First examples of α-(1a→4)-Glycosylation reactions on ionic liquid supports

Article abstract of DOI:10.1002/ejoc.201000754

We have developed the first α-(1a→4)-glycosylation reactions on ionic liquid supports. The purification steps involve simple liquid/liquid extractions. The positive influence of the soluble support on the stereoselectivity was proved, and the recyclable c

Full text of DOI:10.1002/ejoc.201000754

FULL PAPER
DOI: 10.1002/ejoc.201000754
First Examples of α-(1Ǟ4)-Glycosylation Reactions on Ionic Liquid Supports
[
a]
[a]
[a]
[a]
Matthieu Pépin, Marie Hubert-Roux, Claudette Martin, Fréderic Guillen,
[a]
[a]
Catherine Lange, and Géraldine Gouhier*
Keywords: Glycosylation / Ionic liquids / Supported synthesis / Synthetic methods
We have developed the first α-(1Ǟ4)-glycosylation reactions
on ionic liquid supports. The purification steps involve simple
liquid/liquid extractions. The positive influence of the solu-
ble support on the stereoselectivity was proved, and the recy-
clable character of the ionic liquid was demonstrated.
Introduction
2006, Chan developed
a
β-(1Ǟ6)-glycosylation on
[
mim][BF ] support using sulfoxide activation, and achieved
4
The concept of chemistry on supports has made possible
the development of new environmentally friendly methodol-
ogies. To rise to this challenge, chemical reactions on insolu-
[
9]
moderate yields. After an oxidation/coupling sequence, a
trisaccharide was obtained. In the same year, Wang synthe-
sized disaccharides by α- and β-(1Ǟ6)-glycosylation on
[1]
[2]
ble polystyrene solid supports, on fluorinated phases, on
soluble polyethyleneglycol resins,[ or, more recently, on
ionic liquids (ILs) have been extensively studied. Under
these conditions, the purification steps involve simple solid/
liquid filtrations or liquid/liquid extractions, thus avoiding
expensive and time-consuming chromatographic purifica-
tion procedures. Moreover, as the reagents can be used in
excess, higher yields can often be reached.
[
mim][PF ] support with a trichloroacetamide (TCA) donor
3]
6
[10]
at –40 °C, with excellent yields and 90–95% purities. Pa-
thak reported an α-(1Ǟ6)-glycosylation between mannosyl
fluoride anchored on [mim][PF ] and p-thiotolyl glycoside
as acceptor with good yields. By using this latter method-
ology, α-(1Ǟ6)-tetra- and -octamannopyranose were ob-
tained without the need of column purification.
6
[
11]
In this paper, we report the first successive α-(1Ǟ4)-gly-
cosylation reactions on an ionic liquid support. Several con-
secutive coupling steps were realized by using only simple
liquid/liquid extraction to purify the intermediates. The re-
covered ionic liquid support was efficiently recycled. More-
over, we proved that the ionic support had a positive influ-
ence on the stereoselectivity of the coupling reaction.
In the course of our work on the synthesis of modified
cyclodextrins through an opening/homologation/closing se-
quence, we were interested in the use of ionic soluble sup-
ports for glycosylation reactions. In our initial synthetic
strategy, we ascertained the feasibility of two successive α-
selective glycosylations at the anomeric and at the C-4 posi-
tions of a glucose derivative supported on ionic liquid. The
overall synthetic process is depicted in Figure 1. Sugar S1,
conveniently protected and activated, is grafted onto an
ionic liquid support by a covalent linkage on the primary
alcohol function. The α-(1Ǟ4)-glycosylation reaction on
the support would then be carried out in the presence of an
excess of unsupported sugar S2. The supported disaccha-
ride, which should be easily isolated and purified by simple
washing, would then be submitted to a second glycosylation
reaction with the appropriate sugar S3. The supported tri-
saccharide should then be cleaved and isolated in pure form
without requiring chromatography. Finally, the ionic sup-
port may be recycled.
Among these supports, task-specific ionic liquids (TSIL)
form a promising new class of soluble supports for organic
[
4]
synthesis. They combine a higher loading capacity com-
pared to those of solid supports and the advantages of solu-
ble supports, i.e., the ability to run reactions under homo-
[
5]
geneous conditions and to use conventional methodolo-
gies for the analysis of reaction mixtures. Moreover, their
solubilities can usually be tuned by the selection of an ap-
propriate cation/anion pair. Ionic liquid supports have been
[
6]
successfully used in the synthesis of small molecules as
[
7]
[8]
well as peptides, oligoribonucleotides, and oligosaccha-
rides.
In the latter context, three examples of (1Ǟ6)-glycosyla-
tions by using an ionic liquid support are described in the
[
9–11]
literature.
All of the approaches use an ester linkage
that is stable under the glycosylation conditions and is
easily cleavable under mild conditions. The ILs were grafted
onto either the C-6 position of the glycoside donor or onto
the C-4 position of the glycoside acceptor. The stereoselecti-
vities were controlled by the activation methods used. In
[
a] Université de Rouen, UMR CNRS 6014 COBRA, IRCOF,
1
Rue Tesnière, 76821 Mont Saint Aignan cedex, France
Fax: +33-2-35522959
E-mail: geraldine.gouhier@univ-rouen.fr
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201000754.
View this journal online at
wileyonlinelibrary.com
6366
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Eur. J. Org. Chem. 2010, 6366–6371

α-(1Ǟ4)-Glycosylation on Ionic Liquid Supports
1
5
00 °C afforded the ionic compound 4 with 85% yield in
h. Finally, ion metathesis with potassium hexafluorophos-
phate gave the desired hydrophobic ionic liquid 1 quantita-
tively. Thus, supported sugar 1 was obtained in 36% overall
yield from commercial acetylglucose in nine steps
(Scheme 1).
To obtain the more stable α-glycosylation product,
thermodynamic conditions (room temperature, more than
.5 h reaction time) were chosen. However, the use of a par-
1
ticipating solvent was avoided so that the possible influence
of the ionic support on the stereoselectivity could be estab-
lished. The α-(1Ǟ4)-glycosylation reaction was therefore
carried out in dichloromethane by using 1.5 equiv. of TCA
donors and trimethylsilyl triflate (TMSOTf) as a strong
Lewis acid during 3 h (Table 1 and Figure 2). The protected
β-trichloroacetimidates 5β–9β (derived from glucose, galac-
tose, mannose, maltose, and cellobiose, respectively) were
successfully used as substrates. The excess of donor sugar
was quantitatively recovered (in its unactivated form) by ex-
tracting the crude product with diethyl ether. The inorganic
salts were removed by washing a solution of the crude prod-
uct in dichloromethane with water. The corresponding sup-
Figure 1. Overall synthetic process.
Results and Discussion
Stable and easily accessible anomeric thioglycosides are ported α-(1Ǟ4)-disaccharides 10–14 were obtained after
among the most effective and commonly used glycosyl do- purification by simple liquid/liquid extractions, with yields
nors in the chemical synthesis of oligosaccharides. To ranging from 76 to 89% (Table 1). Complete α-selectivity
achieve a double α-(1Ǟ4)-glycosylation, we synthesized the was usually observed, except for the protected mannose 7
original supported acceptor/donor monosaccharide 1 acti- (Table 1, Entry 3) and cellobiose 9 (Table 1, Entry 5), which
vated at the C-1 position and having a free hydroxy group showed a 96:4 α/β selectivity. The α/β ratio was determined
1
at the C-4 position (Scheme 1). To predominantly achieve by H NMR spectroscopic analysis on the basis of inte-
α-glycosylation, we used a nonparticipating benzyl protect- grated ratios of the anomeric hydrogen atom. Except for
1
ing group at the C-2 position. A flexible spacer composed compounds 12 and 14, only one anomeric H NMR signal
of a long chain of five carbon atoms separates the imid- (t, J = 3.0–3.6 Hz) corresponding to the α-isomer was ob-
azolinium cation from the ester linkage.
served at the newly formed glycosidic bond.
Table 1. Glycosylation on ionic liquid supports.
Entry
Donor
Product
α/β
Yield [%]
1
2
3
4
5
6
5β
6β
7β
8β
9β
5α
5β
10
11
12
13
14
10
10
Ͼ99:1
Ͼ99:1
96:4
Ͼ99:1
96:4
85:15
Ͼ99:1
89
84
81
76
78
77
87
Scheme 1. Synthesis of monosaccharide 1.
Ethyl 2,3-di-O-benzyl-1-thio-β--glucopyranoside (2)
was synthesized from acetylglucose in five steps according
to published methods, with a global yield of 63%.
[
12]
To
[a]
7
selectively introduce the spacer at the C-6 position, a stan-
nylene acetal was formed by treatment with dibutyltin di-
[
a] Recycling of the ionic liquid support.
[
13]
methoxide.
with 5-bromopentanoyl chloride in the presence of triethyl-
amine at room temperature during 3 h to give ester 3 with cosylation reaction was carried out with activated glucose
7% yield. Addition of methylimidazole in acetonitrile at derivative 3 in the absence of the imidazolium group
The esterification reaction was carried out
To investigate the influence of the ionic support, the gly-
6
Eur. J. Org. Chem. 2010, 6366–6371
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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6367

G. Gouhier et al.
FULL PAPER
Figure 2. Structures of the reagents and products.
(Scheme 2). The functionalized glucose 3 was treated with was dependent on the anomeric configuration of the donor,
TCA glucoside 5β under the same conditions as those ap- with an inversion of the configuration with low selectivity
plied for the reaction of 1. The disaccharide 15 was ob- usually being reported.
tained with similar yield (90%) but with lower stereoselecti-
From supported disaccharides 10, we developed a second
vity (α/β = 9:1) after tedious purification by column α-(1Ǟ4)-glycosylation reaction with two new acceptors, 16
chromatography. Surprisingly, the use of α-trichloroacetim- and 17. Supported thioglycoside donor 10 was activated by
idate 5α derived from glucose as donor and 1 as acceptor, N-bromosuccinimide (NBS) in the presence of TMSOTf
predominantly afforded the α-glycoside, albeit with a lower (Scheme 3). From protected glucose 16 and galactose 17,
α/β ratio (85:15; see Table 1, Entry 6).
two α-(1Ǟ4)-trisaccharides 18 and 19 were obtained after
successive washing with diethyl ether and extraction with
dichloromethane and water. Good yields (78 and 85%) and
complete α-stereoselectivity after 3 h of stirring at 0 °C were
observed. As for the first coupling reaction, only the α-iso-
1
mers were detected by H NMR spectroscopy.
Scheme 2. Control coupling without the imidazolium group.
Selectivity studies on glycosylation reactions with ionic
[14]
liquids used as solvent were reported by Poletti and To-
[
15]
shima, with a nonparticipating group at the C-2 position.
However, whereas triflate-based ionic liquids induced β- Scheme 3. Second glycosylation of disaccharide 10.
selectivity (presumably by coordination of the triflate coun-
terion on the α-face of the glycosyl donor), no influence of
Cleavage of the ester linkage and the recyclability of the
the hydrophobic, noncoordinating anion PF6– during the ionic liquid were then studied. The ester linker was quanti-
glycosylation of 2-propanol with trichloroacetimidates in 1- tatively cleaved in the presence of lithium hydroxide in a
butyl-3-methylimidazolium hexafluorophosphate [bmim]- water/acetonitrile mixture in 5 h at room temperature
[14]
[
PF ] was observed.
The stereochemistry of the product (Scheme 4). After evaporation of the acetonitrile, the or-
6
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Eur. J. Org. Chem. 2010, 6366–6371

α-(1Ǟ4)-Glycosylation on Ionic Liquid Supports
ganic compounds were extracted with dichloromethane and donor. Very high diastereoisomeric excesses were obtained
washed with water. The dried organic phase was then with β-trichloroacetimidates. Finally, the recyclability of the
washed with diethyl ether to separate disaccharide 20 from IL was demonstrated, and the stereoselectivity was pre-
the insoluble supported acid 21.
served with the recycled ionic support. This methodology
will be applied for the synthesis of more complex oligosac-
charides. Studies on the influence of the counterion and of
the length of the spacer between the saccharide and the IL
are in progress.
Experimental Section
General: Unless otherwise stated, H, 13C, and 19F NMR spectra
were recorded in deuterated solvents with a Bruker AC 300 spec-
trometer, operating at 300, 75, and 282 MHz, respectively. IR spec-
tra were recorded with a Perkin–Elmer 16 PC FTIR instrument,
and data are expressed in cm . Electrospray mass spectra were
recorded with an Esquire-LC ion-trap mass spectrometer (ITMS)
1
Scheme 4. Product isolation.
–
1
To recycle the IL, the carboxylic acid 21 was treated with
thionyl chloride in N,N-dimethylformamide (DMF) at
room temperature for 4 h to afford the corresponding acyl
(
Bruker Daltonics, Wissembourg, France). High-resolution mass
spectra (HRMS) were performed with an LCTOF Premier XE
chloride in 78% yield (Scheme 5). Addition of the protected (Micromass, Manchester, UK) instrument equipped with an ESI
glucose unit 22, activated as its stannylene acetal, led to the source. The spectra were acquired in W mode in positive mode.
desired supported saccharide 1 in 63% yield after 3 h of Elemental compositions were obtained with a mass accuracy better
than 5 ppm. All reactions were monitored by analytical thin-layer
stirring at room temperature in the presence of a base. In
chromatography using pre-coated silica gel plates. Visualization
addition to the possible recyclability of the support, this
was accomplished under UV light (254 nm). Flash chromatography
reaction shows that the ionic support can be grafted onto
was performed by using silica gel (230–400 mesh). Unless otherwise
the glycoside as a whole, rather than constructed stepwise
noted, chemicals were used as received without further purification.
Dichloromethane and acetonitrile were distilled from calcium hy-
as mentioned previously (see Scheme 1).
dride under nitrogen. Toluene was distilled from sodium under ni-
trogen. Cyclohexane and ethyl acetate were distilled prior to use.
Trichloroacetimidates 5β–9β were prepared by using the reported
procedure[ with Cs
16]
2 3
CO as base. Trichloroacetimidate 5α was
purchased from Aldrich.
,3-Di-O-benzyl-6-O-(6-bromohexanoyl)-1-ethylthio-β-
pyranose (3): 2,3-Di-O-benzyl-1-ethylthio-β--glucopyranose (2;
.67 g, 6.61 mmol) was dissolved in toluene (20 mL) in a distillation
apparatus. Bu Sn(OMe) (1.67 mL, 7.27 mmol, 1.1 equiv.) was
2
D-gluco-
2
2
2
added, and the mixture was stirred under argon at 80 °C for 2 h.
The reaction mixture was then concentrated to half of the original
volume by distillation. 6-Bromohexanoyl chloride (1.32 mL,
Scheme 5. Recycling of the IL.
8
3
.59 mmol, 1.3 equiv.) and Et N (0.036 mL, 0.33 mmol, 5%) were
The glycosylation reaction between the recycled IL 1 and
β (Table 1, Entry 7) led to the supported disaccharide 10
added at 0 °C to the concentrated mixture. The reaction mixture
was stirred at room temp. for 3 h, then poured into water. After
5
without loss of reactivity or selectivity. A similar yield evaporation of the organic solvents, the crude product was dis-
87%) was observed after simple extraction with diethyl solved in dichloromethane and washed with water. The organic
), filtered, and the solvent was removed
(
ether and washing with water. Complete α-(1Ǟ4)-stereose- layer was dried (MgSO
lectivity was preserved, thus demonstrating the recyclability
of the ionic liquid.
4
under reduced pressure. The residue was purified by flash
chromatography (cyclohexane/EtOAc, 6:4) to yield 3 (2.58 g,
2
0
4
.43 mmol, 67%) as a yellow oil. [α]
D
= 10.2 (c = 1.00, CHCl
MS (ESI): m/z = 605 [M + Na] . H NMR (300 MHz, CDCl ): δ
7.41–7.31 (m, 10 H, Ar), 4.94 (dd, J = 1.5, 3.0 Hz, 2 H, CH
3
).
+
1
3
=
2
-
Conclusions
2
Ph), 4.75 (dd, J = 4.5, 5.7 Hz, 2 H, CH -Ph), 4.48 (d, J = 9.6 Hz,
1
2
1
2
H, 1-H), 3.51–3.37 (m, 6 H, 2-H, 3-H, 4-H, 5-H, 6-H, 6Ј-H),
.78–2.73 (m, 2 H, CH ), 2.37 (t, J = 7.2 Hz, 2 H, S-CH -CH ),
.90–1.85 (m, 2 H, CH ), 1.68–1.62 (m, 4 H, 2 CH ), 1.50–1.41 (m,
H, CH ), 1.33 (t, J = 4.2 Hz, 3 H, S-CH -CH
) ppm. 1 C NMR
): δ = 173.9 (C=O), 140.2, 138.4, 137.8, 128.7–
28.1 (Ar), 85.7 (C-1), 85.4 (C-3), 81.4 (C-5), 75.6 (CH -Ph), 75.5
-Ph), 70.1 (C-4), 63.5 (C-2), 62.9 (C-6), 33.9 (S-CH -CH ),
3.6 (CH ), 32.4 (CH ), 27.7 (CH ), 25.3 (CH ), 24.1 (CH ), 15.2
We have synthesized new acceptor/donor units supported
on ionic liquid. The first examples of successive selective α-
1Ǟ4)-glycosylation reactions of various mono- and disac-
charides with two methods of activation in good yields have
been developed. All of the purification steps were carried
out by simple washing or liquid/liquid extractions, thus
avoiding the need for inconvenient column chromatography.
2
2
3
2
2
(
3
2
2
3
(75 MHz, CDCl
3
1
2
(CH
2
2
3
3
2
2
2
2
2
The glycosylation reaction with trichloroacetimidate donors (S-CH -CH ) ppm. C H BrO S (581.56): calcd. C 57.83, H 6.41,
2
3
28 37
6
is α-selective, regardless of the configuration (α/β) of the S 5.51; found C 57.90, H 6.52, S 5.48.
Eur. J. Org. Chem. 2010, 6366–6371
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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6369

G. Gouhier et al.
FULL PAPER
[
6-(2,3-Di-O-benzyl-1-ethylthio-β-
-methyl-1H-imidazol-3-ium Bromide 4: Compound 3 (2.1 g,
.61 mmol) and 1-methylimidazole (0.431 mL, 5.42 mmol,
.5 equiv.) in acetonitrile (20 mL) were stirred under argon at reflux
D
-glucopyranos-6-yl)-6-oxohexyl]-
imidazol-3-ium Hexafluorophosphate (10): Compound 5 (20 mg,
29.3 µmol) and 1 (14 mg, 19.5 µmol) in dried dichloromethane
(2 mL) were treated with TMSOTf (1.4 µL, 14.7 µmol) according
to Procedure A. Compound 10 (22 mg, 17.4 µmol, 89%) was ob-
1
3
1
2
0
temperature for 5 h. The mixture was concentrated under reduced
pressure, and the crude product was washed with Et O (3 ϫ
0 mL). The diethyl ether phase was removed by decanting to yield
tained as a yellow oil. [α]
D
= 13.4 (c = 1.00, CHCl
m/z = 1105 [M] . H NMR (300 MHz, CDCl ): δ = 8.50 (s, 1 H,
C-H), 7.40–7.12 (m, 32 H, Ar, Im), 5.23 (t, J = 3.6 Hz, 1 H, 1Ј-
H), 4.97 (d, J = 10.8 Hz, 2 H, CH -Ph), 4.85 (d, J = 9.9 Hz, 2 H,
CH -Ph), 4.82 (d, J = 11 Hz, 2 H, CH -Ph), 4.80 (d, J = 10.8 Hz,
2 H, CH -Ph), 4.79 (d, J = 12 Hz, 2 H, CH -Ph), 4.78 (d, J =
-Ph), 4.77 (d, J = 11 Hz, 1 H, CH- 11 Hz, 2 H, CH -Ph), 4.71 (d, J = 9.6 Hz, 1 H, 1-H), 4.33 (m, 2
H, 2ϫ6-H), 4.15 (m, 2 H, 4-H, 5-H), 4.05–4.01 (m, 1 H, 2Ј-H),
3.96 (t, J = 9.3 Hz, 1 H, 4Ј-H), 3.89 (s, 3 H, CH ), 3.73–3.41 (m, 7
H, 2-H, 3-H, 3Ј-H, 4Ј-H, 5Ј-H, 2ϫ6Ј-H), 2.79–2.71 (m, 2 H, CH
), 2.38 (t, J = 7.2 Hz, 2 H, S-CH -CH ), 1.88–1.79 (m, 2 H, CH
1.69–1.63 (m, 6 H, 3 CH ), 1.38–1.32 (m, 3 H, S-CH -CH
C NMR (75 MHz, CDCl ): δ = 173.1 (C=O), 139.3 (N C), 138.8–
136.3 (Ar), 128.5–127.4 (Ar), 123.5 (Ar), 122.2 (Im), 91.1 (C-1Ј),
85.9 (C-1), 84.4 (C-3), 81.6 (C-5), 81.1 (C-3Ј), 79.8 (CH -Ph), 77.7
Ar), 124.7 (Im), 123.3 (Im), 85.9 (C-1), 85.4 (C-3), 81.4 (C-5), 77.4 (CH -Ph), 77.6 (CH ), 75.6 (CH -Ph), 74.9 (CH -Ph), 74.6 (CH
CH ), 75.6 (CH -Ph), 75.5 (CH -Ph), 70.4 (C-4), 64.3 (C-2), 50.1 Ph), 73.3 (CH -Ph), 73.0 (C-4Ј), 70.4 (C-4), 70.0 (C-5Ј), 68.4 (C-
C-6), 37.0 (CH ), 34.5 (CH ), 30.4 (CH ), 26.1 (S-CH -CH ), 25.4 2Ј), 63.4 (C-2), 49.1 (C-6), 35.9, 33.4, 29.7, 25.0, 24.9, 24.3, 23.8,
CH ), 23.9 (CH ), 15.3 (S-CH -CH ) ppm.
6-(2,3-Di-O-benzyl-1-ethylthio-β- -glucopyranos-6-yl)-6-oxohexyl]-
-methyl-1H-imidazol-3-ium Hexafluorophosphate (1): Potassium
3
). MS (ESI):
+
1
2
3
3
4
1
N
2
2
0
(2.03 g, 3.07 mmol, 85%) as a viscous yellow oil. [α]
D
= 9.2 (c =
). MS (ESI): m/z = 583 [M] . H NMR (300 MHz,
): δ = 8.46 (s, 1 H, N C-H), 7.39–7.22 (m, 12 H, Ar, Im),
.93 (d, J = 9.9 Hz, 2 H, CH
2
+
1
.00, CHCl
3
2
2
CDCl
4
3
2
2
2
2
2
Ph), 4.73 (d, J = 11 Hz, 1 H, CH-Ph), 4.47 (d, J = 9.6 Hz, 1 H, 1-
H), 4.28 (m, 2 H, 6-H, 6Ј-H), 4.11 (m, 2 H, 5-H, 4-H), 3.85 (s, 3
H, CH
3
3
), 3.51–3.37 (m, 4 H, 2-H, 3-H), 2.78–2.71 (m, 2 H, CH
.34 (t, J = 7.2 Hz, 2 H, S-CH -CH ), 1.87–1.79 (m, 2 H, CH
.71–1.65 (m, 4 H, 2 CH ), 1.38–1.28 (m, 3 H, S-CH -CH
CN): δ = 174.2 (C=O), 140.7 (N C), 139.7
Ar), 137.5 (Ar), 129.4 (Ar), 129.3 (Ar), 129.3 (Ar), 129.2 (Ar),
29.1 (Ar), 129.0 (Ar), 128.8 (Ar), 128.7 (Ar), 128.5 (Ar), 128.4
2
),
2
),
),
2
1
2
3
2
2
3
2
2
2
3
) ppm.
2
2
3
) ppm.
1
3
13
C NMR (75 MHz, CD
3
2
3
2
(
1
(
(
(
(
2
2
3
2
2
2
-
3
2
2
2
2
2
2
2
3
1
9
1
2
2
2
3
14.7 ppm. F NMR (282.5 MHz, CDCl
10 Hz) ppm.
3 P,F
): δ = –73.8 (d, J =
7
[
1
D
General Procedure B. Glycosylation with Thioethyl Activation: Ac-
ceptor 16 or 17 (1.5 equiv.) in dichloromethane was added to a
solution of 10 in dichloromethane in the presence of molecular
sieves (4 Å) under argon at 0 °C. NBS (1.2 equiv.) and TMSOTf
hexafluorophosphate (0.625 g, 3.40 mmol, 1.1 equiv.) was stirred
with 4 (2 g, 3.09 mmol) in a mixture of acetonitrile and water (1:1,
2
reduced pressure, and the crude product was dissolved in dichloro-
methane, then washed with water and brine. The organic layer was
4
dried (MgSO ), filtered, and the solvent was evaporated to obtain
1
=
0 mL) at room temp. for 2 h. The solvents were removed under
(
0.75 equiv.) were added, and the mixture was stirred at room temp.
for 3 h. The reaction mixture was concentrated under reduced pres-
sure and washed three times with Et O. The solvents were removed
2
0
2
(2.25 g, 3.09 mmol, 100%) as a viscous yellow oil. [α]
D
= 11.3 (c
). MS (ESI): m/z = 583 [M] . H NMR (300 MHz,
): δ = 8.48 (s, 1 H, N C-H), 7.39–7.16 (m, 32 H, Ar, Im),
+
1
by decantation, and the obtained oil was dissolved in dichloro-
methane and washed with water and brine. The organic phase was
dried (MgSO ), filtered, and the solvent was evaporated under re-
4
duced pressure to obtain the desired trisaccharide as a viscous yel-
low oil.
1.00, CHCl
3
CDCl
3
2
5
.27 (t, J = 3.6 Hz, 1 H, 1Ј-H), 4.99 (d, J = 10.8 Hz, 2 H, CH
Ph), 4.91 (d, J = 9.9 Hz, 1 H, CH -Ph), 4.86 (d, J = 11 Hz, 1 H,
CH -Ph), 4.81 (d, J = 10.6 Hz, 2 H, CH -Ph), 4.80 (d, J = 11.4 Hz,
H, CH -Ph), 4.76 (d, J = 9.6 Hz, 1 H, 1-H), 4.75 (s, 1 H, CH
Ph), 4.71 (s, 1 H, CH -Ph), 4.61 (s, 1 H, CH -Ph), 4.31 (m, 2 H, 2
-H), 4.13 (m, 2 H, 4-H, 5-H), 4.11–4.03 (m, 1 H, 4Ј-H), 4.01 (t, J
9.7 Hz, 1 H, 2Ј-H), 3.87 (s, 3 H, CH ), 3.78–3.61 (m, 5 H), 3.53–
.36 (m, 4 H), 2.98 (d, J = 2.4 Hz, 1 H), 2.81–2.69 (m, 2 H), 2.36
t, J = 7.2 Hz, 2 H), 1.88–1.79 (m, 2 H), 1.72–1.63 (m, 4 H), 1.35–
2
-
2
2
2
1
2
2
-
{
6-[2,3,4,6-Tetra-O-benzyl-α-
benzyl-α- -glucopyranosyl-(1Ǟ4)-2,3,6-tri-O-benzyl-1-methoxy-α-
-glucopyranos-6 -yl]-6-oxohexyl}-1-methyl-1H-imidazol-3-ium
Hexafluorophosphate (18): Compound 10 (20 mg, 15.8 µmol) and
6 (5 mg, 10.1 µmol) in dried dichloromethane (2 mL) were treated
D-glucopyranosyl-(1Ǟ4)-2,3-di-O-
2
2
D
6
=
3
(
1
1
(
7
II
D
3
1
with TMSOTf (1.1 µL, 11.9 µmol) and NBS (3 mg, 19.0 µmol) ac-
cording to Procedure B. Compound 18 (22 mg, 13.4 µmol, 85%)
13
.31 (m, 3 H) ppm. C NMR (75 MHz, CDCl
3
): δ = 174.3 (C=O),
40.5–137.6 (Ar), 129.5–128.6 (Ar), 124.7 (Im), 123.4 (Im), 92.3
C-1Ј), 87.1 (C-1), 85.6 (C-3), 82.8 (C-5), 81.0 (C-3Ј), 78.9, 78.8,
6.8, 76.1, 75.8, 74.5, 74.2 (C-4Ј), 71.6 (C-4), 71.2 (C-5Ј), 69.6 (C-
), 50.3 (C-6), 37.1, 34.6, 30.5, 26.2, 25.5, 25.0, 15.9 ppm. F NMR
2
0
was obtained as a viscous yellow oil. [α]
D
= 45.7 (c = 1.00, CHCl
MS (ESI): m/z = 1508 [M] . H NMR (300 MHz, CDCl ): δ = 8.47
s, 1 H, N C-H), 7.38–7.10 (m, 47 H, Ar, Im), 5.45 (d, J = 3.8 Hz,
H, 1"-H), 5.21 (t, J = 3.6 Hz, 1 H, 1Ј-H), 4.94 (d, J = 10.8 Hz, 2
3
).
+
1
3
(
2
19
2
(
(
1
1
282.5 MHz, CDCl
3
): δ = –72.1 (d, JP,F = 710 Hz) ppm. HRMS
H, CH
2
-Ph), 4.91 (d, J = 9.9 Hz, 1 H), 4.83–4.81 (m, 3 H), 4.79 (d,
-Ph), 4.75–4.71 (m,
-Ph), 4.41–4.36 (m, 2 H, 2ϫ6-H), 4.31 (s, 2 H),
.17–4.03 (m, 2 H, 4Ј-H, 5-H), 4.04–3.90 (m, 3 H, 4ЈЈ-H, 2ЈЈ-H),
.90 (t, J = 9.1 Hz, 1 H, 2Ј-H), 3.86 (s, 3 H, CH ), 3.68–3.43 (m,
3 H), 3.3 (s, 3 H), 2.93 (d, J = 6.8 Hz, 1 H, CH ), 2.71–2.65 (m,
H, CH ), 2.35 (m, 2 H, CH ), 1.86–1.71 (m, 2 H, CH ), 1.66–
.63 (m, 4 H, 2 CH ) ppm. C NMR (75 MHz, CDCl ): δ = 173.5
+
43 2 6
ESI): calcd. for C32H N O S [M] 583.2842; found 583.2858.
J = 10.8 Hz, 1 H), 4.77 (d, J = 12 Hz, 2 H, CH
2
General Procedure A. Glycosylation with TCA Donors: Under ar-
gon, at 0 °C, TCA donor 5–9 (1.5 equiv.) in dichloromethane was
added to a solution of 1 in dichloromethane, in the presence of
molecular sieves (4 Å). TMSOTf (0.75 equiv.) was added, and the
solution was stirred at room temp. for 1.5 h. The reaction mixture
was concentrated under reduced pressure and washed three times
with Et
tained oil was dissolved in dichloromethane and washed with water
and brine. The organic phase was dried (MgSO ), filtered, and the
4
4
3
1
2
1
H, 1-H, CH
2
3
2
2
2
2
13
2
3
2
O. The solvent was removed by decanting, and the ob-
(
C=O), 139.7–136.8 (Ar), 128.9–127.8 (Ar), 123.9 (Im), 122.6 (Im),
9
8
1.8 (C-1ЈЈ), 91.5 (C-1Ј), 86.3 (C-1), 84.7 (C-3), 82.0, 81.5 (C-5),
0.2 (C-3Ј), 80.0, 78.1 (CH -Ph), 78.0 (CH -Ph), 77.5 (CH ), 76.0
-Ph), 75.3 (CH -Ph), 75.0 (CH -Ph), 73.9
-Ph), 73.4 (C-4Ј), 70.9, 70.8 (C-4), 70.7 (C-5Ј), 70.4 (C-2Ј),
4
2
2
3
solvent was evaporated under reduced pressure to obtain the de-
sired disaccharide as a viscous yellow oil.
(CH
CH
2
2
-Ph), 75.7 (CH
2
2
2
(
{
6-[4-O-(2,3,4,6-Tetra-O-benzyl-α-
D
-glucopyranosyl)-2,3-di-O-
63.8 (C-2), 62.9, 55.5, 49.5 (C-6), 36.3, 33.8, 25.4, 24.7, 24.2 ppm.
1
9
1
benzyl-1-ethylthio-β- -glucopyranos-6-yl]-6-oxohexyl}-1-methyl-1H-
D
F NMR (282.5 MHz, CDCl
3
): δ = –73.3 (d, JP,F = 710 Hz) ppm.
6370
www.eurjoc.org
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 6366–6371

α-(1Ǟ4)-Glycosylation on Ionic Liquid Supports
17P (1653.77): calcd. C 66.82, H 6.28; found C 66.81,
92 103 6 2
C H F N O
Acknowledgments
H 6.33.
Hydrolysis of Ester 10: Compound 10 (30 mg, 23.7 µmol) was dis-
solved in an acetonitrile/water mixture (1:1, 4 mL) containing lith-
ium hydroxide (3 mg, 94.8 µmol, 4 equiv.), and the solution was
stirred at room temp. for 5 h. The solvents were evaporated under
reduced pressure, and the crude product was dissolved in dichloro-
methane, and washed with water and brine. The organic phase was
We are grateful to Region Haute-Normandie for PhD financial
support (CBS program).
[
[
[
1] R. C. D. Brown, J. Chem. Soc. Perkin Trans. 1 1998, 3293–
3320.
dried (MgSO
duced pressure. The obtained oil was extracted three times with
Et O, and the solvent was removed by decanting. The resulting
disaccharide 20 (22 mg, 23.7 µmol, 100%) was obtained after evap-
oration of the Et O as a colorless oil. The carboxylic acid sup-
4
), filtered and the solvent was evaporated under re-
2] A. Studer, S. Hadida, R. Ferrito, S.-Y. Kim, P. Jeger, P. Wipf,
D. P. Curran, Science 1997, 275, 823–826.
3] a) T. J. Dickerson, N. N. Reed, K. D. Janda, Chem. Rev. 2002,
2
1
3
02, 3325–3343; b) D. E. Bergbreiter, Chem. Rev. 2002, 102,
2
345–3384.
ported on ionic liquid 21 was recovered as the phase insoluble in
diethyl ether (8 mg, 23.7 µmol, 100%).
[
[
[
4] W. Miao, T. H. Chan, Acc. Chem. Res. 2006, 39, 897–908.
5] S. Handy, M. Okello, J. Org. Chem. 2005, 70, 2874–2877.
20
Compound 20: R
.00, CHCl ). MS (ESI): m/z = 950 [M + Na] . H NMR
300 MHz, CDCl ): δ = 7.85 (m, 2 H), 7.58 (m, 1 H), 7.49–7.34 (m,
H), 7.34–7.14 (m, 25 H), 5.24 (t, J = 3.6 Hz, 1 H), 4.94 (d, J =
f D
= 0.42 (cyclohexane/EtOAc, 7:3). [α] = 9.2 (c =
6] For selected references, see: a) J. Fraga-Dubreuil, J.-P. Ba-
zureau, Tetrahedron Lett. 2001, 42, 6097–6100; b) M. de Kort,
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Legeay, J. Vanden Eynde, J.-P. Bazureau, Tetrahedron 2005, 61,
+
1
1
3
(
3
2
1
4
1
4
3
0.8 Hz, 1 H), 4.93 (d, J = 9.9 Hz, 1 H), 4.89 (d, J = 11 Hz, 1 H),
.84 (d, J = 10.8 Hz, 1 H), 4.82 (d, J = 12 Hz, 1 H), 4.77 (d, J =
1 Hz, 1 H), 4.72 (d, J = 11 Hz, 1 H), 4.64 (d, J = 12 Hz, 1 H),
.55 (s, 1 H), 4.50 (s, 1 H), 4.47 (d, J = 9.6 Hz, 1 H), 4.46 (d, J =
Hz, 1 H), 4.11 (t, J = 7.2 Hz, 2 H), 4.05–4.02 (m, 1 H), 3.96 (t,
12386–12397; d) X.-L. Tao, M. Lei, Y. G. Wang, Tetrahedron
Lett. 2007, 48, 5143–5146; e) H. Xie, C. Lu, G. Yang, Z. Chen,
Synthesis 2009, 205–210; f) B. Maiti, K. Chanda, C.-M. Sun,
Org. Lett. 2009, 11, 4826–4829.
[
7] a) W. Miao, T. Chan, J. Org. Chem. 2005, 70, 3251–3255; b) F.
Bonnette, Z. Mincheva, O. Lavastre, Comb. Chem. High
Throughput Screening 2006, 9, 229–232.
J = 9.3 Hz, 1 H), 3.81–3.29 (m, 19 H), 2.93 (d, J = 6.5 Hz, 1 H),
.73–2.70 (m, 2 H), 1.38–1.28 (m, 3 H) ppm. 13C NMR (75 MHz,
CDCl ): δ = 138.8, 138.4, 138.2, 138.1, 138.0, 137.7, 136.3, 128.5–
28.3 (Ar), 128.1–127.7 (Ar), 127.5, 127.3, 126.9, 126.5, 123.5,
2
3
[
8] R. A. Donga, T.-H. Chan, M. J. Damha, Can. J. Chem. 2007,
1
1
7
4
6
85, 274–282.
22.1, 102.8, 98.0, 86.0, 85.0, 84.5, 82.8, 81.9, 81.5, 81.2, 79.4, 79.3,
8.1, 77.4, 75.6–75.2, 74.4, 73.7, 73.5, 72.3, 71.6, 68.3, 63.9, 62.8,
[
[
9] X. He, T. H. Chan, Synthesis 2006, 1645–1651.
10] J.-Y. Huang, M. Lei, Y.-G. Wang, Tetrahedron Lett. 2006, 47,
9.8, 36.4, 29.8, 14.9 ppm. C56
62
H O10S (927.15): calcd. C 72.54, H
3047–3050.
.74, S 3.46; found C 72.48, H 6.81, S 3.41.
[
11] a) A. K. Pathak, C. K. Yerneni, Z. Young, V. Pathak, Org. Lett.
2008, 10, 145–148; b) C. K. Yerneni, V. Pathak, A. K. Pathak,
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Compound 21: MS (ESI): m/z = 342 [M]+. 1H NMR (300 MHz,
CDCl ): δ = 11.9 (br. s, 1 H), 8.5 (s, 1 H), 6.88 (m, 1 H), 6.84 (m,
H), 3.79 (t, J = 7.2 Hz, 2 H), 3.57 (s, 3 H), 2.61 (t, J = 7.2 Hz, 2
3
[
12] a) R. J. Ferrier, R. H. Furneaux, in Methods in Carbohydrate
Chemistry (Eds.: J. N. BeMiller, R. L. Whistler), John Wiley &
Sons, New York, 1989, vol. 8, pp. 251–253; b) J. J. Gridley, A. J.
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1
1
3
H), 1.52–1.42 (m, 2 H), 1.04–0.91 (m, 2 H) ppm. C NMR
75 MHz, CDCl ): δ = 179.4, 137.0, 123.0, 122.9, 47.9, 37.0, 29.7,
(
2
=
3
9
7.0, 24.4 ppm. 1 F NMR (282.5 MHz, CDCl
710 Hz) ppm. C10 P (342.22): calcd. C 35.10, H 5.01;
found C 35.21, H 5.13.
1
3
): δ = –74.5 (d, JP,F
54, 14925–14946; c) R. J. Tennant-Eyles, B. G. Davis, A. J. Fair-
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H F N O
banks, Tetrahedron: Asymmetry 2000, 11, 231–243; d) G.-T.
Zhang, Z.-W. Guo, Y.-Z. Hui, Synth. Commun. 1997, 27, 1907–
1917; e) J. Dinkelaar, L. J. van den Bos, W. F. J. Hogendorf, G.
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Recycling of Carboxylic Acid Supported on Ionic Liquid 21: Com-
pound 21 (8 mg, 23.7 µmol) was dissolved in distilled dichloro-
methane (2 mL). Thionyl chloride (12.9 µL, 177.8 µmol, 7.5 equiv.)
and dried DMF (1 µL) were then added at 0 °C, and the reaction
mixture was stirred at 0 °C for 3 h, then added dropwise at 0 °C to
a solution ethyl 2,3-di-O-benzyl-4,6-O-dibutyl-stannylidene-1-thio-
β--glucopyranoside (22; 16.6 mg, 26.1 µmol, 1.1 equiv.) in distilled
dichloromethane (2 mL). Et N (0.18 µL, 1.3 µmol, 5.5%) was
3
added at 0 °C and the reaction mixture was stirred at room temp.
for 3 h. After evaporation of the solvents, the crude product was
washed with Et O (3ϫ 30 mL), and the solvents were removed by
2
[
13] G.-J. Boons, G. H. Castle, A. J. Clase, P. Grice, S. V. Ley, C.
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decanting to yield 1 (15.4 mg, 21.1 µmol, 89%) as a viscous yellow
oil.
[
Supporting Information (see footnote on the first page of this arti-
cle): Synthesis and analytical data of products 11–15 and 19.
Received: May 26, 2010
Published Online: October 13, 2010
Eur. J. Org. Chem. 2010, 6366–6371
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
6371