Novel stereocontrolled α- and β-glycosidations of mannopyranosyl sulfoxides using environmentally benign heterogeneous solid acids

Article abstract of DOI:10.1016/S0040-4039(01)00674-8

The environmentally benign and stereocontrolled glycosidations of mannopyranosyl sulfoxides and alcohols using a heterogeneous solid acid, Nafion-H or sulfated zirconia (SO₄/ZrO₂) as a new activator for the direct syntheses of both the α- and β-mannopyranosides have been developed.

Full text of DOI:10.1016/S0040-4039(01)00674-8

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 4159–4162
Novel stereocontrolled a- and b-glycosidations of
mannopyranosyl sulfoxides using environmentally benign
heterogeneous solid acids
Hideyuki Nagai, Kanako Kawahara, 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 12 March 2001; revised 16 April 2001; accepted 20 April 2001
Abstract—The environmentally benign and stereocontrolled glycosidations of mannopyranosyl sulfoxides and alcohols using a
heterogeneous solid acid, Nafion-H or sulfated zirconia (SO4/ZrO2) as a new activator for the direct syntheses of both the a- and
b-mannopyranosides have been developed. © 2001 Elsevier Science Ltd. All rights reserved.
Glycosubstances including glycolipids, glycoproteins
and many antibiotics continue to be the central focus of
research both in chemistry and biology. Since a- and
b-mannopyranosides frequently appear in many natur-
ally occurring bioactive substances, the stereocon-
trolled construction of a- and b-mannopyranosides is of
considerable importance in synthetic organic chem-
istry.1 The stereoselective and direct formation of b-
mannopyranoside has proved particularly difficult to
achieve because the axial b-hydroxy group at the C2
position and the anomeric effect blocks access to the
b-face.2 On the other hand, a practical and environmen-
tally benign glycosidation method without using a
heavy metal or a Lewis acid, which is not reusable and
would make the reaction solvent dirty, is urgently
needed both in the laboratory and in industry. There-
fore, the highly stereocontrolled synthesis of both the a-
and b-mannopyranosides in an environmentally
friendly manner is of particular interest. In a previous
paper, we demonstrated the stereocontrolled mannopy-
ranoside formation with mannopyranosyl fluoride using
a heterogeneous promoter, sulfated zirconia (SO4/
ZrO2).3 Recently, glycosyl sulfoxide has been paid con-
siderable attention as an effective glycosyl donor (as
Kahne’s glycosidation)4 as well as glycosyl fluoride,
because glycosyl sulfoxide can be easily prepared from
another glycosyl donor, thioglycoside, and converted
into the other glycosyl donor, sulfonylglycoside.1,2 In
this context, the intermolecular b-stereoselective
mannopyranosylation of 4,6-O-benzylidene protected
mannopyranosyl sulfoxides using a homogeneous acti-
vator, triflic anhydride (Tf2O), was announced by
Crich.5 In this letter, we now report the novel stereo-
controlled glycosidations of mannopyranosyl sulfox-
ides
1
and
2
with several alcohols using an
environmentally compatible heterogeneous solid acid,
1
2
Nafion-H
OBn
SO4/ZrO2
OBn
O
OBn
O
BnO
BnO
BnO
BnO
BnO
BnO
BnO
MS 5A
MeCN
MS 5A
Et2O
O
BnO
BnO
+
R OH
OR
Y
X
OR
α-Mannopyranoside
β-Mannopyranoside
1: X=S(O)Ph, Y=H
2: X=H, Y=S(O)Ph
Mannopyranosyl sulfoxides
Figure 1. Stereocontrolled mannosylations using heterogeneous solid acids.
Keywords: sulfoxide glycosidation; heterogeneous solid acid; Nafion-H; sulfated zirconia; a- and b-mannopyranosides.
* Corresponding author. Tel./fax: +81 45 566 1576; e-mail: toshima@applc.keio.ac.jp
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)00674-8

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H. Nagai et al. / Tetrahedron Letters 42 (2001) 4159–4162
Nafion-H or SO4/ZrO2, as a new activator for the direct
syntheses of both the a- and b-mannopyranosides in
high yields (Fig. 1).
was confirmed that the b-mannopyranosyl sulfoxide 2 is
a better glycosyl donor than the a-anomer 1 with
respect to both the chemical yield and b-stereoselectiv-
ity (entries 8 and 9), and only the use of SO4/ZrO2 in
Et2O provided b-stereoselectivity among the examined
conditions (entries 9–14). Moreover, the use of 300 wt%
In our first experiments, we examined the glycosida-
tions of the totally benzylated a- and b-mannopyran-
osyl sulfoxides 1 and 2 with cyclohexylmethanol (3)
using several heterogeneous solid acids such as mont-
morillonite K-10,6 Nafion-H7 and SO4/ZrO2,8 all of
which are well known as environmentally benign solid
acids because they could be recovered from the reaction
mixture only by filtration and then reused. These results
are summarized in Table 1. It was found that the
glycosidation of a-mannopyranosyl sulfoxide 1 using
Nafion-H smoothly proceeded to give the mannopyra-
noside 9 in moderate yield (entry 3). It was also con-
firmed that MeCN was shown to be superior to the other
solvents such as CH2Cl2, PhMe and Et2O (entries 3–6).
However, when the reaction was performed in MeCN,
considerable amounts of the corresponding 1-hydroxy
sugar was produced, while the unreacted glycosyl donor
,
SO4/ZrO2 in the presence of an equal amount of 5 A
MS9 led to the satisfactory result for the b-stereoselec-
tive mannopyranosylation (entry 15). Thus, the glycosi-
dation of b-mannopyranosyl sulfoxide 2 and 3 using
,
300 wt% SO4/ZrO2 and 300 wt% 5 A MS in EtO2 at
25°C for 3 h selectively furnished the b-mannopyrano-
side 9b in high yield with high stereoselectivity.
To enhance the synthetic utility of this novel and
environmentally benign protocol, the glycosidations
using other primary and secondary alcohols 4–8 includ-
ing sugar derivatives were examined next. Based on the
results summarized as entries 1–6 in Table 2, all the
glycosidations of 1 and 4–8 using 100 wt% Nafion-H in
MeCN at 25°C for 3 h, as well as that of 3, effectively
proceeded to give the corresponding a-mannopyrano-
sides 10a–14a, respectively, in high yields with high
stereoselectivity. On the other hand, the b-stereoselec-
tive mannopyranosylation using 2 with 4–8 are outlined
as entries 7–12 in Table 2. Although the b-mannopyrano-
side 14b was produced from 2 and 8 with moderate
stereoselectivity, other b-mannopyranosides 10b–13b
were obtained in high yield with good stereoselectivity
by the glycosidations of 2 and 4–7 under the conditions
similar to that for 9b. Since the configuration of the
anomeric position was not epimerized by exposure of
the isolated single anomer of the O-mannopyranoside
was recovered in CH2Cl2, PhMe and Et2O. The use of
9
,
,
5 A molecular sieves (5 A MS) as an additive in MeCN
led to the high chemical yield and stereoselectivity for
the a-mannopyranoside 9a (entry 7). Thus, the glycosi-
dation of a-mannopyranosyl sulfoxide 1 and 3 using
,
100 wt% Nafion-H and 100 wt% 5 A MS in MeCN at
25°C for 3 h exclusively gave the a-mannopyranoside
9a in high yield with high stereoselectivity. On the other
hand, after many attempts for the successful b-stereo-
selective mannopyranosylation, we finally found that
the glycosidation of b-mannopyranosyl sulfoxide 2
using SO4/ZrO2 in Et2O proceeded to selectively give
the b-mannopyranoside 9b (entry 9). Furthermore, it
Table 1. Glycosidations of 1 and 2 with cyclohexylmethanol (3) using solid acidsa
OBn
BnO
OBn
O
solid acid
BnO
BnO
BnO
O
BnO
BnO
+
Y
OH
solvent
O
X
25 °C, 3 h
9
3
1: X=S(O)Ph, Y=H
2: X=H, Y=S(O)Ph
Entry
Glycosyl donor
Solid acid (wt%)
Additive
Solvent
Yield (%)
a/b Ratiob
1
2
3
4
5
6
7
8
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
Montmorillonite K-10 (100)
SO4/ZrO2 (100)
Nafion-H (100)
Nafion-H (100)
Nafion-H (100)
Nafion-H (100)
Nafion-H (100)
SO4/ZrO2 (100)
SO4/ZrO2 (100)
SO4/ZrO2 (100)
SO4/ZrO2 (100)
SO4/ZrO2 (100)
Nafion-H (100)
Montmorillonite K-10 (100)
SO4/ZrO2 (300)
–
–
–
–
–
–
MeCN
MeCN
MeCN
CH2Cl2
PhMe
Et2O
MeCN
Et2O
Et2O
MeCN
CH2Cl2
PhMe
Et2O
Et2O
Et2O
6
38
64
Trace
Trace
Trace
97
2
17
52
4
4
21
8
99
60/40
57/43
77/23
–
–
–
97/3
39/61
32/68
64/36
75/25
74/26
67/33
58/42
19/81
,
5 A MS (100)
–
–
–
–
–
–
–
9
10
11
12
13
14
15
,
5 A MS (300)
a All reactions were carried out using 2.0 equiv. of 3 to the glycosyl donor.
b a:b Ratios were determined by HPLC analysis (column, CrestPack C18S®, 4.6×150 mm; eluent, 10% H2O in MeCN; flow rate, 1.0 ml/min, 40°C;
detection, UV 250 nm).

H. Nagai et al. / Tetrahedron Letters 42 (2001) 4159–4162
4161
Table 2. a- and b-Stereoselective glycosidations of 1 and 2 with several alcoholsa
Nafion-H (100 wt%)
MS 5A (100 wt%)
1
OBn
O
MeCN
25 ˚C, 3 h
BnO
BnO
BnO
OBn
O
BnO
BnO
BnO
Y
+
R OH
SO4/ZrO2 (300 wt%)
MS 5A (300 wt%)
O R
X
1: X=S(O)Ph, Y=H
2: X=H, Y=S(O)Ph
9~14
2
Et2O
25 ˚C, 3 h
2
1
Entry
Yield (%) α/β Ratiob
Yield (%) α/β Ratiob
Alcohol
Product
1, 7
97
97/3
99
19/81
9
HO
3
4
2, 8
3, 9
99
94
96/4
97/3
99
95
21/79
20/80
10
11
HO
HO
5
6
HO
4, 10
5, 11
12
13
94
90
97/3
98/2
93
85
23/77
26/74
OH
O
BnO
BnO
BnO
OMe
7
O
OBn
O
6, 12
14
80
96/4
70
38/62
HO
N3
8
a All reactions were carried out by use of 2.0 equiv. of the alcohol to the glycosyl donor.
bα:β Ratios were determined by HPLC analysis (column, CrestPack C18S®, 4.6 x 150 mm;
eluent, 10% H2O in MeCN; flow rate, 1.0 mL/min, 40 ˚C; detection, UV 250 nm).
for both reaction conditions, the predominant a- and
b-stereoselectivities observed in the present glycosida-
tions must occur kinetically.
(1.0 mmol) in dry Et2O (5.0 ml) were added powdered
5 A MS (300 wt% to 1) and SO4/ZrO2 (300 wt% to 1).
After stirring for 3 h at 25°C, a similar workup and
purification mentioned above gave the mannopyran-
osides which included its b-anomer as the major
product.
,
The general experimental protocols for the preparations
of the a- and b-mannopyranosides.10 a-Mannopyran-
osides: To a stirred solution of the a-mannopyranosyl
sulfoxide 1 (0.5 mmol) and an alcohol (1.0 mmol) in
In conclusion, we have described the novel and stereo-
controlled strategy for the direct syntheses of both a-
and b-mannopyranosides from mannopyranosyl sulfox-
ides and alcohols using an environmentally acceptable
heterogeneous solid acid. Moreover, the results includ-
ing the simple protocol, high yield and stereoselectivity
should find wide application in the synthesis of
biomolecules and functional materials. Further studies
along this line are currently underway.
,
dry MeCN (5.0 ml) were added powdered 5 A MS (100
wt% to 1) and Nafion-H (100 wt% to 1). After stirring
for 3 h at 25°C, the mixture was filtered and the filtrate
was concentrated in vacuo. Purification of the residue
by flash column chromatography gave the mannopy-
ranosides, which predominately contained its a-anomer.
b-Mannopyranosides: To a stirred solution of the b-
mannopyranosyl sulfoxide 2 (0.5 mmol) and an alcohol
.

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H. Nagai et al. / Tetrahedron Letters 42 (2001) 4159–4162
Acknowledgements
643.
4. Kahne, D.; Walker, S.; Cheng, Y.; Van Engen, D. J. Am.
Chem. Soc. 1989, 111, 6881.
This work was partially supported by the New Energy
and Industrial Technology Development Organization
(NEDO) and the Research Institute of Innovative
Technology for the Earth (RITE).
5. (a) Crich, D.; Sun, S. J. Org. Chem. 1996, 61, 4506; (b)
Crich, D.; Sun, S. J. Org. Chem. 1997, 62, 1198; (c) Crich,
D.; Sun, S. J. Am. Chem. Soc. 1998, 120, 435.
6. Montmorillonite K-10 was purchased from Aldrich
Chemical Company, Inc. and dried at 200°C/1 mmHg for
12 h before using.
References
7. 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.
8. SO4/ZrO2 was purchased from Wako Pure Chemical
Industries, Ltd. and dried at 200°C/1 mmHg for 12 h
before using.
1. For some reviews on O-glycosidations, see: (a) Schmidt,
R. R. Angew. Chem., Int. Ed. Engl. 1986, 25, 212; (b)
Sinay¨, P. Pure Appl. Chem. 1991, 63, 519; (c) Toshima,
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G.-J. Tetrahedron 1996, 52, 1095; (e) Preparative Carbo-
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,
9. 5 A MS was shown to be slightly superior to other MS
,
,
such as 3 A MS and 4 A MS.
10. All a- and b-mannopyranosides were purified by silica gel
column chromatography and were fully characterized by
spectroscopic means. The anomeric configuration was
2. For a recent review on b-mannosylation, see: Gridley, J.
J.; Osborn, H. M. I. J. Chem. Soc., Perkin Trans. 1 2000,
1471.
1
assigned in each case with the aid of H NMR analysis
and confirmed by the comparison with the authentic
3. Toshima, K.; Kasumi, K.; Matsumura, S. Synlett 1988,
samples, see: Ref. 3 and references cited therein.
.