Room-temperature ionic liquids enhanced green synthesis of β-glycosyl 1-ester

Article abstract of DOI:10.1016/j.carres.2015.01.010

We herein report an efficient synthesis of β-glycosyl 1-ester in room-temperature ionic liquids (RTILs) promoted via silver salt and quaternary ammonium salt (PTC) with good or excellent yields. All products were isolated exclusively as the β-anomers. Four different RTILs, eight metal salts and four quaternary ammonium salts were screened in the glycosylation reaction. The synergistic effect of C₆mim·OTf, Ag₂O and tetrabutylammonium iodine gave the best results. Their promotion to the system was integral. Thorough study provided insight into the catalytic activity of ionic liquid structure, metal salts and quaternary ammonium salt to these reactions. It is worth mentioning that the yield of aliphatic compound 2,3,4,6-tetra-O-acetyl-β-d-galactopyranosyl butyrate (3l) was highly improved when using C₆mim·OTf as solvent compared with the normal volatile solvents under the same catalysts. This green approach has been proved to be practical and compatible with a wide range from aliphatic to aromatic substrates.

Full text of DOI:10.1016/j.carres.2015.01.010

Carbohydrate Research 407 (2015) 51e54
Contents lists available at ScienceDirect
Carbohydrate Research
journal homepage: www.elsevier.com/locate/carres
Note
Room-temperature ionic liquids enhanced green synthesis
of
b-glycosyl 1-ester
,
Yanli Cui a *, Minghan Xu a, Weirong Yao b, Jianwei Mao c
a Department of Chemistry, Zhejiang University, Hangzhou 310027, PR China
b Carbohydrate Chemistry and Biotechnology Jiangnan University Key Laboratory of Ministry of Education, Wuxi 214122, PR China
c Zhejiang Provincial Key Lab for Chem. & Bio. Processing Technology of Farm Produces, Hangzhou 310023, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
We herein report an efficient synthesis of b-glycosyl 1-ester in room-temperature ionic liquids (RTILs)
Received 29 April 2014
Received in revised form
17 January 2015
Accepted 21 January 2015
Available online 29 January 2015
promoted via silver salt and quaternary ammonium salt (PTC) with good or excellent yields. All products
were isolated exclusively as the -anomers. Four different RTILs, eight metal salts and four quaternary
ammonium salts were screened in the glycosylation reaction. The synergistic effect of C6mim$OTf, Ag2O
and tetrabutylammonium iodine gave the best results. Their promotion to the system was integral.
Thorough study provided insight into the catalytic activity of ionic liquid structure, metal salts and
quaternary ammonium salt to these reactions. It is worth mentioning that the yield of aliphatic com-
b
Keywords:
Glycosyl ester
Ionic liquid
Silver oxide
Green glocosylation
Glycosyl bromide
pound 2,3,4,6-tetra-O-acetyl-b-D-galactopyranosyl butyrate (3l) was highly improved when using
C6mim$OTf as solvent compared with the normal volatile solvents under the same catalysts. This green
approach has been proved to be practical and compatible with a wide range from aliphatic to aromatic
substrates.
© 2015 Elsevier Ltd. All rights reserved.
The exploration of stereocontrolled glocosylation was driven by
the biological application of carbohydrates. It promoted numerous
advances in donor, acceptor, promoter, and solvent technology for
stereocontrolled glycosylation.1 Eco-friendly ionic liquids as sol-
vents and promoters often demonstrate higher product yields,
control over reaction stereoselectivity, and recyclability of the IL
solvent.2 Recently, the utilization of highly polar room-temperature
ionic liquids (RTILs) in glycosylation reactions has been of great
interest as many of these reactions proceed through a cationic
oxocarbenium ion that may interact with the anionic counterpart of
the IL.2b,3
Due to their low toxicity, non-antigenicity and biodegradability,
glycosyl esters have been investigated as potential anti-cancer
agents and antibiotics.4 Other application fields include cos-
metics, detergents, oral-care products and medical supplies. Also
glycosyl esters can be good donors of glycosylation.5 Different
glycosyl donors,2b,3 like glycosyl fluorides, glycosyl tri-
chloroacetimidates, thioglycosides, glycosyl diethyl phosphate and
unprotected sugars, had been applied in the synthesis of glycosyl
esters. Some of the drawbacks to all these donors may include the
need for low or high reaction temperatures, use of inert conditions
and molecular sieves, lengthy preparation of the donor, the usage of
high boiling point solvents like DMF and DMSO,7,8 modest yields or
a low stereoselectivity of C1 conformation.
Despite the many synthetic efforts, there is still a demand for the
exploration of green methods that are applicable to both laboratory
and industrial scale preparation. This O-glycosylation is not as easy
as we imagined. For the reaction couldn't be processed very
smoothly for carboxy that shows weak nucleophilicity, assistant
measures for improving esterification were demanded. If in the
presence of metal ions as promoter glycosyl bromides may be
activated under traditional KoenigseKnorr conditions (Scheme 1).
In this paper, glycosylations were carried out with 2,3,4,5-tetra-O-
acetyl-a-D-galactopyranosyl bromide 1 as glycosyl donor. Although
considered less stable than their fluoride counterpart, glycosyl
bromides offer several advantages over other donors. For example,
they do not require lengthy preparations and are commercially
available.
Ionic liquids have been described as one of the most promising
environmentally benign reaction media, which are non-volatile,
nonexplosive, recyclable, have kinetic and thermodynamic
behavior different from classical solvents. Since many glycosidation
reactions go through an oxocarbenium ion, which could interact
* Corresponding author. Fax: þ86 571 88486676.
E-mail address: hnzzcyl@hotmail.com (Y. Cui).
http://dx.doi.org/10.1016/j.carres.2015.01.010
0008-6215/© 2015 Elsevier Ltd. All rights reserved.

52
Y. Cui et al. / Carbohydrate Research 407 (2015) 51e54
Ag2O performed better than Cs2CO3, Ag2CO3 and was decided as
a model promoter for further optimization. Quaternary ammonium
salts also displayed a special function in the system. The notable
observation was that the yield was poor even when supported by
Ag2O in RTIL (Table 1, entry 15) if there was no quaternary
ammonium salt in the reaction. It verifies that phase transfer
catalyst can decrease multiphase's interfacial tension and activate
reactants. Diverse halogen of quaternary ammonium salts led to
different effects. TBAF hindered the reaction to 0 yield (Table 1,
entry 12), which was worse than in no PTC system (Table 1, entry
15). Tetrabutylammonium iodine (TBAI, Table 1, entry14) achieved
better than its chloride and bromide analogues (Table 1, entry 4,13).
This trend is correlated with the order of the activity of halides,
which increases from chloride to iodine.
Scheme 1. The synthesis of glycosyl esters.
with an anion species contained in ionic liquid, we speculated that
the possibility of stereoselective glycosidation and the improved
yield of the reaction induced by ionic liquid would be achieved.6,9
There are many types of ionic liquids such as N-methyl imidaz-
oles, N-vinyl imidazoles, pyridines, pyrrolidines and quarternary
ammonium-based salts. Besides economic considerations and ease
in popularizing, imidazolium-based RTILs were focused. To the best
of our knowledge, the O-glycosidic bond formation of glycosyl 1-
ester supported by ionic liquid has not been reported.
All the reactions were carried out at room temperature without
sample pretreatment, inert conditions and molecular sieves. In our
initial study, we screened four imidazolium-based RTILs at 25 ꢀC
using silver oxide and TBABr as catalysis (Table 1). The reaction in
the Bmim$HSO4 (Table 1, entry 3) didn't take place. Obviously
The outcomes were all
b configuration, which was inferred from
the chemical shifts and coupling constants of the anomeric proton
signals. Noteworthy, in some IL-mediated glycosylations of the
same donor 1, the a-glycoside was obtained in addition to the b-
product.6b Poletti et al. showed that the stereoselectivity of a gly-
cosidation using a glycosyl trichloroacetimidate was changed by
the ionic liquid.6c Luckily
conditions.
b-anomers were exclusive in our mild IL
The most efficient system was found and a variety of acceptors
was tested for the scope and specificity of the methodology
(Table 2). With electron-donating groups in aromatic substrates
(Table 2, entry 5, 7, 9), the yields were better than ones bearing
electron-withdrawing groups (Table 2, entry 11, 8, 10). Comparing
the effect of nitro group's position on the benzene ring (Table 2,
entry 11, 8, 10), the sequence of the yields was p->m->o-position
substrates. Halide groups had different influences to carboxyl
groups through the benzene ring (Table 2, entry 3, 15, 2). The
bromide and iodine analog' yields were better than chloride ones.
We expanded the scope of the substrates to aliphatic acid (Table 2,
entry 13, 12, 4, 6, 14). To our great surprise butyric acid (Table 2,
entry 12) and cinnamic acids (Table 2, entry 4, 6, 14) all produced
excellent yields. Interestingly, we had published the X-ray crystal
€
Bmim$HSO4 belongs to Bronsted acid that might be adverse to this
reaction. Bmim$BF4 and C6mim$BF4 that are part of neutral ionic
liquid (Table 1, entry 1, 2) afforded the same yield (86%). C6mim$OTf
performed best to lead to the best yield (89%). Thus C6mim$OTf was
chosen as the model RTIL. To compare the catalytic action of the
metal salts, a series of catalysts for this reaction was evaluated. As
shown in Table 1, Cs2CO3, Ag2CO3 and Ag2O (Table 1, entry 4, 5, 8)
could run the reaction better than other salts. An intense study for
the preference of Cs2CO3, Ag2CO3 and Ag2O is underway.
Table 1
structures of aliphatic compound 3l (2,3,4,6-Tetra-O-acetyl-b-D-
galactopyranosyl butyrate). The acetoxymethyl and butyrate
groups are located on the same side of the pyran ring, showing the
Screening of reaction parameters for the synthesis of 3a
b
-configuration for the D-glycosyl ester; the butyl group adopts an
extended conformation, the CeCeCeC torsion angle being 179.1ꢀ.
In the crystal, the molecules are linked by weak CeH/O hydrogen
bonds.10
Comparison experiments were performed (Table 3). The yield of
glycosylation was highly improved when using C6mim$OTf as sol-
vent. RTIL had a striking contribution to the condensation of
glycosyl ester, the yield increased to 93%, relatively 39% in the
normal solvent even when promoted by Ag2O and Bu4NI (Table 3,
entry 1). It led to the implication that RTIL might be pivotal to the
synergistic effect of C6mim$OTf, Ag2O and TBAI.
Theoretically the RTILs would enhance the interaction of
multiphase involving glycosyl bromide, aliphatic or aromatic acids
and Ag2O. TBAI might assist this solubilization capacity. The correct
anionic counterpart of the IL could interact with cationic oxo-
carbenium ion. Finally the intermediate was attacked by carboxylic
ion in a like SN2 mechanism to generate the specific products. More
detailed mechanistic studies to understand the precise role of ionic
liquid, TBAI, catalyst and the synergistic effect in these reactions are
warranted.
Entry
Ionic liquida
Catalyst
PTC
Yield
1
2
3
4
5
6
7
8
Bmim$BF4
Ag2O
Ag2O
Ag2O
Ag2O
Cs2CO3
CsF
CsOAc
Ag2CO3
CdCO3
K3PO4$3H2O
Rb2CO3
Ag2O
Ag2O
Ag2O
Ag2O
TBABr
TBABr
TBABr
TBABr
TBABr
TBABr
TBABr
TBABr
TBABr
TBABr
TBABr
TBAF
86%
86%
0
C6mim$BF4
Bmim$HSO4
C6mim$OTf
C6mim$OTf
C6mim$OTf
C6mim$OTf
C6mim$OTf
C6mim$OTf
C6mim$OTf
C6mim$OTf
C6mim$OTf
C6mim$OTf
C6mim$OTf
C6mim$OTf
89%
89%
50%
69%
87%
26%
64%
24%
0
9
10
11
12
13
14
15
TBACl
TBAI
No PTC
72%
90%
58%
a
Structure of IL cations:
It's the highlight that the C6mim$OTf is non-volatile, nonex-
plosive, recyclable. The glycosylation didn't need lengthy prepara-
tion, inert conditions and molecular sieves. For recycling of
C6mim$OTf and two promoters the final mixture was loaded
directly on silica gel chromatography. The product, the mixture of
C6mim$OTf and promoters were separated due to their polarity. We

Y. Cui et al. / Carbohydrate Research 407 (2015) 51e54
Table 2 (continued )
53
Table 2
The products and yields of the condensation of 2,3,4,6-tetra-a-acetyl-D-gal-
actopyranosyl bromide 1 and carboxylic acids 2ae2o
Entry
14
Donor
Acc.
Product
Yield
94%
a
b
/b ratio
1
2n
only
Entry
1
Donor
Acc.
Product
Yield
a
/b ratio
1
2a
90%
92%
b
only
only
3n
15
1
2o
95%
b
only
I
3a
OAc
OAc
O
2
1
2b
b
AcO
O
OAc
3o
O
3b
3
1
1
1
1
1
1
1
1
2c
2d
2e
2f
87%
94%
94%
90%
96%
65%
95%
75%
b
b
b
b
b
b
b
b
only
only
only
only
only
only
only
only
Table 3
Comparison of the condensation of glycosyl estersa
Way
Solvent
Catalyst
PTC
Tem.
Yield%
3c
1
2
3
Pyridine
DCM/H2O
DMF
Ag2O
NaOH
DMAP
Ag2O
TBAI
No
No
rt
rt
0
39
10
33
93
4
ꢀC
Our method
C6mim$OTf
TBAI
rt
a
3d
Reactants: n-butyl acid and 2,3,4,6-tetra-
identical ratio of reactants.
a-acetyl-D-galacto-pyranosyl bromide;
5
didn't find any apparent loss in the yield using recycled ionic liquid
and promoters. With respect to application of -glycosyl 1-ester,
the Ac groups can be moved selectively by specific catalyst.11
In summary the glycosylation of glycosyl bromide and
3e
b
6
b
aliphatic or aromatic acids was achieved in this RTILs enhanced
system. The diverse influences to reaction and their synergistic
effect were observed. The novel approach is eco-friendly, economic
and without strict controls.
3f
7
2g
2h
2i
1. Experimental
3g
8
1.1. General procedure for the synthesis of glycosyl ester (3a)
All the reaction temperature was at room temperature. Ag2O
(163.8 mg, 0.70 mmol) and TBAI (261.1 mg, 0.70 mmol) were added
in the RTIL (1.0 g) and stirred for 1 h. Then benzoic acid (64.1 mg,
0.53 mmol) was added and stirred for 20 min followed by addition
3h
9
of 2,3,4,6-tetra-a-acetyl-D-galactopyranosyl bromide (146.8 mg,
0.35 mmol) to the reaction mixture. The reaction was stirred
overnight. After completion of the reaction, the mixture was
diluted with 1e2 ml of CH2Cl2 and loaded onto a silica gel column
for purification by silica gel chromatography using a gradient of
Petroleum ether-EtOAc (0e50% EtOAc). The desired product was
obtained as white foam.
3i
10
2j
3j
Corresponding data: 2,3,4,6-tetra-O-acetyl-
b
d
-
D
-galactopyr-
anosyl benzoate (3a): 1H NMR (400 Hz, CDCl3):
¼8.07 (d, 2H,
11
12
13
1
1
1
2k
2l
84%
93%
81%
b
b
b
only
only
only
J¼7.2 Hz), 7.61 (t, 1H, J¼7.6 Hz), 7.47 (t, 2H, J¼7.6 Hz), 5.94 (d, 1H,
J¼8.0 Hz), 5.55 (dd, 1H, J1¼8.4 Hz, J2¼10.4 Hz), 5.50 (d, 1H,
J¼3.2 Hz), 5.21 (dd, 1H, J1¼3.6 Hz, J2¼10.8 Hz), 4.24e4.14 (m, 3H),
2.20 (s, 3H), 2.05 (s, 3H), 2.03 (s, 3H), 2.00 (s, 3H) ppm. 13C NMR
3k
(125 Hz, CDCl3):
d
¼170.1, 170.0, 169.7, 169.3, 164.4, 133.8, 130.0,
128.6, 128.4, 92.6, 71.6, 70.5, 67.7, 66.8, 60.9, 20.42, 20.35 ppm.
HSMS: (ESI) m/z [MþNa]þ calcd for C21H24NaO11: 475.1216, found:
475.1197.
3l
2m
Acknowledgement
3m
The financial support from the National Natural Science Foun-
dation of China under Grant No. 30870553, the International Sci-
ence & Technology Cooperation Program of China under Grant No.

54
Y. Cui et al. / Carbohydrate Research 407 (2015) 51e54
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