Synthetic studies aimed at the elucidation of the stereostructure of the aggregation pheromone, 2-methyl-6-(4′-methylenebicyclo[3.1.0]hexyl)hept-2-en-1-ol, produced by the male stink bug Erysarcoris lewisi

Article abstract of DOI:10.1016/j.tetasy.2007.03.019

The male-produced aggregation pheromone of the stink bug Erysarcoris lewisi Distant was shown to be one of the two diastereomers of (2Z,6R)-2-methyl-6-(4′-methylenebicyclo[3.1.0]hexyl)hept-2-en-1-ol by synthesizing and bioassaying (2E,6R)-, (2E,6S)-, (2Z,6R)-, and (2Z,6S)-isomers. These were synthesized from the enantiomers of citronellal by employing an intramolecular α-ketocarbene addition to a double bond and the E-selective or Z-selective olefination of a formyl group as the key steps. A reliable method was developed for the preparation of ethyl 2-(di-o-tolylphosphono)propanoate, Ando's reagent for Z-selective olefination.

Full text of DOI:10.1016/j.tetasy.2007.03.019

Tetrahedron: Asymmetry 18 (2007) 838–846
Synthetic studies aimed at the elucidation of the stereostructure
of the aggregation pheromone, 2-methyl-6-(40-methylenebicyclo-
[3.1.0]hexyl)hept-2-en-1-ol, produced by the
male stink bug Erysarcoris lewisiI
Kenji Mori*
Photosensitive Materials Research Center, Toyo Gosei Co., Ltd, Wakahagi 4-2-1, Inba-mura, Inba-gun, Chiba 270-1609, Japan
Received 31 January 2007; accepted 20 March 2007
Available online 25 April 2007
Abstract—The male-produced aggregation pheromone of the stink bug Erysarcoris lewisi Distant was shown to be one of the two dia-
stereomers of (2Z,6R)-2-methyl-6-(40-methylenebicyclo[3.1.0]hexyl)hept-2-en-1-ol by synthesizing and bioassaying (2E,6R)-, (2E,6S)-,
(2Z,6R)-, and (2Z,6S)-isomers. These were synthesized from the enantiomers of citronellal by employing an intramolecular a-ketocar-
bene addition to a double bond and the E-selective or Z-selective olefination of a formyl group as the key steps. A reliable method was
developed for the preparation of ethyl 2-(di-o-tolylphosphono)propanoate, Ando’s reagent for Z-selective olefination.
ꢀ 2007 Elsevier Ltd. All rights reserved.
1. Introduction
7
8
2
1
OH
8
4
2
6
4
2'
1'
5'
OH
Erysarcoris lewisi Distant (Heteroptera: Pentatomidae) is a
stink bug found in northern Japan, which damages rice
grains. It usually lives in meadows and fields, and comes
to the rice paddy fields where it attacks rice plants at the
time of their grain formation. Its emergence can hardly
be surveyed by conventional means, especially because it
cannot be attracted by light traps. The possibility of using
its pheromone for the purpose of monitoring its population
was therefore examined by Takita et al. in 2000.2 Takita
then proposed the structure of the male-produced aggrega-
tion pheromone of E. lewisi as (E)-2-methyl-6-(40-methyl-
enebicyclo[3.1.0]hexyl)hept-2-en-1-ol 1 (Fig. 1).3
3
5
3
1
3'
4'
6'
(2E,6R)-1
(2Z,6R)-2
bioactive
7'
OH
OH
(2E,6S)-1'
(2Z,6S)-2'
Figure 1. Structures of the pheromone candidates.
Although the acetate of (Z)-2-methyl-6-(40-methylenebicy-
clo[3.1.0]hexyl)hept-2-en-1-ol 2 has been known since
1982 as a constituent of an African plant Haplocarpha scap-
osa,4 there is no data about whether natural 2 possesses
(2Z,6R)- or (2Z,6S)-stereochemistry. In fact, the synthesis
of either 1 or 2 has not been reported. We became interested
in achieving the synthesis of (2E,6R)-1 and (2E,6S)-10 so as
to supply the pheromone in an amount sufficient for evalu-
ation of its practicality as a population monitoring agent.
Scheme 1 summarizes our retrosynthetic analysis of 1.
Stork and Ficini were the first in 1961 to employ the intra-
molecular addition of a-ketocarbene to an olefin for the
synthesis of bicyclo[4.1.0]heptan-2-one.5 Their method
was employed by us in 1970 to synthesize the racemic sabi-
na ketone, as shown in Scheme 1.6 Intramolecular a-keto-
carbene-olefin addition (D!C) was therefore chosen as the
key ring-forming reaction in the present synthesis.
q Pheromone synthesis, Part 233. For Part 232, see Ref. 1.
*
Tel.: +81 3 3816 6889; fax: +81 3 3813 1516; e-mail: kjk-mori@
arion.ocn.ne.jp
0957-4166/$ - see front matter ꢀ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2007.03.019

K. Mori / Tetrahedron: Asymmetry 18 (2007) 838–846
839
als. Methylenation of (R)-3 with formalin, pyrrolidine,
and propanoic acid was carried out according to Erkkila¨
and Pihko7 to give a,b-unsaturated aldehyde (R)-4 (Scheme
2). Reduction of (R)-4 with lithium aluminum hydride fur-
nished allylic alcohol (R)-5, which was subjected to a John-
son orthoester Claisen rearrangement8 by heating with
triethyl orthoacetate in the presence of propanoic acid to
afford ethyl ester (R)-6a in 78% overall yield, based on cit-
ronellal (R)-3.
Cu/cyclohexane
reflux
CHN2
(Mori et al.6)
O
O
( )-sabina ketone
OH
CO2Et
Alkaline hydrolysis of (R)-6a yielded the corresponding
acid (R)-6b. After converting (R)-6b into its sodium salt
(R)-6c by adding sodium ethoxide in ethanol, the concen-
trated and dried (R)-6c was treated with oxalyl chloride
O
1
A
CHO
a
b
O
O
O
B
C
CHO
CHO
(R)-3
(R)-5
(R)-4
c
f
CHN2
CO2Et
CO2R
D
OH
E
(R)-6a R = Et
(R)-6b R = H
(R)-6c R = Na
d
e
OHC
HO
g
F
Citronellal 3
COCl
COCHN2
Scheme 1. Retrosynthetic analysis of 1.
(R)-7
(R)-8
Pheromone candidate 1 can be prepared from keto ester A,
while E-selective Wittig reaction converts B to A. Aldehyde
B is secured by oxidation of C. Bicyclo[3.1.0]hexane C was
prepared by the intramolecular addition to a double bond
of an a-ketocarbene generated from diazoketone D, which
was synthesized from ester E. The orthoester Claisen
rearrangement when applied to F, affords E. Finally, the
commercially available enantiomers of citronellal 3 were
envisaged as the starting materials. At the step D to C, the
stereochemistry of the ring junction cannot be controlled,
meaning that C is obtained as a diastereomeric mixture.
h
i
j
CHO
O
O
(R)-9
(R)-10
8
2
OH
l
CO2Et
3
1
X
(2E,6R)-11
(2E,6R)-12
X = O
X = CH2
(2E,6R)-1
The 1H and 13C NMR comparison of (2E,6R)-1 or (2E,6S)-
10 with the natural pheromone indicated the latter to be 2
or 20 with a Z-double bond. We therefore synthesized
(2Z,6R)-2 and (2Z,6S)-20 by employing a Z-selective olefin-
ation at the step of B to A. Bioassay of our synthetic 1, 10,
2, and 20 against E. lewisi revealed (2Z,6R)-2 as pheromo-
nally active. Herein, we report in detail the above men-
tioned studies.
k
Similarly
OH
CHO
(S)-3'
(2E,6S)-1'
Scheme 2. Synthesis of (2E,6R)-1 and (2E,6S)-10. Reagents and condi-
tions: (a) 37% CH2O, EtCO2H, pyrrolidine, i-PrOH, 45 ꢁC, 4 h, 90%; (b)
LiAlH4, Et2O, 91%; (c) MeC(OEt)3, EtCO2H, 140 ꢁC, 1 h, 95%; (d) KOH,
EtOH, H2O, reflux, 2 h, 83%; (e) NaOEt, EtOH; (f) (COCl)2, C5H5N
hexane, quant. (2 steps); (g) CH2N2, Et2O, quant.; (h) Cu, CuSO4,
cyclohexane, reflux, 1 h, 58%; (i) OsO4, NalO4, t-BuOH, THF, H2O,
quant. (85% in the presence of 2,6-lutidine); (j) Ph3P@C(Me)CO2Et, THF,
CH2Cl2, 57%; (k) Ph3P(Me)Br, n-BuLi, THF (96%); (l) (i-Bu)2AlH,
toluene, 55%.
2. Results and discussion
2.1. Synthesis of (2E,6R)- and (2E,6S)-2-methyl-6-(40-
methylenebicyclo[3.1.0]hexyl)hept-2-en-1-ol 1 and 10
Commercially available enantiomers of citronellal
(Takasago, 97% ee) were employed as the starting materi-
3

840
K. Mori / Tetrahedron: Asymmetry 18 (2007) 838–846
in hexane in the presence of a small amount of pyridine as
the reaction promotor. The resulting acyl chloride (R)-7 in
hexane was added to an excess amount of diazomethane in
diethyl ether to give diazoketone (R)-8 as a yellow oil. Sub-
sequently, (R)-8 in cyclohexane was added dropwise to a
stirred and refluxing suspension of powdered copper and
copper(II) sulfate in cyclohexane. The product was purified
by silica gel chromatography followed by distillation to
give bicyclic ketone (R)-9, mmax = 1728 cmꢀ1, in 48% over-
all yield based on ester (R)-6a. Ketone (R)-9 was obtained
as a diastereomeric mixture of two isomers with regards to
the newly formed cyclopropane ring with either the a- or b-
orientation. The ratio of the diastereomers was analyzed by
GC–MS, and shown to be 51.9:46.5 with 1.6% of unidenti-
fied impurities. The (R)-configured methyl group of (R)-8
did not exert a significant steric effect over the course of
the intramolecular addition of a-ketocarbene to the double
bond.
pheromone with the literature data,10–12 the latter was
thought to be 2 with a Z-double bond. We, therefore,
turned our attention to the synthesis of 2.
2.2. Synthesis of ethyl 2-(di-o-tolylphosphono)propanoate 15
In order to synthesize the desired pheromone with a Z-dou-
ble bond, there was a need to select a suitable Z-selective
olefination method. We chose Ando’s method for this pur-
pose. Ando reported that methylation of ethyl (di-o-tolyl-
phosphono)acetate 1413 gave a very useful Z-selective
olefination reagent, ethyl 2-(di-o-tolylphosphono)propano-
ate 15.14 By employing 15, (Z)-olefinic esters were obtained
in 78–100% yield with a Z-selectivity of 92–99%.14 For the
methylation of 14, sodium hydride and methyl iodide in
DMSO were employed by Ando.14 When we methylated
commercially available 14 according to Ando,14 the prod-
uct was impure 15, contaminated with small amounts
(about 10% each) of non-methylated 14 and dimethylated
16 (Scheme 3). This result seems natural, because it is well
known that methylation of diethyl malonate gives a mix-
ture of the starting material, the monomethylated, and
dimethylated malonates. The use of this impure olefination
reagent 15 would cause problems for the preparation of
pure 2.
Lemieux-Johnson oxidation of (R)-9 with osmium tetrox-
ide and sodium periodate in aqueous THF was carried
out under the modified conditions reported by Jin et al.9
in the presence of 2,6-lutidine to give keto aldehyde (R)-
10. In this particular case, the yield of (R)-10 was slightly
better when the reaction was done in the absence of 2,6-
lutidine. Treatment of (R)-10 with (carbethoxymethyli-
dene)triphenylphosphorane afforded (2E,6R)-11 as the
major product. Keto ester (2E,6R)-11 was subjected to the
Wittig reaction with 1.1 equiv of methylenetriphenylphos-
phorane in THF at ꢀ78 ꢁC to give (2E,6R)-12. Finally,
reduction of (2E,6R)-12 with diisobutylaluminum hydride
afforded (2E,6R)-2-methyl-6-(40-methylenebicyclo[3.1.0]-
hexyl)hept-2-en-1-ol 1 as a colorless oil. The overall yield
of (2E,6R)-1 was 30% based on (R)-9 or 11% based on
(R)-3 (11 steps). In a similar manner, (2E,6S)-10 was synthe-
sized by starting from (S)-citronellal 30.
Therefore, we made an effort to achieve a reliable synthesis
of pure 15, and prepared 15 in three steps from triethyl
Me
Me
O
O R
CCO2Et
Me
NaH
MeI
14 +
O
PCH2CO2Et
2
O P
2
14
15 R = H
16 R = Me
GC–MS analysis of (2E,6R)-1 and (2E,6S)-10 revealed
them to be 1.06–1.09:1 mixtures of each two diastereomers,
both of which showed identical MS with a molecular ion
peak at m/z = 220 (C15H24O). Their NMR spectra were
then measured in C6D6 to compare them with the data of
the natural pheromone (Table 1). Distinct differences were
O
a
b
(EtO)3P + MeCHCO2Et
Br
(EtO)2PCHCO2Et
Me
17
18
19
Me
1
observed as follows: in the H NMR spectrum, synthetic 1
O
O
P
c
showed signals at d = 1.59 (8-Me), 3.80 (1-CH2OH), and
5.34 (3-CH@C), while the natural pheromone absorbed
at d = 1.75, 3.96, and 5.17. In the 13C NMR spectrum, syn-
thetic 1 exhibited signals at d = 26.0 (C-8), 68.6 (C-1), 125.6
(C-3), and 135.0 (C-2), while the natural pheromone
showed them at 21.3, 61.5, 128.1 and 135.4. These differ-
ences were due to the cis/trans-isomerism of the double
bond. By comparing these d-values of 1 and the natural
Cl2PCHCO2Et
Me
O
CHCO2Et
Me
2
20
15
Scheme 3. Synthesis of ethyl 2-(di-o-tolylphosphono)propanoate (15).
Reagents and conditions: (a) 160 ꢁC, 2 h, 60%; (b) PCl5, 75–80 ꢁC, 14 h,
67%; (c) o-cresol, Et3N, CH2Cl2, 0–5 ꢁC, 30 min, room temperature, 1 h,
60%.
Table 1. Comparison of the NMR data of the natural pheromone with synthetic (2E,6R)-1 and (2Z,6R)-2
1H NMR (d, in C6D6)
13C NMR (d, in C6D6)
8-CH3
1-CH2OH
3-CH@C
C-8
C-1
C-3
C-2
Natural pheromonea
(2E,6R)-1b
(2Z,6R)-1b
1.75
1.59
1.75
3.96
3.80
3.97
5.17
5.34
5.18
21.3
26.0
21.3
61.5
68.6
61.3
128.1
125.6
128.1
135.4
135.0
134.5
a 600 MHz for 1H NMR; 125 MHz for 13C NMR.
b 400 MHz for 1H NMR; 100 MHz for 13C NMR.

K. Mori / Tetrahedron: Asymmetry 18 (2007) 838–846
841
phosphite 17 and ethyl 2-bromopropanoate 18. The
Arbuzov reaction between 17 and 18 gave the known phos-
phonate 19.15 Treatment of 19 with phosphorus pentachlo-
ride at 75–80 ꢁC overnight afforded phosphoryl chloride
20. o-Cresol was esterified with 20 in the presence of trieth-
ylamine to give the desired 15 in 18.6% overall yield based
methylenetriphenylphosphorane furnished (2Z,6R)-22.
This ester was reduced with diisobutylaluminum hydride
to give (2Z,6R)-2-methyl-6-(40-methylenebicyclo[3.1.0]-
hexyl)hept-2-en-1-ol 2 in 22% overall yield based on (R)-
10 or 8% overall yield based on (R)-3: (11 steps). Similarly,
(S)-100 was converted to (2Z,6S)-20.
1
on bromo ester 18. In its H NMR spectrum, 15 showed
a 3H signal at d = 1.69 as dd (JHH = 7, JPH = 19 Hz), indi-
cating the presence of a single methyl group at C-2.
GC–MS analysis of both (2Z,6R)-2 and (2Z,6S)-20 indi-
cated that they were obtained as diastereomeric mixtures
in ratios of 1.46–1.59:1. The MS of 2 was virtually identical
to that of 1 with a molecular ion peak at m/z = 220
(C15H24O), which was in good accordance with that of the
2.3. Synthesis of (2Z,6R)- and (2Z,6S)-2-methyl-6-(40-
methylenebicyclo[3.1.0]hexyl)hept-2-en-1-ol 2 and 20
1
natural pheromone (Table 1). The H and 13C NMR spec-
tra of 2 in C6D6 were carefully compared with those of the
natural pheromone. In the H NMR spectrum (400 MHz),
Olefination of (R)-10 with ethyl 2-(di-o-tolylphosphono)-
propanoate 15 was achieved by using sodium hydride in
THF as a base at ꢀ78 ꢁC. The resulting diastereomeric
1
synthetic 2 showed signals at d = 0.43 (1H, dd, J 4, 8) and
0.61 (1H, dd, J 4, 4) for the cyclopropane protons, 1.75
(3H, 8-Me), 3.97 (2H, 1-CH2OH), 4.78 (1H, s), and 4.99
(1H, s) for olefinic methylene protons, and 5.18 (1H, 3-
CH@C), while the natural pheromone showed signals in
its 600 MHz spectrum at d = 0.40, 0.57, 1.75, 3.96, 4.78,
4.99, and 5.17. In the 13C NMR spectrum (100 MHz), syn-
thetic 2 exhibited signals at d = 21.3 (C-8), 61.3 (C-1), 128.1
(C-3), and 134.5 (C-2), while the natural pheromone
showed them (125 MHz) at d = 21.3, 61.5, 128.1, and
135.4. Although the spectra of synthetic 2 were much more
complicated than those of the natural pheromone due to
the presence of the unnatural diastereomer, all the signals
in the spectra of the natural pheromone could be observed
in the spectra of 2.
1
mixture of ester (2Z,6R)-21 (Scheme 4) showed H NMR
signals at d = 1.89 and 1.90 (total 3H, 13-Me) and also at
d = 5.88 (1H, 10-CH@C). On the other hand, (2E,6R)-11
exhibited signals at d = 1.80 and 1.82 (total 3H) and also
at 6.70 (1H). Ethyl (E)-2-methyl-5-phenyl-2-pentenoate
was reported to show signals at d = 1.78 (3H) and 6.80
(1H), while its (Z)-isomer exhibited signals at d = 1.89
(3H) and 5.96 (1H).16 It was therefore thought that 21 pos-
sessed a Z-double bond. Methylenation of (2Z,6R)-21 with
CO2Et
a
b
CHO
O
O
3. Conclusion
(R)-10
(2Z,6R)-21
Our synthetic products, (2E,6R)-10, (2E,6S)-10, (2Z,6R)-2,
and (2Z,6S)-20 were bioassayed against Erysarcosis lewisi
by Yoshimura and Ishii at Yamagata Prefectural Agricul-
tural Research Center. In three independent field bioas-
says, 0.408 mg of the natural pheromone attracted 107
stink bugs in sum total, while the same amount of
(2Z,6R)-2 attracted 40 Erysarcoris lewisi. Other isomers
attracted only 2–7 bugs. These results suggest that either
(2Z,6R,10S,50S)- or (2Z,6R,10R,50R)-2 is the natural pher-
omone. The synthesis of these two compounds is now
being pursued, and the result will be reported in due
course.
OH
8
1
CO2Et
c
2
3
(2Z,6R)-22
(2Z,6R)-2
bioactive
Similarly
OH
CHO
4. Experimental
4.1. General
O
(S)-10'
(2Z,6S)-2'
OH
OH
Boiling points are uncorrected values. Optical rotations
were measured on a Jasco P-1020 polarimeter. IR spectra
were measured on a Jasco FT/IR-410 spectrometer. 1H
NMR spectra (400 MHz, TMS at d = 0.00 as internal stan-
dard) and 13C NMR spectra (100 MHz, CDCl3 at d = 77.0
as internal standard) were recorded on a Jeol JNM-AL 400
spectrometer. GC–MS were measured on Agilent Technol-
ogies 5975 inert XL. HRMS were recorded on a Jeol JMS-
SX102A. Column chromatography was carried out on
Merck Kieselgel 60 Art 1.07734.
6
1'
or
2
5'
(2Z,6R,1'S,5'S)-2
(2Z,6R,1'R,5'R)-2
Scheme 4. Synthesis of (2Z,6R)-2 and (2Z,6S)-20. Reagents and condi-
tions: (a) (o-MeC6H4O)2P(O)CHMeCO2Et, NaH, THF, ꢀ78 to 5 ꢁC,
quant.; (b) Ph3P(Me)Br, n-BuLi, THF, quant.; (c) (i-Bu)2AlH, toluene,
51% (crude), 22% after purification.

842
K. Mori / Tetrahedron: Asymmetry 18 (2007) 838–846
4.2. 3,7-Dimethyl-2-methylene-6-octenal 4 and 40
for C11H20O (168.3): C, 78.51; H, 11.98. Found: C, 77.81;
H, 12.20.
4.2.1. (R)-(ꢀ)-Isomer 4. Propanoic acid (0.54 g, 7.3
mmol) and pyrrolidine (0.52 g, 7.3 mmol) were added to
a solution of (R)-3 (Takasago, 97% ee; 11.2 g, 73 mmol)
and 37% CH2O aqueous solution (6.5 mL, ca. 73 mmol)
in i-PrOH (8 mL). The mixture was stirred at 45 ꢁC for
4 h. It was then diluted with NaHCO3 aqueous solution,
and extracted with hexane. The extract was washed with
water, NaHCO3 aqueous solution and brine, dried with
MgSO4, and concentrated in vacuo. The residue was dis-
4.4. Ethyl 5,9-dimethyl-4-methylene-8-decenoate 6a and 6a0
4.4.1. (R)-(ꢀ)-Isomer 6a. Propanoic acid (400 mg,
5 mmol) was added to a solution of (R)-5 (10.0 g, 59 mmol)
in MeC(OEt)3 (80 g, 494 mmol), and the mixture was stir-
red and heated at 150–160 ꢁC for 1 h to remove the ethanol
generated. The mixture was then concentrated in vacuo,
and the residue was distilled to give 13.5 g (95%) of (R)-
tilled to give 10.9 g (90%) of (R)-4 as an oil, bp 94–97 ꢁC/
21
6a as an oil, bp 113–115 ꢁC/3 Torr; n2D2 ¼ 1:4562; ½aꢁD
¼
24
12 Torr; n2D1 ¼ 1:4660; ½aꢁD ¼ ꢀ13:6 (c 3.45, hexane); mmax
ꢀ11:6 (c 4.85, hexane); mmax (film): 3078 (m), 1739 (s,
C@O), 1643 (m, C@C), 1160 (s, C–O), 891 (m, C@CH2).
dH(CDCl3): 1.02 (3H, d, J 6.8, CHCH3), 1.26 (3H, t, J
7.2, CH2CH3), 1.28–1.36 (1H, m), 1.40–1.52 (1H, m),
1.59 (3H, s, C@CCH3), 1.68 (3H, s, C@CCH3), 4.13 (2H,
q, J 7.2, OCH2CH3), 4.70 (1H, s, C@CH), 4.78 (1H, s,
C@CH), 5.09 (1H, t-like, J 7, C@CH); dC(CDCl3): 14.2,
17.6, 20.0, 25.7, 25.9, 28.2, 32.8, 35.6, 39.9, 60.3, 107.8,
124.5, 131.3, 152.8, 173.4. HRMS calcd for C15H26O2
(M+) 238.1933; found, 238.1925.
(film): 2696 (w, H–C@O), 1697 (s, C@O), 1624 (w, C@C),
945 (m, C@CH2); dH(CDCl3): 1.06 (3H, d, J 7.2, CHCH3),
1.32–1.42 (1H, m), 1.48–1.54 (1H, m), 1.57 (3H, s,
C@CCH3), 1.67 (3H, s, C@CCH3), 1.88–2.00 (1H, m),
2.62–2.78 (1H, m), 5.08 (1H, t, J = 7, C@CH), 5.98 (1H,
s, C@CHH), 6.23 (1H, s, C@CHH), 9.53 (1H, s, CHO);
dC(CDCl3): 17.6, 19.5, 25.66, 25.71, 30.9, 35.5, 124.1,
131.6, 133.1, 155.4, 194.7. The spectral data of 4 were iden-
tical with those reported by Erkkila¨ and Pihko.7 HRMS
calcd for C11H18O (M+) 166.1358; found, 166.1361.
4.2.2. (S)-(+)-Isomer 40. In the same manner, (S)-30
4.4.2. (S)-(+)-Isomer 6a0. In the same manner, (S)-50
(9.5 g, 56.5 mmol) yielded 12.6 g (94%) of (S)-6a0 as an
(Takasago, 97% ee; 11.2 g, 73 mmol) yielded 10.7 g (86%)
of (S)-40 as an oil, bp 86–88 ꢁC/9 Torr; n2D0 ¼ 1:4661;
24
oil, bp 118–120 ꢁC/4 Torr; n2D2 ¼ 1:4562; ½aꢁ ¼ þ11:5 (c
D
24
½aꢁD ¼ þ13:1 (c 4.72, hexane). Its spectral data were identi-
5.03, hexane). Its spectral data were identical with those
of 6a. HRMS calcd for C15H26O2 (M+) 238.1933; found,
238.1925.
cal with those of 4. HRMS calcd for C11H18O (M+)
166.1358; found, 166.1361.
4.3. 3,7-Dimethyl-2-methylene-6-octen-1-ol 5 and 50
4.5. 5,9-Dimethyl-4-methylene-8-decenoic acid 6b and 6b0
4.3.1. (R)-(ꢀ)-Isomer 5. A solution of (R)-4 (10.5 g,
63 mmol) in dry Et2O (50 mL) was added dropwise to a
stirred and ice-cooled suspension of LiAlH4 (1.3 g,
34 mmol) in dry Et2O (100 mL) at 0–10 ꢁC. The mixture
was stirred for 2 h at 5–10 ꢁC. Subsequently, H2O (10
mL) was added dropwise to the stirred and ice-cooled reac-
tion mixture to destroy the excess LiAlH4. The voluminous
solid was dissolved by the addition of ice-water containing
concd HCl (10 mL) and NH4Cl. Then the organic layer
was separated, and the aqueous layer was extracted with
Et2O. The combined Et2O solution was washed with water,
NaHCO3 aqueous solution and brine, dried with MgSO4,
and concentrated in vacuo. The residue was distilled to give
4.5.1. (R)-(ꢀ)-Isomer 6b. A solution of KOH (7.0 g,
125 mmol) in H2O (30 mL) was added to a solution of
(R)-6a (13.5 g, 57 mmol) in 95% EtOH (100 mL). The mix-
ture was stirred and heated at reflux for 2 h. It was then di-
luted with ice-water, acidified with AcOH (13 mL, ca.
230 mmol), and extracted with hexane. The extract was
washed with water and brine, dried over MgSO4, and con-
centrated in vacuo. The residue was distilled to give 9.9 g
(83%) of (R)-6b as an oil, bp 159–160 ꢁC/7 Torr;
23
n2D1 ¼ 1:4715; ½aꢁD ¼ ꢀ14:0 (c 4.41, hexane); mmax (film):
3080–2615 (m, CO2H), 1712 (s, C@O), 1650 (m, C@C),
890 (m, C@CH2). dH(CDCl3): 1.02 (3H, d, J 6.8, CHCH3),
1.25–1.38 (1H, m), 1.40–1.50 (1H, m), 1.58 (3H, s,
C@CCH3), 1.68 (3H, s, C@CCH3), 2.10–2.20 (1H, m),
2.29–2.36 (2H, m), 2.53 (2H, t-like, J 7.6, CH2CO2H),
4.72 (1H, s, C@CHH), 4.80 (1H, s, C@CHH), 5.09 (1H,
t-like, J 7.2, C@CH); dC(CDCl3):17.7, 20.0, 25.7, 25.9,
27.8, 32.5, 35.5, 39.9, 108.0, 124.5, 131.4, 152.4, 179.8.
Anal. Calcd for C13H22O2 (210.3): C, 74.24; H, 10.54.
Found: C, 74.20; H, 10.79.
10.1 g (91%) of (R)-5 as an oil, bp 113–115 ꢁC/11 Torr;
25
n2D1 ¼ 1:4710; ½aꢁD ¼ ꢀ19:4 (c 4.50, hexane); mmax (film):
3305 (s, OH), 1651 (m, C@C), 1045 (s, C–O), 899 (s,
C@CH2); dH(CDCl3): 1.06 (3H, d, J 6.8, CHCH3), 1.30–
1.40 (1H, m), 1.44 (1H, OH), 1.45–1.54 (1H, m), 1.59
(3H, s, C@CCH3), 1.68 (3H, s, C@CCH3), 1.92–1.98 (2H,
m), 1.92–1.99 (1H, m), 4.09 (2H, d, J 3, CH2OH), 5.05
(1H, s, C@CHH), 5.09 (1H, s, C@CHH). Anal. Calcd for
C11H20O (168.3): C, 78.51; H, 11.98. Found: C, 77.98; H,
12.05.
4.5.2. (S)-(+)-Isomer 6b0. In the same manner, (S)-6a0
(12.6 g, 53 mmol) yielded 9.4 g (86%) of (S)-6b0 as an oil,
23
4.3.2. (S)-(+)-Isomer 50. In the same manner, (S)-40 (10.5
bp 153–156 ꢁC/5 Torr; n2D0 ¼ 1:4712; ½aꢁD ¼ þ13:9 (c
g, 63 mmol) yielded 9.6 g (90%) of (S)-50 as an oil, bp 93–
4.28, hexane). Its spectral data were identical with those
of 6b. Anal. Calcd for C13H22O2 (210.3): C, 74.24; H,
10.54. Found: C, 74.32; H, 10.64.
22
96 ꢁC/4 Torr; n2D1 ¼ 1:4705; ½aꢁD ¼ þ19:0 (c 4.19, hexane).
Its spectral data were identical with those of 5. Anal. Calcd

K. Mori / Tetrahedron: Asymmetry 18 (2007) 838–846
843
4.6. 1-Diazo-6,10-dimethyl-5-methylene-9-undecen-2-one 8
via sodium 5.9-dimethyl-4-methylene-8-decenoate 6c and 5,9-
dimethyl-4-methylene-8-decenoyl chloride 7
of (R)-9 showed the identical MS. HRMS calcd for
C14H22O (M+) 206.1671; found, 206.1668.
4.6.1. (R)-Isomer 8. Sodium ethoxide (2.8 g, 41 mmol)
was added to a solution of (R)-6b (8.0 g, 38 mmol) in
99% EtOH (30 mL) and the solution concentrated in va-
cuo. The residue was dissolved in toluene, and the resulting
solution was concentrated in vacuo. This operation was re-
peated once more to remove EtOH completely. The amor-
phous solid residue 6c was suspended in hexane (100 mL),
and treated with dry C5H5N (0.5 mL) and (COCl)2 (15 g,
118 mmol) with stirring and ice-cooling at 0–5 ꢁC. The mix-
ture was stirred for 1 h at room temp., and then filtered
through Celite (vacuum suction). The Celite layer was
washed with hexane (100 mL), and the combined filtrate
and washings concentrated in vacuo to give 9.0 g (quant.)
of crude (R)-7 as an oil, mmax (film): 1801 (s, C@O), 1643
(m, C@C), 1041 (m), 960 (m), 894 (m), 729 (s). A solution
of (R)-7 (9.0 g, ca. 38 mmol) in hexane (100 mL) was added
dropwise over 15 min to a stirred and ice-cooled solution of
CH2N2 [prepared from 16 g (155 mmol) of N-nitroso-N-
methylurea, 50 mL of 20% KOH aqueous solution, and
Et2O (400 mL)] in Et2O (400 mL). The yellow reaction mix-
ture was stirred at 0–5 ꢁC for 1 h, and then concentrated in
vacuo to give crude (R)-8 (11.0 g, quant.) as a yellow oil,
mmax (film): 3082 (w), 2106 (s, N+„N), 1643 (s, C@O),
891 (m), 733 (m). This was immediately employed for the
next step.
4.7.2. (S)-(+)-Isomer 90. In the same manner, (S)-6b0
(11.8 g, 56 mmol) yielded 5.0 g (43%) of oily (S)-90 after
SiO2 chromatography and distillation, bp 142–146 ꢁC/
25
5 Torr, n2D2 ¼ 1:4866, ½aꢁD ¼ þ2:3 (c 5.55, hexane). Its
spectral data were identical with those of (R)-6b. HRMS
calcd for C14H22O (M+) 206.1671; found, 206.1679.
4.8. 4-(40-Oxobicyclo[3.2.1]hexyl)pentanal 10 and 100
4.8.1. (R)-Isomer 10. A solution of OsO4 (30 mg) in t-
BuOH (3 mL) and powdered NaIO4 (3.2 g, 15 mmol) were
added to a stirred solution of (R)-9 (1.0 g, 5 mmol) in a
mixture of THF (22.5 mL) and H2O (7.5 mL) at room
temp. under N2. The stirring was continued for 2 d at room
temp., while tan-colored mixture turned colorless. It was
then diluted with water, and extracted with Et2O. The ex-
tract was washed with water and brine, dried with MgSO4,
and concentrated in vacuo to give 0.9 g (quant.) of (R)-10
as an oil, mmax (film): 2723 (w, O@CH), 1722 (s, C@O),
1180 (m), 914 (m); dH(CDCl3): 0.99, 1.01 (total 3H, each
d, J 7, CHCH3), 9.78, 9.80 (total 1H each s, CHO);
dC(CDCl3): 201.9, 214.4. This was employed for the next
step without further purification.
4.6.2. (S)-Isomer 80. In the same manner, (S)-6b0 (10.6 g,
50 mmol) yielded 11.0 g (93%) of (S)-80 as a yellow oil. This
was immediately used for the next step.
4.8.2. (S)-Isomer 100. Similarly, (S)-90 (1.0 g, 5 mmol)
1
yielded 0.8 g (91%) of (S)-100, whose IR and H NMR
spectra were identical to those of (R)-10. This was directly
employed for the next step.
4.7. 2-Methyl-6-(40-oxobicyclo[3.1.0]hexyl)hept-2-ene 9
and 90
4.9. Ethyl (E)-2-methyl-6-(40-oxobicyclo[3.1.0]hexyl)hept-2-
4.7.1. (R)-(ꢀ)-Isomer 9. A solution of crude (R)-8 (11.0 g,
38 mmol) in cyclohexane (50 mL) was added dropwise over
30 min to a stirred and refluxing suspension of powdered
copper (1.0 g, 16 mmol) and anhyd CuSO4 (0.5 g, 3 mmol)
in cyclohexane (200 mL). After the addition, the mixture
was stirred and heated at reflux for 1 h, cooled and filtered.
The filtrate was concentrated in vacuo to give 8.5 g (quant.)
of crude (R)-9. This was chromatographed over SiO2
(150 g) in hexane. Elution with hexane/EtOAc (40:1–20:1)
gave ca. 1.0 g of by-products. Further elution with hex-
ane/EtOAc (15:1) afforded 6.9 g (85%) of (R)-9. This was
distilled to give 4.7 g (58%) of oily (R)-9 as a mixture of
enoate 11 and 110
4.9.1. (R)-Isomer 11. A solution of (carbethoxyethylid-
ene)triphenylphosphorane (1.8 g, 5.0 mmol) in dry THF
(10 mL) was added dropwise to a stirred and ice-cooled
solution of (R)-10 (0.90 g, 5.0 mmol) in dry CH2Cl2 (10
mL) at 0–5 ꢁC under N2. The Wittig reaction was exother-
mic. The mixture was further stirred for 2 d at room temp.,
and concentrated in vacuo. The residue was chromato-
graphed over SiO2 (30 g). Elution with hexane/EtOAc
(5:1) yielded 0.74 g (57%) of (R)-11 [contaminated with a
small amount (7%) of its (Z)-isomer] as an oil, mmax (film):
1726 (s, C@O), 1649 (w, C@C), 1261 (m, C–O); dH(CDCl3):
0.99, 1.02 (total 3H, each d, J 7, CHCH3), 1.28 (3H, t, J 7,
CH2CH3), 1.80, 1.82 [total 3H, each s, C@C(CH3)CO2Et],
4.18 (2H, q, J 7, CH2CH3), 5.88 [0.07H, m, (Z)-CH@
C(CH3)CO2Et] 6.70 [0.93H, m, (E)-CH@C(CH3)CO2Et].
This was employed in the next step without further
purification.
two diastereoisomers, bp 143–144 ꢁC/5 Torr, nD22
¼
23
1:4869, ½aꢁD ¼ ꢀ2:8 (c 4.51, hexane); mmax (film): 1728 (s,
C@O), 1182 (m), 916 (m), 775 (m); dH(CDCl3): 0.97, 0.99
(total 3H, each d, J 7, CHCH3), 1.58 (3H, C@CCH3),
1.70 (3H, C@CCH3), 5.06 (1H, m, CH@C); dC(CDCl3):
17.0, 17.4, 17.7, 19.3, 21.4, 22.4, 23.3, 25.7, 25.8, 25.9,
27.9, 33.0, 33.1, 33.4, 34.2, 34.5, 37.1, 37.4, 39.9 124.2,
131.7, 215.0; GC–MS (column: TC-Wax, temp: 100–
190 ꢁC (+3 ꢁC/min)): tR 19.9 min (0.5%) 37.1 (51.9%),
37.4 (1.2%), 37.9 (46.5%); MS (70 eV, EI): m/z: 206 (12)
[M+], 191 (4), 173 (3), 164 (4) 163 (18) 149 (12) 136 (14),
123 (46), 121 (12), 109 (23), 95 (30), 93 (38), 79 (62), 69
(79), 67 (86), 55 (100), 53 (57). Both of the diastereoisomers
4.9.2. (S)-Isomer 110. In the same manner, (S)-100 (0.80 g,
4.4 mmol) afforded 0.62 g (53%) of (S)-110 as an oil. Its
spectral data were identical to those of (R)-11. This was
used directly for the next step.

844
K. Mori / Tetrahedron: Asymmetry 18 (2007) 838–846
4.10. Ethyl (E)-2-methyl-6-(40-methylenebicyclo-
17.6, 18.3, 23.1, 26.0, 26.5, 29.1, 29.8, 30.1, 31.7, 32.3,
34.6, 35.2, 36.6, 38.2, 68.6, 102.3, 125.6, 135.0, 153.7,
GC–MS [Column: HP-5MS, 35% phenylmethylsiloxane,
30 m · 0.25 mm i.d.; press: 60.7 kPa; 70–230 ꢁC (+10 ꢁC/
min)]; tR 14.74 min (2.2%), 14.96 (2.2%) 15.03 (44.5%),
15.18 (40.8%), 15.37 (4.2%), 15.68 (2.6%). The peaks at
tR = 15.03 and 15.18 min were due to the two diastereoiso-
mers (1.09:1) of (R)-1 showing the same MS. MS (70 eV,
EI): m/z: 220 (7) [M+], 202 (9), 187 (12), 161 (13), 159
(10), 145 (19), 133 (24), 132 (32), 121 (52), 120 (32), 119
(78), 105 (37), 93 (100), 91 (59), 79 (41), 77 (41), 69 (23),
67 (20), 55 (23), 43 (35), 41 (26). HRMS calcd for
C15H24O (M+) 220.1827; found, 220.1827.
[3.1.0]hexyl)hept-2-enoate 12 and 120
4.10.1. (R)-Isomer 12. Methylenetriphenylphosphorane
was prepared by the addition of a solution of n-BuLi in
hexane (1.6 M, 2.1 mL, 3.4 mmol) to a suspension of
(C6H5)3P(CH3)Br (1.10 g, 3.0 mmol) in dry THF (10 mL)
at ꢀ78 ꢁC under N2. The mixture was stirred for 15 min
at ꢀ78 ꢁC to generate an orange solution of the Wittig re-
agent. This was added through a syringe to a stirred and
cooled solution of (R)-11 (0.70 g, 2.65 mmol) in dry THF
(7 mL) at ꢀ78 ꢁC under N2. The solution was stirred for
30 min at ꢀ78 ꢁC to room temp. It was then poured into
ice-water, and extracted with Et2O. The extract was washed
with water and brine, dried with MgSO4, and concentrated
in vacuo. The residue was chromatographed over SiO2
(20 g). Elution with hexane/EtOAc (10:3) gave 0.67 g
(96%) of (R)-12, mmax (film): 3074 (w), 1712 (s, C@O),
1651 (m, C@C), 1243 (s, C–O), 863 (m); dH(CDCl3):
0.55–0.78 (2H, m, cyclopropane CH2), 0.84–0.98 (3H, m,
CHCH3), 1.23–1.35 (3H, m, OCH2CH3), 4.16–4.28 (2H,
m, OCH2CH3), 4.62 (1H, s, C@CHH), 4.80 (1H, s,
C@CHH), 6.74 [1H, m, CH@C(CH3)CO2Et]. This was em-
ployed for the next step without further purification.
4.11.2. (S)-Isomer 10. In the same manner, (S)-110
(530 mg, 2 mmol) afforded 380 mg (85%) of (S)-10, nD21
¼
21
1:5053; ½aꢁD ¼ þ4:5 (c 1.08, hexane). Its spectral properties
were identical with those of (R)-1. GC–MS [same condi-
tions as for (R)-1]: tR 14.75 min (3.1%), 14.96 (3.1%),
15.05 (44.8%), 15.20 (42.1%), 15.37 (2.3%), 15.68 (1.3%).
The peaks at tR = 15.05 and 15.20 min were those of the
two diastereoisomers (1.06:1) of (S)-10. Their MS were
identical to those of the two diastereoisomers of (R)-1.
HRMS calcd for C15H24O (M+) 220.1827; found,
220.1833.
4.10.2. (S)-Isomer 120. In the same manner, (S)-110
(0.62 g, 2.35 mmol) gave 0.56 g (91%) of (S)-120. Its
spectral data were identical to those of (R)-12. This was
employed for the next step without further purification.
4.12. 1-Ethoxycarbonylethylphosphonic dichloride 20
According to Ref. 15, 17 and 18 were converted to 19, bp
97–99 ꢁC/2 Torr; mmax (film): 1737 (s, C@O); dH(CDCl3):
1.27–1.37 (9H, m, OCH2CH3), 1.47 (3H, ddd, J 18, 7, 2,
CHCH3), 3.03 (1H, dqd, J 18, 7, 2, CHCH3), 4.13–4.23
(6H, m, OCH2CH3). Solid PCl5 (39 g, 187 mmol) was
added portionwise to stirred and ice-cooled 19 (17.5 g,
73.5 mmol). After stirring for 30 min at 0–5 ꢁC, the stirred
mixture was heated at 75–80 ꢁC for 14 h in a draft cham-
ber. It was then concentrated in vacuo. The residue was dis-
tilled to give 20 (10.8 g 67%) as an oil, bp 87–89 ꢁC/2 Torr;
n2D3 ¼ 1:4748; mmax (film): 1743 (s, C@O), 1279 (s, C–O);
dH(CDCl3): 1.33 (3H, t, J 7, OCH2CH3), 1.69 (3H, dd, J
27, 7, PCHCH3), 2.03–2.32 (sextet, P), 3.67 (1H, dq, J
20, 7, PCHCH3), 4.23–4.51 (2H, m, OCHCH3). HRMS
calcd for C5H8PO3Cl [(MꢀH)+] 216.9588; found, 216.9590.
4.11. (E)-2-Methyl-6-(40-methylenebicyclo[3.1.0]hexyl)hept-
2-en-1-ol 1 and 10
4.11.1. (R)-Isomer 1. A solution of (i-Bu)2AlH in toluene
(1 M, 6 mL, 6 mmol) was added to a stirred and cooled
solution of (R)-11 (0.5 g, 1.9 mmol) in toluene (10 mL) at
ꢀ78 ꢁC under N2. After 5 min at ꢀ78 to 0 ꢁC, an additional
amount (4 mL, 4 mmol) of (i-Bu)2AlH in toluene was
added, and the stirring was continued for 30 min at 0–
5 ꢁC. MeOH (10 mL) was then added to destroy excess
(i-Bu)2AlH, and the mixture was stirred for 30 min at room
temp. It was filtered through Celite, and the Celite layer
was washed with hexane. The combined filtrate and wash-
ings were concentrated in vacuo. The residue was chro-
matographed over SiO2 (10 g). Elution with hexane/
EtOAc (4:1) yielded 0.23 g (55%) of (R)-1. This was further
4.13. Ethyl 2-(di-o-tolylphosphono)propanoate 15
purified by SiO2 chromatography to give pure (R)-1 as a
Triethylamine (10.4 g, 10 mmol) was added dropwise to a
stirred and ice-cooled solution of 20 (9.3 g, 42.5 mmol)
and o-cresol (9.3 g, 86 mmol) in CH2Cl2 (40 mL) at 0–
5 ꢁC. The mixture soon solidified, and then became paste-
like. The stirring was continued for 30 min at 0–5 ꢁC, and
then for 1 h at room temp. The mixture turned to a slurry
of solid Et3NÆHCl, which was stirred vigorously. Subse-
quently, the slurry was poured into ice-water, and extracted
with hexane. The extract was washed with ice-cooled dilute
NaOH aqueous solution, ice-cooled dilute HCl, saturated
NaHCO3 aqueous solution and brine, dried with MgSO4,
and concentrated in vacuo. The residue was distilled to give
15 as a viscous oil (9.3 g, 60%), bp 210–215 ꢁC/2 Torr;
n2D2 ¼ 1:5162; mmax (film): 1738 (s, C@O), 1585 (m, aro-
matic C@C) 1228 (s), 1168 (s), 1109 (s), 949 (vs), 808
(m), 760 (m); dH(CDCl3): 1.24 (3H, t, J 7, OCH2CH3).
24
mixture of two diastereoisomers, n2D1 ¼ 1:5052; ½aꢁD
¼
ꢀ10:7 (c 1.11, hexane); mmax (film): 3344 (s, OH), 1651
(m, C@C) 1116 (m, C–O), 864 (m); dH(CDCl3): 0.56
(0.5H, m, cyclopropane CH), 0.67 (1H, m, cyclopropane
CH), 0.74 (0.5H, m cyclopropane CH), 0.94, 0.97 (total
3H, each d, J 7, CHCH3), 1.68 [3H, CH@C(CH3)], 3.98
(2H, s, CH2OH), 4.65 (1H, s, C@CHH), 4.81 (1H, s,
C@CHH), 5.40 [1H, m, CH@C(CH3)]; dC(CDCl3): 13.7,
16.2, 17.5, 18.1, 18.3, 25.7, 26.3, 26.6, 28.8, 29.7, 31.2,
34.3, 34.9, 36.6, 38.1, 69.0, 101.7, 126.6, 134.5, 154.1; dH-
(C6D6): 0.42, 0.57, 0.60, 0.67 (total 2H, each m, cyclopro-
pane CH2), 0.88, 0.90 (total 3H, each d, J 7, CHCH3),
1.59 [3H, s, CH@C(CH3)], 3.80, 3.82 (total 2H, each s,
CH2OH), 4.78 (1H, s, C@CHH), 4.98 (1H, s, C@CHH)
5.34 [1H, m, CH@C(CH3)]; dC(C6D6): 13.7, 14.3, 16.2,

K. Mori / Tetrahedron: Asymmetry 18 (2007) 838–846
845
1.69 (3H, dd, J 19, 7, PCHCH3), 2.22 (3H, s, C6H4CH3),
2.25 (3H, s, C6H4CH3), 3.43 (1H, dq, J 19, 7, PCHCH3),
4.21 (2H, q, J 7, OCH2CH3), 7.00–7.32 (8H, m, aromatic
H); GC–MS [same conditions as for (R)-1]: tR 23.76 min
(92.7%, 15), 25.25 (4.1%, unknown, M+ = 396); MS
(70 eV, EI): m/z 362 (72) [M+], 317 (31), 273 (36), 227
(100), 108 (23), 91 (35). HRMS calcd for C19H23PO5
(M+) 362.1283; found, 362.1271.
5.90 [1H, m, CH@C(CH3)CO2Et]. This was employed for
the next step without further purification.
4.15.2. (S)-Isomer 220. In the same manner (S)-210 (1.16 g,
4.4 mmol) afforded (S)-220 (0.97 g, 84%). Its spectral data
were identical with those of (R)-22. This was employed
for the next step without further purification.
4.16. (Z)-2-Methyl-6-(40-methylenebicyclo[3.1.0]hexyl)hept-
2-en-1-ol 2 and 20
4.14. Ethyl (Z)-2-methyl-6-(40-oxobicyclo[3.1.0]hexyl)hept-
2-enoate 21 and 210
4.16.1. (R)-Isomer 2. A solution of (i-Bu)2AlH in toluene
(1 M, 12 mL, 12 mmol) was added to a stirred and cooled
solution of (R)-22 (1.19 g, 4.5 mmol) in dry toluene
(10 mL) at ꢀ78 ꢁC under N2. After 5 min at ꢀ78 to 0 ꢁC,
an additional amount of (i-Bu)2AlH (8 mL, 8 mmol) in tol-
uene was added, after which stirring was continued for
30 min at 0–5 ꢁC. MeOH (20 mL) was then added to de-
stroy excess (i-Bu)2AlH, and the mixture was stirred for
1 h at room temp., after which it was filtered through Cel-
ite, and the Celite layer washed with hexane. The combined
filtrate and washings were concentrated in vacuo. The res-
idue was chromatographed over SiO2 (20 g). Elution with
hexane/EtOAc (3:1) gave 0.51 g (51%) of crude (R)-2 con-
taminated with some phosphorus compounds. In order to
remove the phosphorus compounds, crude (R)-2 (510 mg)
was heated at reflux for 1.5 h in the presence of KOH
(0.5 g) in 95% EtOH (4 mL) and H2O (1 mL). The solution
was concentrated in vacuo, diluted with water, and ex-
tracted with Et2O. The extract was washed with water
and brine, dried with MgSO4, and concentrated in vacuo.
The residue was chromatographed over SiO2 (5 g). Elution
with hexane/EtOAc (10:3) gave 220 mg (22%) of (R)-2.
4.14.1. (R)-Isomer 21. A solution of the Horner-type Wit-
tig reagent in THF was prepared by the addition of a solu-
tion of 15 (1.6 g, 4.4 mmol) in dry THF (10 mL) to a stirred
and ice-cooled suspension of NaH (60% in mineral oil,
175 mg, 4.4 mmol) in dry THF (10 mL) at 0–5 ꢁC under
N2. A clear solution of the Wittig reagent was obtained
after stirring for 15 min at 0–5 ꢁC. This solution was added
to a stirred and cooled solution of (R)-10 (800 mg,
4.4 mmol) in dry THF (10 mL) at ꢀ78 ꢁC under N2. The
mixture was stirred for 30 min at ꢀ78 ꢁC and for 1 h at
0–5 ꢁC. It was then poured into ice and NH4Cl aqueous
solution, and extracted with Et2O. The extract was washed
with water and brine, dried over MgSO4, and concentrated
in vacuo. The residue was chromatographed over SiO2
(30 g). Elution with hexane/EtOAc (4:1–3:1) yielded 1.2 g
(quant.) of crude (R)-21 as an oil, mmax (film): 1728 (s,
C@O), 1645 (w, C@C); dH(CDCl3): 0.99, 1.01 (total 3H,
each d, J 7, CHCH3), 1.28 (3H, t, J 7, OCH2CH3), 1.89,
1.90 [total 3H, each s, C@C(CH3)CO2Et], 4.20 (2H, m,
OCH2CH3), 5.88 [1H, m, CH@C(CH3)CO2Et]. This was
employed for the next step without further purification.
This was further purified by SiO2 chromatography,
23
4.14.2. (S)-Isomer 210. In the same manner, (S)-100
(800 mg, 4.4 mmol) gave 1.16 g (quant.) of crude (S)-210.
Its spectral properties were identical with those of (R)-21.
This was employed for the next step without further
purification.
n2D1 ¼ 1:5056; ½aꢁD ¼ þ12:6 (c 1.20, hexane); mmax (film):
3394 (m, OH), 1651 (w, C@C), 1246 (m, C–O); dH(CDCl3):
0.60 (1H, dd, J 4, 8, cyclopropane CH), 0.71 (1H, dd, J 4, 4,
cyclopropane CH), 0.91, 0.93 (total 3H, each d, J 7,
CHCH3), 1.78 [3H, s, CH@C(CH3)CH2OH], 4.15 (2H, s,
CH2OH), 4.63 (1H, s, C@CHH), 4.81 (1H, s, C@CHH),
5.29 [1H, m, CH@C(CH3)CH2OH]; dC(CDCl3): 14.2,
16.2, 17.5, 18.3, 21.3, 22.7, 25.7, 26.3, 26.6, 28.8, 29.7,
31.2, 31.6, 34.9, 35.5, 36.6, 37.9, 38.0, 61.6, 101.7, 128.7,
134.0, 154.1; dH(C6D6): 0.43 (1H, dd, J 4, 8, cyclopropane
CH), 0.61 (1H, dd, J 4, 4, cyclopropane CH), 0.86, 0.87 (to-
tal 3H, each d, J 7, CHCH3), 1.75 (3H, s, C@CCH3), 3.97
(2H, s, CH2OH), 4.78 (1H, s, C@CHH), 4.99 (1H, s,
C@CHH), 5.18 [1H, m, CH@C(CH3)CH2OH]; dC(C6D6):
14.3, 15.9, 16.2, 17.6, 18.2, 18.4, 21.3, 23.0, 25.8, 26.0,
26.4, 26.6 29.0, 29.2, 30.1, 31.7, 32.3, 35.1, 35.7, 36.5,
38.1, 61.3, 102.3, 128.1, 134.5, 153.6, 154.7; GC–MS
[Column: HP-5MS, 35% phenylmethylsiloxane, 30 m ·
0.25 mm i.d.; press: 60.7 kPa; 70–130 ꢁC (+10 ꢁC/min)].
tR 14.74 min (50.1%), 14.95 (34.4%), 15.12 (5.7%), 15.45
(7.3%). The peaks at tR = 14.74 and 14.95 min were due
to the two diastereomers (1.46:1) of (R)-2, showing virtu-
ally the same MS as those of (R)-1 and (S)-10. MS of the
peaks at tR = 15.12 and 15.45 min were different from
those of the major peaks. MS (70 eV, EI): m/z 220 (7)
[M+], 202 (13), 187 (15), 161 (13), 159 (14), 145 (23), 133
(27), 132 (42), 121 (57), 120 (36) 119 (89) 105 (43), 93
(100), 91 (72), 79 (45), 77 (43), 69 (25), 67 (23), 55 (25),
4.15. Ethyl (Z)-2-methyl-6-(40-methylenebicyclo-
[3.1.0]hexyl)hept-2-enoate 22 and 220
4.15.1. (R)-Isomer 22. Methylenetriphenylphosphorane
was prepared by the addition of a solution of n-BuLi in
hexane (1.6 M, 3.6 mL, 5.8 mmol) to a suspension of
(C6H5)3P(CH3)Br (1.7 g, 5.8 mmol) in dry THF (15 mL)
at ꢀ78 ꢁC under N2. The mixture was stirred for 15 min
at ꢀ78 ꢁC to generate an orange solution of the Wittig re-
agent. This was added through a syringe over 5 min to a
stirred and cooled solution of (R)-21 (1.2 g, 4.5 mmol) in
dry THF (7 mL) at ꢀ78 ꢁC under N2. The solution was
stirred for 30 min at room temperature. It was then poured
into ice-water, and extracted with Et2O. The extract was
washed with water and brine, dried with MgSO4, and con-
centrated in vacuo. The residue was chromatographed over
SiO2 (20 g). Elution with hexane/EtOAc (10:3) gave 1.19 g
(quant.) of (R)-22, mmax (film): 1714 (s, C@O), 1651 (m,
C@C), 1225 (s, C–O), 862 (m); dH(CDCl3): 0.55–0.78
(2H, m, cyclopropane CH2), 0.84–0.98 (3H, m, CHCH3),
1.23–1.35 (3H, m, OCH2CH3), 4.15–4.25 (2H, m,
OCH2CH3), 4.62 (1H, s, C@CHH), 4.80 (1H, s, C@CHH),

846
K. Mori / Tetrahedron: Asymmetry 18 (2007) 838–846
43 (37), 41 (29). The MS of (R)-2 was virtually identical
with those of the other isomers, (R)-1, (S)-10, and (S)-20;
HRMS calcd for C15H24O (M+) 220.1827; found,
220.1831.
analysis. Professor H. Watanabe (Univ. Tokyo) kindly
helped my literature survey.
References
4.16.2. (S)-Isomer 20. In the same manner, (S)-220 (970
mg) yielded (S)-20 (550 mg, 67%). This was further purified
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2. Takita, M.; Nagamine, J.; Takeda, T.; Sugie, H. Ann. Report
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by SiO2 chromatography. All of its spectral data were iden-
21
tical with those of (R)-2, n2D1 ¼ 1:5058; ½aꢁD ¼ ꢀ2:2 (c 1.14,
hexane); GC–MS [same conditions as for (R)-2]:
tR = 14.76 min (54.1%), 14.96 (34.0%), 15.13 (5.0%),
15.46 (5.1%). The peaks at tR = 14.76 and 14.96 min were
those of the two diastereomers (1.59:1) of (S)-20. Their
MS were virtually identical to those of (R)-1 and (S)-10.
HRMS calcd for C15H24O (M+) 220.1827; found,
229,1821. The reason for the small rotation value was
unclear.
Acknowledgments
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Thanks are due to Mr. Masateru Kimura (President, Toyo
Gosei Co.) for his support. I am grateful to Ms. Masami
Takita (Yamagata Prefecture Mogami Office) and Dr.
Hajime Sugie (National Institute for Agro-Environmental
1
Sciences) for their supply of the H NMR, 13C NMR and
12. Nicolaou, K. C.; Bulger, P. G.; Brenzovich, W. E. Org.
Biomol. Chem. 2006, 4, 2158–2183.
MS spectral charts of the natural pheromone. Ms. Tomoko
Yoshimura and Dr. Shoichi Ishii (Yamagata Prefectural
Agricultural Research Center) kindly carried out the bioas-
says of (2E,6R)-1, (2S,6S)-10, (2Z,6R)-2, and (2Z,6S)-20.
Dr. Takuya Tashiro (RIKEN) helped the final purification
of the four pheromone candidates as well as the prepara-
tion of the Figure and Schemes. I also thank Mr. Yasu-
masa Shikichi (Toyo Gosei Co.) for NMR and GC–MS
13. Ando, K. J. Org. Chem. 1997, 62, 1934–1939.
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