Asymmetric synthesis of both enantiomers of disparlure

Article abstract of DOI:10.1002/cjoc.201100482

Starting from propargyl alcohol (12), and on the basis of Zhou's modified Sharpless asymmetric epoxidation, the sex pheromone of the Gypsy moth, disparlure (+)-8 and its enantiomer (-)-8 have been synthesized, each in six steps, with overall yields of 29% for (+)-8 and 27% for (-)-8 (ee>98%). The use of the sequential coupling tactic renders the method flexible, which is applicable to the synthesis of other cis-epoxy pheromones. Copyright

Full text of DOI:10.1002/cjoc.201100482

FULL PAPER
DOI: 10.1002/cjoc.201100482
Asymmetric Synthesis of Both Enantiomers of Disparlure
Wang, Zhigang(王志刚)
Zheng, Jianfeng*(郑剑峰)
Huang, Peiqiang(黄培强)
Department of Chemistry and Key Laboratory for Chemical Biology of Fujian Province, College of Chemistry and
Chemical Engineering, Xiamen University, Xiamen, Fujian 361005, China
Starting from propargyl alcohol (12), and on the basis of Zhou’s modified Sharpless asymmetric epoxidation,
the sex pheromone of the Gypsy moth, disparlure (＋)-8 and its enantiomer (－)-8 have been synthesized, each in
six steps, with overall yields of 29% for (＋)-8 and 27% for (－)-8 (ee＞98%). The use of the sequential coupling
tactic renders the method flexible, which is applicable to the synthesis of other cis-epoxy pheromones.
Keywords Gypsy moth, pheromones, Sharpless asymmetric epoxidation, asymmetric synthesis, epoxides
Introduction
O
O
Sex pheromones are signal substances released or
emitted by plants and insects for communication be-
tween individuals within the same species. With the ad-
vantages of being active at very low concentration,
non-toxic, and species-specific, pheromones of many
pests are used to monitor insects and protect plants
against those pests. However, making on practice of
such efficient and sustainable insect management strate-
gies is largely limited by the availability of pheromones
since generally, only μg to ng scales of the pheromones
are available from natural sources. This also constitutes
an obstacle for both unequivocal determination of rela-
tive and absolute stereochemistries, and profound bioac-
tivity-related studies. Thus, enantioselective synthesis of
pheromones have attracted much interest of ecologists
and synthetic organic chemists.[1]
1
n
2. n = 0; 3. n = 1
O
O
4
n
5
6
7
. n = 1; . n = 2; . n = 3
O
8
. disparlure
Among the sex pheromones identified so far, many
are characterized by the cis-epoxy substructure. For
example, epoxides 1—3 (Figure 1) are pheromone
components of the fall webworm moth, Hyphantria cu-
nea;[2] epoxide 1 was also identified as the major
pheromone component of the saltmarsh caterpillar moth
Estigment acrea Drury;[3] epoxide 4 is a pheromone of
the pink moth (the rosy Russian gypsy moth, Lymantria
mathura Moore);[4] alkenyl epoxides 5—7 are the sex
pheromones of the elm spanworm Ennomus subsignaria
(Hübner),[5] the painted apple moth, Teia anartoides
Walker,[6] and the ruby tiger moth, Phragmatobia fu-
liginosa (L.).[7]
Figure 1 Sex pheromones of several species of moth.
Europe to Asia, and then North America, now world-
wide existing. It is also one of the most harmful pests
that damages forest, garden, sericulture and fruiter.
In 1970, Bierl and co-workers identified disparlure as
the sex pheromone of the female gypsy moth and the
structure was elucidated as cis-7,8-epoxy-2-methyl-
octadecane (8).[8] The absolute configuration of dispar-
lure was established by synthesis of both enantiomers,[9a]
which also allowed the conclusion that natural
(＋)-disparlure is more active than the (－)-enantio-
mer.[9a] Studies towards disparlure (8) has attracted
much attention from both biological[10] and synthetic
communities. Up to now more than twenty approaches
have been reported for the enantioselective synthesis of
Gypsy moth, Porthetria dispar L. is a class of wide-
spread and harmful pests with a very broad diet which
causes severe forest losses during outbreaks. Its larva
can spread with the wind, firstly expanding from
*
E-mail: zjf485@xmu.edu.cn
Received October 10, 2011; accepted November 9, 2011; published online December 23, 2011.
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/cjoc.201100482 or from the author.
Chin. J. Chem. 2012, 30, 23—28
© 2012 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
23

Wang, Zheng & Huang
FULL PAPER
(＋)-disparlure,[9,11-17] and eight for (－)-disparlure.[18]
The reported methods are based on either chiral pools,[9]
or asymmetric synthesis.[11-17] Although nine used the
Sharpless asymmetric epoxidation as the key step,[11]
there are drawbacks in those approaches, such as use of
uncommon starting materials,[11f,11g] the need of a deri-
vatization for enantiomer enrichment,[11c,11f-11h] low en-
antiomeric purity of the final product,[11i] low overall
yield or multiple steps required for the chain elonga-
tion.[11a,11b,11d,11e] In short, although a number of methods
have been reported to access both enantiomers of dis-
parlure, short and efficient ones without using expensive
starting material and toxic reagents are still demanding.
In recent years, we have been engaged in the asym-
metric synthesis of pheromones.[19] We recently reported
a divergent synthesis of the two main pheromone com-
ponents of the fall webworm moth, Hyphantria cu-
nea.[19b] As an extension of the latter synthetic strategy,
we now report the syntheses of both enantiomers of
disparlure (8, Scheme 1).
thesis started with the preparation of (Z)-allylic alcohol
11 by Ames’s procedure[21] (Scheme 2). In the event,
treatment of 1-bromodecane with LiC≡CCH2OLi in a
mixed solvent system HMPA/THF produced propargy-
lic alcohol 13 in 84% yield. Partial hydrogenation of
propargylic alcohol 13 over Lindlar catalyst (H2, 5%
Pd/CaCO3, poisoned with 3.5% Pb, n-hex., 0 ℃) gave
(Z)-allylic alcohol (11) in 94% yield.
Scheme 2 Synthesis of (Z)-dodec-2-en-1-ol (11)
n-BuLi (2 equiv.)
HMPA, n-C10H21Br
C9H19-n
THF, –78 ºC, 5 h
84%
OH
12
OH
13
H2, n-hex., 0 ºC
Lindlar cat., 2 h
C10H21-n
OH
94%
11
With allylic alcohol 11 in hand, we proceeded to in-
vestigate its enantioselective epoxidation to prepare ep-
oxide 14a via the Sharpless asymmetric epoxidation. In
this context, many successful examples of asymmetric
epoxidation methods have been documented in the lit-
eratures,[20] and Zhou’s modified Sharpless catalytic
system[22] was adopted according to our previous
results.[19b] Thus, in the presence of Ti(Oi-Pr)4, CaH2,
SiO2 and D-(－)-DIPT, allylic alcohol 11 was treated
with t-BuO2H in CH2Cl2 to produce the corresponding
epoxide 14a in 80% ee.[23] Moderate enantioselectivity
of Sharpless epoxidation for (Z)-allylic alcohol has been
observed.[11,24] Fortunately epoxy 14a is solid and could
be enriched to 98%—99% ee in 60% yield after one
recrystallization from petroleum ether (Scheme 3).
Scheme 1 Retrosynthetic analysis of (＋)-(7R,8S)-disparlure (8)
R1
R1
O
O
R2
9
R2
(+)-(7R,8S)-8
R1
X
C
10H21-n
C10H21-n
OH
O
OTf
OH
12
R3
11
10a
M
Scheme 3 Syntheses of epoxide 14a and 14b
On the basis of our previous work,[19b] and in view of
a general access to epoxy pheromones, our retrosyn-
thetic analysis of disparlure (8) is displayed in Scheme 1.
Given the chiral epoxide as the key structural feature of
8, the Sharpless asymmetric epoxidation (AE) was se-
lected as a convenient method for the enantioselective
formation of the epoxy group.[20] In view of the unsatis-
factory enantioselectivity of the Sharpless AE with
cis-allylic alcohols,[11] longer chain (R1) at the epoxy
carbon was planned to be introduced first, which would
allow an enrichment of the major enantiomer by recrys-
tallization of the epoxide formed. Installation of the
shorter chain (R2) by means of alkynylation would al-
low the access to both alkyl or alkenyl epoxy phero-
mones after reduction or controlled cis-selective reduc-
tion.
Ti(i-PrO)4, D-(−)-DIPT,
t-BuO2H, CaH2, SiO2,
C10H21-n
CH2Cl2, −25 oC, 72 h
O
OH
after one recrystallization
yield 60%,
98%
e.e. ≥
14a
C
10H21-n
Ti( -PrO) , L-(+)-DIPT,
OH
i
4
BuO H, CaH , SiO ,
t-
2
2
2
11
C10H21
OH
-
n
o
−
CH2Cl2, 25 C, 72 h
O
after one recrystallization
yield 61%, e.e. ≥99%
14b
The next task was the activation of the hydroxyl
group in 14a. Thus 14a was converted into the corre-
sponding triflate 10a by treating with triflic anhydride
(Tf2O, NEt3, CH2Cl2, －78 to －45 ℃, yield 88%)
(Scheme 4).
Results and Discussion
With the fragment 10a available, its coupling reac-
tion was undertaken. Treatment of the organometallic
On the basis of the retrosynthetic analysis, the syn-
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Chin. J. Chem. 2012, 30, 23—28

Asymmetric Synthesis of Both Enantiomers of Disparlure
species generated from 4-methylpent-1-yne and n-BuLi
with triflate 10a gave the desired propargyl alcohol 15a
in 85% yield (Scheme 5).
14b under the same condition for 14a except
D-(－)-DIPT was replaced with L-(＋)-DIPT (Scheme
3). In such a manner, 14b was obtained in 61% yield
and ＞99% ee after recrystallization. Using the proce-
dures described for (＋)-8 (Schemes 4—6), compound
14b was converted to (－)-8 in 3 steps with yield of
85%, 85%, and 77%, respectively.
Scheme 4 Syntheses of epoxy triflate 10a and 10b
C10H21
-
n
C10H21-n
Tf2O, Et3N, CH2Cl2
O
O
O
O
In summary, a new and expeditious six-step ap-
proach for the synthesis of the sex pheromone of the
Gypsy moth, disparlure (＋)-8 and its enantiomer (－)-8
has been developed, which features the use of Zhou’s
Sharpless asymmetric epoxidation of allylic alcohol 11
as the key step. Starting from propargyl alcohol 12,
(＋)-(7R,8S)-8 and its enantiomer (－)-8 have been
synthesized with overall yields of 29% and 27%, re-
spectively. The ee values of the final products (＋)-8
and (－)-8 are at least 98%. Our strategy is flexible, and
could also be used for the synthesis of other insect
pheromones having similar cis-epoxy substructure, such
as the sex pheromones 4—7. Further research is in pro-
gress.
OT f
OH
60 oC
－78—－
88%
14a
10a
C10H21-n
C10H21-n
Tf2O, Et3N, CH2Cl2
OT f
－78—－60 oC
OH
85%
10b
14b
Scheme 5 Coupling reactions of triflate 10a and 10b with the
lithium alkynide
C10H21-n
C
10H21-n
4-methylpent-1-yne
O
O
O
OTf
n−BuLi, HMPA, Et2O
−78 oC, 1 h
85%
10a
15a
Experimental
General methods Melting points were determined
on a micro melting point apparatus and were uncor-
rected. Infrared spectra were measured with a FT-IR
spectrometer using film KBr pellet techniques. 1H NMR
and 13C NMR spectra were recorded in CDCl3 at 400
and 100 MHz respectively. Chemical shifts are ex-
pressed in δ units downfield from TMS. Mass spectra
were recorded with a liquid chromatography-mass spec-
trum apparatus (direct injection). Optical rotations were
measured with a polarimeter. Silica gel (300—400 mesh)
was used for flash column chromatography, eluting
(unless otherwise stated) with ethyl acetate/petroleum
ether (PE) (60—90 ℃) mixture. Ether and THF were
distilled over sodium benzophenone ketyl under N2.
Dichloromethane was distilled over calcium hydride
under N2.
C10H21-n
C
10H21-n
4-methylpent-1-yne
O
OTf
n−BuLi, HMPA, Et2O
−78 oC, 1 h
85%
10b
15b
Finally, chemoselective hydrogenation of 15a in the
presence of 5% Pd—C in dry n-hexane under 105 Pa of
hydrogen at r.t. for 2 h produced the desired target
compound (＋)-8 in 81% yield (Scheme 6).
Scheme 6 Syntheses of compounds (＋)-8 and (−)-8
Pd/C, H2, 2 h
C10H21-n
O
hexane
81%
15a
Tridec-2-yn-1-ol (13) To a cooled (－78 ℃) solu-
tion of propynyl alcohol 12 (280 mg, 5 mmol) in THF
(50 mL) was added n-butyllithium (4.7 mL, 10.5 mmol,
2.2 mol/L in hexane) under an argon atmosphere. After
being stirred for 60 min, a solution of 1-bromodecane
(1.1 mL, 5.5 mmol) in hexamethylphosphoramide
(HMPA, 2.3 mL) was added. After being stirred for an-
other 5 h, the reaction was quenched with 0.5 mol/L
aqueous Na2CO3 solution (10 mL), diluted with diethyl
ether (20 mL). The aqueous phase was back-extracted
with diethyl ether (20 mL×2) and the organic layers
were combined, washed with brine, dried over anhy-
drous Na2SO4, filtered and concentrated under reduced
pressure. The residue was purified by flash column
chromatography on silica gel (Rf 0.2, ethyl acetate∶
petroleum ether＝1∶10) to afford compound 13 (823
mg, 84%) as a white solid. m.p. 30—31 ℃ (n-hexane);
1H NMR (400 MHz, CDCl3) δ: 0.88 (t, J＝6.8 Hz, 3H),
O
(+)-(7R,8S)-8
C10H21-n
Pd/C, H2, 2 h
O
hexane
77%
15b
O
(-)-(7S,8R)-8
We next turned to the synthesis of (－)-8. For this
purpose, allylic alcohol 11 was converted to the epoxide
Chin. J. Chem. 2012, 30, 23—28
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25

Wang, Zheng & Huang
FULL PAPER
1.22—1.42 (m, 14H), 1.46—1.56 (m, 3H), 2.21 (tt, J＝
7.1, 2.1 Hz, 2H), 4.25 (s, 2H); 13C NMR (100 MHz,
CDCl3) δ: 14.1, 18.7, 22.7, 28.6, 28.9, 29.1, 29.3, 29.5,
29.6, 31.9, 51.4, 76.7, 86.7; IR (film) νmax: 3326 (OH),
2927, 2853, 2219 (w, C≡C), 1464, 1375, 1138, 1016
cm ; MS (ESI) m/z: 219.1 (M＋Na ). HRMS (ESI)
calcd for C13H24NaO＋ [M＋Na＋ ] 219.1719, found
219.1713.
57.3, 60.9; IR (film) νmax: 3427 (br s, OH), 2911, 2850,
－
1
1634, 1469, 1042 cm ; MS (ESI) m/z (%): 237.2 (M＋
Na＋, 100). HRMS (ESI) calcd for C13H26 NaO＋2 [M＋
Na＋] 237.1825, found 237.1829. The enantiomeric ex-
cess (ee) of epoxide (2R,3S)-14a was determined by
HPLC analysis of the corresponding 3,5-dinitrobenzoyl
ester (column, Chiralpak AD-H 4.6 mm×250 mm;
n-hexane∶ethanol＝60∶40; flow rate, 1.0 mL/min)
tR (min): the product after one recrystallization,
(2R,3S)-ester: ee＝98.2%.
－
＋
1
(Z)-Tridec-2-en-1-ol (11) To a round-bottomed
flask was added Lindlar catalyst (Pd, 15% on CaCO3
poisoned with 3.5% Pb, 5 mg), and the flask was filled
with H2 and cooled to 0 ℃. Compound 13 (30 mg, 0.15
mmol) in 2 mL distilled n-hexane was added to the re-
sultant mixture. After stirring for 2 h at 0 ℃, the prod-
uct was filtered through silica gel to remove the catalyst
and then concentrated to give 11 (28.5 mg, 94%) as a
colorless oil. 1H NMR (400 MHz, CDCl3) δ: 0.88 (t, J＝
6.8 Hz, 3H), 1.24—1.37 (m, 17H), 2.02—2.10 (m, 2H),
4.19 (d, J＝6.1 Hz, 2H), 5.50—5.56 (m, 2H); 13C NMR
(100 MHz, CDCl3) δ: 14.1, 22.7, 27.4, 29.2, 29.3, 29.47,
29.59 (2C), 29.68, 31.9, 58.6, 128.3, 133.3; IR (film)
νmax: 3329 (br s, OH), 3015, 2927, 2847, 1658 (w, C＝
(2R,3S)-2,3-Epoxy-tridecyl trifluoroacetate (10a)
To a vigorously stirred suspension of epoxide 14a (250
mg, 1.17 mmol) in anhydrous CH2Cl2 (65 mL) was
added dropwise triethylamine (0.6 mL, 4.21 mmol) and
trifluoromethanesulfonic anhydride (0.58 mL, 3.5 mmol)
under an argon atmosphere at －78 ℃. The suspension
was allowed to warm slowly to about －60 ℃ and
stirred. Once the solution became clear, the reaction was
recooled to －78 ℃ and stirred for 30 min, then the
reaction was quenched with an aqueous NH4Cl solution
(5.0 mL). The aqueous layer was extracted with CH2Cl2
(20 mL×2). The combined organic layers were washed
with brine, dried over anhydrous Na2SO4, filtered and
concentrated in vacuum. The residue was purified by
flash column chromatography on silica gel (Rf 0.25,
ethyl acetate∶petroleum ether＝1∶50) to afford crude
triflate 10a (354 mg, 88%) as a colorless oil, which was
used in the subsequent step without further purification.
(7R,8S)-7,8-Epoxy-2-methyloctadecane-4-yne
(15a) A solution of n-BuLi (2.2 mol/L in hexane, 0.83
mL, 1.82 mmol) was added dropwise to a solution of
4-methylpent-1-yne (0.24 mL, 2.0 mmol) in anhydrous
diethyl ether (15 mL) at －78 ℃ under an argon at-
mosphere. After being stirred for 10 min, a solution of
triflate (2R,3S)-10a (350 mg, 1.0 mmol) in anhydrous
diethyl ether (2 mL) and anhydrous HMPA (0.4 mL)
was added. After being stirred for 1 h at the same tem-
perature, the reaction was quenched with an aqueous
NH4Cl solution (1.0 mL). The aqueous layer was ex-
tracted with EtOAc (10 mL×3). The combined organic
layers were washed with brine, dried over anhydrous
Na2SO4, filtered and concentrated under reduced pres-
sure. The residue was purified by flash column chroma-
tography on silica gel (Rf 0.25, ethyl acetate∶petroleum
ether＝1∶50) to afford compound 15a (236 mg, 85%)
－
1
C), 1466, 1384, 1015, 721 cm ; MS (ESI) m/z (%):
221.2 (M ＋ Na ＋ , 100). HRMS (ESI) calcd for
C13H26NaO＋ [M＋Na＋] 221.1876, found 221.1878.
(2R,3S)-2,3-Epoxy-tridecan-1-ol (14a) To a mix-
ture of titanium tetraisopropoxide (4.9 mL, 16.7 mmol),
63 mg of calcium hydride and 83 mg of silica gel in 128
mL of anhydrous CH2Cl2 was injected a solution of
D-(－)-diisopropyl tartrate (4.20 g, 18.0 mmol) in an-
hydrous CH2Cl2 (5 mL) via syringe under N2 at －25
℃ . After being stirred for 30 min, a solution of
(Z)-tridec-2-en-1-ol (11) (2.74 g, 13.8 mmol) in anhy-
drous CH2Cl2 (5 mL) was added. After being stirred for
another 30 min, 5.5 mL (30.4 mmol) of anhydrous
tert-butyl hydroperoxide (TBHP, 5.5 mol/L) was then
injected at －25 ℃. The resultant mixture was allowed
to stir at －25 ℃ for 3 d. The reaction was quenched
with 40 mL of 10% aqueous solution of tartaric acid.
The mixture was stirred at －25 ℃ for 1 h, then
warmed to room temperature until the aqueous layer
became clear. After separation of the organic layer, the
aqueous layer was extracted with CH2Cl2 (50 mL×2)
and the combined organic layers were dried over anhy-
drous Na2SO4, filtered and concentrated under reduced
pressure. The residue was purified by flash column
chromatography on silica gel (Rf 0.3, ethyl acetate∶pe-
troleum ether＝1∶3) to afford epoxide 14a, which was
recrystallized from petroleum ether to give 1.78 g (60%)
of epoxide 14a. m.p. 62—63 ℃ (petroleum ether)
(lit.[11a] m.p. 62—63 ℃); [α]2D0 －7.9 (c 1.0, EtOH)
1
as a colorless oil. [α]2D0 －47.2 (c 1.0, CHCl3); H
NMR (400 MHz, CDCl3) δ: 0.87 (t, J＝6.9 Hz, 3H),
0.95 (d, J＝6.6 Hz, 6H), 1.20—1.60 (m, 18H), 1.77
(sept, J＝6.6 Hz, 1H), 2.04 (dt, J＝6.5, 2.4 Hz, 2H),
2.23 (ddt, J＝16.9, 7.4, 2.4 Hz, 1H), 2.57 (ddt, J＝16.9,
5.0, 2.4 Hz, 1H), 2.94 (dt, J＝4.2, 5.9 Hz, 1H), 3.10
(ddd, J＝7.4. 5.0, 4.2 Hz, 1H); 13C NMR (100 MHz,
CDCl3) δ: 14.1, 18.7, 21.9 (2C), 22.6, 26.4, 27.5, 27.9,
28.1, 29.3, 29.47, 29.51 (2C), 29.6, 31.9, 55.4, 57.0,
75.7, 81.2; IR (film) νmax: 2957, 2924, 2850, 2278 (w,
1
[lit.[11a] [α]D20 －7.8 (c 1.0, EtOH)]; H NMR (400
MHz, CDCl3) δ: 0.88 (t, J＝6.9 Hz, 3H), 1.20—1.60 (m,
18H), 1.61—1.68 (m, 1H), 3.03 (ddd, J＝6.6, 5.5, 4.2
Hz, 1H), 3.16 (ddd, J＝6.9, 4.2, 4.2 Hz, 1H), 3.68 (ddd,
J＝11.8, 6.9, 4.9 Hz, 1H), 3.86 (ddd, J＝11.8, 7.6, 4.2
Hz, 1H); 13C NMR (100 MHz, CDCl3) δ: 14.1, 22.7,
26.6, 27.95, 29.3, 29.4, 29.48, 29.51, 29.55, 31.9, 56.7,
－
1
C≡C), 1592, 1464, 1384, 1022 cm ; MS (ESI) m/z
(%): 301.2 (M＋Na＋, 100). HRMS (ESI) calcd for
C19H34NaO＋ [M＋Na＋] 301.2502, found 301.2506.
26
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Chin. J. Chem. 2012, 30, 23—28

Asymmetric Synthesis of Both Enantiomers of Disparlure
(7R,8S)-7,8-Epoxy-2-methyloctadecane [( ＋ )-8]
To a round-bottomed flask was added Pd/C (6 mg, 10%),
and filled with H2. Compound 15a (57 mg, 0.2 mmol) in
1 mL distilled n-hexane was added to the resultant mix-
ture. After being stirred for 2 h at room temperature, the
product was filtered through silica gel to remove the
catalyst and then concentrated. The residue was purified
by flash column chromatography on silica gel (Rf 0.25,
ethyl acetate∶petroleum ether＝1∶100) to afford
(column, Chiralpak AD-H 4.6 mm × 250 mm;
n-hexane∶ethanol＝60∶40; flow rate, 1.0 mL/min)
tR (min): the product after one recrystallization,
(2S,3R)-ester: ee＞99%.
(2S,3R)-2,3-Epoxy-tridecyl trifluoroacetate (10b)
To a vigorously stirred suspension of epoxide 14b (100
mg, 0.47 mmol) in anhydrous CH2Cl2 (26 mL) was
added dropwise triethylamine (0.24 mL, 1.68 mmol)
and trifluoromethanesulfonic anhydride (0.23 mL, 1.40
mmol) under an argon atmosphere at －78 ℃. The
suspension was allowed to warm slowly to about －60
℃ and stirred. Once the solution became clear, the re-
action was recooled to －78 ℃ and stirred for 30 min,
then the reaction was quenched with an aqueous NH4Cl
solution (5.0 mL). The aqueous layer was extracted with
CH2Cl2 (20 mL×2). The combined organic layers were
washed with brine, dried over anhydrous Na2SO4, fil-
tered and concentrated in vacuum. The residue was pu-
rified by flash column chromatography on silica gel (Rf
0.25, ethyl acetate∶petroleum ether＝1∶50) to afford
crude triflate 10b (138 mg, 85%) as a colorless oil,
which was used in the subsequent step without further
purification.
[α]2D0
compound (＋)-8 (47 mg, 81%) as a colorless oil.
1
＋1.0 (c 1.0, CCl4) {lit.14 [α]D ＋0.9 (c 1.1, CCl4)}; H
NMR (400 MHz, CDCl3) δ: 0.84—0.91 (m, 9H), 1.15—
1.59 (m, 27H), 2.84—2.94 (m, 2H); 13C NMR (100
MHz, CDCl3) δ: 14.1, 22.57, 22.58, 22.7, 26.6, 26.8,
27.3, 27.81, 27.84, 27.87, 29.3, 29.54, 29.58, 31.9, 38.9,
57.2; IR (film) νmax: 2951, 2924, 2854, 1464, 1378,
－
1
1263, 1098, 1021, cm ; MS (ESI) m/z (%): 305.3 (M＋
Na＋, 100). HRMS (ESI) calcd for C19H38NaO＋ [M＋
Na＋] 305.2815, found 305.2811.
(2S,3R)-2,3-Epoxy-tridecan-1-ol (14b) To a mix-
ture of titanium tetraisopropoxide (5.6 mL, 18.2 mmol),
71 mg of calcium hydride, and 95 mg of silica gel in
148 mL of anhydrous CH2Cl2 was injected a solution of
L-(＋)-diisopropyl tartrate (4.80 g, 20.6 mmol) in anhy-
drous CH2Cl2 (5 mL) via syringe under N2 at －25 ℃.
After being stirred for 30 min, a solution of (Z)-tridec-
2-en-1-ol (11) (3.14 g, 15.8 mmol) in anhydrous CH2Cl2
(5 mL) was added. After being stirred for another 30
min, 6.3 mL (34.9 mmol) of anhydrous TBHP (5.5
mol/L) was then injected at －25 ℃. The resultant
mixture was allowed to stir at －25 ℃ for 3 d. The
reaction was quenched with 40 mL of 10% aqueous so-
lution of tartaric acid. The mixture was stirred at －25
℃ for 1 h, then warmed to room temperature until the
aqueous layer became clear. After separation of the or-
ganic layer, the aqueous layer was extracted with
CH2Cl2 (50 mL×2) and the combined organic layers
were dried over anhydrous Na2SO4, filtered and con-
centrated under reduced pressure. The residue was puri-
fied by flash column chromatography on silica gel (Rf
0.3, ethyl acetate∶petroleum ether＝1∶3) to afford
epoxide 14b, which was recrystallized from petroleum
ether to give 2.06 g (61%) of epoxide 14b. m.p. 62—63
℃ (petroleum ether) (enantiomer lit.[11a] m.p. 62—63
℃); [α]2D0 ＋7.9 (c 1.0, EtOH) {enantiomer lit.[11a]
[α]2D3 －7.8 (c 1.0, EtOH)}; 1H NMR (400 MHz,
CDCl3) δ: 0.88 (t, J＝6.9 Hz, 3H), 1.20—1.60 (m, 18H),
1.85—1.97 (m, 1H), 3.03 (ddd, J＝6.6, 5.5, 4.2 Hz, 1H),
3.16 (ddd, J＝7.0, 4.2, 4.2 Hz, 1H), 3.67 (ddd, J＝11.8,
7.0, 4.7 Hz, 1H), 3.86 (ddd, J＝11.8, 7.6, 4.2 Hz, 1H);
13C NMR (100 MHz, CDCl3) δ: 14.1, 22.6, 26.6, 27.95,
29.3, 29.4, 29.48, 29.50, 29.55, 31.9, 56.8, 57.3, 60.9;
IR (film) νmax: 3427 (br s, OH), 2911, 2850, 1634, 1469,
(7S,8R)-7,8-Epoxy-2-methyloctadecane-4-yne
(15b) A solution of n-BuLi (2.2 mol/L in hexane, 0.23
mL, 0.50 mmol) was added dropwise to a solution of
4-methylpent-1-yne (0.07 mL, 0.56 mmol) in anhydrous
diethyl ether (3 mL) at －78 ℃ under an argon at-
mosphere. After being stirred for 10 min, a solution of
triflate (2S,3R)-10b (100 mg, 0.28 mmol) in anhydrous
diethyl ether (1 mL) and anhydrous HMPA (0.11 mL)
was added. After being stirred for another 1 h at the
same temperature, the reaction was quenched with an
aqueous NH4Cl solution (1.0 mL). The aqueous layer
was extracted with EtOAc (10 mL×3). The combined
organic layers were washed with brine, dried over an-
hydrous Na2SO4, filtered and concentrated under re-
duced pressure. The residue was purified by flash col-
umn chromatography on silica gel (Rf 0.25, ethyl ace-
tate∶petroleum ether＝1∶50) to afford compound 15b
(66 mg, 85%) as a colorless oil. [α]2D0 ＋47.2 (c 1.0,
1
CHCl3); H NMR (400 MHz, CDCl3) δ: 0.87 (t, J＝6.8
Hz, 3H), 0.95 (d, J＝6.6 Hz, 6H), 1.20—1.60 (m, 18H),
1.76 (sept, J＝6.6 Hz, 1H), 2.04 (dt, J＝6.5, 2.4 Hz, 2H),
2.23 (ddt, J＝16.9, 7.4, 2.4 Hz, 1H), 2.57 (ddt, J＝16.9,
5.0, 2.4 Hz, 1H), 2.94 (dt, J＝4.2, 5.9 Hz, 1H), 3.10
(ddd, J＝7.4, 5.0, 4.2 Hz, 1H); 13C NMR (100 MHz,
CDCl3) δ: 14.1, 18.8, 21.9 (2C), 22.7, 26.5, 27.5, 27.9,
28.1, 29.3, 29.49, 29.53 (2C), 29.6, 31.9, 55.4, 57.0,
75.7, 81.3; IR (film) νmax: 2957, 2924, 2850, 2278 (w,
－
1
C≡C), 1592, 1464, 1384, 1022 cm ; MS (ESI) m/z
(%): 301.2 (M＋Na＋, 100). HRMS (ESI) calcd for
C19H34NaO＋ [M＋Na＋] 301.2502, found 301.2504.
(7S,8R)-7,8-Epoxy-2-methyloctadecane [(－)-8]
To a round-bottomed flask was added Pd/C (2 mg, 10%),
and filled with H2. Compound 15b (18 mg, 0.064 mmol)
in 1 mL distilled n-hexane was added to the resultant
mixture. After being stirred for 2 h at room temperature,
－
＋
1
1042 cm ; MS (ESI) m/z (%): 237.2 (M＋Na , 100).
HRMS (ESI) calcd for C13H26 NaO＋2 [M ＋ Na ＋
]
237.1825, found 237.1828. The enantiomeric excess (ee)
of epoxide (2S,3R)-14b was determined by HPLC
analysis of the corresponding 3,5-dinitrobenzoyl ester
Chin. J. Chem. 2012, 30, 23—28
© 2012 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.cjc.wiley-vch.de
27

Wang, Zheng & Huang
FULL PAPER
J.; Prestwich, E. G.; Prestwich, G. D. Biochemistry 2000, 39, 8953;
(c) Gong, Y.-M.; Pace, T. C. S.; Castillo, C.; Bohne, C.; O'Neill, M.
A.; Plettner, E. Chem. Biol. 2009, 16, 162; (d) Chen, H.; Gong,
Y.-M.; Gries, R. M.; Plettner, E. Bioorg. Med. Chem. 2010, 18, 2920;
(e) Plettner, E.; Gries, R. J. Agric. Food Chem. 2010, 58, 3708.
[11] For the enantioselective synthesis of (＋)-disparlure via Sharpless
asymmetric epoxidation, see: (a) Rossiter, B. E.; Katsuki, T.; Shar-
pless, K. B. J. Am. Chem. Soc. 1981, 103, 464; (b) Mori, K.; Ebata,
T. Tetrahedron Lett. 1981, 22, 4281; (c) Mori, K.; Ebata, T.
Tetrahedron 1986, 42, 3471; (d) Zhou, W.-S.; Wang, Z.-M.; Lin,
G.-Q. Acta Chim. Sinica 1987, 45, 40; (e) Zhou, W.-S.; Wang, Z.-M.;
Lin, G.-Q. Chin. J. Chem. 1988, 46, 132; (f) Marczak, S.; Masnyk,
M.; Wicha, J. Tetrahedron Lett. 1989, 30, 2845; (g) Marczak, S.;
Masnyk, M.; Wicha, J. Liebigs Ann. Chem. 1990, 345; (h) Fukusaki,
E.; Senda, S.; Nakazono, Y.; Yuasa, H.; Omata, T. J. Ferment.
Bioeng. 1992, 73, 284; (i) Li, L. H.; Wang, D.; Chan, T. H.
Tetrahedron Lett. 1997, 38, 101.
the product was filtered through silica gel to remove the
catalyst and then concentrated. The residue was purified
by flash column chromatography on silica gel (Rf 0.25,
ethyl acetate: petroleum ether＝1∶100) to afford com-
pound (－)-8 (14 mg, 77%) as a colorless oil. [α]D20
－1.0 (c 1.0, CCl4) {lit.[14] [α]D －0.9 (c 0.21, CCl4)};
1H NMR (400 MHz, CDCl3) δ: 0.84—0.91 (m, 9H),
1.17—1.56 (m, 27H), 2.84—2.96 (m, 2H); 13C NMR
(100 MHz, CDCl3) δ: 14.1, 22.6, 22.7, 26.6, 26.8, 27.3,
27.81, 27.85, 27.88, 29.3, 29.54, 29.58, 31.9, 38.9, 57.2;
IR (film) νmax: 2951, 2924, 2854, 1464, 1378, 1263,
－
＋
1
1098, 1021 cm ; MS (ESI) m/z (%): 305.3 (M＋Na ,
100). HRMS (ESI) calcd for C19H38NaO＋ [M＋Na＋]
305.2815, found 305.2824.
[12] For the enantioselective synthesis of (＋)-disparlure via chiral sul-
foxide induction, see: (a) Sato, T.; Itoh, T.; Fujisawa, T. Tetrahedron
Lett. 1987, 28, 5677; (b) Satoh, T.; Oohara, T.; Ueda, Y.; Yamakawa,
K. Tetrahedron Lett. 1988, 29, 313; (c) Satoh, T.; Oohara, T.; Ueda,
Y.; Yamakawa, K. J. Org. Chem. 1989, 54, 3130.
[13] For the enantioselective synthesis of (＋)-disparlure via dihydroxy-
lation, see: (a) Keinan, E.; Sinha, S. C.; Sinha-Bagchi, A.; Wang,
Z.-M.; Zhang, X.-L.; Sharpless, K. B. Tetrahedron Lett. 1992, 33,
6411; (b) Ko, S. Y. Tetrahedron Lett. 1994, 35, 3601; (c)
Sinha-Bagchi, A.; Sinha, S. C.; Keinan, E. Tetrahedron: Asymmetry
1995, 6, 2889.
[14] For the enantioselective synthesis of (＋)-disparlure via chiral stan-
nanes, see: Marshall, J. A.; Jablonowski, J. A.; Jiang, H. J. J. Org.
Chem. 1999, 64, 2152.
[15] For the enantioselective synthesis of (＋)-disparlure via asymmetric
chloroallylboration, see: Hu, S.; Jayaraman, S.; Oehlschlager, A. C.
J. Org. Chem. 1999, 64, 3719.
[16] For the enantioselective synthesis of (＋)-disparlure via enzymatic
procedures, see: (a) Brevet, J. L.; Mori, K. Synthesis 1992, 1007; (b)
Tsuboi, S.; Furutani, H.; Ansari, M. H.; Sakai, T.; Utaka, M.; Takeda,
A. J. Org. Chem. 1993, 58, 486.
[17] For the enantioselective synthesis of (＋)-disparlure via asymmetric
organocatalysis, see: (a) Zhang, C.-X.; Da, S.-J.; Zhang, H.-B.; Sun,
B.; Li, Y. Acta Chim. Sinica 2007, 65, 2433; (b) Kim, S.-G. Synthesis
2009, 14, 2418.
Acknowledgement
This work was supported by the National Basic Re-
search Program (973 Program) of China (No.
2010CB833200), the National Natural Science Founda-
tion of China (No. 20832005) and the Natural Science
Foundation of Fujian Province of China (No.
2011J01054).
References and note
[1] (a) Witzgall, P.; Kirsch, P.; Cork, A. J. Chem. Ecol. 2010, 36, 80; (b)
Richard, J. P.; David, W.; Stanley, J. Agric. Food Chem. 2009, 57,
8171.
[2] (a) Hill, A. S.; Kovalev, B. G.; Nikolaeva, L. N.; Roelofs, W. L. J.
Chem. Ecol. 1982, 8, 383; (b) Zhang, Z.-B.; Wang, Z.-M.; Wang,
Y.-X.; Liu, H.-Q.; Lei, G.-X.; Shi, M. Tetrahedron: Asymmetry 1999,
10, 837.
[3] Hill, A. S.; Roelofs, W. L. J. Chem. Ecol. 1981, 7, 655.
[4] Oliver, J. E.; Dickens, J. C.; Zlotina, M.; Mastro, V. C.; Yurchenko,
G. I. Z. Naturforsch. 1999, 54c, 387.
[5] MaGee, D. I.; Silk, P. J.; Wu, J.; Mayo, P. D.; Ryall, K. Tetrahedron
2011, 67, 5329.
[6] Muto, S.-E.; Mori, K. Biosci. Biotechol. Biochem. 2003, 67, 1559.
[7] Descoins, C.; Frerot, B. XVII International Congress of Entomology,
Hamburg, Federal Republic of Germany, August 20, 1984.
[8] Bierl, B. A.; Beroza, M.; Collier, C. W. Science 1970, 170, 87.
[9] (a) Iwaki, S.; Marumo, S.; Saito, T.; Yamada, M.; Katagiri, K. J. Am.
Chem. Soc. 1974, 96, 7842; (b) Mori, K.; Takigawa, T.; Matsui, M.
Tetrahedron Lett. 1976, 17, 3953; (c) Mori, K.; Takigawa, T.; Matsui,
M. Tetrahedron 1979, 35, 833; (d) Lin, G.-Q.; Wu, B.-Q.; Liu, L.-Y.;
Wang, X.-Q.; Zhou, W.-S. Acta Chim. Sinica 1984, 42, 797; (e)
Achmatowicz, O. J.; Andrzej, S. J. Carbohydr. Chem. 1985, 4, 435;
(f) Masaki, Y.; Serizawa, Y.; Nagata, K.; Oda, H.; Nagashima, H.;
Kaji, K. Tetrahedron Lett. 1986, 27, 231; (g) Jigajinni, V. B.;
Wightman, R. H. Carbohydr. Res. 1986, 147, 145; (h) Pikul, S.;
Kozlowska, M.; Jurczak, J. Tetrahedron Lett. 1987, 28, 2627; (i)
Kang, S. K.; Kim, Y. S.; Lim, J. S.; Kim, K. S.; Kim, S. G.
Tetrahedron Lett. 1991, 32, 363; (j) Koumbis, A. E.; Chronopoulos,
D. D. Tetrahedron Lett. 2005, 46, 4353; (k) Prasad, K. R.; Anbarasan,
P. J. Org. Chem. 2007, 72, 3155; (l) Kovalenko, V. N.; Masalov, N.
V.; Kulinkovich, O. G. Russ. J. Org. Chem. 2009, 45, 1318; (m)
Dubey, A. K.; Chattopadhyay, A. Tetrahedron: Asymmetry 2011, 22,
1516.
[18] For the enantioselective synthesis of (－)-disparlure, see: reference
9(e), 9(j), 9(k), 9(m), 11(d), 11(e), 12(a), 13(a), 14.
[19] (a) Huang, P.-Q.; Lan, H.-Q.; Zheng, X.; Ruan, Y.-P. J. Org. Chem.
2004, 69, 3964; (b) Du, Y.; Zheng, J.-F.; Wang, Z.-G.; Jiang, L.-J.;
Ruan, Y.-P.; Huang, P.-Q. J. Org. Chem. 2010, 75, 4619.
[20] (a) Riera, A.; Moreno, M. Molecules 2010, 15, 1041; (b) Johnson, R.
A.; Sharpless, K. B. Catalytic Asymmetric Synthesis, 2nd ed.,
Wiley-VCH, Weinheim, 2000, p. 231; (c) Katsuki, T.; Martin, V. Org.
React. 1996, 48, 1.
[21] Ames, D. E.; Covell, A. N.; Goodburn, T. G. J. Chem. Soc. 1963,
5889.
[22] (a) Wang, Z. M.; Zhou, W. S.; Lin, G. Q. Tetrahedron Lett. 1985, 26,
6221; (b) Wang, Z. M.; Zhou, W. S. Synth. Commun. 1989, 19, 2627.
[23] The enantiomeric excesses (ee) of epoxide 14a and 14b were deter-
mined by HPLC analysis of the corresponding 3,5-dinitrobenzoyl
ester (column, Chiralpak AD-H 4.6×250 mm; n-hexane∶ethanol＝
60∶40; flow rate, 1.0 mL/min).
[24] (a) Zamboni, R.; Milette, L.; Rokach, J. Tetrahedron Lett. 1983, 24,
4899; (b) Nicolaou, K. C.; Veale, P.; Webber, S. E.; Katerinopoulos,
H. J. Am. Chem. Soc. 1985, 107, 7515.
[10] (a) Hansen, K. Physiol. Entomol. 1984, 9, 9; (b) Plettner, E.; Lazar,
(Pan, B.; Qin, X.)
28
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© 2012 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2012, 30, 23—28