Pheromone synthesis, CC: Synthesis of (S)-9-methylgermacrene-B, the male-produced sex pheromone of the sandfly Lutzomyia longipalpis from Lapinha, Brazil, and its (R)-isomer

Article abstract of DOI:10.1002/(sici)1099-0690(200003)2000:6<955::aid-ejoc955>3.0.co;2-y

Both the enantiomers of 9-methylgermacrene-B (1) were synthesized from the enantiomers of methyl 3-hydroxy-2-methylpropanoate (2). The male-produced sex pheromone of the sandfly Lutzomyia longipalpis (the vector of the protozoan parasite Leishmania chagas

Full text of DOI:10.1002/(sici)1099-0690(200003)2000:6<955::aid-ejoc955>3.0.co;2-y

FULL PAPER
Pheromone Synthesis, CC[‡]
Synthesis of (S)-9-Methylgermacrene-B, the Male-Produced Sex Pheromone of
the Sandfly Lutzomyia longipalpis from Lapinha, Brazil, and Its (R)-Isomer
Satoshi Kurosawa[a] and Kenji Mori*[a]
Keywords: Leishmaniasis / Lutzomyia longipalpis / Pheromones / Sandfly / Terpenoids
Both the enantiomers of 9-methylgermacrene-B (1) were syn-
thesized from the enantiomers of methyl 3-hydroxy-2-
methylpropanoate (2). The male-produced sex pheromone of
the sandfly Lutzomyia longipalpis (the vector of the proto-
zoan parasite Leishmania chagasi) from Lapinha, Brazil, was
identified as (S)-1 by GC comparison.
Introduction
The sandfly Lutzomyia longipalpis is the vector of the
protozoan parasite Leishmania chagasi, the causative agent
of visceral leishmainiasis in South and Central America.[1]
In 1996 Hamilton et al. proposed 9-methylgermacrene-B (1)
as the structure of the male-produced sex pheromone of
L. longipalpis from Lapinha, Brazil.[2] In 1999, (±)-1 was
synthesized by us,[3] and was shown to be bioactive as the
pheromone.[4] In continuation of that work, we report
herein the synthesis of both the enantiomers of 9-methyl-
germacrene-B (1).
The present synthesis is the enantioselective version of
our previous one to yield (±)-1.[3] Because there is only a
single stereogenic center at C-9 of 1, methyl (S)-3-hydroxy-
2-methylpropanoate (2) can serve as the commercially avail-
able chiral building block for the synthesis of (R)-1 as
shown in Scheme 1. According to our published synthesis
of (±)-1,[3] the immediate precursor to (R)-1 is the ten-mem-
bered ring ketone (R)-A, which is the deprotected form of
the ethoxyethyl (EE)-protected cyanohydrin (R)-B. This can
be obtained by cyclization of the open-chain precursor (R)-
C according to TakahashiЈs protocol.[5] The acyclic pre-
cursor (R)-C can be prepared from (R)-D and E, the former
of which can be derived from (S)-2. The chloride E is a
known compound obtainable from isoprene.[6]
The above plan has been successfully executed as detailed
below, and the absolute configuration of the naturally oc-
curring 1 is now established as S by its direct GC compar-
ison with the synthetic enantiomers of 1.
Scheme 1. Structures of the enantiomers of 9-methylgermacrene-B
(1) and the retrosynthetic analysis of (R)-1
1
rohydrin 3 (E/Z ϭ Ͼ 99% as estimated by H NMR spec-
Results and Discussion
troscopy) in 22% yield (2 steps) according to Ueda and co-
workers.[6] The corresponding tert-butyldimethylsilyl (TBS)
ether 4 served as one of the building blocks. The synthesis
of the chiral and nonracemic building block (R)-13 (ϭ D)
started from commercially available methyl (S)-3-hydroxy-
2-methylpropanoate (2), which was converted into (R)-5 by
the method of Kakinuma and co-workers.[7] The free hy-
droxy group of (R)-5 was protected as its tert-butyldiphen-
ylsilyl (TBDPS) ether, and the resulting (R)-6 was treated
Scheme 2 summarizes the synthesis of the two building
blocks 4 and (R)-13. Isoprene was converted into the chlo-
[‡]
Part CXCIX: Y. Shirai, M. Seki, K. Mori, Eur. J. Org. Chem.
1999, 3139–3145.
[a]
Department of Chemistry, Faculty of Science, Science
University of Tokyo,
Kagurazaka 1–3, Shinjuku-ku, Tokyo 162–8601, Japan
Fax: (internat.) ϩ 81-3/3235-2214
Eur. J. Org. Chem. 2000, 955Ϫ962
WILEY-VCH Verlag GmbH, D-69451 Weinheim, 2000
1434Ϫ193X/00/0306Ϫ0955 $ 17.50ϩ.50/0
955

S. Kurosawa, K. Mori
FULL PAPER
with aqueous acetic acid to remove the TBS protective oride anion followed by ethyl vinyl ether and p-toluenesul-
group to give (R)-7. Swern oxidation of (R)-7 furnished the fonic acid to provide (R)-20. The acetyl group of (R)-20 was
aldehyde (R)-8, which was converted into the alkyne (R)-10 then removed, and the resulting (R)-21 was converted into
via (R)-9 according to Corey and Fuchs.[8] The alkyne (R)- the corresponding chloride (R)-22. Macrocyclization of (R)-
10 was subjected to the Wipf modification[9] of NegishiЈs 22 under the conditions of Takahashi et al.[5] gave the cyclo-
zirconocene-catalyzed carboalumination reaction,[10] fol- decadiene (R)-23 in 47% yield. Deprotection of the EE
lowed by quenching with formaldehyde to afford the alco- group was followed by base treatment to effect retro-hydro-
hol (R)-11. Treatment of the corresponding chloride (R)-12 cyanation, yielding the crystalline ketone (R)-24. Finally,
with sodium phenylsulfinate gave the phenylsulfone (R)-13, the isopropylidene group was attached to (R)-24 according
the desired building block D. The overall yield of (R)-13 to the method of Utimoto et al.[13] with samarium and
was 16% based on (S)-2 (14 steps).
chromium as the metals to yield (R)-9-methylgermacrene-B
{[α]1D8 ϭ ϩ61.4 (CHCl3)}. The overall yield of (R)-1 was
6.94% based on (R)-13 (14 steps) or 1.11% based on (S)-2
Scheme 2. Synthesis of the two building blocks 4 and (R)-13; re-
agents: (a) TBSCl, imidazole, DMF (quant.); (b) TBDPSCl, imida-
zole, DMF (89%); (c) AcOH, THF, H2O (84%); (d)
(COCl)2,DMSO, Et3N, CH2Cl2; (e) PPh3, CBr4, CH2Cl2 [87%
based on (R)-7]; (f) nBuLi, Et2O (98%); (g) Me3Al, Cp2ZrCl2,
CH2Cl2, H2O; (h) i) nBuLi, hexane; ii) (CH2O)n, THF (85%); (i)
PPh3, CCl4; (j) PhSO2Na 2H2O, DMF [76% based on (R)-11]
Coupling of the two building blocks 4 and (R)-13 and
conversion of the resulting product (R)-14 to (R)-9-methyl-
germacrene-B (1) are summarized in Scheme 3. Alkylation
of the carbanion derived from (R)-13 with 4 yielded (R)-
14, whose TBS protective group was removed with aqueous
acetic acid to give (R)-15. The phenylsulfonyl group of (R)-
15 was reductively detached by treatment with lithium trie-
thylhydroborate in the presence of a palladium catalyst[11]
to give (R)-16 without any appreciable migration of the ad-
jacent double bond. After acetylation of the hydroxy group
of (R)-16, the TBDPS protective group of the resultant (R)-
17 was removed with tetrabutylammonium fluoride to give
the diol monoacetate (R)-18. This was oxidized with Dess–
Martin periodinane[12] to furnish (R)-19. Treatment of (R)-
19 with trimethylsilyl cyanide (TMSCN) and potassium cy-
anide in the presence of 18-crown-6 afforded the corres-
ponding TMS-protected cyanohydrin. Its TMS group was
Scheme 3. Synthesis of the enantiomers of 9-methylgermacrene-B
(1); reagents: (a) nBuLi, THF, HMPA, then 4 (88%); (b) AcOH,
THF, H2O (85%); (c) LiBEt3H, PdCl2(dppp), THF (82%); (d)
Ac2O, C5H5N. (98%); (e) nBu4NF, THF (90%); (f) Dess–Martin
periodinane, CH2Cl2 (85%); (g) TMSCN, KCN-18-crown-6; (h)
BnNMe3F, THF, H2O; (i) EtOCHϭCH2, TsOH, C6H6 (quant.); (j)
K2CO3, MeOH (89%); (k) MsCl, LiCl, DMF, s-collidine (95%); (l)
NaHMDS, THF (47%); (m) PPTS, MeOH, then NaOHaq, Et2O
replaced by the EE group by successive treatments with flu- (57%); (n) CBr2Me2, Sm, SmI2, CrCl3, THF (60%)
956 Eur. J. Org. Chem. 2000, 955Ϫ962

Pheromone Synthesis, CC
FULL PAPER
(28 steps). Similarly (R)-2 afforded (S)-1 {[α]2D0 ϭ –61.3
(CHCl3)} in 1.34% overall yield based on (R)-2 (28 steps).
HPLC analysis of our synthetic (R)- and (S)-1 revealed
them to be of ca. 95% ee, and they showed antipodal CD
spectra (see Experimental Section).
The enantiomers of 1 were sent to Prof. J. A. PickettЈs
laboratory in the U. K. for comparison with the natural
pheromone. GC comparison on a β-cyclodextrin-derived
chiral stationary phase definitively proved the identity of
(S)-1 to be the naturally occurring pheromone of the male
sandfly Lutzomyia longipalpis from Lapinha, Brazil. This
comparison, and the bioassay of our synthetic samples, will
be reported separately by Prof. Pickett.[4]
6.8 Hz, 2 H, 4-H), 7.40 (m, 6 H, o,p-aromatic-H), 7.70 (m, 4 H, m-
aromatic-H). – C27H44O2Si2 (456.82): calcd. C 70.99, H 9.71; found
C 70.87, H 9.57.
(b) (S)-Isomer: In the same manner as described above, (S)-5
(31.5 g, 114 mmol) gave 65.2 g (99%) of (S)-6, whose spectral data
were identical with those of (R)-6, n2D3 ϭ 1.5085. – [α]1D8 ϭ –1.43
(c ϭ 1.02, CHCl3). – C27H44O2Si2 (456.82): calcd. C 70.99, H 9.71;
found C 71.14, H 9.58.
4-(tert-Butyldiphenylsilyloxy)-2-methyl-1-butanol (7). – (a) (R)-Iso-
mer: A solution of (R)-6 (33.5 g, 73.3 mmol) in AcOH/THF/H2O
(3:1:1, 300 mL) was stirred at room temperature for 36 h. The reac-
tion mixture was diluted with diethyl ether and H2O. The organic
phase was separated, and the aqueous phase was extracted with
diethyl ether. The combined organic phase was washed with water,
saturated aq. NaHCO3 and brine, dried with MgSO4, and concen-
trated under reduced pressure. The residue was chromatographed
on silica gel (400 g, hexane/ethyl acetate, 50:1) to give (R)-7 (21.1 g,
84%) as a colorless oil, n2D3 ϭ 1.5388. – [α]1D9 ϭ ϩ6.65 (c ϭ 1.09,
CHCl3). – IR (film): ν˜ ϭ 3360 cm–1 (s, O–H), 1590 (m, aromatic),
1115 (s, Si–O). – 1H NMR (90 MHz, CDCl3): δ ϭ 0.83 (d, J ϭ
7.2 Hz, 3 H, 2-CH3), 1.05 (s, 9 H, tBu), 1.35–1.95 (m, 3 H, 2-H, 3-
H), 2.42 (t, J ϭ 5.8 Hz, 1 H, OH), 3.50 (t, J ϭ 6.8 Hz, 2 H, 1-H),
3.75 (t, J ϭ 6.8 Hz, 1 H, 4-H), 7.40 (m, 6 H, o,p-aromatic-H), 7.70
(m, 4 H, m-aromatic-H). – C21H30O2Si (342.55): calcd. C 73.63, H
8.83; found C 73.35, H 8.67.
In conclusion, the unambiguous synthesis of (R)- and
(S)-9-methylgermacrene-B made it possible to establish the
absolute configuration of the sandfly pheromone as S.
Experimental Section
General: Boiling points and melting points: Uncorrected values. –
IR: Jasco IRA-102. – 1H NMR: Jeol JNM-EX 90A (90 MHz), Jeol
JNM-LA 400 (400 MHz), Jeol JNM-LA 500 (500 MHz), (internal
standard: TMS at δH ϭ 0.00, CHCl3 at δH ϭ 7.26 or [D6]DMSO
at δH ϭ 2.49). – 13C NMR: Jeol JNM-LA 400 (100 MHz), (CDCl3
at δC ϭ 77.0 as an internal standard). – MS: Jeol JMS-SX 102A
and Hitachi M-80B. – Optical rotation: Jasco DIP-1000. – M.p.:
Yanaco MP-S3. – CD spectrum: Jasco J-725. – CC: Merck Kiesel-
gel 60 Art 1.07734. – TLC: 0.25 mm Merck silica gel plates (60F-
254).
(b) (S)-Isomer: In the same manner as described above, (S)-6
(64.9 g, 142 mmol) gave 42.1 g (86%) of (S)-7, whose spectral data
were identical with those of (R)-7, n2D3 ϭ 1.5409. – [α]1D8 ϭ –6.20
(c ϭ 1.09, CHCl3). – C21H30O2Si (342.55): calcd. C 73.63, H 8.83;
found C 73.26, H 8.53.
(E)-4-(tert-Butyldimethylsilyloxy)-1-chloro-2-methyl-2-butene (4):
To a solution of 3 (3.00 g, 24.9 mmol) in DMF (30 mL) were added
imidazole (4.24 g, 62.3 mmol) and TBSCl (4.80 g, 31.8 mmol) at 0
°C and the mixture stirred for 30 min at room temperature. Water
was added and the organic phase was separated. The aqueous
phase was extracted with diethyl ether. The combined organic
phase was washed with water and brine, dried with Na2SO4 and
concentrated under reduced pressure. The residue was chromato-
graphed on silica gel (70 g, hexane/ethyl acetate, 500:1) to give 4
(5.00 g, 97%) as a colorless oil, n2D4 ϭ 1.4569. – IR (film): ν˜ ϭ 1665
cm–1 (w, CϭC), 1260 (s, Si–CH3), 1110 (s, Si–O). – 1H NMR
(500 MHz, CDCl3): δ ϭ 0.07 [s, 6 H, Si(CH3)2], 0.90 (s, 9 H, tBu),
1.75 (s, 3 H, 2-CH3), 4.01 (s, 2 H, 1-H), 4.22 (d, J ϭ 6.1 Hz, 2 H,
4-H), 5.66 (tt, J ϭ 0.7, 6.1 Hz, 1 H, 3-H). – C11H23ClOSi: calcd.
234.1207; found 234.1207 (HRMS).
4-(tert-Butyldiphenylsilyloxy)-2-methylbutanal (8). – (a) (R)-Isomer:
To a solution of oxalyl chloride (6.66 mL, 76.3 mmol) in dry
dichloromethane (50 mL) was added a solution of dimethyl sulfox-
ide (10.8 mL,152 mmol) in dry dichloromethane (50 mL) at –60 °C.
After the mixture had been stirred for 15 min at this temperature,
a solution of (R)-7 (20.1 g, 58.7 mmol) in dry dichloromethane
(100 mL) was added at –60 °C. Stirring was continued for 30 min
at this temperature, and triethylamine (40.0 mL, 287 mmol) was ad-
ded to the mixture that was subsequently warmed to 0 °C. The
mixture was then poured into water and extracted several times
with dichloromethane. The extracts were combined, washed with
water and brine, dried with MgSO4, and concentrated under re-
duced pressure to give (R)-8 (21.4 g, quant.) as a colorless oil. This
was used for the next step without further purification, – IR (film):
–1
˜
ν ϭ 2720 cm (m, CHO), 1730 (vs, CϭO), 1590 (m, aromatic),
1110 (s, Si–O). – 1H NMR (90 MHz, CDCl3): δ ϭ 1.04 (s, 9 H,
tBu), 1.08 (d, J ϭ 7.2 Hz, 3 H, 2-CH3), 1.40–2.20 (m, 2 H, 3-H),
2.40–2.70 (m, 1 H, 2-H), 3.75 (t, J ϭ 6.1 Hz, 2 H, 4-H), 7.38 (m,
6 H, o,p-aromatic-H), 7.64 (m, 4 H, m-aromatic-H), 9.68 (d, J ϭ
1.5 Hz, 1 H, CHO).
1-(tert-Butyldimethylsilyloxy)-4-(tert-butyldiphenylsilyloxy)-2-
methylbutane (6). – (a) (R)-Isomer: To a solution of (R)-5 (18.2 g,
83.3 mmol) in DMF (200 mL) were added imidazole (14.2 g,
209 mmol) and TBDPSCl (25.0 mL, 91.9 mmol) at 0 °C, and the
mixture stirred for 12 h at room temperature. Water was added and
the organic phase was separated. The aqueous phase was extracted
with hexane. The combined organic phase was washed with water,
saturated aq. NaHCO3 and brine, dried with MgSO4, and concen-
trated under reduced pressure. The residue was chromatographed
on silica gel (600 g, hexane/ethyl acetate, 300:1) to give (R)-6
(33.9 g, 89%) as a colorless oil, n2D2 ϭ 1.5065. – [α]1D8 ϭ ϩ1.48 (c ϭ
(b) (S)-Isomer: In the same manner as described above, (S)-7
(18.6 g, 54.3 mmol) gave 19.8 g (quant.) of (S)-8, whose spectral
data were identical with those of (R)-8.
1,1-Dibromo-5-(tert-butyldiphenylsilyloxy)-3-methyl-1-pentene (9). –
(a) (R)-Isomer: To a solution of the crude (R)-8 (21.4 g, ca.
1.02, CHCl3). – IR (film): ν˜ ϭ 1590 cm–1 (w, aromatic), 1255 (s, 62.8 mmol) in dichloromethane (200 mL) were slowly added tri-
1
Si–CH3), 1110 (s, Si–O). – H NMR (90 MHz, CDCl3): δ ϭ 0.03
phenylphosphane (65.9 g, 251 mmol) and carbon tetrabromide
[s, 6 H, Si(CH3)2], 0.82 (d, J ϭ 7.0 Hz, 3 H, 2-CH3), 0.87, 1.05 (98%, 42.5 g, 126 mmol) at 0 °C under argon. The mixture was
(each s, 18 H, tBu), 1.15–1.90 (m, 3 H, 2-H, 3-H), 3.39 (d, J ϭ stirred for 1.5 h at room temperature. Water was added to it at 0
5.8 Hz, 1 H, 1-Ha), 3.41 (d, J ϭ 5.8 Hz, 1 H, 1-Hb), 3.70 (t, J ϭ °C, the organic phase was separated, and the aqueous phase was
Eur. J. Org. Chem. 2000, 955Ϫ962
957

S. Kurosawa, K. Mori
FULL PAPER
extracted with dichloromethane. The combined organic phase was
washed with water and brine, dried with MgSO4, and concentrated
under reduced pressure. The residue was chromatographed on silica
tographed on silica gel (800 g, hexane/ethyl acetate, 200:1) to give
(R)-11 (23.8 g, 85%) as a colorless oil, n2D6 ϭ 1.5402. – [α]1D8 ϭ ϩ3.05
(c ϭ 1.03, CHCl3). – IR (film): ν˜ ϭ 3340 cm–1 (s, O–H), 1665 (m,
1
gel (400 g, hexane/ethyl acetate, 100:1) to give (R)-9 [25.3 g, 87%, CϭC), 1590 (m, aromatic), 1115 (s, Si–O). – H NMR (500 MHz,
based on (R)-7] as a colorless oil, – [α]2D2 ϭ –4.60 (c ϭ 1.05,
CHCl3). – IR (film): ν˜ ϭ 1620 cm–1 (w, CϭC), 1590 (m, aromatic), 1.25 (br s, 1 H, OH), 1.52 (ddq, J ϭ 1.2, 7.0, 14.0 Hz, 1 H, 5-Ha),
1110 (s, Si–O). – 1H NMR (90 MHz, CDCl3): δ ϭ 1.00 (d, J ϭ
1.54 (s, 3 H, 3-CH3), 1.65 (ddq, J ϭ 1.2, 7.0, 14.0 Hz, 1 H, 5-Hb),
7.2 Hz, 3 H, 3-CH3), 1.06 (s, 9 H, tBu), 1.58 (q, J ϭ 6.8 Hz, 2 H, 2.34 (sextet, J ϭ 7.0 Hz, 1 H, 4-H), 3.60 (dt, J ϭ 1.8, 7.0 Hz, 2 H,
4-H), 2.56–2.89 (m, 1 H, 3-H), 3.65 (t, J ϭ 6.8 Hz, 2 H, 5-H), 6.20 6-H), 4.10 (d, J ϭ 6.8 Hz, 2 H, 1-H), 5.37 (dt, J ϭ 1.2, 6.8 Hz, 1
(d, J ϭ 10.0 Hz, 1 H, 2-H), 7.40 (m, 6 H, o,p-aromatic-H), 7.68 (m, H, 2-H), 7.36 (m, 6 H, o,p-aromatic-H), 7.66 (m, 4 H, m-aromatic-
CDCl3): δ ϭ 0.97 (d, J ϭ 7.0 Hz, 3 H, 4-CH3), 1.04 (s, 9 H, tBu),
4 H, m-aromatic-H). – C22H28Br2OSi (496.36): calcd. C 53.24, H
5.69; found C 53.26, H 5.62.
H). – C24H34O2Si (382.62): calcd. C 75.34, H 8.96; found C 75.61,
H 8.80.
(b) (S)-Isomer: In the same manner as described above, (S)-8
(19.8 g) gave 25.1 g [93% based on (S)-7] of (S)-9, whose spectral
data were identical with those of (R)-9, – [α]2D0 ϭ ϩ4.61 (c ϭ 1.10,
CHCl3). – C22H28Br2OSi (496.36): calcd. C 53.24, H 5.69; found C
53.22, H 5.66.
(b) (S)-Isomer: In the same manner as described above, (S)-10
(11.7 g, 34.8 mmol) gave 10.6 g (80%) of (S)-11, whose spectral data
were identical with those of (R)-11, n2D0 ϭ 1.5408. – [α]1D8 ϭ –3.22
(c ϭ 1.10, CHCl3). – C24H34O2Si (382.62): calcd. C 75.34, H 8.96;
found C 75.43, H 8.87.
5-(tert-Butyldiphenylsilyloxy)-3-methylpentyne (10). – (a) (R)-Iso-
mer: To a stirred solution of (R)-9 (24.1 g, 48.6 mmol) in dry diethyl
ether (250 mL) was added a solution of n-butyllithium (3.02  in
hexane, 40.2 mL, 121 mmol) at –78 °C under argon. After stirring
for 1 h at –78 °C and an additional 1 h at 0 °C, water was added
to the mixture, and it was stirred for 1 h. The organic phase was
then separated, and the aqueous phase was extracted with diethyl
ether. The combined organic phase was washed with water and
brine, dried with MgSO4, and concentrated under reduced pressure.
The residue was chromatographed on silica gel (300 g, hexane/ethyl
(E)-6-(tert-Butyldiphenylsilyloxy)-1-chloro-3,4-dimethyl-2-hexene
(12). – (a) (R)-Isomer: To a solution of (R)-11 (10.9 g, 28.5 mmol)
in carbon tetrachloride (50 mL) was added triphenylphosphane
(9.7 g, 37.0 mmol). After stirring for 6 h under reflux, the resulting
mixture was cooled to room temperature, then diluted with cold
pentane, and filtered through Celite. The filtrate was concentrated
under reduced pressure to give (R)-12 (12.3 g quant.) as a colorless
oil. The obtained oil was used for the next step without further
purification, – IR (film): ν˜ ϭ 1670 cm–1 (m, CϭC), 1600 (m, aro-
1
matic), 1110 (s, Si–O). – H NMR (90 MHz, CDCl3): δ ϭ 0.98 (d,
acetate, 200:1) to give (R)-10 (16.1 g, 98%) as a colorless oil, n2D4
ϭ
J ϭ 7.2 Hz, 3 H, 4-CH3), 1.03 (s, 9 H, tBu), 1.60 (s, 3 H, 3-CH3),
1.45–1.75 (m, 2 H, 5-H), 2.40 (sextet, J ϭ 7.2 Hz, 1 H, 4-H), 3.60
(t, J ϭ 6.8 Hz, 2 H, 6-H), 4.05 (d, J ϭ 7.2 Hz, 2 H, 1-H), 5.42 (br
t, J ϭ 7.2 Hz, 1 H, 2-H), 7.38 (m, 6 H, o,p-aromatic-H), 7.65 (m,
4 H, m-aromatic-H).
1.5351. – [α]2D2 ϭ –27.8 (c ϭ 0.99, CHCl3). – IR (film): ν˜ ϭ 3310
cm–1 (m, CϵC–H), 2130 (w, CϵC), 1590 (m, aromatic), 1115 (s,
1
Si–O). – H NMR (90 MHz, CDCl3): δ ϭ 1.03 (s, 9 H, tBu), 1.10
(d, J ϭ 7.0 Hz, 3 H, 3-CH3), 1.68 (dq, J ϭ 6.7, 7.0 Hz, 2 H, 4-H),
2.00 (d, J ϭ 2.6 Hz, 1 H, 1-H), 2.55–2.90 (m, 1 H, 3-H), 3.78 (t,
J ϭ 6.7 Hz, 1 H, 5-Ha), 3.81 (t, J ϭ 7.0 Hz, 1 H, 5-Hb), 7.38 (m,
6 H, o,p-aromatic-H), 7.68 (m, 4 H, m-aromatic-H). – C22H28OSi
(336.55): calcd. C 78.52, H 8.39; found C 78.19, H 8.67.
(b) (S)-Isomer: In the same manner as described above, (S)-11
(12.6 g, 32.9 mmol) gave 16.6 g (quant.) of (S)-12, whose spectral
data were identical with those of (R)-12.
(E)-6-(tert-Butyldiphenylsilyloxy)-3,4-dimethyl-1-phenylsulfonyl-2-
hexene (13). – (a) (R)-Isomer: To a solution of the crude (R)-12
(12.3 g, ca. 30.7 mmol) in DMF (100 mL) was added sodium ben-
zenesulfinate dihydrate (8.50 g, 42.5 mmol). The mixture was
stirred for 15 h at room temperature, then poured into water and
extracted with ethyl acetate. The extracts and the organic layer were
combined and washed with water and brine, dried with MgSO4,
and concentrated under reduced pressure. The residue was purified
by chromatography on silica gel (300 g, hexane/ethyl acetate, 40:1)
to give (R)-13 [11.0 g, 76% based on (R)-11] as a colorless oil, – [α]1D8
ϭ –9.38 (c ϭ 1.15, CHCl3). – IR (film): ν˜ ϭ 1665 cm–1 (m, CϭC),
1595 (m, aromatic), 1310 (s, SO2), 1150 (s, SO2), 1110 (s, Si–O).
(b) (S)-Isomer: In the same manner as described above, (S)-9
(4.23 g, 8.52 mmol) gave 2.81 g (98%) of (S)-10, whose spectral data
were identical with those of (R)-10, n2D3 ϭ 1.5356. – [α]2D0 ϭ ϩ28.5
(c ϭ 1.05, CHCl3). – C22H28OSi (336.55): calcd. C 78.52, H 8.39;
found C 78.20, H 8.50.
(E)-6-(tert-Butyldiphenylsilyloxy)-3,4-dimethyl-2-hexen-1-ol (11). –
(a) (R)-Isomer: To a solution of trimethylaluminum (1.01  in hex-
ane, 220 mL, 222 mmol) and bis(cyclopentadienyl)zirconium
dichloride (98%, 4.38 g, 14.7 mmol) in dry dichloromethane
(100 mL) was slowly added water (2.00 mL, 111 mmol) at –23 °C
with vigorous stirring under argon. After the mixture had been
stirred for 30 min at this temperature, a solution of (R)-10 (24.7 g,
74.0 mmol) in dry dichloromethane (200 mL) was added. The mix-
ture was stirred for 2 h at –23 °C and concentrated under reduced
pressure. The residue was extracted with dry hexane, and the ex-
tract was transferred into another flask under argon via a doubled-
tipped needle. To this was added n-butyllithium (2.52  in hexane,
29.4 mL, 74.1 mmol). THF (100 mL) was then added to dissolve
the precipitate, and the resulting solution was added to paraformal-
dehyde (5.1 g, 170 mmol) under argon. This reaction mixture was
stirred for 18 h at room temperature, and quenched with 1  aq.
HCl. The organic phase was separated and the aqueous phase ex-
tracted with diethyl ether. The combined organic phase was washed
with water, saturated aq. NaHCO3 and brine, dried with MgSO4,
and concentrated under reduced pressure. The residue was chroma-
–
1H NMR (500 MHz, CDCl3): δ ϭ 0.86 (d, J ϭ 7.0 Hz, 3 H,
4-CH3), 1.03 (s, 9 H, tBu), 1.14 (s, 3 H, 3-CH3), 1.43 (dq, J ϭ 7.0,
14.0 Hz, 1 H, 5-Ha), 1.53 (dq, J ϭ 7.0, 14.0 Hz, 1 H, 5-Hb), 2.31
(sextet, J ϭ 7.0 Hz, 1 H, 4-H), 3.53 (dt, J ϭ 7.0, 10.4 Hz, 1 H, 6-
Ha), 3.54 (dt, J ϭ 7.0, 10.4 Hz, 1 H, 6-Hb), 3.73 (dd, J ϭ 7.8,
14.3 Hz, 1 H, 1-Ha), 3.77 (dd, J ϭ 7.8, 14.3 Hz, 1 H, 1-Hb), 5.15
(t, J ϭ 7.8 Hz, 1 H, 2-H), 7.36–7.48 (m, 8 H, Si-o,p-aromatic-H, S-
o-aromatic-H), 7.57 (m, 1 H, S-p-aromatic-H), 7.64 (m, 4 H, Si-m-
aromatic-H), 7.82 (m, 2 H, S-m-aromatic-H). – C30H38O3SSi
(506.78): calcd. C 71.10, H 7.56; found C 71.18, H 7.41.
(b) (S)-Isomer: In the same manner as described above, (S)-12
(16.6 g) gave 14.0 g [84% based on (S)-11] of (S)-13, whose spectral
data were identical with those of (R)-13, – [α]2D0 ϭ ϩ8.81 (c ϭ 1.02,
958
Eur. J. Org. Chem. 2000, 955Ϫ962

Pheromone Synthesis, CC
FULL PAPER
CHCl3). – C30H38O3SSi (506.78): calcd. C 71.10, H 7.56; found C
70.92, H 7.31.
(2E,6E)-10-(tert-Butyldiphenylsilyloxy)-3,7,8-trimethyldeca-2,6-
dien-1-ol (16). – (a) (R)-Isomer: To a solution of (R)-15 (5.74 g,
9.71 mmol) and palladium chloride-1,3-bis(diphenylphosphano)-
propane complex (767 mg, 1.30 mmol) in dry THF (100 mL) was
added a solution of lithium triethylhydroborate (1.0  in THF,
29.0 mL, 29.0 mmol) at 0 °C under argon, and the mixture was
stirred at 4 °C for 6 h. Then the mixture was diluted with 10%
NaCN aqueous solution and extracted with diethyl ether. The ex-
tracts and the organic layer were combined, washed with water and
brine, dried with MgSO4, and concentrated under reduced pressure.
The residue was chromatographed on silica gel (80 g, hexane/ethyl
acetate, 40:1) to give (R)-16 (3.57 g, 82%) as a colorless oil, –
[α]2D2 ϭ ϩ0.628 (c ϭ 1.00, CHCl3). – IR (film): ν˜ ϭ 3345 cm–1 (m,
O–H), 1670 (m, CϭC), 1590 (m, aromatic), 1110 (s, Si–O). – 1H
NMR (500 MHz, [D6]DMSO): δ ϭ 0.90 (d, J ϭ 7.0 Hz, 3 H, 8-
CH3), 0.97 (s, 9 H, tBu), 1.40 (s, 3 H, 7-CH3), 1.48 (dq, J ϭ 14.0,
7.0 Hz, 1 H, 9-Ha), 1.51–1.58 (m, 1 H, 9-Hb), 1.52 (s, 3 H, 3-CH3),
1.84 (t, Jϭ 7.0 Hz, 2 H, 4-H), 1.98 (q, J ϭ 7.0 Hz, 2 H, 5-H), 2.25
(sextet, J ϭ 7.0 Hz, 1 H, 8-H), 3.52 (dt, J ϭ 7.0, 10.1 Hz, 1 H, 10-
Ha), 3.56 (dt, J ϭ 7.0, 10.1 Hz, 1 H, 10-Hb), 3.89 (t, J ϭ 5.2 Hz, 2
H, 1-H), 4.39 (t, J ϭ 5.2 Hz, 1 H, OH), 5.06 (t, J ϭ 7.0 Hz, 1 H,
6-H), 5.21 (dt, J ϭ 1.2, 5.2 Hz, 1 H, 2-H), 7.44 (m, 6 H, o,p-aro-
matic-H), 7.59 (m, 4 H, m-aromatic-H). – C29H42O2Si (450.74):
calcd. C 77.28, H 9.39; found C 77.10, H 9.43.
(2E,6E)-1-(tert-Butyldimethylsilyloxy)-10-(tert-butyldiphe-
nylsilyloxy)-3,7,8-trimethyl-5-phenylsulfonyldeca-2,6-diene
(14).
– (a) (8R)-Isomer: To a solution of (R)-13 (24.1 g, 47.6 mmol) in
dry THF (250 mL) and HMPA (125 mL) was added a solution of
n-butyllithium (1.57  in hexane, 60.6 mL, 95.1 mmol) at –50 °C
under argon, and the mixture was stirred at –50 °C for 30 min.
Then a solution of 4 (12.5 g, 60.5 mmol) in dry THF (100 mL) was
added dropwise, and stirring was maintained for 18 h at 4 °C. After
the addition of water, the mixture was neutralized with acetic acid,
and extracted with diethyl ether. The extracts and the organic layer
were combined and washed with water, saturated aq. NaHCO3 and
brine, dried with MgSO4, and concentrated under reduced pressure.
The residue was chromatographed on silica gel (500 g, hexane/ethyl
acetate, 300:1) to give (R)-14 (29.5 g, 88%) as a colorless oil,
[α]1D8 ϭ –8.63 (c ϭ 1.07, CHCl3). – IR (film): ν˜ ϭ 1665 cm–1 (m,
CϭC), 1590 (m, aromatic), 1305 (s, SO2), 1255 (s, Si–CH3), 1150
1
(s, SO2), 1110 (s, Si–O). – H NMR (500 MHz, CDCl3): δ ϭ 0.01
[s, 6 H, Si(CH3)2], 0.78, 0.82 (each d, J ϭ 7.0 Hz, 3 H, 8-CH3),
0.86, 1.01, 1.03 (each s, 18 H, tBu), 1.04, 1.10 (each s, 3 H, 7-CH3),
1.30–1.37 (m, 1 H, 9-Ha), 1.42–1.52 (m, 1 H, 9-Hb), 1.48, 1.52 (each
s, 3 H, 3-CH3), 2.19–2.31 (m, 2 H, 4-Ha, 8-H), 2.90 (m, 1 H, 4-Hb),
3.45–3.55 (m, 2 H, 10-H), 3.82–4.12 (m, 3 H, 1-H, 5-H), 4.88, 4.92
(each d, J ϭ 12.5 Hz, 1 H, 6-H), 5.26 (t, J ϭ 7.2 Hz, 1 H, 2-H),
7.35–7.50 (m, 8 H, Si-o,p-aromatic-H, S-o-aromatic-H), 7.55 (m, 1
H, S-p-aromatic-H), 7.64 (m, 4 H, Si-m-aromatic-H), 7.80 (m, 2 H,
S-m-aromatic-H). – C41H60O4SSi2 (705.16): calcd. C 69.84, H 8.58;
found C 69.98, H 8.17.
(b) (S)-Isomer: In the same manner as described above, (S)-15
(16.2 g, 27.4 mmol) gave 10.0 g (81%) of (S)-16, whose spectral data
were identical with those of (R)-16, – [α]2D4 ϭ –0.453 (c ϭ 1.06,
CHCl3). – C29H42O2Si (450.74): calcd. C 77.28, H 9.39; found C
77.61, H 9.45.
(b) (8S)-Isomer: In the same manner as described above, (S)-13
(693 mg, 1.37 mmol) gave 837 mg (87%) of (S)-14, whose spectral
data were identical with those of (R)-14, – [α]2D7 ϭ ϩ8.00 (c ϭ 1.13,
CHCl3). – C41H60O4SSi2 (705.16): calcd. C 69.84, H 8.58; found C
69.81, H 8.24.
(2E,6E)-1-Acetoxy-10-(tert-butyldiphenylsilyloxy)-3,7,8-trimethyl-
deca-2,6-diene (17). – (a) (R)-Isomer: To a solution of (R)-16
(10.1 g, 22.4 mmol) in pyridine (100 mL) was added acetic anhyd-
ride (10.6 mL, 112 mmol). The mixture was stirred for 20 h at room
temperature, then poured into water, and extracted with diethyl
ether. The extracts and the organic layer were combined, washed
with water, saturated aq. CuSO4, water, saturated aq. NaHCO3 and
brine, dried with MgSO4, and concentrated under reduced pressure.
The residue was chromatographed on silica gel (200 g, hexane/ethyl
(2E,6E)-10-(tert-Butyldiphenylsilyloxy)-3,7,8-trimethyl-5-phenyl-
sulfonyldeca-2,6-dien-1-ol (15). – (a) (8R)-Isomer: A solution of (R)-
14 (8.92 g, 12.6 mmol) in AcOH/THF/H2O (3:1:1, 100 mL) was
stirred at room temperature for 24 h. The mixture was diluted with
diethyl ether and H2O, the organic phase was separated, and the
aqueous phase was extracted with diethyl ether. The combined or-
ganic phase was washed with water, saturated aq. NaHCO3 and
brine, dried with MgSO4, and concentrated under reduced pressure.
The residue was chromatographed on silica gel (150 g, hexane/ethyl
acetate, 10:1) to give (R)-15 (6.34 g, 85%) as a colorless oil, –
[α]2D7 ϭ –7.33 (c ϭ 1.07, CHCl3). – IR (film): ν˜ ϭ 3530 cm–1 (s, O–
H), 1660 (m, CϭC), 1590 (m, aromatic), 1305 (s, SO2), 1145 (s,
SO2), 1110 (s, C–O). – 1H NMR (500 MHz, CDCl3): δ ϭ 0.76, 0.82
(each d, J ϭ 7.0 Hz, 3 H, 8-CH3), 0.97, 1.09 (each s, 3 H, 7-CH3),
1.02, 1.04 (each s, 9 H, tBu), 1.32–1.40 (m, 1 H, 9-Ha), 1.42–1.52
(m, 1 H, 9-Hb), 1.47, 1.56 (each s, 3 H, 3-CH3), 2.20 (sextet, J ϭ
7.0 Hz, 1 H, 8-H), 2.29 (dd, J ϭ 11.3, 13.4 Hz, 1 H, 4-Ha), 2.91
(m, 1 H, 4-Hb), 3.40–3.54 (m, 2 H, 10-H), 3.81–3.93 (m, 2 H, 1-
Ha, 5-H), 3.93–4.06 (m, 1 H, 1-Hb), 4.88, (m, 1 H, 6-H), 5.29, 5.34
(each t, J ϭ 6.7 Hz, 1 H, 2-H), 7.35–7.52 (m, 9 H, Si-o,p-aromatic-
H, S-o,p-aromatic-H), 7.52–7.70 (m, 4 H, Si-m-aromatic-H), 7.81
(m, 2 H, S-m-aromatic-H). – C35H46NaO4SSi: calcd. 613.2784;
found 613.2770 (HRMS).
acetate, 100:1) to give (R)-17 (10.8 g, 98%) as a colorless oil, n2D4
ϭ
1.5295. – [α]2D2 ϭ ϩ0.231 (c ϭ 1.09, CHCl3). – IR (film): ν˜ ϭ 1745
cm–1 (vs, CϭO), 1670 (w, CϭC), 1590 (w, aromatic), 1240 (s, OAc),
1
1115 (s, Si–O). – H NMR (500 MHz, CDCl3): δ ϭ 0.94 (d, J ϭ
7.0 Hz, 3 H, 8-CH3), 1.05 (s, 9 H, tBu), 1.46 (s, 3 H, 7-CH3), 1.52
(dq, J ϭ 14.0, 7.0 Hz, 1 H, 9-Ha), 1.62 (dq, J ϭ 14.0, 7.0 Hz, 1 H,
9-Hb), 1.69 (s, 3 H, 3-CH3), 2.00 (t, Jϭ 7.0 Hz, 2 H, 4-H), 2.05 (s,
3 H, Ac), 2.07 (dt, J ϭ 6.7, 7.0 Hz, 2 H, 5-H), 2.28 (sextet, J ϭ
7.0 Hz, 1 H, 8-H), 3.57 (dt, J ϭ 7.0, 10.1 Hz, 1 H, 10-Ha), 3.60 (dt,
J ϭ 7.0, 10.1 Hz, 1 H, 10-Hb), 4.57 (d, J ϭ 7.0 Hz, 2 H, 1-H), 5.08
(t, J ϭ 6.7 Hz, 1 H, 6-H), 5.31 (t, J ϭ 7.0 Hz, 1 H, 2-H), 7.35 (m,
6 H, o,p-aromatic-H), 7.66 (m, 4 H, m-aromatic-H). – C31H44O3Si
(492.77): calcd. C 75.56, H 9.00; found C 75.35, H 8.73.
(b) (S)-Isomer: In the same manner as described above, (S)-16
(9.18 g, 20.4 mmol) gave 9.52 g (95%) of (S)-17, whose spectral data
were identical with those of (R)-17, n2D5 ϭ 1.5287. – [α]2D6 ϭ –0.375
(c ϭ 1.10, CHCl3). – C31H44O3Si (492.77): calcd. C 75.56, H 9.00;
found C 75.97, H 9.07.
(b) (8S)-Isomer: In the same manner as described above, (S)-14
(24.7 g, 35.0 mmol) gave 16.7 g (81%) of (S)-15, whose spectral data
were identical with those of (R)-15, – [α]2D0 ϭ ϩ7.67 (c ϭ 1.01,
(4E,8E)-10-Acetoxy-3,4,8-trimethyldeca-4,8-dien-1-ol (18). – (a)
(R)-Isomer: To a solution of (R)-17 (3.10 g, 6.29 mmol) in THF
(30 mL) was added a solution of tetrabutylammonium fluoride (1.0
CHCl3).
– C35H46NaO4SSi: calcd. 613.2784; found 613.2798  in THF, 9.5 mL, 9.5 mmol). The mixture was stirred for 2 h at
(HRMS).
room temperature, then poured into water, and extracted with di-
Eur. J. Org. Chem. 2000, 955Ϫ962
959

S. Kurosawa, K. Mori
FULL PAPER
ethyl ether. The extracts and the organic layer were combined,
trated under reduced pressure. The residue was chromatographed
washed with water, saturated aq. NaHCO3 and brine, dried with on silica gel (12 g, hexane/ethyl acetate, 40:1) to give (R)-20 (1.51 g,
MgSO4, and concentrated under reduced pressure. The residue was
purified by chromatography on silica gel (30 g, hexane/ethyl acetate,
20:1) to give (R)-18 (1.44 g, 90%) as a colorless oil, n2D3 ϭ 1.4790. –
[α]2D3 ϭ ϩ2.65 (c ϭ 1.02, CHCl3). – IR (film): ν˜ ϭ 3450 cm–1 (s,
O–H), 1740 (vs, CϭO), 1670 (w, CϭC), 1240 (s, OAc). – 1H NMR
quant.) as a colorless oil, n2D3 ϭ 1.4648. – [α]2D4 ϭ –6.74 (c ϭ 1.09,
CHCl3). – IR (film): ν˜ ϭ 1745 cm–1 (vs, CϭO), 1670 (m, CϭC). –
1H NMR (500 MHz, CDCl3): δ ϭ 1.012, 1.016, 1.029 and 1.031
(each d, 3 H, each J ϭ 7.0 Hz, 4-CH3), 1.190, 1.198, 1.204 and
1.228 (each t, 3 H, each J ϭ 7.0 Hz, 2"-H), 1.324, 1.329, 1.337 and
(500 MHz, CDCl3): δ ϭ 0.99 (d, J ϭ 7.0 Hz, 3 H, 3-CH3), 1.44 (br 1.356 (each d, 3 H, each J ϭ 5.5 Hz, 2Ј-H), 1.51, 1.52 and 1.53
s, 1 H, OH), 1.52 (s, 3 H, 4-CH3), 1.48–1.65 (m, 2 H, 2-H), 1.69 (s, (each s, 3 H, 5-CH3), 1.69 (s, 3 H, 9-CH3), 1.75–1.93 (m, 2 H, 3-
3 H, 8-CH3), 2.04 (s, 3 H, Ac), 2.06 (t, Jϭ 7.3 Hz, 2 H, 7-H), 2.10
(q, Jϭ 7.3 Hz, 1 H, 6-Ha), 2.13 (q, Jϭ 7.3 Hz, 1 H, 6-Hb), 2.26 (m,
1 H, 3-H), 3.56 (br t, J ϭ 4.3 Hz, 2 H, 1-H), 4.58 (d, J ϭ 7.0 Hz,
H), 2.04 (s, 3 H, Ac), 2.06 (br t, 2 H, J ϭ 7.0 Hz, 8-H), 2.12 (br q,
2 H, J ϭ 7.0 Hz, 7-H), 2.39 (m, 1 H, 4-H), 3.45–3.69 (m, 2 H, 1"-
H), 4.04, 4.11, 4.29 and 4.33 (each dd, 1 H, J ϭ 8.3, 6.1 and 9.2,
2 H, 10-H), 5.15 (t, J ϭ 7.3 Hz, 1 H, 5-H), 5.31 (tt, J ϭ 1.1, 7.0 Hz, 6.1 and 9.2, 6.1 and 8.5, 5.2 Hz, 2-H), 4.58 (d, 2 H, J ϭ 7.0 Hz,
1 H, 9-H). – C15H26O3 (254.37): calcd. C 70.83, H 10.30; found C
70.44, H 10.67.
11-H), 4.47, 4.79, 4.87 and 4.88 (each q, 1 H, each J ϭ 5.5 Hz, 1Ј-
H), 5.14, 5.17 and 5.24 (each t, 1 H, each J ϭ 6.5 Hz, 6-H), 5.33
(m, 1 H, 10-H). – C20H33NO4 (351.49): calcd. C 68.34, H 9.46, N
3.99; found C 68.20, H 9.74, N 3.85.
(b) (S)-Isomer: In the same manner as described above, (S)-17
(9.20 g, 18.7 mmol) gave 3.97 g (83%) of (S)-18, whose spectral data
were identical with those of (R)-18, n2D3 ϭ 1.4781. – [α]1D8 ϭ –2.72
(c ϭ 1.10, CHCl3). – C15H26O3 (254.37): calcd. C 70.83, H 10.30;
found C 70.49, H 10.72.
(b) (4S)-Isomer: In the same manner as described above, (S)-19
(2.69 g, 10.7 mmol) gave 3.53 g (94%) of (S)-20, whose spectral data
were identical with those of (R)-20, n2D3 ϭ 1.4641. – [α]2D0 ϭ ϩ7.14
(c ϭ 1.05, CHCl3). – C20H33NO4 (351.49): calcd. C 68.34, H 9.46,
N 3.99; found C 68.02, H 9.61, N 3.85.
(4E,8E)-10-Acetoxy-3,4,8-trimethyldeca-4,8-dienal (19). – (a) (R)-
Isomer: To a stirred suspension of Dess–Martin periodinane
(10.0 g, 23.6 mmol) in dry dichloromethane (200 mL) was added
a solution of (R)-18 (4.00 g, 15.7 mmol) in dry dichloromethane
(50 mL). The reaction mixture was stirred for 2 h at room temper-
ature, then poured into saturated aq. Na2S2O3-NaHCO3 (400 mL),
and extracted with diethyl ether. The extracts and the organic layer
were combined and washed with water, saturated aq. NaHCO3 and
brine, dried with MgSO4, and concentrated under reduced pressure.
The residue was purified by chromatography on silica gel (60 g,
hexane/ethyl acetate, 40:1) to give (R)-19 (3.37 g, 85%) as a color-
less oil, n2D4 ϭ 1.4738. – [α]2D3 ϭ –1.74 (c ϭ 1.09, CHCl3). – IR
(5E,9E)-2-(1Ј-Ethoxyethoxy)-11-hydroxy-4,5,9-trimethyl-5,9-
undecadienenitrile (21). – (a) (4R)-Isomer: To a solution of (R)-20
(3.26 g, 9.27 mmol) in MeOH (35 mL) was added potassium car-
bonate (1.36 g, 9.84 mmol). The mixture was stirred for 1 h at room
temperature. The reaction mixture was diluted with diethyl ether
and H2O, and the organic phase was separated. The aqueous phase
was extracted with diethyl ether. The combined organic phase was
washed with brine, dried with MgSO4, and concentrated under re-
duced pressure. The residue was purified by chromatography on
silica gel (60 g, hexane/ethyl acetate, 10:1) to give (R)-21 (2.54 g,
(film): ν˜ ϭ 2740 cm–1 (m, CHO), 1740 (s, CϭO), 1730 (s, CϭO). – 89%) as a colorless oil, n2D3 ϭ 1.4719. – [α]2D4 ϭ ϩ1.99 (c ϭ 1.01,
1H NMR (500 MHz, CDCl3): δ ϭ 1.05 (d, J ϭ 7.1 Hz, 3 H, 3-
CHCl3). – IR (film): ν˜ ϭ 3445 cm–1 (s, O–H), 1665 (w, CϭC). –
CH3), 1.56 (s, 3 H, 4-CH3), 1.67 (s, 3 H, 8-CH3), 2.04 (s, 3 H, Ac), 1H NMR (500 MHz, CDCl3): δ ϭ 1.012, 1.017, 1.031 and 1.034
2.05 (m, 2 H, 7-H), 2.10 (m, 2 H, 6-H), 2.31 (ddd, J ϭ 2.4, 7.1, (each d, 3 H, each J ϭ 7.1 Hz, 4-CH3), 1.20, 1.21, 1.22 and 1.24
16.0 Hz, 1 H, 2-Ha), 2.45 (ddd, J ϭ 2.4, 7.6, 16.0 Hz, 1 H, 2-Hb),
2.70 (sextet, J ϭ 7.1 Hz, 2 H, 3-H), 4.57 (d, J ϭ 7.1 Hz, 2 H, 10-
(each t, 3 H, each J ϭ 7.1 Hz, 2"-H), 1.32, 1.33, 1.35 and 1.36 (each
d, 3 H, each J ϭ 5.5 Hz, 2Ј-H), 1.51, 1.52 and 1.53 (each s, 3 H,
H), 5.17 (t, J ϭ 6.8 Hz, 1 H, 5-H), 5.31 (qt, J ϭ 0.7, 7.1 Hz, 1 H, 9-CH3), 1.67 (s, 3 H, 5-CH3), 1.75–1.94 (m, 2 H, 3-H), 2.07 (m, 2
9-H), 9.65 (t, J ϭ 2.5 Hz, 1 H, CHO). – C15H24O3 (252.35): calcd.
C 71.39, H 9.59; found C 71.27, H 9.77.
H, 8-H), 2.13 (m, 2 H, 7-H), 2.33–2.47 (m, 1 H, 4-H), 3.46–3.70
(m, 2 H, 1"-H), 4.07, 4.11, 4.29 and 4.35 (each dd, 1 H, J ϭ 8.0,
6.4 and 9.5, 6.4 and 9.8, 6.4 and 8.6, 5.2 Hz, 2-H), 4.14 and 4.16
(each d, 2 H, J ϭ 6.4 and 6.1 Hz, 11-H), 4.77, 4.81, 4.89 and 4.90
(each q, 1 H, each J ϭ 5.5 Hz, 1Ј-H), 5.14, 5.19 and 5.27 (each t,
1 H, J ϭ 6.5 Hz, 6-H), 5.40 (m, 1 H, 10-H). – C18H31NO3 (309.45):
calcd. C 69.86, H 10.10, N 4.53; found C 69.63, H 10.36, N 4.30.
(b) (S)-Isomer: In the same manner as described above, (S)-18
(3.31 g, 13.0 mmol) gave 2.87 g (87%) of (S)-19, whose spectral data
were identical with those of (R)-19, n2D3 ϭ 1.4738. – [α]2D0 ϭ ϩ1.87
(c ϭ 1.06, CHCl3). – C15H24O3 (252.35): calcd. C 71.39, H 9.59;
found C 71.26, H 9.82.
(b) (4S)-Isomer: In the same manner as described above, (S)-20
(3.06 g, 8.71 mmol) gave 2.31 g (86%) of (S)-21, whose spectral data
were identical with those of (R)-21, n2D3 ϭ 1.4721. – [α]2D0 ϭ –2.15
(c ϭ 1.02, CHCl3). – C18H31NO3 (309.45): calcd. C 69.86, H 10.10,
N 4.53; found C 69.63, H 10.36, N 4.31.
(5E,9E)-11-Acetoxy-2-(1Ј-ethoxyethoxy)-4,5,9-trimethyl-5,9-
undecadienenitrile (20). – (a) (4R)-Isomer: To a mixture of (R)-19
(1.06 g, 4.20 mmol) and TMSCN (5.0 mL, 37.5 mmol) was added
a catalytic amount of KCN 18-crown-6 complex at 0 °C. The mix-
ture was stirred for 12 h at 4 °C, diluted with THF/H2O (5 mL/
1 mL) and benzyltrimethylammonium fluoride (97%, 30 mg, (5E,9E)-11-Chloro-2-(1Ј-ethoxyethoxy)-4,5,9-trimethyl-5,9-
0.172 mmol) added in one portion. The resulting mixture was
stirred for 1 h at room temperature, then poured into brine, and
extracted with diethyl ether. The extract was dried with MgSO4,
and concentrated in vacuo. The residue was diluted with benzene
(4 mL) and ethyl vinyl ether (3 mL, 31.4 mmol) was added. A cata-
lytic amount (2 mg) of TsOH was added at 0 °C and the mixture
undecadienenitrile (22). – (a) (4R)-Isomer: To a solution of (R)-21
(1.15 g, 3.72 mmol) and s-collidine (1.23 mL, 9.31 mmol) in DMF
(15 mL) at 0 °C was added LiCl (315 mg, 7.43 mmol) under argon.
After stirring for 40 min at 0 °C, MsCl (0.576 mL, 7.44 mmol) was
added dropwise. The resulting suspension was stirred for 1.5 h at 0
°C, then diluted with water, and extracted with diethyl ether. The
was stirred for 4 h at 0 °C. The resulting solution was then poured extract was washed with water and brine, dried with MgSO4, and
into saturated aq. NaHCO3, and extracted with diethyl ether. The
extract was washed with brine, dried with MgSO4, and concen-
concentrated under reduced pressure. The residue was flash chro-
matographed on silica gel (10 g, hexane/ethyl acetate, 40:1) to give
960
Eur. J. Org. Chem. 2000, 955Ϫ962

Pheromone Synthesis, CC
FULL PAPER
(R)-22 (1.16 g, 95%) as a colorless oil. This was used for the next
step without further purification, – IR (film): ν˜ ϭ 1660 cm–1 (m,
CϭC). – H NMR (90 MHz, CDCl3): δ ϭ 1.02, 1.03 (each d, J ϭ
–191 (c ϭ 1.04, CHCl3). – C13H20O (192.30): calcd. C 81.20, H
10.48; found C 80.99, H 10.68.
1
(1E,5E)-1,5,10-Trimethyl-8-(1-methylethylidenyl)-1,5-cyclo-
decadiene (1), 9-Methylgermacrene-B. – (a) (R)-Isomer: To a mix-
ture of Sm (159 mg, 1.06 mmol), SmI2 (0.1 , THF) (10.6 mL,
1.06 mmol) and anhydrous CrCl3 (84 mg, 0.530 mmol) was added
a mixture of (R)-24 (102 mg, 0.53 mmol) and 2,2-dibromopropane
(214 mg, 1.06 mmol) in THF (4 mL) at room temperature under
argon. After stirring for 30 min at room temperature, the resulting
mixture was diluted with pentane and filtered through a short silica
gel (10 g) column. The filtrate was concentrated under reduced
pressure. The residue was chromatographed on silica gel (6 g, pent-
ane) to give (R)-1 (69 mg, 60%) as a colorless oil, n2D3 ϭ 1.5150. –
[α]1D8 ϭ ϩ61.4 (c ϭ 0.50, CHCl3). – IR (film): ν˜ ϭ 2920 cm–1 (s),
1660 (w), 1450 (m), 1365 (m). – 1H NMR (400 MHz, CDCl3): δ ϭ
1.03 (d, 3 H, J ϭ 7.1 Hz, 9-CH3), 1.43 (s, 3 H, 10-CH3), 1.54 (s, 3
H, 4-CH3), 1.68 and 1.70 (each s, 6 H, 11-CH3), 1.94 (ddd, J ϭ
11.9, 11.9, 5.2 Hz, 1 H, 8-Ha), 2.01 (m, 1 H, 2-Ha), 2.09 (m, 2 H,
9-H, 3-Ha), 2.31 (m, 4 H, 2-Hb, 3-Hb, 6-Ha, 8-Hb), 3.06 (d, J ϭ
13.4 Hz, 1 H, 6-Hb), 4.39 (d, J ϭ 11.2 Hz, 1 H, 5-H), 4.72 (dd, J ϭ
12.2, 2.9 Hz, 1 H, 1-H). – 13C NMR (100 MHz, CHCl3): δ ϭ 11.1,
16.4, 20.4, 20.7, 20.9, 25.3, 34.4, 38.9, 40.8, 46.3, 125.7, 127.0,
128.7, 130.9, 133.8, 140.2. – HPLC [column: Daicel Chiralcel OD
(0.46 cm ϫ 25 cm) and OD-H (0.46 cm ϫ 25 cm) were combined],
eluent: n-hexane, flow rate: 0.2 mL/min, temperature: 3 °C, detec-
tion: UV (210 nm)]: tr ϭ 43.0 min [(R)-1 (97.7%)], tr ϭ 46.5 min
[(S)-1 (2.3%)]. The enantiomeric purity of (R)-1 was therefore
95.4% ee – CD (c ϭ 0.000504, hexane) ∆ε (λ, nm) ϭ –33.4 (227),
ϩ53.3 (201). – C16H26 (218.38): calcd. C 88.00, H 12.00; found C
87.81, H 12.28.
6.8 Hz, 3 H, 4-CH3), 1.10–1.42 (m, 6 H, 2Ј-H, 2ЈЈ-H) 1.53 (s, 3 H,
5-CH3), 1.73 (s, 3 H, 9-CH3), 1.75–1.95 (m, 2 H, 3-H), 2.02–2.20
(m, 4 H, 7-H, 8-H), 2.22–2.60 (m, 1 H, 4-H), 3.30–3.80 (m, 2 H,
1ЈЈ-H), 3.96–4.44 (m, 1 H, 2-H), 4.09 (d, J ϭ 7.9 Hz, 2 H, 11-H),
4.64–5.00 (m, 1 H, 1Ј-H), 5.00–5.58 (m, 2 H, 6-H, 10-H).
(b) (4S)-Isomer: In the same manner as described above, (S)-21
(1.00 g, 3.23 mmol) gave 993 mg (94%) of (S)-22, whose spectral
data were identical with those of (R)-22.
(4E,8E)-1-(1Ј-Ethoxyethoxy)-3,4,8-trimethyl-4,8-cyclodecadiene-
carbonitrile (23). – (a) (3R)-Isomer: A solution of (R)-22 (1.15 g,
3.1 mmol) in THF (40 mL) was slowly added dropwise over 5 h to
a solution of NaN(SiMe3)2 (1.0  in THF, 17.5 mL, 17.5 mmol) in
dry THF (165 mL) at reflux under argon. After stirring for 30 min
at 70 °C, the resulting mixture was cooled to room temperature,
then diluted with saturated aq. NH4Cl, and extracted with diethyl
ether. The extract was washed with water and brine, dried with
MgSO4, and concentrated under reduced pressure. The residue was
chromatographed on silica gel (30 g, hexane/ethyl acetate, 100:1) to
give (R)-23 (485 mg, 47%) as a colorless oil, n2D4 ϭ 1.4870. –
[α]2D3 ϭ –55.6 (c ϭ 1.08, CHCl3). – IR (film): ν˜ ϭ 2220 cm–1 (w,
1
CϵN), 1640 (m, CϭC). – H NMR (500 MHz, CDCl3): δ ϭ 1.02,
1.03, 1.07 and 1.08 (each d, 3 H, each J ϭ 7.0 Hz, 3-CH3), 1.23
(m, 6 H, 4-CH3, 2"-H), 1.38 (m, 3 H, 2Ј-H), 1.54 (br. s, 3 H, 8-
CH3), 1.70–2.20 (m, 6 H, 2-H, 6-H, 7-H), 2.45 (m, 1 H, 10-Ha),
2.58–2.81 (m, 1 H, 3-H), 2.90 (m, 1 H, 10-Hb), 3.50–3.70 (m, 2 H,
1"-H), 4.55 and 4.67 (m, 1 H, 9-H), 4.81 and 4.88 (m, 1 H, 5-H),
5.03 and 5.12 (m, 1 H, 1Ј-H). – C18H29NO2 (291.43): calcd. C
74.18, H 10.03, N 4.81; found C 74.35, H 10.28, N 4.58.
(b) (S)-Isomer: In the same manner as described above, (S)-24
(61 mg, 0.32 mmol) gave 45 mg (64%) of (S)-1, whose spectral data
were identical with those of (R)-24, n2D3 ϭ 1.5143. – [α]2D0 ϭ –61.3
(c ϭ 0.51, CHCl3). – HPLC [column: Daicel Chiralcel OD and
OD-H were combined]: tr ϭ 43.1 min [(R)-1 (2.6%)], tr ϭ 46.3 min
[(S)-1 (97.4%)] [under the same conditions as described above]. The
enantiomeric purity of (S)-1 was therefore 94.8% ee – CD (c ϭ
0.000687, hexane) ∆ε (λ, nm) ϭ ϩ31.3 (226), –48.5 (201). – C16H26
(218.38): calcd. C 88.00, H 12.00; found C 87.72, H 12.21.
(b) (3S)-Isomer: In the same manner as described above, (S)-22
(965 mg, 2.94 mmol) gave 450 mg (53%) of (S)-23, whose spectral
data were identical with those of (R)-23, n2D2 ϭ 1.4874. – [α]1D8
ϭ
ϩ59.0 (c ϭ 1.10, CHCl3). – C18H29NO2 (291.43): calcd. C 74.18,
H 10.03, N 4.81; found C 74.37, H 10.35, N 4.68.
(4E,8E)-3,4,8-Trimethyl-4,8-cyclodecadien-1-one (24). – (a) (R)-Iso-
mer: To a solution of (R)-23 (372 mg, 1.28 mmol) in MeOH (8 mL)
was added a catalytic amount (2 mg) of PPTS. After stirring for
2 h at 40 °C, the resulting mixture was diluted with saturated aq.
NaHCO3 and extracted with diethyl ether. The extract was washed
with brine, dried with MgSO4, and concentrated in vacuo. The res-
idue was diluted with diethyl ether and the mixture was placed in
a separating funnel and shaken vigorously for 5 min with 0.1  aq.
NaOH (5 mL). The aqueous layer was extracted with diethyl ether.
The combined organic layers were washed with 0.2  aq. HCl,
water, saturated aq. NaHCO3 and brine, dried with MgSO4, and
concentrated under reduced pressure. The residue was chromato-
graphed on silica gel (4 g, pentane/diethyl ether, 50:1) to give (R)-
24 (140 mg, 57%) as needles, m.p. 56–60 °C. – [α]2D6 ϭ ϩ187 (c ϭ
1.18, CHCl3). – IR (KBr): ν˜ ϭ 1690 cm–1 (vs, CϭO), 1660 (m, Cϭ
C), 1425 (s, CH2CO). – 1H NMR (500 MHz, CDCl3): δ ϭ 1.07 (d,
J ϭ 6.4 Hz, 3 H, 3-CH3), 1.46 (s, 3 H, 8-CH3), 1.56 (s, 3 H, 4-
CH3), 2.18 (m, 4 H, 2-Ha, 6-Ha, 7-H), 2.35 (m, 1 H, 6-Hb), 2.57
(m, 1 H, 3-H), 2.72 (m, 1 H, 2-Hb), 2.87 (m, 1 H, 10-Ha), 3.05 (dd,
J ϭ 12.8, 9.8 Hz, 1 H, 10-Hb), 4.96 (d, J ϭ 10.7 Hz, 1 H, 5-H),
5.13 (m, 1 H, 9-H). – C13H20O (192.30): calcd. C 81.20, H 10.48;
found C 80.87, H 10.74.
Acknowledgments
Our thanks are due to Professor John A. Pickett (IACR-Ro-
thamsted, UK) for his co-operation. We acknowledge the financial
support of this work by a Grant-in-Aid for Scientific Research (No.
11480165) from the Japanese Ministry of Education, Science,
Sports and Culture.
[1]
P. D. Wa rd , Adv. Disease Vector Res. 1989, 6, 91–126.
J. G. C. Hamilton, G. W. Dawson, J. A. Pickett, J. Chem. Ecol.
1996, 22, 1477–1491.
S. Muto, Y. Nishimura, K. Mori, Eur. J. Org. Chem. 1999,
2159–2165.
J. G. C. Hamilton, A. M. Hooper, S. Kurosawa, K. Mori, S.
Muto, J. A. Pickett, Chem. Commun. 1999, 2335–2336.
T. Takahashi, H. Nemoto, J. Tsuji, Tetrahedron Lett. 1983, 24,
2005–2008.
M. Ohsugi, S. Takahashi, J. Ichimoto, H. Ueda, Nippon Nogei-
kagaku Kaishi 1973, 47, 807–811.
T. Eguchi, K. Arakawa, T. Terachi, K. Kakinuma, J. Org.
Chem. 1997, 62, 1924–1933.
E. J. Corey, P. L. Fuchs, Tetrahedron Lett. 1972, 3769–3772.
[2]
[3]
[4]
[5]
[6]
ˆ
(b) (S)-Isomer: In the same manner as described above, (S)-23
(250 mg, 0.86 mmol) gave 83 mg (50%) of (S)-24, whose spectral
[7]
[8]
data were identical with those of (R)-24, m.p. 59–62 °C. – [α]2D6
ϭ
Eur. J. Org. Chem. 2000, 955Ϫ962
961

S. Kurosawa, K. Mori
FULL PAPER
[9]
[12]
[13]
P. Wipf, S. Lim, Angew. Chem. Int. Ed. Engl. 1993, 32, 1068–
D. B. Dess, J. C. Martin, J. Org. Chem. 1983, 48, 4155–4156.
S. Matsubara, K. Horiuchi, K. Takai, K. Utimoto, Chem. Lett.
1071; Angew. Chem. 1993, 105, 1095–1097.
[10]
E. Negishi, D. E. V. Horn, O. King, N. Okukado, Synthesis
1995, 259–260.
1979, 501–502.
Received September 5, 1999
[O99554]
[11]
M. Mohri, H. Kinoshita, K. Inomata, H. Kotake, Chem. Lett.
1985, 451–454.
962
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