Synthesis of novel isoxazoline-containing podophyllotoxin/2′(2′,6′)-(di)halogenopodophyllotoxin derivatives and their insecticidal/acaricidal activities

Article abstract of DOI:10.1016/j.bmcl.2018.02.018

In continuation of our program aimed at the development of natural product-based pesticidal agents, a series of isoxazoline-containing podophyllotoxin/2′(2′,6′)-(di)halogenopodophyllotoxin derivatives were prepared, and their structures were well characte

Full text of DOI:10.1016/j.bmcl.2018.02.018

Accepted Manuscript
Synthesis of novel isoxazoline-containing podophyllotoxin/2′(2′,6′)-(di)halo-
genopodophyllotoxin derivatives and their insecticidal/acaricidal activities
Ruige Yang, Yuanyuan Zhang, Hui Xu
PII:
S0960-894X(18)30112-4
https://doi.org/10.1016/j.bmcl.2018.02.018
BMCL 25614
DOI:
Reference:
Bioorganic & Medicinal Chemistry Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
28 December 2017
6 February 2018
9 February 2018
Please cite this article as: Yang, R., Zhang, Y., Xu, H., Synthesis of novel isoxazoline-containing podophyllotoxin/
2′(2′,6′)-(di)halogenopodophyllotoxin derivatives and their insecticidal/acaricidal activities, Bioorganic &
Medicinal Chemistry Letters (2018), doi: https://doi.org/10.1016/j.bmcl.2018.02.018
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Synthesis
of
novel
isoxazoline-containing
podophyllotoxin/2′(2′,6′)-(di)halogenopodophyllotoxin
derivatives
and their insecticidal/acaricidal activities
Ruige Yang a, Yuanyuan Zhanga, and Hui Xu a,b,
*
aResearch Institute of Pesticidal Design & Synthesis, College of Chemistry and
Pharmacy/Crop Protection, Northwest A&F University, Yangling 712100, Shaanxi
Province, China
bShaanxi Key Laboratory of Natural Products & Chemical Biology, Northwest A&F
University, Yangling 712100, Shaanxi Province, China
*Author to whom correspondence should be addressed [(H.X.) E-mail:
orgxuhui@nwsuaf.edu.cn. Tel: +86-29-87091952; Fax: +86-29-87091952].
1

Abstract:
In continuation of our program aimed at the development of natural
product-based pesticidal agents, series of isoxazoline-containing
a
podophyllotoxin/2′(2′,6′)-(di)halogenopodophyllotoxin derivatives were prepared,
1
and their structures were well characterized by H NMR, IR, optical rotation,
HRMS and mp. Especially the structure of compound Ia was further confirmed by
1H-1H COSY and NOESY spectrum. Among them, two compounds showed good
insecticidal and acaricidal activities against Mythimna separata and Tetranychus
cinnabarinus. Their structure-activity relationships were also observed.
Keywords: Podophyllotoxin; Isoxazoline; Natural-product-based; Insecticidal
activity; Acaricidal activity
2

Podophyllotoxin (1, Fig. 1), isolated from the roots and rhizomes of
Podophyllum hexandrum and Juniperus Sabina, contains four almost planar fused
rings (labeled A–D) and four consecutive chiral centers (labeled C-1–C-4).1,2
Compound 1 is usually used as a lead compound for preparation of potent bioactive
derivatives, which displayed a variety of interesting properties including anticancer
activity, insecticidal activity, antifungal activity, antiviral activity, anti-inflammatory
activity, and antirheumatic activity.1-5
Recently, we have investigated halogenation of E-ring of podophyllotoxins, 6 and
found some esters of 2′(2′,6′)-(di)halogenopodophyllotoxins
(2, Fig. 1),7
and
2α-chloro-2′(2′,6′)-(di)halogenopicropodophyllotoxins (3, Fig. 1),8,9
2′-chloro-4′-demethoxyepipodophyllotoxin (4, Fig. 1)10 exhibited more potent
insecticidal activity than toosendanin.6-9 On the other hand, to our delight, it
demonstrated that once a chlorine atom was introduced at the C-2' position of
podophyllotoxin derivatives, the corresponding compounds showed no significant
cytotoxicity.11 Isoxazolines (Fig. 1) also showed some interesting biological activities
including antimicrobial activity, fungicidal activity, mosquitocidal activity,
anti-Alzheimer activity, anticancer activity, and anti-inflammatory activity.12-17
Moreover, we further prepared a series of isoxazolopodophyllic acid-based esters (5,
Fig. 1), isoxazolopodophyllol-based esters (6, Fig. 1) and isoxazolopodophyllal-based
hydrazones (7, Fig. 1), and some derivatives showed more promising insecticidal
activity than their precusors.18,19
3

Fig. 1. The chemical structures of podophyllotoxin (1), podophyllotoxin esters (2–4),
isoxazoline, isoxazoline derivatives of podophyllotoxin (5–7), and target compounds
(I–IV).
In the meantime, Mythimna separata Walker (oriental armyworm) and
Tetranychus cinnabarinus Boisduval (spider mite) are two typical and
crop-threatening insect pests, and hard to control.20 Because of extensive and
unreasonable applications of synthetic pesticides for controlling pests, resistance in
pest populations and negative impacts on human health and environment have already
emerged.21,22 Nowadays, discovery of the potential alternatives from natural products
has received much research attention.23-30 Based on the above results, and in
4

continuation of our program aimed at the development of new potentially pesticidal
agents,31-33 therefore, in this Letter we prepared a series of isoxazoline-containing
podophyllotoxin/2′(2′,6′)-(di)halogenopodophyllotoxin derivatives (Ia–e, IIa–e,
IIIa–e, and IVa–e, Fig. 1) by introduction of the isoxazoline fragment into esters of
podophyllotoxin/2′(2′,6′)-(di)halogenopodophyllotoxins. Their insecticidal and
acaricidal activities were evaluated against Mythimna separata and Tetranychus
cinnabarinus.
As described in Scheme 1, first, a series of aromatic aldehydes (8a–e) were
condensed with hydroxylamine to afford oximes (9a–e), which were chlorined with
N-chlorosuccinimide (NCS) to give hydroximoyl chlorides (10a–e) in 63%–91%
yields.34 Three 2′(2′,6′)-(di)halogenopodophyllotoxins (11–13) were then smoothly
prepared by reaction of compound 1 with N-chlorosuccinimide (NCS, 1.1 or 2 equiv)
or N-bromosuccinimide (NBS, 1.1 equiv).6,7 Subsequently, compounds 1 and 11–13
reacting with acryloyl chloride in the presence of NEt3 gave
4α-acryloyloxy-2′(2′,6′)-(di)halogenopodophyllotoxins (14–17) in 46%–78%
yields.34
Finally,
isoxazoline-containing
podophyllotoxin/2′(2′,6′)-(di)halogenopodophyllotoxin derivatives (Ia–e, IIa–e,
IIIa–e, and IVa–e) were efficiently obtained by 1,3-dipolar cycloaddition of
compounds 14–17 with the nitrile oxide dipoles, which were generated from
compounds 10a–e in the presence of NEt3.35 Their structures were well characterized
by 1H NMR, IR, optical rotation, HRMS and mp (see Supplementary data).36
5

Scheme
1.
Synthesis
of
isoxazoline-containing
podophyllotoxin/2′(2′,6′)-(di)halogenopodophyllotoxin derivatives (Ia–e, IIa–e,
IIIa–e, and IVa–e).
6

Fig. 2. 1H-1H COSY spectrum of compound Ia.
Fig. 3. NOESY spectrum of compound Ia.
7

The assignments of the chemical shifts for the protons of compound Ia were
1
further determined by H-1H COSY spectrum. For example, as shown in Fig. 2, the
1H-1H COSY correlations of H-4′′ and H-5′′, H-3 and H-4, H-3 and H-11, and H-1 and
H-2 were observed. Moreover, based on the NOESY correlation of H-4′′ and H-7′′ (or
H-11′′), the phenyl of the isoxazoline fragment was close to H-4′′, therefore, the
configuration of compound Ia should be as A (Fig. 3). Obviously, it revealed that
1,3-dipolar cycloaddition of the nitrile oxides to the carbon-carbon double bond of
compounds 14–17 was regioselective.
Table 1
Acaricidal activity of compounds 1, 11-17, Ia-e, IIa-e, IIIa-e, and IVa-e against the
female adults of T. cinnabarinus at a concentration of 0.5 mg/mL.
Corrected mortality rate (%) a
Compound
48 hours
1.3 ± 0.7
6.8 ± 0.5
7.1 ± 0.6
5.6 ± 0.7
6.9 ± 0.3
9.9 ± 0.7
14.0 ± 1.6
8.6 ± 1.2
10.7 ± 1.4
13.3 ± 1.2
14.0 ± 1.3
10.6 ± 1.1
7.7 ± 0.8
12.9 ± 1.0
9.0 ± 1.0
3.8 ± 0.4
9.6 ± 2.3
8.4 ± 1.0
9.9 ± 1.7
14.2 ± 1.6
11.5 ± 1.4
5.4 ± 0.6
72 hours
1.9 ± 1.0
6.0 ± 0.4
6.6 ± 0.4
5.6 ± 0.9
1
11
12
13
14
15
16
17
Ia
Ib
Ic
Id
Ie
IIa
IIb
IIc
IId
IIe
IIIa
IIIb
IIIc
IIId
13.3 ± 0.5
11.4 ± 0.7
17.8 ± 1.4
11.7 ± 1.3
19.9 ± 0.4
22.9 ± 1.8
23.4 ± 1.3
20.2 ± 1.5
15.2 ± 1.3
12.2 ± 1.2
21.8 ± 1.0
29.4 ± 0.9
22.5 ± 1.3
15.3 ± 1.1
20.7 ± 1.5
24.2 ± 1.6
34.0 ± 1.2
25.0 ± 1.2
8

7.2 ± 0.8
10.1 ± 0.5
9.2 ± 1.5
9.8 ± 1.7
12.2 ± 1.3
10.1 ± 0.8
29.8 ± 2.6
18.4 ± 0.7
19.0 ± 0.8
13.3 ± 0.8
22.4 ± 1.0
20.1 ± 0.8
15.5 ± 1.3
65.7 ± 0.9
IIIe
IVa
IVb
IVc
IVd
IVe
spirodiclofen
aValues are means ± SE of three replicates.
The acaricidal activity of compounds 1, 11-17, Ia-e, IIa-e, IIIa-e, and IVa-e
against the female adults of Tetranychus cinnabarinus was tested by slide-dipping
method.31,37 Spirodiclofen was used as a positive control. The mortality rates (MRs) at
24 h and 72 h of the tested compounds were shown in Table 1. The MR at 72 h of
compound 1 was only 1.9%, so compound 1 almost had no acaricidal activity against
T.
cinnabarinus.
Meanwhile,
the
MRs
at
72
h
of
three
2′(2′,6′)-(di)halogenopodophyllotoxins (11–13) were less than 7%; however, after
structural modifications of compound 1, all ester derivatives showed more potent
acaricidal activity than compound 1 and their precusors. Especially compounds IIc
and IIIc showed the most promising acaricidal activity. For example, the MRs at 72 h
of compounds IIc and IIIc were 29.4% and 34.0%, respectively; that is, the MRs at
72 h of compounds IIc and IIIc were larger than 18-fold of that of 1. It was
noteworthy that generally introduction of a chlorine atom at the C-4 position on the
phenyl of the isoxazoline fragment of compound Ia, IIa, IIIa or IVa, could give the
most potent compounds Ic, IIc, IIIc and IVc of their own series. For example, the
MRs at 72 h of compounds Ic, IIc, IIIc and IVc were 23.4%, 29.4%, 34.0%, 22.4%,
respectively.
9

Table 2
Insecticidal activity of compounds 1, 14-17, Ia-e, IIa-e, IIIa-e, and IVa-e against M.
separata on leaves treated at a concentration of 1 mg/mL.
Corrected mortality rate (%) a
Compound
10 days
16.7 ± 2.7
23.3 ± 2.7
23.3 ± 2.7
20.0 ± 0
20 days
20.7 ± 2.7
31.0 ± 2.7
37.9 ± 0
35 days
31.0 ± 2.7
37.9 ± 0
44.8 ± 2.7
37.9 ± 0
34.5 ± 2.7
44.8 ± 2.7
55.2 ± 2.7
48.3 ± 0
41.4 ± 2.7
37.9 ± 0
14
15
16
17
Ia
Ib
Ic
Id
Ie
IIa
IIb
IIc
IId
IIe
34.5 ± 2.7
31.0 ± 2.7
41.4 ± 2.7
48.3 ± 0
41.4 ± 2.7
34.5 ± 2.7
31.0 ± 2.7
58.6 ± 0
23.3 ± 2.7
33.3 ± 2.7
40.0 ± 4.7
36.7 ± 2.7
33.3 ± 2.7
26.7 ± 2.7
50.0 ± 0
65.5 ± 2.7
62.1 ± 2.7
58.6 ± 0
40.0 ± 0
46.7 ± 2.7
33.3 ± 2.7
55.2 ± 2.7
55.2 ± 2.7
37.9 ± 4.7
48.3 ± 0
26.7 ± 2.7
36.7 ± 2.7
53.3 ± 2.7
30.0 ± 4.7
23.3 ± 2.7
20.0 ± 0
27.6 ± 0
41.4 ± 2.7
65.5 ± 2.7
44.8 ± 2.7
27.6 ± 0
41.4 ± 2.7
48.3 ± 0
IIIa
IIIb
72.4 ± 2.7
58.6 ± 0
IIIc
IIId
44.8 ± 2.7
44.8 ± 2.7
41.4 ± 2.7
62.1 ± 2.7
51.7 ± 2.7
41.4 ± 2.7
34.5 ± 2.7
55.2 ± 2.7
IIIe
41.4 ± 2.7
34.5 ± 5.4
55.2 ± 2.7
37.9 ± 4.7
37.9 ± 0
IVa
30.0 ± 4.7
43.3 ± 2.7
33.3 ± 2.7
33.3 ± 2.7
20.0 ± 0
IVb
IVc
IVd
IVe
31.0 ± 2.7
37.9 ± 0
1
toosendanin
26.7 ± 2.7
aValues are means ± SE of three replicates.
The insecticidal activity of compounds 1, 14-17, Ia-e, IIa-e, IIIa-e, and
IVa-e against the pre-third-instar larvae of Mythimna separata was tested by
leaf-dipping method.18,31 Toosendanin was used as a positive control. Leaves
treated with acetone alone were used as a blank control group. The symptoms of
10

the treated M. separata were found in the same way as in our previous reports.7,8
For example, some larvae with the wrinkled and slim bodies died at the larval
stage (Fig. 4); as shown in Fig. 5, some larvae molted to malformed pupae and
died during the pupation period; finally, some malformed moth appeared at the
adult emergence stage (Fig. 6).
Fig. 4. Representative abnormal larvae of M. separata produced by compounds Id
(YRG-173), IIb (YRG-181), IId (YRG-183), IIIc (YRG-187), IIId (YRG-188), IVc
(YRG-192) and IVe (YRG-194) at 1 mg/mL during the larval period (CK: blank
control group).
Fig. 5. Representative malformed pupae of M. separata produced by compounds IIb
(YRG-181), IId (YRG-183), IIIc (YRG-187) and IVc (YRG-192) at 1 mg/mL during
the pupation period (CK: blank control group).
11

Fig. 6. Representative malformed moth of M. separata produced by compounds Id
(YRG-173), IId (YRG-183), IIId (YRG-188) and IVe (YRG-194) at 1 mg/mL during
the stage of adult emergence (CK: blank control group).
Fig. 7. The percentages of the final mortality rates at three different growth stages of
compounds Ic, IIb-d, IIIc, IIId, IVc, IVd and toosendanin against of Mythimna
separata.
As depicted in Table 2, among all derivatives, compounds Ic, IIb-d, IIIc,
IIId, IVc, and IVd showed the potent insecticidal activity with the final mortality
rates (FMRs) greater than 50%; For example, the FMRs of compounds Ic, IIb-d,
IIIc, IIId, IVc, and IVd were 55.2%, 65.5%, 62.1%, 58.6%, 72.4%, 58.6%, 62.1%
and 51.7%, respectively; whereas the FMR of their precusor (compound 1) was
only 34.5%. Especially compound IIIc exhibited the most potent pesticidal
12

activity with the FMR of 72.4%. As shown in Fig. 7, the percentages of FMRs at
the larval stage of compounds Ic, IIb-d, IIIc, IIId, IVc, and IVd were all greater
than 56%; especially the percentages of FMRs at the larval stage of compounds Ic,
IIb and IId were 78.5%, 76.3%, and 79.6%, respectively. On the contrary, the
percentages of FMRs at the pupation stage of compounds Ic, IIb-d, IIIc, IIId,
IVc, and IVd were less than 17%, and the percentages of FMRs at the adult stage
of compounds Ic, IIb-d, IIIc, IIId, IVc, and IVd were less than 30%, These
results were different with those of other 2′(2′,6′)-(di)chloropicropodophyllotoxins
derivatives, and more than half of their FMRs were generally at the pupation
stage.38
Generally, as shown in Table 2, introduction of the halogen atom/atoms at the
C-2′/C-2′,6′ position of isoxazoline-containing podophyllotoxins (Ia-e) could
afford more potent 2′(2′,6′)-(di)halogenopodophyllotoxin derivatives (IIa–e,
IIIa–e, and IVa–e). Interestingly, especially compounds Ic, IIc, IIIc and IVc (all
containing 4-Cl on the phenyl of their isoxazoline fragment), exhibited more
potent insecticidal activity than those (except IIb) containing other substituents
(e.g., Ic vs Ia,b,d,e; IIc vs Ia,d,e; IIIc vs IIIa,b,d,e; IVc vs IVa,b,d,e). For
example, once the chlorine atom of compound Ic, IIc, IIIc or IVc was substituted
by other electron-withdrawing groups (such as the fluorine atom or the nitro
group), the insecticidal activity of the corresponding compounds Id,e; IId,e; IIId,e;
and IVd,e was sharply decreased.
In
conclusion,
a
series
of
isoxazoline-containing
13

podophyllotoxin/2′(2′,6′)-(di)halogenopodophyllotoxin derivatives (Ia–e, IIa–e,
IIIa–e, and IVa–e) were prepared, and evaluated for their pesticidal activities against
Mythimna separata and Tetranychus cinnabarinus. Among all derivatives, compounds
IIc and IIIc exhibited good insecticidal and acaricidal activities. It demonstrated that
introduction of the halogen atom/atoms at the C-2′/C-2′,6′ position of podophyllotoxin,
and introduction of a chlorine atom at the C-4 position on the phenyl of their
isoxazoline fragment were very important for their insecticidal and acaricidal
activities. These results will lay the foundation for further structural modifications of
podophyllotoxin as potentially botanical acaricidal and insecticidal agents in crop
protection.
Acknowledgements
The present research was partly supported by National Natural Science Foundation of
China (No. 31672071), and Special Funds of Central Colleges Basic Scientific
Research Operating Expenses (No.2452015096), Northwest A&F University.
Supplementary data
Supplementary data (spectral data, and the protocol used for insecticidal and
acaricidal studies) associated with this article can be found, in the online version.
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36. Representative spectral data for Ia, IIa, IIIa, and IVa: Compound Ia: Yield: 92%,
white solid, mp = 96-98 oC; [α]20 = -24 (c 2.0 mg/mL, CHCl3); IR cm-1 (KBr):
D
1
3004, 2924, 2852, 1775, 1588, 1504, 1483, 1460, 1238, 1125, 998, 764, 692; H
NMR (500 MHz, CDCl3) δ: 7.66-7.69 (m, 2H), 7.40-7.46 (m, 3H), 6.82 (s, 0.5H,
H-5), 6.79 (s, 0.5H, H-5), 6.55 (s, 0.5H, H-8), 6.54 (s, 0.5H, H-8), 6.39 (s, 1H,
H-2′, H-6′), 6.38 (s, 1H, H-2′, 6′), 5.94-6.00 (m, 3H, H-4, OCH2O), 5.23-5.27 (m,
1H, H-5′′ (isoxazoline)), 4.59-4.61 (m, 1H, H-1), 4.36-4.40 (m, 1H, H-11),
4.16-4.23 (m, 1H, H-11), 3.81 (s, 1.5H, 3′-OCH3), 3.80 (s, 1.5H, 3′-OCH3), 3.74
(s, 3H, 5′-OCH3), 3.72 (s, 3H, 4′-OCH3), 3.58-3.70 (m, 2H, H-4′′ (isoxazoline)),
2.87-2.98 (m, 2H, H-2, H-3). HRMS (ESI): Calcd for C32H29NO10Na ([M+Na]+),
610.1689; found, 610.1691. Compound IIa: Yield: 85%, white solid, mp =
128-130 oC; [α]20 = -23 (c 3.7 mg/mL, CHCl3); IR cm-1 (KBr): 3000, 2935,
D
1
2858, 1785, 1741, 1485, 1397, 1238, 1200, 1109, 1037, 1003, 864, 692; H
NMR (500 MHz, CDCl3) δ: 7.68-7.71 (m, 2H), 7.43-7.47 (m, 2H), 6.78 (s, 0.5H,
H-5), 6.77 (s, 0.5H, H-5), 6.43 (s, 0.5H, H-8), 6.40 (s, 0.5H, H-8), 6.22 (s, 1H,
H-6′), 5.93-6.01 (m, 3H, H-4, OCH2O), 5.27-5.31 (m, 1H, H-5′′ (isoxazoline)),
5.24-5.25 (m, 1H, H-1), 4.39-4.46 (m, 1H, H-11), 4.15-4.22 (m, 1H, H-11),
3.915 (s, 1.5H, 3′-OCH3), 3.910 (s, 1.5H, 3′-OCH3), 3.870 (s, 3H, 5′-OCH3),
3.866 (s, 3H, 5′-OCH3), 3.69-3.78 (m, 2H, H-4′′ (isoxazoline)), 3.63 (s, 3H,
4′-OCH3), 3.14-3.23 (m, 1H, H-3), 3.00-3.05 (m, 1H, H-2). HRMS (ESI): Calcd
for C32H28ClNO10Na ([M+Na]+), 644.1299; found, 644.1291. Compound IIIa:
Yield: 91%, white solid, mp = 129-131 oC; [α]20D = -6 (c 2.2 mg/mL, CHCl3); IR
17

cm-1 (KBr): 3005, 2929, 2853, 1786, 1504, 1484, 1411, 1396, 1240, 1190, 1086,
1
1013, 935, 762, 692; H NMR (500 MHz, CDCl3) δ: 7.70-7.72 (m, 2H),
7.43-7.46 (m, 3H), 6.85 (s, 0.5H, H-5), 6.74 (s, 0.5H, H-5), 6.35 (s, 0.5H, H-8),
6.33 (s, 0.5H, H-8), 6.07 (d, J = 10.0 Hz, 0.5H, H-4), 6.02 (d, J = 10.0 Hz, 0.5H,
H-4), 5.94-5.95 (m, 2H, OCH2O), 5.55 (d, J = 2.0 Hz, 0.5H, H-1), 5.34 (d, J =
2.0 Hz, 0.5H, H-1), 5.28-5.32 (m, 1H, H-5′′ (isoxazoline)), 4.36-4.43 (m, 1H,
H-11), 4.11-4.19 (m, 1H, H-11), 3.95 (s, 3H, 3′-OCH3), 3.94 (s, 3H, 5′-OCH3),
3.805 (s, 1.5H, 4′-OCH3), 3.800 (s, 1.5H, 4′-OCH3), 3.65-3.75 (m, 3H, H-3, H-4′′
(isoxazoline)), 3.06-3.13 (m, 1H, H-2). HRMS (ESI): Calcd for
C32H27Cl2NO10Na ([M+Na]+), 678.0909; found, 678.0933. Compound IVa:
Yield: 78%, white solid, mp = 126-128 oC; [α]20 = -22 (c 2.0 mg/mL, CHCl3);
D
IR cm-1 (KBr): 3000, 2936, 2853, 1786, 1744, 1484, 1391, 1237, 1199, 1106,
1
1038, 1002, 929, 692; H NMR (500 MHz, CDCl3) δ: 7.68-7.71 (m, 2H),
7.42-7.48 (m, 3H), 6.78 (s, 0.5H, H-5), 6.76 (s, 0.5H, H-5), 6.43 (s, 0.5H, H-8),
6.41 (s, 0.5H, H-8), 6.24 (s, 1H, H-6′), 5.93-6.00 (m, 3H, H-4, OCH2O),
5.27-5.31 (m, 2H, H-1, H-5′′ (isoxazoline)), 4.40-4.46 (m, 1H, H-11), 4.14-4.22
(m, 1H, H-11), 3.906 (s, 1.5H, 3′-OCH3), 3.901 (s, 1.5H, 3′-OCH3), 3.865 (s,
1.5H, 5′-OCH3), 3.861 (s, 1.5H, 5′-OCH3), 3.68-3.80 (m, 2H, H-4′′
(isoxazoline)), 3.63 (s, 3H, 4′-OCH3), 3.15-3.25 (m, 1H, H-3) 2.99-3.04 (m, 1H,
H-2). HRMS (ESI): Calcd for C32H28BrNO10Na ([M+Na]+), 688.0794; found,
688.0796.
18

37. Shi L, Zhang J, Shen G, Xu Z, Wei P, Zhang Y, Xu Q, He L. Sci. Rep. 2015;
5:15581.
38. Wang R, Zhi XY, Li J, Xu H. J. Agric. Food Chem. 2015;63:6668.
19

Graphic abstract
Synthesis
of
novel
isoxazoline-containing
derivatives
podophyllotoxin/2′(2′,6′)-(di)halogenopodophyllotoxin
and their insecticidal/acaricidal activities
Ruige Yang, Yuanyuan Zhang, and Hui Xu*
Tetranychus cinnabarinus
Against Mythimna separata
20