J = 11.7, 2.7 Hz, 1 H), 1.87 (s, 4 H).
Yield: 99 mg (45%); pale yellow oil.
IR (film): 3144, 3088, 2959, 1739, 1520, 1443, 1255, 1231, 1041, 836,
732 cm–1
.
13C NMR (75 MHz, CDCl3): δ = 170.18, 155.98, 147.90, 146.14, 134.34,
132.31, 130.50, 128.83 (2 C), 128.23, 125.75 (2 C), 124.76, 123.45,
121.02, 119.61, 119.19, 114.32, 69.18, 68.33, 62.71, 53.65, 20.64.
HRMS (ESI): m/z calcd for C25H22N7O3S [M + H]+: 500.1505; found:
500.1461.
1H NMR (300 MHz, CDCl3): δ = 7.96 (s, 1 H), 7.61 (d, J = 8.6 Hz, 2 H),
7.53 (s, 1 H), 7.01 (d, J = 8.5 Hz, 2 H), 6.25 (d, J = 10.1 Hz, 1 H), 6.10 (d,
J = 10.4 Hz, 1 H), 5.82 (s, 1 H), 5.35 (d, J = 2.8 Hz, 1 H), 4.54 (dd, J =
11.5, 5.8 Hz, 1 H), 4.46 (s, 1 H), 4.21 (d, J = 11.5 Hz, 1 H), 3.86 (s, 3 H),
2.13 (s, 3 H), 2.01–1.84 (m, 1 H), 0.92 (d, J = 8.2 Hz, 2 H), 0.82 (s, 2 H).
13C NMR (75 MHz, CDCl3): δ = 170.62, 160.05, 143.89, 130.18, 130.14,
124.83, 122.23 (3 C), 121.65, 119.91, 114.83 (2 C), 69.84, 69.57, 64.50,
55.64, 55.02, 20.87, 7.63, 7.57, 6.72.
HRMS (ESI): m/z calcd for C22H25N6O4 [M + H]+: 437.1937; found:
437.1687.
[(2R,3S,6S)-3-Acetoxy-6-(1-{(2S,3S,6S)-2-(acetoxymethyl)-6-[1-(4-
methoxyphenyl)-1H-1,2,3-triazol-4-yl]-3,6-dihydro-2H-pyran-3-
yl}-1H-1,2,3-triazol-4-yl)-3,6-dihydro-2H-pyran-2-yl]methyl Ace-
tate (5a-6)
Yield: 147 mg (51%); light yellow gummy solid.
{(2S,5R,6S)-5-(4-Cyclopropyl-1H-1,2,3-triazol-1-yl)-6-[1-(4-meth-
oxyphenyl)-1H-1,2,3-triazol-4-yl]-5,6-dihydro-2H-pyran-2-
yl}methyl Acetate (5b-4)
IR (film): 3140, 3115, 2957, 1739, 1600, 1503, 1372, 1231, 1045, 762,
690 cm–1
.
Yield: 71 mg (33%); colorless oil.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–N

K
A. Shamim et al.
Paper
Synthesis
1H NMR (300 MHz, CDCl3): δ = 7.94 (s, 1 H), 7.76 (s, 1 H), 7.64 (d, J =
8.0 Hz, 2 H), 7.05 (d, J = 8.8 Hz, 2 H), 6.67 (dd, J = 10.0, 3.4 Hz, 1 H),
6.42–6.21 (m, 2 H), 5.99 (d, J = 8.6 Hz, 1 H), 5.78 (s, 1 H), 5.53 (s, 1 H),
5.34 (d, J = 4.2 Hz, 2 H), 4.43 (s, 1 H), 4.31–4.05 (m, 4 H), 3.95–3.80 (m,
4 H), 2.09 (s, 6 H), 1.97 (s, 3 H).
1H NMR (300 MHz, CDCl3): δ = 8.07 (s, 1 H), 7.94 (s, 1 H), 7.73 (t, J = 9.0
Hz, 4 H), 7.61–7.41 (m, 3 H), 7.22 (t, J = 6.9 Hz, 2 H), 6.68 (dd, J = 10.0,
2.9 Hz, 1 H), 6.32 (dd, J = 9.8, 5.6 Hz, 1 H), 5.83 (s, 1 H), 5.33 (d, J = 3.2
Hz, 1 H), 4.43 (s, 1 H), 4.31 (dd, J = 7.3, 4.3 Hz, 1 H), 4.21 (d, J = 4.2 Hz,
1 H), 2.37 (s, 3 H), 1.93 (s, 3 H).
13C NMR (75 MHz, CDCl3): δ = 170.78, 170.34, 170.06, 160.15, 146.33,
145.47, 132.56, 130.20, 129.52, 125.85, 123.12, 122.24 (2 C), 122.01,
120.61, 114.92 (2 C), 69.64, 69.01, 68.33, 67.69, 64.97, 63.06, 62.55,
55.65, 53.63, 21.02, 20.72, 20.62.
13C NMR (75 MHz, CDCl3): δ = 170.16, 147.95, 145.85, 138.03, 136.84,
132.36, 129.88 (2 C), 129.51 (2 C), 129.11, 129.07, 127.72, 125.66 (2
C), 123.36, 120.62, 120.58 (2 C), 119.25, 69.17, 68.36, 62.79, 53.64,
21.26.
HRMS (ESI): m/z calcd for C28H31N6O8 [M + H]+: 579.2203; found:
HRMS (ESI): m/z calcd for C25H25N6O3 [M + H]+: 457.1988; found:
579.2181.
457.2011.
[(2R,3S,6S)-3-Acetoxy-6-(1-{(2S,3R,6S)-6-(acetoxymethyl)-2-[1-(4-
methoxyphenyl)-1H-1,2,3-triazol-4-yl]-3,6-dihydro-2H-pyran-3-
yl}-1H-1,2,3-triazol-4-yl)-3,6-dihydro-2H-pyran-2-yl]methyl Ace-
tate (5b-6)
[(2S,3S,6S)-3-(4-Cyclopropyl-1H-1,2,3-triazol-1-yl)-6-(1-phenyl-
1H-1,2,3-triazol-4-yl)-3,6-dihydro-2H-pyran-2-yl]methyl Acetate
(5a-8)
Yield: 39 mg (19%); white solid; mp 182–184 °C.
Yield: 69 mg (24%); light yellow oil.
IR (film): 3144, 3006, 2956, 1739, 1600, 1505, 1233, 1043, 763, 693
IR (film): 3142, 3118, 1745, 1600, 1503, 1372, 1231, 1046, 765, 693
cm–1
.
cm–1
.
1H NMR (300 MHz, CDCl3): δ = 8.04 (s, 1 H), 7.72 (d, J = 8.1 Hz, 2 H),
7.53 (t, J = 7.5 Hz, 3 H), 7.49–7.37 (m, 1 H), 6.25 (d, J = 10.3 Hz, 1 H),
6.11 (d, J = 10.4 Hz, 1 H), 5.84 (s, 1 H), 5.37 (d, J = 3.9 Hz, 1 H), 4.55 (dd,
J = 11.7, 5.9 Hz, 1 H), 4.47 (s, 1 H), 4.21 (dd, J = 11.6, 2.8 Hz, 1 H), 2.13
(s, 3 H), 1.97–1.86 (m, 1 H), 0.92 (d, J = 8.3 Hz, 2 H), 0.88–0.72 (m, 2
H).
1H NMR (300 MHz, CDCl3): δ = 7.90 (s, 1 H), 7.77 (s, 1 H), 7.54 (d, J =
9.0 Hz, 2 H), 6.95 (d, J = 8.9 Hz, 2 H), 6.28–5.98 (m, 3 H), 5.95–5.79 (m,
2 H), 5.41 (s, 1 H), 5.30 (d, J = 3.7 Hz, 1 H), 5.28–5.17 (m, 1 H), 4.51–
4.35 (m, 2 H), 4.10 (ddd, J = 14.8, 10.9, 2.7 Hz, 3 H), 3.89–3.72 (m, 4 H),
2.05 (s, 3 H), 1.99 (d, J = 3.6 Hz, 6 H).
13C NMR (75 MHz, CDCl3): δ = 170.72, 170.65, 170.31, 160.10, 145.96,
143.68, 132.13, 132.00, 130.70, 130.12, 129.71, 128.56, 128.40,
125.54, 124.36, 122.35, 122.20 (2 C), 121.64, 114.87 (2 C), 69.96,
69.69, 69.59, 67.51, 64.84, 64.40, 62.86, 55.64, 55.25, 20.96, 20.87,
20.74.
13C NMR (75 MHz, CDCl3): δ = 170.16, 150.33, 145.94, 136.85, 132.01,
129.88 (2 C), 129.11, 123.46, 120.58 (2 C), 120.45, 119.57, 69.21,
68.30, 62.80, 53.40, 20.63, 7.77, 7.72, 6.79.
HRMS (ESI): m/z calcd for C21H23N6O3 [M + H]+: 407.1832; found:
407.1801.
HRMS (ESI): m/z calcd for C28H31N6O8 [M + H]+: 579.2203; found:
579.2187.
[(2S,5R,6S)-5-(4-Cyclopropyl-1H-1,2,3-triazol-1-yl)-6-(1-phenyl-
1H-1,2,3-triazol-4-yl)-5,6-dihydro-2H-pyran-2-yl]methyl Acetate
(5b-8)
{(2S,3S,6S)-6-(1-Phenyl-1H-1,2,3-triazol-4-yl)-3-[4-(p-tolyl)-1H-
1,2,3-triazol-1-yl]-3,6-dihydro-2H-pyran-2-yl}methyl Acetate (5a-
7)
Yield: 68 mg (34%); light yellow gummy solid.
IR (film): 3142, 3118, 1743, 1600, 1503, 1372, 1231, 1046, 763, 692
Yield: 114 mg (50%); white solid; mp 182–183 °C.
cm–1
.
IR (film): 3140, 2924, 1737, 1600, 1501, 1229, 1045, 761, 732, 693
1H NMR (300 MHz, CDCl3): δ = 8.03 (s, 1 H), 7.76 (d, J = 7.7 Hz, 2 H),
7.63–7.36 (m, 4 H), 6.63 (dd, J = 10.0, 2.6 Hz, 1 H), 6.37–6.18 (m, 1 H),
5.78 (s, 1 H), 5.25 (d, J = 2.9 Hz, 1 H), 4.37 (dd, J = 9.9, 4.5 Hz, 1 H),
4.28–4.11 (m, 2 H), 2.01–1.86 (m, 4 H), 1.07–0.80 (m, 4 H).
13C NMR (75 MHz, CDCl3): δ = 170.59, 149.90, 144.12, 136.76, 130.13,
129.79 (2 C), 129.03, 124.82, 121.55, 120.58 (2 C), 119.89, 69.81,
69.59, 64.46, 55.00, 20.86, 7.63, 7.57, 6.72.
cm–1
.
1H NMR (300 MHz, CDCl3): δ = 8.07 (s, 1 H), 8.01 (s, 1 H), 7.70 (t, J = 6.4
Hz, 4 H), 7.57–7.42 (m, 3 H), 7.20 (d, J = 7.8 Hz, 2 H), 6.32 (d, J = 8.9 Hz,
1 H), 6.15 (d, J = 10.3 Hz, 1 H), 5.95 (s, 1 H), 5.45 (d, J = 4.1 Hz, 1 H),
4.60 (dd, J = 11.7, 5.9 Hz, 1 H), 4.50 (s, 1 H), 4.22 (dd, J = 11.8, 3.0 Hz, 1
H), 2.36 (s, 3 H), 2.11 (s, 3 H).
13C NMR (75 MHz, CDCl3): δ = 170.78, 170.34, 170.06, 160.15, 146.33,
145.47, 132.56, 130.20, 129.52, 125.85, 123.12, 122.24 (2 C), 122.01,
120.61, 114.92 (2 C), 69.64, 69.01, 67.69, 64.97, 63.06, 62.55, 55.65,
53.63, 21.02, 20.72, 20.62.
HRMS (ESI): m/z calcd for C25H25N6O3 [M + H]+: 457.1988; found:
457.2019.
HRMS (ESI): m/z calcd for C21H23N6O3 [M + H]+: 407.1832; found:
407.1811.
[(2S,3R,6S)-3-(4-Cyclopropyl-1H-1,2,3-triazol-1-yl)-6-(1-phenyl-
1H-1,2,3-triazol-4-yl)-3,6-dihydro-2H-pyran-2-yl]methyl Acetate
(5c-8)
Yield: 52 mg (27%); white solid; mp 187–189 °C.
{(2S,5R,6S)-6-(1-Phenyl-1H-1,2,3-triazol-4-yl)-5-[4-(p-tolyl)-1H-
1,2,3-triazol-1-yl]-5,6-dihydro-2H-pyran-2-yl}methyl Acetate (5b-
7)
IR (film): 3142, 3118, 1739, 1600, 1503, 1372, 1231, 1046, 765, 693
cm–1
.
1H NMR (300 MHz, CDCl3): δ = 8.04 (s, 1 H), 7.75 (d, J = 7.4 Hz, 2 H),
7.60–7.44 (m, 4 H), 6.63 (dd, J = 10.1, 3.5 Hz, 1 H), 6.27 (ddd, J = 9.9,
5.7, 1.9 Hz, 1 H), 5.79 (s, 1 H), 5.32–5.20 (m, 1 H), 4.45–4.31 (m, 1 H),
3.83 (dd, J = 11.8, 5.4 Hz, 1 H), 3.70 (dd, J = 11.8, 6.8 Hz, 1 H), 2.05–
1.90 (m, 4 H), 1.02–0.92 (m, 2 H), 0.92–0.84 (m, 2 H).
Yield: 73 mg (32%); white solid; mp 183–185 °C.
IR (film): 3140, 2926, 1737, 1600, 1501, 1229, 1045, 909, 728, 693
cm–1
.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–N

L
A. Shamim et al.
Paper
Synthesis
13C NMR (75 MHz, CDCl3): δ = 170.16, 150.33, 145.94, 136.85, 132.01,
129.88 (2 C), 129.11, 123.46, 120.58 (2 C), 120.45, 119.57, 69.21,
68.30, 62.80, 53.40, 20.63, 7.77, 7.72, 6.79.
HRMS (ESI): m/z calcd for C21H23N6O3 [M + H]+: 407.1832; found:
407.1803.
IR (film): 3130, 3118, 2970, 1601, 1503, 1372, 1231, 1045, 763, 692
cm–1
.
1H NMR (300 MHz, DMSO-d6): δ = 8.98 (s, 1 H), 8.54 (s, 1H), 8.00–
7.80 (m, 4 H), 7.61 (t, J = 7.6 Hz, 2 H), 7.56–7.39 (m, 3 H), 7.34 (t, J = 7.1
Hz, 1 H), 6.42–6.21 (m, 2 H), 5.84 (s, 1 H), 5.44 (d, J = 3.7 Hz, 1 H),
4.69–4.56 (m, 2 H), 4.51 (d, J = 9.3 Hz, 1 H), 3.26 (s, 3 H).
13C NMR (75 MHz, DMSO-d6): δ = 146.89, 144.61, 136.96, 131.03,
130.58, 130.39 (2 C), 129.34 (3 C), 128.44, 125.66 (2 C), 124.98,
122.89, 120.89, 120.64 (2 C), 70.60, 69.95, 69.64, 55.79, 37.35.
[(2S,3S,6S)-3-(4-Phenyl-1H-1,2,3-triazol-1-yl)-6-(1-phenyl-1H-
1,2,3-triazol-4-yl)-3,6-dihydro-2H-pyran-2-yl]methanol (6a)
Yield: 180 mg (90%); yellow solid; mp 200–202 °C.
HRMS (ESI): m/z calcd for C23H23N6O4S [M + H]+: 409.1501; found:
409.1483.
IR (film): 3342, 3118, 2975, 1600, 1503, 1372, 1231, 1046, 765, 693
cm–1
.
1H NMR (300 MHz, CDCl3): δ = 8.05 (s, 1 H), 7.94 (s, 1 H), 7.86 (d, J =
6.9 Hz, 2 H), 7.75 (d, J = 7.2 Hz, 2 H), 7.61–7.29 (m, 6 H), 6.74 (d, J = 9.9
Hz, 1 H), 6.47–6.26 (m, 1 H), 5.81 (s, 1 H), 5.35 (s, 1 H), 4.29 (d, J = 6.3
Hz, 1 H), 3.24 (d, J = 17.4 Hz, 2 H), 2.65 (s, 1 H).
4-[(2S,5S,6R)-6-(Azidomethyl)-5-(4-phenyl-1H-1,2,3-triazol-1-yl)-
5,6-dihydro-2H-pyran-2-yl]-1-phenyl-1H-1,2,3-triazole (8a)
Yield: 102 mg (80%); light yellow gummy solid.
13C NMR (75 MHz, CDCl3): δ = 136.83, 133.28, 130.40, 129.85, 129.11,
128.87, 128.31, 125.76, 122.76, 120.69, 120.61, 119.90, 71.36, 68.25,
61.29, 53.34.
HRMS (ESI): m/z calcd for C22H21N6O2 [M + H]+: 401.1726; found:
401.1731.
IR (film): 3132, 3099, 2924, 2121, 1600, 1506, 1233, 1046, 763, 694
cm–1
.
1H NMR (300 MHz, CDCl3): δ = 7.88 (s, 1 H), 7.78 (d, J = 8.1 Hz, 2 H),
7.43 (ddd, J = 19.8, 16.6, 9.2 Hz, 9 H), 6.55 (dd, J = 10.3, 1.9 Hz, 1 H),
6.10 (dd, J = 10.3, 2.2 Hz, 1 H), 5.65 (d, J = 2.2 Hz, 1 H), 4.87–4.68 (m, 2
H), 4.25 (td, J = 7.6, 3.9 Hz, 1 H), 3.91 (dd, J = 5.0, 2.4 Hz, 1 H).
13C NMR (75 MHz, CDCl3): δ = 148.31, 147.10, 136.80, 131.26 (2 C),
130.04, 129.62 (2 C), 128.97 (2 C), 128.64 (2 C), 125.92 (2 C), 123.12,
120.37 (2 C), 119.46, 72.18, 67.99, 55.82, 54.83.
[(2S,5R,6S)-5-(4-Phenyl-1H-1,2,3-triazol-1-yl)-6-(1-phenyl-1H-
1,2,3-triazol-4-yl)-5,6-dihydro-2H-pyran-2-yl]methanol (6b)
Yield: 190 mg (95%); yellow solid; mp 194–196 °C.
HRMS (ESI): m/z calcd for C22H20N9O [M + H]+: 426.1791; found:
426.1734.
IR (film): 3340, 3118, 2970, 1603, 1505, 1372, 1231, 1045, 765, 693
cm–1
.
1H NMR (300 MHz, CDCl3): δ = 8.13 (s, 1 H), 8.08 (s, 1 H), 7.85 (d, J =
7.8 Hz, 2 H), 7.74 (d, J = 8.0 Hz, 2 H), 7.62–7.30 (m, 6 H), 6.35 (d, J =
10.6 Hz, 1 H), 6.23 (d, J = 10.2 Hz, 1 H), 5.94 (s, 1 H), 5.49 (s, 1 H), 4.36
(s, 1 H), 3.94 (s, 2 H), 2.36 (s, 1 H).
1-[(2S,3R,6S)-6-(Azidomethyl)-2-(1-phenyl-1H-1,2,3-triazol-4-yl)-
3,6-dihydro-2H-pyran-3-yl]-4-phenyl-1H-1,2,3-triazole (8b)
Yield: 115 mg (90%); light yellow gummy solid.
13C NMR (75 MHz, CDCl3): δ = 136.83, 133.28, 130.40, 129.85 (2 C),
129.11, 128.87 (2 C), 128.31, 125.76 (2 C), 122.76, 120.69 (2 C),
120.61, 119.90, 71.36, 68.25, 61.29, 53.34.
HRMS (ESI): m/z calcd for C22H21N6O2 [M + H]+: 401.1726; found:
401.1743.
IR (film): 3132, 3099, 2924, 2099, 1600, 1506, 1233, 1046, 763, 694
cm–1
.
1H NMR (300 MHz, CDCl3): δ = 8.16 (s, 1 H), 8.08 (s, 1 H), 7.84 (d, J =
7.1 Hz, 2 H), 7.72 (d, J = 7.2 Hz, 2 H), 7.58–7.28 (m, 6 H), 6.41–6.29 (m,
1 H), 6.16 (d, J = 10.3 Hz, 1 H), 5.97 (d, J = 1.3 Hz, 1 H), 5.46 (d, J = 2.8
Hz, 1 H), 4.42 (s, 1 H), 3.68–3.54 (m, 2 H).
13C NMR (75 MHz, CDCl3): δ = 147.77, 143.94, 136.73, 131.48, 130.61,
129.85 (2 C), 129.15, 128.83 (2 C), 128.15, 125.74 (2 C), 124.30,
121.44, 120.65 (2 C), 119.79, 70.37, 69.86, 54.89, 53.58.
[(2S,3S,6S)-3-(4-Phenyl-1H-1,2,3-triazol-1-yl)-6-(1-phenyl-1H-
1,2,3-triazol-4-yl)-3,6-dihydro-2H-pyran-2-yl]methyl Methane-
sulfonate (7a)
HRMS (ESI): m/z calcd for C22H20N9O [M + H]+: 426.1791; found:
Yield: 162 mg (85%); light yellow solid; mp 128–130 °C.
426.1751.
IR (film): 3130, 3118, 2970, 1601, 1503, 1372, 1231, 1045, 763, 692
cm–1
.
1H NMR (300 MHz, CDCl3): δ = 8.18 (s, 1 H), 8.05–7.73 (m, 5 H), 7.66–
7.31 (m, 6 H), 6.84 (dd, J = 10.1, 3.6 Hz, 1 H), 6.34 (ddd, J = 10.0, 5.8, 2.1
Hz, 1 H), 5.88 (d, J = 2.2 Hz, 1 H), 5.34 (d, J = 5.5 Hz, 1 H), 4.56–4.39 (m,
1 H), 4.28–4.05 (m, 1 H), 3.75 (dd, J = 11.4, 7.7 Hz, 1 H), 2.96 (s, 3 H).
1-Phenyl-4-{(2S,3R,6S)-3-(4-phenyl-1H-1,2,3-triazol-1-yl)-6-[(4-
phenyl-1H-1,2,3-triazol-1-yl)methyl]-3,6-dihydro-2H-pyran-2-
yl}-1H-1,2,3-triazole (9a)
Yield: 112 mg (85%); light yellow gummy solid.
13C NMR (75 MHz, CDCl3): δ = 148.08, 145.59, 133.21, 130.25, 129.84
(2 C), 129.04, 128.90 (2 C), 128.82, 128.42, 125.79 (2 C), 122.33,
120.60 (3 C), 119.67, 69.87, 68.90, 68.81, 53.28, 37.84.
HRMS (ESI): m/z calcd for C23H23N6O4S [M + H]+: 479.1501; found:
479.1491.
IR (film): 3130, 2957, 2931, 1600, 1505, 1462, 1231, 1076, 1046, 765,
694 cm–1
.
1H NMR (300 MHz, DMSO-d6): δ = 8.98 (s, 1 H), 8.63 (s, 1 H), 8.04 (s, 1
H), 7.87 (dd, J = 15.7, 7.4 Hz, 4 H), 7.75 (d, J = 6.9 Hz, 2 H), 7.61 (t, J =
7.5 Hz, 2 H), 7.43 (ddd, J = 24.3, 15.4, 7.1 Hz, 7 H), 6.47 (d, J = 10.2 Hz,
1 H), 6.29 (d, J = 9.1 Hz, 1 H), 5.82 (s, 1 H), 5.50 (d, J = 3.6 Hz, 1 H), 4.92
(ddd, J = 17.2, 14.4, 5.0 Hz, 2 H), 4.72 (s, 1 H).
13C NMR (75 MHz, DMSO-d6): δ = 146.38, 146.24, 144.01, 136.43,
131.24, 130.58, 130.31, 129.90 (3 C), 128.85 (3 C), 128.76 (2 C),
127.86, 127.83, 125.12 (3 C), 123.96, 122.54, 122.49, 120.15 (2 C),
119.86, 69.54, 69.29, 55.14, 51.42.
[(2S,5R,6S)-5-(4-Phenyl-1H-1,2,3-triazol-1-yl)-6-(1-phenyl-1H-
1,2,3-triazol-4-yl)-5,6-dihydro-2H-pyran-2-yl]methyl Methane-
sulfonate (7b)
Yield: 176 mg (92%); light yellow solid; mp 224–226 °C.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–N

M
A. Shamim et al.
Paper
Synthesis
HRMS (ESI): m/z calcd for C30H26N9O [M + H]+: 528.2260; found:
528.2234.
13C NMR (75 MHz, CDCl3): δ = 149.04, 148.17, 146.51, 136.68, 131.18,
130.97, 129.94, 129.67 (2 C), 128.94 (2 C), 128.77, 128.63, 125.83,
123.83 (2 C), 120.33 (2 C), 120.08, 119.85, 72.13, 67.70, 55.47, 55.39,
31.40, 25.44, 22.34, 13.78.
HRMS (ESI): m/z calcd for C28H30N9O [M + H]+: 508.2573; found:
508.2601.
4-Butyl-1-{[(2S,5R,6S)-5-(4-phenyl-1H-1,2,3-triazol-1-yl)-6-(1-
phenyl-1H-1,2,3-triazol-4-yl)-5,6-dihydro-2H-pyran-2-yl]meth-
yl}-1H-1,2,3-triazole (9b)
Yield: 127 mg (94%); light yellow gummy solid.
IR (film): 3136, 2957, 2931, 1601, 1505, 1462, 1231, 1076, 1046, 765,
696 cm–1
.
Funding Information
1H NMR (300 MHz, CDCl3): δ = 8.07 (s, 1 H), 7.82 (d, J = 7.1 Hz, 2 H),
7.73 (d, J = 7.2 Hz, 2 H), 7.59–7.38 (m, 5 H), 7.35 (d, J = 5.3 Hz, 3 H),
6.43–6.24 (m, 2 H), 5.83 (d, J = 1.4 Hz, 1 H), 5.47 (d, J = 2.7 Hz, 1 H),
4.72 (dd, J = 14.9, 5.9 Hz, 1 H), 4.65–4.56 (m, 2 H), 2.65–2.40 (m, 2 H),
1.50 (tq, J = 13.1, 6.4 Hz, 2 H), 1.22 (dq, J = 14.8, 7.3 Hz, 2 H), 0.81 (t, J =
7.3 Hz, 3 H).
The authors are grateful for the financial support provided by FAPESP
- São Paulo Research Foundation (FAPESP) (Grant 2012/00424-2),
CAPES (to A.S.) and CNPq – the National Council for Scientific and
Technological Development (306119/2014-5 to H.A.S.).FA
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13C NMR (75 MHz, CDCl3): δ = 148.69, 147.57, 143.77, 136.69, 131.80,
130.37 (2 C), 129.86, 129.20, 128.80 (2 C), 128.22, 125.84 (2 C),
123.74, 122.52, 121.35, 120.67 (2 C), 119.36, 70.71, 69.06, 54.54,
52.22, 31.29, 25.26, 22.25, 13.67.
Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0036-1589090.
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HRMS (ESI): m/z calcd for C28H30N9O [M + H]+: 508.2573; found:
528.2554.
References
[(2R,3S,6S)-3-Acetoxy-6-(1-{[(2S,5R,6S)-5-(4-phenyl-1H-1,2,3-tri-
azol-1-yl)-6-(1-phenyl-1H-1,2,3-triazol-4-yl)-5,6-dihydro-2H-
pyran-2-yl]methyl}-1H-1,2,3-triazol-4-yl)-3,6-dihydro-2H-pyran-
2-yl]methyl Acetate (9c)
(1) (a) Reusser, F. J. J. Antibiot. 1979, 32, 1186. (b) Arcamone, F.;
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188, 2.
Yield: 152 mg (92%); light yellow solid; mp 119–121 °C.
IR (film): 1657, 1236, 1052, 1026, 1002, 763, 665 cm–1
.
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1H NMR (300 MHz, DMSO-d6): δ = 8.93 (s, 1 H), 8.26 (s, 1 H), 8.14 (s, 1
H), 7.88 (t, J = 6.8 Hz, 4 H), 7.62 (t, J = 7.6 Hz, 2 H), 7.56–7.42 (m, 3 H),
7.36 (t, J = 7.3 Hz, 1 H), 6.40 (d, J = 10.4 Hz, 1 H), 6.28 (d, J = 10.5 Hz, 1
H), 6.10 (d, J = 10.3 Hz, 1 H), 5.79 (d, J = 10.4 Hz, 2 H), 5.52 (d, J = 4.9
Hz, 1 H), 5.39 (s, 1 H), 5.15 (d, J = 7.9 Hz, 1 H), 4.97 (dd, J = 14.3, 7.5 Hz,
1 H), 4.90 – 4.78 (m, 1 H), 4.74 (s, 1 H), 4.09 (dd, J = 12.0, 5.4 Hz, 1 H),
4.04–3.94 (m, 1 H), 3.78 (dd, J = 5.0, 2.3 Hz, 1 H), 1.98 (s, 3 H), 1.93 (s,
3 H).
13C NMR (75 MHz, DMSO-d6): δ = 170.02, 169.85, 146.38, 144.94,
144.24, 136.42, 130.58, 130.47, 130.22, 129.89 (3 C), 128.84 (2 C),
127.96, 125.23 (2 C), 124.78, 124.53, 122.33, 120.29, 120.09 (3 C),
70.25, 68.68, 68.60, 66.72, 64.31, 62.44, 55.61, 51.00, 20.64, 20.39.
HRMS (ESI): m/z calcd for C34H34N9O6 [M + H]+: 664.2632; found:
664.2601.
4-Butyl-1-{[(2R,3S,6S)-3-(4-phenyl-1H-1,2,3-triazol-1-yl)-6-(1-
phenyl-1H-1,2,3-triazol-4-yl)-3,6-dihydro-2H-pyran-2-yl]meth-
yl}-1H-1,2,3-triazole (9d)
(7) (a) Hein, C. D.; Liu, X.-M.; Wan, D. Pharm. Res. 2008, 25, 2216.
(b) Dedol, S.; Nepogodieva, S. A.; Field, R. A. Org. Biomol. Chem.
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Yield: 113 mg (89%); yellowish green gummy solid.
IR (film): 3136, 2957, 2931, 1601, 1505, 1462, 1231, 1076, 1046, 765,
696 cm–1
.
1H NMR (300 MHz, CDCl3): δ = 7.83 (s, 1 H), 7.76–7.68 (m, 2 H), 7.64
(s, 1 H), 7.58–7.48 (m, 3 H), 7.42–7.32 (m, 6 H), 6.62 (dd, J = 10.3, 2.9
Hz, 1 H), 6.10 (dd, J = 12.4, 2.1 Hz, 1 H), 5.73 (d, J = 2.0 Hz, 1 H), 5.44
(dd, J = 7.9, 2.3 Hz, 1 H), 4.72 (dd, J = 14.2, 8.3 Hz, 1 H), 4.58 (dd, J =
14.2, 3.0 Hz, 1 H), 4.50 (td, J = 8.1, 3.0 Hz, 1 H), 2.72 (t, 2 H), 1.66 (dt,
J = 15.4, 7.5 Hz, 2 H), 1.38 (dq, J = 14.5, 7.3 Hz, 2 H), 0.92 (t, J = 7.3 Hz,
3 H).
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