New synthesis of (11Z,13Z)-11,13-Hexadecadienal, the female sex pheromone of the navel orangeworm

Article abstract of DOI:10.1271/bbb.90611

(11Z,13Z)-11,13-Hexadecadienal, the female sex pheromone of the navel orangeworm (Amyelois transitella), was synthesized from commercially available 10-bromo-1-decanol in a 27% overall yield (8 steps). The synthesis was achieved by using 10-iododecanal, trimethylsilylacetylene and (Z)-1-bromo-12-butene as the key building blocks, employing Sonogashira-Hagihara coupling and Brown's hydroboration-protonolysis as the key reactions. The terminal formyl group was installed in the earlier stage of the synthesis rather than in the final step. This procedure enabled the multi-gram-scale preparation of this economically important pheromone.

Full text of DOI:10.1271/bbb.90611

Biosci. Biotechnol. Biochem., 73 (12), 2727–2730, 2009
New Synthesis of (11Z,13Z)-11,13-Hexadecadienal,
the Female Sex Pheromone of the Navel Orangeworm
*
Kenji MORI
Photosensitive Materials Research Center, Toyo Gosei Co., Ltd.,
4-2-1 Wakahagi, Inba-mura, Inba-gun, Chiba 270-1609, Japan
Received August 18, 2009; Accepted September 7, 2009; Online Publication, December 7, 2009
[doi:10.1271/bbb.90611]
(11Z,13Z)-11,13-Hexadecadienal, the female sex pher-
omone of the navel orangeworm (Amyelois transitella),
was synthesized from commercially available 10-bromo-
1-decanol in a 27% overall yield (8 steps). The synthesis
was achieved by using 10-iododecanal, trimethylsilyl-
acetylene and (Z)-1-bromo-1-butene as the key building
blocks, employing Sonogashira-Hagihara coupling and
Brown’s hydroboration-protonolysis as the key reac-
tions. The terminal formyl group was installed in the
earlier stage of the synthesis rather than in the final
step. This procedure enabled the multi-gram-scale
preparation of this economically important pheromone.
Among these six syntheses, four of them introduced the
formyl group by final oxidation of 1-hexadecadienol
with either pyridinium chlorochromate (PCC)2,4,5) or
pyridinium dichromate (PDC).7) Bishop and Morrow
recorded a synthesis of 2.8 kg of 1, in which the formyl
group was introduced into their intermediate as a
diethylacetal, and final deprotection afforded 1.8) Furber
and Taylor also employed diethylacetal intermediates in
their synthesis of 1.6)
The construction of the (Z,Z)-conjugated diene system
has been achieved in the past by a number of different
protocols: the Wittig reaction coupled with partial
hydrogenation of acetylene,2) hydroboration-protonoly-
sis of 1,3-diyne,4) diimide reduction of acetylene and
palladium-catalyzed coupling,5) organocopper chemis-
try,6) palladium-catalyzed coupling and hydroboration-
protonolysis,7) and copper-catalyzed Grignard coupling
and hydroboration-protonolysis.8)
Key words: Amyelois
transitella;
(Z,Z)-conjugated
diene; hydroboration-protonolysis; phero-
mone; Sonogashira-Hagihara coupling
In 1979, Coffelt and his co-workers at U.S. Depart-
ment of Agriculture isolated, identified and synthesized
(11Z,13Z)-11,13-hexadecadienal (1, Scheme 1) as the
female-produced sex pheromone of the navel orange-
worm (Amyelois transitella).2) This insect is a well-
established primary pest of almonds in California, and is
now also a key pest of pistachios in the same area.3)
Pheromone 1 is an important semiochemical to monitor
the population of A. transitella, and a large amount of 1
is required for pest management by mating disruption.3)
At the request of Shin-Etsu Chemical Company, a
pheromone manufacturer in Japan, I undertook the
present work to develop a scalable synthesis of 1.
There are some organic compounds whose structures
are seemingly simple, although their syntheses are not at
all easy, especially in multi-gram quantities. (11Z,13Z)-
11,13-Hexadecadienal (1) is one such compound
because of the presence of both an unstable (Z,Z)-
conjugated diene system and a labile formyl group.
Highly selective methods must be employed for con-
structing the (Z,Z)-conjugated diene system to obtain
pure 1. In addition, the timing of placing the terminal
formyl group is also important, because oxidation in the
final step may damage or isomerize the (Z,Z)-conjugated
diene system. A mild oxidant like Dess-Martin period-
inane cannot be used due to its high cost.
A critical examination of all the published syntheses
indicates that the preparation of 1 in a multi-gram-scale
was not an easy task due to the non-reproducibility of
some of the earlier works. This paper reports my
experimental result, which gives a multi-gram quantity
of 94–95% pure 1.
Results and Discussion
Scheme 1 shows the synthetic plan for 1. Sonogashira-
Hagihara coupling9,10) of (Z)-1-bromo-1-butene (A) with
1,1-diethoxy-11-dodecyne (B) will give the required
carbon-skeleton as (Z)-1,1-diethoxy-13-hexadecen-11-
yne, whose selective reduction and deprotection will
give 1. Bromoalkene A is readily available from (E)-2-
pentenoic acid (C),11) while B can be prepared from
10-iododecanal (D).
The new eight-step-synthesis of (11Z,13Z)-11,13-
hexadecadienal (1) is summarized in Scheme 2.
Commercially available 10-bromo-1-decanol (2) was
chosen as the starting material. Since a GC-MS analysis
of 2 revealed the presence of a few percent of 1,10-
dibromodecane in it, 10-iodo-1-decanol (3)12) obtained
by treating 2 with sodium iodide in acetone was purified
by chromatography to give pure monoiodide 3 in an
87% yield. PCC oxidation of 3 gave crystalline aldehyde
412) in a 74% yield. This was treated with triethyl
orthoformate and p-toluenesulfonic acid in diethyl ether
to give 56) in a 91% yield. Alkylation of lithium
Among five existing syntheses of 1, four furnished
less than a gram quantity (usually 0.2 g or so) of 1.2,4–6)
A synthesis of (10Z,12Z)-10,12-hexadecadienal by
Cabezas and Oehlschlager generated it in 0.5 g-scale.7)
*
Pheromone Synthesis, Part 241. See Ref. 1 for part 240.
Correspondence: Fax: +81-3-3813-1516; E-mail: kjk-mori@arion.ocn.ne.jp

2728
K. MORI
a
b
(CH2)9CHO
(11Z,13Z)-1
Br(CH2)10OH
I(CH2)10OH
2
3
c
d
I(CH2)9CHO
I(CH2)9CH(OEt)2
Br
HC C(CH2)9CH(OEt)2
4
5
A (= 8)
B (= 7)
e
TMSC C(CH2)9CH(OEt)2
6
I(CH2)9CHO
CO2H
Br
C
D (= 4)
8
HC C(CH2)9CH(OEt)2
Scheme 1. Structure and Retrosynthetic Analysis of (11Z,13Z)-
11,13-Hexadecadienal (1), the Female Sex Pheromone of the Navel
Orangeworm.
f
7
(CH2)9CH(OEt)2
g
trimethylsilylacetylide with 5 in THF/HMPA furnished
6 in a quantitative yield. (The use of 10-bromo-1,1-
diethoxydecane instead of 5 generated impure 6 con-
taminated with 5–10% of the starting bromide. This
eventually resulted in contamination of final product 1
with 5–10% of inseparable 10-bromodecanal.) Desily-
lation of 6 with potassium carbonate in methanol
afforded 1,1-diethoxy-11-dodecyne 7 in an 82% yield.
The next step involved coupling 7 with 8 under the
Sonogashira-Hagihara conditions.9,10) (Z)-1-Bromo-1-
butene (8) prepared by decarboxylative dehydrobromi-
nation of trans-2,3-dibromopentanoic acid11) was pure
enough [97% of 8 with 3% of its (E)-isomer] immedi-
ately after its preparation. Even in a cold and dark
refrigerator, however, it isomerized after a month to give
a mixture of 8 and its (E)-isomer (61:38) as analyzed by
GC-MS. It was therefore important to use freshly
prepared 8 for the coupling reaction. This isomerization
may have been due to a carbocation-mediated process,
because a very faint fume of hydrogen bromide could be
seen when the storage bottle was opened.
Sonogashira-Hagihara coupling of 7 with 8 in ben-
zene/n-propylamine was successfully achieved in the
presence of 2.4 mol % of tetrakis(triphenylphosphine)-
palladium(0) and 8.3 mol % of copper(I) iodide. The
reaction was slightly exothermic, and gave 9 in a
quantitative yield after chromatographic purification.
This coupling reaction was highly reproducible. It must
be added that Sonogashira-Hagihara coupling is still
being intensively studied,13) and a new application to
pheromone synthesis has been published.14)
Z-selective reduction of the triple bond of 9 was the
next problem. This reduction was first attempted by the
method reported by Hungerford and Kitching employing
titanium(II).15) Unfortunately, the reduction was not a
clean process, but gave additional products generated by
1,4-reduction of the enyne system of 9. Consequently,
hydroboration-protonolysis16) was applied to reduce the
triple bond to a (Z)-double bond. As noted previously by
Sonnet and Heath,4) disiamylborane did not effect
complete hydroboration, and therefore dicyclohexylbor-
ane was employed. It was found that 3–4 equivalents of
dicyclohexylborane in THF were necessary to effect
complete hydroboration of the triple bond within 1–2 h.
No over-reduction was apparent, probably because the
presence of an extremely bulky dicyclohexylboryl group
on the carbon chain prevented the approach of the second
9
h
(CH2)9CH(OEt)2
10
(CH2)9CHO
(11Z,13Z)-1
Scheme 2. Synthesis of (11Z,13Z)-11,13-Hexadecadienal (1).
Reagents: (a) NaI, acetone (87%); (b) PCC, Celite, CH2Cl2
(74%); (c) HC(OEt)3, p-TsOH, Et2O (91%); (d) TMSCꢀCH,
n-BuLi, THF/HMPA (quant.); (e) K2CO3, MeOH (82%); (f) 8,
(Ph3P)4Pd, CuI, n-PrNH2, C6H6 (quant.); (g) (1) BH3ꢁMe2S,
cyclohexene, THF; (2) NaOH, 30% H2O2; (h) THF, (CO2H)2,
H2O (56%, 2 steps).
dicyclohexylborane to attack the double bond. The borane
was treated with acetic acid to achieve protonolysis, and
the mixture was poured into ice-cooled aqueous sodium
hydroxide. Subsequently, hydrogen peroxide was added
to the ice-cooled mixture, and the mixture was worked up
after 10 min to give 10 and cyclohexanol. The mixture
also contained 1, which was liberated in the course of
protonolysis with acetic acid. This was purified by
chromatography to remove the cyclohexanol.
The resulting mixture of 1 and 10 was dissolved in
THF and treated with aqueous oxalic acid6) to deprotect
the acetal moiety and give (11Z,13Z)-11,13-hexadeca-
dienal (1) in a 56% yield based on 9. The foregoing
synthesis could be repeated several times without any
problem to give 1–3 g of 1. The IR, H- and 13C-NMR,
1
and MS data for synthetic pheromone 1 were identical
to those reported previously.4–6) The purity of 1 was
analyzed by GC-MS, and the sample consisted of
94.45% of (11Z,13Z)-1, 2.75% of its (11Z,13E)-isomer
and 0.62% of the (11E,13Z)-isomer. It was assumed that
our GC column (phenylmethylsiloxane) gave the same
order of the retention times for 1 and its isomers as
reported by Sonnet and Heath with their cholesterol
cinnamate column.4)
Conclusion
A scalable eight-step-synthesis of (11Z,13Z)-11,13-
hexadecadienal, the female sex pheromone of the navel

Synthesis of the Sex Pheromone of the Navel Orangeworm
2729
CH2I), 3.49 (2H, dq, J 6, 6.8, OCH2CH3), 3.63 (2H, dq, J 6, 6.8,
OCH2CH3), 4.48 [1H, t, J 6, CH(OEt)2]; GC-MS [same conditions as
those for 4]: tR 17.27 min (97.7%). MS of 5 (70 eV, EI) m=z: 355
(<0:5) [Mþ ꢂ H], 311 (14) (Mþ ꢂ OEt), 264 (4), 155 (7), 137 (9), 103
(100), 85 (87), 57 (67). HRMS: calcd. for C14H29O2I–C2H5O,
311.0872; found, 311.0887.
orangeworm (Amyelois transitella), was achieved in a
27% overall yield by starting from 10-bromo-1-decanol.
The present procedure will be useful in manufacturing
the economically important pheromone lure against
A. transitella.
Experimental
1,1-Diethoxy-12-trimethylsilyldodec-11-yne (6).
A solution of
n-butyllithium (1.6 M in hexane, 66 ml, 106 mmol) was added to a
stirred and cooled solution of trimethylsilylacetylene (10.0 g,
102 mmol) in dry THF (100 ml) and dry HMPA (10 ml) while stirring
and cooling with dry ice-acetone under argon at ꢂ50 ꢃC. The stirred
and yellow-colored solution was warmed to ꢂ10 ꢃC and then cooled
again at ꢂ70 ꢃC. A solution of 5 (20.9 g, 59 mmol) in dry THF (20 ml)
was gradually added to the stirred mixture at ꢂ60–ꢂ70 ꢃC. The
mixture was left to stand overnight with gradual warming to room
temperature. It was then poured into ice-cooled water and extracted
with hexane. The hexane solution was successively washed with water
and brine, dried (MgSO4), and concentrated in vacuo to give 24.7 g
(quant.) of crude 6, IR ꢁmax (film) cmꢂ1: 2929 (s), 2856 (s), 2175 (m,
CꢀC), 1250 (m), 1128 (m, C–O), 1061 (m, C–O), 845 (s), 760 (m).
General. Refractive indices (nD) were measured with an Atago
DMT-1 refractometer, and IR spectra with a Jasco FT/IR–410
spectrometer. 1H-NMR spectra (400 MHz, TMS at ꢀ ¼ 0:00 as an
internal standard) and 13C-NMR spectra (100 MHz, CDCl3 at ꢀ ¼ 77:0
as an internal standard) were recorded by a Jeol JNM-AL 400
spectrometer. GC-MS data were measured with an Agilent Technol-
ogies 5975 inert XL instrument. HRMS data were recorded by a Jeol
JMS-SX 102A instrument. Column chromatography was carried out on
Merck Kieselgel 60 Art 1.07734.
10-Iododecan-1-ol (3). Powdered sodium iodide (45 g, 300 mmol)
was added to a stirred solution of 1 (25 g, 105 mmol) in acetone
(200 ml) to make a homogeneous solution. This solution was then
stirred and heated under reflux for 4 h. A colorless precipitate of
sodium bromide separated from the solution. The mixture was
concentrated in vacuo, diluted with water, and extracted with diethyl
ether. The ether layer was successively washed with water, a 1%
Na2S2O3 solution and brine, dried (MgSO4), and concentrated in
vacuo. The resulting residue (32.1 g) was chromatographed over SiO2
(100 g). Elution with hexane/EtOAc (100:1) gave 3.03 g of 1,10-
diiododecane derived from contaminating 1,10-dibromodecane. Fur-
ther elution with hexane/EtOAc (10:1) afforded 25.6 g (87%) of 3 as a
This crude
purification.
6 was employed in the next step without further
1,1-Diethoxydodec-11-yne (7). Powdered potassium carbonate
(7.5 g, 54 mmol) was added to a solution of crude 6 (24.7 g, 59 mmol)
in methanol (150 ml) and water (10 ml). The mixture was stirred and
heated at 50 ꢃC for 1 h, before being concentrated in vacuo. The residue
was diluted with water and extracted with diethyl ether. The ether
solution was successively washed with water and brine, dried
(MgSO4), and concentrated in vacuo to give 14.4 g of crude 7 which
was chromatographed over SiO2 (100 g). Elution with hexane/EtOAc
25
colorless oil which solidified in a refrigerator, nD 1.5032; IR ꢁmax
(film) cmꢂ1: 3336 (m, OH), 2925 (s), 2852 (s), 1055 (m, C–O); NMR
ꢀH (CDCl3): 1.25–1.44 (13H, m), 1.52–1.60 (2H, m), 1.82 (2H, m),
3.19 (2H, t, J 7.2, CH2I), 3.64 (2H, m, t-like, CH2O). HRMS: calcd. for
(10:1) gave 12.2 g (82%) of 7 as a colorless oil, nD 1.4412; IR ꢁmax
25
(film) cmꢂ1: 3313 (m, CꢀC–H), 2976 (s), 2929 (s), 2856 (s), 2117 (w,
CꢀC), 1128 (s, C–O), 1067 (s, C–O), 629 (m); NMR ꢀH (CDCl3): 1.20
(6H, t, J 6.8, OCH2CH3), 1.23–1.45 (12H, m), 1.48–1.56 (2H, m),
1.56–1.65 (2H, m), 1.93 (1H, t, J 6.8, CꢀC–H), 2.18 (2H, dt, J 2.8,
7.2), 3.49 (2H, dq, J 6, 7.2, OCH2CH3), 3.64 (2H, dq, J 6, 7.2,
OCH2CH3), 4.78 [1H, t, J 6, CH(OEt)2]; GC-MS [same conditions as
those for 4]: tR 14.65 min (98.5%). MS of 7 (70 eV, EI) m=z: 253
(<0:5) (Mþ ꢂ H), 209 (3) (Mþ ꢂ OEt), 103 (100), 95 (9), 85 (46), 75
(21), 57 (44), 47 (17). HRMS: calcd. for C16H30O2–OC2H5, 209.1906;
found, 209.1903.
C
10H21IO, 284.0637; found, 284.0650.
10-Iododecanal (4). A solution of 3 (25.5 g, 90 mmol) in dry
dichloromethane (50 ml) was added dropwise in the course of 30 min to
a suspension of pyridinium chlorochromate (PCC, 23.7 g, 110 mmol)
and Celite (30 g) in dry dichloromethane (350 ml) while vigorously
stirring and ice-cooling at 5–15 ꢃC. Stirring was continued for 45 min
after this addition. The mixture was then filtered, and the Celite layer
was washed with dichloromethane. The combined filtrate and washings
were concentrated in vacuo. The dark-colored residue was chromato-
graphed over SiO2 (120 g). Elution with hexane/EtOAc (15:1) gave
18.6 g (74%) of 4 as a colorless oil which slowly solidified to give
colorless crystals, mp 48–50 ꢃC; IR ꢁmax (film) cmꢂ1: 2927 (s), 2854
(s), 2717 (w, O=C–H), 1726 (s, C=O), 1180 (w), 721 (w); NMR ꢀH
(CDCl3): 1.24–1.42 (10H, m), 1.62 (2H, m), 1.82 (2H, quint-like,
J 7.2), 2.42 (2H, dt, J 1.6, 7.2), 3.19 (2H, t, J 6.8, CH2I), 9.76 (1H, t,
J 1.2, CHO); GC-MS [HP-5MS column, 5% phenylmethylsiloxane,
30 m ꢄ 0:25 mm i.d.; 60.7 kPa pressure; 70–230 ꢃC (þ10 ꢃC/min)
temperature]: tR 14.53 min (99.9%). MS of 4 (70 eV, EI) m=z: 282
(<0:5) [Mþ, C10H19OI], 155 (16) [Mþ ꢂ I], 137 (34), 95 (100), 81
(88), 69 (78), 55 (74), 41 (56). This aldehyde was unstable and readily
gave its trimer.
(Z)-1-Bromo-1-butene (8). This was prepared by the method of
Mori and Brevet.11) NMR ꢀH (CDCl3): 1.02 (3H, dt, J 3.2, 7.0, CH3),
2.20 (1H, q, J 7), 2.22 (1H, q, J 7), 6.06–6.13 (2H, m); GC-MS
[HP-5MS column, 5% phenylmethylsiloxane, 30 m ꢄ 0:25 mm i.d.;
48.7 kPa pressure; 40–230 ꢃC temperature (þ5 ꢃC/min)]: tR 2.92 min
[97.2%, (Z)-isomer], 3.21 min [2.8%, (E)-isomer]. MS of 8 (70 eV, EI)
m=z: 136 (29) (Mþ), 134 (30) (Mþ), 121 (11), 119 (12), 55 (100),
39 (27). This was used immediately after preparation; storage in a
refrigerator caused isomerization to the (E)-isomer, the Z/E ratio
having deteriorated to 61:38 after one month.
(Z)-1,1-Diethoxyhexadec-13-en-11-yne (9). Tetrakis(triphenylphos-
phine)palladium(0) (2.1 g, 1.8 mmol) was added to a solution of (Z)-1-
bromo-1-butene (8, 10.3 g, 76 mmol) in dry benzene (100 ml) under
argon, and the yellow-colored mixture was stirred for 30 min at room
temperature. A solution of 7 (9.3 g, 37 mmol) in n-propylamine (35 ml)
and copper(I) iodide (1.2 g, 6.3 mmol) were then added to the solution,
and the homogeneous mixture was stirred under argon. The reaction
was slightly exothermic to reach an internal temperature of 35–40 ꢃC.
The mixture was stirred for 3 d at room temperature, before being
diluted with diethyl ether. The ether-benzene solution was successively
washed with an ammonium chloride solution and brine, dried
(K2CO3), and concentrated in vacuo to give 14.7 g of crude 9. This
was chromatographed over SiO2 (100 g). Elution with hexane/EtOAc
1,1-Diethoxy-10-iododecane (5). Triethyl orthoformate (14.8 g,
100 mmol) and p-toluenesulfonic acid monohydrate (0.2 g, 1 mmol)
were added to a stirred and ice-cooled solution of 4 (18.5 g, 65.6 mmol)
in dry diethyl ether (25 ml). After the exothermic reaction had
subsided, the mixture was left to stand overnight in a refrigerator.
Water (0.5 ml) was then added to destroy the excess triethyl
orthoformate, and the mixture was made basic by adding a sodium
hydrogen carbonate solution. This basic mixture was extracted with
diethyl ether, and the resulting extract was washed with brine, dried
(MgSO4), and concentrated in vacuo. The residue (24.4 g) was
chromatographed over SiO2 (80 g). Elution with hexane/EtOAc
25
(30:1) gave 9 (11.5 g, quant.) as a colorless oil, nD 1.4642; IR ꢁmax
25
(25:1) gave 5 (21.2 g, 91%) as a colorless oil, nD 1.4412; IR ꢁmax
(film) cmꢂ1: 3019 (w, C=C–H), 2972 (s), 2929 (s), 2856 (s), 1616 (w,
C=C), 1128 (s, C–O), 1063 (s, C–O), 737 (m); NMR ꢀH (CDCl3): 1.01
(3H, t, J 7.6, 16–Me), 1.20 (6H, t, J 7.2, OCH2CH3), 1.25–1.45 (12H,
m), 1.50–1.55 (2H, m), 1.55–1.65 (2H, m), 2.24–2.46 (4H, m), 3.49
(film) cmꢂ1: 2974 (m), 2927 (s), 2854 (s), 1126 (s, C–O), 1063 (s, C–
O); NMR ꢀH (CDCl3): 1.20 (6H, t, J 7.2, OCH2CH3), 1.23–1.40 (12H,
m), 1.55–1.62 (2H, m), 1.82 (2H, quint-like, J 6.8), 3.19 (2H, t, J 6.8,

2730
K. MORI
(2H, dq, J 7.2, 7.2, OCH2CH3), 3.63 (2H, dq, J 7.2, 7.2, OCH2CH3),
4.48 [1H, t, J 6, CH(OEt)2]. 5.40 (1H, d, J 10, C=CH), 5.80 (1H, dt,
J 10, 7, HC=C); GC-MS [same conditions as those for 4]: tR 18.85 min
(91.4%). MS of 9 (70 eV, EI) m=z: 263 (16) (Mþ–OEt), 233 (27), 149
(22), 119 (20), 103 (100), 93 (35), 91 (46), 85 (74), 80 (52), 75 (34), 67
(26), 57 (95), 55 (26), 41 (25). HRMS: calcd. for C20H36O2–OC2H5,
263.2375; found, 263.2352.
4]: tR 16.33 [2.75%, (11Z,13E)-isomer], 16.42 [0.62%, (11E,13Z)-
isomer], 15.51 min [94.45%, (11Z,13Z)-1]. MS of (11Z,13Z)-1 (70 eV,
EI): m=z: 236 (19) (Mþ), 109 (15), 95 (60), 82 (71), 81 (52), 68 (40),
67 (100), 55 (32), 41 (30). The other two isomers showed MS data
almost identical to that of (11Z,13Z)-1. HRMS: calcd. for C16H28O,
236.2140; found, 236.2140.
Acknowledgments
(11Z,13Z)-11-Diethoxy-11,13-hexadecadiene (10). A solution of
dicyclohexylborane was prepared by adding dropwise a borane-
dimethyl sulfide complex (1.8 ml, d 1.287, 2.3 g, 30 mmol) to a stirred
and ice-cooled solution of cyclohexene in dry THF (2 M, 26 ml,
52 mmol) at 5–10 ꢃC under argon. The mixture was stirred for 30 min
at 5–10 ꢃC to give a slurry of crystalline dicyclohexylborane. A
solution of 9 (2.7 g, 8.8 mmol, 5 ml) was added dropwise to the stirred
and ice-cooled mixture. Stirring was continued for 15 min at 5–10 ꢃC
and then for 1 h at room temperature under argon. Glacial acetic acid
(4 ml) was then added to the stirred mixture with slight evolution of
hydrogen. The mixture was stirred and heated at 50 ꢃC for 1 h, cooled
and added to a stirred and ice-cooled solution of sodium hydroxide
(12 g, 300 mmol) in water (50 ml). Subsequently, 30% hydrogen
peroxide (6 ml) was added dropwise (exothermic), and stirring was
continued for 10 min while ice-cooling. The mixture was diluted with
water and extracted with hexane. The hexane solution was successively
washed with water and brine, dried (MgSO4), and concentrated in
vacuo. The resulting residue (5.6 g) was chromatographed over SiO2
(25 g). Elution with hexane and hexane/EtOAc (30:1) gave crude 10
(2.05 g, 76%). Further elution gave a mixture of 10 and cyclohexanol.
Crude 10 contained 1 [IR ꢁmax (film) cmꢂ1: 3035 (w, C=C–H), 2927
(s), 2854 (s), 1737 (s, C=O), 1599 (w, C=C), 1242 (s, C–O), 1130 (m,
C–O), 1065 (m, C–O), 1009 (m), 721 (m)]. This was directly employed
for the next step.
My thanks are due to Mr. M. Kimura (President, Toyo
Gosei Co., Ltd.) for his support. I am indebted to
Messrs. K. Ogawa and T. Fukumoto (Shin-Etsu Chemi-
cal Co.) for their proposal to undertake the synthesis. I
thank Mr. Y. Shikichi (Toyo Gosei Co.) for NMR and
GC-MS measurements. The HRMS analysis was carried
out at RIKEN by Dr. T. Nakamura, and the schemes
were prepared by Dr. T. Tashiro (RIKEN). I thank both
of them. This work was financially supported by Toyo
Gosei Co., and Shin-Etsu Chemical Co.
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26
nD 1.4768; IR ꢁmax (film) cmꢂ1: 3035 (w), 3003 (w), 2962 (m, sh),
2927 (s), 2854 (s), 2715 (w), 1728 (s, C=O), 1599 (w, C=C), 1462
(m), 721 (m); NMR ꢀH (CDCl3): 0.997 (3H, t, J 7.6, CH3), 1.20–1.42
(14H, m), 1.58–1.68 (2H, m), 2.12–2.23 (2H, m), 2.41 (2H, dt, J 2.0,
7.2, CH2CHO), 5.43 (1H, dt, J. 7, 10), 5.46 (1H, dt, J 7, 10), 6.18–6.28
(2H, m), 9.76 (1H, t, J 2.0, CHO); NMR ꢀC (CDCl3): 14.19, 20.77,
22.06, 27.43, 29.12, 29.20, 29.25, 29.29, 29.33, 29.58, 43.86, 122.86,
123.32, 131.93, 133.46, 202.67; GC-MS [same conditions as those for
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