An unusual glycosylation product from a partially protected fucosyl donor under silver triflate activation conditions

Article abstract of DOI:10.1039/c3ob42073f

Partially protected glycosyl donors are extremely useful reagents for oligosaccharide synthesis allowing more facile deprotection and enhanced activity due to lower steric restraints. A partially protected fucosyl donor containing tert-butyldimethylsilyl (TBDMS) protecting groups was activated under bromine-silver triflate conditions in the presence of primary alcohols and found to give difucoside products exclusively, in good yield with excellent diastereoselectivity. The dimerisation reaction appears to require a conformational relaxation of steric crowding, induced upon activation of the glycosyl donor. The scope and limitations of this unusual glycosylation methodology are reported.

Full text of DOI:10.1039/c3ob42073f

Organic &
Biomolecular Chemistry
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PAPER
An unusual glycosylation product from a partially
protected fucosyl donor under silver triflate activation
conditions†
Cite this: Org. Biomol. Chem., 2013, 11,
8452
Robin Daly and Eoin M. Scanlan*
Partially protected glycosyl donors are extremely useful reagents for oligosaccharide synthesis allowing
more facile deprotection and enhanced activity due to lower steric restraints. A partially protected fucosyl
donor containing tert-butyldimethylsilyl (TBDMS) protecting groups was activated under bromine–silver
triflate conditions in the presence of primary alcohols and found to give difucoside products exclusively,
in good yield with excellent diastereoselectivity. The dimerisation reaction appears to require a
conformational relaxation of steric crowding, induced upon activation of the glycosyl donor. The scope
and limitations of this unusual glycosylation methodology are reported.
Received 17th October 2013,
Accepted 31st October 2013
DOI: 10.1039/c3ob42073f
www.rsc.org/obc
polymerisation reactions, the use of inverse glycosylation con-
ditions is usually employed with these donors, maintaining a
Introduction
Access to pure synthetic carbohydrates with defined structure higher concentration of the acceptor relative to the donor
and stereochemistry is essential for developing an understand- during the glycosylation.
ing of glycobiology.1–5 Significant effort has been directed
We have recently reported synthetic applications of both
towards the development of efficient glycosylation methodo- fully and partially tert-butyldimethylsilyl (TBDMS) protected
logies that allow for the precise synthesis of defined fucosyl donors as reagents for the preparation of fucose con-
oligosaccharides.5–7 The vast majority of glycosylation methodo- taining oligosaccharides.19 It was determined that the bulky
logies employ protected glycosyl donors as reagents for silyl protecting groups could act as directing groups for achiev-
achieving selective, high yielding, glycosylation reactions.8,9 It ing alpha-selectivity in the glycosylation reactions and more-
is well known that the protecting groups can often participate over, that these protecting groups could be readily removed in
in the glycosylation reaction either directly, to induce stereo- the presence of unsaturated bonds. As part of this study we
control via a participating step10–13 or indirectly, by enhancing developed conditions for the preparation of a partially pro-
the reactivity of the oxocarbenium ion through sterically- tected 2,4-disilyl fucosyl donor. The partially protected donor
induced conformational changes.14,15 In the case of anchio- was found to be highly efficient for the alpha-fucosylation of
meric assistance from neighbouring ester groups, this effect both primary and sterically hindered secondary hydroxyl
only becomes active following activation of the glycosyl groups on activation with N-iodosuccinimide–trimethylsilyl tri-
donor.10 The effects of protecting groups on the outcome of fluoromethanesulfonate (NIS–TMSOTf) (Fig. 1).
glycosylation reactions is an area of intense study in synthetic
carbohydrate chemistry.
Unlike other partially protected glycosyl donors reported to
date, the fucosyl donor 1 does not require the use of inverse
Partially protected glycosyl donors are extremely desirable glycosylation conditions in order to maintain a high concen-
for oligosaccharide synthesis, due to their atom economy and tration of the accepter and avoid unwanted polymerisation
the potential of reducing the overall number of synthetic steps. reactions. We rationalised that glycosylation of the secondary
Despite these advantages, only a very limited number of hydroxyl group at the C-3 position was prevented by the steric
examples of partially protected glycosyl donors have been
reported in the literature.16–18 In order to avoid unwanted
School of Chemistry, Trinity Biomedical Sciences Institute, 152-160 Pearse Street,
Trinity College, Dublin 2, Ireland. E-mail: eoin.scanlan@tcd.ie;
Fax: +353 (1) 671 2896; Tel: +353 (1) 896 2514
†Electronic supplementary information (ESI) available. See DOI: 10.1039/
c3ob42073f
Fig. 1 2,4-Disilyl protected fucosyl donor.
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Fig. 2 Dimerisation–glycosylation reaction observed upon conversion of 1 into
the glycosyl bromide followed by activation with AgOTf.
Scheme 1 Activation of fucosyl donor 1 in the presence of benzyl alcohol
under both NIS–TMSOTf and Br2–AgOTf conditions.
bulk of the neighbouring TBDMS protecting groups that
imposed a steric shielding effect upon the remaining free
3-hydroxyl group.
SN1 and SN2 type reaction mechanisms.25–27 These reactions
are vital for accessing biologically important fucosides with
stereocontrol of the glycosidic linkage. The potential role of
partially protected donors in combinatorial approaches
towards accessing complex glycoconjugate libraries has been
highlighted by Seeberger and co-workers.28 In the course of a
systematic investigation into the synthetic potential of partially
protected fucosyl thioglycoside donor 1, we began to study acti-
vation of the donor under a variety of activation conditions
using benzyl alcohol as an acceptor. We had previously
demonstrated that the glycosyl donor could be activated using
NIS–TMSOTf and DMDS–Tf2O, but we were interested in inves-
tigating if alternative activation conditions could be employed.
In the first instance, a two step glycosylation procedure (with
in situ generation of a glycosyl bromide) between fucosyl donor
As part of our ongoing studies into the synthetic appli-
cations of partially protected glycosyl donors for oligosaccha-
ride synthesis, we have identified a very unusual, highly
selective, dual-glycosylation reaction that occurs upon acti-
vation of the partially protected fucosyl donor 1 with bromine
and silver triflate (Fig. 2). The reaction is unusual in that the
1,3-difucoside is formed as the major product. The result
would not be so noteworthy were it not for the fact that the
3-OH position had previously been demonstrated to be comple-
tely unreactive towards glycosylation.19 Also, the dimerisation
product, which was the major product isolated, was not
observed under NIS activation conditions. Finally, the appa-
rent absence of higher polymers observed suggested the reac-
tion was selective for dimer formation. We postulated that the
product may be formed due to a change in the conformation
of the pyranose ring that occurs upon activation of the glycosyl
donor. The TBDMS protecting groups play a dual role in
directing the stereoselectivity of the glycosylation and also pre-
venting polymerisation of the dimerised product. To the best
of our knowledge, a selective dimerisation reaction of this type
has never previously been reported in the literature and this
system, may offer new insights into the synthetic applications
of partially protected glycosyl donors.
The resulting Fuc-α(1–3)-Fuc disaccharide is of general syn-
thetic interest due to its structural homology with the fucose
based polymer, fucoidan. This polymer has been shown to
possess anti-sperm adhesion properties for use as contracep-
tives,20 anti-HIV activity in vitro,21 anti-tumourocidal pro-
perties,22 and applications as lower molecular weight heparin
mimics.23 Herein we report the synthetic scope of this novel
reaction and discuss some of the mechanistic considerations
and the role of the protecting groups in the specific disaccha-
ride formation.
1
and benzyl alcohol as an acceptor was investigated
(Scheme 1). Based on our previous studies of fucosyl donor 1,
the glycosylation reaction would be expected to furnish the
benzyl fucoside monomer 2 as the major product. This was the
major product that was isolated on activation of 1 with NIS–
TMSOTf. To our surprise, only minor quantities of the
expected monosaccharide product 2 was observed but the dis-
accharide 3 was isolated as the major product in 44% yield
(based on donor 1), as a separable mixture of two diastereo-
isomers (αα and αβ). Since the product formation requires two
equivalents of the glycosyl donor, it can be considered that the
benzyl alcohol acceptor was present in excess. No extended
polymer products (trisaccharides, tetrasaccharides etc.) were
observed and the only other major product isolated was the
hydrolysed glycosyl donor.
The disaccharide product 3 represents a much more sophis-
ticated glycosylation process than the NIS–TMSOTf activated
system and poses a number of questions in relation to the
stereochemistry of the product and the order of the glycosy-
lation reactions. The yield for the disaccharide product,
although modest at 44%, still represents an average yield of
66% per glycosylation step which is synthetically viable for a
one-pot procedure. Other points of note for this reaction are
Results and discussion
Fucosylation reactions employing fucosyl bromide intermedi- the complete lack of the mono fucosyl product 2, the total
ates derived from thiofucosides have been studied in detail by absence of any higher polymers (trisaccharides, tetrasacchar-
a number of groups.24 It has been established that activation ides etc.), the exclusive stereoselectivity of the α(1–3) fucose–
of fucosyl donors in the presence of sterically demanding gly- fucose glycosidic linkage and the mainly alpha-selectivity
cosyl acceptors preferentially form the alpha products via both observed for the glycosylation reaction with benzyl alcohol.
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The variation in products observed between the two different
activation conditions may be due to a greater degree of SN1
character in the silver triflate activation which would promote
conformational changes during the glycosylation. The acti-
vation of glycosyl halides have been studied in detail by
Lemieux and co-workers.24 Given the synthetic novelty of the
product, the apparent selectivity and the synthetic interest in
one-pot glycosylation systems, we decided to investigate this
methodology further to determine the scope and limitations.
An optimisation study of the reaction conditions for the
fucose dimerisation reaction was performed (Table 1). For
mixed solvent systems, the ratio was always DCM–solvent (2 : 1
v : v). Low reaction temperatures and Et2O appeared to increase
the αα stereoselectivity, however all conditions tested gave
exclusive α selectivity for the fucose–fucose glycosidic linkage.
Interestingly, the use of an alternative silver(I) source (Ag2CO3),
prevented the reaction from occurring suggesting that both the
silver source and the counter ion may play a role in the
observed product formation. Why the presence of the carbo-
nate counter ion prevented any formation of the desired
product is not fully understood. Disappointingly the overall
yield could not be improved beyond 44%, but it was interesting
to note that the reaction appeared to function best within a
tight set of reaction conditions.
Fig. 3 NMR analysis of fucosyl bromide 4 formation.
bromide in situ. The formation and characterisation of glycosyl
bromides using in situ NMR analysis has previously been
described by Demchenko and co-workers.30 Formation of the
glycosyl bromide was carried out in CDCl3 in a standard NMR
tube equipped with a septum and immersed in liquid nitrogen
(−196 °C). NMR analysis demonstrated that full conversion of
the thioglycoside to the bromide 4 was complete within five
minutes and that no disaccharide formation or anomerisation
was observed even upon warming of the glycosyl bromide to
room temperature (Fig. 3). The NMR experiments strongly
suggest that both of the glycosylation reactions were occurring
upon activation of the fucosyl bromide 4 with silver triflate.
Once it had been confirmed that no glycosylation–dimerisa-
tion was occurring at the brominating step, we were interested
in determining the order of the two glycosylation reactions.
The predicted order of glycosylation for this process, based on
reactivity of the acceptor alcohol, would involve initial glycosy-
lation of the fucosyl donor 4 with the more reactive primary
benzyl alcohol followed by a second fucosylation of the 3-OH
of the resulting O-benzyl fucoside acceptor 2. Previous studies
on the disilyl protected donor 1 suggested that the 3-OH would
be very sterically hindered and difficult to glycosylate. In order
to investigate the order of the glycosylation events we first pre-
pared acceptor 2 using the NIS–TMSOTf conditions. This is
the glycosyl acceptor that would be formed if the benzyl
alcohol glycosylation reaction was occurring first, and this
product was subsequently fucosylated at the 3-OH position in
a second glycosylation step. The partially protected fucosyl
thioglycoside donor 1 was initiated under Br2–AgOTf con-
ditions in the presence of acceptor 2 but none of the di-
saccharide product 3 was formed after 25 min at −20 °C
(Scheme 2). The fucosyl acceptor molecule 2 was recovered in
almost quantitative yield.
Since the Br2–AgOTf activation conditions involve initial
formation of a glycosyl bromide29 we first investigated if the
unusual glycosylation reaction was due to SN2 type displace-
ment occurring on or during formation of the reactive ano-
meric bromide 4. Attempts to isolate the fucosyl bromide failed
due to the instability of this highly reactive glycosyl donor. In
order to probe the stability of the fucosyl bromide donor 4 we
carried out NMR analysis of the formation of the fucosyl
Table 1 Optimisation of reaction conditions for the formation of disaccharide 3
Timee Yield Anomeric
Entry Activation conditions
°Cd
(min) (%)
ratio αα : αβ
1
2
3
4
5
6
7
8
Br2–AgOTfa, DCM–THF
Br2–AgOTfa, DCM–THF
Br2–AgOTfa, DCM–THF
Br2–AgOTfa, DCM–THF
Br2–AgOTfa, DCM
0
25
25
25
25
25
25
25
25
44
38
22
0
29
14
20
26
0
2 : 1
−20
−40
−60
−20
−20
−20
1.2 : 1
1.4 : 1
3.9 : 1
N/A
1 : 1.4
3.8 : 1
2.5 : 1
9.3 : 1
N/A
Br2–AgOTfa, THF
Br2–AgOTfa, Et2O
Br2–AgOTfa, DCM–THF
Br2–AgOTfa, DCM–Et2O
−60 120
−60 120
9
The result of this reaction strongly suggested that the glyco-
sylation reaction was not occurring in the predicted stepwise
manner via two sequential glycosylation reactions. The result
was significant in that it explained why no further fucosylation
of the disaccharide compound 3 was occurring (in the non-
reducing direction) and why no higher-order oligosaccharides
10
11
12
Br2–Ag2CO3a, DCM–THF −20
25
25
25
Br2–AgOTfb, DCM–THF
Br2–AgOTfc, DCM–THF
−20
−20
0
26
N/A
1.1 : 1
a 2 equivalents. b 0.5 equivalent. c Inverse glycosylation. d Refers to
activation temperature of intermediate, after bromide formation.
e Refers to reaction time following activation of glycosyl bromide.
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Scheme 2 Attempted glycosylation of benzylated fucoside 2.
Fig. 4 Oxocarbenium ion conformations of activated fucosyl donor.
(trisaccharides, tetrasaccharides etc.) were observed. Once the
terminal fucose was in place and the α(1–3) linkage had been
established the terminal fucose moiety was locked in the C4
justify the unusual reactivity of 6-deoxy sugars as well as the
contribution of protecting groups to both arming and disarm-
ing effects. It is clear from these oxocarbenium ion confor-
mations that the steric restraints conferred on the 3-OH group
when the sugar is locked in the 1C4 conformation become
relaxed when the donor is activated and adopts an oxocarbe-
nium ion conformation.
1
conformation which prevented further glycosylation of the free
3-OH position due to the steric bulk of the neighbouring silyl
protecting groups. The system in effect, self-terminated any
further glycosylation reactions at the non-reducing end. This
result however did not explain why extended polymerization
was not occurring in the reducing direction and why more
than two fucosyl residues did not assemble prior to being
trapped by the benzyl alcohol. Finally, this result also
suggested that the fucose–fucose α(1–3) glycosidic linkage was
forming prior to the glycosylation with benzyl alcohol. This
type of glycosylation pathway would be highly unusual in con-
temporary oligosaccharide synthesis. In an attempt to improve
the overall yield of the desired disaccharide product and to
gain further mechanistic insight into the process we investi-
gated preactivation of the fucosyl bromide donor at 0, −20 and
−40 °C, followed by delayed addition of the benzyl alcohol
acceptor (addition following donor activation with AgOTf after
1, 10 and 15 min at each temperature). Despite several
attempts at the preactivation strategy, only complex and in-
separable mixtures of products were observed. Activation of
the donor in the absence of any alcohol acceptor resulted in a
complex mixture of products and hydrolysed donor.
The potential implications of conformational changes on
the 3-OH are presented in Fig. 4. It can be observed that in A,
the 3-OH has dropped out of the plane of the ring, and is
much less hindered. At the same time, the steric interactions
of axial groups in the 2, 3, and 6 positions make nucleophilic
attack at the oxocarbenium more difficult from both faces.
Meanwhile for B, the oxocarbenium ion is much more accessi-
ble from the α-face, but the 3-OH is more hindered than in A.
In order to explain the unusual dimer formation, but the
complete absence of polymerisation products, it can be postu-
lated that the energy barrier between the interconversion of A
and B is likely to be low enough to allow both to exist in solu-
tion.35 If the accessible oxocarbenium in B were to be attacked
from its least hindered face, by the less hindered 3-OH of A,
then the intermediate resulting would be that shown in
Scheme 3. It can be seen in the product that the terminal
fucose has now reformed the sterically crowded 1C4 confor-
mation, thereby preventing further reaction at the unprotected
3-OH, meanwhile at the reducing terminus, the axial
2-OTBDMS group together with the axial 3-O-glycoside and axial
6-CH3 create a steric pocket that severely restricts the accessi-
bility of the remaining oxocarbenium, which could now be
attacked at the reducing end, by a non-sterically hindered
alcohol, over another oxocarbenium ion A. Such an attack
would provide the experimentally observed α–β mixtures
(Table 1). Why the initial fucose–fucose dimerisation reaction
Based on the experimental data acquired, we postulated
that glycosylation of the 3-OH group of the 2,4-disilyl protected
fucosyl donor would require an initial conformational change
to occur that would induce a change the orientation of the
bulky silyl protecting groups and would make the 3-OH posi-
tion more accessible to glycosylation. NMR coupling constants
are consistent with both the fucosyl bromide donor 4 and the
1
fucosyl acceptor 2 occupying the C4 conformation and there-
fore the 3-OH position is not available for glycosylation. It is
widely accepted that the mechanism for glycosylation reactions
proceeds via an oxocarbenium ion intermediate10,31,32 and
that formation of this electrophilic species requires a flatten-
ing of the carbohydrate ring that induces conformation
changes to the side chains. The conformation of an oxocarbe-
nium ion as proposed by Woods33 and investigated by
Woerpel34 is described by a linear arrangement of C-5–O-5–
C-1–C-2. When applied to the fucosyl donor 4 (Fig. 4), two
possible conformations of oxocarbenium ion A (4H3) and B
(3H4), can be drawn. Alabugin has described the importance of
hyper conjugation in stabilising the oxocarbenium ion. The
findings from this paper have been applied by Woerpel to
Scheme 3 Proposed pathway for formation of difucoside product 3.
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Table 2 Investigation of the scope of the glycosylation reaction
Entry
1
Acceptor
Activation conditions
Yield
Anomeric ratio αα : αβ
AgOTf, DCM–THF (2 : 1)
3 44%
5 53%
1.2 : 1
2
3
AgOTf, DCM–THF (2 : 1)
AgOTf, DCM–THF (2 : 1)
5.6 : 1
7 8%
αα (only)
4
AgOTf, DCM–THF (2 : 1)
9 0%
N/A
would be kinetically favoured to trapping with benzyl alcohol
is not fully understood and remains under investigation.
The proposed pathway outlined in Scheme 3 is most likely
an over simplification of what is actually occurring in solution,
however, it can explain some of the unusual requirements for
the isolated dimer products. The approach of two oxocarbe-
nium ions should be highly energetically disfavoured, however
counter ions play a large and not entirely understood role in
glycosylations,36 possibly explaining why the reaction failed
using a different source of Ag(I) (entry 10, Table 1). The pro-
posed route (Scheme 3), would require a large concentration of
oxocarbenium ions to be present in solution. Two equivalents
of AgOTf were used to activate the fucosyl halide in accordance
with literature procedure.29 The excess Ag(I) would have the
effect of largely increasing the rate of oxocarbenium formation
versus a catalytic process. We also investigated the effect of low-
ering the AgOTf concentration to 0.5 equivalents (entry 11,
Table 1). The reaction mixture showed a large amount of un-
identified products by TLC, and no fucose–fucose dimer pro-
ducts were observed. Another unexpected result was the
isolation of significant quantities of the fucosyl dimers, after
adopting inverse glycosylation conditions (entry 12, Table 1).
In this case benzyl alcohol should remain in excess compared
to the fucosyl bromide acceptor. It was predicted that this
method would prevent any disaccharide product formation,
but from the observed results, the rate of dimer formation
appears sufficiently high to furnish the fucosyl dimer product
3 in 26% yield. This result does indeed suggest that the
fucose–fucose dimerisation reaction does occur faster than the
benzyl trapping even though this result may be difficult to
rationalize theoretically. Although we were unable to establish
the exact mechanism of this process, the experimental results
certainly pertain to a highly unusual glycosylation process. The
reaction mechanism may also proceed via a concerted pathway
where both glycosylation reactions occur simultaneously but
this is difficult to determine experimentally.
Fig. 5 Difucosyl products obtained on initiation of fucosyl donor 1 in the pres-
ence of various alcohol acceptors.
product in the presence of benzyl alcohol (Table 1, entry 2), a
number of other alcohols were screened. The results are out-
lined in Table 2 and Fig. 5.
From the data in Table 2 it was observed that the size of the
acceptor alcohol was an important factor in determining the
yield of the difucose products formed. The use of propargyl
alcohol, which has a similar reactivity, but slightly less steric
bulk than benzyl alcohol, furnished the desired O-propargyl
difucoside 5 in 53% isolated yield. This represents an average
of 73% yield per glycosylation and represented an improved
yield over that obtained with benzyl alcohol. The reaction was
also highly diastereoselective for the alpha-product in both gly-
cosylation steps. The reaction provides, in one-pot, a propargyl
functionalised disaccharide that can be employed in [Cu]I cata-
lysed 1,3-dipolar cycloaddition ‘click’ reactions.37,38 For entries
3 and 4, we investigated if the methodology was applicable to
the primary hydroxyl group on a monosaccharide and to a
highly sterically hindered secondary alcohol on a lactosamine
disaccharide.39 For the one pot trisaccharide synthesis the
desired trisaccharide 7 was isolated in 8% yield which,
although low, still represents an average of 29% per glycosyla-
tion step. This is significantly lower than the yields observed
In order to investigate the scope and generality of this reac-
tion we screened a number of alcohols with varying reactivity
to verify if the fucose dimerisation reaction was general. Using
the conditions that gave the best yield of the disaccharide
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for propargyl alcohol and for benzyl alcohol and suggest that 12 A. V. Demchenko, Handbook of Chemical Glycosylation,
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We have reported an unusual glycosylation reaction involving a
partially protected fucosyl donor activated under bromine–
silver triflate conditions. The activation conditions promote
formation of difucosyl glycosides as the major products in
moderate to good yields. The methodology is robust and
stereoselective, allowing rapid access to disaccharide deriva-
tives with high yields under carefully controlled conditions. An
investigation into the order of glycosylation and the steric con-
straints imposed by the protecting groups suggest that the
reaction proceeds by an unusual glycosylation pathway.
Further mechanistic studies are ongoing to understand the gly-
cosylation pathway in more detail. Studies involving other par-
tially protected monosaccharides are also ongoing. The
methodology may offer an additional advantage to the use of
partially protected donors in glycosylation reactions.
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