Synthesis of Tetradecapentaenoic Acid Derivatives

Article abstract of DOI:10.1134/S1070363219100037

A 12-stage method for the stereoselective synthesis of tetradecapentaenoic acid derivatives using phosphoric reagents was developed. The key step in the synthesis is the Z-selective Wittig reaction between sorbaldehyde and triphenylphosphonium (6-methoxycarbonyl)hexanilide, as well as the Ramirez-Corey-Fuchs reaction and the Trost-Kazmaier rearrangement. The synthesized (2E,4E,8Z,10E,12E)-N-isobutyltetradeca-2,4,8,10,12-pentaenamide corresponds to a natural compound called γ-Sansho?l.

Full text of DOI:10.1134/S1070363219100037

ISSN 1070-3632, Russian Journal of General Chemistry, 2019, Vol. 89, No. 10, pp. 1998–2004. © Pleiades Publishing, Ltd., 2019.
Russian Text © The Author(s), 2019, published in Zhurnal Obshchei Khimii, 2019, Vol. 89, No. 10, pp. 1496–1503.
Synthesis of Tetradecapentaenoic Acid Derivatives
A. O. Kolodyazhnayaa and O. I. Kolodyazhnya*
V.P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry of the National Academy of Sciences of Ukraine,
ul. Murmanskaya 1, Kiev, 02094 Ukraine
*e-mail: olegkol321@gmail.com
Received May 4, 2019; revised May 4, 2019; accepted May 12, 2019
Abstract―A12-stage method for the stereoselective synthesis of tetradecapentaenoic acid derivatives using phos-
phoric reagents was developed. The key step in the synthesis is the Z-selective Wittig reaction between sorbaldehyde
and triphenylphosphonium (6-methoxycarbonyl)hexanilide, as well as the Ramirez–Corey–Fuchs reaction and
the Trost–Kazmaier rearrangement. The synthesized (2E,4E,8Z,10E,12E)-N-isobutyltetradeca-2,4,8,10,12-penta-
enamide corresponds to a natural compound called γ-Sanshoöl.
Keywords: Wittig reaction, Horner–Emmons reaction, Ramirez–Corey–Fuchs reaction, Trost–Kazmaier rear-
rangement, tetradecapentaenoic acid derivatives
DOI: 10.1134/S1070363219100037
Tetradecapentaenoic acid derivatives are a class of
polyunsaturated fatty acid amides found in various species
of tropical plants, in particular Zanthoxylum bungeanum
Maxim, Zanthoxylum piperitum, Zanthoxylum ailanthoi-
des, etc., which attract the attention of many chemists.
These aroma trees or shrubs grow in Africa, South and
North America regions, as well as in Australia, Japan
and China. In Asian countries, zanthoxylum is known
as Japanese (or Sichuan) pepper [1–4]. To date, about
50 compounds of the class of polyunsaturated fatty acid
amides have been isolated from various species of zan-
thoxylum and related plants. Amides of polyunsaturated
fatty acids, which exhibit a diverse biological activity, are
of special interest. They show antioxidant, anthelmintic,
pronounced antiproliferative and apoptotic activity [5, 6].
Of particular interest are representatives of Sanshoöl se-
ries. γ-Sanshoöl 1 inhibits human acyl-CoA-cholesterol-
α-cyltransferase. Some representatives of the Sanshoöl
series are presented in Scheme 1 [7].
Despite the interesting pharmacological characteris-
tics, the instability of these compounds (isomerization,
oxidation, polymerization and/or photodegradation) due
to the presence of a conjugated triene structure makes
it difficult to obtain them by synthetic methods. Of par-
ticular difficulty is the achievement of high selectivity
in the formation of Z- and E-configurations of multiple
carbon-carbon bonds. Several synthetic approaches to the
preparation of tetradecapentaenoates have been known.
Scheme 1.
CONHR
C(O)NHR
C(O)NHR
H-Sanshoöl
,
-Sanshoöl
1
J
D-Sanshoöl
R = i-Bu, CH
2CMe2OH
CONHR
CONHR
-Sanshoöl
E
-Sanshoöl
G
R = i-Bu, CH
,
Me.
C(OH)
CH2
2
2C(OH)Me2
1998

SYNTHESIS OF TETRADECAPENTAENOIC ACID DERIVATIVES
1999
Most often, the Horner reaction or the Wadsworth–Em-
mons reaction is used the key stage to construct the
2,4-diene motif [5–10]. Several known synthetic ap-
proaches involve the Horner reaction to form the C2–C3
double bond [2–9]. Crombie and Fisher [5, 6] have
used MEM-protected 4-pentyn-1-ol in the synthesis of
tetradecapentaenoates. 4-Pentyn-1-ol was converted in
two steps into MEM-protected (E)-6-hydroxyhex-2-enal
by reacting with ethyl orthoformate in the presence of
Grignard reagent followed by stereoselective reduction
of the triple bond and pH-controlled deacetalization.
The Wadsworth–Emmons condensation and the Wittig
reaction with (2E,4E)-hexa-2,4-dienal leads to the for-
mation of the corresponding tetradecapentaenoate [5–8].
The strategy of these syntheses was the formation of the
double bonds C2=C3, C4=C5 and C8=C9 through stereose-
lective hydrogenation, the Wadsworth–Emmons reaction,
and the Wittig reaction at key stages [7, 8]. The authors
have studied the formation of E-configured double bond
C8=C9, the availability of basic synthetic blocks and the
possibility of obtaining modified analogues. In [9], the
Wadsworth–Emmons,Arbuzov, andAppel reactions have
been used to construct the dodecpentaene backbone. In
[8], the Horner reaction has been used, which proceeded
with the formation of the E- and Z-configured double
bond C4=C5 [7].
of butyllithium (or palladium acetate, potassium tert-bu-
toxide) in toluene. Further treatment of the alkyne formed
with triphenylphosphine according to the Trost–Kazmaier
method [14] provided tetradecapentaenoic acid.
The 12-stage method for the synthesis of tetradecapen-
taenoicacidbasedonthisstrategyispresentedinScheme2.
Initially, hexadieneol 2 was oxidized with pyridine sul-
fur trioxide complex according to the Parikh–Doering
procedure [15, 16] with the formation of sorbaldehyde
3. The second reaction component, phosphonium salt 6,
was obtained from 6-bromohexanoic acid 4 and ester 5.
Phosphonium salt 6 was then used in the Wittig reaction
with aldehyde 3 (Scheme 2).
The most important synthesis task was to achieve
high stereoselectivity (Z) at the stage of formation of
compound 7 having a Z,E-system of double bonds. To
this end, we developed a Z-selective Wittig reaction
without the use of metal salts. Thus, methyl (6Z,8E,10E)-
dodeca-6,8,10-trienoate 7 was obtained as a result of the
Z-selective Wittig reaction between phosphonium salt 6
and sorbaldehyde 3 (Scheme 2). First, phosphonium salt
6 reacted with sodium hexamethyldisilazane to generate
phosphorus ylide not complexed with a metal halide,
which was then introduced into the Wittig reaction with
sorbaldehyde. When carrying out the Wittig reaction in
salt-free conditions, it is possible to significantly increase
the Z-selectivity of the reaction [17]. The direct reaction
of phosphonium salts with aldehydes in the presence of
appropriate bases, for example butyl lithium, furnished
α-carbon metallized phosphonium salts, which react
with aldehydes by the Wittig reaction to give single E-
isomer or a mixture of E- and Z-alkenes. For example,
as a result of the reaction of phosphonium salt 6 with
sorbaldehyde in the presence of cesium carbonate, a
mixture of Z- and E-isomers of methyl (8E,10E)-dodeca-
6,8,10-trienoate 7 was obtained in low yield [18]. The
Z-stereoselectivity of the Wittig reaction is explained by
the simultaneous [2+2] cycloaddition of the C=O group
to the ylide P=C bond. As a result of synchronous [2+2]
cycloaddition of the ylide to the carbonyl group, oxa-
phosphetane having a cis configuration is formed. This
type of transformation is achieved if the convergence of
the reagents takes place in accordance with the Wood-
ward–Hoffmann rules and leads to minimal adverse steric
repulsion between the substituents R1 and R2 (Scheme 3).
At the second stage of the reaction, syn-elimination oc-
curs, which leads to the formation of the Z-configured
olefin. Thus, simultaneous cycloaddition happens with
a four-site transition state, in which steric factors and
Of some interest is the development of the synthesis
of compound 1, which would make it possible to obtain
a stereochemically pure product containing a Z,E-2,4-
diene group [9, 10]. To obtain a compound such as
γ-Sanshoöl, the stereoselective Wittig reaction can be
used. Therefore, we set a goal to obtain a diene fragment
of this compound using the Ramirez–Corey–Fuchs reac-
tion [11, 12], which should result in the formation of an
alkyne moiety with its subsequent rearrangement into
diene [3, 13]. The Ramirez–Corey–Fuchs reaction is
used to convert aldehyde to alkyne. At the first stage, the
reaction of triphenylphosphine with tetrabromomethane
afforded dibromomethylenephosphorane. Further the
Wittig reaction with aldehyde resulted in 1,1-dibromole-
fin. At the second stage, the obtained dibromolefin was
converted into alkyne by the Fritsch–Buttenberg–Wiehell
rearrangement (the reaction whereby haloethylenes rear-
ranges to alkynes under the action of strong bases) [13].
The Ramirez–Corey–Fuchs reaction is combination of
the Wittig reaction and the Fritsch–Buttenberg–Wiehell
rearrangement, as a result of which 1,1-dibromalkene is
converted into the corresponding alkyne in the presence
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 89 No. 10 2019

2000
KOLODYAZHNAYA, KOLODYAZHNY
Scheme 2.
Py·SO3
OH
O
Me
N
2SO, Et3
2
3
Me] Br-
CO2
PPh3
MeOH
P+
Br
H
CO2
Br
Me
CO2
[Ph3
4
5
6
LiAlH4
NaN(SiMe
3
)
3 2
Ph3P
Me
CO2
OH
H
C6
Me
CO2
6
8
7
Ph3P + CBr4
Ph3P=CBr2
Br
Py·SO3
Me
(1) BuLi
(2) H2O
O
N
2SO, Et3
Br
H
11
9
10
NaOH
MeOH
BuLi
Me
Ph3P, toluene, ǻ
ClCO2
PhOH
H
CO2
Me
CO2
Me
CO2
12
13
14
RNH2
HATU
CONHR
15, 16
R = i-Bu (15), Bu (16).
the hybridization of the phosphorus atom favor the Z-
stereoselectivity of the reaction [17].
hyde 9 was reacted with triphenylphosphine and carbon
tetrabromide to obtain dibromolefin 10, which was then
converted to alkyneoate 11 [3] under the action of butyl
lithium. The reaction of compound 11 with butyl lithium
and methyl chloroformate makes it possible to replace the
hydrogen atom in the terminal CH alkynyl group with a
methoxycarbonyl group.At the next stage, alkyne 12 was
rearranged to pentaene 13 with high stereoselectivity and
yield according to the Trost–Kazmaier method by heating
alkyne with triphenylphosphine and phenol in toluene.
Further hydrolysis of ester 13 with sodium hydroxide
in methanol led to the formation of 2E,4E,8Z,10E,12E-
tetradecapentaenoic acid 14 with high stereochemical
The Wittig reaction in the presence of cesium carbon-
ate is an asynchronous cycloaddition at the P=C and C=O
bonds due to the formation of cesium complex with the
phosphonium salt, which reacts with sorbaaldehyde and
favors the E-stereoselectivity of the Wittig reaction. As a
result, a mixture of Z- and E-alkenes was formed.
At the next stage of the synthesis, compound 7 was
reduced with lithium aluminum hydride to alcohol 8,
which was oxidized using the Parikh–Doering procedure
to give aldehyde 9 in high yield (Scheme 2). Then, alde-
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 89 No. 10 2019

SYNTHESIS OF TETRADECAPENTAENOIC ACID DERIVATIVES
2001
Scheme 3.
O
R1
Ph3P
H
Ph3P=CHR1
+
R2
H
Ph
R1
H
R1
H
R2
H
R2
P
Ph
Ph
ꢀ
Ph3PO
O
R2
CH=O
O
R1
H
H
Ph3P
R2
H
R1 = (CH ) CO Me; R2 = CH CH=CH–CH=C.
2 5
2
3
purity. At the last stage of the synthesis, amidation of
acid 14 with such primary amines as isobutylamine or
n-butylamine in the presence of Carpino reagent (HATU)
[19] led to the formation of amides 15 and 16 with yields
of 30 and 32%.
NMR spectra were recorded on a BrukerAvance DRX
400 or 500 spectrometer from CDCl3 solutions. GLC-MS
analysis was performed using an Agilent 1100 HPLC
instrument equipped with diode array and mass selective
detector Agilent LC/MSD SL.
Methyl 6-bromohexanoate (5). To 300 mL of
methanol were added dropwise with cooling and stirring
30 mL (0.384 mol) of thionyl chloride and then 50 g
(0.256 mol) of 6-bromohexanoic acid. The reaction
mixture was refluxed for 3 h with stirring. After removal
of the solvent, a viscous liquid was obtained, which was
used without further purification. Yield 53.5 g (100%).
1Н NMR spectrum, δ, ppm: 1.45 m (2H, CH2), 1.64 m
(2H, CH2), 1.77 m (1H, CH2), 1.86 m (1H, CH2), 2.31
m (2H, CH2), 3.39 m (1H, CH2Br), 3.52 m (1H, CH2Br),
3.65 s (3H, МeO).
Structure, stereochemical homogeneity and purity of
compounds 15 and 16 were confirmed by NMR spectros-
copy and GLC mass spectrometry methods. In the 1H and
13C NMR spectra, signals of all the groups included in the
molecule of compounds 15 and 16 of the corresponding
intensity and multiplicity were detected. In particular, the
signals of protons of multiple C=C bonds there were in
the region of 5–6 ppm, and the signals of carbon atoms
are in the region of 120–130 ppm. The signal of the C=O
group was also detected at ~167 ppm. The spectral and
physicochemical characteristics of amide 15 correspond
to those of the natural compound γ-Sanshoöl isolated
from Zanthoxylum piperitum, Zanthoxylum ailanthoides
plants, etc. [20]. Chromatography-mass spectrometry data
indicate a high purity of the obtained compounds.
(6-Methoxy-6-oxohexyl)triphenylphosphonium
bromide (6). A solution of 67.1 g (0.26 mol) of triphe-
nylphosphine in 500 mL of chloroform was added to a
solution of 53.5 g (0.26 mol) of methyl 6-bromohexano-
ate 5 in 500 mL of chloroform. The reaction mixture was
refluxed for 3 days, then cooled to room temperature.
The solvent was evaporated under reduced pressure. To
the residue was added 500 mL of methyl tert-butyl ether.
The resulting mixture was stirred for 1 h, then filtered and
evaporated. The residue was dried in vacuum. Yield 83 g
(70%). 1НNMRspectrum, δ, ppm:1.59m(2H, CH2), 1.7m
(2H, CH2), 2.4 m (2H, CH2), 3.6 s (3H, CH3O), 3.857 m
(2H, CH2Br), 7.3 m and 7.6 m (15H, C6H5). 13C NMR
In conclusion, a stereoselective 12-stage method for
the synthesis of tetradecapentaenoic acid derivatives
using phosphorus reagents (Z-selective Wittig reaction,
Ramirez–Corey–Fuchs
reaction,
Trost–Kazmaier
rearrangement) was developed. A key step in the
synthesis is the Z-selective Wittig reaction between
synthetically available sorbaldehyde and (6-ethoxy-6-
oxohexyl)triphenylphosphonium bromide.
spectrum, δC, ppm (J, Hz):22.7, 22.3, 22.7, 24.0 d (1JPC
7.0), 30.0 d (3JPC = 8.0), 33.9, 52.5, 117.8 d (1JPC
=
=
EXPERIMENTAL
90.0), 130, 133 d (JPC = 10.0), 134.5, 174. 31P NMR
spectrum: δР 25.0 ppm.
Reagents, silica gel and TLC plates (Polygram SILG/
UV254) were purchased from Fluka and Merck.
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 89 No. 10 2019

2002
KOLODYAZHNAYA, KOLODYAZHNY
(2E,4E)-Hexa-2,4-dienal (3). To a solution of 20 g
cooling to 0°C to a suspension of 2.55 g (0.067 mol) of
lithium aluminum hydride in 100 mL of THF. The result-
ing mixture was stirred for 1 h at room temperature, and
then water was added. The precipitate was filtered off, the
filtrate was evaporated. The residue was chromatographed
(methylene chloride–ethyl acetate–hexane, 20 : 5 : 75).
(0.2 mol) of (2E,4E)-hexa-2,4-diene-1-ol 2 in 300 mL of
DMSO were added 85 mLof triethylamine (0.6 mol) and
97.3 g (0.6 mol) of Py.SO3 complex with cooling. The
resulting mixture was stirred at room temperature for 3 h,
then poured into ice water and extracted with methyl tert-
butyl ether. The combined organic extracts were washed
several times with water. The solvent was evaporated
and the residue was distilled. Yield 15 g (84%), bp 60°C
(20 mm Hg). 1Н NMR spectrum, δ, ppm (J, Hz): 1.89 s
(3H, CH3), 6.07 m (1H, CH), 6.29 m (1H, CH), 7.02 m
(1H, CH), 7.26 m (1H, CH), 9.52 d (1H, CHO, J = 8.0).
1
Yield 5 g (82%), yellow liquid. Н NMR spectrum, δ,
ppm (J, Hz): 1.4 m (4H, CH2), 1.5 m (4H, CH2), 1.77 m
(3H, CH3), 2.2 m (2H, CH2), 3.64 t (2H, CH2O, J = 8.0),
5.39 m (1H, CH), 5.69 m (2H, CH), 6.00 m (1H, CH),
6.12 m (1H, CH), 6.34 m (1H, CH).
(8E,10E)-Dodeca-6,8,10-trienal (9). To a solution of
5.0 g (0.028 mol) of (8E,10E)-dodeca-6,8,10-trien-1-ol
8 in 100 mL of absolute dimethyl sulfoxide was added
11.5 mL (0.083 mol) of triethylamine, then was added
portionwise with cooling 13.25 g (0.083 mol) Py.SO3
complex. The resulting mixture was stirred at room tem-
perature for 3 h, then poured into ice water and extracted
with methyl tert-butyl ether. The combined extracts were
washed three times with water and a saturated solution of
sodium chloride. The resulting solution was concentrated
under reduced pressure, the residue was chromatographed
(methylene chloride–ethyl acetate–hexane, 20 : 5 : 75).
Yield 4 g (80%). 1Н NMR spectrum, δ, ppm (J, Hz):1.64
m (2H, СH2), 1.77 m (3H, СH3), 2.22 m (2H, СH2), 2.30
Methyl (8E,10E)-dodeca-6,8,10-trienoate (7). a. To
a solution of 73 g (0.16 mol) of (6-ethoxy-6-oxohexyl)
triphenylphosphonium bromide 6 and 15 g (0.16 mol)
of (2E,4E)-hexa-2,4-dienal 3 in 1000 mL of methylene
chloride was added 200 g (0.62 mol) of cesium carbon-
ate. The resulting mixture was refluxed for 24 h, then
celite was added. The mixture was stirred for another
10 min at room temperature, then filtered and evaporated.
To precipitate of triphenylphosphine oxide, 100 mL of
hexane was added to the residue. The precipitate was
filtered off, the filtrate was evaporated. The residue was
chromatographed (ethyl acetate–hexane, 10 : 90). Yield
7 g (21%), yellowish liquid, a mixture of Z- and E-isomers
in a ratio of 3 : 1 [18].
m (2H, СН2), 5.40 d. t (1H, CH=C, 3JHH = 11.0, 3JHH
=
8.0), 5.73 d. q (1H, CH=C, 3JHH = 14.0, 3JHH = 8.0), 6.05
m (3H, CH=C), 6.31 m (1H, CH=C), 9.76 s (1H, CHO).
13C NMR spectrum, δC, ppm: 18.5, 22.0, 27.5, 28.2, 43.7,
126.0, 127.6, 131.0, 131.8, 132.2, 132.6, 202.4. Found,
%: C 81.05; H 10.38. C12H18O. Calculated, %: C 80.85;
H 10.18.
b. The corresponding ylide was generated by the Best-
mann method [21, 22] from 73 g (0.16 mol) of (6-ethoxy-
6-oxohexyl)triphenylphosphonium bromide 6 in 500 mL
of benzene and 0.2 mol of lithium hexamethylsilazane.
To the reaction mixture was added 15 g (0.16 mol) of
aldehyde 3. The mixture was stirred overnight at room
temperature, then filtered and evaporated. To precipitate
triphenylphosphine oxide, 100 mL of hexane was added
to the residue. The precipitate was filtered off, and filtrate
was evaporated. The residue was chromatographed (ethyl
acetate–hexane, 10:90). Yield 22 g (65%), yellowish liq-
uid. 1Н NMR spectrum, δ, ppm: 1.42 m (2H, CH2), 1.65
m (2H, CH2), 1.77 m (3H, CH3), 2.21 m (2H, CH2), 2.32
m (2H, CH2), 3.67 s (3H, CH3), 5.64 m (1H, CH), 5.72
m (1H, CH), 6.02 m (2H, CH + CH), 6.19 m (1H, CH),
6.35 m (1H, CH), 6.46 m (1H, CH). 13C NMR spectrum,
δC, ppm: 18.0, 18.4, 24.5, 28.0, 29.1, 34.0, 60.0, 126.0,
128.6, 130.7, 131.2, 132.0, 133.0, 173.9. Found, %: C
75.6; H 9.8. C13H20O2. Calculated, %: C 74.96; H 9.68.
(9E,11E)-1,1-Dibromotrideca-1,7,9,11-tetraene
(10). A solution of 26.23 g (0.1 mol) of triphenylphos-
phine in 100 mL of methylene chloride was added
dropwise with cooling to –70°C to a solution of 17.8 g
(0.054 mol) of carbon tetrabromide in 100 mL of methy-
lene chloride. The mixture was stirred for 30 min, then
the temperature was raised to 0°C, and a solution of 4 g
(0.022 mol) of (8E,10E)-dec-6,8,10-trienal 9 in 15 mLof
methylene chloride was added. The resulting mixture was
stirred for 1 h at room temperature, and then hexane was
added to precipitate triphenylphosphine oxide. The solu-
tion was decanted from the precipitate. The precipitate
was dissolved in methylene chloride, and then hexane was
added followed by decantation. The combined extracts
were evaporated in vacuum, the residue was chroma-
tographed (methylene chloride–hexane, 20 : 80). Yield
(8E,10E)-Dodeca-6,8,10-trien-1-ol (8). A solution
of 7 g (0.034 mol) of methyl dodec-6,8,10-trienoate 7
in 100 mL of THF was added dropwise with stirring and
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SYNTHESIS OF TETRADECAPENTAENOIC ACID DERIVATIVES
2003
3.6 g (48%). 1Н NMR spectrum, δ, ppm (J, Hz): 1.24 d.
d (2H, CH2, 3JНН = 4.0, 3JНН = 4.0), 1.54 m (2H, CH2),
1.75 d (3H, CH3, 3JНН = 8.0), 2.07 m (2H, СН2), 2.2 m
(2H, СН2), 5.38 m (1H, CH=C), 5.70 m (1H, CH=C),
6.08 m (2H, CH=C), 6.37 m (1H, CH=C). Found, %: C
46.28; H 5.25; Br 48.21. C13 H18 Br2. Calculated, %: C
46.74; H 5.43. Br 47.83.
with stirring 1.9 g (0.047 mol) of sodium hydroxide. The
mixture was stirred at room temperature for 2 h. Methanol
was evaporated under reduced pressure, and the residue
was dissolved in 30 mL of water. The reaction product
was extracted three times with diethyl ether, the aqueous
layer was acidified with 1 N. HCl solution to pH = 1. The
combined extracts were washed with saturated sodium
chloride solution, dried with Na2SO4 and concentrated
under reduced pressure. The residue was recrystallized
from CHCl3–hexane. Stereochemically pure acid 14 ob-
tained was unstable when heating. Yield 0.55 g (25%).
1Н NMR spectrum, δ, ppm (J, Hz): 1.78 d (3H, CH3,
3JНН = 7.0), 2.30 m (4H, CH2), 5.34 m (1H, HC=C), 5.74
m (2H, СН=С), 5.77 m (1H, CH=C), 6.08 t (1H, СН=С,
3JНН = 11.0), 6.20 m (4H, СН=С), 6.30 m (1H, СН=С),
7.33 d. d (1H, СН=С, 3JНН = 16.0, 4JНН = 10). 13C NMR
spectrum, δC, ppm: 18.5, 27.1, 32.2, 120.8, 124.4, 125.9,
126.7, 127.2, 130.7, 131.3, 1321, 139.0, 148.4, 170.4.
Methyl tetradec-8,10,12-triene-2-ynoate (12).
To a solution of 3.6 g (0.0108 mol) of (9E,11E)-1,1-
dibromotrideca-1,7,9,11-tetraene 10 in 100 mL of
THF was added with stirring and cooling to –78°C
9.5 mL of a 2.5 M. solution of butyl lithium in hexane
(0.024 mol). The reaction mixture was stirred for 1 h at
–78°C,then1hatroomtemperature.Afteraddingof0.65mL
(8.4 mmol) of methyl chloroformate at –78°С, the
mixture was gradually heated to room temperature and
stirred for 16 h, then treated with a saturated solution of
ammonium chloride and extracted with diethyl ether (3×
50 mL). The combined extracts were dried with Na2SO4,
and then evaporated under reduced pressure. The residue
was chromatographed (ethyl acetate–hexane, 5:95). Yield
(2E,4E,8Z,10E,12E)-N-Isobutyltetradeca-
2,4,8,10,12-pentaenamide (γ-Sanshoöl) (15). To a
solution of 0.28 g (0.00128 mol) of 2E,4E,8Z,10E,12E-
tetradecapentaenoic acid in a mixture of 2 mL of aceto-
nitrile and 1 mL of CHCl3 were added 0.2 g (0.002 mol)
of isobutylamine, 0.35 mL (0.0025 mol) of triethylamine
and 0.62 g (0.0019 mol) of HATU under nitrogen at-
mosphere. The mixture was stirred for 30 min at room
temperature, then diluted with 50 mLof diethyl ether and
washed successively with a saturated solution of sodium
chloride, 1 N. HCl solution, water and 5% NaHCO3 solu-
tion. The organic layer was dried with Na2SO4, filtered
and evaporated in vacuum. Yield 0.15 g (43%), colorless
solid [20]. 1Н NMR spectrum, δ, ppm (J, Hz): 0.93 d (6H,
1
2.2 g (83%). Н NMR spectrum, δ, ppm: 1.24 m (2H,
CH2), 1.42 m (2H,CH2), 1.54 m (2H, CH2), 1.75 s (3H,
CH), 2.07 m (2H, CH2), 2.2 m (2H, CH2), 5.38 m (1H,
CH), 5.70 m (1H, CH), 6.08 m (1H, CH), 6.37 m (1H,
CH). 13C NMR spectrum, δC, ppm: 17.8, 18.5, 27.5,
27.9, 29.8, 52.3, 72.8, 89.9, 128.6, 129.3, 130.2, 131.2,
132.2, 154.2.
Methyl (2E,4E,8Z,10E,12E)-tetradeca-2,4,8,10,12-
pentaenoate (13). To a solution of 2.2 g (0.001 mol) of
methyl tetradec-8,10,12-trien-2-enoate 12 in 30 mL of
toluene was added 2.48 g (0.01 mol) of triphenylphos-
phine and 0.89 g (5.0 mmol) of phenol. The mixture was
stirred at 50°C under nitrogen atmosphere for 16 h, and
then concentrated under reduced pressure. The residue
was chromatographed (methylene chloride–hexane,
10:90, then ethyl acetate–hexane, 10:90). Yield 2.2 g
(100%), yellowish oil [18]. 1Н NMR spectrum, δ, ppm:
1.8 m (3Н, CH3), 2.05 m (2Н, CH2), 3.75 s (3H, OCH3),
5.4 m (1H, CH), 5.7 m (1H, CH), 5.8 m (1H, CH), 6.2 m
(1H, CH), 6.3 m (1H, CH), 6.4 m (1H, CH), 6.5 m (1H,
CH), 6.7 m (1H, CH). 13C NMR spectrum, δC, ppm: 18.4,
27.0, 33.1, 51.5, 119.2, 125.4, 128.9, 129.7, 129.8, 130.2,
131.9, 133.6, 143.7, 145.2, 167.8. Found, %: 78.03; H
9.12. C16H22O2. Calculated, %: 78.01; H 9.00.
3
3
CH3, JHH = 7.0), 1.77 d (3H, CH3, JHH = 7.0), 1.7 m
(1H, СН), 2.25 t (2H, СН2, 3JНН = 7.0), 2.30 t (2H, CH2,
3JНН = 7.0), 3.15 m (2H, СН2), 5.34 d. t (1H, CH=C,
3JНН = 10.0, 3JНН = 8.0), 5.47 d. t (1H, CH=C, 3JHH 14.0,
3JHH = 7.0), 6.45 d (1H, CH=C, 3JHH = 15.0), 6.06–6.13
m (5H, CH=C), 6.29–6.33 m (1H, CH=C), 7.16 d. d (1H,
3
3
CH=C, JHH = 15.0, JHH = 11.0). 13C NMR spectrum,
δC, ppm: 18.43, 20.2, 27.2, 28.7, 33.0, 47.0, 122.4, 125.4,
128.9, 129.5, 130.0, 130.1, 132.0, 133.4, 141.0, 141.8,
166.5. Mass spectrum, m/z: 274.4 [М + H]+.
(2E,4E,8Z,10E,12E)-N-Butyltetradeca-2,4,8,10,12-
pentaenamide (16) was obtained similarly.Yield 50%. 1Н
NMR spectrum, δ, ppm (J, Hz): 0.84 t (3H, CH3, 3JHH
=
7.0), 1.3 m (4H, CH2), 1.84 q (3H, CH3, 3JHH = 7.0), 2.1
m (2H, СН2, 3JHH = 7.0), 2.30 t (2H, СН2, 3JHH = 7.0),
3.15 t (2H, CH2N, 3JНН = 7.0), 5.34 d. t (1H, СH=С,
(2E,4E,8Z,10E,12E)-Tetradeca-2,4,8,10,12-pentae-
noic acid (14). To a solution of 2.2 g (9.5 mmol) of methyl
tetradecapentanoate in 30 mL of methanol was added
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 89 No. 10 2019

2004
KOLODYAZHNAYA, KOLODYAZHNY
3JНН = 10, 3JНН = 7.5), 5.47 d. t (1H, CH=C, 3JНН = 14.0,
3JHH = 7.0), 6.45 d (1H, CH=C, 3JНН = 15.0), 6.06–6.13 m
(5H, СН=С), 6.29–6.33 m (1H, CH=C), 7.16 d. d (1H,
CH=C, JНН = 15.0, JНН = 11.0). 13C NMR spectrum,
δC, ppm: 14.23, 18.5, 20.2, 28.7, 31.5, 32.2, 40.0, 43.0,
122.2, 125.2, 129.0, 129.9, 130.5, 130.9, 132.0, 133.6,
141.2, 142.0, 167.0. Mass spectrum, m/z: 274.4 [М + H]+.
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p. 3769.
3
3
https://doi.org/10.1016/S0040-4039(01)94157-7
12. Heravi, M.M., Asadi, S., Nazari, N., and Lashkariani, B.M.,
Curr. Org. Chem., 2015, vol. 19, no. 22, p. 2196.
https://doi.org/ 10.2174/1385272819666150619174010
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CONFLICT OF INTEREST
No conflict of interest was declared by the authors.
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