A novel and efficient ionic liquid supported synthesis of oligosaccharides

Article abstract of DOI:10.1016/j.tetlet.2006.03.002

A novel and efficient ionic liquid supported synthesis of oligosaccharides with a general protocol of coupling and purification is described. The method represents an attractive alternative to the classical solid- and fluorous-phase synthesis strategies a

Full text of DOI:10.1016/j.tetlet.2006.03.002

Tetrahedron Letters 47 (2006) 3047–3050
A novel and efficient ionic liquid supported synthesis
of oligosaccharides
Jian-Ying Huang,a,b Ming Leia and Yan-Guang Wanga,*
aDepartment of Chemistry, Zhejiang University, Hangzhou 310027, China
bDepartment of Chemistry, Ningbo University, Ningbo 315211, China
Received 26 January 2006; revised 28 February 2006; accepted 1 March 2006
Abstract—A novel and efficient ionic liquid supported synthesis of oligosaccharides with a general protocol of coupling and puri-
fication is described. The method represents an attractive alternative to the classical solid- and fluorous-phase synthesis strategies
and combines the advantage of performing homogeneous chemistry on a relatively large scale while avoiding large excesses of
reagents.
ꢀ 2006 Elsevier Ltd. All rights reserved.
Increased awareness of the biological and therapeutic
importance of oligosaccharides has stimulated the devel-
opment of efficient methods for synthesis of these
compounds. Different strategies for the assembly of oli-
gosaccharides on polymeric supports have proven to be
the most challenging task and have recently received
much attention.1 The solid-phase approach is attractive
due to the facile purification process of removing the ex-
cess reagents and side products, which allows for the
ease of product isolation and makes automation possi-
ble.2 On the other hand, the soluble polymers such as
polyethylene glycol (PEG), polyvinyl alcohol and other
ingenious variants of these polymers have received con-
siderable attention because of their homogeneous phase
chemistry strategies, which have been employed success-
fully in the synthesis of oligopeptides2 and oligosaccha-
rides.3 However, there were some limitations such as low
loading capacity, limited solubility during the reaction
processes, aqueous solubility, and insolubility in ether
solvents.4 Recently, ionic liquids (ILs) have attracted
considerable interest as environmentally benign reaction
media because of their many fascinating and intriguing
properties.5 Numerous chemical reactions, including
some enzymatic reactions, can be carried out in ionic liq-
uids.6 An attractive feature of ionic liquids is that their
solubility can be tuned readily. Therefore, phase separa-
tion from organic solvent or aqueous phase is allowed
depending on the choice of cations and anions. This sug-
gests the possibility of using these small molecular ionic
liquids as soluble supports for organic synthesis. Sub-
strates anchored on ionic liquids are expected to retain
their reactivity, as in solution reactions, and allowed
the use of conventional spectroscopic analysis during the
synthetic process. Several groups have demonstrated
the feasibility of ionic liquid supported organic synthesis
of small molecules7 and peptides,8 in which the excess
reagents and by-products in the multistep reactions
can be removed easily by simple washing with a solvent.
Herein, we describe an ionic liquid supported synthesis
of oligosaccharides. To the best of our knowledge, this
is the first report on the synthesis of oligosaccharides
utilizing IL support strategy.
As shown in Scheme 1, the 4-OH of phenyl 2,3-di-O-acet-
yl-6-O-tert-butyldimethylsilyl-1-thio-b-D-glucopyrano
side (1), which was prepared from D-glucose in six steps
according to the published methods,9,10 was esterified
with chloroacetyl chloride in the presence of pyridine.
The resulting ester 2 was immobilized to N-methylimi-
dazole via a nucleophilic substitution reaction to give
the ionic liquid bounded glucoside 3. Then the anion
Clꢀ of 3 was exchanged to anion PF6 to afford the
ꢀ
ionic liquid bounded glucoside 4. The subsequent depro-
tection of TBDMS group was readily performed using
concentrated HCl at room temperature to give the cor-
responding glucoside 5. With ionic liquid supported 5
in hand, we coupled it with different glycosyl donors
6a–f, that had been activated with trichloroacetimidates,
*
Corresponding author. Tel./fax: +86 571 87951512; e-mail: orgwyg@
zju.edu.cn
0040-4039/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.03.002

3048
J.-Y. Huang et al. / Tetrahedron Letters 47 (2006) 3047–3050
O
OTBDMS
OTBDMS
Cl
i
O
O
O
HO
AcO
SPh
SPh
AcO
99%
OAc
OAc
O
OTBDMS
ii
IL
Cl
2
O
O
1
SPh
92%
AcO
OAc
N
N
3
Me
iii
O
O
OTBDMS
OH
O
iv
96%
IL
PF6
IL
O
O
O
SPh
SPh
AcO
AcO
OAc
PF6
OAc
5
4
v
7a: R = Glu, 92%
7b: R = Rha, 94%
7c: R = Xyl, 90%
7d: R = Man, 91%
7e: R = Fuc, 89%
7f: R = Mal, 85%
O
OR
O
IL
O
AcO
SPh
PF6
OAc
7
vi
8a: R = Glu, 93%
8b: R = Rha, 92%
8c: R = Xyl, 95%
8d: R = Man, 91%
8e: R = Fuc, 90%
8f: R = Mal, 95%
OR
O
=
IL
+
N
N
HO
AcO
Me
SPh
OAc
8
Scheme 1. Reagents and conditions: (i) ClCH2COCl (1.2 equiv), Py (1.5 equiv), CH2Cl2, 0 ꢁC, 30 min; (ii) N-methylimidazole (1.0 equiv), CH3CN,
˚
N2, 80 ꢁC, 12 h; (iii) KPF6 (1.0 equiv), CH3CN, rt, 24 h; (iv) concd HCl, THF, 15–30 min; (v) 6 (3.0 equiv), TMSOTf (cat.), 4 A MS, CH2Cl2, N2,
ꢀ40 to 0 ꢁC, 2 h; (vi) saturated aq NaHCO3 (2 mL), TBAB (0.1 g), Et2O, 15 min.
Table 1. Ionic-liquid-supported synthesis of oligosaccharides
Entry
1
R
Product
Yielda (%)
Purityb (%)
OAc
O
OAc
O
AcO
AcO
AcO
O
85
95
AcO
O
HO
SPh
Ac
O
OAc AcO
OAc
OTCA 6a
8a
OAc
OAc
OAc
CH3
OTCA
O
H3C
AcO
O
2
3
4
86
86
83
93
92
92
O
O
AcO
HO
OAc
6b
SPh
AcO
OAc
8b
O
O
O
AcO
AcO
AcO
AcO
O
O
HO
Ac
SPh
OAc AcO
OAc
8c
OTCA 6c
AcO
OAc
O
AcO
AcO
AcO
AcO
AcO
OAc
O
O
O
HO
OTCA
SPh
6d
AcO
OAc
8d

J.-Y. Huang et al. / Tetrahedron Letters 47 (2006) 3047–3050
3049
Table 1 (continued)
Entry
R
Product
Yielda (%)
Purityb (%)
OAc
CH3
AcO
O
OTCA
OAc
AcO
O
5
80
90
H3C
O
O
HO
AcO
SPh
OAc
OAc
6e
OAc
8e
OAc
OAc
O
O
AcO
AcO
AcO
AcO
OAc
O
OAc
O
Ac
O
Ac
O
6
81
94
AcO
O
AcO
O
O
O
HO
SPh
O
Ac
OAc
AcO
OAc
6f
OTCA
8f
a Isolated yields are based on the conversion of 5.
b Purity are detected by HPLC.
to provide five disaccharides 7a–e and one trisaccharide
7f. Finally, cleavage of the ester linkage with saturated
aqueous sodium bicarbonate solution in the presence
of TBAB and solvent extraction gave the corresponding
free disaccharides 8a–e and trisaccharide 8f in high
yields with excellent purities.11 The results are summa-
rized in Table 1.
to the classical solid- and fluorous-phase synthesis strat-
egies and combines the advantage of performing homo-
geneous chemistry on a relatively large scale while
avoiding large excesses of reagents. Expansion of the
method presented here towards differently functional-
ized ionic supports and the synthesis of more complex
target molecules are currently being pursued.
As a suitable model reaction for ionic liquid-phase-sup-
ported organic synthesis, we have chosen to use chloro-
acetyl chloride bound to the ionic liquid moiety. It was
stable in a series of reactions and it could be cleaved in a
short time (15 min) under mild conditions (e.g., TBAB/
aq NaHCO3/Et2O). After being unbound, the oligosac-
charide products were transferred into organic phase
giving high purity as shown in HPLC analysis, so fur-
ther chromatography is not necessary.
Acknowledgments
Authors thank the National Natural Science Founda-
tion of China (No. 20272051) as well as the Teaching
and Research Award Program for Outstanding Young
Teachers in Higher Education Institutions of MOE,
PRC.
All of the ionic liquid supported oligosaccharides pre-
pared thus far are soluble in polar organic solvents
such as acetone, acetonitrile, methanol, chloroform,
and dichloromethane, but are essentially not soluble in
diethyl ether or hexane. During the whole synthetic
sequence, every IL-bounded intermediate could be puri-
fied by consecutively washing with diethyl ether and
EtOAc, in which the excess reagents and by-products
were removed. It is noteworthy that all of the intermedi-
ates, including the IL-bounded saccharides, and final
products could be confirmed with 1H NMR, 13C
NMR and MS in our procedure.12 The mass spectra
of the ionic liquid supported saccharides 3–7 were help-
ful for the structural characterization because the peak
corresponding to the cation bearing the saccharides was
detected easily as the most intense peak in the spectrum.
References and notes
1. (a) Seeberger, P. H.; Haase, W. C. Chem. Rev. 2000, 100,
4349–4393; (b) Ito, Y.; Manabe, S. Curr. Opin. Chem. Biol.
1998, 2, 701–708.
2. For the cross-linked polymer supported synthesis of oligo-
saccharides and oligopeptides, see: (a) Tolborg, J. F.;
Petersen, L.; Jensen, K. J.; Mayer, C.; Jakeman, D. L.;
Warren, R. A. J.; Withers, S. G. J. Org. Chem. 2002, 67,
4143; (b) Wu, X. Y.; Schmidt, R. R. J. Org. Chem. 2004,
69, 1853; (c) Palmacci, E. R.; Hewitt, M. C.; Seeberger, P.
H. Angew. Chem., Int. Ed. 2001, 40, 4433; (d) Ando, H.;
Manabe, S.; Nakahara, Y.; Ito, Y. Angew. Chem., Int. Ed.
2001, 40, 4725; (e) Zhu, T.; Boons, G.-J. Chem. Eur. J. 2001,
7, 2382; (f) Nicolaou, K. C.; Wassinger, N.; Pastor, J.;
DeRoose, F. J. Am. Chem. Soc. 1997, 119, 449; (g) Yan, L.;
Taylor, C. M.; Goodnow, R., Jr.; Kahne, D. J. Am. Chem.
Soc. 1994, 116, 6953; (h) Schuster, M.; Wang, P.; Paulson,
J. C.; Wong, C. H. J. Am. Chem. Soc. 1994, 116, 1135.
3. For the soluble polymers (PEG) supported synthesis of
oligosaccharides and oligopeptides, see: (a) Mutter, M.;
Hagenmaier, H.; Bayer, E. Angew. Chem., Int. Ed. Engl.
1971, 10, 811; (b) Bayer, E.; Mutter, M. Nature 1972, 237,
512; (c) Douglas, S. P.; Whitfield, D. M.; Krepinsky, J. J.
J. Am. Chem. Soc. 1995, 117, 2116; (d) Zhu, T.; Boons, G.
In summary, we have developed a novel ionic liquid sup-
ported synthesis of oligosaccharides. Using this proce-
dure, the intermediates could be purified by simple
washing. This strategy provides a fast and efficient ap-
proach to diversify the oligosaccharides for biological
testing. Our method represents an attractive alternative

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J.-Y. Huang et al. / Tetrahedron Letters 47 (2006) 3047–3050
J. J. Am. Chem. Soc. 2000, 122, 10222; (e) Jiang, L.;
addition of two drops of concd HCl, and stirred for
15 min. After evaporated in vacuo, the residue was washed
twice with Et2O (3 · 5 mL) and dried in vacuo to yield the
ionic liquid 5. To a mixture of 5 (0.25 mmol), O-acetylated
monosaccharide trichloroacetimidate donor (0.75 mmol)
Hartley, R. C.; Chan, T.-H. Chem. Commun. 1996, 2193;
(f) Ando, H.; Manabe, S.; Nakahaa, Y.; Ito, Y. J. Am.
Chem. Soc. 2001, 123, 3848.
4. For reviews, see: (a) Gravert, D. J.; Janda, K. D. Chem.
Rev. 1997, 97, 489; (b) Toy, P. H.; Janda, K. D. Acc.
Chem. Res. 2000, 33, 546.
˚
and 4 A MS (1 g) in dry CH2Cl2 (20 mL) was added
dropwise trimethylsilyl triflate (0.06 mmol) in dry CH2Cl2
(2 mL) under nitrogen at ꢀ40 ꢁC, and then the reaction
temperature was allowed to increase to 0 ꢁC. The mixture
was filtered and the solvent was removed under vacuum.
The residue was washed with Et2O (5 mL), and then
dissolved in CH2Cl2 (1 mL) and washed with Et2O
(3 · 5 mL) to afford the ionic liquid supported disaccha-
ride 7a. To a solution of 7a (0.2 mmol) in Et2O/H2O (1:1,
3.0 mL) was added saturated aqueous NaHCO3 solution
(2 mL) and TBAB (0.1 g). The mixture was stirred at room
temperature for 30 min. The Et2O phase was filtered
through a short pad of silica gel. Removal of the solvent
gave free disaccharide 8a as a white solid. All products
5. For recent reviews, see: (a) Welton, T. Chem. Rev. 1999,
99, 2071; (b) Wasserscheid, P.; Keim, W. Angew. Chem.,
Int. Ed. 2000, 39, 3772; (c) Wilkes, J. S. Green Chem. 2002,
4, 73; (d) Wasserscheid, P.; Welton, T. Ionic Liquids in
Synthesis; Wiley-VCH: Weinheim, Germany, 2003.
6. (a) Sheldon, R. Chem. Commun. 2001, 2399; (b) Sheldon,
R. A.; Lau, R. M.; Sorgedrager, M. J.; Rantwijk, F. v.;
Seddon, K. R. Green Chem. 2002, 4, 147; (c) Earle, M. J.;
Seddon, K. R. Pure Appl. Chem. 2000, 72, 1391.
7. (a) Fraga-Dubreuil, J.; Bazureau, J. P. Tetrahedron Lett.
2001, 42, 6097; (b) Fraga-Dubreuil, J.; Bazureau, J. P.
Tetrahedron 2003, 59, 6121; (c) Handy, S. T.; Okello, M.
Tetrahedron Lett. 2003, 44, 8399; (d) Hakkou, H.; Vanden
Eynde, J. J.; Bazureau, J. P.; Hamelin, J. Tetrahedron
2004, 60, 3745; (e) Miao, W.; Chan, T. H. Org. Lett. 2003,
5, 5003; (f) Anjaiah, S.; Chandrasekhar, S.; Gree, R.
Tetrahedron Lett. 2004, 45, 569; (g) de Kort, M.; Tuin, A.
W.; Kuiper, S.; Overkleeft, H. S.; van der Marel, G. A.;
Buijsman, R. C. Tetrahedron Lett. 2004, 45, 2171; (h)
Legeay, J.-C.; Vanden Eynde, J. J.; Bazureau, J. P.
Tetrahedron 2005, 61, 12386.
1
gave satisfactory H NMR, 13C NMR, H–H COSY and
HMQC.
12. All compounds reported here were duly characterized.
1
Selected data: 7b: H NMR (500 MHz, CDCl3): d = 1.19
(d, J = 6.2 Hz, 3H), 1.95 (s, 3H), 2.03 (s, 3H), 2.05 (s, 6H),
2.11 (s, 3H), 3.80 (d, J = 10.0 Hz, 1H), 4.00–3.94 (m, 5H),
4.70 (d, J = 10.0 Hz, 1H), 4.90 (t, J = 9.6 Hz, 1H), 4.96 (s,
1H), 5.03 (t, J = 10.0 Hz, 1H), 5.22–5.14 (m, 4H), 5.30–
5.26 (m, 2H), 6.04 (d, J = 17.6 Hz, 1H), 7.32–7.30 (m,
4H). 7.45–7.44 (m, 2H), 7.67 (s, 1H), 10.12 (s, 1H); 13C
NMR (125 MHz, CDCl3): d = 17.8, 20.96, 20.97, 21.02,
21.05, 21.2, 36.6, 66.3, 66.7, 69.2, 69.4, 70.1, 70.2, 70.7,
73.4, 75.9, 83.8, 97.8, 118.7, 124.1, 128.5, 129.8, 131.9,
132.3, 138.3, 138.4, 166.5, 169.7, 170.34, 170.36, 170.42,
170.43; ESI (MS): m/z = 751 [MꢀPF6]+.
8. Miao, W. S.; Chan, T. H. J. Org. Chem. 2005, 70, 3251.
9. Ritter, T. K.; Mong, K. T.; Liu, H. T.; Nakatani, T.;
Wong, C.-H. Angew. Chem., Int. Ed. 2003, 42, 4657.
10. Stick, R. V.; Stubbs, K. A. Tetrahedron: Asymmetry 2005,
16, 321.
11. Typical procedure for the synthesis of 8a: To a stirred
solution of phenyl 2,3-di-O-acetyl-6-O-tert-butyldimethyl-
20
Compound 8b: mp: 70–72 ꢁC; ½aꢁD ꢀ50.4 (c 1.05, CHCl3).
silyl-1-thio-b-D-glucopyranoside
1
(1.0 mmol) and Py
1H NMR (500 MHz, CDCl3): d = 1.21 (d, J5,6 = 9.6 Hz,
3H, H-6, Rha), 2.01 (s, 3H, COCH3), 2.04 (s, 3H,
COCH3), 2.06 (s, 3H, COCH3), 2.08 (s, 3H, COCH3),
2.14 (s, 3H, COCH3), 3.02 (d, J = 2.6 Hz, 1H, 4-OH, Glu),
3.57–3.54 (m, 1H, H-5, Glu), 3.76–3.70 (m, 2H, H-4, H-6a,
Glu), 4.04–3.97 (m, 2H, H-6b, Glu, H-5, Rha), 4.71 (d,
J = 10.0 Hz, 1H, H-1, Glu), 4.79 (d, J = 0.5 Hz, 1H, H-1,
Rha), 4.92 (d, J = 9.5 Hz, 1H, H-2, Glu), 5.10–5.02 (m,
2H, H-3, Glu, H-4, Rha), 5.26 (d, J = 3.5 Hz, 1H, H-3,
Rha), 5.28 (t, J = 1.4 Hz, 1H, H-2, Rha), 7.35–7.29 (m,
3H), 7.47–7.35 (m, 2H); 13C NMR (125 MHz, CDCl3):
d = 17.6 (C-6, Rha), 21.00 (COCH3), 21.03 (COCH3),
21.09 (COCH3), 21.15 (COCH3), 66.7 (C-6, Glu), 66.8,
68.8, 68.9, 69.4, 69.6, 70.0, 71.0, 77.5, 79.0, 86.0 (C-1, Glu),
98.0 (C-1, Rha), 128.4, 129.2, 132.4, 132.6, 169.7, 170.3,
170.4, 171.9; ESI (MS): m/z = 650.9 [M+Na]+.
(1.5 mmol) in CH2Cl2 (15 mL) was added dropwise chloro-
acetyl chloride (1.2 mmol) in CH2Cl2 (5 mL) at 0 ꢁC over
30 min. The mixture was poured into water (5 mL),
quickly washed with dilute HCl, saturated aqueous
NaHCO3 solution and water, and dried over anhydrous
Na2SO4. After evaporation in vacuo, the residue was
chromatographed on silica gel with hexane–EtOAc
(2:1) to give pure 2. A solution of 2 (1.0 mmol) and
N-methylimidazole (1.0 mmol) in CH3CN (15 mL) was
stirred at 80 ꢁC for 24 h. KPF6 (1.0 mmol) was added and
the mixture was stirred for another 24 h. After it was
filtered and evaporated in vacuo, the residue was washed
with Et2O (3 · 5 mL) and then EtOAc (3 · 5 mL) to give
4, which was used directly for the next reaction. The ionic
liquid 4 was dissolved in THF (10 mL), followed by the