Preparative scale syntheses of isomerically pure (10E,12E,14Z)- and (10E,12E,14E)-hexadeca-10,12,14-trienals, sex pheromone components of Manduca sexta

Article abstract of DOI:10.1055/s-2000-6227

Short, efficient syntheses yielding products of very high isomeric purity have been developed for (10E,12E,14Z)-hexadeca-10,12,14-trienal 1 and the (10E,12E,14E)-isomer 2, the key pheromone components of the tobacco hornworm moth Manduca sexta. The penultimate (EEZ)-trienol, and aldehyde 1, were freed from isomeric impurities by selective reaction of the impurities with tetracyanoethylene. (EEE)-Aldehyde 2 was prepared by Wittig reaction of (2E,4E)-hexa-2,4-dienyltriphenylphosphonium bromide with 10-acetoxydecanal, deprotection, selective crystallization of the (EEE)-trienol from the resulting mix of isomers, and oxidation. The yield of the (EEE)-trienol was increased further by iodine-catalyzed isomerization of the mix of isomers in the liquor, and further recrystallization.

Full text of DOI:10.1055/s-2000-6227

PAPER
113
Preparative Scale Syntheses of Isomerically Pure (10E,12E,14Z)- and
(10E,12E,14E)-Hexadeca-10,12,14-trienals, Sex Pheromone Components of
Manduca sexta
Xin Chen, Jocelyn G. Millar*
Department of Entomology, University of California, Riverside, CA 92521, USA
Fax 1(909)7873086; E-mail: jocelyn.millar@ucr.edu
Received 17 June 1999; revised 10 September 1999
pheromone components is crucial, particularly when elu-
cidating the roles of minor components in pheromone
gland extracts. On paper, the syntheses of trienals 1 and 2
appear straightforward. In practice, synthesis of these la-
Abstract: Short, efficient syntheses yielding products of very high
isomeric purity have been developed for (10E,12E,14Z)-hexadeca-
10,12,14-trienal 1 and the (10E,12E,14E)-isomer 2, the key phero-
mone components of the tobacco hornworm moth Manduca sexta.
The penultimate (EEZ)-trienol, and aldehyde 1, were freed from bile compounds in very high purity and in significant
isomeric impurities by selective reaction of the impurities with tet-
racyanoethylene. (EEE)-Aldehyde 2 was prepared by Wittig reac-
tion of (2E,4E)-hexa-2,4-dienyltriphenylphosphonium bromide
the target compounds heavily contaminated with isomeric
with 10-acetoxydecanal, deprotection, selective crystallization of
the (EEE)-trienol from the resulting mix of isomers, and oxidation.
The yield of the (EEE)-trienol was increased further by iodine-cat-
alyzed isomerization of the mix of isomers in the liquor, and further
recrystallization.
quantities is not trivial. Two syntheses of 1 and 2 have
been published,2,3 but both produced small quantities of
impurities. A third synthesis of the analogous hexadecatri-
enyl alcohols has been reported, but the routes used were
not stereoselective, and produced mixtures of isomers,
which could only be separated on milligram scale by
HPLC.4
Key words: (10E,12E,14Z)-hexadeca-10,12,14-trienal, (10E,12E,-
14E)-hexadeca-10,12,14-trienal, tetracyanoethylene, Diels-Alder
adduct, pheromone
Our objective was to develop short, efficient syntheses of
1 and 2, and of equal or greater importance, to develop
straightforward preparative scale methods of attaining
very high chemical and isomeric purity of the target com-
pounds, to provide pure materials for further elaboration
of the full pheromone blend of M. sexta. In developing
syntheses of 1 and 2, high stereochemical purity on a pre-
parative scale could be obtained in two ways. First, highly
stereoselective or stereospecific reactions, if available,
could be used. Alternatively, one or more of the interme-
diates or the final products must be easily separable from
all stereoisomeric and chemical contaminants. Both of
these principles were used in the syntheses described be-
low.
The tobacco hornworm moth, Manduca sexta (Lepi-
doptera: Sphingidae), is a pest of tobacco and other solan-
aceous crops in the New World. It is also of importance to
science because it has become the experimental animal of
choice for studies of insect biochemistry, physiology, en-
docrinology, and olfaction on account of its relatively
large size, fast growth rate, and ease of rearing.1 However,
the sex pheromone resisted identification for a number of
years, in part due to the large number of possible phero-
mone components in female pheromone glands (12 satu-
rated, and mono-, di-, and tri-unsaturated aldehydes), but
principally due to the instability of one of the key compo-
nents, (10E,12E,14Z)-hexadeca-10,12,14-trienal 1, which
was destroyed during preparative GC isolation attempts.1
This compound, and the corresponding EEE-isomer 2,
were eventually isolated by reverse phase HPLC, and the
bioactive pheromone blend was determined to consist of
1 in combination with (10E,12Z)-hexadeca-10,12-dienal.1
In wind tunnel bioassays, the EEE-isomer was not attrac-
tive, and because of the ease of isomerization of 1, its
presence may be artifactual. Furthermore, the possible
roles of the other aldehyde components in both inter- and
intra-specific communication has not yet been resolved.1
Synthesis of (10E,12E,14Z)-Hexadeca-10,12,14-
trienal (1)
10-Undecyn-1-ol (3) was hydroborated with catecholbo-
rane, followed by hydrolysis of the adduct to produce (E)-
11-hydroxy-1-undecenylboronic acid (4)5 (Scheme 1).
The key steps in assembling the remainder of the carbon
skeleton were two sequential palladium-catalyzed cross-
coupling reactions, first coupling 4 with trans-1,2-dichlo-
roethylene to give the chlorodienol 5, which was then cou-
pled with cis-1-propenylmagnesium bromide.
The Suzuki cross-coupling reaction6 between boronic acid
4 and trans-1,2-dichloroethylene proved more difficult
than anticipated. Typical Suzuki reaction conditions with
Isomeric and related impurities frequently exert dramatic
effects on the behavioral responses of insect species to
their pheromones, with well-documented cases of strong
synergism or strong antagonism of responses at concen-
trations of less than 1% of the major component(s). Con-
sequently, the chemical and isomeric purity of synthetic
7
either aq Na2CO3 in 1,2-dimethoxyethane (DME) (entry
5, Table) or NaOEt5 in benzene (entry 11) gave coupling
product 5 in poor yield, with a major side product, 10-un-
Synthesis 2000, No. 1, 113–118 ISSN 0039-7881 © Thieme Stuttgart · New York

114
X. Chen, J. G. Millar
PAPER
Cl
1) Catecholborane
2) H2O
Cl
(HO)2B
OH
(Ph3P)4Pd, K2CO3
OH
50%
100%
4
3
1) Swern oxidation
MgBr
(Ph3P)4Pd, C6H6
OH
Cl
OH
NC
NC
CN
CN
2)
96%
5
6
H
O
1
Scheme 1
decen-1-ol, resulting from deboronation. Use of DME as zation, but it proved more expeditious and efficient to re-
solvent8 or cosolvent did not completely suppress debor- move the unwanted EEE-isomer by selective Diels-Alder
onation, but DME/EtOH solvent mixtures enhanced the reaction with the powerful dienophile tetracyanoethylene
yield of 5 (Table, compare entries 3-7), in part because (TCNE).10 The sterically less hindered EEE-isomer react-
the mixed solvent resulted in a homogeneous reaction ed faster with TCNE at 0∞C than the EEZ-isomer 6, giving
mixture which appeared to favor the coupling reaction a mixture of the adducts 7a or 7b (Scheme 2) with un-
over deboronation. Among the bases tested, aq K2CO3 changed 6. Isomerically pure 6 was readily isolated from
proved most efficacious (Table). Surprisingly, addition of the mixture by flash chromatography on Florisil (chroma-
a large excess of trans-1,2-dichloroethylene decreased the tography on silica resulted in isomerization). The im-
yield of 5 (Table, entries 1 vs. 2 and 3 vs. 4).
provement in chemical and isomeric purity as compared
to previous reports is indicated by the melting point (48-
49ºC), 10-11ºC higher than previously reported (38ºC).3
Coupling of chloride 5 with excess cis-1-propenylmagne-
sium bromide9 proceeded smoothly in benzene at 0∞C, af-
fording triene alcohol 6 in excellent yield (96%), but Because the conjugated trienes were sensitive to acid,
contaminated with 6% of the corresponding EEE-isomer heat, and electrophilic attack, oxidation of 6 to the corre-
3. Compound 6 could be purified by repeated recrystalli- sponding aldehyde 1 proved problematic. It had been re-
Table Cross-coupling Reaction of Boronic Acid 4 with trans-1,2-Dichloroethylenea
Entry
Base
Molar ratio
Solvent
Conditions
Ratio of Productsb
dichloride:4
5:10-undecenol
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
aq K2CO3
aq K2CO3
2:1
5:1
2:1
5:1
2:1
2:1
2:1
2:1
2:1
2:1
3:1
2:1
2:1
2:1
2:1
4:1
DME/EtOH
DME/EtOH
DME/EtOH
DME/EtOH
DME
EtOH
THF
DME/EtOH
DME
DME/EtOH
C6H6
DME/EtOH
DME
DME/EtOH
DME/EtOH
THF
45°C, 22 h
45°C, 15 h
45°C, 20 h
45°C, 15 h
45°C, 15 h
45°C, 15 h
45°C, 20 h
45°C, 20 h
45°C, 5 h
25°C, 15 h
45°C, 4 h
45°C, 23 h
45°C, 23 h
25°C, 20 h
45°C, 16 h
25°C, 15 h
64
3
2
10
7
8
9
45
50
35
22
13
15
20
10
9
17
16
10
0
aq Na2CO3
aq Na2CO3
aq Na2CO3
aq Na2CO3
aq Na2CO3
aq NaHCO3
aq KOH
NaOH, EtOH
NaOEt, EtOH
KOBut, tBuOH
KOBut, tBuOH
KN(TMS)2
DBU
6
10
30
31
4
25
32
4
5
13
4
3
Ag2O
aTypical procedure, e.g., entry 3:trans-1,2-dichloroethylene (2 mmol) was added under Ar to a soln of (Ph3P)4Pd (6 mol%) in DME (5 mL) and
the mixture was stirred for 30 min at r.t. Compound 4 (1 mmol) in EtOH (2 mL) and 2M aq Na2CO3 (1 mL) were added sequentially, and the
mixture was heated at 45ºC with vigourous stirring for 20 h. After concentration, the residue was diluted with H2O and extracted with hexane.
The hexane layer was washed with brine and dried (Na2SO4).
bDetermined by GC. Semiquantitative comparisons of yields between entries were obtained by comparison of the peak areas of products
with those of triphenylphosphine from the catalyst.
Synthesis 2000, No. 1, 113–118 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Preparative Scale Syntheses
115
ported that oxidizing agents such as PCC and PDC thetic analysis of 2 revealed a convenient disconnection
resulted in degradation,2 and even the relatively mild between carbons 10 and 11. Thus, (2E,4E)-hexa-2,4-dien-
Dess-Martin periodinane reagent11 caused variable and 1-ol (sorbic alcohol) (8) was brominated with phosphorus
uncontrollable isomerization.2 In our hands, Swern tribromide at -10 ∞C,16 then treated with triphenylphos-
oxidation12-14 (oxalyl chloride and DMSO in CH2Cl2) with phine in toluene at room temperature to afford (2E,4E)-
a careful, cold workup gave a good yield of 1, albeit with hexa-2,4-dienyltriphenylphosphonium bromide (9) in
a small amount of isomerization (3%). Substituting THF 68% yield (Scheme 3). Wittig reaction of 9 with aldehyde
for CH2Cl2 as the solvent15 decreased isomerization 11 (prepared from 1,10-decanediol (10) in 2 steps) gave
(<1%), but the reaction did not go to completion.
10,12,14-hexadecatrienyl acetates 12 in 93% yield (EEE:
ZEE-isomer, 64:36).
NC
NC
CN
CN
1) PBr3, CH2Cl2
2) Ph3P, toluene
+
OH
PPh3Br-
+
OH
6
68%
6
8
9
1) Ac2O, Py
OH 2) Swern
(CH2)9OH
(CH2)9OH
HO
and/or
NC
NC
CN
CN
NC
NC
CN
CN
21%
10
11
7a
7b
9, n-BuLi, THF
93%
H
AcO
O
R
R
For EEE-isomer
For EEZ-isomer
NC
NC
CN
CN
NC
NC
CN
CN
K2CO3, MeOH
(CH2)9OAc
(CH2)9OH
12
1) Recrystallize
2) I2
3) Recrystallize
R
79% from 12
NC
NC
CN
CN
(EEE:ZEE=64:36)
13
Swern oxidation
83%
(CH2)9OH
Scheme 2
13
O
However, as with alcohol 6, treatment of crude aldehyde
1 with TCNE selectively removed the unwanted EEE-iso-
mer. After Florisil chromatography, 1 was obtained in
32% overall yield from 3, with isomeric purity > 99%. It
was difficult to determine the isomeric purity more accu-
rately because of slight isomerization (~1.5%) of 1 during
GC analysis, even with injector temperatures of 200 ºC.
Also, pure 1 was quite unstable, and polymerized to a
white solid at -20∞C, either as the pure material or in hex-
ane solution with 2,6-di-tert-butyl-4-methylphenol (BHT)
stabilizer, over the course of a few days to weeks. Conse-
quently, the purified material was stored as a dilute solu-
tion in frozen cyclohexane at -70ºC.
H
2
Scheme 3
The acetates 12 were hydrolyzed to crude alcohols 13
with anhydrous potassium carbonate in methanol, and the
ratio of EEE- to ZEE-isomers at this point remained un-
changed. Pure (10E,12E,14E)-hexadeca-10,12,14-trienol
(13) was readily obtained by recrystallization of the
trienol mixture from 5% Et2O in hexane (isolated yield
55%), with the remaining mother liquor being enriched in
the ZEE-isomer (84%). The mixed isomers in the liquor
were isomerized to a mixture rich in EEE-13 (71%) by ad-
dition of a catalytic amount of iodine and exposure to
light.2 Recrystallization yielded a second portion of EEE-
13 (24%), for a combined yield of 79%. Finally, Swern
oxidation gave 2 in 83% yield after recrystallization, with
no detectable isomerization during oxidation and purifica-
Synthesis of (10E,12E,14E)-Hexadeca-10,12,14-
trienal (2)
The synthesis of 2 was designed to take advantage of the
crystallinity of a logical precursor, the corresponding al-
cohol 13, and of the ease with which other stereoisomers
could be isomerized to the EEE configuration. Retrosyn-
Synthesis 2000, No. 1, 113–118 ISSN 0039-7881 © Thieme Stuttgart · New York

116
X. Chen, J. G. Millar
PAPER
13C NMR (CDCl3): d = 25.74, 29.03, 29.13, 29.40, 29.53, 32.63,
32.80, 63.08 (2¥C), 118.22, 126.04, 133.88, 136.31.
tion. Overall yield of 2 from 8 was 41%. The NMR spectra
of 2 closely matched those previously reported.2
MS: m/z 194 (M-HCl, 12), 135 (3), 114 (10), 101 (12), 90 (33), 88
In summary, short and efficient syntheses yielding alde-
hydes 1 and 2 in high isomeric purity have been devel-
oped. These syntheses, and the key purification steps, are
amenable to scaling up to multigram quantities. Further-
more, the route developed for 1 should also be applicable
to stereoselective syntheses of the EZZ- and EZE-isomers
by substitution of cis-1,2-dichloroethylene and trans-pro-
penylmagnesium bromide synthons into the appropriate
steps.
(100), 79 (45), 67 (42), 65 (64), 55 (50), 41 (75).
(10E,12E,14Z)-Hexadeca-10,12,14-trien-1-ol (6)
1,2-Dibromoethane (10 drops, approx. 0.4 mL) was added to a mix-
ture of Mg powder (50 mesh, 1.92 g, 80 mmol; Aldrich) in anhyd
THF (25 mL) to initiate the Grignard reaction. This was followed
by dropwise addition (Caution: vigorously exothermic!) of a solu-
tion of 97% cis-1-bromopropene (4.84 g, 40 mmol; Aldrich) in THF
(15 mL) at a rate sufficient to maintain gentle refluxing (Caution:
commercial batches of cis-1-bromopropene varied in isomeric puri-
ty. Purity was checked easily by GC, programming from 15 ºC). Af-
ter the addition was complete, the mixture was heated at 48-50 ∞C
for 1 h to assure completion of the reaction.
Mps are not corrected. 1H NMR (300 MHz) and 13C NMR (75 MHz)
spectra were recorded on a General Electric QE-300 instrument.
Electron impact mass spectra (70 eV) were recorded with a HP 5970
mass selective detector interfaced to an HP 5890 GC fitted with a
DB-5 column (20m ¥ 0.25mm i.d.). Routine GC analyses were car-
ried out on a HP 5890 GC fitted with a DB-5 column (20m ¥
0.32mm i.d.), and an injector temperature of 200 ºC to minimize
isomerizations. THF was purified by distillation from sodium/ben-
zophenone ketyl under Ar. Solvents for flash chromatography (hex-
ane and EtOAc), were distilled prior to use. All other solvents and
reagents were used as received. Unless otherwise specified, flash
chromatography was carried out using Florisil (100-200 mesh,
Acros Organics) because the weak acidity of silica gel resulted in
extensive isomerization of triene compounds. Moisture- and air-
sensitive reactions were carried out in oven-dried glassware under
Ar. Unless otherwise stated, extracts were dried over anhyd Na2SO4
and concentrated by rotary evaporation under reduced pressure.
NMR spectra of trienes were taken in DMSO-d6 rather than CDCl3
to avoid acid-catalyzed isomerization.
A mixture of 5 (2.31 g, 10 mmol) and (Ph3P)4Pd (0.58 g, 0.5 mmol)
in anhyd benzene (60 mL) was stirred at r.t. for 30 min, then cooled
to 0 ∞C. The freshly prepared cis-1-propenylmagnesium bromide
was added dropwise by syringe to the resulting suspension, and the
mixture was stirred at 0 ∞C for 2 h. The reaction was quenched with
ice-cold dilute aq NH4Cl (150 mL) and the resulting mixture was
extracted with hexane (600 mL). The organic extract was washed
with H2O (2¥80 mL) and brine (80 mL), dried, and concentrated.
Flash chromatography (30% Et2O in hexane) followed by recrystal-
lization from 5% Et2O in hexane (120 mL) at 5 ºC afforded 6 (2.26
g, 96% yield) as white needles, contaminated by 6% of the EEE-iso-
mer. To remove the EEE-isomer, TCNE (0.019 g, 0.15 mmol) was
added to a solution of 6 (0.35 g, 1.5 mmol) in Et2O (5 mL) at 0∞C,
and stirred for 30 min at 0 ºC. After removal of the solvent at r.t.,
the residue was purified by flash chromatography followed by re-
crystallization from hexane (10 mL) at 5 ºC to give pure 6 as white
crystals (0.32 g; mp: 48-49 ∞C (Lit.3 38 ∞C)) with no detectable iso-
meric or other impurities.
1H NMR (DMSO-d6): d = 1.21-1.36 (m, 14H), 1.68 (dd, 3H,
J = 7.2, 1.1 Hz), 2.03 (dt, 2H, J = 7.0, 6.9 Hz), 3.33 (dt, 2H, J = 6.2,
5.3 Hz), 4.28 (t, 1H, J = 5.3 Hz, OH), 5.42 (dq, 1H, J = 10.6, 7.2
Hz), 5.68 (dt, 1H, J = 14.2, 7.1 Hz), 5.94-6.19 (m, 3H), 6.40 (m,
1H).
13C NMR (DMSO-d6): d = 13.72, 25.94, 29.04, 29.18, 29.29, 29.38,
29.49, 32.61, 32.99, 61.15, 126.04, 126.26, 129.99, 131.06, 133.11,
135.26.
(1E)-11-Hydroxy-1-undecenylboronic Acid (4)
Boronic acid 4 was prepared by modification of a reported proce-
dure.5 Catecholborane (14.8 mL, 116 mmol; Lancaster) was added
dropwise to 10-undecyn-1-ol (3) (9.8 g, 58 mmol) in anhyd THF (20
mL) at r.t. After the evolution of H2 ceased, the mixture was heated
at 75 ∞C for 15 h. H2O (350 mL) was added to the cooled reaction
mixture, and the mixture was stirred at r.t. for 4 h. The resulting
white slurry was cooled in an ice-bath and filtered, rinsing the solid
with ice-cold H2O (3¥50 mL). The solids were re-suspended in H2O
(100 mL), cooled to 0 ∞C again and filtered off. The sticky white bo-
ronic acid 4 (12.4 g, 100%) was dried under aspirator vacuum, and
used without further purification.
MS: m/z 236 (M+, 30), 150 (2), 135 (4), 121 (5), 107 (20), 93 (49),
79 (100), 67 (10), 55 (11), 41 (30).
(E10,E12,Z14)-Hexadeca-10,12,14-trienal (1)
(10E,12E)-13-Chlorotrideca-10,12-dien-1-ol (5)
DMSO (1.1 mL, 15.6 mmol) in CH2Cl2 (5 mL) was added dropwise
to a stirred solution of oxalyl chloride (0.7 mL, 8.1 mmol) in CH2Cl2
(60 mL) at -78 ∞C. After stirring at -78 ºC for 5 min, impure alco-
hol 6 (1.3 g, 5.5 mmol) in CH2Cl2 (30 mL) was added dropwise. The
mixture was stirred at -78 ∞C for 20 min, Et3N (4.6 mL, 32.9 mmol)
was then added dropwise, the mixture was stirred a further 5 min,
and then allowed to warm to 0 ∞C. Ice-cold sat. NaHCO3 (50 mL)
was added and the resulting mixture was extracted with ice-cold
hexane (300 mL). The hexane extract was washed with ice-cold
brine (2¥50 mL), and dried. GC analysis indicated that the oxidation
was complete, but that there was about 9% of EEE-trienal 2 in the
mixture. The solvent was removed by rotary evaporation below 20
∞C, and the residue was dissolved in Et2O (20 mL) and cooled to 0
∞C. TCNE (0.10 g, 0.78 mmol) was added, and the mixture was
stirred at 0 ∞C for 30 min, monitoring by GC. The undesired EEE-
isomer was completely removed, although the GC chromatogram
still showed 1.5% of the EEE-isomer because of thermally induced
isomerization of the EEZ-isomer during the GC run. This small
amount of isomerization during analysis was confirmed by adding
A three-necked flask charged with (Ph3P)4Pd (2.08 g, 1.8 mmol)
and anhyd DME (120 mL) was flushed with Ar, and trans-1,2-
dichloroethylene (4.62 mL, 60 mmol) was introduced by syringe.
After stirring at r.t. for 30 min, a solution of boronic acid 4 (6.44 g,
30 mmol) in EtOH (60 mL) and 2M aq K2CO3 (30 mL) were added
sequentially. Heating at 45-50 ∞C with vigorous stirring for 22 h re-
sulted in a dark brown solution and a sticky white sludge on the bot-
tom of the flask. After concentration of the liquid portion by rotary
evaporation, the black residue was diluted with H2O (100 mL), ex-
tracted with hexane (600 mL), and the hexane extract was washed
with brine (2¥100 mL), dried and concentrated. The crude product
was purified by flash chromatography (10% EtOAc in hexane) to
afford 5 (3.46 g, 50% yield) as a viscous oil. Recrystallization from
hexane (150 mL) at -20ºC gave a white solid, mp: 36.0-37.5 ∞C.
1H NMR (CDCl3): d = 1.28-1.58 (m, 14H), 2.06 (dt, 2H, J = 6.9,
6.8 Hz), 3.64 (t, 2H, J = 6.5 Hz), 5.70 (dt, 1H, J = 15.1, 6.9 Hz),
5.97 (dd, 1H, J = 15.1, 10.6 Hz), 6.07 (d, 1H, J = 13.1 Hz), 6.41 (dd,
1H, J = 13.1, 10.6 Hz).
Synthesis 2000, No. 1, 113–118 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Preparative Scale Syntheses
Hexadeca-10,12,14-trienyl Acetates 12
117
another 15 mg of TCNE, and stirring for 20 min, after which the ra-
tio of EEE- to EEZ-isomers in the GC trace remained unchanged,
although the absolute amount of both was decreased. After concen-
tration, the crude product was purified by flash chromatography
(8% Et2O in hexane) to furnish aldehyde 1 (0.88 g, 68% yield) as an
almost colorless liquid.
1H NMR (DMSO-d6): d = 1.21-1.47 (m, 12H), 1.69 (dd, 3H,
J = 7.2, 1.1 Hz), 2.03 (dt, 2H, J = 7.0, 6.9 Hz), 2.37 (dt, 2H, J = 7.2,
1.3 Hz), 5.42 (dq, 1H, J = 10.6, 7.2 Hz), 5.67 (dt, 1H, J = 14.2, 7.1
Hz), 5.93-6.19 (m, 3H), 6.40 (m, 1H), 9.62 (t, 1H, J = 1.3 Hz).
A mixture of phosphonium salt 9 (21.5g, 51 mmol) and THF (120
mL) was cooled to -30 ∞C with a dry ice-acetone bath, BuLi (2.5M
in hexanes, 20.4 mL, 51 mmol) was added dropwise, and the mix-
ture was stirred at -30 ºC for 1 h. Aldehyde 11 (9.0 g, 42 mmol) in
THF (50 mL) was then added dropwise. After the addition was com-
plete, the mixture was warmed to r.t. over 1 h, then quenched with
ice-water (250 mL), and extracted with hexane (800 mL). The hex-
ane extract was washed with H2O (2¥100 mL) and brine (2¥100
mL), dried, and concentrated. Flash chromatography (10% Et2O in
hexanes) of the residue gave acetates 12 (8.9g, 76% yield based on
11, EEE: ZEE, 64:36 by GC), followed by alcohols 13 (1.7g, 17%
yield).
13C NMR (DMSO-d6): d= 13.70, 21.94, 28.98 (2¥C), 29.15 (2¥C),
29.21, 32.61, 43.42, 126.03, 126.25, 129.99, 131.06, 133.09,
135.23, 203.89.
MS: m/z 234 (M+, 8), 148 (1), 135 (1), 121 (5), 107 (15), 93 (35), 79
(E10,E12,E14)-Hexadeca-10,12,14-trien-1-ol (13)
Anhyd K2CO3 (4.8g, 34.8 mmol) was added in portions to an ice-
cold solution of the acetates 12 (8.8 g, 31.6 mmol) in MeOH (50
mL), the mixture was stirred at r.t. for 1 h, then quenched with ice-
cold H2O (40 mL). The mixture was extracted with hexane (400
mL), and the hexane phase was washed with brine (2¥50 mL),
dried, and concentrated. The ratio of EEE- to ZEE-isomers was un-
changed by GC analysis. After concentration at r.t., the residue was
purified by flash chromatography (20% Et2O in hexanes) to afford
the mixed trienols 13 (7.1g, 95% yield) as a white solid. Recrystal-
lization from 5% Et2O in hexane (400 mL) at 5 ºC gave pure EEE-
trienol 13 (4.1 g, 55% yield) as colorless needles, mp: 73-74 ∞C
(Lit.2 71-72.5 ∞C; Lit.3 42 ∞C).
1H NMR (CDCl3): d = 1.27-1.58 (m, 14H), 1.76 (d, 3H, J = 6.5
Hz), 2.07 (dt, 2H, J = 7.0 Hz), 3.63 (t, 2H, J = 6.6 Hz), 5.63-5.69
(m, 2H), 6.00-6.07 (m, 4H).
13C NMR (CDCl3): d = 18.25, 25.72, 29.15, 29.34, 29.40 (2¥C),
29.52, 32.79 (2¥C), 63.07, 128.74, 130.40, 130.61, 130.68, 131.78,
134.46.
(100), 67 (10), 55 (10), 41 (40).
(2E,4E)-Hexa-2,4-dienyltriphenylphosphonium Bromide (9)
Bromide 9 was prepared from (2E,4E)-hexa-2,4-dien-1-ol (8) (10 g,
102 mmol; Aldrich) by the reported procedure,16 with the workup
procedure modified as follows. After the reaction was quenched
with ice-cold sat. NaHCO3 (30 mL) at -10 ∞C, the resulting mixture
was extracted with pentane (350 mL), and the organic phase was
washed with brine (2¥50 mL), and dried. After removal of the pen-
tane and CH2Cl2 by rotary evaporation at r.t., the crude bromide (~
16 g) was transferred to a wide-mouth brown glass bottle containing
triphenylphosphine (28 g, 107 mmol) and anhyd toluene (160 mL).
The mixture was kept at r.t. for 3 d, and the resulting crystalline
product was collected by suction filtration, rinsing the solids with a
small amount of toluene. After pumping under vacuum (0.01 mm
Hg) at r.t. for 6 h to remove traces of toluene, 29 g of the crystalline
phosphonium salt 9 were obtained (68% from 8); mp: 158–160 °C.
1H NMR (CDCl3): d = 1.65 (br d, 3H, J = 7.1 Hz), 4.66 (dd, 2H,
J = 7.5; JP-H = 15.3 Hz), 5.27 (dq, 1H, J = 14.7, 7.1 Hz), 5.63 (m,
1H), 5.88 (dd, 1H, J = 14.7, 10.6 Hz), 6.31 (ddd, 1H, J = 15.2, 10.2;
JP-H = 5.1 Hz), 7.56–7.95 (m, 15H).
MS: m/z 236 (M+, 50), 149 (2), 135 (2), 121 (6), 107 (35), 93 (55),
79 (100), 67 (10), 55 (10), 41 (42).
The mother liquor containing 84% of the ZEE-isomer was evaporat-
ed to dryness, the residue was dissolved in 1:1 hexane-Et2O (1 L)
containing a few crystals I2 (~ 5 mg), and kept in laboratory light for
10 min. The solution was washed with sat. Na2S2O3 (30 mL) and
brine (2¥100 mL), and dried. GC analysis showed that the EEE-iso-
mer now constituted 71% of the mixture. After concentration and
recrystallization as before, a further 1.8g (24%) of pure EEE-13 was
obtained.
10-Acetoxydecanal (11)
1,10-Decanediol (10) (34.8 g, 200 mmol) was dissolved in a mix-
ture of THF (250 mL), pyridine (17 mL, 210 mmol) and dimethyl-
aminopyridine (0.5 g) at r.t. over 3 h. The homogeneous solution
was cooled to 0 ∞C, and Ac2O (18.9 mL, 200 mmol) was added
dropwise over 45 min with a syringe pump. The resulting white sus-
pension was stirred at 0 ∞C for 1 h and at r.t. for a further 19 h. After
concentration, the mixture was partitioned between hexane (250
mL) and 1M HCl (250 mL). The aqueous phase was extracted again
with hexane (3¥100 mL), the combined organic phase was washed
with 1M HCl (100 mL) and brine (2¥100 mL), dried, and concen-
trated. Silica gel flash chromatography (35% EtOAc in hexanes)
gave a moderate yield of 10-acetoxydecanol (11.7 g), which was
oxidized to 10-acetoxydecanal (11) using the standard Swern oxida-
tion procedure,12 giving 11 (9.1 g) as a viscous oil after silica gel
flash chromatography (25% EtOAc in hexane). The yield was not
optimized in either of the two steps.
(E10,E12,E14)-Hexadeca-10,12,14-trienal (2)
Employing the same Swern oxidation procedure used for 1, EEE-al-
cohol 13 (5.5 g, 23.3 mmol) was oxidized to aldehyde 2. Recrystal-
lization from hexane at -20 ∞C gave 2 (4.5g, 83%) as white crystals,
mp: 43-44 ∞C. Previously, this compound had only been reported
as a liquid.2,3
1H NMR (CDCl3): d = 1.29-1.64 (m, 12H), 1.76 (d, 3H, J = 6.5
Hz), 2.07 (dt, 2H, J = 7.0 Hz), 2.41 (dt, 2H, J = 7.3, 1.8 Hz), 5.62-
5.70 (m, 2H), 5.99-6.09 (m, 4H), 9.76 (t, 1H, J = 1.8 Hz).
13C NMR (CDCl3): d = 18.26, 22.06, 29.07, 29.13, 29.25, 29.29
(2¥C), 32.76, 43.90, 128.78, 130.45, 130.57, 130.72, 131.77,
134.36, 202.94.
MS: m/z 234 (M+, 10), 148 (1), 135 (1), 121 (2), 107 (15), 93 (20),
79 (100), 67 (10), 55 (12), 41 (30).
1H NMR (CDCl3): d = 1.28-1.67 (m, 14H), 2.05 (s, 3H), 2.42 (dt,
2H, J = 7.3, 1.5 Hz), 4.05 (t, 2H, J = 6.7 Hz), 9.76 (t, 1H, J = 1.5
Hz).
13C NMR (CDCl3): d = 20.97, 22.01, 25.84, 28.55, 29.08, 29.12,
29.22 (2¥C), 43.85, 64.95, 173.20, 202.85.
MS: m/z 171 (M-CH3CO, 2), 136 (1), 126 (2), 111 (15), 97 (5), 83
(7), 69 (32), 55 (30), 43 (100), 41 (25).
Acknowledgement
This work was supported by the Defense Advanced Research Pro-
jects Agency, contract # 66001-98-C-8628.
Synthesis 2000, No. 1, 113–118 ISSN 0039-7881 © Thieme Stuttgart · New York

118
X. Chen, J. G. Millar
PAPER
(10) Ramaiah, P.; Pegram, J. J.; Millar, J. G. J. Org. Chem. 1995,
60, 6211.
References
(1) Tumlinson, J. H.; Brennan, M. M.; Doolittle, R. E.; Mitchell,
E. R.; Brabham, A.; Mazemenos, B. E.; Baumhouer, A. H.;
Jackson, D. M. Arch. Insect Biochem. Physiol. 1989, 10, 255.
(2) Doolittle, R. E.; Brabham, A.; Tumlinson, J. H. J. Chem. Ecol.
1990, 16, 1131.
(3) Tellier, F. Bioorg. Med. Chem. Lett. 1991, 1, 635.
(4) Ando, T.; Ogura, Y.; Koyama, M.; Kurane, M.; Uchiyama,
M.; Seol, K. Y. Agric. Biol. Chem. 1988, 52, 2459.
(5) Miyaura, H.; Suginome, H. Tetrahedron 1983, 39, 3271.
(6) A recent review: Miyaura, N.; Suzuki, A. Chem. Rev. 1995,
95, 2457.
Dhar, D. N. Chem. Rev. 1967, 67, 611.
(11) Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4155.
(12) Mancuso, A. J.; Huang, S. L.; Swern, D. J. Org. Chem. 1978,
43, 2480.
(13) Mancuso, A. J.; Swern, D. Synthesis 1981, 165.
(14) Tidwell, T. T. Synthesis 1990, 857.
(15) Lewis, M. D.; Duffy, J. P.; Heck, J. V.; Menes, R. Tetrahedron
Lett. 1988, 29, 2279.
(16) Kim, T.; Mirafzal, G. A.; Liu, J.; Bauld, N. L. J. Am. Chem.
Soc. 1993, 115, 7653.
(7) Watanabe, T.; Miyaura, N.; Suzuki, A. Synlett 1992, 207.
(8) Gronowitz, S.; Bobosic, V.; Lawitz, K. Chem. Scr. 1984, 23,
120.
(9) Ratovelomanana, V.; Linstrumelle, G. Tetrahedron Lett.
1981, 22, 315.
Article Identifier:
1437-210X,E;2000,0,01,0113,0118,ftx,en;M01299SS.pdf
Synthesis 2000, No. 1, 113–118 ISSN 0039-7881 © Thieme Stuttgart · New York