Synthesis of novel 9R/S-acyloxy derivatives of cinchonidine and cinchonine as insecticidal agents

Article abstract of DOI:10.1080/10286020.2020.1729136

Endeavor to discover biorational natural products-based insecticides, two series (27) of novel 9R/S-acyloxy derivatives of cinchonidine and cinchonine 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 6l and 6o exhibited the best insecticidal activity with final mortality rates of 75.0% and 71.4%, respectively. 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; 6’-OCH₃ moiety is not necessary, removal of it is also acceptable. (Figure presented.).

Full text of DOI:10.1080/10286020.2020.1729136

Journal of Asian Natural Products Research
ISSN: 1028-6020 (Print) 1477-2213 (Online) Journal homepage: https://www.tandfonline.com/loi/ganp20
Synthesis of novel 9R/S-acyloxy derivatives of
cinchonidine and cinchonine as insecticidal agents
Zhi-Ping Che, Jin-Ming Yang, Song Zhang, Di Sun, Yue-E Tian, Sheng-Ming Liu,
Xiao-Min Lin, Jia Jiang & Gen-Qiang Chen
To cite this article: Zhi-Ping Che, Jin-Ming Yang, Song Zhang, Di Sun, Yue-E Tian, Sheng-Ming
Liu, Xiao-Min Lin, Jia Jiang & Gen-Qiang Chen (2020): Synthesis of novel 9R/S-acyloxy derivatives
of cinchonidine and cinchonine as insecticidal agents, Journal of Asian Natural Products Research,
DOI: 10.1080/10286020.2020.1729136
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JOURNAL OF ASIAN NATURAL PRODUCTS RESEARCH
https://doi.org/10.1080/10286020.2020.1729136
Synthesis of novel 9R/S-acyloxy derivatives of
cinchonidine and cinchonine as insecticidal agents
Zhi-Ping Che, Jin-Ming Yang, Song Zhang, Di Sun, Yue-E Tian, Sheng-Ming Liu,
Xiao-Min Lin, Jia Jiang and Gen-Qiang Chen
Laboratory of Pesticidal Design & Synthesis, Department of Plant Protection, College of Forestry,
Henan University of Science and Technology, Luoyang 471023, China
ABSTRACT
ARTICLE HISTORY
Received 22 November 2019
Accepted 9 February 2020
Endeavor to discover biorational natural products-based insecti-
cides, two series (27) of novel 9R/S-acyloxy derivatives of cinchoni-
dine and cinchonine 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, espe-
cially derivatives 6l and 6o exhibited the best insecticidal activity
with final mortality rates of 75.0% and 71.4%, respectively.
Overall, a free 9-hydroxyl group is not a prerequisite for insecti-
cidal activity and C9-substitution is well tolerated; the configur-
ation of C8/9 position is important for insecticidal activity, and 9S-
configuration is optimal; 6’-OCH3 moiety is not necessary, removal
of it is also acceptable.
KEYWORDS
Cinchonidine; cinchonine;
quinine analogues; acyloxy;
insecticidal activity
1. Introduction
Oriental armyworm also known as Mythimna separata Walker (Lepidoptera:
Noctuidae), is a gluttonous, omnivorous insect. Its larvae and adults can cause exten-
sive 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 loss [1]. For example, M. separata intermittent
outbreaks in China in 2012, about 4 million hectares of crops were completely loss
[2]. Although, existing chemical insecticides were used to control M. separate, many
problems have arisen, such as residue, resistance, and resurgence (3R) [3]. So how 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
CONTACT Zhi-Ping Che
zhipingche@163.com
Laboratory of Pesticidal Design & Synthesis, Department of
Plant Protection, College of Forestry, Henan University of Science and Technology, Luoyang 471023, China
ß 2020 Informa UK Limited, trading as Taylor & Francis Group

2
Z.-P. CHE ET AL.
Figure 1. Chemical structures of quinine (1), cinchonidine (2), and cinchonine (3).
use it to the plant), are properly applied. According to the Change Advisory Board
(CAB) scientific report, botanical insecticide has grown rapidly over the past three
decades [4]. By 2014, the Environmental Protection Agency (EPA) of the United
States data showed that about 69 botanical pesticides were registered and commercial-
ized [5]. Nowadays, azadirachtin, rotenone, matrine, pyrethrins, and so forth, all are
commercial botanical insecticides, which are made by plants as widely defenses
against insect pests [6].
Cinchonidine (2, Figure 1) and cinchonine (3, Figure 1) are the analogue of quin-
ine (1, Figure 1) and have similar biological activities to quinine. Quinine is the main
alkaloids in the bark of cinchona tree as well as in plants in the same genus [7].
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. fal-
ciparum strains has severely limited the use of quinines to treat malaria [8]. Besides
its use as the lead compound for the preparation of catalysts and ligands which can
effectively catalyze the reaction such as Michael/Mannich [9], Aza-Henry [10], cyclo-
addition [11], and asymmetric olefin isomerization [12], 1 has also exhibited numer-
ous interesting insecticidal and antibacterial activities [13–16]. However, research on
structure optimizations and structure–activity relationship (SAR) of 9R/S-acyloxy
derivatives of cinchonidine and cinchonine as insecticidal agents has not yet been
reported. Therefore, in this study, 27 novel 9R/S-acyloxy derivatives of cinchonidine
and cinchonine were designed and semisynthesized, and used as insecticidal agents
against the pre-third-instar larvae of M. separata Walker in vivo for the first time.
Furthermore, the SAR of these compounds was also described.
2. Results and discussion
2.1. Chemistry
The synthetic route to prepare two series of novel 9R/S-acyloxy derivatives of cincho-
nidine and cinchonine (5a–j,l–o and 6a,c,e–o) is depicted in Scheme 1. Target ester
compounds 5a–j,l–o and 6a,c,e–o were smoothly obtained by reaction of 2 or 3 with
the corresponding carboxylic acids (4) in the presence of DCC and DMAP [17–19].
The structures of all derivatives were well characterized by 1H NMR, HRMS,
and m.p.

JOURNAL OF ASIAN NATURAL PRODUCTS RESEARCH
3
Scheme 1. Route for the synthesis of 9R/S-acyloxy derivatives of cinchonidine and cinchonine
5a–j,l–o and 6a,c,e–o.
2.2. Insecticidal activity
The insecticidal activity of two series (27) of novel 9R/S-acyloxy derivatives of cincho-
nidine and cinchonine (5a–j,l–o and 6a,c,e–o) against the pre-third-instar larvae of
M. separata was assessed at 1 mg/mL by the leaf-dipping method. Toosendanin, a tri-
terpenoid extracted and isolated from Meliaceae plants, is currently a commercial
botanical insecticide, and 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 parent and target compounds after 10 and 20 days were generally lower than
those after 30 days. For example, the CMRs of 3 against M. separata after 10, 20, and
30 days were 20.0%, 44.8%, and 67.9%, respectively. That is, the CMRs of 30 days
were more than 3 times of that of 10 days. Additionally, the symptoms of death of
the tested M. separata during the whole process of growth were similar to our previ-
ous reports [17–19]: owing to feeding too many compounds coated leaves during the
first 2 days, some larvae of the tested M. separata exhibited developmental abnormal-
ities during three stages (larval, pupation, and adult emergence; Figures 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 appeared in the pupation process (Figure 3); certainly, some of the tested

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Z.-P. CHE ET AL.
Table 1. Insecticidal activity of two series of 9R/S-acyloxy derivatives of cinchonidine and cinchon-
ine (5a–j,l–o and 6a,c,e–o) at 1 mg/mL against M. separata.
Corrected mortality rate (%)a
Compounds
10 days
10.0
13.3 4.7
6.7 9.4
26.7 4.7
13.3 4.7
16.7 4.7
23.3 4.7
10.0 8.2
20 days
30 days
1
2
5a
5b
5c
5d
5e
5f
5g
5h
5i
5j
5l
5m
5n
5o
3
6a
6c
6e
6f
6g
6h
6i
6j
6k
6l
6m
6n
6o
0
17.2
27.6
0
0
32.1 4.7
50.0 4.7
42.9 4.7
50.0 4.7
28.6 4.7
39.3 4.7
50.0 4.7
39.3 9.4
32.1 4.7
28.6 4.7
53.6 4.7
53.6 4.7
60.7 4.7
39.3 4.7
46.4 8.2
53.6 4.7
20.7 4.7
48.3
17.2
0
0
27.6 8.2
44.8 4.7
10.3 4.7
13.8 4.7
10.0
0
3.3 4.7
17.2
27.6
0
0
20.0
20.0
0
0
44.8 9.4
34.5 4.7
16.7 4.7
26.7 9.4
37.9
17.2
0
0
6.7
20.0 8.2
20.0
0
34.5 4.7
44.8 9.4
31.0 4.7
20.7 4.7
0
67.9 0
50.0 4.7
42.9 4.7
26.7 4.7
16.7 4.7
23.3 9.4
23.3 4.7
13.3 4.7
26.7 4.7
26.7 9.4
23.3 4.7
37.9
27.6
0
0
57.1 0
53.6 9.4
42.9 4.7
39.3 4.7
64.3 4.7
64.3 4.7
34.5 4.7
31.0 4.7
31.0 4.7
34.5 4.7
31.0 4.7
44.8 9.4
44.8 4.7
34.5 4.7
10.0
0
35.7 0
26.7 4.7
23.3 4.7
16.7 4.7
23.3 4.7
75.0 4.7
53.6 4.7
60.7 4.7
71.4 4.7
50.0 4.7
6.7 4.7
58.6 0
31.0 4.7
3.3 4.7
Toosendanin
Blank control
10.0
0
0
0
aValues are means SD of three replicate.
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 17
compounds have equal to or higher insecticidal activity than the botanical insecticide
toosendanin. Seven compounds, 5l, 3, 6i, 6j, 6l, 6n, and 6o displayed more potent
insecticidal activity with the final mortality rates (FMRs) ꢀ60%. Especially 2 deriva-
tives (6l and 6o) exhibited the best insecticidal activity with FMRs of 75.0% and
71.4%, respectively.
At the same time, some interesting and valuable views are obtained by analyzing
the structure–activity relationships (SAR). 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 2 and 3 could significantly affect the insecticidal activity. For
example, the FMRs of 2 and 3 were 50.0% and 67.9%, respectively. Simultaneously,
the FMRs of the corresponding esterification products 5l and 6l were 60.7% and
75.0%, respectively. (2) 6’-OCH3 moiety is not necessary, and removal of it is also
acceptable (e.g. 32.1% for 1 vs. 50.0% for 2 and 67.9% for 3). (3) The configuration
of C8/9 position is important for insecticidal activity, and 9S-configuration is optimal

JOURNAL OF ASIAN NATURAL PRODUCTS RESEARCH
5
Figure 2. The representative abnormal larvae pictures of 5b, 5e, 5j, 5m, 6e, and 6l during the lar-
val period (CK: blank control group).
Figure 3. The representative malformed pupae pictures of 5b, 5e, 5j, 5l, 6g, and 6m during the
pupation period (CK: blank control group).
(e.g. 1 and 2 vs. 3). In general, The insecticidal activities of 9S-acyloxycinchonine
derivatives are generally higher than that of 9R-acyloxycinchonidine derivatives (e.g.
5a,c,e–j,l–o vs. 6a,c,e–j,l–o). This further demonstrated that 9S-configuration of ana-
logs of quinine was important for obtaining the most potent derivatives.
Interestingly, the tested experiments indicated that for the n-alkyloyloxy series
derivatives, the appropriate chain length of R was very significant for their insecticidal
activity. For example, the FMRs of 5a–d and 6a,c were 42.9%/50.0%/28.6%39.3%, and
50.0%/42.9%, respectively. In addition, when the methyl or nitro group was intro-
duced at the meta-position (e.g. 5f, 5l, 6f, and 6l) on the phenyl ring, the insecticidal

6
Z.-P. CHE ET AL.
Figure 4. The representative malformed moth pictures of 5i, 5l, 3, 6i, 6l, and 6o during the emer-
gence period (CK: blank control group).
activity was more potent than the para-position (e.g. 5g, 5m, 6g, and 6m). For
example, the FMRs of 5f, 5l, 6f, 6l and 5g, 5m, 6g, 6m were 39.3%/60.7%/53.6%/
75.0% and 32.1%/39.3%/42.9%/53.6%, respectively. To 5g–i and 6g–i, introduction of
the p-tert-butylphenyloyloxy group (e.g. 5i and 6i) at the hydroxyl position of 2 and
3 could lead to more potent compounds than possessing p-methylphenyloyloxy (e.g.
5g and 6g) and p-methoxylphenyloyloxy (e.g. 5h and 6h) groups. For example, the
FMRs of 5g–i and 6g–i were 32.1%/28.6%/53.6% and 42.9%/39.3%/64.3%, respect-
ively. Similarly, when the chlorine atom (6j) was introduced at the para-position on
the phenyl ring, the insecticidal activity was bettter than the bromine atom (6k) at
the same position on the phenyl ring (64.3% for 6j vs. 35.7% for 6k). In addition,
when R ¼ benzylidene, the corresponding derivatives (e.g. 5o and 6o) were more
active than that of R ¼ 1-naphthylmethylene (e.g. 5n and 6n). For example, the FMRs
of 5n,o and 6n,o were 46.4%/53.6% and 60.7%/71.4%, respectively.
3. Experimental
3.1. General experimental procedures
Optical rotation was measured on Rudolph Research Analytical Autopol III automatic
polarimeter (Hackettstown, New Jersey, America). Proton nuclear magnetic resonance
(1H NMR) spectra was carried out with a Bruker Avance III 400 MHz instrument
(Bruker Daltonik, Bremen, Germany) in deuterated chloroform (CDCl3) using tetra-
methylsilane (TMS) as the internal standard. High resolution mass spectrometry
(HRMS) was determined on an IonSpec 4.7T FTMS instrument (Tesla, Lake Forest,
CA, USA). Melting points (m.p.) of all compounds were detected on a digital melting
point apparatus (Beijing Tech Instrument Co., Ltd.), and are uncorrected. As shown
in Figure 1, quinine (1), cinchonidine (2), and cinchonine (3) were purchased from
Wuhan Yuancheng Technology Development Co., Ltd. (Hubei, China). N,N’-
Dicyclohexylcarbodiimide (DCC), 4-(N,N-dimethylamino)pyridine (DMAP), 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

JOURNAL OF ASIAN NATURAL PRODUCTS RESEARCH
7
Figure 5. Brief description of structure–insecticidal activity relationships of quinine derivatives.
Reagent Factory (Tianjin, China). Detected thin layer chromatography (TLC) was
performed with silica gel 60 GF254 (Qingdao Haiyang Chemical Co., Ltd., Qingdao,
China). Silica gel column chromatography (CC) was performed with silica gel
200–300 mesh (Qingdao Haiyang Chemical Co., Ltd., Qingdao, China).
3.2. General procedure for the synthesis of 9R/S-acyloxy derivatives of
cinchonidine and cinchonine 5a–j,l–o and 6a,c,e–o
A mixture of 2 or 3 (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 completed, and checked by TLC, the mix-
ture 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 NaHCO3 (30 mL), and brine (30 mL), dried over anhydrous
Na2SO4, concentrated in vacuo, and purified by CC to give the pure 9R/S-acyloxy
derivatives of cinchonidine and cinchonine 5a–j,l–o and 6a,c,e–o [17–19]. The data
of target compounds are shown as follows.
3.2.1. Data for 5a
Yield ¼ 39%, Pale yellow oily liquid; [a]2D0 －28 (c 3.8 mg/mL, CHCl3). Its spectro-
scopic characteristics of this compound were consistent with those previously
reported in the Refs. [20–22].
3.2.2. Data for 5b
Yield ¼ 80%, Pale yellow oily liquid; [a]2D0 －19 (c 3.1 mg/mL, CHCl3). Its spectro-
scopic characteristics of this compound were consistent with those previously
reported in the Ref. [21].
3.2.3. Data for 5c
Yield ¼ 42%, Pale yellow oily liquid; [a]2D0 －7 (c 3.7 mg/mL, CHCl3). Its spectro-
scopic characteristics of this compound were consistent with those previously
reported in the Ref. [22].
3.2.4. Data for 5d
1
Yield ¼ 54%, Pale yellow oily liquid; [a]2D0 － 3 (c 4.3 mg/mL, CHCl3). H NMR
(400 MHz, CDCl3) d: 8.88 (d, J ¼ 4.4 Hz, 1H), 8.25 (dd, J ¼ 8.4, 1.2 Hz, 1H), 8.13 (dd,
J ¼ 8.4, 1.2 Hz, 1H), 7.69–7.73 (m, 1H), 7.57–7.61 (m, 1H), 7.39 (d, J ¼ 4.8 Hz, 1H),

8
Z.-P. CHE ET AL.
6.54 (d, J ¼ 7.6 Hz, 1H), 5.79–5.87 (m, 1H), 4.98–5.03 (m, 2H), 3.40 (q, J ¼ 8.0 Hz,
1H), 3.08–3.16 (m, 1H), 3.06 (dd, J ¼ 14.0, 10.0 Hz, 1H), 2.55–2.67 (m, 2H), 2.34–2.38
(m, 2H), 2.27 (s, 1H), 1.84–1.92 (m, 2H), 1.69–1.77 (m, 1H), 1.49–1.62 (m, 4H),
1.21–1.27 (m, 6H), 0.82–0.86 (m, 3H). HRESIMS: m/z 407.2695 [M þ H]þ (calcd for
C26H35N2O2, 407.2693).
3.2.5. Data for 5e
Yield ¼ 44%, Pale yellow solid, m.p. 67–69 ꢁC; [a]2D0 þ103 (c 3.6 mg/mL, CHCl3). Its
spectroscopic characteristics of this compound were consistent with those previously
reported in the Ref. [23].
3.2.6. Data for 5f
1
Yield ¼ 52%, Pale yellow solid, m.p. 36–38 ꢁC; [a]2D0 þ116 (c 3.1 mg/mL, CHCl3). H
NMR (400 MHz, CDCl3) d: 8.87 (d, J ¼ 4.4 Hz, 1H), 8.33 (dd, J ¼ 8.4, 1.2 Hz, 1H),
8.14 (dd, J ¼ 8.4, 1.2 Hz, 1H), 7.88–7.91 (m, 2 H), 7.70–7.75 (m, 1H), 7.61–7.65 (m,
1H), 7.47 (d, J ¼ 4.4 Hz, 1H), 7.34–7.41 (m, 2H), 6.80 (d, J ¼ 6.4 Hz, 1H), 5.80–5.89
(m, 1H), 4.98–5.04 (m, 2H), 3.52 (q, J ¼ 8.0 Hz, 1H), 3.18–3.26 (m, 1H), 3.11 (dd,
J ¼ 14.0, 10.0 Hz, 1H), 2.61–2.71 (m, 2H), 2.41 (s, 3H), 2.29 (s, 1H), 1.88–1.98 (m,
2H), 1.69–1.82 (m, 2H), 1.54–1.6 (m, 1H). HRESIMS: m/z 413.2222 [M þ H]þ (calcd
for C27H29N2O2, 413.2224).
3.2.7. Data for 5g
Yield ¼ 60%, Pale yellow oily liquid; [a]2D0 þ81 (c 4.1 mg/mL, CHCl3). Its spectro-
scopic characteristics of this compound were consistent with those previously
reported in the Ref. [23].
3.2.8. Data for 5h
Yield ¼ 46%, Pale yellow solid, m.p. 63–65 ꢁC; [a]2D0 þ123 (c 3.8 mg/mL, CHCl3). Its
spectroscopic characteristics of this compound were consistent with those previously
reported in the Ref. [24].
3.2.9. Data for 5i
1
Yield ¼ 58%, White solid, m.p. 68–70 ꢁC; [a]2D0 þ86 (c 4.5 mg/mL, CHCl3). H NMR
(400 MHz, CDCl3) d: 8.86 (d, J ¼ 4.8 Hz, 1H), 8.14 (dd, J ¼ 8.4, 1.2 Hz, 1H), 8.14 (dd,
J ¼ 8.4, 1.2 Hz, 1H), 8.02–8.05 (m, 2H), 7.70–7.75 (m, 1H), 7.61–7.65 (m, 1H),
7.48–7.51 (m, 2H), 7.46 (d, J ¼ 4.8 Hz, 1H), 6.83 (d, J ¼ 6.0 Hz, 1H), 5.78–5.87 (m,
1H), 4.97–5.04 (m, 2H), 3.45–3.51 (m, 1H), 3.20–3.28 (m, 1H), 3.13 (dd, J ¼ 14.0,
10.0 Hz, 1H), 2.64–2.74 (m, 2H), 2.31 (s, 1H), 1.87–1.95 (m, 2H), 1.73–1.85 (m, 2H),
1.55–1.62 (m, 1H), 1.34 (s, 9H). HRESIMS: m/z 455.2699 [M þ H]þ (calcd for
C30H35N2O2, 455.2693).
3.2.10. Data for 5j
1
Yield ¼ 47%, White solid, m.p. 131–133 ꢁC; [a]2D0 þ125 (c 4.4 mg/mL, CHCl3). H
NMR (400 MHz, CDCl3) d: 8.88 (d, J ¼ 4.8 Hz, 1H), 8.31 (dd, J ¼ 8.4, 1.2 Hz, 1H),
8.14 (dd, J ¼ 8.4, 1.2 Hz, 1H), 8.02 (d, J ¼ 8.4 Hz, 2H), 7.75 (t, J ¼ 7.6 Hz, 1H), 7.65 (t,

JOURNAL OF ASIAN NATURAL PRODUCTS RESEARCH
9
J ¼ 7.6 Hz, 1H), 7.43–7.45 (m, 3H), 6.78 (d, J ¼ 7.2 Hz, 1H), 5.80–5.89 (m, 1H),
4.99–5.04 (m, 2H), 3.53 (q, J ¼ 8.0 Hz, 1H), 3.14–3.22 (m, 1H), 3.09 (dd, J ¼ 14.0,
10.0 Hz, 1H), 2.60–2.71 (m, 2H), 2.30 (s, 1H), 1.88–1.99 (m, 2H), 1.72–1.79 (m, 1H),
1.64–1.69 (m, 1H), 1.54–1.61 (m, 1H). HRESIMS: m/z 433.1678 [M þ H]þ (calcd for
C26H26ClN2O2, 433.1677).
3.2.11. Data for 5l
1
Yield ¼ 55%, Yellow solid, m.p. 66–68 ꢁC; [a]2D0 þ151 (c 3.3 mg/mL, CHCl3). H
NMR (400 MHz, CDCl3) d: 8.89–8.91 (m, 2H), 8.43–8.46 (m, 1H), 8.36–8.39 (m, 1H),
8.33 (dd, J ¼ 8.4, 1.2 Hz, 1H), 8.16 (dd, J ¼ 8.4, 1.2 Hz, 1H), 7.72–7.77 (m, 1H),
7.64–7.70 (m, 2H), 7.49 (d, J ¼ 4.8 Hz, 1H), 6.83 (d, J ¼ 7.2 Hz, 1H), 5.83–5.92 (m,
1H), 5.01–5.06 (m, 2H), 3.54–3.60 (m, 1H), 3.14–3.22 (m, 1H), 3.10 (dd, J ¼ 14.0,
10.0 Hz, 1H), 2.62–2.72 (m, 2H), 2.29–2.33 (m, 1H), 2.02–2.04 (m, 1H), 1.91–1.93 (m,
1H), 1.74–1.82 (m, 1H), 1.57–1.68 (m, 2H). HRESIMS: m/z 444.1921 [M þ H]þ (calcd
for C26H26N3O4, 444.1918).
3.2.12. Data for 5m
Yield ¼ 42%, Yellow oily liquid; [a]2D0 þ113 (c 3.5 mg/mL, CHCl3). Its spectroscopic
characteristics of this compound were consistent with those previously reported in
the Ref. [25].
3.2.13. Data for 5n
1
Yield ¼ 55%, Pale yellow solid, m.p. 50–51 ꢁC; [a]2D0 －33 (c 5.0 mg/mL, CHCl3). H
NMR (400 MHz, CDCl3) d: 8.66 (d, J ¼ 4.4 Hz, 1H), 8.03–8.09 (m, 2H), 7.86–7.89 (m,
2H), 7.84 (dd, J ¼ 8.4, 1.2 Hz, 1H), 7.65–7.69 (m, 1H), 7.47–7.51 (m, 2H), 7.40–7.44
(m, 3H), 6.95 (d, J ¼ 4.8 Hz, 1H), 6.51 (d, J ¼ 6.4 Hz, 1H), 5.63–5.71 (m, 1H),
4.89–4.94 (m, 2H), 4.13 (s, 2H), 3.13–3.19 (m, 1H), 2.98 (dd, J ¼ 14.0, 10.0 Hz, 1H),
2.82–2.90 (m, 1H), 2.43–2.53 (m, 2H), 2.14–2.20 (m, 1H), 1.65–1.68 (m, 1H),
1.50–1.57 (m, 1H), 1.30–1.36 (m, 2H), 1.22–1.28 (m, 1H). HRESIMS: m/z 463.2383
[M þ H]þ (calcd for C31H31N2O2, 463.2380).
3.2.14. Data for 5o
Yield ¼ 56%, White oily liquid; [a]2D0 － 20 (c 3.9 mg/mL, CHCl3). 1H NMR
(400 MHz, CDCl3) d: 8.82 (d, J ¼ 4.8 Hz, 1H), 8.18 (dd, J ¼ 8.4, 1.2 Hz, 1H), 8.13 (dd,
J ¼ 8.4, 1.2 Hz, 1H), 7.69–7.73 (m, 1H), 7.55–7.59 (m, 1H), 7.23–7.25 (m, 3H),
6.96–7.01 (m, 1H), 6.82–6.86 (m, 2H), 6.63 (d, J ¼ 7.2 Hz, 1H), 5.75–5.84 (m, 1H),
4.97–5.01 (m, 2H), 4.68 (d, J ¼ 5.2 Hz, 2H), 3.37 (q, J ¼ 8.0 Hz, 1H), 2.97–3.07 (m,
2H), 2.52–2.62 (m, 2H), 2.25 (s, 1H), 1.79–1.85 (m, 2H), 1.64–1.72 (m, 1H),
1.42–1.55 (m, 2H). HRESIMS: m/z 413.2225 [M þ H]þ (calcd for
C27H29N2O2, 413.2224).
3.2.15. Data for 6a
Yield ¼ 21%, Pale yellow oily liquid; [a]2D0 þ89 (c 3.1 mg/mL, CHCl3). Its spectro-
scopic characteristics of this compound were consistent with those previously
reported in the Refs. [21,22].

10
Z.-P. CHE ET AL.
3.2.16. Data for 6c
Yield ¼ 39%, Pale yellow oily liquid; [a]2D0 þ72 (c 3.9 mg/mL, CHCl3). Its spectro-
scopic characteristics of this compound were consistent with those previously
reported in the Ref. [22].
3.2.17. Data for 6e
Yield ¼ 54%, Pale yellow oily liquid; [a]2D0 －14 (c 4.2 mg/mL, CHCl3). Its spectro-
scopic characteristics of this compound were consistent with those previously
reported in the Ref. [23].
3.2.18. Data for 6f
1
Yield ¼ 46%, Pale yellow oily liquid; [a]2D0 － 12 (c 3.1 mg/mL, CHCl3). H NMR
(400 MHz, CDCl3) d: 8.87 (d, J ¼ 4.8 Hz, 1H), 8.31 (dd, J ¼ 8.4, 1.2 Hz, 1H), 8.14 (dd,
J ¼ 8.4, 1.2 Hz, 1H), 7.88–7.90 (m, 2H), 7.70–7.74 (m, 1H), 7.61–7.65 (m, 1H), 7.47
(d, J ¼ 4.4 Hz, 1H), 7.32–7.41 (m, 2H), 6.81 (d, J ¼ 6.8 Hz, 1H), 6.00–6.09 (m, 1H),
5.06–5.14 (m, 2H), 3.46 (q, J ¼ 8.4 Hz, 1H), 2.90–3.04 (m, 2H), 2.80–2.87 (m, 1H),
2.69–2.77 (m, 1H), 2.41 (s, 3H), 2.25–2.32 (m, 1H), 1.96–2.03 (m, 1H), 1.84–1.88 (m,
1H), 1.54–1.66 (m, 3H). HRESIMS: m/z 413.2228 [M þ H]þ (calcd for
C27H29N2O2, 413.2224).
3.2.19. Data for 6g
Yield ¼ 39%, Pale yellow solid, m.p. 161–163 ꢁC; [a]2D0 －45 (c 4.7 mg/mL, CHCl3).
1H NMR (400 MHz, CDCl3) d: 8.86 (d, J ¼ 4.8 Hz, 1H), 8.31 (dd, J ¼ 8.4, 1.2 Hz, 1H),
8.13 (dd, J ¼ 8.4, 1.2 Hz, 1H), 7.96–7.99 (m, 2H), 7.69–7.73 (m, 1H), 7.60–7.64 (m,
1H), 7.46 (d, J ¼ 4.4 Hz, 1H), 7.24–7.27 (m, 2H), 6.78 (d, J ¼ 7.2 Hz, 1H), 5.99–6.07
(m, 1H), 5.06–5.13 (m, 2H), 3.46 (q, J ¼ 8.4 Hz, 1H), 2.89–3.03 (m, 2H), 2.68–2.85
(m, 2H), 2.41 (s, 3H,), 2.24–2.31 (m, 1H), 1.94–2.00 (m, 1H), 1.85 (s, 1H), 1.54–1.67
(m, 3H). HRESIMS: m/z 413.2226 [M þ H]þ (calcd for C27H29N2O2, 413.2224).
3.2.20. Data for 6h
Yield ¼ 53%, Pale yellow oily liquid; [a]2D0 －31 (c 3.7 mg/mL, CHCl3). Its spectro-
scopic characteristics of this compound were consistent with those previously
reported in the Ref. [24].
3.2.21. Data for 6i
1
Yield ¼ 50%, Pale yellow oily liquid; [a]2D0 － 25 (c 3.3 mg/mL, CHCl3). H NMR
(400 MHz, CDCl3) d: 8.86 (d, J ¼ 4.4 Hz, 1H), 8.32 (dd, J ¼ 8.4, 1.2 Hz, 1H), 8.13 (dd,
J ¼ 8.4, 1.2 Hz, 1H), 8.01–8.04 (m, 2H), 7.69–7.74 (m, 1H), 7.60–7.64 (m, 1H),
7.45–7.49 (m, 3H), 6.79 (d, J ¼ 7.2 Hz, 1H), 5.99–6.08 (m, 1H), 5.06–5.14 (m, 2H),
3.47 (q, J ¼ 8.4 Hz, 1H), 2.91–3.04 (m, 2H), 2.69–2.85 (m, 2H), 2.32 (q, J ¼ 8.4 Hz,
1H), 1.94–2.00 (m, 1H), 1.86 (s, 1H), 1.56–1.66 (m, 3H), 1.34 (s, 9H). HRESIMS: m/z
455.2695 [M þ H]þ (calcd for C30H35N2O2, 455.2693).

JOURNAL OF ASIAN NATURAL PRODUCTS RESEARCH
11
3.2.22. Data for 6j
Yield ¼ 22%, Pale yellow solid, m.p. 157–159 ꢁC; [a]2D0 －23 (c 3.3 mg/mL, CHCl3).
1H NMR (400 MHz, CDCl3) d: 8.88 (d, J ¼ 4.4 Hz, 1H), 8.29 (dd, J ¼ 8.4, 1.2 Hz, 1H),
8.14 (dd, J ¼ 8.4, 1.2 Hz, 1H), 8.03 (t, J ¼ 2.4 Hz, 1H), 8.01 (t, J ¼ 2.4 Hz, 1H),
7.70–7.75 (m, 1H), 7.60–7.65 (m, 1H), 7.42–7.45 (m, 3H), 6.78 (d, J ¼ 7.6 Hz, 1H),
5.97–6.05 (m, 1H), 5.06–5.14 (m, 2H), 3.47 (q, J ¼ 8.4 Hz, 1H), 2.89–3.00 (m, 2H),
2.68–2.79 (m, 2H), 2.25–2.32 (m, 1H), 1.85–1.96 (m, 2H), 1.55–1.68 (m, 3H).
HRESIMS: m/z 433.1678 [M þ H]þ (calcd for C26H26ClN2O2, 433.1677).
3.2.23. Data for 6k
Yield ¼ 36%, Pale yellow solid, m.p. 181–182 ꢁC; [a]2D0 －44 (c 3.4 mg/mL, CHCl3).
1H NMR (400 MHz, CDCl3) d: 8.88 (d, J ¼ 4.8 Hz, 1H), 8.29 (dd, J ¼ 8.4, 1.2 Hz, 1H),
8.14 (dd, J ¼ 8.4, 1.2 Hz, 1H), 7.92–7.95 (m, 2H), 7.70–7.74 (m, 1H), 7.58–7.64 (m,
3H), 7.44 (d, J ¼ 4.4 Hz, 1H), 6.77 (d, J ¼ 7.6 Hz, 1H), 5.96–6.05 (m, 1H), 5.06–5.14
(m, 2H), 3.47 (q, J ¼ 8.4 Hz, 1H), 2.89–2.99 (m, 2H), 2.68–2.84 (m, 2H), 2.25–2.32
(m, 1H), 1.85–1.96 (m, 2H), 1.54–1.68 (m, 3H). HRESIMS: m/z 477.1177 [M þ H]þ
(calcd for C26H26BrN2O2, 477.1172).
3.2.24. Data for 6l
Yield ¼ 48%, Yellow oily liquid; [a]2D0 － 30 (c 3.5 mg/mL, CHCl3). 1H NMR
(400 MHz, CDCl3) d: 8.92 (t, J ¼ 2.0 Hz, 1H), 8.90 (d, J ¼ 4.4 Hz, 1H), 8.43–8.46 (m,
1H), 8.36–8.39 (m, 1H), 8.31 (dd, J ¼ 8.4, 1.2 Hz, 1H), 8.15 (dd, J ¼ 8.4, 1.6 Hz, 1H),
7.72–7.76 (m, 1H), 7.63–7.69 (m, 2H), 7.48 (d, J ¼ 4.8 Hz, 1H), 6.83 (d, J ¼ 7.6 Hz,
1H), 6.00–6.09 (m, 1H), 5.07–5.16 (m, 2H), 3.54 (q, J ¼ 8.4 Hz, 1H), 2.96 (dd, J ¼ 8.8,
1.2 Hz, 2H), 2.80–2.86 (m, 1H), 2.69–2.76 (m, 1H), 2.26–2.34 (m, 1H), 1.88–1.98 (m,
2H), 1.68–1.73 (m, 1H), 1.56–1.64 (m, 2H). HRESIMS: m/z 444.1919 [M þ H]þ (calcd
for C26H26N3O4, 444.1918).
3.2.25. Data for 6m
1
Yield ¼ 32%, Yellow solid, m.p. 203–204 ꢁC; [a]2D0 －29 (c 3.2 mg/mL, CHCl3). H
NMR (400 MHz, CDCl3) d: 8.90 (d, J ¼ 4.8 Hz, 1H), 8.23–8.32 (m, 5H), 8.15 (dd,
J ¼ 8.4, 1.2 Hz, 1H), 7.72–7.76 (m, 1H),7.62–7.66 (m, 1H), 7.46 (d, J ¼ 4.4 Hz, 1H),
6.81 (d, J ¼ 7.6 Hz, 1H), 5.96–6.05 (m, 1H), 5.07–5.16 (m, 2H), 3.52 (q, J ¼ 8.4 Hz,
1H), 2.95 (d, J ¼ 8.8 Hz, 2H), 2.68–2.85 (m, 2H), 2.26–2.34 (m, 1H), 1.87–1.93 (m,
2H), 1.65–1.72 (m, 1H), 1.56–1.62 (m, 2H). HRESIMS: m/z 444.1923 [M þ H]þ (calcd
for C26H26N3O4, 444.1918).
3.2.26. Data for 6n
1
Yield ¼ 32%, Pale yellow oily liquid; [a]2D0 þ88 (c 3.3 mg/mL, CHCl3). H NMR
(400 MHz, CDCl3) d: 8.59 (d, J ¼ 4.8 Hz, 1H), 8.07 (dd, J ¼ 8.4, 1.2 Hz, 1H), 8.02 (dd,
J ¼ 8.4, 1.2 Hz, 1H), 7.89 (dd, J ¼ 8.4, 1.2 Hz, 1H), 7.81–7.83 (m, 2H), 7.63–7.67 (m,
1H), 7.36–7.49 (m, 5H), 6.88 (d, J ¼ 4.4 Hz, 1H), 6.50 (d, J ¼ 7.2 Hz, 1H), 5.82–5.91
(m, 1H), 5.02–5.10 (m, 2H), 4.12 (s, 2H), 3.16 (q, J ¼ 8.4 Hz, 1H), 2.80–2.83 (m, 2H),
2.58–2.68 (m, 2H), 2.15–2.66 (m, 1H), 1.66–1.70 (m, 1H), 1.54–1.61 (m, 1H),

12
Z.-P. CHE ET AL.
1.41–1.46 (m, 2H), 1.18–1.25 (m, 1H). HRESIMS: m/z 463.2387 [M þ H]þ (calcd for
C31H31N2O2, 463.2380).
3.2.27. Data for 6o
1
Yield ¼ 38%, Pale yellow oily liquid; [a]2D0 þ162 (c 3.2 mg/mL, CHCl3). H NMR
(400 MHz, CDCl3) d: 8.81 (d, J ¼ 4.4 Hz, 1H), 8.11–8.17 (m, 2H), 7.69–7.73 (m, 1H),
7.55–7.59 (m, 1H), 7.23–7.25 (m, 2H), 7.22 (d, J ¼ 4.4 Hz, 1H), 6.97–7.01 (m, 1H),
6.83–6.86 (m, 2H), 6.66 (d, J ¼ 7.6 Hz, 1H), 5.98–6.07 (m, 1H), 5.07–5.12 (m, 2H),
4.68 (d, J ¼ 2.4 Hz, 2H), 3.34 (q, J ¼ 8.4 Hz, 1H), 2.89 (d, J ¼ 8.4 Hz, 2H), 2.64–2.79
(m, 2H), 2.22–2.28 (m, 1H), 1.77–1.80 (m, 2H), 1.47–1.55 (m, 3H). HRESIMS: m/z
413.2222 [M þ H]þ (calcd for C27H29N2O2, 413.2224).
3.3. Biological assay
The insecticidal activity of 1–3, 9R/S-acyloxy derivatives of cinchonidine and cinchon-
ine (5a–j,l–o and 6a,c,e–o) and toosendanin (positive control) against M. separate
(pre-third-instar larvae) was assessed at 1 mg/mL by the leaf-dipping method as
reported previously [17–19].
Disclosure statement
No potential conflict of interest was reported by the authors.
Funding
The present research was financially supported by the National Natural Science Foundation of
China [Grant No. U1604105, 31901863].
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