The Design, Synthesis, and Evaluation of 1,5,7-Trisubstituted-3-Pyridyl-Xanthones for Use as Insecticides Starting from Pyripyropene A

Article abstract of DOI:10.1002/chem.201603980

A readily accessible template of 1,5,7-trisubstituted-3-pyridyl-xanthones was designed starting from naturally occurring pyripyropene A for agrichemical development. Our originally developed Ag₂CO₃-mediated oxidative cyclization enabled ready access to the key scaffold, 1,5,7-trihydroxy-3-chloro-xanthone. The chemo- and regioselective sequential introduction of four substituents to the scaffold rapidly afforded the desired, structurally diverse 1,5,7-trisubstituted-3-pyridyl-xanthones. An evaluation of insecticidal activity revealed that one of the synthesized compounds retained insecticidal activity against vetch aphid and green peach aphid. The observed insecticidal spectrum was similar to that of pyripyropene A. The developed template could be a valuable aid for future agrichemical development.

Full text of DOI:10.1002/chem.201603980

DOI: 10.1002/chem.201603980
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&
Insecticides |Hot Paper|
The Design, Synthesis, and Evaluation of 1,5,7-Trisubstituted-3-
Pyridyl-Xanthones for Use as Insecticides Starting from
Pyripyropene A
Shinichiro Fuse,*[a, b] Keisuke Matsumura,[b] Kohei Johmoto,[c] Hidehiro Uekusa,[c]
[b]
[d]
[d]
[d]
¯
Hiroshi Tanaka, Tomoyasu Hirose, Toshiaki Sunazuka, Satoshi Omura, and
Takashi Takahashi[e]
Abstract: A readily accessible template of 1,5,7-trisubstitut-
ed-3-pyridyl-xanthones was designed starting from naturally
occurring pyripyropene A for agrichemical development. Our
originally developed Ag2CO3-mediated oxidative cyclization
enabled ready access to the key scaffold, 1,5,7-trihydroxy-3-
chloro-xanthone. The chemo- and regioselective sequential
introduction of four substituents to the scaffold rapidly af-
forded the desired, structurally diverse 1,5,7-trisubstituted-3-
pyridyl-xanthones. An evaluation of insecticidal activity re-
vealed that one of the synthesized compounds retained in-
secticidal activity against vetch aphid and green peach
aphid. The observed insecticidal spectrum was similar to
that of pyripyropene A. The developed template could be
a valuable aid for future agrichemical development.
Introduction
a sterol-acylating enzyme that participates in the storage and
transport of sterols and in the activation and degradation of
hormones. Indeed, Kim et al. confirmed that ACAT inhibitors,
which included pyripyropene A, exert insecticidal activity
against both the corn earworm and the mealworm.[4] More-
over, Goto et al. recently reported that pyripyropenes also
retain potent insecticidal activity against aphids.[5]
Pyripyropene A is a mixed polyketide-terpenoid that was isolat-
¯
ed from Aspergillus fumigatus by Omura and co-workers more
than two decades ago (Figure 1).[1] Pyripyropene A retains the
highest degree of inhibitory activity against cholesterol acyl-
transferase (ACAT) among naturally occurring compounds.[1a,c]
ACAT is regarded as a promising target for the development of
anti-hypercholesterolemia agents.[2] In 1995, the Gloer group
isolated pyripyropene A from Eupenicillium reticulisporum, and
first reported the insecticidal activity of pyripyropene A against
the corn earworm.[3] Ten years later, Kim et al. assumed that
ACAT inhibitors would be good insecticidal agents because in-
sects essentially require sterols for their growth and utilize
¯
Omura, Smith and co-workers achieved the first total synthe-
sis of pyripyropene A in a highly convergent manner,[6] and
¯
Omura, Nagamitsu and colleagues more recently developed
a practical, linear synthetic route for the total synthesis of pyri-
pyropene A.[7] We recently reported the convergent synthesis
of ent-pyripyropene A based on our originally developed
[a] Dr. S. Fuse
Laboratory for Chemistry and Life Science, Institute of Innovative Research
Tokyo Institute of Technology
4259 Nagatsuta-cho, Midori-ku, Yokohama 226-8503 (Japan)
E-mail: sfuse@res.titech.ac.jp
[b] Dr. S. Fuse, K. Matsumura, Dr. H. Tanaka
Department of Chemical Science and Engineering
School of Material and Chemical Technology, Tokyo Institute of Technology
2-12-1 Ookayama, Meguro-ku, Tokyo 152-8552 (Japan)
[c] Dr. K. Johmoto, Dr. H. Uekusa
Department of Chemistry, School of Science, Tokyo Institute of Technology
2-12-1 Ookayama, Meguro-ku, Tokyo 152-8552 (Japan)
¯
[d] Dr. T. Hirose, Prof. Dr. T. Sunazuka, Prof. Dr. S. Omura
Kitasato Institute for Life Sciences, Kitasato University
5-9-1 Shirokane, Minato-ku, Tokyo 108-8641 (Japan)
Figure 1. Structures of a) pyripyropene A (1) and b) the designed 1,5,7-tri-
substituted-3-pyridyl-xanthone template I. Most stable conformation of c) 1
and d) template I (R1 =R2 =Ac, R3 =H). Construction of 3D models and
energy minimization was performed by using the OPLS-AA force field in the
conformational search algorithm in the MacroModel program (Schrçdinger,
LLC).
[e] Prof. Dr. T. Takahashi
Yokohama University of Pharmacy
601, Matano-cho, Totsuka-ku, Yokohama-shi, Kanagawa 245-0066 (Japan)
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201603980.
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tandem radical cyclization using a catalytic amount of a TiIII re-
agent.[8] Although the total synthesis of pyripyropene A was
accomplished, many synthetic steps (more than 15) were re-
quired. For further development of pyripyropene-based agri-
chemicals, the development of more synthetically accessible
templates[9] that retain an insecticidal spectrum similar to that
of pyripyropene A is an important starting point. Here, we
wish to report the design and synthesis of new pyridyl xan-
thone analogues of pyripyropene A, and describe their insecti-
cidal activity against pest insects.
Results and Discussion
Theoretical calculations have progressed dramatically in recent
years and they now provide a powerful tool for the design of
templates. However, no biological target for the insecticidal ac-
tivity of pyripyropene A has yet been determined. Therefore,
we designed a readily accessible pyridyl-xanthone template by
focusing on the planar structure of pyripyropene A (1)
(Figure 1). In detail, 1 features a highly planar, tetracyclic core
structure (Figure 1a and c). We speculated that this planar core
could be replaced by a xanthone structure (Figure 1b and d)
based on a comparison between the most stable calculated
conformations of 1 and the template I (Figure 1c and d).
Scheme 1. Synthetic plan for 1,5,7-trisubstituted-3-pyridyl-xanthones I.
and DMSO (entry 4), AgOAc and DMSO (entry 7), and Ag2CO3
and MeCN (entry 9) gave the best results. Since the conditions
detailed in Table 1, entry 4 require 4 equiv of oxidant, further
examinations were performed based on the conditions shown
in entries 7 and 9. To our delight, lower concentrations (2a:
0.1m) afforded better results (entries 11 and 12). The best yield
(68%, 3/4=5:2) was obtained by using the conditions shown
in entry 12. The addition of 2,2,6,6-tetramethylpiperidine-1-oxyl
(TEMPO) dramatically decreased the yield (entry 13) and indi-
cated that the reaction had proceeded through a single-elec-
tron transfer mechanism. In addition, the 3’-OH group was cru-
cial for this cyclization (entries 14–16).
Our synthetic plan is shown in Scheme 1. The intended com-
pound I was expected to be obtained through the sequential
chemo- and regioselective introduction of four substituents
(R1–R3 and a 3-pyridyl group) to the xanthone scaffold II, while
retaining three phenolic alcohols and one halogen atom. We
speculated that the 1-OH group of II was the least reactive be-
cause of hydrogen-bond formation with a neighbor carbonyl
group, and the 5-OH group of II was less reactive than the 7-
OH group because of steric hindrance. Therefore, we envis-
aged that the substituents R1–R3 could be sequentially intro-
duced in the order indicated in Scheme 1. In our total synthe-
sis of pyripyropene A,[8] introduction of the 3-pyridyl group de-
creased the solubility of the compound against various organic
solvents. Therefore, we planned to introduce the 3-pyridyl
group in the final step. Scaffold II would be constructed
through acylation of IV with acid chloride V and a subsequent
oxidative cyclization of 2,3’,5’,6-hydroxybenzophenone III.
Although the oxidative cyclization of various hydroxy benzo-
phenones has been reported,[10] the cyclization of 2,3’,5’,6-ben-
zophenone has not. We examined oxidative cyclization condi-
tions using readily available model substrate 2,3’,5-trihydroxy
benzophenone (2a) (Table 1). Lewis and co-workers reported
the KMnO4-mediated oxidative cyclization of 2a to afford 3
and 4 in 32 and 5% yields, respectively.[10b] We confirmed that
the Lewis group conditions afforded 3 and 4 in a 41% com-
bined yield (3/4=9:1) (entry 1). A somewhat limited variety of
oxidants such as KMnO4, K3Fe(CN)6, CrO3, and 2,3-dichloro-5,6-
dicyano-p-benzoquinone (DDQ) have been used for oxidative
cyclization. Therefore, we examined the use of silver salts as
oxidants, because these have not been used for oxidative cycli-
zation. An examination of combinations of silver salts (AgF,
AgOAc, and Ag2CO3) and solvents (DMF, MeCN, DMSO)
(Table 1, entries 2–10) revealed that the combinations of AgF
A plausible cyclization mechanism is shown in Scheme 2.
Ag2CO3 induces a single-electron transfer to form the xanthone
skeleton.[11] Stabilization of the generated radical of 5 by the 3-
OH group is critical for cyclization to proceed (Table 1, en-
tries 14–16). A second single-electron transfer and subsequent
aromatization affords 3.
Scheme 2. Plausible mechanism of Ag2CO3-mediated oxidative cyclization.
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Table 1. Oxidative cyclization of hydroxy benzophenone 2.
Entry
2 (x m)
Oxidant
Solvent
T
[8C]
t
[h]
Yield
[%][a]
1
2
3
4
5
6
7
8
9
10
11
12
13[b]
14
15
16
2a (0.2 m)
2a (0.2 m)
2a (0.2 m)
2a (0.2 m)
2a (0.2 m)
2a (0.2 m)
2a (0.2 m)
2a (0.2 m)
2a (0.2 m)
2a (0.2 m)
2a (0.1 m)
2a (0.1 m)
2a (0.1 M)
2b (0.1 m)
2c (0.1 m)
2d (0.1 m)
KMnO4
AgF
AgF
acetone
DMF
MeCN
DMSO
DMF
MeCN
DMSO
DMF
MeCN
DMSO
DMSO
MeCN
MeCN
MeCN
MeCN
MeCN
RT
60
60
2.5
9
9
6
1
1
1
1
1
1
2
2
2
2
2
2
41
43
25
56
19
44
58
34
56
50
67
68
trace
AgF
100
100
100
100
100
100
100
100
100
100
100
100
100
AgOAc
AgOAc
AgOAc
Ag2CO3
Ag2CO3
Ag2CO3
AgOAc
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Scheme 3. Synthesis of cyclization precursor 12. Reagents and conditions:
a) Br2, CHCl3, then Na2SO3, NaOH, H2O; b) MeI, K2CO3, DMF, 2 steps 91%;
c) nBuLi, THF, À788C, 1 h, for 8a; d) AlCl3, CH2Cl2, 08C to RT for 8b; e) BBr3,
CH2Cl2, 98%.
n.d.[c]
n.d.[c]
n.d.[c]
[a] Isolated combined yield of 3 and 4. [b] 2.1 equiv of TEMPO was
added. [c] The desired product was not detected.
Scheme 4. Ag2CO3-mediated oxidative cyclization of 12.
The cyclization precursor 12 was prepared for the synthesis
of 13, as shown in Scheme 3. Our preliminary attempts to
obtain 10b through a Friedel–Crafts acylation of commercially
available 8b and 9 afforded undesired 11 in 44% yield. There-
fore, 8a, which retained bromo- and chloro groups, was pre-
pared from readily available 7 and was used for nucleophilic
acyl substitution against 9. The desired ketone 10a was ob-
tained in 72% yield. All methyl groups were removed by using
BBr3 to afford the desired tetraol 12.
Ag2CO3-mediated oxidative cyclization was examined based
on the optimized conditions (Table 1, entry 12). To our delight,
the desired tetrasubstituted xanthone was obtained in 62%
yield (Scheme 4).
Regioselective modification of alcohol 13 was investigated.
Initially, regioselective benzoylation was examined (Scheme 5).
Treatment of 13 with an equimolar amount of benzoyl chloride
(BzCl) at À788C afforded the desired monoacylated product
14 (70%) with diacylated product 15 (13%). Unexpectedly, X-
ray crystallographic analysis of 14 revealed that benzoylation
had preferentially proceeded at the 5-OH group.[12]
Scheme 5. Regioselective benzoylation of triol 13 and X-ray crystallographic
analysis of monoacylated product 14.
lective introduction of cyclopropane carbonyl, benzoyl, and
acetyl groups to the 7-OH groups of 14, 16, and 17 afforded
the desired products 19 and 21–23 in good to excellent yields,
whereas K2CO3-mediated regioselective methylation at the 7-
OH groups of 14 and 17 in acetone solvent afforded the de-
sired products 20 and 24 in moderate yields because of unde-
sired elimination/migration of the acyl groups at the 5-OH
group. Accordingly, regioselective methylation at the 7-OH
group of 16 afforded a complex mixture. The subsequent
Cs2CO3-mediated methylation at the 1-OH groups of 18, 19,
and 21–23 in DMF solvent afforded the desired products 25–
Structurally diverse 1,5,7-trisubstituted-3-pyridyl-xanthones
were synthesized through chemo- and regioselective, sequen-
tial introduction of substituents to scaffold 13, as shown in
Scheme 6. Regioselective introduction of acetyl and cyclopro-
panecarbonyl groups at the 5-OH group afforded the desired
esters 16 and 17 in 59 and 64% yields, respectively. Treatment
of 13 with 2.0 equiv of cyclopropanecarbonyl chloride afforded
5,7-diacylated product 18 in 65% yield. The following regiose-
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29 in good to excellent yields. Notably, no undesired elimina-
tion/migration of the acyl groups was observed in these meth-
ylation reactions. These results indicated that the generation of
a phenoxide anion at the 7-OH group under basic conditions
caused an undesired elimination/migration of acyl groups. In
fact, the dimethylation of 1,7-dihydroxy compounds 14, 16,
and 17 resulted in low yields because of the undesired migra-
tion of acyl groups. In detail, the dimethylation-Suzuki–Miyaura
coupling sequence of 14 afforded an inseparable 1:1 mixture
of 30 (non-migrated product) and 31 (migrated product). The
same reaction sequences in 16 and 17 afforded the migrated
product 32 and non-migrated product 33 as major products,
respectively, in low yields. We speculated that this undesired
acyl migration proceeded in an intermolecular manner because
a phenoxy anion at the 7-position cannot approach an ester at
the 5-position intramolecularly due to the planarity of the aro-
matic ring (see the Supporting Information for details). The
final step was the Suzuki–Miyaura coupling[13] of 18–29, which
afforded the desired coupling products 34–45. It should be
noted that Suzuki–Miyaura coupling of aryl chlorides 18–24 re-
tained the free 1-OH group with pyridine-3-ylboronic acid in
the existence of Pd(OAc)2, Cy3PHBF4, and K3PO4, which afforded
the desired products. Suzuki–Miyaura coupling of aryl chlorides
25–29, however, retained the 1-OMe group under the same
conditions, but did not afford the desired products. Instead,
base-free conditions using cyclic triolborate[14] 46 were effec-
tive for the Suzuki–Miyaura coupling of 25–29, with the excep-
tion of 26. The coupling of 26 under the base-free conditions
afforded a complex mixture.
The insecticidal activity of synthesized 1,5,7-trisubstituted-3-
pyridyl-xanthones against five types of pest insects was investi-
gated, as shown in Table 2. Compounds 30 and 31 (entry 1),
34 (entries 9 and 10), 36 (entry 13), and 43 (entry 21), pos-
sessed weak to moderate insecticidal activity against Anthono-
mus grandis (boll weevil). None of the synthesized compounds
possessed insecticidal activity against Ceratitis capitata (medi-
terranean fruit fly) or Heliothis virescens (tobacco budworm).
Compounds 32 (entry 3), 39 (entry 16), 42 (entry 19), and 44
(entry 23) showed weak to moderate insecticidal activity
against Megoura viciae (vetch aphid). Compounds 30 and 31
(entry 1) and 32 (entries 3–6) exerted moderate to good insec-
ticidal activity against Myzus persicae (green peach aphid). In
terms of the insecticidal activity against Anthonomus grandis,
all the active compounds had benzoyloxy or cyclopropanecar-
Scheme 6. Sequential chemo- and regio-selective introduction of substituents to scaffold 13. Reagents and conditions: a) BzCl (1.0 equiv), pyridine, THF,
À788C; b) AcCl (1.0 equiv), pyridine, THF, À788C; c) cyclopropanecarbonyl chloride (1.0 equiv), pyridine, THF, À788C; d) cyclopropanecarbonyl chloride
(2.0 equiv), pyridine, THF, À788C; e) cyclopropanecarbonyl chloride (1.0 equiv), pyridine, THF, À788C; f) MeI (20.0 equiv), K2CO3, acetone, reflux; g) MeI
(6.0 equiv), K2CO3, DMF, RT; h) 46, Pd(OAc)2, Cy3PHBF4, 1,4-dioxane, H2O, 1008C; i) BzCl, pyridine, THF, À788C; j) AcCl, pyridine, THF, À788C; k) MeI (30 equiv),
Cs2CO3, DMF, RT; l) pyridine-3-ylboronic acid, Pd(OAc)2, Cy3PHBF4, K3PO4, 1,4-dioxane, H2O, 1008C.
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bonyloxy groups at their 5-position. It seemed that the ester
group at the 5-position was important for the insecticidal ac-
tivity. In terms of the insecticidal activity against Megoura
viciae, almost all active compounds have ester groups at their
5- and 7-positions. In particular, the cyclopropanecarbonyloxy
group at the 5-position seemed to be important for insecticidal
activity. In terms of the insecticidal activity against Myzus persi-
cae, all the active compounds have two methyl groups at their
1-, and 5- or 7-position. In particular, the methoxy group at the
5-position seemed to be important for the insecticidal activity.
Notably, compound 32 retained insecticidal activity against Me-
goura viciae and Myzus persicae. This insecticidal spectrum was
similar to that of pyripyropene A (1). Thus, we started with pyr-
ipyropene A and successfully created a template that is readily
accessible and useful for agrichemical development. The ob-
served insecticidal activity of 32 was lower than that of 1. The
biggest structural difference between 32 and 1 is the A-ring
moiety that contains two acetates. Therefore, synthesis of ana-
logues based on 32, with various substituents at the 7-OH
group, may lead to an improved level of insecticidal activity.
Conclusion
We designed a readily accessible template of 1,5,7-trisubstitut-
ed-3-pyridyl-xanthones for agrichemical development starting
from pyripyropene A (1). Our originally developed Ag2CO3-
mediated oxidative cyclization enabled rapid access to the key
xanthone scaffold 13. The chemo- and regioselective, sequen-
tial introduction of four substituents to scaffold 13 rapidly af-
forded the desired structurally diverse 1,5,7-trisubstituted-3-
pyridyl-xanthones. An evaluation of insecticidal activity re-
vealed that compound 32 retained weak to good insecticidal
activity against Megoura viciae and Myzus persicae. The ob-
served insecticidal spectrum of 32 was similar to that of 1. The
developed template could be a valuable aid for future agri-
chemical development.
Experimental Section
Experimental details are given in the Supporting Information.
These include details of the synthetic procedures, spectroscopic
data, copies of the H and 13C NMR spectra, and biological assays.
1
Acknowledgements
The authors thank Dr. Juergen Langewald and Mr. Felix
Schneider, BASF SE, Limburgerhof, for carrying out the insecti-
cidal activity assay.
Table 2. Evaluation of insecticidal activity of 1,5,7-trisubstituted-3-pyridyl-
xanthones against pest insects.
Mortality rate [%]
Entry Comp. Dose [ppm] ANT[a] CER[b] HEL[c] MEG[d] MYZ[e]
Keywords: cyclization
regioselectivity · terpenoids
· drug discovery · insecticides ·
1
2
3
4
5
6
7
8
30, 31 2500
25
–
0
–
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–
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–
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0
0
–
0
–
0
0
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–
–
0
–
0
–
–
–
–
0
0
–
–
0
0
–
0
0
0
0
0
–
0
–
0
0
0
–
–
0
–
25
–
–
–
–
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–
–
0
0
–
0
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0
50
0
100
0
1415
32
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100
100
100
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0
0
0
–
–
0
0
–
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0
0
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0
¯
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1415
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¯
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10
[a] Anthonomus grandis boll weevil. [b] CERTCA Ceratitis capitata mediter-
ranean fruit fly. [c] HELIVI Heliothis virescens tobacco budworm.
[d] MEGHVI Megoura viciae vetch aphid. [e] MYZUPE Myzus persicae green
peach aphid. [f] We previously reported ED50 (The concentration corre-
sponding to 50% mortality) of pyripyropene A against MYZUPE (8 ppm).[8]
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[10] K3FeCN6-mediated oxidative cyclizations of 1,2’,3,5-, 1,2’,3,3’,5-, and
1,1’,3,4’-hydroxyxanthone were reported. See: a) R. C. Ellis, W. B. Whalley,
K. Ball, Chem. Commun. 1967, 803–804; b) J. E. Atkinson, J. R. Lewis, J.
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[11] A radical aromatic substitution mechanism is proposed in Fe3CN6-medi-
ated xanthone formation. See: a) M. Fetizon, V. Balogh, M. Golfier, J.
Org. Chem. 1971, 36, 1339–1341; Ag2CO3-mediated generation of phen-
oxy radical was proposed. See: b) P. D. McDonald, G. A. Hamilton, J. Am.
Chem. Soc. 1973, 95, 7752–7758.
[12] CCDC 1489730 contains the supplementary crystallographic data for
this paper. These data are provided free of charge by The Cambridge
Crystallographic Data Centre.
[13] a) N. Miyaura, A. Suzuki, J. Chem. Soc. Chem. Commun. 1979, 866–867;
b) N. Miyaura, K. Yamada, A. Suzuki, Tetrahedron Lett. 1979, 20, 3437–
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[14] Y. Yamamoto, M. Takizawa, X.-Q. Yu, N. Miyaura, Angew. Chem. Int. Ed.
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Received: August 22, 2016
Published online on && &&, 0000
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Insecticides
S. Fuse,* K. Matsumura, K. Johmoto,
H. Uekusa, H. Tanaka, T. Hirose,
¯
T. Sunazuka, S. Omura, T. Takahashi
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The Design, Synthesis, and Evaluation
of 1,5,7-Trisubstituted-3-Pyridyl-
Xanthones for Use as Insecticides
Starting from Pyripyropene A
Beating the pest: A readily accessible
template of 1,5,7-trisubstituted-3-pyrid-
yl-xanthones was designed starting
from pyripyropene A for use in agri-
chemical development (see scheme).
Ag2CO3-mediated oxidative cyclization
enabled ready access to the key xan-
thone scaffold. The chemo- and regiose-
lective sequential introduction of sub-
stituents to the scaffold rapidly afforded
structurally diverse substituted xan-
thones. One synthesized compound re-
tained an insecticidal spectrum similar
to that of pyripyropene A.
Chem. Eur. J. 2016, 22, 1 – 7
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