N-Substituted 3(10H)-Acridones as Visible-Light, Water-Soluble Photocatalysts: Aerobic Oxidative Hydroxylation of Arylboronic Acids

Article abstract of DOI:10.1021/acs.joc.7b00487

We disclosed a novel water-soluble photocatalyst that could promote aerobic oxidative hydroxylation of arylboronic acids to furnish phenols in excellent yields. This transformation uses visible-light irradiation under environmentally friendly conditions, that is, water-soluble catalyst, metal-free, green oxidant, room temperature.

Full text of DOI:10.1021/acs.joc.7b00487

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Article
N-Substituted-3(10H)-acridones as Visible-Light, Water-Soluble
Photocatalyst: Aerobic Oxidative Hydroxylation of Arylboronic Acids
Hong-Yan Xie, Li-Shuai Han, Shan Huang, Xiantao Lei, Yong Cheng,
Wenfeng Zhao, Hongbin Sun, Xiaoan Wen, and Qing-Long Xu
J. Org. Chem., Just Accepted Manuscript • Publication Date (Web): 25 Apr 2017
Downloaded from http://pubs.acs.org on April 26, 2017
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N-Substituted-3(10H)-acridones as Visible-Light, Water-Soluble
Photocatalyst: Aerobic Oxidative Hydroxylation of Arylboronic Acids
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Hong-Yan Xie, Li-Shuai Han, Shan Huang, Xiantao Lei, Yong Cheng, Wenfeng Zhao,
Hongbin Sun, * Xiaoan Wen * and Qing-Long Xu *
Jiangsu Key Laboratory of Drug Discovery for Metabolic Disease and State Key
Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tongjia Xiang,
Nanjing 210009, China
ABSTRACT: We disclosed a novel water-soluble photocatalyst, that could promote
aerobic oxidative hydroxylation of arylboronic acids to furnish phenols in excellent
yields. This transformation uses visible-light irradiation under environment-friendly
conditions, that is, water-soluble catalyst, metal-free, green oxidant, room temperature.
INTRODUCTION
Nowadays, the sustainability has not only become the theme of the development of
human society, but also a new research hot-topic in the field of chemistry, that was
1
known as green chemistry. Visible-light prompted organic transformation has witnessed
as one of the hot research field to chemistry community and was considered to be the
main branch of green chemistry, due to its high efficiency, mild and environmentally-
2
friendly reaction conditions. Despite the significant advances in the field of
photocatalysis in the past decade, the discovery and exploration of new photocatalyst is
still highly desirable, especially the water-soluble photocatalyst, that accords with the
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demand of green chemistry, and the most attractive feature of water as a solvent is its
utility in the development of environmentally-friendly chemical processes.
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We recently found that N-substituted-3(10H)-acridones represented a new class of
organic photocatalysts with good water-solubility and high atom-economy. These
properties attracted our considerable interest. To our delight, these photocatalysts showed
excellent performance in visible-light catalyzed conversion of arylboronic acid to phenol
with using oxygen as oxidant in aqueous solution.
Phenols are widely found in natural products and pharmaceutical compounds, also
used as versatile intermediates and employed in the synthesis of natural products, organic
3
and materials chemistry. Recently, the hydroxylation of arylboronic acid was considered
as the effective method to furnish phenols. Until now, various reaction conditions to
realize the hydroxylation of arylboronic acid have been developed as follows: (1) using
4
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8
transition-metal catalysts such as copper, palladium, gold, ruthenium, or silver, either
in the presence of a strong base or under base-free conditions; (2) using stoichiometric
9
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12
18
amounts of oxidants such as hydrogen peroxide, TBHP, MCPBA, oxone,
1
3
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16
17
2 2
hydroxylamine, amine oxide, ozone, PhI(OAc) , benzoquinone and NaClO ;
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(3) electrochemical reaction; (4) aerobic oxidative hydroxylation using organocatalysis
2
0
and photocatalysts such as ruthenium complex, iron complex, methylene blue, quinine
21
and 2-chloroanthraquinone.
In the reported photocatalytic approaches, almost all the reactions were conducted
with using organic solvents. Given the fact that the N-substituted-3(10H)-acridones had
good water-solubility, we reasoned that the photocatalytic conversion of arylboronic acid
to phenol could be conducted in water instead of the organic solvents. Herein, we
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describe the photocatalytic aerobic oxidative hydroxylation of arylboronic acids with
using water as a solvent.
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RESULTS AND DISCUSSION
Initially, 4-formylphenylboronic acid (1a) was chosen as the model substrate to optimize
reaction conditions including the solvents, bases, light sources and reaction time under
O
2
atmosphere (Table 1). Firstly, various solvents including DMSO, DMF, MeCN,
MeOH, H O and co-solvents were evaluated (entries 1-9, Table 1) with using 1 mol% of
2
N-methyl-3(10H)-acridones (cat. I) as the catalyst (see the UV-VIS, Fluorescence spectra
and Cyclic Voltammetry in the supporting information for details). To our delight, the
transformation proceeded smoothly in water after 17 h of irradiation with a 6 W blue
LED at room temperature, affording the desired product 2a in 95% yield (entry 9, Table
1
). Then the reaction was conducted under air and N
found that the reaction proceeded smoothly under air condition, but with a longer reaction
time (entry 10, Table 1). However, no reaction took place under N atmosphere (entry 11,
2
atmosphere, respectively. It was
2
2
Table 1). This indicated that O plays a critical role in this transformation. And, control
experiments were conducted, no reaction was taken place when the reaction was
conducted under dark condition (entry 12, Table 1). When the free radical capture agent
was added (TEMPO, DPPH 20 mol%), the reactions proceeded smoothly, but give the
desired product in low yields (46%, 49%, respectively). Secondly, a range of amines such
i
as Pr NEt, (p-MeOC H )NPh , and NEt were examined with using water as the solvent.
2
6
4
2
3
i
2
We found that Pr NEt (5.0 equiv.) was the optimal amine (entries 9, 13-17, Table 1).
Interestingly, the reaction gave low yield in the absence of the base (entry 18, Table 1)
that might act as a sacrificial electron donor. So we found that excess base is beneficial
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for this transformation. Thirdly, different types of light sources were evaluated, and the
blue light was found to be the optimal light source (entries 18-21, Table 1). The loading
of the photocatlayst was also examined, and it was found that 0.1-1 mol% cat. I was
enough to furnish the product in excellent yields (entries 9, 22, Table 1), and 0.01 mol%
catalyst loading led to significantly decreased reaction speed (entry 23, Table 1). Control
experiments indicated that the desired product was formed in the absence of the catalyst,
but with very poor yield (12%). In this transformation, the reaction can proceed in the
absence of base or catalyst (entries 17, 24, Table 1), since the boronic acid under oxygen
condition for long time was converted to phenol, but with low reactivity. Together, we
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determined the optimal reaction conditons as follows: 1a (1.0 equiv.), cat. I (1 mol%),
i
Pr
2
NEt (5.0 equiv.), H
2
O, 6W blue LED, O
2
balloon, rt.
a
Table 1. Optimization of reaction conditions.
b
entry
amine
solvent
DMSO
DMF
light time (h) yield (%)
i
i
i
i
i
i
i
1
2
3
4
5
6
8
Pr
Pr
Pr
Pr
Pr
Pr
Pr
2
NEt
2
NEt
2
NEt
2
NEt
2
NEt
2
NEt
2
NEt
Blue
Blue
Blue
Blue
Blue
90
90
90
65
90
42
27
29
61
82
84
55
92
99
MeCN
MeOH
EtOH
MeCN:H
2
O (4:1) Blue
O (4:1) Blue
MeOH:H
2
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i
i
i
i
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Pr
Pr
Pr
2
2
2
NEt
NEt
NEt
H
H
H
2
2
2
O
O
O
Blue
Blue
Blue
Blue
Blue
Blue
Blue
Blue
Blue
Green
White
Yellow
Red
17
40
48
48
90
90
42
72
72
70
91
91
91
40
48
48
95
93
c
d
e
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1
1
1
1
1
1
1
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1
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NR
NR
NR
31
12
Pr NEt
2
H O
2
1
1
3
(pMeOC
6
H
4
)NPh
2
H
H
2
2
O
O
4
NEt
3
f
i
i
i
i
i
i
i
i
i
i
1
5
Pr NEt
H O
92
2
2
g
h
16
Pr
Pr
Pr
Pr
Pr
Pr
Pr
Pr
Pr
2
2
2
2
2
2
2
2
2
NEt
NEt
NEt
NEt
NEt
NEt
NEt
NEt
NEt
H
H
H
H
H
H
H
H
H
2
2
2
2
2
2
2
2
2
O
O
O
O
O
O
O
O
O
20
17
14
1
8
75
1
9
66
20
NR
NR
97
2
1
i
j
22
Blue
Blue
Blue
23
48
k
24
12
a
Reaction condition: 1a (0.67 mmol), amine (5.0 equiv.), cat. I (1 mol%), solvent (5.0
b
c
d
e
mL), O
2
balloon, light. Isolated yield. Under air atmosphere. under N
2
atmosphere.
f
i
g
i
h
Under dark condition. Using Pr
2
NEt (2.5 equiv.). Using Pr
2
NEt (1.0 equiv.). No base
i
j
k
added. Using 0.1% cat. I. Using 0.01% cat. I. No cat. I. NR = No Reaction.
With the optimal reaction condition in hand, we turned our attention to evaluate the
photocatalyst activities of various N-substituted-3(10H)-acridone derivatives, the results
are shown in Table 2. Interestingly, all the synthesized N-substituted-3(10H)-acridones
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were found to be efficient photocatalysts in this transformation. Due to the decreased
water solubility of some catalysts derived from cat. I, MeOH had to be added to dissolve
the catalyst. It was noted that the substituents adjacent to the benzene ring led to low
catalyst efficiency, giving the desired product in moderated yields (entries 1-3, Table 2).
However, the substituents linked to C9 and N10 position of the catalyst almost had no
influence on the reactivity.
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Table 2. Comparison of photocatalyst capabilities of various N-substituted-3(10H)-
a
acridones.
b
entry
1
Catalyst
solvent
time (h)
48
yield (%)
55
MeOH:H
2
2
O (1:4)
O (1:4)
2
3
MeOH:H
22
48
83
67
MeOH:H O (1:4)
2
4
MeOH:H
2
O (1:4)
22
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MeOH:H
2
O (1:4)
22
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93
95
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H O
a
i
2
Reaction condition: 1a (0.67 mmol), Pr NEt (5.0 equiv.), cat. I (1 mol%), solvent (5.0
b
mL), O
2
balloon, 6W Blue LED. Isolated yield.
Encouraged by the finding that acridone cat. I was an efficient photocatalyst for the
aerobic oxidative hydroxylation of arylboronic acids, we further compared cat. I with the
.
common photocatalysts, including MB, [Ru(bpy) Cl ] 6H O, Eosin Y, Rose Bengal,
3
2
2
FMN, and TPP (Table 3). To our delight, under the same reaction condition, cat. I
showed the best photocatalytic reactivity, affording a complete conversion after 36 h with
1
mol% catalyst loading (entry 1, Table 3), while other photocatalysts were not as well as
this catalyst in this transformation with using water as the solvent. In this case, only EY
could give a reasonable yield (entry 4, Table 3). Together, cat. I exhibited higher
photocatalytic efficiency in this aqueous oxidative reaction than other photoredox
catalysts.
Table 3. Comparison of photocatalysis capabilities of various organic photocatalysts.
a
b
entry
catalyst
time (h)
yield (%)
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cat. I
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MB
0
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0
.
[Ru(bpy) Cl
3 2
] 6H
2
O
EY
RB
FMN
TPP
a
i
Reaction condition: 1a (0.5 mmol), Pr
2
NEt (5.0 equiv.), catalyst (1 mol%), H
2
O (5.0
b
mL), O
2
balloon, 6W Blue LED. Isolated yield.
Under the optimal reaction condition, the substrate scope of the visible-light
prompted photoredox catalytic aerobic oxidative hydroxylation of arylboronic acids was
explored and the results are summarized in Scheme 1. We found that a wide range of
arylboronic acids regardless of the substituent position and electronic property were
proceeded smoothly to furnish the corresponding phenols in good to excellent yields,
except some electron-rich substrates (2e-2g). The substrates (1p-1r) had bad water
solubility, and some MeOH should be added to improve the solubility, affording the
desired phenols in good yields.
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i
Scheme 1. Substrate scope. Reaction condition: 1 (0.67 mmol), Pr
2
NEt (5.0 equiv.), cat.
a
b
I (1 mol%), H
2
O (5.0 mL), O
2
balloon, 6W Blue LED. MeOH:H
2
O (4:1). Using EY
as catalyst.
21g
Based on the above results and the previous reports,
we propose the mechanism
of the oxidative hydroxylation of arylboronic acids as depicted in Scheme 2. Firstly, blue
LED irradiation of cat. I provides the excited intermediate I* with enhanced oxidative
i
ability. Oxidation of Pr NEt by I* via a single electron transfer (SET) process gives
2
i
radical cation Pr
2
NEt together with radical anion A. Radical anion A is then oxidized
by O
2
to allow for regeneration of cat. I for the next catalytic cycle. Meanwhile,
is formed. The radical anion O then reacts with boronic
superoxide radical anion O
2
2
acid to generate the intermediate B. The radical anion B then abstracts a hydrogen atom
i
from the radical cation Pr
2
NEt
to give intermediate C. The formation of phenol
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product 2 takes place by rearrangement of C into D with subsequent hydrolysis.
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Scheme 2. Proposed mechanism for the oxidative hydroxylation of arylboronic acids.
CONCLUSION
In conclusion, a photocatalytic aerobic oxidative hydroxylation of arylboronic acids
catalyzed by an acridone catalyst has been developed with using water as a solvent,
giving an eco-friendly access to phenols. In comparison with the previous reported
phenol synthesis from arylboronic acids, this transformation proceeded smoothly with
wide substrate scope under an aqueous solution, metal-free, ambient pressure and room
temperature conditions. Further exploration of these new photocatalysts in other type of
reactions is undergoing in our laboratory.
EXPERIMENT SECTION
General Methods. Reagents were purchased from commercial sources and were used as
1
received unless mentioned otherwise. Reactions were monitored by TLC. H NMR and
1
3
C NMR (300 and 75 MHz, respectively) spectra were recorded in CDCl
H NMR chemical shifts are reported in ppm relative to tetramethylsilane (TMS) with the
at 7.26 ppm, DMSO-d at
.50 ppm). Data are reported as follows: chemical shift, multiplicity (s = singlet, br s =
3 6
and DMSO-d .
1
solvent resonance employed as the internal standard (CDCl
3
6
2
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broad singlet, d = doublet, t = triplet, q = quartet, m = multiplet), coupling constants (Hz)
13
and integration. C NMR chemical shifts are reported in ppm from tetramethylsilane
1
1
1
1
1
1
1
1
1
1
2
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2
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(
3
TMS) with the solvent resonance as the internal standard (CDCl at 77.16 ppm).
General Procedure. To a mixture of arylboronic acid 1 (0.67 mmol), cat. I (1 mol%) in
i
H
2
O (5.0 mL) was added Pr
2
NEt (3.35 mmol). The solution was stirred at room
. After boronic acid was
completely consumed (monitored by TLC), the reaction mixture quenched carefully by
aqueous solution of HCl (10%, 5 mL). The resultant mixture was extracted with Et O (3
x 10 mL). The combined organic layers were washed with brine (10 mL) and dried over
Na SO . After removal of the solvent in vacuum (Low Temperature), the residue was
purified by FC (silica gel, EtOAc:PE = 1:5 or Et
temperature irradiated with 6W blue LED in the presence of O
2
2
2
4
2
O:PE=1:3) to give the desired product 2.
2
1f
1
4
-Hydroxybenzaldehyde (2a),
white solid (78 mg, 95% yield). H NMR (300 MHz,
CDCl
3
) δ 9.88 (s, 1H), 7.84 (d, J = 8.7 Hz, 2H), 7.00 (d, J = 8.7 Hz, 2H), 6.59 (br s, 1H).
1
3
o
C NMR (75 MHz, CDCl
3
) δ 191.69, 162.17, 132.69, 129.56, 116.13. m.p. 111-113 C.
21f
1
Phenol (2b), colorless solid (61 mg, 97% yield). H NMR (300 MHz, CDCl
3
) δ 7.30-
1
3
7
.17 (m, 2H), 6.97-6.88 (m, 1H), 6.87-6.78 (m, 2H), 5.42 (br s, 1H). C NMR (75 MHz,
o
CDCl
3
) δ 155.32, 129.78, 121.00, 115.44. m.p. 39-41 C.
2
1f
1
o-Cresol (2c), yellow oil (68 mg, 96% yield). H NMR (300 MHz, CDCl
3
) δ 7.17-7.04
(
m, 2H), 6.84 (d, J = 7.2 Hz, 1H), 6.76 (d, J = 7.8 Hz, 1H), 4.84 (br s, 1H), 2.25 (s, 3H).
1
3
3
C NMR (75 MHz, CDCl ) δ 153.76, 131.01, 127.12, 123.69, 120.75, 114.89, 15.64.
2
1f
1
m-Cresol (2d), colorless oil (66 mg, 93% yield). H NMR (300 MHz, CDCl
3
) δ 7.10 (t,
J = 7.5 Hz, 1H), 6.74 (d, J = 7.5 Hz, 1H), 6.70-6.60 (m, 2H), 5.48 (br s, 1H), 2.28 (s, 3H).
22a
1
2
,3-Dimethlphenol (2e),
colorless solid (43 mg, 55% yield). H NMR (300 MHz,
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CDCl
3
) δ 6.96 (t, J = 7.8 Hz, 1H), 6.75 (d, J = 7.5 Hz, 1H), 6.63 (d, J = 8.1 Hz, 1H), 4.67
o
(br s, 1H), 2.27 (s, 3H), 2.16 (s, 3H). m.p. 68-69 C.
0
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2
3
4
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8
9
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18
1
3
7
-Methoxyphenol (2f), colorless oil (60 mg, 64% yield). H NMR (300 MHz, CDCl
3
) δ
.17-7.08 (m, 1H), 6.54-6.48 (m, 1H), 6.46-6.40 (m, 2H), 5.53 (br s, 1H), 3.76 (s, 3H).
1
3
C NMR (75 MHz, CDCl
3
) δ 146.61, 145.72, 121.48, 120.14, 114.55, 110.77, 55.88.
21f
1
4
6
2
-Methoyphenol (2g), white solid (49 mg, 59% yield). H NMR (300 MHz, CDCl
3
) δ
o
.85-6.75 (m, 4H), 5.02 (br s, 1H), 3.77 (s, 3H). m.p. 54-56 C.
2
2b
1
3
-Chlorophenol (2h), colorless oil (74 mg, 86% yield). H NMR (300 MHz, CDCl ) δ
7.34 (dd, J = 7.8, 1.5 Hz, 1H), 7.25-7.15 (m, 1H), 7.04 (dd, J = 8.1, 1.5 Hz, 1H), 6.95-
13
6
1
3
.85 (m, 1H), 5.65 (br s, 1H). C NMR (75 MHz, CDCl
3
) δ 151.38, 128.99, 128.41,
21.36, 119.89, 116.26.
9
e
1
3
-Chlorophenol (2i), white solid (79 mg, 92% yield). H NMR (300 MHz, CDCl ) δ
7.15 (t, J = 8.1 Hz, 1H), 6.91 (d, J = 7.8 Hz, 1H), 6.86 (s, 1H), 6.73 (d, J = 7.8 Hz, 1H),
1
3
5
1
2
.86 (br s, 1H). C NMR (75 MHz, CDCl
3
) δ 156.58, 135.04, 130.58, 121.10, 116.08,
o
13.94. m.p. 32-34 C.
2
2c
1
,3-Dichlorophenol (2j),
white solid (96 mg, 88% yield). H NMR (300 MHz, CDCl
3
)
δ 7.13 (t, J = 8.0 Hz, 1H), 7.05 (dd, J = 8.0, 1.5 Hz, 1H), 6.96 (dd, J = 8.0, 1.5 Hz, 1H),
o
5
2
.72 (br s, 1H). m.p. 55-56 C.
22d
1
,3-Difluorophenol (2k),
3
white solid (85 mg, 98% yield). H NMR (300 MHz, CDCl )
δ 7.11 (t, J = 8.1 Hz, 1H), 7.03 (dd, J = 8.1, 1.5 Hz, 1H), 6.94 (dd, J = 8.1, 1.5 Hz, 1H),
o
5
.71 (br s, 1H). m.p. 53-54 C.
22e
1
3-Hydroxybenzonitrile (2l),
white solid (88 mg, 98% yield). H NMR (300 MHz,
3
CDCl ) δ 7.34 (t, J = 7.8 Hz, 1H), 7.23 (t, J = 7.8 Hz, 1H), 7.15-7.06 (m, 2H), 5.08 (br s,
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o
1
3
H). m.p. 76-78 C.
22f
1
-Hydroxybenzaldehyde (2m),
white solid (74 mg, 90% yield). H NMR (300 MHz,
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
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5
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5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
3
CDCl ) δ 9.90 (s, 1H), 7.44-7.28 (m, 3H), 7.08 (dt, J = 6.9, 2.4 Hz, 1H), 5.72 (br s, 1H).
o
m.p. 98-100 C.
2
1f
1
3-Nitrophenol (2n),
3
white solid (75 mg, 80% yield). H NMR (300 MHz, CDCl ) δ
7
.82 (dd, J = 8.0, 1.2 Hz, 1H), 7.71 (appt, J = 2.0 Hz, 1H), 7.41 (t, J = 8.1 Hz, 1H), 7.20
o
(
dd, J = 8.1, 2.4 Hz, 1H), 5.75 (br s, 1H). m.p. 94-96 C.
2
2g
1
Ethyl 4-hydroxybenzoate (2o),
white solid (98 mg, 88% yield). H NMR (300 MHz,
3
CDCl ) δ 7.98 (d, J = 8.4 Hz, 2H), 6.90 (d, J = 8.7 Hz, 2H), 6.01 (br s, 1H), 4.38 (q, J =
1
3
7
1
2
.2 Hz, 2H), 1.40 (t, J = 7.2 Hz, 3H). C NMR (75 MHz, CDCl
3
) δ 167.40, 160.64,
o
32.06, 122.54, 115.44, 61.18, 14.43. m.p. 121-123 C.
1
4
1
,3-Dihydrobenzo[b][1,4]dioxin-6-ol (2p), colorless oil (90 mg, 88% yield). H NMR
(300 MHz, CDCl
3
) δ 6.72 (d, J = 8.7 Hz, 1H), 6.39 (d, J = 2.7 Hz, 1H), 6.33 (dd, J = 8.7,
2
.7 Hz, 1H), 5.55 (br s, 1H), 4.23-4.18 (m, 4H).
21f
1
Naphthalen-2-ol (2q), white solid (72 mg, 75% yield). H NMR (300 MHz, CDCl
3
) δ
7
.80 (t, J = 8.1 Hz, 2H), 7.71 (d, J = 8.1 Hz, 1H), 7.48 (dt, J = 7.2, 1.0 Hz, 1H), 7.38 (dt,
o
J = 8.1, 1.0 Hz, 1H), 7.23-7.08 (m, 2H), 5.42 (br s, 1H). m.p. 113-115 C.
2
1f 1
Pyren-1-ol (2r), white solid (99 mg, 68% yield).
6
H NMR (300 MHz, DMSO-d ) δ
1
0.60 (s, 1H), 8.33 (d, J = 9.0 Hz, 1H), 8.17-8.10 (m, 3H), 8.07-7.95 (m, 3H), 7.90 (d, J =
o
9
.0 Hz, 1H), 7.59 (d, J = 8.4 Hz, 1H). m.p. 179-180 C.
ASSOCIATED CONTENT
Supporting Information
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Characterization data for all reported compounds. This material is available free of
charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
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Corresponding Author
*E-mail: wxagj@126.com; qlxu@cpu.edu.cn; hbsun2000@yahoo.com
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
Financial support from National Natural Science Foundation of China (grants
8
1473080, 81573299, 21502230 and 31501182) is gratefully acknowledged. This
project was also supported by the Jiangsu Province Natural Science Foundation
BK20150688), the “111 Project” from the Ministry of Education of China, the
(
State Administration of Foreign Expert Affairs of China (No. 111-2-07) and
program for Changjiang Scholars and Innovative Research Team in University
(
IRT1193), Project Program of State Key Laboratory of Natural Medicines, China
Pharmaceutical University (No. SKLNMZZYQ201607), the Program for Jiangsu
Province Innovative Research Team.
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