Asymmetric synthesis of unnatural (Z,Z,E)-octadecatrienoid and eicosatrienoid by lipoxygenase-catalyzed oxygenation

Article abstract of DOI:10.1016/S0957-4166(03)00369-0

The asymmetric synthesis of unnatural 13-hydroxy-(6Z,9Z,11E,13S)-octadecatrienoid and 15-hydroxy-(8Z,11Z,13E,15S)-eicosatrienoid is described using a biomimetic oxidation route. The main highlights of this synthesis are the asymmetric hydroxylation of the substrate with soybean lipoxygenase and cis selective Wittig olefination.

Full text of DOI:10.1016/S0957-4166(03)00369-0

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 14 (2003) 1799–1806
Asymmetric synthesis of unnatural (Z,Z,E)-octadecatrienoid and
eicosatrienoid by lipoxygenase-catalyzed oxygenation
S. Nanda* and J. S. Yadav
Organic Division, Indian Institute of Chemical Technology, Hyderabad 500007, India
Received 25 February 2003; accepted 17 March 2003
Dedicated to Professor A. Ian Scott on his 75th Birthday.
Abstract—The asymmetric synthesis of unnatural 13-hydroxy-(6Z,9Z,11E,13S)-octadecatrienoid and 15-hydroxy-
(8Z,11Z,13E,15S)-eicosatrienoid is described using a biomimetic oxidation route. The main highlights of this synthesis are the
asymmetric hydroxylation of the substrate with soybean lipoxygenase and cis selective Wittig olefination. © 2003 Published by
Elsevier Science Ltd.
1. Introduction
except the above-mentioned two octadecenoids in natu-
ral sources is in insignificant amounts.
Fatty acids such as leukotrienes (eicosanoids) and
unsaturated C-18 hydroxy fatty acids (octadecenoids)
have been the subject of much interest because of the
wide range of their biological properties. The
leukotrienes are associated with the pharmacological
activities related to immune hypertensive reactions such
as asthma and inflammation,1–3 whereas octadecenoids
have an altogether different biological role such as
ionophoric activity, self-defensive properties against
blast disease in the rice plant etc. Coriolic and dimor-
phecolic acids, the two octadecenoids, which were iso-
lated from beef heart mitochondria,4 were shown to
possess unique divalent cation ionophoric activity.
These acids seem to inhibit the spore germination and
germ tube growth of Conidia of rice blast fungus thus
playing a self-defensive role in the rice plant against
being infected by the disease.5 Samuelson6 established
the presence of these two octadecenoids in the sera of
patients with Familial Mediterranean Fever (FMF), an
autosomal recessive disorder. The presence of these
fatty acids in the lipid extract of sera of patients of
FMF suggests that the defects formation features elimi-
nation of these compounds and might play a role in the
pathogenesis of FMF. The presence of these fatty acids
Therefore there is a need for obtaining these products
as well as their unnatural counterparts to study the
physiological properties and to understand the mecha-
nism of action, which in turn, may help in designing
products with better therapeutic action. A large number
of organic chemists7–18 are engaged in the synthesis of
these molecules mainly the octadecenoids. In view of
their importance and rapid expansion, it is pertinent to
synthesize these fatty acids and their analogues.
2. Results and discussion
Herein I describe for the first time a biomimetic
approach to the total synthesis of unnatural unsatu-
rated hydroxy fatty acids 13-S-HOTE and 15-S-
HETrE. Both of these oxidative metabolites have
anti-inflammatory properties.19 15-S-HETrE induces a
concentration dependent inhibition or potentiation of
platelet aggregation.20–22 It has been shown to inhibit
5-LO and 12-LO. Hence formation of LTB4 from
arachidonic acid in A23187-stimulated neutrophils
(IC50=0.2 mM) was blocked. The role of lipoxygenase
in the biosynthesis of leukotrienes is well known, and in
our previous communication we described the synthesis
of some chiral (Z,E)-diene-diols by lipoxygenase cata-
lyzed asymmetric oxygenation of unnatural substrates
mimicking linoleic acid. A careful analysis revealed that
the target compounds (Z,Z,E)-hydroxy fatty acids 1a
* Corresponding author. Present address: Department of Chemistry,
Texas A&M University, 3255 TAMU, College station, TX 77843,
USA. Fax: +1-979-845-5992; e-mail: snanda@mail.chem.tamu.edu
0957-4166/03/$ - see front matter © 2003 Published by Elsevier Science Ltd.
doi:10.1016/S0957-4166(03)00369-0

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S. Nanda, J. S. Yada6 / Tetrahedron: Asymmetry 14 (2003) 1799–1806
and 1b can be constructed from the (Z,E)-diene-diol 2.
The C-6 to C-18 fragment in 1a and C-9 to C-20
fragment in 1b should remain intact as in the starting
material and we need to construct an extra (Z)-double
bond. A cis selective Wittig reaction was chosen for
construction of the (6Z and 8Z) double bonds. The
(Z,E)-diene-diol 2 was used as the aldehydic partner 3
as well as Wittig ylide 4 for the construction of the
double bond (Scheme 1).
ꢀCH2-CH2-OH, 2H), 3.7 (t, -CH2OH, 2H), 3.8 (m,
-CH-OBn, 1H), 4.28 (d, benzylic proton, 1H), 4.6 (d,
benzylic proton, 1H), 5.48–6.5 (olefinic protons, 4H),
7.2-7.4 (aromatic protons, 5H). The primary hydroxy
group in 10 was converted to the corresponding iodo
compound 11 by treatment with I2/TPP/imidazole in
85% yield.27 1H NMR spectrum of 11 showed peaks at
l 2.8 (q, ꢀCH2-CH2I, 2H), 3.2 (t, -CH2I, 2H). Com-
pound 11, when refluxed with TPP in acetonitrile,
generated the phosphonium salt 4 as a white solid.
Condensation of 4 with the appropriate monotetra-
hydropyranyl protected aldehyde (6a–b) in the presence
of n-BuLi and subsequent removal of the tetra-
hydropyranyl group with methanolic PTSA afforded
12a–b in 60% yield. Oxidation of 12a–b under Jones
conditions afforded the carboxylic acids 13a–b in 75%
yield. Finally removal of benzyl group with Li–NH3
(l)28 yielded the target compound 1a–b in 60% and
overall 12% yield starting from 7 (Scheme 2).
The synthesis starts from the unnatural substrate 7
mimicking linoleic acid and having a hydroxy end
group. Upon oxygenation with lipoxygenase, subse-
quent reduction of the peroxides with HRP and hydrol-
ysis of the ester moiety 2 was obtained with excellent
regio and stereocontrol.23,24 The primary hydroxy func-
tionality in 2 was selectively monoprotected as its
PMB-ether by treatment with NaH and PMB-Br to
yield 8. The secondary alcohol group in 8 was protected
25
as its benzyl ether by treating with benzylimidate in
1
the presence of CSA to give 9 in 82% yield. H NMR
In another approach the primary alcohol group in 10
was subjected to oxidation under various conditions to
obtain 3. Several oxidation reactions were tested, e.g.
PCC, Swern, TPAP/NMO, but in all the cases poor
(10–25%) yields were obtained. Though it is well known
that oxidation of homoallylic alcohols are problematic
due to probable isomerization and migration of the
double bond towards the more stable a,b-unsaturated
aldehyde. The best result was obtained with the Dess–
spectrum of 9 showed peaks at l 2.5 (q, ꢀCH2-CH2-
OPMB, 2H), 3.5 (t, -CH2-OPMB, 2H), 5.2–6.4 (olefinic
protons, 4H) and 6.8–7.2 (aromatic protons, 9H). Its 13C
NMR spectrum showed peaks at 130.5, 129.5, 128.2
and 127.6 indicates the presence of (Z,E)-double bonds.
Deprotection of the PMB ether with DDQ26 in the
presence of the benzyl group yielded 10 in 80% yields.
1H NMR spectrum of 10 showed peaks at l 2.5 (q,
Scheme 1.

S. Nanda, J. S. Yada6 / Tetrahedron: Asymmetry 14 (2003) 1799–1806
1801
Scheme 2. Reagents and conditions: (a) SBLO, 0°C, sodium borate buffer, pH 9.0, HRP, sodium phosphate buffer, pH 6.5,
KOH/MeOH, rt, 12 h; (b) NaH, PMB-Br, nBu4N+I−; (c) BnO (-NHꢀCCl3), CSA; (d) DDQ, DCM:H2O (19:1); (e) I2, TPP,
imidazole, CH3CH:ether (1:3); (f) TPP, CH3CN, reflux, 48 h (g) nBuLi, THPO-(CH2)nCHO (n=5,7), MeOH, PTSA; (h)
CrO3–H2O (8N); (i) LiNH3 (l).
Martin periodinane29 (65%). The corresponding Wittig
ylide was generated from the appropriate diol. It was
mono-brominated with 48% HBr30 to yield the mono-
bromo alkanol. Jones oxidation of the monobromo
alkanol provides the corresponding acid 14a–b in good
yield. Treatment of 14a–b with triphenyl phosphine in
refluxing acetonitrile yielded the Wittig ylide 5a–b as a
white solid. A cis selective Wittig reaction of 5a–b
with aldehyde 3 in presence of NaHMDS as a base,
and subsequent removal of benzyl functionality with
Li/NH3 (l) afforded 1a–b in moderate yield (Scheme
3).
Scheme 3. Reagents and conditions: (a) DMP, DCM, 0°C, 1 h, 65%; (b) HBr, benzene, 60%; (c) CrO3, H2SO4 (8N); (d) TPP,
CH3CN, reflux; (e) NaHMDS, −30°C, 40%; (f) Li/NH3 (l).

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S. Nanda, J. S. Yada6 / Tetrahedron: Asymmetry 14 (2003) 1799–1806
3. Conclusion
then extracted several times with ether, dried (Na2SO4)
and evaporated to afford the crude hydroperoxide. The
crude hydroperoxide (105 mg) was taken in 5 mL of 0.1
M phosphate buffer and to this solution HRP (50 mg)
was added and the reaction mixture was agitated for 1
h at rt. After the completion of reaction (indicated by
TLC) it was extracted with ether. Evaporation of the
ethereal solution and chromatographic separation 44
mg (40%) of the diol was obtained. IR (g, TF): 3400,
An efficient asymmetric total synthesis of unsaturated
hydroxy fatty acid has been established. The key step in
the synthesis is to construct the asymmetric center by
lipoxygenase-catalyzed oxygenation of the unnatural
substrates. Currently we are actively engaged in the
total synthesis of several unsaturated hydroxy fatty
acids and their analogues, which have tremendous bio-
logical potential. Although numerous synthetic
approaches have appeared after the isolation of these
fatty acids, their mechanisms of self-defensive action
against rice blast disease or other physiological proper-
ties are still to be understood. Further, how these
compounds are synthesized by the plants under stress
conditions remains to be studied.
1
1740 cm−1. [h]D25=+11.0 (c 0.5, CHCl3). H NMR: 0.9
(t, J=7.0 Hz, 3H), 1.3 (brs, 6H), 1.5–1.8 (m, 4H), 2.3 (t,
J=7.0 Hz, 2H), 2.4 (t, J=7.0 Hz, 2H), 2.5 (brs, 2H,
-OH), 3.6 (m, 2H), 4.1 (m, 3H), 5.46 (dd, J=7.0, 10.4
Hz, 1H), 5.73 (dd, J=7.0, 15 Hz, 1H), 6.15 (dd, J=
10.0, 10.4 Hz, 1H), 6.52 (dd, J=10.0, 15 Hz, 1H). 13C
NMR: 14, 20.9, 22.5, 26, 26.9, 27.1, 29.4, 31.6, 34, 62.1,
64, 72, 124, 127.4, 128.5, 130.2, 173. EIMS (m/z): 298
(M+).
4. Experimental
4.1. General
For the removal of the prosthetic modifier the com-
pound obtained in the previous step (44 mg, 0.147
mmol) was dissolved in 2 mL of methanol, followed by
addition of KOH (1 g), and the mixture was stirred for
12 h at rt. The mixture was diluted with water and
extracted several times with EtOAc. Evaporation and
purification by column chromatography gave (30 mg)
the diol 2 as yellow oil in 90% yield. Enantioselection
(Ee) was 97% as determined from Chiral HPLC mea-
surement. IR (g, TF): 3400, 980 cm−1. [h]D25=+52.0 (c
Unless otherwise stated, materials were obtained from
commercial suppliers and used without further purifica-
tion. THF and diethyl ether were distilled from sodium
benzophenone ketyl. HMPA was distilled from BaO
,
and stored over 3 A molecular sieves. Dichloromethane
(DCM) was distilled from calcium hydride. Lipoxyge-
nase (type-1, activity=127,000 u/mg protein) and per-
oxidase (from horseradish, type-VI-A, 1100 u/mg
protein) were obtained from Sigma Co. (USA) and
used as obtained. Reactions were monitored by thin-
layer chromatography (TLC) carried out on 0.25 mm
silica gel plates with UV light and 2.5% ethanolic
anisaldehyde (with 1% AcOH and 3% conc. H2SO4)
heat as developing agents. Silica gel 100–200 mesh was
used for column chromatography. Yields refer to chro-
matographically and spectroscopically homogeneous
materials unless otherwise stated. NMR spectra were
recorded on 200 MHz spectrometers at rt in CDCl3
using tetramethyl silane as internal standard and the
chemical shifts are shown in l. 13C NMR spectra were
recorded with a complete proton decoupling instru-
ment. Infrared spectra were recorded on a Perkin–
Elmer 1420 spectrometer. Optical rotations were
measured on a JASCO Dip 360 digital polarimeter. TF
denotes thin film. HPLC analysis was performed on a
Shimadzu liquid chromatography LC-6A. The column
was 4.6×250 mm, chiral cell OD column (Daicell). The
eluents were hexane–iPrOH (HPLC Grade, 85:15) at 0.5
mL/min flow rate and monitored at a wavelength of
240 nm. For compounds 1a–b HPLC was performed on
m-porasil column at a flow rate 1 mL/min. The eluent
used was hexane:iPrOH:AcOH (991:8:1).
1
1.0, CHCl3). H NMR: 0.85 (t, J=7.0 Hz, 3H), 1.26
(m, 6H), 1.44 (m, 2H), 2.2 (brs, 2H, -OH), 2.4 (q,
J=7.0 Hz, 2H), 3.69 (t, J=7.0 Hz, 2H), 4.1 (q J=7.0
Hz, 1H), 5.46 (dd, J=7.0, 10.4 Hz, 1H), 5.73 (dd,
J=7.0, 15 Hz, 1H), 6.15 (dd, J=10.0, 10.4 Hz, 1H),
6.52 (dd, J=10.0, 15 Hz, 1H). 13C NMR: 130.3, 128.6,
127.5, 124.3, 65.0, 62.5, 32.0, 29.5, 27.0, 26.0, 22.5, 13.9.
EIMS (m/z): 198 (M+).
4.3. 12-(4-Methoxybenzyloxy)-1-pentyl (1S,2E,4Z)-2,4-
heptadienyl alcohol 8
(3Z,5E,7S)-3,5-Dodecadiene-1,7-diol
2 (0.5 g, 2.5
mmol) was taken in 8 mL of dry THF and NaH (60%
dispersion in mineral oil, 0.1 g, 4.2 mmol) was added to
it portionwise at 0°C. The reaction mixture was stirred
at 0°C for 1 h under a nitrogen atmosphere. Tetra-
butylammoniumiodide (catalytic) was added to it fol-
lowed by the addition of 4-methoxybenzylbromide (0.5
g, 2.5 mmol). Stirred for a further 2 h at rt. Water was
added to the reaction mixture and extracted with
EtOAc. Washed with brine and dried (Na2SO4). Purifi-
cation by means of column chromatography gave the
product 8 (0.64 g) in 80% yield. [h]2D5=+19.1 (c 1.1,
1
CHCl3). H NMR: 0.9 (m, 3H), 1.2–1.6 (m, 8H), 2.5 (q,
4.2. (3Z,5E,7S)-3,5-Dodecadiene-1,7-diol 2
J=7.0 Hz, 2H), 3.5 (t, J=7.0 Hz, 2H), 3.9 (s, 3H), 4.0
(m, 1H), 4.4 (s, 2H), 5.4–5.7 (m, 2H), 6.15 (dd, J=10.0,
10.4 Hz, 1H), 6.4 (dd, J=10.0, 15.0 Hz, 1H), 6.8 (d,
J=6.2 Hz, 2H), 7.2 (d, J=6.2 Hz, 2H). 13C NMR:
159.2, 130.3, 130, 129, 128.6, 127.5, 124.3, 114, 72.5,
69.4, 65.0, 55.2, 32, 29.5, 27, 26, 22.5, 14. FABMS
(m/z): 318 (M+)
To a homogeneous solution of 100 mg (0.35 mmol) of
7 in 20 mL of 0.2 M sodium borate buffer (pH 9.0), at
0°C was added 50 mg of Lipoxygenase type-1. While O2
was bubbled through the solution at such a rate to
produce minimum of foaming. After 1 h the reaction
mixture was acidified with citric acid to pH 5.0, and

S. Nanda, J. S. Yada6 / Tetrahedron: Asymmetry 14 (2003) 1799–1806
1803
4.4. 1-[7-Benzyloxy-(3Z,5E,7S)-3,5-dodecadienyloxy-
mmol). The reaction mixture was stirred for 45 min at
rt. After that it was filtered and the filtrate was concen-
trated to give a semisolid mass, which was purified
through column chromatography to give the pure
iodide 11 (0.44 g) in 85% yield. [h]2D5=+69.0 (c 2.0,
methyl]-4-methoxy benzene 9
NaH (0.1 g, 4.2 mmol) was suspended in anhydrous
ether (4 mL) and a solution of benzyl alcohol (4.5 g, 42
mmol) in ether (6 mL) was added drop wise with
stirring under nitrogen. After 20 min the solid had
dissolved and the solution was cooled to 0°C. TCA
(5.78 g, 40 mmol) was then added dropwise during 5
min and the mixture was allowed to warm at rt for 1 h.
A small amount of brown ppt formed during the
addition of TCA but did not appear to influence the
course of the reaction. The reaction mixture was con-
centrated to syrup and pentane containing anhyd.
MeOH (4 mL+0.2 mL) was added, followed by vigor-
ous shaking, filtration and concentration of the filtrate.
The resulting imidate was obtained as a colorless liquid.
1
CHCl3). H NMR: 0.9 (t, J=7.0 Hz, 3H), 1.2–1.4 (m,
4H), 1.5–1.8 (m, 4H), 2.8 (q, J=7.0 Hz, 2H), 3.2 (t,
J=7.0 Hz, 2H), 3.78 (m, 1H), 4.3 (d, J=6.0 Hz, 1H),
4.58 (d, J=6.0 Hz, 1H), 5.38 (dd, J=7.0, 10.4 Hz, 1H),
5.6 (dd, J=7.0, 15.0 Hz, 1H), 6.12 (dd, J=10.0, 10.4
Hz, 1H), 6.38 (dd, J=10.0, 15.0 Hz, 1H), 7.2–7.4 (m,
5H). FABMS: 398 (M+).
4.7. Phosphonium salt 4
Compound 11 (0.44 g, 1.1 mmol) was taken in 8 mL
dry acetonitrile. Triphenylphosphine (0.29 g, 1.1 mmol)
was added to it, and the reaction mixture was heated at
60°C for 48 h under a nitrogen atmosphere. Acetoni-
trile was evaporated and dry ether 30 mL was added to
the semisolid mass and shaken vigorously. Evaporation
of the ether gave the phosphonium salt 4 (0.6 g) as a
white solid.
To a solution of 8 (0.64 g, 2 mmol) in 5 mL of
cyclohexane and 2.5 mL of DCM was added benzyl
2,2,2-trichloro acetamide (0.632 g, 2.5 mmol) followed
by addition of CSA (0.2 mmol). The solution was
stirred overnight at rt. After 24 h the mixture was
filtered, and the filtrate was washed with water, aq.
NaHCO3 and brine. The organic extract was dried
(Na2SO4) and purified by column chromatography to
afford the compound 9 (0.67 g) in 82% yield. [h]2D5=
4.8. 8-Tetrahydro-2H-pyranyloxy-1-octanol31
1,8-Octanediol (2 g, 13.7 mmol) was taken in 25 mL
anhyd. DCM. 3, 4-dihydro-2H-pyran (1 g, 13 mmol)
was added to it dropwise followed by addition of
catalytic amount of PTSA. After 30 min, the reaction
mixture was washed with satd NaHCO3 and brine. The
organic extract was dried (Na2SO4) and purified
through column chromatography to yield 1.9 g in 60%
yield. 1H NMR: 1.2–1.4 (m, 8H), 1.42–1.6 (m, 8H),
1.6–1.8 (m, 2H), 3.3 (m, 1H), 3.45 (m, 1H), 3.6 (t,
J=7.0 Hz, 2H), 3.7 (m, 1H), 3.8 (m, 1H), 4.58 (t,
J=4.0 Hz, 1H).
1
+33.6 (c 1.3, CHCl3). H NMR: 0.9 (m, 3H), 1.2–1.6
(m, 8H), 2.52 (q, J=7.0 Hz, 2H), 3.5 (t, J=7.0 Hz,
2H), 3.9 (m, 4H), 4.25 (d, J=6.0 Hz, 1H), 4.45 (s, 2H),
4.52 (d, J=6.0 Hz, 1H), 5.2–5.7 (m, 2H), 6.18 (dd,
J=10.0, 10.4 Hz, 1H), 6.4 (dd, J=10, 15.0 Hz, 1H), 6.8
(d, J=6.2 Hz, 2H), 7.2–7.4 (m, 7H). 13C NMR: 159.2,
138.8, 134.8, 130.5, 129.5, 129.1, 128.2, 128.05, 127.65,
127.4, 127.27, 113.75, 79.8, 72.5, 70.03, 69.34, 55.2,
35.7, 31.7, 28.5, 25.04, 22.5, 13.9. FABMS: 408 (M+).
4.5. 7-Benzyloxy-(3Z,5E,7S)-3,5-dodecadiene-1-ol 10
4.9. 6-Tetrahydro-2H-pyranyloxy-1-hexanol31
Compound 9 (0.67 g, 1.6 mmol) was taken in 10 mL of
dichloromethane: water (19:1). DDQ (0.56 g, 2.46
mmol) was added to it, and the solution stirred for 1 h
at rt. The reaction mixture was filtered off, and the
filtrate was washed with 5% NaHCO3 solution, brine
and dried (Na2SO4). Purification by chromatography
gave 10 (0.387 g) in 80% yield. [h]2D5=+13.9 (c 1.25,
MeOH). 1H NMR: 0.9 (m, 3H), 1.2–1.8 (m, 8H), 2.5 (q,
J=7.0 Hz, 2H), 3.7 (t, J=7.0 Hz, 2H), 3.8 (m, 1H),
4.28 (d, J=6.0 Hz, 1H), 4.6 (d, J=6.0 Hz, 1H), 5.48
(dd, J=7.0, 10.4 Hz, 1H), 5.7 (dd, J=7.0, 15.0 Hz,
1H), 6.15 (dd, J=10.0, 10.4 Hz, 1H), 6.52 (dd, J=10.0,
15.0 Hz, 1H), 7.2–7.4 (m, 5H). 13C NMR: 138.8, 130.5,
129.5, 129.1, 128.2, 128.05, 127.65, 124.27, 72.5, 69.34,
65.2, 35.7, 31.7, 28.5, 25.04, 22.5, 13.9. FABMS (m/z):
288 (M+).
Prepared in the same way as described above from 1,
6-hexanediol. H NMR: 1.2–1.4 (m, 6H), 1.45–1.62 (m,
6H), 1.7–1.83 (m, 2H), 3.34 (m, 1H), 3.46 (m, 1H), 3.62
(t, J=7.0 Hz, 2H), 3.7 (m, 1H), 3.82 (m, 1H), 4.6 (t,
J=4.0 Hz, 1H).
1
4.10. 8-Tetrahydro-2H-pyranyloxy-1-octanal 6b32
To oxallylchloride (0.72 mL, 8.2 mmol) and DMSO
(1.2 mL, 16.4 mmol) in DCM (50 mL) at −78°C was
added monoprotected 1,8-octanediol (1.9 g, 8.2 mmol)
in DCM and the temperature was allowed to maintain
the same for a further 1 h. Triethylamine (5.3 mL, 41
mmol) was added and after 5 min the temperature was
allowed to raise to 25°C. Stirred for a further 30 min at
the same temperature. Water was added to the solution,
extracted with DCM. Washed with water, brine and
dried (Na2SO4). Evaporation and purification by means
of column chromatography gave corresponding alde-
4.6. 1-[7-Iodo-1-pentyl-(1S,2E,4Z)-2,4-heptadienyloxy-
methyl] benzene 11
1
Compound 10 (0.378 g, 1.3 mmol) was taken in 7.5 mL
acetonitrile: ether (3:1). Imidazole (0.133 g, 1.96 mmol)
was added to it at rt, followed by addition of I2 (0.5 g,
1.96 mmol) and triphenylphosphine (0.515 g, 1.96
hyde in 90% yield (1.7 g). H NMR: 1.2–1.4 (m, 8H),
1.4–1.8 (m, 8H), 2.4 (t, J=7.0 Hz, 2H), 3.32 (m, 1H),
3.5 (m, 1H), 3.65 (m, 1H), 3.8 (m, 1H), 4.58 (t, J=4.0
Hz, 1H), 9.8 (s, 1H).

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S. Nanda, J. S. Yada6 / Tetrahedron: Asymmetry 14 (2003) 1799–1806
4.11. 6-Tetrahydro-2H-pyranyloxy-1-hexanal 6a31
127.5, 127.3, 126.5, 124.3, 72, 69.5, 33.6, 32.5, 31, 29.2,
27, 26.3, 26, 25.4, 23.2, 22.5, 21.6, 14. FABMS: 412
(M+).
It was prepared by the Swern oxidation of mono tetra-
hydropyranyl protected 1,6-hexane di-ol as described in
1
Section 4.10. H NMR: 1.2–1.4 (m, 6H), 1.42–1.8 (m,
4.15. 13-Benzyloxy-(6Z,9Z,11E,13S)-6,9,11-octadeca-
trienoicacid 13a
6H), 2.38 (t, J=7.0 Hz, 2H), 3.35 (m, 1H), 3.5 (m, 1H),
3.68 (m, 1H), 3.85 (m, 1H), 4.6 (t, J=4.0 Hz, 1H), 9.78
(s, 1H).
Compound 13a was prepared by Jones oxidation of 12a
as described in Section 4.14. [h]2D5=+15.8 (c 1.8,
1
4.12. 15-Benzyloxy-(8Z,11Z,13E,15S)-8, 11, 13-eicosa-
triene-1-ol 12b
CHCl3). H NMR: 0.9 (m, 3H), 1.2–1.75 (m, 12H), 2.1
(m, 2H), 2.5 (t, J=7.0 Hz, 2H), 2.8 (t, J=7.0 Hz, 2H),
4.1 (m, 1H), 4.6 (s, 2H), 5.3 (m, 1H), 5.6 (m, 1H),
5.9–6.12 (m, 3H), 6.38 (m, 1H), 7.2–7.4 (m, 5H). 13C
NMR: 181.2, 138.8, 134.2, 130.4, 128.5, 128.1, 127.9,
127.4, 127.1, 126.5, 124.5, 72.6, 69.4, 33.6, 32.0, 31,
29.4, 26.3, 25.4, 23.4, 22.8, 21.7, 14.1. FABMS (m/z):
384 (M+).
Ylide (4, 0.6 g, 0.9 mmol) was taken in 5 mL THF:
HMPA (6:1). n-BuLi (0.4 mL, 3.0 M in hexane) was
added to it at 0°C. The orange colored solution was
stirred at the same temperature for 1 h. 8-Tetra-
hydropyranyl octanal (0.2 g, 0.9 mmol) in 1 mL THF
was added and the reaction mixture stirred for a further
2 h at the same temperature. Quenched with satd
NH4Cl solution and then extracted with ether. Washed
with water, brine and dried (Na2SO4). The crude
product was dissolved in 5 mL of methanol and cata-
lytic amount of PTSA was added to it, stirred for 1 h at
rt. Evaporation of methanol and purification by
column chromatography afforded the (Z,Z,E) trienol
12b in 60% yield. [h]2D5=+39.2 (c 1.8, CHCl3). 1H
NMR: 0.9 (m, 3H), 1.2–1.75 (m, 18H), 2.1 (m, 2H), 2.8
(t, J=7.0 Hz, 2H), 3.6 (t, J=7.0 Hz, 2H), 4.1 (m, 1H),
4.4 (s, 2H), 5.3 (m, 2H), 5.6 (m, 1H), 5.9–6.12 (m, 2H),
6.38 (m, 1H), 7.2–7.4 (m, 5H). 13C NMR: 138.8, 134.0,
130.2, 128.6, 128.2, 127.7, 127.5, 127.3, 126.5, 124.3, 72,
69.5, 65, 32.5, 31, 29.2, 27, 26.3, 26, 25.4, 24.1, 23.2,
22.5, 21.6, 14. FABMS (m/z): 398 (M+).
4.16. 15-Hydroxy-(8Z,11Z,13E,15S)-8,11,13-eicosa-
trienoicacid 1b
Compound 13b (0.15 g) in anhydrous THF (2 mL) was
added to liq. NH3 (10 mL). Finely chopped metallic
lithium was added to it until the blue color persists. The
mixture was stirred for a further 2 h at the same
temperature. NH4Cl was added to it and the ammonia
was allowed to evaporate. Extracted with ether, washed
with brine and dried (Na2SO4). After purification by
column chromatography (MeOH/CHCl3, 1:4) at −20°C
in a cold room and lypholization of the organic sol-
vents afforded polyunsaturated hydroxy fatty acid 1b in
60% yield (0.07 g). The acid was obtained as a yellow
oil and can be stored in ethanol at −70°C. [h]2D5=+9.2 (c
1
1.8, CHCl3). H NMR: 0.9 (m, 3H), 1.2–1.75 (m, 16H),
4.13. 13-Benzyloxy-(6Z,9Z,11E,13S)-6,9,11-octadeca-
2.1 (m, 2H), 2.5 (t, J=7.0 Hz, 2H), 2.75 (t, J=7.0 Hz,
2H), 4.1 (m, 1H), 5.3 (m, 1H), 5.6 (m, 1H), 5.9–6.12 (m,
3H), 6.38 (m, 1H). 13C NMR: 180.5, 130.2, 128.6,
128.2, 127.5, 126.5, 124.3, 69.5, 33.6, 32.5, 31, 29.2, 27,
26.3, 26, 25.4, 23.2, 22.5, 21.6, 14. FABMS: 322 (M+).
triene-1-ol 12a
Comound 12a was prepared from ylide 4 and 6-tetra-
hydropyranyl hexanal 6b as described in the previous
1
step. H NMR: 0.9 (m, 3H), 1.2–1.8 (m, 14H), 2.15 (m,
2H), 2.8 (t, J=7.0 Hz, 2H), 3.62 (t, J=7.0 Hz, 2H), 4.1
(m, 1H), 4.4 (s, 2H), 5.3 (m, 2H), 5.6 (m, 1H), 5.9–6.12
(m, 2H), 6.38 (m, 1H), 7.2–7.4 (m, 5H). 13C NMR:
138.8, 134.2, 130.4, 128.5, 128.1, 127.9, 127.4, 127.1,
126.5, 124.5, 72.6, 69.4, 65, 33.5, 31, 29.4, 26.3, 25.4,
24.1, 23.4, 22.8, 21.7, 14.1. FABMS (m/z): 370 (M+).
4.17. 13-Hydroxy-(6Z,9Z,11E,13S)-6,9,11-octadeca-
trienoicacid 1a
Compound 1a was obtained as described in Section
4.16 from debenzylation of 13a in 60% yield. [h]2D5=
1
+9.2 (c 1.8, CHCl3). H NMR: 0.9 (m, 3H), 1.2–1.75
(m, 12H), 2.1 (m, 2H), 2.5 (t, J=7.0 Hz, 2H), 2.75 (t,
J=7.0 Hz, 2H), 4.1 (m, 1H), 5.3 (m, 1H), 5.6 (m, 1H),
5.9–6.12 (m, 3H), 6.38 (m, 1H). 13C NMR: 181.2, 130.4,
128.5, 128.1, 127.4, 126.5, 124.5, 69.4, 33.6, 32.0, 31,
29.4, 26.3, 25.4, 23.4, 22.8, 21.7, 14.1. FABMS: 294
(M+).
4.14. 15-Benzyloxy-(8Z,11Z,13E,15S)-8,11,13-eicosa-
trienoicacid 13b
Compound 12b (0.2 g, 0.5 mmol) was taken in 5 mL of
distilled acetone at 0°C. Freshly prepared Jones reagent
was added dropwise at the same temperature until the
orange brown color persists. The reaction mixture was
allowed to attain rt and stirred for a further 30 min.
Water was added, and it was extracted with EtOAc.
Purification by chromatography gave the acid 13b as a
gummy white solid (0.15 g) in 75% yield. [h]2D5=+39.2 (c
4.18. 8-Bromo-octan-1-ol30
1,8-Octane diol (2 g, 13.7 mmol) was taken in benzene
(30 mL), and the solution was heated to reflux by
addition of 48% aq. HBr (2 mL) for 18 h. While
trapping the water formed was performed using a
Dean–Stark water separator. The mixture was washed
with 6N NaOH, 10% HCl, water and brine. The
organic layer was dried with Na2SO4 and evaporated
under reduced pressure. The residue was purified by
1
1.8, CHCl3). H NMR: 0.9 (m, 3H), 1.2–1.8 (m, 16H),
2.0 (m, 2H), 2.5 (t, J=7.0 Hz, 2H), 2.8 (t, J=7.0 Hz,
2H), 4.1 (m, 1H), 4.6 (s, 2H), 5.3 (m, 1H), 5.6 (m, 1H),
5.9–6.12 (m, 3H), 6.38 (m, 1H), 7.2–7.4 (m, 5H). 13C
NMR: 180.5, 138.8, 134.0, 130.2, 128.6, 128.2, 127.7,

S. Nanda, J. S. Yada6 / Tetrahedron: Asymmetry 14 (2003) 1799–1806
1805
Kugelrohr distillation (bp=110–120°C/2 torr) to yield
1.7 g of the monobromo compound (60%). IR (g, TF):
3500, 2900, 1040 cm−1. 1H NMR: 1.2–2.0 (m, 12H),
3.40 (t, J=7.0 Hz, 2H), 3.65 (t, J=7.0 Hz, 2H). EIMS
(m/z): 209 (M+).
J=2.0 Hz, 1H). 13C NMR: 200, 130.5, 129.1, 128.2,
128.05, 127.65, 127.4, 127.27, 118.5, 70.03, 68.34, 42.5,
31.7, 28.5, 25.04, 22.5, 13.9. FABMS (m/z): 286 (M+).
4.24. 15-Benzyloxy-(8Z,11Z,13E,15S)-8, 11, 12-eicosa-
trienoicacid 13b
4.19. 6-Bromo-hexan-1-ol30
Wittig salt 5b (0.230 g, 0.5 mmol) was dissolved in 3
mL of THF: HMPA (6:1). The solution was cooled at
−30°C. A 1 M solution of NaHMDS (0.5 mL in THF,
0.5 mmol) was added to it dropwise to produce an
orange colored solution. The reaction mixture was kept
at the same temperature for 1 h, after that aldehydic
partner 3 (0.045 g, 0.017 mmol) was added to it. The
reaction was allowed to attain rt. The reaction mixture
was quenched with satd NH4Cl and extracted with
EtOAc. The organic layer was washed with water and
brine and dried over Na2SO4. Evaporation and purifi-
cation through column chromatography afforded 13b
in 40% yield.
This was prepared from 1,6-hexane diol by treatment
with aq. HBr as described in Section 4.18.
1
IR (g, TF): 3500, 2900, 1040 cm−1. H NMR: 1.2–2.1
(m, 8H), 3.40 (t, J=7.0 Hz, 2H), 3.65 (t, J=7.0 Hz,
2H). EIMS (m/z): 181 (M+).
4.20. 8-Bromo-octanoic acid 14b9
8-Bromo-octan-1-ol (1.7 g, 8.2 mmol) was dissolved in
25 mL distilled acetone at 0°C. Freshly prepared Jones
reagent was added dropwise at the same temperature
until the orange brown color persisted. The reaction
mixture was allowed to attain rt and stirred for a
further 30 min. Water was added, and it was extracted
with EtOAc. Purification by chromatography gave the
4.25. 3-Benzyloxy-(6Z,9Z,11E,13S)-6,9,11-octadecaa-
trienoicacid 13a
1
acid (1.45 g, 80%) as a heavy viscous liquid. H NMR:
Compound 13a was obtained as described in Section
4.24 from Wittig ylide 5a and aldehyde 3 in 38% yield.
1.2–1.4 (m, 6H), 1.42–1.8 (m, 4H), 2.48 (t, J=7.0 Hz,
2H), 3.6 (t, J=7.0 Hz, 2H). EIMS (m/z): 223 (M+).
4.21. 6-Bromo-hexanoic acid 14a33
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Hz, 2H), 3.66 (t, J=7.0 Hz, 2H). EIMS (m/z): 195
(M+).
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1
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