A fluorous-assisted synthesis of oligosaccharides using a phenyl ether linker as a safety-catch linker

Article abstract of DOI:10.1016/j.tet.2011.09.030

We report on the fluorous-assisted synthesis of oligosaccharides using a phenyl ether linker. The phenyl ether linker is stable under both acidic and basic conditions but can be cleaved under mildly acidic conditions after reduction to a vinyl ether. The utility of the method was demonstrated by the synthesis of a trisaccharide. A protected trisaccharide with a light-fluorous tag was directly prepared by one-pot glycosylation using three building blocks that contained a building block with a light-fluorous tag though a phenyl ether. A Birch reduction of the trisaccharide provided a fully deprotected trisaccharide with the fluorous tag attached through a vinyl ether, which was easily purified by solid-phase extraction. The tag was cleaved from the sugar portion by treatment with 3% TFA in MeOH.

Full text of DOI:10.1016/j.tet.2011.09.030

Tetrahedron 67 (2011) 10011e10016
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
A fluorous-assisted synthesis of oligosaccharides using a phenyl ether linker
as a safety-catch linker
*
Hiroshi Tanaka, Yosuke Tanimoto, Tetsuya Kawai, Takashi Takahashi
Department of Applied Chemistry, Graduate School of Science and Engineering, Tokyo Institute of Technology, 2-12-1-H-101 Ookayama, Meguro, Tokyo 152-8552, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 30 July 2011
Received in revised form 8 September 2011
Accepted 9 September 2011
Available online 19 September 2011
We report on the fluorous-assisted synthesis of oligosaccharides using a phenyl ether linker. The phenyl
ether linker is stable under both acidic and basic conditions but can be cleaved under mildly acidic
conditions after reduction to a vinyl ether. The utility of the method was demonstrated by the synthesis
of a trisaccharide. A protected trisaccharide with a light-fluorous tag was directly prepared by one-pot
glycosylation using three building blocks that contained a building block with a light-fluorous tag
though a phenyl ether. A Birch reduction of the trisaccharide provided a fully deprotected trisaccharide
with the fluorous tag attached through a vinyl ether, which was easily purified by solid-phase extraction.
The tag was cleaved from the sugar portion by treatment with 3% TFA in MeOH.
Keywords:
One-pot glycosylation
Oligosaccharides
Hydroquinone
Vinyl ether
Ó 2011 Elsevier Ltd. All rights reserved.
Birch reduction
1. Introduction
provide 7, followed by removal of the protecting groups on the solid
to afford 8. Birch reduction was found to be effective for removing
Oligosaccharides play important roles in cell surface events via
carbohydrateeprotein and carbohydrateecarbohydrate in-
teractions.1 The chemical synthesis of structurally defined oligo-
saccharides would be highly desirable for use in structureeactivity
relationship studies, due to the fact that oligosaccharides from
natural sources can be produced in only limited qualities. Recent
progress in oligosaccharide synthesis has resulted in a number of
new and efficient glycosidation methodologies, which are amena-
ble to the synthesis of protected oligosaccharides by standardized
and routine protocols.2 We recently reported on the development
of an efficient method for the synthesis of oligosaccharides, that is,
based on one-pot glycosylation3,4 and polymer-assisted depro-
tection5 (Scheme 1). The one-pot glycosylation involved the se-
quential chemo- and regioselective glycosylation to provide the
protected oligosaccharides 4 from several simple building blocks 1,
2, and 3 in one pot. This methodology was effective, not only for the
synthesis of single target oligosaccharides, but also for the syn-
thesis of an oligosaccharide library.6 The protected oligosaccharides
4 were loaded on a solid-support via the prelinker 6 containing an
activated ester and a vinyl ether and the solid-supported amine 5 to
benzyl ethers on solid-supported oligosaccharides. Release from
the solid-support was achieved using a volatile acid, such as TFA, to
provide the fully deprotected trisaccharide 9. The solid-support
acts as a tag for ease of treating the partially and fully depro-
tected oligosaccharides. If the tag for purification is attached to one
of the building blocks for the synthesis of oligosaccharides, the tag-
installation process can be omitted. However, the solid-supported
substrates would not be suitable substrate for one-pot glycosyla-
tion and the acetal linker is not sufficiently stable to survive acidic
glycosidation conditions used.
Fluorous-assisted solution synthesis involving the use of per-
fluoroalkanes as tags for purification is an effective method for
high-speed synthesis of organic compound with minium manipu-
lations for workup and purificaiton.7,8 The heavy-fluorous tag en-
ables selective extraction of the tagged compounds in fluorous
solvents. However, it could reduce the reactivity of the tagged
compounds. On the other hand, the light-fluorous tag enables the
tagged compounds to be separated by solid-phase extraction with
minimum effects on their reactivity.9
Applications of the both heavy- and light-fluorous tag to the
oligosaccharide synthesis have been reported from several research
groups.10,11 They are mainly focused on the purification after gly-
cosylations. Herein we report on the fluorous-assisted liquid-phase
synthesis of oligosaccharides using a phenyl ether linker as a safety-
catch linker.
* Corresponding author. Tel.: þ81 3 5734 2120; fax: þ81 3 5734 2884; e-mail
address: ttak@apc.titech.ac.jp (T. Takahashi).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.09.030

10012
Previous works
H. Tanaka et al. / Tetrahedron 67 (2011) 10011e10016
Solid-
Loading on solid
Deprotection
One-pot
Solid-
support
on solid
glycosylation
support
O
NH
Solid-
O
NH
support
OP
O
NH2
O
X
OP
O
O
O
OP
O
O
O
OH
O
P'O
5
P'O
O
OP
O
1
OP
O
OH
O
6
X1
OP
O
O
O
O
OP
OP
O
OH
O
HO
O
O
O
O
X2
2
OP
OR
OR
OR
HO
O
4
7
8
3
OR
Cleavage
This works
Deprotection
and
reduction of the linker
One-pot
Fluorous tag
Fluorous tag
Cleavage
Fluorous tag
glycosylation
OH
O
OP
OH
OP
O
HO
O
O
OH
O
O
O
O
OP
O
OH
O
O
OH
O
O
O
X1
10
OP
O
OP
O
OH
O
O
HO
O
O
OR
X2
2
OR
11
OR
12
OP
O
HO
9
3
OR
Scheme 1. Strategy for the synthesis of oligosaccharides based on a one-pot glycosylation and a tag-assisted deprotection.
2. Results and discussion
hydroquinone 13 with tosylate 14 under basic conditions for 30 min
70 ꢀC, followed by the addition of sodium azide to the reaction
mixture provided the azido compound 15. The subsequent removal
of the THP ether under acidic conditions provided phenol 16 in 90%
yield. O-Alkylation of the phenol with the tosylate 17 provided the
tri-O-benzyl glucoside 18 in 80% yield. Attaching the light-fluorous
tag to the sugar unit 18 was achieved by reduction of the azido
group to an amine, followed by acylation with trideca-
fluoroheptanoyl chloride to provide the tri-O-benzyl glucoside 19
with a fluorous tag through the phenyl ether linker. Cleavage of the
phenyl ether linker was examined next. The phenyl ether 19 was
treated with sodium in liquid ammonia in the presence of EtOH at
reflux for 1 h. After the reaction mixture was concentrated in vacuo,
the residue was directly subjected to fluorous column chromatog-
raphy. 1H NMR analysis of the crude material indicated that the
phenyl ether was reduced to a vinyl ether and all of the benzyl ether
protecting groups had been removed. In addition, it should be
noted that mass spectrum of 20 indicated that the alkylfluorides
had been partially reduced. Treatment of the crude material under
mildly acidic conditions provided a-methyl glucoside (21) in 78%
based on 19. The released fluorous tag was easily removed by solid-
phase extraction.
We next examined the fluorous-assisted synthesis of di-
saccharide 30 from the glycosyl donor 26 attached to a fluorous tag
(Scheme 3). Treatment of thioglycoside 22 and phenol 23 with
tributylphosphine and 1,10-(azodicarbonyl) dipiperidine at 60 ꢀC for
18 h provided the phenyl ether 24 in 72% yield. The chloride 24 was
Our strategy for the light-fluorous-assisted synthesis of oligo-
saccharides using the phenyl ether linker is shown in Scheme 1. The
first step involves the synthesis of protected oligosaccharides by
a one-pot glycosylation using the sugar units 2, 3, and 10, in which
one of the building blocks 10 contains a light-fluorous tag attached
through a phenyl ether. The phenyl ether linker is stable under the
acidic and/or oxidative glycosylation conditions employed in the
synthesis. This method enables the direct preparation of the tag-
installed oligosaccharides. 11 The second step involves the depro-
tection of the protected oligosaccharides and reduction of the
phenyl ether linker to a vinyl ether. Exposure of the fluorous-
attached oligosaccharides 11 to Birch reduction conditions would
result in, not only the removal of esters and benzyl ethers, but also
the reduction of the phenyl ether to the vinyl ether 12. Purification
of the highly polar oligosaccharides was achieved by solid-phase
extraction. The third step involves the cleavage of the vinyl ether
linker by treatment with a volatile acid such as TFA to provide the
fully deprotected oligosaccharides 9. Although applications of the
phenyl ether linker for the fluorous-assisted synthesis of oligosac-
charides have been reported by Goto and Mizuno,10a,11e,12 the use of
the volatile reagents for cleaving the tag are critical for the ease of
workup and purification of the fully deprotected oligosaccharides.
We first examined cleavage of the phenyl linker by reduction
and hydrolysis (Scheme 2). The preparation of the substrate 19 is
shown in Scheme 2. Treatment of the mono-THP protected

H. Tanaka et al. / Tetrahedron 67 (2011) 10011e10016
10013
TsO
BnO
O
O
Cl
O
O
23
nBu3P
TsO
Cl
OTag
O
O
O
O
X
BnO
OMe
O
14
O
O
N3
OBn
OH
O
K2CO3
O
N
O
N3
OH
17
HO
BnO
N
N
N
DMF, 70 o
C
1) Zn NH4Cl
O
O
2)
O
Cl C6F13
then NaN3
70 o
BnO
BzO
NaH, DMF
80 %
72%
BnO
BzO
O
BnO
BnO
O
C
BzO
SPh
OR
OTHP
O
SPh
OBz
SPh
NEt3, THF
13
15 : R = THP
16 : R = H
OMe
OBz
26
CSA, MeOH, 90%
OBz
OBn
22
65%
18
1) Zn, NH4Cl
24 : X = Cl
25 : X = N3
NaN3, TBAI, quant.
HO
O
O
F
F
F
F
F
F
F
O
O
N
Tag =
O
O
O
N
H
C6F13
H
F
F
F
51%
F
F
then NEt3,
F
Cl
C6F13
BnO
BnO
(1.5 equv)
O
Tag
Na
OMe
NH3(l)
NIS/cat TfOH, CH2Cl2, 72%
OTag
O
OBn
27
THF/EtOH
refux, 1 h
BnO
BnO
O
HO
HO
OMe
3% TFA
MeOH
OBn
O
OTag
OTag
O
78%
then MeOH
HO
OMe
19
HO
HO
HO
HO
O
OH
21
Na
NH3(l)
OMe
3% TFA
in MeOH
O
O
OH
20
THF/EtOH
HO
O
HO
HO
O
BnO
BzO
then MeOH
OH
HO
67%
O
based on 28
O
Scheme 2.
O
O
OH
HO
OMe
OBz
BnO
HO
HO
O
OH
O
converted to the azido compound 25 in quantitative yield. Re-
duction of the azido 25 to an amine, followed by acylation with
tridecafluoroheptanoyl chloride provided the thioglycoside 26 at-
tached to a fluorous tag. Glycosylation of the glycoside 27 with the
thioglycoside 26 was next examined. Treatment of tetra-O-benzyl
glucoside 27 and the thioglycoside 26 with NIS/cat TfOH provided
OMe
OH
BnO
OMe
OBn
28
29
30
Scheme 3. Synthesis of the disaccharide 30.
the b-linked disaccharide 28 in 72% yield as a single diastereomer.
The disaccharide 28 was treated with sodium in liquid ammonia in
the presence of EtOH for 1 h at reflux. The reaction mixture was
quenched by the addition of MeOH. Product 29 was purified by
fluorous column chromatography, followed by treatment with 3%
TFA in MeOH to provide disaccharide 30 in 67% based on 28.
We next examined the synthesis of the trisaccharide 34 by one-
pot glycosylation involving the chemoselective glycosylation of
thioglycoside 22 with the glycosyl bromide 31, which was prepared
from thioglycoside 26 (Scheme 4). The thioglycoside 22 and the
glycosyl bromide 31 were treated with AgOTf. After TLC analysis,
which indicated the generation of disaccharide 32, the primary
alcohol 27, NIS and a catalytic amount of TfOH were added to the
reaction mixture to produce trisaccharide 33. The purification of 33
was achieved by gel permeation chromatography. Purification of
the reaction mixture by gel permeation chromatography after one-
pot glycosylation was one of the best ways for isolation of the de-
sired product since it should be the largest oligosaccharide among
the reaction products. On the other hand, fluorous column chro-
matography is difficult to separate the tagged products involving
different numbers of sugar units. The yield of the trisaccharide 33
was not estimated at this stage because the products contained
partially iodinated products at the linker. Reduction of the linker
and removal of the protecting group was archived under Birch re-
duction conditions, followed by exposure of the product to acidic
be cleaved under mildly acidic conditions after reduction to a vinyl
ether by Birch reduction. The Birch reduction simultaneously
removes protecting groups, such as esters and benzyl ethers.
Therefore, this method enables the efficient workup and purifica-
tion of the highly polar oligosaccharides by taking advantage of
fluorous tags.
3. Experimental section
3.1. General
NMR spectra were recorded on a JEOL Model EX-270 (270 MHz
for 1H, 67.5 MHz for 13C) or a JEOL Model ECP-400 (400 MHz for 1H,
100 MHz for 13C) instrument in the indicated solvent. Chemical
shifts are reported in units parts per million (ppm) relative to the
signal (0 ppm) for internal tetramethylsilane for solutions in CDCl3.
1H NMR spectrum data are reported as follows: CDCl3 (7.26 ppm) or
CD3OD (3.30 ppm) or D2O (HOD (4.8654 ppm at 285 K, 4.7015 ppm
at 303 K, 4.6201 ppm at 311 K, 4.3560 ppm at 339 K as internal
standard using 3-(trimethylsilyl)-1-propanesulfonicacid sodium
salt as external standard)). 13C NMR spectrum data are reported as
follows: CDCl3 (77.1 ppm) or CD3OD (49.3 ppm) or acetone-d6
(30.3 ppm) as internal standard for D2O. Multiplicities are reported
by using the following abbreviations: s; singlet, d; doublet, t;
triplet, q; quartet, m; multiplet, br; broad, J; coupling constants in
Hertz. IR spectra were recorded on a PerkineElmer Spectrum One
FT-IRspectrophotometer. Only the strongest and/or structurally
important peaks are reported as the IR data given in cmꢁ1. Optical
rotation was measured on a JASCO model P-1020 polarimeter. All
conditions provided the
b-linked trisaccharide 34 in 59% yield
based on 22 as a single diastereomer.
In conclusion, an efficient fluorous-assisted synthesis of oligo-
saccharides using a phenyl ether linker as a safety-catch linker is
described. The phenyl ether linker was stable under the acidic
glycosidation conditions and basic deprotection conditions, but can

10014
H. Tanaka et al. / Tetrahedron 67 (2011) 10011e10016
OTag
OTag
O
HO
HO
OTag
I
O
1) Na, NH3(l)
THF/EtOH
O
HO
O
NIS
O
AgOTf
then MeOH
BnO
BzO
OH
cat TfOH
CH2Cl2
O
HO
BnO
BzO
BnO
BzO
2) 3% TFA, MeOH
O
O
O
O
HO
X
O
OBz
O
59%
BnO
OH
HO
OBz
HO
OBz
based on 22
O
BnO
O
O
26 : X = -SPh
31 : X = -Br
BnO
BzO
BzO
O
O
HO
OMe
OBz
BnO
BzO
SPh
IBr, CH2Cl2
SPh
OH
OBz
O
OBz
22
HO
BnO
BnO
OMe
34
32
OBn
O
BnO
OMe
33
OBn
27
Scheme 4. Synthesis of the disaccharide 34 by one-pot glcysoyaltion.
reactions were monitored by thin-layer chromatography carried
out on 0.2 mm E. Merck silica gel plates (60F-254) with UV light,
visualized by 10% ethanolic phosphomolybdic acid, p-anisaldehyde
solution or 0.5% ninhydrin n-butanol solution. Daiso silica gel or
Merk silica gel was used for column chromatography. Gel perme-
ation chromatography (GPC) for qualitative analysis were per-
formed on Japan Analytical Industry Model LC908 (recycling
preparative HPLC), on a Japan Analytical Industry Model RI-5 re-
fractive index detector and on a Japan Analytical Industry Model
310 ultra violet detector with a polystylene gel column (JAIGEL-1H,
20ꢂ600 mm), using CHCl3 as solvent (3.5 mL/min). ESI-TOF Mass
spectra were measured with P. E. Biosystems TK-3500 Bio-
spectrometry Workstation mass spectrometers and Waters LCT
PremierÔ XE. HRMS (ESI-TOF) were calibrated with angiotensin I
(SIGMA), bradykinin (SIGMA), and neurotensin (SIGMA) as an in-
ternal standard. Dry dichloromethane, dry THF, and dry toluene
were obtained from solvent purification columns. N-Iodosuccini-
d
6.73e6.85 (m, 4H), 4.10 (t, 2H, J¼4.9 Hz), 3.84 (t, 2H, J¼4.9 Hz),
3.74 (t, 2H, J¼5.3 Hz), 3.41 (t, 2H, J¼5.3 Hz); 13C NMR (100 MHz,
CDCl3)
d 152.2, 149.9, 115.9, 115.7, 69.9, 69.6, 68.0, 50.4; IR (neat):
3377, 2929, 2106, 1603, 1509, 1452, 1346, 1233, 1129, 1063, 927, 829,
755, 643, 521 cmꢁ1; HRMS (ESI-TOF) calcd for C10H13O3 [MþH]þ m/
z¼224.1035, found: 224.1037.
3.1.2. Methyl 2,3,4-tri-O-benzyl-6-O-{4-[2-(2-azidoethoxy)-ethoxy]
phenyl}-
azidoethoxy)ethoxy]phenol (16) (147 mg, 660
(1.00 mL) were added 63 wt % sodium hydride (50.0 mg,
1.32 mmol) and a solution of DMF (2.00 mL) and methyl 6-O-p-
toluenesulfonyl-2,3,4-tri-O-benzyl-
mg, 989
3 h, the reaction mixture was poured into ice-cooled 3 M HCl. The
aqueous layer was extracted with two portions of ethyl acetate. The
combined organic layer was washed with H2O, saturated aq
NaHCO3 and brine, dried over MgSO4, filtered, and concentrated in
vacuo. The residue was chromatographed on silica gel with 20:80
ethyl acetateehexane to give methyl 2,3,4-tri-O-benzyl-6-O-(4-[2-
(2-azidoethoxy)ethoxy]phenyl)-a-D-glucopyranoside (18) (354 mg,
528
CDCl3):
a-D-glucopyranoside (18). To a stirred solution of 4-[2-(2-
mmol) in DMF
a-D-glucopyranoside (17) (612 -
m
mol) at room temperature. After being stirred at 70 ꢀC for
ꢀ
mide was recrystallized from CCl4e1,4-dioxane. Pulverized MS-4A
was activated by heating at 350 ꢀC for 8 h. FluoroFlash SPE car-
tridges (2 g, 8 cc tube) were purchased from Fluorous Technologies
Inc.
m
mol, 80%). ½a 1D8
ꢃ
þ51.7 (c 0.51, CHCl3); 1H NMR (270 MHz,
3.1.1. 4-[2-(2-Azidoethoxy)-ethoxy]-phenol (16). To a mixture of 2-
(2-chloroethoxy)ethyl p-toluenesulfonate (14) (2.04 g, 7.34 mmol)
and p-(tetrahydropyran-2-yloxy)phenol (13) (950 mg, 4.89 mmol),
DMF (25.0 mL) was added K2CO3 (1.35 g, 9.78 mmol) at room
temperature under argon. After the reaction mixture was stirred at
70 ꢀC for 30 h, sodium azide (1.30 g, 19.6 mmol) and tetra-n-buty-
lammonium iodide (1.80 g, 4.89 mmol) were added to the reaction
mixture at the same temperature. After being stirred at same
temperature for 30 h, the reaction mixture was poured into ice-
cooled 3 M HCl. The aqueous layer was extracted with two por-
tions of ethyl acetate. The combined organic layer was washed with
saturated aq NaHCO3 and brine, dried over MgSO4, filtered, and
concentrated in vacuo. The residue was used for the next reaction
without further purification. To a stirred solution of the above
residue in methanol (10.0 mL) and THF (5.00 mL) was added a cat-
alytic amount of 10-camphorsufonic acid at room temperature
under argon. After being stirred at same temperature for 5 min, the
reaction mixture was concentrated in vacuo. The residue purified
by chromatography on silica gel with 75:25 ethyl acetateehexane
to give 4-[2-(2-azidoethoxy)ethoxy]phenol (16) (981 mg,
4.39 mmol, 90% in three steps). 1H NMR (270 MHz, CDCl3):
d
7.16e7.36 (m, 15H), 6.80 (d, 4H, J¼10.6 Hz), 4.49e5.03 (m,
7H), 4.07e4.10 (m, 4H), 4.03 (dd, 1H, J¼9.6, 9.6 Hz), 3.82e3.91 (m,
3H), 3.74 (t, 2H, J¼5.3 Hz), 3.72 (dd, 1H, J¼9.6, 9.6 Hz), 3.60 (dd, 1H,
J¼3.3, 9.6 Hz,), 3.39e3.42 (m, 5H); 13C NMR (100 MHz, CDCl3)
d
165.7, 165.2, 153.2, 153.0, 137.0, 133.2, 132.8, 132.4, 129.9, 129.7,
129.4, 129.3, 128.8, 128.3ꢂ2, 128.0, 127.9, 115.7ꢂ2, 86.3, 78.2, 76.4,
75.6, 74.9, 70.7, 70.2, 69.9, 68.2, 67.1, 50.7; FT-IR (neat): 3030, 2925,
2103, 1508, 1454, 1231, 1071, 915, 825, 738, 698 (cmꢁ1); HRMS (ESI-
TOF) calcd for C38H43N3O8[MþH]þ m/z¼670.3128, found: 670.3124.
3.1.3. Methyl 2,3,4-tri-O-benzyl-6-O-{4-[2-(2- tridecafluorohex-an-
ecarboxamidoethoxy)ethoxy]phenyl}-
stirred solution of methyl 2,3,4-tri-O-benzyl-6-O-(4-[2-(2-
azidoethoxy)ethoxy]phenyl)- -glucopyranoside (18) (314 mg,
470
a-D-glucopyranoside (19). To
a
a-D
mmol) in dry THF (3.00 mL) and H2O (1.00 mL) were added Zn
(461 mg, 7.05 mmol) and NH4OAc (361 mg, 4.70 mmol) at 0 ꢀC.
After being stirred at room temperature for 10 min, the reaction
mixture was filtered through a pad of Celite with THF (6.00 mL). To
the solution, triethylamine (532
tridecafluoroheptanoyl chloride, which was freshly prepared
from tridecafluoroheptanoic acid (100 mg, 275 mol) and
mL, 3.82 mmol) and a solution of
m

H. Tanaka et al. / Tetrahedron 67 (2011) 10011e10016
10015
dichloromethyl methyl ether (243
0
m
L, 2.75 mmol), were added at
J¼10.2 Hz), 4.14 (dd, 1H, J¼4.0,10.6 Hz), 4.11 (t, 2H, J¼4.6 Hz), 4.07 (dd,
1H, J¼9.2, 9.6 Hz), 3.85 (m, 3H), 3.74 (t, 2H, J¼4.9 Hz), 3.41 (t, 2H,
ꢀC. After being stirred at room temperature for 2 h, the reaction
mixture was poured into ice-cooled 1 M NaOH. The aqueous layer
was extracted with two portions of ethyl acetate. The combined
organic layer was washed with 1 M HCl, saturated aq NaHCO3 and
brine, dried over MgSO4, filtered, and concentrated in vacuo.
The residue was purified by chromatography on silica gel with
20:80 ethyl acetateehexane to give methyl 2,3,4-tri-O-benzyl-6-O-
(4-[2-(2-tridecafluorohexanecarboxamidoethoxy)ethoxy]phenyl)-
J¼4.9 Hz); 13C NMR (67.8 MHz, CDCl3):
d 165.6, 165.2, 153.2, 152.9,
137.0, 133.1, 132.7, 132.4, 129.8, 129.6, 129.8, 129.6, 129.3, 128.8, 128.3,
128.2,128.0,115.7,115.6,86.2,78.2,76.4, 75.5,74.8,70.7,70.2, 69.8,68.1,
67.0, 50.6; FT-IR (neat): 2924, 2102,1726,1507,1452,1274,1088,1069,
1027, 824 (cmꢁ1); HRMS (ESI-TOF) calcd for C43H41N3O9S [MþH]þ m/
z¼776.2642, found: 776.2638.
a
½
-
-glucopyranoside (19) (38.1 mg, 38.5
m
mol, 51% in two steps).
3.1.6. Phenylthio 2,3-O-di-benzoyl-4-O-benzyl-6-O-(4-(2-(2-
aꢃD1D8 þ10.5 (c 1.55, CHCl3); 1H NMR (270 MHz, CDCl3):
d
7.23e7.36
tridecafluorohexanecarboxamido)ethoxy)ethoxy)phenyl-
pyranoside (26). To a stirred solution of phenylthio 2,3-O-di-benzoyl-
4-O-benzyl-6-O-(4-[2-(2-azidoethoxy)ethoxy]phenyl)- -glucopyr-
anoside (25) (500 mg, 650 mol) in dry THF (5.00 mL) and H2O
b-D-gluco-
(m, 15H), 6.80e6.89 (m, 5H), 4.50e5.03 (m, 6H), 4.64 (d, 1H, J¼3.9),
4.00e4.07 (m, 5H), 3.58e3.91 (m, 9H), 3.39 (s, 3H); 13C NMR
b-D
(67.8 MHz, CDCl3):
d
155.5, 153.2, 152.9, 141.9, 138.7, 138.1, 130.7,
m
128.8,128.5, 128.4, 128.1,128.0, 127.9, 127.7, 127.6, 115.5,115.4,102.9,
100.5, 99.9, 99.6, 99.1, 98.3, 82.1, 81.9, 80.0, 78.0, 77.6, 77.3, 77.2, 77.1,
76.9, 76.8, 75.8, 75.2, 73.4, 71.2, 69.8, 69.3, 68.9, 67.9, 67.1, 55.2, 53.5,
40.2, 39.8, 30.3, 28.9, 23.0, 21.4; FT-IR (neat): 3341, 3064, 3032,
2929, 1721, 1508, 1454, 1360, 1235, 1210, 1096, 737, 698 (cmꢁ1).
(2.00 mL) were added Zn (425 mg, 6.50 mmol) and NH4Cl (348 mg,
6.50 mmol)at 0 ꢀC.Afterbeingstirredatroomtemperaturefor10 min,
the reaction mixture was filtered through a pad of Celite with THF
(10.0 mL). To the solution, triethylamine (2.26 mL, 16.2 mmol) and
a solution of tridecafluoroheptanoyl chloride, which was freshly pre-
pared from tridecafluoroheptanoic acid (473 mg, 130 mmol) and
dichloromethyl was stirred at 0 ꢀC. After being stirred at room tem-
perature for 1 h, the reaction mixture was poured into saturated aq
NH4Cl. The aqueous layer was extracted with two portions of ethyl
acetate. The combined organic layer was washed with brine, dried
over MgSO4, filtered, and concentrated in vacuo. The residue purified
by chromatography on silica gel with 27:63 ethyl acetateehexane
to give phenylthio 2,3-O-di-benzoyl-4-O-benzyl-6-O-(4-[2-(2-
3.1.4. Phenylthio 2,3-O-di-benzoyl-4-O-benzyl-6-O-{4-[2-(2-
chloroethoxy)ethoxy]phenyl}-b-D-glucopyranoside (24). To a stirred
solution of 4-[2-(2-chloroethoxy)ethoxy]phenol (23) (819 mg,
3.78 mmol, 1.50 equiv) and phenylthio 2,3-O-di-benzoyl-4-O-benzyl-
b-D-glucopyranoside (22) (1.44 g, 2.52 mmol) in dry THF (10.0 mL)
were added tributylphosphine (944 mL, 3.78 mmol) and 1,10-(azodi-
carbonyl) dipiperidine (954 mg, 3.78 mmol) at room temperature
under argon. After being stirred at 60 ꢀC for 18 h, the reaction mixture
was poured into ice-cooled 1 M HCl. The aqueous layer was extracted
with two portions of ethyl acetate. The combined organic layer was
washed with saturated aq NaHCO3 and brine, dried over MgSO4, fil-
tered, and concentrated in vacuo. The residue purified by chroma-
tography on silica gel with 98:2 tolueneeethyl acetate to give
phenylthio 2,3-O-di-benzoyl-4-O-benzyl-6-O-(4-[2-(2-chloroethoxy)
tridecafluorohexanecarboxamidoethoxy)ethoxy]phenyl)-
b
-
-gluco-
pyranoside (26) (461 mg, 421
m
mol, 65% in two steps). ½a D18
ꢃ
Dþ46.0 (c
1.20, CHCl3); 1H NMR (270 MHz, CDCl3):
d7.90e7.96(m, 4H, aromatic),
7.05e7.51 (m,16H), 6.87 (m, 5H), 5.76 (dd,1H, J¼9.2, 9.6 Hz), 5.39 (dd,
1H, J¼9.6, 9.9 Hz), 4.95 (d, 1H, J¼9.9 Hz), 4.57 (d, 1H, J¼10.9 Hz), 4.50
(d, 1H, J¼10.9 Hz), 4.26 (d, 1H, J¼11.8 Hz), 4.15 (dd, 1H, J¼4.6, 11.8 Hz),
4.10 (t, 2H, J¼4.3 Hz), 4.06 (dd,1H, J3,4¼9.2, 9.6 Hz), 3.86 (dd,1H, J¼9.6,
4.6 Hz), 3.84 (t, 2H, J¼4.3 Hz), 3.70 (t, 2H, J¼4.6 Hz), 3.64 (t, 2H,
ethoxy]phenyl)-b-D-glucopyranoside (24) (1.41 g, 1.83 mmol, 72%).
½
a 2D5
ꢃ
þ65.3 (c 0.55, CHCl3); 1H NMR (270 MHz, CDCl3):
d
7.90e7.96 (m,
J¼4.6 Hz); 13C NMR (67.8 MHz, CDCl3):
d 165.7, 165.3, 158.3, 157.6,
4H), 7.03e7.51 (m, 16H), 6.88 (br d, 4H), 5.76 (dd, 1H, J¼9.2, 9.6 Hz),
5.39 (dd, 1H, J¼9.6, 9.9 Hz), 4.95 (d, 1H, J¼9.9 Hz), 4.57 (d, 1H,
J¼11.1 Hz), 4.50 (d, 1H, J¼11.1 Hz), 4.26 (dd, 1H, J¼2.3, 10.6 Hz), 4.15
(dd, 1H, J¼4.6, 10.6 Hz), 4.12 (t, 2H, J¼4.9 Hz), 4.06 (dd, 1H, J¼9.2,
9.6 Hz), 3.87 (ddd,1H, J¼2.3, 4.6, 9.6 Hz), 3.86 (t, 2H, J¼4.9 Hz), 3.84 (t,
2H, J¼5.9 Hz), 3.67 (t, 2H, J¼5.9 Hz); 13C NMR (100 MHz, CDCl3)
153.1, 153.0, 144.3, 137.0, 133.2, 132.5, 129.8, 129.7, 129.3, 129.0, 128.8,
128.3, 128.2, 128.0, 127.9, 115.7, 115.6, 86.3, 78.2, 78.0, 77.2, 76.4, 75.6,
74.9, 70.7, 70.6, 69.9, 69.7, 69.1, 68.9, 67.9, 67.1, 40.0, 39.8, 29.7, 22.9; FT-
IR (neat): 3336, 3063, 2931, 1724, 1508, 1452, 1274, 1088, 709 (cmꢁ1);
HRMS (ESI-TOF) calcd for C50H42F13NO10S [MþH]þ m/z¼1096.2400,
found: 1096.2446.
d
165.6,165.2,157.1, 145.2, 143.4, 137.0, 136.8, 133.2,133.1, 132.7, 132.6,
132.4,132.3,132.2,129.8,129.7,128.8,128.3ꢂ2,128.2,123.4,115.2, 86.3,
78.2, 76.4, 75.5, 75.4, 74.8, 70.7, 70.6, 66.8, 29.6, 21.6; IR (neat): 2926,
1728, 1502, 1373, 1274, 1092, 1027, 844, 750, 710 cmꢁ1; HRMS (ESI-
TOF) calcd for C43H41ClO9S [MþH]þ m/z¼769.2238, found: 769.2202.
3.1.7. Methyl 2,3,4-tri-O-benzyl-6-O-[2,3-O-di-benzoyl-4-O-benzyl-
6-O-{4-[2-(2-tridecafluorohexanecarboxamidoethoxy) ethoxy]phe-
nyl}-
phenylthio
orohexanecarboxamidoethoxy)ethoxy]phenyl)-
(26) (211 mg, 193 mol), methyl 2,3,4-tri-O-benzyl-
side (27) (134 mg, 289 mol), and pulverized activated MS4A
b
-D
-glucopyranosyl]-
2,3-O-di-benzoyl-4-O-benzyl-6-O-(4-[2-(2-tridecaflu-
-glucopyranoside
-glucopyrano-
a-D-glucopyranoside (28). A mixture of
b-D
3.1.5. Phenylthio 2,3-O-di-benzoyl-4-O-benzyl-6-O-{4-[2-(2-
m
a-D
ꢀ
azidoethoxy)ethoxy]phenyl}-
solution of phenylthio 2,3-O-di-benzoyl-4-O-benzyl-6-O-(4-[2-(2-
chloroethoxy)ethoxy]phenyl)- -glucopyranoside (24) (1.74 g,
b
-D
-glucopyranoside (25). To a stirred
m
(193 mg) in dry CH2Cl2 (4.00 mL) was stirred at room temperature for
1 h under argon to remove a trace amount of water. Then the reaction
mixture was cooled to ꢁ30 ꢀC. After 5 min, N-iodosuccinimide
b-D
2.27 mmol) in DMF (10.0 mL) were added sodium azide (442 mg,
6.80 mmol) and tetra-n-butylammonium iodide (838 mg, 3.40 mmol)
at room temperature under argon. After being stirred at 60 ꢀC for 30 h,
the reaction mixture waspoured into ice-cooled 3 M HCl. The aqueous
layer was extracted with two portions of ethyl acetate. The combined
organic layer was washed with water, saturated aq NaHCO3 and brine,
dried over MgSO4, filtered, and concentrated in vacuo. The residue
purified by chromatography on silica gel with 20:80 ethyl aceta-
teehexane to give phenylthio 2,3-O-di-benzoyl-4-O-benzyl-6-O-(4-
(52.0 mg, 231
mmol) and a catalytic amount of trifluoro-meth-
anesulfonic acid (8.57
mL, 96.3 mmol) were added to the reaction
mixtureatthesametemperature. Afterbeingstirredfor1 hwithbeing
allowed to ꢁ10 ꢀC, the reaction mixture was neutralized with trie-
thylamine, filteredthroughapadofCeliteandpouredintoamixtureof
saturated aq NaHCO3 and 10% aq Na2S2O3. The aqueous layer was
extracted with two portions of ethyl acetate. The combined extract
was washed with a mixture of saturated aq NaHCO3 and 10% aq
Na2S2O3, and brine, dried over MgSO4, filtered, and concentrated in
vacuo. Theresiduepurified bychromatography on silica gel with 87:13
tolueneeethyl acetate and further purified by gel permeation chro-
matography (GPC) to give methyl 2,3,4-tri-O-benzyl-6-O-(2,3-O-di-
benzoyl-4-O-benzyl-6-O-(4-[2-(2-tridecafluorohexanecarboxamido
[2-(2-azidoethoxy)ethoxy]phenyl)-b-D-glucopyranoside (25) (1.76 g,
2.27 mmol, quant.). ½a D19
ꢃ
þ14.4 (c 0.51, CHCl3); 1H NMR (270 MHz,
CDCl3): d 7.90e7.96 (m, 4H), 7.06e7.49 (m, 16H,), 6.88 (br d, 4H), 5.77
(dd, 1H, J¼9.2, 9.6 Hz), 5.40 (dd, 1H, J¼9.6, 9.9 Hz), 4.96 (d, 1H,
J¼9.9 Hz), 4.57 (d, 1H, J¼10.9 Hz), 4.50 (d, 1H, J¼10.9 Hz), 4.25 (d, 1H,

10016
H. Tanaka et al. / Tetrahedron 67 (2011) 10011e10016
-ethoxy)ethoxy]phenyl)-
b
-
D
-glucopyranosyl)-
a
-
D
-glucopyranoside
with 84:16 tolueneeethyl acetate and further purified by gel
(28) (200 mg, 138
(400 MHz, CDCl3):
m
mol, 72%). ½a 1D8
ꢃ
þ17.1 (c 1.34, CHCl3);1H NMR
permeation chromatography (GPC) to give the trisaccharide (33)
(130 mg). The partial of the trisaccharide (33) (58.8 mg) was
stirred in dry THF (1.00 mL) and EtOH (1.00 mL) at room tem-
perature for 5 min. Then liq. NH3 (8.00 mL) and sodium (20.0 mg)
were added at ꢁ50 ꢀC. After being stirred under reflux for
30 min, the reaction mixture was quenched with MeOH. The
residue was evaporated in vacuo and separated with fluorous
column chromatography (Fluoro FlashÒ SPE) to give the tri-
saccharide linked fluorous tag. To a stirred solution of the above
trisaccharide linked fluorous tag in dry CH2Cl2 (1.50 mL) and
d
7.85e7.93 (m, 4H), 7.02e7.52 (m, 26H), 6.83e6.86
(m, 5H, NH), 5.73 (dd, 1H, J¼9.7, 9.7 Hz), 5.46 (dd, 1H, J¼9.7, 9.7 Hz),
4.25e4.89 (m, 10H), 4.02e4.20 (m, 6H), 3.86 (dd, 1H, J¼9.2, 9.2 Hz),
3.82 (t, 2H, J¼4.8 Hz), 3.76e3.81 (m, 2H), 3.60e3.70 (m, 6H), 3.41 (dd,
1H, J¼3.4, 9.7 Hz), 3.31 (dd,1H, J3,4¼9.2, 9.2 Hz), 3.17 (s, 3H); 13C NMR
(100 MHz, CDCl3): d 220.8,165.7,157.6,153.1,153.0,147.9,138.8,138.2,
137.0, 133.2, 132.9, 129.7, 129.4, 128.4, 128.3, 128.2, 128.1, 127.9, 127.8,
127.7,127.5,115.7,115.5,101.2, 97.9, 81.9, 79.8, 77.5, 77.2, 75.7, 75.5, 75.1,
74.8, 74.7, 74.2, 73.3, 72.0, 69.8, 69.5, 68.9, 68.2, 67.9, 67.1, 60.4, 54.9,
40.5, 39.8; FT-IR (neat): 3338, 3032, 2924,1725,1509,1453,1359,1278,
1234, 1154, 1097, 1071, 1028, 913, 823, 738, 710, 698, 529 (cmꢁ1).
MeOH (100
mL) was added TFA (50.0 mL) at room temperature.
After being stirred at room temperature for 10 min, the reaction
mixture was concentrated in vacuo. The residue was evaporated
in vacuo and separated with fluorous column chromatography
3.1.8. Fluorous-assisted synthesis of disaccharide 30. Methyl 2,3,4-
tri-O-benzyl-6-O-[2,3-O-di-benzoyl-4-O-benzyl-6-O-(4-[2-(2-tri-
(Fluoro FlashÒ SPE) to give methyl 6-O-(6-O-(
b
-
D
-glucopyr-
-glucopyranoside (34) (11.2 mg,
mol, 59% based on 22). 1H NMR (400 MHz, D2O):
4.81 (d,
decafluorohexanecarboxamidoethoxy)ethoxy]phenyl)-
pyranosyl]- -glucopyranoside (28) (61.0 mg, 42.1
b-
D-gluco-
anosyl)-
21.7
b-D-glucopyranosyl)-a-D
a
-D
mmol) was
m
d
stirred in dry THF (1.00 mL) and EtOH (1.00 mL) at room temper-
ature for 5 min. Then liq. NH3 (8.00 mL) and Na (20.0 mg) were
added at ꢁ50 ꢀC. After being stirred under reflux for 1 h, the re-
action mixture was quenched with MeOH. The residue was evap-
orated in vacuo and separated with fluorous column chro-
matography (Fluoro FlashÒ SPE) to give the glucopyranoside linked
fluorous tag (29). To a stirred solution of the glucopyranoside linked
1H, J¼4.5 Hz), 4.56 (d, 1H, J¼8.5 Hz), 4.48 (d, 1H, J1,2¼8.5 Hz), 4.22
(d, 1H, J¼11.5 Hz), 4.19 (dd, 1H, J¼1.0, 12.0 Hz), 3.95e3.87 (m, 3H),
3.81 (dd, 1H, J¼3.0, 9.5 Hz), 3.74 (dd, 1H, J¼5.5, 12.5 Hz), 3.68 (dd,
1H, J¼9.5, 9.5 Hz), 3.65e3.62 (m, 1H), 3.57 (dd, 1H, J¼4.0, 9.5 Hz),
3.53e3.39 (m, 6H), 3.44 (s, 3H), 3.36e3.30 (m, 2H); 13C NMR
(100 MHz, CDCl3):
73.8, 72.0, 71.4, 70.4, 70.2, 70.1, 69.4, 69.3, 61.5, 56.1; HRMS (ESI-
d
103.6ꢂ2, 100.2, 76.7, 76.5, 76.4, 75.8, 73.9,
fluorous tag (29) in dry CH2Cl2 (1.50 mL) and MeOH (100
mL) was
TOF) calcd for C19H34O16[MþH]þ m/z¼519.1925, found: 519.1917.
added TFA (50.0 L) at room temperature. After being stirred at
m
room temperature for 10 min, the reaction mixture was concen-
trated in vacuo. The residue was evaporated in vacuo and separated
with fluorous column chromatography (Fluoro FlashÒ SPE) to give
References and notes
1. (a) Varki, A. Glycobiology 1993, 3, 97e130; (b) Dwek, R. A. Chem. Rev. 1996, 96,
683e720; (c) Hakomori, S. Arch. Biochem. Biophys. 2004, 426, 173e181; (d)
Bucior, I.; Burger, M. M. Curr. Opin. Struct. 2004, 14, 631e637.
2. (a) Seeberger, P. H.; Haase, W.-C. Chem. Rev. 2000, 100, 4349e4393; (b) Zhu, X.;
Schmidt, R. R. Angew. Chem., Int. Ed. 2009, 48, 1900e1934; (c) Wu, C. Y.; Wong,
C.-H. Chem. Commun. 2011, 6201e6207.
3. Review for the one-pot glycosylationsee: (a) Tanaka, H.; Yamada, H.; Takahashi,
T. Trends Glycosci. Glycotechnol. 2007, 19, 183e193; (b) Wang, Y.; Ye, X.-S.;
Zhang, L.-H. Org. Biomol. Chem. 2007, 5, 2189e2200.
methyl 6-O-(
b
-
D
-glucopyranosyl)-
a
-
D
-glucopyranoside (30) (10.0
4.81 (d,
mg, 28.1
m
mol, 67%, two steps). 1H NMR (400 MHz, D2O):
d
1H, J¼4.5 Hz), 4.50 (d, 1H, J¼11.5 Hz), 4.16 (dd, 1H, J¼1.0, 12.0 Hz),
3.91 (m, 2H), 3.80 (dd, 1H, J¼3.0, 9.5 Hz), 3.74 (dd, 1H, J¼5.5,
12.5 Hz), 3.68 (dd, 1H, J¼9.5, 9.5 Hz), 3.57 (dd, 1H, J¼4.0, 9.5 Hz),
3.39e3.53 (m, 4H), 3.44 (s, 3H), 3.33 (m, 2H); 13C NMR (67.8 MHz,
CDCl3):
d 103.5, 100.2, 76.7, 76.5, 74.0, 73.8, 72.0, 71.4, 70.5, 70.2,
4. (a) Yamada, H.; Harada, T.; Takahashi, T. J. Am. Chem. Soc. 1994, 116, 7919e7920;
(b) Tanaka, H.; Adachi, M.; Takahashi, T. Chem.dEur. J. 2005, 11, 849e862.
5. (a) Tanaka, H.; Ishida, T.; Matoba, N.; Tsukamoto, H.; Yamada, H.; Takahashi, T.
Angew. Chem., Int. Ed. 2006, 45, 6349e6352; (b) Tanaka, H.; Tateno, Y.; Nishiura,
Y.; Takahashi, T. Org. Lett. 2008, 10, 5597e5600.
69.3, 61.6, 56.1; HRMS (ESI-TOF) calcd for C13H24O11[MþH]þ m/
z¼357.1393, found: 357.1391.
6. (a) Takahashi, T.; Adachi, M.; Matsuda, A.; Doi, T. Tetrahedron Lett. 2000, 41,
2599e2603; (b) Tanaka, H.; Matoba, N.; Tsukamoto, H.; Takimoto, H.; Yamada,
H.; Takahashi, T. Synlett 2005, 824e828.
7. Studer, A.; Hadida, S.; Ferritto, R.; Kim, S.; Jeger, P.; Wipf, P.; Curran, D. P. Science
1997, 275, 823e826.
8. (a) Zhang, W.; Curran, D. P. Tetrahedron 2006, 62, 11837e11865; (b) Zhang, W.
Chem. Rev. 2009, 109, 749e795.
9. (a) Curran, D. P.; Hadida, S.; He, M. J. Org. Chem. 1997, 62, 6714e6715; (b)
Curran, D. P.; Luo, Z. J. Am. Chem. Soc. 1999, 121, 9069e9072.
3.1.9. Methyl 2,3,4-tri-O-benzyl-6-O-[2,3-O-di-benzoyl-4-O-benzyl-
6 - O - ( 2 , 3 - O - d i - b e n z o y l - 4 - O - b e n z y l - 6 - O - { 4 - [ 2 - ( 2 -
tridecafluorohexanecarboxamidoethoxy)ethoxy]phenyl}-
pyranosyl)- -glucopyranosyl]- -glucopyranoside (34). A mix-
ture of the glycosyl bromide (31) prepared from thioglycoside 26
(100 mg, 91.2 mol) and CH2Cl2 solution of IBr (137 mL,
137 mol), phenylthio 2,3-O-di-benzoyl-4-O-benzyl- -gluco-
pyranoside (22) (47.3 mg, 82.9 mol) and pulverized activated
b-D-gluco-
b
-D
a-D
m
m
m
b-D
10. Selected results of applications of heavy fluorous-tag assisted synthesis of oligo-
saccharide. (a) Goto, K.; Mizuno, M. Tetrahedron Lett. 2010, 51, 6539e6541; (b)
Miura, T.;Goto, K.; Hosaka, D.;Inazu, T. Angew. Chem., Int. Ed. 2003, 42, 2047e2051;
(c) Miura, T.; Hirose, Y.; Ohmae, M.; Inazu, T. Org. Lett. 2001, 3, 3947e3950; (d)
Curran, D. P.; Ferritto, R.; Hua, Y. Tetrahedron Lett. 1998, 39, 4937e4940.
11. Selected results of applications of light fluorous-tag assisted synthesis of oligo-
saccharide. (a)Ali, A.;vandenBerg, R. J. B. H. N.; Overkleeft, H. S.;Filippov, D. V.; van
der Marel, G. A.; Codee, J. D. C. Tetrahedron Lett. 2009, 50, 2185e2188; (b) Zhang, F.;
Zhang, W.; Zhang, Y.; Curran, D. P.; Liu, G. J. Org. Chem. 2009, 74, 2594e2597; (c)
Kim, S.; Tsuruyama, A.; Ohmori, A.; Chiba, K. Chem. Commun. 2008,1816e1818; (d)
Ko, K.-S.; Park, G.; Yu, Y.; Pohl, N. L. Org. Lett. 2008, 10, 5381e5384; (e) Tojino, M.;
Mizuno, M. Tetrahedron Lett. 2008, 49, 5920e5923; (f) Park, G.; Ko, K.-S.; Zakhar-
ova, A.; Pohl, N. L. J. Fluorine Chem. 2008, 129, 978e982; (g) Jaipuri, F. A.; Pohl, N. L.
Org. Biomol. Chem. 2008, 6, 2686e2691; (h) Chen, G.-S.; Pohl, N. L. Org. Lett. 2008,
10, 785e788; (i) Jaipuri, F. A.; Collet, B. Y. M.; Pohl, N. L. Angew. Chem., Int. Ed. 2008,
47,1707e1710; (j) Kojima, M.; Nakamura, Y.; Takeuchi, S. Tetrahedron Lett. 2007, 48,
m
ꢀ
MS4A (83.0 mg) in dry CH2Cl2 (2.00 mL) was stirred at room
temperature for 1 h under argon to remove a trace amount of
water. Then the reaction mixture was cooled to ꢁ78 ꢀC. After
5 min, a dry toluene (500
108
mL) solution of AgOTf (27.7 mg,
m
mol) was added to the reaction mixture at the same tem-
perature. After being stirred for 1.5 h with being allowed to
ꢁ40 ꢀC, methyl 2,3,4-tri-O-benzyl-
a
-
D
-glucopyranoside (27)
mol) and
L,
mol) were added to the reaction mixture at the same
(54.0 mg, 116 mmol), N-iodosuccinimide (22.4 mg, 99.5 m
a catalytic amount of trifluoromethanesulfonic acid (2.21
24.9
m
m
temperature. After being stirred for 1 h with being allowed to
ꢁ10 ꢀC, the reaction mixture was neutralized with triethylamine,
filtered through a pad of Celite and poured into a mixture of
saturated aq NaHCO3 and 10% aq Na2S2O3. The aqueous layer was
extracted with two portions of ethyl acetate. The combined ex-
tract was washed with a mixture of saturated aq NaHCO3 and 10%
aq Na2S2O3, and brine, dried over MgSO4, filtered, and concen-
trated in vacuo. The residue was chromatographed on silica gel
ꢁ
4431e4436; (k) Carrel, F. R.;Geyer, K.; Codee, J. D. C.; Seeberger, P. H. Org. Lett. 2007,
9, 2285e2288; (l) Manzoni, L.; Castelli, R. Org. Lett. 2006, 8, 955e957; (m) Kasuya,
M. C. Z.; Ito, A.; Cusi, R.; Sato, T.; Hatanaka, K. Chem. Lett. 2005, 34, 856e857;
(n) Manzoni, L.; Castelli, R. Org. Lett. 2004, 6, 4195e4198; (o) Jing, Y.; Huang, X.
Tetrahedron Lett. 2004, 45, 4615e4618; (p) Kasuya, M. C. Z.; Cusi, R.; Ishihara, O.;
Miyagawa, A.; Hashimoto, K.; Sato, T.; Hatanaka, K. Biochem. Biophys. Res. Commun.
2004, 316, 599e604; (q) Manzoni, L. Chem. Commun. 2003, 2930e2931.
12. (a) Goto, K.; Mizuno, M. Tetrahedron Lett. 2007, 48, 5605e5608; (b) Mizuno, M.;
Kitazawa, S.; Goto, K. J. Fluorine Chem. 2008, 129, 955e960.