Ionic liquid-assisted catalysis for glycosidation of two triterpenoid sapogenins

Article abstract of DOI:10.1039/c9nj04271g

In order to both investigate the universality of ionic liquid-based catalytic systems for synthesis of triterpene saponins and explore their effective application methods together with the catalytic behaviors of ionic liquids in related reactions by comparison between different initiators, oleanolic acid and ursolic acid were selected to establish a catalytic system for glycosylation in this study as typical representatives of pentacyclic triterpene sapogenins. As a result, it was found that the system of [C₄mim][OTf] + TMSOTf in the reactions between the glycosyl receptors and donors showed obvious catalytic effects; also, the system was stable and could be recycled. The functions of IL include solvent, cocatalyst and stabilizer, simultaneously; thus, the current catalytic system is greener, simpler and more efficient. The reaction time was short, and only β-type products were obtained. This study offers a reference for developing a new glucoside synthesis technology and provides sufficient preliminary exploration and basic data for further large-scale applications.

Full text of DOI:10.1039/c9nj04271g

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Ionic liquid-assisted catalysis for glycosidation
of two triterpenoid sapogenins†
Cite this: New J. Chem., 2019,
43, 16881
Tenghe Zhang, Xinlu Li, Hang Song and Shun Yao
*
In order to both investigate the universality of ionic liquid-based catalytic systems for synthesis of
triterpene saponins and explore their effective application methods together with the catalytic behaviors
of ionic liquids in related reactions by comparison between different initiators, oleanolic acid and ursolic
acid were selected to establish a catalytic system for glycosylation in this study as typical representatives
of pentacyclic triterpene sapogenins. As a result, it was found that the system of [C4mim][OTf] +
TMSOTf in the reactions between the glycosyl receptors and donors showed obvious catalytic effects;
also, the system was stable and could be recycled. The functions of IL include solvent, cocatalyst and
stabilizer, simultaneously; thus, the current catalytic system is greener, simpler and more efficient. The
reaction time was short, and only b-type products were obtained. This study offers a reference for
developing a new glucoside synthesis technology and provides sufficient preliminary exploration and
basic data for further large-scale applications.
Received 17th August 2019,
Accepted 2nd October 2019
DOI: 10.1039/c9nj04271g
rsc.li/njc
Currently, continuous progress is being achieved in reactions
involving ILs to form glycoside bonds because of the high efficiency
Introduction
In recent years, as a new green medium, the excellent solubility and recyclability of these ‘‘designer’’ solvents. Researchers have
and catalytic functions of ionic liquids (ILs) have promoted the made numerous explorations of the effects of ILs as solvents
occurrence of various chemical transformations, including and catalyst carriers on the yield, by-product formation and
acetylation of sugars, ortho-esterification, carbonylation,1–3 and stereoselectivity of glycosidation in polysaccharide synthesis.
glycosylation reactions.4–7 Galan et al.1 reviewed the present Since Fisher’s glycosylation reaction was reported,11 many
situation and application of new ILs as solvents and catalytically innovative strategies have continuously emerged. For example,
active carriers in oligosaccharide synthesis. Initially, ionic liquids Park et al.12 reported the glycosidation of unprotected and
were used in related reactions as solvents due to their unique inactivated donors in [Emim][ba] at room temperature. Oligo-
physical and chemical properties, and many ILs exhibit solubi- saccharides with simple structures were obtained in good yield.
lities similar to those of organic solvents with medium polarity. Kuroiwa et al.13 added a small amount of the protonic acid
Many manuscripts have reported that ionic liquids as reaction HNTf2, corresponding to the anion of the IL ([C6mim][NTf2]), to
solvents can not only accelerate reaction rates and increase the improve the glycosylation yield of inactive glycosyl donors,
yields of products, but also improve the selectivity of reactions. which could be reused several times under decreased pressure
The mechanism can be summarized as follows: (1) the reaction conditions without any loss in efficiency. Sau et al.14 reported a
products are insoluble in ILs, which will be precipitated or new method for the preparation of 1,2-trans-thio and selenogly-
transferred to another phase, so the reaction process is promoted;8 cosides, which is environmentally friendly and odourless. Under
(2) ILs with specific spatial structures can interact and change the one-pot conditions, triethylsilane and BF3ꢀOEt2 in combination with
catalysts and/or ligands, thus improving the catalytic activity and various imidazolium ILs were successfully applied for the reductive
selectivity;9 (3) the presence of ILs provides milder reaction cleavage of disulfides and diselenides, and the glycosylation of
conditions, which is conducive to process activation and the sulfides and selenides with acetyl glycosyl derivatives took place
formation of unstable intermediates or products;10 (4) the in situ. It was found that the best solvent was [Bmim][BF4].
acidity of some Lewis acids dissolved in ILs will be improved
so that their catalytic activity increases.9
The biological activities and related applications of carbo-
hydrates have driven researchers to focus on the stereoselectivity of
glycosylation15 and also promote the improvement of donor,
acceptor, catalyst and solvent technology for stereoglyco-
sylation.16–18 As solvents and catalysts, environmentally friendly
ILs have been proved to have advantages of high yields, stereo-
School of Chemical Engineering, Sichuan University, Chengdu 610065,
People’s Republic of China. E-mail: cusack@scu.edu.cn; Fax: +86-28-8540-5221;
Tel: +86-28-8540-5221
† Electronic supplementary information (ESI) available. See DOI: 10.1039/c9nj04271g selectivity and recyclability.19 Although there have been many efforts,
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it is still necessary to explore more green synthetic methods suitable (Chengdu, China). 1,8-Diazabicyclo[5.4.0]undec-7-ene (DBU),
for both laboratory and industrial preparation. Recently, Cui et al.10 potassium trifluoromethanesulfonate, benzoyl chloride, hydrazine
reported that b-glycosyl-1-ester was synthesized in [C6mim][OTf] in a acetate, D-glucose, oleanolic acid and ursolic acid were obtained
high yield of 93% by adding Ag2O and tetrabutylammonium iodine from Aladdin Chemical Co., Ltd (each of purity 498.5%,
(TBAI), while the yield in ordinary solvents was only 39%; also, the Shanghai, China). Macroporous resin, CH3ONa, PdCl2, NaHCO3,
products were all in b-configuration. Moreover, the IL used after Ag2O and anhydrous Na2SO4 were purchased from Saibole
recycling showed no obvious detrimental effects on the yield of Technology Co., Ltd (Chengdu, China). Silica gel was produced
the reaction. In theory, room temperature ionic liquids will by Ocean Chemical Plant Branch (Qingdao, China). All the
increase the interaction between bromoglycosyl, fatty acids or solvents were of analytical grade or higher. Ultrapure (UP) water
aromatic acids and Ag2O, and TBAI can also help increase the was used in the experimental processes and was prepared with
mutual solubility of the reactive system.
an ultra-pure water system (0.4 mm filter) from Ultrapure
Saponins are important bioactive natural compounds, and Technology Co. Ltd (Chengdu, China).
their synthesis is focused on by researchers20 because their
Apparatus
content in various natural materials is very low. To date, no
research on the use of ionic liquids in saponin synthesis has Fourier transform infrared (FT-IR) spectra were recorded on a
been reported. The key to saponin synthesis is glycosylation of Spectrum Two L1600300 spectrometer (PerkinElmer, USA) in
glycosides and aglycones. The selection of glycosyl donors, the range of 500–4000 cmꢁ1 with KBr pellets. 1H NMR and
preparation of glycosyl receptors and efficiency of the catalytic 13C NMR spectra of the intermediates were acquired on an AV
system are the three main factors affecting the reaction results. II-600 MHz spectrometer (Bruker, Switzerland), and the samples
Structurally, saponin contains two quite distinct parts, including were dissolved in deuterated solvents. ESI-MS was conducted on
a sugar part and a sapogenin part that is a triterpene or steroid; a TSQ quantum ultra mass spectrometer (ThermoFisher, USA),
meanwhile, saccharide synthesis is a glycosylation reaction and the mass range is m/z 50–1000 in positive or negative
between sugars. It is worth noting that all these are within the ionization mode. N2 was used as a drying gas with a flow rate
scope of Schmidt glycosylation.8 However, the molecular volumes of 700 L hꢁ1 at 400 1C; the capillary voltage was 3.0 kV, and the
of aglycones are often much larger than those of sugars; thus, capillary temperature was set at 150 1C. The PHS-25C digital pH
aglycones are more difficult to glycosylate. Especially, the steric meter was provided by Kangyi Instrument Co., Ltd (Shanghai,
hindrance resulting from the two methyl groups at C-4 of China). All material masses were weighed with an ESJ200-4A
oleanolic acid-type aglycones is greater; thus, the connection electronic analytical balance with an uncertainty of ꢂ0.0001 g
between C-3-O and sugars is more difficult, and high stereo- (Longteng Electronic Co., Ltd, Shenyang, China). An Autopol IV
selectivity is also not easily achieved. At the same time, there may polarimeter (Rudolph Research Analytical, Hackettstown, NJ,
be other reactive sites on aglycones that can participate in USA) was used to measure the optical rotation data. Specific
glycosidation, such as the carboxyl group at C-28, which must rotation [a] = (10a)/(l ꢃ c), where a is the value of the measured
be protected in advance. In addition, some stronger reaction rotation, l is the tube length (cm), and c is the concentration of
conditions can also lead to changes in the structure of aglycones. the optically active substance (g mLꢁ1).
These are the reasons why the synthesis of saponins is more
complex than that of polysaccharides. In order to establish a new
Synthetic strategy
catalytic system for glycosylation of sapogenins, the universality, The overall process in this study included three steps: (1) preparation
application modes and roles of ionic liquids were explored in the of glycosyl receptors; (2) preparation of a glycosyl donor; (3) reactions
reaction between glycosyl receptors and donors. The related between the glycosyl receptors and donor, which is the most
reaction conditions were investigated by comparison with those important step during saponin synthesis. Firstly, allyl groups were
reported in the current literature. Moreover, the commonalities used to protect the carboxyl group at the C-28 position in the
of the synthetic conditions together with the reactive rules for structures of ursolic acid and oleanolic acid in order to avoid its
oleanolic acid and ursolic acid were analyzed and summarized to involvement in subsequent glycosidation with 3-OH; consequently,
develop a new integrated method which is expected to provide their allyl esters could be obtained. Because oleanolic acid and
useful references for the synthesis of triterpenoid glucosides.
ursolic acid have similar molecular structures of pentacyclic triter-
penoids, both compounds have rigid molecular skeletons and two
methyl groups at the C-4 position that cause steric hindrance; thus, it
is difficult to glycosylate the adjacent C-3 hydroxyl group. Therefore,
the glycosyltrichloroacetimide ester with very high reactivity was
chosen as the glycosyl donor, and the benzoyl group with larger
Experimental
Materials and reagents
Methyl imidazole and bromoalkanes were purchased from volume was chosen as the protective group of the hydroxyl groups on
Best Reagent Inc. (AR, each of purity 498%, Chengdu, China). glucose in order to obtain glycosides with b-configuration and avoid
Pyridine, allyl bromide, methanol, N,N-dimethylformamide, the formation of by-products such as orthoesters. In the last step of
trimethylsilyltrifluoromethanesulfonate (TMSOTf), trichloro- forming the C-3 glycoside bond by the reaction between the glycosyl
acetonitrile, triethylamine, and petroleum ether (boiling range: receptors and donors, some ionic liquids were introduced to explore
60–90 1C) were provided by Kelong Chemical Reagent Company a greener catalytic system with higher efficiency and selectivity.
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Preparation of glycosyl receptors and donor
Similar to previous research,20 the specific operation of allyl
protection for –COOH at C-28 is as follows: 2 g (4.38 mmol) of
oleanolic acid was weighed and dissolved in 10 mL dried DMF
by stirring; then, 0.5 mL (5.78 mmol) allyl bromide and 0.5 mL
DBU were added to the solution successively. After reaction for
24 h, the reaction mixture was extracted using UP water and
ethyl acetate. Allyl esters of oleanolic acid (compound 1) were
extracted to the ethyl acetate phase. Then, the ethyl acetate
phase was washed with UP water and dried with anhydrous
Na2SO4. The filtrate was loaded into a silica gel column for
chromatography and was eluted by petroleum ether–ethyl
acetate (4 : 1, v/v). 1 was obtained in a yield of 83.1%. For the
allyl esters of ursolic acid (compound 2), 3 g (6.57 mmol) of
ursolic acid was dissolved in 120 mL anhydrous DMF; then,
1.8 g (13.0 mmol) K2CO3 was added to the solution, which was
further mixed with 3.6 mL (41.6 mmol) allyl bromide. After
reaction for 24 h, the residual allyl bromide was removed under
vacuum; then, a large volume of saturated salt water was added
to the remaining organic phase. The white product 2 was
obtained in a yield of 90.4% by extraction with ethyl acetate,
washing with UP water and drying with anhydrous Na2SO4,
successively.
The glycosyl donor was synthesized through the following
procedure: 3.60 g (0.02 mol) of b-D-glucose, 15.82 g (0.2 mol) of
pyridine and 80 mL of dichloromethane were thoroughly mixed
in a 250 mL three-necked round bottom flask and then cooled
under 0 1C in an ice bath. A dichloromethane solution of
16.87 g (0.12 mol) benzoyl chloride was added to the mixture
dropwise at the rate of 1 drop per s under the protection of
nitrogen. After the reaction time of 24 h at room temperature,
the filtrate obtained by filtration was washed 3–4 times with 2%
HCl, saturated NaHCO3 and saturated salt solutions, successively.
Then, the filtrate was dried with anhydrous Na2SO4 and chroma-
tographed with petroleum ether–ethyl acetate (3 : 1, v/v). The
yield of total benzoyl glucose (compound 3) was 93%. In
the second step, 1.257 g (3.59 mmol) of the above product,
164.33 mg (3.59 mmol) NH2NH2ꢀHOAc and 10 mL DMF were
dissolved completely in a yellow solution by magnetic stirring.
After reaction for 30 h at room temperature, the reaction
mixture was extracted with UP water and dichloromethane.
The organic phase was washed three times with saturated salt
solution and UP water, successively. After drying with anhydrous
Na2SO4, trichloroacetonitrile (1.93 mL) and DBU (149 mL) were
added to the organic phase, and the reaction lasted for 1 h
under stirring at room temperature. Finally, the organic phase
was concentrated and the total benzoyl trichloroacetimide ester
(compound 4) was obtained with a yield of 58.3% after silica gel
column chromatography eluted with petroleum ether–ethyl
acetate (4 : 1, v/v). The overall steps for the preparation of the
glycosyl receptors and donor are shown in Fig. 1.
Fig. 1 Synthesis of allyl esters of oleanolic acid (a) and ursolic acid (b)
together with glucose trichloroacetimidate (c).
as the solvent and TMSOTf as the catalyst. The former is a volatile
organic solvent (VOS), which are unfriendly to operators and the
environment; the latter is a spontaneous combustion liquid with a
slightly higher price which is very sensitive to air and water and
can cause serious skin and eye injury through violent reactions.
Therefore, its dosage should be decreased by the introduction
of a cocatalyst. In this study, green medium ionic liquids
with both solvent and cocatalyst functions were employed
in the final step to realize glycosidation reactions between
glycosyl receptors and a donor for glucoside synthesis. 0.72 g
(0.97 mmol) of glucose trichloroacetimidate and 0.37 g
(0.74 mmol) of C-28 protected oleanolic acid or ursolic acid
were mixed thoroughly in a flask, and then a certain volume of
alternative IL was added under stirring at room temperature
until the solids were completely dissolved; the reaction began
upon addition of 0.055 mmol TMSOTf. At the end, 3 drops
of triethylamine were added to terminate the reaction, and
the light yellow solid target product was separated from
the mixture by silica gel column chromatography eluted with
petroleum ether–ethyl acetate (4 : 1, v/v). Then, the allyl
ester products of two triterpenoid sapogenins and the benzoyl
trichloroacetimide ester of glucose were confirmed by spectral
data. Finally, these products (0.40 g, 0.37 mmol) were reacted
with 20 mg CH3ONa in 10 mL CH2Cl2–MeOH (r.t.) under
stirring to remove the benzoyl groups on glucose, and the
products (400 mg, 0.6 mmol) were further reacted with 5 mg
PdCl2 for 24 h for deprotection of the C-28 carboxyl group. After
Reactions between glycosyl receptors and donor
Referring to the published synthetic routes for glycosidic that, the triterpenoid saponins with monosaccharides were
bonds,13,21,22 it can be found that all of them apply dichloromethane obtained.
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Results and discussion
Comparison among different ILs
In previous studies, ILs have played the role of solvent/co-solvent
or glycosyl promoter.1 For economic considerations and ease in
popularizing, imidazolium ILs usually receive focus. For example,
[Bmim][PF6] was used to drastically enhance the catalytic ability
of bismuth nitrate pentahydrate as a solvent and BF3ꢀOEt2 as a
co-solvent of CH2Cl2 in glycosylation,23,24 and several Brønsted
acid ionic liquids (10 mol%) were compared as catalysts in their
aqueous solutions.21 This study focused on their application in
the reactions between the abovementioned glycosyl receptors
and donor. After preliminary screening, here, the catalytic
performance of [C4mim][Tf2N], [C4mim][MeSO4], [C4mim][PF6],
[C4mim][BF4] and [C4mim][OTf] was compared without addition
of another catalyst, and the frequently used traditional catalyst
TMSOTf in CH2Cl2 was used as a reference. These parallel
reactions were carried out under the same reaction conditions,
i.e., the molar ratio was n(acceptor) : n(donor) : n(catalyst) =
1 : 1.3 : 0.07 and the reaction was performed for 2 h at room
temperature.
Fig. 3 (a) Catalytic mechanism of [C4mim][OTf]in glycosylation; (b) molecular
simulation results (red: O, blue: N, white: H, yellow: S, purple: F, green: C).
The results are shown in Fig. 2, and it can be found the basic
trends are similar for the catalysis of oleanolic acid and ursolic
acid. Among the catalysts, [C4mim][OTf] is the best, even better
than TMSOTf; it can interact with the glycosyl receptors and
donor through H-bond, p–p and electrostatic forces (as shown
in Fig. 3a). In order to further analyze the complex hybrid
mechanism by computational chemistry, molecular simulations
of the donors, acceptor and supported ionic liquid were per-
formed with the wavefunction analysis method using Multiwfn
3.5 open source software (Multifunctional Wavefunction Analyzer)
to verify the effective sites and mechanism of the reaction
process.25 The 2D structures of the molecules were firstly obtained
with Chemdraw tools, and energy minimization of the related
structures was carried out using the Gauss 9.0 program; the
Ground State method was adopted to optimize the molecules,
and the basis set was B3lyp/6-31g*. After analyzing the interaction
with Multiwfn software, the results of wavefunction analysis were
plotted to a high-quality graphic file using Chemcraft. The result is
in accord with experiments, as shown in Fig. 3b, and various
mentioned interactions between corresponding sites are marked.
The hydrophobic IL [C4mim][PF6] afforded the worst results.
Moreover, the catalytic activity of [C4mim][BF4] is similar to that
of TMSOTf, and the ionic liquids of [C4mim][Tf2N] and
[C4mim][MeSO4] show weaker catalytic activity. Considering
the essential acidity of the catalytic system, the acidity of the
above ILs may be insufficient when they are used as both solvent
and catalyst. Four Brønsted acidic ILs, including [C4mim][HSO4],
[C4mim][H2PO4], [PSmim][HSO4] and [PSmim][H2PO4], were
further included as candidates for comparison, and their acidity
order is [PSmim][HSO4] 4 [PSmim][H2PO4] 4 [C4mim][HSO4] 4
[C4mim][H2PO4]. Subsequently, the yields resulting from the
catalysis of these ILs was in the range of 40.1–43.2%, and
[PSmim][HSO4] afforded the lowest yield. This phenomenon
demonstrated that the glycoside bond will become unstable
and lead to a lower yield in the case of excessive acid strength.
Therefore, [C4mim][OTf] was selected as a solvent in the following
studies, and the usage of toxic chloroalkanes (e.g. CHCl3,
CH2Cl2), MeCN and PhMe can be avoided when ILs are used as
co-solvents or promoters of glycosylation.
Potential influence of protic acids on product yield
In the above study, no significant improvement was found in
the application of acidic ILs. Meanwhile, metal salts26 or protic
acids13 with the same anions with ILs are also commonly used
by researchers to adjust the Lewis acidity of ILs and promote
glycosylation, and the combination of ILs and Lewis acids has
Fig. 2 Comparison of the effects of different IL catalysts on the yield of
glycosylation.
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Table 1 Catalytic results of the IL–protonic acid system for preparing
glucosides of oleanolic acid (GOA) and ursolic acid (GUA)
unchanged. The experimental results are shown in Table 2,
and the trends are similar for the allyl esters of the two
triterpenoid sapogenins. The data indicate that the catalytic
performance of ionic liquids assisted by protonic acids is better
than that of traditional Lewis acids; furthermore, the combination
of [C4mim][OTf] and TMSOTf could achieve the best catalytic
performance, and the related yields for GOA and GUA increased
by 79.5% and 56.8%, respectively, compared to those resulting
from traditional catalytic systems composed of CH2Cl2 and
TMSOTf in previous reports. Under these conditions, protonic
acid is no longer needed; meanwhile, the reaction can be com-
pleted within 2 h, and detection by thin layer chromatography
indicated that there were almost no by-products. Especially, the
molecular sieves commonly used for dehydration in the reported
reaction process are also unnecessary under the catalysis of
[C4mim][OTf] and TMSOTf. In summary, the composition of the
new catalytic system becomes simpler and more effective. For
comprehensive comparison with current methods, the effects of a
phase transfer catalyst (IL-TBAI) and Ag2O10 were also taken into
account in experiments no. 10 and 11; however, their catalytic
effects were poorer.
Protic Protic acid dosage Yield of Yield of
Entry Catalyst
acid
(mol per % of IL) GOA/% GUA/%
1
2
3
4
5
6
7
[C4mim][OTf] HOTf
[C4mim][OTf] HOTf
[C4mim][OTf] HOTf
1
0.01
0.1
70.1
50.2
63.7
35.8
61.3
60.1
55.2
69.3
48.1
59.7
36.4
61.8
57.9
45.0
[C4mim][OTf] HOTf 10
[C4mim][BF4] HBF4
[C4mim][Tf2N] HNTf2
[C4mim][PF6] HPF6
1
1
1
also been achieved to obtain b-selectivity in many cases. In
order to explore the possible effects of protic acids on the final
result of the product yield, here, four different protic acids
(HOTf, HBF4, HNTf2, HPF6) with various dosages (0.01 to
10 mol per % of the IL) were used in the developed IL-involved
system for the synthesis of oleanolic acid/ursolic acid glucosides,
and the changes in the catalytic results were investigated. The
results in Table 1 indicate that the catalytic activity of the reaction
system can be obviously increased, as expected, by adding the
corresponding protonic acid; the product yield reaches the highest
level (70.1%) when [C4mim][OTf] is added to the reactive system and
TMSOTf with 1 mol per % of the IL is used as the catalyst.
By comparison, the maximum yield of 59% was obtained
when [C6mim][BF4] + HBF4 was applied in glycosylation
between 1-hydroxy sugars and alcohols;13 the dosage of the
protic acid HBF4 (30 mol per % of IL) was much higher than
that in this study. It was also found when the dosage of
protonic acid was increased 10 times (10 mol per % of IL) in
the above investigation, the yield of the target product
decreased to the lowest value instead. On the contrary, HOTf
with a dosage of 0.01 mol per % of the IL can result in higher
yields. This trend is the same as in a previous report,27 which
indicates there is no simple positive relationship between
protic acid dosage and product yield.
Effects of the reaction conditions on the final product yield
In the previous preliminary experiments, the reaction could be
completed within two hours. In this section, the influence of
the other reactive conditions will be explored in detail. Firstly,
the effects of the alkyl substituent group on the cation of
[Cnmim][OTf] with different lengths (C2–C10) on the catalytic
results were investigated. When the anion remains unchanged,
the length of the carbon chain on the same cation nucleus can
be used to regulate the hydrophobicity of the corresponding
ionic liquids, which determines the degree of miscibility of the
catalytic system and thus affects the yield of the reaction. From the
experimental results in Fig. 4, it can be found that the product
yields were highest for both aglycones when the branched alkyl
chain of the ionic liquid was C4. Therefore, [C4mim][OTf] was
taken as the research object in subsequent experiments.
Potential influence of protic acids on the product yield
Temperature often affects the stability of the reactants and
Through the above research, it was found that there was room yields together with the configuration of glycosides. Generally,
for further improvement of the yield. On the basis of the the temperature of IL-involved glycosylation in water (e.g. 80 1C)21
original reaction, every candidate protonic acid with a dosage is higher than that in organic solvents. Under reduced pressure
of 1 mol per % IL was firstly applied for the glycosylation of (4.0 mmHg), the temperature of glycosylation in [C6mim][NTf2] +
oleanolic acid, and the other reaction conditions remained HNTf2 (10 mol per % of IL) also reached 70 1C without
Table 2 Glycosidation in different catalytic systems for preparing glucosides of oleanolic acid (GOA) and ursolic acid (GUA)
Entry
Solvent
Catalysts
Yield of GOA/%
Yield of GUA/%
1
2
3
4
5
6
7
8
CH2Cl2
CH2Cl2
CH2Cl2
PhMe
PhMe
MeCN
MeCN
[C4mim][OTf]
[C4mim][BF4]
[C4mim][OTf]/TBAI
[C4mim][BF4]/TBAI
TMSOTf
40.6
70.1
61.3
56.4
50.7
65.2
58.6
72.9
63.0
47.8
40.5
47.5
69.3
61.8
58.3
52.6
63.9
58.7
74.5
66.0
52.1
46.8
[C4mim][OTf]/HOTf
[C4mim][BF4]/[HBF4]
[C4mim][OTf]/HOTf
[C4mim][BF4]/[HBF4]
[C4mim][OTf]/HOTf
[C4mim][BF4]/[HBF4]
TMSOTf
TMSOTf
Ag2O
Ag2O
9
10
11
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Fig. 4 Yields of [Cnmim][OTf] with different C-chain lengths.
Fig. 6 Yields resulting from different ratios of n(acceptor) : n(donor) : n(catalyst).
other solvents;13 therefore, more severe reaction conditions
were required than room temperature and standard pressure.
In this section, four reaction temperatures in the range from
0 1C to 50 1C were selected to investigate the catalytic activity of
the system. The experimental results in Fig. 5 show that the
catalytic behavior of [C4mim][OTf] + TMSOTf for the two
substrates is similar within this temperature range. In the
reported process, TMSOTf was generally suggested to react
below room temperature at lower temperatures.
However, it was found in this study that when the reaction
temperature is too low, the reaction time will increase and the
yield will remain at a lower level; when the temperature rises to
25 1C, the product yield is highest. If the temperature is further
increased, the catalytic effects will decrease. This proves that
high temperature can affect the stability of the reactant-catalyst
system, resulting in a decrease of the product yield.
and expense. From the investigation results for the two aglycones
shown in Fig. 6, it can be seen that when the molar ratio of glycosyl
receptor to catalyst is fixed, the yield of the target glucoside will
increase gradually with increasing amount of glycosyl donor and
finally remain basically unchanged. When the molar ratio of donor
to acceptor is fixed, the yield will increase with increasing amount
of catalyst; if the dosage of catalyst is too high, the yield will begin
to decrease instead. It is presumed that the instability of glycoside
bonds under strong acidic conditions leads to the decrease of the
yield. Considering the yield and reaction consumption com-
prehensively, the ideal molar ratio was finally determined
as n(acceptor) : n(donor) : n(catalyst) = 1 : 1.3 : 0.05, where the
highest yield can reach 74.5%.
Durability/reusability of the catalytic system
Considering the sensitivity of TMSOTf as a catalyst to water, a
large amount of 4 Å molecular sieves is applied in most previous
reports for dehydration by adsorption effects.28,29 According to
the former research, when [C4mim][OTf] was used to assist the
catalysis of TMSOTf and replace CH2Cl2 as the solvent, the
whole catalytic system became greener, simpler and highly
efficient. As a key and also low-dosage component, the stability
of TMSOTf in the reaction system will affect the durability/
reusability of the new method. Here, in the absence of dehydra-
tion operation, its possible loss in the IL and frequently used
solvents in references was investigated and compared. A certain
amount of TMSOTf was carefully added to 5 mL dichloro-
methane, [C4mim][OTf], acetonitrile and toluene under stirring,
and the corresponding solutions were sampled after different
times. The loss percentage (A, %) of TMSOTf in these solvents
can be calculated according to the following equation:
In addition, the ratio of the catalyst and reactants is an
important factor affecting the product yield, reaction efficiency
C0 ꢁ Cn
A ¼
ꢃ 100%
C0
where C0 and Cn (mg mLꢁ1) are the initial concentration and
Fig. 5 Yields under different temperatures (0–50 1C).
sampled concentration of TMSOTf, respectively, as determined
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Table 3 Loss percentage of TMSOTf in different solvents after different
times
In the same way, the protected product of GUA can be
confirmed through the following data, which are in accord with
those in ref. 33. ESI-MS (m/z): 579.34 (for [C34H27O9]+); 1052.85
(for [C66H68O12]+); 475.32 (for [C33H47O2]+). IR (KBr, cmꢁ1):
3448.14, 2953.33, 1730.58, 1601.85, 1584.48, 1452.05, 1384.51,
1267.57, 1171.92, 708.70. 1H-NMR (600 MHz, CDCl3) d 8.07–7.78
(m, 8H), 7.62–7.26 (m, 12H), 5.99–5.82 (m, 2H), 5.63–5.52 (m, 2H),
5.41–5.15 (m, 2H), 4.84 (d, J = 7.9 Hz, 1H, terminal hydrogen of
glucose), 4.54–4.47 (m, 4H), 4.11 (ddd, J = 20.9, 10.4, 5.4 Hz, 1H),
3.22 (dd, J = 10.9, 4.8 Hz, 1H), 2.25 (d, J = 11.5 Hz, 1H), 1.05 (s,
3H), 0.98 (s, 3H), 0.97 (s, 3H), 0.93 (s, 3H), 0.91 (s, 3H), 0.79 (s,
3H), 0.76 (s, 3H). 13C-NMR (100 MHz, CDCl3) d 176.17 (C-28),
166.03–165.01 (Ph–CQO), 137.05 (C-13), 131.55 (CH2CHQCH2),
129.91–127.13 (C6H5), 124.61 (C-12), 116.75 (CH2CHQCH2),
103.02 (C-10), 90.72 (C-3), 78.01 (C-30), 77.03 (C-20), 76.72 (C-50),
75.67 (C-40), 64.80 (C-29), 63.80 (C-60), 54.17 (C-5), 51.85 (C-18),
48.12 (C-17), 46.52 (C-9), 42.37 (C-14), 39.63 (C-8), 39.03 (C-20),
38.82 (C-19), 38.71 (C-4), 38.05 (C-10), 36.91 (C-1), 35.66 (C-7),
33.18 (C-21), 29.65 (C-15), 28.61 (C-23), 28.06 (C-2), 26.97 (C-16),
24.23 (C-11), 23.68 (C-27), 23.20 (C-30), 22.26 (C-6), 18.09 (C-22),
17.28 (C-26), 16.00 (C-29), 14.6 (C-25), 14.00 (C-24). [a]2D5 = +59.0.
It was also found that the b-configuration of the glycoside bond
was obtained.
Solvent
20 min
40 min
60 min
90 min
120 min
[C4mim][OTf]
CH2Cl2
MeCN
0
0
0
0.4%
7.2%
18%
28%
0.6%
7.5%
19%
28%
6.4%
16%
24%
6.6%
16%
25%
6.7%
17%
26%
PhMe
by a UV spectrometer at 252 nm. As shown in Table 3, the
catalyst is much more stable in the ionic liquid [C4mim][OTf]
than in other solvents within the reaction time of 2 h; the loss of
TMSOTf in PhMe is the highest. Therefore, these results prove
that the functions of IL actually include solvent, cocatalyst and
stabilizer, simultaneously. After the last reaction step, the
mixture of product, catalyst and IL was loaded on a chromato-
graphic column of HPD-100 macroporous resin after moderate
dilution with water; the IL was not adsorbed by the resin and
was present in the effluent. After concentration and washing
with acetone, [C4mim][OTf] could be effectively reused several
times, and the glucoside yield of ursolic acid changed from
74.5% (the first run) to 70.3% (the fifth run). The glucoside
product could be eluted from the resin by 80% ethanol–water
and recovered for further purification.
Spectroscopic identification of products
Conclusions
The spectral data of the reaction product of the propanol ester
of oleanolic acid and the benzoyl trichloroacetimide ester of
glucose are listed as follows. ESI-MS (m/z): 579.34 (for [C34H27O9]+);
953.58 (for [C60H73O10]+); 475.33 (for [C33H47O2]+). IR (KBr, cmꢁ1):
3066.38, 2959.77, 1730.05, 1649.16, 1452.04, 1383.79, 1270.55,
1178.47, 937.36; among these, the characteristic peak of the
In the above study, an ionic liquid-assisted catalytic system was
applied for the synthesis of triterpene saponins for the first
time, and the effective applied methods and functions of ionic
liquids were explored to obtain b-type products of oleanolic
acid and ursolic acid. ILs can provide more intermolecular
forces with the reactants than common Lewis acids; the glyco-
sylation system is also simpler, more effective and recyclable.
From the comparison results of different ILs and catalytic
systems, the combination [C4mim][OTf] + TMSOTf was found
to be better than [C4mim][OTf] + HOTf, and only [C4mim][OTf]
was involved in the reaction between the glycosyl receptor and
donor; also, it was stable and could be recycled. The method
was successfully developed through a detailed investigation of
the related conditions, including the alkyl substituted chain
length on the IL, temperature and molar ratio of acceptor/donor/
catalyst; it offers a synthesis example for triterpenoid glucosides
and proves both the potential and universality of related IL
applications. The functions of the IL include solvent, cocatalyst
and stabilizer, simultaneously; thus, the current catalytic system
is greener, simpler and more efficient.
CQO stretching vibration exists at 1730 cmꢁ1 and 1270/1178 cmꢁ1
,
corresponding to the asymmetric/symmetrical stretching vibra-
tion of C–O–C, and the peak of the CQC stretching vibration
can be found at 1649 cmꢁ1. 1H-NMR (400 MHz, CDCl3) d 8.02–
7.69 (m, 20H), 5.91–5.88 (m, 2H), 5.58–5.54 (m, 2H), 5.29–5.28
(m, 2H), 5.19–5.16 (m, 1H), 4.85 (d, J = 8.2 Hz, 1H), 4.49–4.45
(m, 2H), 4.11–3.78 (m, 1H), 3.20 (dd, J = 4.8, 11.4 Hz, 1H), 2.87
(dd, J = 4.8, 14.4 Hz, 1H), 1.55–1.39 (m, 2H), 1.54–1.35 (m, 1H),
1.09 (s, 3H), 0.91 (s, 3H), 0.89 (s, 3H), 0.82 (s, 3H), 0.81 (s, 3H),
0.78 (s, 3H), 0.75 (s, 3H); the signal at 4.85 ppm is ascribed to
the proton on C-1 of glucose, and its coupling constant con-
firms the b-configuration of the glycoside bond. 13C-NMR (100
MHz, CDCl3) d 177.30 (C-28), 166.03–165.01 (Ph–CQO), 143.70
(C-13), 132.55 (CH2CHQCH2), 128.86–128.41 (C6H5), 122.41 (C-
12), 117.00 (CH2CHQCH2), 103.02 (C-10), 90.72 (C-3), 76.31 (C-30),
75.99 (C-20), 75.67 (C-50), 70.21 (C-40), 64.76 (CH2CHQCH2), 63.42
(C-60), 55.23 (C-5), 47.56 (C-9), 46.73 (C-19), 45.94 (C-17), 41.69 (C-18), Conflicts of interest
41.37 (C-14), 39.33 (C-8), 38.71 (C-1), 38.26 (C-4), 36.60 (C-10), 33.94
There are no conflicts to declare.
(C-21), 33.18 (C-29), 32.65 (C-7), 32.45 (C-22), 30.71 (C-20), 27.61
(C-23), 27.60 (C-15), 25.86 (C-27), 25.82 (C-2), 23.68 (C-30), 23.34
(C-11), 23.30 (C-16), 18.09 (C-6), 16.91 (C-26), 16.28 (C-24), 15.29
Acknowledgements
(C-25). [a]2D5 = +60.2. As a reported compound, it can be determined
to be the protected product of GOA through comparison with the Preparation of this paper was supported by the National Natural
data in a previous report.30–32
Science Foundation of China (No. 81673316) and 2017 ‘‘Stars of
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