Synthesis and insecticidal efficacy of pyripyropene derivatives. Part II—Invention of afidopyropen

Article abstract of DOI:10.1038/s41429-019-0193-9

The synthesis and insecticidal activity of a series of pyripyropene derivatives with cyclopropanecarbonyloxy group(s) at the C-1, C-7 and/or C-11 position(s) were investigated to find novel insecticides. Insecticidal screening of the synthesized PP derivatives revealed that derivative 13, which had cyclopropanecarbonyloxy groups at the C-1 and C-11 positions and a hydroxyl group at the C-7 position, showed the highest insecticidal activity against aphids in laboratory tests. Finally, we selected 13 as a new insecticide candidate for agricultural sucking pests, which is now commercialized under the common name afidopyropen.

Full text of DOI:10.1038/s41429-019-0193-9

The Journal of Antibiotics
https://doi.org/10.1038/s41429-019-0193-9
ARTICLE
Synthesis and insecticidal efficacy of pyripyropene derivatives.
Part II—Invention of afidopyropen
Kimihiko Goto1 Ryo Horikoshi1 Masaaki Mitomi1 Kazuhiko Oyama1 Tomoyasu Hirose2 Toshiaki Sunazuka2
●
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●
●
●
Satoshi Ōmura2
Received: 20 September 2018 / Revised: 22 April 2019 / Accepted: 23 April 2019
© The Author(s), under exclusive licence to the Japan Antibiotics Research Association 2019
Abstract
The synthesis and insecticidal activity of a series of pyripyropene derivatives with cyclopropanecarbonyloxy group(s) at the
C-1, C-7 and/or C-11 position(s) were investigated to find novel insecticides. Insecticidal screening of the synthesized PP
derivatives revealed that derivative 13, which had cyclopropanecarbonyloxy groups at the C-1 and C-11 positions and a
hydroxyl group at the C-7 position, showed the highest insecticidal activity against aphids in laboratory tests. Finally, we
selected 13 as a new insecticide candidate for agricultural sucking pests, which is now commercialized under the common
name afidopyropen.
Introduction
revealed that several PP derivatives, such as PP-I and
derivative 1 (see Fig. 1), had higher aphicidal activity than
that of PP-A [16].
In previous studies, pyripyropene (PP) analogs were iso-
lated from the culture broth of Aspergillus fumigatus FO-
1289 and shown to be inhibitors of acyl-CoA:cholesterol O-
acyltransferase (ACAT) by Ōmura et al. at the Kitasato
Institute [1–5] and from Penicillium coprobium PF1169 as
anthelmintic compounds by Meiji Seika Pharma [6],
separately.
The research group at the Kitasato Institute has investi-
gated the synthesis and evaluation of several series of PP
derivatives that function as potent ACAT inhibitors [7–14].
Previously, we found that PP-A exhibited high aphicidal
activity through Meiji’s insecticidal screening tests of nat-
ural products [15]. Further research on chemical derivati-
zation at the C-1, C-7 and C-11 positions of PP derivatives
Sucking pests such as aphids are serious pests that infest
a variety of crops, including cereals, vegetables, fruits and
ornamentals. They can greatly damage crop production and
quality [17] by direct growth inhibition and by mediating
the transmission of plant viruses to crops through sucking.
Furthermore, a variety of resistance problems to existing
insecticides have been reported [18]. As well as aphids,
whiteflies also damage crops and have become resistant to
many insecticides [19].
Surprisingly, 1 showed quite high aphicidal activity
under laboratory conditions, but it did not show stable
efficacy under field conditions, especially at the vegetative
stage when many new leaves emerges. Thus, since it is not
so effective on the untreated leaves newly emerging, then
overall field efficacy will be diminished.
In this study, we focused on PP derivatives with a
cyclopropanecarbonyl group, the most effective substituent
group for aphicidal activity [16]. We investigated the
structure–activity relationship (SAR) of these PP derivatives
to select those with the highest efficacy against aphids,
superior to that of derivative 1, taking systemic activity into
consideration. In the control of sucking pests like aphid, it is
essential that the insecticidal ingredient is translocated or
moved from treated roots, leaves, or stems to untreated
newly emerging young leaves and its insecticidal activity
appears (in other words, systemic activity). After screening
Supplementary information The online version of this article (https://
doi.org/10.1038/s41429-019-0193-9) contains supplementary
material, which is available to authorized users.
* Kimihiko Goto
kimihiko.gotou@meiji.com
1
Agricultural & Veterinary Research Labs., Agricultural &
Veterinary Division, Meiji Seika Pharma Co., Ltd,
Yokohama, Japan
2
Graduate School of Infection Control Sciences, Kitasato Institute
for Life Sciences, Kitasato University, Tokyo, Japan

K. Goto et al.
Fig. 1 Structures of PP-A, PP-I
and 1 and insecticidal activities
(LC90) against M. persicae
O
H
O
N
O
H
O
N
O
H
O
N
HO
HO
HO
O
O
O
O
O
O
O
O
O
O
O
O
1
1
1
O
O
O
7
H
11
7
7
H
11
H
11
O
O
O
PP-A
0.56 ppm
PP-I
O
1
O
O
0.026 ppm
0.043 ppm
for insecticidal and systemic activity, we identified a can-
didate insecticide to control sucking pests such as aphid and
whitefly. In this report, we explain the SAR of PP deriva-
tives and the process to select the best PP derivative.
The insecticidal activities of the synthesized mono-
substituted and di-substituted derivatives against aphids,
Myzus persicae and Aphis gossypii were evaluated.
The structures and insecticidal activities are shown in
Table 1. Interestingly, 13, which had two cyclopropane-
carbonyloxy groups at the C-1 and C-11 positions and a
hydroxyl group at the C-7 position, exhibited much higher
insecticidal activity against both aphids than PP-A (four
times higher against M. persicae and six times higher
against A. gossypii compared with the lead compound 1).
The mono-substituted derivatives 3 and 12 showed mod-
erate to low activity against both aphids, while 7 showed
low activity against both aphids. The insecticidal activity of
mono-substituted derivatives was inferior to that of PP-A.
These results suggested that the presence of two cyclo-
propanecarbonyloxy groups at the C-1 and C-11 positions
of the PP structure were important for high insecticidal
activity.
Next, chemical modifications at the hydroxyl group at
the C-7 position of 13 were made to try and improve its
insecticidal activity. As shown in Scheme 2, derivatives
17a-g were prepared by a previously reported procedure
[8, 9], in which the hydroxyl group at the C-7 position of 13
was acylated using a corresponding carboxylic anhydride
with triethylamine or carboxylic acid with 1-(3-dimethyla-
minopropyl)-3-ethylcarbodiimide hydrochloride (EDCI),
respectively. As shown in Scheme 3, 18 was synthesized
from 13 by regioselective oxidation at the C-7 position
using Dess–Martin periodinan (DMP). The intermediate
compound 19 was synthesized from 13 and 20 was obtained
by treating 19 with tributyltin hydride (Bu3SnH) using a
previously reported method [10].
Results and discussion
First, we explored the effects of adding different numbers of
cyclopropanecarbonyloxy groups at different substituent
positions by synthesizing several PP derivatives with one or
two cyclopropanecarbonyloxy group(s) at the C-1, C-7 or
C-11 position(s).
As shown in Scheme 1, mono-substituted derivatives
(3, 7 and 12) and di-substituted derivatives (4, 13 and 16)
were obtained by the following methods: The acylation of
2 obtained by hydrolysis of the triacetate of PP-A gave a
mixture of 3 and 4, which was successively separated by
silica gel chromatography to afford pure 3 and 4 as single
compounds. Then, 7 was obtained by three steps from
2: acetonide protection of diol at the C-1 and C-11 positions
of 2 [20]; introduction of a cyclopropanecarbonyl group
into the hydroxy group at the C-7 position; and then
deprotection of the foregoing acetonide-protecting group of
6 using acetic acid. Next, 12 was synthesized by five steps
from acetonide 5: tert-butyldimethylsilyl (TBS) protection
of the hydroxyl group at the C-7 position of 5 [20];
deprotection of the acetonide-protecting group of 8 [20];
TBS protection of the hydroxyl group at the C-11 position
of 9; introduction of a cyclopropanecarbonyl group into the
hydroxy group at the C-1 position; and finally deprotection
of the TBS-protecting groups of 11 using the hydrogen
fluoride-pyridine complex.
Furthermore, some epimers at the C-7 position (21, 22
and 23) were synthesized by the reaction [21] with triflate
and the corresponding organolithium reagent, followed by
the regioselective hydrolysis of the acetyl group at the C-7
position of 22 to produce 23, as shown in Scheme 4.
The insecticidal activities of the synthesized derivatives
with two cyclopropanecarbonyloxy groups at the C-1 and
C-11 positions against M. persicae and A. gossypii were
evaluated in a screening assay (Table 2).
Derivative 13 was synthesized by regioselective hydro-
lysis at the C-7 position of 1 by treatment with 1,8-diaza-
bicyclo[5.4.0]undec-7-ene (DBU). Then, 16 was obtained
from 2 in three steps: TBS protection of the hydroxyl group
at the C-11 position of 2; introduction of cyclopropane-
carbonyl groups into the hydroxy groups at the C-1 and C-7
positions; and last, deprotection of the TBS-protecting
group of 15.

Synthesis and insecticidal efficacy of pyripyropene derivatives. Part II—Invention of afidopyropen
O
H
O
N
O
H
O
N
O
H
O
N
O
H
O
N
HO
HO
HO
HO
H
ref. 9,10
O
O
a
O
O
O
O
O
O
1
O
O
+
1
HO
1
HO
7
OH
HO
HO
OH
H
7
7
H
H
O
11
O
11
O
11
PP-A
2
3 (39%)
4 (33%)
O
O
O
O
O
N
O
H
O
N
O
O
N
HO
HO
HO
ref. 9,11
b
48%
c
O
O
O
O
O
2
O
O
1
1
O
40%
1
HO
H
H
O
OH
O
7
7
7
H
H
H
O
11
O
11
HO
11
7
5
6
O
N
O
H
O
O
N
O
H
O
N
HO
HO
HO
ref. 20
ref. 20
d
O
O
5
1
1
HO
1
HO
H
O
OTBS
OTBS
7
OTBS
7
7
H
H
H
O
TBSO
11
HO
11
11
9
8
10
O
H
O
N
O
H
O
O
N
HO
HO
a
e
60%
O
O
74%
1
O
O
1
O
(2 steps)
OTBS
7
OH
H
7
H
TBSO
11
HO
12
11
11
O
H
O
N
O
H
O
N
HO
HO
O
O
ref. 16
f
O
O
O
2
1
O
1
O
26%
O
OH
7
7
H
H
O
O
11
11
1
13
O
O
O
H
O
N
O
H
O
N
O
H
O
N
HO
HO
HO
a
75%
e
16%
d
67%
O
O
O
O
O
2
O
O
O
O
1
1
O
1
O
HO
OH
7
7
7
H
H
11
H
11
TBSO
TBSO
HO
11
16
15
14
Scheme 1 Synthesis of PP derivatives having one or two cyclopropa-
necarbonyl group(s): a cyclopropanecarboxylic acid, EDCI, DMAP,
DMF; b cyclopropanecarbonyl chloride, pyridine, AcOEt; c AcOH-H2O,
THF; d TBSCl, pyridine; e HF-pyridine complex, pyridine, THF;
f DBU, 90% MeOH aq
The insecticidal activities of 18 and 20 against M. per-
sicae and those of 17a, 17f, 17g, 18, 20 and 21 against A.
gossypii, were nearly equal to that of 13. The derivatives
with smaller groups tended to show higher activity. Deri-
vatives with a configuration inversion at the C-7 position
such as 21 (Cl) and 23 (OH) also showed high insecticidal
activity. However, no derivatives in this series showed
higher insecticidal activities than that of 13 against both M.
persicae and A. gossypii.
The results of this study and those reported previously
[16] indicated that relatively smaller substituent groups
may, in terms of insecticidal activity, be preferable to bulky
ones at the C-1, C-7 or C-11 position(s). Therefore, we
introduced some small acyl groups such as acetyl groups or

K. Goto et al.
Table 1 Insecticidal activity of PP derivatives having one or two acyl group(s) for M. percicae and A. gossypii
Insecticidal activity
R1
R2
R3
compound
M . persicae
A. gossypii
(LC90, ppm)
(LC90, ppm)
PP-A
1
0.56
0.026
0.91
0.30
0.078
>1.3
0.36
12
3
H
H
H
H
H
1.0
H
H
7
>1.3
0.0066
>1.3
0.60
>1.3
0.012
>1.3
>1.3
13
16
4
H
H
propionic anhydride. Successive regioselective hydrolysis
of the acyl group at the C-7 position of 24a or 24b gave 25a
or 25b, respectively.
Table 3 shows the insecticidal activities of 24a–b and
25a–b. Although these derivatives showed moderate
activities, they were inferior to those of 1 and 13, especially
against A. gossypii.
O
H
O
N
O
H
O
O
N
HO
HO
a, b or c
O
O
O
1
1
O
OH
O
OR
7
7
H
11
H
11
O
O
13
17a-g
O
O
Through a series of optimization studies for substituent
groups at the C-1, C-7 and C-11 positions, we concluded
that the preferable combination for high insecticidal activity
was two cyclopropanecarbonyl groups at the C-1 and C-11
positions and one hydroxyl group at the C-7 position.
Subsequently, we chemically modified the hydroxyl
group at the C-13 position of 13 with two cyclopropane-
carbonyloxy groups at the C-1 and C-11 positions and a
hydroxyl group at the C-7 position to find a suitable
Scheme 2 Synthesis of PP derivatives 17a–g: a R2O, Et3N, DMAP,
DMF; b ROH, EDCI, DMAP, DMF; c CH3SO2Cl, pyridine
propionyl groups at the C-1 and C-7 positions of a PP
derivative with a cyclopropanecarbonyl group at the C-11
position.
As shown in Scheme 5, 24a and 24b were, respectively,
obtained by acylation of 3 using acetic anhydride or

Synthesis and insecticidal efficacy of pyripyropene derivatives. Part II—Invention of afidopyropen
substituent at the C-13 position of PP derivatives as shown
in Scheme 6.
We obtained 26 by regioselective oxidation at the C-13
position of 13. Elimination of the hydroxyl group at the
C-13 position of 13 by treatment with p-toluenesulfonic
acid monohydrate gave 27.
Compared with the LC90 value of 13, those of 30 and 32
against A. gossypii were nearly equal. However, these
derivatives were inferior to 13 in terms of their insecticidal
activity against M. persicae. Compared with 13, derivatives
26 and 27 showed much weaker insecticidal activity against
both aphids.
Derivative 30 was synthesized from 17a by three steps;
acetylation and methoxylation at the C-13 position and
successive regioselective hydrolysis of the acetyl group at
the C-7 position. We prepared 32 from 17a using two steps;
introduction of a cyclopropanecarbonyl group into the
hydroxy group at the C-13 position and regioselective
hydrolysis of the acetyl group at the C-7 position.
Table 4 shows the insecticidal activities of 26, 27, 30
and 32.
The results of this study showed that the preferable
substituent group at the C-13 position should be a hydroxyl
group, the same substituent group as that in PP-A, for high
insecticidal activity against M. persicae and A. gossypii.
Finally, derivatives with cyclopropanecarbonyl group(s)
derived from the major PP natural analogs such as PP-E,
PP-O, 13-deoxy PP-A [22] (37) and phenylpyropene A
were investigated.
The syntheses of 34, 36 and 40 are shown in Scheme 7.
First, 33 was obtained from PP-O by hydrolysis of the two
acetyl groups. Acylation of the hydroxyl groups at the C-1
and C-11 positions by treatment with cyclopropanecarbonyl
chloride gave 34. Then, using similar method to that of 34,
36 was obtained from PP-E in two steps.
O
H
O
N
O
H
O
N
HO
HO
a
Derivative 40 was synthesized from 37 in three steps:
hydrolysis of three acetyl groups [6]; introduction of
cyclopropanecarbonyl groups into hydroxyl groups; and
successive regioselective hydrolysis at the C-7 position,
similar to the synthesis of 13.
O
O
O
O
O
1
1
27%
O
OH
O
7
7
H
11
H
11
O
O
13
18
O
O
b
69%
As shown in Scheme 8, 46 with a phenyl ring moiety
was synthesized from 41 [23] by a previously reported
procedure [12] with minor modifications; that is, the
rearrangement of the PP skeleton by introducing a phenyl
ring moiety instead of a 3-pyridine ring moiety into the PP
structure.
Table 5 shows the insecticidal activities of derivatives
34, 36, 40 and 46, which had similar substitution patterns as
PP natural analogs.
O
H
O
O
N
O
H
O
O
N
N
HO
HO
c
O
O
S
1
1
10%
O
O
O
N
7
7
H
11
H
11
O
O
20
19
O
O
Scheme 3 Synthesis of PP derivatives 18 and 20: a Dess–Martin
Derivative 40 did not have a hydroxyl group at the C-13
position and showed lower but still relatively high
periodinan, CH2Cl2;
c Bu3SnH, toluene
b 1, 1′-thiocarbonylimidazole, toluene;
Scheme 4 Synthesis of PP
derivatives 21 and 23: a Tf2O,
DMAP, CH2Cl2; b LiCl DMF;
c LiOAc, DMF-HMPA;
O
H
O
N
O
H
O
N
O
H
O
N
HO
HO
HO
O
O
O
b
74%
a
O
O
O
1
O
1
O
1
O
d K2CO3, 90% MeOH aq
OTf
Cl
OH
7
7
7
H
H
H
O
11
O
O
11
11
21
13
O
O
O
c
85%
O
O
N
O
H
O
O
N
HO
HO
d
20%
O
O
O
O
1
O
1
H
OH
O
O
7
7
H
H
O
11
O
11
23
22
O
O

K. Goto et al.
Table 2 Structures and insecticidal activity for M. percicae and A. gossypii of PP derivatives having various substituent groups at the C-7 position
Insecticidal activity
R1
R2
compound
M . persicae
A. gossypii
(LC90, ppm)
(LC90, ppm)
1
0.026
0.0066
0.052
0.28
0.078
0.012
0.014
0.14
13
H
17aa)
17ba)
17ca)
17da)
17eb)
0.072
0.31
0.11
0.55
0.44
0.13
17fb)
0.17
0.051
0.015
0.016
0.056
0.73
0.039
0.053
0.023
0.034
0.061
0.15
17gc)
18
20
21
23
a) reaction condition; R2O, Et3N, DMAP, DMF.
b) reaction condition; ROH, EDCI, DMAP, DMF.
c) reaction condition; CH3SO2Cl, pyridine.

Synthesis and insecticidal efficacy of pyripyropene derivatives. Part II—Invention of afidopyropen
Scheme 5 Synthesis of PP
O
O
N
O
O
N
O
H
O
N
derivatives 24a–b and 25a–b: a
Ac2O, Et3N, DMAP, DMF; b
(CH3CH2CO)2O, Et3N, DMAP,
DMF; c DBU, 90% MeOH aq
HO
HO
HO
O
a or b
c
O
O
1
H
1
1
H
HO
OH
RO
OR
7
7
RO
OH
H
11
7
H
11
H
11
O
O
O
3
O
24a R=Acetyl
25a R=Acetyl
O
O
24b R=Propionyl
25b R=Propionyl
Table 3 Structures and insecticidal activities for M. persicae and A. gossypii of PP derivatives 24a–b and 25a–b
Insecticidal activity
R1
R2
compound
M . persicae
A. gossypii
(LC90, ppm)
(LC90, ppm)
1
0.026
0.0066
0.20
0.078
0.012
0.32
0.25
0.14
0.99
13
H
H
H
24a
25a
24b
25b
0.13
0.078
0.097
insecticidal activity compared with that of 13. Derivatives 34
and 36, with the absence of two or three hydroxyl groups at
the C-7, C-11, or C-13 positions, showed much lower
activities. Interestingly, 46, which had a phenyl ring, showed
no insecticidal activity, even at the maximum dose rate.
These results suggested that the PP-A structure with a 3-
pyridine ring and three hydroxyl groups at C-7, C-11 and C-
13 positions was preferable in terms of high insecticidal
activity.
Table 6 shows the insecticidal activities of the highly
potent derivatives 1, 13 and 18. Among these derivatives,
13 was the most potent. Its LC90 against M. persicae and A.
gossypii was 85 and 25 times higher, respectively, than that
of the original lead compound, PP-A. The LC90 value of 18
was also much higher than those of PP-A and 1. The
activities of 13 and 18 against Trialeurodes vaporariorum
were similar to that of PP-A and both derivatives showed
low activity against Frankliniella occidentalis (Table 7).

K. Goto et al.
Scheme 6 Synthesis of PP
derivatives 26, 27, 30, and 32:
a Dess–Martin periodinan,
CH2Cl2; b p-TsOH, THF;
c Ac2O, Et3N, DMAP, DMF;
d 5% HCl, MeOH; e K2CO3,
90% MeOH aq.;
O
13
O
N
O
13
O
N
O
O
N
O
H
HO
13
O
O
O
O
O
a
b
93%
1
O
H
H
O
OH
21%
O
OH
7
O
OH
H
11
H
O
O
O
26
13
O
O
27
f cyclopropanecarbonyl
O
chloride, pyridine, AcOEt
O
13
O
N
O
O
O
O
N
O
13
O
N
13
HO
O
H
MeO
H
O
O
c
82%
O
O
d
8%
O
O
O
O
O
O
1
O
O
H
H
H
O
O
7
O
H
11
O
O
O
17a
O
28
29
O
e
81%
f
20%
O
13
O
N
O
O
O
O
N
O
O
O
O
N
13
MeO
H
13
O
O
O
e
O
O
O
O
O
O
H
81%
H
H
O
OH
7
O
OH
O
7
H
H
O
O
O
30
O
32
31
O
To select the best candidates in the test against another
problematic species of aphid, we compared the activities of
13 and 18. These derivatives were applied to the leaves of
wheat to test their efficacy against Rhopalosiphum padi. In
this screening test, 13 exhibited higher activity than 18
(Fig. 2). Consequently, we selected 13 as the candidate for a
new insecticide. In the test by systemic application, where
the compound was absorbed by plant roots and transported
to upper leaves and stems, 13 showed outstandingly
improved activity against M. persicae, compared with those
of PP-A and 1 (shown in Fig. 3). We prepared prototype
wettable powder (WP) formulations of 1 and 13 and applied
these WPs to the leaves of 5-week-old cabbage plants.
Derivative 13 exhibited much better and quicker activity
than that of 1 (Fig. 4). Similar results were obtained in an A.
gossypii test (data not shown). According to these results,
13 proved to be the most promising candidate among all the
tested derivatives as a control agent for sucking pests.
Table 4 Structures and insecticidal activities for M. persicae and A.
gossypii of PP derivatives 26, 27, 30, and 32
Insecticidal activity
compound
R
M . persicae
A. gossypii
(LC90, ppm)
(LC90, ppm)
H
–
13
26
27
30
32
0.0066
>1.3
>1.3
0.91
0.012
0.29
–
>1.3
CH3
Conclusion
0.017
0.019
The results of SAR studies on PP derivatives with and
without substitutions at the C-1, C-7 and C-11 positions
revealed that the cyclopropanecarbonyl group was the key
0.12

Synthesis and insecticidal efficacy of pyripyropene derivatives. Part II—Invention of afidopyropen
Scheme 7 Synthesis of PP
O
O
N
O
O
O
N
O
H
O
O
N
derivatives 34, 36, and 40:
a K2CO3, 90% MeOH aq.,
b cyclopropanecarbonyl
chloride, pyridine, AcOEt,
c DBU, 90% MeOH aq
O
a
92%
b
60%
O
O
1
H
1
1
H
O
HO
O
H
11
H
11
H
O
HO
O
11
PP-O
33
34
O
O
O
O
O
N
O
O
O
N
O
O
N
13
a
68%
b
O
O
71%
1
O
1
H
1
H
H
O
7
HO
O
H
H
11
H
PP-E
35
36
O
O
N
O
O
N
O
O
ref. 6
b
23%
O
O
O
1
H
1
H
O
HO
OH
7
H
7
H
11
O
11
HO
O
37
38
O
O
H
N
O
H
O
N
O
O
O
c
19%
O
O
1
1
O
O
O
OH
7
7
H
11
H
11
O
O
39
40
O
O
Scheme 8 Synthesis of PP
derivative 46: a (i) LHMDS,
TMEDA, THF, (ii) 1-
benzoylbenzotriazole, THF;
b NaBH4, CeCl3·7H2O, EtOH;
c AcOH-H2O, THF;
d cyclopropanecarbonyl
chloride, pyridine, DMF;
e HF-pyridine complex,
pyridine, THF
O
H
OMe
O
H
O
O
H
O
O
O
H
O
H
HO
O
a
c
b
O
1
O
45%
79%
1
O
1
O
OTBS
7
OTBS
OTBS
7
7
H
O
11
O
11
O
11
41
42
43
O
O
O
O
H
O
O
O
HO
HO
HO
d
e
78%
O
O
O
O
1
O
65%
(2 steps)
1
O
H
1
HO
H
OTBS
OH
7
OTBS
7
H
H
7
H
O
O
11
11
HO
11
45
46
44
O
O
substituent group at these positions for high aphicidal
activity. Among all the tested derivatives with chemical
modifications at the C-1, C-7 and C-11 positions, 13 with
two cyclopropanecarbonyloxy groups at the C-1 and C-11
positions and a hydroxyl group at the C-7 position showed
the highest insecticidal activity against M. persicae and A.
gossypii. None of the derivatives with different substituents
at the C-13 position or a pyridine ring moiety exhibited
higher activity than that of 13.
Figure 5 summarizes the SAR between PP derivatives
and insecticidal activity against M. persicae. The LC90
values of PP-A, 1, and 13 were 0.56 ppm, 0.026 ppm and

K. Goto et al.
Table 5 Structures and insecticidal activities for M. persicae and A. gossypii of PP derivatives 34, 36, 40 and 46
Insecticidal activity
compound
Ar
R
M . persicae
A. gossypii
(LC90, ppm)
(LC90, ppm)
3-pyridyl
OH
–
13
34
36
40
46
0.0066
0.31
0.012
0.26
–
–
–
>1.3
0.31
3-pyridyl
phenyl
H
0.083
>1.3
0.063
>1.3
OH
0.0066 ppm, respectively. Thus, the insecticidal activity of
13 was more than 80 times higher than that of PP-A, the
lead natural analog and more than four times higher than
that of 1, the second lead compound.
Table 6 Historical aphicidal activity of PP derivatives
Compound
M. persicae
A. gossypii
LC90 (ppm)
LC90 (ppm)
In this study, 13 showed stable efficacy across several
species of aphids and significantly better systemic activity
than those of PP-A and 1, the other derivatives with three
acyl groups at C-1, C-7 and C-11. In the greenhouse tests
(except the test summarized in Fig. 4), foliar-applied 13
showed stable and high efficacy repeatedly. We presume
that 13 will show good persistence on crops, leading to
reproducible excellent efficacy in controlling aphids.
Physico-chemical properties such as log P or water
solubility, compared with those of commercial standards,
are often referred as indexes of systemicity. The log P
value of 13 was lower than that of 1 (Log P; 3.45 for 13,
4.80 for 1) and tended to be higher than those of standard
compounds used to control sucking pests (log P of imi-
dacloprid, clothianidin and sulfoxaflor with good sys-
temicity are around 0–3) [24]. Considering both the
contact insecticidal activity in aphid tests with leaf disks
and the systemic activity, optimization to maximize the
efficacy was achieved. Other than 13, 18 also showed high
PP-A
1
0.56
0.3
0.026
0.0066
0.015
0.078
0.012
0.023
13
18
Table 7 Efficacy of high aphicidal derivatives against other
sucking pests
Compound
T. vaporariorum
F. occidentalis
% mortality
against adult
% mortality against
1st instar larvae
5 ppm
1.25 ppm
200 ppm
PP-A
1
80
9
0
100
100
100
0
60
43
39
13
16
14
18

Synthesis and insecticidal efficacy of pyripyropene derivatives. Part II—Invention of afidopyropen
Fig. 2 Efficacy of high aphicidal
derivatives, 1, 13, and 18,
against R. padi on wheat by
foliar application; The number
of aphids per plant in untreated
plot at the timing of 0 day (just
after aphids released), 4 day and
7 day after released was 4, 28.5,
and 20.5
Fig. 3 Efficacy of high aphicidal derivatives, PP-A, 1 and 13, against
Fig. 4 Efficacy of 13 and the lead compound 1 against M. persicae by
M. persicae on cabbage by soil drenching; The number of aphids per
plant in untreated plot at the timing of 0 day (just after aphids
released), 1, 3, and 7 day after released was 5, 13, 44, and 47
foliar application to cabbage pot; The number of aphids per plant in
untreated plot at the timing of 0 day (before application), 1 day and
2 day after application was 17, 23, and 33.5
aphicidal activity. However, its efficacy was slightly but
apparently lower than that of 13 in the R. padi test under
the conditions where systemic activity contributed to
efficacy. Strangely, all the highly active derivatives
showed similar efficacy against whitefly adults. The
contribution of contact and oral exposure to insecticidal
activity may differ between aphids and whiteflies. As well
as insecticidal properties, toxicological and eco-
toxicological properties are also important. It is desir-
able for any insecticide to have low impacts against non-
target organisms. We have not described these properties
in this paper, but this issue and the potential practical uses
will be discussed separately.
Although PP derivatives have been studied as ACAT
inhibitors, they also might work as insecticides by
activating TRPV (vanilloid-type transient receptor
potential) channels in insect chordotonal organs. Com-
pound 13 is the most potent insect TRPV channel mod-
ulator known [25].
preferable insecticidal activity, better systemic efficacy and
improved performance on crops than the lead compound 1.
Experimental procedure
General methods
The PP natural analogs PP-A, PP-E, PP-O and 13-deoxy
PP-A (37) were produced and purified according to our
established methods [6]. The reagents were obtained from
commercial suppliers and were used without purification.
1
The H and 13C NMR spectra were measured using JEOL
Lambda 400 MHz, BRUKER Ascend 400 MHz and 500
MHz spectrometers in CDCl3. Mass spectra were obtained
using a JEOL JMS-FAB mate spectrometer, a JEOL JMS-
700 mass spectrometer, or an Agilent Technologies 6530-
Q-TOF LC/MS mass spectrometer. Column chromato-
graphy was carried out on silica gel (Mega Bond Elut,
Varian) and preparative thin-layer chromatography (PTLC)
(Silica Gel 60 F254 0.5 mm, Merck).
In summary, we selected 13, which is now known as the
common name afidopyropen, as a promising insecticide
candidate for agricultural sucking pests because it showed

K. Goto et al.
O
H
O
N
O
H
O
N
O
H
O
N
HO
HO
HO
O
O
O
O
O
O
O
O
O
O
1
1
1
O
O
O
OH
7
7
7
H
11
H
11
H
11
O
O
O
PP-A
1
13
O
O
O
0.56 ppm
0.026 ppm
0.0066 ppm
Fig. 5 Summary of SAR between PP derivatives and insecticidal activity (LC90) against M. percicae
11-O-Cyclopropylcarbonyl-1, 7, 11-tri-deacetylpyripy
ropene A (3)
7, 11-Di-O-cyclopropylcarbonyl-1, 7, 11-tri-deacetyl
pyripyropene A (4)
71.6, 65.9, 60.3, 54.9, 51.3, 45.6, 42.4, 38.1, 36.7, 25.5,
17.7, 16.4, 13.3, 12.9, 12.6, 12.0, 9.0, 8.9, 8.7; MS (ESI) m/
z 594 (M + H)+; HRMS (ESI) m/z calcd. for C33H40NO9
594.2703, found 594.2706 (M+H)+.
To a solution of 2 (20 mg, 0.0436 mmol), which syn-
thesized by the method previously reported [9, 10] and
cyclopropanecarboxylic acid (19 mg, 0.218 mmol) in
anhydrous N,N-dimethylformamide (DMF) (1 ml) were
7-O-Cyclopropylcarbonyl-1, 7, 11-tri-deacetyl-1, 11-
O-isopropylidenepyripyropene A (6)
To a solution of 5 (100 mg, 0.201 mmol), which syn-
thesized by the method previously reported [9, 11], in
AcOEt (2 ml) were added pyridine (126 mg, 1.61 mmol)
and cyclopropanecarbonyl chloride (63 mg, 1.21 mmol) and
the mixture was stirred at room temperature for 24 h. The
reaction mixture was poured into water and extracted with
AcOEt. The organic layer was washed with water and brine,
dried over anhydrous MgSO4, filtered and concentrated in
vacuo. The resulting residue was purified by PTLC (acet-
one: hexane = 1: 1) to afford 6 (54.1 mg, 0.0958 mmol) as a
solid in 48% yield. 1H NMR (CDCl3) δ 0.95–0.98 (m, 2H),
1.10 (s, 3H), 1.04–1.15 (m, 3H), 1.37 (dt, J = 13.2, 3.2 Hz,
1H), 1.43 (s, 3H), 1.44 (s, 6H), 1.50 (d, J = 4.0 Hz, 1H),
1.58-1.66 (m, 3H), 1.71 (s, 3H), 1.68-1.74 (m, 1H),
1.76–1.83 (m, 1H), 2.22 (m, 1H), 3.04 (brs, 1H), 3.48 (s,
2H), 3.54 (dd, J = 12.0, 3.6 Hz, 1H), 4.97–5.01 (m, 2H),
6.47 (s, 1H), 7.42 (dd, J = 8.0, 4.8 Hz, 1H), 8.11 (ddd, J =
8.0, 2.0, 2.0 Hz, 1H), 8.69 (dd, J = 4.8, 2.0 Hz, 1H), 9.02
(d, J = 2.0 Hz, 1H); MS (ESI) m/z 566 (M + H)+.
added
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide
hydrochloride (EDCI) (84 mg, 0.436 mmol) and 4-
(dimethylamino)pyridine (DMAP) (5 mg, 0.0436 mmol)
and the mixture was stirred at room temperature for 6 h.
The reaction mixture was poured into water and extracted
with AcOEt. The organic layer was washed with water
and brine, dried over anhydrous MgSO4, filtered and
concentrated in vacuo. The resulting residue was purified
by PTLC (CHCl3: MeOH = 10: 1) to afford 3 (9.0 mg,
0.0171 mmol) as a solid in 39% yield and 4 (8.6 mg,
0.0145 mmol) as a solid in 33% yield.
1
3: H NMR (CDCl3) δ 0.83 (s, 3H), 0.88–0.95 (m, 2H),
1.00–1.08 (m, 2H), 1.26 (m, 1H), 1.33 (m, 1H), 1.40 (s,
3H), 1.43 (m, 1H), 1.57–1.74 (m, 2H), 1.67 (s, 3H),
1.79–1.88 (m, 2H), 1.93 (m, 1H), 2.15 (m, 1H), 2.97 (s,
1H), 3.41 (dd, J = 11.2, 5.2 Hz, 1H), 3.75 (d, J = 11.6 Hz,
1H), 3.82 (dd, J = 11.6, 5.2 Hz, 1H), 4.28 (d, J = 11.6 Hz,
1H), 5.00 (d, J = 4.0 Hz, 1H), 6.53 (s, 1H), 7.43 (dd, J =
8.0, 4.4 Hz, 1H), 8.12 (d, J = 8.4 Hz, 1H), 8.70 (m, 1H),
9.02 (m, 1H); MS (ESI) m/z 526 (M + H)+; high resolution
mass spectrometry (HRMS) (ESI) m/z calcd. for C29H36NO8
526.2441, found 526.2440 (M + H)+.
7-O-Cyclopropylcarbonyl-1, 7, 11-tri-deacetylpyripyr
opene A (7)
To a cold (0 °C) solution of 6 (42 mg, 0.0743 mmol) in
THF (2 ml) were added AcOH (1 ml) and water (0.6 ml) and
the mixture was stirred at room temperature for 21 h. CHCl3
and saturated aqueous NaHCO3 were added to the mixture.
The precipitate was washed with cooled CHCl3 and dried in
vacuo to give 7 (15.7 mg, 0.0299 mmol) as a solid in 40%
yield. 1H NMR (DMSO) δ 0.57 (s, 3H), 0.89–0.99 (m, 4H),
1.14–1.25 (m, 1H), 1.30 (s, 3H), 1.40–1.70 (m, 6H), 1.67
(s, 3H), 1.78 (m, 1H), 1.94 (m, 1H), 2.99 (m, 1H), 3.34 (m,
1H), 3.46 (m, 1H), 4.27 (d, J = 4.8 Hz, 1H), 4.51 (t, J = 4.8
Hz, 1H), 4.78 (m, 1H), 4.88 (dd, J = 11.2, 5.2 Hz, 1H), 5.43
(d, J = 5.6 Hz, 1H), 6.88 (s, 1H), 7.52 (dd, J = 8.0, 4.8 Hz,
1H), 8.27 (d, J = 8.0 Hz, 1H), 8.66 (d, J = 4.8 Hz, 1H), 9.08
1
4: H NMR (CDCl3) δ 0.82 (s, 3H), 0.89–0.98 (m, 4H),
1.02-1.13 (m, 4H), 1.28 (dt, J = 12.0, 4.4 Hz, 1H),
1.39–1.42 (m, 1H), 1.42 (s, 3H), 1.51 (d, J = 4.0 Hz, 1H),
1.61–1.73 (m, 3H), 1.72 (s, 3H), 1.81–1.84 (m, 2H), 1.90
(m, 1H), 2.16 (m, 1H), 3.37 (dd, J = 11.2, 5.2 Hz, 1H), 3.62
(d, J = 12.0 Hz, 1H), 4.35 (d, J = 12.0 Hz, 1H), 5.00
(d, J = 4.4 Hz, 1H), 5.02–5.06 (m, 1H), 6.46 (s, 1H), 7.42
(m, 1H), 8.11 (d, J = 8.0 Hz, 1H), 8.70 (m, 1H), 9.02 (m,
1H); 13C NMR (CDCl3) δ 176.0, 174.1, 164.3, 162.5, 157.5,
151.7, 147.0, 133.3, 127.3, 124.0, 103.1, 99.7, 83.7, 77.9,

Synthesis and insecticidal efficacy of pyripyropene derivatives. Part II—Invention of afidopyropen
(s, 1H); MS (ESI) m/z 526 (M + H)+; HRMS (ESI) m/z
calcd. for C29H36NO8 526.2441, found 526.2439.
7, 11-Di-O-tert-butyldimethylsilyl-1, 7, 11-tri-deacet
ylpyripyropene A (10)
To a solution of 9 (700 mg, 1.23 mmol), which synthe-
sized by the method previously reported [20], in pyridine (7
ml) was added tert-butyldimethylsilyl chloride (550 mg,
3.68 mmol) and the mixture was stirred at room temperature
for 14 h. The reaction mixture was concentrated and the
residue was dissolved in AcOEt. The organic layer was
washed with water and brine, dried over anhydrous MgSO4,
filtered and concentrated in vacuo. This residue was used in
the following step with no further purification. MS (ESI)
m/z 686 (M + H)+.
1, 11-Di-O-cyclopropylcarbonyl-1, 7, 11-tri-deace-
tylpyripyropene A (13)
To a solution of 1 (2.95 g, 4.46 mmol), synthesized by
the method previously reported [16], in an 90% aqueous
MeOH solution (200 ml) was added 1,8-diazabicyclo[5.4.0]
undec-7-ene (DBU) (0.75 g, 4.91 mmol) and the mixture
was stirred at room temperature for 14 h. The reaction was
quenched with AcOH and the mixture was concentrated
under reduced pressure and the residue was dissolved in
CHCl3. The organic layer was washed with brine, dried over
anhydrous MgSO4, filtered and concentrated in vacuo. The
resulting residue was purified by chromatography on silica
gel (acetone: hexane) to afford 13 (0.69 g, 1.17 mmol) as a
solid in 26% yield. 1H NMR (CDCl3) δ 0.85–0.88 (m, 4H),
0.92 (s, 3H), 0.96–1.01 (m, 4H), 1.35 (dt, J = 12.6, 4.0 Hz,
1H), 1.42 (s, 3H), 1.45–1.50 (m, 2H), 1.56–1.63 (m, 3H),
1.66 (s, 3H), 1.79–1.93 (m, 3H), 2.14 (m, 1H), 2.17 (d, J =
3.6 Hz, 1H), 2.85 (d, J = 2.0 Hz, 1H), 3.74 (d, J = 12. 0 Hz,
1H), 3.78-3.82 (m, 1H), 3.86 (d, J = 11.6 Hz, 1H), 4.82 (dd,
J = 11.6, 5.2 Hz, 1H), 4.99 (m, 1 H), 6.52 (s, 1H), 7.42 (dd,
J = 8.0, 4.8 Hz, 1H), 8.11 (dt, J = 8.1, 1.9 Hz, 1H), 8.70
(dd, J = 4.8, 1.6 Hz, 1H), 9.00 (d, J = 2.0 Hz, 1H); 13C
NMR (CDCl3) δ 174.5, 174.1, 164.0, 162.4, 157.3, 151.6,
146.8, 133.0, 127.3, 123.7, 103.2, 99.3, 85.5, 77.6, 73.4,
65.1, 60.3, 54.4, 45.7, 40.7, 38.1, 36.2, 27.6, 22.7, 17.6,
15.4, 13.2, 12.9, 8.7, 8.6, 8.5; MS (FAB) m/z 594 (M + H)
+; HRMS (ESI) m/z calcd. for C33H39NNaO9 616.2523,
found 616.2518 (M+Na)+.
7, 11-Di-O-tert-butyldimethylsilyl-1-O-cyclopropylcar
bonyl-1, 7, 11-tri-deacetylpyripyropene A (11)
Reaction of crude 10 with cyclopropanecarbonyl chlor-
ide (1.0 g, 9.84 mmol) gave 11 (684 mg, 0.908 mmol) as a
solid in 74% yield (2 steps from 9) by a similar procedure to
1
6. H NMR (CDCl3) δ -0.01 (s, 3H), 0.01 (s, 3H), 0.12
(s, 3H), 0.16 (s, 3H), 0.78 (s, 3H), 0.82–0.84 (m, 2H), 0.88
(s, 9H), 0.96 (s, 9H), 0.94–0.98 (m, 2H), 1.24–1.28 (m, 1H),
1.38 (s, 3H), 1.38–1.40 (m, 1H), 1.55–1.63 (m, 3H), 1.59
(s, 3H), 1.67–1.71 (m, 1H), 1.75–1.82 (m, 1H), 1.88–1.94
(m, 1H), 2.08–2.11 (m, 1H), 2.79 (d, J = 1.7 Hz, 1H), 3.18
(d, J = 10.4 Hz, 1H), 3.24 (d, J = 10.0 Hz, 1H), 3.72
(dd, J = 10.4, 5.0 Hz, 1H), 4.82 (dd, J = 11.9, 4.6 Hz, 1H),
4.97–4.98 (m, 1H), 6.35 (s, 1H), 7.41 (dd, J = 8.1, 4.8 Hz,
1H), 8.10 (dt, J = 8.4, 1.8 Hz, 1H), 8.69 (dd, J = 4.8, 1.7
Hz, 1H), 9.00 (d, J = 1.6 Hz, 1H); MS (ESI) m/z 754
(M + H)+.
11-O-tert-Butyldimethylsilyl-1, 7, 11-tri-deacetylpyrip
yropene A (14)
Reaction of 2 (20 mg, 0.0437 mmol), which synthesized
by the method previously reported [9, 10], with tert-butyl-
dimethylsilyl chloride (39 mg, 0.262 mmol) gave 14 (17
mg, 0.0292 mmol) as a solid in 67% yield by a similar
1-O-Cyclopropylcarbonyl-1, 7, 11-tri-deacetylpyripy
ropene A (12)
To a cold (0 °C) solution of 11 (350 mg, 0.465 mmol) in
THF (2 ml) were added pyridine (0.5 ml) and HF-pyridine
complex (0.6 ml) and the mixture was stirred at room tem-
perature for 22 h. The reaction mixture was cooled to 0 °C and
saturated aqueous NaHCO3 was added and the mixture was
extracted with AcOEt. The organic layer was washed with
brine, dried over anhydrous MgSO4, filtered and concentrated
in vacuo. The resulting residue was purified by silica gel
column chromatography (CHCl3: MeOH) to afford 12 (146
mg, 0.279 mmol) as a solid in 60% yield. 1H NMR (CDCl3) δ
0.75 (s, 3H), 0.87–0.95 (m, 2H), 1.01–1.05 (m, 2H),
1.24–1.35 (m, 2H), 1.41 (s, 3H), 1.49 (m, 1H), 1.59-1.74 (m,
3H), 1.65 (s, 3H), 1.95-2.06 (m, 2H), 2.18 (m, 1H), 2.45 (brs,
1H), 2.90 (s, 1H), 2.93 (d, J = 12.7 Hz, 1H), 3.34 (m, 1H),
3.91 (dd, J = 11.6, 5.2 Hz, 1H), 4.89 (dd, J = 12.2, 4.6 Hz,
1H), 4.97 (d, J = 4.0 Hz, 1H), 6.54 (s, 1H), 7.41 (dd, J = 8.0,
4.4 Hz, 1H), 8.11 (ddd, J = 8.4, 1.6, 1.4 Hz, 1H), 8.69 (dd, J
= 4.6, 1.6 Hz, 1H), 9.01 (d, J = 1.7 Hz,); MS (ESI) m/z 526
(M + H)+; HRMS (ESI) m/z calcd. for C29H36NO8 526.2441,
found 526.2432 (M+H)+.
1
procedure to 10. H NMR (CDCl3) δ 0.09 (s, 6H), 0.88
(s, 3H), 0.91 (s, 9H), 1.22–1.28 (m, 2H), 1.37 (m, 1H), 1.39
(s, 3H), 1.61–1.67 (m, 1H), 1.65 (s, 3H), 1.74–1.81 (m, 3H),
2.11–2.15 (m, 2H), 2.82 (d, J = 2.1 Hz, 1H), 3.03 (s, 1H),
3.33 (d, J = 9.4 Hz, 1H), 3.62–3.67 (m, 1H), 3.65 (d, J =
9.4 Hz, 1H), 3.77–3.80 (m, 1H), 4.90 (m, 1H), 6.50 (s, 1H),
7.41 (dd, J = 7.4, 4.8 Hz, 1H), 8.10 (dt, J = 8.3, 1.8 Hz,
1H), 8.69 (dd, J = 4.8, 1.5 Hz, 1H), 9.00 (d, J = 1.6 Hz,
1H); MS (ESI) m/z 572 (M + H)+.
11-O-tert-Butyldimethylsilyl-1, 7-di-O-cyclopropylcar
bonyl-1, 7, 11-tri-deacetylpyripyropene A (15)
Reaction of 14 (12 mg, 0.0210 mmol) with cyclopropa-
necarboxylic acid (22 mg, 0.252 mmol) gave 15 (11 mg,
0.0158 mmol) as a solid in 75% yield by a similar procedure
1
to 3. H NMR (CDCl3) δ -0.05 (s, 3H), 0.03 (s, 3H), 0.79
(s, 3H), 0.81–0.84 (m, 2 H), 0.88 (s, 9H), 0.91–0.97
(m, 4H), 1.01–1.06 (m, 1H), 1.10–1.14 (m, 1H), 1.29–1.37
(m, 1H), 1.42 (s, 3H), 1.48 (d, J = 4.0 Hz, 1H), 1.56–1.68
(m, 4H), 1.70 (s, 3H), 1.77–1.94 (m, 3H), 2.11 (dt, J = 13.0,

K. Goto et al.
3.1 Hz, 1H), 2.88 (d, J = 1.8 Hz, 1H), 3.19 (s, 2H), 4.87
(dd, J = 11.8, 4.7 Hz, 1H), 4.97-5.01 (m, 2H), 6.46 (s, 1H),
7.40 (dd, J = 8.1, 4.8 Hz, 1H), 8.08–8.11 (m, 1H), 8.68
(dd, J = 4.9, 1.6 Hz, 1H), 9.01 (d, J = 2.3 Hz, 1H); MS
(ESI) m/z 708 (M + H)+.
1H NMR (CDCl3) δ 0.84–0.89 (m, 4H), 0.90 (s, 3H),
0.96–1.16 (m, 4H), 1.23 (t, J = 7.6 Hz, 3H), 1.34–1.41
(m, 1H), 1.44 (s, 3H), 1.53–1.65 (m, 4H), 1.69 (s, 3H),
1.78–1.94 (m, 4H), 2.15–2.18 (m, 1H), 2.41–2.48 (m, 2H),
2.94 (s, 1H), 3.74 (d, J = 12.0 Hz, 1H), 3.81 (d, J = 12.0
Hz, 1H), 4.81 (dd, J = 11.6, 4.8 Hz, 1H), 5.00–5.05
(m, 2H), 6.44 (s, 1H), 7.41 (dd, J = 7.9, 4.8 Hz, 1H), 8.10
(m, 1H), 8.69 (d, J = 4.6 Hz, 1H), 9.01 (s, 1H); MS (ESI)
m/z 650 (M+H)+; HRMS (ESI) m/z calcd. for C36H44NO10
650.2965, found 650.2965 (M + H)+.
1, 7-Di-O-cyclopropylcarbonyl-1, 7, 11-tri-deacetylpy
ripyropene A (16)
To a solution of 15 (11 mg, 0.0156 mmol) in THF (0.5
ml) was added tetrabutylammonium fluoride in 1.0 M THF
solution (47 μl, 0.0467 mmol) and the mixture was stirred at
room temperature for 17 h. The reaction mixture was then
poured into water, extracted with AcOEt. The organic layer
was washed with brine, dried over anhydrous Na2SO4, fil-
tered and concentrated in vacuo. The resulting residue was
purified by PTLC (acetone: hexane = 1: 1) to afford 16 (1.5
mg, 0.00253 mmol) as a solid in 16% yield. 1H NMR
(CDCl3) δ 0.74 (s, 3H), 0.87–1.01 (m, 6H), 1.08–1.16
(m, 2H), 1.34–1.41 (m, 1H), 1.43 (s, 3H), 1.50–1.65
(m, 4H), 1.67–1.69 (m, 1H), 1.71 (s, 3H), 1.75–1.81
(m, 3H), 1.95–2.01 (m, 1H), 2.16–2.19 (m, 1H), 2.87
(s, 1H), 3.65 (s, 2H), 4.92 (dd, J = 12.1, 4.5 Hz, 1H), 4.98
(m, 1H), 5.11 (dd, J = 11.6, 4.8 Hz, 1H), 6.46 (s, 1H), 7.40
(dd, J = 8.0, 4.9 Hz, 1H), 8.09–8.11 (m, 1H), 8.69 (d, J =
3.7 Hz, 1H), 9.02 (d, J = 2.2 Hz, 1H); MS (ESI) m/z 594
(M + H)+.
1, 11-Di-O-cyclopropylcarbonyl-1, 7, 11-tri-deacetyl-
7-O-isobutyrylpyripyropene A (17c)
Reaction of 13 (20 mg, 0.0337 mmol) with isobutyric
anhydride (32 mg, 0.202 mmol) gave 17c (18 mg, 0.0277
mmol) as a solid in 82% yield by a similar procedure to 17a.
1H NMR (CDCl3) δ 0.83–0.89 (m, 4H), 0.91 (s, 3H),
0.96–1.09 (m, 4H), 1.26 (d, J = 6.8 Hz, 6H), 1.35–1.42
(m, 1H), 1.45 (s, 3H), 1.53–1.67 (m, 4H), 1.71 (s, 3H),
1.78–1.94 (m, 4H), 2.15–2.18 (m, 1H), 2.58–2.74 (m, 1H),
2.98 (d, J = 1.9 Hz, 1H), 3.73 (d, J = 12.0 Hz, 1H), 3.83
(d, J = 12.0 Hz, 1H), 4.81 (dd, J = 11.7, 4.9 Hz, 1H),
4.94–5.13 (m, 2H), 6.39 (s, 1H), 7.41 (dd, J = 8.0, 4.9 Hz,
1H), 8.09 (dt, J = 8.2, 2.0 Hz, 1H), 8.69 (d, J = 3.9 Hz, 1H),
9.01 (s, 1H); MS (ESI) m/z 664 (M + H)+; HRMS (ESI)
m/z calcd. for C37H46NO10 664.3122, found 664.3119
(M + H)+.
1, 11-Di-O-cyclopropylcarbonyl-1, 11-di-deacetylpy
ripyropene A (17a)
1, 11-Di-O-cyclopropylcarbonyl-1, 7, 11-tri-deacetyl-
To a solution of 13 (30 mg, 0.0506 mmol) in anhy-
drous DMF (1 ml) were added triethylamine (Et3N) (46
mg, 0.455 mmol), 4-(dimethylamino)pyridine (DMAP)
(12 mg, 0.101 mmol) and acetic anhydride (31 mg, 0.303
mmol) and the mixture was stirred at room temperature
for 30 min. The reaction mixture was poured into water
and extracted with AcOEt. The organic layer was washed
with water and brine, dried over MgSO4, filtered and
concentrated in vacuo. The resulting residue was purified
by PTLC (acetone: hexane = 1: 1) to afford 17a (30 mg,
7-O-pivaloylpyripyropene A (17d)
Reaction of 13 (20 mg, 0.0337 mmol) with pivalic
anhydride (38 mg, 0.202 mmol) gave 17d (3.2 mg, 0.00472
mmol) as a solid in 14% yield by a similar procedure to 17a.
1H NMR (CDCl3) δ 0.84–0.89 (m, 4H), 0.91 (s, 3H),
0.96–1.07 (m, 4H), 1.29 (s, 9H), 1.38–1.42 (m, 1H), 1.45
(s, 3H), 1.53–1.66 (m, 4H), 1.71 (s, 3H), 1.78–1.92 (m, 4H),
2.15–2.18 (m, 1H), 2.89 (d, J = 1.9 Hz, 1H), 3.71 (d, J =
11.6 Hz, 1H), 3.85 (d, J = 11.6 Hz, 1H), 4.80 (dd, J = 11.4,
5.1 Hz, 1H), 4.98-5.01 (m, 2H), 6.35 (s, 1H), 7.41 (dd, J =
8.2, 5.0 Hz, 1H), 8.09 (dt, J = 8.1, 2.0 Hz, 1H), 8.69 (d, J =
4.1 Hz, 1H), 9.00 (s, 1H); MS (ESI) m/z 678 (M + H)+;
HRMS (ESI) m/z calcd. for C38H48NO10 678.3278, found
678.3286 (M + H)+.
7-O-Benzoyl-1, 11-di-O-cyclopropylcarbonyl-1, 7, 11-
tri-deacetylpyripyropene A (17e)
Reaction of 13 (20 mg, 0.0337 mmol) with benzoic acid
(25 mg, 0.202 mmol) gave 17e (21 mg, 0.0300 mmol) as a
solid in 89% yield by a similar procedure to 3. H NMR
(CDCl3) δ 0.86-0.91 (m, 4H), 0.92 (s, 3H), 0.96-0.99 (m,
2H), 1.03–1.11 (m, 2H), 1.39–1.45 (m, 1H), 1.50 (s, 3H),
1.55–1.69 (m, 4H), 1.76–2.05 (m, 4H), 1.86 (s, 3H),
2.18–2.22 (m, 1H), 2.99 (s, 1H), 3.75 (d, J = 11.6 Hz, 1H),
3.85 (d, J = 11.6 Hz, 1H), 4.84 (dd, J = 11.4, 4.4 Hz, 1H),
5.04 (m, 1H), 5.30 (dd, J = 11.6, 4.7 Hz, 1H), 6.43 (s, 1H),
7.38–7.39 (m, 1H), 7.48-7.52 (m, 2H), 7.60–7.64 (m, 1H),
1
0.0479 mmol) as a solid in 95% yield. H NMR (CDCl3) δ
0.84–0.89 (m, 4H), 0.89 (s, 3H), 0.90–1.06 (m, 4H), 1.37
(dt, J = 13.2, 3.8 Hz, 1H), 1.45 (s, 3H), 1.53 (d, J = 4.0 Hz,
1H), 1.55–1.67 (m, 4H), 1.70 (s, 3H), 1.79–1.87 (m, 2H),
1.89–1.94 (m, 2H), 2.14–2.18 (m, 1H), 2.16 (s, 3H), 2.97
(d, J = 2.0 Hz, 1H), 3.77 (s, 2H), 4.81 (dd, J = 11.7, 4.8 Hz,
1H), 5.00 (m, 1H), 5.02 (dd, J = 11.4, 5.0 Hz, 1H), 6.46
(s, 1H), 7.40 (dd, J = 8.0, 4.9 Hz, 1H), 8.09 (dt, J = 8.1, 1.9
Hz, 1H), 8.68 (dd, J = 4.8, 1.6 Hz, 1H), 9.00 (d, J = 2.0 Hz,
1H); MS (ESI) m/z 636 (M + H)+; HRMS (ESI) m/z calcd.
for C35H42NO10 636.2809, found 636.2809 (M + H)+.
1, 11-Di-O-cyclopropylcarbonyl-1, 7, 11-tri-deacetyl-
7-O-propionylpyripyropene A (17b)
1
Reaction of 13 (20 mg, 0.0337 mmol) with propionic
anhydride (26 mg, 0.200 mmol) gave 17b (14 mg, 0.0216
mmol) as a solid in 64% yield by a similar procedure to 17a.

Synthesis and insecticidal efficacy of pyripyropene derivatives. Part II—Invention of afidopyropen
8.06 (dd, J = 8.0, 1.7 Hz, 1H), 8.13 (d, J = 8.0 Hz, 2H),
8.67 (d, J = 4.6 Hz, 1H), 8.97 (s, 1H); MS (ESI) m/z 698
(M + H)+; HRMS (ESI) m/z calcd. for C40H44NO10
698.2965, found 698.2957 (M + H)+.
1, 11-Di-O-cyclopropylcarbonyl-1, 7, 11-tri-deacetyl-
7-O-(2-pyridylcarbonyl)pyripyropene A (17 f)
1.87 (m, 2H), 1.94–1.97 (m, 1H), 2.21 (m, 1H), 2.53 (dd, J
= 14.9, 2.6 Hz, 1H), 2.78 (t, J = 14.9 Hz, 1H), 2.91 (d, J =
1.5 Hz, 1H), 3.66 (d, J = 12.0 Hz, 1H), 3.84 (d, J = 12.0
Hz, 1H), 4.82 (dd, J = 11.7, 4.8 Hz, 1H), 5.06 (m, 1H), 6.71
(s, 1H), 7.41 (dd, J = 8.0, 4.8 Hz, 1H), 8.09 (dt, J = 8.0, 1.7
Hz, 1H), 8.70 (dd, J = 4.8, 1.7 Hz, 1H), 9.02 (d, J = 1.7 Hz,
1H); MS (ESI) m/z 592 (M + H)+; HRMS (ESI) m/z calcd.
for C33H38NO9 592.2547, found 592.2545 (M + H)+.
1, 11-Di-O-cyclopropylcarbonyl-1, 7, 11-tri-deacetyl-
7-O-thiocarbonylimidazoyl pyripyropene A (19)
Reaction of 13 (20 mg, 0.0337 mmol) with picolinic acid
(25 mg, 0.202 mmol) gave 17 f (23 mg, 0.0327 mmol) as a
1
solid in 97% yield by a similar procedure to 3. H NMR
(CDCl3) δ 0.85-0.90 (m, 4H), 0.92 (s, 3H), 0.97–1.16 (m,
4H), 1.38–1.46 (m, 1H), 1.50 (s, 3H), 1.56–1.60 (m, 1H),
1.63–1.73 (m, 3H), 1.81–2.05 (m, 4H), 1.87 (s, 3H), 2.18-
2.22 (m, 1H), 2.99 (d, J = 2.0 Hz, 1H), 3.75 (d, J = 12.0 Hz,
1H), 3.83 (d, J = 12.0 Hz, 1H), 4.84 (dd, J = 11.4, 4.9 Hz,
1H), 5.05 (m, 1H), 5.41 (dd, J = 11.6, 5.5 Hz, 1H), 6.43 (s,
1H), 7.38 (dd, J = 8.0, 4.9 Hz, 1H), 7.53 (dd, J = 7.6, 4.6
Hz, 1H), 7.90 (t, J = 7.2 Hz, 1H), 8.06 (d, J = 8.0 Hz, 1H),
8.19 (d, J = 7.8 Hz, 1H), 8.67 (d, J = 4.4 Hz, 1H), 8.84 (d,
J = 4.4 Hz, 1H), 8.97 (d, J = 1.9 Hz, 1H); MS (ESI) m/z
699 (M + H)+; HRMS (ESI) m/z calcd. for C39H43N2O10
699.2918, found 699.2906 (M + H)+.
To a solution of 13 (50 mg, 0.0843 mmol) in toluene (3
ml) was added 1, 1’-thiocarbonyldiimidazole (90 mg, 0.506
mmol) and the mixture was refluxed for 3 h. The reaction
mixture was cooled to room temperature and AcOEt and
water were added to the mixture. The organic layer was
washed with brine, dried over anhydrous MgSO4, filtered
and concentrated in vacuo. The resulting residue was pur-
ified by PTLC (acetone: hexane = 1: 1) to afford 19 (41 mg,
1
0.0584 mmol) as a solid in 69% yield. H NMR (CDCl3) δ
0.86–0.91 (m, 4H), 0.93 (s, 3H), 0.98–1.01 (m, 2H),
1.04–1.08 (m, 2H), 1.39–1.45 (m, 1H), 1.51 (s, 3H),
1.64–1.72 (m, 4H), 1.75–1.84 (m, 2H), 1.87 (s, 3H),
1.95–1.98 (m, 1H), 2.18–2.25 (m, 2H), 2.95 (d, J = 1.7 Hz,
1H), 3.73 (d, J = 12.0 Hz, 1H), 3.81 (d, J = 12.0 Hz, 1H),
4.86 (dd, J = 11.7, 4.6 Hz, 1H), 5.05 (m, 1H), 5.69 (dd, J =
11.0, 4.9 Hz, 1H), 6.48 (s, 1H), 7.10 (s, 1H), 7.40 (dd, J =
8.2, 5.0 Hz, 1H), 7.69 (s, 1H), 8.09 (dt, J = 8.2, 1.9 Hz, 1H),
8.40 (s, 1H), 8.69 (d, J = 3.4 Hz, 1H), 9.00 (d, J = 1.7 Hz,
1H); MS (ESI) m/z 704 (M + H)+.
1, 11-Di-O-cyclopropylcarbonyl-1, 7, 11-tri-deacetyl-
7-O-methanesulfonylpyripyropene A (17 g)
To a cold (0 °C) solution of 13 (40 mg, 0.0674 mmol) in
pyridine (1 ml) was added methanesulfonyl chloride (23
mg, 0.202 mmol) and the mixture was stirred at 0 °C for 1 h.
The reaction mixture was concentrated in vacuo. The
resulting residue was purified by PTLC (CHCl3: MeOH =
10: 1) to afford 17 g (7.4 mg, 0.0110 mmol) as a solid in
16% yield. 1H NMR (CDCl3) δ 0.87–0.90 (m, 4H), 0.93 (s,
3H), 0.98–1.00 (m, 2H), 1.04–1.16 (m, 2H), 1.32–1.39 (m,
1H), 1.45 (s, 3H), 1.48–1.51 (m, 1H), 1.56–1.65 (m, 3H),
1.71 (s, 3H), 1.78–1.95 (m, 3H), 2.06–2.10 (m, 1H),
2.15–2.18 (m, 1H), 2.93 (d, J = 2.0 Hz, 1H), 3.18 (s, 3H),
3.72 (d, J = 12.0 Hz, 1H), 3.98 (d, J = 11.7 Hz, 1H), 4.67
(dd, J = 12.2, 5.1 Hz, 1H), 4.82 (dd, J = 11.8, 4.8 Hz, 1H),
5.01 (m, 1H), 6.45 (s, 1H), 7.42 (dd, J = 7.9, 4.8 Hz, 1H),
8.10 (d, J = 8.1 Hz, 1H), 8.70 (s, 1H), 9.02 (s, 1H); MS
(ESI) m/z 672 (M + H)+; HRMS (ESI) m/z calcd. for
C34H42NO11S 672.2479, found 672.2476 (M + H)+.
1, 11-Di-O-cyclopropylcarbonyl-1, 7, 11-tri-deacetyl-
7-dehydropyripyropene A (18)
To a cold (0 °C) solution of 13 (20 mg, 0.0337 mmol) in
CH2Cl2 (1 ml) was added Dess–Martin periodinan (21 mg,
0.0506 mmol) and the mixture was stirred at 0 °C for 3 h.
The reaction was quenched with 10% aqueous Na2SO3 and
CHCl3 was added to the mixture. The organic layer was
washed with brine, dried over MgSO4, filtered and con-
centrated in vacuo. The resulting residue was purified by
PTLC (acetone: hexane = 1: 1) to afford 18 (5.4 mg,
0.00913 mmol) as a solid in 27% yield. 1H NMR (CDCl3) δ
0.83–1.00 (m, 8H), 0.96 (s, 3H), 1.44 (m, 1H), 1.53–1.61
(m, 2H), 1.63 (s, 3H), 1.76 (d, J = 3.7 Hz, 1H), 1.81 (s, 3H),
1, 11-Di-O-cyclopropylcarbonyl-7-deacetoxy -1, 11-di-
deacetylpyripyropene A (20)
To a solution of tributyltin hydride (20 mg, 0.700 mmol)
in toluene (2 ml) was added 19 (41 mg, 0.0583 mmol) in
toluene (1 ml) and the mixture was refluxed for 3 h. After
cooled to room temperature, AcOEt and water were added
to the mixture. The organic layer was washed with brine,
dried over anhydrous Na2SO4, filtered and concentrated in
vacuo. The resulting residue was purified by PTLC (acet-
one: hexane = 1: 1) to afford 20 (3.5 mg, 0.00606 mmol) as
a solid in 10% yield. 1H NMR (CDCl3) δ 0.84-1.00 (m, 8H),
0.90 (s, 3H), 1.12-1.16 (m, 1H), 1.25 (s, 1H), 1.35–1.46 (m,
1H), 1.41 (s, 3H), 1.56–1.70 (m, 5H), 1.66 (s, 3H),
1.78–1.89 (m, 2H), 2.12–2.17 (m, 2H), 2.82 (d, J = 1.4 Hz,
1H), 3.69 (d, J = 11.9 Hz, 1H), 3.91 (d, J = 11.9 Hz, 1H),
4.83 (dd, J = 11.5, 5.1 Hz, 1H), 4.99 (m, 1H), 6.46 (s, 1H),
7.42 (m, 1H), 8.11 (dt, J = 8.0, 1.7 Hz, 1H), 8.69 (m, 1H),
9.01 (m, 1H); MS (ESI) m/z 578 (M + H)+; HRMS (ESI)
m/z calcd. for C33H40NO8 578.2754, found 578.2748
(M + H)+.
1, 11-Di-O-cyclopropylcarbonyl-7-deacetoxy-1, 11-di-
deacetyl-7- epichloropyripyropene A (21)
To a cold (0 °C) solution of 13 (50 mg, 0.0843 mmol) in
CH2Cl2 (3 ml) were added DMAP (30 mg, 0.253 mmol) and

K. Goto et al.
trifluoromethanesulfonic anhydride (35 mg, 0.126 mmol)
and the mixture was stirred at room temperature for 3 h.
CHCl3 and water were added to the reaction mixture. The
organic layer was washed with brine, dried over anhydrous
MgSO4, filtered and concentrated in vacuo to afford a crude
compound (82 mg). To a cold (0 °C) solution of this crude
compound in DMF (1 ml) and was added lithium chloride
(130 mg, 3.07 mmol) and stirred at room temperature for
20 h. The reaction mixture was diluted with AcOEt and
washed with water and brine, dried over Na2SO4, filtered
and concentrated in vacuo. The resulting residue was pur-
ified by PTLC (acetone: hexane = 1: 1) to afford 21 (38 mg,
1, 11-Di-O-cyclopropylcarbonyl-7-deacetoxy-1, 11-di-
deacetyl-7- epihydroxypyripyropene A (23)
To a cold (0 °C) solution of 22 (270 mg, 0.425 mmol) in
an 90% aqueous MeOH solution (5 ml) was added potas-
sium carbonate (58 mg, 3.56 mmol) and the mixture was
stirred at 0 °C for 4 h. The reaction was quenched with
AcOH and the mixture was concentrated under reduced
pressure and the residue was dissolved in CHCl3. The
organic layer was washed with brine, dried over anhydrous
MgSO4, filtered and concentrated in vacuo. The resulting
residue was purified by PTLC (acetone: hexane = 1: 1) to
afford 23 (51 mg, 0.0860 mmol) as a solid in 20% yield. 1H
NMR (CDCl3) δ 0.80–0.86 (m, 4H), 0.89 (s, 3H), 0.96–1.10
(m, 4H), 1.40 (s, 3H), 1.42–1.44 (m, 1H), 1.56–1.62 (m,
2H), 1.64 (s, 3H), 1.77–1.81 (m, 2H), 1.83–1.91 (m, 2H),
1.96 (d, J = 4.0 Hz, 1H), 2.03 (dd, J = 12.5, 2.0 Hz, 1H),
2.13 (dt, J = 13.1, 3.4 Hz, 1H), 2.41 (s, 1H), 2.87 (d, J =
1.8 Hz, 1H), 3.61 (d, J = 11.6 Hz, 1H), 3.96 (d, J = 11.6
Hz, 1H), 3.97 (m, 1H), 4.86 (dd, J = 11.6, 4.8 Hz, 1H), 5.01
(m, 1H), 6.51 (s, 1H), 7.41 (dd, J = 7.8, 4.7 Hz, 1H), 8.11
(dt, J = 8.2, 2.1 Hz, 1H), 8.69 (dd, J = 4.8, 1.6 Hz, 1H),
9.01 (d, J = 2.0 Hz, 1H); MS (ESI) m/z 594 (M + H)+;
HRMS (ESI) m/z calcd. for C33H40NO9 594.2703, found
594.2703 (M + H)+.
1
0.0622 mmol) as a solid in 74% yield. H NMR (CDCl3) δ
0.81–0.87 (m, 4H), 0.90 (s, 3H), 0.98–1.03 (m, 4H), 1.45 (s,
3H), 1.45–1.54 (m, 1H), 1.56–1.64 (m, 2H), 1.78 (s, 3H),
1.80–1.88 (m, 1H), 1.92–1.96 (m, 1H), 1.99–2.00 (m, 2H),
2.10–2.22 (m, 3H), 2.88 (d, J = 3.5 Hz, 1H), 3.61 (d, J =
11.9 Hz, 1H), 3.95 (d, J = 11.9 Hz, 1H), 4.43 (t, J = 2.7 Hz,
1H), 4.93 (dd, J = 11.7, 4.8 Hz, 1H), 5.05 (dd, J = 3.4, 3.2
Hz, 1H), 6.53 (s, 1H), 7.41 (dd, J = 8.0, 4.8 Hz, 1H), 8.10
(ddd, J = 8.0, 1.8, 1.2 Hz, 1H), 8.69 (dd, J = 4.8, 1.2 Hz,
1H), 9.02 (d, J = 1.8 Hz, 1H); MS (ESI) m/z 612 (M + H)+;
HRMS (ESI) m/z calcd. for C33H39ClNO8 612.2364, found
612.2368 (M + H)+.
1, 11-Di-O-cyclopropylcarbonyl-7-deacetoxy-1, 11-di-
11-O-Cyclopropylcarbonyl-11- deacetylpyripyropene
deacetyl-7- epiacetoxypyripyropene A (22)
A (24a)
To a cold (0 °C) solution of 13 (300 mg, 0.506 mmol) in
CH2Cl2 (3 ml) were added DMAP (246 mg, 2.01 mmol) and
trifluoromethanesulfonic anhydride (285 mg, 1.01 mmol)
and the mixture was stirred at room temperature for 2 h.
Water was added to the mixture and the mixture was
extracted with CHCl3. The organic layer was washed with
brine, dried over anhydrous MgSO4, filtered and con-
centrated in vacuo. To a cold (0 °C) solution of the residue
in DMF (2 ml) and hexamethylphosphoric triamide
(HMPA) (2 ml) was added lithium acetate (334 mg, 5.06
mmol) and stirred at 60 °C for 14 h. The reaction mixture
was diluted with AcOEt and washed with water and brine,
dried over Na2SO4, filtered and concentrated in vacuo. The
resulting residue was purified by chromatography on silica
gel (acetone: hexane) to afford 22 (274 mg, 0.431 mmol) as
Reaction of 3 (30 mg, 0.0571 mmol) with acetic anhy-
dride (70 mg, 0.685 mmol) gave 24a (27 mg, 0.0445 mmol)
as a solid in 78% yield by a similar procedure to 17a. H
1
NMR (CDCl3) δ 0.86–0.90 (m, 2H), 0.89 (s, 3H), 1.02–1.06
(m, 1H), 1.12–1.16 (m, 1H), 1.35–1.41 (m, 1H), 1.45 (s,
3H), 1.53–1.65 (m, 3H), 1.70 (s, 3H), 1.75–1.95 (m, 4H),
2.05 (s, 3H), 2.09 (m, 1H), 2.17 (s, 3H), 2.97 (d, J = 2.2 Hz,
1H), 3.73 (d, J = 12.0 Hz, 1H), 3.82 (d, J = 12.0 Hz, 1H),
4.79 (dd, J = 11.7, 4.6 Hz, 1H), 5.01–5.05 (m, 2H), 6.46 (s,
1H), 7.41 (dd, J = 8.0, 4.9 Hz, 1H), 8.10 (dt, J = 8.0, 1.9
Hz, 1H), 8.69 (dd, J = 4.7, 1.3 Hz, 1H), 9.01 (d, J = 1.7 Hz,
1H); MS (ESI) m/z 610 (M + H)+.
11-O-Cyclopropylcarbonyl-7, 11-di-deacetylpyripyro
pene A (25a)
Reaction of 24a (27 mg, 0.0445 mmol) with DBU (7 mg,
0.0491 mmol) gave 25a (6.6 mg, 0.0116 mmol) as a solid in
26% yield by a similar procedure to 13. 1H NMR (CDCl3) δ
0.87–0.92 (m, 2H), 0.90 (s, 3H), 0.99–1.02 (m, 1H),
1.11–1.16 (m, 1H), 1.33–1.36 (m, 1H), 1.43 (s, 3H),
1.46–1.51 (m, 2H), 1.58–1.63 (m, 2H), 1.66 (s, 3H),
1.79–1.89 (m, 3H), 2.05 (s, 3H), 2.10–2.18 (m, 1H), 2.28
(m, 1H), 2.90 (s, 1H), 3.77–3.85 (m, 3H), 4.78–4.81 (m,
1H), 5.00 (s, 1H), 6.53 (s, 1H), 7.41–7.44 (m, 1H), 8.11 (d,
J = 6.8 Hz, 1H), 8.70 (s, 1H), 9.01 (s, 1H); MS (ESI) m/z
568 (M + H)+; HRMS (ESI) m/z calcd. for C31H38NO9
568.2547, found 568.2536 (M + H)+.
1
a solid in 85% yield. H NMR (CDCl3) δ 0.81–0.88 (m,
4H), 0.91 (s, 3H), 0.96–1.04 (m, 4H), 1.44 (s, 3H),
1.45–1.49 (m, 1H), 1.54–1.59 (m, 2H), 1.72 (s, 3H),
1.79–1.84 (m, 2H), 1.85–1.92 (m, 3H), 1.95–1.98 (m, 1H),
2.07 (s, 3H), 2.16–2.20 (m, 1H), 2.90 (s, 1H), 3.74 (s, 2H),
4.87 (dd, J = 11.5, 5.1 Hz, 1H), 5.03 (dd, J = 3.8, 2.7 Hz,
1H), 5.29 (dd, J = 3.0, 2.4Hz, 1H), 6.44 (s, 1H), 7.40 (dd,
J = 8.0, 4.8 Hz, 1H), 8.09 (ddd, J = 8.1, 2.2, 1.8 Hz, 1H),
8.69 (dd, J = 4.8, 1.6 Hz, 1H), 9.02 (d, J = 1.7 Hz, 1H); MS
(ESI) m/z 636 (M + H)+; HRMS (ESI) m/z calcd. for
C35H42NO10 636.2809, found 636.2813 (M + H)+.

Synthesis and insecticidal efficacy of pyripyropene derivatives. Part II—Invention of afidopyropen
11-O-Cyclopropylcarbonyl-1, 7, 11-tri-deacetyl-1, 7-
di-O-propionylpyripyropene A (24b)
layer was washed with brine, dried over MgSO4, filtered
and concentrated in vacuo. The resulting residue was pur-
Reaction of 3 (30 mg, 0.0571 mmol) with propionic
anhydride (89 mg, 0.685 mmol) gave 24b (18 mg, 0.0284
mmol) as a solid in 50% yield by a similar procedure to 17a.
1H NMR (CDCl3) δ 0.88–0.90 (m, 2H), 0.90 (s, 3H),
1.02–1.06 (m, 1H), 1.12–1.18 (m, 1H), 1.13 (t, J = 7.2 Hz,
3H), 1.23 (t, J = 7.6 Hz, 3H), 1.37–1.40 (m, 1H), 1.45 (s,
3H), 1.54–1.64 (m, 3H), 1.70 (s, 3H), 1.78–1.92 (m, 4H),
2.15–2.18 (m, 1H), 2.29–2.35 (m, 2H), 2.44–2.47 (m, 2H),
2.95 (s, 1H), 3.72 (d, J = 12.0 Hz, 1H), 3.83 (d, J = 12.0
Hz, 1H), 4.77–4.81 (m, 1H), 5.01–5.07 (m, 2H), 6.44 (s,
1H), 7.40–7.43 (m, 1H), 8.10 (d, J = 7.6 Hz, 1H), 8.69 (s,
1H), 9.02 (s, 1H); MS (ESI) m/z 638 (M + H)+.
ified by PTLC (acetone: hexane = 1: 1) to afford 27 (90 mg,
0.157 mmol) as a solid in 93% yield. H NMR (CDCl3) δ
1
0.84–0.88 (m, 4H), 0.91 (s, 3H), 0.96–1.00 (m, 4H), 1.24 (s,
3H), 1.56 (s, 3H), 1.57–1.65 (m, 5H), 1.74–1.80 (m, 1H),
1.87–1.91 (m, 1H), 1.95–1.99 (m, 1H), 2.04–2.07 (m, 1H),
2.58 (d, J = 3.2 Hz, 1H), 3.75 (d, J = 12.0 Hz, 1H), 3.92
(d, J = 12.0 Hz, 1H), 4.05 (dd, J = 7.3, 3.8Hz, 1H), 4.81
(dd, J = 11.8, 4.6Hz, 1H), 6.33 (s, 1H), 6.57 (s, 1H), 7.41
(dd, J = 8.0, 4.9Hz, 1H), 8.12 (dt, J = 8.1, 1.9Hz, 1H), 8.67
(dd, J = 4.7, 1.6Hz, 1H), 9.01 (d, J = 2.2Hz, 1H); MS (ESI)
m/z 576 (M + H)+; HRMS (ESI) m/z calcd. for C33H38NO8
576.2597, found 576.2590 (M + H)+.
11-O-Cyclopropylcarbonyl-1, 7, 11-tri-deacetyl-1-O-
13-O-Acetyl-1, 11-di-O-cyclopropylcarbonyl-1, 11-di-
propionylpyripyropene A (25b)
deacetylpyripyropene A (28)
Reaction of 24b (18 mg, 0.0284 mmol) with DBU (5 mg,
0.0312 mmol) gave 25b (5.8 mg, 0.00998 mmol) as a solid
in 35% yield by a similar procedure to 13. 1H NMR
(CDCl3) δ 0.85–0.92 (m, 2H), 0.91 (s, 3H), 0.97–1.01 (m, 2
H), 1.14 (t, J = 7.6 Hz, 3H), 1.34–1.37 (m, 1H), 1.42 (s,
3H), 1.46–1.51 (m, 2H), 1.57–1.64 (m, 2H), 1.66 (s, 3H),
1.78–1.94 (m, 3H), 2.14–2.18 (m, 1H), 2.30–2.36 (m, 3H),
2.91 (d, J = 1.5 Hz, 1H), 3.75–3.83 (m, 1H), 3.77 (d, J =
12.0 Hz, 1H), 3.84 (d, J = 12.0 Hz, 1H), 4.80 (dd, J = 11.7,
4.9 Hz, 1H), 5.00 (m, 1H), 6.53 (s, 1H), 7.43 (dd, J = 8.0,
4.9 Hz, 1H), 8.11 (dt, J = 8.0, 1.8 Hz, 1H), 8.70 (d, J = 3.7
Hz, 1H), 9.01 (s, 1H); MS (ESI) m/z 582 (M + H)+; HRMS
(ESI) m/z calcd. for C32H40NO9 582,2703, found 582.2702
(M + H)+.
Reaction of 17a (1.0 g, 1.57 mmol) with acetic anhy-
dride (1.6 g, 15.7 mmol) gave 28 (0.88 g, 1.29 mmol) as a
solid in 82% yield by a similar procedure to 17a. H
1
NMR (CDCl3) δ 0.83–0.90 (m, 4H), 0.87 (s, 3H),
0.96–0.98 (m, 2H), 1.02–1.08 (m, 2H), 1.13 (s, 3H),
1.26–1.32 (m, 1H), 1.53–1.69 (m, 4H), 1.71 (s, 3H), 1.75
(m, 2H), 1.79–1.90 (m, 2H), 2.11 (s, 3H), 2.18 (s, 3H),
2.34–2.47 (m, 1H), 3.74 (d, J = 12.0Hz, 1H), 3.78 (d,
J = 12.0Hz, 1H), 4.82 (dd, J = 11.7, 4.6Hz, 1H), 5.02-
5.06 (m, 1H), 6.38 (d, J = 3.4Hz, 1H), 6.42 (s, 1H), 7.41
(dd, J = 7.6, 4.9Hz, 1H), 8.11 (dt, J = 8.1, 2.0Hz, 1H),
8.69 (dd, J = 4.8, 1.6Hz, 1H), 9.00 (d, J = 1.7Hz, 1H);
MS (ESI) m/z 678 (M + H)+.
1, 11-Di-O-cyclopropylcarbonyl-1, 11-di-deacetyl-13-
1, 11-Di-O-cyclopropylcarbonyl-1, 7, 11-tri-deacetyl-
O-methylpyripyropene A (29)
13-dehydropyripyropene A (26)
To a solution of 28 (2.3 g, 3.40 mmol) in MeOH (50 ml)
was added 5% hydrochloric acid (2 ml) and the mixture was
stirred at room temperature for 4 days. The reaction was
quenched with Et3N and the mixture was concentrated in
vacuo. The resulting residue was purified by chromato-
graphy on silica gel (acetone: hexane) to afford 29 (172 mg,
Reaction of 13 (20 mg, 0.0337 mmol) with Dess–Martin
periodinan (21 mg, 0.0506 mmol) gave 26 (4 mg, 0.00693
mmol) as a solid in 21% yield by a similar procedure to 18.
1H NMR (CDCl3) δ 0.83–0.92 (m, 4H), 0.90 (s, 3H),
0.94–1.03 (m, 4H), 1.14–1.20 (m, 1H), 1.22 (s, 3H),
1.42–1.49 (m, 1H), 1.53 (s, 3H), 1.55–1.66 (m, 4H),
1.74–1.84 (m, 1H), 1.87–1.91 (m, 1H), 2.54 (s, 1H), 2.79
(dt, J = 13.6, 3.4 Hz, 1H), 3.65 (s, 1H), 3.74 (d, J = 12.0
Hz, 1H), 3.89 (d, J = 11.7 Hz, 1H), 4.03 (dd, J = 11.0, 4.6
Hz, 1H), 4.81 (dd, J = 11.4, 5.2 Hz, 1H), 6.57 (s, 1H), 7.46
(dd, J = 8.1, 4.9 Hz, 1H), 8.19 (dt, J = 8.1, 1.8 Hz, 1H),
8.76 (d, J = 3.7 Hz, 1H), 9.05 (s, 1H); MS (ESI) m/z 592
(M + H)+; HRMS (ESI) m/z calcd. for C33H38NO9
592.2547, found 592.2543 (M + H)+.
1
0.265 mmol) as a solid in 8% yield. H NMR (CDCl3) δ
0.84–0.88 (m, 4H), 0.90 (s, 3H), 0.97–1.06 (m, 4H),
1.33–1.36 (m, 1H), 1.38 (s, 3H), 1.46 (d, J = 3.0Hz, 1H),
1.52–1.66 (m, 4H), 1.71 (s, 3H), 1.78–1.86 (m, 2H),
1.92–1.96 (m, 1H), 2.02–2.05 (m, 1H), 2.16 (s, 3H), 3.61
(s, 3H), 3.76 (s, 2H), 4.68 (d, J = 3.0Hz, 1H), 4.81 (dd, J =
11.8, 4.7Hz, 1H), 4.96 (dd, J = 11.5, 5.0Hz, 1H), 6.38
(s, 1H), 7.39 (ddd, J = 8.0, 4.9, 0.7Hz, 1H), 8.08–8.11
(m, 1H), 8.68 (dd, J = 4.8, 1.6Hz, 1H), 9.00 (d, J = 1.7Hz,
1H); MS (ESI) m/z 650 (M + H)+.
1, 11-Di-O-cyclopropylcarbonyl-1, 7, 11-tri-deacetyl-
5-dehydro-13-deoxypyripyropene A (27)
1, 11-Di-O-cyclopropylcarbonyl-1, 7, 11-tri-deacetyl-
To a solution of 13 (100 mg, 0.169 mmol) in anhydrous
THF (1 ml) was added p-toluenesulfonic acid monohydrate
(160 mg, 0.841 mmol) and the mixture was stirred at room
temperature for 25 h. The reaction mixture was diluted with
AcOEt and washed with aqueous NaHCO3. The organic
13-O-methylpyripyropene A (30)
Reaction of 29 (170 mg, 0.262 mmol) with potassium
carbonate (36 mg, 0.262 mmol) gave 30 (129 mg, 0.212
mmol) as a solid in 81% yield by a similar procedure to 23.
1H NMR (CDCl3) δ 0.84-0.87 (m, 4H), 0.91 (s, 3H), 0.94-

K. Goto et al.
1.04 (m, 4H), 1.31–1.43 (m, 1H), 1.36 (s, 3H), 1.39 (d, J =
3.0Hz, 1H), 1.45 (d, J = 12.0Hz, 1H), 1.56–1.63 (m, 3H),
1.68 (s, 3H), 1.79–1.93 (m, 3H), 2.01–2.05 (m, 1H), 3.61 (s,
3H), 3.70–3.75 (m, 2H), 3.85 (d, J = 11.8Hz, 1H), 4.67 (d,
J = 2.8Hz, 1H), 4.81 (dd, J = 11.6, 4.9Hz, 1H), 6.46 (s,
1H), 7.41 (dd, J = 8.0, 4.9Hz, 1H), 8.11 (m, 1H), 8.68 (dd,
J = 4.8, 1.2Hz, 1H), 8.99 (d, J = 1.9Hz, 1H); MS (ESI) m/z
608 (M + H)+; HRMS (ESI) m/z calcd. for C34H42NO9
608.2860, found 608.2859 (M + H)+.
3.5Hz, 1H), 2.11–2.14 (m, 1H), 2.25 (dd, J = 17.1, 12.8Hz,
1H), 2.54 (dd, J = 17.1, 4.6Hz, 1H), 3.45 (d, J = 10.3Hz,
1H), 3.68 (dd, J = 11.2, 5.0Hz, 1H), 3.75 (d, J = 10.3Hz,
1H), 6.42 (s, 1H), 7.39 (dd, J = 8.0, 4.8Hz, 1H), 8.10 (dt,
J = 8.0, 2.0Hz, 1H), 8.65 (dd, J = 4.8, 1.6Hz, 1H), 8.99 (d,
J = 2.0Hz, 1H); MS (ESI) m/z 426 (M + H)+.
1, 11-Di-O-cyclopropylcarbonyl-1, 11-di-deacetylpyr-
ipyropene O (34)
Reaction of 33 (22 mg, 0.0517 mmol) with cyclopropane-
carbonyl chloride (22 mg, 0.207 mmol) gave 34 (17 mg,
0.0310 mmol) as a solid in 60% yield by a similar procedure
to 6. 1H NMR (CDCl3) δ 0.88 (s, 3H), 0.99 (s, 3H), 0.84–1.08
(m, 8H), 1.21 (dt, J = 13.4, 3.6Hz, 1H), 1.28 (s, 3H),
1.43–1.48 (m, 2H), 1.56–1.73 (m, 6H), 1.81–1.85 (m, 2H),
2.13–2.16 (m, 1H), 2.26 (dd, J = 17.1, 12.8Hz, 1H), 2.55 (dd,
J = 17.1, 4.6Hz, 1H), 3.71 (d, J = 11.7Hz, 1H), 3.93 (d, J =
11.7Hz, 1H), 4.82 (dd, J = 12.0, 4.7Hz, 1H), 6.44 (s, 1H),
7.41 (dd, J = 8.0, 4.8Hz, 1H), 8.12 (ddd, J = 8.0Hz, 1H, 2.0,
1.4), 8.66 (dd, J = 4.8, 1.4Hz, 1H), 9.00 (d, J = 2.0Hz, 1H);
MS (ESI) m/z 562 (M + H)+; HRMS (ESI) m/z calcd. for
C33H40NO7 562.2805, found 562.2809 (M + H)+.
1, 11, 13-Tri-O-cyclopropylcarbonyl-1, 11-di-deace-
tylpyripyropene A (31)
To a cold (0 °C) solution of 17a (1.0 g, 1.57 mmol) in
AcOEt (10 ml) were added pyridine (3.73 g, 47.1 mmol)
and cyclopropanecarbonyl chloride (4.90 g, 47.1 mmol) and
the mixture was stirred at 40 °C for 8 h. The reaction was
quenched with MeOH and the mixture was concentrated
under reduced pressure and the residue was dissolved in
AcOEt. The organic layer was washed with water and brine,
dried over anhydrous Na2SO4, filtered and concentrated in
vacuo. The resulting residue was purified by chromato-
graphy on silica gel (acetone: hexane) to afford 31 (0.223 g,
1
0.317 mmol) as a solid in 20% yield. H NMR (CDCl3) δ
1-Deacetylpyripyropene E (35)
0.83–0.92 (m, 6H), 0.87 (s, 3H), 0.96–1.16 (m, 6H), 1.14 (s,
3H), 1.24–1.30 (m, 1H), 1.53–1.66 (m, 4H), 1.67–1.74 (m,
1H), 1.73 (s, 3H), 1.75–1.90 (m, 3H), 2.18 (s, 3H),
2.42–2.45 (m, 1H), 3.73–3.79 (m, 2H), 4.82 (dd, J = 12.0,
4.7Hz, 1H), 5.01–5.05 (m, 1H), 6.39 (d, J = 3.0Hz, 1H),
6.41 (s, 1H), 7.40 (dd, J = 8.0, 4.1Hz, 1H), 8.10 (dt, J =
8.2, 1.9Hz, 1H), 8.68 (dd, J = 4.8, 1.6Hz, 1H), 9.00 (d, J =
2.2Hz, 1H); MS (ESI) m/z 704 (M + H)+.
Reaction of PP-E (29 mg, 0.0643 mmol) with potassium
carbonate (53 mg, 0.384 mmol) gave 35 (18 mg, 0.0440
mmol) as a solid in 68% yield by a similar procedure to 23.
1H NMR (CDCl3) δ 0.82 (s, 3H), 0.92 (s, 3H), 0.99–1.02
(m, 1H), 1.03 (s, 3H), 1.12 (dt, J = 12.8, 4.0Hz, 1H), 1.27
(s, 3H), 1.40-1.46 (m, 1H), 1.50 (dd, J = 12.8, 4.4Hz, 1H),
1.62–1.74 (m, 3H), 1.79–1.83 (m, 2H), 2.14 (dt, J = 12.4,
3.2Hz, 1H), 2.24 (dd, J = 16.8, 12.4Hz, 1H), 2.53 (dd, J =
16.8, 4.8Hz, 1H), 3.25 (dd, J = 11.2, 4.0Hz, 1H), 6.42 (s,
1H), 7.38 (dd, J = 8.0, 4.8Hz, 1H), 8.10 (dt, J = 8.0, 2.0Hz,
1H), 8.65 (dd, J = 4.8, 1.6Hz, 1H), 8.99 (d, J = 2.0Hz, 1H);
MS (ESI) m/z 410 (M + H)+.
1, 11, 13-Tri-O-cyclopropylcarbonyl-1, 7, 11-tri-dea-
cetylpyripyropene A (32)
Reaction of 31 (430 mg, 0.612 mmol) with potassium
carbonate (24 mg, 0.184 mmol) gave 32 (328 mg, 0.496
mmol) as a solid in 81% yield by a similar procedure to 23.
1H NMR (CDCl3) δ 0.84–0.92 (m, 6H), 0.88 (s, 3H),
0.95–1.03 (m, 6H), 1.23 (s, 3H), 1.24–1.26 (m, 1H),
1.45–1.48 (m, 1H), 1.54–1.62 (m, 4H), 1.65 (d, J = 3.5Hz,
1H), 1.70 (s, 3H), 1.72–1.75 (m, 1H), 1.84–1.88 (m, 2H),
2.31 (br s, 1H), 2.42 (dt, J = 13.2, 3.0Hz, 1H), 3.72 (d, J =
12.0Hz, 1H), 3.79–3.82 (m, 1H), 3.86 (d, J = 11.8Hz, 1H),
4.82 (dd, J = 12.0, 4.7Hz, 1H), 6.38 (d, J = 3.4Hz, 1H),
6.48 (s, 1H), 7.41 (dd, J = 8.5, 5.0Hz, 1H), 8.11 (dt, J = 8.1,
1.9Hz, 1H), 8.69 (dd, J = 4.8, 1.6Hz, 1H), 9.00 (d, J =
1.7Hz, 1H); MS (ESI) m/z 662 (M + H)+; HRMS (ESI) m/z
calcd. for C37H44NO10 662.2965, found 662.2955 (M + H)+.
1, 11-Di-deacetylpyripyropene O (33)
1-O-Cyclopropylcarbonyl-1 -deacetylpyripyropene E
(36)
Reaction of 35 (10 mg, 0.0244 mmol) with cyclopropa-
necarbonyl chloride (10 mg, 0.0976 mmol) gave 36 (8.3 mg,
0.0174 mmol) as a solid in 71% yield by a similar procedure
1
to 6. H NMR (CDCl3) δ 0.84–0.88 (m, 2H), 0.91 (s, 3H),
0.92 (s, 3H), 0.95 (s, 3H), 0.98–1.01 (m, 2H), 1.07–1.11 (m,
1H), 1.18 (dt, J = 13.1, 3.6Hz, 1H), 1.27 (s, 3H), 1.40–1.48
(m, 1H), 1.52 (dd, J = 12.8, 4.8Hz, 1H), 1.59–1.74 (m, 4H),
1.79–1.83 (m, 2H), 2.14 (dt, J = 12.6, 3.1Hz, 1H), 2.24 (dd,
J = 17.2, 13.0Hz, 1H), 2.52 (dd, J = 17.2, 4.7Hz, 1H), 4.51
(dd, J = 11.6, 4.8Hz, 1H), 6.43 (s, 1H), 7.39 (dd, J = 8.0,
4.8Hz, 1H), 8.11 (ddd, J = 8.0, 1.6, 1.6Hz, 1H), 8.66 (dd,
J = 4.8, 1.6Hz, 1H), 9.00 (d, J = 1.6Hz, 1H); MS (FAB) m/
z 478 (M + H)+; HRMS (ESI) m/z calcd. for C29H36NO5
478.2593, found 478.2589 (M + H)+.
Reaction of PP-O (30 mg, 0.0589 mmol) with potassium
carbonate (20 mg, 0.145 mmol) gave 33 (23 mg, 0.0541
mmol) as a solid in 92% yield by a similar procedure to 23.
1H NMR (CDCl3) δ 0.89 (s, 3H), 0.97 (s, 3H), 1.14 (dt, J =
12.8, 4.2Hz, 1H), 1.20–1.25 (m, 1H), 1.28 (s, 3H),
1.45–1.59 (m, 3H), 1.64–1.75 (m, 3H), 1.82 (dt, J = 9.6,
1, 7, 11-Tri-deacetyl-13-deoxypyripyropene A (38)
The crude 38 (5.0 g), including 2 as a major component,
which was obtained by the method previously reported [6],

Synthesis and insecticidal efficacy of pyripyropene derivatives. Part II—Invention of afidopyropen
was purified by chromatography on silica gel (CHCl3:
MeOH) and HPLC (CH3CN: H2O) to afford 38 (0.44 g) as a
solid. 1H NMR (DMSO) δ 0.55 (s, 3H), 0.85 (s, 3H),
0.97–1.03 (m, 1H), 1.14 (s, 3H), 1.26–1.34 (m, 1H),
1.37–1.44 (m, 2H), 1.53–1.57 (m, 3H), 1.72 (m, 1H), 2.19
(dd, J = 17.0, 12.6Hz, 1H), 2.31 (dd, J = 17.0, 4.8Hz, 1H),
3.06 (dd, J = 10.5, 4.8Hz, 1H), 3.35–3.38 (m, 1H),
3.43–3.47 (m, 1H), 3.60 (m, 1H), 4.24 (d, J = 5.1Hz, 1H),
4.51 (t, J = 5.0Hz, 1H), 4.99 (d, J = 5.2Hz, 1H), 6.91 (s,
1H), 7.51 (dd, J = 7.9, 4.8Hz, 1H), 8.21 (dt, J = 7.9, 2.0Hz,
1H), 8.65 (dd, J = 4.8, 1.8Hz, 1H), 9.03 (d, J = 2.0Hz, 1H);
MS (ESI) m/z 442 (M + H)+.
added 1-benzoylbenzotriazole (1.25 g, 5.60 mmol) in THF
(10 ml) at −20 °C. The reaction mixture was stirred at same
temperature for 2 h, then quenched with AcOH. The reac-
tion mixture was poured into water and extracted with
AcOEt. The organic layer was washed with saturated aqu-
eous NaHCO3 and brine, dried over Na2SO4, filtered and
concentrated in vacuo. To a solution of the residue in
benzene (15 ml) was added DBU (853 mg, 5.60 mmol) at
room temperature. The mixture was stirred at 40 °C for 15
min, then cooled to room temperature and quenched with
AcOH. The reaction mixture was poured into water and
extracted with AcOEt. The organic layer was washed with
saturated aqueous NaHCO3 and brine, dried over Na2SO4,
filtered and concentrated in vacuo. The resulting residue
was purified by chromatography on silica gel (acetone:
hexane) to afford 42 (773 mg, 1.27 mmol) as a solid in 45%
1, 7, 11-Tri-O-cyclopropylcarbonyl-1, 7, 11-tri-dea-
cetyl-13-deoxypyripyropene A (39)
Reaction of 38 (1.0 g, 2.27 mmol) with cyclopropane-
carbonyl chloride (2.4 g, 22.7 mmol) gave 39 (0.34 g, 0.527
mmol) as a solid in 23% yield by a similar procedure to 6.
1H NMR (CDCl3) δ 0.84–0.89 (m, 4H), 0.89 (s, 3H),
0.91–0.99 (m, 4H), 1.02 (s, 3H), 1.03–1.11 (m, 4H),
1.16–1.24 (m, 1H), 1.34 (s, 3H), 1.50–1.77 (m, 7H),
1.81–1.91 (m, 3H), 2.34 (dd, J = 17.2, 12.8Hz, 1H), 2.58
(dd, J = 17.2, 4.8Hz, 1H), 3.73 (d, J = 11.6Hz, 1H), 3.84
(d, J = 11.6Hz, 1H), 4.79 (dd, J = 11.6, 4.8Hz, 1H), 5.04
(dd, J = 11.6, 4.8Hz, 1H), 6.43 (s, 1H), 7.38 (dd, J = 8.0,
4.8Hz, 1H), 8.10 (ddd, J = 8.0, 2.0, 2.0Hz, 1H), 8.65 (dd,
J = 4.8, 2.0Hz, 1H), 9.00 (d, J = 2.0Hz, 1H); MS (ESI) m/z
646 (M + H)+; HRMS (ESI) m/z calcd. for C37H44NO9
646.3016, found 646.3014 (M + H)+.
1
yield. H NMR (CDCl3) δ 0.15 (s, 3H), 0.20 (s, 3H), 0.96
(s, 9H), 1.05–1.07 (m, 1H), 1.09 (s, 3H), 1.09–1.16 (m, 1H),
1.21 (s, 3H), 1.44 (s, 3H), 1.46 (s, 3H), 1.47 (s, 3H),
1.48–1.57 (m, 3H), 1.67–1.75 (m, 1H), 2.54 (s, 1H),
2.78–2.87 (m, 1H), 3.35–3.60 (m, 3H), 3.98 (dd, J = 11.3,
4.9Hz, 1H), 6.37 (s, 1H), 7.51–7.63 (m, 3H), 7.74–7.86 (m,
2H); MS (ESI) m/z 609 (M + H)+.
7-O-tert-Butyldimethylsilyl-1, 7, 11-tri-deacetyl-1, 11-
O-isopropylidenephenylpyropene A (43)
To a solution of 42 (770 mg, 1.27 mmol) in EtOH (50
ml) was added cerium (III) chloride heptahydrate
(CeCl3·7H2O, 2.4 g, 6.35 mmol) and mixture was stirred at
room temperature for 10 min, then cooled to 0 °C. To a cold
mixture was added sodium borohydride (NaBH4, 480 mg,
12.7 mmol) and the reaction mixture was stirred for 15 h.
The reaction mixture was diluted with CHCl3 and washed
with 0.1N aqueous NaOH. The organic layer was washed
with brine, dried over Na2SO4, filtered and concentrated in
vacuo. The resulting residue was purified by chromato-
graphy on silica gel (acetone: hexane) to afford 43 (610 mg,
1, 11-Di-O-cyclopropylcarbonyl-1, 7, 11-tri-deacetyl-
13-deoxypyripyropene A (40)
Reaction of 39 (0.34 g, 0.527 mmol) with DBU (40 mg,
0.264 mmol) gave 40 (57 mg, 0.0988 mmol) as a solid in
19% yield by a similar procedure to 13. 1H NMR (CDCl3) δ
0.83–0.90 (m, 4H), 0.89 (s, 3H), 0.96–1.04 (m, 4H), 1.00 (s,
3H), 1.15–1.22 (m, 1H), 1.29 (s, 3H), 1.50–1.62 (m, 5H),
1.65–1.76 (m, 1H), 1.80–1.89 (m, 3H), 2.34 (dd, J = 16.8,
13.2Hz, 1H), 2.56 (dd, J = 16.8, 4.8Hz, 1H), 3.77 (d, J =
11.6Hz, 1H), 3.81–3.84 (m, 1H), 3.87 (d, J = 11.6Hz, 1H),
4.81 (dd, J = 11.6, 4.8Hz, 1H), 6.49 (s, 1H), 7.40 (dd, J =
8.0, 4.8Hz, 1H), 8.11 (ddd, J = 8.0, 1.6, 1.6Hz, 1H), 8.67
(dd, J = 4.8, 1.6Hz, 1H), 8.99 (d, J = 1.6Hz, 1H); MS (ESI)
m/z 578 (M + H)+; HRMS (ESI) m/z calcd. for C33H40NO8
578.2754, found 578.2746 (M + H)+.
7-O-tert-Butyldimethylsilyl-1, 7, 11-tri-deacetyl-1, 11-
O-isopropylidene-13-dehydrophenylpyropene A (42)
To a cold (0 °C) solution of lithium bis(trimethylsilyl)
amide (LHMDS, 1.6M solution in THF, 8.7 ml, 14.0 mmol)
was added N, N, N’, N’-tetramethylethylenediamine
(TMEDA, 0.39 ml, 3.36 mmol) and after stirring for 10 min,
41 (1.5 g, 2.80 mmol), which was synthesized by the
method previously reported [23], in THF (10 ml) was
added. The reaction mixture was stirred at 0 °C for 1 h, then
cooled to −20 °C. To the resulting mixture was slowly
1
1.00 mmol) as a solid in 79% yield. H NMR (CDCl3) δ
0.12 (s, 3H), 0.17 (s, 3H), 0.96 (s, 9H), 1.02–1.05 (m, 1H),
1.11 (s, 3H), 1.25–1.45 (m, 2H), 1.40 (s, 3H), 1.447 (s, 3H),
1.454 (s, 3H), 1.55–1.68 (m, 3H), 1.59 (s, 3H), 1.78–1.84
(m, 1H), 2.19–2.20 (m, 1H), 3.44 (d, J = 10.5Hz, 1H),
3.50–3.56 (m, 2H), 3.72 (dd, J = 11.7, 5.1Hz, 1H), 5.02 (d,
J = 4.1Hz, 1H), 6.31 (s, 1H), 7.35–7.50 (m, 3H), 7.76–7.78
(m, 2H); MS (ESI) m/z 611 (M + H)+.
7-O-tert-Butyldimethylsilyl-1, 7, 11-tri-deacetylphenyl
pyropene A (44)
To a solution of 43 (0.92 g, 1.51 mmol) in THF (20 ml)
was added 80% aqueous AcOH solution (30 ml) and mix-
ture was stirred at room temperature for 10 days. The
reaction mixture was cooled to 0 °C and then saturated
aqueous NaHCO3 was added to the mixture. The mixture
was extracted with AcOEt and the organic layer was
washed with brine, dried over anhydrous Na2SO4, filtered

K. Goto et al.
and concentrated in vacuo. This residue (0.86 g) was used in
the following step with no further purification. MS (ESI) m/
z 571 (M + H)+.
gossypii), greenhouse whitefly (T. vaporariorum)
and western flower thrips (F. occidentalis) was
conducted using the methods reported previously
[26, 27].
7-O-tert-Butyldimethylsilyl-1, 11-Di-O-cyclopropylcar
bonyl-1, 7, 11-tri-deacetylphenylpyropene A (45)
To a solution of crude 44 (0.86 g) in DMF (5 ml) were
added pyridine (1.1 g, 13.6 mmol) and cyclopropanecarbo-
nyl chloride (0.95 g, 9.1 mmol) and the mixture was stirred
at room temperature for 8 h. The reaction mixture was then
poured into water, extracted with AcOEt. The organic layer
was washed with water and brine, dried over anhydrous
Na2SO4, filtered and concentrated in vacuo. The resulting
residue was purified by chromatography on silica gel
(acetone: hexane) to afford 45 (0.70 g, 0.986 mmol) as a
solid in 65% yield (two steps from 43). 1H NMR (CDCl3) δ
0.11 (s, 3H), 0.16 (s, 3H), 0.83–0.89 (m, 4H), 0.90 (s, 3H),
0.96 (s, 9H), 0.96–1.00 (m, 4H), 1.30–1.36 (m, 1H), 1.41 (s,
3H), 1.42 (m, 1H), 1.44–1.47 (m, 1H), 1.59 (s, 3H),
1.55–1.64 (m, 4H), 1.78–1.91 (m, 2H), 2.13–2.18 (m, 1H),
2.85 (d, J = 1.6Hz, 1H), 3.65 (d, J = 11.7Hz, 1H),
3.67–3.72 (m, 1H), 3.91 (d, J = 12.0Hz, 1H), 4.81 (dd, J =
11.7, 4.7Hz, 1H), 4.98 (dd, J = 3.9, 2.0Hz, 1H), 6.30 (s,
1H), 7.39–7.54 (m, 3H), 7.73–7.84 (m, 2H); MS (ESI) m/z
707 (M + H)+.
(2) Efficacy against wheat aphid (R. padi) on wheat
by foliar application:
The trial was conducted using 2-week-old
seedlings grown in pots in a greenhouse. The leaves
of each seedling were sprayed with 1.5 ml of the test
compound dissolved in 10% aqueous acetone
solution containing 0.05% Tween 20. After the
leaves dried, four adult aphids were released onto
each plant. At 4 and 7 days after application, the
number of aphids was counted in each plot. This test
was conducted in duplicate. The density index was
calculated as follows:
Density index ¼ ðnumber of aphids in treated plot at
4 or 7 days after applicationÞ=ðnumber of aphids in
untreated plot at 4 or 7 days after applicationÞÂ100:
ð1Þ
Then, compared with untreated plot, the control
percentage was calculated as follows:
1, 11-Di-O-cyclopropylcarbonyl-1, 7, 11-tri-deacetyl
phenylpyropene A (46)
% control ¼ 100Àðdensity indexÞ:
ð2Þ
To a cold (0 °C) solution of 45 (200 mg, 0.283 mmol) in
THF (1 ml) were added pyridine (0.3 ml) and HF-pyridine
complex (0.36 ml) and mixture was stirred at room tem-
perature for 2 days. The reaction mixture was cooled to 0 °C
and then saturated aqueous NaHCO3 was added to the
mixture. The mixture was extracted with AcOEt and the
organic layer was washed with brine, dried over anhydrous
Na2SO4, filtered and concentrated in vacuo. The resulting
residue was purified by chromatography on silica gel
(acetone: hexane) to afford 46 (130 mg, 0.220 mmol) as a
solid in 78% yield. 1H NMR (CDCl3) δ 0.83–0.89 (m, 4H),
0.91 (s, 3H), 0.95–1.04 (m, 4H), 1.35 (dt, J = 13.2, 3.9Hz,
1H), 1.42 (s, 3H), 1.45 (d, J = 4.1Hz, 1H), 1.48–1.50 (m,
1H), 1.55–1.64 (m, 3H), 1.66 (s, 3H), 1.79–1.91 (m, 3H),
2.14–2.15 (m, 1H), 2.24 (d, J = 3.8Hz, 1H), 2.91 (d, J =
1.9Hz, 1H), 3.75 (d, J = 11.7Hz, 1H), 3.77–3.81 (m, 1H),
3.86 (d, J = 11.7Hz, 1H), 4.82 (dd, J = 11.5, 4.9Hz, 1H),
4.99 (dd, J = 3.8, 2.5Hz, 1H), 6.45 (s, 1H), 7.34–7.49 (m,
3H), 7.78–7.80 (m, 2H); MS (ESI) m/z 593 (M + H)+;
HRMS (ESI) m/z calcd. for C34H41O9 593.2751, found
593.2743 (M + H)+.
(3) Efficacy against green peach aphid (M. persicae)
on cabbage by soil drenching:
The trial was conducted using 5-week-old cab-
bage seedlings grown in pots in a greenhouse. The
test compound (5 ml of the test compound dissolved
in 10% aqueous acetone solution) was added to the
soil in each pot. At 3 days after application, five
adult aphids were released onto each plant. At 4 and
7 days after application, the number of aphids on
each plant was counted. This test was conducted in
duplicate. The density index and % control were
calculated using the formulae shown above.
(4) Efficacy of compound 1 and 13 against green
peach aphid (M. persicae) on cabbage by foliar
application:
The trial was conducted on 5-week-old cabbage
seedlings grown in pots in a greenhouse. Each test
compound was formulated into a wettable powder
(WP). This formulation, including 5% (w/w) each
derivative, was prepared as described previously
[27]. Four adult aphids were placed on each plant.
After 6 days, 2 ml diluted solution of 1 and 13 WP in
water was sprayed onto each plant. The number of
aphids on each plant was counted before application
and at 1 and 2 days after application. This test was
(1) Insecticidal test against agricultural pests:
The PP derivatives were evaluated by an
insecticidal test against green peach aphid (M.
persicae), using the method described in our
previous report [15]. Tests against cotton aphid (A.

Synthesis and insecticidal efficacy of pyripyropene derivatives. Part II—Invention of afidopyropen
conducted in duplicate. The corrected density index
was calculated as follows:
inhibitor of acyl-CoA:cholesterol acyltransferase (ACAT). J Am
Chem Soc. 1994;116:12097–8.
8. Obata R, Sunazuka T, Li Z, Tomoda H, Ōmura S. Structure-
activity relationships of pyripyropenes fungal Acyl-CoA: Cho-
lesterol Acyltransferase inhibitors. J. Antibiot. 1995;48:749–50.
9. Obata R, Sunazuka T, Tomoda H, Harigaya Y, Ōmura S. Che-
mical modification and structure-activity relationships of pyr-
ipyropenes; Potent bioavailable inhibitor of acyl-CoA:cholesterol
acyltransferase (ACAT). Bioorg Med Chem Lett. 1995;5:2683–8.
10. Obata R, Sunazuka T, Li Z, Tian Z, Harigaya Y, Tabata N,
Tomoda H, Ōmura S. Chemical modification and structure-
activity relationships of pyripyropenes 1 Modification at the four
hydroxyl groups. J. Antibiot. 1996;49:1133–48.
11. Obata R, Sunazuka T, Kato Y, Tomoda H, Harigaya Y, Ōmura S.
Chemical modification and structure-activity relationships of pyr-
ipyropenes 2 1, 11-cyclic analogs. J. Antibiot. 1996;49:1149–56.
12. Obata R, Sunazuka T, Tian Z, Tomoda H, Harigaya Y, Ōmura S.
Chemical modification and structure-activity relationships of
pyripyropenes 3 Synthetic conversion of pyridine-pyrone moiety.
J. Antibiot. 1997;50:229–36.
Corrected density index ¼
ꢀ
ꢁ
ðnumber of aphids on treated plant at 1 or 2 days after applicationÞ=
Â
ðnumber of aphids on treated plant before applicationÞ
ꢀ
ꢁ
ðnumber of aphids on untreated plant before applicationÞ=
Â100:
ðnumber of aphids on untreated plant at 1 or 2 days after applicationÞ
ð3Þ
Then, compared with the untreated plants, the
control percentage was calculated as follows:
% control ¼ 100Àðcorrected density indexÞ:
ð4Þ
13. Obata R, Sunazuka T, Tian Z, Tomoda H, Harigaya Y, Ōmura S,
Smith AB. New analogs of the pyripyropene family of ACAT
inhibitors via α-pyrone fragmentation and γ-acylation/cyclization.
Chem Lett. 1997;26:935–6.
Acknowledgements We thank Dr. N. Minowa, Ms. K. Yamamoto and
Ms. Y. Mitani for valuable scientific discussion. We are also grateful
to Ms. T. Miyara, Ms. S. Miki, Ms. F. Nango and Dr. T. Murata for
their contributions to the analytical chemistry.
14. Obata R, Sunazuka T, Harigaya Y, Hayashi M, Rho MC, Tomoda
H, Ōmura S. Structure-activity relationships study of pyripyr-
openes: reversal of cancer cell multidrug resistance. J. Antibiot.
2000;53:422–5.
Compliance with ethical standards
Conflict of interest The authors declare that they have no conflict of
interest.
15. Horikoshi R, Goto K, Mitomi M, Oyama K, Sunazuka T, Ōmura
S. Identification of pyripyropene A as a promising insecticidal
compound in a microbial metabolite screening. J. Antibiot.
2017;70:272–6.
16. Goto K, Horikoshi R, Mitomi M, Oyama K, Sunazuka T, Ōmura
S. Synthesis and insecticidal efficacy of pyripyropene derivatives
focusing on the C-1, C-7 and C-11 positions’ substituent groups.
J. Antibiot. 2018;71:785–97.
Publisher’s note: Springer Nature remains neutral with regard to
jurisdictional claims in published maps and institutional affiliations.
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