Synthesis of quinolactacide via an acyl migration reaction and dehydrogenation with manganese dioxide, and its insecticidal activities

Article abstract of DOI:10.1271/bbb.70.303

Quinolactacide isolated from Penicillium citrinum F 1539 was synthesized and evaluated for its insecticidal activities. The key steps of the total synthesis were an acyl migration reaction of the enol ester intermediate and dehydrogenation of tetrahydroqu

Full text of DOI:10.1271/bbb.70.303

Biosci. Biotechnol. Biochem., 70 (1), 303–306, 2006
Note
Synthesis of Quinolactacide via an Acyl Migration Reaction and
Dehydrogenation with Manganese Dioxide, and Its Insecticidal Activities
Masaki ABE,y Tetsuya IMAI, Naoki ISHII, and Makio USUI
Naruto Research Center, Otsuka Chemical Co., Ltd., 615 Hanamen, Satoura-cho,
Naruto, Tokushima 772-8601, Japan
Received September 8, 2005; Accepted October 6, 2005
Quinolactacide isolated from Penicillium citrinum F
1539 was synthesized and evaluated for its insecticidal
activities. The key steps of the total synthesis were an
acyl migration reaction of the enol ester intermediate
and dehydrogenation of tetrahydroquinolactacide with
manganese dioxide. The synthesized quinolactacide
showed 100% and 42% mortality against the green
peach aphid (Myzus persicae) and diamondback moth
(Plutella xylostella) at 500 ppm, respectively.
tive syntheses of quinolactacins A and B have also been
reported,6,7) but there was no description on their
insecticidal activity in the reports.
We report here the first total synthesis of quinolacta-
cide (1) and its insecticidal activities.
The synthetic route used for quinolactacide (1) is
shown in Scheme 1. Proline ethyl ester 8 was prepared
by esterification of L-proline (7) in ethanol with thionyl
chloride. The amino group of 8 was acetylated with
acetyl chloride and pyridine in tetrahydrofuran (THF) to
give 9. The cyclopenta-1,3-dione ring was successfully
constructed by Dieckmann-type cyclization to give 10
in a 59% yield.8) Esterification of 1,3-dione 10 with
triethylamine (TEA) and 2-nitrobenzoyl chloride afford-
ed enol ester 11.9) Acyl migration of 11 catalyzed with
acetone cyanohydrin proceeded quantitatively to give
trione 12.9) Hydrogenation of the nitro group of trione 12
resulted in spontaneous cyclization to give tetrahydro-
quinolactacide 13 in a 52% yield. Compound 13 showed
poor solubility in almost all organic solvents, including
dimethyl sulfoxide (DMSO), so 13 was suspended in a
mixture of chloroform and N,N-dimethylformamide
(DMF) and dehydrogenated with manganese dioxide
(MnO2) to give quinolactacide (1) in a 21% yield.10)
Starting compound 13 was not found in the reaction
mixture. In an attempt to improve the yield of the
dehydrogenation reaction, the reaction was conducted
Key words: quinolactacide; insecticidal activity; acyl
migration reaction; dehydrogenation
In our previous study,1) we have reported the isolation
of a new insecticidal quinolone, quinolactacide (1), from
Penicillium citrinum Thom F 1539 and determined its
chemical structure (Fig. 1). Quinolactacide (1) showed
88% mortality against the green peach aphid (Myzus
persicae) at 250 ppm. However, we could not conduct
further biological tests due to the limited amount of the
isolated compound. We therefore started a synthetic
study on quinolactacide (1) to obtain a sufficient amount
of the compound.
Quinolactacide (1) is structurally related to quinolac-
tacins (2–6) isolated from Penicillium sp., which are
known to show some biological activities.2–5) The
synthesis of racemic quinolactacin B and enantioselec-
O
O
O
O
8
7
9
6
8a
4a
9a
1
6a
5a
5
7
6
8
9
N 4
2
NH
3
2
11
3a
3
10a
11a
N
R2
N
H
11b
5
4
10
R1
1'
1
2'
Quinolactacide (1)
Quinolactacin A (2) : R = CH , R = H
1
3
2
Quinolactacin B (3) : R = R = H
1
2
Quinolactacin C (4) : R = CH , R = OH
1
3
2
Quinolactacin A1 (5) : (3S*, 1'R*)-2
Quinolactacin A2 (6) : (3S*, 1'S*)-2
Fig. 1. Structures of Quinolactacide (1) and Related Compounds, Quinolactacins (2–6).
y
To whom correspondence should be addressed. Fax: +81-88-685-6040; E-mail: mabe@otsukac.co.jp
Abbreviations: THF, tetrahydrofuran; TEA, triethylamine; DMSO, dimethyl sulfoxide; DMF, N,N-dimethylformamide; MnO2, manganese dioxide;
DDQ, 2,3-dichloro-5,6-dicyano-1,4-benzoquinone; mp, melting point; TMS, tetramethylsilane; EtOAc, ethyl acetate

304
M. ABE et al.
a
c
b
d
CO2H
O
N
CO2Et
CO2Et
N
N
N
H
H
O
O
L-Proline (7)
8
10
9
O
O
O
H
O
O
O
g
e
N
O
f
O
N
N
N
NO2
0.7Hz
H
N
H
O
N
O
H
NO2
11
12
13
Quinolactacide (1)
Scheme 1. Synthetic Scheme for Quinolactacide (1).
Reagents and conditions: (a) SOCl2, ethanol, reflux (quant.); (b) acetyl chloride, pyridine, THF (90%); (c) potassium tert-butoxide, THF–
toluene, reflux (59%); (d) 2-nitrobenzoyl chloride, TEA, THF (80%); (e) acetone cyanohydrin, TEA, acetonitrile (quant.); (f) H2, Pd–C,
methanol (52%); (g) MnO2, CHCl3–DMF (3:1), reflux (21%).
with MnO2 in a mixture of chloroform and methanol,
because of the good solubility of compound 13 in the
mixed solvent, and also carried out with 2,3-dichloro-
5,6-dicyano-1,4-benzoquinone (DDQ) in the same
mixed solvent, but both reactions did not proceed well.
Although the yield of the dehydrogenation reaction was
not improved, sufficient quinolactacide (1) was obtained
for further biological tests. The physico-chemical prop-
erties of synthetic 1 were identical with those of the
natural compound.
The insecticidal and the miticidal activities of
quinolactacide (1) against five different insects and
one mite were evaluated at 500 ppm. The insects used
for the tests were the green peach aphid,1) diamondback
moth (Plutella xylostella), common cutworm (Spodop-
tera litura), western flower thrips (Frankliniella occi-
dentalis), silverleaf whitefly (Bemisia argentifolii), and
two-spotted spider mite (Tetranychus urticae). Synthetic
quinolactacide (1) showed 100% and 42% mortality
against the green peach aphid and diamondback moth,
respectively, but did not show any activity against the
others.
against the green peach aphid was conducted in the same
manner as that described in our previous report,1) and
against the silverleaf whitefly was conducted in almost
the same manner as that against the aphid. In the test,
first instar larvae of the silverleaf whitefly were treated
with formulated quinolactacide (1), and the mortality
was assessed after 6 d. The insecticidal test against the
common cutworm was conducted in almost the same
manner as that against the diamondback moth, second
instar larvae of the common cutworm being used for the
test. The insecticidal test against the western flower
thrips was conducted in almost the same manner as that
against the two-spotted spider mite, fifteen first instar
larvae of the western flower thrips being used for
the test.
Ethyl pyrrolidine-2-carboxylate (8). To a solution of 7
(10.0 g, 87.0 mmol) in dry ethanol (200 ml) was added
dropwise thionyl chloride (20.7 g, 174 mmol) at 60 ꢀC.
The mixture was refluxed for 4 h and then stirred for 12 h
at 20 ꢀC. The reaction mixture was concentrated under
reduced pressure, neutralized with 4 N NaOH (22 ml) at
0 ꢀC and then successively extracted with ethyl acetate
(EtOAc) and chloroform. Each organic layer was
washed with brine and dried over anhydrous MgSO4.
The combined organic layers were concentrated to
afford 8 (12.5 g, quant.) as a pale yellow oil. The crude
product thus obtained was used for the next step without
further purification. 1H-NMR (CDCl3, TMS) ꢀ: 1.28
(3H, t, J ¼ 7:1 Hz), 1.70–1.90 (3H, m), 2.05–2.15 (1H,
m), 2.90 (1H, dt, J ¼ 10:3, 6.5 Hz), 3.08 (1H, dt,
J ¼ 10:3, 6.5 Hz), 3.74 (1H, dd, J ¼ 8:5, 5.5 Hz), 4.18
(2H, q, J ¼ 7:1 Hz); NH was not detected.
Our future study will be focused on the structure-
activity relationships between quinolactacide (1) and its
related compounds, and their insecticidal activity.
Experimental
General. The following instruments were used in the
experiments: a Bruker DPX 300 FT NMR (300 MHz)
1
spectrometer for the H-, 13C-NMR, and DEPT spectra,
a Jeol The MStation JMS-700 mass spectrometer for the
mass spectra, a Shimadzu FTIR-8100A IR spectrometer
for the IR spectra, a Shimadzu UV-160 UV–VIS
recording spectrophotometer for the UV spectra, and
Ethyl 1-acetylpyrrolidine-2-carboxylate (9). To a
mixture of compound 8 (8.00 g, 55.9 mmol) and pyridine
(5.30 g, 67.1 mmol) in THF (150 ml) was added drop-
wise acetyl chloride (5.27 g, 67.1 mmol) dissolved in
THF (10 ml) at 0 ꢀC. The mixture was stirred for 1 h at
0 ꢀC and then for 2 h at 20 ꢀC. The reaction mixture was
poured into 1 N HCl (20 ml) at 0 ꢀC and extracted with
EtOAc. The EtOAc extract was successively washed
with sat. NaHCO3 and brine, dried over anhydrous
Buchi B-545 melting point apparatus for measuring the
¨
melting point (mp). The NMR spectra were measured by
using CDCl3 containing 0.03% tetramethylsilane (TMS)
or DMSO-d6 as a solvent. Kanto Chemical 60N silica
gel (spherical, neutral, 100–200 mm) was used for
column chromatography. The optical purity of inter-
mediates 8–13 was not measured. The insecticidal test

Synthesis and Insecticidal Activities of Quinolactacide
305
MgSO4, and concentrated to afford 9 (9.32 g, 90%) as a
pale yellow oil. The crude product was used for the next
8.4, 3.2 Hz), 3.57 (1H, dt, J ¼ 11:2, 8.2 Hz), 4.37 (1H,
dd, J ¼ 9:6, 5.9 Hz), 6.07 (1H, d, J ¼ 0:7 Hz), 7.70–7.82
(2H, m), 7.82–7.90 (1H, m), 7.95–8.05 (1H, m). HR-
EIMS m=z (Mþ): calcd. for C14H12O5N2, 288.0746;
found, 288.0731.
step without further purification. IR (film) ꢁmax cmꢁ1
:
1740 (s), 1650 (s), 1420 (s), 1375 (m), 1360 (m), 1280
(m), 1240 (m), 1190 (s), 1090 (m), 1030 (m), 1000 (w),
1
920 (w), 620 (w), 540 (w). H-NMR (CDCl3, TMS) ꢀ:
1-Aza-3-(2-nitrobenzoyl)bicyclo[3,3,0]octane-2,4-di-
one (12). To a mixture of compound 11 (800 mg, 2.78
mmol) and TEA (562 mg, 5.56 mmol) in dry acetonitrile
(15 ml) was added acetone cyanohydrin (118 mg, 1.39
mmol) at 0 ꢀC. After stirring for 2 h at 20 ꢀC, the reaction
mixture was concentrated under reduced pressure. The
residue was dissolved in ether and extracted with 1 N
NaOH. The 1 N NaOH extract was acidified with 4 N HCl
to pH 3 and extracted with EtOAc. The EtOAc extract
was washed with brine, dried over anhydrous MgSO4,
and concentrated to afford 12 (800 mg, quant.) as a
brown oil. IR (film) ꢁmax cmꢁ1: 3700–2200 (br. m), 1700
(br. s), 1630 (br. s), 1530 (s), 1450 (m), 1350 (s), 1310
(m), 1240 (m), 1190 (m), 1140 (w), 1110 (w), 1070 (w),
940 (w), 860 (m), 780 (m), 760 (m), 720 (w), 700 (w).
1H-NMR (DMSO-d6) ꢀ: 1.30–1.45 (1H, m), 1.90–2.15
(3H, m), 2.91–3.01 (1H, m), 3.34 (1H, dt, J ¼ 10:9,
7.8 Hz), 4.09 (1H, dd, J ¼ 8:9, 7.2 Hz), 7.43 (1H, d,
J ¼ 7:2 Hz), 7.67 (1H, pseudo t, J ¼ 7:7, 7.2 Hz), 7.79
(1H, pseudo t, J ¼ 7:7, 7.0 Hz), 8.10 (1H, d, J ¼ 8:0
Hz); an enol proton was not detected. 13C-NMR
(DMSO-d6) ꢀ: 27.23 (CH2), 27.72 (CH2), 43.25 (CH2),
64.42 (CH), 103.91 (C), 123.54 (CH), 129.15 (CH),
130.57 (CH), 134.38 (CH), 135.67 (C), 146.49 (C),
173.68 (C), 184.69 (C), 188.14 (C). HR-EIMS m=z
(Mþ): calcd. for C14H12O5N2, 288.0746; found,
288.0736.
1.23–1.31 (3H, m), 1.85–2.40 (4H, m), 3.45–3.55 (1H,
m), 3.61–3.75 (1H, m), 4.10–4.24 (2H, m), 3.38 (0.3H,
dd, J ¼ 8:5, 3.5 Hz), 4.47 (0.7H, dd, J ¼ 8:5, 3.5 Hz).
HR-EIMS m=z (Mþ): calcd. for C9H15O3N, 185.1052;
found, 185.1054.
1-Azabicyclo[3,3,0]octane-2,4-dione (10). To a sus-
pension of potassium tert-butoxide (1.36 g, 12.2 mmol)
in a mixture of THF (10 ml) and dry toluene (10 ml) was
added dropwise compound 9 (1.50 g, 8.11 mmol) dis-
solved in THF (10 ml) at 80 ꢀC. The mixture was
refluxed for 12 h. After cooling, the reaction mixture was
successively extracted with water and 1 N NaOH. The
combined water layers were acidified with 4 N HCl to
pH 3 and successively extracted with EtOAc and
chloroform. The each organic layer was washed with
brine and dried over anhydrous MgSO4. The combined
organic layers were concentrated to afford 10 (670 mg,
59%) as a brown oil. The crude product was used for
the next step without further purification. IR (film)
ꢁ
max cmꢁ1: 3430 (br. m), 2700 (br. m), 2600 (br. m),
1770 (s), 1690 (br. s), 1610 (br. s), 1420 (br. s), 1375
(br. s), 1320 (br. s), 1260 (m), 1230 (br. m), 1075 (w),
1
820 (w), 630 (w), 590 (w), 560 (w). H-NMR (CDCl3,
TMS) ꢀ: 1.65–1.75 (1H, m), 1.97–2.22 (3H, m), 3.02
(1H, dd, J ¼ 21:4, 1.2 Hz), 3.15–3.25 (1H, m), 3.37 (1H,
d, J ¼ 21:4 Hz), 3.95 (1H, dt, J ¼ 11:8, 7.5 Hz), 4.20
(1H, pseudo t, J ¼ 8:5, 7.9 Hz). HR-EIMS m=z (Mþ):
calcd. for C7H9O2N, 139.0633; found, 139.0638.
1,2,3,11b-Tetrahydroquinolactacide (13). A solution
of 12 (300 mg, 1.04 mmol) in methanol (15 ml) was
vigorously stirred over Pd/C 10% (20 mg) under hydro-
gen at atmospheric pressure for 3 d at 20 ꢀC. The
reaction mixture was filtered and successively washed
with methanol and chloroform. The combined filtrates
were concentrated under reduced pressure. The crude
solid thus obtained was washed with a mixture of
methanol and EtOAc and dried in vacuo to give 13
(130 mg, 52%) as a pale brown solid, mp 393–398 ꢀC
(dec.). IR (KBr) ꢁmax cmꢁ1: 3700–2400 (br. w), 1690 (s),
1630 (s), 1620 (s), 1590 (s), 1540 (s), 1470 (s), 1420 (w),
1370 (m), 1340 (w), 1300 (m), 1280 (w), 1220 (m), 1170
(w), 1140 (w), 1090 (w), 1030 (w), 980 (w), 960 (w),
880 (w), 870 (w), 800 (w), 780 (m), 770 (m), 750 (m),
4-(1-Azabicyclo[3,3,0]oct-3-ene-2-one) 2-nitrobenzo-
ate (11). To a mixture of compound 10 (3.00 g, 21.6
mmol) and TEA (2.39 g, 23.7 mmol) in THF (50 ml) was
added dropwise 2-nitrobenzoyl chloride (4.40 g, 23.7
mmol) dissolved in THF (30 ml) at 0 ꢀC. The mixture
was stirred for 1 h at 0 ꢀC and then for 2 h at 20 ꢀC. The
reaction mixture was poured into 1 N HCl at 0 ꢀC and
extracted with EtOAc. The organic layer was succes-
sively washed with sat. NaHCO3 and brine, dried over
anhydrous MgSO4, and concentrated to give a crude
brown solid. This solid was washed with ether and dried
in vacuo to afford 11 (4.96 g, 80%) as a pale brown
solid. The crude product was used for the next step
without further purification. To measure mp of 11, the
pure compound was prepared as a pale yellow powder
by recrystallizing from a mixture of hexane and ether,
1
730 (m), 680 (m), 660 (m), 530 (m). H-NMR (DMSO-
d6) ꢀ: 1.38–1.56 (1H, m), 2.05–2.33 (3H, m), 3.05–3.18
(1H, m), 3.44 (1H, dt, J ¼ 10:9, 8.2 Hz), 4.67 (1H, dd,
J ¼ 9:5, 6.5 Hz), 7.39 (1H, t, J ¼ 7:5 Hz), 7.56 (1H, d,
J ¼ 8:0 Hz), 7.71 (1H, dt, J ¼ 8:0, 1.3 Hz), 8.15 (1H, d,
J ¼ 8:0 Hz), 12.72 (1H, br. s). HR-EIMS m=z (Mþ):
calcd. for C14H12O2N2, 240.0899; found, 240.0915.
Quinolactacide (1). A mixture of 13 (20 mg, 0.083
mmol) and MnO2 (145 mg, 1.67 mmol) in a mixture of
DMF (10 ml) and chloroform (30 ml) was refluxed. After
12 h, to the mixture was added a further 145 mg of
mp (hexane–ether) 132–133 ꢀC. IR (KBr) ꢁmax cmꢁ1
:
3150 (w), 3090 (w), 3040 (w), 1770 (s), 1690 (s), 1610
(m), 1575 (w), 1530 (s), 1440 (w), 1375 (m), 1350 (s),
1330 (m), 1310 (m), 1276 (m), 1275 (m), 1240 (s), 1170
(s), 1090 (m), 1050 (s), 1040 (m), 1020 (m), 900 (w),
870 (m), 850 (m), 790 (m), 770 (w), 740 (m), 730 (m),
690 (w), 670 (m). 1H-NMR (CDCl3, TMS) ꢀ: 1.40–1.60
(1H, m), 2.10–2.40 (3H, m), 3.25 (1H, ddd, J ¼ 11:2,

306
M. ABE et al.
MnO2, and then the mixture was refluxed for 12 h more.
The reaction mixture was cooled to room temperature
and chromatographed in a silica gel column by eluting
with chloroform–methanol (30:1!15:1). The fraction
containing quinolactacide (1) was concentrated under
reduced pressure. The residue was dissolved in EtOAc,
washed with water to remove residual DMF, dried over
anhydrous MgSO4, and concentrated to give 1 as a
yellow solid. Quinolactacide (1) was further washed
with water to remove residual DMF, and dried in vacuo
to give pure 1 (4.1 mg, 21%) as a yellow powder. To
measure mp of 1, the pure compound was prepared as a
yellow powder by recrystallizing from a mixture of
chloroform and methanol, mp (chloroform–methanol)
372–373 ꢀC (dec.). IR (KBr) ꢁmax cmꢁ1: 3440 (br. w,
NH), 1740 (s, N–C=O), 1645 (s, C=O), 1620 (m), 1580
(s), 1540 (m), 1525 (m), 1475 (m), 1395 (w), 1220 (w),
1050 (w), 770 (m). UV ꢂmax (CHCl3:CH3OH ¼ 1:1,
leaf and air-dried. The leaf was left to stand in the
thermostatic chamber (25 ꢃ 2 ꢀC, 16L, 8D). After 2 d,
the mortality from the formulation of the sample against
the two-spotted spider mite was assessed by comparing
it with that without the sample.
Acknowledgment
We express our sincere gratitude to Mr. K. Kiryu
(of Otsuka Pharmaceutical Factory, Inc.) for measuring
the MS data.
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1
26 ꢀC) nm ("): 242.4 (12100), 288.1 (33900). H-NMR
(DMSO-d6) ꢀ: 6.37 (1H, t, J ¼ 3:1 Hz), 6.72 (1H, d,
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(100 ppm) of Sorpol 355 (Toho Chemical Industry,
Tokyo, Japan) to a methanol solution containing a
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from a bean plant at the primary leaf stage was placed on
a piece of non-woven fabric containing sufficient water.
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were settled on the leaf and then placed in a thermostatic
chamber (25 ꢃ 2 ꢀC, 16L, 8D). After 4 d, an insecticidal
formulation (500 ppm) was prepared by adding an
aqueous solution (100 ppm) of Sorpol 355 (Toho
Chemical Industry, Tokyo, Japan) to a methanol solution
containing a 1.25% DMSO solution of quinolactacide
(1), and 4.0 ml of the formulation was sprayed over the
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