[R4N] [AOT]: A surfactant ionic liquid as a mild glycosylation promoter

Article abstract of DOI:10.1080/07328303.2011.609626

[RN₄][AOT] is a versatile surfactant ionic liquid that can be used in combination with N-Iodosuccinimide to promote the room temperature glycosylation of thiophenyl glycoside donors. The conditions are mild, with no requirement for molecular si

Full text of DOI:10.1080/07328303.2011.609626

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[R4N] [AOT]: A Surfactant Ionic Liquid as
a Mild Glycosylation Promoter
M. Carmen Galan a , Anh Tuan Tran a , Julien Boisson a , David Benito
a , Craig Butts a , Julian Eastoe a & Paul Brown a
a School of Chemistry , University of Bristol , Bristol , BS8 1TS , UK
Published online: 14 Dec 2011.
To cite this article: M. Carmen Galan , Anh Tuan Tran , Julien Boisson , David Benito , Craig Butts ,
Julian Eastoe & Paul Brown (2011) [R4N] [AOT]: A Surfactant Ionic Liquid as a Mild Glycosylation
Promoter, Journal of Carbohydrate Chemistry, 30:7-9, 486-497, DOI: 10.1080/07328303.2011.609626
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Journal of Carbohydrate Chemistry, 30:486–497, 2011
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C
Copyright Taylor & Francis Group, LLC
ISSN: 0732-8303 print / 1532-2327 online
DOI: 10.1080/07328303.2011.609626
[R4N] [AOT]: A Surfactant Ionic
Liquid as a Mild Glycosylation
Promoter
M. Carmen Galan, Anh Tuan Tran, Julien Boisson,
David Benito, Craig Butts, Julian Eastoe, and Paul Brown
School of Chemistry, University of Bristol, Bristol BS8 1TS, UK
[RN4][AOT] is a versatile surfactant ionic liquid that can be used in combination with
N-Iodosuccinimide to promote the room temperature glycosylation of thiophenyl gly-
coside donors. The conditions are mild, with no requirement for molecular sieves, and
are compatible with a wide range of donors and protecting groups. Under these condi-
tions, a different range of disaccharides have been obtained in good to excellent yields
and good stereoselectivities. Furthermore, the anomeric outcome of the glycosylation
reaction using glycosyl donors with no participating group at C-2 could be tuned by
switching the solvent from DCM to MeCN.
Keywords Oligosaccharides; Glycosylation; Ionic liquids; Surfactant ionic liquids
INTRODUCTION
Many synthetic efforts have been devoted over the years toward finding
reagents that could efficiently promote glycosidic bond formation.[1–3] However,
despite the many efforts, there is still a need for the development of reliable
reagents that can be generally applied to oligosaccharide synthesis and that
are applicable to both laboratory and industrial-scale preparation.
Herein, we describe the first synthetic application of ionic liquids based on
surfactant sulphonate anions ([R4N][AOT] 1a–1d, figure in Table 1). This new
class of ionic liquids can be used in combination with N-Iodosuccinimide (NIS)
as a selective and mild promoter in glycosylation reactions with thiophenyl
glycoside donors.
Received May 18, 2011; accepted July 27, 2011.
Address correspondence to M. Carmen Galan, School of Chemistry, University of Bris-
tol, Bristol BS8 1TS UK. E-mail: M.C.Galan@bristol.ac.uk
486

Surfactant Ionic Liquid as a Mild Glycosylation Promoter
487
Table 1: Summary of glycosylation reactions with thioglycoside donor 2 and model
acceptor 3 in the presence of different ILs 1a–d at rt to yield disaccharide 4
Entrya
Donor
Promoterb
Temp. (◦C)
Solvent
Yield (%)
α/β ratioc
1
2
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2b
1a
rt
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
MeCN
MeCN
DCM
45
2:1
1.2:1
1.3:1
1.1:1
1:1
1b
rt
90
3
1c
rt
88
4
1d
NaAOT
1b (50% w/w)
1b
rt
92
5
rt
50c + s.m.
6
rt
−78
82
s.m.d
94
1:1
7
—
1:1
8
1b
−40 to 0
−40 to 0
rt
9
1b (50% w/w)
1b
84
1.3:1
1:3
10
11
12
80
TMSOTf/NIS
1b
−40
75
1:3
0
88
Only β
aUnless indicated otherwise, all reactions at rt.
bUnless indicated, IL is used in 10% w/w.
cDetermined by NMR spectroscopy (1H and HMQC data).
dReaction quenched after 18 h.
s.m., recovered starting material (glycosyl donor); rt, room temperature.
In the last few years, ionic liquids (ILs) have emerged as a new class of en-
vironmentally attractive solvents that can be used for a broad number of syn-
thetic applications.[4–7] The high polarity of ILs can provide strong accelerating
effects to reactions involving cationic intermediates. ILs possess many unique
physicochemical properties, such as excellent solubilizing properties for most
organic and inorganic compounds, and having high thermal stability and wide
liquid temperature ranges. ILs are considered green solvents due to the very
low vapor pressures and their potential for recyclability. ILs are also chemi-
cally diverse owing to the huge number of possible cation/anion combinations

M.C. Galan et al.
488
that can be synthesized and have been used to facilitate a wide range of chem-
ical transformations, including acetylation, ortho-esterification, benzylidena-
tion, and glycosylation reactions of carbohydrates.[8–16] As part of our program
to develop new methods and strategies for oligosaccharide synthesis, we be-
came interested in the application of ionic liquids in this area of research. We
have recently reported the use of [bmim][OTf] (1-butyl-3-methylimidazolium
triflate) as a mild, recyclable, and versatile IL solvent/promoter of room tem-
perature (rt) glycosylation reactions using trichloroacetimidate and thiophenyl
glycoside donors.[12] We also showed that [bmim][OTf] could selectively acti-
vate “armed” glycosyl donors in the presence of “disarmed” ones and we demon-
strated its applicability in regio- and chemoselective glycosylation reactions
and in reactivity-based one-pot coupling reactions.[15]
Studies from our group aimed at understanding the scope and limitations
of imidazolium-based ILs on the rt activation of glycosyl donors[13] showed that
the choice of counterion in the IL is key to promote these types of reactions,
while modifications on the imidazolium cation did not have a significant effect
on the IL reactivity toward the glycosylation reaction or on the stereoselectivity
of the products.
Although the use of imidazolium-based ILs offers many attractive fea-
tures,[7] there are also some known drawbacks associated with imidazolium
salts, such as relative expense, unknown toxicity, environmentally hazardous
starting materials, issues with purification of the IL materials, and incompat-
ibility with reactions involving active metals or strong bases due to the acidity
of the C-2 proton of the imidazolium ion.[7,17,18] A new class of ionic liquid sur-
factants has recently been reported as an alternative to imidazolium-based
systems.[19,20] A key feature of this new class of ionic salts is the use of quater-
nary ammonium as cations and bis(2-ethyl-1-hexyl) sulfosuccinate (AOT) as
the anion component. Moreover, this new class of ILs is easily prepared from
cheap, environmentally benign, and commercially available starting materials
by a simple ion-exchange process.
RESULTS AND DISCUSSION
Based on our previous observations with respect to the imidazolium trifluo-
romethylsulfonate [mim] (OTf) ILs, combined with our search for a more ver-
satile promoter with a wider range of activation toward glycosylation reactions
than [bmim][OTf], we have explored the application of AOT-based ILs in rt gly-
cosylation reactions. We focused on thioglycosides as a suitable leaving group
due to their wide applicability and effectiveness on this type of transforma-
tion.[21] To that end, a series of tetra-alkyl ammonium-based ILs, with differing
alkyl groups and AOT as the counterion (X−), compounds [R4N][AOT] 1a–d,
were prepared following slightly modified reported procedures.[20]

Surfactant Ionic Liquid as a Mild Glycosylation Promoter
489
Initial experiments to test the ability of ILs 1a–d to efficiently promote
glycosidic bond formation were performed with armed thioglycoside donor 2a
and commercial 1,2:3,4-di-O-isopropylidene-α-D-galactopyranose 3 as model
acceptor in the presence of NIS (Table 1). Thus, activation of 2a at rt in
dichloromethane proceeded smoothly with ILs 1b–d and as a result disaccha-
ride 4a was obtained in excellent yields of 88% to 92% as approximately 1:1
α/β-mixtures within 2 h (Table 1, entries 2–4). When [NH4][AOT] 1a was used
as promoter (Table 1, entry 1), the reaction procedeed faster than with ILs
1b–d, but only 45% of the desired product was obtained along with hydrolyzed
donor 5.[22] As a control, sodium AOT was used as a promoter under the same
reaction conditions described above (Table 1, entry 5); however, the reaction
proceeded very slowly and stalled after 24 h, with only 50% of desired product
4a isolated.
It has been shown that when using [emim][OTf] (1-ethyl-3-methyli-
midazolium trifluoromethanesulfonate) as a solvent in glycosylation reaction
with TMSOTf at low temperatures, the anion can take part in the glycosyla-
tion and biases the attack of the glycosyl acceptor reaction by the formation of
a transient α-glycosyl triflate, which preferentially leads to β-glycoside prod-
ucts.[23] We hypothesized that due to the bulk of the AOT anion, if such par-
ticipation took place during the reaction at low temperatures, it should lead to
α-glycosides as the anion would prefer the less hindered β-face. To that pur-
pose, thioglycosyl donor 2a was subjected to the glycosylation reaction condi-
tions described above at −78◦C using IL 1b as the promoter (Table 1, entry
7); however, no reaction was observed as 1b froze at such low temperature.
Performing the glycosylation reaction at slightly higher temperatures (−40◦C
to 0◦C) did not change the stereo-outcome of the product 1:1 α/β, 94% yield)
(Table 1, entry 9). It is important to note that increasing the amount of IL to
50% (w/w) did not have an effect on the stereoselectivity of the glycosylation
and the overall yield of the reaction was slightly lower (82% to 84%) due to par-
tial hydrolysis of the donor. This was observed at both low (−40◦C to 0◦C) or
room temperatures presumably due to low levels of water in the IL, which be-
come more relevant at increased amounts of IL in the reaction (Table 1, entries
6 and 9).
The nature of the solvent is known to represent a key factor in the stereos-
electivity of glycosylation reactions.[24–26] For instance, reactions in acetonitrile
of glucopyranosides tend to yield 1,2-trans-glucoside (β linkage) as the major
product via an axial nitrilium ion intermediate that directs the attack of the
incoming nuclophile to the β-face.[27] The solvent effect dominates the stereos-
electivity as long as there is no participating effect of neighboring groups (i.e.,
participation of a C-2 neighboring group in the glycosyl donor, predominantly
leading to a 1,2-trans-glycosidic linkage irrespective of the solvent).[28] To in-
vestigate if a participating solvent could be used to affect the stereo-outcome
of the product in the presence of IL 1d during the reaction, donor 2a was

M.C. Galan et al.
490
subjected to the same reaction conditions previously described but using ace-
tonitrile as the solvent. Disaccharide product 4a[29] was obtained in 80% yield
as a 1:3 (α/β ratio), showing an increase in β selectivity (Table 1, entry 10). Re-
action of 2a with acceptor 3 under traditional activation using NIS /TMSOTf at
−40◦C also afforded a similar yield and α/β ratio (75%, 1:3 a/b, Table 1, entry
11). Reaction of 2b, which bears an ester neighboring participating group at
C-2 with acceptor 3 at 0◦C using 1d as promoter in DCM, afforded product
4b[30] in good yields (88%) as exclusively the β-anomer (Table 1, entry 12).
These results suggest that the AOT counterion of 1d does not directly partic-
ipate in the reaction mechanism but that [RN4][AOT] works by activation of
NIS to slowly form I+, which in turn can activate thioglycosyl donor 2a. Fur-
thermore, no interference of the IL with solvent or neighboring participating
effects during the glycosylation reaction were observed, demonstrating that
traditional approaches to control the stereoselectivity of the products are com-
patible with this new class of IL activators.
Previous thioglycoside activation by [bmim][OTf]/NIS combinations was
not efficient at temperatures below 0◦C.[12] On the basis that AOT-based ILs
are more reactive toward promoting glycosylation at low temperatures, we ra-
tionalized that perhaps this new class of surfactant ILs could be used in gly-
cosylations with a wider range of glycosyl donors in terms of reactivity toward
glycosylation. To explore the reactivity boundaries of differently protected thio-
glycosides, a series of glucose-based thioglycoside donors (6a,[31] 6b,[32] 6c,[33]
6d,[34] and 6e[35]) possessing different reactivity profiles[36–43] were prepared
in good yields following reported procedures and their couplings with 3 as a
model acceptor in the presence of 1b and NIS were monitored (Table 2).
Thus, activation of 6a and 6b proceeded smoothly under the reaction con-
ditions described above at rt and within 2 h and as a result products 7a[44] and
7b[45] were isolated in 72% (1.4:1 α/β) and 78% (3:1 α/β), respectively (Table 2,
entries 1 and 3). Changing the reaction solvent from dichlomethane to a par-
ticipating solvent such acetonitrile increased the amount of β-anomer in the
final product, as expected, and afforded a slightly better overall yield. In this
instance, 7a was isolated in 80% (1:3 α/β), and 7b in 98% (1:4 α/β) (Table 2,
entries 2 and 4). “Super-armed”[46] donor 6c, which bears a neighboring partic-
ipating group at C-2, yielded the corresponding disaccharide product 7c[47] in
95% yield within 15 min at 0◦C as the β-anomer (Table 2, entry 5). The same
reaction conditions were applied to the reaction of less active thioglycosides 6d
and 6e. It is expected that acyl substituents have a disarming effect on thiogly-
cosides,[48] and thus it was not surprising the stability observed for peracety-
lated 6d under the mild reaction conditions (Table 2, entry 6). When 0.03 equiv.
of TMSOTf was added to the reaction, the desired product 7d[44] was obtained
in 76% yield as the β-anomer (Table 2, entry 7). It has also been shown that al-
though more active than peracetylated glycosides, 4,6-O-benzylidene-protected
pyranosyl systems, such as 6e, are also less active glycosyl donors than their

Surfactant Ionic Liquid as a Mild Glycosylation Promoter
491
Table 2: Summary of glycosylation reactions with thioglycoside donor 6a–h and
model acceptor 3 in the presence of ILs 1b/NIS at rt to yield disaccharide 7a–h
Entrya
Donor
Solvent
Yield (%)
Product
α/β ratiob
1
2
3
4
5
6
7
8
6a
6a
6b
6b
6c
6d
6d
6e
DCM
MeCN
DCM
MeCN
DCM
DCM
DCM
DCM
72
80
7a
7a
7b
7b
7c
7d
7d
7e
1.4:1
1:3
78c
98d
95e,f
s.m.g
76h
75
3:1
1:4
Only β
—
Only β
Only β
aUnless indicated otherwise, all reactions at rt.
bDetermined by NMR spectroscopy (1H and HMQC data).
cReaction time = 5 h.
dReaction time = 30 min.
eReaction time = 15 min.
fReaction temperature = 0◦C.
gReaction quenched after 18 h.
h0.03 equiv TMSOTf used.
s.m., recovered starting material (glycosyl donor).
4,6-di-O-benzyl congeners, because the formation of oxycarbenium cations is
disfavored, due to the greater strain the conformational deformation imposes
on the transfused bicyclic nucleus.[37,48] To further probe the scope of activation
of 1b at rt, 4,6-O-benzylidene, N-Trichloethylchloroformate (N-Troc)-protected
6e was subjected to the reaction conditions and disaccharide 7e was isolated
in 75% yield (β-anomer only) (Table 2, entry 8).
In general, conversion yields for reactions where 1b was used as the glyco-
syl activator at rt were comparable and in some cases exceeded those achieved
in reactions where TMSOTf was used at −40◦C as the activator.[12,13]
CONCLUSIONS
In conclusion, we have shown the first synthetic application of a new class
of surfactant ILs 1b–1d in the mild activation of thioglycosides when used

M.C. Galan et al.
492
in combination with NIS. The glycosylation conditions are mild and com-
patible with a range of hydroxyl-protecting groups, such as acetates, benzyl
ethers, and acetals, and are also amenable to NH2-masking strategies, that is,
trichloroethylcarbamate (Troc). Mechanistically, we suggest 1b works by slow
activation of NIS to release I+ in situ, which in turn activates the thioglyco-
sides. We have also shown that 1b is a more reactive activator than [mim][OTf]
while still discerning the less active (peracetylated) donors. Work is under way
to utilize this new class of ILs in one-pot glycosylation reactions where chemos-
elective activation of the glycoside donors is important.
EXPERIMENTAL
General Methods
General
Chemicals were purchased from Aldrich and Fluka and used without fur-
ther purification. Molecular sieves were activated at 350◦C for 3 h and cooled
under vacuum. Dry solvents, where necessary, were obtained by distillation us-
ing standard procedures or by passage through a column of anhydrous alumina
using equipment from Anhydrous Engineering (University of Bristol) based on
the Grubbs design. Reactions requiring anhydrous conditions were performed
under an atmosphere of dry nitrogen; glassware, syringes, and needles were
either flame dried immediately prior to use or placed in an oven (150◦C) for at
least 2 hours and allowed to cool either in a desiccator or under an atmosphere
of dry nitrogen; liquid reagents, solutions, or solvents were added via syringe
or cannula through rubber septa; solid reagents were added via Schlenk-type
adapters. Typical reactions were carried out in 40- to 50-mg scale. Reactions
were monitored by TLC on Kieselgel 60 F254 (Merck). Detection was by ex-
amination under UV light (254 nm) and by charring with 10% sulfuric acid
in methanol. Flash chromatography was performed using silica gel (Merck,
230–400 mesh [40–63 µm]), and the crude material was applied to the column
as a solution in CH2Cl2 or by preadsorption onto silica, as appropriate. Ex-
tracts were concentrated under reduced pressure using both a Bu¨chi rotary
evaporator (bath temperatures up to 40◦C) at a pressure of either 15 mm Hg
(diaphragm pump) or 0.1 mm Hg (oil pump), as appropriate, and a high vac-
1
uum line at rt. H NMR and 13C NMR spectra were measured in the solvent
stated with 400 or 500 MHz Varian INOVA 400 and 500 instruments, respec-
tively. Chemical shifts quoted in parts per million from SiMe4 and coupling
constants (J) are given in hertz. Multiplicities are abbreviated as br (broad),
s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), or combinations
thereof. Negative ion matrix–assisted laser desorption ionization time-of-flight

Surfactant Ionic Liquid as a Mild Glycosylation Promoter
493
(MALDI-TOF) mass spectra were recorded using an HP-MALDI instrument
using gentisic acid matrix.
Synthesis of ILs 1a–1d
Synthesis of the compounds has been described elsewhere.[19] Na-AOT
was purchased from Sigma-Aldrich and purified by Soxhlet extraction using
dry acetone and subjected to repeated centrifugation. Five grams of Na-AOT
was then dissolved in a 30-mL water:ethanol mix (1:1 v/v) and slowly passed
through an ion-exchange resin (Amberlite IR-120, Sigma-Aldrich). The H-
AOT solutions were neutralized by tetra-alkylammonium hydroxide solutions
(1 equiv.) (Sigma-Aldrich, used as bought). The solvent was then removed and
dried in vacuo for 24 h. The synthesized surfactants were characterized by
elemental analysis and NMR, all being consistent with experimental chemi-
cal structures. The solvent was removed under reduced pressure and dried in
vacuo for 24 h. ILs were redissolved in toluene and concentrated under vac-
uum to coevaporate any traces of residual water and left drying for 18 h under
high vacuum at rt before being used in glycosylation reactions.
General Protocols for Glycosylation Reactions
Typical IL-promoted glycosylation procedures
IL (1a–1d) (10% to 50% w/w) was added to a stirred suspension of thiogly-
coside donor (1.5 equiv.), glycosyl acceptor (1 equiv.), and NIS (2 equiv.) in dry
dichloromethane (2–3 mL). The mixture was left stirring for 2 h at rt unless
stated otherwise in the table. TLC (hexane/ethyl acetate, 1:1, v/v) indicated
completion of the reaction. The mixture was neutralized with triethylamine
(2 equiv.) and concentrated under reduced pressure. The syrup mixture was
then washed with diethyl ether (4 × 30 mL) to extract the product from the
ionic liquid, which was monitored by TLC to ensure all the product was in
the ether phase. The washes were then collected and after evaporation of the
solvent, the residue was further purified by flash silica gel chromatography
(gradient hexane/ethyl acetate, 3:1 to 1:1, v/v) to yield the corresponding
oligosaccharide products.
Typical IL(1d) + TMSOTf-promoted glycosylation procedure
Trimethylsilyl trifluoromethanesulfonate (0.03 equiv.) and 1d (10% w/w)
were added to a stirred suspension of thioglycoside donor 6d (50 mg, 1.5 equiv.),
glycosyl acceptor (1 equiv.), and NIS (2 equiv.) in dry dichloromethane (2–
3 mL). The mixture was left stirring at rt for 3 h. TLC (hexane/ethyl acetate,
1:1, v/v) indicated completion of the reaction. The mixture was neutralized
with triethylamine (2 equiv.) and concentrated under reduced pressure. The

M.C. Galan et al.
494
mixture was then washed with diethyl ether (4 × 30 mL) to extract the prod-
uct from the ionic liquid, which was monitored by TLC to ensure all the product
was in the ether phase. Interestingly, the washes were then collected and af-
ter evaporation of the solvent, the residue was further purified by flash silica
gel chromatography (gradient hexane/ethyl acetate, 3:1 to 1:1, v/v) to yield the
corresponding oligosaccharide 7d.
1,2:3,4-Di-O-isopropylidene-6-O-(4,6-O-benzylidene-2-deoxy-2-(2,2,2-
trichloroethoxycarbonyl-amino)-β-D-glucopyranosyl)-β-D-
galactopyranoside 7e
1H NMR (CD3OCD3, 400 MHz): δ = 7.51–7.49 (m, 2H, Ph), 7.37–7.36 (m,
3H, Ph), 5.63 (s, 1H, CHPh), 5.45 (d, 1H, J1,2 = 5.0 Hz, H-1), 4.80 (d, 1H, J =
12.0 Hz, CH2 Troc), 4.77 (d, 1H, 1H, JNH,2 = 10.5 Hz, NH), 4.73 (d, 1H, J =
12.0 Hz, CH2 Troc), 4.72 (d, 1H, J1,2 = 8.5 Hz, H-1ꢁ), 4.60 (dd, 1H, J3,4 = 2.5 Hz,
J3,2 = 8.0 Hz, H-3), 4.32 (dd, 1H, J2,3 = 2.5 Hz, J2,1 = 5.0 Hz, H-2) 4.30–4.27 (m,
2H, H-4ꢁ, H6aꢁ), 4.97–3.93 (m, 3H), 3.75 (t, 1H, J6b,5 = J6b,6a = 10.5 Hz, H-6bꢁ),
3.62–3.54 (m, 3H), 3.45 (td, 1H, H-5ꢁ), 1.50 (s, 3H, CH3), 1.37 (s, 3H, CH3), 1.31
(s, 6H, 2xCH3). 13C NMR (CD3OCD3, 100 MHz): δ = 156.1 (CO, Troc), 139.7,
(Cq, Ph), 130.7, 129.3, 178.7 (CH, Ph), 101.0, 109.6 (CH3CCH3), 101.2 (C-1ꢁ),
102.7 (CHPh), 97.6 (C-1), 84.2 (CCl3, Troc), 83.3 (C-5), 75.5 (CH2 Troc), 72.4,
72.0, 71.9, 70.0, 69.7, 68.3, 67.8, 60.0, 58.8 27.1, 26.9, 25.8, 25.2. ESI-HRMS
for C28H36Cl3NNaO12), calcd.: 706.1201; found: 706.1198.
ACKNOWLEDGEMENTS
We gratefully acknowledge financial support from the EPSRC, The Royal Soci-
ety, and EC Marie Curie FP7 for financial support.
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