Pheromone synthesis. Part 263: Synthesis of the racemate and the enantiomers of (E)-cis-6,7-epoxy-2-nonenal, the male-produced pheromone of the red-necked longhorn beetle, Aromia bungii

Article abstract of DOI:10.1016/j.tet.2018.01.052

The racemate and the enantiomers of (E)-cis-6,7-epoxy-2-nonenal, the male pheromone of Aromia bungii, were synthesized by olefin cross metathesis between crotonaldehyde and (±)-, (+)- and (?)-cis-3,4-epoxy-7-octene. The epoxide was prepared by the Grignar

Full text of DOI:10.1016/j.tet.2018.01.052

Accepted Manuscript
Pheromone synthesis. Part 263: Synthesis of the racemate and the enantiomers
of (E)-cis-6,7-epoxy-2-nonenal, the male-produced pheromone of the red-necked
longhorn beetle, Aromia bungii
Kenji Mori
PII:
S0040-4020(18)30112-1
10.1016/j.tet.2018.01.052
TET 29267
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 4 January 2018
Revised Date: 25 January 2018
Accepted Date: 30 January 2018
Please cite this article as: Mori K, Pheromone synthesis. Part 263: Synthesis of the racemate and the
enantiomers of (E)-cis-6,7-epoxy-2-nonenal, the male-produced pheromone of the red-necked longhorn
beetle, Aromia bungii, Tetrahedron (2018), doi: 10.1016/j.tet.2018.01.052.
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ACCEPTED MANUSCRIPT

ACCEPTED MANUSCRIPT
Pheromone synthesis. Part 263: Synthesis of the racemate and the enantiomers of
(E)-cis-6,7-epoxy-2-nonenal, the male-produced pheromone of the red-necked longhorn
beetle, Aromia bungiiꢀ
Kenji Mori*
Photosensitive Materials Research Center, Toyo Gosei Co., Ltd, 4-2-1 Wakahagi,
Inzai-shi, Chiba 270-1609, Japan
ARTICLE INFO
Article history:
Received 4, January 2018
Received in revised form
February 2018
February 2018
February 2018
Accepted
Available online
Keywords:
Aromia bungii
Grignard coupling
Olefin cross metathesis
Pheromone
Sharpless asymmetric epoxidation
ABSTRACT
The racemate and the enantiomers of (E)-cis-6,7-epoxy-2-nonenal, the male pheromone
of Aromia bungii, were synthesized by olefin cross metathesis between crotonaldehyde
and (±)-, (+)- and (-)-cis-3,4-epoxy-7-octene. The epoxide was prepared by the
Grignard coupling between allylmagnesium bromide and (±)-, (+)- and
(-)-cis-2,3-epoxypentyl triflate.
(±)-cis-2,3-Epoxy-1-pentanol was prepared by
MCPBA epoxidation of (Z)-2-penten-1-ol, while its enantiomers were synthesized by
the Sharpless asymmetric epoxidation of the allylic alcohol.
For Part 262, see Ref.1
ꢀ
* Corresponding author.
E-mail address: kjk-mori@arion.ocn.ne.jp (K. Mori).
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1. Introduction
The red-necked longhorn beetle Aromia bungii (Faldermann) (Coleoptera:
Cerambycidae) is a wood-boring beetle native to China, Korea, Mongolia and eastern
Russia. It recently invaded and became established in Japan, and attacks mainly cherry,
peach, plum and apricot trees, causing a big problem in both ornamental and
horticultural trees.2
Its male-produced sex-aggregation pheromone was identified in 2017 as
(E)-cis-6,7-epoxy-2-nonenal (1, Fig. 1) by Millar and co-workers.3 The synthetic (±)-1
was pheromonally active, and incorporated into effort to detect and manage the pest
beetles in Japan. Millar’s synthesis of (±)-1 was straight-forward by epoxidation of the
commercially available violet leaf aldehyde, (2E,6Z)-2,6-nonadienal (A)3. Millar and
co-workers subsequently synthesized the enantiomers of 1, and (6R,7S)-1 was shown to
be the naturally occurring one (J.G. Millar, personal communication, December 23,
2017).
Fig.1. Structures of the pheromone [(6R,7S)-1] of Aromia bungii and related
compounds.
This paper reports my own synthesis of the enantiomers of 1, which is based on the
Sharpless asymmetric epoxidation,4 Grignard coupling, and olefin cross metathesis.5
Our previous experience in the synthesis of the mammalian blood odorant B was
advantageously utilized to introduce the chirality by the Sharpless procedure.6
2. Results and discussion
2.1. Retrosynthetic analysis of (6R,7S)-1
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Fig.2 shows the retrosynthetic analysis of (6R,7S)-1. The target pheromone
(6R,7S)-1 would be prepared by olefin cross metathesis of epoxyalkene C with
crotonaldehyde D,5,7 while C would be available by coupling of triflate E8,9 with
allylmagnesium bromide F. The epoxytriflate E would be prepared from G,10 which is
a known product of the Sharpless asymmetric epoxidation of (Z)-2-penten-1-ol H. The
present work allowed the synthesis of the racemate as well as both the enantiomers of 1
in quantities sufficient for further biological works.
Fig.2. Retrosynthetic analysis of (6R,7S)-1.
2.2. Synthesis of (±)-1
Prior to the synthesis of the enantiomers of 1, synthesis of (±)-1 was first carried out
as shown in Scheme 1 to find out the proper reaction conditions for each of the
synthetic steps.
The known epoxy alcohol (±)-39 was prepared by epoxidation of (Z)-2-penten-1-ol
(2) with m-chloroperbenzoic acid (MCPBA) in 58-70% yield. It was noticed in this
step that the epoxy alcohol 3 was readily soluble in water, and its work-up should be
executed by using a minimal amount of water. Otherwise, only a low yield (58%) of 3
was obtained.
Regioselective elongation of the carbon chain of 3 at C-1 without cleaving the
epoxy ring was found to be possible in the course of the synthesis of chiral
epoxyalkanes as pheromones. Copper-catalyzed Grignard coupling of epoxy tosylate
(4, R=Ts instead of Tf) was proved to be successful in 1986.11 However, it was later
found that the corresponding triflate 4 showed greater reactivity at C-1 than the
tosylate.8,9 Accordingly, (±)-3 was treated with n-BuLi and Tf2O to give (±)-4, which
was immediately coupled with allylmagnesium bromide in the presence of Li2CuCl4 to
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give volatile and thermally unstable epoxide (±)-5 in 41% yield based on (±)-3.
Purification of (±)-5 was first achieved by SiO2 chromatography employing
pentane/EtOAc as the eluent, and then by careful distillation below 100oC (bath
temperature).
Scheme 1. Synthesis of (±)-1. Reagents: (a) MCPBA, CH2Cl2 (70%); (b) n-BuLi,
Tf2O, THF; (c) CH2=CHCH2MgBr, Li2CuCl4, THF, Et2O (41%, 2 steps); (d)
MeCH=CHCHO, Hoveyda-Grubbs II, CH2Cl2 (23% after chromatog. and distillation).
The final step of olefin cross metathesis between (±)-5 and crotonaldehyde was
successfully achieved employing Hoveyda-Grubbs second generation catalyst12 to give
(±)-1, which was thermally labile and obtained in 23% yield after chromatographic
purification and distillation. The product was 96.8% pure (E)-1 contaminated with
3.2% of its (Z)-isomer. More careful distillation in the cases of (+)- and (-)-1 gave
better yields (vide infra). The synthetic (±)-1 showed 1H and 13C NMR and MS
spectra identical with those of the natural pheromone and Millar’s synthetic (±)-1. The
overall yield of (±)-1 was 6.6% based on 2 (4 steps).
2.3. Synthesis of the enantiomers of 1
Scheme 2 summarizes the synthesis of the enantiomers of 1. Sharpless asymmetric
epoxidation of 2 was reported by Baker and co-workers to give (2S,3R)-(-)-3 of 80% ee
{[α]D20-11.8 (c 1.7, CH2Cl2)}.10,13,14 Because the goal of the present work was to
secure the pure enantiomers of 1 for bioassay, it was necessary to enrich the
enantiomeric purities of both the enantiomers of 3. For that purpose, purification of
epoxy alcohols via their crystalline 3,5-dinitrobenzoates was quite useful.6,11,13,14,15
With these past experience, the synthesis started from (Z)-2-penten-1-ol (2).
Catalytic asymmetric epoxidation4 of 2 with -(-)-diethyl tartrate (DET), Ti(OPri)4
D
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and t-BuOOH in CH2Cl2 was executed in the presence of powdered MS 3A for 24 h at
-10oC to give (2R,3S)-3, [α]D23+9.96 (c 3.05, CH2Cl2), (78.0% ee as determined by
chiral GC) in 88% yield. Treatment of the oily (+)-3 with 3,5-dinitrobenzoyl chloride
(DNBCl) and pyridine afforded crystalline (2R,3S)-6. Its three recrystallizations from
EtOAc/hexane gave pure 3,5-dinitrobenzoate (2R,3S)-6, mp 75-76oC, [α]D23+30.2 (c
3.11, CH2Cl2) in 42% yield. The crystalline (2R,3S)-6 was almost enantiomerically
pure (99.94% ee) as determined by chiral HPLC. To recover the purified alcohol (+)-3,
(+)-6 was treated with K2CO3 in MeOH to effect methanolysis. Aqueous work-up at
this stage gave a miserable yield (20% based on 6) of (+)-3 due to the water solubility of
3. Accordingly, after methanolysis, the solution was concentrated in vacuo, and the
residue was diluted with pentane. The insoluble K2CO3 and methyl
3,5-dinitrobenzoate were filtered off, and the filtrate was concentrated. The residue
was distilled to give pure (2R,3S)-3, [α]D19+14.3 (c 1.26, CH2Cl2), (99.4% ee as
determined by chiral GC) in 67% yield.
Scheme 2. Synthesis of the enantiomers of 1. Reagents: (a) D
-(-)-DET, Ti(OPri)4,
t-BuOOH, MS 3A, CH2Cl2 (88%); (b) DNBCl, C5H5N, CH2Cl2, recryst’n (x 3) (42%);
(c) K2CO3, MeOH (67%); (d) n-BuLi, Tf2O, THF; (e) CH2=CHCH2MgBr, Li2CuCl4,
THF, Et2O (58%, 2 steps); (f) MeCH=CHCHO, Hoveyda-Grubbs II, CH2Cl2 (57%).
Chain-elongation of (2R,3S)-3 was executed in the same manner as in the case of
(±)-3 to give (3S,4R)-5 in 58% yield after chromatographic purification and distillation.
The final cross metathesis between (3S,4R)-5 and crotonaldehyde was followed by
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chromatographic purification and distillation to give (6R,7S)-1, [α]D22+12.8 (c 2.33,
pentane), (99.2% ee as determined by chiral GC) in 57% yield. The product contained
3.3% of its (Z)-isomer. The spectroscopic data of (6R,7S)-1 were identical with those
of (±)-1. The overall yield of (6R,7S)-1 was 8% based on 2 (six steps).
Similarly, by using L-(+)-diethyl tartrate as the catalyst for asymmetric epoxidation,
(6S,7R)-1, [α]D20-13.6 (c 2.33, pentane), (99.6% ee as determined by chiral GC) was
obtained in 8% overall yield based on 2 (six steps). The product contained 1.3% of its
(Z)-isomer. The amounts of the enantiomers of 1 thus synthesized was 1.96 g for (+)-1
and 1.88 g for (-)-1.
3. Conclusion
The racemate as well as both the enantiomers of (E)-cis-6,7-epoxy-2-nonenal (1)
were synthesized in amounts sufficient for biological works. Chirality was introduced
by Sharpless asymmetric epoxidation, while the chain-elongation was executed by
Grignard coupling and olefin cross metathesis. Nearly enantiopure (6R,7S)-(+)-1 and
(6S,7R)-(-)-1 could be secured by enantiomer enrichment through recrystallization of
the 3,5-dinitrobenzoate 6 of the epoxy alcohol 3 obtained by asymmetric epoxidation of
2. Although the natural pheromone was known to be (6R,7S)-(+)-1 whose pheromone
activity was slightly stronger than that of (±)-1 (J.G. Millar, personal communication,
December 23, 2017 and H. Yasui, personal communication, October 3, 2017), the
present synthesis provided materials sufficient for further biological works in Japan in
the summer, 2018.
4. Experimental
4.1. General
All bps and mps are uncorrected values. Refractive indices were measured on an
Atago DMT-1 refractometer. IR spectra were measured on a Jasco FT/IR-410
spectrometer. 1H NMR spectra (400 MHz, TMS at δ=0.00 as the internal standard)
and 13C NMR spectra (100 MHz, CDCl3 at δ=77.0 as the internal standard) were
recorded on a Jeol JNM-ECZ 400S/L1 spectrometer. GC-MS were measured on
Agilent Technologies 5975 inert XL. HRMS were recorded on Jeol JMS-700V or
JMS-T100GCV. Silica gel column chromatography was carried out on Merck
Kieselgel 60 Art 1.00734.
4.2. cis-2,3-Epoxy-1-pentanol (3)
4.2.1. Racemate
Epoxidation of 2 with MCPBA in CH2Cl2 as reported previously9 gave (±)-3 as a
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colorless oil in 58-70% yield after distillation, bp 74-76oC/1 kPa. The product 3 is
soluble in water, and excessive washing with aqueous NaHCO3 solution in the course of
work-up resulted in a reduced yield (58%) of 3. Its IR, 1H NMR and MS spectra were
identical with those recorded in ref. 9. δC (CDCl3): 10.74, 21.40, 57.20, 58.56,60.86.
4.2.2. (2R,3S)-(+)-Isomer by Sharpless asymmetric epoxidation
Activated (heating at 160oC under 0.1 kPa for 3 h) and powdered MS 3A(5.0 g) was
added to dry CH2Cl2 (110 mL) under argon, and cooled to -10oC with a dry ice/CCl4
bath. To this mixture were added with stirring and cooling a solution of
g, 21 mmol) in CH2Cl2 (20 mL), a solution of Ti(OPri)4 (4.26 g, 15 mmol) in CH2Cl2
(20 mL) and a solution of t-BuOOH (5.5
in nonane, 54.5 mL, 300 mmol) at -10oC.
D-(-)-DET (4.32
M
A solution of 2 (12.9 g, 150 mmol) in CH2Cl2 (20 mL) was added over 10 min to the
stirred mixture at -20 to -10oC. Stirring was continued for 24 h at -10oC. The
mixture was then warmed to 0oC. Subsequently, 30% NaOH solution (30 mL), 15%
Na2S2O3 solution (20 mL) and NaCl (10 g) were added to the stirred mixture under
ice-cooling. After stirring for 10 min, the CH2Cl2 layer was separated, and aqueous
layer was extracted with CH2Cl2. The combined CH2Cl2 solution was dried (MgSO4),
filtered through a cotton plug, and the filtrate was concentrated under atmospheric
pressure with a Vigreux column. The residue was distilled to give (2R,3S)-(+)-3 (13.4
g, 88%) as a colorless oil, bp 72-74oC/0.8 kPa; nD24=1.4312; [α]D23+9.96 (c 3.05,
CH2Cl2); νmax (film); 3408 (br s), 2973 (s), 2936 (s), 2878 (m), 1460 (m), 1042 (s), 894
(m), 818 (m), 800 (m); δH (CDCl3): 1.00 (3H, t, J = 7.2 Hz), 1.42-1.62 (2H, m), 2.48
(1H, br), 2.92-2.98 (1H, m), 3.10-3.15 (1H, m), 3.62-3.64 (1H, m), 3.79-3.82 (1H, m);
δC (CDCl3): 10.75, 21.41, 57.28, 58.57, 60.85; GC-MS [column: HP-5MS, 5%
phenylmethylsiloxane, 0.25 mm i.d. x 30 m; carrier gas He; press 61 kPa; temp
70-230oC (+10oC/min)]: tR 3.38 min (99.3%); MS (70 eV, EI): m/z: 102 (<1) [M+], 60
(7), 59 (100), 57 (18), 45 (8), 44 (26), 43 (37), 42 (13), 41 (43), 39 (17), 31 (37).
4.2.3. (2S,3R)-(-)-Isomer by Sharpless asymmetric epoxidation
In the same manner as described above for (2R,3S)-(+)-3 but by employing
L-(+)-DET, 2 (12.9 g) gave 13.8 g (91%) of (2S,3R)-(-)-3 as a colorless oil, bp
72-73oC/0.8 kPa; ; nD24=1.4320; [α]D23-10.1 (c 2.31, CH2Cl2); {ref. 10. [α]D20-11.8 (c
1.7, CH2Cl2); 80% ee}; GC-MS [same conditions as those used for (+)-3]: tR 3.35 min
(100%). Its IR, 1H and 13C NMR, and MS spectra were identical with those of (+)-3.
4.3. cis-2,3-Epoxypentyl 3,5-dinitrobenzoate (6)
4.3.1. (2R,3S)-(+)-Isomer
3,5-Dinitrobenzoyl chloride (DNBCl, 31.1 g, 135 mmol) was added portionwise to a
stirred and ice-cooled solution of (2R,3S)-(+)-3 (78.0% ee, 13.4 g, 131 mmol) in CH2Cl2
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(100 mL) and C5H5N (40 mL) at 5-10oC. After the addition, the mixture was left to
stand in a refrigerator for 3 d. It was then diluted with ice and water, and extracted
with EtOAc. The extract was washed successively with CuSO4 solution, NaHCO3
solution and brine, dried (MgSO4), and concentrated in vacuo. The residual crystalline
mass was recrystallized from EtOAc/hexane to give 22.3 g (57%) of (2R,3S)-6, mp
72-74oC; [α]D22+29.2 (c 2.59, CH2Cl2). It was recrystallized again from
EtOAc/hexane to give 17.6 g (45%) of purer (2R,3S)-6, mp 75-76oC, [α]D25+30.1 (c
2.65, CH2Cl2). It was further recrystallized from EtOAc/hexane to give 16.5 g (42%)
of pure (2R,3S)-6 as pale yellow leaflets, mp 77-78oc; [α]D23+30.2 (c 3.11, CH2Cl2);
νmax (nujol); 3112 (w), 3094 (w), 1724 (s), 1629 (m), 1544 (s), 1348 (s), 1295 (s), 1178
(m), 1074 (m), 731 (m), 720 (m); δH (CDCl3): 1.09 (3H, t, J = 7.6 Hz), 1.55-1.74 (2H,
m), 3.08 (1H, dt, J = 4, 6 Hz), 3.53 (1H, dt, J = 4, 7.6 Hz), 4.38 (1H, dd, J = 8, 12 Hz),
4.71 (1H, dd, J = 3.6, 12 Hz); 9.17 (2H), 9.22 (1H); δC (CDCl3): 10.86, 21.60, 53.57,
57.90, 65.47, 122.78, 129.72, 133.48, 148.81, 162.56; HRMS (APCI+) calc for
C12H12N2O7 + H: 297.0723, found: 297.0723.
4.3.2. (2S,3R)-(-)-Isomer
In the same manner as described above for (2R,3S)-(+)-6, (2S,3R)-(-)-3 (80.4% ee,
13.8 g) gave 19.2 g (47%) of pure (2S,3R)-(-)-6 as pale yellow leaflets, mp 77-78oC;
[α]D17-30.7 (c 3.20, CH2Cl2). Its IR, 1H and 13C NMR data were identical with those
of (+)-6. HRMS (APCI+) calc for C12H12N2O7 + H; 297.0723, found: 297.0729.
4.4. Enantiomers of cis-2,3-epoxy-1-pentanol (3) by methanolysis of the enantiomers
of 6
4.4.1. (2R,3S)-(+)-Isomer
Potassium carbonate (1.60 g, 12 mmol) was added to a solution of (2R,3S)-(+)-6
(16.5 g, 56 mmol) in THF (35 mL) and MeOH (90 mL). The mixture was stirred at
0-5oC for 1 h to give a dark red mixture, which was concentrated in vacuo at 30oC (bath
temp). The residual semi-solid was triturated with pentane, and filtered to remove
K2CO3 and methyl 3,5-dinitrobenzoate. The solid was washed thoroughly with
pentane. The combined filtrate and washings were concentrated under atmospheric
pressure with a Vigreux column. The residue was distilled to give 3.81 g (67%) of
(2R,3S)-(+)-3 as a colorless oil, bp 64-65oC/0.4 kPa; nD21=1.4344; [α]D19+14.3 (c 1.26,
CH2Cl2). Its IR, 1H and 13C NMR, and MS spectra were identical with those described
in 4.2.2. GC-MS (same conditions as recorded in 4.2.2): tR 3.36 min (100%). HRMS
(isobutane CI+) calc for C5H10O2 + H: 103.0759, found: 103.0760.
4.4.2. (2S,3R)-(-)-Isomer
In the same manner as described above for (2R,3S)-(+)-3, (2S,3R)-(-)-6 (19.2 g)
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gave 4.00 g (60%) of (2S,3R)-(-)-3 as a colorless oil, bp 67-70oC/ 0.7 kPa; nD23= 1.4344;
[α]D22-14.0 (c 3.94, CH2Cl2). Its IR, 1H and 13C NMR, and MS spectra were identical
with those described in 4.2.2. GC-MS (same conditions as recorded in 4.2.2): tR 3.27
min (98.8%). HRMS (isobutane CI+) calc for C5H10O2 + H: 103.0759, found:
103.0760.
4.5. cis-3,4-Epoxy-7-octene (5)
4.5.1. Racemate
A solution of n-BuLi (1.6
M in hexane, 20.2 mL, 32.4 mmol) was added dropwise
over 15 min to a stirred and cooled solution of (±)-3 (3.30 g, 32.4 mmol) in dry THF (60
mL) at -70 to -60oC under argon. The mixture was stirred for 15 min at -70oC to
complete the formation of the lithium alkoxide. Then Tf2O (9.13 g, 5.45 mL, 32.4
mmol) was added over 10 min to the stirred and cooled mixture at -60 to -50oC. After
stirring for 15 min at -60oC to complete the formation of (±)-4, a solution of Li2CuCl4
(0.1
M in THF, 3 mL, 0.3 mmol) and allylmagnesium bromide (1.0 M in Et2O, 32.4 mL,
32.4 mmol) were added over 10 min to the stirred and cooled mixture at -70oC to -60oC.
The mixture was stirred for 30 min at -60oC, and left to stand at room temperature for
30 min. It was then poured into ice and NH4Cl solution, and extracted with Et2O.
The Et2O solution was washed successively with water, NaHCO3 solution and brine,
dried (MgSO4), and concentrated under atmospheric pressure with a Vigreux column.
the residue was further concentrated in vacuo (rotatory evaporator) for a short period
(3-5 min). The residue (4.89 g) was chromatographed over SiO2 (40 g). Elution with
pentane gave hydrocarbon impurities (0.33 g). Further elution with pentane/EtOAc
(50:1) gave 2.61 g (64%) of crude (±)-5. (Use of hexane for chromatography
decreased the yield of (±)-5 drastically due to the high volatility of 5. Concentration of
the eluted fractions was carried out under atmospheric pressure with a Vigreux column.).
Distillation of crude (±)-5 gave 1.69 g (41%) of pure (±)-5 as a colorless oil, bp
63-65oC/3.0 kPa; nD25=1.4322; νmax (film): 3079 (w), 2973 (s), 2934 (m), 2878 (m),
1642 (m), 1457 (m), 996 (m), 911 (s), 816 (m), δH (CDCl3): 1.04 (3H, t, J = 7.6 Hz),
1.45-1.70 (4H, m), 2.15-2.32 (2H, m), 2.85-2.91 (1H, m), 2.92-2.97 (1H, m), 4.90-5.10
(2H, m), 5.80-5.90 (1H, m); δC (CDCl3): 10.73, 21.25, 27.25, 30.91, 56.94, 58.58;
115.30, 137.85; GC-MS (same conditions as reported in 4.2.2): tR 4.02 min (94%); MS
(70 eV, EI): m/z: 111 (3) [(M-15)+], 97 (16), 85 (47), 67 (100), 59 (53), 41 (94).
HRMS calc for C8H14O: 126.1045, found: 126.1056.
4.5.2. (3S,4R)-(-)-Isomer
In the same manner as described above for (±)-5, (2R,3S)-3 (3.95 g) gave 2.82 g
(58%) of (3S,4R)-(-)-5 as a colorless oil, bp 62-65oC/2.4 kPa; nD22=1.4356; [α]D20-8.53
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(c 1.81, pentane). Its IR, 1H and 13C NMR, and MS spectra were identical with those
of (±)-5. GC-MS (same conditions as reported in 4.2.2): tR 4.01 (90.0%), 4.38 min
(10.0%). HRMS calc for C8H14O: 126.1045, found: 126.1061.
4.5.3. (3R,4S)-(+)-Isomer
In the same manner as described above for (±)-5, (2S,3R)-3 (3.99 g) gave 2.53 g
(52%) of (3R,4S)-(+)-5 as a colorless oil, bp 64-67oC/2.8 kPa; nD18=1.4350; [α]D17+6.43
(c 1.28, pentane). Its IR, 1H and 13C NMR, and MS spectra were identical with those
of (±)-5. GC-MS (same conditions as reported in 4.2.2): tR 4.02 (94.4%), 4.38 min
(5.6%). HRMS calc for C8H14O: 126.1045, found: 126.1066.
4.6. (E)-cis-6,7-Epoxy-2-nonenal (1)
4.6.1. Racemate
Hoveyda-Grubbs second generation catalyst (H-G II, 52 mg, 0.08 mmol, 0.6 mol%
based on 5) was added to a solution of (±)-5 (1.69 g, 13 mmol) and MeCH=CHCHO
(3.64 g, 52 mmol, 4 eq) in CH2Cl2 (30 mL) under argon. The solution was stirred and
heated under reflux for 30 min until gas evolution (MeCH=CH2) ceased. The slightly
brown-colored solution was concentrated in vacuo, and the residue (4.8 g) was
chromatographed over SiO2 (20 g). Elution with hexane gave 0.37 g of hydrocarbon
impurities. Further elution with hexane/EtOAc (20 : 1) gave 2.20 g (quant.) of crude
(±)-1. The crude (±)-1 (1.67 g) was distilled to give 470 mg (23% based on 5 or 30%
based on crude 1 submitted to distillation) of pure (±)-1 as a colorless oil (The product 1
was thermally unstable and polymerized to give residual oil or amorphons solid.), bp
91-93oC/0.1 kPa; nD27=1.4704; νmax (film): 2972 (s), 2937 (m), 2878 (m), 2819 (w),
2738 (w), 1692 (vs), 1637 (m), 1457 (m), 1390 (w), 1308 (w), 1273 (w), 1130 (m),
1095 (w), 1015 (w), 975 (m), 905 (m), 816 (m), 741 (w); δH (CDCl3): 1.04 (3H, t, J =
7.2 Hz), 1.44-1.62 (2H, m), 1.63-1.72 (1H, m), 1.74-1.84 (1H, m), 2.44-2.62 (2H, m),
2.88-2.98 (2H, m), 6.12-6.20 (1H, m), 6.84-6.94 (1H, m), 9.50 (1H, dd, J = 2.8, 6.0 Hz);
δC (CDCl3): 10.69, 21.24, 26.35, 30.02, 56.41, 58.51, 133.48, 157.13, 194.02; GC-MS
(same conditions as described in 4.2.2): tR 9.31 [3.2%, (Z)-isomer], 9.57 min (96.8%);
MS (70 eV, EI): m/z: 154 (<1) [M+], 125 (3) 112 (4), 97 (37), 85 (60), 83 (32), 68 (86),
67 (85), 59 (56), 57 (36), 55 (40), 41 (100), 39 (55). [MS of the (Z)-isomer of (±)-1
with tR 9.31 min (70 eV, EI): m/z: 154 (<1) [M+], 125 (9), 107 (8), 95 (48), 83 (29), 81
(44), 70 (32), 69 (33), 68 (100), 67 (57), 55 (62), 41 (71), 39 (49).]. HRMS calc for
C9H14O2: 154.0994, found: 154.0997.
4.6.2. (6R,7S)-(+)-Isomer
In the same manner as described above for (±)-1, (3S,4R)-5 (2.80 g) gave 3.15 g
(92%) of crude (6R,7S)-1 after SiO2 chromatography. This was distilled to give 1.96 g
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(57%) of (6R,7S)-(+)-1 as a colorless oil, bp 91-92oC/0.1 kPa: nD23=1.4742; [α]D22+12.8
(c 2.33, pentane). Its IR, 1H and 13C NMR, and MS spectra were identical with those
of (±)-1. GC-MS (same conditions as described in 4.2.2): tR 9.31 [(3.3%), (Z)-isomer],
9.56 min (96.7%). HRMS calc for C9H14O2: 154.0994, found: 154.0992.
4.6.3. (6S,7R)-(-)-Isomer
In the same manner as described above for (±)-1, (3R,4S)-5 (2.50 g) gave 2.82 g
(92%) of crude (6S,7R)-1 after SiO2 chromatography. This was distilled to give 1.88 g
(62%) of (6S,7R)-(-)-1 as a colorless oil, bp 91-92oC/0.1 kPa; nD25=1.4728; [α]D20-13.6
(c 2.38, pentane). Its IR, 1H and 13C NMR, and MS spectra were identical with those
of (±)-1. GC-MS (same conditions as reported in 4.2.2): tR 9.32 [1.3%, (Z)-isomer],
9.55 min (98.7%). HRMS calc for C9H14O2: 154.0994, found: 154.0997.
4.7. Determination of the enantiomeric purities of the enantiomers of crude 3 obtained
by AE, purified 3 obtained by methanolysis of 6, 5 and 1 by enantioselective GC
analysis
4.7.1. GC analysis of the enantiomers of crude 3
Instrument: Agilent Technologies 7890A + 5975C (ionization voltage: 70 eV);
column: heptakis-2,3-di-O-acetyl-6-O-t-butyldimethylsilyl)-β-cyclodextrin (0.25 mm
i.d. x 30 m); column temp: 40-180oC (+0.7oC/min); carrier gas, He; flow rate, 0.7
mL/min; detector, TIM. (2R,3S)-3: tR 106.4 min; (2S,3R)-3: tR 108.1 min. Ee of
crude (2R,3S)-3: 78.0%; ee of crude (2S,3R)-3: 80.4%.
4.7.2. GC analysis of the enantiomers of purified 3
Same conditions as described in 4.7.1. Ee of purified (2R,3S)-3: 99.4%; ee of
purified (2S,3R)-3: >99.8%.
4.7.3. GC analysis of the enantiomers of 5
Column: Chiramix®,16 (0.25 mm i.d. x 30 m). Other conditions are same as
described in 4.7.1. (3S,4R)-5: tR 53.9 min; (3R,4S)-5: tR 54.5 min. Ee of (3R,4S)-5;
98.8%; ee of (3S,4R)-5; 99.4%.
4.7.4. GC analysis of the enantiomers of 1
Same conditions as described in 4.7.1. (6R,7S)-1: tR 159.9 min; (6S,7R)-1: tR 163.6
min. Ee of (6R,7S)-1: 99.2%; ee of (6S,7R)-1: 99.6%.
4.8. Determination of the enantiomeric purities of the enantiomers of
3,5-dinitrobenzoate 6 by enantioselective HPLC analysis
System configuration (Shimadzu): system controller, CBM-20A; solvent delivery
unit, LC-20ADSP; degassing unit, DGU-20A5R; auto injector, SIL-20Ac; column oven,
CTO-20ACSP; PDA detector: SPD-M20A; column: Chiralpak® IA (4.6 x 250 mm,
Daicel); temp: 30oC; mobile phase: n-hexane/EtOH= 60 : 40; flow rate: 1.0 mL/min;
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detection: 254 nm. (2R,3S)-6: tR 50.1 min; (2S,3R)-6: tR 37.6 min. Ee of (2R,3S)-6:
99.94%; ee of (2S,3R)-6: 99.94%.
.Acknowledgements
I thank Mr. M. Kimura (President, Toyo Gosei Co., Ltd) and Mr. Y. Kimura (CEO,
Toyo Gosei Co., Ltd) for their support. My thanks are due to Prof. J.G. Millar
(University of California, Riverside) and Dr. H. Yasui (National Agriculture and Food
Research Organization, Tsukuba) for sharing their unpublished results with me. Dr. K.
Sakaguchi (Toyo Gosei Co., Ltd) is thanked for NMR and GC-MS measurements. Dr.
T. Nakamura (RIKEN) kindly carried the HRMS analyses. Enantioselective GC and
LC analyses were executed by Dr. M. Amaike, Ms. M. Kurosawa and Mr. S. Takishima
(T. Hasegawa Co.). Dr. T. Tashiro (Niigata University of Pharmacy and Applied Life
Sciences) and Mr. K. Kikusato (RIKEN) helped me in preparing the manuscript.
Supplementary data
Supplementary data [IR, 1H and 13C NMR, and MS spectra of (±)-1, (6R,7S)-1 and
(6S,7R)-1 and also MS of the (Z)-isomer of (6R,7S)-1] related to this article can be
found at http://dx.doi.org/10.1016/j.tet.2018.00.000 as a PDF file.
References
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M, Xu T, Teale SA, Millar JG. Abstract of papers. S12-0-08; The joint meeting of
the 33rd annual meeting of the International Society of Chemical Ecology and the
9th meeting of the Asia-Pacific Association of Chemical Ecologists. August 23-27,
2017, Kyoto, Japan.
3. Xu T, Yasui H, Teale SA, Fujiwara-Tsuji N, Wickham JD, Fukaya M, Hansen L,
Kiriyama S, Hao D, Nakano A, Zhang L, Watanabe T, Tokoro M, Millar JG. Sci
Rep. 2017; 7:7330 (1-7).
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9. Mori K. Biosci Biotechnol Biochem. 2011; 75: 976-981.
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Legends of Figs. and Schemes
Fig.1. Structures of the pheromone [(6R,7S)-1] of Aromia bungii and related
compounds.
Fig.2. Retrosynthetic analysis of (6R,7S)-1.
Scheme 1. Synthesis of (±)-1. Reagents: (a) MCPBA, CH2Cl2 (70%); (b) n-BuLi,
Tf2O, THF; (c) CH2=CHCH2MgBr, Li2CuCl4, THF, Et2O (41%, 2 steps); (d)
MeCH=CHCHO, Hoveyda-Grubbs II, CH2Cl2 (23% after chromatog. and distillation).
Scheme 2. Synthesis of the enantiomers of 1. Reagents: (a) D
-(-)-DET, Ti(OPri)4,
t-BuOOH, MS 3A, CH2Cl2 (88%); (b) DNBCl, C5H5N, CH2Cl2, recryst’n (x 3) (42%);
(c) K2CO3, MeOH (67%); (d) n-BuLi, Tf2O, THF; (e) CH2=CHCH2MgBr, Li2CuCl4,
THF, Et2O (58%, 2 steps); (f) MeCH=CHCHO, Hoveyda-Grubbs II, CH2Cl2 (57%).
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Pheromone synthesis. Part 263: Synthesis of the racemate and the enantiomers of
(E)-cis-6,7-epoxy-2-nonenal, the male-produced pheromone of the red-necked longhorn
beetle, Aromia bungii
Kenji Mori
NO2
O
O
1) AE
CHO
H-G II
O
OH
NO2
2) DNBCl
O
(99.94% ee)
NO2
Similarly
O
O
O
CHO
O
NO2
CHO
(6R,7S)-1
(99.2% ee)
(6S,7R)-1
(99.6% ee)
O
K. Mori, Graphical Abstract.
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O
a
c
OR
OH
2
( )-3 R = H
( )-4 R = Tf
b
d
O
O
CHO
( )-5
( )-1
N
N
Cl
Ru
Cl
O
Hoveyda-Grubbs II
K. Mori, Scheme 1.
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