Imidazolium cation supported solution-phase assembly of homolinear α(1→6)-linked octamannoside: An efficient alternate approach for oligosaccharide synthesis

Article abstract of DOI:10.1021/jo901169u

(Chemical Equation Presented) An efficient, simple convergent assembly of a homolinear α(1→6)-linked octamannosyl thioglycoside was obtained starting from imidazolium cation-tagged mannosyl fluoride and thiomannoside using block couplings. During chain el

Full text of DOI:10.1021/jo901169u

pubs.acs.org/joc
solution-phase as well as polymer-supported solution- or
Imidazolium Cation Supported Solution-Phase
Assembly of Homolinear r(1f 6)-Linked
Octamannoside: An Efficient Alternate Approach for
Oligosaccharide Synthesis
solid-phase organic synthesis.2,3 Although highly successful,
solid-phase synthesis suffers from a series of drawbacks due
to heterogeneous reaction conditions and stepwise charac-
terization. Alternate solution-phase polymer-supported
methods allow efficient homogeneous conditions, but issues
with loading capacity and product losses during purification
are still challenging. Fluorous chemistry using a fluorous
biphasic system and fluorous tag for fluorous separations
have also been recently exploited for the synthesis of oligo-
saccharides.4
Charu K. Yerneni, Vibha Pathak,† and Ashish K. Pathak*,†
Department of Chemistry, Western Illinois University, 1
University Circle, Macomb, Illinois 61455
†Current address: Organic Chemistry Department,
Southern Research Institute, Birmingham, AL 35205.
Access to newer, straightforward, and efficient methods to
produce biologically relevant oligosaccharides is still war-
ranted, and the use of imidazolium-type cationic species
(ionic liquids, ILs)5 as support during glycosylation pro-
cesses can be approached to facilitate and condense the
process of oligosaccharide synthesis. Imidazolium cationic
species are reported to be used as anchors for reaction
substrates in the synthesis of peptides,6 nucleotides7 and
other types of organic molecules.5,8 IL-linkers are real
molecules and have defined structures and molecular weights
in contrast to polymer linkers, which are functionalized
materials with variable loading capabilities. Recently, we
and others have successfully utilized imidazolium cations
as phase-separation tags on glycosyl donors in glycosylation
reactions.9,10 The main feature of IL-supported substrates
are their solubility properties, as solubility can be altered
toward particular types of solvents by simply varying the
anions. Thereafter, IL-supported species can be purified
from the reaction mixture by simply washing the product
with a solvent in which the IL-tagged compounds are not
soluble. Whenever required, the IL support can be clipped
off and purified by a simple phase-separation technique.
In principle, synthesis of almost pure oligosaccharides can
be achieved efficiently with minimal column chromato-
graphic purification via this approach in homogeneous
reaction conditions. In addition, IL-tagged substrates are
easily characterized by conventional spectroscopic techni-
ques. A mannosyl fluoride donor linked with imidazolium
ak-pathak@wiu.edu; pathaka@sri.org
Received June 2, 2009
An efficient, simple convergent assembly of a homolinear
R(1f6)-linked octamannosyl thioglycoside was obtained
starting from imidazolium cation-tagged mannosyl fluor-
ide and thiomannoside using block couplings. During
chain elongation glycosylation reactions no column chro-
matographic purifications were used.
(3) (a) Seeberger, P. H. Chem. Soc. Rev. 2008, 37, 19–28. (b) Seeberger,
P. H. Solid Support oligosaccharide Synthesis and Combinatorial Carbohy-
drate Libraries; John Wiley: New York, 2001, and references cited therein.
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451. (b) Miao, W.; Chan, T. H. Acc. Chem. Res. 2006, 39, 897–908. (c) El
Seoud, O. A.; Koschella, A.; Fidale, L. C.; Dorn, S.; Heinze, T. Biomacro-
molecules 2007, 8, 2629–2647. (d) Martin, M. A. P.; Frizzo, C. P.; Moreira,
D. N.; Zanatta, N.; Bonacorso, H. G. Chem. Rev. 2008, 108, 2015–2050.
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The significance of carbohydrates is now well valued as
these play pivotal roles in several key biological systems and
are essential parts of every cell surface that is crucial in cell-
to-cell recognition and communication.1 Access to pure well-
defined oligosaccharide and glycoconjugate structures
needed as biochemical tools is still a challenge to chemists.
However, the synthesis of these compounds is made possible
by controlled stereo- and regiospecific, chemoselective,
orthogonal, and bidirectional glycosylation reactions via
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DOI: 10.1021/jo901169u
r
Published on Web 07/22/2009
J. Org. Chem. 2009, 74, 6307–6310 6307
2009 American Chemical Society

Yerneni et al.
JOCNote
SCHEME 1. Synthesis of IL-Tagged Thiomannopyranoside
Donor 2
FIGURE 1. Retrosynthetic analysis of IL-supported synthesis of
R(1f 6)-octamannoside using imidazolium cation-tagged donors.
hexafluorophosphoacetyl was previously used by us, and
iterative coupling11 with thioglycoside acceptors led to the
solution-phase synthesis of a linear R(1f 6)-linked tetra-
mannoside in an efficient manner.9
linear R(1f 6)-octamannosyl fluorescent probe17 via the
two-stage activation procedure for the synthesis of oligosac-
charides,19 combining the chemistry of thioglycosides with
that of glycosyl fluorides.
The physical properties of imidazolium cation-tagged
protected sugars beyond tetrasaccharide are not clear, and
we sought to further examine the solubility properties of the
growing chain as well as their phase-tag purification by
simple washing with solvents. To test the limits of a IL-tag
assisted approach to oligosaccharide synthesis, access to a
model homolinear R(1f 6)-linked octamannosyl thioglyco-
side 1 on imidazolium cation-tagged substrates using che-
moselective/orthogonal glycosylation was chosen (Figure 1).
D-Mannose oligomers are profoundly present in nature and
are essential substructures in many biologically important
glycoconjugates such as N-glycans, fungal, and bacterial cell
wall mannans and GPI anchors.12 Branched oligomannan
syntheses are reported in the literature using several different
methodologies13 including solution- and solid-phase poly-
mer supports14 and fluorous-tag15 assisted solution phase.
Specifically, the homolinear R(1f 6) oligomannans were
previously synthesized in the solution phase16,17 and by an
automated solid-phase18 approach. In a tedious conven-
tional solution-phase process, we recently synthesized a
With our interest in developing newer simple and efficient
approaches to synthesize oligosaccharides in small to large
quantities, we report herein a convergent synthesis of octa-
saccharide 1 by means of conveniently accessible IL-tagged
p-thiotolyl mannoside 2 and IL-tagged mannosyl fluoride
3 and block glycosylation. The IL-tagged mannosyl synthons
2 and 3 were synthesized from a common known p-thiotolyl
mannoside 4.9,17 The thioglycoside 4 was chosen as the start-
ing precursor because it can be prepared on a multigram scale
in just two steps from D-mannose through a known precursor
1,6-di-O-acetyl-2,3,5-tri-O-benzoyl-R-D-mannose.20 The thio-
glycoside 4 was converted to IL-tagged glycosyl fluoride
3 using DAST and NBS at -20 °C followed by installation
of the imidazolium tag as reported in excellent yield.9
IL-tagged thioglycoside 2 was synthesized on large scale
from 4 in three steps as shown in Scheme 1. First, the selective
removal of the acetyl group at C-6 in compounds 4 was
induced by an AcCl/MeOH/CH2Cl2 mixture (0.1:20:20 v/v,
12.0 mL/mmol) and afforded 6-OH glycosides 5 in 93%
yield.9 Glycoside 5 was then treated with chloroacetyl chlor-
ide to 6-O-chloroacetylated product 6. Lastly, glycoside
6 was treated overnight with N-methylimidazole under reflux
conditions in CH3CN, and subsequent exchange of chloride
anion with hexafluorophosphino anion (PF6-) was obtained
in the same pot by reaction with KPF6. The reaction was
cooled to room temperature, and removal of solvent af-
forded a solid which was then suspended in CHCl3 and
filtered. The filtrates were concentrated to a solid and
washed several times with diethyl ether to produce almost
pure IL-tagged thioglycoside 2 on large scale, equipped with
a robust participating benzoyl group at C2 to ensure
R-selectivity and a removable temporary imidazolium ca-
tion-tagged O-acetyl protecting group at the C6 for further
chemical manipulations.
(11) In this process, after each coupling reaction between IL-tagged
mannosyl fluoride donor and thiomannosyl acceptor, the IL-tag was re-
moved from the glycosylated product to obtain thiomannoside acceptor. In
the next glycosylation step, this thiomannoside acceptor was further coupled
with another equivalent of IL-tagged mannosyl fluoride donor, and chain
elongation was achieved.
(12) Few selected articles, see: (a) Kobayashi, H.; Mitobe, H.; Takahashi,
K.; Yamamoto, T.; Shibata, N.; Suzuki, S. Arch. Biochem. Biophys. 1992,
294, 662–669. (b) Mandal, D. K.; Bhattacharya, L.; Koenig, S. H.; Brown
R. D.; Oscarson, S.; Brewer, C. F. Biochemistry 1994, 33, 1157–1162.
(c) Brennan, P. J. Annu. Rev. Biochem. 1995, 64, 29–63. (d) Chatterjee, D.;
Khoo, K. H. Glycobiology 1998, 8, 113–120. (e) Hadar, F.; Daniel, A. M.;
Kurt, D.; William, I. W. Science 2001, 294, 2163–2166. (f) Carole, A. B.;
Shigeki, K.; Hamachi, I. J. Mol. Biol. 2002, 322, 881–889. (g) Botos, I.;
O’Keefe, B. R.; Shenoy, S. R.; Cartner, L. K.; Ratner, D. M.; Seeberger,
P. H.; Boyd, M. R.; Wlodawer, A. J. Biol. Chem. 2002, 277, 34336–34342.
(13) Few selected articles, see: (a) Heng, L.; Ning, J.; Kong, F. J.
Carbohydr. Chem. 2001, 20, 285–296. (b) Zhu, Y.; Chen, L.; Kong, F.
Carbohydr. Res. 2002, 337, 207–215. (c) Ning, J.; Heng, L.; Kong, F.
Tetrahedron Lett. 2002, 43, 673–675. (d) Xing, Y.; Ning, J. Tetrahedron:
Assymetry 2003, 14, 1275–1283. (e) Ratner, D. M.; Plante, O. J.; Seeberger,
P. H. Eur. J. Org. Chem. 2002, 826–833. (f) Crich, D.; Banerjee, A.; Yao, Q.
A detailed IL-supported synthesis of target octasaccharide
1 is illustrated in Scheme 2. With large quantities of IL-
tagged p-tolylthio mannoside 2 and mannosyl fluoride
3 available, we assembled IL-tagged disaccharides 8 and 9.
Glycosylation of IL-tagged mannosyl fluoride donor 3
with thiomannoside acceptor 5 using coupling reagents21
ꢀ
J. Am. Chem. Soc. 2004, 126, 14930–14934. (g) Lopez, J. C.; Agocs, A.; Uriel,
C.; Gomeza, A. M.; Fraser-Reid, B. Chem. Commun. 2005, 5088–5090.
ꢀ
(h) Jayaprakash, K. N.; Chaudhuri, S. R.; Murty, C. V.; Fraser-Reid, B. J.
Org. Chem. 2007, 72, 5534–5545.
(14) (a) Douglas, S. P.; Whitfield, D. M.; Krepinsky, J. J. J. Am. Chem.
Soc. 1995, 117, 2116–2117. (b) Andrade, R. B.; Plante, O. J.; Melean, L. G.;
Seeberger, P. H. Org. Lett. 1999, 1, 1811–1814.
(15) Jaipuri, F. A.; Pohl, N. L. Org. Biomol. Chem. 2008, 6, 2686–2691.
(16) Zhu, Y.; Kong, F. Carbohydr. Res. 2001, 332, 1–21.
(17) Aqueel, M. S.; Pathak, V.; Pathak, A. K. Tetrahedron Lett. 2008, 49,
7157–7160.
(18) Liu, X.; Wada, R.; Boonyarattanakalin, S.; Castagner, B.; Seeberger,
P. H. Chem. Commun. 2008, 3510–3512.
(19) Nicolaou, K. C.; Ueno. H. In Preparative Carbohydrate Chemistry;
Hanessian, S., Ed.; Marcel Dekker: New York, 1996; pp 313-338 and
references cited therein.
(20) Heng, L.; Ning, J.; Kong, F. Carbohydr. Res. 2001, 331, 431–437.
(21) Suzuki, K.; Maeta, H.; Matsumoto, T.; Tsuchihashi, G.-I. Tetrahe-
dron Lett. 1988, 29, 3571–3574.
6308 J. Org. Chem. Vol. 74, No. 16, 2009

Yerneni et al.
JOCNote
SCHEME 2. Synthesis of R(1f6)-Linked Octamannan 1
Cp2HfCl2 and AgClO4 in CH2Cl2 progressed as expected to
give almost pure IL-tagged thiodisaccharide 8 after the
product was washed with diethyl ether and the product
was analytically compared with the previously prepared
sample by us.9 On the other hand, glycosylation of IL-tagged
thiomannosyl donor 2 with fluoride acceptor 7 was carried
out in the presence of promoter NIS and triflic acid. The
workup and simple washing purification protocol with di-
ethyl ether produced almost pure IL-tagged dimannosyl
fluoride 9 in 80% yield. The 1H and 13C NMR and ESIMS
spectral studies of 9 supported the structure, and the redu-
cing end anomeric carbon was observed as a doublet at
δ 105.39 (JC-F=223.3 Hz) in the 13C NMR spectrum.
In the present process, the IL-tagged glycosylated pro-
ducts, after purification by simple washing, were split into
two portions. In the subsequent glycosylation reaction,
one portion was used as a glycosyl donor and the other
portion was utilized as a glycosyl acceptor after removal of
the IL-tag and purification by a biphasic separation techni-
que. In comparison to our previous iterative glycosylation
approach11 for the IL-supported synthesis of linear tetra-
mannoside in which the monosaccharide block was added
one at a time, this block glycosylation efficiently produced
the target octasaccharide in fewer steps.
Now, to proceed further, each IL-tagged disaccharide
8 and 9 was divided into two portions. On one portion of
each disaccharide, the IL-tag was conveniently detached by
stirring with aqueous saturated NaHCO3 in a H2O/ether
(1:1) biphasic solvent mixture in the presence of a phase-
transfer catalyst Bu4NþI-. Concentration of the ether layer
provided almost pure acceptor disaccharides 10 and 11 as
shown by their 1H and 13C NMR spectra, and they
were further used as such in glycosylation reactions.
With the acceptor thiodisaccharide 10 and glycosyl fluo-
ride 11 in hand, we next executed the [2þ2] block glycosyla-
tion reaction and accessed IL-supported R(1f 6)-tetraman-
nose thioglycoside 12 and R(1f 6)-tetramannosyl fluoride
13. In a glycosylation process similar to that for the synthesis
of disaccharides 8 and 9, the IL-tagged thioglycoside 8 was
reacted with mannosyl fluoride acceptor 11 and IL-tagged
J. Org. Chem. Vol. 74, No. 16, 2009 6309

Yerneni et al.
JOCNote
mannosyl fluoride 9 was reacted with thioglycoside acceptor
11 in the presence of coupling promoters NIS-TfOH and
Cp2HfCl2-AgClO4, respectively. The workup and simple
washing purification protocol with diethyl ether produced
almost pure IL-tagged tetrasaccharides 12 and 13 for next
step usage.
was washed with 10% Na2S2O3 (10 mL), and the organic layer
was dried over anhydrous Na2SO4. It was concentrated under
vacuum to a solid which was purified by repeated washing with
diethyl ether, and the solvent was removed by decantation. The
solid residue was then dried under vacuum to afford IL-sup-
ported fluoride saccharide.
General Procedure for Coupling with IL-Tagged Fluoride
Donor. The IL-tagged fluoride (1.0 equiv) and the acceptor
thioglycosides (1.1 equiv) were dissolved in CH2Cl2 under Ar
Again, a portion of synthesized IL-tagged thiomannosyl
tetrasaccharide 12 was treated with an aqueous saturated
NaHCO3 in a H2O/ether (1:1) biphasic solvent mixture in
the presence of Bu4NþI-. After concentration of the ether
layer, almost pure acceptor thiomannosyl tetrasaccharide 14
was obtained and further utilized in glycosylation reaction
without purification. To facilitate the synthesis of IL-tagged
R(1f 6)-linked octamannosyl thioglycoside 15, a convergent
block coupling of [4 þ 4] was commenced with the overnight
coupling reaction of donor IL-tagged mannosyl fluoride 13
and acceptor thiomannoside 14 in CH2Cl2 using coupling
reagentsCp2HfCl2 and AgClO4. The usual workup and simple
washing purification protocol with diethyl ether produced
almost pure IL-tagged octasaccharides 15. Finally, the IL
support from the octasaccharide 15 was removed, as described
for 14, and resulted in almost pure homolinear R(1f 6)-linked
octamannosyl thioglycoside 1 in 83% yield. The structure of
1 was supported by its 1H and 13C NMR spectra, and the final
structural confirmation was obtained by ESIMS analysis of
1, which showed a peak at 3942.8 [MþNa]þ corresponding to
the molecular formula C223H184O64SNa.
In conclusion, we demonstrate a successful, orthogonal
block synthesis of an octasaccharide on an imidazolium
cation support with minimal column chromatographic pur-
ification as an alternative to existing oligosaccharide syn-
thetic approaches on support materials. The IL-tagged
thioglycosides and IL-tagged glycosyl fluorides were chemo-
selectively activated in presence of each other by coupling
reagents NIS-TfOH and Cp2HfCl2-AgClO4 respectively.
All intermediate products were analyzed by 1H and 13C
NMR, and MS spectral techniques. Further development
of IL-supported solution-phase techniques will provide car-
bohydrate chemists a new tool to achieve their synthetic
goals in an efficient and cost-effective approach and will
broaden the diversity of targets for glycobiology.
˚
atmosphere in the presence of activated 4 A molecular sieves.
The reaction mixture was cooled to 0 °C, and coupling reagents
AgClO4 (1.5 equiv) and Cp2HfCl2 (1.1 equiv) were added. The
reaction mixture was stirred overnight, filtered, and concen-
trated under vacuum. The residue was washed with diethyl ether
several times, and the solvent was removed by decantation. The
residue was finally dried under vacuum to give pure IL-tagged
thioglycoside.
p-Tolyl 2,3,4-Tri-O-benzoyl-r-D-mannopyranosyl-(1f6)-2,3,4-
tri-O-benzoyl-r-D-mannopyranosyl-(1f6)-2,3,4-tri-O-benzoyl-r-D-
mannopyranosyl-2,3,4-tri-O-benzoyl-r-D-mannopyranosyl-(1f6)-2,
3,4-tri-O-benzoyl-r-D-mannopyranosyl-(1f 6)-2,3,4-tri-O-ben-
zoyl-r-D-mannopyranosyl-(1f 6)-2,3,4-tri-O-benzoyl-r-D-manno-
pyranosyl-(1f 6)-1-thio-2,3,4-tri-O-benzoyl-r-D-mannopyrano-
side (1). IL-tagged octaasaccharide 15 (500 mg, 0.12 mmol) was
dissolved in biphasic solvent mixture diethyl ether-water
(15 mL, 1:1 v/v). To it were added saturated aqueous NaHCO3
solution (10 mL) and Bu4NþI- (70 mg). The reaction mixture
was stirred for 8 h at room temperature; the ether layer was
separated and washed with brine (2 ꢀ 10 mL). The ether layer
was dried over anhydrous Na2SO4 and concentrated, and the
residue was dried under high vacuum to produce octasaccharide
1 as a colorless solid (388 mg, 83% yield): mp 110 °C; Rf = 0.2
(2:1 cyclohexane-EtOAc); 1H NMR (300 MHz, CDCl3) δ 8.20
(m, 12H), 8.08 (m, 20H), 7.88 (m, 18H), 7.54 (m, 30H), 7.43 (m,
22H), 7.28 (m, 34H), 7.14 (d, 2H, J = 8.0 Hz), 6.42 (t, 1H, J =
10.2 Hz), 6.22 (m, 5H), 6.10 (m, 4H), 6.00 (m, 7H), 5.90 (m, 4H),
5.74 (m, 4H), 5.23 (s, 1H), 5.14 (d, 1H, J=8.3 Hz), 5.05 (s, 1H),
4.97 (m, 5H), 4.81 (s, 1H), 4.38 (dd, 1H, J=3.9, 11.4 Hz), 4.18
(m, 7H), 3.96 (m, 2H), 3.81 (m, 5H), 3.65 (d, 1H, J = 8.3 Hz),
3.55 (d, 1H, J = 10.1 Hz), 3.35 (m, 7H), 2.22 (s, 3H); 13C NMR
(75 MHz, CDCl3) δ 166.9, 165.8, 165.7, 165.5, 165.5, 165.3,
165.2, 138.5, 133.8, 133.6, 133.4, 133.2, 133.1, 132.9, 130.2,
130.0, 129.8, 129.5, 129.5, 129.4, 129.3, 129.1, 128.9, 128.8,
128.6, 128.43, 98.4, 98.2, 97.9, 86.9, 72.1, 71.1, 70.9, 70.6, 70.2,
69.7, 69.6, 69.3, 67.2, 66.9, 66.6, 66.5, 66.3, 65.9, 65.8, 60.8, 21.2;
ESIMS m/z 3942.8737 [M þ Na]þ calcd for C223H184O64SNa,
found 3942.7.
Experimental Section
General Procedure for Coupling with IL-Tagged Thioglyco-
side. IL-supported donor thioglycoside (1.0 equiv), acceptor
Acknowledgment. This work was made possible by Grant
No. R21AI059270 from the National Institutes of Health
and a Seed grant from Western Illinois University Research
Council.
˚
fluoride glycoside (1.2 equiv), and activated powdered 4 A
molecular sieves in CH2Cl2 were cooled at -20 °C under
argon atmosphere. The mixture was stirred for 10 min, and
NIS (1.2 equiv) followed by TfOH (0.1 equiv) was added to
initiate coupling. The reaction mixture was allowed to stir for
30 min, and the reaction was quenched by the addition of
saturated aqueous NaHCO3. It was diluted with CHCl3, and
the organic phase was filtered through a Celite pad. The filtrate
Supporting Information Available: Complete experimental
procedures and characterization (1H and 13C NMR spectra).
This material is available free of charge via the Internet at http://
pubs.acs.org.
6310 J. Org. Chem. Vol. 74, No. 16, 2009