Concise total synthesis of (3Z,6Z,9S,10R)-9,10-epoxy-1,3,6-heneicosatriene, sex pheromone component of Hyphantria Cunea

Article abstract of DOI:10.1016/j.tet.2004.12.060

The total synthesis of (3Z,6Z,9S,10R)-9,10-epoxy-1,3,6-heneicosatriene, sex pheromone component of Hyphantria cunea, using a convergent synthetic strategy, was achieved through the regioselective coupling of the two fragments, chiral epoxy tosylate and 1,

Full text of DOI:10.1016/j.tet.2004.12.060

Tetrahedron 61 (2005) 2187–2193
Concise total synthesis of
(3Z,6Z,9S,10R)-9,10-epoxy-1,3,6-heneicosatriene,
sex pheromone component of Hyphantria Cunea
Chao Chea,b and Zhong-Ning Zhanga,
*
aState Key Laboratory of Integrated Management of Pest Insects and Rodents, Institute of Zoology, Chinese Academy of Sciences, No. 19,
Zhongguancun Road, Beijing 100080, People’s Republic of China
bGraduate School of the Chinese Academy of Sciences, Beijing 100039, People’s Republic of China
Received 17 September 2004; revised 13 December 2004; accepted 15 December 2004
Available online 21 January 2005
Abstract—The total synthesis of (3Z,6Z,9S,10R)-9,10-epoxy-1,3,6-heneicosatriene, sex pheromone component of Hyphantria cunea, using
a convergent synthetic strategy, was achieved through the regioselective coupling of the two fragments, chiral epoxy tosylate and 1,4-diyne.
The former fragment was synthesized in two efficient and convenient approaches starting from the same available material using Sharpless
AE kinetic resolution as the key step.
q 2005 Elsevier Ltd. All rights reserved.
1. Introduction
have been published.6 These methods suffered from
some limitations, mostly importantly being long reaction
sequences, very low total yield and/or uncontrolled
semihydrogenation of conjugated terminal enyne. Our
interest in the synthesis of 1 arises from several
considerations. Firstly, due to the strong dependence
of pheromone activity on the configuration, the stereo-
selective synthesis of 1 is of great interest and allows
further exploration of the mechanism of pheromone–
receptor interaction and the relationship between
structure and biological activity. Furthermore, an
efficient and concise procedure to 1 would make it
possible to allow its use as a pest control agent in
pheromone traps, which could lead to environmental-
friendly pest management. Moreover, the novel structure
itself poses intrinsic problems for a total synthesis.
Herein, we describe a concise synthesis of 1.
Optically active epoxides are an important class of natural
products encountered as sex pheromones of Lepidopteran
pests,1 self-defensive substances against rice blast disease2
and antifeedants.3 The principal member of Lepidopteran
epoxy pheromones, (3Z,6Z,9S,10R)-9,10-epoxy-1,3,6-
henicosatriene 1, featured a disubstituted chiral epoxide as
the central structural element, was first assigned in 1989 in
the sex pheromone gland of Hyphantria cunea4 (Fig. 1).
Subsequently, 1 was also found in the sex pheromone
secretion of Diacrisia oblique.5
As compared with the synthesis of other members of
chiral epoxide pheromones, the synthesis of 1 was more
challenging due to the labile 1,3,6-triene subunit. To
date, only two studies on the asymmetric synthesis of 1
Figure 1. Sex pheromone epoxy components of Hyphantria cunea.
Keywords: Sex pheromone; Hyphantria cunea; Total synthesis.
* Corresponding author. Tel. C86 10 62612241; fax: C86 10 62565689; e-mail: zhangzn@ioz.ac.cn
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2004.12.060

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C. Che, Z.-N. Zhang / Tetrahedron 61 (2005) 2187–2193
2. Results and discussion
Sharpless AE kinetic resolution as the key step (Scheme 2,
(G)-12/(S)-12). In order to obtain (S)-12 with high
enantiomeric excess, the catalytic selectivities of various
D-(K)-tartrate esters, diethyl (DET), diisopropyl (DIPT),
dicyclohexyl (DCHT), dicyclododecyl tartrate (DCDT)
were investigated, and the sterically demanding D-(K)-
DCHT gave the best result.10 Thus, the asymmetric
epoxidation of alkenol (G)-12 using D-(K)-DCHT as
ligand gave (S)-12 with excellent yield and enantio-
selectivity (98.2% ee) upon 50.8% completion of the
reaction. Epoxidation on (S)-12 with m-CPBA gave a 2:1
ratio of threo to erythro epoxy alcohols (3S)-13. The
compound (3S)-13 were converted into diastereomeric
tosylates, which was flash chromatographed to afford
(2S,3S)-4. To circumvent the drawbacks of kinetic resolu-
tion, on the other hand, we employed an inversion of the
configuration11 to convert (2S,3R)-13, the epoxy product of
kinetic resolution, into (2S,3S)-14 without the loss of
material. Thus, the chemical yields were markedly beyond
the 50% limitation set for kinetic resolution. The cleavage
of the acetyl group in (2S,3S)-14 provided the epoxy
alcohols (2S,3S)-13, which were converted to (2S,3S)-4 in
good yield. The specific optical rotation of (2S,3S)-4 was
very close to that in the literature {[a]2D5ZC8.8 (cZ1,
CHCl3); lit.8 [a]D20ZC8.6 (cZ1, CHCl3)}.
Our synthetic strategy was based on two main building
blocks, that is, epoxy-tosylate (2S,3S)-4 and 1,4-diyne 5
(Fig. 2). We envisaged that the former could be coupled
with diynyl trifluoroborates which were readily generated in
situ by the addition of BF3$Et2O to diynyllithiums and
mediated the regioselective ring cleavage of oxirane.7 Our
initial experiments involved the use of 1,4-heptdiyne 5a.
The coupling proceeded smoothly to afford the desired ring-
opening product. In contrast, the coupling of (2S,3S)-4 with
5b under the similar condition had proven abortive.
Repeated attempts by the modification of numerous
experimental variations in base, reaction solvent and
temperature, failed to furnish the product. Presumably, the
introduction of electron-withdrawing vinyl led to the
isomerization of molecules mainly due to deprotonation of
a methylene between two triple bonds. To probe the effects
of structural variations of 1,4-diyne on the course of
coupling, additional two 1,4-diyne (5c, 5d) were studied.
Only 5d underwent the coupling to deliver the desired
product 6d. In addition, 1,4-enyne 5e was synthesized and
employed in the coupling reaction. To our delight, we
observed that (2S,3S)-4 underwent, on treatment of 5e, a
smooth ring-opening to furnish 6e (Fig. 3).
In conclusion, we have developed two efficient and
convenient procedures for the synthesis of (2S,3S)-epoxy
Figure 2. Retrosynthetic analysis of (9S,10R)-1.
As matters developed, it seemed that there were two
possible routes to the target molecule, respectively derived
from the intermediate 6e and 6d (Scheme 1). The former
which might appear to be a more direct one, however, was
not successful on the step of catalytic hydrogenation. We
therefore adopt the route b employing 6d as the inter-
mediate. We found that the presence of THP protecting
group in 6d was unfavorable for the formation of oxirane.
After removal of THP protecting group in 6d, the resulting
diol underwent cyclization in the presence of K2CO3 to
afford 9 in good yield. The hydrogenation of 9 over Lindlar
catalyst provided 10, which was converted into the
corresponding bromide 11. The following elimination
afforded the target molecule in good yield.
Expoxy tosylate (2S,3S)-4 was a vital intermediate in the
synthesis of epoxy pheromones and several approaches to it
have been reported. However, the methods either employed
expensive chiral catalyst system,8 or were prohibitively
lengthy and impractical for large scale preparation.7b,9
Given those considerations, the present synthesis of (2S,3S)-
4 employed readily available material and utilized the
Figure 3. Coupling of various 1,4-diyne with (2S,3S)-4.

C. Che, Z.-N. Zhang / Tetrahedron 61 (2005) 2187–2193
2189
Scheme 1. Synthesis of (9S,10R)-1. Reagents and conditions: (a) K2CO3, CH3OH, rt, 30 min; (b) PTSA, CH3OH, rt, 5 h; (c) H2, Pd-CaCO3, quinoline, CH3OH,
rt; (d) (i) MsCl, Et3N, CH2Cl2, 0 8C/rt, 1 h; (ii) LiBr, NaHCO3, THF, 8 h. (e) K2CO3, CH3OH, rt, 48 h. PTSA, p-toluenesulfonic acid.
tosylate starting from the same available material, and then
explored the possibility of its coupling with 1,4-diyne or
1,4-enyne via alkylative epoxide rearrangement, through
which (3Z,6Z,9S,10R)-9,10-epoxy-1,3,6-heneicosatriene 1,
the sex pheromone component of Hyphantria cunea, was
successfully synthesized. The implementation of the new
efficient approach to 1 would pave the way to the synthesis
of other members of those highly stereoselective chemo-
reception insect pheromones or other structurally related
polyacetylenic natural products.
3. Experimental
3.1. General methods
NMR spectra were recorded on a Bruker AMX-400
spectrometer using TMS as internal standard. All the
coupling constants are reported in Hz. 13C NMR spectra
were recorded on the same instrument, and chemical shifts
were measured relative to residual solvent resonances (d
(CDCl3)Z77.0). IR spectra were determined by Bruker
Tensor 27 spectrometer. High-resolution mass spectra were
obtained on a Micromass UK GCT-MS instrument with EI
ionization methods. The optical rotations were determined
for solution in CDCl3 at 25 8C by using a Perkin–Elmer
Model 241-Mc automatic polarimeter. Elemental micro-
analyses were performed by Italian Carloerba ST-2
˚
Scheme 2. Synthesis of (2S,3S)-4. Reagents and conditions: (a) 4 A MS,
analyzer. Melting points were determined on a Yanagimoto
apparatus and were uncorrected. 1,4-Diyne and 1,4-enyne
5a–5e were synthesized based on the general procedures
described in the literature.12 Anhydrous solvents were
prepared as follows: THF and diethyl ether were freshly
distilled under N2 from Na/benzophenone. CH2Cl2 was
D-(K)-DCHT, Ti(O-i-Pr)4, TBHP, CH2Cl2, K20 8C (refrigerator);
(b) m-CPBA, CH2Cl2, rt, 24 h; (c) (i) TsCl, powered KOH, Et2O,
K5 8C/0 8C, 3 h; (ii) flash chromatography employed to separate
diastereoisomer; (d) AcOH, PPh3, DIAD, THF, rt, 24 h; (e) K2CO3,
CH3OH, 0 8C, 1 h. D-(K)-DCHT, dicyclohexyl D-(K)-tartrate; TBHP, tert-
butyl hydroperoxide; DIAD, diisopropyl azodicarboxylate.

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C. Che, Z.-N. Zhang / Tetrahedron 61 (2005) 2187–2193
˚
distilled under N2 over CaH2 and stored over 4 A molecular
sieves. Purification of products was performed by flash
column chromatography on silica gel (200–300 mesh).
carbinol methine proton resonances. IR (neat) n 3310,
1
2910 cmK1; H NMR (CDCl3) d 3.84 and 3.43 (2m, 1H,
CHOH) (1:2), 2.96–3.04 (m, 1H, oxirane CH), 2.82 (dd,
3
2
2JZ4.9 Hz, JZ4.1 Hz, 1H, oxirane CH2), 2.72 (dd, JZ
3
4.9 Hz, JZ2.7 Hz, 1H, oxirane, CH2), 1.55–1.60 (m, 2H,
3.1.1. (S)-Tetradec-1-en-3-ol (S)-12 and (2S,3R)-1,2-
epoxy-3-tetradecanol (2S,3R)-13. To a stirred and cooled
˚
(K20 8C) suspension of activated powered 4 A molecular
CH2CHOH), 1.26 (br, s,18H, (CH2)9), 0.88 (t, JZ6.9 Hz,
3H, CH3); Anal. Calcd for C14H28O2: C, 73.63; H, 12.36.
Found: C, 73.55; H, 12.14.
sieves (2.1 g) in 40 mL dry CH2Cl2 under nitrogen were
added D-(K)-DCHT (0.44 g, 1.4 mmol) and Ti(O-i-Pr)4
(0.284 g, 1 mmol) and stirred for 20 min. Then compound
(G)-12 (2.12 g, 10 mmol) and 0.4 mL n-dodecane (internal
standard for GC monitoring of percent conversion) were
added and stirred for further 30 min, during which a small
aliquot (ca. 0.1 mL) was taken for a T0GC sample. The
reaction was then treated with a solution of TBHP in toluene
(0.7 equiv, 3.3 M) added by gastight syringe. The reaction
mixture was kept at K20 8C (refrigerator) and monitored by
GC. When the conversion reached 50%, the reaction was
quenched with an aqueous solution of FeSO4 and citric acid
and stirred for 30 min. The organic phase was separated and
the aqueous phase was extracted twice with CH2Cl2. The
combined organic phases were washed with saturated brine
and dried over Na2SO4. The crude product was then purified
by flash chromatography (petroleum ether/ether, 2/1) to give
(S)-12 (0.9 g, 87% based on 50.8% conversion) and (2S,3R)-
13 (1.06 g, 91% based on 50.8% conversion). (S)-12, a
colorless oil, [a]2D5ZC5.5 (cZ1, CHCl3), lit.6b [a]2D5Z
3.1.3. (2S,3S)-1,2-Epoxy-3-acetyloxytetradecane (2S,3S)-
14. To a solution of the epoxy alcohol (2S,3R)-13 (1.14 g,
5 mmol) in anhydrous THF (100 mL) was added AcOH
(1.50 g, 25 mmol) and PPh3 (5.24 g, 20 mmol), followed by
the addition of diisopropylazodicarboxylate (3.03 g,
15 mmol) over a period of 5 min. The orange-red color of
diisopropylazodicarboxylate faded immediately with slight
liberation of heat. The solution was stirred at room
temperature for 1 day. The mixture was diluted with ether
(100 mL) then washed with H2O and brine. The aqueous
washings were extracted with ether (50 mL) and the
extraction was washed with brine. The combined organic
layers were dried over anhydrous Na2SO4. The solvent was
removed at reduced pressure. Flash chromatography
(petroleum ether/ether, 5/1) of the residue afforded
(2S,3S)-14 (0.90 g, 67%) as a colorless oil. [a]2D5ZC2.7
1
(cZ1, CHCl3); IR (neat) n 2930, 1730 cmK1; H NMR
(CDCl3) d 4.68–4.73 (m, 1H, CHOAc), 3.05–3.08 (m, 1H,
oxirane CH), 2.82 (dd, 2JZ4.8 Hz, 3JZ4.1 Hz, 1H, oxirane
CH2), 2.63 (dd, 2JZ4.8 Hz, 3JZ2.6 Hz, 1H, oxirane CH2),
2.08 (s, 3H, O]CCH3), 1.63–1.66 (m, 2H, CH2CHOAc),
C5.2 (cZ1, CHCl3); IR (neat) n 3390, 3020, 2930,
3
1650 cmK1
;
1H NMR (CDCl3) d 5.86 (ddd, Jtrans
Z
3
3
17.1 Hz, JcisZ10.4 Hz, JZ6.3 Hz, 1H, CH2]CH), 5.18
1.26 (br, s, 18H, (CH2)9), 0.88 (t, JZ6.7 Hz, 3H, CH3); 13
C
(dt, JtransZ17.1 Hz, 2JZ4JZ1.4 Hz, 1H, CHH]CH),
3
5.08 (dt, JcisZ10.4 Hz, JZ4JZ1.4 Hz, 1H, CHH]CH),
4.05–4.12 (m, 1H, CHOH), 1.45–1.56 (m, 2H, CH2CHOH),
3
2
NMR (CDCl3) d 170.3 (O]C); 74.0 (CHOAc); 52.9, 44.8
(CH(O)CH); 31.8, 31.3, 29.5, 29.4, 29.3, 29.2, 25.1, 22.6,
20.9, 14.0; Anal. Calcd for C16H30O3: C, 71.07; H, 11.18.
Found: C, 70.92; H, 11.07.
1.26 (br, s, 18H, (CH2)9), 0.88 (t, JZ6.9 Hz, 3H, CH3); 13
C
NMR (CDCl3) d 141.3, 114.3 (CH]CH2), 73.2 (CHOH),
37.0, 31.9, 29.6, 29.5, 29.3, 25.3, 22.6, 14.0; Anal. Calcd for
C14H28O: C, 79.18; H, 13.29. Found: C, 79.28; H, 13.12.
(2S,3R)-13, white solid, mp 47–49 8C; [a]2D5ZK12.5 (cZ1,
CHCl3); IR (neat) n 3310, 2910 cmK1; 1H NMR (CDCl3) d
3.81–3.83 (m, 1H, CHOH), 3.00–3.02 (m, 1H, oxirane CH),
3.1.4. (2S,3S)-1,2-Epoxy-3-tetradecanol (2S,3S)-13. To a
solution of (2S,3S)-14 (0.54 g, 2 mmol) in methanol
(10 mL) was added anhydrous K2CO3 (0.5 g) at 0 8C
while stirring. The mixture was stirred at 0 8C for 1 h, and
then filtered. Concentration of the filtrate and purification by
flash chromatography (petroleum ether/ether, 1/1) gave
(2S,3S)-13 (0.43 g, 94%) as a white solid, mp 40–428C;
2
3
2.81 (dd, JZ5.1 Hz, JZ3.2 Hz, 1H, oxirane CH2), 2.72
(dd, 2JZ5.1, 3JZ4.0 Hz, 1H, oxirane, CH2), 1.46–1.55 (m,
2H, CH2CHOH), 1.26 (br, s,18H, (CH2)9), 0.88 (t, JZ
6.7 Hz, 3H, CH3); 13C NMR (CDCl3) d 68.4 (CHOH), 54.6,
43.4 (CH(O)CH), 33.4, 31.9, 29.6, 29.5, 29.3, 25.2, 22.6,
14.0; Anal. Calcd for C14H28O2: C, 73.63; H, 12.36. Found:
C, 73.55; H, 12.14.
[a]2D5ZC1.6 (cZ1, CHCl3); IR (neat) n 3310, 2910 cmK1
;
1H NMR (CDCl3) d 3.41–3.43 (m, 1H, CHOH), 2.97–2.99
(m, 1H, oxirane CH), 2.83 (dd, 2JZ4.8 Hz, 3JZ4.2 Hz, 1H,
oxirane CH2), 2.71 (dd, 2JZ4.8 Hz, 3JZ2.7 Hz, 1H,
oxirane, CH2), 1.57–1.61 (m, 2H, CH2CHOH), 1.26 (br, s,
18H, (CH2)9), 0.88 (t, JZ6.8 Hz, 3H, CH3); 13C NMR
(CDCl3) d 71.7 (CHOH), 55.4, 45.1 (CH(O)CH), 34.3, 31.9,
29.6, 29.5, 29.4, 29.3, 25.3, 22.6, 14.0; Anal. Calcd for
C14H28O2: C, 73.63; H, 12.36. Found: C, 73.55; H, 12.14.
3.1.2. (3S)-1,2-Epoxy-3-tetradecanol (3S)-13. A solution
of (S)-12 (2.12 g, 10 mmol) in 20 mL of anhydrous CH2Cl2
was cooled to 0 8C and stirred vigorously under nitrogen
atmosphere. To this was added a solution of 75% m-CPBA
(3.23 g, 14 mmol) in CH2Cl2. The resulting white mixture
was warmed to room temperature and stirred for 24 h. The
solution was filtered and washed with three 20 mL portions
of saturated aqueous NaHCO3. The aqueous layer was
extracted with CH2Cl2, and the combined organic layers
were dried over anhydrous Na2SO4. After the concentration
and purification by flash chromatography (petroleum ether/
ether, 2/1) epoxy alcohol (3S)-13 (1.9 g, 84%) was obtained
as a colorless oil which solidified upon standing at room
temperature. The ratio of threo to erythro epoxy alcohols
was determined to be ca. 2:1 by 1H NMR integration of the
3.1.5. (2S,3S)-1,2-Epoxy-3-tosyloxytetradecane (2S,3S)-
4. To a solution of epoxy alcohols (3S)-13 (2.28 g,
10 mmol) in 50 mL of anhydrous Et2O was added
tosylchloride (2.85 g, 15 mmol) and the mixture was cooled
to K5 to K10 8C. Freshly and finely machine-powdered
KOH (6 g) was added with efficient stirring over 15 min
while maintaining the temperature between K5 and 0 8C.
The mixture was stirred for additional 2 h at 0 8C and then
poured into 50 mL of ice water. After vigorous shaking, the
layers were separated. The organic layer and two ethereal

C. Che, Z.-N. Zhang / Tetrahedron 61 (2005) 2187–2193
2191
extracts were washed with brine and dried over anhydrous
Na2SO4. Concentration and purification by flash chroma-
tography (petroleum ether/ether, 2/1) yielded threo-epoxy
tosylate (2S,3S)-4 (1.72 g) as white solid and erythro-epoxy
tosylate (0.94 g) as colorless oil. Threo-epoxy tosylate
(2S,3S)-4, mp 66–68 8C; [a]2D5ZC8.8 (cZ1, CHCl3), lit.8
mp 71–72 8C, [a]2D0ZC8.6 (cZ1, CHCl3); IR (KBr) n
3.2.2. (9S,10S)-9-Hydroxy-10-tosyloxyhenicosa-3,6-
diyne 6a. Colorless oil (0.40 g, 84%); [a]2D5ZK11.7 (cZ
1, CHCl3); IR (neat) n 3410, 3065, 2925, 2210 (weak),
1
1595 cmK1; H NMR (CDCl3) d 7.81 (d, JZ8.3 Hz, 2H,
2,6-Ar), 7.33 (d, JZ8.3 Hz, 2H, 3,5-Ar), 4.63–4.67 (m, 1H,
CHOTs), 3.88 (dt, JZ3.9, 6.9 Hz, 1H, CHOH), 3.11–3.13
(m, 2H, ChCCH2ChC), 2.45 (s, 3H, Ar–CH3), 2.34–2.37
(m, 2H, ChCCH2CHOH), 2.16–2.19 (m, 2H, ChCCH2-
CH3), 1.51–1.60 (m, 2H, TsOCHCH2CH2), 1.26 (br, s, 18H,
(CH2)9), 1.12 (t, JZ7.5 Hz, 3H, ChCCH2CH3), 0.88 (t, JZ
6.8 Hz, 3H, CH3); Anal. Calcd for C28H42O4S: C, 70.85; H,
8.92. Found: C, 70.56; H, 8.68.
1
3050, 2925, 1595 cmK1; H NMR (CDCl3) d 7.81 (d, JZ
8.3 Hz, 2H, 2,6-Ar), 7.32 (d, JZ8.3 Hz, 2H, 3,5-Ar), 4.34
(dt, JZ6.3, 7.2 Hz, 1H, CHOTs), 3.03–3.06 (m, 1H, oxirane
2
CH), 2.78 (t, JZ3JZ4.6 Hz, 1H, oxirane CH2), 2.63 (dd,
2JZ4.6 Hz, 3JZ2.6 Hz, 1H, oxirane CH2), 2.44 (s, 3H, Ar–
CH3), 1.66–1.70 (m, 2H, CH2CHOTs), 1.26 (br, s, 18H,
(CH2)9), 0.88 (t, JZ6.6 Hz, 3H, CH3); 13C NMR (CDCl3) d
144.5, 134.3, 129.6, 127.8 (Ar); 83.4 (CHOTs); 52.6, 44.8
(CH(O)CH); 31.9, 31.8, 29.5, 29.4, 29.2, 29.1, 24.8, 22.6,
21.6, 14.1; Anal. Calcd for C21H34O4S: C, 65.93; H, 8.96.
Found: C, 65.98; H, 8.93.
3.2.3. (9S,10S)-9-Hydroxy-10-tosyloxy-1-(tetrahydro-
2H-pyran-2-yloxy)henicosa-3,6-diyne 6d. Colorless oil
(0.42 g, 73%); [a]2D5ZK18.6 (cZ1, CHCl3); IR (neat) n
3430, 3065, 2925, 2216 (weak), 1598 cmK1 1H NMR
;
(CDCl3) d 7.83 (d, JZ8.2 Hz, 2H, 2,6-Ar), 7.35 (d, JZ
8.2 Hz, 2H, 3,5-Ar), 4.63–4.66 (m, 2H, CHOTs, OCHO),
3.80–3.91 (m, 2H, ChCCH2CH2OTHP), 3.69–3.73 (m, 1H,
CHOH), 3.11–3.15 (m, 2H, ChCCH2ChC), 2.49 (dt, 3JZ
7.1 Hz, 5JZ2.1 Hz, 2H, HOCHCH2ChC), 2.45 (s, 3H, Ar–
CH3), 2.36 (t, JZ6.2 Hz, 2H, ChCCH2CH2OTHP), 1.50–
1.80 (m, 8H, TsOCHCH2, (CH2)3), 1.26 (br, s, 18H,
(CH2)9), 0.88 (t, JZ6.4 Hz, 3H, CH3); 13C NMR (CDCl3)
d 144.8, 134.1, 129.7, 127.9 (Ar); 98.7 (OCHO), 84.6
(TsOCH); 77.6, 75.7, 75.2, 68.5 (2ChC); 70.3 (CHOH);
65.7, 62.2 (2CH2O); 31.9, 30.6, 30.5, 29.6, 29.5, 29,3, 29.2,
25.4, 24.9, 23.8, 22.7, 21.6, 20.2, 19.4, 19.3, 14.1, 9.8, 9.6;
Anal. Calcd for C33H50O6S: C, 68.95; H, 8.77. Found: C,
68.77; H, 8.73.
The same procedure as described above was applied for the
conversion of (2S,3S)-13 to (2S,3S)-4.
3.2. Typical procedure for the preparation of 6a, 6d and
6e
3.2.1. (Z,9S,10S)-9-Hydroxy-10-tosyloxyhenicosa-1,3-
dien-6-yne 6e. A solution of 5e (0.28 g, 3 mmol) in
15 mL of anhydrous THF was stirred at K78 8C as a
solution of n-BuLi in hexanes (1 mL, 2.5 mmol) was added
slowly by syringe. The resulting dark green solution was
stirred for 15 min, and then BF3$ Et2O (0.31 mL, 2.5 mmol)
was added via syringe. After another 15 min, a solution of 4
(0.38 g, 1 mmol) in 4 mL of THF was added also by syringe,
and the reaction mixture was stirred for further 3 h at
K78 8C. The reaction mixture was then quenched with
10 mL saturated NH4Cl. The aqueous layer was separated
and extracted with ether (10 mL!2). The combined organic
layer was dried over anhydrous Na2SO4, and concentrated
to afford a brown residue which was purified through flash
chromatography (petroleum ether/ether, 1/1) to give 6e
(0.37, 79%) as a colorless oil. [a]2D5ZK4.1 (cZ1, CHCl3);
IR (neat) n 3524, 3080, 3030, 2925, 2285 (weak), 1645,
3.2.4. (Z,9S,10R)-9,10-Epoxyhenicosa-1,3-dien-6-yne 7.
To a solution of 6e (0.47 g, 1 mmol) in 10 mL of anhydrous
methanol was added anhydrous K2CO3 (0.4 g) with stirring
at room temperature. After 30 min, the reaction mixture was
filtered. Concentration of the filtrate and purification by
flash chromatography (petroleum ether/diethyl ether, 10/1)
afforded 7 (0.25 g, 82%) as a colorless oil which solidified
upon standing at room temperature. [a]2D5ZC21.4 (cZ1,
CHCl3); IR (neat) n 3030, 2925, 2285 (weak), 1645 cmK1
;
3
3
1H NMR (CDCl3) d 6.63 (ddd, JtransZ16.7 Hz, JcisZ
10.2 Hz, 3JZ10.7 Hz, 1H, CH]CHCH]CH2), 6.04 (t,
3JZ3J cisZ10.7 Hz, 1H, CH]CHCH]CH2), 5.44 (dt,
1
1597 cmK1; H NMR (CDCl3) d 7.82 (d, JZ8.3 Hz, 2H,
3
3JcisZ10.7 Hz, JZ7.2 Hz, 1H, CH]CHCH]CH2), 5.24
2,6-Ar), 7.33 (d, JZ8.3 Hz, 2H, 3,5-Ar), 6.63 (dddd,
3
3
3
4
3JtransZ16.7 Hz, JcisZ10.2 Hz, JZ10.7 Hz, JZ1.0 Hz,
(d, JtransZ16.7, 1H, CH]CHCH]CHH), 5.16 (d,
3JcisZ10.2 Hz, 1H, CH]CHCH]CHH), 3.06–3.12 (m,
3H, ChCCH2CH]CH, oxirane CH), 2.95 (dt, JZ4.2,
1H, CH]CHCH]CH2), 6.05 (t, JZ3JcisZ10.7 Hz, 1H,
CH]CHCH]CH2), 5.44 (dt, JcisZ10.7 Hz, JZ7.2 Hz,
1H, CH]CHCH]CH2), 5.25 (d, JtransZ16.7 Hz, 1H,
CH]CHCH]CHH), 5.17 (d, JcisZ10.2 Hz, 1H,
3
3
3
2
3
3
5.5 Hz, 1H, oxirane CH), 2.52–2.58 (ddt, JZ17 Hz, JZ
5.5 Hz, 5JZ2.7 Hz, 1H, ChCCHHCH(O)CH), 2.22–
2.28 (ddt, 2JZ17, 3JZ7.2 Hz, 5JZ2.5 Hz, 1H,
ChCCHHCH(O)CH), 1.50–1.56 (m, 2H, CH(O)CHCH2),
3
CH]CHCH]CHH), 4.62–4.67 (m, 1H, CHOTs), 3.76–
3.80 (m, 1H, CHOH), 3.04 (dd, 3JZ7.2 Hz, 4JZ1.8 Hz, 2H,
HChCCH2C]CH), 2.44 (s, 3H, Ar–CH3), 2.35–2.37 (m,
2H, ChCCH2CHOH), 1.50–1.70 (m, 2H, TsOCHCH2),
1.26 (br, s, 18H, (CH2)9), 0.88 (t, JZ6.6 Hz, 3H, CH3); 13
C
NMR (CDCl3) d 131.3, 130.3, 126.5, 118.5 (2CH]CH);
79.9, 75.4 (ChC); 57.1, 55.3 (CH(O)CH); 31.9, 29.7, 29.6,
29.5, 29.3, 27.6, 26.5, 22.7, 18.8, 17.7, 14.1; HRMS (m/z)
Calcd for C21H34O 302.2610, found 302.2613.
1.26 (br, s, 18H, (CH2)9), 0.88 (t, JZ6.6 Hz, 3H, CH3); 13
C
NMR (CDCl3) d 144.7, 134.1, 129.8, 127.9 (Ar); 131.3,
130.4, 126.3, 118.7 (2C]C); 84.7 (TsOCH); 81.0, 76.7
(ChC); 70.4 (CHOH); 31.9, 30.6, 29.6, 29.5, 29.4, 29.3,
29.2, 24.9, 23.9, 22.7, 22.6, 21.7, 17.6, 14.1; HRMS (m/z)
Calcd for C28H42O4S 474.2804, found 474.2801.
3.2.5. (9S,10S)-1,9-Dihydroxy-10-tosyloxyhenicosa-3,6-
diyne 8. PTSA (catalytic) was added to a solution of 6d
(1.15 g, 2 mmol) in 30 mL of methanol and stirred for 5 h at
room temperature. Methanol was removed under reduced
pressure and the residue was dissolved in ether. The ether
Compounds 6a and 6d were prepared in the same manner to
that described above.

2192
C. Che, Z.-N. Zhang / Tetrahedron 61 (2005) 2187–2193
layer was washed with water, saturated aqueous NaHCO3,
brine respectively and dried over anhydrous Na2SO4.
Concentration at reduced pressure and purification by
flash chromatography (petroleum ether/ether, 1/4) afforded
8 (0.89 g, 91%) as a colorless oil. [a]2D5ZK8.6 (cZ1,
CHCl3); IR (neat) n 3390, 3065, 2925, 2217 (weak),
(0.74 g, 6.3 mmol) with stirring. The mixture was stirred for
additional 1 h, and then washed with water. The methylene
chloride solution was dried over anhydrous Na2SO4 and
concentrated to give an oil residue. The residue was
dissolved in dry THF (10 mL), and added anhydrous LiBr
(1.72 g, 20 mmol) and NaHCO3 (1.76 g, 15 mmol) at 0 8C.
The mixture was stirred for 8 h at room temperature and
then filtered. Concentration of the filtrate and flash
chromatography (petroleum ether/ether, 10/1) afforded 11
(1.57 g, 82%) as a colorless oil. [a]2D5ZC4.2 (cZ1,
1
1598 cmK1; H NMR (CDCl3) d 7.83 (d, JZ8.3 Hz, 2H,
2,6-Ar), 7.35 (d, JZ8.3 Hz, 2H, 3,5-Ar), 4.64–4.66 (m, 1H,
CHOTs,), 3.79–3.82 (m, 1H, CHOH), 3.71 (t, JZ6.2 Hz,
2H, ChCCH2CH2OH), 3.13–3.15 (m, 2H, ChCCH2-
ChC), 2.42–2.47 (m, 5H, Ar–CH3, HOCHCH2ChC),
2.36–2.38 (m, 2H, ChCCH2CH2OH), 1.50–1.60 (m, 2H,
TsOCHCH2), 1.26 (br, s, 18H, (CH2)9), 0.88 (t, JZ6.6 Hz,
3H, CH3); 13C NMR (CDCl3) d 144.8, 134.1, 129.7, 127.8
(Ar); 84.6 (CHOTs); 77.3, 76.1, 75.8, 68.7 (2ChC); 70.3
(CHOH); 61.0 (CH2OH); 31.9, 30.5, 29.6, 29.5, 29.3, 29.2,
24.9, 23.7, 23.0, 22.9, 22.7, 21.6, 14.1, 9.8, 9.6; Anal. Calcd
for C28H42O5S: C, 68.54; H, 8.63. Found: C, 68.41; H, 8.74.
CHCl3); IR (neat) n 3030, 2925, 1640 cmK1 1H NMR
;
(CDCl3) d 5.41–5.54 (m, 4H, CH]CHCH2CH]CH), 3.38
(t, JZ7.1 Hz, 2H, CH2Br), 2.79–2.96 (m, 4H, oxirane,
CH]CHCH2CH]CH), 2.63 (dt, JZ6.5 Hz, 7.0, 2H,
CH]CHCH2CH2Br), 2.29 and 2.37 (2m, 2H,
CH(O)CHCH2CH]CH), 1.50–1.55 (m, 2H, CH(O)-
CHCH2CH2), 1.26 (br, s, 18H, (CH2)9), 0.89 (t, JZ
6.6 Hz, 3H, CH3); 13C NMR (CDCl3) d 130.5, 130.1,
126.5, 124.3 (2C]C); 57.3, 56.4 (CH(O)CH); 31.9, 30.8,
29.9, 29.6, 29.5, 29.4, 29.3, 26.0, 25.9, 22.6, 14.1; HRMS
(m/z) Calcd for C21H37OBr 384.2028, found 384.2031.
3.2.6. (9S,10R)-9,10-Epoxyhenicos-3,6-diyn-1-ol 9. The
procedure described for the preparation of 7 was followed.
White solid (0.26 g, 83%), mp 48–50 8C; [a]2D5ZC23.5
(cZ1, CHCl3); IR (KBr) n 3390, 2930, 2280 (weak) cmK1
;
3.2.9. (3Z,6Z,9S,10R)-9,10-Epoxy-1,3,6-henicostriene 1.
To a solution of 11 (0.38 g, 1 mmol) in 10 mL anhydrous
methanol was added anhydrous K2CO3 (0.4 g) with stirring
at room temperature. After 48 h, the reaction mixture was
filtered. Concentration of the filtrate and purification by
flash chromatography (petroleum ether/ether, 20/1) afforded
1 (0.26 g, 86%) as a colorless oil. [a]2D5ZK0.6 (cZ3,
CHCl3), lit.6a [a]D16ZK0.41 (cZ1.97, CHCl3); IR (neat) n
1H NMR (CDCl3) d 3.71 (t, JZ6.2 Hz, 2H, CH2OH), 3.14–
3.17 (m, 2H, ChCCH2ChC), 3.11 (dt, JZ5.5 Hz, 1.6, 1H,
oxirane CH), 2.95 (dt, JZ4.5, 5.5 Hz, 1H, oxirane CH), 2.29
and 2.52 (2m, 2H, ChCCH2CH(O)CH), 2.45 (tt, 3JZ
5
6.2 Hz, JZ2.3 Hz, 2H, ChCCH2CH2OH), 1.48–1.53 (m,
2H, CH(O)CHCH2CH2), 1.26 (br, s, 18H, (CH2)9), 0.88 (t,
JZ6.6 Hz, 3H, CH3); 13C NMR (CDCl3) d 77.1, 76.3, 76.2,
75.7 (2ChC); 61.1 (CH2OH); 57.1, 55.0 (CH(O)CH); 31.9,
29.6, 29.5, 29.4, 29.3, 27.5, 26.4, 23.1, 22.7, 18.7, 14.1, 9.8;
HRMS (m/z) Calcd for C21H34O2 318.2559, found
318.2553.
1
3030, 2925, 1640 cmK1; H NMR (CDCl3) d 6.64 (dddd,
3
3
4
3JtransZ16.8 Hz, JcisZ10.1 Hz, JZ10.9 Hz, JZ1.1 Hz,
1H, CH]CHCH]CH2), 6.01 (t, JZ10.9 Hz, 1H,
CH]CHCH]CH2), 5.38–5.55 (m, 3H, CH]CHCH2-
CH]CH), 5.23 (dd, JtransZ16.8 Hz, 2JZ1.8 Hz, 1H,
CH]CHCH]CHH), 5.14 (d, JcisZ10.1 Hz, 1H,
3
3
3.2.7. (3Z,6Z,9S,10R)-9,10-Epoxyhenicos-3,6-dien-1-ol
10. Lindlar catalyst (5% palladium on CaCO3, poisoned
with lead, 15 mg) and 5 mg quinoline was placed in a 50 mL
flask equipped with side arm and a rubber septum. The flask
was alternately evacuated and filled with hydrogen several
times. A solution of 9 (0.32 g, 1 mmol) in 20 mL of
methanol was added via syringe and the suspension was
stirred at room temperature until required amount of
hydrogen gas (44.8 mL). The reaction mixture was filtered
and concentrated under reduced pressure to afford 10 in
almost quantitative yields. White solid, mp 39–42 8C;
[a]2D5ZK2.5 (cZ1, CHCl3); IR (neat) n 3300, 3025,
CH]CHCH]CHH), 2.80–2.96 (m, 4H, oxirane,
CH]CHCH2CH]CH), 2.29 and 2.39 (2m, 2H,
CH(O)CHCH2CH]CH), 1.55–1.60 (m, 2H, CH(O)-
CHCH2), 1.26 (br, s, 18H, (CH2)9), 0.89 (t, JZ6.7 Hz,
3H, CH3); 13C NMR (CDCl3) d 131.8, 130.1, 129.9, 129.5,
124.4, 117.6 (3C]C); 57.2, 56.4 (CH(O)CH); 31.9, 29.9,
29.6, 29.5, 29.4, 29.3, 26.2, 26.0, 22.7, 14.1; HRMS (m/z)
Calcd for C21H36O 304.2766, found 304.2770.
1
2920, 1645 cmK1; H NMR (CDCl3) d 5.39–5.57 (m, 4H,
Acknowledgements
CH]CHCH2CH]CH) 3.66 (t, JZ6.3 Hz, 2H, CH2OH),
2.83–2.97 (m, 4H, CH(O)CH, CH]CHCH2CH]CH), 2.25
and 2.39 (2m, 2H, CH]CHCH2CH(O)CH), 2.35–2.41 (m,
2H, HC]CHCH2CH2OH), 1.46–1.55 (m, 2H,
CH(O)CHCH2CH2), 1.26 (br, s, 18H, (CH2)9), 0.88 (t, JZ
6.6 Hz, 3H, CH3); 13C NMR (CDCl3) d 130.7, 130.3, 126.0,
124.6 (2C]C); 62.2 (CH2OH); 57.2, 56.4 (CH(O)CH);
31.9, 30.9, 29.6, 29.5, 29.4, 27.8, 26.6, 26.3, 25.9, 22.7,
14.1; HRMS (m/z) Calcd for C21H38O2 322.2872, found
322.2874.
We thank Beijing forestry station for generous financial
support of the study.
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