2-Pyridyl glycoside: An alternative glycosyl donor in preactivation protocol

Article abstract of DOI:10.1016/j.tetlet.2014.11.066

2-Pyridyl glycosides have been identified to be powerful glycosyl donors for the preactivation-based oligosaccharide synthesis. By using stoichiometric amount of Tf₂O, the 2-pyridyl glycosides were pre-activated, which subsequently underwent gl

Full text of DOI:10.1016/j.tetlet.2014.11.066

Tetrahedron Letters 56 (2015) 211–214
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
2-Pyridyl glycoside: an alternative glycosyl donor in preactivation
protocol
⇑
De-Cai Xiong, An-Qi Yang, Yang Yu, Xin-Shan Ye
State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Xue Yuan Road No. 38, Beijing 100191, China
a r t i c l e i n f o
a b s t r a c t
Article history:
2-Pyridyl glycosides have been identified to be powerful glycosyl donors for the preactivation-based
oligosaccharide synthesis. By using stoichiometric amount of Tf2O, the 2-pyridyl glycosides were
pre-activated, which subsequently underwent glycosylation reactions smoothly to produce the coupled
products in high yields. Furthermore, the 2-pyridyl glycosides were applied to the efficient oligosaccha-
ride assembly by the preactivation-based one-pot oligosaccharide synthesis protocol.
Ó 2014 Elsevier Ltd. All rights reserved.
Received 31 August 2014
Revised 8 November 2014
Accepted 14 November 2014
Available online 21 November 2014
Keywords:
2-Pyridyl glycoside
Trifluoromethanesulfonic anhydride
Preactivation
Glycosylation
One-pot synthesis
As the most abundant class of biomolecules on Earth, carbohy-
drates play important roles in numerous biological processes
including energy storage, viral and bacterial infection, inflammation
and immune response, fertilization, cell growth, and proliferation.1
Since most carbohydrates cannot be obtained easily from natural
sources in good purity and quantity, complex oligosaccharides are
mainly obtained by chemical or enzymatic synthesis. Many meth-
ods and strategies have been developed for the construction of com-
plex oligosaccharides and glycoconjugates.2 Among them, the
preactivation-based one-pot oligosaccharide synthesis is one of
the most efficient strategies.3 Preactivation protocol refers to the
activation of a glycosyl donor in the absence of a glycosyl acceptor
to provide a reactive intermediate, which is immediately treated
with glycosyl acceptor to yield a coupled saccharide.4 Many com-
plex oligosaccharides have been assembled by this protocol,5 and
various methods have been also developed to improve the stereose-
lectivity and efficacy.6 In preactivation protocol, thioglycoside is the
most widely-used glycosyl donor. Thioglycoside is a powerful
donor,7 but sometimes it still has some drawbacks, for instance,
the regeneration of donor via aglycon transfer or the erosion of
acceptor by thiophilic species.8 Therefore, to overcome these prob-
lems, it is necessary to find an alternative glycosyl donor for the pre-
activation-based oligosaccharide synthesis.
reported previously.9 This type of building blocks can be used as
both glycosyl donors and acceptors.10 It was found that the 2-pyr-
idyl glycoside was activated by MeOTf, TfOH, or Cu(OTf)2 at room
temperature,9a however, the glycosylation yield was not good
(31–77% yields). This severely hinders the application of 2-pyridyl
glycoside in glycosylations. New promoters should be explored to
improve the glycosylation efficiency. Therefore, pyridyl glycosides
might be suitable building blocks for the preactivation-based gly-
cosylation protocol. Herein we choose the more stable 2-pyridyl
glycosides as glycosyl donors to test the reactions.
The 2-pyridyl glycoside 1a9,10 was used for the reaction. We rea-
soned that when triflic anhydride (Tf2O) was used as the promoter
for glycosylation reactions, a highly reactive glycosyl triflate might
be generated under low temperature. Thus, donor 1a was treated
with Tf2O (1.0 equiv) at À72 °C in anhydrous dichloromethane
(DCM), most of 1a was consumed by TLC detection after 20 min,
indicating donor 1a was preactivated. The acceptor 2a was then
added to the reaction mixture, as expected, the coupled product
disaccharide 3a11 was obtained in 72% yield (Table 1, entry 1). The
yield was improved gradually as the equivalent of Tf2O increased
(entries 2 and 3). The donor 1a was observed with complete con-
sumption when using 1.1 equiv of Tf2O. The yield was improved fur-
ther by decreasing the amount of glycosyl acceptor 2a (entries 4 and
5). The best donor/acceptor ratio is 1/0.8 (entry 5). The addition of
hindered base 2,4,6-tri-tert-butylpyrimidine (TTBP) did not affect
The usages of 2-pyridyl glycosides or methoxy-2-pyridyl (MOP)
glycosides as glycosyl donors in the saccharide synthesis were
⇑
Corresponding author. Tel.: +86 10 8280 5736; fax: +86 10 8280 2724.
E-mail address: xinshan@bjmu.edu.cn (X.-S. Ye).
http://dx.doi.org/10.1016/j.tetlet.2014.11.066
0040-4039/Ó 2014 Elsevier Ltd. All rights reserved.

212
D.-C. Xiong et al. / Tetrahedron Letters 56 (2015) 211–214
Table 1
Optimization of the reaction conditions using donor 1a and acceptor 2a
BnO
AcO
AcO
AcO
BnO
O
O
O
HO
O
O
AcO
+
OPy
BnO
2a
AcO
AcO
BnO
BnO
AcO
AcO
1a
BnO
3a
OMe
OMe
Entry
1a (equiv)
2a (equiv)
Activator (equiv)
Additive (equiv)
Yielda,b (%)
1
2
3
4
5
6
7
8
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
0.9
0.8
0.8
0.8
0.8
Tf2O (1.0)
Tf2O (1.05)
Tf2O (1.1)
Tf2O (1.1)
Tf2O (1.1)
Tf2O (1.1)
TfOH (1.1)
MeOTf (1.0)
—
—
—
—
72
76
81
89
96
93
—
—
TTBP (2.0)
—
—
—
a
Conditions: À72 °C, DCM, 4 Å molecular sieves.
b
Isolated yield.
Table 2
The scope of glycosylations of donors (1a–j) and acceptors (2a–d)
PGO
HO
PGO
Tf2O (1.1 equiv.)
O
O
O
O
O
PGO
+
PGO
OPy
OMe
2a-d (0.8 equiv.)
OMe
4
MS, CH2Cl2
3b-p
1a-j (1.0 equiv.)
-72 oC
Glycosyl
Disaccharide
Ph
Glycosyl
Yielda,b
94%
Entry
acceptor
donor
AcO
AcO
O
O
AcO
O
Ph
O
O
O
O
O
AcO
AcO
AcO
1
2
O
HO
OPy
AcO
BnO
3b
BnO
MeO
AcO
OMe
1a
1a
2b
BnO
OBn
BnO
BnO
BnO
BnO
O
AcO
AcO
O
87%
O
HO
2c
O
OMe
OMe
AcO
AcO
3c
AcO
AcO
O
O
AcO
HO
O
AcOBnO
BnO
3d
AcO
56%
O
BnO
BnO
1a
3
BnO
OMe
BnO
OMe
2d
O
BnO
BnO
40%
BnO
4
BzO
OMe
O
BzO
BzO
O
BzO
BzO
O
O
BzO
BnO
4
2d
99%
92%
OPy
BzO
1b
BnO
BzO
BnO
3e
BnO
OMe
O
BzO
BzO
BzO
BnO
O
HO
O
BnO
O
5
6
1b
BnO
BnO
3f
OMe
BzO
2a
BnO
OMe
99%
PivO
PivO
PivO
PivO
O
O
O
OPy
PivO
PivO
2d
O
BnO
BnO
3g
PivO
1c
PivO
BnO
OMe

D.-C. Xiong et al. / Tetrahedron Letters 56 (2015) 211–214
213
Table 2 (continued)
Glycosyl
Glycosyl
donor
Disaccharide
acceptor
Yielda,b
97%
Entry
7
PivO
PivO
OBn
O
O
1c
2a
O
PivO
BnO
PivO
3h
BnO
OMe
OAc
OAc
O
AcO
AcO
AcO
AcO
BnO
O
O
O
8
9
91%
2a
2a
OPy
BnO
AcO
AcO
BnO
OMe
3i
1d
OAc
O
AcO
AcO
OAc
O
AcO
OBn
O
AcO
92%
AcO
AcO
1e
O
BnO
OPy
3j BnO
OMe
AcO
AcO
AcO
AcO
BnO
HO
OBn
O
10
O
O
O
O
OPy
95%
OMe
AcO
AcO
BnO
BnO
3k
BnO
PhthN
PhthN
BnO
BnO
2a
OMe
1f
OPy
O
O
O
91%
2a
BnO
3l
11 AcO
BnO
AcO
1g
O
OMe
O
OAc
AcO
AcO
BnO
BnO
OAc
HO
BnO
12 BnO
O
O
O
O
BnO
98%
OPy
BnO
BnO
BnO
α/β = 3/1e
BnO
OBn
BnO
OBn
OPy
BnO
2d
1h
OMe
3m
BnO
OMe
BzO
O
O
BzO
O
O
2d
BnO
BnO
81%
OMe
13
14
BnO
BzO OBz
BzO OBz 3n
1i
BnO
O
1i
2a
O
BzO
BnO
O
84%
OMe
BnO
3o
BzO OBz
OBn
O
OBn
91%c
OBn
O
OBn
BnO
HO
BnO
BnO
2d
O
α/β = 1.6/1e
O
15
OPy
BnO
89%c,d
O
BnO
OBn
α/β = 3.4/1e
BnO
OBn
BnO
1j
OMe
3p
BnO
OMe
a Donor (1.0 equiv), acceptor (0.8 equiv), Tf2O (1.1 equiv), À72 °C, DCM, 4 Å molecular sieves. b Isolated yield. c 1.0 equiv of Tf2O was
used. d Et2O as the solvent. e Determined by 1H NMR analysis.
the coupling yield (entry 6). On the other hand, promoters such as
MeOTf and TfOH did not activate the donor at low temperature
(from À72 °C to 0 °C) at all (entries 7 and 8). Thus, the optimized
conditions are: donor (1.0 equiv), acceptor (0.8 equiv), Tf2O
(1.1 equiv), À72 °C, DCM, 4 Å molecular sieves.
transfer byproduct 413 was also isolated in 40% yield (entry 3).
The acetyl transfer byproduct was avoided when the benzoylated
glucosyl donor (1b,14 entry 4), the pivaloylated glucosyl donor
(1c, entry 6), the benzylated glucosyl/galactosyl donor (1h and
1j,9e entry 12 and 15), or the benzoylated ribosyl donor (1i,15 entry
13) were employed. The glycosylation reactions of hindered accep-
tor 2a with the acetylated galactosyl (1d,10 entry 8), mannosyl
(1e,16 entry 9), glucosaminyl (1f, entry 10), rhamnosyl (1g,16 entry
11), and the benzoylated/pivaloylated glucosyl/ribosyl donors
(entries 5, 7, 14) produced 4-O-linked disaccharides in high yields
as well. Glycosylation reactions of 2-acyl protected donors with
acceptors provided the expected 1,2-trans-linked disaccharides by
virtue of neighboring group participation. When donors with
With the optimized conditions in hand,12 the scope of glycosyl-
ation reactions was investigated by varying both the donors and the
acceptors based on the preactivation protocol (Table 2). The glyco-
sylation reactions of glucosyl donor 1a with the glucosyl acceptors
2b and 2c, having a free hydroxyl group at the C-3 and C-2 posi-
tions, respectively, proceeded in high yields (entries 1–2). When
the acceptor 2d with the C-6 hydroxyl exposed was used, the
desired disaccharide 3d was obtained in 56% yield and the acetyl

214
D.-C. Xiong et al. / Tetrahedron Letters 56 (2015) 211–214
2e
(0.8 eq)
PivO
2d
(0.72 eq)
Tf2O
(1.1 eq)
Tf2O
(0.88 eq)
O
PivO
PivO
O
PivO
O
PivO
OPiv
OPy
PivO
O
BzO
OPiv
(1.0 eq)
O
BzO
5
HO
1c
OBz
-72 oC
BzO
-72 o
OPy
C
O
rt
HO
BnO
O
BnO
BnO
2d
O
84%
BnO
BnO
BzO
2e
BnO
OMe
OMe
BzO
Scheme 1. The assembly of trisaccharide 5 by preactivation-based one-pot oligosaccharide synthesis strategy.
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non-participating groups at the 2-position were used, the
a-ano-
meric selectivity could be improved by using Et2O as the solvent
(entry 15). All these reactions indicated that this protocol works
well in the construction of disaccharides.
After having verified the high efficiency of the 2-pyridyl glyco-
sides in the construction of a single glycosidic bond, the next issue
was to determine if this protocol could be used in the preactiva-
tion-based iterative one-pot oligosaccharide synthesis. As shown
in Scheme 1, preactivation of the glycosyl donor 1c (1.0 equiv) by
Tf2O (1.1 equiv) at À72 °C was followed by the addition of building
block 2e (0.8 equiv). The reaction mixture was allowed to warm up
to room temperature, and then cooled down back to À72 °C. Preac-
tivation of the newly-formed disaccharide with Tf2O (0.88 equiv)
was followed by the addition of acceptor 2d (0.72 equiv), success-
fully affording the trisaccharide 5 in 84% isolated yield.
In summary, we have identified the 2-pyridyl glycoside to be an
excellent glycosyl donor for the preactivation-based oligosaccha-
ride synthesis. This donor was preactivated by stoichiometric
amount of Tf2O, and reacted smoothly with the sequentially added
acceptors to produce the coupled products in high yields. Further-
more, the 2-pyridyl glycoside building blocks were applied to the
efficient assembly of a trisaccharide by the preactivation-based
one-pot oligosaccharide synthesis. 2-Pyridyl glycoside could over-
come some limitations of the thioglycoside encountered in glyco-
sylation. It is an alternative glycosyl donor which should find
more applications in oligosaccharide synthesis.
7. Codée, J. D. C.; Litjens, R. E. J. N.; van den Bos, L. J.; Overkleeft, H. S.; van der
Marel, G. A. Chem. Soc. Rev. 2005, 34, 769.
8. Peng, P.; Xiong, D.-C.; Ye, X.-S. Carbohydr. Res. 2014, 384, 1.
Acknowledgements
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This work was financially supported by the Grants (2012
CB822100, 2012ZX09502001-001, 2012AA021504) from the
Ministry of Science and Technology of China, the National Natural
Science Foundation of China (Grant No. 21102008, 21232002),
Beijing Natural Science Foundation (2142015) and Beijing Higher
Education Young Elite Teacher Project (YETP0063).
10. Hanessian, S.; Saavedra, O. M.; Mascittia, V.; Marterer, W.; Oehrlein, R.; Mak,
C.-P. Tetrahedron 2001, 57, 3267.
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12. A solution of 2-pyridyl glycoside (0.08 mmol, 1.0 equiv) and activated 4 Å
powdered molecular sieves in dichloromethane (4.0 mL) was stirred at room
temperature under an argon atmosphere for 10 min. Then the mixture was
cooled to À72 °C and Tf2O (0.088 mmol, 1.1 equiv) was added. After the TLC
detection indicated that the donor was completely consumed, acceptor
(0.064 mmol, 0.8 equiv) was added. The reaction was further stirred for
15 min and gradually warmed to room temperature. The reaction mixture was
filtered off through a pad of Celite. The filtrate was concentrated and the
residue was purified by column chromatography on silica gel to afford product.
13. Gin, D. Y.; Garcia, B. A. J. Am. Chem. Soc. 2000, 122, 4269.
Supplementary data
Supplementary data (experimental procedures, analytical
instrumentation, 1H and 13C NMR, and mass spectra) associated
with this article can be found, in the online version, at http://
dx.doi.org/10.1016/j.tetlet.2014.11.066.
References and notes
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