Synthesis of some monosaccharide-related ester derivatives as insecticidal and acaricidal agents

Article abstract of DOI:10.1016/j.bmcl.2017.08.031

To develop natural-product-based pesticidal agents, a series of monosaccharide-related ester derivatives (17a–q and 18a–f), glucose (xylose)-piperic acid/piperic acid-like conjugates, were synthesized. Three-dimensional structures of compounds 17b, 17g, 17h, and 17n were unambiguously determined by single-crystal X-ray diffraction. Especially compounds 18e and 18f exhibited the most potent insecticidal and acaricidal activities against Mythimna separata and Tetranychus cinnabarinus. Their structure-activity relationships were also discussed.

Full text of DOI:10.1016/j.bmcl.2017.08.031

Accepted Manuscript
Synthesis of some monosaccharide-related ester derivatives as insecticidal and
acaricidal agents
Xiaobo Huang, Bingchuan Zhang, Hui Xu
PII:
S0960-894X(17)30832-6
DOI:
http://dx.doi.org/10.1016/j.bmcl.2017.08.031
BMCL 25225
Reference:
Bioorganic & Medicinal Chemistry Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
11 June 2017
12 August 2017
14 August 2017
Please cite this article as: Huang, X., Zhang, B., Xu, H., Synthesis of some monosaccharide-related ester derivatives
as insecticidal and acaricidal agents, Bioorganic & Medicinal Chemistry Letters (2017), doi: http://dx.doi.org/
10.1016/j.bmcl.2017.08.031
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Synthesis of some monosaccharide-related ester derivatives as
insecticidal and acaricidal agents
Xiaobo Huang a, Bingchuan Zhanga, and Hui Xu a,b,
*
aResearch Institute of Pesticidal Design & Synthesis, College of Plant Protection,
Northwest A&F University, Yangling 712100, Shaanxi Province, China
bShaanxi Key Laboratory of Natural Products & Chemical Biology, College of
Chemistry and Pharmacy, 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:
To develop natural-product-based pesticidal agents,
monosaccharide-related ester derivatives (17a-q and 18a-f), glucose
(xylose)-piperic acid/piperic acid-like conjugates, were synthesized.
a
series of
Three-dimensional structures of compounds 17b, 17g, 17h, and 17n were
unambiguously determined by single-crystal X-ray diffraction. Especially
compounds 18e and 18f exhibited the most potent insecticidal and acaricidal
activities against Mythimna separata and Tetranychus cinnabarinus. Their
structure-activity relationships were also discussed.
Keywords: Ester; Monosaccharide; Piperine; Insecticidal activity; Acaricidal activity
2

Oriental armyworm (Mythimna separata Walker) and spider mite (Tetranychus
cinnabarinus Boisduval) are two crop-threatening insect pests, and their outbreaks are
generally hard to control.1-3 Meanwhile, due to extensive and unreasonable application
of synthetic agrochemicals, development of resistance in pest populations and
negative impacts on human health and environment has occurred.4,5 Consequently,
development of the potential alternatives to efficiently control insect pests is highly
desirable.6-8
Piperine (Figure 1), a simple alkaloid isolated as from Piper nigrum Linn.,
exhibited a variety of biological properties including anti-inflammatory activity,
antimicrobial activity, antitumor activity, and insecticidal activity.9 Previously, by
using piperine as a lead compound, we prepared a series of piperine-based hydrazone
derivatives (I, Figure 1),10 and piperine-based phenylsulfonylhydrazone derivatives
(II,
Figure
1)11
as
insecticidal
agents;
and
especially
piperine-based
piperine-based
4-ethylphenylsulfonylhydrazone
4-bromophenylsulfonylhydrazone exhibited more potent narcotic activity against M.
separata than wilfortrine and wilforgine, two macrocyclic alkaloids isolated from
Tripterygium hypoglaucum Hutch.11 On the other hand, Xu et al. pioneeringly
reported some glucose-fipronil conjugates (III and IV, Figure 1) showing excellent
phloem mobility.12-16 Huang et al. found that some fluorine-containing saccharide
esters (V and VI, Figure 1) showed potent antiviral activities against tobacco mosaic
virus.17 In continuation of our program aimed at the development of
natural-product-based pesticidal agents,18-20 therefore, in this Letters some glucose
3

(xylose)-piperic acid conjugates (VII, Figure 1) were prepared by combination of
glucosides with the piperic acid together. Meanwhile, to study the structure-activity
relationships of these type compounds, other glucose (xylose)-piperic acid-like
conjugates (VIII and IX, Figure 1) were also synthesized. Their insecticidal and
acaricidal activities were evaluated against Mythimna separata and Tetranychus
cinnabarinus.
Figure 1. The chemical structures of piperine, its derivatives (I and II),
monosaccharide-related derivatives (III- VI), and target compounds VII-IX.
4

Scheme 1. Synthesis of 2,3,4-tri-O-acetyl-β-D-xylopyranosylbromine (3a) and
2,3,4,6-tetra-O-acetyl-β-D-glucopyranosylbromine (3b).
As shown in Scheme 1, 1,2,3,4-tetra-O-acetylxylose (2a) and
1,2,3,4,6-penta-O-acetylglucose (2b) were firstly prepared by reaction of iodine with
xylose (1a) and glucose (1b), respectively.21 Then two intermediates,
2,3,4-tri-O-acetyl-β-D-xylopyranosylbromine
(3a)
and
2,3,4,6-tetra-O-acetyl-β-D-glucopyranosylbromine (3b), were smoothly obtained by
reaction of bromine with 2a and 2b, respectively.22
COOH
CO2CH3
O
R3
R3
Malonic acid/Py/Piperidine
reflux, 10 h, 78%-91%
CH3OH/H2SO4(con.)
reflux,16 h, 97%-98%
R3
4a-c
5a-c
6a-c
MnO2/THF
AlCl3/LiAlH4/THF
0oC, 1-1.5 h, 86%-92%
OH
O
R3
R3
reflux, 5-6 h, 80%-91%
7a-c
8a-c
R3 =
COOH
Malonic acid/Py/Piperidine
reflux, 10 h, 51%-67%
R3
a
b
c
: H; : p-CH3; : p-Cl
9a-c
COOH
O
O
HO
12
O
O
O
DCM/K2CO3/DMF
105 oC, 4 h, 41%
O
HO
10
11
COOH
O
O
13
O
N
O
O
O
O
OH
KOH/CH3CH2OH (95%)
reflux, 16 h, 93%
O
14
15
Scheme 2. Synthesis of different aromatic carboxylic acids (5a-c, 9a-c, 12, 13, and
15).
As described in Scheme 2, malonic acid reacted with benzaldehydes (4a-c) to
give cinnamic acids (5a-c);23 methyl cinnamates (6a-c) were prepared by reaction of
5

5a-c with methanol in the presence of conc. sulfuric acid.10 Then reduction of 6a-c
with LiAlH4 and AlCl3 afforded γ-phenylallyl alcohols (7a-c), which were oxidized by
MnO2 to produce phenylacrolein (8a-c).10 Finally, 5-phenyl-2,4-pentadienoic acids
(9a-c) were obtained by reaction of 8a-c with malonic acid.23
3,4-Methylenedioxybenzoic acid (12) and 3,4-methylenedioxycinnamic acid (13)
were obtained from 3,4-methylenedioxybenzaldehyde (11),24 which was prepared
from 3,4-dihydroxybenzaldehyde (10).25 The piperic acid (15) was obtained from
piperine (14) by the basic hydrolysis.26
Scheme
3.
Synthesis
of
2,3,4-tri-O-acetyl-β-D-xylopyranosylcarbonyl/
2,3,4,6-tetra-O-acetyl-β-D-glucopyranosylcarbonyl derivatives (17a-q and 18a-f).
As shown in Scheme 3, target compounds 17a-q, and 18a-f were obtained by
reaction
of
2,3,4-tri-O-acetyl-β-D-xylopyranosylbromine
(3a)/2,3,4,6-tetra-O-acetyl-β-D-glucopyranosylbromine (3b) with the corresponding
6

carboxylic acids (5a-c, 9a-c, 12, 13, 15, and 16a-c). Their structures were well
characterized by 1H NMR, optical rotation, HRMS and mp (see Supplementary data).
Figure 2. X-ray crystal structure of compound 17b.
The represental three-dimensional structure of 17b was shown in Figure 2, and
other X-ray crystal structures of compounds 17g, 17h, and 17n were depicted in
Figures S1-S3 (see Supplementary data). The substituents on the C=C double bond of
17b, 17h, and 17n all adopted E configuration. Crystallographic data (excluding
structure factors) for the structures of 17b, 17g, 17h, and 17n have been deposited
with the Cambridge Crystallographic Data Centre as supplementary publication
number CCDC 1552146, 1552149, 1552147, and 1552150, respectively. Copies of the
data can be obtained, free of charge, on application to CCDC, 12 Union Road,
Cambridge CB2 1EZ, UK [fax: +44 (0)1223 336033 or e-mail:
deposit@ccdc.cam.ac.uk].
7

Figure 3. The percentages of the final mortality rates of Mythimna separata at
different growth stages of compounds 17n, 18b, 18c, 18e, 18f and toosendanin.
The insecticidal activity of compounds 17a-q and 18a-f against the
pre-third-instar larvae of Mythimna separata was evaluated by leaf-dipping
method at a concentration of 1 mg/mL.27-29 Toosendanin, a commercial botanical
insecticide isolated from Melia azedarach, was used as a positive control at 1
mg/mL. Leaves treated with acetone alone were used as a blank control group. The
symptoms of M. separata treated with the above compounds only during larval and
pupation stages were in the same way as in our previous reports.27-29 For example,
some larvae with the wrinkled bodies died at the larval stage (Figure S4, see
Supplementary data), and some larvae molted to malformed pupae or died during
the pupation period (Figure S5, see Supplementary data). Interestingly, in this
experiment malformed moth did not appear during the adult emergence stage.
Finally, the percentages of the final mortality rates (FMRs) at different growth
stages of 17n, 18b, 18c, 18e, 18f and toosendanin were described in Figure 3. The
percentages of FMRs at larval, pupation, and adult emergence stages of
8

toosendanin were 53.3%, 16.1% and 28.6%, respectively. On the contrary, the
percentages of FMRs of 17n, 18b, 18c, 18e, and 18f were only at larval and
pupation stages. Especially more than half of FMRs for compounds 17n, 18b, 18c,
18e, and 18f were at the pupation stage. As shown in Table 1, among all
derivatives, only 2,3,4-tri-O-acetyl-β-D-xylopyranosylcarbonyl derivative 18f
showed higher insecticidal activity than piperine and toosendanin; for instance,
FMRs of 18f, piperine and toosendanin were 51.7%, 44.8%, and 48.3%,
respectively. Generally, the insecticidal activity of 18a-f was more potent than that
of 17a-q, and it suggested that the 3,4-methylenedioxy of 18a-f was necessary for
the
activity.
The
insecticidal
activity
of
2,3,4-tri-O-acetyl-β-D-xylopyranosylcarbonyl derivatives 18d-f was more potent
than that of 2,3,4,6-tetra-O-acetyl-β-D-glucopyranosylcarbonyl derivatives 18a-c.
Among derivatives 18a-f, it demonstrated that introduction of one C=C double
bond or two C=C double bonds on 18a or 18d was important for the insecticidal
activity (e.g., 18a vs. 18b vs. 18c; 18d vs. 18e vs. 18f).
Table 1
Insecticidal activity of compounds 17a-q and 18a-f against M. separata on leaves
treated at a concentration of 1 mg/mL.
Corrected mortality rate (mean SD, %) a
Compound
10 days
6.7 3.3
10.0 5.8
6.7 3.3
13.3 3.3
16.7 3.3
10.0 5.8
6.7 3.3
6.7 3.3
25 days
36 days
17a
17b
17c
17d
17e
17f
17.2 5.8
31.0 3.3
27.6 5.8
34.5 3.3
31.0 3.3
34.5 6.7
24.1 3.3
20.7 3.3
24.1 8.8
34.5 3.3
31.0 8.8
34.5 3.3
37.9 5.8
34.5 6.7
24.1 3.3
24.1 6.7
17g
17h
9

17i
17j
3.3 3.3
13.3 3.3
13.3 3.3
24.1 6.7
27.6
27.6 5.8
31.0 3.3
34.5 3.3
34.5 6.7
0
17k
31.0 3.3
31.0 3.3
17l
10.0
0
17m
17n
16.7 8.8
16.7 3.3
13.3 8.8
13.3 3.3
6.7 3.3
6.7 3.3
37.9
0
37.9
0
34.5 3.3
37.9 5.8
31.0 3.3
24.1 3.3
31.0 3.3
34.5 3.3
41.4 3.3
34.5 6.7
41.4 6.7
44.8 3.3
37.9 5.8
41.4 3.3
37.9 5.8
34.5 6.7
27.6 5.8
34.5 3.3
41.4 3.3
44.8 3.3
37.9 5.8
44.8 3.3
51.7 3.3
44.8 3.3
17o
17p
17q
18a
18b
10.0
0
18c
16.7 3.3
13.3 6.7
16.7 3.3
16.7 3.3
18d
18e
18f
piperine (14)
20.0
0
toosendanin
16.7 3.3
34.5 3.3
48.3
0
aValues are the mean SD of three replicates.
Table 2
Acaricidal activity of compounds 1a, 1b, 2a, 2b, 17a-q and 18a-f against the female
adults of Tetranychus cinnabarinus at a concentration of 1 mg/mL.
Corrected mortality rate (mean SD, %) a
Compound
24 hours
48 hours
2.1 2.1
1.1 1.1
2.7 0.1
2.6 2.1
4.2 0.6
6.2 1.1
8.1 0.5
6.7 1.3
8.9 1.2
6.5 0.9
9.8 0.5
8.7 0.9
8.7 1.1
8.5 0.4
9.3 1.0
7.3 0.6
10.4 0.7
72 hours
1.0 1.8
1a
1b
0
0
1.1 1.1
2.6 1.3
2.4 2.4
3.4 0.7
1.6 0.6
2.2 0.7
2.3 0.9
1.7 0.5
2.6 0.9
6.7 0.9
1.9 0.4
3.8 0.9
2.3 0.4
1.9 0.6
2.3 0.7
3.4 0.7
2.3 2.2
2a
2.9 1.3
2b
4.1 1.2
17a
17b
17c
17d
17e
17f
17g
17h
17i
17j
17k
17l
17m
25.9 3.6
43.8 3.0
23.2 2.8
32.3 4.1
34.6 5.4
24.9 1.9
36.2 2.9
37.9 2.4
24.6 1.5
26.4 2.9
42.5 2.4
28.9 1.5
25.5 4.0
10

17n
17o
2.2 0.4
3.0 0.9
2.0 0.1
2.6 0.1
1.9 0.8
1.6 0.6
2.7 0.8
2.8 0.6
3.1 1.2
2.6 1.0
3.4 1.1
21.5 1.7
10.2 1.1
9.7 1.3
39.9 3.2
39.4 2.8
26.0 3.1
43.0 4.1
37.6 3.5
40.3 3.1
26.3 2.5
44.0 1.3
49.0 4.1
47.4 2.6
17.9 2.4
88.1 1.6
17p
13.1 1.2
13.0 0.6
10.3 0.7
10.4 0.5
9.6 1.3
17q
18a
18b
18c
18d
12.6 1.0
14.1 0.6
13.9 1.1
10.4 0.6
69.3 2.2
18e
18f
piperine (14)
spirodiclofen
aValues are the mean SD of three replicates.
The acaricidal activity of compounds 1a, 1b, 2a, 2b, 17a-q and 18a-f against
the female adults of Tetranychus cinnabarinus was evaluated by slide-dipping
method at a concentration of 1 mg/mL.30,31 Spirodiclofen was used as a positive
control at 1 mg/mL. As shown in Table 2, the mortality rates at 72 h of tested
compounds were generally higher than those at 24 and 48 h. Xylose (1a), glucose
(1b), 1,2,3,4-tetra-O-acetylxylose (2a), 1,2,3,4,6-penta-O-acetylglucose (2b), and
piperine (14) nearly had no acaricidal activity against T. cinnabarinus; for
example, the mortality rates (MRs) at 72 h of 1a, 1b, 2a, and 2b were all less than
5%. However, the glucose (xylose)-piperic acid conjugates (18a-f) and glucose
(xylose)-piperic acid-like conjugates (17a-q) exhibited the potent acaricidal
activity. The MRs at 72 h of all compounds were indicated in Table 2, the best
candidates being those who were in the range of 32-49%. Among all derivatives,
the acaricidal activity of 2,3,4-tri-O-acetyl-β-D-xylopyranosylcarbonyl derivatives
18d-f was more potent than that of other derivatives; especially compounds 18e
and 18f showed the most potent acaricidal activity. The MRs at 72 h of 18e (49.0%)
11

and 18f (47.4%) were improved more than 2-fold of that of 14. It also showed that
the 3,4-methylenedioxy of 18e and 18f was necessary for the activity (e.g., 18e
(49.0%) vs. 17q (43.0%), 17n (39.9%) and 17k (42.5%); 18f (47.4%) vs. 17o
(39.4%) and 17l (28.9%)). Meanwhile, it suggested that introduction of the xylose
moiety into piperic acid conjugates could give more potent compounds than those
containing glucose moiety (e.g., 18d vs. 18a; 18e vs. 18b; 18f vs. 18c).
In summary, we have prepared a series of glucose (xylose)-piperic
acid/piperic acid-like conjugates. Four single-crystal structures of 17b, 17g, 17h,
and 17n were well confirmed by X-ray diffraction. Among all derivatives,
compounds 18e and 18f exhibited the most promising insecticidal and acaricidal
activities against Mythimna separata and Tetranychus cinnabarinus. It suggested
that the 3,4-methylenedioxy group of glucose (xylose)-piperic acid conjugates was
important for insecticidal and acaricidal activities, and introduction of the xylose
moiety into piperic acid conjugates could give more potent compounds than those
containing glucose one.
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) to H. X.
Supplementary data
Supplementary data (spectral data, X-ray crystal structures, and the protocol used for
insecticidal and acaricidal studies) associated with this article can be found, in the
12

online version.
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14

Synthesis of some monosaccharide-related ester derivatives as
insecticidal and acaricidal agents
Xiaobo Huang, Bingchuan Zhang, and Hui Xu*
15