Development of fully and partially protected fucosyl donors for oligosaccharide synthesis

Article abstract of DOI:10.1021/jo302487c

The use of fully and partially tert-butyldimethylsilyl (TBDMS) protected fucose thioglycosides as glycosyl donors for oligosaccharide synthesis is described. Both the trisilyl- and disilyl-protected thioglycoside donors were prepared, and their reactivity under a range of activation conditions was investigated. Both silyl-protected donors were found to give good yields of the desired α products and the silyl protecting groups could be removed in the presence of unsaturated bonds. The disilyl-protected donor was found to behave as an efficient, partially protected glycosyl donor. The synthetic scope and limitations of these new donors is presented. Both donors were applied to the synthesis of a Lewis X trisaccharide displaying a propargyl group at the anomeric position. It was determined that the additional steric bulk of the TBDMS group inferred unusual reactivity on these fucosyl donors.

Full text of DOI:10.1021/jo302487c

Article
pubs.acs.org/joc
Development of Fully and Partially Protected Fucosyl Donors for
Oligosaccharide Synthesis
Robin Daly, Thomas McCabe, and Eoin M. Scanlan*
Trinity Biomedical Sciences Institute, Trinity College, 152-160 Pearse Street, Dublin 2, Ireland
S
* Supporting Information
ABSTRACT: The use of fully and partially tert-butyldime-
thylsilyl (TBDMS) protected fucose thioglycosides as glycosyl
donors for oligosaccharide synthesis is described. Both the
trisilyl- and disilyl-protected thioglycoside donors were
prepared, and their reactivity under a range of activation
conditions was investigated. Both silyl-protected donors were
found to give good yields of the desired α products and the
silyl protecting groups could be removed in the presence of
unsaturated bonds. The disilyl-protected donor was found to
behave as an efficient, partially protected glycosyl donor. The
synthetic scope and limitations of these new donors is
presented. Both donors were applied to the synthesis of a
Lewis X trisaccharide displaying a propargyl group at the
anomeric position. It was determined that the additional steric bulk of the TBDMS group inferred unusual reactivity on these
fucosyl donors.
are known to have more facile deprotection, for example the
meta-NO2-benzyl protecting group can be removed photo-
chemically, and the p-OMe-benzyl protecting group can be
removed by milder hydrogenation conditions or oxidation.14 In
glycosylation reactions, the use of ether protecting groups offers
enhanced reactivity due to the “arming” effect,15 but this is
offset by a reduction in stereocontrol at the newly formed
glycosidic linkage. For this study, we were interested in
investigating the reactivity of silyl protected fucosyl donors.
The use of a per-TMS protected fucosyl donor has been
reported by Hindsgaul and co-workers.16 Activation with TMSI
resulted in α-selective fucosylations via the glycosyl iodide,
however the temporary nature of the TMS protecting groups,
which are hydrolyzed upon workup, means that further
protecting group manipulation of the glycosylated product is
restricted. As part of our studies into the synthesis of
biologically active glycoconjugates for therapeutic applica-
tions17,18 we became interested in the development of a
fucosylation protocol that would allow for removal of the
fucosyl protecting groups in the presence of unsaturated groups
such as alkynes. We envisaged that silyl protecting groups
would be appropriate for the fucosyl donor due to their
orthogonality to other protecting groups and relatively mild
deprotection conditions.14 In order to confer a degree of
stability onto the donor, we decided to investigate the use of
the more robust TBDMS protecting groups rather than the
labile TMS groups reported by Hindsgaul.16 It was determined
INTRODUCTION
■
Fucose is an important monosaccharide in glycobiology and is
often displayed on N-linked glycoproteins.1,2 In mammals,
fucose-containing glycans have important roles in a diverse
array of biological functions, including selectin-mediated
leukocyte−endothelial adhesion, host−microbe interactions,
and several ontogenic events.3 The ABO blood group antigens
are among the most well-known fucosylated glycans in
mammals. To date, 13 fucosyl transferase genes have been
identified in the human genome, and aberrant fucosylation
patterns have been observed in several pathogenic processes
including cancer,4 chronic hepatitis,5 and liver cirrhosis.6 Core
fucose is found exclusively α-1,6-linked to the reducing N-
acetylglucosamine (GlcNAc) moiety of the chitobiose core.7
The core fucosylation of the plasma protein, α-fetoprotein is a
well-known tumor marker for hepatocellular carcinomas.8 α-1,3
fucosylation is often found in plants and insects.9 Access to
synthetically pure samples of fucosylated glycans is important
for understanding their biology and for the development of new
therapeutics. For the synthesis of fucosylated oligosaccharides,
α-fucosylation has generally been achieved either enzymatically,
through the use of fucosyl transferase enzymes,10 or else
chemically, through the use of non participating protecting
groups, the most commonly employed being the OBn
protecting group.11−13 These reactions work well and give
the desired α-fucosylated product in good yield. However,
removal of benzyl protecting groups often relies on catalytic
hydrogenation or birch reduction conditions which may be
unsuitable for molecules containing unsaturated bonds or
sensitive functional groups. Other variants of the OBn group
Received: November 15, 2012
Published: December 26, 2012
© 2012 American Chemical Society
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that the additional steric bulk of the TBDMS group inferred
unusual reactivity on these compounds. The results of these
studies are reported herein.
Table 1. Optimization of Ethyl 2,3,4-Tri-TBDMS-Fuc-α-
thioglycoside 7 Synthesis
% yield
temp
time
(h)
RESULTS AND DISCUSSION
■
entry
reagent
solvent/base
(°C)
5
7
A number of per-silylated glycosyl donors have been
successfully employed in oligosaccharide and glycoconjugate
synthesis.16,19 These compounds are readily converted into the
reactive anomeric iodide on treatment with TMS-iodide. We
first investigated conditions for the per-silylation of L-
fucopyranose 1 on treatment with tert-butyl dimethylsilyl
chloride (TBDMS chloride). The per-silylation of fucose with
TMS chloride as reported by Hindsgaul and co-workers
proceeded in good yield to furnish the desired pyranose
product 2; however, the reaction with the more bulky tert-butyl
reagent furnished the furanose product 3 as the major isomer
(Scheme 1). Marino and co-workers have recently reported the
a
a
a
1
TBDMSCl
DMF,
40
16
48
96
26
86
22
trace
imidazole
DMF,
2
3
TBDMSCl
TBDMSCl
50
5
imidazole
DMF,
100
46
lutidine,
DMAP (cat.)
pyridine,
DMAP (cat.)
pyridine,
DMAP (cat.)
a
4
5
TBDMSCl
0−60
0−60
24
36
83
97
b
TBDMSOTf
a
b
5 equiv. 4.5 equiv.
Scheme 1. Preparation of Persilylated Derivatives from L-
Fucose
protected donor. Following formation of 5, further function-
alization of the remaining unprotected hydroxyl group, 3-OH,
is sterically hindered by the bulky neighboring TBDMS
protecting groups. The regioisomer 6 displaying 2,3 di-
TBDMS substitution was also isolated in a 3% yield. The fact
that the 2,4 substitution pattern of 5 was the major isolated
isomer requires some rationalization. Given the long reaction
time required for optimum yields of 5, it is likely that this
reaction is under thermodynamic control. Kinetically, one
would expect the axial 4-OH to be the least reactive so either
the 2- or 3-OH should be protected first. Literature precedent
for imidazole and/or alternative base-mediated intramolecular
transfer of silyl protecting groups, to neighboring hydroxyls has
been presented by Santos et al.24 and Tadano et al.25 A similar
process of silyl group migration may be responsible for the
observed partially protected product regioisomer 5 in high
yield. A single literature example of the preparation of a di-
TBDMS protected fucosyl donor has been reported by Du and
co-workers.26 They found that the use of TBDMSCl and
imidazole in DMF at 40 °C for 12 h furnished the 3,4 di-
TBDMS regioisomer as the major product. The reported
characterization data of that product is identical to our observed
characterization for the 2,4 regioisomer 5. Through high-
resolution 2D NMR, (HSQC, and HMBC experiments, see the
Supporting Information), the structure of the 2,4 regioisomer 5
was unambiguously assigned. The remaining unprotected
hydroxyl was found to be located in the 3-C position. Although
trace amounts (3%) of the 2,3 di-TBDMS isomer 6, were
isolated none of the 3,4 di-TBDMS substituted fucose
thioglycoside was observed in our studies. We anticipated
that both the fully and partially protected thioglycosides 5 and
7 would be able to function as fucosyl donors.
furanose product under similar conditions starting from D-
galactose and have successfully applied this molecule as a
galactofuranose donor on treatment with TMS iodide.20 For
our synthetic targets, including the human histo blood group
oligosaccharide, Lewis X, we required the pyranose form of
fucose and so it was decided to employ β-thioglycoside 4 as a
starting material for the per-silylation reaction (Scheme 2).
Thioglycoside donors are robust enough to withstand
protecting group manipulation and have the advantage of
having several modes of activation.21,22
Scheme 2. Preparation of Fully and Partially Protected
Fucosyl Thioglycosides
The synthesis of TBDMS-protected pyranoside thioglycoside
donors has been reported by Bols and co-workers, who coined
the term “super armed” by virtue of the observed increased
reactivity of per-TBDMS donors over armed donors.23
Interestingly, despite intensive research in this area, the
TBDMS-protected fucose thioglycoside derivatives have not
previously been reported. Fucosyl thioglycoside 4 was treated
under a number of silylating conditions (Table 1), and it was
found that, depending on the reagents used, both the fully
protected 7 and the partially protected compound 5 could be
isolated in high yields (Scheme 2).
NMR characterization of the trisilylated donor 7 suggested
that some conformational change was occurring due to the
steric bulk of the protecting groups. Full “ring flipping” has
been observed in the “super armed” donors previously prepared
by Bols and co-workers.23 Significant line broadening in the
NMR suggested that the molecule was being forced out of the
1
usual C4 conformation due to steric interactions between the
bulky silyl protecting groups. Interestingly, an X-ray crystal
structure of the donor showed that it had crystallized
1
The observation that the less reactive chloro reagent
furnished mainly the partially protected donor 5 is of interest
since this isomer could potentially be employed as a partially
exclusively in the C4 conformation (Figure 1).
In contrast to the trisilylated donor, the proton NMR
spectrum of the partially protected donor 5 was completely
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labile protecting groups. The addition of these buffers resulted
in the isolation of the desired product 9 in 13% and 21% yields,
respectively, with reasonable anomeric selectivity as determined
by NMR. The absence of any basic buffer resulted in none of
the disaccharide product being isolated (entry 1). A two-stage
activation procedure involving formation of the anomeric
bromide followed by reaction with AgOTf has been widely used
for the activation of thioglycosides. Activation of donor 7 with
Br2 was performed according to literature procedure,31 and the
excess bromine was either quenched with cyclohexene or
removed through evaporation (entry 4). The fucosyl bromide
intermediate was not isolated but reacted directly with acceptor
8 at −40 °C, followed by silver triflate activation of the
anomeric bromide. After 30 min, complete consumption of the
donor 7 had occurred (by TLC), but the expected disaccharide
product was only visible in trace amounts by HRMS analysis of
the crude reaction mixture. NMR studies were carried out in
order to monitor formation of the anomeric bromide and to
ensure that no deprotection was taking place at the
bromination step (see the Supporting Information for NMR
studies).
The NMR studies on Br2 activation of donor 7 confirmed the
stability of the TBDMS groups during activation and that the
expected intermediate fucosyl bromide was formed quantita-
tively. It was concluded that the problems observed with the
two-stage glycosylation must occur after the bromination step.
A number of literature examples of α-Fuc-(1−6)-GlcNAc
synthesis highlight the extremely labile nature of the bio-
logically important α-(1−6) linkage.32,33 Kunz et al. showed
that the presence of arming groups such as benzyl protection
on the fucose increase the instability of the α-(1−6) glycosidic
bond.34 The highly reactive nature of the donor 7, coupled with
the sensitive glycosidic bond in the product 9, was identified as
the main reason for the low yields in the glycosylation reactions
screened. Schmidt et al. pioneered the inverse glycosylation
method, which provided increased glycosylation yields when
using highly reactive trichloroacetimidate donors.35 Inverse
glycosylation therefore seemed an appropriate approach in our
efforts to prepare α-Fuc-(1−6)-O-propargyl-β-GlcNAc. Inverse
glycosylation maintains the acceptor and activator concen-
trations higher than the donor, encouraging glycosylation of the
acceptor before side product formation or hydrolysis can occur.
Gratifyingly, the reaction under these conditions proceeded
very cleanly with the isolation of 9 in 71% yield along with high
α-selectivity (10.2:1, α:β) and short reaction times (entry 5).
The successful synthesis of 9 under inverse glycosylation
conditions demonstrated the synthetic application of 7 as a
fucosyl donor. The use of Br2 for donor activation is not ideal,
however, due to the gradual decrease in pH of Br2 over time on
storage. Addition of wet bromine leads to partial TBDMS
deprotection and reduced yields due to contamination from
HBr. Therefore, NIS/TMSOTf activation of donor 7 was also
investigated. Activation of 7, with NIS, once maintained at, or
below −20 °C did not result in any iodine addition across the
propargyl triple bond (a side reaction observed in our earlier
studies). The acceptor 8 was consumed within 80 min, and the
disaccharide product 9 was isolated in a high yield of 86%, with
good α anomeric selectivity (8.1:1 α/β) (entry 6). Following
the screening of various activation conditions for the thioglyco-
side donor 7, it was determined that NIS/TMSOTf activation
was optimum for fucosyl donor 7. Using the optimized
activation conditions, the glycosylation reactions of the donor 7
Figure 1. X-ray crystal structure of donor 7.
resolved (see the Supporting Information). The clearly resolved
OH peak suggested slow proton exchange resulting from the
buttressing of neighboring TBDMS groups. No ring flipping
was observed by NMR and the donor existed exclusively in the
1C4 conformation.
INVESTIGATION OF SYNTHETIC APPLICATIONS OF
GLYCOSYL DONORS
■
With both the fully and partially protected fucosyl donors 5 and
7 in hand, we set out to investigate their application as
fucopyranosyl donors. O-Propargyl NAc glycosamine acceptor
8 was chosen as an acceptor for optimization studies since the
acceptor contains a propargyl group at the anomeric position
that cannot tolerate hydrogenation conditions (Scheme 3).
Scheme 3. Investigation of Glycosylation Conditions for
Donor 7
Also, the 1,6 disaccharide formed is a highly specific substrate
for the fucose binding lectin isolated from R. solanacearum.27,28
We first investigated glycosylation conditions for the fully
protected trisilyl donor 7. A number of common activation
conditions for thioglycosides were investigated. The results of
these studies are outlined in Table 2.
A recent thioglycoside activation technique reported by
Fugedi and co-workers is the DMDS/Tf2O method.29 Entries
1−3 show our attempts at glycosylation using this activator
both in the presence and absence of a hindered basic buffer.
Both DTMP and TMU30 have been used as buffers in
glycosylation reactions in order to minimize the loss of acid-
Table 2. Conditions for Glycosylation Conditions for Donor
7
temp
(°C)
time
% yield (α/β) of
entry
activation conditions
(min)
9
1
2
3
4
5
6
DMDS, Tf2O
−40
−40
−40
−40
−40
−20
30
30
30
30
25
80
not isolated
13, (5.1:1)
21, (5.4:1)
trace product
71, (10.2:1)
86, (8.1:1)
DMDS, Tf2O, DTMP
DMDS, Tf2O, TMU
Br2, AgOTf, cyclohexene
a
Br2, AgOTf
NIS, TMSOTf
a
Inverse glycosylation.
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Table 3. Synthetic Scope of Fucosyl Donor 7
a
1
Anomeric ratio determined by H NMR.
with a number of acceptor molecules were investigated. The
results of this study are presented in Table 3.
Glycosylation reactions with primary alcohols under NIS/
TMSOTf activation proceeded in good yield with high alpha
selectivity (entries 1−3). Glycosylation with a monosaccharide
acceptor containing a single free secondary hydroxyl also
proceeded in good yield with exclusive α selectivity (entry 4).
This result also demonstrated how the armed thioglycoside
donor 7 could be selectively activated in the presence of a less
reactive thioglycoside donor 14 (Figure 2). A regioselective
glycosylation on galactosyl diol acceptor 16 furnished a single
product with complete alpha selectivity, albeit in a low yield of
30%. Only the 1,3-linked disaccharide was formed, none of the
1,2 regioisomer was observed. For the fucosylation of
lactosamine acceptor18 18, the yield of the desired trisaccharide
19 was particularly low. Increasing the reaction time and raising
the donor ratio to 3 equiv did not result in any measurable
increase in yield. The steric bulk of fucose donor 7 may cause
difficulty in approaching the free 3-OH on the disaccharide
acceptor 18, given the close proximity of the Gal moiety. Dwek
et al.36 reported that the Lewis X trisaccharide is a very rigid
molecule even when fully deprotected. The extra steric
constraints imparted by the TBDMS groups in close proximity
may increase the energy barriers for this glycosylation. Kondo
et al. showed that the steric bulk around the 3-OH of GlcNAc
in Lewis X synthesis dramatically affects glycosylation yields at
that hydroxyl.12 The use of alternative activation conditions,
namely DMDS-Tf2O and the highly reactive Br2/AgOTf
inverse glycosylation did not improve the yield of trisaccharide
Figure 2. Products obtained from the fucosylation reactions with
fucosyl donor 7.
19. Conversion of thioglycoside donor 7 to a highly reactive
trichloroacetimidate was performed in situ, after NBS-
promoted hydrolysis of 7, followed by reaction with
trichloroacetonitrile and Cs2CO3. The trichloroacetimidate
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was extremely unstable, so the crude material was not purified
but used directly in the glycosylation following removal of
Cs2CO3 by filtration and distillation of the excess trichlor-
oacetonitrile. The trisaccharide 19 was only isolated in reduced
yields of 10−12% using the TCA donor. These studies
demonstrated that the donor 7 is valuable for fucosylation of
sterically accessible hydroxyl groups but that its scope may be
limited for glycosylation reactions at sterically crowded centers.
Following the successful synthesis of the fucosyl-containing
disaccharide 9 and trisaccharide 19, we investigated the removal
of the silyl protecting groups in order to validate the synthetic
application of the TBDMS protected donor. Davis et al. have
reported an efficient one pot desilylation/deacetylation
procedure using BF3OEt2 in MeCN as a fluoride source,
followed by the addition of Na2CO3 and MeOH.37 Application
of this procedure to disaccharide 9 unfortunately resulted only
in complete hydrolysis of the α-(1−6) glycosidic bond and
yielded none of the deprotected disaccharide. As a milder
alternative, the route was modified to a protecting group
interconversion. Following BF3OEt2 mediated removal of the
TBDMS groups at room temperature, the Lewis acid was
quenched with an excess of pyridine and the mixture acetylated
overnight to furnish the peracetylated disaccharide in 52%. It
was observed by TLC and mass spectroscopic analysis that the
sensitive 1,6 glycosidic linkage was undergoing hydrolysis in the
presence of the Lewis acid so this deprotection strategy was
abandoned. TBAF deprotection is commonly used for the
removal of primary hydroxyl TBDMS groups; however, an
attempted deprotection of disaccharide 9 with 1.1 equiv of
TBAF per TBDMS group at rt did not succeed. Bols and co-
workers noted the difficulty in the deprotection of TBDMS
groups on super armed donors23 and recommended the use of
3 or more equiv of TBAF per TBDMS protecting group.
Disaccharide 9 was treated with 3.3 equiv of TBAF per
TBDMS group and stirred at rt for 16 h. The naked F− ion in
THF is a very strong base and promotes acetyl migration. For
this reason, the reaction was quenched with the addition of
pyridine and acetic anhydride to ensure per-acetylation of the
final product (Scheme 4). Two products were isolated
product 20 in 87% yield. Deacetylation with NaOMe/MeOH
yielded the target disaccharide 21, in 94% after freeze-drying.
TBAF deprotection followed by acetylation was also
successfully applied to the Lewis X trisaccharide 19, albeit
with an increased reaction time of 64 h. The reaction time was
reduced to 16 h without any reduction in yield by increasing
the reaction temperature from rt to 50 °C. No hydrolysis of any
of the glycosidic linkages was observed under these conditions.
The per-acetylated trisaccharide was isolated in 77% over two
steps. Quantitative deacetylation, followed by freeze-drying
allowed the isolation of O-propargyl Lewis X trisaccharide 23 in
97% yield (Scheme 5).
Scheme 5. Deprotection of Lewis X Trisaccharide 19
The deprotection reactions of disaccharide 9 and trisacchar-
ide 19 demonstrated that the trisilylated fucosyl donor 7 could
be employed as a useful fucosyl donor for oligosaccharide
synthesis, albeit with long reaction times for the deprotection
reaction. The steric bulk of the protecting groups assisted
formation of the alpha anomer but may have resulted in
diminished yields for sterically challenging glycosylation
reactions such as the formation of trisaccharide 19. It was
anticipated that both of these issues may be resolved through
the use of the partially protected donor 5, since it does not
possess the steric bulk of donor 7. Examples of partially
protected glycosyl donors in oligosaccharide synthesis are rare
but a small number of examples have been reported in the
literature. This is due to the fact that it is extremely difficult to
avoid polymerization reactions unless the hydroxyl group on
the donor is particularly unreactive due to steric or electronic
constraints. Using a large excess of the acceptor molecule can
help avoid formation of unwanted side products but this is
often impractical for oligosaccharide synthesis. Partially
protected donors are extremely desirable in terms of atom
efficiency and also in terms of offering reduced numbers of
steps in oligosaccharide synthesis. The potential role of partially
protected donors in combinatorial approaches toward accessing
complex glycoconjugate libraries has been highlighted by
Seeberger et al.38 Linhardt and co-workers have reported the
use of partially protected galactosyl thioglycoside donors for the
efficient synthesis of saponins. The partially protected donors
were found to be efficient for glycosylation of primary alcohols
and unhindered secondary alcohols but when a glycosyl
acceptor containing a single secondary hydroxyl was examined,
low yields or complex product mixtures were observed.39 Fraser
Reid and co-workers have reported the use of a partially
protected n-pentenyl orthoester donor with a primary
alcohol.40 Kahne and co-workers have achieved glycosylation
of a secondary hydroxyl group on a glycosyl acceptor using a
partially protected sulfoxide donor. Inverse glycosylation
conditions were employed in order to maintain a high
concentration of the acceptor sugar and to avoid polymer-
ization reactions.41 Despite these elegant examples, the use of
Scheme 4. Deprotection of Disaccharide 9
following this reaction, the starting material 9 in 71% yield
and the required per-acetylated disaccharide 20 in 28% yield.
The SN2 elimination of a glycoside from a silyl protecting group
proceeds via a proposed pentacoordinate Si atom. The high
steric hindrance of multiple TBDMS groups may cause a
comparatively high energy barrier for the first deprotection,
thereby slowing down the deprotection process. Once an initial
TBDMS group is removed, the steric bulk should be lowered
and due to the large excess of TBAF, subsequent deprotection
should occur more readily. Applying this hypothesis, TBAF
deprotection was repeated for 30 h and following per-
acetylation successfully furnished the desired disaccharide
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partially protected glycosyl donors in oligosaccharide synthesis
remains relatively unexplored.
compounds were detected under these conditions. This
glycosylation reaction therefore demonstrated that the partially
protected fucosyl donor 5 could be employed for glycosylation
reactions. This represents the first example of a partially
protected fucosyl donor for glycosylation reactions.
In the case of the 2,4-TBDMS-protected thioglycoside 5, the
3-OH group is sterically shielded by the presence of the bulky
protecting groups on the adjacent hydroxyl groups. Before
investigating the partially protected monosaccharide 5 as a
potential fucosyl donor, we first investigated the reactivity of
the free 3-OH group. Attempts to silyl protect, benzyl protect,
and acetylate the free OH resulted in mainly starting material or
decomposition products. Under one set of conditions the 3-OH
group was acetylated, but this required reaction with acetic
anhydride, pyridine, and DMAP at rt for 18 days. This time
scale is well outside the scope of synthetic glycosylation
reactions.
In order to investigate the reactivity of the free OH group
toward glycosylation reactions, a trichloroacetimidate donor 24
was activated in the presence of thioglycoside donor 5. No
disaccharide product was formed, therefore confirming that the
3-OH is essentially unreactive toward glycosylation reactions.
However, due to the unreactivity of the 3-OH, and the presence
of a thioether group on donor 5 an unusual rearrangement
reaction occurred to give compounds 25 and 26 (Scheme 6).
In order to investigate the synthetic scope of the partially
protected fucosyl donor 5 and in order to compare it directly
with the persilylated donor 7, we investigated the glycosylation
reaction with the lactosamine disaccharide acceptor 18
(Scheme 8). We predicted that the reduced steric strain of
the partially protected donor should improve the yield of the
glycosylation reaction. Gratifyingly, the partially protected
donor furnished the trisaccharide 28 in 53% yield, almost
double the yield obtained when using the fully protected donor.
This is equivalent to the literature yields reported using OBn
protected fucosyl donors. We attribute the improvement in
yield to the reduced steric bulk of the partially protected donor
however, more complex electronic factors relating to the
relative ease of formation of the oxocarbenium ion intermediate
cannot be ruled out.23
Finally, we attempted to apply the deprotection protocol
previously employed for the trisaccharide 19 to trisaccharide
28. We expected that the TBDMS groups on the partially
protected donor would be easier to remove since they should
be more accessible to the fluoride ions from the TBAF reagent.
It was found that the TBDMS groups could be removed under
much milder conditions relative to the per-silylated fucose in
compounds 9 and 19. No heating was required for full
deprotection in 24 h. TBAF deprotection followed by
deacetylation furnished the desired O-propargyl-containing
Lewis X trisaccharide 23 in good yield (Scheme 9).
Scheme 6. Attempted Glycosylation of 3-OH on Donor 7
Similar rearrangement reactions been reported previously when
an unreactive thioglycoside acceptor was used in the presence
of a trichloroacetimidate donor.42−45 Boons et al. previously
described the transfer of an anomeric thioether group from
acceptor to donor.46 Analyzing the products from Scheme 6, it
can be assumed that upon formation of the glycosyl
oxocarbenium ion resulting from activation of trichloroaceti-
midate 24, the lone pair on the sulfur of fucosyl donor 5 is
more accessible than the lone pair on the 3-OH. The SEt group
is transferred onto the galactose donor to give thioglycoside 26
and the resulting fucosyl oxocarbenium ion reacts with
trichloroacetamide to furnish 25. This reaction, although not
synthetically useful for our fucosyl donor, highlights the lack of
reactivity of the 3-OH in partially protected donor 5.
Following our investigation into the reactivity of thioglyco-
side 5 as an acceptor molecule, we then set about investigating
its reactivity as a partially protected donor for fucosylation
reactions. Activation of the fucosyl donor 5 under the
conditions optimized for the fully protected fucosyl donor 7
in the presence of a benzyl alcohol acceptor furnished the O-
benzyl product 27 in a high yield of 88% with good α selectivity
(Scheme 7). None of the disaccharide or associated polymeric
CONCLUSION
■
In conclusion, we have developed both fully and partially
protected fucosyl donors 5 and 7 that have general applications
for the synthesis of fucose containing compounds where
catalytic hydrogenation cannot be carried out. Both of the new
donors could be prepared in high yield and gave good yields
and high alpha selectivity in fucosylation reactions with a
number of acceptors. The partially protected donor was of
particular use when glycosylating sterically confined centers
within an oligosaccharide. It is the first example of a partially
protected glycosyl donor that can be used to efficiently
glycosylate hindered secondary alcohols under “normal”
glycosylation conditions without any requirement for excess
acceptor or reverse activation. Deprotection reactions were
carried out to prove the synthetic utility of these donors. We
anticipate that these fucosyl donors will find general application
within synthetic carbohydrate chemistry. The partially
protected donor is particularly novel, and further investigations
of other partially protected glycosyl donors are ongoing.
EXPERIMENTAL SECTION
■
General Experimental Methods. For NMR spectra, a 400 MHz
spectrometer was employed for H (400.13 MHz) and 13C (100.61
1
1
Scheme 7. Glycosylation of Benzyl Alcohol with Partially
Protected Donor 5
MHz) spectra, and a 600 MHz spectrometer was employed for H
(600.13 MHz) and 13C (150.90 MHz) spectra. Resonances δ are in
ppm units downfield from an internal reference in CDCl3 (δH = 7.26
ppm, δC = 77.0 ppm), MeOH (δH = 3.31 ppm, δC = 49.0 ppm). For
oligosaccharides, the notation a, b, c... refers to the monosaccharide
from the reducing end. Mass spectrometry analysis was performed
with Maldi-quadrupole time-of-flight (Q-Tof) mass spectrometer
equipped with Z-spray electrospray ionization (ESI). Silica gel (200
mesh) was used for column chromatography. Analytical thin-layer
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Scheme 8. Glycosylation of Lactosamine Acceptor 18 with Fucosyl Donor 5
(Si(CH3)2); m/z HRMS (ESI-TOF) calcd for C20H44O4NaSSi2
459.2397 (M + Na)+, found 459.2401.
Scheme 9. Deprotection of Trisaccharide 28
1-Ethylthio-2,3-di-O-TBDMS-α-L-fucopyranoside, 6. Side
product from the synthesis of 5 to yield the product 6 as a clear oil
(80 mg, 3% yield): [α]20 = 39 (c = 0.1 in CHCl3); νmax (thin film)
D
1
3492 cm−1 (OH), 2929 cm−1 (CH); H NMR (600 MHz, CDCl3) δ
4.28 (1H, d, J1,2 = 8.8 Hz, H-1), 3.69 (1H, app t, J2,3 = J2,1 = 8.3 Hz, H-
2), 3.67 (1H, m, H-4), 3.65 (1H, dd, J3,2 = 8.0 Hz, J3,4 = 2.0 Hz, H-3),
3.60 (1H, q, J5,6 = 6.5 Hz, H-5), 2.70 (2H, m, SCH2CH3), 2.35 (1H, d,
J = 1.5 Hz, OH), 1.36 (3H, d, J6,5 = 6.5 Hz, H-6), 1.29 (3H, t, J = 7.4
Hz, SCH2CH3), 0.97, (9H, s, SiC(CH3)3), 0.94 (9H, s, SiC(CH3)3),
0.22, 0.18, 0.15, 0.11 (3H, s, Si(CH3)2); 13C NMR (150 MHz, CDCl3)
δ 86.4 (C-1), 77.8 (C-3), 73.9 (C-5), 72.9 (C-4), 71.4 (C-2), 26.4,
26.3 (SiC(CH3)3, 24.8 (SCH2CH3), 18.3, 18.2 (SiC(CH3)3), 16.7 (C-
6), 14.8 (SCH2CH3), −2.1, −3.4, −3.4, −4.0 (Si(CH3)2); m/z HRMS
(ESI-TOF) calcd for C20H44O4NaSSi2 459.2397 (M + Na)+, found
459.2392.
chromatography was performed using silica gel (precoated sheets, 0.2
mm thick, 20 cm × 20 cm) and visualized by UV irradiation or
molybdenum staining. DCM, MeOH, THF and toluene were dried
over flame-dried 3 Å or 4 Å sieves. Dimethylformamide (DMF),
triethylamine (Et3N) and trifluoroacetic acid (TFA) were used dry
from sure/seal bottles. Other reagents were purchased from an
industrial supplier.
Ethyl-2,3,4-Tri-O-tert-butyldimethylsilyl-1-thio-α-L-fucopyra-
noside, 7. To a solution of 1-ethylthio-α-L-fucopyranoside 4 (0.87 g,
4.20 mmol) and DMAP (50 mg) in pyridine (10 mL) was added
TBDMSOTf (5.0 g, 18.92 mmol) at 0 °C under N2. The mixture was
stirred for 5 min before being heated to 60 °C for 36 h. The reaction
was cooled over ice and quenched with deionized H2O (10 mL). The
mixture was diluted with EtOAc (50 mL) and washed sequentially
with brine (100 mL), 10% CuSO4 (2 × 50 mL), and deionized H2O (2
× 50 mL). The organic layer was dried over MgSO4 and filtered and
the solvent removed in vacuo. The product was purified by column
chromatography (EtOAc/Hex, 1:49 v/v) and recrystallized from 2%
Et2O/Hex to yield the product 132, as a white crystalline solid (2.2 g,
1,2,3,5-Tetra-O-TBDMS-α-L-fucofuranoside 3. To a stirred
solution of L-fucopyranoside 1 (0.20 g, 3.84 mmol) in DMF (5 mL)
were added 2,6-lutidine (1.20 mL, 12.10 mmol) and DMAP (0.05 g).
A solution of TBDMSCl (1.47 g, 9.76 mmol) in DCE (5 mL) was
added and the mixture stirred at 100 °C with condenser attached for
24 h under N2. The mixture was quenched with the addition of
deionized H2O (40 mL) over ice and the product diluted with EtOAc
(150 mL). The organic layer was collected and washed with brine, 1 M
HCl, and satd aqueous NaHCO3 solution and dried over MgSO4. The
mixture was filtered and the solvent removed in vacuo. The crude
material was purified by column chromatography (EtOAc/Hex, 1:99
v/v) to yield the product 3, as a clear oil (643 mg, 85%): [α]22D = 54
(deg cm3 g−1 dm−1) (c = 0.1 in CHCl3); νmax (thin film) 2929 cm−1
(CH); 1H NMR (600 MHz, CDCl3) δ 5.16 (1H, s, H-1), 3.92 (2H, m,
H-2, H-3), 3.88 (1H, m, H-5), 3.85 (1H, dd, J4,5 = 5.5 Hz, J4,3 = 3.5 Hz,
H-4), 1.19 (3H, d, J6,5 = 6 Hz, H-6), 0.92, 0.91, 0.90, 0.90 (9H, s,
SiC(CH3)3), 0.12, 0.12, 0.10, 0.10, 0.10, 0.10, 0.09, 0.08 (3H, s,
Si(CH3); 13C NMR (150 MHz, CDCl3) δ 103.3 (C-1) 90.3 (C-4),
85.2 (C-2), 79.8 (C-3), 69.1 (C-5), 26.0, 25.8, 25.7, 25.7 (SiC(CH3)3),
−4.2, −4.2, −4.4, −4.4, −4.5, −4.6, −4.8, −5.2 (Si(CH3); m/z HRMS
(ESI-TOF) calcd for C30H68O5NaSi4 643.4042 (M + Na)+, found
643.4022.
97%); [α]20 = 65 (c = 0.1 in CHCl3); mp = 62−63 °C; νmax (thin
D
1
film) 2929 cm−1 (CH); H NMR (400 MHz, DMSO 75 °C) δ 4.43
(1H, d, J1,2 = 7.2 Hz, H-1), 3.90 (1H, br s, H-4), 3.85 (1H, app, t, J2,3
=
J2,1 = 7.2 Hz, H-2), 3.81 (1H, m, H-5), 3.71 (1H, dd, J3,2 = 7.1 Hz, J3,4
= 1.9 Hz, H-3), 2.60 (2H, m, SCH2CH3), 1.23 (3H, d, J6,5 = 4.4 Hz, H-
6), 1.21 (3H, t, J = 7.5 Hz, SCH2CH3), 0.95, 0.94, 0.92 (9H, s,
SiC(CH3)3), 0.15, 0.14, 0.14, 0.14, 0.10, 0.09 (Si(CH3)2); 13C NMR
(150 MHz, CDCl3) δ (Signals too broad for full characterization); m/z
HRMS (ESI-TOF) calcd for C26H58O4NaSSi3 573.3261 (M + Na)+,
found 573.3257 (X-ray data supplied in the Supporting Information).
2-Acetamido-3,4-di-O-acetyl-2-deoxy-1-O-propargyl-6-O-
triphenylmethyl-α-D-glucopyranoside, 8a. To a mixture of 2-
acetamido-2-deoxy-1-O-propargyl-α-D-glucopyranoside (300 mg, 1.16
mmol) and trityl chloride (387 mg, 1.39 mmol) was added pyridine (5
mL). The solution was heated to 90 °C for 5 h. The reaction was
cooled over ice, and Ac2O (0.43 mL, 4.64 mmol) was added. The
mixture was stirred for 2 h. The reaction was quenched with H2O (10
mL) and diluted with EtOAc (30 mL). The organic layer was washed
sequentially with brine (10 mL), 10% CuSO4 solution (2 × 20 mL),
and H2O (10 mL). The organic layer was dried over MgSO4 and
filtered and the solvent removed in vacuo. The crude material was
purified using column chromatography (EtOAc/Hex, 8:2 v/v) to yield
the product 8a as a white amorphous solid (477 mg, 70% yield):
1-Ethylthio-2,4-di-O-TBDMS-α-L-fucopyranoside, 5. To a
solution of 1-ethylthio-α-L-fucopyranoside 4 (1.3 g, 1.63 mmol) and
imidazole (1.47 g, 21.98 mmol) in DMF (10 mL) was added
TBDMSCl (1.47 g, 9.77 mmol). The mixture was heated to 50 °C for
48 h. The reaction was cooled to rt and quenched over ice with
deionized H2O (10 mL). The mixture was diluted with EtOAc (100
mL), sequentially washed with brine (3 × 100 mL) and deionized
H2O (2 × 100 mL), and dried over MgSO4. The mixture was filtered,
and the solvent removed in vacuo. The crude material was purified by
column chromatography (Et2O/hexane, 1:25 v/v) to yield the product
5, as a yellow oil (2.34 g, 86%): [α]20 = 78 (c = 0.1 in CHCl3); νmax
D
(thin film) 3602 cm−1 (OH), 2928 cm−1 (CH); 1H NMR (600 MHz,
CDCl3) δ 4.24 (1H, d, J1,2 = 9.1 Hz, H-1), 3.80 (1H, d, J4,5 = 2.7 Hz,
H-4), 3.67 (1H, app t, J2,3 = J2,1 = 8.9 Hz, H-2), 3.57 (1H, q, J5,6 = 6.4
Hz, H-5), 3.46 (1H, m, H-3), 2.74 (1H, m, SCH(H)), 2.65 (1H, m,
SCH(H)), 1.98 (1H, d, J = 6.7 Hz, OH), 1.30 (3H, t, J = 7.5 Hz,
SCH2CH3), 1.35 (3H, d, J6,5 = 6.3 Hz, H-6), 0.96 (9H, s, SiC(CH3)3),
[α]20 = −28 (c = 0.1 in CHCl3); νmax (thin film) 3276 cm−1 (C
D
CH), 3250 cm−1 (NH), 3091 cm−1 (Ar CH), 2932 cm−1 (CH), 1743
cm−1 (CO), 1654 cm−1 (NHCO); 1H NMR (400 MHz, CDCl3)
δ 7.48 (6H, d, J = 7.8 Hz, o-Ph), 7.32 (6H, t, J = 7.9 Hz, m-Ph), 7.25
(3H, t, J = 7.5 Hz, p-Ph), 5.49 (1H, d, J = 9.1 Hz, NH), 5.20 (2H, m,
H-3, H-4), 4.84 (1H, d, J1,2 = 8.6 Hz, H-1), 4.50 (2H, d, J = 2.1 Hz,
0.94 (9H, s, SiC(CH3)3), 0.20, 0.16, 0.15, 0.11 (3H, s, Si(CH3)2); 13
C
NMR (150 MHz, CDCl3) δ 85.7 (C-1), 76.8 (C-3), 74.9 (C-5), 73.5
(C-4), 71.9 (C-2), 26.1, 26.0 (SiC(CH3)3, 23.9 (SCH2CH3), 18.4, 18.4
(SiC(CH3)3), 17.7 (C-6), 14.9 (SCH2CH3), −3.9, −4.0, −4.1, −4.2
OCH2), 4.10 (1H, m, H-2), 3.61 (1H, m, H-5), 3.27 (1H, dd, J6′,6
=
10.5 Hz, J6′,5 = 1.8 Hz, H-6′), 3.13 (1H, dd, J6,6′ = 10.4 Hz, J6,5 = 4.8
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Hz, H-6), 2.51 (1H, t, J = 2.2 Hz, CCH), 2.05, 2.01 (3H, s, CH3),
1.76 (NHCOCH3); 13C NMR (100 MHz, CDCl3) δ 171.3, 170.3,
168.9 (CO), 143.6, 143.6, 143.6, (Ar C), 128.7, 128.7, 128.7, 128.7,
128.7, 128.7 (Ar CH), 127.8, 127.8, 127.8, 127.8, 127.8, 127.8 (Ar
CH), 127.0, 127.0, 127.0 (Ar CH), 98.3 (C-1), 86.6 (C(Ph)3), 78.6
(CCH), 75.3 (CCH), 73.6 (C-5), 72.9 (C-3), 68.7 (C-4), 62.0
(C-6), 55.4 (OCH2), 54.3 (C-2), 23.4, 20.8, 20.4 (CH3); m/z HRMS
(ESI-TOF) calcd for C34H35NO8Na 608.2260 (M + Na)+, found
608.2253.
Hz, J3,4 = 2.2 Hz), 3.89 (1H, br q, J5,6 = 6.6 Hz, H-5), 3.77 (1H, br s,
H-4), 2.37 (1H, t, J = 2.3 Hz, CCH), 1.20 (3H, d, J6,5 = 6.6 Hz, H-
6), 0.94, 0.93, 0.92 (3H, s, SiC(CH3)3), 0.16, 0.14, 0.12, 0.10, 0.09.
0.08 (3H, s, Si(CH3)2; 13C NMR (100 MHz, CDCl3) δ (C-1−6 not
visible, due to broadening) 79.7 (−CCH), 74.0 (−CCH), 54.4
(OCH2), 26.6, 26.2, 26.1 (SiC(CH3)3, 18.8, 18.6, 18.3 (SiC(CH3)3,
−3.4, −3.9, −4.1, −4.2, −4.6, −4.6 (Si(CH3)2; m/z HRMS (ESI-
TOF) calcd for C27H56O5NaSi3 567.3333 (M + Na)+, found 567.3351.
2,3,4-Tri-O-tert-butyldimethylsilyl-1-O-benzyl-α-L-fucopyra-
noside, 13. General procedure (from the synthesis of 9) with benzyl
alcohol 12 as an acceptor (14.7 μL, 0.14 mmol) at −20 °C for 40 min.
The crude material was purified by column chromatography (EtOAc/
Hex, 1:19) to yield the required product 13 as a clear oil (54 mg, 86%
(3:2 α/β); Data for α anomer: [α]20D = −38 (c = 0.1 in CHCl3); νmax
2-Acetamido-3,4-di-O-acetyl-2-deoxy-1-O-propargyl-α-D-
glucopyranoside, 8. Et2O/formic acid (1:1 v/v) (6 mL) was added
to 8a (470 mg, 0.8 mmol) and the mixture stirred at rt for 2 h. The
solvent was removed in vacuo by coevaporation with toluene/MeOH.
The crude material was loaded in DCM and purified by column
chromatography (EtOAc/hexane, 4:1 v/v) to yield the product 8 as a
1
(thin film) 2953 cm−1 (CH); H NMR (400 MHz, CDCl3) δ 7.40−
white amorphous solid (213 mg, 77%): [α]20 = −60 (c = 0.1 in
7.28 (5H, m, Ar CH), 4.86 (1H, d, J1,2 = 2.9 Hz, H-1), 4.73 (1H, d, J =
12.4 Hz, OCHH), 4.52 (1H, d, J = 12.4 Hz, OCHH), 4.12 (1 H, dd,
J2,3 = 9.5 Hz, J2,1 = 2.5 Hz, H-2), 4.08 (1H, dd, J3,2 = 9.4 Hz, J3,4 = 1.8
Hz, H-4), 3.90 (1H, q, J5,6 = 6.6 Hz, H-5), 3.77 (1H, br s, H-4), 1.16
(3H, d, J6,5 = 6.5 Hz, H-6), 0.95, 0.93, 0.90 (SiC(CH3)3), 0.16, 0.15,
0.12, 0.08, 0.06, 0.05 (Si(CH3)2); 13C NMR (100 MHz, CDCl3) δ
138.5 (Ar C), 138.2 127.3 (Ar CH), 99.2 (C-1), 75.8 (C-4), 72.3 (C-
3), 70.1 (C-2), 69.3 (OCH2), 68.4 (C-5), 26.6, 26.2, 26.1
(SiC(CH3)3), 18.8, 18.6, 18.3 (SiC(CH3)3), 16.9 (C-6), −3.5, −3.9,
−4.1, −4.3, −4.6, 4.6 (Si(CH3)2); m/z HRMS (ESI-TOF) calcd for
C31H60O5NaSi3 619.3646 (M + Na)+, found 619.3636.
D
CHCl3); νmax (thin film) 3460 cm−1 (OH), 3268 cm−1 (CCH),
3089 cm−1 (NH), 2939 cm−1 (CH), 1745 cm−1 (CO), 1650 cm−1
(NHCO); 1H NMR (400 MHz, CDCl3) δ 5.59 (1H, d, J = 9.4 Hz,
NH), 5.34 (1H, app t, J3,4 = J3,2 = 9.6 Hz, H-3), 5.06 (1H, app t, J4,3
=
J4,5 = 9.6 Hz, H-4), 4.88 (1H, d, J1,2 = 8.7 Hz, H-1), 4.42 (2H, br s,
OCH2), 4.10 (1H, app q, J2,1 = J2,H = J2,3 = 9.3 Hz, H-2),, 3.78 (1H, d,
J6′,6 = 12.2 Hz, H-6′), 3.63 (1H, dd, J6,6′ = 12.1 Hz, J6,5 = 3.9 Hz, H-6),
3.57 (1H, m, H-5), 2.50 (1H, s, CCH), 2.09, 2.07 (3H, s, CH3),
1.99 (NHCOCH3); 13C NMR (100 MHz, CDCl3) δ 170.6, 169.9,
169.8 (CO), 98.1 (C-1), 78.2 (CCH), 74.9 (CCH), 73.8 (C-
5), 71.8 (C-3), 68.3 (C-4), 60.8 (C-6), 55.6 (OCH2), 53.9 (C-2), 22.9,
20.3, 20.3 (CH3); m/z HRMS (ESI-TOF) calcd for C15H21NO8Na
366.1165 (M + Na)+, found 366.1183.
(2,3,4-Tri-O-tert-butyldimethylsilyl-α-L-fucopyranoside)-1−
2-(ethyl 6-tert-butyldimethylsilyl-3,4-O-isopropylidene-1-thio-
β-D-galactopyranoside), 15. General procedure (from the synthesis
of 9) with acceptor 14 (130 mg, 0.34 mmol), at −30 °C for 60 min.
The crude material was purified by column chromatography (EtOAc/
Hex, 1:24 v/v) to yield the product 15 as a clear oil (198 mg, 66%):
O-(2,3,4-TBDMS-α-L-fucopyranoside)-(1−6)-2-acetamido-
3,4-di-O-acetyl-2-deoxy-1-O-propargyl-α-D-glucopyranoside,
9. To a stirred solution of acceptor 8 (100 mg, 0.29 mmol), donor 7
(400 mg, 0.44 mmol), and NIS (98 mg, 0.44 mmol) in DCM (15 mL)
with activated 3 Å ms at −20 °C under N2 was added a catalytic
amount of TMSOTf. The solution was stirred at −20 °C for 4 h before
quenching with Et3N (0.5 mL) and diluting with DCM (20 mL). The
organic layer was washed with satd aqueous Na2S2O3 solution (2 × 10
mL) and deionized H2O (10 mL). The organic layer was dried over
MgSO4 and filtered and the solvent removed in vacuo. The crude
mixture was purified by column chromatography (EtOAc/Hex, 3:2 v/
v) to yield the product 9 as an amorphous white solid (208 mg, 86%):
[α]20 = −25 (c = 0.1 in CHCl3); νmax (thin film) 2929 cm−1 (CH);
D
1H NMR (400 MHz, CDCl3) δ 5.27 (1H, d, J1,2 = 1.7 Hz, H-1B), 4.39
(1H, d, J1,2 = 9.4 Hz, H-1A), 4.19 (3H, m, H-5B, H-4A, H-3A), 4.12
(2H, br s, H-2B, H-3B), 3.89 (1H, dd, J6,6′ = 10.1 Hz, J6,5 = 7.1 Hz, H-
6A), 3.8 (1H, dd, J6′,6 = 10.0 Hz, J6′,5 = 5.7 Hz, H-6′A), 3.79 (1H, dd,
J5,6 = 10.5 Hz, J5,4 = 1.6 Hz, H-5A), 3.79 (1H, br s, H-4B), 3.73 (1H,
dd, J2,1 = 9.4 Hz, J2,3 = 5.9 Hz, H-2A), 2.78 (1H, dq, Jgem = 12.8 Hz, J =
7.9 Hz, SCH(H)), 2.68 (1H, dq, Jgem = 12.8 Hz, J = 7.5 Hz, SCH(H)),
1.15, 1.30 (3H, s, C(CH3)2), 1.29 (2H, t, J = 7.3 Hz, SCH2CH3), 1.16
(3H, d, J6,5 = 6.3 Hz, H-6B), 0.96, 0.95, 0.95, 0.92 (SiC(CH3)3), 0.16,
0.16, 0.13, 0.13, 0.11, 0.10. 0.10, 0.90 Si(CH3)2); 13C NMR (100 MHz,
CDCl3) δ 109.6 (C(CH3)2), 97.1 (C-1B), 83.2 (C-1A), 79.3 (C-3A),
76.9 (C-5A, 76.8 (C-4B), 74.1 (C-2A), 73.0 (C-4A), 71.6 (C-3B), 69.5
(C-2B), 68.7 (C-5B), 62.1 (C-6A), 27.7 (CCH3(CH3), 26.5, 26.2, 26.1
(SiC(CH3)3), 25.9 (CCH3(CH3), 25.7 (SiC(CH3)3), 24.0
(SCH2CH3), 18.8, 18.5, 18.2, 18.1 (SiC(CH3)3), 16.8 (C-6B), 14.9
(SCH2CH3), −3.7, −4.2, −4.3, −4.4, −4.6, −4.6, −5.5, −5.7
(Si(CH3)2; m/z HRMS (ESI-TOF) calcd for C41H86O9SSi4Na
889.4967 (M + Na)+, found 889.4956.
[α]22 = −55 (c = 0.1 in CHCl3); νmax (thin film) 3286 cm−1 (C
D
CH), 3100 cm−1 (NH), 2931 cm−1 (CH), 1754 cm−1 (CO), 1661
cm−1 (NHCO); 1H NMR (400 MHz, CDCl3) δ 5.48 (1H, d, J = 8.8
Hz, NH), 5.22 (1H, app t, J3,2 = 10.2 Hz, J3,4 = 9.4 Hz, H-3A), 4.96
(1H, app t, J4,3 = J4,5 = 9.6 Hz, H-4A), 4.78 (1H, d, J1,2 = 8.4 Hz, H-
1A), 4.7 (1H, d, J1,2 = 2.8 Hz, H-1B), 4.36 (2H, d, J = 2.2 Hz, OCH2),
4.01 (1H, br d, J3,2 = 7.4 Hz, H-3B), 3.94 (3H, br m, H-2A, H-2B, H-
5B), 3.79 (1H, br s, H-4B), 3.71 (1H, dd, J6′,6 = 11.4 Hz, J6′,5 = 1.6 Hz,
H-6′A), 3.70 (1H, m, 5-A), 3.58 (1H, dd, J6,6′ = 11.6 Hz, J6,5 = 6.4 Hz,
H-6A), 2.42 (1H, t, J = 2.2 Hz, CCH), 2.02, 2.00 (3H, s, CH3), 1.96
(NHCOCH3), 1.18 (3H, d, J6,5 = 6.5 Hz, H-6B), 0.92, 0.91, 0.89 (9H,
s, SiC(CH3)3), 0.13, 0.12, 0.09, 0.06, 0.06, 0.05 (Si(CH3)2); 13C NMR
(100 MHz, CDCl3) δ 171.1, 170.3, 169.2 (CO), 99.1 (C-1B), 98.0
(C-1A), 78.6 (CCH), 75.2 (CCH), 73.6 (C-5A), 73.4 (C-4B),
72.8 (C-3A), 72.4 (C-2B), 70.3 (C-3B), 69.2 (C-4A), 68.9 (C-5B),
67.2 (C-6A), 55.4 (OCH2), 54.2 (C-2A), 26.5, 26.1, 26.1 (SiC-
(CH3)3), 23.4, (NHCOCH3), 20.3, 20.3 (CH3), 18.7, 18.5, 18.3,
(SiC(CH3), 16.6 (C-6B), −3.6, −4.0, −4.2, −4.3, −4.6 (Si(CH3)2);
m/z HRMS (ESI-TOF) calcd for C39H73NO12NaSi3 854.4338 (M +
Na)+, found 854.4331.
(2,3,4-Tri-O-tert-butyldimethylsilyl-α-L-fucopyranoside)-1−
3-(4,6-O-benzylidene-1-methyl-β-D-galactopyranoside), 17.
General procedure (from the synthesis of 9) with acceptor 16 (130
mg, 0.34 mmol) at −20 °C for 40 min. The crude material was purified
by column chromatography (EtOAc/Hex, 2:3 v/v) to yield the
product 17, as a clear oil (104 mg, 31%): [α]20 = −18 (c = 0.01 in
D
1
CHCl3); νmax (thin film) 3574 cm−1 (OH), 2931 cm−1 (CH); H
NMR (100 MHz, CDCl3) δ 7.50 (2H, m, Ar CH), 7.37 (3H, m, Ar
CH), 5.55 (1H, s, PhCHO2), 4.96 (1H, d, J1,2 = 2.8 Hz, H-1b), 4.38
(2H, m, H-1a, H-6′a), 4.35 (1H, d, J4,3 = 3.3 Hz, H-4a), 4.19 (1H, m,
H-5b), 4.16 (1H, m, H-2b), 4.13 (1H, dd, J3,2 = 8.1 Hz, J3,4 = 1.7 Hz,
H-3b), 4.10 (1H, dd, J6,6′ 10.7 Hz, J6,5 = 1.7 Hz, H-6a), 4.00 (1H, dd,
J2,3 = 9.5 Hz, J2,1 = 7.9 Hz, H-2a), 3.69 (1H, br s, H-4b), 3.61 (3H, s,
OCH3), 3.49 (2H, m, H-5a, H-3a) 1.06 (3H, d, J6,5 = 6.6 Hz, H-6b),
0.95, 0.94, 0.93 (9H, s, SiC(CH3)3), 0.16, 0.14, 0.13, 0.13, 0.12, 0.06
(3H, s, Si(CH3)2); 13C NMR (100 MHz, CDCl3) δ 137.8 (Ar C),
128.8, 128.1, 128.1, 125.9, 125.9 (Ar CH), 103.3 (C-1a), 103.1 (C-1b),
100.7 (PhCHO2), 83.0 (C-3a), 75.9 (C-4b), 75.2 (C-4a), 71.8 (C-3b),
70.2 (C-5b), 69.4 (C-6a), 69.4 (C-2a), 69.0 (C-2b), 64.5 (C-5a), 56.7
2,3,4-Tri-O-tert-butyldimethylsilyl-1-O-propargyl-α-L-fuco-
pyranoside, 11. General procedure (from the synthesis of 9) with
propargyl alcohol 10 as an acceptor (8.16 μL, 0.14 mmol) at −20 °C
for 40 min. The crude material was purified by column
chromatography (EtOAc/Hex, 1:19 v/v) to yield the required product
11 as a clear oil (51 mg, 86%): [α]20D = −30 (c = 0.1 in CHCl3); νmax
1
(thin film) 3313 cm−1 (CCH), 2886 cm−1 (CH); H NMR (400
MHz, CDCl3) δ 4.99 (1H, d J1,2 = 3.2 Hz, H-1), 4.25 (2H, m, OCH2),
4.11 (1H, dd, J2,3 = 9.2 Hz, J2,1 = 3.0 Hz, H-2), 3.95 (1H, dd, J3,2 = 9.4
1087
dx.doi.org/10.1021/jo302487c | J. Org. Chem. 2013, 78, 1080−1090

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Article
(OCH3), 26.7, 26.4, 26.1 (SiC(CH3)3), 19.0, 18.6, 18.5 (SiC(CH3)3,
17.2 (C-6), −3.2, −3.9, −3.9, −4.3, −4.4, −4.8 (Si(CH3)2); m/z
HRMS (ESI-TOF) Calcd. for C38H70O10Si3Na 793.4175, (M + Na)+,
found 793.4193.
0.1 in MeOH); νmax (thin film) 3284 cm−1 (OH), 3924 cm−1 (CH),
1
cm−1, 1648 cm−1 (CONH); H NMR (600 MHz, MeOD) δ 4.86
(1H, d, J1,2 = 2.9 Hz, H-1B), 4.62 (1H, d, J1,2 = 8.5 Hz, H-1A), 4.35
(2H, d, J = 2.0 Hz, OCH2), 4.11 (1H, q, J5,6 = 6.5 Hz, H-5B), 3.96
(1H, d, J6′,6 = 11.3 Hz, H-6′A), 3.77 (3H, m, H-6A, H-3B, H-2B), 3.69
(1H, br s, H-4B), 3.68 (1H, app t, J2,3 = J2,1 = 9.0 Hz, H-2A), 3.51 (1H,
m, H-3A), 3.43 (2H, m, H-4A, H-5A), 2.88 (1H, t, J = 2.0 Hz, −C
CH), 2.00 (3H, s, CH3), 1.24 (3H, d, J6,5 = 6.6 Hz, H-6B); 13C NMR
(150 MHz, CDCl3) δ 172.8 (CO), 99.9 (C-1B), 99.5 (C-1A), 78.99
(−CCH), 75.9 (C-5A),75.2 (CCH), 74.6 (C-3A), 72.7 (C-4B),
70.8 (C-4A), 70.7 (C-3B), 69.1 (C-2B), 67.1 (C-6A), 66.6 (C-5B),
56.2 (C-2A), 55.4 (OCH2), 21.9 (CH3), 15.7 (C-6B); m/z HRMS
(ESI-TOF) calcd for C17H27NO10Na = 428.1533 (M + Na)+, found
428.1532.
(O-(2,3,4,6-Tetra-O-acetyl-β-D-galactopyranosyl)-(1−4))-
((2,3,4-tri-O-tert-butyl-dimethylsilyl-α-L-fuco-pyranoside)-(1−
3))-2-acetamido-2-deoxy-6-O-tert-butyldimethylsilyl-1-O-
propargyl-β-D-glucopyranoside, 19. General procedure (from the
synthesis of 9) with acceptor 18 (90 mg, 0.128 mmol) at −20 °C for 4
h. The crude material was purified by column chromatography
(EtOAc/Hex, 1:1 v/v) to yield the product 19 as a white solid (41 mg,
24%): [α]20 = −67 (c = 0.01 in CHCl3); νmax (thin film) 3407 cm−1
D
(NH), 3296 cm−1 (CCH), 2930 cm−1 (CH), 1751 cm−1 (CO),
1678 cm−1 (CONH); 1H NMR (400 MHz, CDCl3) δ 6.36 (1H, d, J
= 9.9 Hz, NH), 5.41 (1H, d, J4,3 = 3.2 Hz, H-4b), 5.16 (1H, dd, J2,3
=
(O-(2,3,4,6-Tetra-O-acetyl-β-D-galactopyranosyl)-(1−4))-
((2,3,4-tri-O-acetyl-α-L-fucopyranoside)-(1−3))-2-acetamido-2-
deoxy-6-O-acetyl-1-O-propargyl-β-D-glucopyranoside, 22. To a
solution of 19 (24 mg, 0.02 mmol) in THF (2.5 mL) was added TBAF
(1 M in THF) (0.3 mL, 0.30 mmol) at 0 °C. The mixture was heated
to 50 °C and stirred for 16 h. The solvent volume was reduced in
vacuo and the residue dissolved in pyridine (1 mL). Ac2O (1 mL) was
added at 0 °C, and the mixture was stirred for 16 h, warming to rt. The
reaction was quenched by the addition of MeOH (1 mL) followed by
dilution with EtOAc (30 mL). The organic layer was washed with
H2O, 10% CuSO4 solution, and H2O, dried over MgSO4, and filtered
and the solvent removed in vacuo. The crude material was purified by
column chromatography (EtOAc/Hex, 4:1 v/v) to yield the product
10.3 Hz, J2,1 = 7.7 Hz, H-2b), 5.03 (1H, dd, J3,2 = 10.6 Hz, J3,4 = 3.5
Hz, H-3b), 4.90 (1H, br s, H-1c), 4.67 (1H, d, J1,2 = 2.0 Hz, H-1a),
4.41 (1H, d, J1,2 = 7.8 Hz, H-1b), 4.32 (1H, br d, J = 10 Hz, H-2a),
4.25 (2H, m, OCH2), 4.20 (1H, m, H-6b), 4.08 (4H, m, H-6′b, H-6a,
H-5c, H-5b), 3.94 (1H, m, H-4c), 3.89 (3H, m, H-2c, H-3c, H-5a),
3.84 (1H, app t, J3,2 = J3,4 = 6.1 Hz, H-3a), 3.76 (1H, dd, J6′,6 = 10.1
Hz, J6′,5 = 5.2 Hz, H-6′a), 3.64 (1H, dd, J4,5 = 9.8 Hz, J4,3 = 5.8 Hz, H-
4a), 2.36 (1H, t, J = 2.3 Hz, CCH), 2.18, 2.12, 2.07, 2.04, 2.01 (3H,
s, CH3), 1.17 (3H, br s, H-6c), 0.95, 0.93, 0.93, 0.92 (9H, s,
SiC(CH3)3), 0.14, 0.13, 0.13, 0.12, 0.11, 0.10, 0.08, 0.06 (Si(CH3)2);
13C NMR (100 MHz, CDCl3) δ (C-1c-6c not visible, due to
broadening), 99.2 (C-1b), 98.0 (C-1a), 79.1 (-CCH), 76.2 (C-4a),
74.9 (C-5a), 74.3 (CCH), 72.3 (C-4c), 71.0 (C-3a), 70.2 (C-3b),
68.8 (C-2b), 66.7 (C-4b), 62.7 (C-6a), 61.0 (C-6b), 54.8 (OCH2),
48.3 (C-2a), 26.6, 26.4, 26.1, 25.8 (SiC(CH3)3), 22.9 (NHCOCH3),
21.0, 20.7, 20.6, 20.6 (CH3), 18.7, 18.6, 18.2, 18.0 (SiC(CH3)3), −4.0,
−4.0, −4.2, −4.7, −5.0, −5.2, −5.2 (Si(CH3)2), (a = GlcNAc, b = Gal,
22 as a white solid (14 mg, 77%): [α]20 = 77 (c = 0.01 in CHCl3);
D
νmax (thin film) 3300 cm−1 (NH), 3281 cm−1 (CCH), 2927 cm−1
1
(CH), 1740 cm−1 (CO), 1672 cm−1 (CONH); H NMR (600
MHz, CDCl3) δ 5.52 (1H, d, J = 8.8 Hz, NH), 5.46 (1H, d, J1,2 = 3.8
Hz, H-1c), 5.44 (1H, d, J4,3 = 3.3 Hz, H-4b), 5.39 (1H, d, J4,3 = 3.0 Hz,
H-4c), 5.23 (1H, dd, J3,2 = 10.9 Hz, J3,4 = 3.1 Hz, H-3c), 5.12 (1H, d,
c = Fuc); m/z HRMS (ESI-TOF) calcd for C55H101NO19NaSi4
=
1214.5943 (M + Na)+, found 1214.5894.
J2,3 = 10.4 Hz, J2,1 = 8.2 Hz, H-2b), 5.05 (1H, dd, J2,3 = 10.8 Hz, J2,1
3.8 Hz, H-2c), 5.01 (1H, dd, J3,2 = 10.4 Hz, J3,4 = 3.5 Hz, H-3b) 4.82
(1H, m, H-5c), 4.81 (1H, d, J1,2 = 7.3 Hz, H-1a), 4.63 (1H, dd, J6′,6
=
2-Acetamido-3,4-di-O-acetyl-2-deoxy-6-(2,3,4-tri-O-acetyl-
α-L-fucopyranosyl)-1-O-propargyl-β-D-glucopyranoside, 20. To
a solution of 9 (450 mg, 0.54 mmol) in THF (10 mL) was added
TBAF (1 M in THF) (5.4 mL, 5.4 mmol) at 0 °C. The mixture was
allowed to warm to rt and stirred for 30 h. The solvent volume was
reduced in vacuo and the residue dissolved in pyridine (3 mL). Ac2O
(1.5 mL) was added at 0 °C, and the mixture was stirred for 16 h,
warming to rt. The reaction was quenched by the addition of MeOH
(1 mL) followed by dilution with EtOAc (30 mL). The organic layer
was washed with H2O, 10% CuSO4 solution, and H2O, dried over
MgSO4, and filtered and the solvent removed in vacuo. The crude
material was purified by column chromatography (EtOAc/Hex, 9:1 v/
=
12.1 Hz, J6′,5 = 2.8 Hz, H-6′a), 4.49 (1H, dd, J6′,6 = 11.9 Hz, J6′,5 = 5.6
Hz, H-6′b), 4.49 (1H, d, J1,2 = 8.0 Hz, H-1b), 4.33 (2H, m, OCH2),
4.30 (1H, J6,6′ = 7.5 Hz, J6,5 = 11.8 Hz, H-6b), 4.19 (1H, dd, J6,6′ = 11.9
Hz, J6,5 = 4.9 Hz, H-6a), 4.13 (1H, m, H-3a), 3.90 (1H, t, J5,6 = 6.8 Hz,
H-5b), 3.87 (1H, m, H-5a), 3.83 (1H, m, H-2a), 3.62 (1H, m, H-4a),
2.45 (1H, J = 2.2 Hz, CCH), 2.22, 2.17, 2.16, 2.13, 2.10, 2.19, 2.02,
2.00, 1.99 (3H, s, CH3), 1.23 (3H, d, J6,5 = 6.6 Hz, H-6b), (a =
GlcNAc, b = Gal, c = Fuc); 13C NMR (150 MHz, CDCl3) δ 171.1,
170.8, 170.7, 170.6, 170,4, 170.3, 170.03, 169.87, 169.3 (CO), 100.4
(C-1b), 97.8 (C-1a), 95.1 (C-1c), 78.6 (−CCH), 75.2 (−CCH),
74.2 (C-5a), 72.9 (C-4a), 72.9 (C-3a), 71.3 (C-4c), 71.0 (C-5b), 70.8
(C-3b), 68.9 (C-2b), 68.1 (C-2c), 68.0 (C-3c), 66.6 (C-4b), 64.2 (C-
5c), 61.9 (C-6a), 60.7 (C-6b), 55.8 (C-6b), 55.0 (C-2a), 23.5
(NHCOCH3), 21.0, 20.9, 20.8, 20.8, 20.7, 20.7, 20.6, 20.6 (CH3), 15.8
(C-6c); m/z HRMS (ESI-TOF) calcd for C39H53NO23Na 926.2906
(M + Na)+, found 926.2895.
2-Acetamido-2-deoxy-(β-D-galactopyranosyl-(1−4))-((-α-L-
fucopyranosyl)-(1−3))-1-O-propargyl-β-D-glucopyranoside, 23.
General deacetylation method with 22 (132 mg, 0.15 mmol), followed
by freeze-drying to yield the product 23, as a white solid (78 mg, 87%)
after freeze-drying: [α]20D = 35 (c = 0.01 in CH2Cl2/MeOH 1:1); νmax
(thin film) 3274 cm−1 (OH), 2924 cm−1 (CH), 1646 cm−1 (C
ONH); 1H NMR (600 MHz, CDCl3) δ 5.05 (1H, d, J1,2 = 3.6 Hz, H-
1c), 4.86 (1H, m, H-5c), 4.69 (1H, d, J1,2 = 7.6 Hz, H-1a), 4.46 (1H, d,
J1,2 = 7.6 Hz, H-1b), 4.37 (2H, s, OCH2), 3.95 (2H, br s, C-6a), 3.92
(3H, m, H-2a, H-5b, H-4a), 3.88 (1H, dd, J3,2 = 10.5 Hz, J3,4 = 3.3 Hz,
H-3c), 3.82 (1H, d, J4,3 = 2.5 Hz, H-4b), 3.79 (1H, dd, J6,6′ = 11.2 Hz,
J6,5 = 6.9 Hz, H-6b), 3.74 (1H, d, J4,3 = 3.0 Hz, H-4c), 3.69 (1H, dd,
v) to yield the product 20 as a white foam (285 mg, 86%): [α]20
=
D
−120 (c = 0.1 in CHCl3); νmax (thin film) 3276 cm−1 (CCH), 3083
cm−1, (NH), 2927 cm−1 (CH), 2115 cm−1 (CCH), 1741 (CO),
1655 (CONH); 1H NMR (600 MHz, CDCl3) δ 5.50 (1H, d, J = 8.9
Hz, NH), 5.36 (1H, dd, J3,2 = 10.6 Hz, J3,4 =3.3 Hz, H-3B), 5.32 (1H,
d, J4,3 = 3.4 Hz, H-4B), 5.31 (1H, app t, J3,2 = J3,4 = 9.9 Hz, H-3A), 5.13
(1H, dd, J2,3 = 10.5 Hz, J2,1 = 3.5 Hz, H-2B), 5.09 (1H, d, J1,2 = 3.6 Hz,
H-1B), 5.07 (1H, app t, J4,3 = J4,5 = 9.5 Hz, H-4A), 4.87 (1H, d, J1,2
=
8.3 Hz, H-1), 4.40 (2H, m, OCH2), 4.18 (1H, m, H-5B), 3.93 (1H, m,
H-2A), 3.76 (1H, J6′,6 = 11.4 Hz, J6,5 = 2.2 Hz, H-6′A), 3.70 (1H, m,
H-5A), 3.59 (1H, dd, J6,6′ = 11.6 Hz, J6,5 = 5.1 Hz, H-6A), 2.50 (1H, t, J
= 1.9 Hz, -CCH), 2.18, 2.13, 2.05, 2.05, 2.01, 1.99 (3H, s, CH3),
1.16 (3H, d, J6,5 = 6.6 Hz, H-6B); 13C NMR (150 MHz, CDCl3) δ
170.9, 170.6, 170.6, 170.2, 169.9, 169.3 (COCH3), 98.2 (C-1A),
96.7 (C-1B), 78.6 (CCH), 75.3 (CCH), 73.2 (C-5A), 72.5 (C-
3A), 71.0 (C-4B), 69.0 (C-4A), 68.0 (C-2B), 67.9 (C-3B), 66.5 (C-
6A), 64.5 (C-5B), 55.7 (CH2CCH), 54.3 (C-2A), 23.3
(NHCOCH3), 20.8, 20.7, 20.7, 20.6, 20.6 (COCH3), 15.9 (C-6B);
m/z HRMS (ESI-TOF) calcd for C27H37NO15Na 638.2061 (M +
Na)+, found 638.2051.
J6′,6 = 11.5 Hz, J6′,5 = 5.1 Hz, H-6′b), 3.65 (1H, dd, J2,3 = 10.2 Hz, J2,1
=
3.5 Hz, H-2c), 3.53 (1H, J2,3 = 9.6 Hz, J2,1 = 7,3 Hz, H-2b), 3.48 (1H,
dd, J3,2 = 9.7 Hz, J3,4 = 2.8 Hz, H-3b), 3.46 (2H, m, H-5a, H-3a), 2.88
(1H, br s, −CCH), 1.99 (3H, s, CH3), 1.20 (3H, d, J6,5 = 6.6 Hz, H-
6c); 13C NMR (150 MHz, CDCl3) δ 172.9 (CO), 102.9 (C-1b),
99.3 (C-1c), 99.0 (C-1c), 78.9 (-CCH), 76.5 (C-3a), 75.6 (C-5a),
2-Acetamido-2-deoxy-6-(α-L-fucopyranosyl)-1-O-propargyl-
β-D-glucopyranoside, 21. General deacetylation using Zemplen
́
conditions with 20 (108 mg, 0.16 mmol, followed by freeze-drying to
yield the product 21 as a white solid (67 mg, 94%): [α]20D = −83 (c =
1088
dx.doi.org/10.1021/jo302487c | J. Org. Chem. 2013, 78, 1080−1090

The Journal of Organic Chemistry
Article
75.5 (-CCH), 75.2 (C-4a), 74.2 (C-5b), 73.9 (C-3b), 72.7 (C-4c),
71.7 (C-2b), 70.2 (C-3c), 69.0 (C-2c), 68.9 (C-4b), 66.7 (C-5c), 61.8
(C-6b), 60.3 (C-6a), 56.2 (C-2a), 55.4 (OCH2), 22.0 (CH3), 15.6 (C-
6c), (a = GlcNAc, b = Gal, c = Fuc); m/z HRMS (ESI-TOF) calcd for
C23H37NO15Na = 590.2061 (M + Na)+, found 590.2055.
H-3), 2.02 (1H, d, J = 4.7 Hz, OH), 1.29 (3H, d, J6,5 = 6.4 Hz, H-6),
0.98, 0.90 (9H, s, Si C(CH3)3), 0.16, 0.13, 0.12, 0.06 (3H, s, Si(CH3)2;
13C NMR (100 MHz, CDCl3) δ 137.5 (Ar C), 128.3 (Ar CH), 128.1
(Ar CH), 127.5 (Ar CH), 102.0 (C-1), 75.5 (C-3), 73.0 (C-4), 72.7
(C-2), 71.2 (C-5), 70.5 (OCH2Ph), 26.1, 25.9 (SiC(CH3)3), 18.6, 18.2
(SiC(CH3)), 17.3 (C-6), −4.1, −4.1, −4.2, −4.7 (Si(CH3)); m/z
HRMS (ESI-TOF) calcd for C25H46O5NaSi2 505.2782 (M + Na)+,
found 505.2786.
((2,3,4,6-Tetra-O-acetyl-β-D-galactopyranosyl)-(1−4))-((2,4-
di-O-tert-butyldimethylsilyl-α-L-fucopyranoside)-(1−3))-2-acet-
amido-2-deoxy-6-O-tert-butyldimethylsilyl-1-O-propargyl-β-D-
glucopyranoside, 28. To a stirred solution of acceptor 18 (225 mg,
0.32 mmol), donor 5 (251 mg, 0.57 mmol), and NIS (108 mg, 0.57
mmol) in DCM (5 mL) at −20 °C under argon was added TMSOTf
(cat.). The mixture was stirred at −20 °C for 3 h. The reaction was
quenched with the addition of Et3N (0.5 mL) and diluted with DCM
(10 mL). The organic layer was washed with satd aqueous Na2S2O3
solution (10 mL) and deionized H2O (10 mL), dried over MgSO4,
and filtered and the solvent removed in vacuo. The crude material was
purified by column chromatography (EtOAc/Hex, 25−50%) to yield
the product 28 as a white solid (182 mg, 53%): [α]20D = −54 (c = 0.1
in CHCl3); νmax (thin film) 3598 cm−1 (OH), 3335 (NH), 3328 (C
CH), 2930 cm−1 (CH), 1754 cm−1 (CO), 1663 cm−1 (CONH);
1H NMR (600 MHz, CDCl3) δ 6.04 (1H, J = 8.6 Hz, NH), 5.38 (1H,
1-N-Trichloroacetamido-2,4-di-O-TBDMS-α-L-fucopyrano-
side, 25. To a stirred solution of acceptor 5 (100 mg, 0.22 mmol) and
donor 24 (135 mg, 0.27 mmol) in DCM (3 mL) with preactivated 3 Å
MS at 0 °C was added BF3·OEt2 (37 μL, 0.27 mmol). The reaction
was stirred for 16 h with warming to rt before quenching with satd
aqueous NaHCO3 solution (5 mL). The reaction was diluted with
DCM (10 mL) and filtered through a plug of Celite. The solvent was
removed in vacuo and purified using column chromatography
(EtOAc/hexane, 1:49 v/v) to yield the product 25, as an off white
amorphous solid (57 mg, 46% yield): [α]20D = 49 (c = 0.1 in CHCl3);
νmax (thin film) 3501 cm−1 (OH), 3389 cm−1 (NH), 2929 cm−1 (CH),
1708 cm−1 (CO);1H NMR (400 MHz, CDCl3) δ 7.27 (1H, d, J =
6.4 Hz, NH), 5.54 (1H, d, J1,2 = 4.2 Hz, H-1), 4.10 (1H, dd, J2,3 = 7.3
Hz, J2,1 = 4.2 Hz, H-2), 3.95 (1H, app t, J4,3 = J4,5 = 2.9 Hz, H-5), 3.91
(1H, dq, J5,6 = 6.5 Hz, J5,4 = 2.8 Hz, H-5), 3.69 (1H, dd, J3,2 = 7.6 Hz,
J3,4 = 3.0 Hz, H-3), 1.33 (3H, d, J6,5 = 6.4 Hz, H-6), 0.96, 0.94 (9H, s,
SiC(CH3)3), 0.17, 0.15, 0.14, 0.13 (3H, s, Si(CH3)2); 13C NMR (100
MHz, CDCl3) δ 162.1 (CO), 98.2 (COCCl3), 76.6 (C-1), 72.2 (C-
3), 70.6 (C-4), 69.8 (C-5), 69.1 (C-2), 25.9, 25.7 (SiC(CH3)3), 18.0,
17.7 (SiC(CH3)3, 16.0 (C-6), −4.3, −4.6, −4.7, −4.7 (Si(CH3)2; m/z
HRMS (ESI-TOF) calcd for C20H40NO5NaSi2Cl3 558.1408 (M +
Na)+, found 558.1414.
d, J4,3 = 3.0 Hz, H-4b), 5.10 (1H, dd, J2,3 = 10.6 Hz, J2,1 = 7.7 Hz, H-
2b), 5.05 (1H, d, J1,2 = 3.4 Hz, H-1c), 5.00 (1H, dd, J3,2 = 10.6 Hz, J3,4
= 3.3 Hz, H-3b), 4.69 (1H, d, J1,2 = 6.0 Hz, H-1a), 4.61 (1H, d, J1,2
8.0 Hz, H-1b), 4.26 (2H, d, J = 2.0 Hz, OCH2), 4.14 (1H, dd, J6,6′
11.4 Hz, J6,5 = 7.5 Hz, H-6b), 4.13 (1H, m, H-5c), 4.10 (1H, dd, J6′,6
=
=
=
Ethyl 2,3,4,6-Tetra-O-acetyl-1-thio-β-D-glucopyranoside, 26.
As the synthesis of 25 and purified using column chromatography
(EtOAc/hexane, 1:49 v/v) to yield the product 26 as an off-white
11.4 Hz, J6′,5 = 6.4 Hz, H-6′b), 4.04 (1H, app t, J3,4 = J3,2 = 6.0 Hz, H-
3a), 3.95 (1H, app t, J4,3 = J4,5 = 5.7 Hz, H-4a), 3.92 (2H, m, H-6a, H-
2c), 3.89 (1H, m, H-2a), 3.82 (2H, m, H-5b, H-4c), 3.78 (2H, m, H-
6′a, H-3c), 3.45 (1H, m, H-5a), 2.36 (1H, br s, −CCH), 2.17, 2.07,
2.02, 2.01, 1.98 (3H, s, CH3), 1.91 (1H, d, J = 4.2 Hz, OH), 1.16 (3H,
d, J6,5 = 6.2 Hz, H-6c), 0.92, 0.92, 0.90 (9H, s, SiC(CH3)3), 0.13, 0.11,
0.11, 0.09, 0.08, 0.07 (Si(CH3)2); 13C NMR (150 MHz, CDCl3) δ
170.2, 170.0, 169.9, 169.7, 169.7 (CO), 99.12 (C-1b), 98.0 (C-1a),
97.8 (C-1c), 78.9 (−CCH), 75.7 (C-5a), 74.4 (−CCH), 73.8 (C-
3c), 73.0, 73.0 (C-3a, C-4a), 70.7 (C-4c), 70.4 (C-3b), 70.3 (C-2c),
69.9 (C-5b), 68.9 (C-2b), 67.3 (C-5c), 66.8 (C-4b), 61.6 (C-6a), 60.9
(C-6b), 54.7 (OCH2), 52.5 (C-2a), 25.9, 25.8, 25.7 (SiC(CH3)3), 23.3
(NHCOCH3), 20.7, 20.6, 20.5, 20.4 (CH3), 18.4, 18.0, 18.0
(SiC(CH3)3), 17.1 (C-6c), −4.0, −4.4, −4.7, −4.9, −5.3, −5.4
(Si(CH3)2), (a = GlcNAc, b = Gal, c = Fuc); m/z HRMS (ESI-TOF)
calcd for C49H87NO19NaSi3 1100.5078 (M + Na)+, found 1100.5076.
amorphous solid (64 mg, 71% yield): [α]20 = −22 (c = 0.1 in
D
1
CHCl3); νmax (thin film) 2964 cm−1 (CH), 1737 cm−1 (CO); H
NMR (400 MHz, CDCl3) δ 5.24 (1H, app t, J3,2 = J3,4 = 9.5 Hz, H-3),
5.10 (1H app t, J4,3 = J4,5 = 9.8 Hz, H-4), 5.05 (1H, app t, J2,3 = J2,1
=
9.5 Hz, H-2), 4.51 (1H, d, J1,2 = 9.8 Hz, H-1), 4.26 (1H, dd, J6,6′ = 12.4
Hz, J6,5 = 4.9 Hz, H-6), 4.15 (1H, dd, J6′6 = 12.3 Hz, J6′,5 = 2.2 Hz, H-
6′), 3.73 (1H, ddd, J5,4 = 10.0 Hz, J5,6 = 4.8 Hz, J5,6′ = 2.3 Hz, H-5),
2.72 (2H, m, SCH2CH3), 2.09, 2.08, 2.04, 2.03 (3H, s, CH3), 1.29
(3H, t, J = 7.4 Hz, SCH2CH3); 13C NMR (100 MHz, CDCl3) δ 170.2,
169.9, 169.0, 169.0 (CO), 83.1 (C-1), 75.4 (C-5), 73.4 (C-3), 69.3
(C-2), 67.8 (C-4), 61.7 (C-6), 23.7 (SCH2CH3), 20.3, 20.3, 20.2, 20.1
(CH3), 14.4 (SCH2CH3); m/z HRMS (ESI-TOF) calcd for
C16H24O9SNa 415.1039 (M + Na)+, found 415.1054.
2,4-Di-O-tert-butyldimethylsilyl-1-O-benzyl-α-L-fucopyrano-
side, 27a, and 2,4-Di-O-tert-butyldimethylsilyl-1-O-benzyl-β-L-
fucopyranoside, 27b. General procedure (for the synthesis of 9)
with donor 7 (150 mg, 0.32 mmol) and benzyl alcohol 12 (0.1 mL,
0.96 mmol) for 150 min at −30 °C before purification by column
chromatography (DCM/hexane, 3:2 v/v) to yield the product 27a and
27b as clear oils (145 mg, 88% (2.6:1, α/β). Data for α anomer, 27a:
ASSOCIATED CONTENT
■
S
* Supporting Information
1H and 13C NMR spectra for all compounds. X-ray data for
compound 7. This material is available free of charge via the
Internet at http://pubs.acs.org.
20
[α]D = 37 (c = 0.1 in CHCl3); νmax (thin film) 3599 cm−1 (OH),
2929 cm−1 (CH); 1H NMR (400 MHz, CDCl3) δ 7.40 (2H, d, J = 7.8
Hz, o-Ph), 7.35−7.32 (3H, m, m,p-Ph), 4.83 (1H, d, J1,2 = 3.2 Hz, H-
1), 4.71 (1H, d, J = 12.1 Hz, PhCH2), 4.57 (1H, d, J = 12.1 Hz,
PhCH2), 3.98 (1H, dd, J2,3 = 9.7 Hz, J2,1 = 3.4 Hz, H-2), 3.97 (1H, q,
J5,6 = 6.5 Hz, H-5), 3.92 (1H, m, H-3), 3.88 (1H, dd, J4,3 = 2.6 Hz, J4,5
= 0.8 Hz, H-4), 1.98 (1H, br s, OH), 1.20 (3H, d, J6,5 = 6.6 Hz, H-6),
0.96, 0.92 (Si C(CH3)3), 0.16, 0.12, 0.08, 0.01 (3H, s, Si(CH3)2; 13C
NMR (100 MHz, CDCl3) δ 137.5 (Ar C), 128.4 (Ar CH), 128.3 (Ar
CH), 127.7 (Ar CH), 97.9 (C-1), 73.5 (C-4), 70.6 (C-3), 70.7 (C-2),
69.2 (OCH2Ph), 67.2 (C-5), 26.1, 25.8 (SiC(CH3)3), 18.5, 18.2
(SiC(CH3)), 17.2 (C-6), −4.0, −4.5, −4.5, −4.7 (Si(CH3)); m/z
HRMS (ESI-TOF) calcd for C25H46O5NaSi2 505.2782, (M + Na)+,
AUTHOR INFORMATION
Corresponding Author
*E-mail: eoin.scanlan@tcd.ie.
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We thank Prof Henrik Jensen for helpful discussions and The
Irish Research Council for funding.
■
found =505.2777. Data for β anomer, 27b: [α]20 = 20 (c = 0.1 in
D
1
CHCl3); νmax (thin film) 3595 cm−1 (OH), 2929 cm−1 (CH); H
REFERENCES
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■
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dx.doi.org/10.1021/jo302487c | J. Org. Chem. 2013, 78, 1080−1090

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