A facile preparation of geometrically pure alkenyl, alkynyl, and aryl conjugated Z-alkenes: Stereospecific synthesis of bombykol

Article abstract of DOI:10.1016/S0040-4020(00)00271-4

Ni- and Pd-catalyzed cross coupling reactions of 2-alkenyl, 2-alkynyl, and 2-aryl substituted (1Z)-1-bromoalkene with alkyl Grignard reagents gave 1-alkyl substituted (1Z,3E)-diene, (1Z)-en-3-yne, and (1Z)-2-arylethene, each in good yield. When (trimethylsilyl)-methylmagnesium chloride was used as the Grignard reagent, conjugated Z-allylsilane was produced. Bombykol, (10E, 12Z)-10,12-hexadecadien-1-ol, a sex pheromone of female moss, Bombyx mori, was synthesized stereospecifically. 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4020(00)00271-4

TETRAHEDRON
Pergamon
Tetrahedron 56 (2000) 3493±3500
A Facile Preparation of Geometrically Pure Alkenyl, Alkynyl, and
Aryl Conjugated Z-Alkenes: Stereospeci®c Synthesis of Bombykol
b
b
b
Jun'ichi Uenishi,a, Reiko Kawahama, Yoshiyuki Izaki and Osamu Yonemitsu
*
aFaculty of Pharmaceutical Science, Kyoto Pharmaceutical University, Misasagi, Yamashina, Kyoto 607-8412, Japan
bDepartment of Chemistry, Faculty of Science, Okayama University of Science, Ridaicho, Okayama 700-0005, Japan
Received 21 February 2000; accepted 27 March 2000
AbstractÐNi- and Pd-catalyzed cross coupling reactions of 2-alkenyl, 2-alkynyl, and 2-aryl substituted (1Z)-1-bromoalkene with alkyl
Grignard reagents gave 1-alkyl substituted (1Z,3E)-diene, (1Z)-en-3-yne, and (1Z)-2-arylethene, each in good yield. When (trimethylsilyl)-
methylmagnesium chloride was used as the Grignard reagent, conjugated Z-allylsilane was produced. Bombykol, (10E,12Z)-10,12-hexa-
decadien-1-ol, a sex pheromone of female moss, Bombyx mori, was synthesized stereospeci®cally. q 2000 Elsevier Science Ltd. All rights
reserved.
Stereo- and regio-de®ned structures of conjugated E,Z-diene
and E-enyne have often been observed in a wide variety of
natural products.1 Stereocontrolled preparation of such
conjugated E,Z-diene and E-enyne is very important for
modern organic synthesis. A number of methodologies for
the synthesis of Z-alkenyl bonds have been developed;
for example, Wittig ole®nation reaction under kinetic con-
ditions,2 and cis semi-hydrogenation of alkyne.3 However,
for the synthesis of conjugated E,Z-diene, the major
problem for the Wittig-type reaction is how to control selec-
tive formation of the desired E,Z-diene prior to formation of
thermodynamically stable E,E-diene. In fact, preparation of
conjugated Z-alkene by the Wittig reaction gave a mixture
of E,Z- and E,E-dienes.4 cis Semi-hydrogenation of Z-enyne
gave E,Z-diene stereoselectively but sometimes in low yield
due to poor reactivity and chemo-selectivity.5 A metal-
catalyzed cross coupling reaction is the most reliable for
preparation of such conjugated alkenes with retention of
the con®guration6 (Scheme 1).
We have reported the stereospeci®c synthesis of E,Z-diene
and Z-enyne by the Pd-catalyzed coupling reaction of (1Z)-
1-bromoalkene with alkenylboronic acid and 1-alkyne, in
which the reaction occurred on an sp2 carbon of Z-alkenyl
bromide with an sp2 and an sp carbon center of alkenyl
metal or alkyne.7 A coupling reaction of (1Z)-1-bromo-
1,3-diene with an sp3 carbon center could serve as an
alternative stereospeci®c synthesis of such dienes or
enynes.8 In this paper, we report coupling reactions of
conjugated 2-alkenyl, 2-alkynyl, and 2-aryl substituted
(1Z)-1-bromoalkene with alkyl Grignard reagent promoted
by a Ni or Pd catalyst, which afforded E,Z-diene or Z-enyne
Scheme 1.
Keywords: cross-coupling; stereospeci®c reaction; Z-alkene; Z-allylsilane; bombykol.
* Corresponding author. Fax: 181-075-595-4763; e-mail: juenishi@mb.kyoto-phu.ac.jp
0040±4020/00/$ - see front matter q 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(00)00271-4

3494
J. Uenishi et al. / Tetrahedron 56 (2000) 3493±3500
Scheme 2.
and Z-b-bromostyrene derivatives stereospeci®cally
(Scheme 2).
chloride was used as the Grignard reagent for the coupling
of 1a, conjugated allyltrimethylsilane (7) was obtained in
79% yield. Other results for 1b±1e are shown in Table 1.
Yields were generally good (entries 9±13), and the stereo-
chemistries have been completely retained. Allyltrimethyl-
silane is one of the most useful functional groups in organic
synthesis.9 Substituted allylsilanes, (E)- and (Z)-(alkenyl-
methyl)trimethylsilanes, have been used as an important
building block for stereoselective synthesis.10 Therefore,
the synthesis of geometrically pure (E)- or (Z)-allylsilanes
is of value for stereoselective C±C bond formations.
The requisite Z-bromoalkenes were prepared from the
corresponding aldehyde by dibromomethylenation and
successive Pd-catalyzed hydrogenolysis with Bu3SnH by
the method reported previously.7 Bromodiene (1a) (Rˆ4-
phenylbutenyl) was treated with methylmagnesium bromide
in the presence of 4 mol% NiCl2(dppp) at room temperature.
The reaction was completed in 1 h to give 2a (Rˆ4-phenyl-
butenyl, R0ˆH) in 78% yield, as shown in Scheme 3. The
results, including those of other substrates and reagents, are
listed in Table 1. Geometric purity of 1a was con®rmed by
its proton NMR spectrum. The coupling constants were
identical with 10.8 Hz for Z-ole®nic and 15.2 Hz for E-ole-
®nic bonds, which clearly indicated the structure of E,Z-
diene. The reaction with ethyl, and allylmagnesium bromide
with 1a gave the corresponding alkylated 1,3-dienes, 2b and
2c, in 74 and 58% yields, respectively (entries 2 and 3). The
reaction of (1Z,3E)-1-bromo-4-cyclohexyl-1,3-butadiene
(1b) also gave diene (3) in 82% yield (entry 4). (1Z)-
Bromoalkene conjugated with alkyne 1c can be alkylated
with ethyl and allyl Grignard reagents to give 4a and 4b
with retention of the con®guration in good yields (entries 5
and 6). 2-Alkyl substituted Z-styrenes were obtained by the
coupling of Z-b-bromostyrene with alkyl Grignard reagents.
The reactions of (Z)-b-bromo-2-methyl and 4-methyl-
styrenes, 1d and 1e, gave ethyl substituted compounds 5
and 6 in each 74% yield, respectively (entries 7 and 8). In
all cases, the reactions took place stereospeci®cally. On
the other hand, when (trimethylsilyl)methylmagnesium
Since the preparation of 1Z-1-bromoalkene from 1,1-dibro-
moalkene was performed by a Pd catalyst in the presence of
Bu3SnH, and the above coupling reaction also occurred with
the same catalyst, these two step reactions could be
performed successively in one-pot. Hydrogenolysis of
1,1-dibromo-6-phenyl-1,3-hexadiene with Bu3SnH in the
presence of Pd(PPh3)4 (4 mol%) afforded (1Z,3E)-1-
bromo-1,3-butadiene (1a), to which an excess of
Me3SiCH2MgCl was added. The reaction proceeded
smoothly and gave (Z)-allylsilane (7) in 73% yield. This
process also worked well in the case of alkynyl- and aryl-
conjugated 1,1-dibromoalkenes. These results are shown in
Table 2. Since the hydrogenolysis of 1 occurred stereo-
selectively and the cross coupling proceeded with retention
of con®guration, resulting (Z)-allysilanes were obtained in
geometrically pure form. Bu3SnCH2SiMe3 was a major
by-product due to the reaction of Bu3SnBr and
Me3SiCH2MgCl, but it was easily separated by silica gel
column chromatography. The reaction is operationally
Scheme 3.

J. Uenishi et al. / Tetrahedron 56 (2000) 3493±3500
3495
Table 1. Ni-catalyzed coupling reaction of conjugated (Z)-1-bromoalkenes (1a±e) with Grignard reagents (R0CH2MgBr)
Entry
1
(Z)-Bromoalkene
R0
(Z)-Alkene
Yield (%)
78
1a
H
2a
2
3
1a
1a
Me
2b
2c
74
58
vinyl
4
5
1b
1c
Me
Me
3
82
85
4a
6
7
8
1c
1d
1e
vinyl
Me
4b
83
74
74
5
Me
6
9
1a
1b
SiMe3
SiMe3
7
8
79
74
10
11
1c
SiMe3
9
73
12
13
1d
1e
SiMe3
SiMe3
10
11
67
73

3496
J. Uenishi et al. / Tetrahedron 56 (2000) 3493±3500
Table 2. Pd catalyzed one-pot synthesis of (Z)-allylsilanes from 1,1-dibromoalkenes
Entry
1
Dibromoalkene
ClMgCH2SiMe3 (eq)
4
(Z)-Allylsilanea
Yield (%)b
73
7
2
3
5
5
8
9
77
73
4
5
6
6
10
11
77
73
1
a Geometric purities were determined to be greater than 98% by H NMR.
b Isolated yield.
simple, and the yield is generally better than that obtained
by the stepwise reaction process.
of E-enynes,12 Wittig reaction of enal and ylide or aldehyde
and unsaturated ylide,13 cross coupling reaction of alkenyl
metal and haloalkene,14 isomerization of allene,15 and
others16 have been reported. Since a lack of facile methods
to prepare 1Z,3E-1-halodiene, construction of Z,E-diene
from 1Z,3E-1-halodiene by Kumada±Tamao±Corriu
coupling has not been attempted. We have succeeded in
the synthesis of geometrically pure bombykol by this
strategy. The synthesis is described in Scheme 4. For the
introduction of a propyl group, 1Z,3E-1-bromodiene (17) is
required. This can be derived from dibromodiene (16) by the
stereoselective hydrogenolysis. Compound 16 will be easily
led from a,b-unsaturatedaldehyde (15). This aldehyde can
be prepared from aldehyde (12) by the standard method.
Therefore, the known aldehyde (12)17 is the starting material
Synthesis of Bombykol
Bombykol is a component of the female sex pheromone of
Bombix mori,and it was identi®ed and synthesized by Bute-
nant et al. in 1959.11 It is famous as the ®rst isolated insect
sex pheromone. The speci®c structure, which possesses a
consecutive E,Z-diene unit on C-16 carbon chain alcohol,
has attracted the interest of many synthetic chemists. In fact,
a number of the syntheses have been reported so far.11±16
The most important part of this synthesis is the stereoselec-
tive preparation of the E,Z-diene moiety. Partial reduction
Scheme 4. Reagents and conditions; a, (EtO)2POCH2COOEt, NaH, THF; b, DIBAL, CH2Cl2; c, Swern oxi.; d, CBr4, Ph3P, Benzene, e, Bu3SnH, cat.
Pd(PPh3)4; f, PrMgCl, cat. Ni(dppp), Et2O; g, Bu4NF, THF.

J. Uenishi et al. / Tetrahedron 56 (2000) 3493±3500
3497
of this synthesis. Wittig±Horner±Emmons reaction of 12
with triethyl phosphonoacetate gave a,b-unsaturated ester
(13) in 83% yield. Reduction of the ester with DIBAL-H to
alcohol followed by oxidation under Swern conditions gave
a,b-unsaturated aldehyde (15) in 67% yield in two steps.
Dibromomethylenation with carbon tetrabromide and
triphenylphosphine in dichloromethane gave dibromodiene
(16) in 88% yield. Stereoselective hydrogenolysis with
Bu3SnH in the presence of a Pd catalyst afforded the desired
Z,E-bromodiene (17) exclusively in 85% yield. Cross
coupling reaction of 17 was performed in the presence of
NiCl2(dppp) with propylmagnesium chloride in THF for
22 h at room temperature to give 18 in 84% yield.18 The
geometrical purity of 18 was con®rmed to be greater than
was removed and the residual oil was puri®ed by column
chromatography on silica gel.
(2Z,4E)-7-Phenyl-2,4-heptadiene (2a). Oil, Rfˆ0.50 (hex-
1
ane). H NMR (500 MHz, CDCl3) d 1.73 (3H, dd, Jˆ7.1
and 1.7 Hz), 2.43 (2H, dt, Jˆ7.2 and 7.3 Hz), 2.72 (2H, t,
Jˆ7.3 Hz), 5.40 (1H, dq, Jˆ10.8 and 7.1 Hz), 5.70 (1H, dt,
Jˆ15.2 and 7.1 Hz), 5.97 (1H, ddd, Jˆ11.0, 10.8 and
1.7 Hz), 6.37 (1H, ddd, Jˆ15.2, 11.0 and 1.0 Hz), 7.16±
7.32 (5H, m), 13C NMR (75 MHz, CDCl3) d 13.3, 34.7,
35.9, 124.5, 125.8 (2C), 125.9, 128.3, 128.4 (2C), 129.3,
133.2, 141.9: MS (EI) m/z (relative intensity) 172 (M1,
base), 156 (16), 143 (32), 141 (30), 115 (55), 99 (23), 98
(21), 97 (21). HRMS (EI) Calcd for C13H16: M1, 172.1252.
Found: m/z 172.1246.
1
98% by H NMR spectrum. Finally, deprotection of the
TBDMS with Bu4NF in THF gave bombykol in 93%
yield. All of the spectroscopic data of our synthetic sample
reported in the literature.
(3E,5Z)-1-Phenyl-3,5-octadiene (2b). 1H NMR (500 MHz,
CDCl3) d 0.99 (3H, t, Jˆ7.5 Hz), 2.17 (2H, double quintet,
Jˆ1.5 and 7.5 Hz), 2.42 (2H, dt, Jˆ7.3 and 7.4 Hz), 2.71
(2H, t, Jˆ7.4 Hz), 5.32 (1H, dt, Jˆ10.7 and 7.5 Hz), 5.70
(1H, dt, Jˆ15.0 and 7.3 Hz), 5.91 (1H, dd, Jˆ10.9 and
10.7 Hz), 6.34 (1H, ddd, Jˆ15.0, 10.9 and 1.5 Hz), 7.19±
7.30 (5H, m), 13C NMR (75 MHz, CDCl3) d 14.3, 21.0,
34.7, 35.8, 125.8, 126.1 (2C), 127.8, 128.3, 128.4 (2C),
132.2, 133.3, 141.8: MS (EI) m/z (relative intensity) 186
(M1, base), 143 (9), 130 (17), 115 (14), 95 (83), 91 (36),
67 (14). HRMS (EI) Calcd for C14H18: M1, 186.1409.
Found: m/z 186.1417.
In summary, we have described the synthetic utility of the
Ni- and Pd-catalyzed coupling of 1Z,3E-1-bromo-1,3-
dienes with Grignard reagents. The results will be useful
not only for the preparation of stereo-de®ned conjugated
Z-alkenes but also for the synthesis of polyene natural
products bearing
pheromones.
a
Z-alkenyl unit, including insect
Experimental
(4Z,6E)-9-Phenyl-1,4,6-nonatriene (2c). 1H NMR (300
MHz, CDCl3) d 2.43 (2H, dt, Jˆ7.3 and 7.2 Hz), 2.72
(2H, t, Jˆ7.2 Hz), 2.91 (2H, ddd, Jˆ7.2, 6.9 and 1.5 Hz),
4.99 (1H, ddt, Jˆ10.2, 1.7 and 1.5 Hz), 5.05 (1H, ddt,
Jˆ17.1, 1.7 and 1.5 Hz), 5.34 (1H, dt, Jˆ10.8 and
7.2 Hz), 5.74 (1H, dt, Jˆ15.0 and 7.3 Hz), 5.82 (1H, ddt,
Jˆ17.1, 10.2 and 6.9 Hz), 6.02 (1H, dd, Jˆ10.9 and
10.8 Hz), 6.33 (1H, ddd, Jˆ15.0, 10.9 and 1.1 Hz), 7.18±
7.31 (5H, m), 13C NMR (75 MHz, CDCl3) d 31.9, 34.7,
35.8, 114.9, 125.8, 125.9 (2C), 126.9, 128.3, 128.4 (2C),
129.5, 134.2, 136.6, 141.8: MS (EI) m/z (relative intensity)
198 (M1, 4), 167 (7), 131 (11), 115 (8), 107 (14), 91 (base),
79 (65), 77 (24), 65 (22). HRMS (EI) Calcd for C15H18: M1,
198.1409. Found: m/z 198.1434.
General
1H and 13C NMR spectra were recorded on JEOL LA500
and Varian Gemini 300 for 1H (500 or 300 MHz) and for 13
C
(125 or 75 MHz). The chemical shifts were shown as
d-values using tetramethylsilane (0 ppm) for proton spectra
and CHCl3 (77.0 ppm) for carbon spectra as an internal
standard. Infrared spectra (IR) were recorded by the use of
a JASCO FT/IR 230 spectrometer and were taken as liquid
®lms on NaCl plates or as tablets. Low and high resolution
mass spectra (LRMS and HRMS) were obtained on a JMS
MS700 spectrometer at the Analytical Center of Okayama
University of Science by the electron impact (EI) method at
70 eV unless otherwise stated. Only signi®cant peaks are
described here for IR and MS spectra. Silica gel (Merck
7734, 70±300 mesh) was used for gravity column chroma-
tography and silica gel (Merck 9385, 230±400 mesh) for
¯ash column chromatography. Precoated silica gel plates
(Merck 5715, 60F254) were used for thin layer chroma-
tography. All air sensitive reactions were conducted in
¯ame-dried glass ware under an Ar atmosphere. THF and
ether were dried over sodium benzophenone ketyl, and
methylene chloride was dried over phosphorus pentoxide.
These solvents were freshly distilled before use.
1
(1E,3Z)-1-Cyclohexyl-1,3-hexadiene (3). H NMR (300
MHz, CDCl3) d 1.00 (3H, t, Jˆ7.6 Hz),1.08±1.30 (6H,
m), 1.62±1.75 (4H, m), 1.96±2.12 (1H, m), 2.18 (2H, qdd,
Jˆ7.6, 7.6 and 1.5 Hz), 5.30 (1H, dt, Jˆ11.0 and 7.6 Hz),
5.61 (1H, dd, Jˆ15.2 and 7.1 Hz),5.91 (1H, dd, Jˆ11.1 and
11.0 Hz), 6.27 (1H, ddd, Jˆ15.2, 11.1 and 1.5 Hz), 13C
NMR (75 MHz, CDCl3) d 14.3, 21.0, 26.0 (2C), 26.2
(2C), 32.9, 41.0, 122.9, 128.3, 131.8, 140.5: MS (EI) m/z
(relative intensity) 164 (M1, base), 135 (79), 121 (34).
HRMS (EI) Calcd for C12H20: M1, 164.1565. Found: m/z
164.1575.
General coupling conditions
(Z)-1-Phenyl-3-hexen-1-yne (4a). 1H NMR (300 MHz,
CDCl3) d 0.99 (3H, t, Jˆ7.5 Hz), 2.34 (2H, dq, Jˆ7.3 and
7.5 Hz), 5.57 (1H, d, Jˆ10.6 Hz), 5.90 (1H, dt, Jˆ10.6 and
7.3 Hz), 7.22±7.38 (5H, m), 13C NMR (75 MHz, CDCl3)
d 13.4, 23.8, 86.3, 93.4, 108.3, 123.6, 128.0, 128.3, 131.4,
145.8: MS (EI) m/z (relative intensity) 156 (M1, base),
155 (53), 141 (97), 128 (29), 115 (78), 91 (24). HRMS
To a mixture of bromoalkene (1 mmol) and NiCl2(dppp)
(4 mol%) in ether (5 mL) was added Grignard reagent (ca
2 mmol) in THF or ether at 08C. If it needed, the reaction
allow to warm up to room temperature. After the reaction
completed, the mixture was diluted with hexane, washed
with water and brine, and dried over MgSO4. The solvent

3498
J. Uenishi et al. / Tetrahedron 56 (2000) 3493±3500
(EI) Calcd for C12H12: M1, 156.0939. Found: m/z
156.0962.
(Z)-1-Phenyl-5-trimethylsilyl-3-penten-1-yne (9). 1H NMR
(300 MHz, CDCl3) d 0.09 (9H, s), 1.94 (2H, d, Jˆ8.8 Hz),
5.57 (1H, d, Jˆ10.2 Hz), 6.06 (1H, dt, Jˆ10.2 and 8.8 Hz),
7.28±7.44 (5H, m), 13C NMR (75 MHz, CDCl3) d 21.5,
23.1, 87.3, 93.3, 106.1, 124.1, 127.7, 128.3 (3C), 131.3
(3C), 141.5: MS (EI) m/z (relative intensity) 214 (M1,
21), 199 (21), 73 (base). HRMS (EI) Calcd for C14H18Si:
M1, 214.1178. Found: m/z 214.1184.
(Z)-7-Phenyl-1,4-heptadien-6-yne (4b). 1H NMR (300
MHz, CDCl3) d 3.16 (2H, ddm, Jˆ7.3 and 6.9 Hz), 5.06
(1H, dm, Jˆ10.1 Hz), 5.13 (1H, dm, Jˆ17.1 Hz), 5.74 (1H,
dm, Jˆ10.7 Hz), 5.88 (1H, ddt, Jˆ17.1, 10.1 and 6.9 Hz),
5.99 (1H, dt, Jˆ10.7 and 7.3 Hz), 7.30±7.74 (5H, m), 13C
NMR (75 MHz, CDCl3) d 34.6, 86.0, 94.0, 110.0, 115.7,
123.5, 128.1, 128.3, 131.4, 135.5, 140.8: MS (EI) m/z
(relative intensity) 168 (M1, 41), 167 (base), 165 (46),
153 (35), 152 (57). HRMS (EI) Calcd for C13H12: M1,
168.0939. Found: m/z 168.0977.
(Z)-2-[3-(Trimethylsilyl)propenyl]toluene (10). Oil, Rfˆ
1
0.71 (hexane). H NMR (300 MHz, CDCl3) d 20.02 (9H,
s), 1.64 (2H, d, Jˆ8.7 Hz), 2.25 (3H, s), 5.76 (1H, dt,
Jˆ11.4 and 8.7 Hz), 6.32 (1H, d, Jˆ11.4 Hz), 7.12±7.23
(4H, m), 13C NMR (75 MHz, CDCl3) d 21.7 (3C), 19.1,
19.9, 125.2, 126.1, 126.4, 128.6, 129.0, 129.8, 136.2, 137.1:
MS (EI) m/z (relative intensity) 204 (M1, base), 189 (21),
115 (13), 74 (15), 73 (100). HRMS (EI) Calcd for C13H20Si:
M1, 204.1334. Found: m/z 204.1340.
(Z)-2-(1-Butenyl)toluene (5). 1H NMR (300 MHz, CDCl3)
d 1.00 (3H, t, Jˆ7.4 Hz), 2.16 (2H, dq, Jˆ7.4 and 7.3 Hz),
2.27 (3H, s), 5.07 (1H, dt, Jˆ11.4 and 7.3 Hz), 6.39 (1H, d,
Jˆ11.4 Hz), 7.12±7.19 (4H, m), 13C NMR (75 MHz,
CDCl3) d 14.4, 19.9, 21.7, 125.2, 126.7, 127.2, 129.0,
129.7, 134.4, 136.2, 136.8: MS (EI) m/z (relative intensity)
146 (M1, 53), 131 (base). HRMS (EI) Calcd for C11H14:
M1, 146.1096. Found: m/z 146.1081.
(Z)-4-[3-(Trimethylsilyl)propenyl]toluene (11). Oil, Rfˆ
1
0.68 (hexane). H NMR (300 MHz, CDCl3) d 0.03 (9H,
s), 1.82 (2H, dd, Jˆ9.1 and 1.5 Hz), 2.34 (3H, s), 5.66
(1H, dt, Jˆ11.6 and 9.1 Hz), 6.29 (1H, d, Jˆ11.6 Hz),
7.15 (2H, d, Jˆ8.1 Hz), 7.23 (2H, d, Jˆ8.1 Hz), 13C NMR
(75 MHz, CDCl3) d 21.6 (3C), 19.6, 21.1, 126.7, 128.2,
128.5 (2C), 128.8 (2C), 135.3, 135.6: MS (EI) m/z (relative
intensity) 204 (M1, 89), 189 (19), 74(24), 73 (base). HRMS
(EI) Calcd for C13H20Si: M1, 204.1334. Found: m/z
204.1353.
(Z)-4-(1-Butenyl)toluene (6). 1H NMR (300 MHz, CDCl3)
d 0.90 (3H, t, Jˆ7.4 Hz), 2.18 (3H, s), 2.19 (2H, qd, Jˆ7.4
and 1.8 Hz), 5.45 (1H, dt, Jˆ11.6 and 7.4 Hz), 6.20 (1H, d,
Jˆ11.6 Hz), 6.97 (2H, d, Jˆ8.2 Hz), 7.02 (2H, d,
Jˆ8.2 Hz), 13C NMR (75 MHz, CDCl3) d 14.5, 21.1,
22.0, 128.1, 128.6 (2C), 128.8 (2C), 134.0, 134.9, 136.0:
MS (EI) m/z (relative intensity) 146 (M1, base), 131
(100). HRMS (EI) Calcd for C11H14: M1, 146.1096.
Found: m/z 146.1073.
One pot synthesis of allylsilanes, 7±11 from dibromo-
diene
To a THF solution of Pd catalyst, prepared from Pd(OAc)2
(4 mol%) and Ph3P (16 mol%) in THF (5 mL) with stirring
for 15 min at room temperature, were added 1,1-dibromo-
1,3-diene (1 mmol) in THF (5 mL) and Bu3SnH (1.1±
1.2 mmol). After the hydrogenolysis was completed, an
excess of Me3SiCH2MgCl (4±6 mmol, 1M in Et2O) was
added and the mixture was stirred for 1±6 h. The standard
work up and puri®cation by silica gel chromatography gave
7±11.
Synthesis of allylsilane
(Trimethylsilyl)methylmagnesium chloride (1 M solution in
ether) was used as the Grignard reagent under the above
conditions.
1
(2Z,4E)-7-Phenyl-1-trimethylsilyl-3,5-heptadiene (7). H
NMR (300 MHz, CDCl3) d 0.00 (9H, s), 1.61 (2H, d,
Jˆ9.2 Hz), 2.41 (2H, dt, Jˆ7.5 and 7.3 Hz), 2.70 (2H, t,
Jˆ7.5 Hz), 5.36 (1H, dt, Jˆ10.1 and 9.2 Hz), 5.64 (1H,
dt, Jˆ14.7 and 7.3 Hz), 5.88 (1H, dd, Jˆ10.8 and
10.1 Hz), 6.27 (1H, ddt, Jˆ14.7, 10.8 and 1.2 Hz), 7.14±
7.29 (5H, m), 13C NMR (75 MHz, CDCl3) d 21.8 (3C),
19.4, 34.7, 36.0, 125.8, 126.3, 126.4 (2C), 126.7, 128.3,
128.4 (2C), 131.9, 141.9: MS (EI) m/z (relative intensity)
244 (M1, 5), 153 (15), 91 (7), 72 (base). HRMS (EI) Calcd
for C16H24Si: M1, 224.1647. Found: m/z 224.1664.
Synthesis of bombykol
Ethyl (E)-12-(tert-butyldimethylsilyl)oxy-2-dodecenoate
(13). To a suspension of NaH (1.54 mmol, 62 mg, 60% in
mineral oil) in THF (1.5 mL) was added triethyl phospho-
noacetate (0.31 mL, 1.54 mmol) slowly on an ice bath. After
the mixture became clear, 10-(tert-butyldimethylsilyl)oxy-
decanal (12) (400 mg, 1.4 mmol) in THF (1 mL) was
dropped at room temperature. After the reaction mixture
was stirred for 1 h, ice water (10 mL) was added and the
mixture was extracted with 20% EtOAc in hexane (60 mL).
The extract was washed with water and brine, and dried over
MgSO4. The solvent was removed and the residual oil was
puri®ed by column chromatography on silica gel eluted with
5% EtOAc in hexane to give 13 (417 mg) in 83% yield. Oil,
Rfˆ0.39 (5% EtOAc in hexane). 1H NMR (300 MHz,
CDCl3) d 0.05 (6H, s), 0.89 (9H, s), 1.28 (3H, t,
Jˆ7.1 Hz), 1.28 (10H,m), 1.39±1.52 (4H, m), 2.19 (2H,
tdd, Jˆ6.0, 6.0, and 1.6 Hz), 3.59 (2H, t, Jˆ6.6 Hz), 4.19
(2H, q, Jˆ7.1 Hz), 5.81 (1H, dt, Jˆ15.6 and 1.6 Hz), 6.95
(1E,3Z)-1-Cyclohexyl-5-trimethylsilyl-1,3-hexadiene (8).
1H NMR (300 MHz, CDCl3) d 0.01 (9H, s), 1.00±1.38 (6H,
m),1.62 (2H, dd, Jˆ8.9 and 1.3 Hz), 1.67±1.99 (4H, m),
1.94±2.08 (1H, m), 5.36 (1H, dt, Jˆ10.4 and 8.9 Hz),
5.57 (1H, dd, Jˆ15.2 and 6.8 Hz), 5.88 (1H, dd, Jˆ10.8
and 10.4 Hz), 6.21 (1H, ddt, Jˆ15.2, 10.8 and 1.3 Hz),
13C NMR (75 MHz, CDCl3) d 21.7 (3C), 19.3, 26.1 (2C),
28.2 (2C), 33.1, 40.9, 123.2, 126.3, 126.7, 139.0: MS (EI)
m/z (relative intensity) 222 (M1, 16), 148 (22), 73 (base).
HRMS (EI) Calcd for C14H26Si: M1, 222.1804. Found:
m/z 222.1770.

J. Uenishi et al. / Tetrahedron 56 (2000) 3493±3500
3499
(1H, td, Jˆ15.6 and 6.8 Hz); 13C NMR (100 MHz, CDCl3) d
25.4, 14.2, 18.3, 25.7, 25.9, 27.9, 29.0, 29.2, 29.3, 29.4,
32.1, 32.8, 60.0, 63.2, 121.1, 149.3, 166.6; IR (neat) 1720,
1650 cm21; MS (FAB) m/z 357 (MH1, base). HRMS Calcd
for C20H41O3Si: MH1, 357.2825. Found: m/z 357.2829.
0.05 (6H, s), 0.89 (9H, s), 1.24±1.53 (14H, m), 2.09 (2H,
tdd, Jˆ6.8, 6.8 and 1.3 Hz), 3.60 (2H, t, Jˆ6.6 Hz), 5.90
(1H, dt, Jˆ15.3 and 6.8 Hz), 6.08 (1H, ddt, Jˆ15.3, 10.0
and 1.3 Hz), 6.89 (1H, d, Jˆ10.0 Hz); 13C NMR (75 MHz,
CDCl3) d 25.2 (2C), 18.4, 25.8, 26.0 (3C), 28.8, 29.1, 29.4
(2C), 29.5, 32.9, 33.0, 63.3, 88.3, 127.1, 137.12, 139.6; MS
(FAB) m/z 467, 469, 471 (MH1). HRMS Calcd for
C19H37O2SiBr2: MH1, 467.0980, 469.0960, 471.0940.
Found: m/z467.0988, 469.0970, 471.0951.
(E)-12-(tert-Butyldimethylsilyl)oxy-2-dodecen-1-ol (14).
To a stirred solution of 13 (772 mg, 2.16 mmol) in anhy-
drous CH2Cl2 (10 mL) was dropped DIBAL-H (4.28 mmol,
4.5 mL in 0.95 M hexane solution) at 2788C. After the
mixture was stirred for 30 min at the same temperature,
sat. NH4Cl (30 mL) was added and stirred for 15 min. The
formed precipitate was ®ltered through a Celite pad under
vacuum. The ®ltrate was extracted with EtOAc (130 mL)
and washed with water and brine. After drying over MgSO4,
the solvent was removed. The residue was chromatographed
on silica gel eluted with 20% EtOAc in hexane to give 14
(679 mg) quantitatively. Oil; Rfˆ0.42 (20% EtOAc in hex-
ane); 1H NMR (300 MHz, CDCl3) d 0.04 (6H, s), 0.89 (9H,
s), 1.23±1.56 (15H,m), 2.00±2.07 (2H, dt, Jˆ7.1, 6.0 Hz),
3.59 (2H, t, Jˆ6.5 Hz), 4.08 (2H, d, Jˆ4.9 Hz), 5.55±5.74
(2H, m); 13C NMR (75 MHz, CDCl3) d 25.4 (2C), 18.3,
25.7, 25.9 (3C), 29.1, 29.1, 29.3 (2C), 29.5, 32.1, 32.7, 63.2,
63.4, 128.3, 133.0; IR (neat) 3350 cm21; MS (FAB) m/z 315
(MH1, 54). HRMS Calcd for C18H39O2Si: MH1, 315.2719.
Found: m/z 315.2708.
(1Z,3E)-1-Bromo-13-(tert-butyldimethylsilyl)oxy-1,3-tri-
decadiene (17). A palladium catalyst was generated at room
temperature by stirring of Pd(OAc)2 (5.3 mg) and triphenyl-
phosphine (28 mg) in anhydrous benzene (2 mL) for
15 min, which was added to 16 (293 mg, 0.63 mmol) in
benzene (4.3 mL). To this mixture Bu3SnH (0.19 mL,
0.7 mmol) was added, and the mixture was stirred for 1 h
at room temperature. Then, it was diluted with hexane
(100 mL), and washed with water and brine. The organic
layer was dried over MgSO4, condensed, and chroma-
tographed on silica gel eluting with 5% EtOAc in hexane
to give 17 (207 mg) in 85% yield. Oil, Rfˆ0.24 (2.5%
1
EtOAc in hexane). H NMR (300 MHz, CDCl3) d 0.05
(6H, s), 0.89 (9H, s), 1.23±1.57 (14H, m), 2.13 (2H, td,
Jˆ7.1 and 7.0 Hz), 3.59 (2H, t, Jˆ6.6 Hz), 5.92 (1H, dt,
Jˆ15.0 and 7.0 Hz), 6.02 (1H, d, Jˆ7.0 Hz), 6.36 (1H,
dd, Jˆ15.0 and 10.1 Hz), 6.58 (1H, dd, Jˆ10.1 and
7.0 Hz); 13C NMR (100 MHz, CDCl3) d 25.2 (2C), 18.4,
25.8, 26.0 (3C), 28.9, 29.2, 29.4, 29.6, 32.9, 33.0 (2C), 63.3,
105.4, 126.0, 132.8, 139.7; MS (FAB) m/z 389, 391 (MH1).
HRMS Calcd for C19H38OSiBr: MH1, 389.1875, 391.1855.
Found: m/z 389.1885, 391.1870.
(E)-12-(tert-Butyldimethylsilyl)oxy-2-dodecen-1-al (15).
To a cooled solution of oxalyl chloride (0.28 mL) in
CH2Cl2 (5 mL) at 2788C was added dropwise DMSO
(0.46 mL), and the mixture was stirred for 15 min at the
same temperature. A CH2Cl2 solution (2 mL) of alcohol
14 (680 mg, 2.16 mmol) was added slowly. After stirring
for 30 min, it was quenched with Et3N (1.5 mL) at 2788C.
The mixture was slowly warmed up to 08C for 1 h. Sat.
NH4Cl (5 mL) was added and the mixture was extracted
with EtOAc (150 mL). The extract was washed with
water, brine and dried over MgSO4. After solvent was
removed the residue was puri®ed by column chroma-
tography on silica gel eluting with 5% EtOAc in hexane
to give 15 (556 mg) in 67% yield. Oil, Rfˆ0.29 (5%
(4Z,6E)-16-(tert-Butyldimethylsilyl)oxy-4,6-hexadecadiene
(18). To an ice cooled solution of 17 (63 mg, 0.162 mmol)
and NiCl2(dppp) (3.6 mg, 6.6 mmol) in ether (1 mL), was
added propylmagnesium bromide (0.34 mmol, 0.36 mL in
0.94 M THF solution) at room temperature. The reaction
was stirred for 20 min at the same temperature, and diluted
with hexane (40 mL). The mixture was washed with water,
brine, dried over MgSO4, and evaporated. The residual oil
was puri®ed by column chromatography on silica gel
eluting with hexane to give 18 (47.8 mg) in 84% yield.
Oil, Rfˆ0.24 (2.5% EtOAc in hexane). 1H NMR
(300 MHz, CDCl3) d 0.05 (6H, s), 0.89 (9H, s), 0.92 (3H,
t, Jˆ7.3 Hz), 1.28±1.55 (16H, m), 2.08 (2H, dt, Jˆ7.6 and
7.6 Hz), 2.14 (2H, dt, Jˆ7.1 and 7.1 Hz), 3.59 (2H, t,
Jˆ6.6 Hz), 5.30 (1H, td, Jˆ7.6 and 10.9 Hz), 5.65 (1H,
td, Jˆ7.1 and 15.0 Hz), 5.95 (1H, dd, Jˆ10.9 and
10.9 Hz), 6.29 (1H, ddd, Jˆ1.3, 10.9 and 15.0 Hz); 13C
NMR (75 MHz, CDCl3) d 25.3 (2C), 13.7, 18.4, 22.9,
25.8, 26.0 (3C), 29.2, 29.3, 29.4, 29.6, 29.7, 32.9 (3C),
63.3, 125.6, 128.8, 129.8, 134.7; MS (FAB) m/z 353
(MH1, 25). HRMS Calcd for C22H45OSi: MH1, 535.3240.
Found: m/z 353.3242.
1
EtOAc in hexane); H NMR (300 MHz, CDCl3) d 0.04
(6H, s), 0.89 (9H, s), 1.30±1.53 (14H, m), 2.33 (2H, tdd,
Jˆ6.8, 6.8 and 1.6 Hz), 3.60 (2H, t, Jˆ6.6 Hz), 6.12 (1H,
ddt, Jˆ15.6, 7.8 and 1.6 Hz), 6.85 (1H, dt, Jˆ15.6 and
6.8 Hz), 9.50 (1H, d, Jˆ7.8 Hz); 13C NMR (75 MHz,
CDCl3) d 25.4 (3C), 18.2, 25.6, 25.9 (2C), 27.7, 29.0,
29.2, 29.2, 29.3, 32.6, 32.7, 63.1, 132.8, 158.8, 193.8; IR
(neat) 1690 cm21; MS (FAB) m/z 313 (MH1, 93). HRMS
Calcd for C18H37O2Si: MH1, 313.2563. Found: m/z
313.2544.
(E)-1,1-Dibromo-13-(tert-butyldimethylsilyl)oxy-1,3-tri-
decadiene (16). To an ice cooled solution of 15 (222 mg,
0.71 mmol) and carbon tetrabromide (401 mg, 1.21 mmol)
in CH2Cl2 (7.2 mL), was added triphenylphosphine
(653 mg, 2.49 mmol) by several portions. After the addition,
the reaction completed. The mixture was diluted with hex-
ane (20 mL) and passed through short silica gel column.
Fractions containing 16 was condensed and re-puri®ed by
silica gel column chromatography eluting 5% EtOAc in
hexane to give 16 (293 mg) in 88% yield. Oil, Rfˆ0.24
Bombykol. A mixture of 18 (47.8 mg, 0.136 mmol) in THF
(1.5 mL) and Bu4NF (0.14 mmol, 0.14 mL in 1 M THF
solution) was stirred for 2 h at 08C. Then, the reaction
mixture was diluted with ether (60 mL) and washed with
water, brine, and dried over MgSO4. After solvent was
evaporated, the residue was puri®ed by column chroma-
tography on silica gel eluted with 20% EtOAc in hexane
1
(2.5% EtOAc in hexane). H NMR (300 MHz, CDCl3) d

3500
J. Uenishi et al. / Tetrahedron 56 (2000) 3493±3500
Chem. 1996, 61, 5716; Uenishi, J.; Kawahama, R.; Yonemitsu,
O.; Tsuji, J. J. Org. Chem. 1998, 63, 8965.
to give bombykol (30 mg) in 93% yield. Oil, Rfˆ0.40 (20%
EtOAc in hexane). 1H NMR (300 MHz, CDCl3) d 0.92 (3H,
t, Jˆ7.4 Hz), 1.27±1.49 (16H, m), 2.09 (2H, dt, Jˆ7.7 and
7.7 Hz), 2.16 (2H, dt, Jˆ6.9 and 6.9 Hz), 3.64 (2H, t,
Jˆ6.6 Hz), 5.30 (1H, dt, Jˆ10.9 and 7.7 Hz), 5.65 (1H,
dt, Jˆ15.2 and 6.9 Hz), 5.86 (1H, dd, Jˆ10.9 and
10.9 Hz), 6.20 (1H, dd, Jˆ15.2 and 10.9 Hz); 13C NMR
(75 MHz, CDCl3) d 13.8, 22.9, 25.7 (2C), 29.2, 29.4 (2C),
29.5, 29.7, 32.8, 32.9, 63.1, 125.7, 128.8, 129.8, 134.6.
8. Metal catalyzed cross coupling reaction of haloalkene with
Grignard reagent is well known as Kumada-Tamao-Corriu reac-
tion, see; Kumada, M. Pure Appl. Chem. 1980, 52, 669; Tamao, K.;
Ishida, N.; Kumada, M. J. Org. Chem. 1983, 48, 2120; Metal
catalyzed cross coupling reaction of Z-alkenyl halide with
Grignard reagent, see; Fe; Tamura, M.; Kochi, J. K. J. Am.
Chem. Soc., 1971, 93, 1487; Ni; Duboudin, J. G.; Jousseaume,
B.; Bonakder, A. J. Orgnomet. Chem. 1979, 168, 227; Negishi,
E.; Luo, F.-T.; Rand, C. L. Tetrahedron Lett. 1982, 23, 27;
Fiandanese, V.; Marchese, G.; Naso, F.; Ronzini, L. J. Chem.
Soc., Chem. Commun. 1982, 647; Tamao, K.; Ishida, N.; Kumada,
M. J. Org. Chem. 1983, 48, 2120; Pd; Dang, H. P.; Linstrumelle,
G. Tetrahedron Lett. 1978, 191; Kondo, K.; Murahashi, S.
Tetrahedron Lett. 1979, 1237.
Acknowledgements
The authors thank Mr Kusaka and Misses Fujisaki and
Yuyama for collecting the data after the late Mr Y. Izaki.
This work was supported by the Grant-in-Aid for Scienti®c
research from the Ministry of Education, Science, Sports
and Culture, of Japanese Government, and a Special Grant
for Cooperative Research administered by the Japan Private
School Promotion Foundation.
9. Ni catalyzed synthesis of non-conjugated allylsilanes, see
Hayashi, T.; Kabeta, K.; Hamachi, I.; Kumada, M. Tetrahedron
Lett. 1983, 24, 2865 and references cited there in.
10. Tokoroyama, T.; Pan, L.-R. Tetrahedron Lett. 1989,30, 197;
Pan, L.-R.; Tokoroyama, T. Chem. Lett. 1980, 21, 4021; Pan,
L.-R.; Tokoroyama, T. Tetrahedron Lett. 1992, 33, 1469; Kuroda,
C.; Ohnishi, Y.; Satoh, J. Y. Tetrahedron Lett. 1993, 34, 2613;
Danishefsky, S. J.; Selnick, H. G.; Zelle, R. E.; DeNinno, M. P.
J. Am. Chem. Soc. 1988, 110 4368.
References
1. The Chemistry of Dienes and Polyenes; Rappoport, Z. Ed.;
Wiley; Omura, S.; Tanaka, Y.; Kanaya, I.; Shinose, M.; Takahashi,
Y. J. Anitbiot. 1990, 43, 1034; Serhan, C. N.; Hamberg, M.;
Samuelsson, B. Biochem. Biophys. Res. Commun. 1984, 118,
943; Kim, Y. J.; Furihata, K.; Yamanaka, S.; Fudo, R.; Seto, H.
J. Anitbiot. 1991, 44, 553; Schummer, D.; Irschik, H.; Reichen-
bach, H.; Ho¯e, G. Liebigs Ann. Chem. 1994, 283; Danishefsky,
S. J.; Shair, M. D. J. Org. Chem. 1996, 61, 16; Grissom, J. W.;
Gunawardena, G. U.; Klingberg, D.; Huang, D. Tetrahedron 1996,
52, 6453; Wang, K. K. Chem. Rev. 1996, 96, 207; Maier, M. E.
Synlett. 1995, 13.
11. Butenandt, A.; Beckmann, R.; Stamm, D.; Hecker, E. Z.;
Naturforsch. 1959, 14b, 283; Butenandt, A.; Hecker, E. Angew,
Chem. 1961, 73, 349.
12. Negishi, E.; Yoshida, T.; Abramovitch, A.; Lew, G.; Williams,
R. M. Tetrahedron Lett. 1991, 47, 343; Samain, D.; Descoins, C.
Bull. Soc. Chim. Fr. 1979, II-71; Normant, J. F.; Commercon, A.;
Villieras, J. Tetrahedron Lett. 1975, 1465; Negishi, E.; Lew, G.;
Yoshida, T. J. Chem. Soc., Chem. Commun. 1973, 874; Cabezas,
J. A.; Oehlschlager, A. C. Synthesis 1999, 107.
13. Dasaradhi, L.; Neelakantan, P.; Rao, S. J.; Bhalerao, U. T. Syn.
Commun. 1991, 21, 183; Yadav, J. S.; Balakrishnan, K.; Sivadasan,
L. Indian J. Chem. 1989, 28B, 297; Ranganathan, S.; Maniktala,
V.; Kumar, R.; Singh, G. P. Indian J. Chem. 1984, 23B, 1197;
Bestmann, H. J.; Vostrowsky, O.; Paulus, H.; Billmann, W.;
Stransky, W. Tetrahedron Lett. 1977, 121; Alexakis, A.; Jachiet,
D. Tetrahedron 1989, 45, 381.
2. Gosney, I.; Lloyd, S. In Comprehensive Organic Functional
Group Transformations, Katritzky, A. R., Meth-Cohn, O., Rees,
C. W. Eds.; Pergamon Press: New York, 1995; Vol. 1, p 719.
3. Siegel, S. In Comprehensive Organic Synthesis; Trost, B. M.,
Fleming, I., Eds.; Pergamon Press: New York, 1991, Vol. 8, pp.
417; Hudlicky, M. Reduction in Organic Chemistry; Wiley; New
York, 1984; Rylander, P. N., Hydrogenation Methods; Academic
Press: Orlando, 1985.
14. Fiandanese, V.; Marchese, G.; Naso, F.; Ronzini, L.; Rotunno,
D. Tetrahedron Lett. 1989, 30, 243; Gardette, M.; Jabri, N.;
Alexakis, A.; Normant, J. F. Tetrahedron 1984, 40, 2741; Miyaura,
N.; Suginome, H.; Suzuki, A. Tetrahedron 1983, 39, 3271;
Normant, J. F.; Commercon, A.; Villieras, J. Tetrahedron Lett.
1975, 18, 1465.
4. For example, Adams, J.; Fitzsimmons, B. J.; Girard, Y.;
Leblanc, Y.; Evans, J. F.; Rokach, J. J. Am. Chem. Soc. 1985,
107, 464; Bestmann, H. J.; SuÈû, J., Vostrowsky, O. Liebigs Ann.
Chem. 1981, 2117.
5. Nicolaou, K. C.; Petasis, N. A.; Zipkin, R. E.; Uenishi, J. J. Am.
Chem. Soc. 1982, 104, 5555.
15. Tsuboi, S.; Masuda, T.; Makino, H.; Takeda, A. Tetrahedron
Lett. 1982, 23, 209.
6. Metal-Catalyzed Cross-coupling Reactions; Diederich, F.,
Stang, P. J., Eds.; Wiley-VCH: Weinheim, 1998; Knight, D. W.
In Comprehensive Organic Synthesis; Trost, B. M., Fleming, I.,
Eds.; Pergamon Press: New York, 1991, Vol. 3, pp. 481; Miyaura,
N.; Suzuki, A. Chem. Rev. 1995, 95, 2457; Stille, J. K. Angew.
Chem. Int. Ed. Engl. 1986, 25, 508; Sonogashira, K. In Compre-
hensive Organic Synthesis; Trost, B. M., Fleming, I., Eds.;
Pergamon Press: New York, 1991, Vol. 3, pp. 521.
16. Miyake, H.; Yamamura, K. Chem. Lett. 1994, 897; Alexakis,
A.; Jachiet, D. Tetrahedron 1989, 45, 381; Trost, B. M.; Fortunak,
J. M. J. Am. Chem. Soc. 1980, 102, 2841.
17. Sonnet, P. E.; Osman, S. F.; Gerard, H. C.; Dudley, R. L.
Chem. Phys. Lipids. 1994, 69, 121; Trost, B. M. Synthesis 1991,
1235.
18. One pot procedure by Pd catalyst gave the diene in a similar
yield.
7. Uenishi, J.; Kawahama, R.; Yonemitsu, O.; Tsuji, J. J. Org.