Environmentally benign and stereoselective formation of β-O-glycosidic linkages using benzyl-protected glucopyranosyl phosphite and montmorillonite K-10

Article abstract of DOI:10.1016/S0040-4039(01)02252-3

An environmentally benign and highly stereoselective β-glucopyranosylation without neighboring group participation has been developed employing benzyl-protected glucopyranosyl diethyl phosphite as a glycosyl donor and montmorillonite K-10 as an activator.

Full text of DOI:10.1016/S0040-4039(01)02252-3

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 847–850
Environmentally benign and stereoselective formation of
b-O-glycosidic linkages using benzyl-protected glucopyranosyl
phosphite and montmorillonite K-10
Hideyuki Nagai, Shuichi Matsumura and Kazunobu Toshima*
Department of Applied Chemistry, Faculty of Science and Technology, Keio University, 3-14-1 Hiyoshi, Kohoku-ku,
Yokohama 223-8522, Japan
Received 29 October 2001; revised 21 November 2001; accepted 22 November 2001
Abstract—An environmentally benign and highly stereoselective b-glucopyranosylation without neighboring group participation
has been developed employing benzyl-protected glucopyranosyl diethyl phosphite as a glycosyl donor and montmorillonite K-10
as an activator. © 2002 Elsevier Science Ltd. All rights reserved.
Carbohydrates are a naturally abundant and recyclable
feedstock. On the other hand, a number of glycosides
and oligosaccharides are found in many bioactive or
functional molecules. One of the most important trans-
formation reactions of carbohydrates is a chemical
glycosidation,1 which is very useful for preparing both
natural and unnatural glycosides. Therefore, a highly
effective, simple and environmentally benign glycosida-
tion method is now urgently needed both in the labora-
tory and in industry. In this context, the greening of
chemical glycosidation may include the use of a hetero-
geneous and reusable solid acid as an activator. In
previous studies, we have demonstrated several
stereoselective O-glycosidations using glycals,2 glycosyl
fluorides,3 glycosyl sulfoxides4 and 1-hydroxy sugars5 as
glycosyl donors and montmorillonite K-10, sulfated
zirconia (SO4/ZrO2) or Nafion®-H as environmentally
friendly promoters. Glycosyl phosphites have also
attracted considerable attention as effective glycosyl
donors,6–10 and Wong7c and Hashimoto9a have indepen-
dently announced the highly stereoselective 1,2-trans-b-
glycosidation reactions of glycopyranosyl phosphites
OBn
O
OBn
O
montmorillonite K-10
BnO
BnO
BnO
+
R OH
BnO
OP(OEt)2
OR
OBn
OBn
10:1 CH2Cl2-MeCN
-20 °C, 30 min
(β>>α)
1
HO
HO
HO
HO
2
3
4
5
OMe
OH
O
Me
HO
BnO
BnO
O
O
Ph
O
O
O
O
BnO
BnO
OMe
HO
OMe
6
8
7
Figure 1.
Keywords: glycosidation; glycosyl phosphite; b-glucopyranoside; solid acid; montmorillonite K-10.
* Corresponding author. Tel./fax: +81 45 566 1576; e-mail: toshima@applc.keio.ac.jp
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)02252-3

848
H. Nagai et al. / Tetrahedron Letters 43 (2002) 847–850
using a homogeneous promoter. In this letter, we dis-
close the novel and environmentally benign glycosida-
tions of glucopyranosyl phosphite and alcohols using a
heterogeneous and reusable solid acid, montmorillonite
K-10, for the highly stereoselective synthesis of b-
glucopyranosides with a non-participating group (Fig.
1). To the best of our knowledge, this is the first
example of heterogeneous solid acid-mediated glycosi-
dation of glycosyl phosphite.
It was confirmed that the highest yield was obtained in
CH2Cl2 while the highest b-stereoselectivity was
observed in MeCN. In addition, the glycosidation effec-
tively proceeded even at 0°C for 30 min in both cases.
Furthermore, the addition of 100 wt% montmorillonite
K-10 to the glycosyl donor 1 led to the best results and
the use of a smaller or larger amount of montmoril-
lonite K-10 was less effective in both cases. Therefore,
we further examined the glycosidations of 1 and 2 using
100 wt% montmorillonite K-10 in mixed-solvents of
CH2Cl2 and MeCN. After several attempts, we finally
found that the glycosidation of 1 and 2 using 100 wt%
montmorillonite K-10 in 10:1 CH2Cl2–MeCN at −20°C
for 30 min was the best combination to afford the
corresponding glucopyranosides in 94% yield with 6:94
a/b-stereoselectivity.
In our first experiments, we examined the glycosida-
tions of the totally benzylated glucopyranosyl diethyl
phosphite 1 (a/b=73/27) and cyclohexylmethanol (2)
using several heterogeneous solid acids such as
Nafion®-H,11 sulfated zirconia (SO4/ZrO2)12 and mont-
morillonite K-10.13 These heterogeneous solid acids are
well known as environmentally benign solid acids
because they are easily handled due to their nonvolatile,
noncorrosive and odorless properties, and they can be
recovered from the reaction mixture by only filtration
and then reused. These results are summarized in Table
1. It was found, for the first time, that the glucosyl
phosphite 1 was effectively activated by these heteroge-
neous solid acids in CH2Cl2 under mild conditions and
smoothly coupled with the alcohol 2 to give the corre-
sponding glucopyranosides in high yield. Among them,
montmorillonite K-10 was shown to be superior to the
other solid acids with respect to both the chemical yield
and unusual b-stereoselectivity.14 Next our attention
turned to the solvent effect on this glycosidation.
Therefore, the glycosidations of 1 and 2 using montmo-
rillonite K-10 in several solvents such as MeCN, PhMe
and Et2O were tested and compared to that in CH2Cl2.
To enhance the synthetic utility of this novel glycosida-
tion, the glycosidations using other primary and sec-
ondary alcohols 3–8 including sugar derivatives 6–8
were next examined. Based on the results summarized
in Table 2, the glycosidations of 1 and 3–5 using 100
wt% montmorillonite K-10 in 10:1 CH2Cl2–MeCN at
−20°C for 30 min, as well as that of 2, effectively
proceeded to give the corresponding b-glucopyrano-
sides in high yields. When the sugar derivatives 6–8
were employed as the glycosyl acceptors, a longer reac-
tion time (2 h) was required, and 3.0 equiv. of the
glycosyl acceptor was needed in the case of the low
reactive glycosyl acceptor such as 7 to obtain the good
yields of the corresponding b-glucopyranosides. Since
the configuration of the anomeric position was not
Table 1. Glycosidations of 1 and 2 by a solid acid under several conditionsa
OBn
O
OBn
O
solid acid
BnO
BnO
BnO
BnO
+
HO
OP(OEt)2
OR
OBn
OBn
2
1
Entry
Solid acid (wt%)
Solvent (0.1 M)
Temp. (°C)
Time (h)
Yield (%)b
a/b ratioc
1
2
3
4
5
6
7
8
Nafion®-H (100)
SO4/ZrO2 (100)
K-10 (100)
K-10 (100)
K-10 (100)
K-10 (100)
K-10 (50)
K-10 (100)
K-10 (200)
K-10 (50)
K-10 (100)
K-10 (200)
K-10 (100)
K-10 (100)
K-10 (100)
CH2Cl2
CH2Cl2
CH2Cl2
Et2O
MeCN
PhMe
CH2Cl2
CH2Cl2
CH2Cl2
MeCN
MeCN
MeCN
25
25
25
25
25
25
0
0
0
0
0
15
15
15
15
15
15
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
83
73
90
62
75
80
89
93
92
83
86
84
82
94
87
28/72
55/45
27/73
56/44
18/82
26/74
23/77
23/77
24/76
11/89
11/89
14/86
6/94
9
10
11
12
13
14
15
0
CH2Cl2–MeCN (5:1)d
CH2Cl2–MeCN (10:1)d
CH2Cl2–MeCN (15:1)d
−20
−20
−20
6/94
10/90
a All reactions were carried out by use of 2.0 equiv. of 2 to 1.
b Isolated yields after purification by column chromatography.
c a:b Ratios were determined by HPLC analysis (column, CrestPak C18S®, 4.6×150 mm; eluent, 10% H2O in MeCN; flow rate, 1.0 mL/min, 40°C;
detection, UV 250 nm).
d 0.05 M solvent was used. K-10: montmorillonite K-10.

H. Nagai et al. / Tetrahedron Letters 43 (2002) 847–850
849
Table 2. Glycosidations of 1 and several alcohols 2–8 by montomorillonite K-10
OBn
O
OBn
O
montmorillonite K-10
(100 wt%)
BnO
BnO
BnO
BnO
+
R OH
OP(OEt)2
OR
OBn
10:1 CH2Cl2-MeCN
-20 ˚C
OBn
2-8
1
Entry
Alcohola
Time (h)
Yield (%)b
a/b Ratioc
1
2
3
4
5
6
7
2
3
4
5
0.5
0.5
0.5
0.5
2
94
88
88
86
77
74
73
6/94
6/94
7/93
8/92
7/93
6
7d
8
2
2
16/84
13/87
a All reactions were carried out by use of 2.0 equiv. of alcohol to 1.
b Isolated yields after purification by column chromatography.
c a:b Ratios were determined by HPLC analysis (column, CrestPak C18S®, 4.6×150 mm; eluent, 10% H2O in MeCN for entries 1–4, 6 and 7,
12.5% H2O in MeCN for entry 5; flow rate, 1.0 mL/min, 40°C; detection, UV 250 nm).
d 3.0 equiv. of alcohol was used.
epimerized under the present glycosidation conditions,
the predominant b-stereoselectivity must arise from
kinetic control.
Acknowledgements
This research was partially supported by grants from
the New Energy and Industrial Technology Develop-
ment Organization (NEDO) and the Research Institute
of Innovative Technology for the Earth (RITE).
Finally, we tested the solid acid recycling. After filtra-
tion, washing with methanol and heating at 100°C/1
mmHg for 12 h, the montmorillonite K-10 was reused
for at least three times and showed good to high yields
and high stereoselectivities as described in Table 3.
References
The general experimental protocol:15 To a stirred solu-
tion of 2,3,4,6-tetra-O-benzyl-D-glucopyranosyl diethyl
1. For some reviews on O-glycosidations, see: (a) Schmidt,
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phosphite 1 (a/b=73/27, 0.1 mmol) and an alcohol (0.2
mmol) in dry 10:1 CH2Cl2–MeCN (2 mL) was added
montmorillonite K-10 (100 wt% to the glycosyl donor
1). After stirring at −20°C for 30 min, the mixture was
filtered and the filtrate was concentrated in vacuo.
Purification of the residue by flash column chromato-
graphy gave the corresponding glucopyranosides which
predominately contained the b-anomer.
In conclusion, we have presented the novel and highly
stereoselective synthesis of b-glucopyranosides by the
glycosidations of benzyl-protected glucopyranosyl
diethyl phosphite and alcohols using a heterogeneous
and environmentally acceptable solid acid, montmoril-
lonite K-10. The results including the simple and envi-
ronmentally friendly protocol, high yield and
stereoselectivity should find widespread application for
the synthesis of carbohydrate-containing bioactive or
functional molecules.
Table 3. Recycling of montmorillonite K-10 in glycosida-
tion of 1 and 2
8. (a) Watanabe, Y.; Nakamoto, C.; Ozaki, S. Synlett 1993,
115; (b) Watanabe, Y.; Nakamoto, C.; Yamamoto, T.;
Ozaki, S. Tetrahedron 1994, 50, 6523.
9. (a) Hashimoto, S.; Umeo, K.; Sano, A.; Watanabe, N.;
Nakajima, M.; Ikegami, S. Tetrahedron Lett. 1995, 36,
Recycling number
0
1st
2nd
3rd
Yield (%)
a/b ratio
94
6/94
90
5/95
86
5/95
70
7/93

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H. Nagai et al. / Tetrahedron Letters 43 (2002) 847–850
2251; (b) Hashimoto, S.; Sano, A.; Sakamoto, H.; Naka-
before using.
jima, M.; Yamagiya, Y.; Ikegami, S. Synlett 1995, 1271;
(c) Tanaka, H.; Sakamoto, H.; Nakamura, S.; Nakajima,
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13. Montmorillonite K-10 was purchased from Aldrich
Chemical Company, Inc. and dried at 200°C/1 mmHg for
12 h before using.
14. It is noteworthy that the tendency during the stereoselec-
tivity of the present glycosidation is similar to those in
Wong’s, Watanabe’s and Hashimoto’s glycosidations, all
of which use benzyl-protected glucopyranosyl phosphite
and a homogeneous promoter, see: Refs. 7c, 8a and 9a.
15. All a- and b-glucopyranosides were purified by silica gel
column chromatography and were fully characterized by
spectroscopic means. The configurations of the anomeric
centers were clearly confirmed by the coupling constants
10. (a) Schene, H.; Waldmann, H. Eur. J. Org. Chem. 1998,
1227; (b) Schene, H.; Waldmann, H. Synthesis 1999,
1411.
11. Nafion®-H was purchased from Aldrich Chemical Com-
pany, Inc. as Nafion® perfluorinated ion-exchange pow-
der and dried at 25°C/1 mmHg for 2 h before using.
12. SO4/ZrO2 was purchased from Wako Pure Chemical
Industries, Ltd. and dried at 200°C/1 mmHg for 12 h
1
between H-1 and H-2 in the H NMR analyses.