Improved Synthesis and Deployment of (2S,3R)-2-(2Z,5Z-Octadienyl)-3-nonyloxirane, a Pheromone of the Pink Moth, Lymantria mathura

Article abstract of DOI:10.1021/jf035506q

We report two new syntheses of (2S,3R)-2-(2Z,5Z-octadienyl)-3-nonyloxirane, the main sex pheromone component of the pink moth, Lymantria mathura. The key step in the first route was the construction of (Z,Z)-1-bromo-1,4-heptadiene (6), which was coupled i

Full text of DOI:10.1021/jf035506q

2890 J. Agric. Food Chem. 2004, 52, 2890−2895
Improved Synthesis and Deployment of
(2S,3R)-2-(2Z,5Z-Octadienyl)-3-nonyloxirane, a Pheromone of the
Pink Moth, Lymantria mathura
ASHOT KHRIMIAN,*,† JAMES E. OLIVER,† ROGER C. HAHN,‡ NIKKI H. DEES,†
|
JEFF WHITE,§ AND VICTOR C. MASTRO
Chemicals Affecting Insect Behavior Laboratory, BARC-West, PSI, ARS, USDA,
Beltsville, Maryland 20705, Department of Chemistry, Syracuse University,
Syracuse, New York 13244, Scentry Biologicals, Inc., Billings, Montana 59102, and
Otis ANGB, Otis Methods Development Center, APHIS, USDA, Massachusetts 02542
We report two new syntheses of (2S,3R)-2-(2Z,5Z-octadienyl)-3-nonyloxirane, the main sex pheromone
component of the pink moth, Lymantria mathura. The key step in the first route was the construction
of (Z,Z)-1-bromo-1,4-heptadiene (6), which was coupled in the final step with 2-iodomethyl-3-
nonyloxirane 4 via a Grignard reaction. The second approach employed alkylation of 1,4-
heptadiynyllithium with epoxy triflates 7 in ether/hexane and provided the pheromone in g37% overall
yield from alcohol 2. The 4:1 ratio of pheromone enantiomers, reportedly the most attractive to pink
moth males, can be directly crafted from appropriately selected Sharpless asymmetric epoxidation
conditions.
KEYWORDS: Pink moth; Lymantria mathura; (2S,3R)-2-(2Z,5Z-octadienyl)-3-nonyloxirane; (3Z,6Z,9S,-
10R)-9,10-epoxy-3,6-nonadecadiene; pheromone; syntheses
INTRODUCTION
identified both 1b [Gries et al. (4) referred to S,R oxirane 1b as
(-)-mathuralure whereas it is dextrorotatory as are S,R diene
epoxides in general (see, e.g., ref 5)] and 1c in the insect
abdominal tips using chiral gas chromatography (GC) and
reported that neither the individual enantiomers nor the racemate
was attractive to male moths in field tests but that a mixture of
1b and 1c in a 4:1 ratiosas produced by femalesswas active
in their field trials.
The pink moth, also known as the rosy Russian gypsy moth
(Lymantria mathura Moore), is a widespread pest in Asia,
including Russia, China, Japan, and India. It is a polyphagous
defoliator of hardwood forest and orchard trees, but it rarely
rises to pest status in its native range. Females of L. mathura
are readily attracted to artificial lights (1), and they and their
egg masses have been detected on ships originating from Asian
seaports bound for the United States and Canada. Newly hatched
larvae can readily disperse from these ships by ballooning on
wind currents to habitats favorable for establishment and
development (2). Traps baited with L. mathura pheromone can
play an essential part in monitoring at possible introduction sites.
The main component of the pink moth pheromone was
identified by Oliver et al. (3) as (2S,3R)-2-(2Z,5Z-octadienyl)-
3-nonyloxirane (1b). This compound was active in electro-
physiological tests, whereas the enantiomer 1c evoked weaker
responses that were speculated to result from the presence of
∼5% of 1b as a contaminant in the sample of 1c. Both the single
enantiomer 1b and the racemate were active in our initial field
tests, as was the racemic monoepoxide mixture from random
epoxidation of the parent triene. In contrast, Gries et al. (4)
The exact percentage of enantiomer 1c required for maximum
attractiveness remains unclear. Questions of practical importance
are whether the racemic epoxide 1 is active enough to be used
for monitoring of pink moth populations and whether the 4:1
ratio of pheromone enantiomers could be conveniently produced
from a single stereoselective reaction.
Syntheses of both enantiomers of epoxide 1 have been
accomplished (3, 5) based on a method developed by Mori et
al. (6, 7) for analogous pheromones. The route combines the
Sharpless asymmetric epoxidation of (2Z,5Z,8Z)-undecatrien-
1-ol and the coupling of epoxy tosylates with dialkyl cuprates.
Even though the epoxidation did not provide very high
asymmetric induction (84% ee), optically pure epoxy alcohols
were obtained by repeated crystallizations of the corresponding
3,5-dinitrobenzoates (6, 7). The requirement for (2Z,5Z,8Z)-
undecatrien-1-ol constitutes a limitation of this route, as its
precursor, 2,5,8-undecatriyn-1-ol, is unstable and because Lind-
lar semihydrogenation was not entirely selective, providing
trienol of ∼90% purity (6). Alternative reductions were no
better: P2-Ni reduction afforded a low yield [24% (8)], and
* To whom correspondence should be addressed. Tel: 301-504-6138.
Fax: 301-504-6580. E-mail: khrimiaa@ba.ars.usda.gov.
† ARS, USDA.
‡ Syracuse University.
§ Scentry Biologicals, Inc..
| APHIS, USDA.
10.1021/jf035506q CCC: $27.50 © 2004 American Chemical Society
Published on Web 04/27/2004

Pheromone of the Pink Moth, Lymantria mathura
J. Agric. Food Chem., Vol. 52, No. 10, 2004 2891
(5-20% ethyl acetate in hexanes). The desired ester (2.76 g, Rf 0.20,
10% ethyl acetate in hexanes) was recrystallized from hexane plus 5%
ether to give 1.33 g of dinitrobenzoate of 97% ee, as determined by
GC analysis of the parent alcohol on a Chiraldex B-DM column.
Another crystallization from methanol provided 0.50 g of dinitroben-
zoate of 99% ee. This was dissolved in methanol (5 mL) and treated
with 1 N sodium hydroxide (1.6 mL). After it was stirred at room
temperature for 1 h, the mixture was partitioned between ice water
and ether. The organic layer was rinsed again with dilute sodium
hydroxide, water, and finally with brine, then was dried (Na2SO4) and
concentrated to provide 0.24 g of a white solid that was recrystallized
borane-dimethyl sulfide reduction, besides being cumbersome
for preparative scale reactions, also afforded only 47% yield
(5). The Wittig reaction offers another approach to oxiranes with
“skipped” diene substituents (9, 10). However, general in-
accessibility of the required unsaturated reagents, low temper-
atures (-100 °C), and moderate yields often make the Wittig
approaches less attractive than some offered by acetylenic
chemistry. Here, we wish to report two new syntheses of both
enantiomers of 1 based on the Sharpless asymmetric epoxida-
tion, one using a novel preparation of (Z,Z)-1-bromo-1,4-
heptadiene (6) and coupling of that compound with iodoepoxide
4 via a Grignard reaction, and the second employing alkylation
of 1,4-heptadiynyllithium with epoxytriflate 7 to produce the
key intermediate, diyne epoxide 8. Because a 4:1 ratio of the
two enantiomers has been reported (4) to be the most effective,
we also adopted the practice of intentionally selecting epoxi-
dation conditions that would normally be considered slightly
suboptimal for maximizing the content of (S,R)-epoxide 1b but
that directly provided the desired 4:1 composition.
from hexane to give 0.20 g of 3b of 99% ee; mp 58 °C, [R]25 -3.5°
D
(c 1.1, CHCl3). GC-MS (CI, NH3, m/z): 200 (M+), 202 (M+ + 2), 218
(M+ + 18). GC-MS (EI): 169 (M+ - 31, 2), 109 (5), 97 (45), 83
(100), 69 (72), 55 (78), 43 (48). MS (EI) data are in agreement with
literature (11).
B. The following epoxidation conditions were used specifically to
prepare 3b of about 60% ee. Alcohol 2 (263 mg, 1.43 mmol) was
epoxidized with anhydrous t-C4H9OOH (521 µL of 5.5 M in decane,
2.86 mmol) in the presence of titanium tetra(isopropoxide) (421 µL,
1.43 mmol) and (L)-diisopropyl tartrate (201 mg, 0.86 mmol, 0.6 equiv)
in dichloromethane (20 mL) at -18 °C for 120 h. The alcohol-
catalyst-tartrate mixture was “aged” for 30 min before addition of
peroxide as prescribed (11, 17). The mixture was then treated with
10% (L)-tartaric acid (3 mL) for 1 h at -23 to -25 °C, the layers were
separated, and the aqueous layer was extracted with CH2Cl2. The
combined organic extract was washed with water, dried (Na2SO4),
concentrated, dissolved in ether (7-10 mL), and stirred with 1 N NaOH
(3 mL) at 0 °C for 30 min. The layers were separated, the aqueous
layer was extracted with ether, and then the combined ethereal extracts
were washed with brine, dried (Na2SO4), and concentrated. Flash
chromatography (hexane/ethyl acetate, 3:2) afforded 204 mg (71%) of
the mixture of epoxy alcohols 3b and 3c in the ratio 18.4:81.5 (63%
ee).
MATERIALS AND METHODS
Melting points and boiling points are uncorrected. 1H NMR and 13
C
NMR spectra were recorded with tetramethylsilane as an internal
standard on a Bruker QE-300 spectrometer. 1H NMR coupling constants
are reported in Hz. GC analyses were performed on a Shimadzu 17A
gas chromatograph using a 60 m × 0.25 mm RTX-1701 column (Restek
Corporation) and H2 as the carrier gas. Optical purities of the
epoxyalcohols were determined on a Chiraldex B-DM GC column (â-
cyclodextrin, dimethyl), 30 m × 0.25 mm (Advanced Separation
Technologies, Inc). Electron impact ionization mass spectra (70 eV)
were obtained with a Hewlett-Packard 5971 GC-MS equipped with a
30 m × 0.25 mm DB-5MS column (J&W Scientific). Chemical
ionization spectra were recorded on a Shimadzu GCMS-QP 5050A
equipped with a 30 m × 0.25 mm DB-5MS column, using ammonia
as the reagent gas. Specific rotations were measured on a Perkin-Elmer
241 polarimeter. Combustion analyses were conducted by Galbraith
Laboratories Inc. (Knoxville, TN). Flash chromatography was carried
out with 230-400 mesh silica gel (Whatman). The reagents were
purchased from Aldrich Chemical Co. unless otherwise specified.
Anhydrous tert-butyl hydroperoxide was purchased from Fluka Chemi-
cal Corp. Tetrahydrofuran (THF) and ether were freshly distilled from
sodium-benzophenone ketyl under N2. Methylene chloride and hex-
amethylphosphoramide (HMPA, highly toxic!) were distilled from P2O5.
2-Dodecyn-1-ol was synthesized from 1-undecyne and paraformalde-
hyde (11). (Z)-2-Dodecen-1-ol (2) was prepared by reduction of
2-dodecyn-1-ol with activated zinc (12). 1,4-Heptadiyne was synthe-
sized by alkylation of 1-butynylmagnesium bromide with propargyl
tosylate catalyzed by copper(I) bromide (13). Ethyl (Z)-3-bromo-2-
propenoate was made by hydrobromination of ethyl 2-propynoate (14),
and the latter was reduced with lithium aluminum hydride to (Z)-3-
bromo-2-propen-1-ol (15). Copper(I) iodide and copper(I) bromide were
purified according to Kauffman and Teter (16). Mention of a proprietary
company or product does not imply endorsement by the U.S. Depart-
ment of Agriculture.
(2R,3S)-3-Nonyloxiranemethanol (3c). Compound 3c was prepared
analogously to the S,R-enantiomer using (D)-diethyl tartrate; [R]25
D
+3.6° (c 1.0, CHCl3), and racemic (cis)-3-nonyloxiranemethanol (3a)
was synthesized in 80% yield by epoxidation of (Z)-2-dodecenol with
m-chloroperbenzoic acid in methylene chloride at 0 °C as described
by Magnusson et al. (18).
cis-2-Iodomethyl-3-nonyloxirane (4a). A solution of 3a (200 mg,
1.0 mmol) in benzene (10 mL) plus ether (20 mL) was treated with
imidazole (272 mg, 4.0 mmol) and triphenylphosphine (394 mg, 1.50
mmol) following Marshall et al. (19). A solution of iodine (375 mg,
1.48 mmol) in ether (6 mL) was added dropwise at 5-10 °C. After
the addition was complete, the mixture was stirred at room temperature
for 1 h, then much of the solvent was removed and replaced with 1:1
ether-petroleum ether. The soluble portion was filtered into a separatory
funnel and rinsed with water and saturated sodium bicarbonate, then
dried (Na2SO4), and concentrated. The residue was flash chromato-
graphed (0-10% ethyl acetate in hexanes) to give 266 mg of pure
iodooxirane 4a (86%, Rf 0.41, 5% ethyl acetate in hexanes). 1H NMR:
0.87 (t, 3H), 1.30 (m, 14H), 1.50 (m, 2H), 2.95-3.10 (m, 2H), 3.25-
3.35 (m, 2H). GC-MS (CI, NH3): 328 (M+ + 18). GC-MS (EI): 183
(29, M+-I), 97 (47), 69 (75), 55 (78), 83 (100). Anal. calcd for C12H23-
IO: C, 46.46; H, 7.47. Found: C, 46.91; H, 7.55.
(2R,3R)-2-Iodomethyl-3-nonyloxirane (4b) and (2S,3S)-2-Iodo-
methyl-3-nonyloxirane (4c). Compounds 4b,c were prepared in an
(2S,3R)-3-Nonyloxiranemethanol (3b). A. Compound 3b was
synthesized according to a literature procedure (11) from (Z)-2-dodecen-
1-ol (2) but using 1 equiv of titanium tetra(isopropoxide) and 1.12 equiv
of (L)-diethyl tartrate. The reaction was run for 4 days at -20 °C and
afforded 66% of the epoxy alcohol of 80% ee after crystallization from
cyclohexane. Further crystallizations gave little or no improvement of
the optical purity; hence, the crude mixture of epoxyalcohols (2.70 g,
9:1 SR/RS) was dissolved in benzene (10 mL) and pyridine (5 mL).
The solution was stirred in an ice bath while a solution of 3,5-
dinitrobenzoyl chloride (from 15 mmol of 3,5-dinitrobenzoic acid and
oxalyl chloride) in about 15 mL of benzene was added dropwise. The
ice bath was removed, and the mixture was stirred at room temperature
for 1.5 h, added to ice, and partitioned between ethyl acetate and water.
The crude product (5.17 g) was flash chromatographed on silica gel
analogous manner from the respective chiral epoxyalcohols; [R]25
D
+65.0° (c 1.0, CHCl3) for 4b and -63.0° (c 1.2, CHCl3) for 4c.
(Z)-1,3-Dibromopropene (5). To a solution of triphenylphosphine
(27.5 g, 0.11 mol) in dry dichloromethane (125 mL) was added bromine
(5.4 mL, 0.11 mol) dissolved in dry dichloromethane (10-15 mL) at
0 to -5 °C. (Z)-3-Bromo-2-propen-1-ol (13.7 g, 0.10 mmol) in CH2-
Cl2 (20 mL) was added slowly to the resulting suspension at -20 °C.
After it was stirred for 0.5-1.0 h at that temperature, the mixture was
quenched with 2-3 mL of MeOH and carefully concentrated on a rotary
evaporator (bath temp 25-30 °C). The residue was suspended in
pentane (∼200 mL) and filtered, and the solid (Ph)3PO was washed
with pentane (2 × 40 mL). The combined pentane extracts were rinsed
with saturated NaHCO3, dried (Na2SO4), concentrated, and distilled to

2892 J. Agric. Food Chem., Vol. 52, No. 10, 2004
Khrimian et al.
give 5 (15.0 g, 75%, >98% purity); bp 58-60 °C/25 mmHg. GC-MS
(EI): 202, 200, 198 (21, 40, and 19%, M+), 121 (100, M+-Br) and
119 (98, M+-Br).
h, poured into saturated NH4Cl (∼100 mL), and extracted with ether/
hexane, 1:1 (3 × 50 mL). The organic extract was dried over Na2SO4,
concentrated, and flash chromatographed with hexane/ethyl acetate,
98:2, to give 3.75 g of material, containing ∼15% unreacted iodoep-
oxide 4b. This was dissolved in dry DMF (25 mL) and treated with
anhydrous lithium acetate (0.6 g) at 78-80 °C for 12 h to convert
starting iodoepoxide to the corresponding acetate. The reaction mixture
was added to water (∼40 mL) and extracted with ether/hexane 1:1 (3
× 30 mL), and the extract was dried, concentrated, and flash
chromatographed with hexane/ethyl acetate, 95:5 to 90:10. The coupling
products (2.44 g, 53% yield based on initial amount of 4b) containing
83% of 1b were isolated from the less polar fraction [(2S,3R)-3-
Nonyloxiranemethanol acetate (0.62 g) was isolated from a more polar
fraction. GC-MS (CI, NH3): 243 (M + 1), 260 (M + 18). Hydrolysis
(aqueous NaOH/MeOH) and subsequent chromatography facilitated the
recovery of optically pure 3b that could be reused.] The main impurity
(∼10%) had the same molecular weight as 1b based on GC-MS (CI,
NH3): 261 (M - 17), 279 (M + 1), 296 (M + 18). Further purification
by flash chromatography on 15% AgNO3-SiO2, hexane/ethyl acetate,
9:1, gave 1b (1.79 g, 39%) of 98% chemical purity and g99% ee as
determined by conversion to diastereomeric aziridines following (23);
[R]25 +5.3° (c 1.0, CHCl3). Lit. (5) [R]23 +3.5° (c 8.57, CHCl3).
(Z,Z)-1-Bromo-1,4-heptadiene (6). An oven-dried flask equipped
with a thermometer, mechanical stirrer, dry ice condenser, rubber
septum, and N2 inlet was loaded with dry THF (100 mL) and cooled
to -20 to -25 °C. A previously prepared, freezer-cooled solution of
1-butyne (GFS Chemicals, Powell, OH) in THF (23 mL, 115.5 mg/
mL, 49.0 mmol) was added quickly via syringe. A solution of
ethylmagnesium bromide in ether (16 mL, 3 M, 48 mmol) was added
slowly at -25 to 0 °C, and the resulting mixture was warmed to ambient
temperature, heated at 35-40 °C for ∼40 min, and cooled again to
-20 °C. Copper(I) iodide (457 mg, 2.4 mmol) was added followed by
dry HMPA (17.2 mL, 96 mmol), and the suspension was stirred at
-20 to -25 °C for 0.5 h. A solution of 5 (4.85 g, 24.3 mmol) in THF
(ca. 10 mL) was added at -25 °C, and the mixture was stirred at that
temperature for 3-4 h during which time a thick white precipitate
formed. GC analysis indicated that the reaction was essentially
complete. The reaction mixture was poured into saturated NH4Cl, treated
with a solution of potassium cyanide (5.80 g in 35 mL H2O), and
extracted with pentane (3 × 50 mL). The organic extract was washed
with saturated NH4Cl solution, dried (Na2SO4), and concentrated to
leave crude product (4.30 g) containing 92% (Z)-1-bromo-1-hepten-
4-yne. Because the bromoenyne is very unstable in air, most of the
sample was reduced to the corresponding diene without purification
following a procedure of Brown and Ahuja (20) as modified by Millar
and Oehlschlager (21). [An analytical sample of the (Z)-1-bromo-1-
hepten-4-yne of 94% purity was obtained by flash chromatography
D
D
1
GC-MS (CI, NH3): 261 (M - 17), 279 (M + 1), 296 (M + 18). H
NMR (CDCl3): 0.89 (t, J ) 7.0, H-19), 0.98 (t, J ) 7.5, H-1), 1.26 (br
s, 14H), 1.53 (m, H-11), 2.08 (dq, J1) J2 ) 7.5, H-2), 2.23 (ddd, 2J )
3
3
2
3
3
14.5, J1 ) J2 ) 6.5, HA-8), 2.41 (ddd, J ) 14.5, J1 ) J2 ) 6.5,
3
3
HB-8), 2.81 (dd, J1 ) J2 ) 6.5, H-5), 2.92 (m, 2H, H-9, 10), 5.26-
5.53 (m, 4H, H-3, 4, 6, 7). 13C NMR: 14.1, 14.2 (C-1, 19), 20.6, 22.7,
25.8, 26.3, 26.6, 27.8, 29.3, 29.5, 29.6 (double intensity), 31.9 (CH2),
56.4, 57.2 (C-9, 10), 124.3, 126.8, 130.8, 132.3 (C-3, 4, 6, 7). Both 1H
and 13C NMR data are in close agreement with literature values for an
analogous C-21 dienic epoxide (5, 22).
1
3
using pentane. H NMR (CDCl3): 1.10 (t, J ) 7.5, H-7), 2.14 (tq, J
) 7.5, 5J ) 2.5, H-6), 3.05 (m, H-3), 6.14 (dt, J2-1 ∼ J2-3 ) 7.0, H-2),
6.20 (dt, J ) 7.0 and 1.5, H-1). MS (EI): 172, 174 (both 6%, M+), 93
(100), 91 (53), 77 (76), 78 (25), 65 (21)]. A suspension of nickel acetate
tetrahydrate (3.10 g, 12.4 mmol) in ethanol (30 mL, 95%) was cooled
in an ice bath and reduced with a sodium borohydride solution in ethanol
(1 M, 25 mL, 25.0 mmol). After H2 evolution ceased, ethylenediamine
(1.67 mL, 25.0 mmol) and finally crude bromoheptenyne (4.30 g)
dissolved in ethanol (10 mL) were added. The mixture was stirred under
a H2 atmosphere at 0-5 °C and monitored by GC until hydrogenation
was complete. The reaction products were filtered under N2 pressure
through activated granular charcoal, and the solids were washed with
ethanol (3 × 35 mL). The filtrate was diluted with ice water (∼200
mL) and extracted with pentane (6 × 50 mL), and the combined pentane
extracts were washed with 3% HCl and water and then dried over Na2-
SO4. The pentane was removed by careful distillation through a 15 cm
Vigreux column under N2, and the residue was distilled using a water
aspirator. Bromide 6 (1.94 g, 46% from 5) of 93-95% purity was
collected at 72-74 °C/31 mmHg and used in the next step. It is more
stable than the enyne precursor and could be stored in a freezer for
several months without noticeable change. A sample of >98% purity
was obtained by flash chromatography of crude material on 15%
AgNO3-SiO2 with pentane. 1H NMR (CDCl3): 1.00 (t, J ) 7.5, H-7),
2.10 (dq, J1 ) J2 ) 7.2, H-6), 2.94 (dd, J1 ) J2 ) 7.0, H-3), 5.26-
5.38 (m, 1H), 5.40-5.51 (m, 1H), 6.06 (dt, J1 ) J2 ) 7.0, H-2), 6.15
(dt, J ) 7.0 and 1.5, H-1). The data are in close agreement with
literature values (22). MS (EI): 174, 176 (each 11%, M+), 145 (5),
147 (5), 132 (70), 134 (69), 95 (100), 67 (49), 55 (66).
(2R,3S)-2-(2Z,5Z-Octadienyl)-3-nonyloxirane (1c). Compound 1c
was synthesized in an analogous manner from 6 (1.6 equiv) and 4c;
[R]25 -4.3° (c 1.15, CHCl3). Lit. (5) [R]23 -4.3° (c 8.89, CHCl3).
D
D
2-(2,5-Octadiynyl)-3-nonyloxirane (8a). To a solution of 3a (2.14
g, 10.70 mmol) in dry CH2Cl2 (35 mL) containing 2,6-lutidine (1.26
g, 11.77 mmol) was added triflic anhydride (1.98 mL, 11.77 mmol) in
CH2Cl2 at -60 °C. The solution was stirred for 0.5 h while slowly
warming to -45 °C, and then ice water and pentane were added, and
the layers were separated. The aqueous layer was extracted twice with
pentane, and then the pentane extracts were washed with aqueous
NaHSO4 and aqueous NaHCO3, dried with Na2SO4, and concentrated.
Flash chromatography (hexane/ethyl acetate, 9:1) afforded pure triflate
7a (3.24 g, 91%). MS (CI, NH3): 350 (M+ + 18).
To a solution of 1,4-heptadiyne (202 mg, 2.2 mmol) in dry ether (5
mL) at -78 °C was slowly added a hexane solution of butyllithium
(1.8 mL, 1.11 M, 2.0 mmol) keeping the temperature around -75 °C.
After the mixture was stirred at -78 °C for 1.5 h, a pale yellow
suspension formed to which was added triflate 7a (330 mg, 1.0 mmol)
dissolved in dry ether (1 mL). The solution was allowed to warm to
-50 to -40 °C (whereupon a white precipitate separated) and placed
overnight in a freezer at -25 °C. The resulting thick suspension was
poured into saturated NH4Cl and extracted with ether/hexane (1:1), and
the organic extract was washed with aqueous NH4Cl, dried with Na2-
SO4, and concentrated. Flash chromatography (hexane/ethyl acetate,
95:5) gave diyne oxirane 8a (220 mg, 80% yield, 98% purity). GC-
(2S,3R)-2-(2Z,5Z-Octadienyl)-3-nonyloxirane (1b). 1,2-Dibromo-
ethane (0.94 g, 5 mmol) was added under a N2 atmosphere to
magnesium turnings (1.03 g, 42.4 mmol) in THF (15 mL). After the
exothermic reaction ceased, a solution of 6 (5.0 g, 28.6 mmol) in THF
(15 mL) was added dropwise over 0.5 h, maintaining the reaction
temperature between 60 and 65 °C. Upon completion of the bromide
addition, the dark brown mixture was stirred at 60-70 °C for 0.5 h,
then cooled to ambient temperature, diluted with THF (20 mL), and
cannulated into a dropping funnel. In a separate oven-dried flask were
placed CuI (0.248 g, 1.3 mmol), THF (10 mL), and HMPA (10 mL).
The mixture was stirred at 20-25 °C to form a faint green solution to
which 4b (5.10 g, 16.5 mmol) in THF (10 mL) was added in one
portion. The resulting mixture was cooled to -30 °C, and the Grignard
reagent was slowly added maintaining the temperature from -25 to
-30 °C. The resulting yellow suspension was stirred at -20 °C for 1
1
MS (CI, NH3): 275 (M+ + 1), 292 (M+ + 18). H NMR (CDCl3):
0.87 (t, J ) 6.5, 3H), 1.12 (t, J ) 7.5, 3H), 1.15-1.60 (br m, 14H),
2
3
1.50 (m, 2H), 2.17 (br q, H-7′), 2.27 (br dd, J ) 17.1, J ) 7.0, 1H,
2
3
5
H-1′), 2.56 (ddt, J ) 17.1, J ) 5.5, J ) 2.6, 1H, H-1′), 2.94 (dt,
3J ) 5.5, 4.5, 1H, H-3), 3.13 (m, 3H, H-2, H-4′). The signals are in
close agreement with the literature data for an analogous diyne oxirane
(22). Anal. calcd for C19H30O: C, 83.15; H, 11.02. Found: C, 82.89;
H, 11.00.
cis-2-(2Z,5Z-Octadienyl)-3-nonyloxirane (1a). Oxirane 8a (296 mg,
1.08 mmol) was dissolved in a mixture of methanol (13 mL) and
cyclohexene (0.5 mL) plus quinoline (40 µL) and stirred in the presence
of 5% Pd on CaCO3 (31 mg, Lindlar catalyst, lead poisoned, Strem
Chemicals, Newburyport, MA) in a hydrogen atmosphere. After about
1 h, the reaction was complete by GC analysis. The mixture was filtered

Pheromone of the Pink Moth, Lymantria mathura
J. Agric. Food Chem., Vol. 52, No. 10, 2004 2893
Scheme 1 a
Scheme 2 a
a Reagents and conditions: (a) (Tf)2O, 2,6-lutidine (91%). (b) Two equiv
EtCtCCH CtCLi, ether/hexane, −70 to −40 °C (80%). (c) H , Pd−CaCO ,
2
2
3
MeOH/cyclohexene (93%, 95% purity).
a Reagents and conditions: (a) MCPBA, CH Cl2, (80%). (b) 1. t-BuOOH/
to bromodiene 6. The yield of distilled 6 after the two-step
process was 46%, an improvement over the previously reported
yield of less than 20% resulting from hydroboration of 1-bromo-
1,4-heptadiyne (22).
2
Ti(Oi-Pr)4/(D)-or (L)-DET (3b, 66%, 80% ee); 2. 3,5-(NO ) C H COCl/Py,
3 2
6 3
crystallization, NaOH/MeOH, (99% ee for 3b and 3c). (c) t-BuOOH, 1 equiv
Ti(Oi-Pr)4, 0.6 equiv (L)-DIPT (3b, 71%, 63% ee. (d) Ph3P, imidazole, I2 (86%).
(e) 1. EtCtCMgBr, CuI/HMPA; 2. H , P2−Ni (46% from 5). (f) 1. Mg, THF,
2
In the final step, bromodiene 6 was converted to a Grignard
reagent in refluxing THF and added to iodooxirane 4b (0.58
equiv) in the presence of 10% CuI in HMPA/THF at -30 °C
following the original alkylation procedure of Nicolaou et al.
(27), which was also employed by Mori and Brevet in
pheromone chemistry (25). Some unreacted 4b was converted
to the corresponding acetate and removed from the coupling
products by flash chromatography affording 1b in 53% yield
but only 83% purity. The 1b was further purified on AgNO3-
SiO2 to give material of 98% purity in 39% yield based on
starting 4b. The main impurity formed during the coupling had
the same molecular weight as 1b and apparently originated from
Z/E isomerization at C-1 during Grignard formation. Partial loss
of geometric purity (though to a lesser extent) was reported also
by Mori and Brevet (25), who conducted a similar coupling
with a Grignard reagent prepared from (Z)-1-bromo-1-butene
at room temperature. Our attempts to prepare the Grignard
reagent from 6 at room temperature resulted in lower yields of
1.
The second synthesis involved construction of diyne epoxide
8 (Scheme 2) and stereospecific semihydrogenation to epoxy-
diene 1, an approach frequently employed in preparations of
epoxydiene pheromones such as (Z,Z)-cis-2-(2,5-octadienyl)-
3-undecyloxirane, the principal sex pheromone component of
several lepidopteran species (22, 28, 29). Different schemes
toward the construction of the diyne epoxides have been
describedsfor example, cis-9-heneicosene-3,6-diyne was ep-
oxidized with m-chloroperbenzoic acid toward preparation of
an achiral pheromone (28). One chiral synthesis utilized the
reaction of 1,4-heptadiynyllithium with (2R,3R)-1,2-epoxy-3-
tetradecanol benzoate (29) in the key step. Yet another scheme
made use of alkylative rearrangement of chiral 1,2-epoxy-3-
alkan-1-ol tosylates with 1,4-heptadiynyllithium, with the ep-
oxide construction carried out in situ (22). To incorporate the
Sharpless epoxidation into such a scheme, the most straight-
forward approach appeared to be utilization of iodoepoxide 4
in the displacement reaction with an anion of 1,4-heptadiyne.
This type of displacement, however, has frequently been
unsuccessful, resulting instead in the reductive epoxide opening
to allylic alcohols as discussed by Millar and Underhill (21,
30) [see also (31) and references therein]. Wasserman and Oku
(32) and others (31, 33, 34) have described successful alkylation
of alkyne anions with epoxytriflates. Epoxytriflates 7 were easily
prepared from alcohols 3 and were stable to chromatography
and storage in a refrigerator. However, our attempts to react
1,4-heptadiynyllithium (generated from 1,4-heptadiyne and
BuLi) with triflate 7a under the conditions described in the
literature (THF/HMPA, ether/HMPA, or pure THF) resulted in
complex mixtures even at -80 °C, apparently through proto-
reflux; 2. 0.58 equiv 4, CuI, HMPA/THF, −30 to −25 °C, AgNO −SiO (39%
3
2
from 4).
through a short pad of Celite, the pad was rinsed with 5 mL of MeOH,
the filtrate was concentrated, and the residue was flash chromatographed
with hexane/ethyl acetate, 30:1, plus 0.1% MeOH to give 280 mg (93%)
of oxirane 1a of 95% purity. A product of 99% purity was obtained by
chromatography on 15% AgNO3-SiO2 as described above. The spectral
data of 1a and chiral epoxide 1b were identical.
Analogous to the above procedures, chiral epoxyalcohol 3b of 63%
ee (2.14 g, 10.7 mmol) was converted to the corresponding triflate (3.20
g, 91%), which was alkylated with 2.0 equiv of 1,4-heptadiynyllithium
to give 8b (1.96 g, 74%). Reduction of the latter with Lindlar catalyst
afforded 1b (1.55 g, 78%) of 97% chemical purity.
RESULTS AND DISCUSSION
Synthesis of both enantiomers and racemic 1 via a copper-
(I)-catalyzed Grignard coupling is illustrated in Scheme 1. (Z)-
2-Dodecen-1-ol was epoxidized either with MCPBA in the
achiral route or via the Sharpless asymmetric epoxidation
protocol (17) affording epoxyalcohols 3. The optical purities
of 3b and 3c (∼80% ee) were further enriched by recrystalli-
zation of their respective 3,5-dinitrobenzoates to 99% ee (judged
by GC analyses of the regenerated alcohols 2a and 2b on a
Chiraldex B-DM column) following published procedures
(3, 6).
We examined a variety of conditions in order to fine-tune
the asymmetric epoxidation to produce the desired 4:1 (60%
ee) ratio of epoxides 3, which was expected to remain unchanged
throughout the synthesis. It turned out that running the epoxi-
dation of 2 in the presence of 1 equiv of titanium tetra-
(isopropoxide) and 0.57-0.70 equiv of (L)-diisopropyl tartrate,
with other conditions as described in the original version (24),
furnished 3b of 55-65% ee (with 0.60 equiv of tartrate the ee
was 63%). The epoxyalcohols 3 were smoothly converted to
the corresponding iodo epoxides 4 using iodine/triphenylphos-
phine/imidazole (19, 25).
For synthesis of the second building block 6, we used (Z)-
1,3-dibromopropene 5, easily prepared in three steps from ethyl
2-propynoate in 45% yield (14, 15). Initial attempts toward
cuprous chloride-catalyzed alkylation (26) of 1-butynyllithium
with 5 resulted in a partial (∼5%) Z/E isomerization, along with
some (12%) homocoupling of the alkyne. We found that the Z
configuration remained virtually intact and the homocoupling
could be contained to ∼5% if 1-butyne was alkylated with 5
via a Grignard reagent in the presence of CuI in THF/HMPA
at -30 to -20 °C. Thus, crude (Z)-1-bromo-1-hepten-4-yne of
92% purity was prepared but it was too unstable in air to isolate
so it was hydrogenated without purification with P2-Ni catalyst

2894 J. Agric. Food Chem., Vol. 52, No. 10, 2004
Khrimian et al.
bioassays with the individual enantiomers of the pheromone and
the mixtures thereof will be published elsewhere. Table 1
presents trapping data of L. mathura with a 4:1 mixture of 1b
and 1c impregnated on cotton wicks and PVC-coated string
dispensers prepared according to Leonhardt et al. (35).
Table 1. Trapping of L. mathura Males with a 4:1 Blend of 1b and 1c
between July 7 and July 21, 2002, in Terney, Russian Far East
mean no. males
treatment
dispenser
loading (mg)
captured per trapa
1b/1c (4:1)
1b/1c (4:1)
1b/1c (4:1)
hexane
cotton wickb
stringd
1
1
2.5
1.38 bcc
5.67 a
6.07 a
0.00 c
Despite the low moth population, string dispensers caught
significantly greater numbers of male pink moths than cotton
wicks that had been used in the previous study (3). It is
reasonable to anticipate that the string, or twine, formulation
could serve as a standard lure for detection and monitoring of
L. mathura since it has also been particularly effective for (+)-
disparlure, a pheromone of similar molecular weight used by
the gypsy moth, Lymantria dispar (35).
stringd
cotton wick
a Test was run using traps with six replicates × seven observations for each
treatment (42 observations/treatment). b A 100 µL solution of pheromone was
injected into ∼10 mm slice of standard dental cotton roll. c Means followed by the
same letter are not significantly different according to a Scheffe’s test at the .05
level of significance. Analysis done with the log (number of males captured + 1),
actual means presented. d Prepared according to Leonhardt et al. (35); loading 64
µg pheromone per cm.
ACKNOWLEDGMENT
tropic rearrangements of the base-sensitive 1,4-diyne group. The
side reactions were slowed dramatically when the alkylation
was conducted in a less polar ether/hexane mixture. Thus,
reaction of 2.2 equiv of 1,4-heptadiyne and 2.0 equiv of BuLi
at -75 °C, followed by addition of the triflates 7a or 7b, slowly
raising the temperature to about -40 °C, and continuing the
alkylation at -25 °C resulted in complete conversion of triflate
and 80% yield of diyne epoxides 8a and 8b isolated in high
purity (98-99%) by flash chromatography. When the alkylation
was conducted with 1.5 equiv of BuLi, the yield dropped to
65-70%. We also found that the ether should be freshly distilled
from sodium-benzophenone ketyl to obtain reproducible results
and that the reaction should be driven to completion since
unreacted triflates complicated chromatographic purification.
In the last step, the diyne epoxides 8 were hydrogenated with
a Lindlar catalyst in the presence of quinoline in cyclohexene/
MeOH to give racemic 1a or the 2S,3R enantiomer 1b in 90-
93% yield. The optical purities of both enantiomers of 1
synthesized by two routes were confirmed by conversion of the
epoxides to diastereomeric aziridines and GC analysis (23). The
enantiomeric excesses of 1b and 1c from both methods were
found to be g99%, consistent with the optical purities of the
starting epoxy alcohols 3a and 3b, and thus indicating that there
was no loss of chirality during alkylation. The most practical
composition for attracting L. mathura, epoxide 1b of ∼63%
ee, was prepared in an overall yield of 37% from alcohol 2
using the tuned asymmetric epoxidation conditions.
In summary, we examined the applicability of two routes
toward the preparation of the main component of the L. mathura
pheromone. Both methods conveniently provided ∼4:1 ratio of
S,R and R,S enantiomers of 1 using the tuned Sharpless
asymmetric epoxidation. However, the sequence illustrated in
Scheme 1 appeared to be limited mainly because of incomplete
stereoselectivity of the copper(I)-catalyzed coupling reaction.
On the other hand, the second synthesis advantageously used a
straightforward alkylation of 1,4-heptadiynyllithium with ep-
oxytriflate 7 in ether-hexane and an uncomplicated semi-
hydrogenation of diyne epoxide 8 thus offering a higher overall
yield. It also seemed to overcome the shortcomings of the
existing route mentioned in the Introduction, which also included
burdensome organocuprate chemistry in assembling a 19 carbon
skeleton (3, 5). As compared to other syntheses of chiral diene
epoxides, our approach benefits from the tuned Sharpless
asymmetric epoxidation, whereas the potential of alternative
methods in direct preparation of the desired ratio of the
enantiomers of oxirane 1 remains to be shown.
We thank Kimberly Petersen for assistance in syntheses, Dave
DeVilbiss for help in mass spectroscopic analyses and prepara-
tion of string dispensers, Galina Yurchenko for conducting field
tests, and Walter Schmidt for assistance with NMR.
LITERATURE CITED
(1) Wallner, W. E.; Humble, L. M.; Levin, R. E.; Baranchikov, Y.
N.; Carde´, R. T. Response of adult Lymantriid moths to
illumination devices in the Russian Far East. J. Econ. Entomol.
1995, 88, 337-342.
(2) Zlotina, M. A.; Mastro, V. C.; Elkinton, J. S.; Leonard, D. E.
Dispersal tendencies of neonate larvae of Lymantria mathura
and the Asian form of Lymantria dispar (Lepidoptera: Lyman-
triidae). EnViron. Entomol. 1999, 28, 240-245.
(3) Oliver, J. E.; Dickens, J. C.; Zlotina, M.; Mastro, V. C.;
Yurchenko, G. I. Sex attractant of the rosy Russian gypsy moth
(Lymantria mathura Moore). Z. Naturforsch. 1999, 54c, 387-
394.
(4) Gries, G.; Gries, R.; Schaefer, P. W.; Gotoh, T.; Higashiura, Y.
Sex pheromone components of pink gypsy moth, Lymantria
mathura. Naturwissenschaften 1999, 86, 235-238.
(5) Wong, J. W.; Underhill, E. W.; MacKenzie, S. L.; Chisholm,
M. D. Sex attractants for geometrid and noctuid moths. Field
trapping and electroantennographic responses to triene hydro-
carbons and monoepoxydiene derivatives. J. Chem. Ecol. 1985,
11, 727-756.
(6) Mori, K.; Ebata, T. Syntheses of optically active pheromones
with an epoxy ring, (+)-disparlure and both the enantiomers of
(3Z,6Z)-cis-9,10-epoxy-3,6-heneicosadiene. Tetrahedron 1986,
42, 3471-3478.
(7) Mori, K.; Takeuchi, T. Synthesis of the enantiomers of (3Z,6Z)-
cis-9,10-epoxy-1,3,6-henicosatriene and (3Z,6Z)-cis-9,10-epoxy-
1,3,6-icosatriene, the new pheromone components of Hyphantria
cunea. Liebigs Ann. Chem. 1989, 453-457.
(8) Mori, K.; Ebata, T. Synthesis of optically active pheromone with
an epoxy ring, (+)-disparlure and the saltmarsh caterpillar moth
pheromone [(Z,Z)-3,6-cis-9,10-epoxyheneicosadiene]. Tetrahe-
dron Lett. 1981, 22, 4281-4282.
(9) Mosset, P.; Yadagiri, P.; Lumin, S.; Capdevila, J.; Falk, J. R.
Arachidonate epoxygenase: total synthesis of both enantiomers
of 8,9- and 11,12-epoxyeicosatrienoic acid. Tetrahedron Lett.
1986, 27, 6035-6038.
(10) Yadav, J. S.; Valli, M. Y.; Prasad, A. R. Total synthesis of
enantiomers of (3Z,6Z)-cis-9,10-epoxy 1,3,6-henicosatriene-the
pheromonal component of Diacrisia obliqua. Tetrahedron 1998,
54, 7551-7562.
(11) Blumenstein, J. J.; Michejda, C. J.; Oroszlan, S.; Copeland, T.
2,3-Epoxy derivatives as anti retroviral chemotherapeutic agents.
U.S. Patent 5,190,969, 1993.
Multigram quantities of pheromone have been prepared and
tested in Russia in 2002 and 2003. Detailed results of field

Pheromone of the Pink Moth, Lymantria mathura
J. Agric. Food Chem., Vol. 52, No. 10, 2004 2895
(12) Khrimian, A.; Klun, J. A.; Hijji, Y.; Baranchikov, Y. N.; Pet’ko,
V. M.; Mastro, V. C.; Kramer, M. H. Syntheses of (Z,E)-5,7-
dodecadienol and (E,Z)-10,12-hexadecadienol, Lepidoptera phero-
mone components, via zinc reduction of enyne precursors. Test
of pheromone efficacy against the Siberian moth. J. Agric. Food
Chem. 2002, 50, 6366-6370.
(13) Brandsma, L.; Verkriujsse, H. D. Synthesis of Acetylenes, Allenes
and Cumulenes; Elsevier Scientific Publishing Company: Am-
sterdam, 1981; p 71.
(14) Ma, S.; Lu, X.; Li, Z. A novel regio- and stereospecific
hydrohalogenation reaction of 2-propynoic acid and its deriva-
tives. J. Org. Chem. 1992, 57, 709-713.
(15) Wei, X.; Taylor, R. J. K. In situ manganese dioxide alcohol
oxidation-Wittig reactions: Preparation of bifunctional dienyl
building blocks. J. Org. Chem. 2000, 65, 616-620.
(16) Kauffman, G. B.; Teter, L. A. 3. Tetrakis[Iodo(tri-n-butylphos-
phine)-copper(I)] and iodo-(2,2′-bipyridine)-(tri-n-butylphos-
phine)copper(I). Inorg. Synth. 1963, 7, 9-12.
(17) Gao, Y.; Hanson, R. M.; Klunder, J. M.; Ko, S. Y.; Masamune,
H.; Sharpless, K. B. Catalytic asymmetric epoxidation and kinetic
resolution: Modified procedure including in situ derivatization.
J. Am. Chem. Soc. 1987, 109, 5765-5780.
(18) Magnusson, G.; Thoren, S. A new route to cyclopentene-1-
carboxaldehydes by rearrangement of 2,3-epoxycyclohexanols.
J. Org. Chem. 1973, 38, 1380-1384.
(19) Marshall, J. A.; Johns, B. A. Stereoselective synthesis of C5-
C20 and C21-C34 subunits of the core structure of the
aplyronines. Application of enantioselective additions of chiral
allenylindium reagents to chiral aldehydes. J. Org. Chem. 2000,
65, 1501-1510.
(20) Brown, C. A.; Ahuja, V. K. Catalytic hydrogenation. VI. The
reaction of sodium borohydride with nickel salts in ethanol
solution. P-2 Nickel, a highly convenient, new, selective
hydrogenation catalyst with great sensitivity to substrate structure.
J. Org. Chem. 1973, 38, 2226-2230.
(25) Mori, K.; Brevet, J.-L. Pheromone synthesis; CXXXIII. Synthesis
of both the enantiomers of (3Z,9Z)-cis-6,7-epoxy-3,9-nonadeca-
diene, a pheromone component of Erannis defoliaria. Synthesis
1991, 1125-1129.
(26) Matveeva, E. D.; Erin, A. S.; Kurz, A. L. Regioselectivity of
reaction of cuprous acetylides with 1-bromo-2-butene. Russ. J.
Org. Chem. 1997, 33, 1061-1064.
(27) Nicolaou, K. C.; Duggan, M. E.; Ladduwahetty, T. Reactions
of 2,3-epoxyhalides. Synthesis of optically active allylic alcohols
and homoallylic epoxides. Tetrahedron Lett. 1984, 25, 2069-
2072.
(28) Nikolayeva, L. A.; Kovalev, B. G. Synthesis of racemic cis-
3,cis-6,cis-9,10-epoxyheneicosadiene-a component of the sex
pheromone of the American white butterfly Hyphantria cunea
Drury. J. Org. Chem. USSR 1985, 21, 676-679.
(29) Tolstikov, A. G.; Khakhalina, N. V.; Spirikhin, L. V.; Khalilov,
L. M.; Panasenko, A. A.; Odinokov, V. N.; Yolstikov, G. A.
tri-O-Acetyl-D-galactal in the synthesis of (3Z,6Z,9S,10R)-cis-
9,10-epoxy-3,6-heneicosadiene-a component of the sex phero-
mone of the American white butterfly (Hyphantria cunea drury
(sic)). J. Org. Chem. USSR 1991, 27, 679-684.
(30) Millar, J. G.; Underhill, E. W. Synthesis of chiral bis-homoallylic
epoxides. A new class of lepidopteran sex attractants. J. Org.
Chem. 1986, 51, 4726-4728.
(31) Muto, S.; Mori, K. Synthesis of all four stereoisomers of
leucomalure, components of the female sex pheromone of the
satin moth, Leucoma salicis. Eur. J. Org. Chem. 2003, 1300-
1307.
(32) Wasserman, H. H.; Oku, T. The carbonyl epoxide rearrangement.
A chiral synthesis of the Mus musculus pheromone. Tetrahedron
Lett. 1986, 27, 4913-4916.
(33) Lizarraga, J. R.; Mori, K. Synthesis of (()-leucomalure
[(3Z,6R*,7S*,9R*,10S*)-cis-6,7-cis-9,10-diepoxy-3-henico-
sene], the major component of the female sex pheromone of the
satin moth. Nat. Prod. Lett. 2001, 15, 89-92.
(34) Uehara, H.; Oishi, T.; Yoshikawa, K.; Michida, K.; Hirama, M.
The absolute configuration and total synthesis of korormicin.
Tetrahedron Lett. 1999, 40, 8641-8645.
(35) Leonhardt, B. A.; Mastro, V. C.; DeVilbiss, E. D. New dispenser
for the pheromone of the gypsy moth (Lepidoptera: Lymantri-
idae). Forest Entomol. 1993, 86, 821-827.
(21) Millar, J. G.; Oehlschlager, A. C. Synthesis of Z,Z-skipped diene
macrolide pheromones for Cryptolestes and Oryzaephilus grain
beetles (Coleoptera: Cucujidae). J. Org. Chem. 1984, 49, 2332-
2338.
(22) Bell, T. W.; Ciaccio, J. A. Alkylative epoxide rearrangement. A
stereospecific approach to chiral epoxide pheromones. J. Org.
Chem. 1993, 58, 5153-5162.
(23) Oliver, J. E.; Waters, R. M. Determining enantiomeric composi-
tion of disparlure. J. Chem. Ecol. 1995, 21, 199-211.
(24) Sharpless, K. B.; Katsuki, T. The first practical method for
asymmetric epoxidation. J. Am. Chem. Soc. 1980, 102, 5974-
5976.
Received for review December 23, 2003. Revised manuscript received
March 10, 2004. Accepted March 12, 2004.
JF035506Q