Total Synthesis of (±)-Isocembrene: A Tactic for both Diene Construction and Macrocycle Formation

Article abstract of DOI:10.1081/SCC-120025185

The total synthesis of (±)-isocembrene 1, a naturally occurring cembrene diterpenoid, has been achieved via a unified, convergent and highly efficient strategy by imploying an intramolecular Stille sp²-sp ² macrocyclization as the key step and it presents an ideal opportunity to extend the effectiveness of the tactic for both 1,3-diene construction and macrocycle formation.

Full text of DOI:10.1081/SCC-120025185

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Total Synthesis of (±)-Isocembrene: A Tactic for Both
Diene Construction and Macrocycle Formation
Fengzhi Zhang a , Lizeng Peng a , Tao Zhang a , Tiansheng Mei a , Huawei Liu a & Yulin Li a
a National Laboratory of Applied Organic Chemistry , and Institute of Organic Chemistry ,
Lanzhou University , Lanzhou, Gansu, P.R. China
Published online: 16 Aug 2006.
To cite this article: Fengzhi Zhang , Lizeng Peng , Tao Zhang , Tiansheng Mei , Huawei Liu & Yulin Li (2003) Total Synthesis of
(±)-Isocembrene: A Tactic for Both Diene Construction and Macrocycle Formation, Synthetic Communications: An International
Journal for Rapid Communication of Synthetic Organic Chemistry, 33:21, 3761-3770, DOI: 10.1081/SCC-120025185
To link to this article: http://dx.doi.org/10.1081/SCC-120025185
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SYNTHETIC COMMUNICATIONSÕ
Vol. 33, No. 21, pp. 3761–3770, 2003
Total Synthesis of (1)-Isocembrene:
2
A Tactic for Both Diene Construction and
Macrocycle Formation
Fengzhi Zhang, Lizeng Peng, Tao Zhang, Tiansheng Mei,
*
Huawei Liu, and Yulin Li
National Laboratory of Applied Organic Chemistry,
and Institute of Organic Chemistry,
Lanzhou University, Lanzhou, Gansu, P.R. China
ABSTRACT
The total synthesis of (ꢀ)-isocembrene 1, a naturally occurring
cembrene diterpenoid, has been achieved via a unified, convergent
and highly efficient strategy by imploying an intramolecular Stille
sp2–sp2 macrocyclization as the key step and it presents an ideal
opportunity to extend the effectiveness of the tactic for both
1,3-diene construction and macrocycle formation.
Key Words: Cembrane diterpenoid; Stille cyclization; Total
synthesis.
*Correspondence: Yulin Li, National Laboratory of Applied Organic
Chemistry, and Institute of Organic Chemistry, Lanzhou University, Lanzhou,
Gansu 730000, P.R. China; E-mail: liyl@lzu.edu.cn.
3761
DOI: 10.1081/SCC-120025185
Copyright & 2003 by Marcel Dekker, Inc.
0039-7911 (Print); 1532-2432 (Online)
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3762
Zhang et al.
INTRODUCTION
Cembranoids, a large family of diterpenoid natural products
characterized by the presence of a fourteen-membered ring, have been
isolated from various marine sources as well as some terrestrial organisms
since the 1960’s.[1] These diterpenoids have become of great interest to
synthetic chemists and biologists because of their unusual structural
features and remarkably wide range of biological activities.[2] There is
an important family of cembrane diterpenoids that are characteristic of
bearing a 1,3-diene unit in the macrocyclic cembrane skeleton, such as
isocembrene 1,[3] cembrene 2,[4] cembrane C 3,[5] sarcophytol A 4.[6] In
continuation of our on-going project on the total synthesis and novel
macrocyclization methods of cembrane-type diterpenoids, we intended
to explore a novel macrocyclization method to construct the macrocyclic
skeleton that bears a 1,3-diene unit. Intramolecular Pd-catalyzed
cross coupling between alkenylstannane and alkenyl halide (or triflate)
functionality is now firmly established as an important methodology for
the construction of unsaturated heterocycles and carbocycles.[7,8]
Furthermore, this reaction is relatively insensitive to moisture and air,
tolerates a variety of functional groups on either coupling partner, and is
both stereospecific and regioselective. Thus, this reaction appeared to be
ideal for the synthesis of a variety of cembrane-type compounds. We
reasoned that the unique architecture of the cembrane diterpenoids
that was characteristic of bearing a 1,3-diene unit would present an
ideal opportunity to extend the effectiveness of this tactic for both
diene construction and macrocycle formation. To gain experience of
this chemistry, it was decided initials to develop a total synthesis of
isocembrene 1, a cembrane diterpenoid isolated in 1968 by Kashtanova
and co-workers from the Russia pine tree Pinus sibirica.[3,9]
OH
Sarcophytol A
4
Cembrene C 3
Cembrene 2
(-)-Isocembrene 1
The diol 6, readily available from 5,[10] was selectively protected
employing NaH/TBSCl in THF[11] to furnish the monosilylated product
7 (Sch. 1), which was then converted into the sulphone 8 in 2 steps. Allylic
iodide 9, readily available from (E)-geranyl acetone,[12] was used in the

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Synthesis of (1)-Isocembrene
3763
2
SO2Ph
OH
OH
c
a
b
TBSO
TBSO
CH2(COOEt)2
HO
5
O
O
67
8
O
O
O
d
e
f
OH
OTBS
O
O
O
O
I
12
11
O
10
9
g
SnBu3
SnBu3
i
OTf
h
1
14
13
Scheme 1. Reagents and conditions: (a) i. KOH, DMSO, isopropylbromide,
50ꢀC; ii. LAH, Et2O, 0ꢀC (65% two steps); (b) NaH, THF, TBDMSCl, r.t.
(95%); (c) i. Ph3P, imidazole, I2, Et2O/CH3CN (3:2); ii. PhSO2Na, DMF, r.t.
(60% two steps); (d) i. n-BuLi, 8, THF, À40ꢀC, then added 9/HMPA, À40ꢀC
to r.t.; ii. Na (Hg), Na2HPO4, CH3OH, r.t. (72% two steps); (e) n-Bu4NF, THF,
r.t. (95%); (f ) oxalyl chloride, DMSO, Et3N, CH2Cl2, À78ꢀC (92%); (g) i. p-TsOH,
acetone, 40ꢀC; ii. CrCl2, DMF, Bu3SnCHI2, 0ꢀC to r.t. (70% two steps);
(h) N-phenyl triflimide, hexamethyldisilazide (NaHMDS), THF, À78ꢀC (84%);
(i) tetrakis (triphenylphosphine)palladium, THF, LiCl, reflux (76%).
coupling reaction with the lithium salt of 8 (formed by treatment with
n-BuLi in THF at ꢁ40ꢂC) in THF at ꢁ40ꢂC proceeded smoothly to
afford a coupling adduct, which gave the reduced product 10 by
treatment with Na (Hg)[13] in MeOH. Desilylation of 10 with tetra-n-
butylammonium fluoride in THF at room temperature gave the alcohol
11, and this was converted into the desired product aldehyde 12 under
Swern oxidation. Treatment of 12 with a catalytic amount of p-TsOH led
to complete deprotection, and then the deprotected product was treated
with gem-dichromium reagents (CrCl2/Bu3SnCHI2, DMF) to furnish
exclusively E-alkenylstannane 13. For formation of the vinyl triflate 14
in high yields, Stork’s procedure[14] was used. Adding sodium hexa-
methyldisilazide (NaHMDS) rapidly to a diluted solution of vinyl tin
13 and N-phenyl triflimide in excess (1.5–1.7 equiv.) at ꢁ78ꢂC gave the
triflate 14 containing only small amounts (<6% in 400 MHz 1H NMR) of
thermodynamic enolate in yield of 84%. Cyclization[15] of 14
containing the vinyl tin and vinyl triflate groups at the termini of the
chain was accomplished with tetrakis(triphenylphosphine)palladium
(5 mol%) in the presence of lithium chloride (3 equiv.) under high dilution

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3764
Zhang et al.
(10ꢁ3 M) in refluxing THF. Under these mild reaction conditions, no E to
Z isomerization and no rearrangement of the exocyclic double bond
occurred. Synthetic 1 showed identical spectral data with those of natural
product 1 reported.[3,9]
In summary, the total synthesis of (ꢀ)-isocembrene 1 has been
accomplished via an efficient palladium-catalyzed intramolecular
Stille cross-coupling reaction as the key step. The approach proved
highly convergent, straightforward and efficient. Thus, a novel strategy
towards the 1,3-diene based cembrane-type macrocyclic diterpenoids,
featuring sp2–sp2 coupling reaction, has been realized, which should be
applicable to other cembrane-type diterpenoids, such as cembrene-C,
sarcophytols, etc.
EXPERIMENTAL
1H NMR and 13C NMR spectra were recorded on Advance
DXR-200 spectrometer or Bruker AM-400 Bruker in CDCl3 solution
using TMS as internal reference. IR spectra were obtained using a
FT-170SX spectrophotometer. LRMS were measured on
a VG
ZAB-HS spectrometer by direct inlet at 70 eV, and signals given in m/z
with relative intensity (%) in brackets. HRMS were determined on a
Bruker Daltonics APEXII 47 e Fourier Transfer spectrometer with
either of EI, CI, FAB or SIMS ionization methods. All solvents were
freshly purified and dried by standard techniques prior to use. Organic
extractive phases were dried over anhydrous MgSO4. Purification of
products was performed by Flash Column Chromatography (FCC) on
silica gel (200–300 mesh) purchased from Qing Dao Marine Chemical Co.
(Qingdao, China) and eluting with a solvent mixture (v/v) of petroleum
spirit (60–90ꢂC) (PS) and ethyl acetate (EA).
1,3-Dihydroxy-2-isopropylpropane 6
To a stirred solution of KOH (2.52 g, 45 mmol) in DMSO (60 mL)
was added 5 (4.5 mL, 30 mmol), after 10 min isopropylbromide (4.5 mL,
45 mmol) was added slowly and the resulting mixture was stirred for 2 h
at 50ꢂC to complete the reaction. Diluted with Et2O and washed with
water (4 ꢃ 10 mL) and brine. Evaporation of the solvent afforded the
alklated adduct, which was then added dropwise to the anhydrous
Et2O (30 mL) suspension of LAH (1.8 g, 48 mmol) at 0ꢂC. The mixture
was stirred at room temperature for 2 h, and the excess LAH was

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Synthesis of (1)-Isocembrene
3765
2
quenched with MeOH (1 mL). Then the mixture was extracted with ether
(3 ꢃ 50 mL), washed successively with 5% HCl, water and brine. Dried
and concentrated in vacuum, followed by FCC (PS/EA, 2:1) gave the diol
6 (2.3 g, 65% two steps). vmax (film)/cmꢁ1 3328, 2933, 2870, 1669, 1057,
1006, and 920. ꢀH (400 MHz; CDCl3) 0.91 (6H, d, J 6.8 Hz, CH(CH3)2),
1.51–1.55 (1H, m, CH(CH2)2), 1.68–1.74 (1H, m, CH(CH3)2), 3.40 (2H,
brs, OH), 3.73 (2H, dd, J 10.6 and 7.8 Hz, CH2), 3.83 (2H, dd, J 10.6 and
3.8 Hz, CH2). m/z (EI) 100 (Mþꢁ18, 29%).
3-Methyl-2-(tert-butyldimethyl-silyloxymethyl)-1-butanol 7
To a stirred solution of NaH (0.5 g, 18 mmol, 80% wt.) in THF
(70 mL) was added dropwise the diol 6 (2.1 g, 18 mmol) in THF (20 mL).
The resulting mixture was stirred at room temperature for 1 h. TBSCl
(2.7 g, 18 mmol) in THF (15 mL) was added dropwise into the mixture.
The reaction mixture was stirred at room temperature for 2 h to complete
the reaction, diluted with ether (200 mL), washed successively with 10%
aq. K2CO3 (30 mL) and brine (30 mL). Dried and concentrated in
vacuum followed by FCC (PS/EA, 6:1) to give the monosilylated product
7 (4.0 g, 95%). vmax (film)/cmꢁ1 3405, 1450, 1310, 1154, 1080, and 745. ꢀH
(400 MHz; CDCl3) 0.09 (6H, s, 2 ꢃ CH3), 0.89 (9H, s, C(CH3)3),
0.91 (6H, d, J 7.3 Hz, CH(CH3)2), 1.48–1.53 (1H, m, CH(CH2)2),
1.70–1.78 (1H, m, CH(CH3)2), 3.73–3.88 (4H, m, 2 ꢃ CH2O). m/z (EI)
189 (Mþꢁ43, 9%).
3-Methyl-2-(tert-butyldimethyl-silyloxymethyl)-1-
(penthylsulfonyl)butane 8
To a stirred solution of alcohol 7 (1.58 g, 6.8 mmol) in dry Et2O
(18 mL) and CH3CN (12 mL) were added sequentially Ph3P (2.67 g,
10.2 mmol), imidazole (0.81 g, 12 mmol) and I2 (3.45 g, 13.6 mmol) at
0ꢂC. The resulting mixture was stirred at r.t. for 0.5 h, diluted with
ether (100 mL), and washed successively with aqueous Na2S2O3, brine,
and dried. Evaporation of the solvent in vacuum, the resulting residue
was dissolved in anhydrous DMF (5 mL), anhydrous PhSO2Na (1.4 g,
7 mmol) was added, and the mixture was stirred for 24 h under Ar.
Diluted with ether (100 mL), and washed with water, brine and dried.
Concentrated in vacuum, followed by FCC (PS/EA, 8:1) to give the
benzene sulphone 8 (1.45 g, 60% two steps). vmax (film)/cmꢁ1 1477,
1448, 1425, 1307, 1110, 827, and 755. ꢀH (200 MHz; CDCl3) 0.02 (6H,

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3766
Zhang et al.
s, 2 ꢃ CH3), 0.89 (9H, s, C(CH3)3), 0.81 (6H, d, J 7.3 Hz, CH(CH3)2), 0.89
(9H, s, C(CH3)3), 1.91–1.97 (2H, m, 2 ꢃ CH), 2.94–3.30 (2H, m,
CH2SO2Ph), 3.64 (2H, d, J 4.6 Hz, CH2O), 7.48–7.93 (5H, m, ArH).
m/z (EI) 341 (MþꢁCH3, 6%).
(5E,9E )-2-Ethylenedioxy-6,10,14-trimethyl-13-(tert-
butyldimethyl-silyloxymethyl)pentadeca-5,9-diene 10
To a stirred solution of 8 (0.97 g, 2.7 mmol) in anhyd. THF (6 mL)
was added n-BuLi (1.7 mL, 2.7 mmol, 1.6 M in n-hexane) at ꢁ40ꢂC over
5 min under Ar. After stirring for 30 min at ꢁ40ꢂC, a solution of iodide 9
(1.27 g, 3.5 mmol) in anhyd. THF (7 mL) was added over 5 min the result-
ing mixture was stirred at ꢁ78ꢂC for 30 min, allowed to warm to r.t. over
4 h, and quenched with sat. NH4Cl. The mixture was extracted with Et2O
(3 ꢃ 50 mL); the organic phase was washed with water and brine, and
dried. Evaporation of the solvent in vacuum, followed by FCC (PS/EA,
8:1) to give the coupling adduct, which was then dissolved in absolute
MeOH (15 mL) without purification. To the stirred mixture was added
Na2HPO4 (0.75 g, 5.3 mmol) and Na (Hg) (2.9 g, 7.2 mmol, 6% wt) at
0ꢂC, and the mixture was stirred at r.t. for 6 h, diluted with ether, washed
successively with 5% HCl, sat. NaHCO3, water and brine, and dried.
Concentration in vacuum was followed by FCC (PS/EA, 16:1) to give
10 (0.88 g, 72% two steps) as oil (Found: C, 71.55; H, 11.68. C27H52O3Si
requires C, 71.62; H, 11.58%). vmax (film)/cmꢁ1 1254, 1111, 1065, 836 and
776. ꢀH (400 MHz; CDCl3) 0.02 (6H, s, 2 ꢃ CH3), 0.87 (3H, d, J 6.8 Hz,
CH3), 0.90 (3H, d, J 6.8 Hz, CH3), 0.92 (9H, s, 3 ꢃ CH3), 1.33 (6H, s,
2 ꢃ CH3), 1.59–2.12 (13H, m, 6 ꢃ CH2, CH), 3.55 (2H, d, J 5.6 Hz,
CH2OTBS), 3.92–3.95 (4H, m, OCH2CH2O), 5.10–5.14 (2H, m,
2 ꢃ CH¼). m/z (EI) 395 (Mþ ꢁ57, 12).
(5E,9E )-2-Ethylenedioxy-13-hydroxy-6,10,
14-trimethylpentadeca-5,9-diene 11
To a stirred solution of 10 (0.68 g, 1.5 mmol) in THF (4 mL) was
added dropwise n-Bu4NF (3 mL, 3 mmol, 1 M in THF). The resulting
mixture was stirred at r.t. for 2 h. Diluted with Et2O (50 mL), the
combined organic layer was washed successively with water and brine,
dried. Evaporation of the solvent in vacuum was followed by FCC
(PS/EA, 8:1) to give the desilylated product 11 (0.48 g, 95%) (Found:
C, 74.39; H, 11.40. C21H38O3 requires C, 74.51; H, 11.31%). vmax

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Synthesis of (1)-Isocembrene
3767
2
(film)/cmꢁ1 3386, 1254, 1111, 1065, 836 and 776. ꢀH (400 MHz; CDCl3)
0.86 (3H, d, J 6.8 Hz, CH3), 0.89 (3H, d, J 6.8 Hz, CH3), 1.33 (3H, s,
CH3), 1.58 (3H, s, CH3), 1.61 (3H, s, CH3), 1.65–1.79 (5H, m, 2 ꢃ CH2,
CH), 1.83 (1H, m, CH), 1.98–2.25 (8H, m, 4 ꢃ CH2), 3.58–3.59 (2H, m,
CH2OH), 3.94–3.96 (4H, m, OCH2CH2O), 5.10–5.14 (2H, m, 2 ꢃ CH¼).
m/z (EI) 320 (Mþꢁ18, 9).
(5E,9E )-2-Ethylenedioxy-6,10,14-trimethyl-13-
formylpentadeca-5,9-diene 12
To a stirred mixture of oxalyl chloride (0.5 mL, 5.6 mmol) in dry
CH2Cl2 (20 mL) was added dropwise DMSO (0.8 mL, 11.2 mmol)
under a nitrogen atmosphere at ꢁ78ꢂC. After stirring for a period of
15 min at that temperature, a solution of desilylated alcohol 11 (1.4 g,
4.0 mmol) in CH2Cl2 (4 mL) was added and the reaction mixture
was stirred for 30 min at ꢁ78ꢂC. Et3N (2.5 mL, 17.6 mmol) was added
dropwise and the solution was allowed to warm to room temperature
gradually. The mixture was diluted with Et2O and washed with water and
brine, dried over MgSO4. Evaporation of the solvent in vacuuo was
followed by FCC (PS/EA, 20/1) to give the title compound 12 (1.2 g,
92%) as a colorless oil (Found: C, 74.98; H, 10.71. C21H36O3 requires
C, 74.95; H, 10.78%). vmax (film)/cmꢁ1 3413, 2962, 2379, 1720, 1442, 1260,
and 1061. ꢀH (400 MHz; CDCl3) 0.96 (6H, d, J 7.3 Hz, CH(CH3)2), 1.33
(3H, s, CH3), 1.56–2.25 (17H, m, 6 ꢃ CH2, 2 ꢃ CH, CH3), 3.91–3.94 (4H,
m, OCH2CH2O), 5.10–5.12 (2H, m, 2 ꢃ CH¼), 9.65 (1H, d, J 3.0 Hz,
CHO). m/z (EI) 336 (Mþ, 5).
(1E,6E,10E )-6,10-Dimethyl–3-isopropyl-1-tributylstannyl-14-
oxopentadeca-1,6,10-triene 13
A mixture of 12 (0.15 g, 0.46 mmol) and p-TSOH (3 mg, 16 mmmol) in
acetone (15 mL) was stirred at 40ꢂC for 4 h under Ar. The mixture was
diluted with ether (50 mL), washed with sat. NaHCO3, H2O and brine,
and dried, evaporation of the solvent in vacuum was followed by FCC
(PS/EA, 8:1) to give the deprotected keto aldehyde (0.13 g), which was
used for the following step. Dry, deoxygenated DMF (7 mL) was added
dropwise to well-stirred CrCl2 (0.527 g, Aldrich 95% w/w pure, 4.3 mmol)
in a flask under argon in an ice-bath. After allowing the flask to warm to
room temperature over 15 min, it was surrounded by aluminium foil to
exclude light and a mixture of keto aldehyde (0.13 g, 0.43 mmol) and

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3768
Zhang et al.
Bu3SnCHI2 (478 mg, 0.86 mmol) in dry, deoxygenated DMF (2 mL) was
added dropwise to the reaction mixture. After 2.5 h at 25ꢂC, water
(14 mL) was added and the mixture was extracted with ether (3 ꢃ
10 mL). The combined organic layers were washed with water (10 mL),
brine (10 mL), and dried. And evaporated under reduced pressure.
Purification by FCC (PS/EA, 20:1) gave exclusively E-alkenylatannane
13 (0.18 g, 70% two steps) as colourless oil (Found: C, 66.11; H, 10.51.
C32H60OSn requires C, 66.32; H, 10.44%). vmax (film)/cmꢁ1 2956, 2926,
2871, 1716, 1617, 1596, 1464, 1376, and 997. ꢀH (400 MHz; CDCl3)
0.78–0.91 (21H, m, Sn(CH2CH2CH2CH3)3 and CH(CH3)2), 1.22–1.29
(6H, m, Sn(CH2CH2CH2CH3)3), 1.39–1.66 (7H, m, Sn(CH2CH2CH2
CH3)3 and CH(CH3)2), 1.90–2.45 (13H, m, CH, 6 ꢃ CH2), 2.15 (3H, s,
CH3CO), 5.07–5.10 (2H, m, 2 ꢃ CH¼), 5.65 (1H, dd, J 18.9 and 8.7 Hz,
CH¼CHSn), 5.75 (1H, d, J 18.9 Hz, ¼CHSn).
(5E,9E,14E )-6,10-Dimethyl-13-isopropyl-2-
((trifluoromethyl)sulfonyl)oxy)-15-tributyl-stannylpentadeca-
1,5,9,14-tetraene 14
In a flame-dried 10-mL round-bottom flask fitted with an argon inlet
on a rubber septum was placed a solution of Keto 13 (46 mg, 0.084 mmol)
and N-phenyltrifluonimide (54 mg, 0.15 mmol) in tetrahydrofuran (4 mL),
The mixture was cooled to ꢁ78ꢂC. To this solution was added sodium
bis(trimethylsilyl)amide (90 mL, 0.09 mmol, 1.0 M in THF) by syringe.
The resulting solution was stirred at ꢁ78ꢂC for a period of 20 min.
Into the solution was introduced phosphate buffer (pH 7.0, 5%, 5 mL)
to quench the reaction. The cold mixture was poured into hexane
(200 mL) in a separation funnel and washed with saturated sodium chlo-
ride solution (2 ꢃ 10 mL), the organic layer drived over magnesium sulfate
and concentrated under reduced pressure. The excess of N-phenyltrifluo-
methanesulfonimide was separated by crystallization in hexane at ꢁ20ꢂC.
The residue was purified by flash chromatography (PS/EA, 16:1);
the product 14 was obtained as pale yellow oil (50 mg, 84%), which
contained <6% of thermodynamic enolate (Found: C, 55.35; H, 8.14.
C33H59F3O3SSn requires C, 55.70; H, 8.36%). vmax (film)/cmꢁ1 2957,
2927, 1601, 1472, 1072, and 1016. ꢀH (400 MHz; CDCl3) 0.78–0.91
(21H, m, Sn(CH2CH2CH2CH3)3 and CH(CH3)2), 1.22–1.29 (6H, m,
Sn(CH2CH2CH2CH3)3), 1.39–1.66 (7H, m, Sn(CH2CH2CH2CH3)3 and
CH(CH3)2), 1.90–2.00 (8H, m, 4 ꢃ CH2), 2.20–2.28 (2H, m,
CH2C(OTf )¼C), 4.85 (1H, d, J 3.4 Hz, cis-TfOC¼CHH), 5.02 (1H, d,
J 3.4 Hz, trans-TfOC¼CHH), 5.11 (2H, m, 2 ꢃ CH¼), 5.65 (1H, dd,

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Synthesis of (1)-Isocembrene
3769
2
J 18.9 and 8.7 Hz, CH¼CHSn), 5.75 (1H, d, J 18.9 Hz, ¼CHSn). m/z (EI)
655 (MþꢁBu, 5), 547 (12), 505 (42).
(1E,5E,10E )-9-Isopropyl-2,6-dimethyl-12-methylene-1,5,10-
cyclotetradecatriene 1
In a flame-dried 50-mL round-bottom flask fitted with a reflux
condenser was placed the precusor 14 (70 mg, 0.1 mmol) in the presence
of tetrakis(triphenylphosphine) palladium (2.3 mg, 2 mol %), lithium
chloride (13 mg, 0.3 mmol) under high dilution (10ꢁ3 M) in THF, the
resulting solution was stirred to accomplish the coupling under refluxing
conditions. Diluted with ether (50 mL), the combined organic layer
was washed with water and brine. Dried and concentrated in vacuum
followed by FCC (pure PE) to give the target product 1 (21 mg, 76%) as
colorless oil. vmax (film)/cmꢁ1 2930, 2855, 1470, and 978; ꢀH (400 MHz;
CDCl3) 0.84 (3H, d, J 7.0 Hz, Me), 0.89 (3H, d, J 7.0 Hz, Me), 1.25–1.40
(2H, m, CH(Me)2 and CHCHMe)2), 1.68 (3H, s, CH¼CMe), 1.70 (3H, s,
CH¼CMe), 1.90–2.00 (8H, m, 4 ꢃ CH2), 2.45 (1H, m, CHHC¼CHH),
4.85 (1H, br s, C¼CHH), 4.90 (1H, br s, C¼CHH), 5.09 (1H, t, J 7.0 Hz,
CH¼CMe), 5.19 (1H, t, J 7.0 Hz, CH¼CMe), 5.50 (1H, dd, J 15.6 and
9.6 Hz, CH¼CHCH), 5.94 (1H, d, J 15.6 Hz, CH2¼CCH¼CH). ꢀC
(100 MHz, CDCl3) 146.0, 137.8, 135.8, 134.0, 132.3, 124.9, 123.8, 113.6,
50.0, 34.2, 33.0, 32.6, 32.2, 29.6, 28.4, 28.0, 24.0, 23.5, 20.7, and 19.8. m/z
(EI) 272 (Mþ, 5), 257 (MþꢁMe, 12) [Found (HRMS) (ESI): Mþ þ H,
273.2571. Calc. for C20H32 þ H: Mþ þ H, 273.2577].
ACKNOWLEDGMENT
This work was financially supported by the National Natural
Science Foundation of China (Grant No. 20072012) and the Special
Research Grant for Doctoral Sites in Chinese Universities (Grant No.
20010730001).
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©2003 Marcel Dekker, Inc. All rights reserved. This material may not be used or reproduced in any form without the express written permission of Marcel Dekker, Inc.
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Received in Japan April 9, 2003