Synthesis and Structure of Cyclic Trisaccharide with Expanded Glycosidic Linkages

Article abstract of DOI:10.1021/acs.joc.6b00462

A new cyclic trisaccharide is synthesized by cycloglycosylation of a linear trisaccharide, modified with hydroxymethyl moiety at C4 of glucopyranose moiety. The cyclic trisaccharide possesses a rarely observed perfect trigonal symmetry in the P3 space group, in a narrow cone shape, and a brick-wall type arrangement of molecules in the solid state, and exhibits a significantly enhanced binding affinity to 1-aminoadamantane in aqueous solution.

Full text of DOI:10.1021/acs.joc.6b00462

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Article
Synthesis and Structure of Cyclic Trisaccharide
with Expanded Glycosidic Linkages
Krishnagopal Maiti, and Narayanaswamy Jayaraman
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b00462 • Publication Date (Web): 16 May 2016
Downloaded from http://pubs.acs.org on May 17, 2016
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Synthesis and Structure of Cyclic Trisaccharide with Expanded Glycosidic Linkages
Krishnagopal Maiti and Narayanaswamy Jayaraman*
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Department of Organic Chemistry, Indian Institute of Science, Bangalore, 560 012, India
E-mail: jayaraman@orgchem.iisc.ernet.in
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Abstract: A new cyclic trisaccharide is synthesized by cycloglycosylation of a linear trisaccharide,
modified with hydroxymethyl moiety at C4 of glucopyranose moiety. The cyclic trisaccharide
possesses a rarely observed perfect trigonal symmetry in the P3 space group, in a narrow cone
shape, and a brick-wall type arrangement of molecules in the solid state, and exhibits a significantly
enhanced binding affinity to 1-aminoadamantane in aqueous solution.
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Introduction
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Cyclodextrins, the most abundant naturally-occurring cyclic oligosaccharides, are valuable synthetic
hosts, primarily as a result of their properties to form inclusion complexes with guest molecules.1-6
The host-guest relationship are exploited elegantly in a number of instances, few among them are
supra- and supermolecular assembly formation,7-12 analytical separations and pharmacotherapies,13
and pharmaceutical formulations.14 In spite of voluminous literature on the application of
cyclodextrins, through modifications of hydroxyl groups, modifications at the backbone continue to
be a challenge, although such backbone modifications can be rewarding in order to alter their
macrocyclic host properties.15-20 Skeletal modifications using aromatic, triazole, diyne, thioether,
thiourea, phosphate and disulfide moieties, that replace the native glycosidic bond, were developed
previously to alter the cavity properties of cyclodextrins.21-31 For example, Davis, Bayley and co-
workers demonstrated a breadth in fine sensitivity and diversity of interactions of backbone disulfide
modified β-cyclodextrins, analytes and protein pores.26 We recently reported a skeletal modification
through incorporation of an additional methylene moiety at the glycoside linkages, so as to form
backbone modified cyclic di- and tetrasaccharides. The cavity properties changed dramatically in
the case of the cyclic tetrasaccharide, by which the cyclic oligomer became amphiphilic, a property
so far unknown to a cyclic oligosaccharide retained fully with free hydroxyl groups. Due to
amphiphilic nature, the host solubilizes both water-insoluble and organic solvent insoluble guests in
aqueous and organic solutions, respectively.32 The study thus opened up possibilities to synthesize
backbone modified cyclic oligosaccharides modified at the glycosidic linkage, yet retained with
glycosidic oxygen at the backbone. Synthesis of a backbone modified cyclic oligosaccharide is
achieved using a monomer wherein a one carbon insertion is conducted at C4 of a pyranose, such
that the hydroxyl moiety at C4 is replaced with a hydroxymethyl moiety. In an approach, a linear
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trisaccharide monomer was anticipated to provide cyclic oligosaccharides in multiples of such a
monomer.33-36 In the event, a trisaccharide linear monomer was found to afford a cyclic
trisaccharide as the major cyclo-oligomer. Subsequent solid state structural studies show that the
molecule confers a perfect trigonal symmetry in the P3 space group, such a geometry is hither-to
unknown to a cyclic oligosaccharide. We further identify that the cyclic trisaccharide exhibits
strong binding affinities to organic bases in aqueous solutions, as determined by isothermal
measurements.
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Results and Discussion
Preparation of a disaccharide from a suitably modified monosaccharide 1 initiated the synthesis
towards cyclic trisaccharide (Scheme 1). Monosaccharide 1 was synthesized from the alcohol 3,32,37
by performing two following steps (i) acetylation of the primary hydroxyl group and (ii) removal of
p-methoxybenzyl alcohol group. Monosaccharide hemiacetal 1 was O-acetylated, followed by
Scheme 1
Reagents and conditions: (i) Ac2O, Pyridine, DMAP, 0 °C-rt, 4 h; (ii) p-Thiocresol, BF3.OEt2,
CH2Cl2, rt, 4 h (85%, 2 steps); (iii) NIS, TfOH, PhMe, MS (4 Å), 0 °C, 1 h; (iv) NaOMe, MeOH, rt,
6 h (67%, 2 steps).
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treatment with p-thiocresol in the presence of BF3.OEt2, to afford thioglycoside donor 2 (α:β =
1:0.4). The activated thioglycoside donor38 2 was subjected to glycosylation with the glycosyl
acceptor 3 in the presence of NIS/TfOH in PhMe at 0 °C, and a subsequent O-deacetylation
provided disaccharide acceptor 4, in a moderate yield. The α-anomeric configuration at the non-
reducing end of 4 was inferred by the appearance of a peak at 4.77 ppm as a doublet (J = 3.2 Hz) for
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anomeric proton (Hα-1') and 97.8 ppm for anomeric carbon (Cα-1') in H and C NMR spectrum,
respectively.
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Glycosyl acceptor 4 and donor 2 on treatment with NIS/TfOH in toluene at 0 C underwent
glycosylation to form trisaccharide which was further O-deacetylated to afford 5 (Scheme 2).
Scheme 2
Reagents and conditions: (i) NIS, TfOH, PhMe, MS (4 Å), 0 °C, 1 h; (ii) NaOMe, MeOH, rt, 6 h
(68%, 2 steps); (iii) Ac2O, Pyridine, DMAP, 0 °C-rt, 3 h; (iv) CF3COOH, CH2Cl2/H2O, 0 °C-rt, 4 h
(74%, 2 steps); (v) Ac2O, Pyridine, DMAP, 0 °C-rt, 4 h; (vi) p-Thiocresol, BF3.OEt2, CH2Cl2, rt, 4
h; (vii) NaOMe, MeOH, rt, 6 h (75%, 3 steps).
The O-deacetylation to afford 5 and an O-acetylation to afford 6 were conducted in order to
facilitate purification by column chromatography (SiO2, PhMe/EtOAc linear gradient). In 1H NMR
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spectrum of 5, the appearance of chemical shift at 4.83 ppm (d, J = 3.6 Hz) for H-1 and in 13C NMR
spectrum, resonance at 98.5 ppm for anomeric carbon C-1 suggested α-anomeric configuration of
the newly formed glycosidic linkage at the non-reducing end. Acetylation of primary hydroxyl
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group followed by removal of p-methoxybenzyl group in 5, using TFA at 0 C to rt, afforded
trisaccharide hemiacetal 6, as an anomeric mixture (α:β = 1:0.9). Lactal 6 was converted further to
an activated trisaccharide monomer 7 (Scheme 2), using the following three steps sequence (i)
acetylation (Ac2O/Py) of the anomeric hydroxyl group; (ii) installation of thioglycoside (p-
thiocresol/BF3.OEt2) and (iii) O-deacetylation using NaOMe/MeOH at the non-reducing end.
Cyclo-glycosylation of 7 (20 mM) was performed in the presence of NIS/TMSOTf in PhMe
for 12 h to afford a crude product, which was subjected to a purification (SiO2, PhMe/EtOAc, linear
gradient). A major product was isolated, which was subjected to O-debenzylation (H2/Pd-C). The
resulting crude product was purified (SiO2, CHCl3/MeOH, linear gradient) to afford a major product.
From a series of subsequent analysis, the major product was identified to be the cyclic trisaccharide
8 (Scheme 3). Changes in the glycosylation reaction conditions, such as the reagent or solvent, did
not markedly improve the product formation. The fully functionalized cyclic trisaccharide (8) was
readily soluble in aqueous solution, whereas weekly soluble in organic solvents (e.g., CHCl3).
Scheme 3
Reagents and conditions: (i) NIS, TMSOTf, PhMe, MS (4 Å), 0 °C-rt, 12 h; (ii) H2, Pd/C (10%),
EtOAc/MeOH (1:1), rt, 12 h (52%, 2 steps).
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The constitution and configuration of cyclic trisaccharide 8 was ascertained by 1H, 13C NMR
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spectroscopies and mass spectrometry. The molecular ion peak at 551.1967 [M+ Na]+ corresponds
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to the major peak in the ESI-mass spectrum of 8. In H NMR spectrum of 8, anomeric proton
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resonated at 4.93 ppm, as a doublet (J = 4 Hz), whereas anomeric carbon resonated at 98.6 ppm in
13C NMR spectrum, concluded the α-configuration of the glycosidic linkage. Further, a JC1-H1 of
169 Hz conformed to an α-anomeric configuration of the glycosidic linkage in 8. The assignments
were confirmed further by COSY and HMQC NMR spectroscopies. In addition to 8, cyclic
oligosaccharides in multiples, corresponding to cyclic hexa- and nona-saccharides were also
observed in the mass spectrum of the crude product of cyclo-glycosylation reaction, however, such
higher cyclic oligosaccharides could not be isolated in a pure form at present. In this respect,
reaction conditions remain to be identified that promote an intermolecular cyclo-glycosylation,
which was observed in our previous report using disaccharide monomer leading to cyclic
tetrasaccharide as a major product,32 overtaking the intramolecular reaction when trisaccharide is the
monomer for cyclo-glycosylation.
Solid state structure of 8: Crystals, suitable for single crystal X-ray structural determination, was
secured by vapor diffusion of acetone into a methanolic aqueous solution of 8. The structural
determination revealed that the molecule crystallized in the P3 space group, with a perfect trigonal
symmetry, with three molecule in the unit cell. Crystallographic parameters of 8 can be found in the
Supporting Information 39 Bond lengths are in the range of 1.28 – 1.53 Å (C – O) and 1.49 – 1.56 Å
(C – C) and bond angles are largely in the range of 107 – 125o. Dihedral angles of primary
hydroxymethyl substituent (C6) conformed to gauche-gauche (-67 and 55o) conformation. Primary
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and secondary hydroxyl groups are seen to be residing away from the macrocyclic cavity and the
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hydrogen atoms at C-3 and C-5 moieties are directed inward the cavity.
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Further analysis show that the molecule possesses a bowl-shape, with primary hydroxyl
groups placed in the narrower side, whereas secondary hydroxyl groups located in the wider face of
the bowl, similar to that in cyclodextrin.6 Figure 1a shows the crystal structure diagram of 8,
included with approximate locations of methylene and methine hydrogens. Cremer-Pople puckering
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parameter40,41 analysis shows that the glucose units adopted nearly a C1 conformation, with set of
polar coordinate values: Q = 0.559±0.027 Å, θ = 4±3.5o and φ = 176±33o for the individual sugar
ring in 8. The observed φ value indicates that there is a small deviation of the pyranose ring from
perfect 4C1 conformation towards the direction of a skew conformation.
Figure 1. (a) Stick model of the crystal structure of 8, as viewed along the crystallographic c-axis;
(b) cartoon representation provided with molecular dimensions; (c) packing diagram crystal lattice,
as viewed along the crystallographic b-axis, and without solvent inclusion and (d) packing diagram
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included with methanol (grey) and water (red) solvents, as viewed along the crystallographic c-axis.
Hydrogen atoms are omitted for clarity in (c and d).
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A perfect three-fold symmetry exists with the glycosidic oxygen and other exocyclic
substituents. The inner cavity diameter of the bowl at the wider face is 4.07 Å, whereas the narrow
lower rim diameter is 2.58 Å. The height of the torus is 5.84 Å and the glycosidic oxygens are equi-
distant, at 4.46 Å from one another. A cartoon representation showing the structural dimensions is
given in Fig. 1b. The ratio of upper-to-lower rim cavity diameter in 8 is 1.58, implying a rather
sharp cone-shape of 8. Similar in the case of CDs, the wider upper rim is constituted by the
secondary hydroxyl groups, whereas the narrow lower rim is occupied by the primary hydroxyl
groups of the sugar moieties. A packing diagram of the molecules of 8 is presented in Fig. 1c. A
wider rim-to-wider rim and narrow rim-to-narrow rim arrangement of a block of three molecules
form repeating unit in the crystal lattice. In a ‘brick-wall’ type arrangement of the block of three
molecules, one molecule is translationally and rotationally correlated to two neighboring molecules.
Thus, the arrangement of the molecules in the crystal lattice appears to provide a space for one
molecule within the block to undergo translational and rotational transition. Such a brick-type
arrangement wherein one molecule of the trimeric block retaining wider rim-to-wider rim and
narrow rim-to-narrow rim positioning with the adjacent molecules is rather unusual to a cyclic
oligosaccharide molecular packing. In this arrangement, the channel running through the
macrocyclic interior cavity is partially blocked. Yet, solvents in a ratio of one water and one
methanol molecules to one molecule of 8 occupy the channels and voids in the lattice (Fig. 1d). A
network of hydrogen bonding interactions42,43 are observed among hydroxyl groups of the sugar
within the trimer blocks of the lattice. Two-centre and three-centre, bifurcated hydrogen bonding
interactions are observed in an intermolecular fashion, involving wider and narrower rim hydroxyl
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groups. Within donor (D)–acceptor (A) bond length limits of 3.2 Å, hydrogen bonding interactions
with solvents are also seen from analysis. In addition, intramolecular hydrogen bonding interactions
within a macrocycle exist in the crystal lattice.
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Host-guest interactions of 8 with organic bases: In order to evaluate encapsulation properties of
new glycosidic bond expanded cyclic trisaccharide 8, inclusion complexation with few guest
molecules were conducted. After an initial screening of alcohols, amines, carboxylic acids and
polyaromatic guest molecules, amines were chosen to identify the host-guest properties of 8. A
preliminary evaluation in aqueous solution showed that amines possessed higher binding affinities,
in comparison to other types of guest molecules. Two amines, namely, 1-aminoadamantane (AMT)
and hexamethylene tetramine (HMT), as shown in Figure 2a, were studied and the associated
thermodynamic parameters were evaluated by isothermal titration calorimetry (ITC), in aqueous
solutions.44 Amines are known to bind with β-cyclodextrin (β-CD) in water, as assessed by
calorimetry.45 ITC titrations of 8 with amines were performed at 30 oC, resulting thermograms were
corrected for dilution effects and analyzed. Binding isotherm for AMT with cyclic trisaccharide is
shown in Figure 2b. Analysis of the thermodynamic parameters revealed that binding followed an
one-site binding stoichiometry (Table 1). The binding constant was 13,200 M-1, with negative
binding enthalpy and free energy changes. Interaction of β-CD with AMT was undertaken as a
comparison.46,47 The binding parameters are given in Table 1. The comparison shows that the
binding of AMT with 8 was about two-and-half times stronger than to the binding with β-CD.
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(c)
(b)
(a)
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Figure 2. (a) Molecular structures of AMT and HMT; (b) ITC isotherm of the interaction of 8 (1
o
mM) and AMT (15 mM) at 30 C in water; (c) a cartoon of the binding of AMT with 8, without
measuring solvent accessible surface area.
We premise that AMT occupies the upper rim of 8, with adamantane moiety occupying the
macrocycle cavity, amine moiety exposed to the hydroxyl groups and water molecules of the
aqueous environment, as in the case of AMT binding to CDs.46,47 Lengths of AMT48 and 8, as
derived from crystal structure analysis, are given in Figure 2c. Enhanced binding strength of AMT
with 8, when compared to AMT binding to β-CD might prove to be useful, as AMT is an anti-viral
drug49 and its slow release when complexed with CD is beneficial.
A binding study of 8-HMT complexation was undertaken further. The binding in this
instance was promoted by a much weaker enthalpy change and the stoichiometry of host-guest was
found to be ~ 2:1 in this instance. Positive enthalpy and entropic changes indicated that the binding
was favored by hydrophobic interaction mediated host-guest complexation. This observation was
distinctly different from that of the β-CD-HMT complexation, in which the binding interaction was
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favored by a large negative enthalpic change. The resulting binding constants were also
significantly different, with β-CD binding having close to four-and-half times higher binding affinity
than HMT with 8 (Table 1). The 2:1 host-to-guest complexation was verified through monitoring
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the H NMR resonance shift as a function of the host-to-guest mole fraction. A bell-shaped curve
was observed in the Job plot when the mole fraction was plotted against the product of change in
chemical shift and host concentration. A nearly matching host-guest 2:1 stoichiometry was
observed in the Job plot, in agreement with the results from ITC studies.
Table 1. Binding parameters of the interaction of 8 and β-CD with AMT and HMT.
Binding
Stoichiometry
(N)
∆H
T∆S
∆G
Host
Guest
constant
(K) (M-1)
(cal/mol)
(kcal/mol)
(kcal/mol)
1.04
13,200
±1,640
-573.4
±17.1
5.15
4.67
3.64
3.79
-5.71
-4.57
-5.15
-5.50
AMT
HMT
±0.02
8
0.51
2,020
±388
95.24
±7.23
±0.01
1.12
5,210
±384
-1522
AMT
HMT
±0.02
±30.60
β-CD
0.98
9,090
-1715
±65.1
±0.02
±1,470
Conclusion
In conclusion, the present work illustrates that the cyclo-oligomerization strategy of a linear
monomer is a valuable approach to mitigate existing major challenges in the backbone modification
of the general class of cyclic oligosaccharides, as modifications at each sugar moiety are conducted
at the linear monomer level, prior to cyclization, through synthetic manipulations of the monomer
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moiety. The present study demonstrates cyclization of a linear trisaccharide monomer in which the
inter-sugar glycosic bonds are expanded with an additional methylene moiety. Resulting newly
formed cyclic trisaccharide conforms elegantly to structural features of the naturally-occurring CDs,
even when the glycosidic bond with non-reducing end of the sugar is expanded with an extra
methylene moiety. The cyclic trisaccharide adopts a perfect trigonal symmetry in the P3 space
group, a more sharp-cone than CDs, a brick-wall type arrangement of a block of three molecules in a
wider rim-to-wider rim and narrow rim-to-narrow rim packing in the crystal lattice. Such a
symmetry and molecular packing are hither-to unknown to a CD derivative. The molecule hosts
solvent and water molecules in its cavity and at the interstitial void spaces, and hydrogen bonding
interactions are abound. The cyclic trisaccharide shows preferential binding to AMT and HMT in
aqueous solution in a 1:1 and 2:1 host-to-guest ratio, with binding constant significantly higher than
β-CD in the case of AMT.
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Experimental Section
General information. Solvents were dried and distilled according to literature procedures. All
chemicals were purchased from commercial sources and were used without further purification.
Silica gel (100–200 and 230-400 mesh) was used for column chromatography and TLC analysis was
performed on commercial plates coated with silica gel 60 F254. Visualization of the spots on TLC
plates was achieved by UV radiation or spraying 5% sulfuric acid in ethanol. High resolution mass
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spectra were obtained from Q-TOF instrument by electrospray ionization (ESI). H and C NMR
spectral analyses were performed on a spectrometer operating at 400 MHz and 100 MHz,
respectively. Chemical shifts are reported with respect to tetramethylsilane (TMS) for 1H NMR and
the central line (77.0 ppm) of CDCl3 for 13C NMR. Coupling constants (J) are reported in Hz.
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Standard abbreviations s, d, t, dd, br s, m and app t refer to singlet, doublet, triplet, doublet of
doublet, broad singlet, multiplet and apparent triplet. For disaccharide and trisaccharide derivatives,
H and C denote the proton and carbon of reducing sugar moiety, whereas H′ and C′ denote the
proton and carbon of non-reducing pyranose moiety. H-7 and C-7 denote proton and carbon of 4-C-
hydroxymethyl moiety of the pyranose ring.
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α/β
2,3,6-Tri-O-benzyl-4-C-acetoxymethyl- -D-glucopyranose (1)
Acetic anhydride (0.46 mL, 4.93 mmol) was added to a solution of 3 (2.4 g, 4.11 mmol) in pyridine
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(15 mL) and DMAP (0.05 g, 0.41 mmol) at 0 C and stirred for 2 h at room temperature. The
reaction mixture was diluted with water (50 mL), extracted with CHCl3 (3 x 70 mL), washed with
aq. HCl (2 N), satd. aq. NaHCO3 (2 x 50 mL), dried (Na2SO4), filtered, concentrated in vacuo.
Triflouroacetic acid (0.61 mL, 7.98 mmol) was added to a solution of crude residue (2.5 g) in aq.
CH2Cl2 (10 mL) at 0 oC, stirred for 4 h at room temperature. The reaction mixture was diluted with
water (50 mL), washed with aq. NaHCO3 (10 % w/v, 2 x 50 mL), extracted with CH2Cl2 (3 x 70
mL), dried (Na2SO4), filtered and concentrated in vacuo. The crude product was purified (SiO2)
(hexane/EtOAc = 3:2) to afford 1 (1.35 g, 65%, α/β = 2:1), as a colorless oil. Rf = 0.2
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(hexane/EtOAc = 3:2); H NMR (CDCl3, 400 MHz): δ 7.38-7.25 (m, 24 H), 5.30 (d, J = 3.2 Hz, 1
H), 5.01 (d, J = 10.8 Hz, 0.5 H), 4.93 (d, J = 11.2 Hz, 1 H), 4.90 (d, J = 10.8 Hz, 0.5 H), 4.76 (d, J =
6.8 Hz, 0.5 H), 4.73 (d, J = 7.2 Hz, 1 H), 4.69 (d, J = 12 Hz, 1 H), 4.64 (d, J = 11.6 Hz, 1 H), 4.60
(d, J = 10.8 Hz, 1.5 H), 4.56 (app s, 1 H), 4.50 (d, J = 12.4 Hz, 0.5 H), 4.46 (d, J = 12 Hz, 1 H), 4.30
(dd, J = 2.8 Hz, 11.6 Hz, 1 H), 4.25 (dd, J = 2.8 Hz, 12 Hz, 0.5 H), 4.17-4.13 (m, 1 H), 4.05-4.00
(m, 1.5 H), 3.94 (d, J = 9.2 Hz, 0.5 H), 3.91 (d, J = 9.6 Hz, 0.5 H), 3.64-3.55 (m, 5 H), 3.44-3.40 (m,
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0.5 H), 2.07-2.00 (m, 1.5 H), 1.92 (s, 3 H), 1.90 (s, 1.5 H); C NMR (CDCl3, 100 MHz): 170.7,
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170.5, 140.8, 138.3, 138.2, 138.0, 137.8, 137.7, 137.6, 128.4, 128.3, 128.2, 128.1, 128.0, 127.9,
127.8, 127.7, 127.6, 127.5, 126.8, 97.5, 91.3, 84.6, 81.4, 75.2, 75.0, 74.6, 74.2, 73.4, 73.3, 72.6,
72.4, 69.6, 68.0, 65.0, 60.1, 42.4, 42.2, 20.6, 20.5; HRMS (ESI/TOF-Q) m/z: [M + Na]+ Calcd for
C30H34O7Na, 529.2202; Found 529.2207.
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p-Tolyl 4-deoxy-4-C-acetoxymethyl-2,3,6-tri-O-benzyl-1-thio-α/β-D-glucopyranoside (2)
Acetic anhydride (0.25 mL, 2.6 mmol) and dimethylamino pyridine (0.026 g, 0.217 mmol) was
added to a solution of 1 (1.1 g, 2.17 mmol) in pyridine (5 mL) at 0 °C, stirred for 4 h at room
temperature. The reaction mixture was diluted with CH2Cl2 (100 mL), washed with dil. aq. HCl (2 x
50 mL), satd. aq. NaHCO3 (1 x 50 mL) and brine (50 mL), dried (Na2SO4), filtered and concentrated
in vacuo. The crude product was co-evaporated with PhMe (2 x 5 mL) to afford diacetate
intermediate (1.1 g), as a gum. p-Thiocresol (0.29 g, 2.4 mmol) was added to a solution of diacetate
intermediate (1.1 g, 2.0 mmol) in CH2Cl2 (10 mL) and BF3.OEt2 (0.25 mL, 2 mmol) was added
dropwise at room temperature and stirred for 1 h under N2 atmosphere. The reaction mixture was
quenched with Et3N (0.5 mL), filtered, concentrated in vacuo and purified (SiO2) (pet. ether/EtOAc
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= 9:1) to afford 2 (1.13 g, 85%, α/β = 1:0.4); H NMR (CDCl3, 400 MHz): δ 7.40-7.23 (m, 24 H),
7.06 (d, J = 8 Hz, 2 H), 7.03 (d, J = 8 Hz, 0.8 H), 5.67 (d, J = 5.2 Hz, 1 H), 5.00 (d, J = 8 Hz, 0.4 H),
4.97 (d, J = 10.8 Hz, 1 H), 4.89 (d, J = 11.2 Hz, 0.4 H), 4.78 (d, J = 11.6 Hz, 1 H), 4.76-4.71 (m, 0.8
H), 4.65 (d, J = 13.2 Hz, 2 H), 4.60 (d, J = 4.8 Hz, 1.4 H), 4.55 (d, J = 12.4 Hz, 1.4 H), 4.50-4.46
(m, 1.4 H), 4.43 (d, J = 12 Hz, 1 H), 4.34 (dd, J = 2.8 Hz, 12 Hz, 1 H), 4.10 (dd, J = 2 Hz, 12 Hz,
0.4 H), 4.06 (dd, J = 2 Hz, 12 Hz, 1 H), 3.93 (dd, J = 5.2 Hz, 9 Hz, 1 H), 3.81 (t, J = 9.8 Hz, 1 H),
3.75 (dd, J = 2 Hz, 10.8 Hz, 0.4 H), 3.69-3.64 (m, 2.8 H), 2.31 (s, 3 H), 2.30 (s, 1.2 H), 2.14-2.04
(m, 1.4 H), 1.98 (s, 3 H), 1.91 (s, 1.2 H); 13C NMR (CDCl3, 100 MHz): δ 170.7, 170.5, 138.2, 138.1,
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138.0, 137.9, 137.8, 137.7, 137.6, 137.1, 133.1, 132.5, 131.7, 131.0, 130.1, 129.6, 129.5, 128.5,
128.4, 128.3, 128.2, 128.1, 128.0, 127.9, 127.7, 127.6, 127.5, 88.1, 87.6, 82.2, 81.1, 79.5, 75.3, 75.2,
75.1, 74.8, 73.5, 73.4, 71.9 70.2, 69.6, 69.0, 60.1, 42.7, 42.1, 21.0, 20.7, 20.6; HRMS (ESI/TOF-Q)
m/z: [M + Na]+ Calcd for C37H40O6SNa, 635.2443; Found 635.2443.
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p-Methoxybenzyl 2,3,6-tri-O-benzyl-4-deoxy-4-C-methyl-α-D-glucopyranosyl-(1→4)-2,3,6-tri-
O-benzyl-4-deoxy-4-C-methyl-β-D-glucopyranoside (4)
N-Iodosuccinimide (0.22 g, 0.98 mmol) was added to a mixture of 2 (0.5 g, 0.817 mmol) and 3 (0.38
g, 0.654 mmol) and MS (4 Å) (1.6 g) in PhMe (5 mL) at 0 °C, stirred for 10 min. TfOH (7 µL,
0.082 mmol) was added and stirred for 1 h under N2 atmosphere. The reaction mixture was
neutralised with Et3N, filtered, extracted with EtOAc, washed with aq. Na2S2O3 (2 x 50 mL), satd.
aq. NaHCO3 (2 x 50 mL) and brine (50 mL), dried (Na2SO4) and concentrated in vacuo, purified
(SiO2) (pet. ether/EtOAc = 4:1) to afford acetyl protected disaccharide derivative. NaOMe in
MeOH (1 M, 0.2 mL) was added to a solution of disaccharide derivative in MeOH, stirred for 6 h at
room temperature, neutralised with amberlite resin (H+), filtered, concentrated in vacuo.
Purification (SiO2) (pet. ether/EtOAc = 3:1) afforded 4 (0.45 g, 67%), as a gum. [α]D -3.13 (c 0.25,
CHCl3); 1H NMR (CDCl3, 400 MHz): δ 7.33-7.14 (m, 32 H), 6.85 (d, J = 8.4 Hz, 2 H), 4.96 (dd, J =
4 Hz, 10.8 Hz, 2 H), 4.91 (dd, J = 3.2 Hz, 11.2 Hz, 2 H), 4.77 (d, J = 3.2 Hz, 1 H), 4.72-4.56 (m, 8
H), 4.51 (d, J = 8 Hz, 1 H), 4.49-4.41 (m, 2 H), 3.91-3.86 (m, 2 H), 3.82 (d, J = 4.8 Hz, 1 H), 3.79
(d, J = 2.8 Hz, 1 H), 3.78 (s, 3 H), 3.77-3.70 (m, 4 H), 3.67 (dd, J = 4.4 Hz, 10.8 Hz, 2 H), 3.55 (dd,
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J = 3.2 Hz, 9.6 Hz, 1 H), 3.52-3.48 (m, 3 H), 2.01-1.96 (m, 1 H), 1.84-1.80 (m,1 H); C NMR
(CDCl3, 100 MHz): δ 159.3, 138.8, 138.7, 138.4, 138.3, 138.1, 137.7, 129.8, 129.6, 128.5, 128.4,
128.3, 128.2, 128.1, 127.8, 127.7, 127.6, 127.5, 127.4, 113.8, 102.5, 97.8, 83.6, 81.4, 78.4, 75.3,
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75.0, 74.9, 74.7, 73.6, 73.4, 73.2, 72.7, 70.7, 70.5, 70.4, 68.7, 63.7, 59.2, 55.2, 45.8, 43.9; HRMS
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(ESI/TOF-Q) m/z: [M + Na]+ Calcd for C64H70O12Na, 1053.4765; Found 1053.4763.
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p-Methoxybenzyl 2,3,6-tri-O-benzyl-4-deoxy-4-C-methyl-α-D-glucopyranosyl-(1→4)-2,3,6-tri-
O-benzyl-4-deoxy-4-C-methyl-α-D-glucopyranosyl-(1→4)-2,3,6-tri-O-benzyl-4-deoxy-4-C-
methyl-β-D-glucopyranoside (5)
N-Iodosuccinimide (0.14 g, 0.629 mmol) was added to a mixture of 2 (0.32 g, 0.524 mmol) and 4 (
0.45 g, 0.437 mmol) and MS (4 Å) (1 g) in PhMe (4 mL) at 0 °C, stirred for 10 min. TfOH (5 µL,
0.052 mmol) was added and stirred for 1 h under N2 atmosphere. The reaction mixture was
neutralised with Et3N, filtered, extracted with EtOAc, washed with aq. Na2S2O3 (2 x 50 mL), satd.
aq. NaHCO3 (2 x 50 mL) and brine (50 mL), dried (Na2SO4) and concentrated in vacuo, purified
(SiO2) (pet. ether/EtOAc = 5.6:1) to afford acetyl protected trisaccharide derivative. NaOMe in
MeOH (1 M, 0.15 mL) was added to a solution of trisaccharide derivative in MeOH, stirred for 6 h
at room temperature, neutralised with amberlite resin (H+), filtered, concentrated in vacuo.
Purification (SiO2) (pet. ether/EtOAc = 4:1) afforded 5 (0.43 g, 68%), as a gum. [α]D +0.26 (c 0.2,
CHCl3); 1H NMR (CDCl3, 400 MHz): δ 7.28-7.10 (m, 47 H), 6.77 (d, J = 8.4 Hz, 2 H), 4.91 (d, J =
10.4 Hz, 3 H), 4.87 (d, J = 5.6 Hz, 1 H), 4.83 (d, J = 3.6 Hz, 1 H), 4.78 (d, J = 3.2 Hz, 1 H), 4.72 (d,
J = 10.8 Hz, 1 H), 4.69-4.52 (m, 12 H), 4.49-4.42 (m, 2 H), 4.38 (dd, J = 4.2 Hz, 12.2 Hz, 2 H),
4.00-3.94 (m, 2 H), 3.86-3.78 (m, 3 H), 3.76 (s, 3 H), 3.75-3.70 (m, 5 H), 3.64-3.53 (m, 6 H), 3.49-
3.38 (m, 4 H), 3.30 (d, J = 10 Hz, 1 H), 2.11-2.00 (m, 2 H), 1.82-1.77 (m, 1 H); 13C NMR (CDCl3,
100 MHz): 159.1, 138.9, 138.6, 138.5, 138.4, 138.3, 138.2, 137.9, 129.9, 129.3, 128.4, 128.3, 128.2,
128.1, 128.0, 127.9, 127.8, 127.7, 127.6, 127.5, 127.4, 127.3, 127.2, 113.6, 102.9, 98.5, 97.6, 83.6,
81.2, 81.1, 78.3, 75.4, 75.3, 75.2, 74.6, 73.6, 73.5, 73.4, 73.3, 72.8, 72.5, 70.8, 69.9, 69.6, 69.4, 68.8,
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68.3, 65.6, 64.6, 63.8, 55.2, 44.8, 43.8, 43.3; HRMS (ESI/TOF-Q) m/z: [M + Na]+ Calcd for
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C92H100O17Na, 1499.6858; Found 1499.6859.
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2,3,6-Tri-O-benzyl-4-deoxy-4-C-acetoxymethyl-α-D-glucopyranosyl-(1→4)-2,3,6-tri-O-benzyl-
4-deoxy-4-C-methyl-α-D-glucopyranosyl-(1→4)-2,3,6-tri-O-benzyl-4-deoxy-4-C-methyl-α/β-D-
glucopyranose (6)
Acetic anhydride (33 µL, 0.35 mmol) and dimethylamino pyridine (0.004 g, 0.029 mmol) was added
to a solution of 5 (0.43 g, 0.29 mmol) in pyridine (2 mL) at 0 °C, stirred for 3 h at room temperature.
The reaction mixture was diluted with CH2Cl2 (80 mL), washed with dil. aq. HCl (2 x 30 mL), satd.
aq. NaHCO3 (1 x 30 mL) and brine (30 mL), dried (Na2SO4), filtered and concentrated in vacuo.
The crude product (0.44 g) was dissolved in aq. CH2Cl2, stirred at 0 °C, trifluoroacetic acid (0.045
mL, 0.58 mmol) was added to it and stirred for 4 h at room temperature. The reaction mixture was
diluted with CH2Cl2 (80 mL), washed with H2O (2 x 30 mL), satd. aq. NaHCO3 (2 x 30 mL) and
brine (30 mL), dried (Na2SO4), filtered and concentrated in vacuo, purified (SiO2) (pet. ether/EtOAc
= 3:1) to afford 6 (0.30 g, 74%, α/β = 1:0.91); 1H NMR (CDCl3, 400 MHz): δ 7.31-7.17 (m, 86 H),
5.23 (d, J = 2.8 Hz, 1 H), 4.94-4.83 (m, 10 H), 4.78 (d, J = 3.2 Hz, 1 H), 4.70-4.35 (m, 33 H), 4.21-
4.08 (m, 6 H), 3.82-3.69 (m, 14 H), 3.62-3.55 (m, 12 H), 3.41-3.39 (m, 3 H), 2.20-2.01 (m, 6 H),
1.84 (s, 6 H); 13C NMR (CDCl3, 100 MHz): δ 170.8, 170.7, 138.9, 138.7, 138.6, 138.4, 138.3, 138.2,
138.1, 138.0, 137.9, 128.5, 128.4, 128.3, 128.2, 128.1, 128.0, 127.9, 127.8, 127.7, 127.6, 127.5,
127.4, 98.1, 98.0, 97.9, 97.7, 91.5, 84.6, 81.6, 81.4, 81.2, 81.0, 78.2, 75.6, 75.4, 75.2, 75.1, 75.0,
74.9, 74.6, 73.6, 73.4, 72.7, 72.6, 72.5, 70.3, 70.1, 70.0, 69.9, 69.8, 69.7, 69.5, 69.1, 69.0, 64.8, 64.7,
64.4, 64.2, 61.2, 60.8, 60.4, 43.5, 43.4, 43.3, 43.2, 42.1, 41.9, 20.7; HRMS (ESI/TOF-Q) m/z: [M +
Na]+ Calcd for C86H94O17Na, 1421.6389; Found 1421.6387.
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p-Tolyl 2,3,6-tri-O-benzyl-4-deoxy-4-C-methyl-α-D-glucopyranosyl-(1→4)-2,3,6-tri-O-benzyl-
4-deoxy-4-C-methyl-α-D-glucopyranosyl-(1→4)-2,3,6-tri-O-benzyl-4-deoxy-4-C-methyl-1-thio-
α/β-D-glucopyranoside (7)
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Acetic anhydride (24 µL, 0.258 mmol) and dimethylamino pyridine (0.003 g, 0.021 mmol) was
added to a solution of 6 (0.3 g, 0.214 mmol) in pyridine (2 mL) at 0 °C, stirred for 4 h at room
temperature. The reaction mixture was diluted with CH2Cl2 (80 mL), washed with dil. aq. HCl (2 x
30 mL), satd. aq. NaHCO3 (1 x 30 mL) and brine (30 mL), dried (Na2SO4), filtered and concentrated
in vacuo. The crude product was co-evaporated with PhMe (2 x 2 mL) to afford diacetate
intermediate (0.305 g), as a gum. p-Thiocresol (0.032 g, 0.254 mmol) was added to a solution of
diacetate intermediate (0.305 g, 0.212 mmol) and MS (4 Å) (0.4 g) in CH2Cl2 (5 mL) and BF3.OEt2
(26 µL, 0.212 mmol) was added dropwise at room temperature and stirred for 1 h under N2
atmosphere. The reaction mixture was quenched with Et3N (0.1 mL), filtered, extracted with
CH2Cl2 (80 mL), washed with satd. aq. NaHCO3 (1 x 30 mL) and brine (30 mL), dried (Na2SO4),
filtered and concentrated in vacuo. The crude product (0.31 g) in MeOH (2 mL) was subjected to
deacetylation using NaOMe in MeOH (1 M, 0.1 mL) for 6 h at room temperature, neutralised with
amberlite resin (H+), filtered, concentrated in vacuo and purified (SiO2) (pet. ether/EtOAc = 5.2:1)
to afford 7 (0.23 g, 75%, α/β = 1:1.4); 1H NMR (CDCl3, 400 MHz): δ 7.45 (d, J = 8 Hz, 5 H), 7.31-
7.18 (m, 108 H), 6.96 (d, J = 8.4 Hz, 2 H), 6.91 (d, J = 7.6 Hz, 3 H), 5.63 (d, J = 4.8 Hz, 1 H), 4.96-
4.80 (m, 14 H), 4.74-4.47 (m, 36 H), 3.95-3.69 (m, 26 H), 3.66-3.39 (m, 24 H), 2.26 (s, 3 H), 2.22
(s, 4.4 H), 2.08-2.03 (m, 7 H); 13C NMR (CDCl3, 100 MHz): δ 139.2, 138.8, 138.7, 138.5, 138.4,
138.3, 138.2, 138.1, 138.0, 137.7, 137.5, 136.9, 133.0, 132.6, 132.1, 131.7, 129.6, 129.5, 128.4,
128.3, 128.2, 128.1, 128.0, 127.8, 127.7, 127.6, 127.5, 127.4, 98.7, 98.3, 97.8, 97.3, 87.8, 87.3, 81.9,
81.5, 81.2, 81.1, 81.0, 80.9, 80.3, 77.6, 77.2, 75.9, 75.7, 75.6, 75.4, 75.3, 75.2, 75.1, 74.9, 73.5, 73.4,
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73.3, 73.2, 73.1, 73.0, 72.8, 72.6, 72.4, 71.8, 71.2, 70.4, 70.2, 70.1, 69.8, 69.7, 69.6, 68.4, 65.3, 64.7,
64.2, 58.4, 57.9, 44.8, 44.7, 43.8, 43.5, 43.4, 43.1, 21.1, 21.0; HRMS (ESI/TOF-Q) m/z: [M + Na]+
Calcd for C91H98O15SNa, 1485.6524; Found 1485.6525.
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Cyclo[(1→4)-4-deoxy-4-C-methyl-α-D-glucopyranosyl-(1→4)-4-deoxy-4-C-methyl-α-D-
glucopyranosyl-(1→4)-4-deoxy-4-C-methylenyl]-α-D-glucopyranoside (8)
Linear trisaccharide 7 (0.1 g, 0.068 mmol) was dissolved in PhMe (2 mL), freeze-dried and the
process repeated twice. N-Iodosuccinimide (NIS) (0.018 g, 0.0816 mmol) was added to a solution
of freeze-dried 7 (20 mM) and MS (4 Å) (0.1 g) in PhMe (3.4 mL) at 0 °C, stirred for 10 min.
Trimethylsilyltrifluoromethane sulfonate (TMSOTf) (1.2 µL, 0.0068 mmol) was added to it and
stirred for 12 h under N2 atmosphere. The reaction mixture was neutralised with Et3N, filtered and
concentrated in vacuo, purified (SiO2) (pet. ether/EtOAc = 7:1) to afford protected derivative of
cyclic trisaccharide. A solution of benzyl group protected cyclic trisaccharide (0.059 g, 0.022
mmol) in MeOH and EtOAc (1:1, 10 mL) was subjected to hydrogenolysis over H2/Pd (10%, 0.11
g) under positive pressure of H2 gas for 12 h, at room temperature. The reaction mixture was
filtered through celite, concentrated in vacuo, purified (SiO2) (CHCl3/MeOH = 4:1) to afford 8
(0.018 g, 80%); [α]D +3.78 (c 0.05, MeOH); 1H NMR (D2O, 400 MHz): δ 4.93 (d, J = 3.6 Hz, 3 H,
H-1), 4.10 (d, J = 10.4 Hz, 3 H, H-3), 4.07-4.05 (m, 3 H, H-7a), 3.93 (d, J = 11.2 Hz, 3 H, H-5),
3.84-3.76 (m, 6 H, H-6a, H-6b), 3.71 (d, J = 10 Hz, 3 H, H-7b), 3.58 (dd, J = 3.6 Hz, 10 Hz, 3 H, H-
13
2), 1.78 (app t, J = 10.6 Hz, 3 H, H-4); C NMR (D2O, 100 MHz): δ 98.6 (C-1), 72.4 (C-2), 70.1
(C-5), 66.1 (C-3), 64.3 (C-7), 61.0 (C-6), 43.1 (C-4); HRMS (ESI/TOF-Q) m/z: [M + Na]+ Calcd for
C21H36O15Na, 551.1962; Found 551.1967.
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Acknowledgement
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We thank Department of Science and Technology and Council of Scientific and Industrial Research
(CSIR), New Delhi, for a financial support of the work. CSIR is acknowledged for a research
fellowship to KM. We thank Mr. Prodip Howlader, Department of Inorganic and Physical
Chemistry, IISc., for his helps in single crystal X-ray structural analysis.
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Supporting Information Available
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1H and C NMR spectra of all new compounds. This material is available free of charge via the
Internet at http://pubs.acs.org. Details of host-guest binding studies and crystallographic analysis of
8 are given in the supporting information.
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