A novel glycosylation of inactive glycosyl donors using an ionic liquid containing a protic acid under reduced pressure conditions

Article abstract of DOI:10.1016/j.tetlet.2010.09.108

The glycosylation of inactive glycosyl donors, such as methyl glycosides and 1-hydroxy sugars with nearly stoichiometric amounts of various alcohols (1.1 equiv) in an ionic liquid containing a protic acid (acid-IL) under reduced pressure conditions proceeded effectively to give the corresponding glycosides in good to high yields. Furthermore, the acid-IL could be reused for additional glycosylations without the loss of efficiency.

Full text of DOI:10.1016/j.tetlet.2010.09.108

Tetrahedron Letters 51 (2010) 6294–6297
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
A novel glycosylation of inactive glycosyl donors using an ionic liquid
containing a protic acid under reduced pressure conditions
⇑
Yasutaka Kuroiwa, Maiko Sekine, Satoshi Tomono, Daisuke Takahashi, Kazunobu Toshima
Department of Applied Chemistry, Faculty of Science and Technology, Keio University, 3-14-1 Hiyoshi, Kohoku-ku, Yokohama 223-8522, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
The glycosylation of inactive glycosyl donors, such as methyl glycosides and 1-hydroxy sugars with
nearly stoichiometric amounts of various alcohols (1.1 equiv) in an ionic liquid containing a protic acid
(acid-IL) under reduced pressure conditions proceeded effectively to give the corresponding glycosides
in good to high yields. Furthermore, the acid-IL could be reused for additional glycosylations without
the loss of efficiency.
Received 23 August 2010
Revised 16 September 2010
Accepted 22 September 2010
Available online 29 September 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Glycosylation
Ionic liquids
Green chemistry
Inactive sugar
Reduced pressure
Carbohydrates in living cells play important roles in many bio-
logical events including inflammation, cell adhesion, signal trans-
duction, etc. Furthermore, many carbohydrates are found in
various functional materials, such as biodegradable surfactants.
Development of a practical and environmentally benign glycosyla-
tion reaction, which is one of the most important and fundamental
transformations of carbohydrates, is therefore now becoming
increasingly important and urgently needed both in the laboratory
and in the industry.1 Greener processes2 for glycosylation may in-
clude the use of environmentally benign catalysts and solvents,
both of which could be reused. Recently, ionic liquids3,4 (ILs) have
attracted growing interest as one of the most promising environ-
mentally benign reaction media owing to their many unique prop-
erties including non-volatility, reusability, designability, and
immiscibility with certain organic solvents and/or water. In this
context, several greener O- and C-glycosylation reactions using
ILs have been demonstrated by us5 and other groups.6 In these
studies, the reusability of the ionic liquids as greener solvents for
the glycosylation reactions was well demonstrated.
competition with the glycosyl acceptors, and thus a large excess
of the glycosyl acceptors is consequently required to obtain a high
yield of the desired glycosylation product (glycoside). While our
research was in progress, Auge and Sizun9 reported the glycosyla-
tion of unprotected and non-activated monosaccharides using io-
nic liquids containing catalytic amounts of Lewis acids at
atmospheric pressure. In their study, however, except for in a
few cases, a large excess of the acceptor was used in these reac-
tions. To overcome this general problem, we focused on the impor-
tant non-volatile5c,d characteristics of ILs. We anticipated that the
glycosylation reaction under reduced pressure conditions would
be an effective means of selectively removing the water or metha-
nol from the reaction mixture.10 Herein we report the glycosylation
of inactive glycosyl donors with nearly equimolar amounts of gly-
cosyl acceptors utilizing ILs containing catalytic amounts of a prot-
ic acid under reduced pressure conditions and the significant effect
of this approach on the glycosylation reaction.
Methyl glycoside 1 was selected as the initial inactive glycosyl
donor, with 6-O-Bn-hexanediol (2) as the glycosyl acceptor. Three
ionic liquids each containing a protic acid with an anion in common
with the ionic liquid (acid-IL), such as 1-n-hexyl-3-methylimidazo-
lium tetrafluoroborate (C6mim[BF4]) with HBF4, 1-n-hexyl-3-meth-
ylimidazolium trifluoromethanesulfonate (C6mim[OTf]) with HOTf,
and 1-n-hexyl-3-methylimidazolium trifluoromethanesulfonimide
(C6mim[NTf2]) with HNTf2, were chosen as the reaction media.5
We then examined the glycosylation of 1 with 2 (1.1 equiv) using
the three acid-ILs (0.2 M for 1) at 80 °C for 30 min under reduced
pressure conditions (4.0 mmHg). These results are summarized in
Table 1. It was found that the glycosylation of 1 with 2 (1.1 equiv)
From an economical point of view, the glycosylation of inactive
glycosyl donors, such as methyl glycosides7 and 1-hydroxy sugars,8
which are readily available from naturally occurring carbohy-
drates, has recently gained much attention as it can reduce the
number of synthetic steps. Glycosylations using these inactive gly-
cosyl donors are generally ineffective, however, because produc-
tion of methanol or water during the reaction leads to
⇑
Corresponding author. Tel./fax: +81 45 566 1576.
E-mail address: toshima@applc.keio.ac.jp (K. Toshima).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.09.108

Y. Kuroiwa et al. / Tetrahedron Letters 51 (2010) 6294–6297
6295
Table 1
Glycosylation of 1 with 2 using acid-ILs under reduced pressure conditions
ionic liquid
or
PhMe
OBn
OBn
O
O
OBn
BnO
BnO
BnO
+
HO
BnO
OBn
5
BnO
1
O
protic acid
BnO
OMe
5
º
2
3
80 C, 30 min
(1.1 eq.)
Entry
Ionic liquid (0.2 M for 1)
Protic acid (equiv to IL)
Pressure (mmHg)
Yield (%)
a
/b ratioa
1
2
3
4
5
C6mim[NTf2]
C6mim[OTf]
C6mim[BF4]
C6mim[BF4]
PhMe
HNTf2 (0.05)
HOTf (0.2)
HBF4 (0.3)
HBF4 (0.3)
HBF4 (0.3)
4
4
4
760
760
35
41
59
30
34
63/37
65/35
60/40
66/34
60/40
a
a
/b ratios were determined by HPLC analysis (column, CrestPak C18SÒ, 4.6 Â 150 mm; eluent, 12% H2O in MeOH; flow rate, 0.5 mL/min, 40 °C; detection, UV 250 nm).
in C6mim[BF4] containing HBF4 (0.3 equiv) under reduced pressure
conditions proceeded smoothly to give the corresponding glycoside
3
uids containing a protic acid were less effective than C6mim[BF4]/
HBF4 (entries 1–3).
Next, in order to confirm the effects of both ionic liquid and
reduced pressure on this glycosylation, we performed the reaction
under atmospheric pressure (760 mmHg) in toluene, which is a
conventional organic solvent for glycosylations, and in C6mim[BF4].
It was found that in both cases the chemical yields of the glycosyl-
ation at 760 mmHg were much lower than that of the reaction
using C6mim[BF4] at 4.0 mmHg (entries 3–5). These results clearly
indicated that reduced pressure was effective for the glycosylation
of methyl glycoside 1 with just slightly over an equimolar amount
of glycosyl acceptors. In addition, we confirmed that 1.5 M metha-
nol was removed from the C6mim[BF4] after only 1 min of decom-
pression at 80 °C, as shown in Table 2 (entries 1 and 2).
We further examined the glycosylation of 1-hydroxy sugar 4
with 2 (1.1 equiv) using the above three acid-ILs under reduced
pressure conditions (Table 3, entries 1–3). In the glycosylation of
4, although the C6mim[BF4]/HBF4 system provided the glycoside
3 in good yield, C6mim[NTf2]/HNTf2 (0.1 equiv) at 70 °C and
4.0 mmHg gave the best result, with 3 obtained in 82% yield (entry
3). In addition, it was found that the chemical yields of the glycosy-
lations at 70 °C and 760 mmHg using toluene/HNTf2 or
C6mim[NTf2]/HNTf2 were lower than that of the reaction using
C6mim[NTf2]/HNTf2 at 4.0 mmHg (entries 3–5). These results also
showed that the use of the reduced pressure conditions was effec-
tive for the direct glycosylation of inactive glycosyl donors such as
1-hydroxy sugars. Furthermore, we measured the removal rate of
1.5 M water from C6mim[NTf2] under reduced pressure conditions
at 70 °C, as shown in Table 4. It was found that although a trace
amount of water remained after 1 min of decompression at 70 °C
and 4 mmHg, the water was completely removed from the mixture
after 5 min of decompression (Table 4, entries 1 and 2).
11 in 59% yield (25% of 1 was recovered), while the other ionic liq-
Table 2
The removal rate of methanol from an ionic liquid under reduced pressure conditions
MeOH
+
C6mim[BF4]
MeOH
C6mim[BF4]
º
80 C, 4.0 mmHg
Entry
Time (min)
Remaining MeOHa (%)
1
2
0
1
100
0
a
The quantity was determined by 1H NMR analysis.
Table 3
Glycosylation of 4 with 2 using acid-ILs under reduced pressure conditions
ionic liquid
OBn
OBn
O
or
O
PhMe
OBn
BnO
BnO
BnO
+
HO
BnO
OBn
5
protic acid
30 min
BnO
4
O
BnO
OH
5
2
3
(1.1 eq.)
Entry
Ionic liquid (0.2 M for 4)
Protic acid (equiv to IL)
Pressure (mmHg)
Temp (°C)
Yield (%)/a
/ba
1
2
3
4
5
C6mim[OTf]
C6mim[BF4]
C6mim[NTf2]
C6mim[NTf2]
PhMe
HOTf (0.1)
HBF4 (0.3)
HNTf2 (0.1)
HNTf2 (0.1)
HNTf2 (0.1)
4
4
4
760
760
80
80
70
70
70
27 (67/33)
62 (68/32)
82 (65/35)
68 (53/47)
58 (62/38)
a
a/b ratios were determined by HPLC analysis.

6296
Y. Kuroiwa et al. / Tetrahedron Letters 51 (2010) 6294–6297
Table 4
Table 6
The removal rate of water from an ionic liquid under reduced pressure conditions
Recycling of C6mim[NTf2] for the glycosylation of 4 with 2 under reduced pressure
conditions
H2O
HNTf2, C6mim[NTf2]
4
+
2
3
+
C6mim[NTf2]
H2O
C6mim[NTf2]
º
70 C, 4.0 mmHg,
70 oC, 4.0 mmHg
(1.1 eq.)
30 min
Entry
Time (min)
Remaining H2Oa (%)
Entry
Additive/HNTf2 (equiv)
Yield (%) of 3
a
/b ratioa
1
2
0
5
100
0
1
2
3
4
1st run
1st reuse
2nd reuse
3rd reuse
—
0
0
0.05
82
69
52
84
65/35
52/48
46/54
68/32
The quantity was determined by 1H NMR analysis.
a
a
a/b ratios were determined by HPLC analysis.
With these favorable results in hand, we next carried out the
glycosylation of 4 with the alcohols 5–8 (1.1 equiv), including the
poorly reactive secondary alcohols 6, 7, and 8, to examine the
scope and limitations of the reaction. These results are summa-
rized in Table 5. It was found that the glycosylations of 4 with just
slightly more than an equimolar amount (1.1 equiv) of these glyco-
syl acceptors proceeded smoothly in C6mim[NTf2]/HNTf2
(0.1 equiv) at 70 °C and 4.0 mmHg for 30 min, as well as with 2,
to afford the corresponding glycosides 9–12 in good yields (entries
1–5). These results clearly indicated that the use of a non-volatile
acid-IL under reduced pressure conditions provided significant
advantages for the direct glycosylation of inactive glycosyl donors
without the need for an excess quantity of glycosyl acceptor.
Finally, the reusability of the acid-IL C6mim[NTf2]/HNTf2 for
the glycosylation of 4 with 2 under reduced pressure conditions
was investigated. First, we attempted to reuse the recovered
C6mim[NTf2]/HNTf2 after extraction of the products from the
reaction mixture with a 5:1 mixture of hexane and EtOAc fol-
lowed by drying. It was found, however, that the chemical yield
gradually decreased as the recycle number increased (ꢀ15%
decrease for each reaction Table 6, entries 1–3) due to loss of
the protic acid HNTf2 during the glycosylation reaction at 70 °C
and 4.0 mmHg for 30 min. Therefore, we next examined the reuse
of the acid-IL after addition of HNTf2 (0.05 equiv) to the recovered
solvent. It was found that the efficiency of C6mim[NTf2]/HNTf2
thus recovered was identical with that of the freshly prepared
system and could be reused for the glycosylation under reduced
pressure conditions without any loss in efficiency (entry 4).
In conclusion, we have developed a novel O-glycosylation of
inactive glycosyl donors under reduced pressure conditions using
a reusable ionic liquid containing a protic acid without the need
for excess amounts of glycosyl acceptors. Furthermore, the effect
of the reduced pressure conditions on the efficiency of the glyco-
sylation was clearly demonstrated. Although this method pre-
sented herein is still not applicable for glycosylations using
volatile glycosyl acceptors, and the stereoselectivity is not satisfac-
tory, the results achieved with this simple and environmentally be-
nign protocol should open a novel green process and find wide
application in the synthesis of biomolecules and functional materi-
als containing carbohydrate structures. Further studies along this
line are currently in progress.
Table 5
Glycosylation of
4 with glycosyl acceptors 5–8 using C6mim[NTf2]/HNTf2 under
reduced pressure conditions
Acknowledgments
OBn
O
HNTf2 (0.1 eq. to IL)
C6mim[NTf2] (0.2 M for 4)
This research was supported by the High-Tech Research Center
Project for Private Universities: Matching Fund Subsidy, 2006–
2011, from the Ministry of Education, Culture, Sports, Science
and Technology of Japan (MEXT).
BnO
BnO
HO
5-8
R
4
+
º
70 C, 4.0 mmHg,
BnO
9-12
OR
(1.1 eq.)
30 min
Supplementary data
OBn
R=
12
Supplementary data (experimental procedures and character-
ization of new compounds) associated with this article can be
found, in the online version, at doi:10.1016/j.tetlet.2010.09.108.
5, 9
6, 10
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