[bmim][OTf] as co-solvent/promoter in room temperature reactivity-based one-pot glycosylation reactions

Article abstract of DOI:10.1039/b926177j

[bmim][OTf] can promote regio- and chemo-selective glycosylation reactions at room temperature. Furthermore, the applicability to ambient three-component reactivity-based one-pot glycosylation reactions is demonstrated for the synthesis of several trisacc

Full text of DOI:10.1039/b926177j

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[bmim][OTf] as co-solvent/promoter in room temperature reactivity-based
one-pot glycosylation reactionsw
M. Carmen Galan,* Anh Tuan Tran and Simon Whitaker
Received (in Cambridge, UK) 11th December 2009, Accepted 26th January 2010
First published as an Advance Article on the web 10th February 2010
DOI: 10.1039/b926177j
[bmim][OTf] can promote regio- and chemo-selective glycosyl-
ation reactions at room temperature. Furthermore, the applic-
ability to ambient three-component reactivity-based one-pot
glycosylation reactions is demonstrated for the synthesis of
several trisaccharides.
exhibit excellent solubilising properties and have been
used to facilitate a wide range of chemical transformations,
including acetylation, ortho-esterification, benzylidenation and
glycosylation reactions of carbohydrates.7–9 As part of our
programme to develop new methods and strategies for oligo-
saccharide synthesis, we became interested in the application
of ionic liquids for glycosylation reactions. We have recently
reported the use of 1 as a mild and versatile ionic liquid (IL)
recyclable solvent/promoter of room temperature glycosyl-
ation reactions using trichloroacetimidate and thiophenyl
glycoside donors.8 The conditions are mild, and compatible
with a range of hydroxyl and amine protecting groups and we
further demonstrated the importance of the IL counter ion
component to promote glycosylation reactions.9 We also
showed that the reaction of ‘armed’ glycoside donor 2a with
model acceptor 3 in the presence of NIS and 1 as promoter
and co-solvent gave disaccharide product 4a in good yields
(70%, 0.7/1 (a/b)), while ‘disarmed’ donor 2b could not be
activated by these mild conditions and required the presence of
catalytic Lewis acid.8
Since the emergence of glycobiology, there has been consider-
able interest in understanding glycan diversity and function.
Carbohydrates are sophisticated carriers of biomolecular
information involved in a myriad of biological processes.1
Despite the many synthetic efforts,2 there is still a need for
the development of reliable methods that are applicable to
both laboratory and industrial scale preparation.
Herein, we describe the investigation and use of [bmim][OTf] 1
as a mild room temperature promoter in combination with
N-iodosuccinimide (NIS) in chemo- and regio-selective glycosyl-
ation reactions and the application to three-component
one-pot oligosaccharide synthesis.
Typically, oligosaccharide synthesis entails sequential addi-
tion of monosaccharides to a growing oligosaccharide chain,
where each addition involves laborious protecting group
manipulations and purification procedures. A very attractive
alternative to traditional approaches is the commonly known
‘‘one-pot glycosylation’’, which facilitates that multiple glycosyl-
ation steps can be performed in a single reaction vessel.3
Many of these one-pot convergent approaches are based on
the selective activation of one glycosyl donor leaving group
(LG) over another. The concept was initially exemplified by
Fraser-Reid’s armed–disarmed methodology4 and although
this approach has been successfully utilised by others,5 most
strategies require exquisite control of reaction temperatures to
avoid side reactions. Orthogonal, chemo- and stereo-selective
glycosylation approaches are an essential feature of one-pot
strategies, since the most reactive saccharide derivative first
acts as the glycosyl donor and the resulting product is
immediately ready to act as a glycosyl donor in the next
coupling step.
The application of room temperature regio- and chemo-
selective glycosylation strategies involving ILs could not only
simplify carbohydrate synthesis but also lead to its auto-
mation. To that end, we focused on the development of a
reactivity-based one-pot strategy for oligosaccharide synthesis
at ambient temperature. Initial experiments were aimed at
further examining the versatility and selectivity of IL promoter
1 towards the choice of protecting groups in the glycoside
donor. To explore the reactivity boundaries of differently
protected thioglycosides with 1 as promoter, a series of glucose
based thioglycoside donors 2c,10 2d,11 2e,12 2f, 2g13 and 2h
possessing different reactivity profiles5 were prepared in good
yields and their couplings with commercial 1,2:3,4-di-O-iso-
propylidene-a-D-galactopyranose 3 as model acceptor in presence
of 1 and NIS were monitored. (Table 1) Thus, activation
of 2d and 2e proceeded smoothly, and as a result products
4d (60%, b) and 4e (83%, 0.95/1 (a/b)) were isolated from each
glycosylation reaction. (Table 1, entries 4 and 5) When the
same reaction conditions were applied to the reaction of less
active thioglycoside 2c, 2f, 2g or 2h no product formation was
detected after 2 h. It is expected that acyl substituents have a
disarming effect on thioglycosides, hence the stability of 2c–2g
under the mild reaction conditions. Furthermore, as Fraser-
Reid has shown,7 4,6-O-benzylidene-protected pyranosyl
systems, such as 2g and 2h, are also less active glycosyl donors
than their 4,6-di-O-benzyl congeners, because the formation of
oxycarbenium cations is disfavoured, due to the greater strain
the conformational deformation imposes on the trans-fused
bicyclic nucleus. To further probe that the activation with 1 at
Room temperature ionic liquids (RTILs) have recently
emerged as a new class of solvent for a broad range of
synthetic applications.6 The high polarity of RTILs can pro-
vide strong accelerating effects to reactions involving cationic
intermediates and in particular they have been shown to
School of Chemistry, Cantock’s Close, University of Bristol,
Bristol, UK BS8 1TS. E-mail: M.C.Galan@bristol.ac.uk;
Fax: +44 (0)117 925 1295
w Electronic supplementary information (ESI) available: Experimental
details, characterization data and 1H and 13C NMR spectra for all new
compounds. See DOI: 10.1039/b926177j
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Table 1 Comparative reactivity of the differently protected
thioglycosides 2a–g in the presence of IL 1
Entrya
Donor
Product
Yield (%)
a/b ratiob
1
2
3
4
5
6
7
8
9
10
2a
2b
2c
2d
2e
2f
2g
2h
2a, 2b
2e, 2h
4a
70
—
—
60
83
—
—
—
0.7/1
—
—
Only b
0.95/1
—
s.m.
s.m.
4d
Scheme 1
4e
s.m.
s.m.
s.m.
4a, 2b
4e, 2h
—
—
regioselective glycosylation, it was decided to validate the
methodology on three-component one-pot synthesis of
trisaccharides 14 and 15, as model systems, also at room
temperature. (Scheme 2) In situ double differential glycosyl-
ation, as exemplified by Fraser-Reid using 2,6 and 3,6 diol
acceptors in one-pot sequential glycosylation reactions, relies
on the difference in reactivity between a primary and a
secondary OH present in the same sugar moiety.18 The strategy
is very useful in terms of synthesizing branched oligosaccharides,
thus, to test the feasibility of our approach, a step-wise
component addition to generate branched trisaccharide 14 in
one pot was first investigated. (Scheme 2A) Thus, perbenzylated
glycoside donor 2a (2 equiv.) was reacted with 4,6-diol 5 in
the presence of NIS and 1, resulting in the exclusive glycosyl-
ation of the more reactive 6-OH to give the intermediate
disaccharide 6, which was not isolated. Instead, peracetylated
thioglycoside 2b (3 equiv.), another 2 equivalents of NIS and
TMSOTf (1 equiv.) were added to the reaction to glycosylate
the remaining 4-OH to give, following purification, trisaccharide
14 in 29% yield (0.45/1 (a/b)). The synthesis of linear
trisaccharide 15 in one pot was then attempted following the
above step-wise addition. (Scheme 2B) Unlike traditional
one-pot synthesis, our strategy entails the coupling of a
selectively protected armed thioglycoside donor 8 containing
a free secondary OH, which acts as donor in the first
instance and becomes the acceptor in the second step. Thus,
thioglycoside 8 (2 equiv.) was reacted with acceptor 7, bearing
a primary and therefore more reactive OH, in the presence of
NIS and 1 to give selectively the 1–6-linked disaccharide 9,
with the 2-OH free for further coupling. Peracetylated
thioglycoside 2b (3 equiv.) was then added to intermediate 9
in the same pot followed by the addition of excess NIS
(2 equiv.) and TMSOTf (1 equiv.) to give trisaccharide 15 in
41% yield after purification (0.3/1 (a/b)).
68, 92
80, 94
0.7/1 (4a)
0.95/1 (4e)
a
b
All reactions at room temperature. Determined by NMR spectro-
scopy (1H and HMQC data). s.m. recovered starting material.
room temperature could discern between armed and disarmed
glycosides in a one-pot environment, chemoselective one-pot
competition reactions whereby reactive donor (2a or 2e),
unreactive donor (2b or 2h, respectively) and acceptor 3
were subjected to the same glycosylation conditions at room
temperature as before in the presence of NIS and 1 (10% v/v).
(Table 1, entries 9 and 10) In every case, only the products
derived from the ‘‘armed’’ donors were detected with almost
complete recovery of the ‘‘disarmed’’ thioglycosides. As a
result, disaccharide 4a (68%, 0.7/1 (a/b)) or 4e (80%, 0.95/1
(a/b)) was obtained along with unreacted thiophenyl 2b (92%)
or 2h (94%) after column chromatography.
Regioselective glycosylation strategies are particularly
important for the assembly of branched oligosaccharides.
With the aim of exemplifying that regioselective coupling
reactions with donors and acceptors both containing a free
hydroxyl group could be carried out at room temperature in
the presence of IL 1, partially protected glycoside acceptors 514
and 715 and donors 8,16 1017 and 12 were prepared. (Scheme 1)
Regioselective glycosylation of 4,6-diol 5 with armed donor
2a, at room temperature with 1 as promoter yielded exclusively
(1–6)-linked disaccharide
6 in 69% yield (0.8/1 (a/b)).
Reaction of glycoside acceptor 7 with thioglycoside 8, which
contains a free OH at C-2, gave disaccharide 9 in 65% yield
(1/10 (a/b)). In the case of disarmed derivatives 10 or 12, the
addition of TMSOTf (0.8 equiv.) to the room temperature
reaction mixture containing 1 and NIS was required, and
disaccharides 11 and 13 were obtained in yields of 60% and
67% respectively. In all cases, no self glycosylation products
were detected under the mild conditions of the reaction albeit
the reactions were carried out at room temperature.
On the basis that IL 1 can selectively activate armed
glycosides in the presence of deactivated donors, an alternative
and more attractive one-pot strategy whereby all of the
glycoside building blocks are combined at the start of the
reaction, was attempted. (Scheme 2C) Thus, the reaction to
form 15 was carried out with the three components, donors 8
and 2b and acceptor 7, mixed together in the presence of 1 and
Having found an IL based promoter that allows for selective
activation at room temperature of ‘‘armed’’ thioglycosides in
the presence of ‘‘disarmed’’ donors and that can be applied in
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NIS. After 3 h at room temperature (to allow disaccharide 9 to
form) excess NIS and TMSOTf were added to activate 2b.
Product 15 was isolated in 44% yield following purification
on silica.
These experiments demonstrate the applicability of a mild
promoter such as 1 for room temperature one-pot reactions
where the reactivity of the building blocks can be tuned
accordingly by choosing the right combination of protecting
groups. It is important to note that although yields for the
one-pot reactions are moderate, they correspond to the
formation of two glycosidic bonds with no purification by
column chromatography in between steps.
In conclusion, we have shown the versatility of IL 1 in
combination with NIS to selectively promote at room
temperature activated glycosyl donors in presence of less
active glycosides. We have exemplified the usefulness of IL 1
in regio- and chemo-selective glycosylation reactions where
both donor and acceptor bear a free OH of distinct reactivity.
Furthermore, we have demonstrated that a mild promoter
such as 1 can be used for room temperature reactivity-based
one-pot reactions, whereby the building block reactivity is
tuned by the choice of protecting groups. To the best of our
knowledge, we have presented the first example of a one-pot
glycosylation reaction where a partially protected ‘armed’
monosaccharide glycoside is used firstly as the glycosyl donor
and the resulting product becomes the glycosyl acceptor in the
following step, without any protecting group manipulations,
in both a sequential synthetic approach and where all the
components are mixed together in one vessel at the beginning
of the synthesis. The recyclability properties of the IL
promoter are also very attractive in terms of green chemistry
and this combined with the ability of 1 to promote glycosyl-
ation reactions at room temperature makes this strategy
convenient and cost effective for automated oligosaccharide
synthetic protocols where no strict control of low temperatures
will be required.
We gratefully acknowledge financial support from EPSRC,
The Royal Society and BBSRC DTA and we thank
Dr Gregory M. Watt for fruitful discussions.
18 K. N. Jayaprakash, S. R. Chaudhuri, C. Murty and B. Fraser-
Reid, J. Org. Chem., 2007, 72, 5534–5545.
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2108 | Chem. Commun., 2010, 46, 2106–2108