One-pot synthesis of oligosaccharides by combining reductive openings of benzylidene acetals and glycosylations

Article abstract of DOI:10.1021/ol801076w

(Chemical Equation Presented) Combining triflic acid-promoted glycosylations of trichloroacetimidates with reductive opening of benzylidene acetals with triflic acid and triethylsilane as one-pot procedures provides access to a wide range of disaccharides and 2,4- and 3,4-branched trisaccharides.

Full text of DOI:10.1021/ol801076w

ORGANIC
LETTERS
2008
Vol. 10, No. 15
3247-3250
One-Pot Synthesis of Oligosaccharides
by Combining Reductive Openings of
Benzylidene Acetals and Glycosylations
Yusuf Vohra, Mahalakshmi Vasan, Andre Venot, and Geert-Jan Boons*
Complex Carbohydrate Research Center, The UniVersity of Georgia, 315 RiVerbend
Road, Athens, Georgia 30602
gjboons@ccrc.uga.edu
Received May 9, 2008
ABSTRACT
Combining triflic acid-promoted glycosylations of trichloroacetimidates with reductive opening of benzylidene acetals with triflic acid and
triethylsilane as one-pot procedures provides access to a wide range of disaccharides and 2,4- and 3,4-branched trisaccharides.
Protein- and lipid-bound saccharides are ubiquitous in
biological systems involved in many important molecular
processes such as fertilization, embryogenesis, neuronal
development, hormone activities, and the proliferation of cells
and their organization into specific tissues.1,2 These interac-
tions are also important in health science and are involved
in the invasion and attachment of pathogens, inflammation,
metastasis, blood group immunology, and xenotransplanta-
tion.3–5 A major obstacle to advances in glycobiology is the
lack of pure and structurally well-defined carbohydrates and
glycoconjugates. These compounds are often found in low
concentrations and in microheterogeneous forms, greatly
complicating their isolation and characterization. In many
cases, well-defined oligosaccharides can only be obtained
by organic synthesis.6–9
Although the methods for oligosaccharide synthesis have
improved considerably during the past decade, the construc-
tion of complex carbohydrates remains a significant challenge
due to the combined demands of elaborate procedures for
glycosyl donor and acceptor preparation and the requirements
of regio- and stereoselectivity in glycoside bond formation.
To streamline the preparation of complex oligosaccharides,
one-pot multistep approaches for selective monosaccharide
protection and oligosaccharide assembly are being pursued,
which do not require an intermediate workup and purification
step and hence speed-up the process of chemical synthesis
considerably.10,11 For example, the observation that acetal
formation, regioselective reductive opening of arylidene
acetals, reductive etherification, and acetylation can be
catalyzed by triflic acid (TfOH) or trimethylsilyl triflate
(TMSOTf) made it possible to program these reactions in
tandem by sequential addition of reagents to give easy access
to a wide variety of selective protected monosaccharide
building blocks. Furthermore, many laboratories have dem-
onstrated that chemoselective, orthogonal and iterative gly-
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10.1021/ol801076w CCC: $40.75
Published on Web 06/26/2008
2008 American Chemical Society

cosylation strategies, which exploit differential reactivities
of anomeric leaving groups, allow several selected glycosyl
donors to react in a specific order resulting in a single
oligosaccharide product.12–18
Scheme 1
.
One-Pot Synthesis of Disaccharides by Glycosylation
and Benzylidene Acetal Opening
Several reports have also shown that removal of silyl and
trityl ethers can be combined with glycosylations.19–22
To further streamline the process of oligosaccharide
assembly, we report here a strategy whereby a regioselective
opening of a benzylidene acetal and glycosylations are
combined in a one-pot multistep synthetic procedure (Scheme
1). The attraction of the approach is that it makes it possible
to assemble branched oligosaccharides by a one-pot proce-
dure, a task that cannot readily be accomplished by chemose-
lective, orthogonal, and iterative glycosylations. In this
respect, differential reactivities of hydroxyls have been
exploited for the synthesis of branched oligosaccharides by
one-pot procedures23–30 but the scope of this approach is
limited because of the need of exceptional high
regioselectivities.
Trichloroacetimidates were selected as glycosyl donors
because their activation requires only catalytic TfOH or
TMSOTf.31 Furthermore, TfOH combined with triethylsilane
(Et3SiH) was employed for the opening of a 4,6-O-ben-
zylidene acetals32,33 because these conditions provide in
general high regioselectivies and excellent yields, and
furthermore it was anticipated that these reaction conditions
would be compatible with TfOH mediated glycosylations of
trichloroacetimidates.
(12) Boons, G. J. Tetrahedron 1996, 52, 1095–1121.
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Thus, a mixture of trichloroacetimidate 134 (1.5 equiv) and
benzylidene acetal protected glycosyl acceptor 435 (1.0 equiv)
.
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3248
Org. Lett., Vol. 10, No. 15, 2008

in dichloromethane at 0 °C was treated with a catalytic
amount of TfOH. After a reaction time of 30 min, TLC and
MALDI-MS analysis indicated consumption of the starting
material and the formation of the expected disaccharide. The
reaction mixture was cooled to -78 °C followed by addition
of TfOH (1.8 equiv) and Et3SiH (2.0 equiv). After being
stirred for 30 min at -78 °C, the reaction was quenched by
the addition of triethylamine and methanol, and purification
by silica gel column chromatography gave disaccharide 8
in a yield of 70%. As expected, only a ꢀ-galactoside was
formed due to the presence of a 2,5-difluorobenzoyl group36
at C-2 of the galactosyl donor 1.34 This protecting group is
an excellent neighboring group participant and unlike benzoyl
and pivaloyl esters can be cleaved under mild conditions by
using a catalytic amount of sodium methoxide in methanol.
In the next set of experiments, the sequence of reactions
was repeated; however, in this case the fucosyl donor 237
was employed instead of 1. Fortunately, disaccharide 9 was
isolated in an overall yield of 74% as a single regio- and
stereoisomer demonstrating that the methodology is compat-
ible with acid-sensitive fucosides. It was also found that
fucosylation of 2-azido-containing glycosyl acceptor 738
followed by a regioselective opening of the benzylidene
acetal, using standard conditions, of the resulting disaccharide
led to the facile formation of disaccharide 10.
purification by silica gel column chromatography gave regio-
and stereoisomerically pure disaccharides 12 and 13, respec-
tively, in yields of 72% and 70%.
Recently, we demonstrated that glycosylations with gly-
cosyl donors modified at C-2 with a (S)-(phenylthiometh-
yl)benzyl moiety give exclusively R-anomeric selectivity due
to neighboring group participation resulting in an intermedi-
ate trans-fused 1,2-sulfonium ion.40,41 To explore the pos-
sibility of a one-pot procedure involving benzylidine acetal
opening and glycosylation with such a donor, compound 542
(1.0 equiv) was treated with TfOH (1.8 equiv) and Et3SiH
(2.0 equiv) followed by subsequent addition of 340 (1.8
equiv) and 2,6-di-tert-butyl-4-methylpyridine (DTBMP) (3.0
equiv) to give 14 as only the R-anomer.
Scheme 2. One-Pot Synthesis of Trisaccharides by
Glycosylations and Benzylidene Acetal Opening
It has been established that the regioselective ring opening
of 4,6-O-benzylidene acetals can be reversed to provide
saccharides with a free C-6 hydroxyl by employing Cu(OTf)2
in combination with borane39 instead of TfOH and Et3SiH.
Furthermore, it was anticipated that trichloroacetimidates can
be activated by Cu(OTf)2 and thus it may be possible to
glycosylate the C-3 hydroxyl of 4 followed by a regiose-
lective opening of the benzylidene acetal of the resulting
product to give a disaccharide having a C-6 hydroxyl. Indeed,
a Cu(OTf)2 (0.15 equiv) mediated glycosylation of glucosyl
donor 1 (1.5 equiv) with acceptor 4 (1.0 equiv) gave, after
a reaction time of 2 h at room temperature, a disaccharide,
which was treated with borane-THF complex (2.0 equiv)
to provide after an additional 4 h of stirring at ambient
temperature disaccharide 11 in a yield of 45%. In our efforts
to improve the reaction yield, it was found that prolonged
reaction times led to decomposition and formation of
byproduct.
Next, attention was focused on a reaction sequence
whereby a regioselective benzylidene acetal opening is
followed by glycosylation. Thus, Et3SiH (2.0 equiv) and
TfOH (1.8 equiv) were added to a cooled (-78 °C) solution
of compound 5 (1.0 equiv) in dichloromethane and after a
reaction time of 30 min, glycosyl donor 1 or 2 (1.8 equiv)
was added followed by gradually raising the temperature to
0 °C over a period of 30 min. Standard workup and
Next, we explored the possibility of synthesizing branched
trisaccharides by a reaction sequence involving glycosylation,
(36) Sjolin, P.; Kihlberg, J. J. Org. Chem. 2001, 66, 2957–2965.
(37) Rencurosi, A.; Lay, L.; Russo, G.; Caneva, E.; Poletti, L. J. Org.
Chem. 2005, 70, 7765–7768.
(40) Kim, J. H.; Yang, H.; Park, J.; Boons, G. J. J. Am. Chem. Soc.
2005, 127, 12090–12097
(41) Kim, J. H.; Yang, H.; Boons, G. J. Angew. Chem., Int. Ed. 2005,
44, 947–949
(42) Ogawa, T.; Katano, K.; Matsui, M. Tetrahedron 1980, 36, 2727–
2733.
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325–329.
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(39) Shie, C. R.; Tzeng, Z. H.; Kulkarni, S. S.; Uang, B. J.; Hsu, C. Y.;
Hung, S. C. Angew. Chem., Int. Ed. 2005, 44, 1665–1668.
Org. Lett., Vol. 10, No. 15, 2008
3249

reductive benzylidene acetal opening, followed by another
glycosylation (Scheme 2). Thus, a mixture of trichloroace-
timidate 2 (1.5 equiv) and benzylidene protected glycosyl
acceptor 4 (1.0 equiv) in dichloromethane at 0 °C was treated
with a catalytic amount of TfOH. After a reaction time of
30 min, the reaction mixture was cooled to -78 °C followed
by addition of TfOH (1.8 equiv) and Et3SiH (2.0 equiv), and
after a further reaction time of 30 min, galactosyl donor 1
(1.8 equiv) was added and the reaction mixture was allowed
to warm to 0 °C over a period of 30 min, to give after
standard workup and purification by silica gel column
chromatography trisaccharide 15 in a yield of 63%. A similar
procedure gave trisaccharide 16 by a glycosylation of 1 with
4, followed by reductive opening of the benzylidene acetal
and glycosylation of the resulting acceptor with fucosyl donor
2. Furthermore, a TfOH-promoted glycosylation of 2-azido-
2-deoxyglucoside 7 with 2 followed by benzylidene acetal
opening with TfOH/Et3SiH gave a disaccharide acceptor,
which was glycosylated with galactosyl donor 1 to give
protected Lewisx trisaccharide 17 in an excellent yield of
67%. Removal of the anomeric thexyldimethylsilyl (TDS)
protecting group of 17 followed by conversion of the
resulting lactol into the leaving group provides an opportunity
to prepare more complex oligosaccharides. Finally, it was
demonstrated that the methodology can also be employed
for the preparation of 2,4-branched trisaccharides by glyco-
sylation of acceptor 643 with fucosyl donor 2 to give a 2,4-
linked disaccharide, which was subjected to Et3SiH/TfOH
to regioselectively open the benzylidene to afford a glycosyl
acceptor having a C-4 hydroxyl. Addition of galactosyl donor
1 to the latter compound followed by standard workup and
purification by silica gel column chromatography gave
trisaccharide 18 in 60% yield.
In conclusion, it has been demonstrated that one-pot
procedures involving reductive opening of benyzlidene
acetals and glycosylations can give easy access to a wide
range of di- and trisaccharides. It is to be expected that the
utility of the methodology can be further extended by
combining acid-catalyzed reductive etherifications and acety-
lations with glycosylations. Also the use of a thioglycoside
as the initial acceptor may provide an opportunity to prepare
more complex structures by employing the resulting thiogly-
coside product as a glycosyl donor.
Acknowledgment. This research was supported by a grant
from the NIH NIGM (R01GM065248).
Supporting Information Available: Experimental pro-
1
cedures and H and 13C NMR spectra. This material is
available free of charge via the Internet at http://pubs.acs.org.
OL801076W
(43) Methyl 4,6-O-benzylidene-3-O-benzyl-r-D-glucopyranoside (6):
To a solution of methyl 4,6-benzylidene-R-D-glucopyranoside (50 mg, 0.18
mmol) in DCM (1.0 mL) was added benzaldehyde (22 µL, 0.21 mmol)
and triethylsilane (34 µL, 0.21 mmol), and the mixture was stirred under
an atmosphere of argon for 30 min. The mixture was cooled (-78 °C) and
TfOH (0.3 eq) was added. The reaction mixture was quenched after 30
min with pyridine (50 µL), diluted with DCM (5 mL), and washed with
sat. aq NaHCO3 (3 mL) and brine (3 mL). The organic layer was dried
(MgSO4), concentrated in vacuo, and purified by silical gel column
chromatography (hexane/ethyl acetate, 4/1, v/v) to give 6 as a white solid
in 50% yield.
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Org. Lett., Vol. 10, No. 15, 2008