Concise synthesis of (4R,9Z)-octadec-9-en-4-olide, the female sex pheromone of Janus integer

Article abstract of DOI:10.1002/ejoc.200400830

(4R,9Z)-Octadec-9-en-4-olide, the female sex pheromone of the currant stem girdler (Janus integer), was synthesized in gram quantities by employing Sharpless asymmetric dihydroxylation (AD) and Jacobsen hydrolytic kinetic resolution (HKR). Crystalline (R)-hexadec-7-yne-1,2-diol (87% ee), obtained by AD and purified by recrystallization, was converted into (R)-1,2-epoxyhexadec-7- yne (87%ee), which was further purified to 96% ee by HKR. The epoxide was converted into the target lactone in 14% overall yield based on hex-5-en-1-ol (11 steps). Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2005.

Full text of DOI:10.1002/ejoc.200400830

FULL PAPER
Concise Synthesis of (4R,9Z)-Octadec-9-en-4-olide, the Female Sex Pheromone
of Janus integer[
‡]
Kenji Mori*[a]
Keywords: Dihydroxylation / Epoxides / Lactones / Natural products / Pheromones
(
4R,9Z)-Octadec-9-en-4-olide, the female sex pheromone of
into (R)-1,2-epoxyhexadec-7-yne (87% ee), which was fur-
ther purified to 96% ee by HKR. The epoxide was converted
into the target lactone in 14% overall yield based on hex-5-
en-1-ol (11 steps).
the currant stem girdler (Janus integer), was synthesized in
gram quantities by employing Sharpless asymmetric dihy-
droxylation (AD) and Jacobsen hydrolytic kinetic resolution
(
HKR). Crystalline (R)-hexadec-7-yne-1,2-diol (87% ee), ob-
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2005)
tained by AD and purified by recrystallization, was converted
Introduction
In 2001 Cossé et al. isolated and identified (Z)-octadec-
9-en-4-olide (1) as a female-specific and antennally active
compound from the female currant stem girdler, Janus inte-
ger Norton (Hymenoptera: Cephidae), a pest of red currant
[
1]
in North America. It was then found to be the sex phero-
mone of that insect, and its (R) absolute configuration was
proposed on the basis of the synthesis of a trace amount
of (R)-1 starting from (S)-glutamic acid.[ Subsequently we
developed another synthesis, which enabled us to obtain
both (R)- and (S)-1 in 50–100 mg quantities.[ By bioassay
of our synthetic samples, (R)-1 was definitely confirmed as
the sex pheromone of J. integer, while (S)-1 was pheromon-
ally inactive. To test the feasibility of utilizing (R)-1 as the
pest managing agent against J. integer in the U.S.A., Dr.
D. G. James at Washington State University asked me to
synthesize gram quantities of (R)-1. This paper describes a
successful account of the synthesis of (R)-1 in an amount
2]
3]
(4 g) sufficient for a practical field test.
As shown in Scheme 1, the key intermediate in our pre-
[
3]
vious synthesis was acetylenic alcohol (R)-A, prepared by
enzymatic kinetic resolution of (±)-A with lipase PS(Am-
ano) and vinyl acetate. In the current synthesis, epoxide (R)-
B was envisaged as the key intermediate, to be prepared by
[4]
Sharpless asymmetric dihydroxylation (AD) and Jacobsen
hydrolytic kinetic resolution (HKR).[
was to enable the enrichment of the enantiomeric purity of its synthesis.
R)-B prepared by AD. The results detailed below confirm
the practicality of these asymmetric processes.
5,6]
The HKR process Scheme 1. Structure of the target pheromone and two strategies for
(
Results and Discussion
[
‡] Pheromone Synthesis, 229. Part 228: K. Mori, Tetrahedron:
Asymmetry 2005, 16, 685–692.
Scheme 2 summarizes the synthesis and purification of
the key epoxide (R)-10. Commercially available hex-5-en-1-
ol (2) was converted into the corresponding iodide 4 in 92%
yield via tosylate 3. Alkylation of dec-1-yne with n-butyl-
[
a] Insect Pheromone and Traps Division, Fuji Flavor Co., Ltd.,
Midorigaoka 3-5-8, Hamura-City, Tokyo 205–8503, Japan
Fax: +81-42-555-7920;
E-mail: kjk-mori@arion.ocn.ne.jp
2040
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
DOI: 10.1002/ejoc.200400830
Eur. J. Org. Chem. 2005, 2040–2044

Synthesis of (4R,9Z)-Octadec-9-en-4-olide
FULL PAPER
lithium and 4 furnished enyne 5 in 71% yield. Sharpless aqueous methanol, without purification, to provide epoxide
AD of 5 with AD-mix-β® afforded crystalline (R)-diol 6 (R)-10 (= B) in 87% yield based on (R)-6. The enantiomeric
[4]
(
(
about 75% ee) in 84% yield. The enantiomeric purity of purity of (R)-10 could be determined by GC analysis on a
R)-6 was analyzed by HPLC after derivatization to the cor- chiral stationary phase: octakis(2,3-di-O-methoxymethyl-6-
responding
bis-(R)-α-methoxy-α-trifluoromethylphenyl- O-tert-butyldimethylsilyl)-γ-cyclodextrin (MOM-TBDMS-
acetate (MTPA ester) 7.[
7]
GCD). A sample of (R)-10 (87% ee) prepared from recrys-
tallized (R)-6 was subjected to further purification by Ja-
cobsen’s HKR in the presence of his (R,R)-salen cobalt cat-
[
5,6]
alyst 11.
Treatment of (R)-10 in THF with 0.7 mol% of
11 and 0.4 equiv. of water for 3 days at room temperature
(25 °C) was followed by chromatographic workup to give
(R)-10 (96% ee, 72% yield) together with crystalline (S)-6
(49% ee, 20%). Purification of (R)-10 by Jacobsen’s pro-
cedure was time-saving and more efficient than the purifica-
tion of (R)-6 by recrystallization.
Actually, although the diol (R)-6 could be purified by
recrystallization from hexane, the recovery of the purified 6
was low due to its high solubility and low melting point.
Diol (R)-6 of 87% ee could be obtained in 60% yield based
on 5, while that of 98% ee could be secured only in 20%
yield.
Two unsuccessful attempts were made to purify (R)-6 en-
zymatically. Treatment of diol (R)-6 with lipase PS and vinyl
acetate in diisopropyl ether afforded monoacetate (R)-12 of
no improved enantiomeric purity. In this particular case,
the stereochemistry at C-2 of 6 did not affect the rate of
acetylation of the hydroxy group at C-1. The sterically more
demanding tert-butyldimethylsilyl (TBS) group was then at-
tached to (R)-12 to give (R)-13, which was treated with po-
tassium carbonate in aqueous methanol to furnish (R)-14.
Attempted lipase-catalyzed acetylation of (R)-14 with li-
pase PS and vinyl acetate did not proceed at all, presumably
due to excessively severe steric hindrance caused by the TBS
group. The enzymatic approach was therefore abandoned.
It should be added that the lipase-catalyzed kinetic resolu-
tion of 1-TBSoxyhexadec-7-yn-2-ol might be possible, in
view of a recent publication dealing with a similar sub-
[
9]
strate.
Scheme 3 shows the conversion of epoxide (R)-10 into
Scheme 2. Synthesis of (R)-1,2-epoxyhexadec-7-yne (10). Reagents:
the target lactone (4R,9Z)-1. Classic treatment of (R)-10
(
a) TsCl, C
nBuLi, THF (71%); (d) AD-mixβ , tBuOH, H
room temp. overnight; recrystallization from hexane [1× (84%) for
5
H
5
N; (b) NaI, DMF (92%, 2 steps); (c) nC
8
H17CϵCH,
[10]
with diethyl sodiomalonate in ethanol
did not give a
®
2
O, 0–5 °C, 6 h, then
good result in this case. Although many methods for the
R)-6 of 75% ee; 2× (60%) for (R)-6 of 87% ee; 5× (20%) for (R)- synthesis of lactonic pheromones from epoxides have been
(
6
[
11]
[12,13]
of 98% ee]; (e) (S)-MTPACl, DMAP, C
5
H
5
N; (f) MeC(OMe)
3
,
employed, Meyers’ oxazoline alkylation method
adopted to convert (R)-10 into (R)-octadec-9-yn-4-olide
16) via (R)-15. Accordingly, epoxide (R)-10 was added to
was
PPTS, CH
2
Cl ; (g) AcBr, CH Cl ; (h) K CO
2
2
2
2
3
, MeOH [87%. for
(
R)-10, 3 steps; quant. for (R)-14,]; (i) Jacobsen’s (R,R)-salen cobalt
catalyst (11), 0.4 equiv. H O, THF [72% of (R)-10 (96% ee) and
0% of (S)-6 (49% ee)]; (j) lipase PS, CH =CHOAc, iPr O (99%);
k) TBSCl, imidazole, DMF (86%).
(
2
the anion generated from 2,4,4-trimethyl-2-oxazoline by
treatment with n-butyllithium, and the resulting (R)-15 was
heated with dilute hydrochloric acid to give (R)-16 in 58%
yield based on (R)-10. Finally, semihydrogenation of (R)-16
2
2
2
(
2+
Conversion of diol (R)-6 into epoxide (R)-10 was exe- over Lindlar’s catalyst (Pd–CaCO –Pb ) in hexane at –5
3
cuted by the method of Kolb and Sharpless.[ Accordingly, to 0 °C under atmospheric pressure afforded (4R,9Z)-octa-
recrystallized (R)-6 (87% ee, vide infra) was treated with tri- dec-9-en-4-olide (1) in 94% yield. Its GC analysis revealed
methyl orthoacetate and pyridinium p-toluenesulfonate it to be of 96% ee with a Z/E ratio of 13:1.
8]
(PPTS) to give water-labile orthoacetate (R)-8, to which
In conclusion, a concise synthesis of Janus integer phero-
acetyl bromide was added. The resulting (S)-1-acetoxy-2- mone (4R,9Z)-1 was achieved in an overall yield of 14%
bromo compound 9 [contaminated with (R)-2-acetoxy-1- based on hex-5-en-1-ol 2 (11 steps). The result of the field
bromo isomer] was mixed with potassium carbonate in test will be reported in due course.
Eur. J. Org. Chem. 2005, 2040–2044
www.eurjoc.org
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
2041

K. Mori
FULL PAPER
Hexadec-1-en-7-yne (5): nBuLi (1.6 m in hexane, 36.5 mL,
58.4 mmol) was added at –78 °C under Ar to a stirred and cooled
(
(
(
dry ice/acetone) solution of dec-1-yne (8.0 g, 58 mmol) in dry THF
120 mL). The mixture was stirred at –78 to 20 °C for 1 h. Then 4
13.0 g, 62 mmol) was added dropwise by syringe, and the mixture
was stirred and heated under reflux (65 °C) for 3 h. It was left to
stand at room temp. for 2 d, and was then poured into ice and sat.
NH
washed with water and brine, dried with MgSO
in vacuo. The residue was distilled to give 9.1 g (71%) of 5, b.p.
4
Cl solution, and extracted with pentane. The extract was
4
, and concentrated
2
2
1
1
0
1
24–127 °C/4 Torr. n
.86 (t, J = 6.6 Hz, 3 H, 16-H
.40–1.55 (m, 4 H), 2.08 (m, 2 H), 2.10–2.20 (m, 4 H), 4.91–5.05
D
= 1.4567. H NMR (300 MHz, CDCl
3
): δ =
3
), 1.18–1.40 [1.28 (br.s), m, 12 H],
1
3
(
m, 2 H, 1-H
2
), 5.70–5.88 (m, 1 H, 2-H) ppm. C NMR (75 MHz,
CDCl
3
): δ = 14.1, 18.6, 18.7, 22.7, 28.0, 28.6, 28.9, 29.13, 29.14,
29.2, 31.8, 33.3, 79.9, 80.4, 114.4, 138.7 ppm. IR (film): ν˜ = 3075
(
w), 2930 (s), 2860 (s), 1645 (m, C=C), 1460 (s), 990 (m), 910 (s)
–
1
cm . C16
1
2
H
28 (220.4): calcd. C 87.19, H 12.81: found C 86.89, H
2.92. HRMS (EI) [M]+ (C16
28): calcd. 220, 2191; found 220.
187.
H
(
R)-Hexadec-7-yne-1,2-diol (6): AD-mix-β® (33.7 g) was added to
Scheme 3. Synthesis of (4R,9Z)-octadec-9-en-4-olide (1). Reagents:
a stirred mixture of tBuOH (120 mL) and water (120 mL), and the
stirring was continued to generate a reddish biphasic mixture. This
was then cooled in an ice-bath, and 5 (5.3 g, 24 mmol) was added
dropwise. The stirring was continued for 6 h at 0–5 °C and then
overnight at room temp. to give a yellowish suspension. The excess
(
a) 2,4,4-trimethyl-2-oxazoline, nBuLi, THF, –78 °C to room temp.;
(
b) dil. HCl, THF, 60 °C, 30 min (58%, 2 steps); (c) H
2
, Lindlar
–Pb2+, hexane, –5 to 0 °C (94%).
Pd–CaCO
3
2 3
oxidant was then destroyed by addition of Na SO (36 g) with stir-
ring and ice-cooling over 30 min. The mixture was concentrated in
vacuo, and extracted with ethyl acetate. The extract was washed
Experimental Section
General: IR: Horiba FT-720. 1H NMR: Varian Mercury 300
300 MHz) (TMS at δ = 0.00 ppm or CHCl at δ = 7.26 ppm as
internal standard). 13C NMR: Varian Mercury 300 (75 MHz)
CDCl at δ = 77.0 ppm as internal standard). Melting points (Yan-
aco MP-S3) and boiling points: Uncorrected values. n : Atago
DNT-1. [α] : Jasco DIP-320. CC: Merck Kieselgel 60 Art 1.07734.
4
with brine, dried with MgSO , and concentrated in vacuo. The re-
(
3
sidual semi-solid was recrystallized from hexane to give crude (R)-
2
0
6
(5.1 g, 84%, 75% ee), [α]
D
= +4.7 (c = 3.7, MeOH). A second
(
3
recrystallization of 6.4 g of crude (R)-6 gave 4.6 g (60% based on
D
2
2
5
, 87% ee) of the diol, [α]
D
= +6.2 (c = 3.2, MeOH). In another
D
experiment, recrystallization was repeated five times to give (R)-6
2
1
Hex-5-enyl Tosylate (3): TsCl (55 g, 294 mmol) was added portion-
wise to a stirred and ice-cooled solution of 2 (25.4 g, 254 mmol) in
dry pyridine (150 mL). The mixture was stirred for 3 h at 0–5 °C,
poured into ice and dil. HCl., and extracted with hexane. The ex-
of 98% ee, [α]D = +7.4 (c = 3.2, MeOH), in 20% yield based on 5,
1
as leaflets, m.p. 50.5–52.0 °C. H NMR (300 MHz, CDCl ): δ =
3
0.88 (t, J = 6.3 Hz, 3 H, 16–H ), 1.20–1.40 [1.27 (br.s), m, 16 H],
3
1.40–1.60 (m, 4 H), 2.09–2.19 (m, 4 H), 3.44 (dd, J = 11, 11 Hz, 1
tract was washed successively with water, sat. NaHCO
and brine, dried with MgSO , and concentrated in vacuo to give
4.5 g (quant.) of 3 as a colorless oil. H NMR (300 MHz, CDCl
δ = 1.41 (apparently quint, J = 6 Hz, 2 H), 1.61 (apparently quint,
J = 6 Hz, 2 H), 2.01 (dt, J = 6, 6 Hz, 2 H), 2.42 (s, 3 H, ArCH ),
), 5.70 (m, 1 H, 11.89; found C 75.23, H 12.11.
-H), 7.36 (d, J = 6 Hz, 2 H, Ar), 7.80 (d, J = 6 Hz, 2 H, Ar) ppm.
3
solution,
H, 1-H), 3.66 (dd, J = 11, 11 Hz, 1 H, 1–H), 3.73 (m, 1 H, 2-H)
1
3
4
ppm. C NMR (75 MHz, CDCl ): δ = 14.1, 18.6, 18.7, 22.6, 24.7,
3
1
6
3
):
28.9, 29.0, 29.11, 29.13, 29.2, 31.8, 32.6, 66.8, 72.2, 79.7, 80.6 ppm.
IR (nujol): ν˜ = 3370 (s, OH), 3295 (sh.), 1115 (m), 1070 (m), 1000
–
1
3
16 30 2
(m), 860 (s), 725 (s) cm . C H O (254.4): calcd. C 75.53, H
4
5
2 2
.01 (t, J = 6 Hz, 2 H, 1-H ), 4.95 (m, 2 H, 6-H
Determination of the Enantiomeric Purity of (R)-Hexadec-7-yne-
IR (film): ν˜ = 1640 (w, C=C), 1595 (m, Ar), 1360 (s), 1175 (s), 935
,2-diol (6): In the usual manner,[ samples of 6 were treated with
7]
1
–1
(s), 665 (s), 555 (s) cm . This compound was employed for the
(
S)-MTPACl and DMAP in pyridine to give (R)-MTPA esters 7.
next step without further purification.
®
These were analyzed by HPLC (PEGASIL silica , 25 cm×4.6 mm;
–
1
Hex-5-enyl Iodide (4): Powdered sodium iodide (80 g, 533 mmol)
was added to a stirred solution of 3 (64.5 g, 254 mmol) in DMF
eluent: hexane/EtOAc, 50:1; flow rate: 1.0 mLmin ). Compound
(R)-6 obtained immediately after AD: tR = 45.9 (87.5%), 49.2
(12.5%) min; 75% ee. (R)-6 obtained after two recrystallizations: tR
= 46.2 (93.5%), 49.4 (6.5%) min; 87% ee. (R)-6 obtained after five
(220 mL). After the exothermic reaction, the mixture was stirred
for 4 d at room temp. It was then poured into water, and extracted
with pentane. The pentane extract was washed successively with
1
recrystallizations: tR = 47.0 (98.9%), 50.5 (1.1%) min; 98% ee. H
water, sodium thiosulfate solution, and brine, dried with MgSO
and concentrated in vacuo. The residue was distilled to give 49.3 g
4
,
NMR analysis of 7 did not give useful information, due to the
complexity of the spectrum.
1
(
92% based on 2) of 4, b.p. 84–85 °C/40 Torr. H NMR (300 MHz,
CDCl ): δ = 1.48 (apparently quint, J = 6 Hz, 2 H), 1.80 (appar-
ently quint, J = 6 Hz, 2 H), 2.04 (dt, J = 6, 6 Hz, 2 H), 3.18 (t, J (i) Preparation of Orthoacetate (R)-8: PPTS (30 mg, 0.1 mmol) was
6 Hz, 2 H, 1-H ), 5.00 (m, 2 H, 6-H ), 5.80 (m, 1 H, 5-H) ppm. added to a stirred solution of (R)-6 (87% ee, 3.45 g, 13.6 mmol)
IR (film): ν˜ = 3075 (m), 2930 (s), 2885 (m), 1640 (m, C=C), 1215 and trimethyl orthoacetate (3.5 g, 18.4 mmol) in CH Cl (30 mL),
(
R)-1,2-Epoxyhexadec-7-yne (10)
3
=
2
2
2
2
–1
(
s), 1170 (s), 990 (m), 915 (s) cm . This compound was immedi-
and the solution was left to stand overnight in a refrigerator. The
solution was then concentrated in vacuo, and the residue was
ately used for the next step.
2042
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2005, 2040–2044

Synthesis of (4R,9Z)-Octadec-9-en-4-olide
FULL PAPER
stirred and heated at 50–60 °C in vacuo (20 Torr) to remove
through Celite. The filtrate was concentrated in vacuo. The residual
MeOH, affording 5.2 g (quant.) of oily (R)-8. IR (film): ν˜ = 1240
oil (2.3 g, 99%) was homogeneous, and was identified as (R)-12.
–1
26
24
1
(m), 1155 (s), 1055 (s), 890 (m) cm . This orthoester was labile
n
D
= 1.4638. [α]
D
= +0.8 (c = 3.2, hexane). H NMR (300 MHz
), 1.20–1.40 [1.27 (br.s),
against water, and was used immediately in the next step.
CDCl ): δ = 0.88 (t, J = 6.9 Hz, 3 H, 16-H
3
3
m, 15 H], 1.40–1.60 (m, 4 H), 2.10 (s, 3 H, Ac), 2.10–2.25 (m, 4
H), 3.86 (m, 1 H, 2-H), 3.96 (dd, J = 11, 11 Hz, 1 H, 1-H), 4.18
(
ii) Preparation of Acetoxy Bromide (S)-9: Acetyl bromide (1.5 mL,
about 2.5 g, 20 mmol) was added at 0–5 °C to a stirred and ice-
cooled solution of (R)-8 (5.2 g, 13.6 mmol) in CH Cl (30 mL). The
1
3
(
=
6
dd, J = 11, 11 Hz 1 H, 1-H) ppm. C NMR (75 MHz, CDCl
14.1, 18.7, 20.8, 22.6, 24.6, 28.9, 29.0, 29.1, 29.2, 31.8, 32.7, 66.7,
8.7, 69.8, 72.1, 79.6, 80.6, 171.2 ppm. IR (film): ν˜ = 3480 (m, OH),
3
): δ
2
2
mixture was stirred for 1 h at 0–5 °C, and was then concentrated
in vacuo to give about 5.9 g (quant.) of (S)-9 as a yellowish oil. IR
–
1
+
–
1
1745 (s, C=O), 1240 (s) cm . HRMS (EI) [M] (C18
96.2351; found 296.2357.
H
32
O
3
): calcd.
(film): ν˜ = 1745 (s, C=O), 1375 (m), 1235 (s), 1025 (m) cm . This
2
bromide was used in the next step without further purification.
(
1
iii) Preparation of Epoxide (R)-10: A solution of (S)-9 (5.9 g,
3.6 mmol) in THF (10 mL) was added dropwise to a stirred sus-
pension of K CO (4.5 g, 19 mmol) in MeOH (30 mL) and water
5 mL). The mixture was stirred and heated at 50 °C for 1 h, and
(R)-1-Acetoxy-2-tert-butyldimethylsilyloxyhexadec-7-yne
(13):
TBSCl (1.6 g, 10 mmol) was added to a stirred and ice-cooled solu-
tion of (R)-12 (2.2 g, 7.4 mmol) and imidazole (2.7 g, 40 mmol) in
dry DMF (30 mL). The mixture was stirred for 3 d at room temp
(20 °C), poured into ice water, and extracted with hexane. The ex-
2
3
(
concentrated in vacuo. The residue was diluted with water and ex-
tracted with EtOAc. The extract was washed with water and brine,
tract was washed with water and brine, dried (MgSO
trated in vacuo. The residue was chromatographed over SiO
Elution with hexane/EtOAc (50:1) gave 2.6 g (86%) of (R)-13, n
4
), and concen-
dried with MgSO
chromatographed over SiO
EtOAc (100:1) afforded 2.9 g (91% based on 6) of oily (R)-10 = 1.4547. [α]
4
, and concentrated in vacuo. The residue was
2
(40 g).
2
6
2
(30 g in hexane). Elution with hexane/
D
2
2
1
D
= –2.4 (c = 3.2, hexane). H NMR (300 MHz,
): δ = 0.08 [s, 6 H, Si(CH ], 0.88 (br.s, 12 H, tBu, 16-H ),
.20–1.55 (m, 18 H), 2.05 (s, 3 H, Ac), 2.08–2.20 (m, 4 H), 3.84 (m,
87% ee), n2
1
= 1.4608. [α]
26
= +7.5 (c = 3.1, Et
O).
(
D
D
2
CDCl
3
3
)
2
3
1
1
1
(
iv) Purification of (R)-10 by Jacobsen’s HKR: A mixture of (R,R)-
H, 2-H), 3.92 (dd, J = 11, 11 Hz, 1 H, 1-H), 4.40 (dd, J = 11,
1 Hz, 1 H, 1-H) ppm. IR(film): ν˜ = 1745 (s, C=O), 1235 (s), 1120
salen cobalt catalyst (Aldrich, 130 mg, 0.2 mmol), toluene
0.8 mL), and acetic acid (15 μL) was stirred for 1 h, while open to
(
–
1
+
(
(
m), 1045 (m), 835 (s), 775 (m) cm . HRMS (EI) [M]
Si): calcd. 410.3216; found 410.3223.
the air at room temp (25 °C). The solvent was then removed in
vacuo to dry up the dark brown residue 11. To this was added a
solution of (R)-10 (87% ee, 6.5 g, 27.5 mmol) in dry THF (13 mL)
and water (0.18 mL, 10 mmol). The resulting dark solution was
stirred for 3 d at room temp (24–25 °C) and was then poured onto
24 46 3
C H O
(R)-2-tert-Butyldimethylsilyloxyhexadec-7-yn-1-ol (14): K CO
(1.2 g, 8.7 mmol) was added to a stirred solution of (R)-13 (2.0 g,
2
3
4.9 mmol) in THF (5 mL), MeOH (15 mL), and H O (1 mL). The
2
a column of SiO
2
(50 g) in hexane. Elution with hexane/EtOAc
mixture was stirred and heated at 50 °C for 1.5 h, and was then
(100:1) gave crude (R)-10 (5.1 g). Subsequent elution with hexane/
concentrated in vacuo. The residue was diluted with water and ex-
EtOAc (1:1) gave crude (S)-6 (1.4 g). Recrystallization of (S)-6 from tracted with hexane. The extract was washed with water and brine,
EtOAc/hexane furnished 1.36 g (20%) of (S)-6 [49% ee as deter-
dried (MgSO ), and concentrated in vacuo to give 1.8 g (quant.) of
mined by HPLC analysis of (S)-7: t = 46.1 (25.4%), 49.3 (R)-14, nD = 1.4594. H NMR (300 MHz, CDCl ): δ = 0.08 [s, 6
74.6%) min] as leaflets, m.p. 45–46 °C. [α]
MeOH). Its IR and NMR spectra were identical to those of (R)-6.
Further purification of (R)-10 was executed by SiO (35 g)
chromatography. Elution with hexane/EtOAc (75:1) gave 4.7 g
4
2
6
1
R
3
2
4
(
D
= –3.6 (c = 3.37,
3 2 3
H, Si(CH ) ], 0.88 (t, J = 6.9 Hz, 3 H, 16-H ), 0.90 (s, 9 H, tBu),
1.20–1.60 (m, 18 H), 2.10–2.22 (m, 4 H), 2.40 (s, 1 H, OH), 3.38
2
(dd, J = 11, 11 Hz, 1 H, 1-H) 3.62 (dd, J = 11, 11 Hz, 1 H, 1-H),
3.78 (m, 1 H, 2-H) ppm. IR (film): ν = 3580 (w), 3460 (m, OH),
˜
2
5
22
–1
+
(
3
3
72%) of pure (R)-10 (96% ee), n
D
= 1.4596. [α]
O). H NMR (300 MHz, CDCl ): δ = 0.88 (t, J = 6.9 Hz, (C H O Si): calcd. 368.3111; found 368.3112.
H, 16-H ), 1.20–1.60 [1.27 (br.s), 1.50 (br.s), m, 18 H], 2.10–2.18
D
= +7.93 (c =
1255 (s), 1120 (s), 835 (s), 780 (s) cm . HRMS (EI) [M]
1
.12, Et
2
3
2
2
44
2
3
(
(
R)-Octadec-9-yn-4-olide (16): A solution of nBuLi in hexane
1.6 m, 12.5 mL, 20 mmol) was added dropwise at –78 °C under Ar
(
m, 4 H), 2.47 (apparently dd, J = 2.7, 5.1 Hz, 1 H, 1-H), 2.75
apparently dd, J = 5.1, 5.1 Hz, 1 H, 1-H), 2.92 (m, 1 H, 2-H) ppm.
(
1
3
to a stirred and cooled solution of 2,4,4-trimethyl-2-oxazoline
2.3 g, 20 mmol) in THF (12 mL). The solution was stirred at
78 °C for 30 min. A solution of (R)-10 (96% ee, 2.8 g, 12 mmol)
C NMR (75 MHz, CDCl
8.8, 28.9, 29.09, 29.11, 29.2, 31.8, 32.0, 47.0, 52.2, 79.6, 80.6 ppm.
IR (film): ν˜ = 3045 (w), 2930 (s), 1460 (m), 1335 (w), 1260 (w),
3
): δ = 14.1, 18.65, 18.72, 22.6, 25.1,
(
–
2
–1
in THF (3 mL) was then added dropwise to the stirred and cooled
solution at –78 to –70 °C. The mixture was stirred at –78 °C for
1
130 (w), 920 (m), 835 (m), 725 (w) cm . C16
C 81.29, H 11.94; found C 80.92, H 12.22.
H28O (236.4): calcd.
30 min, and gradually warmed to room temp (22 °C) over 3 h. It
Determination of the Enantiomeric Purity of 1,2-Epoxyhexadec-7-
yne (10): Samples of 10 were analyzed by GC on a chiral stationary
phase by Dr. S. Tamogami of T. Hasegawa Co., Ltd. (instrument:
was then acidified with 3 m HCl (about 50 mL), and diluted with
THF (30 mL). The resulting acidic and homogeneous solution was
stirred and heated under reflux (60–70 °C) for 30 min. The solution
was concentrated in vacuo to remove THF and was extracted with
hexane. The hexane extract was washed with water and brine, dried
Agilent
3
6890N;
column:
50%
MOM-TBDMS-GCD,
0 m×0.25 mm, df
=
0.25 μm; column temp: 40–180 °C
2
; flow rate: 0.6 mLmin ; detector:
FID; injection temp: 230 °C; detector temp: 250 °C). Compound
R)-10 prior to Jacobsen’s HKR: t
6.5%) min; 87% ee. Compound (R)-10 after Jacobsen’s HKR: t
254.2 (98.0%), 259.4 (2.0%) min; 96% ee.
–1
–1
(+0.5 °Cmin ); carrier gas: N
with MgSO
4
, and concentrated in vacuo. The residue was chro-
matographed over SiO
2
(20 g, hexane). Elution with hexane/EtOAc
(
(
=
R
= 254.3 (93.5%), 259.4
22
(
1
D
10:1) afforded 1.93 g (58%) of (R)-16 as a colorless oil, n =
R
23
1
.4732. [α]
D
= +21.7 (c = 3.21, CHCl
3
). H NMR (300 MHz,
), 1.20–1.70 [1.28 (br.s),
CDCl
3
): δ = 0.88 (t, J = 6.9 Hz, 3 H, 18-H
3
(
R)-1-Acetoxyhexadec-7-yn-2-ol (12): Lipase PS (Amano, 1.2 g) was m, 18 H], 1.70–1.80 (m, 1 H), 1.80–1.95 (m, 1 H), 2.10–2.20 (m, 4
added to a stirred solution of crude (R)-6 (75% ee, 2.0 g, 7.9 mmol) H, 8-H , 12-H ), 2.33 (ddt, J = 6, 7, 11 Hz, 1 H, 3-H), 2.53 (ddd,
and vinyl acetate (50 mL) in iPr O (100 mL). Stirring was contin- J = 0.6, 7, 11 Hz, 2 H, 2-H ), 4.49 (quint, J = 6 Hz, 1 H, 4-H)
ued for a week at room temp. (20 °C), and the mixture was filtered ppm. C NMR (75 MHz, CDCl ): δ = 14.0, 18.5, 18.6, 22.6, 24.3,
2
2
2
2
1
3
3
Eur. J. Org. Chem. 2005, 2040–2044
www.eurjoc.org
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
2043

K. Mori
FULL PAPER
2
1
7.9, 28.6, 28.7, 28.77, 28.78, 28.9, 29.1, 31.7, 35.0, 79.4, 80.6, 80.8, (4R,9E)-1 = 5.7%; (R)-octadecan-4-olide = 3.9%. The purity of the
77.1 ppm. IR (film): ν˜ = 2990 (s), 2860 (s), 1778 (s, C=O), 1460 sample was therefore Ͼ98% ee, Z/E = 16:1, unsaturated lactone/
saturated lactone = 24.6:1. C18 (280.4); calcd. C 77.09, H,
(278.4): calcd. C 77.65, H 10.80; found C 77.47, 11.50; found C 76.96, H 11.64. HRMS (EI) [M] (C18
(
(
m), 1355 (w), 1175 (s), 1020 (w), 915 (w), 805 (w), 725 (w), 650
w) cm . C18
32 2
H O
–1
+
H
30
O
2
32 2
H O ): calcd.
+
H 10.96. HRMS (EI) [M] (C18
78.2243.
4R,9Z)-Octadec-9-en-4-olide (1): Lindlar’s Pd catalyst (Aldrich, 5
wt.-% on CaCO , poisoned with lead, 49 mg) was added to a solu-
30 2
H O ): calcd. 278.2246; found 280.2402; found 280.2402.
2
(
Acknowledgments
3
tion of (R)-16 (96% ee, 500 mg, 1.8 mmol) in hexane (10 mL). The
suspension was cooled with an ice/salt bath (–5 to 0 °C), and was
My thanks are due to Drs. R. J. Bartelt (U.S. Department of Agri-
culture) and S. Tamogami (T. Hasegawa Co., Ltd.) for GC analyses
of (4R,9Z)-1 and (R)-13, respectively. Determination of the enan-
tiomeric purity of 6 was kindly carried out by Dr. T. Tashiro
vigorously stirred under H
then removed by filtration through a small column of SiO
2
(1 atm) for 75 min. The catalyst was
(2 g),
2
and the column was washed with hexane. The hexane solution was
concentrated in vacuo, and the residue was chromatographed over
(
RIKEN). I appreciate the support of this work by Mr. M. Hagi-
wara, Drs. T. Chuman, and S. Muto, Fuji Flavor Co., Ltd.
SiO
2
(5 g in hexane). Elution with hexane/EtOAc (10:1) afforded
450 mg (94%) of (4R,9Z)-1. When hydrogenation was executed at
room temperature (20–25 °C), the product 1 was impure, and con-
taminated with substantial amounts of (R)-octadecan-4-olide and
[
1] A. A. Cossé, R. J. Bartelt, D. G. James, R. J. Petroski, J. Chem.
Ecol. 2001, 27, 1841–1851.
(
4R,9E)-octadec-9-en-4-olide. In order to avoid loss of the material
by overreduction and isomerization, the Lindlar hydrogenation of
R)-16 was carried out repeatedly in small portions. By repeating
[2] D. G. James, R. J. Petroski, A. A. Cossé, B. W. Zilkowski, R. J.
Bartelt, J. Chem. Ecol. 2003, 29, 2189–2199.
(
[3] C. Shibata, K. Mori, Eur. J. Org. Chem. 2004, 1083–1088.
[4] H. C. Kolb, M. S. VanNieuwenhze, K. B. Sharpless, Chem. Rev.
this hydrogenation three times, 1.72 g of (R)-16 gave 1.50 g (91%)
of (4R,9Z)-1 as a colorless oil, which solidified in a deep freezer
1994, 94, 2485– 2547.
2
5
23
[3]
[5] M. Tokunaga, J. F. Larrow, F. Kakiuchi, E. N. Jacobsen, Sci-
ence 1997, 277, 936–938.
(
–20 °C), n
D
= 1.4670. [α]
= +24 (c = 0.50, CHCl
.88 (t, J = 6.9 Hz, 3 H, 18-H
.81–1.90 (m, 1 H), 1.96–2.10 (m, 4 H, 8-H
D
= +24.2 (c = 3.20, CHCl
3
) {ref.:
)}. H NMR (300 MHz, CDCl ): δ =
), 1.20–1.80 [1.27 (br.s), m, 18 H],
, 11-H ), 2.32 (ddt, J
6, 7.5, 13 Hz, 1 H, 3-H), 2.53 (ddd, J = 1.3, 7.5, 9.2 Hz, 2 H, 2-
), 4.48 (quint, J = 6 Hz, 1 H, 4-H), 5.35 (ddt, J = 7, 12, 18 Hz,
25
1
[α]
D
3
3
[
[
[
6] E. N. Jacobsen, Acc. Chem. Res. 2000, 33, 421–431.
7] J. A. Dale, H. S. Mosher, J. Am. Chem. Soc. 1973, 95, 512–519.
8] H. C. Kolb, K. B. Sharpless, Tetrahedron 1992, 48, 10515–
10530.
0
1
=
H
2
3
2
2
2
[9] Y. Aoyagi, Y. Saitoh, T. Ueno, M. Horiguchi, K. Takeya, R. M.
13
H, 9-H, 10-H) ppm. C NMR (75 MHz, CDCl
3
): δ = 14.1, 22.7,
Williams, J. Org. Chem. 2003, 68, 6899–6904.
[
10] T. Sugai, K. Mori, Agric. Biol. Chem. 1984, 48, 2497–2500.
2
8
4.9, 27.0, 27.1, 27.2, 28.0, 28.8, 29.3, 29.4, 29.5, 29.7, 31.9, 35.5,
0.9, 129.1 [(9Z) isomer, major, 95%], 129.4 [(9E) isomer, very
[11] K. Mori, in The Total Synthesis of Natural Products, vol. 9
(
2
Ed.: J. ApSimon), John Wiley & Sons, New York, 1992, 216–
73.
12] A. I. Meyers, E. D. Mihelich, R. L. Nolen, J. Org. Chem. 1974,
9, 2783–2787.
13] P. H. G. Zarbin, A. R. M. Oliveira, F. Simonelli, J. A. F. P. Vil-
lar, O. Delay, Jr., Tetrahedron Lett. 2004, 45, 7399–7400.
Received: November 22, 2004
minor, 5%], 130.5 [(9Z) isomer, major, 95%], 130.7 [(9E) isomer,
very minor, 5%], 177.2 ppm. IR (film): ν˜ = 2925 (s), 2855 (s), 1780
[
[
(
1
2
s, C=O), 1650 (w, C=C), 1460 (m), 1355 (m), 1285 (w), 1175 (s),
020 (m), 915 (m), 825 (w), 720 (m) cm . GC analysis on a BDEX-
25 column of this sample by Dr. Bartelt (U.S. Department of Ag-
3
–1
riculture) revealed its composition as follows: (4R,9Z)-1 = 90.4%;
2044
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2005, 2040–2044