Semi-Synthesis of C-Ring Cyclopropyl Analogues of Fraxinellone and Their Insecticidal Activity against Mythimna separata Walker

Article abstract of DOI:10.3390/molecules25051109

Fraxinellone (1) is a naturally occurring degraded limonoid isolated from Meliaceae and Rutaceae plants. As a potential natural-product-based insecticidal agent, fraxinellone has been structurally modified to improve its activity. Furan ring of fraxinellone is critical in exhibiting its insecticidal activity, but with few modifications. Herein, C-ring-modified cyclopropyl analogues were semi-synthesized by Rh(II)-catalyzed cyclopropanation. The structures of the target compounds were well characterized by NMR and HRMS. The precise three-dimensional structural information of 3a was established by X-ray crystallography. Their insecticidal activity was evaluated against Mythimna separata Walker by a leaf-dipping method. Compound 3c exhibited stronger insecticidal activity than 1 and toosendanin against M. separata with teratogenic symptoms during the different periods, implying that cyclopropanation of the furan ring could strengthen the insecticidal activity of fraxinellone.

Full text of DOI:10.3390/molecules25051109

molecules
Article
Semi-Synthesis of C-Ring Cyclopropyl Analogues
of Fraxinellone and Their Insecticidal Activity
Against Mythimna separata Walker
Xiao-Jun Yang 1, Qing-Miao Dong 2, Min-Ran Wang 2 and Jiang-Jiang Tang 2,
*
1
School of Chemistry & Chemical Engineering, Yanan University, Yanan 716000, China;
yangxiaojun2002@126.com
Shaanxi Key Laboratory of Natural Products & Chemical Biology, College of Chemistry & Pharmacy,
Northwest A&F University, Yangling 712100, China; qingmiaodong@nwafu.edu.cn (Q.-M.D.);
13833683803@163.com (M.-R.W.)
2
*
Correspondence: tangjiang11@nwafu.edu.cn; Tel.: +86-2987-09-2662
ꢀꢁꢂꢀꢃꢄꢅꢆꢇ
ꢀꢁꢂꢃꢄꢅꢆ
Received: 31 January 2020; Accepted: 28 February 2020; Published: 2 March 2020
Abstract: Fraxinellone (1) is a naturally occurring degraded limonoid isolated from Meliaceae and
Rutaceae plants. As a potential natural-product-based insecticidal agent, fraxinellone has been
structurally modified to improve its activity. Furan ring of fraxinellone is critical in exhibiting its
insecticidal activity, but with few modifications. Herein, C-ring-modified cyclopropyl analogues
were semi-synthesized by Rh(II)-catalyzed cyclopropanation. The structures of the target compounds
were well characterized by NMR and HRMS. The precise three-dimensional structural information
of 3a was established by X-ray crystallography. Their insecticidal activity was evaluated against
Mythimna separata Walker by a leaf-dipping method. Compound 3c exhibited stronger insecticidal
activity than 1 and toosendanin against M. separata with teratogenic symptoms during the different
periods, implying that cyclopropanation of the furan ring could strengthen the insecticidal activity
of fraxinellone.
Keywords: fraxinellone; insecticidal agent; cyclopropanation
1. Introduction
Natural products (NPs) continue to provide a rich source for drug discovery [
decades of controlling agricultural pests, NPs also played a key role in the discovery of novel pesticides
owing to their potential target sites, low toxicity, and environment-friendly characteristics [ ].
1–8]. In the past
4–8
In order to improve the hit rate, NPs were always synthesized with diverse structures in a screening
molecules library [9].
Fraxinellone (
1, Figure 1) containing three rings (labeled A–C) is a degraded limonoid isolated
from barks and roots of Dictamnus dasycarpus Turcz. and exhibits interesting insecticidal activity [10
,
11].
The activity relationships of fraxinellone showed that the furan ring (C-ring) is essential for its
insecticidal activities [12]. Several NPs examples with the furan ring as an important pharmacophore
exhibit various bioactivities [4,13–17]. For example, toosendanin (Figure 1) showed potent antifeedant
and growth inhibitory effects against armyworm Mythimna separata and cutworm Peridroma saucia,
in which the furan ring is critical [16,17].
To improve the agrochemical activities of fraxinellone, structural modifications of its A-ring
and B-ring have been carried out by Xu group [18], and some fraxinellone-based esters and
hydrazones analogues at C-4/C-10 position (A-ring) displayed stronger insecticidal activities against
Mythimna separata Walker and Plutella xylostella Linnaeus. However, the furan ring of fraxinellone
Molecules 2020, 25, 1109; doi:10.3390/molecules25051109
www.mdpi.com/journal/molecules

Molecules 2020, 25, 1109
2 of 9
remains with few modifications. Recently, the modification of aromatic (furan ring) functionalities
was reported by us [19 20]. A series of C-ring selective brominations and further palladium-catalyzed
,
transformations analogues of fraxinellone have been prepared. To our delight, some compounds
displayed more potent insecticidal activity than toosendanin. On the basis of the above furan-modified
results and in our endeavor aiming at finding more active natural-product-based insecticidal
hits [19,21–24], herein, we semi-synthesized C-ring cyclopropyl analogues of fraxinellone by
Rh(II)-catalyzed cyclopropanation as insecticidal agents against M. separata.
Figure 1. Chemical structures of fraxinellone (1) and its furan-modified analogues, and toosendanin.
2. Results and Discussion
2.1. Semi-Synthesis
An attractive approach to utilize the furan ring for the generation of resourceful analogues
is the [2 + 1] addition of carbenes [25
aromatic ethyl esters firstly reacted with p-toluenesulfonyl azide (TsN3) to form
2a 2c) in the presence of base 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) in high yields (67–90%).
,26]. As shown in Scheme 1, the commercial substrate
α
-carbonyldiazoesters
(
–

Molecules 2020, 25, 1109
3 of 9
Yet, when trimethylamine (Et3N) was used as the base, this reaction did not occur. If methyl
2-thiophene acetate was used to react with TsN3 under the above reaction conditions, the target
compound cannot be prepared.
Scheme 1. Synthesis of fraxinellone C-ring cyclopropyl analogues (3a–3c). Reagents and conditions:
(a) TsN3 (1.2 equiv), 1,8-Diazabicyclo[5.4.0]undec-7-ene (DBU) (1.5 equiv), MeCN, 25 oC, 15 h, 67–90%
isolated yields; (b) Rh2(OAc)4 (0.01 equiv), PhMe, 0 ◦C, 13 h, 3a: 20%, 3b: 37%, 3c: 10% isolated yields.
With acceptor diazoesters (2a
–
2c) in hand, fraxinellone (
1) as a starting brick was converted into
the corresponding monocyclopropanated adducts (3a
–
3c). Rh2(OAc)4-catalyzed cyclopropanation of
1
mainly provides stereoselective adducts by thin-layer chromatography (TLC) isolation. The absolute
configuration of 3a was unambiguously established by X-ray crystallography (Figure 2), indicating the
cyclopropyl ring of 4’ and 5’ positions was formed in
this product can be rationalized on steric ground in the asynchronous concerted cyclopropanation
that the reaction of the Rh-bound carbene occurs from the si face of the carbene [27 28]. Using the
same orientation of attack, the observed stereochemistry is consistent with the attack occurring at the
-position for 3b and 3c in NOE spectra. Furthermore, the configuration of 3a indicated the top chiral
β configuration of the furan ring. Formation of
,
β
carbon of the cyclopropyl ring oriented the ester group onto the convex face of the bicycle, which is
same as synthetic methodology [29]. Unfortunately, the yields were too low (10–37%), with just 50–60%
conversion of diazoesters and about 70% conversion of fraxinellone, perhaps because of the complexity
of the fraxinellone structure. The structures of all analogues were determined by NMR and HRMS and
were stable for at least five days in solid or in acetone solution at room temperature. Their spectra can
be found in the Supplementary Materials.
Figure 2. X-ray crystal structure of compound 3a (CCDC number: 1549251 at https://www.ccdc.cam.ac.uk).

Molecules 2020, 25, 1109
4 of 9
2.2. Insecticidal Activity
The insecticidal activity of all cyclopropanated analogues was tested against M. separata Walker
by the leaf-dipping method as the mortality rates at 1 mg/mL [30]. Toosendanin, a commercial
natural-product-based insecticide, was used as a positive control and leaves treated with acetone alone
were used as a blank group. The corrected mortality rate at different stages was outlined in Table 1.
Fraxinellone and its prepared analogues exhibited the delayed insecticidal activity against M. separata.
For example, the mortality rates of 3a against M. separata after 10 and 20 days were 8.3% and 12.5%,
respectively. However, it was increased to 29.2% after 35 days with over three-fold of that after 10 days.
Among all tested analogues, 3c displayed stronger insecticidal activity than their precursor
toosendanin. The final mortality rates of 3c were 34.5%, whereas the final mortality rates of
toosendanin were 17.4% and 33.3%, respectively.
1
1
and
and
Table 1. Insecticidal activity of fraxinellone C-ring cyclopropyl analogues 3a–3c against M. separata on
leaves treated with a concentration of 1 mg/mL.
Corrected Mortality Rate [%]1
Compound
20 days
35 days
10 days
1
3a
3b
0.0
8.3
4.2
4.2
29.2
0.0
11.3
12.5
8.3
12.5
29.2
0.0
17.4
29.2
33.3
37.5
33.3
0.0
3c
toosendanin
blank control
1
The corrected mortality rate was calculated in three different periods (larvae, pupae, and moth). All data (mean
SD) are the average of four independent groups (six larvae per group).
±
Notably, these analogues have good teratogenic activity on three different stages. During the larval
period, the symptoms of the larvae of M. separata treated by these compounds were slim and wrinkled
bodies (not shown). Many larvae molted to malformed pupae or died in the treated groups during the
stage of pupation (Figure 3a). Many malformed moths of the treated groups appeared with imperfect
wings during the emergence period (Figure 3b), implying that these analogues might have affected the
insect molting hormone [31,32]. These symptoms in the three different periods tested by compounds
were consistent with those of fraxinellone funan ring-coupling analogues [19]. This demonstrated that
inserting the clopropyl group on C-ring of fraxinellone resulted in more promising analogues.
Figure 3. Representative malformed pictures: (
the pupation period; ( ) malformed moth of 3a (10a), 3b (10b) and 3c (10c) during the stage of adult
emergence (CK = blank control group, toosendanin = positive control group).
a) Malformed pupae of 3a (10a) and 3c (10c) during
b

Molecules 2020, 25, 1109
5 of 9
3. Materials and Methods
3.1. General
All NMR spectra were recorded on a Bruker Advance III 500 instrument (Bruker Daltonics Inc.,
Bremen, Germany) in CDCl3 or CD3OD with TMS as internal standard for protons and solvent signals
as internal standard for carbon spectra. Chemical shift values are mentioned in
δ (ppm) and coupling
constants (J) are given in Hz. HR-ESI-MS spectra were recorded on an AB Sciex 5600 Triple TOF mass
spectrometer (AB SCIEX Inc., Singapore). Melting points (m.p.) were determined on an auto-melting
point apparatus (Hanon Instruments Co., Ltd., Jinan, China). Column chromatography (CC) was
performed over silica gel (200–300 mesh, Qingdao Marine Chemical Ltd.). All reactions were monitored
by thin-layer chromatography (TLC) carried out on pre-coated silica gel GF254 plates with a thickness of
0.25 mm (Qingdao Marine Chemical Group, Co.) with UV light (254 nm and 365 nm). All commercial
solvents and reagents were freshly purified and dried by standard techniques prior to use. Fraxinellone
(1) was isolated from root bark of Dictamnus dasycarpus and established on the basis of extensive
spectroscopic analyses, referring to a previous report [19].
3.2. Synthesis of α-Diazocarbonyl Esters (2a–2c)
The stirring solution of 1.58 mmol phenylacetate in 20 mL acetonitrile (MeCN) was added
dropwise 379.1 mg (1.90 mmol) of p-toluenesulfonyl azide (TsN3) in 4 mL MeCN at room temperature.
Then, 337.48 mg of 1,8-Diazabicyclo[5.4.0]undec-7-ene (DBU) (1.58 mmol) was added and the solution
was stirred for 15 h. After monitoring the completion of the reaction by TLC, water was added to
terminate the reaction. The reaction solution was extracted with anhydrous ether (2
×
30 mL) and the
organic phase was dried in anhydrous sodium sulfate (Na2SO4). The organic phase was concentrated
in vacuum to give a yellow oil. A silica gel column (300–400 mesh, petroleum ether: ethyl acetate,
40:1–20:1, v/v) was used for column chromatography to obtain the products 2a–2c.
Methyl2-diazo-2-phenylacetate (2a): yellow solid, 67% yield. NMR data were consistent with a previous report [29].
1
Ethyl 2-diazo-2-phenylacetate (2b): yellow solid, 89% yield. H-NMR (500 MHz, MeOD)
δ 7.54 – 7.45
(m, 2H), 7.39 (ddd, J = 8.6, 7.4, 1.6 Hz, 2H), 7.19 (td, J = 7.4, 1.3 Hz, 1H), 4.32 (qd, J = 7.1, 1.8 Hz, 2H),
1.34 (td, J = 7.1, 1.5 Hz, 3H); 13C-NMR (126 MHz, MeOD)
δ
173.49, 166.59, 130.25, 129.90, 129.47 (2C),
126.87, 125.11, 62.13, 49.51, 49.34, 49.17, 49.00, 48.83, 48.66, 48.49, 14.76.
1
Ethyl 2-(4-bromophenyl)-2-diazoacetate (2c): yellow solid, 88% yield. H-NMR (500 MHz, CDCl3)
δ 7.52
(dd, J = 8.9, 2.4 Hz, 1H), 7.39 (dd, J = 8.9, 2.4 Hz, 1H), 4.37 (qd, J = 7.1, 1.8 Hz, 1H), 1.38 (td, J = 7.1, 1.6
Hz, 2H); 13C-NMR (126 MHz, CDCl3)
77.42, 77.16, 61.50, 14.82.
δ 171.35, 165.10, 132.31 (2C), 125.65 (2C), 125.23, 119.58, 77.67,
3.3. Synthesis of C-Ring Cyclopropyl Analogues (3a–3c) of Fraxinellone
First, 40 mg (172.21 mol) of fraxinellone ( ) and 0.76 mg (1.72
into a dry reaction tube sealed with a rubber tap. In the tube, air was replaced four times with argon,
and the tube was placed in an ice bath. Then, 378.21 mol phenyldiazoesters (2a 2c) dissolved in 4 mL
µ
1
µmol) of Rh2(OAc)4 were added
µ
–
of toluene was added dropwise to the tube and stirred in an ice bath for 13 h. After the reaction was
monitored for completion by TLC, the solvent was removed directly and the sample was separated in
silica gel column chromatography (300–400 mesh, petroleum ether: ethyl acetate, 40:1–10:1, v/v) to
afford the analogues 3a–3c.
Methyl-4-((1R,7aR)-4,7a-dimethyl-3-oxo-1,3,5,6,7,7a-hexahydroisobenzofuran-1-yl)-6-phenyl-2-oxabicyclo
[3.1.0]hex-3-ene-6-carboxylate (3a): white solid, 20% yield, Rf = 0.25 (petroleum ether: EtOAc = 40:1),
m.p. = 141–143 ◦C. 1H-NMR (500 MHz, CDCl3)
δ
7.33–7.29 (m, 3H, H-2”, H-4”, and H-6”), 7.21 (dd,
J = 7.4, 1.9 Hz, 2H, H-3”, and H-5”), 6.05 (d, J = 0.8 Hz, 1H, H-20), 5.19 (d, J = 6.2 Hz, 1H, H-50), 4.53 (d,

Molecules 2020, 25, 1109
6 of 9
J = 1.7 Hz, 1H, H-8), 3.67 (s, 3H, -Me), 3.18 (d, J = 5.7 Hz, 1H, H-40), 2.32 (dd, J = 19.7, 6.4 Hz, 1H, H-4),
2.22 (dd, J = 10.9, 7.3 Hz, 1H, H-4), 2.14 (s, 3H, H-10), 2.04 (dt, J = 12.2, 3.3 Hz, 1H, H-5), 1.81-1.93
(m, 2H, H-5, 6), 1.61 (td, J = 12.9, 3.8 Hz, 1H, H-6), 1.02 (s, 3H, H-11); 13C-NMR (126 MHz, CDCl3)
δ
173.99, 169.48, 149.04, 144.80, 131.94, 130.03, 128.33, 128.03, 127.35, 113.61, 84.11, 71.29, 52.93, 42.72,
39.01, 32.83, 32.18, 28.54, 20.77, 18.69, 18.61; HR-ESI-MS m/z: Found 403.1496 [M+Na]+ (calcd for
C23H24NaO5, 403.1521).
Ethyl-4-((1R,7aR)-4,7a-dimethyl-3-oxo-1,3,5,6,7,7a-hexahydroisobenzofuran-1-yl)-6-phenyl-2- oxabicyclo[3.1.0]
hex-3-ene-6-carboxylate (3b): white solid, 37% yield, Rf = 0.21 (petroleum ether: EtOAc = 40:1), m.p. =
144–145 ◦C. 1H-NMR (500 MHz, CDCl3)
δ 7.22–7.15 (m, 3H, H-2”, H-4”, and H-6”), 7.09 (dd, J = 7.5, 1.8
Hz, 2H, H-3”, and H-5”), 5.93 (d, J = 0.8 Hz, 1H, H-20), 5.07 (d, J = 5.7 Hz, 1H, H-50), 4.41 (d, J = 1.7 Hz, 1H,
H-8), 4.04–3.98 (m, 2H, Et-H ), 3.05 (d, J = 5.7 Hz, 1H, H-40), 2.24–2.09 (m, 2H, H-4), 2.02 (s, 3H, H-10),
1.92 (dt, J = 12.2, 3.3 Hz, 1H, H-5), 1.79–1.66 (m, 2H, H-5, and H-6), 1.53–1.47 (m, 1H, H-6), 1.07 (t, J = 7.1
Hz, 3H, Et-H), 0.90 (s, 3H, H-11); 13C-NMR (126 MHz, CDCl3)
δ 173.22, 169.26, 148.69, 144.60, 131.74,
130.07, 128.02, 127.67, 127.28, 113.44, 83.97, 70.96, 61.42, 42.54, 38.53, 32.66, 32.00, 28.50, 20.56, 18.49,
18.44, 14.17; HR-ESI-MS m/z: Found 417.1647 [M+Na]+ (calcd for C24H26NaO5, 417.1678).
Ethyl-6-(4-bromophenyl)-4-((1R,7aR)-4,7a-dimethyl-3-oxo-1,3,5,6,7,7a-hexahydroisobenzofuran-1-yl)-2- oxabicyclo
[3.1.0]hex-3-ene-6-carboxylate (3c): white solid, 10% yield, Rf = 0.30 (petroleum ether: EtOAc = 30:1), m.p. =
160–162 ◦C. 1H-NMR (500 MHz, CDCl3)
δ 7.48 (d, J = 7.5 Hz, 2H, H-3”, and H-5”), 7.37 (d, J = 7.9 Hz,
2H, H-2”, and H-6”), 5.81 (s, 1H, H-20), 5.11 (d, J = 5.5 Hz, 1H, H-50), 4.33 (s, 1H, H-8), 4.08–4.03 (m, 2H,
Et-H), 3.37 (d, J = 5.5 Hz, 1H, H-40), 2.23 (dd, J = 19.8, 6.4 Hz, 1H, H-4, and H-10), 2.12–2.05 (m, 4H, H-4,
and H-10), 1.81–1.61 (m, 3H, H-5, and H-6), 1.30 (dd, J = 14.4, 7.3 Hz, 1H, H-6), 1.13 (t, J = 7.1 Hz, 3H,
Et-H), 1.06 (s, 3H, H-11 ); 13C-NMR (126 MHz, CDCl3)
δ 172.75, 170.04, 148.98, 143.71, 132.03, 129.74,
129.37, 127.14, 121.73, 115.17, 83.22,70.64, 61.79, 44.45, 40.19, 32.34, 31.29, 28.08, 20.44, 18.65, 18.17, 14.36;
HR-ESI-MS m/z: Found 495.0762 [M+Na]+ (calcd for C24H25BrNaO5, 495.0783).
3.4. X-Ray Experimental of 3a
Single crystals of 3a (C23H24O5) were obtained by recrystallization in ethanol. A suitable crystal
was selected and analyzed on a SuperNova, Dual, Cu at zero, Eos diffractometer (Bruker Daltonics
Inc., Bremen, Germany). The crystal was kept at 293(2) K during data collection. Using Olex2 [33],
the structure was solved with the Superflip [34] structure solution program using charge flipping and
refined with the ShelXL [35] refinement package using least squares minimisation.
3.5. The Insecticidal Activity Assay
The insecticidal activity of 3a
method against the pre-third-instar larvae of M. separata using the reported procedure [30
–
3c was tested as the mortality rate using the leaf-dipping
36].
,
Briefly, 24 pre-third-instar larvae (6 larvae per group) were used for each sample. Each treatment was
performed four times. Acetone solutions of samples and toosendanin (positive control) were prepared
at 1 mg/mL. Fresh wheat leaf discs (1
taken out and dried. Several pieces of treated leaf discs were kept in each six-well plate, which was
then placed in a conditioned room (25
2 ◦C, 65–80% relative humidity (RH), 12 h/12 h (light/dark).
×
1 cm) were dipped into the corresponding solution for 3 s, then
±
After two days, untreated fresh leaves were added to the all dish until the adult pupae emergence.
The corrected mortality rates of the tested compounds against M. separata Walker were calculated in
three different periods by the following formula:
mortality rate of test − mortality rate of control
corrected mortality rate (%) =
4. Conclusions
× 100%
(1)
100%−mortality rate of control
Natural-product analogues attract extensive attention because of their high hit rate in the process
the discovery of new drugs. To enrich the fraxinellone-based structures, we semi-synthesized

Molecules 2020, 25, 1109
7 of 9
C-ring-modified cyclopropyl analogues by Rh(II)-catalyzed cyclopropanation for the first time.
Notably, this cyclopropanation of fraxinellone provided products with orienting cyclopropyl ring in
β
configuration and ester group on the convex face of the bicycle, but without altering other functional
groups. Although their yield is not high, the reaction applied the synthetic strategy for modification of
diverse furan-containing NPs. An evaluation of insecticidal activity showed that 3c displayed stronger
insecticidal activity than parental counterpart and toosendanin. Their corresponding pharmacological
data and target of action are undergoing.
Supplementary Materials: The following are available online, Figure S1–S5: NMR spectra of compounds 2b
and 3a
for 3a.
,
2c
,
–3c; Figure S6–S8: HR-ESI-MS spectra of compounds 3a–3c; Table S1: Crystal data and structure refinement
Author Contributions: Conceptualization, X.-J.Y. and J.-J.T.; methodology, Q.-M.D. and M.-R.W.; validation,
X.-J.Y., Q.M.D., and J.-J.T.; formal analysis, J.-J.T.; investigation, M.-R.W. and Q.M.D.; resources, X.-J.Y.; data
curation, Q.M.D.; writing—original draft preparation, X.-J.Y.; writing—review and editing, J.-J.T.; supervision,
J.-J.T.; project administration, X.-J.Y.; funding acquisition, X.-J.Y. All authors have read and agreed to the published
version of the manuscript.
Funding: This research was funded by the National Natural Science Foundation of China (31860089), Yangling
Demonstration Zone Science and Technology Plan Project (2017NY-07), China and Science and Technology
Department of Shaanxi Province (2019JM-516).
Acknowledgments: This work was given some technical support by Instrument Shared Platform of Northwest
A&F University.
Conflicts of Interest: The authors declare no conflict of interest.
References
1.
2.
3.
Machida, S.; Mukai, S.; Kono, R.; Funato, M.; Saito, H.; Uchiyama, T. Synthesis and comparative
structure-activity study of carbohydrate-based phenolic compounds as alpha-glucosidase inhibitors and
antioxidants. Molecules 2019, 24, 4340. [CrossRef] [PubMed]
Richers, J.; Pothig, A.; Herdtweck, E.; Sippel, C.; Hausch, F.; Tiefenbacher, K. Synthesis and neurotrophic
activity studies of illicium sesquiterpene natural product analogues. Chem.-Eur. J. 2017, 23, 3178–3183.
[CrossRef] [PubMed]
Liao, L.-X.; Song, X.-M.; Wang, L.-C.; Lv, H.-N.; Chen, J.-F.; Liu, D.; Fu, G.; Zhao, M.-B.; Jiang, Y.;
Zeng, K.-W.; et al. Highly selective inhibition of IMPDH2 provides the basis of antineuroinflammation
therapy. Proc. Natl. Acad. Sci. 2017, 114, E5986–E5994. [CrossRef] [PubMed]
4.
5.
6.
7.
Cantrell, C.L.; Dayan, F.E.; Duke, S.O. Natural products as sources for new pesticides. J. Nat. Prod. 2012, 75,
1231–1242. [CrossRef]
Bolzani Vda, S.; Davies-Coleman, M.; Newman, D.J.; Singh, S.B.; Gordon, M.; Cragg, D.; Phil, D. Sc. (h.c.):
A man for all natural products. J. Nat. Prod. 2012, 75, 309–310. [CrossRef]
Xu, H. Natural products as leads for new drugs and pesticides discovery. Mini Rev. Org. Chem. 2012, 9, 125.
[CrossRef]
Fuse, S.; Matsumura, K.; Johmoto, K.; Uekusa, H.; Tanaka, H.; Hirose, T.; Sunazuka, T.; Omura, S.; Takahashi, T.
The design, synthesis, and evaluation of 1,5,7-trisubstituted-3-pyridyl-xanthones for use as insecticides
starting from pyripyropene A. Chem.-Eur. J. 2016, 22, 18450–18455. [CrossRef]
Copping, L.G.; Duke, S.O. Natural products that have been used commercially as crop protection agents.
Pest. Manag. Sci. 2007, 63, 524–554. [CrossRef]
8.
9.
Newman, D.J.; Cragg, G.M. Natural products as sources of new drugs from 1981 to 2014. J. Nat. Prod. 2016
,
79, 629–661. [CrossRef]
10. Liu, Z.L.; Ho, S.H.; Goh, S.H. Effect of fraxinellone on growth and digestive physiology of Asian corn borer,
Ostrinia furnacalis Guenee. Pestic. Biochem. Physiol. 2008, 91, 122–127. [CrossRef]
11. Liu, Z.L.; Ho, S.H.; Goh, S.H. Modes of action of fraxinellone against the tobacco budworm, Heliothis virescens.
Insect Sci. 2009, 16, 147–155. [CrossRef]
12. Zhao, W.; Wolfender, J.L.; Hostettmann, K.; Xu, R.; Qin, G. Antifungal alkaloids and limonoid derivatives
from Dictamnus dasycarpus. Phytochemistry 1998, 47, 7–11. [CrossRef]

Molecules 2020, 25, 1109
8 of 9
13. Riley, A.P.; Day, V.W.; Navarro, H.A.; Prisinzano, T.E. Palladium-catalyzed transformations of salvinorin A,
a neoclerodane diterpene from Salvia divinorum. Org. Lett. 2013, 15, 5936–5939. [CrossRef] [PubMed]
14. Harding, W.W.; Schmidt, M.; Tidgewell, K.; Kannan, P.; Holden, K.G.; Dersch, C.M.; Rothman, R.B.;
Prisinzano, T.E. Synthetic studies of neoclerodane diterpenes from Salvia divinorum: Selective modification of
the furan ring. Bioorg. Med. Chem. Lett. 2006, 16, 3170–3174. [CrossRef] [PubMed]
15. Riley, A.P.; Groer, C.E.; Young, D.; Ewald, A.W.; Kivell, B.M.; Prisinzano, T.E. Synthesis and kappa-opioid
receptor activity of furan-substituted salvinorin A analogues. J. Med. Chem. 2014, 57, 10464–10475. [CrossRef]
[PubMed]
16. Chen, W.; Isman, M.B.; Chiu, S.F. Antifeedant and growth-inhibitory effects of the limonoid toosendanin and
melia-toosendan extracts on the variegated cutworm, Peridroma-Saucia (Lep, Noctuidae). J. Appl. Entomol.
1995, 119, 367–370. [CrossRef]
17. Shi, Y.L.; Wang, W.P.; Liao, C.Y.; Chiu, S.F. Effect of toosendanin on the sensory inputs of chemoreceptors of
the armyworm larvae Mythimna-Separata. Acta Entomol. Sin. 1986, 29, 233–238.
18. Guo, Y.; Qu, H.; Zhi, X.Y.; Yu, X.; Yang, C.; Xu, H. Semisynthesis and insecticidal activity of some fraxinellone
derivatives modified in the B ring. J. Agric. Food Chem. 2013, 61, 11937–11944. [CrossRef]
19. Dong, Q.M.; Dong, S.; Shen, C.; Cao, Q.H.; Song, M.Y.; He, Q.R.; Wang, X.L.; Yang, X.J.; Tang, J.J.; Gao, J.M.
Furan-site bromination and transformations of fraxinellone as insecticidal agents against Mythimna separata
Walker. Sci. Rep. 2018, 8, 8372. [CrossRef]
20. Xiang, P.; Cao, Q.H.; Dong, Q.M.; Yang, X.J.; Tang, J.J.; Bai, H. Furan-site transformations of obacunone as
potent insecticidal agents. Heliyon 2018, 4, e01064. [CrossRef]
21. Wang, D.M.; Zhang, C.C.; Zhang, Q.; Shafiq, N.; Pescitelli, G.; Li, D.W.; Gao, J.M. Wightianines A-E,
Dihydro-beta-agarofuran sesquiterpenes from Parnassia wightiana, and their antifungal and insecticidal
activities. J. Agric. Food Chem. 2014, 62, 6669–6676. [CrossRef] [PubMed]
22. Fan, N.J.; Wei, S.P.; Gao, J.M.; Tang, J.J. Potential insecticidal activity of steroidal C-17 pyrazolinyl derivatives.
J. Braz. Chem. Soc. 2015, 26, 389–392. [CrossRef]
23. Xiao, J.; Zhang, Q.; Gao, Y.Q.; Tang, J.J.; Zhang, A.L.; Gao, J.M. Secondary metabolites from the endophytic
Botryosphaeria dothidea of Melia azedarach and their antifungal, antibacterial, antioxidant, and cytotoxic
activities. J. Agric. Food Chem. 2014, 62, 3584–3590. [CrossRef] [PubMed]
24. Zhang, X.Y.; Shen, J.; Zhou, Y.; Wei, Z.P.; Gao, J.M. Insecticidal constituents from Buddlej aalbiflora Hemsl.
Nat. Prod. Res. 2017, 31, 1446–1449. [CrossRef]
25. Wenkert, E.; Khatuya, H. The effect of substituents of alpha-alkyl sidechains on furan-diazoester interactions.
Tetrahedron Lett. 1999, 40, 5439–5442. [CrossRef]
26. Wenkert, E.; Khatuya, H.; Klein, P.S. Reactions of ethyl diazoacetate with beta-methylfurans. Tetrahedron Lett.
1999, 40, 5171–5174. [CrossRef]
27. Lindsay, V.N.G.; Lin, W.; Charette, A.B. Experimental evidence for the all-up reactive conformation of
chiral rhodium(II) carboxylate catalysts: Enantioselective synthesis of cis-cyclopropane alpha-amino acids.
J. Am. Chem. Soc. 2009, 131, 16383–16385. [CrossRef]
28. Liao, K.B.; Pickel, T.C.; Oyarskikh, V.B.; Acsa, J.B.; Usaev, D.G.M.; Davies, H.M.L. Site-selective and
stereoselective functionalization of non-activated tertiary C-H bonds. Nature 2017, 551, 609–613. [CrossRef]
29. Lehner, V.; Davies, H.M.L.; Reiser, O. Rh(II)-catalyzed cyclopropanation of furans and its application to the
total synthesis of natural product derivatives. Org. Lett. 2017, 19, 4722–4725. [CrossRef]
30. Xu, H.; He, X.Q. Natural products-based insecticidal agents 6. Design, semisynthesis, and insecticidal activity
of novel monomethyl phthalate derivatives of podophyllotoxin against Mythimna separata Walker in vivo
.
Bioorg. Med. Chem. Lett. 2010, 20, 4503–4506. [CrossRef]
31. Guo, Y.; Yan, Y.Y.; Yu, X.; Wang, Y.; Zhi, X.Y.; Hu, Y.; Xu, H. Synthesis and insecticidal activity of some novel
fraxinellone-based esters. J. Agric. Food Chem. 2012, 60, 7016–7021. [CrossRef] [PubMed]
32. Guo, Y.; Yan, Y.Y.; Yang, C.; Yu, X.; Zhi, X.Y.; Xu, H. Regioselective synthesis of fraxinellone-based hydrazone
derivatives as insecticidal agents. Bioorg. Med. Chem. Lett. 2012, 22, 5384–5387. [CrossRef] [PubMed]
33. Dolomanov, O.V.; Bourhis, L.J.; Gildea, R.J.; Howard, J.A.; Puschmann, H. OLEX2: A complete structure
solution, refinement and analysis program. J. Appl. Crystallogr. 2009, 42, 339–341. [CrossRef]
34. Palatinus, L.; Chapuis, G. SUPERFLIP-a computer program for the solution of crystal structures by charge
flipping in arbitrary dimensions. J. Appl. Crystallogr. 2007, 40, 786–790. [CrossRef]

Molecules 2020, 25, 1109
9 of 9
35. Sheldrick, G.M. A short history of SHELX. Acta Crystallogr. Sect. A 2007, 64, 112–122. [CrossRef]
36. Tang, J.J.; Zhang, F.Y.; Wang, D.M.; Tian, J.M.; Dong, S.; Gao, J.M. Semisynthesis and antifeedant activity of
new derivatives of a dihydro-beta-agarofuran from Parnassia wightiana. Int. J. Mol. Sci. 2013, 14, 19484–19493.
[CrossRef]
Sample Availability: Samples of the compounds are available from the authors.
©
2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access
article distributed under the terms and conditions of the Creative Commons Attribution
(CC BY) license (http://creativecommons.org/licenses/by/4.0/).