Ionic catch and release oligosaccharide synthesis (ICROS)

Article abstract of DOI:10.1039/c0cc05580h

A general and efficient chromatography-free ionic-liquid-supported "catch-and-release" strategy for oligosaccharide synthesis (ICROS) is reported. The methodology is compatible with current glycosylation strategies and amenable to protecting group manipulations. A series of β-(1→6) and β-(1→2)-linked glycan structures have been prepared to showcase the versatility of the strategy.

Full text of DOI:10.1039/c0cc05580h

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COMMUNICATION
Ionic catch and release oligosaccharide synthesis (ICROS)w
Anh-Tuan Tran, Richard Burden, Daugirdas T. Racys and M. Carmen Galan*
Received 14th December 2010, Accepted 22nd February 2011
DOI: 10.1039/c0cc05580h
A
general and efficient chromatography-free ionic-liquid-
to access fluorinated compounds and solubility of large oligo-
mers in the fluorinated solvent tends to decrease.5
supported ‘‘catch-and-release’’ strategy for oligosaccharide
synthesis (ICROS) is reported. The methodology is compatible
with current glycosylation strategies and amenable to protecting
group manipulations. A series of b-(1-6) and b-(1-2)-linked
glycan structures have been prepared to showcase the versatility
of the strategy.
Ionic liquids (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.6 ILs consist of poorly
coordinating ion pairs and their physical and chemical properties
can be tuned by altering the cation or the anion structure.
More recently, a new strategy based on the use of ILs as a
soluble functional support has been developed and homolinear
a(1-6)-linked oligosacharides have been prepared.7 The
methodology is based on the ability to separate, by phase
extractions with the appropriate solvents, the non-ITag-
materials from the ITag-products without the need for
chromatography. The current methods, although commendable,
are still troublesome and not applicable to general oligo-
saccharide syntheses. The ionic linker tag (ITag) is typically
incorporated at C-6 or C-4 of the glycosyl donor as an ester
functionality, which increases the linearity of the approach
since the ITag is introduced in each building block and then
removed to allow the next glycosylation step to take place.
Moreover, the approach is limited to protecting group strategies
that are compatible and orthogonal to an ester-linked ionic
label, since ester functionalities are known to be labile to mild
basic conditions or even strong acidic media.8 More impor-
tantly, 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. Thus, having the ITag on the glycosyl donor could
potentially lead to mixtures of ITagged compounds on the
more challenging glycosylation steps.
Carbohydrates are the most diverse group of molecules in
nature, being abundant on cell surfaces and involved in a
myriad of physiological and pathological processes.1
Approaches to prepare diverse libraries of oligosaccharides
in a rapid manner are greatly lacking and progress in glyco-
biology research has been hindered by having to rely on either
isolated materials or lengthy target-oriented oligosaccharide
syntheses. The development of methods that could potentially
be automated for the synthesis of these complex molecules will
make carbohydrates more accessible to mainstream chemists
and not only enhance glycobiology research, but also carbo-
hydrate-based drug discovery.
Herein, we report the development of an efficient, chromato-
graphy-free, ionic based ‘‘catch-and-release’’ strategy for
the synthesis of oligosaccharides. We demonstrate the
versatility and generality of the technique with the synthesis
of biologically relevant b-(1-6) and b-(1-2)-linked oligo-
saccharides.
One of the main stumbling blocks for the automation of
oligosaccharide synthesis is the required purification after each
step, which is normally accomplished by chromatography.
Polymer supported oligosaccharide syntheses have been
developed as a viable alternative.2 However, solid phase based
strategies are typically associated with slow reaction rates,
whereas soluble polymer supports suffer from low loading of
saccharide, low solubility during the reaction and difficulties
with product recovery. As an alternative, surface-tethered
iterative carbohydrate synthesis (STICS) has been developed,3
but the technology is currently limited to low milligram scale.
Fluorinated soluble support strategies have also been
developed,4 still, the methodology requires the use of difficult
Our initial efforts were directed towards finding the most
efficient and general method for incorporating the ITag to
carbohydrate moieties in a manner that will be compatible
with commonly used protecting groups and suited to efficient
product release. It was determined that the anomeric position
of the reducing end saccharide would be the ideal attachment
place for the ionic label, as ITags can be introduced at the start
of the synthesis and the product can be released once the
desired oligosaccharide sequence is constructed as a hemi-
acetal or a glycoside. The hemiacetal can be further processed
by the introduction of a leaving group, such as trichloro-
acetimidate, so that the product can be subsequently utilized
as a glycosyl donor (Fig. 1).
School of Chemistry, University of Bristol, Cantock’s Close, Bristol,
BS8 1TS, UK. E-mail: M.C.Galan@bristol.ac.uk;
Fax: +44 (0)1179298611; Tel: +44 (0)1179287654
w Electronic supporting information (ESI) available: Experimental
procedures and full spectroscopic data for all new compounds. See
DOI: 10.1039/c0cc05580h
To that end, two types of ITags with different release
mechanisms were developed for orthogonal attachment to
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4526 Chem. Commun., 2011, 47, 4526–4528
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among the most effective and commonly used glycosyl donors
in oligosaccharides synthesis,12 thus, peracetylated galactosyl
trichloroacetimidate 2 was reacted with ITagged acceptor 7,
which contains a free OH at C-2, in the presence of TMSOTf
as the promoter. Disaccharide 15 was obtained, after simple
diethyl ether/hexanes washes of the ITag-material, in a yield
of 87% as the b anomer, as MS and NMR data showed13
(see ESIw for details). Global deprotection of the ester groups
with Et3N in MeOH/H2O followed by concurrent TIPS and
ITag removal by either acidic hydrolysis or acid catalysed
methanolysis afforded 1714 and 1815 in yields of 78% and
82%, respectively.
Fig. 1 General ICROS methodology.
Encouraged by our previous results, we decided to investi-
gate the application of the ICROS methodology in multistep
oligosaccharide synthesis (Scheme 2). For this purpose, the
fungal cell wall component16 b-(1-6)-D-glucan tetrasaccharide
was chosen. In this instance, glycosyl acceptor 11 containing
ITag-1 as the ionic label was used as the starting material.
Removal of the 6-O-triisopropyl silyl ether (O-TIPS) ortho-
gonal protecting group with HCl in MeOH afforded acceptor
19 that was subsequently coupled with glycosyl donor 9 in the
presence of TMSOTf (0.3 equiv.) to give disaccharide 20
in a yield of 94% after purification. Selective removal of the
60-O-TIPS protecting group of 20 gave disaccharide acceptor
21 ready to be glycosylated further. The iterative process
described above was repeated twice more and ITagged-
tetrasaccharide 24 was afforded in a yield of 80% after 3 steps.
It is important to highlight that each reaction intermediate was
purified by diethyl ether/hexanes washes and fully characterized
(see ESIw). Having demonstrated that sequential glycosylation
reactions with glycosyl trichloroacetimidates and that selective
protecting group manipulations could be accomplished
efficiently while the oligosaccharides are attached to the ITags,
we decided to explore the scope of using another common class
of glycoside donors, the thioglycosides.12 To that purpose,
reaction of 6-O-TIPS-protected thiophenyl donor 8 with
ITagged acceptor 19 was conducted using triflic anhydride/
dimethyl disulfide combinations17 as the glycosylation promoter
and disaccharide 20 was prepared in a good yield of 76%.18
While anomeric acid hydrolysis or methanolysis can be used
to release the products when utilizing the more simple ITag-1,
some glycosidic linkages maybe susceptible to these conditions
resulting in the formation of truncated structures.19 In those
instances, ITag-2 can be used as a viable alternative and
Scheme 1 ITag-1 and ITag-2 incorporation.
saccharides (Scheme 1). In the first instance, ITag-1 was
developed, which can be prepared by a 2 step process entailing
glycosylation of the sugar moiety to 3-bromopropanol 3
followed by alkyl halide displacement with N-methylimidazole.
ITag-1 cleavage can be attained by acidic hydrolysis or
by methanolysis to yield either the hemiacetal or the methyl
glycoside, respectively. As an alternative, benzyl derived ITag-2
was devised. ITag-2 offers the advantage of being compatible
with most protecting group strategies9 and can be also intro-
duced by the same 2 step process as before, by glycosylation
with 4-(chloromethyl)benzyl alcohol 12, followed by halide
displacement to form the ionic component. Product release
can be achieved, in this instance, by catalytic hydrogenolysis to
afford the hemiacetal.
The introduction of the ITags is straightforward and
compatible with different frenquently used protecting group
strategies. This was demonstrated by preparing a series of
ITag bearing monosaccharides starting from glycosyl donors 1
and newly synthesized 8 and 9 (see ESIw for details), which
were reacted with 3 to yield 3-bromopropyl glycosides 4,10
5
and 10. Subsequent reaction with N-methylimidazole in the
presence of KOTf or KBF4 under reflux conditions gave ITag-1
labeled-compounds 6, 7 and 11 in yields of 80–90%. On the
other hand, glycoside 13, that was prepared by glycosylation
reaction between donor 9 and alcohol 12, afforded ITag-2
substrate 14 in 89% yield after chloride displacement of 13
under the same conditions as described above.
With the ITags in place, we turned our attention to their use
in oligosaccharide synthetic protocols. In order to identify the
best donor/promoter combination and to demonstrate that
glycosylation reactions could be performed efficiently, we
decided to synthesize b-(1-2)-disaccharides 17 and 18, which
are ligands for plant and avian lectins,11 using ITag-1 as the
ionic purification label. Anomeric trichloroacetimidates are
Scheme 2 Application to oligosaccharide synthesis.
Chem. Commun., 2011, 47, 4526–4528 4527
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This journal is The Royal Society of Chemistry 2011

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3 P. Pornsuriyasak, S. C. Ranade, A. X. Li, M. C. Parlato,
C. R. Sims, O. V. Shulga, K. J. Stine and A. V. Demchenko,
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Y. Q. Jing and X. F. Huang, Eur. J. Org. Chem., 2010, 1290;
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J. Org. Chem., 2009, 74, 2594.
Scheme 3 Oligosaccharide synthesis with ITag-2.
5 M. Mizuno, K. Goto, T. Miura, T. Matsuura and T. Inazu,
Tetrahedron Lett., 2004, 45, 3425.
b-(1-6)-D-glucan disaccharide was chosen as our next target
to demonstrate the versatility of this new ITag. Selective 6-OH
unmasking from ITag-2 derivatized 14 by O-TIPS removal
using a mixture of HCl in MeOH provided pure acceptor 25,
after a simple phase extraction, in 95%. Glycosylation of 25
with trichloroacetimidate 9 in the presence of TMSOTf
(0.3 equiv.) afforded disaccharide 26 in 98% yield, exclusively
as the b anomer. Although ILs have been reported as being
able to promote glycosylation reactions,20,21 in our strategy,
the concentration of IL is much lower than in the reported
examples22 and reactions did not seem to be affected by the
presence of the ITag (Scheme 3).
6 (a) T. Welton, Chem. Rev., 1999, 99, 2071; (b) M. Picquet,
D. Poinsot, S. Stutzmann, I. Tkatchenko, I. Tommasi,
P. Wasserscheid and J. Zimmermann, Top. Catal., 2004, 29, 139;
(c) O. A. El Seoud, A. Koschella, L. C. Fidale, S. Dorn and
T. Heinze, Biomacromolecules, 2007, 8, 2629; (d) S. Murugesan and
R. J. Linhardt, Curr. Org. Synth., 2005, 2, 437; (e) M. C. Galan,
C. Brunet and M. Fuensanta, Tetrahedron Lett., 2009, 50, 442;
(f) M. C. Galan, K. Jouvin and D. Alvarez-Dorta, Carbohydr.
Res., 2010, 345, 45; (g) M. C. Galan, A. T. Tran and S. Whitaker,
Chem. Commun., 2010, 46, 2106; (h) M. C. Galan, A. T. Tran and
C. Bernard, Chem. Commun., 2010, 46, 8968.
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Selective cleavage of the ionic component (ITag-2) in the
presence of hydrogen and Pd black afforded hemiacetal 27,
which was then converted to trichloroacetimidate 28 in 83%
by reaction with acetonitrile and DBU.
8 F. Y. Yan, S. Mehta, E. Eichler, W. W. Wakarchuk, M. Gilbert,
M. J. Schur and D. M. Whitfield, J. Org. Chem., 2003, 68, 2426.
9 ITag-2 is not orthogonal to benzyl ethers as both groups will be
reactive towards catalytic hydrogenolysis.
10 Reaction of 1 with 3 in the presence of NIS and TMSOTf gave
concomitantly product 4 in 41% yield and 5 in also 41%. We
suggest that selective C-2 deacetylation occurs due to the presence
of HBr released during the reaction. See ESIw for details.
11 S. Bharadwaj, H. Kaltner, E. Y. Korchagina, N. V. Bovin,
H.-J. Gabius and A. Surolia, Biochim. Biophys.Acta, Gen. Subj.,
1999, 1472, 191.
In summary, the use of ITags in oligosaccharide synthesis
shows great promise. We have demonstrated, for the first time,
that it is possible to successfully perform both chemoselective
protecting group manipulations and chemical glycosylation
reactions under conditions typically used for solution-phase
chemistry without the need for chromatography based
purification after each step, since non-ITagged materials can
be selectively washed away with the appropriate solvents.
Moreover, we demonstrate for the first time that the intro-
duction of the ionic labels at the anomeric position of the
reducing end oligosaccharide target is versatile and compatible
with different protecting group strategies. Product release
leads to glycosides in a form suitable for further oligosaccharide
elaboration and, reaction progress is easily monitored by MS
and NMR, to ensure that each glycosylation step is driven to
completion (by choosing the most suitable glycosylation
conditions) and with complete stereo-control (with help from
neighbouring group participation). The methodology described
is compatible with common trichloracetimidate and thioglycoside
glycosylation strategies and generally applicable to the synthesis of
differently linked glycosides. Efforts are currently underway to
apply the ICROS methodology to more complex targets.
We gratefully acknowledge financial support from EPSRC,
The Royal Society and Bristol Chemical Synthesis Doctoral
Training Centre. Also thanks to Dr Gregory M. Watt for
useful discussions.
12 T. J. Boltje, T. Buskas and G.-J. Boons, Nat. Chem., 2009, 1, 611;
X. M. Zhu and R. R. Schmidt, Angew. Chem., Int. Ed., 2009, 48,
1900.
.
13 When milder promoters such as BF3 Et2O, Yb(OTf)3 or AgBF4
were used, the glycosylatiom reaction failed to reach completion,
which is not unexpected due to the ‘‘disarmed’’ chemical nature
of 2.
14 J. D. Fontana, J. H. Duarte, M. Iacomini and P. A. J. Gorin,
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17 J. Tatai and P. Fugedi, Org. Lett., 2007, 9, 4647.
18 Other glycosylation promoters for thioglycosides such as NIS/TMSOTf
or TfOH or AgOTf combinations or dimethyl(thiomethyl) sulfonium
trifluoromethane sulfonate were unsuccessful in catalysing the
reaction to completion and different oligomerization products were
isolated probably due to the instability of the TIPS group in the
presence of TfOH released during the reaction. Yield obtained is
lower than with trichloroacetimidate glycosylations due to losses
during product purification (see ESIw).
19 H. Kunz and C. Unverzagt, Angew. Chem., Int. Ed., 1988, 27, 1697;
C. J. Biermann, in Adv. Carbohydr. Chem. Biochem., ed. R. S.
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Notes and references
1 A. Varki and J. B. Lowe, in Essentials of glycobiology, ed. A. Varki,
Cold Spring Harbor Laboratory Press, New York, 2009.
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21 M. C. Galan and A. P. Corfield, Biochem. Soc. Trans., 2010, 038,
1368.
22 In our strategy only 1 equiv. of IL (covalently linked to the
glycoside) is used in comparison to the reported methods where
IL is used as a co-solvent or solvent.
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4528 Chem. Commun., 2011, 47, 4526–4528
This journal is The Royal Society of Chemistry 2011