Synthesis and stereostructure-activity relationship of three asymmetric center pyrethroids: 2-Methyl-3-phenylcyclopropylmethyl 3-phenoxybenzyl ether and cyanohydrin ester

Article abstract of DOI:10.1016/S0968-0896(00)00217-0

2-Methyl-3-phenylcyclopropylmethyl 3-phenoxybenzyl ether 2 and cyanohydrin ester 3, a couple of pyrethroids with three asymmetric centers, were synthesized. Of each of the four diastereomers of 2 and 3, only the (1R*,2R*,3R*)-2a and 3a showed significant insecticidal activities. Dual sets of enantiomers [(1R,2R,3R)-(-)-2a and (1S,2S,3S)-(+)-2a] and [(1R,2R,3R)-(-)-3a and (1S,2S,3S)-(+)-3a] were synthesized through the asymmetric cyclopropanation using the Aratani catalyst. Significant separations of insecticidal activities were observed between both the enantiomers against the tobacco cutworm (Spodoptera litura) and the common mosquito (Culex pipiens pallens); (1S,2S,3S)-(+)-2a and (+)-3a showed higher activities than their antipodes (1R,2R,3R)-(-)-2a and (-)-3a. This result is the second example of such synthetic pyrethroids with three asymmetric centers.

Full text of DOI:10.1016/S0968-0896(00)00217-0

Bioorganic & Medicinal Chemistry 9 (2001) 33±39
Synthesis and Stereostructure±Activity Relationship of Three
Asymmetric Center Pyrethroids: 2-Methyl-3-phenylcyclopropyl-
methyl 3-Phenoxybenzyl Ether and Cyanohydrin Ester
Yoshinori Nishii,a Nobuo Maruyama,b Kazunori Wakasugib and Yoo Tanabeb,*
aThe Physical Chemical Research Institute (RIKEN), 2-1 Hirosawa, Wako, Saitama 351±0198, Japan
bSchool of Science, Kwansei Gakuin University, 1-1-155 Uegahara, Nishinomiya, Hyogo 662±8501, Japan
Received 25 May 2000; accepted 29 July 2000
AbstractÐ2-Methyl-3-phenylcyclopropylmethyl 3-phenoxybenzyl ether 2 and cyanohydrin ester 3, a couple of pyrethroids with
three asymmetric centers, were synthesized. Of each of the four diastereomers of 2 and 3, only the (1R*,2R*,3R*)-2a and 3a showed
signi®cant insecticidal activities. Dual sets of enantiomers [(1R,2R,3R)-( )-2a and (1S,2S,3S)-(+)-2a] and [(1R,2R,3R)-( )-3a and
(1S,2S,3S)-(+)-3a] were synthesized through the asymmetric cyclopropanation using the Aratani catalyst. Signi®cant separations
of insecticidal activities were observed between both the enantiomers against the tobacco cutworm (Spodoptera litura) and the
common mosquito (Culex pipiens pallens); (1S,2S,3S)-(+)-2a and (+)-3a showed higher activities than their antipodes (1R,2R,3R)-
( )-2a and ( )-3a. This result is the second example of such synthetic pyrethroids with three asymmetric centers. # 2000 Elsevier
Science Ltd. All rights reserved.
Introduction
This background and information prompt us to further
investigate the pyrethroid derivative of type-[e] 1 with
three asymmetric centers. In close connection with our
continuing interest in the utilization of gem-dihalo- and
halocyclopropanes,8 we report here syntheses and ste-
reostructure±activity relationships of a new isoster of
cyclopropane pyrethroids with three asymmetric centers:
3-methyl-2-phenylcyclopropylmethyl 3-phenoxybenzyl
ether 2 and cyano(3-phenoxyphenyl)methyl 3-methyl-2-
phenylcyclopropanecarboxylate 3.
Extensive research on the stereostructure±activity rela-
tionship of synthetic pyrethroid insecticides has pro-
gressed in the past few decades.1 Considerable attention
has been focused on the di€erences in insecticidal activ-
ities between their comparable diastereoisomers and
enantioisomers, due to both the academic interest and
recent environmental requirements for the pesticides.
Apparent chiral discrimination for insecticidal activities
is observed in several cyclopropanecarboxylic acid series
and related isosters (parentheses indicate the absolute
con®guration of the active form): [a] chrysanthemic acid
and the dihalovinyl analogues1 (1R, 3R or 3S); [b] fen-
cyclate2 (S); [c] the ring-opening analogues, fenvalerate,3
¯uvalinate,4 and ¯ucythrinate5 (S); [d] their CF3 analo-
gue6 (R); and [e] the 2-chloro-1-methyl-3-phenylcyclo-
propane-type 17 (1R,2S,3S).
Results and Discussion
Synthesis of all four racemic diastereomers of 2-methyl-
3-phenylcyclopropane ether-type pyrethroids (2a±d)
Cu catalyzed cyclopropanation of ethyl diazoethylace-
tate with E-1-phenyl-1-propene (trans-b-methylstylene)
*Corresponding author. Tel.: +81-798-54-6396; fax: +81-798-51-0914;
e-mail: tanabe@kwansei.ac.jp
0968-0896/01/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved.
PII: S0968-0896(00)00217-0

34
Y. Nishii et al. / Bioorg. Med. Chem. 9 (2001) 33±39
Scheme 1.
gave ethyl (1R*,2R*,3R*)-2-methyl-3-phenylcyclopro-
pane carboxylate 4a (44%) and the (1R*,2S*,3S*)-dia-
stereomer 4b (25%). Similarly, the reaction using Z-1-
phenyl-1-propene (cis-b-methylstylene) gave the dia-
stereomeric compounds (1R*,2S*,3R*)-4c (28%) and
(1R*,2R*,3S*)-4d (10%). The LAH reduction of 4a±d
gave the corresponding 2-methyl-3-phenylcyclopropyl-
methanols 5a±d, respectively. The independent couplings
of 5a±d with 3-phenoxybenzyl bromide furnished the
desired four ether compounds (1R*,2R*,3R*)-2a, (1R*,
2S*,3S*)-2b, (1R*,2S*,3R*)-2c, and (1R*,2R*,3S*)-2d.
Scheme 1 illustrates these transformations.
Results of the bioassay revealed that only (1R*,2R*,
3R*)-2a racemic diastereomer showed signi®cant insec-
ticidal activities against the tobacco cutworm and the
common mosquito (vide infra).
Synthesis of all four racemic diastereomers of 2-methyl-
3-phenylcyclopropane cyanohydrin-type pyrethroids (3a±d)
Ethyl esters 4a±d were hydrolyzed with KOH/MeOH-H2O
to give the corresponding carboxylic acids 6a±d, respec-
tively. The independent couplings of the acids 6a±d with
bromo(3-phenoxyphenyl)acetonitrile gave the desired
cyanohydrin esters (1R*,2R*,3R*)-3a, (1R*,2S*,3S*)-
3b, (1R*,2S*,3R*)-3c, and (1R*,2R*,3S*)-3d. Scheme 2
illustrates these transformations.
The results of bioassay revealed that only one racemic
diastereomer (1R*,2R*,3R*)-3a showed signi®cant insec-
ticidal activity against the tobacco cutworm (vide infra).
Synthesis of a couple of optically active enantiomers of
the most insecticidally active racemic diastereomers
(1R*,2R*,3R*)-2a and -3a
For this purpose, we applied asymmetric cyclopropana-
tion utilizing the Aratani catalyst.9 As depicted in
Scheme 3, the reaction of ethyl diazoacetate with trans-
b-methylstylene by the action of the S-type catalyst
mainly yielded (1R,2R,3R)-( )-4a (20%; [a]2D5 105.3)
and (1R,2S,3S)-( )-4b (8%; [a]2D5 10.2). Following the
similar manner using the antipodal R-type catalyst pro-
duced (1S,2S,3S)-(+)-4a (17%; [a]2D5 +103.2) and (1S,
2R,3R)-(+)-4b (7%; [a]2D5 +10.3). Ethyl esters ( )-4a
and (+)-4a were hydrolyzed to give carboxylic acids
(1R,2R,3R)-( )-6b ([a]D25 125.9) and (1S,2S,3S)-(+)-
6a ([a]2D4 +124.3). The optical purities of these acids
( )-6a and (+)-6b were enriched by a further resolution
Scheme 2.

Y. Nishii et al. / Bioorg. Med. Chem. 9 (2001) 33±39
35
Scheme 3.
using optically active 1-(1-naphthyl)ethanamine (abbre-
viated NEA): use of R-(+)-NEA gave a purer sample of
( )-6a ([a]2D4 220.4) and use of S-( )-NEA gave that of
(+)-6a ([a]2D4 +206.5).
diastereomer of 2-chloro-1-methyl-3-phenylcyclopro-
pane-type (1R*,2S*,3S*)-1. Moreover, the absolute
con®gurations of both 1- and 3-positions in (1S,2S,3S)-
(+)-2a and -3a were reverse against the active (1R,
2S,3S)-1 (cf. the reverse con®guration of the C-3 position
in 2 and 3 is indicated due to the sequence rule). This is
the second example of the separation of activities of
cyclopropane-type pyrethroids having three asymmetric
centers in the cyclopropane ring. The stereochemistry of
(1S,2S,3S)-2a and -3a would be superimposable to that
of chrysanthemates and their dihalovinyl analogues1
(1R,3R or 3S) (cf. also here, the reverse con®gurations
of C-1 and C-3 positions are indicated). Cyanohydrin
(+)-3a showed somewhat higher activities against both
insects than ether (+)-2a. These results indicate the
subtle nature of the relationship between insecticidal
activity and geometry around the asymmetric center of
these pyrethroids.
The absolute con®guration of these enantiomers was
determined by applying Aratani's proposed mechanism
according to the result of styrene.9 The enriched sam-
ples of ( )-4a and (+)-4a were reduced by LAH to give
alcohols (1R,2R,3R)-( )-5d (92% ee by HPLC analysis)
and (1S,2S,3S)-(+)-5c (86% ee by HPLC analysis), which
were converted into the desired ethers (1R,2R,3R)-( )-2a
and (1S,2S,3S)-(+)-2a, respectively. Cyanohydrin esters
(1R,2R,3R)-( )-3a and (1S,2S,3S)-(+)-3a were also
synthesized from ( )-4a and (+)-4a with bromo(3-
phenoxyphenyl)acetonitrile, respectively.
Stereostructure±activity relationship of dual sets of four
racemic diastereomers, 2a±d and 3a±d, and dual sets of
(+)- and ( )-2a, (+)- and ( )- 3a
Taking these results into consideration, we interpret that
2a and 3a would resemble the chrysanthemate series
whose cyanohydrins showed potent activities, rather
than ether-type 1. This study would shed some light on
the question of which prochiral methyl group of chry-
santhemate analogues orients itself to the receptor site
in three dimensions.10
The insecticidal activity against the tobacco cutworm
(Spodoptera litura) and the common mosquito (Culex
pipiens pallens) was assessed for dual sets of all four
racemic diastereomers 2a±d. As listed in Table 1, the
bioassay showed that racemic ether (1R*,2R*,3R*)-2a
had more signi®cant insecticidal activities than the other
three diastereomers 2b±d. A similar tendency was
observed on the stereostructure±activity relationship of
cyanohydrin esters 3a±d. In addition, there appeared a
distinctive di€erence in the activities of both sets of the
enantiomers 2a and 3a; (1S,2S,3S)-(+)-2a and -3a were
active, while, in contrast (1R,2R,3R)-( )-2a and -3a
were inactive.
In conclusion, of the eight stereoisomers including the
enantiomers of the synthetic pyrethroids, 2-methyl-3-
phenylcyclopropylmethyl 3-phenoxybenzyl ether 2 and
the cyanohydrin ester 3, which have been synthesized,
their (1S,2S,3S)-forms showed signi®cant insecticidal
activity against the tobacco cutworm and the common
mosquito. These results suggest that total geometry
around the three asymmetric centers of the (1R,2S,3S)-
enantiomers is signi®cant for the compound to be an
active insecticide.Scheme 2.
It should be noted that the relative con®guration of
either 2a or 3a was di€erent from that of the active

36
Y. Nishii et al. / Bioorg. Med. Chem. 9 (2001) 33±39
Table 1. Insecticidal activity of ethers 2 and cyanohydrin esters 3a
Mortality (%)
Tobacco cutworm
200
Common mosquitob
200
Compound
500
50 (ppm)
500
50 (ppm)
1R*,2R*,3R*
1R*2S*3S*
1R*,2S*,3R*
1R*,2R*,3S*
1R,2R,3R
2a
2b
2c
2d
100
0
0
Ð
Ð
Ð
Ð
15
90
Ð
Ð
Ð
Ð
55
100
0
Ð
Ð
Ð
Ð
0
45
Ð
Ð
Ð
Ð
5
A-B
C
C
B-C
B
A
A
C
B
C
Ð
Ð
Ð
Ð
C
Ð
Ð
Ð
Ð
C
0
(
)-2a
95
100
100
0
0
0
100
100
0
1S,2S,3S
(+)-2a
3a
3b
3c
3d
( )-3a
(+)-3a
Ð
B
C
1R*,2R*,3R*
1R*,2S*,3S*
1R*,2S*,3R*
1R,2R*,3S*
1R,2R,3R
Ð
Ð
Ð
Ð
B-C
A
Ð
Ð
Ð
Ð
C
B
A
C
1S,2S,3S
Untreated
100
0
A
C
C
aMethod of bioassay is described in Experimental section.
bCriteria of the mortality are as follows: A, >90%; B, 10±90%; C, <10%.
Experimental
Ethyl (1R*,2S*,3R*)- and (1R*,2R*,3S*)-2-methyl-3-
phenylcyclopropanecarboxylates (4c and 4d).11 Follow-
ing similar procedure using Z-1-phenyl-1-propene in the
place of E-1-phenyl-1-propene, (1R*,2S*,3R*)-4c (28%)
and (1R*,2R*,3S*)-4d (10%) were obtained. 4c: 1H
NMR (400 MHz) d 0.92 (3H, d, J=6.1 Hz), 1.30 (3H, t,
J=7.3 Hz), 1.68±1.95 (2H, m), 2.76 (1H, dd, Jcis=
9.5 Hz, Jtrans=5.1 Hz), 4.18 (2H, q, J=7.3 Hz), 7.15±
Melting points were determined on a hot stage micro-
1
scope apparatus (Yanagimoto) and are uncorrected. H
NMR spectra were recorded on a JEOL a (400 MHz) or
EX-90 (90 MHz) spectrometer using a TMS internal
standard in CDCl3. IR spectra were recorded on a
JASCO FT/IR-8000 spectrophotometer. All reagents
and solvents were puri®ed prior to use. Silica gel column
chromatography was performed on a Merck Art. 7734
and 9385. Optical rotations were recorded on a JASCO
DIP-360 digital polarimeter and given in units of
1
7.34 (5H, m). 4d: H NMR (400 MHz) d 1.18 (3H, t,
J=7.1 Hz), 1.30 (1H, d, J=6.6 Hz), 1.69±1.93 (1H, m),
2.06 (1H, dd, Jcis=9.0 Hz, Jcis=8.8 Hz), 2.62 (1H, dd,
Jcis=9.3 Hz, Jcis=9.6 Hz), 4.05 (2H, q, J=7.3 Hz),
7.15±7.34 (5H, m).
10 1 deg cm2
g
1. HPLC analyses were performed
using a Shimadu LC-10A system with UV (254 nm)
detector.
(1R*,2R*,3R*)-2-Methyl-3-phenylcyclopropylmethanol
(5a).12 Ester (1R*,2R*,3R*)-4a (262 mg, 1.49 mmol) in
THF (1.0 mL) was added to a stirred suspension of
LiAlH4 (57 mg, 1.49 mmol) in THF (1.0 mL) at 0±5 ꢀC,
and the mixture was stirred for 1 h at that temp. Aqu-
eous satd. Na2SO4 was added to the mixture, which was
®ltered with Celite using ether. The organic phase was
washed with water, brine, dried (Na2SO4), and con-
centrated. The crude oil was subjected to SiO2 column
chromatography (hexane:AcOEt=3:1) to give (1R*,2R*,
3R*)-5a (241 mg, 70%). Colourless liquid; 1H NMR
(400 MHz) d 1.27 (3H, d, J=5.9 Hz), 1.26±1.38 (1H, m),
1.47±1.57 (2H, m), 1.50±1.77 (1H, br, OH), 3.54±3.72
(1H, m), 3.87±3.93 (1H, m), 7.00±7.36 (5H, m).
Ethyl (1R*,2R*,3R*)- and (1R*,2S*,3S*)-2-methyl-3-
phenylcyclopropanecarboxylates (4a and 4b).11 Ethyl di-
azoacetate (1 M CH2Cl2 solution; 11.0 mL, 11 mmol)
was added to a stirred suspension of E-1-phenyl-1-pro-
pene (5.39 g, 46 mmol) and Cu-powder (50 mg) at 60±
65 ꢀC, and the mixture was stirred for 2 h at that temp.
The mixture was ®ltered through paper and was sub-
jected to SiO2 column chromatography (hexane:ether=
20:1) to give (1R*,2R*,3R*)-4a (987 mg, 44%) and
1
(1R*,2S*,3S*)-4b (561 mg, 25%). 4a: Colourless oil; H
NMR (400 MHz) d 1.28 (3H, t, J=7.2Hz), 1.35 (3H, d,
J=6.1Hz), 1.63±1.73 (1H, m), 2.02 (1H, dd, Jtrans=
4.9 Hz, Jcis=9.3 Hz), 2.41 (1H, dd, Jtrans=5.0Hz, Jtrans=
6.5 Hz), 4.17 (2H, q, J=7.2 Hz), 7.06±7.11 (2H, m),
7.14±7.22 (1H, m), 7.24±7.35 (2H, m). 4b: 1H NMR
(400MHz) d 0.98 (3H, t, J=7.2 Hz), 1.35 (3H, d, J=
6.1 Hz), 1.82 (1H, dd, Jtrans=5.1 Hz, Jcis=9.3Hz), 2.03±
2.12 (1H, m), 2.35 (1H, dd, Jtrans=6.8 Hz, Jcis=9.3 Hz),
3.87 (2H, q, J=7.2 Hz), 7.15±7.35 (5H, m).
Following a similar procedure as described above, alco-
hols (1R*,2S*,3S*)-5b (81%), (1R*,2S*,3R*)-5c (79%)
and (1R*,2R*,3S*)-5d (74%) were prepared from esters
4b, 4c and 4d, respectively. 5b: Colourless liquid; H
NMR (400MHz) d 1.20±1.33 (2H, m), 1.24 (3H, d,
J=5.4Hz), 1.65 (H, brs, OH), 1.99 (1H, dd, Jcis=8.5 Hz,
1

Y. Nishii et al. / Bioorg. Med. Chem. 9 (2001) 33±39
37
Jtrans=5.4 Hz), 3.30 (1H, dd, J=8.2 Hz, J=11.6 Hz),
3.44±3.60 (1H, dd, J=6.1 Hz, J=11.6 Hz), 7.14±7.31
(5H, m). 5c: colourless liquid; H NMR (400 MHz) d
Jtrans=5.0Hz, Jcis=9.1 Hz), 2.47 (1H, dd, Jtrans=5.0 Hz,
Jtrans=6.8 Hz), 7.06±7.11 (2H, m), 7.16±7.23 (1H, m),
7.24±7.32 (2H, m).
1
0.86 (3H, d, J=6.1 Hz), 1.06±1.16 (1H, m), 1.34±1.42
(1H, m), 2.00 (1H, dd, Jcis=9.3 Hz, Jtrans=5.1 Hz), 3.66
(2H, d, J=7.1 Hz), 7.16±7.32 (5H, m). 5d: colourless
liquid; H NMR (90 MHz) d 0.70±1.70 (3H, m), 1.02
(3H, d, J=6.3 Hz), 2.25 (1H, m), 3.30±3.62 (1H, m),
3.60±3.96 (1H, m), 7.08±7.62 (5H, m).
Following a similar as procedure described above, acids
(1R*,2S*,3S*)-6b (94%), (1R*,2S*,3R*)-6c (92%) and
(1R*,2R*,3S*)-6d (92%) were prepared from esters 4b,
4c and 4d, respectively. 6b: Colourless crystals; mp 87±
1
91 ꢀC; H NMR (400 MHz) d 1.26 (3H, d, J=5.9 Hz),
1
1.78 (1H, dd, Jcis=9.1 Hz, Jtrans=5.0 Hz), 1.95±2.08 (1H,
m), 2.41 (1H, dd, Jtrans=7.3 Hz, Jcis=9.1 Hz), 7.15±7.35
(5H, m). 6c: Colourless crystals; mp 63±67 ꢀC; 1H NMR
(400MHz) d 0.94 (3H, d, J=5.9 Hz), 1.78±1.83 (1H, m),
1.82±1.92 (2H, m), 2.84 (1H, dd, Jtrans=5.0Hz,
Jcis= 9.5 Hz), 7.20±7.40 (5H, m). 6d: Colourless crystals;
1H NMR (400 MHz) d 1.28 (3H, d, J=6.6 Hz), 1.76±
1.87 (1H, m), 2.05 (1H, dd, Jcis=8.6 Hz, Jcis=8.8 Hz),
2.70 (1H, dd, Jcis=8.7 Hz, Jcis=9.0 Hz), 7.20±7.40 (5H,
m).
(1R*,2R*,3R*)-2-Methyl-3-phenylcyclopropylmethyl 3-
phenoxybenzyl ether (2a). A mixture of alcohol (1R*,
2R*,3R*)-5a (162 mg, 1.0 mmol) and 3-phenoxybenzyl
bromide (316 mg, 1.2 mmol) in DMF (1.0 mL) was
added to a stirred suspension of NaH (60%, 29 mg,
1.2 mmol) in DMF (1.0 mL) at 0±5 ꢀC and the mixture
was stirred at room temp for 2 h. Water was added to the
mixture, which was extracted with ether. The organic
phase was washed with water, brine, dried (Na2SO4), and
concentrated. The crude oil was subjected to SiO2 col-
umn chromatography (hexane:AcOEt=20:1) to give the
desired ether (1R*,2R*,3R*)-2a (241 mg, 70%). Colour-
less liquid; 1H NMR (400 MHz) d 1.19 (3H, d, J=
6.1 Hz), 1.24±1.36 (1H, m), 1.45 (1H, dd, Jtrans=5.1 Hz,
Jtrans=5.1 Hz), 1.46±1.55 (1H, m), 3.46 (1H, d, J=
Cyano(3-phenoxyphenyl)methyl (1R*,2R*,3R*)-2-methyl-
3-phenylcyclopropanecarboxylate (3a). Et3N (58 mg,
0.57 mmol) was added to a stirred mixture of carboxylic
acid 6a (92 mg, 0.52mmol) and bromo(3-phenoxyphenyl)
acetonitrile (150 mg, 0.52 mmol) in acetone (1.0 mL) at
0±5 ꢀC, and the mixture was stirred at room temp. for
2 h. Aqueous 1 M HCl was added to the mixture, which
was extracted with ether. The organic phase was washed
with water, brine, dried (Na2SO4), and concentrated.
The crude oil was subjected to SiO2 column chromato-
graphy (hexane:AcOEt=12:1) to give cyanohydrin ester
8.5 Hz, Jgem=10.2 Hz), 3.75 (1H, dd, J=5.9 Hz, Jgem
10.2 Hz), 4.49 (1H, d, Jgem=12.2 Hz), 4.55 (1H, d, Jgem
=
=
12.2 Hz), 6.90±7.38 (14H, m); IR (neat) 2866, 1586,
1487 cm 1. Anal. calcd for C24H24O2: C, 83.69; H, 7.02.
Found: C, 83.3; H, 6.7.
1
Following a similar procedure as described above,
ethers (1R*,2S*,3S*)-2b (67%), (1R*,2S*,3R*)-2c
(65%), and (1R*,2R*,3S*)-2d (60%) were prepared
from alcohols 5b, 5c and 5d, respectively. 2b: Colourless
(1R*,2R*,3R*)-3a (139 mg, 70%). Yellow oil; H NMR
(400 MHz) d 1.31 (3HÂ1/2, d, J=6.1 Hz), 1.39 (3HÂ
1/2, d, J=6.4 Hz), 1.75±1.90 (1H, m), 2.08 (1HÂ1/2, dd,
Jtrans=4.4 Hz, Jcis=9.3 Hz), 2.08 (1HÂ1/2, dd, Jtrans
=
1
liquid; H NMR (400 MHz) d 1.17±1.28 (2H, m), 1.22
4.6 Hz, Jcis=9.0 Hz), 2.47 (1HÂ1/2, dd, Jtrans=4.9Hz,
Jtrans=6.8Hz), 2.51 (1HÂ1/2, dd, Jtrans=4.9Hz,
Jtrans= 6.8 Hz), 6.40 (1HÂ1/2, s), 6.43 (1HÂ1/2, s), 7.00±
7.43 (14H, m); IR (neat) 2359, 1740, 1588cm 1. Anal.
calcd for C25H21NO3: C, 78.31; H, 5.52. Found: C, 78.1;
H, 5.1.
(3H, d, J=6.3 Hz), 1.96 (1H, dd, Jtrans=4.5 Hz,
Jcis=8.7 Hz), 3.15 (1H, dd, J=6.2 Hz, Jgem=10.4 Hz),
3.28 (1H, d, J=7.4 Hz, Jgem=10.4 Hz), 4.24 (1H, d,
Jgem=12.0 Hz), 4.27 (1H, d, Jgem=12.0 Hz), 6.84±7.40
(14H, m); IR (neat) 2866, 1586, 1489 cm 1. 2c: Colour-
less liquid; 1H NMR (400 MHz) d 0.84 (3H, d,
J=6.3 Hz), 1. 08-1.12 (1H, m), 1.29±1.37 (1H, m), 1.96
(1H, dd, Jtrans=5.1 Hz, Jcis=9.3 Hz), 3.43±3.50 (1H, m),
3.54±3.60 (1H, m), 4.55 (2H, s), 6.90±7.38 (14H, m); IR
Following the similar procedure described above, cya-
nohydrin esters (1R*,2S*,3S*)-3b (47%), (1R*,2S*,
3R*)-3c (60%), and (1R*,2R*,3S*)-3d (66%) were pre-
1
1
(neat) 2865, 1586, 1487 cm 1. 2d: Colourless liquid; H
pared from esters 6b, 6c and 6d, respectively. 3b: H
NMR (400 MHz) d 1.29 (3HÂ1/2, d, J=6.1 Hz), 1.31
NMR (400 MHz) d 0.97 (3H, d, J=6.6 Hz), 1.29±1.40
(1H, m), 1.43±1.53 (1H, m), 2.23 (1H, dd, Jcis=9.0 Hz,
Jcis=9.0 Hz), 3.28±3.36 (1H, m), 3.52±3.58 (1H, m), 4.44
(3HÂ1/2, d, J=6.1 Hz), 1.91 (3HÂ1/2, dd, Jtrans
=
4.9 Hz, Jcis=8.8 Hz), 1.93 (3HÂ1/2, dd, Jtrans=5.1 Hz,
Jcis=9.0 Hz), 2.07±2.20 (1H, m), 2.46±2.56 (1H, m), 6.11
(1HÂ1/2, s), 6.12 (1HÂ1/2, s), 6.90±7.43 (14H, m); IR
(neat) 2365, 1741, 1588 cm 1. 3c: 1H NMR (400 MHz) d
0.93 (3HÂ1/2, d, J=6.1 Hz), 0.96 (3HÂ1/2, d,
J=6.1 Hz), 1.84±1.95 (2H, m), 2.82±2.90 (1H, m), 6.41
(1HÂ1/2, s), 6.42 (1HÂ1/2, s), 7.00±7.43 (14H, m); IR
(neat) 2361, 1740, 1588 cm 1. 3d; 1H NMR (400 MHz) d
1.27 (3HÂ1/2, d, J=6.6 Hz), 1.31 (3HÂ1/2, d,
J=6.8 Hz), 1.76±1.96 (1H, m), 2.16 (1HÂ1/2, dd,
Jcis=9.0 Hz, Jcis=8.5 Hz), 2.17 (1HÂ1/2, dd, Jcis=
9.0 Hz, Jcis=8.5 Hz), 2.77 (1HÂ1/2, dd, Jcis= 9.0 Hz,
Jcis=9.3 Hz), 2.82 (1HÂ1/2, dd, Jcis=9.0 Hz, Jcis=
(2H, s), 6.90±7.36 (14H, m); IR (neat) 2857, 1586,
1
1487 cm
.
(1R*,2R*,3R*)-2-Methyl-3-phenylcyclopropanecarboxylic
acid (6a).13 A mixture of ester (1R*,2R*,3R*)-4a
(0.50 g, 2.43 mmol) and KOH (1.37 g, 24.4 mmol) in
H2O:MeOH (1:2, 9 mL) was stirred at room temp. for
3 h. After evaporation of MeOH, aqueous 4 M HCl was
added to the mixture for adjusting this to pH 2. The
mixture was extracted with ether and the organic phase
was washed with water, brine, dried (Na2SO4), and
concentrated to give (1R*,2R*,3R*)-6a (400mg, 93%).
Colourless crystals; mp 66±68 ꢀC; 1H NMR (400MHz) d
1.40 (3H, d, J=6.3 Hz), 1.78±1.83 (1H, m), 2.03 (1H, dd,
9.3 Hz), 6.32 (1HÂ1/2, s), 6.33 (1HÂ1/2, s), 6.99±7.44
1
(14H, m); IR (neat) 2361, 1750, 1588 cm
.

38
Y. Nishii et al. / Bioorg. Med. Chem. 9 (2001) 33±39
Ethyl (1S,2S,3S)-(+)- and (1S,2R,3R)-(+)-2-methyl-3-
phenylcyclopropanecarboxylates [(+)-4a and (+)-4b].14
Ethyl diazoacetate (1 M CH2Cl2 solution; 10.0 mL, 10
mmol) was added to a stirred suspension of E-1-phenyl-
1-propene (1.53 g, 13 mmol) and the ꢀR-type Aratani
catalyst9 (160 mg, 0.10 mmol) at 60±65 C, and the mix-
ture was stirred for 2 h at 80 ꢀC. After being cooled
down, the mixture was subjected to SiO2 column chro-
matography (hexane:ether=20:1) to give (1R,2R,3R)-
(+)-4a (400mg, 17%) and (1R,2S,3S)-(+)-4b (158mg,
7%). (+)-4a: Colourless oil; [a]2D5 +103.2 (c 0.47, CHCl3);
55% ee estimated by that of (+)-5a determined by
HPLC analysis. (+)-4b: Colourless oil; [a]2D5 +10.3 (c
0.77, CHCl3).
[a]2D5 +27.4 (c 0.93, CHCl3). ( )-2a: Colourless oil, [a]D25
27.7 (c 0.98, CHCl3).
Cyano(3-phenoxyphenyl)methyl (1S,2S,3S)-(+)- and (1S,
2R,3R)-( )-2-methyl-3-phenylcyclopropanecarboxylate
[(+)-3a and ( )-3a]. Following the similar procedure
for the coupling using acid 6a, cyanohydrin esters (1S,
2S,3S)-(+)-3a (60%) and (1R,2R,3R)-( )-3a (68%)
were prepared from acids (+)-6a and ( )-6a, respectively.
(+)-3a: Colourless oil; [a]2D5 +98.3 (c 0.53, CHCl3). ( )-
3a: Colourless oil, [a]2D5 99.7 (c 0.48, CHCl3).
Assay of the insecticidal activity against tobacco
cutworm (Spodoptera litura) and common mosquito
(Culex pipiens pallens)
Ethyl (1R,2R,3R)-( )- and (1R,2S,3S)-( )-2-methyl-3-
phenylcyclopropanecarboxylates [( )-4a and ( )-4b].
Following a similar procedure as described above,
using the S-type catalyst9 in the place of R-type catalyst,
(1R,2R,3R)-( )-4a (20%) and (1R,2S,3S)-( )-4b (8%)
were prepared. ( )-4a: Colourless oil; [a]2D5 105.3 (c
0.75, CHCl3), 56% ee. ( )-4b: Colourless oil; [a]2D5 10.2
(c 0.11, CHCl3).
1. For the tobacco cutworm (Spodoptera litura), an
arti®cial diet method was used. To an arti®cial diet
(13 g, of Insecta.LF; Nippon Nousan Kogyo Co.,
Ltd.) in a plastic cup were added 2 mL portions of
pre-determined concentrations of test samples
(500, 200, and 50 ppm). Ten fourth-instar larvae
were released on the diet. Six days after the treat-
ment at 25 ꢀC, the mortality was observed (two
replicants).
2. For the common mosquito (Culex pipiens pallens),
an immersion method was used. To de-ionized
water (100 mL) was applied 0.7 mL portions of
pre-determined concentrations of test samples
(500, 200, and 50 ppm). Twenty last-instar larvae
were released therein. Mortality was assessed after
24 h (two replicants).
(1S,2S,3S)-(+)- and (1R,2R,3R)-( )-2-Methyl-3-phenyl-
cyclopropanecarboxylic acids [(+)-6a and ( )-6a]. Fol-
lowing similar procedure for the hydrolysis of 4a,
carboxylic acid a (1S,2S,3S)-(+)-6a {[a]2D5 +124.3 (c
0.32, CHCl3)} and (1S,2R,3R)-( )-6a {[a]2D5 125.9 (c
1.00, CHCl3)} were prepared from esters (+)-4a and
( )-4a, respectively. This (+)-6a (400 mg, 2.3 mmol)
and S-( )-NEA (393 mg, 2.3 mmol) in EtOH (8 mL)
was seeded with material from a small-scale recrystalli-
zation, and allowed to stand at room temp. for 24 h.
The ®rst salt (271 mg, 34%) obtained was decomposed
with 1 M HCl and extracted with ether. The organic
phase was dried (Na2SO4) and concentrated to give
more optically active (+)-6a (137 mg, 59%) as colour-
less crystals: mp 80±84 ꢀC; [a]D25 +206.5 (c 0.40, CHCl3).
Similarly, more optically active ( )-6a was obtained
using R-(+)-NEA as colourless crystals: mp 83±87 ꢀC,
[a]2D5 220.4 (c 1.00, CHCl3).
Acknowledgements
We appreciate Dr. Tadatoshi's kindness in giving us the
Aratani Catalyst. We also thank Agricultural Chemicals
Research Laboratory, Sumitomo Chem. Co., Ltd., for
carrying out the bioassay. This work was partially sup-
ported by a Grant-in-Aid for Scienti®c Research from
the Ministry of Education, Science, Sports and Culture
(Japan). One of the authors (Y. N.) acknowledges the
JSPS fellowship for Japanese Junior Scientists.
(1S,2S,3S)-(+)- and (1R,2R,3R)-( )-2-Methyl-3-phenyl-
cyclopropylmethanol [(+)-5a and ( )-5a]. Following a
similar procedure for the reduction of 6a, alcohols
(1S,2S,3S)-(+)-5a and (1R,2R,3R)-(-)-5a were prepared
from (+)-6a (91%) and ( )-6a (92%), respectively.
(+)-5a: Colourless oil; [a]2D4 +9.5 (c 0.20, CHCl3); 86%
ee (HPLC analysis). ( )-5a: [a]2D5 10.0 (c 0.15, CHCl3),
92% ee (HPLC analysis). Procedure of the determina-
tion of ee: (+)-5a was analyzed with HPLC (Chiralcel
OB; Daicel, 4.6fÂ250 mm, C6H14:MeOH 98:2, 1.0 ml/
min as eluent, column temperature of 24.0 ꢀC, UV
detection at 255 nm). Rt of ( )-5a was 24.0 min, and Rt
of (+)-5a was 27.0 min.
References
1. (a) Chamberlain, K.; Matsuo, N.; Kaneko, H.; Khambay,
B. P. S. In Chirality in Agrochemicals; Kurihara, N.; Miya-
moto, J., Eds., Wiley: New York, 1998; pp 9±84. (b) Naumann,
K. In Chemistry of Plant Protection 5, Synthetic Pyrethroid
Insecticides; Springer-Verlag: Berlin, 1990. (c) Matsui, M.;
Yamamoto, I. Naturally Occurring Insecticides; Marcel Dek-
ker: New York, 1971. (d) Elliot, M.; Janes, N. F. Pyrethrum,
The Natural Insecticides; Academic Press: New York, 1973.
2. (a) Holan, G.; O'Keefe, D. F.; Vergona, C.; Walser, R. Nat-
ure 1978, 272, 734. (b) Holan, G.; Johnson, W. M. P.; Jarvis, K.
E.; Virgona, C. T.; Walser, R. A. Pestic. Sci. 1976, 17, 715.
3. Ohno, N.; Fujimoto, K.; Okuno, Y.; Mizutani, T.; Hirano,
M.; Itaya, N.; Honda, T.; Yoshioka, H. Pestic. Sci. 1976, 7,
241 and Agric. Biol. Chem. 1974, 38, 881.
(1S,2S,3S)-(+)- and (1R,2R,3R)-( )-2-Methyl-3-phenyl-
cyclopropylmethyl 3-phenoxybenzyl ethers [(+)-2a and
( )-2a]. Following a similar procedure for the coupling
using alcohol 4a, ethers (1S,2S,3S)-(+)-2a (71%) and
(1R,2R,3R)-( )-2a (70%) were prepared from alcohols
(+)-4a and ( )-4a, respectively. (+)-2a: Colourless oil;

Y. Nishii et al. / Bioorg. Med. Chem. 9 (2001) 33±39
39
4. Henrick, C. A.; Garcia, B. A.; Staal, G. B.; Cerf, D. C.;
Anderson, R. J.; Gill, K.; Chinn, H. R.; Labovitz, J.; Leippe,
M. M.; Woo, S. L.; Carney, R. L.; Gordon, D. C.; Kohn, G.
K. Pestic. Sci. 1980, 11, 224.
Y.; Matsumura, H.; Muroya, Y.; Tsuchiya, T.; Tanabe, Y.
Biosci. Biotech. Biochem. 1995, 59, 1355.
8. Tanabe, Y.; Nishii, Y. J. Synth. Org. Chem. Jpn. 1999, 57,
170.
5. Berkelhammer, G.; Kameswaran, V. USP 4199595/1978;
Chem. Abstr. 1980, 92, 128580f.
9. Aratani, T. Pure Appl. Chem. 1985, 57, 1839.
10. Racemic 2-desmethyl cis-chrysanthemic acid was repor-
ted. Krief, A.; Surleraux, D.; Robson, M. J. Synlett 1991, 276.
11. Feldman, K. S.; Simpson, R. E. J. Am. Chem. Soc. 1989,
111, 4878.
12. Vincens, M.; Dumont, C.; Vidal, M.; Domnin, I. N. Tet-
rahedron 1983, 39, 4281.
13. Tatsuya, S.; Nishiguchi, I.; Yamane, S.; Oda, R. Tetra-
hedron Lett. 1965, 1969.
14. Ito, K.; Katsuki, T. Synlett 1993, 638.
6. (a) Bushell, M. J.; Carr, R. A. E. GP 2199825/1988; Chem.
Abstr. 1988, 109, 210696b. Tsushima, K.; Yano, T.; Takagaki,
T.; Matsuo, N.; Hirano, M.; Ohno, N. Agric. Biol. Chem. 1988,
52, 1323. (b) Carr, R. A. E.; Lyn, P. EP 280383/1988; Chem.
Abstr. 1989, 110, 75025k. (c) Nicholds, M. J. D.; David, H. G.;
Harvey, I. GP 2241953/1991; Chem. Abstr. 1992, 116, 83362g.
7. (a) Nishii, Y.; Wakimura, K.; Tsuchiya, T.; Nakamura, S.;
Tanabe, Y. J. Chem. Soc., Perkin Trans. 1 1996, 1243. (b) Nishii,