Synthesis of Novel (9S)-Acyloxy Derivatives of Quinidine and Dihydroquinidine as Insecticidal Agents

Article abstract of DOI:10.1002/cbdv.201900696

Endeavor to discover biorational natural products-based insecticides, two series (30) of novel (9S)-acyloxy derivatives of quinidine and dihydroquinidine were prepared and assessed for their insecticidal activity against Mythimna separata in vivo by the leaf-dipping method at 1 mg/mL. Among all the compounds, especially four derivatives exhibited the best insecticidal activity with final mortality rates of 71.4 %, 75.0 %, 71.4 %, and 75.0 %, respectively. Relatively speaking, 9-hydroxy group is well tolerated, and the results showed that after modification of the hydroxy group with an acyloxy group, the insecticidal activity was significantly increased; the configuration at C8/9 position is important for insecticidal activity, and the (9S)-configuration is optimal; modification of the out-ring double bond is acceptable, and hydrogenation of the double bond enhances insecticidal activity. These preliminary results will pave the way for further modification of quinidine in the development of potential new insecticides.

Full text of DOI:10.1002/cbdv.201900696

Title: Synthesis of novel 9S-acyloxy derivatives of quinidine and
dihydroquinidine as insecticidal agents
Authors: Zhiping Che, Jinming Yang, Di Sun, Yuee Tian, Shengming
Liu, Xiaomin Lin, Jia Jiang, and Genqiang Chen
This manuscript has been accepted after peer review and appears as an
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To be cited as: Chem. Biodiversity 10.1002/cbdv.201900696
Link to VoR: http://dx.doi.org/10.1002/cbdv.201900696

Chemistry & Biodiversity
10.1002/cbdv.201900696
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Synthesis of novel 9S-acyloxy derivatives of quinidine and dihydroquinidine as
insecticidal agents
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Zhiping Che,* Jinming Yang, Di Sun, Yuee Tian, Shengming Liu, Xiaomin Lin, Jia
Jiang, Genqiang Chen
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Laboratory of Pesticidal Design & Synthesis, Department of Plant Protection,
College of Forestry, Henan University of Science and Technology, Luoyang 471023,
Henan Province, PR China
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*Corresponding
author:
Z.P.
Che
(zhipingche@163.com),
Tel./fax:
+86-0379-64389603.
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Abstract:
Endeavor to discover biorational natural products-based insecticides, two series (30)
of novel 9S-acyloxy derivatives of quinidine and dihydroquinidine were prepared and
assessed for their insecticidal activity against Mythimna separata in vivo by the
leaf-dipping method at 1 mg/mL. Among all the compounds, especially derivatives 3k,
3m, 3u, and 4k exhibited the best insecticidal activity with final mortality rates of
71.4%, 75.0%, 71.4%, and 75.0%, respectively. Relatively speaking, 9-hydroxyl
group is well tolerated, and the results showed that after modification of hydroxyl
group with acyloxy, the insecticidal activity was significantly increased; the
configuration of C8/9 position is important for insecticidal activity, and
9S-configuration is optimal; modification of out-ring double-bond is acceptable, and
hydrogenation of double-bond enhances insecticidal activity. These preliminary
results will pave the way for further modification of quinidine in the development of
potential new insecticides.
Keywords: Quinidine, Dihydroquinidine, Acyloxy, Structural modification,
Insecticidal activity
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Introduction
Lepidoptera (moths and butterflies) represent one of the most studied insect species
orders in the world. The larvae of many moths and butterflies groups are significant
[
1]
pests in agriculture and forestry. The oriental armyworm also known as Mythimna
separata Walker (Lepidoptera: Noctuidae), is a gluttonous, omnivorous insect. Its
larvae and adults can cause extensive damage to many crops, such as the larvae
damage the leaves of the grass family (Gramineae), the adult is an important
migratory pest in the world, and sometimes its outbreaks result in complete crop
[
2-4]
loss.
million hectares of crops were complete loss.
insecticides were used to control M. separate, many problems have arisen, such as
For example, the M. separata intermittent outbreaks in China in 2012, about 4
[5]
Although existing chemical
[
6]
residue, resistance and resurgence (3R). Thus, try to solve these troubles has
become a thorny problem in agriculture insect pest control. Fortunately, biopesticides,
especially botanical insecticides (take it from the plant and use it to the plant), are
properly applied. According to the Change Advisory Board (CAB) scientific report,
[
7,8]
botanical insecticide has grown rapidly over the past three decades.
Up to 2014,
the Environmental Protection Agency (EPA) of the United States data showed that
[
9]
about 69 botanical pesticides were registered and commercialized. Nowadays,
azadirachtin, rotenone, matrine, pyrethrins, and so on, all are commercial botanical
[10]
insecticides, which are made by plants as widely defenses against insect pests.
The crop pest is one of the main factors that restrict food security and bumper. With
the increasing crop pests resistance, research and development of novel pesticides is
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Chemistry & Biodiversity
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an urgent task for the pesticide science and pesticide industry. In view of the
present situation, discovery of new pesticidal compounds from natural products as
lead compounds for further structural modifications has recently been one of the
[
12-15]
important procedures in the research and development of new pesticides.
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Figure 1. Chemical structures of quinine (i) and quinidine (1).
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Quinidine (1; Figure 1) is the analogue of quinine (i; Figure 1) and has similar
biological activity to quinine. Quinine is the main alkaloids in the bark of cinchona
[
16]
tree as well as in plants in the same genus.
Strains of the human parasite
Plasmodium falciparum resistant to the quinine and its analogs are widespread, and
the prevalence of multiple types of drug-resistant P. falciparum strains has severely
[
17-19]
limited the use of quinines to treat malaria.
Besides its use as the lead compound
for the preparation of catalysts and ligands which can effectively catalyze the reaction
[
20-22]
[23]
[24-26]
such as Michael/Mannich,
Aza-Henry,
cycloaddition,
and asymmetric
[27]
olefin isomerization,
quinine (i) has also exhibited numerous interesting
[28-33]
insecticidal and antibacterial activities.
However, systematic research on
structure optimizations and structure-activity relationship (SAR) of quinidine
derivatives as insecticidal agents has not yet been reported. Therefore, in this study,
21 novel 9S-acyloxyquinidine derivatives and 9 novel 9S-acyloxydihydroquinidine
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Chemistry & Biodiversity
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derivatives were designed and semisynthesized, and as insecticidal agents against the
pre-third-instar larvae of M. separata Walker in vivo for the first time. Furthermore,
the SARs of these compounds were also described.
Results and discussion
Chemistry
As depicted in Scheme 1, dihydroquinidine (2) was obtained in 92% yields by
catalytic hydrogenolysis of 1 in the presence of 10% Pd-C under 3 atm of
[
34,35]
hydrogen.
Novel 9S-acyloxy derivatives of quinidine and dihydroquinidine (3a-u,
and 4b,c,f,h,k,l,q-s) were smoothly obtained by reaction of 1 or 2 with the
[
36-39]
corresponding carboxylic acids (5) in the presence of DCC and DMAP.
Their
1
structures were well characterized by H NMR, HRMS, and m.p..
Scheme 1. Route for the synthesis of 9S-acyloxy derivatives of quinidine and
dihydroquinidine 3a-u and 4b,c,f,h,k,l,q-s.
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Insecticidal activity
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The insecticidal activity of two series (30) of novel 9S-acyloxy derivatives of
quinidine and dihydroquinidine (3a-u, and 4b,c,f,h,k,l,q-s) against the pre-third-instar
larvae of M. separata was assessed at 1 mg/mL by the leaf-dipping method.
Toosendanin, a triterpenoid, extracted and isolated from Meliaceae plants, it is
currently a commercial botanical insecticide, was used as a positive control at a
concentration of 1 mg/mL. As shown in Table 1, the corresponding corrected
mortality rates (CMRs) caused by the intermediate and target compounds after 10 and
20 days were generally lower than after 30 days. For example, the CMRs of 4k
against M. separata after 10, 20 and 30 days were 6.7%, 34.5% and 75.0%,
respectively. That is, the CMRs of 30 days were more than 11 times of that of 10 days.
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Additionally, the symptoms of death of the tested M. separata during the whole
[
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process of growth were similar to our previous reports:
owing to feeding too
many compounds coated leaves during the first 2 days, some larvae of the tested M.
separata exhibited developmental abnormalities during three stages (larval, pupation,
and adult emergence) (Figure 2-4). Specifically, the larval stage was mainly
manifested as wrinkled bodies caused by ecdysial stasis, and slim bodies attributed to
antifeedant (Figure 2); even though the tested insects were normal in larval stage,
deformed pupae or half-larva and half-pupae was appeared in the pupation process
(Figure 3); certainly, some of the tested insects can reach the adult stage, but there
were malformed moths, such as imperfect wing or half-pupae and half moth
(Figure 4). On the other hand, Table 1 shows 26 compounds have equal to or higher
insecticidal activity than the botanical insecticide toosendanin. Thirteen compounds,
3c, 3e, 3h, 3k, 3m, 3q, 3u, 4b, 4c, 4f, 4h, 4k, and 4q displayed more potent
insecticidal activity with the final mortality rates (FMRs) ≥60%. Especially 4
derivatives, 3k, 3m, 3u, and 4k exhibited the best insecticidal activity with FMRs of
71.4%, 75.0%, 71.4%, and 75.0%, respectively.
Table 1. Insecticidal activity of two series of 9S-acyloxy derivatives of quinidine and
dihydroquinidine (3a-u and 4b,c,f,h,k,l,q-s) at 1 mg/mL against M. separata.
[
a]
corrected mortality rate (%)
20 days
Compounds
1
0 days
30 days
32.1 ± 4.7
39.3 ± 4.7
50.0 ± 4.7
53.6 ± 4.7
60.7 ± 4.7
50.0 ± 4.7
i
10.0 ± 0
26.7 ± 4.7
20.0 ± 0
17.2 ± 0
1
27.6 ± 0
3
3
a
37.9 ± 0
b
23.3 ± 9.4
26.7 ± 4.7
13.3 ± 4.7
34.5 ± 4.7
3c
41.4 ± 4.7
3d
17.2 ± 8.2
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e
23.3 ± 9.4
20.0 ± 8.2
20.0 ± 0
44.8 ± 9.4
24.1 ± 4.7
24.1 ± 4.7
44.8 ± 4.7
31.0 ± 4.7
20.7 ± 4.7
48.3 ± 8.2
20.7 ± 4.7
34.5 ± 4.7
44.8 ± 4.7
55.2 ± 4.7
20.7 ± 9.4
37.9 ± 0
67.9 ± 0
3
f
53.6 ± 4.7
46.4 ± 8.2
60.7 ± 4.7
50.0 ± 4.7
35.7 ± 0
3
3
g
h
16.7 ± 4.7
23.3 ± 4.7
13.3 ± 4.7
20.0 ± 0
3
i
3
j
3k
71.4 ± 4.7
42.9 ± 4.7
75.0 ± 4.7
50.0 ± 4.7
57.1 ± 0
3
l
16.7 ± 4.7
26.7 ± 4.7
20.0 ± 0
3m
3
n
o
p
q
3
16.7 ± 4.7
3.3 ± 4.7
26.7 ± 4.7
16.7 ± 4.7
16.7 ± 9.4
30.0 ± 0
3
3
39.3 ± 4.7
64.3 ± 4.7
46.4 ± 0
3r
31.0 ± 4.7
31.0 ± 4.7
41.4 ± 4.7
48.3 ± 0
3
s
53.6 ± 4.7
50.0 ± 0
3
t
3u
23.3 ± 4.7
13.3 ± 4.7
20.0 ± 0
71.4 ± 4.7
53.6 ± 4.7
60.7 ± 4.7
64.3 ± 4.7
60.7± 4.7
67.9 ± 0
2
34.5 ± 4.7
48.3 ± 0
4b
4c
20.0 ± 0
37.9 ± 0
4
f
16.7 ± 4.7
20.0 ± 8.2
6.7 ± 4.7
16.7 ± 4.7
16.7 ± 4.7
26.7 ± 4.7
16.7± 4.7
10.0 ± 0
37.9 ± 0
4
4
h
k
44.8 ± 4.7
34.5 ± 4.7
34.5 ± 4.7
41.4 ± 4.7
31.0 ± 4.7
34.5 ± 4.7
31.0 ± 4.7
3.3 ± 4.7
75.0 ± 4.7
50.0 ± 4.7
67.9 ± 8.2
53.6 ± 4.7
57.1 ± 0
4
l
4q
4r
4
s
Toosendanin
Blank control
50.0 ± 4.7
6.7 ± 4.7
0 ± 0
1
30
[a] Values are means ± S.D. of three replicate.
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Figure 2. The representative abnormal larvae pictures of 3c, 3e, 3m, 3n, 4h and 4r
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during the larval period (CK: blank control group).
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Figure 3. The representative malformed pupae pictures of 3e, 3k, 3o, 3u, 4b and 4k
during the pupation period (CK: blank control group).
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Figure 4. The representative malformed moth pictures of 3e, 3k, 3m, 3u, 4k and 4s
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during the emergence period (CK: blank control group).
At the same time, some interesting and valuable views are obtained by analyzing the
structure-activity relationships (SARs). Overall, as described in Figure 5, 1) a free
9-hydroxyl group is not a prerequisite for insecticidal activity, and C9-substitution is
well tolerated. The bioassay results indicated that introduction of acyloxy groups at
the C9 position on 1 or 2 could significantly affected the insecticidal activity. For
example, the FMRs of 1 and 2 were 39.3% and 53.6%, respectively. Simultaneously,
the FMRs of the corresponding esterification products 3k and 4k were 71.4% and
75.0%, respectively. 2) In addition, the configuration of C8/9 position is important for
insecticidal activity, and 9S-configuration is optimal (e.g., 32.1% for i versus 39.3%
for 1 and 53.6% for 2). 3) Modification of out-ring double-bond is acceptable, and
hydrogenation of double-bond enhances insecticidal activity (e.g., 1 versus 2 and
3b,c,f,h,k,l,q-s versus 4b,c,f,h,k,l,q-s).
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Figure 5. Brief description of structure-insecticidal activity relationships of quinidine
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derivatives.
Interestingly, the tested experiments indicated that for the n-alkyloyloxy series
derivatives, the appropriate chain length of R were very significant for their
insecticidal activity. For example, the FMRs of 3a-e and 4b,c were
50.0%/53.6%/60.7%/50.0%/67.9% and 60.7%/64.3%, respectively. In addition, when
the methyl or nitro group was introduced at the para-position (e.g., 3i and 3r) on the
phenyl ring, the insecticidal activity was more potent than the ortho-position (e.g., 3g
and 3p), but they were not as high as that of the meta-position (e.g., 3h and 3q). For
example, the FMRs of 3h/3q and 3i/3r were 60.7%/64.3% and 50.0%/46.4%,
respectively; however, the FMRs of 3g/3p were 46.4%/39.3%, respectively. Similarly,
when the halogen (e.g., chlorine or bromine) group was introduced at the
para-position (e.g., 3m and 3o) on the phenyl ring, the insecticidal activity was bettter
than the ortho-position (e.g., 3l and 3n), and chlorine atom was more potent (e.g., 75.0%
for 3m, and 57.1% for 3o versus 42.9% for 3l, and 50.0% for 3n.). To 3i-k,
introduction of the p-tert-butylphenyloyloxy group (3k) at the hydroxyl position of 1
could lead to more potent compounds than possessing p-methylphenyloyloxy (3i) and
p-methoxylphenyloyloxy (3j) groups. For example, the FMRs of 3i-k were 50.0%,
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35.7% and 71.4%, respectively. In addition, when R = benzylidene, the corresponding
derivatives (71.4% for 3u) were more active than that of R = 1-naphthylmethylene
(50.0% for 3t).
Conclusion
In summary, two series (30) of novel 9S-acyloxy derivatives of quinidine and
dihydroquinidine (3a-u, and 4b,c,f,h,k,l,q-s) were prepared and assessed for their
insecticidal activity against M. separata in vivo by the leaf-dipping method at 1
mg/mL. Among all the compounds, especially 4 derivatives, 3k, 3m, 3u, and 4k
exhibited the best insecticidal activity with FMRs of 71.4%, 75.0%, 71.4%, and
75.0%, respectively. Furthermore, the SAR of these compounds was also described.
Overall, a free 9-hydroxyl group is not a prerequisite for insecticidal activity and
C9-substitution is well tolerated. The configuration of C8/9 position is important for
insecticidal activity, and 9S-configuration is optimal. Modification of out-ring
double-bond is acceptable, and hydrogenation of double-bond enhances insecticidal
activity. These preliminary results will pave the way for further modification of
quinidine in the development of potential new insecticides. Further research on the
structure-insecticidal activity relationships of quinine derivatives are being pursued in
our laboratory.
Experimental section
Chemistry
Quinine (i), and quinidine (1) were purchased from Wuhan Yuancheng Technology
Development Co., Ltd. (Hubei, China). N,N'-Dicyclohexylcarbodiimide (DCC),
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4-(N,N-dimethylamino)pyridine (DMAP), 10% palladium/carbon (10% Pd-C), and
the corresponding acids RCOOH were ordered online from Aladdin Chemistry Co.,
Ltd. (Shanghai, China). Anhydrous methanol, dry ethyl acetate, petroleum ether and
dichloromethane were analytical grade, and obtained from Beichen Fangzheng
Reagent Factory (Tianjin, China). Detected thin layer chromatography (TLC) was
performed with silica gel 60 GF254 (Qingdao Haiyang Chemical Co., Ltd.). Silica gel
column chromatography (CC) was performed with silica gel 200-300 mesh (Qingdao
Haiyang Chemical Co., Ltd.). Optical rotation was measured on Rudolph Research
1
Analytical Autopol III automatic polarimeter. Proton nuclear magnetic resonance ( H
1
3
NMR) spectra and carbon nuclear magnetic resonance ( C NMR) spectra were
carried out with a Bruker Avance III 400 MHz instrument in deuterated chloroform
(CDCl ) using tetramethylsilane (TMS) as the internal standard. High resolution mass
3
spectrometry (HRMS) was determined on an IonSpec 4.7 T FTMS instrument.
Melting points (m.p.) of all compounds were detected on a digital melting point
apparatus, and were uncorrected.
Synthesis of dihydroquinidine (2)
To a solution of 1 (10.00 g, 30.83 mmol) in methanol (50 mL ) was added 10% Pd-C
(3.50 g, 32.89 mmol) in a hydrogenation reaction vessel. Then the reactor was flushed
with argon three times. The reaction solution was stirred under 3 atm of hydrogen for
5 h. After removing the catalyst by filtration and concentrating the reaction solvent in
vacuo to give the crude residue, which was further dissolved in dichloromethane (150
mL). Subsequently, the mixture was washed by water (3 x 80 mL), dried over
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Chemistry & Biodiversity
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anhydrous Na SO , and concentrated in vacuo to afford 2.
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4
[
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o
Data for 2:
CAS no. 1435-55-8; Yield = 92%, White solid, m.p. 271-273 C;
2
0
1
[α] = +220 (c 3.4 mg/mL, CHCl ). H NMR (400 MHz, CDCl ) δ: 8.67 (dd, J = 4.8
D
3
3
Hz, 1.2 Hz, 1H), 7.98 (d, J = 9.2 Hz, 1H), 7.53 (d, J = 4.4 Hz, 1H), 7.32 (dd, J = 9.2
Hz, 2.8 Hz, 1H), 7.19 (d, J = 2.8 Hz, 1H), 5.61 (d, J = 4.4 Hz, 1H), 3.84 (s, 3H),
3.00-3.09 (m, 2H), 2.83-2.92 (m, 2H), 2.70-2.78 (m, 2H), 1.90-1.97 (m, 1H), 1.69 (s,
1H), 1.47-1.53 (m, 2H), 1.37-1.43 (m, 3H), 1.10-1.17 (m, 1H), 0.82-0.90 (m, 3H).
+
HRMS (ESI): Calcd for C H N O ([M+H] ), 327.2067; found, 327.2071.
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General procedure for the synthesis of 9S-acyloxy derivatives of quinidine and
dihydroquinidine 3a-u, and 4b,c,f,h,k,l,q-s
A mixture of 1 (0.50 mmol), the corresponding acids RCOOH (0.60 mmol), DCC
(0.60 mmol), DMAP (0.1 mmol) in dry dichloromethane (15 mL) was stirred at room
temperature. When the reaction was complete, checked by TLC, the mixture was
filtered to remove urea from the reaction, and the filtrate was diluted by
dichloromethane (45 mL). Subsequently, the diluted organic phase was washed by
saturated aqueous NaHCO (30 mL), and brine (30 mL), dried over anhydrous
3
Na SO , concentrated in vacuo, and purified by CC to give the pure 9S-acyloxy
2
4
[
36-41]
derivatives of quinidine and dihydroquinidine 3a-u, and 4b,c,f,h,k,l,q-s.
The
data of target compounds are shown as follows.
20
1
Data for 3a: Yield = 46%, Yellow oily liquid; [α] = +87 (c 5.3 mg/mL, CHCl ). H
D
3
NMR (400 MHz, CDCl ) δ: 8.73 (d, J = 4.4 Hz, 1H), 8.02 (d, J = 9.2 Hz, 1H),
3
7.33-7.45 (m, 3H), 6.57 (d, J = 6.8 Hz, 1H), 5.98-6.07(m, 1H), 5.08-5.13 (m, 2H),
This article is protected by copyright. All rights reserved.

Chemistry & Biodiversity
10.1002/cbdv.201900696
2
2
2
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2
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2
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2
2
2
37
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3.96 (s, 3H), 3.31 (q, J = 8.0 Hz, 1H), 2.95 (d, J = 9.2 Hz, 2H), 2.80-2.87 (m, 1H),
2.70-2.78 (m, 1H), 2.31 (q, J = 8.4 Hz, 1H), 2.14 (s, 3H), 1.85-1.96 (m, 3H),
1
3
1.54-1.57(m, 2H). C NMR (100 MHz, CDCl ) δ: 169.9, 157.9, 147.3, 144.6, 143.6,
3
140.1, 131.7, 126.9, 121.9, 118.4, 114.9, 101.3, 73.5, 58.9, 55.7, 49.8, 49.1, 39.6, 27.8,
+
26.2, 23.1, 21.1. HRMS (ESI): Calcd for C H N O ([M+H] ), 367.2016; found,
2
2
27
2
3
367.2021.
o
20
Data for 3b: Yield = 38%, Pale yellow solid, m.p. 104-105 C; [α]
= +75 (c 4.3
D
1
mg/mL, CHCl ). H NMR (400 MHz, CDCl ) δ: 8.73 (d, J = 4.4 Hz, 1H), 8.02 (d, J =
3
3
9.2 Hz, 1H), 7.32-7.42 (m, 3H), 6.56 (d, J = 8.4 Hz, 1H), 5.98-6.07 (m, 1H),
5.08-5.13 (m, 2H), 3.96 (s, 3H), 3.84-3.87 (m, 1H), 3.65-3.70 (m, 1H), 3.45-3.51 (m,
3H), 3.32 (q, J = 8.4 Hz, 1H), 2.44-2.49 (m, 2H), 1.97-2.04 (m, 3H), 1.67-1.70 (m,
1
3
2H), 1.13-1.17 (m, 3H). C NMR (100 MHz, CDCl ) δ: 174.9, 157.9, 154.0, 147.3,
3
144.6, 140.0, 131.7, 126.9, 121.9, 118.4, 115.0, 101.2, 73.1, 58.9, 55.6, 49.7, 49.1,
+
39.6, 32.7, 30.8, 27.7, 26.4, 24.7. HRMS (ESI): Calcd for C H N O ([M+H] ),
2
3
29
2
3
381.2173; found, 381.2173.
o
20
Data for 3c: Yield = 63%, White solid, m.p. 147-148 C; [α] = +72 (c 5.1 mg/mL,
D
1
CHCl ). H NMR (400 MHz, CDCl ) δ: 8.73 (d, J = 4.8 Hz, 1H), 8.02 (d, J = 9.2 Hz,
3
3
1H), 7.31-7.44 (m, 3H), 6.56 (d, J = 7.2 Hz, 1H), 5.98-6.07 (m, 1H), 5.07-5.13 (m,
2H), 3.96 (s, 3H), 3.32 (q, J = 8.0 Hz, 1H), 2.94 (d, J = 8.8 Hz, 2H), 2.69-2.84 (m,
2H), 2.35-2.39 (m, 2H), 2.31 (q, J = 8.4 Hz, 1H), 1.82-1.88 (m, 2H), 1.64-1.69 (m,
1
3
2H), 1.47-1.58 (m, 3H), 0.94 (t, J = 7.2 Hz, 3H). C NMR (100 MHz, CDCl ) δ:
3
173.7, 156.8, 154.0, 146.9, 142.7, 141.3, 133.5, 129.8, 120.3, 119.8, 114.8, 101.6,
This article is protected by copyright. All rights reserved.

Chemistry & Biodiversity
10.1002/cbdv.201900696
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
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2
2
2
2
2
59
60
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64
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80
73.7, 55.9, 49.7, 37.7, 32.7, 30.8, 26.3, 25.4, 25.3, 24.7, 18.8, 13.7. HRMS (ESI):
+
Calcd for C H N O ([M+H] ), 395.2329; found, 395.2332.
2
4
31
2
3
20
Data for 3d: Yield = 26%, Pale yellow oily liquid; [α] = +53 (c 3.8 mg/mL, CHCl3).
D
1
H NMR (400 MHz, CDCl ) δ: 8.73 (d, J = 4.4 Hz, 1H), 8.02 (d, J = 8.8 Hz, 1H),
3
7.32-7.41 (m, 3H), 6.54 (d, J = 7.2 Hz, 1H), 5.98-6.07 (m, 1H), 5.07-5.13 (m, 2H),
3.95 (s, 3H), 3.32 (q, J = 8.4 Hz, 1H), 2.93 (d, J = 8.8 Hz, 2H), 2.69-2.85 (m, 2H),
2.36-2.40 (m, 2H), 2.24-2.30 (m, 1H), 1.80-1.85 (m, 2H), 1.61-1.66 (m, 2H),
1
3
1.50-1.57 (m, 3H), 1.24-1.30 (m, 4H), 0.84-0.87 (m, 3H). C NMR (100 MHz,
CDCl ) δ: 172.7, 157.8, 147.3, 144.6, 143.9, 140.2, 131.7, 127.0, 121.8, 118.5, 114.9,
3
101.3, 73.2, 58.9, 55.6, 49.8, 49.1, 39.7, 34.4, 31.2, 27.7, 26.3, 24.5, 23.4, 22.2, 13.8.
+
HRMS (ESI): Calcd for C H N O ([M+H] ), 423.2642; found, 423.2648.
26
35
2
3
20
Data for 3e: Yield = 31%, Pale yellow oily liquid; [α] = +27 (c 3.1 mg/mL, CHCl3).
D
1
H NMR (400 MHz, CDCl ) δ: 8.73 (d, J = 4.4 Hz, 1H), 8.02 (d, J = 9.2 Hz, 1H),
3
7.32-7.42 (m, 3H), 6.55 (d, J = 6.8 Hz, 1H), 5.98-6.07 (m, 1H), 5.07-5.13 (m, 2H),
3.95 (s, 3H), 3.31 (q, J = 8.4 Hz, 1H), 2.94 (d, J = 8.8 Hz, 2H), 2.69-2.85 (m, 2H),
2.36-2.40 (m, 2H), 2.25-2.31 (m, 1H), 1.85-1.96 (m, 2H), 1.53-1.61 (m, 3H),
13
1.23-1.32 (m, 8H), 0.83-0.87 (m, 3H). C NMR (100 MHz, CDCl ) δ: 172.6, 157.7,
3
147.1, 144.4, 143.7, 140.0, 131.5, 126.8, 121.7, 118.3, 114.7, 101.0, 73.0, 58.7, 55.4,
49.5, 48.9, 39.5, 34.3, 32.2, 28.6, 27.6, 26.0, 24.6, 23.2, 22.2, 13.8. HRMS (ESI):
+
Calcd for C H N O ([M+H] ), 437.2799; found, 437.2795.
2
7
37
2
3
o
20
Data for 3f: Yield = 51%, White solid, m.p. 200-201 C; [α] = －12 (c 4.3 mg/mL,
D
1
CHCl ). H NMR (400 MHz, CDCl ) δ: 8.72 (d, J = 4.4 Hz, 1H), 8.08-8.11 (m, 2H),
3
3
This article is protected by copyright. All rights reserved.

Chemistry & Biodiversity
10.1002/cbdv.201900696
2
2
2
2
2
2
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2
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3
3
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81
82
83
84
85
86
87
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89
90
91
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93
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95
96
97
98
99
00
01
02
8.02 (d, J = 9.2 Hz, 1H), 7.57-7.62 (m, 1H), 7.43-7.52 (m, 3H), 7.42 (d, J = 4.8 Hz,
1H), 7.38 (dd, J = 9.2 Hz, 2.4 Hz, 1H), 6.78 (d, J = 7.2 Hz, 1H), 5.98-6.07 (m, 1H),
5.05-5.12 (m, 2H), 3.98 (s, 3H), 3.40-3.49 (m, 2H), 2.93-3.01 (m, 2H), 2.72-2.79 (m,
1
3
1H), 2.26-2.32 (m, 1H), 1.94-2.01 (m, 2H), 1.56-1.62 (m, 3H). C NMR (100 MHz,
CDCl ) δ: 165.4, 157.8, 147.3, 144.5, 143.7, 139.9, 133.3, 131.6, 129.6, 129.5, 128.4,
3
126.8, 121.8, 118.3, 114.8, 101.1, 74.0, 59.2, 55.5, 49.7, 49.1, 39.4, 27.5, 26.1, 23.4.
+
HRMS (ESI): Calcd for C H N O ([M+H] ), 429.2173; found, 429.2175.
27
29
2
3
20
1
Data for 3g: Yield = 27%, White oily liquid; [α] = －22 (c 3.7 mg/mL, CHCl ). H
D
3
NMR (400 MHz, CDCl ) δ: 8.73 (d, J = 4.4 Hz, 1H), 8.07 (dd, J = 7.6 Hz, 1.6 Hz,
3
1H), 8.03 (d, J = 9.2 Hz, 1H), 7.51 (d, J = 2.8 Hz, 1H), 7.41-7.45 (m, 2H), 7.39 (dd, J
= 9.2 Hz, 2.4 Hz, 1H), 7.28-7.30 (m, 1H), 7.24 (t, J = 0.8 Hz, 1H), 6.75 (d, J = 6.8 Hz,
1H), 5.98-6.06 (m, 1H), 5.04-5.11 (m, 2H), 3.97 (s, 3H), 3.45 (q, J = 8.4 Hz, 1H),
2.92-3.04 (m, 2H), 2.73-2.87 (m, 2H), 2.54 (s, 3H), 2.32 (q, J = 8.4 Hz, 1H),
1
3
1.91-1.98 (m, 1H), 1.67-1.74 (m, 2H), 1.58-1.64 (m, 2H). C NMR (100 MHz,
CDCl ) δ: 166.0, 157.9, 147.4, 144.7, 141.0, 132.4, 131.9, 131.8, 130.4, 128.7, 127.0,
3
125.7, 122.0, 118.5, 115.0, 101.3, 73.6, 59.3, 55.7, 49.8, 49.1, 29.7, 27.7, 25.5, 24.9,
+
21.8. HRMS (ESI): Calcd for C H N O ([M+H] ), 443.2329; found, 443.2332.
2
8
31
2
3
o
20
Data for 3h: Yield = 25%, White solid, m.p. 129-130 C; [α] = －14 (c 3.6 mg/mL,
D
1
CHCl ). H NMR (400 MHz, CDCl ) δ: 8.72 (d, J = 4.4 Hz, 1H), 8.02 (d, J = 9.2 Hz,
3
3
1H), 7.89-7.91 (m, 2H), 7.50 (d, J = 2.8 Hz, 1H), 7.33-7.43 (m, 4H), 6.76 (d, J = 6.8
Hz, 1H), 6.00-6.09 (m, 1H), 5.06-5.13 (m, 2H), 3.98 (s, 3H), 3.45 (q, J = 8.4 Hz, 1H),
2.84-3.05 (m, 3H), 2.74-2.80 (m, 1H), 2.42 (s, 3H), 2.26-2.33 (m, 1H), 1.98-2.04 (m,
This article is protected by copyright. All rights reserved.

Chemistry & Biodiversity
10.1002/cbdv.201900696
1
3
3
3
3
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3
3
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3
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1H), 1.86-1.87 (m, 1H), 1.54-1.61 (m, 3H). C NMR (100 MHz, CDCl ) δ: 165.6,
3
157.8, 1474, 144.6, 143.8, 140.1, 138.3, 134.2, 131.7, 130.2, 130.1, 129.5, 128.4,
126.9, 121.9, 118.4, 114.8, 101.2, 74.1, 59.2, 55.6, 49.8, 49.3, 39.5, 27.6, 26.3, 23.4,
+
21.2. HRMS (ESI): Calcd for C H N O ([M+H] ), 443.2329; found, 443.2326.
2
8
31
2
3
o
20
Data for 3i: Yield = 44%, White solid, m.p. 65-66 C; [α] = －43 (c 3.3 mg/mL,
D
1
CHCl ). H NMR (400 MHz, CDCl ) δ: 8.71 (d, J = 4.4 Hz, 1H), 7.98-8.02 (m, 3H),
3
3
7.50 (d, J = 2.4 Hz, 1H), 7.42 (d, J = 4.8 Hz, 1H), 7.38 (dd, J = 9.2 Hz, 2.4 Hz, 1H),
7.25-7.27 (m, 2H), 6.75 (d, J = 6.8 Hz, 1H), 5.99-6.07 (m, 1H), 5.05-5.13 (m, 2H),
3.97 (s, 3H), 3.45 (q, J = 8.4 Hz, 1H), 2.82-3.01 (m, 3H), 2.71-2.79 (m, 1H), 2.42 (s,
13
3H), 2.32 (q, J = 8.4 Hz, 1H), 1.97-2.04 (m, 2H), 1.55-1.62 (m, 3H). C NMR (100
MHz, CDCl ) δ: 165.5, 157.8, 147.4, 144.6, 144.2, 144.0, 140.1, 131.7, 129.7, 129.2,
3
126.9, 126.8, 121.9, 118.5, 114.8, 101.2, 74.0, 59.3, 55.6, 49.8, 49.2, 39.5, 27.6, 26.3,
+
23.5 21.7. HRMS (ESI): Calcd for C H N O ([M+H] ), 443.2329; found, 443.2335.
2
8
31
2
3
o
20
Data for 3j: Yield = 32%, White solid, m.p. 187-188 C; [α] = －31 (c 4.1 mg/mL,
D
1
CHCl ). H NMR (400 MHz, CDCl ) δ: 8.71 (d, J = 4.4 Hz, 1H), 8.04-8.08 (m, 2H),
3
3
8.00-8.02 (m, 1H), 7.52 (d, J = 2.4 Hz, 1H), 7.41 (d, J = 4.4 Hz, 1H), 7.38 (dd, J = 9.2
Hz, 2.8 Hz, 1H), 6.92-6.96 (m, 2H), 6.81 (d, J = 6.4 Hz, 1H), 5.99-6.07 (m, 1H),
5.06-5.14 (m, 2H), 3.97 (s, 3H), 3.87 (s, 3H), 3.39-3.51 (m, 3H), 2.97-3.08 (m, 2H),
1
3
2.28-2.32 (m, 1H), 1.90-1.96 (m, 3H), 1.56-1.58 (m, 2H). C NMR (100 MHz,
CDCl ) δ: 163.7, 158.0, 147.3, 144.6, 143.7, 139.7, 131.8, 131.7, 126.8, 122.1, 121.9,
3
118.2, 115.2, 113.8, 113.1, 101.2, 73.3, 59.1, 55.5, 49.6, 48.9, 39.1, 27.5, 25.5, 24.9,
+
22.9. HRMS (ESI): Calcd for C H N O ([M+H] ), 459.2278; found, 459.2281.
2
8
31
2
4
This article is protected by copyright. All rights reserved.

Chemistry & Biodiversity
10.1002/cbdv.201900696
o
20
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
Data for 3k: Yield = 32%, Brown solid, m.p. 75-76 C; [α] = －25 (c 4.4 mg/mL,
D
1
CHCl ). H NMR (400 MHz, CDCl ) δ: 8.70 (d, J = 4.4 Hz, 1H), 8.00-8.05 (m, 3H),
3
3
7.53 (d, J = 2.4 Hz, 1H), 7.47-7.50 (m, 2H), 7.41 (d, J = 4.4 Hz, 1H), 7.39 (dd, J = 9.6
Hz, 2.8 Hz, 1H), 6.83 (d, J = 6.4 Hz, 1H), 6.00-6.08 (m, 1H), 5.07-5.16 (m, 2H), 3.98
(s, 3H), 3.40-3.46 (m, 1H), 2.88-3.10 (m, 3H), 2.75-2.83 (m, 1H), 2.35 (q, J = 8.4 Hz,
1
3
2H), 1.87-1.88 (m, 1H), 1.52-1.62 (m, 3H), 1.34 (s, 9H). C NMR (100 MHz, CDCl )
3
δ: 165.4, 158.0, 157.2, 147.3, 144.6, 143.7, 139.8, 131.7, 129.6, 126.9, 126.7, 125.5,
122.0, 118.3, 115.1, 101.2, 73.6, 59.1, 55.7, 49.7, 49.1, 39.3, 35.1, 31.2, 31.0, 29.6,
+
27.6, 26.0, 23.2. HRMS (ESI): Calcd for C H N O ([M+H] ), 485.2799; found,
3
1
37
2
3
485.2802.
o
20
Data for 3l: Yield = 62%, Pale yellow solid, m.p. 140-141 C; [α]
= －7 (c 3.3
D
1
mg/mL, CHCl ). H NMR (400 MHz, CDCl ) δ: 8.75 (d, J = 4.8 Hz, 1H), 8.03 (d, J =
3
3
8.8 Hz, 1H), 7.87 (dd, J = 7.6 Hz, 1.2 Hz, 1H), 7.28-7.51 (m, 6H), 6.79 (d, J = 7.6 Hz,
1H), 5.97-6.05 (m, 1H), 5.03-5.08 (m, 2H), 3.97 (s, 3H), 3.43-3.52 (m, 3H), 2.93-2.96
(m, 1H), 2.70-2.78 (m, 1H), 2.31 (q, J = 8.4 Hz, 1H), 1.90-1.95 (m, 3H), 1.56-1.61 (m,
1
3
2H). C NMR (100 MHz, CDCl ) δ: 164.7, 157.9, 153.0, 147.4, 144.7, 136.7, 133.8,
3
133.0, 131.6, 131.3, 130.4, 129.6, 127.1, 126.7, 122.0, 118.9, 115.0, 101.2, 74.6, 59.3,
55.7, 49.7, 49.1, 39.6, 27.7, 26.2, 24.5. HRMS (ESI): Calcd for C H ClN O
3
2
7
28
2
+
([M+H] ), 463.1783; found, 463.1784.
o
20
Data for 3m: Yield = 40%, White solid, m.p. 101-102 C; [α]
= －23 (c 5.0
D
1
mg/mL, CHCl ). H NMR (400 MHz, CDCl ) δ: 8.72 (d, J = 4.4 Hz, 1H), 8.01-8.04
3
3
(m, 3H), 7.36-7.48 (m, 5H), 6.76 (d, J = 7.2 Hz, 1H), 5.97-6.05 (m, 1H), 5.05-5.14 (m,
This article is protected by copyright. All rights reserved.

Chemistry & Biodiversity
10.1002/cbdv.201900696
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
47
48
49
50
51
52
53
54
55
56
57
58
59
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61
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68
2H), 3.97 (s, 3H), 3.39-3.51 (m, 2H), 2.98 (d, J = 9.2 Hz, 2H), 2.71-2.79 (m, 1H),
1
3
2.26-2.33 (m, 1H), 1.91-1.97 (m, 3H), 1.66-1.72 (m, 2H). C NMR (100 MHz,
CDCl ) δ: 164.7, 157.9, 147.4, 144.6, 143.5, 140.0, 139.9, 131.8, 131.1, 128.9, 128.0,
3
126.9, 121.9, 118.4, 115.0, 101.2, 74.3, 59.3, 55.6, 49.8, 49.2, 39.3, 27.5, 26.2, 23.5.
+
HRMS (ESI): Calcd for C H ClN O ([M+H] ), 463.1783; found, 463.1788.
27
28
2
3
20
1
Data for 3n: Yield = 64%, White oily liquid; [α] = －18 (c 3.1 mg/mL, CHCl ). H
D
3
NMR (400 MHz, CDCl ) δ: 8.76 (d, J = 4.4 Hz, 1H), 8.03 (d, J = 9.2 Hz, 1H),
3
7.81-7.84 (m, 1H), 7.66-7.69 (m, 1H), 7.49-7.50 (m, 2H), 7.33-7.40 (m, 3H), 6.79 (d,
J = 7.6 Hz, 1H), 5.97-6.06 (m, 1H), 5.03-5.08 (m, 2H), 3.97 (s, 3H), 3.47 (q, J = 8.4
Hz, 1H), 2.94-2.97 (m, 2H), 2.70-2.83 (m, 2H), 2.32 (q, J = 8.4 Hz, 1H), 1.85-2.00 (m,
1
3
2H), 1.63-1.70 (m, 1H), 1.56-1.60 (m, 2H). C NMR (100 MHz, CDCl ) δ: 165.0,
3
157.9, 147.4, 144.7, 143.3, 139.9, 134.5, 132.9, 131.8, 131.5, 131.4, 127.2, 127.0,
122.0, 121.7, 118.9, 115.0, 101.3, 74.6, 59.3, 55.7, 49.7, 49.1, 39.6, 27.7, 26.1, 23.9.
+
HRMS (ESI): Calcd for C H BrN O ([M+H] ), 507.1278; found, 507.1281.
27
28
2
3
o
20
Data for 3o: Yield = 25%, White solid, m.p. 56-57 C; [α] = －41 (c 3.8 mg/mL,
D
1
CHCl ). H NMR (400 MHz, CDCl ) δ: 8.72 (d, J = 4.8 Hz, 1H), 8.03 (d, J = 9.2 Hz,
3
3
1H), 7.93-7.97 (m, 2H), 7.59-7.62 (m, 2H), 7.49 (d, J = 2.8 Hz, 1H), 7.36-7.39 (m,
2H), 6.78 (d, J = 6.8 Hz, 1H), 5.96-6.05 (m, 1H), 5.05-5.14 (m, 2H), 3.98 (s, 3H),
3.39-3.45 (m, 1H), 2.98 (d, J = 8.8 Hz, 2H), 2.72-2.93 (m, 2H), 2.26-2.33 (m, 1H),
1
3
1.97-2.00 (m, 1H), 1.87-1.88 (m, 1H), 1.56-1.63 (m, 3H). C NMR (100 MHz,
CDCl ) δ: 164.8, 158.0, 147.4, 144.7, 143.5, 139.9, 131.9, 131.8, 131.2, 128.6, 128.5,
3
126.9, 122.0, 118.3, 115.0, 101.2, 59.2, 55.6, 49.8, 49.2, 39.3, 29.7, 26.2, 23.5. HRMS
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Chemistry & Biodiversity
10.1002/cbdv.201900696
+
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
69
70
71
72
73
74
75
76
77
78
79
80
81
82
83
84
85
86
87
88
89
90
(ESI): Calcd for C H BrN O ([M+H] ), 507.1278; found, 507.1279.
27 28 2 3
o
20
Data for 3p: Yield = 61%, Pale yellow solid, m.p. 80-81 C; [α]
= －27 (c 3.8
D
1
mg/mL, CHCl ). H NMR (400 MHz, CDCl ) δ: 8.93 (t, J = 2.0 Hz, 1H), 8.74 (d, J =
3
3
4.4 Hz, 1H), 8.44-8.47 (m, 1H), 8.38-8.41 (m, 1H), 8.04 (d, J = 9.2 Hz, 1H), 7.70 (t, J
= 8.0 Hz, 1H), 7.50 (d, J = 2.8 Hz, 1H), 7.38-7.42 (m, 2H), 6.82 (d, J = 7.6 Hz, 1H),
6.00-6.09 (m, 1H), 5.07-5.17 (m, 2H), 4.00 (s, 3H), 3.53 (q, J = 8.4 Hz, 1H), 2.98 (d,
J = 9.2 Hz, 2H), 2.85-2.91 (m, 1H), 2.73-2.81 (m, 1H), 2.35 (q, J = 8.4 Hz, 1H),
13
1.90-2.00 (m, 2H), 1.59-1.70 (m, 3H). C NMR (100 MHz, CDCl ) δ: 164.3, 158.0,
3
147.9, 147.4, 139.9, 132.9, 132.1, 131.8, 129.9, 126.8, 123.9, 122.0, 118.9, 115.0,
101.2, 75.3, 59.5, 55.7, 49.6, 48.9, 39.5, 27.5, 26.1, 24.2. HRMS (ESI): Calcd for
+
C H N O ([M+H] ), 474.2023; found, 474.2029.
27
28
3
5
o
20
Data for 3q: Yield = 30%, White solid, m.p. 73-74 C; [α] = －30 (c 4.5 mg/mL,
D
1
CHCl ). H NMR (400 MHz, CDCl ) δ: 8.79 (d, J = 4.8 Hz, 1H), 8.04 (d, J = 9.2 Hz,
3
3
1H), 7.89-7.93 (m, 1H), 7.64-7.67 (m, 3H), 7.46 (d, J = 2.4 Hz, 1H), 7.37-7.41 (m,
2H), 6.70 (d, J = 8.4 Hz, 1H), 5.95-6.04 (m, 1H), 5.03-5.09 (m, 2H), 3.95 (s, 3H),
3.43 (q, J = 8.8 Hz. 1H), 2.88-2.94 (m, 2H), 2.66-2.76 (m, 2H), 2.30 (q, J = 8.4 Hz,
1
3
1H), 1.68-1.72 (m, 3H), 1.55-1.60 (m, 2H). C NMR (100 MHz, CDCl ) δ: 163.5,
3
158.1, 148.2, 147.4, 144.7, 142.9, 139.8, 135.5, 131.9, 131.3, 129.9, 127.9, 126.8,
124.4, 122.0, 118.6, 115.1, 101.1, 75.2, 59.1, 55.6, 49.8, 49.2, 39.3, 27.5, 26.2, 23.7.
+
HRMS (ESI): Calcd for C H N O ([M+H] ), 474.2023; found, 474.2024.
27
28
3
5
o
20
Data for 3r: Yield = 32%, Yellow solid, m.p. 85-86 C; [α] = －29 (c 4.3 mg/mL,
D
1
CHCl ). H NMR (400 MHz, CDCl ) δ: 8.74 (d, J = 4.4 Hz, 1H), 8.24-8.33 (m, 4H),
3
3
This article is protected by copyright. All rights reserved.

Chemistry & Biodiversity
10.1002/cbdv.201900696
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
4
4
4
91
92
93
94
95
96
97
98
99
00
01
02
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11
12
8.04 (d, J = 9.2 Hz, 1H), 7.48 (d, J = 1.2 Hz, 1H), 7.38-7.41 (m, 2H), 6.79 (d, J = 6.4
Hz, 1H), 5.97-6.05 (m, 1H), 5.16 (d, J = 10.4 Hz, 1H), 5.07-5.12 (m, 1H), 3.99 (s, 3H),
3.49 (q, J = 8.4 Hz, 1H), 2.86-2.98 (m, 3H), 2.73-2.80 (m, 1H), 2.31-2.35 (m, 1H),
1
3
1.61-1.64 (m, 5H). C NMR (100 MHz, CDCl ) δ: 163.7, 158.0, 150.7, 147.4, 144.7,
3
143.1, 139.9, 134.9, 131.9, 130.8, 126.9, 123.7, 122.0, 118.3, 115.0, 101.1, 75.0, 59.2,
+
55.6, 49.8, 49.2, 39.2, 27.4, 26.2, 23.6. HRMS (ESI): Calcd for C H N O ([M+H] ),
2
7
28
3
5
474.2023; found, 474.2030.
o
20
Data for 3s: Yield = 66%, Pale yellow solid, m.p. 84-85 C; [α]
= －78 (c 3.9
D
1
mg/mL, CHCl ). H NMR (400 MHz, CDCl ) δ: 8.74 (d, J = 4.8 Hz, 1H), 8.56 (d, J =
3
3
2.0 Hz, 1H), 8.20 (dd, J = 8.4 Hz, 2.0 Hz, 1H), 8.04 (d, J = 9.2 Hz, 1H), 7.68 (d, J =
8.4 Hz, 1H), 7.46 (d, J = 2.8 Hz, 1H), 7.37-7.41(m, 2H), 6.78 (d, J = 6.8 Hz, 1H),
5.97-6.05 (m, 1H), 5.06-5.16 (m, 2H), 3.99 (s, 3H), 3.42-3.54 (m, 3H), 3.18-3.22 (m,
1H), 2.93-2.97 (m, 1H), 2.34 (q, J = 8.0 Hz, 1H), 1.93-1.96 (m, 3H), 1.57-1.59 (m,
1
3
2H). C NMR (100 MHz, CDCl ) δ: 162.8, 158.1, 147.9, 147.3, 144.7, 142.7, 139.8,
3
133.8, 132.4, 132.3, 131.9, 129.4, 126.8, 126.4, 122.0, 118.3, 115.1, 101.0, 75.2, 59.0,
55.7, 49.8, 49.2, 39.1, 27.3, 26.1, 23.5. HRMS (ESI): Calcd for C H ClN O
5
2
7
27
3
+
([M+H] ), 508.1634; found, 508.1635.
2
0
1
Data for 3t: Yield = 27%, White oily liquid; [α] = +88 (c 3.1 mg/mL, CHCl ). H
D
3
NMR (400 MHz, CDCl ) δ: 8.45 (d, J = 4.4 Hz, 1H), 7.97 (d, J = 9.2 Hz, 1H), 7.88
3
(dd, J = 8.0 Hz, 1.2 Hz, 1H), 7.83 (dd, J = 8.0 Hz, 1.2 Hz, 2H), 7.27-7.49 (m, 6H),
6.84 (d, J = 4.4 Hz, 1H), 6.55 (d, J = 4.0 Hz, 1H), 5.79-5.88 (m, 1H), 5.02-5.09 (m,
2H), 4.13 (s, 2H), 3.83 (s, 3H), 3.13-3.19 (m, 1H), 2.80-2.86 (m, 2H), 2.64-2.78 (m,
This article is protected by copyright. All rights reserved.

Chemistry & Biodiversity
10.1002/cbdv.201900696
1
3
4
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4
4
4
4
4
4
4
4
4
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4
4
4
4
4
4
4
4
4
4
13
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15
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29
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31
32
33
34
2H), 2.23 (q, J = 8.4 Hz, 1H), 1.42-1.70 (m, 5H). C NMR (100 MHz, CDCl ) δ:
3
170.5, 157.8, 147.1, 144.5, 143.1, 139.9, 133.7, 131.9, 131.6, 129.9, 128.7, 128.3,
128.1, 126.7, 126.4, 125.9, 125.4, 123.6, 121.8, 118.3, 114.9, 101.0, 73.9, 58.6, 55.5,
+
49.7, 49.1, 39.7, 39.6, 27.6, 26.0, 22.9. HRMS (ESI): Calcd for C H N O ([M+H] ),
3
2
33
2
3
493.2486; found, 493.2491.
20
Data for 3u: Yield = 33%, Yellow oily liquid; [α] = +162 (c 4.2 mg/mL, CHCl3).
D
1
H NMR (400 MHz, CDCl ) δ: 8.66 (d, J = 4.8 Hz, 1H), 7.99-8.02 (m, 1H), 7.35-7.38
3
(m, 2H), 7.23-7.27 (m, 2H), 7.18 (d, J = 4.8 Hz, 1H), 6.97-7.01 (m, 1H), 6.83-6.87 (m,
2H), 6.66 (d, J = 7.2 Hz, 1H), 5.98-6.06 (m, 1H), 5.07-5.13 (m, 2H), 4.69 (d, J = 2.4
Hz, 2H), 3.91 (s, 3H), 3.34 (q, J = 8.4 Hz, 1H), 2.92 (d, J = 8.8 Hz, 2H), 2.71-2.86 (m,
13
2H), 2.23-2.30 (m, 1H), 1.78-1.80 (m, 2H), 1.52-1.57(m, 2H), 1.40-1.48(m, 1H). C
NMR (100 MHz, CDCl ) δ: 168.3, 157.4, 147.2, 144.6, 142.5, 139.8, 136.5, 131.7,
3
129.6, 129.3, 126.7, 122.0, 121.9, 120.6, 117.4, 115.2, 114.4, 101.0, 74.1, 65.3, 58.6,
+
55.6, 49.6, 49.0, 39.5, 27.7, 25.9, 23.1. HRMS (ESI): Calcd for C H N O ([M+H] ),
2
8
31
2
3
443.2329; found, 443.2333.
o
20
Data for 4b: Yield = 42%, White solid, m.p. 89-90 C; [α] = +186 (c 3.1 mg/mL,
D
1
CHCl ). H NMR (400 MHz, CDCl ) δ: 8.73 (d, J = 4.8 Hz, 1H), 8.01 (d, J = 8.8 Hz,
3
3
1H), 7.42 (d, J = 2.8 Hz, 1H), 7.38 (dd, J = 9.2 Hz, 2.8 Hz, 1H), 7.34 (d, J = 4.8 Hz,
1H), 6.55 (d, J = 7.2 Hz, 1H), 3.96 (s, 3H), 3.30 (q, J = 8.4 Hz, 1H), 2.93 (dd, J = 13.6
Hz, 8.8 Hz, 1H), 2.63-2.81 (m, 3H), 2.38-2.45 (m, 2H), 1.73-1.81 (m, 2H), 1.43-1.60
13
(m, 6H), 1.18 (t, J = 7.6 Hz, 3H), 0.93 (t, J = 7.2 Hz, 3H). C NMR (100 MHz,
CDCl ) δ: 173.4, 157.8, 147.4, 144.6, 143.9, 131.7, 127.0, 121.8, 118.5, 101.3, 73.3,
3
This article is protected by copyright. All rights reserved.

Chemistry & Biodiversity
10.1002/cbdv.201900696
4
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4
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4
4
4
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4
4
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4
4
4
4
4
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
59.0, 55.5, 50.7, 49.9, 37.2, 27.7, 27.1, 25.9, 25.4, 23.3, 12.0. HRMS (ESI): Calcd for
+
C H N O ([M+H] ), 383.2329; found, 383.2331.
23
31
2
3
20
Data for 4c: Yield = 63%, Yellow oily liquid; [α] = +197 (c 4.2 mg/mL, CHCl3).
D
1
H NMR (400 MHz, CDCl ) δ: 8.73 (d, J = 4.4 Hz, 1H), 8.01 (d, J = 9.2 Hz, 1H), 7.42
3
(d, J = 2.8 Hz, 1H), 7.37 (dd, J = 9.2 Hz, 2.8 Hz, 1H), 7.33 (d, J = 4.8 Hz, 1H), 6.55
(d, J = 7.2 Hz, 1H), 3.96 (s, 3H), 3.29 (q, J = 8.4 Hz, 1H), 2.93 (dd, J = 13.6 Hz, 8.8
Hz, 1H), 2.64-2.79 (m, 3H), 2.35-2.38 (m, 2H), 1.73-1.79 (m, 2H), 1.64-1.70 (m, 2H),
13
1.44-1.57 (m, 6H), 0.90-0.94 (m, 6H). C NMR (100 MHz, CDCl ) δ: 172.6, 157.8,
3
147.3, 144.6, 144.0, 131.7, 127.0, 121.9, 118.5, 101.3, 73.3, 59.0, 55.6, 50.7, 49.9,
37.2, 36.3, 27.1, 26.0, 25.4, 23.2, 18.3, 13.7, 11.9. HRMS (ESI): Calcd for
+
C H N O ([M+H] ), 397.2486; found, 397.2488.
24
33
2
3
20
D
1
Data for 4f: Yield = 24%, Yellow oily liquid; [α] = －3 (c 5.0 mg/mL, CHCl ). H
3
NMR (400 MHz, CDCl ) δ: 8.72 (d, J = 4.4 Hz, 1H), 8.10-8.12 (m, 1H), 8.09-8.10 (m,
3
1H), 8.02 (d, J = 9.2 Hz, 1H), 7.57-7.62 (m, 1H), 7.52 (d, J = 2.8 Hz, 1H), 7.45-7.49
(m, 2H), 7.43 (d, J = 4.4 Hz, 1H), 7.38 (dd, J = 9.2 Hz, 2.8 Hz, 1H), 6.78 (d, J = 7.2
Hz, 1H), 3.98 (s, 3H), 3.45 (q, J = 8.4 Hz, 1H), 2.70-2.97 (m, 4H), 1.90-1.96 (m, 1H),
1
3
1.77 (s, 1H), 1.49-1.62 (m, 6H), 0.88-0.92 (m, 3H). C NMR (100 MHz, CDCl ) δ:
3
165.5, 157.9, 147.4, 144.7, 143.7, 133.4, 131.7, 129.7, 129.6, 128.5, 126.9, 122.0,
118.5, 101.2, 74.0, 59.3, 55.7, 50.7, 49.9, 37.2, 26.9, 26.1, 25.3, 23.3, 11.8. HRMS
+
(ESI): Calcd for C H N O ([M+H] ), 431.2329; found, 431.2325.
2
7
31
2
3
20
Data for 4h: Yield = 80%, Yellow oily liquid; [α] = －32 (c 4.7 mg/mL, CHCl3).
D
1
H NMR (400 MHz, CDCl ) δ: 8.70 (d, J = 4.8 Hz, 1H), 8.04 (d, J = 9.2 Hz, 1H),
3
This article is protected by copyright. All rights reserved.

Chemistry & Biodiversity
10.1002/cbdv.201900696
4
4
4
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4
4
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4
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4
4
4
4
57
58
59
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61
62
63
64
65
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76
77
78
7.91-7.94 (m, 2H), 7.84-7.87 (m, 1H), 7.60 (d, J = 2.8 Hz, 1H), 7.44 (d, J = 7.6 Hz,
1H), 7.37 (d, J = 5.2 Hz, 1H), 7.29 (d, J = 4.8 Hz, 1H), 7.08 (d, J = 1.2 Hz, 1H), 3.98
(s, 3H), 3.44-3.49 (m, 1H), 2.88-3.09 (m, 4H), 2.43 (s, 3H), 2.16-2.22 (m, 1H), 1.86 (s,
1
3
1H), 1.58-1.68 (m, 5H), 1.43-1.50 (m, 1H), 0.95 (t, J = 7.2 Hz, 3H). C NMR (100
MHz, CDCl ) δ: 165.0, 158.4, 147.1, 144.6, 142.8, 138.5, 137.4, 134.3, 131.6, 130.1,
3
128.5, 127.8, 126.8, 122.5, 117.8, 100.9, 72.9, 58.4, 56.0, 49.9, 49.3, 36.5, 29.7, 26.2,
+
25.8, 25.2, 21.2, 11.7. HRMS (ESI): Calcd for C H N O ([M+H] ), 445.2486;
28
33
2
3
found, 445.2487.
20
Data for 4k: Yield = 53%, Yellow oily liquid; [α] = －20 (c 3.2 mg/mL, CHCl3).
D
1
H NMR (400 MHz, CDCl ) δ: 8.70 (d, J = 4.8 Hz, 1H), 8.02-8.05 (m, 2H), 8.02 (d, J
3
= 9.2 Hz, 1H), 7.58 (s, 1H), 7.50 (dd, J = 6.4 Hz, 2.0 Hz, 2H), 7.36-7.40 (m, 2H), 6.93
(d, J = 2.8 Hz, 1H), 4.01 (s, 3H), 3.47 (dd, J = 15.2 Hz, 8.8 Hz, 1H), 2.82-3.03 (m,
4H), 1.98-2.08 (m, 1H), 1.83 (s, 1H), 1.50-1.64 (m, 6H), 1.35 (s, 9H), 0.94 (t, J = 7.2
13
Hz, 3H). C NMR (100 MHz, CDCl ) δ: 165.2, 158.1, 157.3, 147.2, 144.6, 143.4,
3
131.7, 129.5, 126.7, 125.6, 124.8, 122.2, 118.2, 101.1, 73.2, 59.0, 55.9, 50.4, 49.7,
36.9, 35.1, 31.2, 31.0, 29.6, 26.4, 26.0, 25.2, 22.6, 11.8. HRMS (ESI): Calcd for
+
C H N O ([M+H] ), 487.2955; found, 487.2955.
31
39
2
3
20
Data for 4l: Yield = 31%, Yellow oily liquid; [α] = －14 (c 3.7 mg/mL, CHCl3).
D
1
H NMR (400 MHz, CDCl ) δ: 8.76 (d, J = 4.4 Hz, 1H), 8.03 (d, J = 9.2 Hz, 1H), 7.87
3
(dd, J = 7.6 Hz, 1.2 Hz, 1H), 7.42-7.51 (m, 4H), 7.31-7.39 (m, 2H), 6.79 (d, J = 7.6
Hz, 1H), 3.97 (s, 3H), 3.46 (q, J = 8.4 Hz, 1H), 2.69-2.95 (m, 4H), 1.87-1.95 (m, 1H),
1
3
1.76 (s, 1H), 1.46-1.61 (m, 6H), 0.85-0.88 (m, 3H). C NMR (100 MHz, CDCl ) δ:
3
This article is protected by copyright. All rights reserved.

Chemistry & Biodiversity
10.1002/cbdv.201900696
4
4
4
4
4
4
4
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4
4
4
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4
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4
4
4
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5
79
80
81
82
83
84
85
86
87
88
89
90
91
92
93
94
95
96
97
98
99
00
164.8, 157.9, 147.4, 144.7, 143.4, 133.7, 132.9, 131.7, 131.5, 131.2, 129.5, 127.1,
126.7, 122.0, 119.0, 101.3, 74.7, 59.3, 55.6, 50.6, 49.8, 37.2, 27.0, 26.1, 25.3, 23.9,
+
11.9. HRMS (ESI): Calcd for C H ClN O ([M+H] ), 465.1939; found, 465.1945.
2
7
30
2
3
20
Data for 4q: Yield = 66%, Yellow oily liquid; [α] = －27 (c 3.2 mg/mL, CHCl3).
D
1
H NMR (400 MHz, CDCl ) δ: 8.94 (t, J = 2.0 Hz, 1H), 8.74 (d, J = 4.4 Hz, 1H),
3
8.45-8.48 (m, 1H), 8.38-8.40 (m, 1H), 8.04 (d, J = 9.2 Hz, 1H), 7.71 (t, J = 8.0 Hz,
1H), 7.55 (s, 1H), 7.38-7.41 (m, 2H), 6.89 (d, J = 5.6 Hz, 1H), 4.03 (s, 3H), 3.52 (dd,
J = 16.0 Hz, 8.4 Hz, 1H), 2.78-3.07 (m, 4H), 1.88-1.98 (m, 1H), 1.84 (s, 1H),
13
1.56-1.66 (m, 6H), 0.94 (t, J = 7.2 Hz, 3H). C NMR (100 MHz, CDCl ) δ: 163.5,
3
158.1, 148.2, 147.4, 144.7, 142.8, 135.5, 131.9, 131.3, 129.9, 127.9, 126.8, 124.3,
122.1, 118.6, 101.1, 75.0, 59.2, 55.7, 50.8, 49.8, 37.1, 26.8, 25.9, 25.4, 23.4, 11.9.
+
HRMS (ESI): Calcd for C H N O ([M+H] ), 476.2180; found, 476.2183.
27
30
3
5
o
20
Data for 4r: Yield = 69%, Yellow solid, m.p. 70-71 C; [α] = －26 (c 3.9 mg/mL,
D
1
CHCl ). H NMR (400 MHz, CDCl ) δ: 8.74 (d, J = 4.8 Hz, 1H), 8.30-8.33 (m, 2H),
3
3
8.24-8.27 (m, 2H), 8.04 (d, J = 9.2 Hz, 1H), 7.51-7.52 (m, 1H), 7.38-7.41 (m, 2H),
6.85 (d, J = 4.8 Hz, 1H), 4.00 (s, 3H), 3.50 (dd, J = 16.4 Hz, 8.4 Hz, 1H), 2.73-2.97
(m, 4H), 1.88-1.94 (m, 1H), 1.81 (s, 1H), 1.49-1.64 (m, 6H), 0.93 (t, J = 7.2 Hz, 3H).
1
3
C NMR (100 MHz, CDCl ) δ: 163.6, 158.1, 150.7, 147.3, 144.7, 134.9, 131.9, 131.6,
3
130.7, 130.2, 126.8, 123.7, 123.0, 122.1, 118.3, 101.1, 74.6, 59.1, 55.7, 50.6, 49.7,
+
36.9, 26.6, 25.9, 25.4, 23.2, 11.8. HRMS (ESI): Calcd for C H N O ([M+H] ),
27
30
3
5
476.2180; found, 476.2185.
20
Data for 4s: Yield = 52%, Yellow oily liquid; [α] = －42 (c 3.5 mg/mL, CHCl3).
D
This article is protected by copyright. All rights reserved.

Chemistry & Biodiversity
10.1002/cbdv.201900696
1
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01
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H NMR (400 MHz, CDCl ) δ: 8.74 (d, J = 4.4 Hz, 1H), 8.57 (d, J = 2.0 Hz, 1H), 8.19
3
(dd, J = 8.4 Hz, 2.0 Hz, 1H), 8.04 (d, J = 9.2 Hz, 1H), 7.69 (d, J = 8.4 Hz, 1H), 7.51 (s,
1H), 7.37-7.41 (m, 2H), 6.48 (d, J = 7.2 Hz, 1H), 4.01 (s, 3H), 3.50 (dd, J = 16.4 Hz,
8.8 Hz, 1H), 2.64-3.01 (m, 4H), 1.88-1.95 (m, 1H), 1.83 (s, 1H), 1.52-1.65 (m, 6H),
1
3
0.90-0.94 (m, 3H). C NMR (100 MHz, CDCl ) δ: 162.7, 158.1, 147.8, 147.3, 144.7,
3
133.8, 132.5, 132.4, 131.9, 131.2, 129.4, 126.8, 126.4, 122.1, 118.4, 101.0, 74.9, 59.0,
55.7, 50.7, 49.7, 36.9, 26.6, 25.8, 25.4, 23.2, 11.8. HRMS (ESI): Calcd for
+
C H ClN O ([M+H] ), 510.1790; found, 510.1794.
27
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Bioassay method
The insecticidal activity of i, 1, 9S-acyloxy derivatives of quinidine and
dihydroquinidine (3a-u, and 4b,c,f,h,k,l,q-s) against the M. separate (armyworms are
raised in laboratory for pre-third-instar larvae) was assessed at 1 mg/mL by the
leaf-dipping method. Toosendanin, a commercial plant secondary metabolite, was
used as the positive control. For each compound, thirty pre-third-instar larvae (ten
larvae per group, three groups) were used. Acetone solutions of the tested compounds
i, 1, 3a-u, 4b,c,f,h,k,l,q-s and toosendanin were prepared at 1 mg/mL. Fresh maize
leaves were dipped into the corresponding solution for 3 s and then taken out,
naturally air dried in a room. Leaves treated with acetone alone were used as a control
group (CK). Several treated leaves were kept in each dish, where every 10 larvae were
raised. If the treated leaves were consumed, the corresponding ones were added to the
dish. After 48 h, compound-soaked leaves were removed, and untreated fresh leaves
were added to all dishes until pupae. The experiment was carried out at 25 ± 2 °C and
This article is protected by copyright. All rights reserved.

Chemistry & Biodiversity
10.1002/cbdv.201900696
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relative humidity (RH) 65-80% on a 12 h/12 h (light/dark) photoperiod. The
insecticidal activity of the tested compounds against the pre-third-instar larvae of M.
separate was calculated by the formula: corrected mortality rate (%) = [(T − C) × 100]
/ (T – C). Where T is the mortality rate of the treated M. separate and C is the
mortality rate of CK.
Acknowledgements
The present research was supported by the National Natural Science Foundation of
China (Grant No. U1604105, 31901863).
Author Contribution Statement
Designed the experiments, synthesized the compounds, and analyzed the data:
Jinming Yang, Di Sun, Shengming Liu, Xiaomin Lin, Jia Jiang and Genqiang Chen;
Wrote the paper: Zhiping Che and Yuee Tian; All authors approved the final
manuscript.
Conflicts of Interest
The authors declare no conflict of interest.
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