-
Accepted Manuscript
Minireview
Recent Developments of Ionic Liquids in Oligosaccharide
Synthesis. The Sweet
Side of Ionic Liquids
M. Carmen Galan, Rachel A. Jones, Anh-Tuan Tran
PII: S0008-6215(13)00139-0
DOI: http://dx.doi.org/10.1016/j.carres.2013.04.011
Reference: CAR 6454
To appear in: Carbohydrate Research
Received Date: 21 February 2013
Revised Date: 9 April 2013
Accepted Date: 10 April 2013
Please cite this article as: Carmen Galan, M., Jones, R.A.,
Tran, A-T., Recent Developments of Ionic Liquids in
Oligosaccharide Synthesis. The Sweet Side of Ionic Liquids,
Carbohydrate Research (2013), doi: http://dx.doi.org/
10.1016/j.carres.2013.04.011
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1
Recent Developments of Ionic Liquids in Oligosaccharide
Synthesis. The Sweet
Side of Ionic Liquids.
M. Carmen Galan,a* Rachel A. Jones
a and Anh-Tuan Tran
a,b
aSchool of Chemistry, University of Bristol, Bristol BS8 1TS,
UK
bCurrent Address: Institut Parisien de Chimie Molculaire,
Universit Pierre et
Marie Curie , 75252 Paris Cedex 05
*Corresponding author: Tel: +44(0)1179287654; Fax:
+44(0)1179298611;
E-mail:[email protected]
Keywords:
Carbohydrates
Oligosaccharide synthesis
Glycosylation at room temperature
Ionic liquids
Supported oligosaccharide synthesis
Abstract
The area of ionic liquid (IL) research has seen tremendous
growth over the last few
decades. The development of novel ILs with new and attractive
physical and chemical
properties has had a direct impact on organic synthesis.
In particular, ILs have had many applications in carbohydrate
chemistry including
their use as solvents for dissolving high molecular weight
carbohydrate polymers such
as cellulose and as solvents and catalysts in oligosaccharide
synthesis. In this area, ILs
have been involved in protecting group manipulation reactions as
well as glycosidic
couplings leading to new methodologies and enhanced procedures.
In addition, ILs
have been successfully utilized as solution-phase purification
supports.
This review focuses on the most recent advances in the
application of ILs to
oligosaccharide synthesis. This is an emerging area that offers
great promise at
addressing some of the obstacles that remain on the path towards
the automation of
oligosaccharide synthesis.
1. Introduction
Carbohydrates are one of the most diverse and important classes
of biomolecules
in nature. Oligosaccharides found on the surface of cells as
part of glycoproteins and
glycolipids play key roles in the control of various normal and
pathological processes
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2
in living organisms, such as protein folding, cell-cell
communication, bacterial
adhesion, viral infection, masking of immunological epitopes,
fertilization,
embryogenesis, neural development and cell proliferation and
organization into
specific tissues.1-3
It is the multitude of biological roles carbohydrates and their
glyco-
conjugates play, which has stimulated scientists to devote their
efforts to determine
the mechanisms of interaction involved in both healthy and
disease processes. The
nature of cell-surface carbohydrates can differ considerably
between sick and normal
cells. For instance, if unique glycan markers for diseased cells
are found, scientists
can develop diagnostic tools to identify diseases at an early
state when treatment is
more likely to be effective, develop vaccines or novel drugs
that could inhibit the
interaction of those glycans with their binding partners.4
Glycan heterogeneity,
although instrumental to the coding of biological information in
intra- and
intercellular recognition processes (Glycocode), makes isolation
of pure samples and
in sufficient amounts from biological sources extremely
difficult.
If we are to understand glycan diversity and function, it is
essential to have access
to oligosaccharides in sufficient purity and quantity to be able
to carry out biological
studies. Chemical synthesis offers the advantage of producing
pure and structurally
defined oligosaccharides for biological investigations. However,
approaches to
prepare diverse libraries of complex carbohydrates in a rapid
manner are greatly
lacking and that has had a detrimental effect on the progress of
glycobiology research,
as it has had to rely either on isolated materials,
target-oriented lengthy chemical
syntheses or enzymatic approaches. It is not surprising then
that much effort has been
devoted over the last twenty years towards the development of
oligosaccharide
methodologies that can be automated.4-7
While the methods differ on the nature of
their approach, they all share the identical goal of making
carbohydrates more
accessible to mainstream chemists and biologists.
One of the main difficulties in the automation of
oligosaccharide synthesis is the
requirement for purification after each reaction step, which is
normally accomplished
by chromatography. Researchers have endeavoured to circumvent
the issue by
developing one-pot synthetic strategies whereby multiple
glycosylation reactions can
be performed in a single reaction vessel, reducing the number of
purification steps.8
Supported oligosaccharide syntheses have been developed as a
viable alternative to
traditional methodologies, where purification is simplified by
the use of a covalently
attached purification label to either the glycoside donor or
acceptor and which allows
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3
for chromatography-free isolation of the product after each
reaction step. The nature
of the purification label differs from approach to approach.
Solid and soluble
polymers supports, fluorinated labels, gold platforms and more
recently ionic liquids
(ILs) have been used within this strategy.4
Figure 1. General schematic representation for common
oligosaccharide assembly strategies: A)
Supported phase oligosaccharide assembly on a polymer resin,
fluorous tag, ionic-liquid-based tag or
gold sticks. The glycan units are attached by means of a linker
to the support and the cycle consists of
activation and deprotection steps. Finally the linker is cleaved
to procure the desired oligosaccharide.
B) Reactivity-based one-pot glycosylation synthesis. P =
temporary protecting groups, LG = leaving
group, R = hydrocarbon residue, A = arming protecting group, D =
disarming protecting group.
ILs are a new class of solvents which have attracted growing
interest over the past
few years due to their unique physical and chemical properties
for a broad number of
synthetic and enzymatic applications.9-15
ILs consist of poorly coordinating ion pairs
with physical and chemical properties that can be tuned by
altering the cation or the
anion structure.
The last few decades have seen an explosion of research in the
field of ILs applied
to organic synthesis with some ILs able to act as recyclable
catalysts as well as
reaction media in organic reactions.15,16
In particular, ILs have had many applications
2
1
'Disarmed' Donor
Acceptor
Activation of 2:NIS + TMSOTf
Activation of 1:IL, NIS, DCM
Solvent evaporation
Product extraction and purification
IL
Product
Activation
Linker OHActivation
LinkerDeprotection
Linker Cleavage
A)
B)
'Armed' Donor
O LG
PO
O
OP
Linker O
OH
O LG
PO
Linker O
O O
OP
ORO
O O
OP
O OR
HO
O LG
AO
OH
O LG
DO
R.T.
O OR
OO
AO
OO
OD
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4
in carbohydrate chemistry including their use as solvents for
dissolving high
molecular weight oligomers, mainly cellulose, for further
processing17
and as solvents
and catalysts in protecting group manipulation reactions as well
as glycoside
couplings leading to new methodologies and enhanced procedures
and also as
purification supports to simplify purification.18
Additionally, carbohydrate scaffolds
have been used as a source of ILs and chiral ILs.19
This review will focus on the most recent advances on the
application of ILs in
oligosaccharide synthesis. This is an emerging area that offers
great promise at
addressing some of the obstacles that remain on the path towards
the automation of
oligosaccharide synthesis.
2. Ionic Liquids as solvents in oligosaccharide synthesis.
ILs have been shown to exhibit excellent solubilising
properties, facilitating a wide
range of chemical transformations, including acetylation,
ortho-esterification,
benzylidenation and glycosylation reactions of
carbohydrates.20-24
The high polarity of
ILs can provide strong accelerating effects to reactions
involving cationic
intermediates and as a result, reactions in ILs have kinetic and
thermodynamic
behaviour different from classical solvents, which often leads
to improved process
performance.25
The use of ILs as solvents for the transformation of
carbohydrates was first
reviewed by Linhardt in 2005.23
Subsequently, in 2011 Afonso and co-workers
discussed the application of ILs in carbohydrate
dissolution.18
Therefore, this review
will only describe the most recent developments in this
particular area over the last
few years.
In the context of glycosylation reactions, changes in the
diastereoselectivity of the
reactions have been observed when ILs were used as reaction
media. For instance, the
group of Poletti reported that the stereoselectivity outcome of
reactions with
trichloroacetimidate glycoside donors bearing a nonparticipating
group at C-2, in
different ILs as solvents and using catalytic TMSOTf as
promoter, was significantly
affected by the reaction media, the catalyst and by the anomeric
configuration of the
donor.26
In their report, when [bmim][PF6] was used as the solvent in the
presence of
catalytic TMSOTf, -glycosides were favoured, whereas when
[emim][OTf] was used
as the solvent in the presence of the Lewis acid, no anomeric
selectivity was
observed. A greater degree of -selectivity was achieved when the
reaction was
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5
performed with [emim][OTf] in the absence of the Lewis acid and
when the starting
trichloroacetimidate was in the -anomeric configuration. Their
1H NMR studies on
protected glucoside - and -trichloroacetimidates suggested that
triflated-based ILs
participate in glycosylation reactions, by formation of a
transient -glycosyl triflate
that yields predominantly -glycoside products (Scheme 1,
A).22
Scheme 1. IL effect on the stereoselectivity of the
glycosylation reaction: A) Trichloroacetimidate
glycoside donors; B) Glycosyl phosphites; C) Glycosyl
fluorides.
These results are in agreement with Toshima et al.s observations
when using
glucopyranosyl diethyl phosphite as glycosyl donors in the
presence of catalytic
amounts of a protic acid when an IL was the solvent. When
[1-hexyl-3-methyl][NTf2]
was used as the solvent then -glycoside products were
favoured.27 Interestingly,
when the same group used glucopyranosyl fluorides as glycoside
donors in the
presence of [1-hexyl-3-methyl][NTf2] and a protic acid (HNTf2),
the -product was
preferred. These results were independent of the anomeric
configuration of the
glycoside donor (Scheme 1, B and C).28
In the case of unprotected glycosides, glycosylations in ILs
tend to give products
with increased -selectivity. This can be rationalized by a
mechanism in which the
glycosylation occurs via an oxocarbenium ion that can be
stabilized by the IL.29
At
higher temperatures, reactions proceed under thermodynamic
conditions, thus
favouring -glycoside formation.24
A recent example on the use of ILs as solvents has come from the
lab of Misra et
al.30
who reported the use of ILs as solvents for the facile
preparation of
thioglycosides (Scheme 2). A range of ILs were screened and
[bmim][BF4] was found
to be the most suitable IL. Treatment of peracetylated
glycosides with aryldisulfide in
the presence of Et3SiH and BF3.OEt2 at room temperature in
[bmim][BF4], yielded
thio-arylglycosides in good to excellent yields (80 90%). The
key advantages of the
O
OBnBnO
BnO
OBn
OO
OBnBnO
BnO
OBn
O
IL, RT
[bmim][PF6] 76 : 24
[emim][OTf] 45 : 55
OH IL
Lewis acid
Lewis acid a : b
TMSOTf
TMSOTf
[emim][OTf] none 20 : 80
O
OBnBnO
BnO
OBn
OP(OEt)2
A
B
C
[hexmim][NTf2]
O
OBnBnO
BnO
OBn
F[hexmim][NTf2]
ROH
HNTf2 O
BnOBnO
BnO
OBn
OR
a favoured
ROH
HNTf2 O
OBnBnO
BnO
OBn
OR b favoured
NH
CCl3
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6
protocol is that chlorinated solvents such as CH2Cl2 can be
avoided and that the IL
can be recycled and re-used up to four times without any
significant losses in yield
and selectivity.
Misra and colleagues also showed that the optimised conditions
were also
applicable to the synthesis of selenoglycosides, using aryl
diselenides in place of aryl
disulfides, resulting in the rapid formation of a range of
selenoglycosides in good to
excellent yield (70 90%).
Scheme 2: One-pot preparation of thio- and selenoglycosides
using [bmim][BF4] as the solvent at
room temperature.
It was subsequently shown that [bmim][BF4] could be used as a
recyclable solvent for
the BF3OEt2 assisted thioglycosylation of peracetylated
glycosides using aryl thiols.31
3. Ionic Liquids as co-solvent/promoters in glycosylation
reactions.
Glycosidic bond formation is a crucial step in oligosaccharide
synthesis. A great
deal of research has been devoted to finding improved reagents
for performing
glycosylations with the best yields and with complete regio- and
stereocontrol.5 There
is still a need however, to identify reliable glycosylation
promoters that can be
generally applied to oligosaccharide synthesis and that are
applicable to both
laboratory and industrial scale preparation. Traditional
glycosylation reagents tend to
suffer from several drawbacks, typically, low temperature and
molecular sieves are
required. The ocurrence of side reactions with by-products
resulting from the use of
promoters is also another limitation.32
ILs offer an interesting alternative to traditional reagents.
There are currently many
applications of ILs as solvents in chemistry, with some able to
act as recyclable
catalysts as well as reaction media in organic
reactions.12,33,34
More recently, uses of
ILs in the area of oligosaccharide synthesis have
emerged.20-22,27,35
Galan et al. reported the first application of [bmim][OTf] as a
mild and versatile IL
co-solvent and promoter for the room temperature glycosylation
of both thiophenyl
and trichloroacetimidate glycoside donors (Scheme 3).11
The conditions are mild, and
compatible with a range of hydroxyl protecting groups, such as
acetates, benzyl
ethers, acetals. They are also amenable to NH2 masking
strategies i.e. phthalimido
OOAc
OSR
R = Ph, Tol, Naph, pNP
RS-SR or RSe-SeR
Et3SiH, BF3.OEt2
[bmim][BF4]80-90%
OSeRor
70-90%
AcO AcO AcO
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7
(Phth) and trichloroethoxycarbonyl (Troc). The team also showed
that the triflated IL
could selectively promote activated (armed) thiophenyl and
trichloroacetimidate
glycosyl donors, while less active (disarmed) donors required
the addition of catalytic
triflic acid. Initial mechanistic studies suggested that
[bmim][OTf] can facilitate
glycosylation reactions by the slow release of catalytic amounts
of triflic acid and that
the IL also protects the newly formed glycosidic linkage from
hydrolysis.
Scheme 3: Glycosylations of thioglycosides and
trichloroacetimidate donors using [bmim][OTf] as the
co-solvent and glycosylation promoter at room temperature.
Studies from the same group explored the scope and limitations
of imidazolium-
based ILs by generating a series of substituted imidazolium ILs
1a-n, with differing
R1 and R
2 groups and a range of counter ions (X
-) and testing their effectiveness in
glycosylation reactions (Scheme 4 and Table 1).11
Those experiments further
demonstrated the importance of the choice of counter ion when
choosing an IL to
promote this type of glycosidic bond forming reaction. It was
shown that imidazolium
based ILs bearing triflate or triflimide counter ions serve as
room temperature
selective glycosylation promoters for armed thiophenyl glycosyl
donors. Furthermore,
substitutions at R1 of the imidazolium cation did not have an
effect on the reactivity or
diastereoselectivity of glycosylations with thioglycoside
donors, while modifications
at R2 had an effect on the rate of glycosidic bond forming
reactions.
Interestingly, Galans results also demonstrated that the
stereoselectivity of the
glycosylation reactions was significantly affected by the IL. In
their examples,
glycosylations with activated thioglycosides bearing
non-participating groups at C-2
showed an increase in -glycoside products in comparison to
reactions carried out
using TMSOTf at low temperatures (Table 1).11,36
Using ILs to promote these type of reactions offers several
advantages over other
traditional promoters. For example, the ability to recycle the
IL promoter is very
attractive in terms of green chemistry, and in general the
ability of ILs to promote
Br Ph O
NP
SPh
Acceptors (ROH)
P=HTroc P=Phth
R= OO
O
OO
OLG
BnO OOR
BnOIL/CH2Cl2
r.t.Activated Donor Product
ROH+ IL
Recycling
LG = OC(NH)CCl3
Solvent evaporation
Product extraction
IL
OOR
BnO
ProductLG = SPh
NIS
N N+
-OTfIL
OO
Ph
TMSOTf
-
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8
glycosylation reactions at room temperature is amenable to cost
effective automated
oligosaccharide synthetic protocols where no strict control of
low temperatures will
be required.
Scheme 4: Screening of ILs (1a-1n) as the co-solvent and
glycosylation promoter at room temperature
in glycosylation reactions with thioglycosides.
Table 1. Representative examples of glycosylation reactions with
screened ILs
Entry Promoter Yield
%
Ratio
/ Reaction
time, h
1 TMSOTfb 75 0.02/1 3
2 1a 97 0.78/1 3
3
1l 90 0.75/1 2
4 1m 72 0.67/1 1
Having demonstrated that the [bmim][OTf]/NIS system was
excellent for activating
armed thioglycoside donors in the presence of disarmed
thioglycosides, Galan et al.14
showcased the versatility of the IL/NIS promoter in a series of
regio- and
O
O
O
OO
OH
N NR1
X-
R2
Ionic Liquids (ILs)
2
1a R1=Me, R2=H, X=OTf
1b R1=Me, R2=H, X=N(Tf)21c R1=Me, R2=H, X=BF41d R1=Me, R2=H,
X=PF61e R1=Me, R2=H, X=Br
1f R1=Me, R2=H, X=Cl
1g R1=Me, R2=H, X=AlCl41h R1=Me, R2=H, X=HSO31i R1=CH2COOH,
R2=H, X=BF41j R1=CH2COOH, R2=H, X=OTf
Glycoside Acceptor
+
1l R1=Me, R2=CH3, X=OTf
1m R1=Me, R2=Ph, X=OTf
1n R1=Me, R2=Ph, X=N(Tf)2
1k R1= , R2=H, X=OTfO
O
OR
RO
OR
OR
SPhORO
ROOR
OR
SPh
R=Bn R=Ac
R=BnR=Ac
Thioglycoside Donnors
OLG
RO OOR
BnO
IL/ DCMroom temp.
Glycosyl DonorProduct
ROH
NIS
Glycoside Acceptor
OO
O
OO
OHOBnO
BnOOBn
SPh
OBn
+
OBnOBnO
OBn
OBn
OO
O
OO
O
PromoterNIS(2 equiv.)/DCM
Room Temp.
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9
chemoselective glycosylation reactions at room temperature where
both donor and
acceptor bear a free OH of distinct reactivity.
One-pot synthetic strategies have been developed as an
alternative to traditional
sequential approaches to oligosaccharide synthesis, since
multiple glycosylation steps
can be formed in a single reaction vessel and purification
between individual steps
can be avoided. Many of these one-pot convergent approaches are
based on the
selective activation of one glycosyl donor over another, a
concept initally exemplified
by Fraser-Reids armed-disarmed methodology (Figure 1, B).37 In
this context, it was
demonstrated that the mild IL/NIS promoter system can be used
for room temperature
reactivity-based one-pot reactions, whereby the reactivity of
the building blocks is
tuned by the choice of protecting groups. Branched and linear
trisaccharides 2 and 3
were synthesized following a one-pot glycosylation reaction
where partially protected
armed monosaccharide glycoside, 5 (branched approach) or 8
(linear approach), was
used firstly as the glycosyl donor with glycosyl acceptor 4
(branched approach) or 7
(linear approach). The resulting product became the glycosyl
acceptor in the
following step, which was reacted directly with less reactive
glycoside donor 6 under
TMSOTf/NIS catalytic conditions. This could be achieved in both
a sequential
approach (Scheme 5, A) or in a strategy where all the components
were mixed
together in one vessel at the beginning of the synthesis (Scheme
5, B).14
Scheme 5. One-pot reactivity based synthesis of branched and
linear trisaccharides 2 and 3.
O
OBnBnO
OBn
BnO
O
BnOBnO
HO
OMe
OH
OAcO
OAc
AcOSPh
+ TMSOTf, NIS
O
BnOBnO
OMe
O
O
OAcAcO
OAc
AcO O
O
OBnBnO
OBn
BnOSPh
O
OBnO
OBn
BnO
O
BnOBnO
BnO
OMe
OH
O
OAcAcO
OAc
AcOSPh
+ TMSOTf, NIS
O
BnOBnO
OMe
O
O
OAcAcO
OAc
AcO
BnO
O
OHBnO
OBn
BnOSPh
2
OAc
A
Branched trisaccharide
3
Linear trisaccharide
41%
(0.3/1)29%
(0.45/1)
B TMSOTf, NIS
+ +
[bmim][OTf]
NIS
3
44%
(0.3/1)
RT
4
5 6
7
8 6
7 8 6
CH2Cl2
[bmim][OTf]
NIS
CH2Cl2, r.t.
[bmim][OTf]
NIS
CH2Cl2, r.t.
-
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10
A) Sequential addition of glycosides; B) Mixing of glycosides at
the start of the synthesis.
Imidazolium based ILs can be used as a source to access
N-heterocyclic carbenes
(NHCs).38
The group of Malhotra have shown that O-glycosylation reactions
can be
promoted via silver NHC complexes formed in situ in ILs using
silver carbonate.39
In
a subsequent study, the same group decided to explore the
effects of adding an IL
salt.40,41
Seven different room temperature ILs (RTILs) were screened for
the
glycosidation of 4-nitrophenol with
tetra-O-acetyl--D-galactopyranosyl bromide.
They showed that anion metathesis of the ILs with inexpensive
alkylammonium
halides also resulted in silver NHC formation and subsequent
O-glycosidation in the
presence of silver carbonate. Interestingly, the yields for the
glycosylations using
silver carbonate increased by 50 60% when an imidazolium halide
was added to the
reaction mixture. This was attributed to the increased ability
of NHCs to deprotonate
phenols relative to silver carbonate (Scheme 6).
Benzyltriethylammonium chloride
(BTEACl) was shown to be the best salt for promoting metathesis
in the
glycosylations, while the best yields were achieved with either
[bmim][BF4] or
[bmim][PF6] as the IL source. To test the scope of the reaction,
a range of aryl
alcohols were used including phenols, flavones, steroids and
coumarins with the
glycosylations proceeding in good to excellent yields (51 94%)
with exclusive
selectivity in most cases.
Scheme 6: In-situ formation of silver NHCs for glycosylation
reactions.
Although the use of imidazolium based ILs offers many attractive
features, there
are also some known drawbacks associated with imidazolium salts
such as relative
expense, unknown toxicity and environmentally hazardous starting
materials. In
addition, there are issues with the purification of the IL
materials and their
incompatibility with reactions involving active metals or strong
bases due to the
acidity of the C-2 proton of the imidazolium ion.15,42,43
A new class of IL surfactants
has been reported recently as an alternative to
imidazolium-based systems.44,45
A key
feature of this new class of ionic salts is the use of
quaternary ammonium as cations
O
OAcAcO
AcO
BrAcO
Ag2CO3
[bmim][BF4], BTEACl, RT
O
OAcAcO
AcOOAc
OArArOH
87%b only
-
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47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65
11
and bis(2-ethyl-1-hexyl) sulfosuccinate (AOT) as the anion
component. Moreover,
this new class of ILs are easily prepared from cheap,
environmentally benign and
commercially available starting materials by a simple ion
exchange process. Recently,
it has been shown by Galan et al. that ILs based on surfactant
sulfonate anions
([R4N][AOT]) in combination with NIS, could also be used as
selective, mild
promoters for thioglycosylations (Scheme 5).46
A range of surfactant ILs 9a-d were
tested in model glycosylations and it was shown that 9b was the
most reactive
activator. The scope of the reaction, with glucose based
thioglycoside donors 10a-e
possessing different reactivity profiles, model glycosyl
acceptor 11 and IL 9b was
subsequently probed (Table 2). Surfactant IL 9b was shown to be
a more reactive
activator than [bmim][OTf], while still being able to discern
the less active
(peracetylated) donor 10d. As expected, reactions with armed
glycosyl donors 10a
and 10b and super-armed donor 10c yielded disaccharides 11a-c in
good yields.
Interestingly, less reactive 4,6-O-benzylidene,
N-trichloroethoxycarbonyl (N-Troc)
protected 10e, which could not be activated by the
[bmim][OTf]/NIS combination,11
afforded disaccharide 12e in 75% yield as the -anomer only
(Table 2). For disarmed
glucosyl donor 10d, however, catalytic TMSOTf was required to
affect the
glycosylation thus allowing AOT-based ILs to potentially be used
as glycosyl
promoters in one-pot reactions. The stereoselectivity of the
product was shown to be
influenced by the co-solvent used. For instance, changing the
reaction solvent from
dichloromethane to a participating solvent such as acetonitrile
increased the amount
of -anomer in the final product, as expected, and afforded a
slightly better overall
yield. (Table 2)
Table 2: Summary of glycosylation reactions with thioglycoside
donors 10a-e and model acceptor 11
in the presence of IL 9b/NIS at R.T.
OR2
R1
SPh
R4R3
10a-e
9b
NIS, solventr.t
O
OH
O
O
O O OO
O
O O
12a-e
OO
R1
R2R3
R4
a R1 = R2 = R3 = R4 = OBn
b R1 = OAc, R2 = R3 = R4 = OBn
c R1 = R2 = R3 = OBn, R4 = OAc
d R1 = R2 = R3 = R4 = OAc
e R1 = R2 = OCHPh, R3 = OAc R4 = NHTroc
O
O
O
O
S
OO
O
AOT
N
R
R RR
9a: R = H9b: R = Me9c: R = Et9d: R = Pr
11
-
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24
25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46
47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65
12
Entry
Donor Solvent Yield (%) Product / ratioa
1 10a CH2Cl2 72 12a 1.4:1
2 10a MeCN 80 12a 1:3
3 10b CH2Cl2 78b
12b 3:1
4 10b MeCN 98
12b 1:4
5 10c CH2Cl2
95
12c only 6 10d CH2Cl2
s.m.
12d -
7 10d CH2Cl2
76c
12d only 8 10e CH2Cl2 75 12e only
aDetermined by NMR spectroscopy (1H and HMQC data), breaction
temp.= 0C,
c0.03 eq. of TMSOTf used, s.m. = recovered starting material
(glycosyl donor)
4. Ionic Liquid Supported Oligosaccharide Synthesis
Following the success of solid phase peptide synthesis (SPPS),
polymer supported
oligosaccharide syntheses were developed.47-49
(Figure 1, B) However, solid
supported strategies have been typically associated with slow
reaction rates and the
need for excess reagents to drive reactions to completion. In
the context of
oligosaccharide synthesis this means using excesses of expensive
and often laborious
to prepare orthogonally protected monosaccharide building
blocks. Soluble polymer
supports were devised to overcome some of the issues mentioned
above,50
but low
loading of the saccharides, low solubility during the reaction
and difficulties with
product recovery made this strategy far from ideal. Despite the
initial hurdles with
polymer supported strategies, recent advances in the area
brought about by the use of
new polymers, linkers and novel synthetic methodology has lead
to the synthesis of
many complex oligosaccharides51-54
and glycoconjugates.55
Another interesting recent
development in the area of solid supports is the
surface-tethered iterative carbohydrate
synthesis (STICS) reported by the groups of Demchenko and
Stine56
whereby
functionalized high surface area porous gold is used as an
alternative to solid phase
technologies to perform cost efficient and simple synthesis of
oligosaccharide chains.
In an effort to address some of the inherent problems of
performing chemistry on a
solid support, fluorinated soluble support strategies that show
great potential have
also been developed.57-61
The methodology is of particular interest since protecting-
group manipulations and glycosylations can be conducted under
conditions typically
used for solution-phase chemistry. One of the drawbacks of this
approach however, is
the requirement for potentially difficult-to-access fluorinated
compounds and the
decreasing solubility of large oligomers in the fluorinated
solvent as the size of the
oligomer increases.62
-
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24
25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46
47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65
13
The unique and tunable physical and chemical properties of ILs
make this class of
molecules particularly useful as new vehicles for the
immobilisation of reagents.12
The use of ILs as soluble functional supports in oligosaccharide
synthesis shows great
promise as it combines the features of solution phase chemistry
with the added
advantage of fast, chromatography free purification. IL labeled
substrates (I-Tag-
substrates) are soluble in polar solvents such as those used in
glycosylations (i.e.
dichloromethane, acetonitrile). In the absence of the polar
solvent, the I-Tag-products
become insoluble in non-polar solvents such as diethyl ether,
isopropyl ether or
hexanes. This means that non-I-Tag-materials (i.e. excess
reagents, unreacted
material) can be removed from the I-Tag-products by simple
biphasic extractions or
by precipitation.
The groups of Chan63
and Huang64
reported almost in parallel the first application
of ILs as soluble, functional supports in oligosaccharide
synthesis. Both approaches
rely on the incorporation of an imidazolium cation via an ester
linkage through either
the C-663 or C-464
position of the glycoside building block. For instance, in
Chans
work (Scheme 7, A), the IL label (I-Tag) was incorporated by
acylation of
thioglycoside 13, with bromoacetic acid, DCC and DMAP, of the
free OH at C6
followed by SN2 halide displacement of 14 with 1-methylimidazole
and sodium
tetrafluoroborate to give 15.
I-Tag-linked-2,3,4,tri-O-benzylated thioglycoside donor
15 was oxidized with m-chloroperbenzoic acid to form activated
sulfoxide 16 which
was used as the glycoside donor in a subsequent glycosylation to
yield I-Tagged
disaccharide 17. This two step procedure was repeated to yield
trisaccharide 18 and
the final product 19 was accessed by cleaving the I-Tag with
cesium carbonate. On
the other hand, Huangs approach involved the incorporation of
the IL, also as an
ester functionality, at the C-4 position of glycoside acceptor
20 by reacting the free
OH with chloroacetyl chloride in pyridine followed by treatment
with 1-
methylimidazole and subsequent reaction with potassium
hexafluorophosphate.
Trichloroacetimidate 21 was used as the glycoside donor in the
presence of catalytic
TMSOTf to form disaccharide 22. Following this strategy a series
of
oligosaccharides, mainly disaccharide structures, were prepared.
(Scheme 7, B).
-
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24
25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46
47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65
14
Scheme 7. IL-supported synthesis using ester-linked I-Tags.
Subsequently, the group of Pathak demonstrated that the
IL-supported methodology
could be successfully applied to the preparation of homolinear
-1,6-
oligomannans.65,66
Starting from imidazolium cation-tagged mannosyl fluoride 25
as
the glycoside donor and mono-hydroxylated
1-thio-toluene--D-mannoside 24 as the
glycoside acceptor, using block couplings the authors were able
to synthesize a series
of linear -1,6-linked di-, tri- tetra- and octamannosides.
(Scheme 8 shows the
synthesis of tetramannoside 27 using this approach). In their
reports, an ester linkage
is also used to covalently link the IL component to the
glycoside donor at C-6, which
was removed after each glycosylation step to allow for the next
oligosaccharide
coupling to take place, as in previous strategies.
O
OH
BnOBnO
OBn
SPhO
O
BnOBnO
OBnSPh
OBrHO
OBr
DMAP, DCC
13 14
OBnOBnO
OBn
SPh
I-TagO
16
OBnOBnO
OBn
SPh
OBnOBnO
BnO
O
I-Tag
OBnOBnO
OBn
SPh
OBnOBnO
OBnO
OBnOBnO
OBnO
I-Tag
17
18
Cs2CO3, MeOH
OBnOBnO
OBn
SPh
OBnOBnO
OBnO
OBnOBnO
OBnO
OH
19
97%
mCPBA, -78 C
50%
53% quantitative
N N
+
15
13, Tf2O, 2,6-di-tert-butyl-4-
methylpyridine, CH2Cl2
O
O
BnOBnO
OBnSPh
O
N N
NaBF4
87% (over 2 steps)
1. mCPBA, -78 C
2. 13, Tf2O, 2,6-di-tert-butyl-4-
methylpyridine, CH2Cl2
A)
B)
O
OH
OAc
SPhAcO
O
OAc
AcOAcO
O
NH
CCl3
AcO
O
OAc
SPhAcO
O
OAc
AcOAcO
AcOO
HO
21
2392%
Tag-I
20X= PF6
X-
O
OAc
SPhAcO
O
OAc
AcOAcO
AcOO
Tag-I22TMSOTf, CH2Cl2, -40 to 0 C
NaHCO3, Bu4NBr,Et2O
93%
X-
I-Tag =
N
N
O
O
+
X= BF4
OTag-I
BzOBzO
OBz
F
24
OHO
BzOBzO
OBz
STol
25
1. 25, Cp2HfCl2, AgClO4, r.t.
2. NaHCO3, Bu4NBr
O
OBz
O
BzOBzO
HO
O
OBz
STol
BzOBzO
2666%
(over two steps)
repeat steps 1-2for another 2 rounds
O
OBz
STol
BzOBzO
O
O
OBz
BzOBzO
O
OBz
O
BzOBzO
HO
2
2747%
(over four steps)PF6-
I-Tag =
N
N
O
O
+
-
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24
25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46
47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65
15
Scheme 8. IL-supported methodology applied to the synthesis of
-1,6-oligomannans. Ester-linked I-
Tags.
Gouhier and co-workers subsequently reported the synthesis of
-1,4-glycosides
on an ionic support (Scheme 9).67
The I-Tag was introduced selectively at the C-6
position of thioglycoside 28 in a 4 step process (57% overall
yield). To that end, a
stannylene acetal was formed on partially protected
thioglycoside 28 with dibutyltin
dimethoxide followed by esterification with 5-bromopentanoyl
chloride in the
presence of triethylamine. Halide displacement from 29 by
refluxing in acetonitrile in
the presence of methylimidazole followed by anion metathesis
using KPF6 as the salt,
afforded hydrophobic I-Tag-thioglycoside 30.
It is interesting to note the dual use of the I-Tag-building
block, firstly as the glycosyl
acceptor and then as the glycoside donor by using a set of
chemo-selective leaving
groups. In the first instance, I-Tag-thioglycoside 30 was used
as the glycoside
acceptor by reaction with trichloroacetimidate 31 to form
disaccharide 32 in 81%
yield. The anomeric thioethyl was then activated in the
subsequent reaction step using
NBS and catalytic TMSOTf to afford -linked trisaccharide 34 upon
reaction with 33
in 85% yield.
Scheme 9. IL-supported methodology applied to the synthesis of
-(14)-glycosides. Ester-linked I-
Tags.
Initial reports in the area of IL supported oligosaccharide
synthesis were
commendable and pioneering, however the use of ester-linked
ionic labels is limiting
in terms of the protecting group strategies that can be
employed. Ester functionalities
are often used in oligosaccharide synthesis as transient
protecting groups and are
known to be labile to mild basic conditions (such as those used
to cleave the ester-
PF6-
I-Tag =
N
N
O
O
+
OHOBnO
OH
OBn
SEt
28
OHOBnO
O
OBn
SEt
Br5
O
29
1. Bu2Sn(OMe)2
2. Br(CH2)5COCl, Et3N
3. N-methylimidazole
4. KPF6 OHOBnO
I-Tag
OBn
SEt
30
5
OBnOBnO
BnO
OC(NH)CCl3
OBn
31
OOBnO
OBn
SEt
I-TagOBnO
BnOBnO
OBn
OOBnO
BnO
I-Tag
OBnOBnO
BnO
OBn
OMe
OOBnO
BnO
OBn OMe
O
BnOBnO
OBn
32
HO
33
34
TMSOTf
NBS, TMSOTf
67% 85% 81%
85%
-
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24
25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46
47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65
16
linked-ILs) or even strong acidic media.68 Furthermore, having
the I-Tag on the
glycoside donor increases the linearity of the approach since
the I-Tag is introduced in
each building block and then removed to allow the next
glycosylation step to take
place. More importantly, in a typical glycosylation reaction,
the glycosyl donor is
required in slight excess to drive reactions to completion and
unwanted hydrolysis of
the glycoside donor is often a side product. The presence of the
I-Tag on the glycosyl
donor could potentially lead to mixtures of I-Tagged compounds
on the more
challenging glycosylation steps.
More recently, Galan et al. addressed these issues by
introducing the IL labels at the
anomeric position of the reducing end of the saccharide as alkyl
functionalities. The I-
Tags were introduced at the start of the synthesis by
glycosylation to the
corresponding halide containing alcohol and once the desired
oligosaccharide
sequence has been constructed, the product can be released as a
hemiacetal or a
glycoside in a form suitable for further oligosaccharide
elaboration (Scheme 10).69
Scheme 10. General Ionic Catch and Release Oligosaccharide
Synthesis (ICROS) methodology.
Two types of I-Tags with different release mechanisms were
developed for
orthogonal attachment to saccharides. Alkyl I-Tag1 was prepared
by a two step
process entailing glycosylation of glycosyl donors 35 or 36 to
3-bromo-1-propanol
followed by alkyl halide displacement with N-methylimidazole to
give 38. Cleavage
of I-Tag1 could be achieved by acidic hydrolysis or by
methanolysis to yield either
the hemiacetal or the methyl glycoside, respectively. Benzyl
derived I-Tag2 was
devised as a more versatile alternative to I-Tag1 as it is
compatible with most
protecting group strategies. I-Tag2 was introduced by the same 2
step process
described previously, glycosylation of 36 with
4-(chloromethyl)benzyl alcohol
OOP'LG
LG = SPh, OC(NH)CCl3
O
OOP'
I-Tag incorporation
I-Tag cleavage - carbohydrate release
N N
-X+
R=
R= Br
Linker R
ITagging
Linker incorporationvia anomeric glycosylation
Oligosaccharide elongation
Linker cleavage
R= Me, H, C(NH)CCl3
O
OI-TagOP'
PO
OLG
PO
O
OO
OI-TagPO
PO
chemoselective protecting group manipulations and carbohydrate
elongation
P and P'= orthogonal protecting groups
OHLinker R PO
PO
O
OO
ORPO
PO
-
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24
25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46
47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65
17
followed by halide displacement to form ionically labeled 40.
Product release can be
achieved, in this instance, by catalytic hydrogenolysis to
afford the hemiacetal.
(Scheme 11)
Scheme 11. I-Tag incorporation at the anomeric position.
The versatility of this strategy was demonstrated with the
synthesis of biologically
relevant -1,6 and -1,2-linked di-, tri- and tetrasaccharides
using trichloracetimidate
and thioglycoside glycosyl donors. A typical reaction sequence
is shown in Scheme
12; selective 6-OH unmasking from I-Tag2 labelled compound 40 by
O-TIPS
removal using a mixture of HCl in MeOH provided acceptor 41
after a simple
extraction in 95% yield. Glycosylation of 41 with
trichloroacetimidate 36, in the
presence of TMSOTf afforded disaccharide 42 in 98% yield,
exclusively as the -
anomer. Selective cleavage of the ionic component (I-Tag2) in
the presence of H2 and
Pd black afforded hemiacetal 43, which was then converted to
trichloroacetimidate 44
in 83% by reaction with acetonitrile and DBU.
Scheme 12. IL supported synthesis using I-Tag2 as the IL
support.
The methodology was subsequently further demonstrated by the Li
et al.70
with the
synthesis of an -linked nonamannoside 47 using the same
benzyl-type linker (I-
Tag2). Their approach also involved covalently attaching the
linker at the anomeric
position of the glycoside acceptor. However, it differs in that
I-Tag2, is installed by
direct coupling of orthogonally protected mannose
trichloroacetimidate 45 with a
benzyl-type IL-linker containing a free OH, which was prepared
in 3 steps from -
dibromo-p-xylene (Scheme 13).
-
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24
25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46
47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65
18
Scheme 13. IL supported synthesis using I-Tag2 applied to the
synthesis of an -linked nonamannoside.
This year, Galan et al. demonstrated that the Ionic Catch and
Release
Oligosaccharide Synthesis (ICROS) is ideally suited for the
combinatorial synthesis
of small libraries of oligosaccharides.71
The team has developed a combinatorial
ionic-liquid-supported catch-and-release strategy for
oligosaccharide synthesis
(combi-ICROS) where all the oligosaccharide targets are prepared
in one pot, in a
matter of days, without the use of silica gel chromatography
purification in between
steps. The strategy was exemplified in the preparation of a
series of -1,6-glucan
oligosaccharides 51, 53 and 55 in one pot. They showed that HPLC
in combination
with MALDI-TOF and NMR can be used to efficiently monitor
reaction progress in
situ and that several I-Tag-species can be prepared at once in
one reaction vessel. The
mixture of oligomers can then be deconvoluted by size exclusion
chromatography to
yield the individual components (Scheme 14).
OBnO
BnOBnO
OAc
OC(NH)CCl3
PF6-
N
N
HO
+
TMSOTf
OBnO
BnOBnO
OAcPF6-
N
N
O
+ 1. NaOMe2. 45, TMSOTf
45repeat 8 times PF6
-
N
N
O
+
OBnO
BnOBnO
O
OBnO
BnOBnO
O
OBnO
BnOBnO
OAc
7
46
47
-
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24
25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46
47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65
19
Scheme 14. IL supported synthesis using I-Tag2 applied to the
synthesis of an -linked nonamannoside.
5. Ionic liquid tags in enzyme reactions. ILs are also ideal as
mass spectroscopy (MS) probes for fast analysis due to their
greater spectral peak intensities and lower limits of
detection.72
This has been
exploited recently by Galan et al. for the development of an
inexpensive and versatile
IL-based chemical label (I-Tag) for fast and sensitive enzyme
monitoring by MS as an
alternative to using expensive radioactive or fluorescence
labelled carbohydrates.73
The authors demonstrated the potential of using
IL-labelled-glycans for the biological
screening of glycosyltransferases in enzymatic reactions with
bovine milk -1,4-
galactosyltransferase (-1,4-GalT). A trifunctional cross-linker
was developed for this
purpose, that enabled orthogonal attachment to substrates
(I-Tag3, Scheme 15). The
linker contained an alkyne group for facile coupling to
azide-containing sugar
moieties, the ionic component for MS analysis and a disulfide
bond for mild product
41b) Et2O/Hexanes wash
c) TIPS deprotection with HCl/MeOH
repeat steps a-c
x2
a) 36, TMSOTf
OOBzOBzO
BzO OBzOBzO
OBzOI-Tag2
HOO
OBzOBzOBzO
OOBzOBzO
BzO OBzOBzO
OBzOI-Tag2
OOBzOBzO
BzO
HOO
OBzOBzOBzO
OOHOHO
OH OHOHO
OHOP
HOO
OHOHOOH
OOHOHO
OH OHOHO
OHOP
OOHOHO
OH
HOO
OHOHOOH
Size exclusionLH-20 sephadex
48
49
50
Global deprotection with:
Et3N in MeOH/H2O
OOHOHO
OH OHOHO
OHOP
HO51 P= I-Tag252 P= H
53 P= I-Tag254 P= H
55 P= I-Tag256 P= H
H2, Pd/C
H2, Pd/C
H2, Pd/C
90% (over 2 steps)
95% (over 2 steps)
85% (over 2 steps)
(10%)
(14%)
(30%)
48
49
50
42
OOBzOBzO
BzO OBzOBzO
OBzOI-Tag2
HO
-
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24
25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46
47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65
20
release.
Scheme 15. IL-based MS labels for enzyme monitoring.
In a more recent report, the applicability and versatility of
using I-Tags for
monitoring enzymatic oligosaccharide transformations and as
purification handles
was further demonstrated with the development of a new
N-benzenesulfonyl-based
ionic-liquid label (I-Tag4).74
The new I-Tag was chemically more stable and simpler
to prepare than the previously reported disulfide-based I-Tag3
(Scheme 16). A three-
step procedure consisting of conjugation of commercially
available 4-
(bromomethyl)benzenesulfonyl chloride with the corresponding
protected
aminopropyl N-acetylglucosamine 56 under basic conditions was
followed by halide
displacement with methyl imidazole and KBF4. Subsequent
unmasking of the OH
groups yielded I-Tag4-labelled N-acetylglucosamine (GlcNAc) 59
ready to be used in
enzymatic reactions. From 59, I-Tag2-LacNAc (Gal(1-4)GlcNAc) 60
and I-Tag2-
LewisX (Gal(1-4)[Fuc(1-3)]GlcNAc) 61, oligosaccharides of
significant biological
relevance, were prepared enzymatically. The apparent kinetic
parameters for the
enzyme catalysed transformations with -1,4-Galactosyltransferase
(-1,4-GalT) and
Fucosyltransferase VI (FucT VI) were determined by LC-MS. This
demonstrates that
the new I-Tag4 was compatible with the glycosyltransferases used
in the study, thus
opening the door for applications of these new types of
IL-labels with other
glycosyltransferases and potentially other enzymes outside the
area of oligosaccharide
synthesis.
N3
N
NN HN
SS
NH
O
O
N N
+
BF4-
HN
SS
NH
O
O
R
[m/z]
LC-MS
V
[C]
qualitative and quantitative analysis
Michaelis-Menten
I-Tag facilitates reaction monitongSubtrate
Subtrate
I-Tag3
-
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24
25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46
47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65
21
Scheme 16. Enzymatic synthesis of I-Tag4-LacNAc 48 and I-Tag2
LewisX
49
6. Conclusions
The preparation of complex structures that can be used in
biological studies is key
to understanding glycan diversity and function. Despite the many
advances in the area
of carbohydrate chemistry over the last three decades, the field
of oligosaccharide
synthesis still remains a difficult quest.
The challenges chemists face associated with carbohydrate
synthesis include
laborious protecting group manipulations, the need for high
yielding regio- and
stereoselective glycosylation reactions and facile purification
of products such as
those already available for other less complex biomolecules i.e.
peptides, or
nucleotide sequences.
The unique and tunable physical and chemical properties of ILs
make this class of
reagents particularly useful in the field of oligosaccharide
synthesis. This has led to
the use of ILs as solvents for the solubilisation of
carbohydrate polymers.
Furthermore, the high polarity of ILs can provide strong
accelerating affects to
reactions involving cationic intermediates and, as a result, ILs
have been used
successfully as reaction media in carbohydrate synthesis. ILs
have been used as
recyclable, mild glycosylation promoters that are amenable to
one-pot reactivity-
based glycosylation protocols. Finally, ILs have been used as
soluble functional
supports in the chemical and enzymatic synthesis of
oligosaccharide. This shows
great promise as it combines the features of solution-phase
chemistry with the added
advantage of fast, chromatography free purification and in situ
reaction monitoring by
MS.
ClSO2PhCH2Br,
K2CO3, CH2Cl2
O
AcONHAc
OAc
O
NH
S OO
Br
AcO
OAcO
NHAc
OAc
O
NH2
AcO
80% over 2 steps
O
RONHAc
OR
O
NH
S OO
NN+
-BF4
RON N
KBF4,
58 R= Ac59 R=H
Et3N, MeOH99%
90%
97%
90%
b-1,4-GalT,UDP-Gal
a-1,3-FucT VI, GDP-Fuc
I-Tag4
61
OHO
NHAc
OH
O-ITag4OOHO
HO
OH
OHO
ONHAc
OH
O-ITag4OO
HO
HOOH
OH
O
HOOH
OH60
56
57
-
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24
25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46
47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65
22
The application of ILs in the preparation of complex
oligosaccharides is an
emerging area that, over the last few years, has shown very
promising developments
towards addressing some of the obstacles that remain on the path
towards the
automation of oligosaccharide synthesis.
Acknowledgments
We gratefully acknowledge financial support from the EPSRC for a
Career
Acceleration Fellowship (MCG) and Novartis for a Case type
studentship (RAJ).
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-
1
Recent Developments of Ionic Liquids in Oligosaccharide
Synthesis. The Sweet
Side of Ionic Liquids.
M. Carmen Galan,a* Rachel A. Jonesa and Anh-Tuan Tranb aSchool
of Chemistry, University of Bristol, Bristol BS8 1TS UK, bInstitut
Parisien De Chimie Molculaire, Universit Pierre et Marie Curie ,
75252 Paris Cedex 05
Graphical Abstract
OLGPO
IL/CH2Cl2r.t.
ROH
Recycling
IL
OORBnO
Product
N N+-X
Ionic Liquids (IL)
Solvents and Promoters in Oligosaccharide Synthesis
Ionic Liquid Supported Oligosaccharide Synthesis
Carbohydrate Elongation
[m/z]LC-MS
Reaction MonitoringProductRELEASE
CLEAVABLE LINKER
CLEAVABLE LINKER
I-Tag
N N
+
N N
+
