Novel chiral lipoxygenase substrates: Design and synthesis. Part 2

Article abstract of DOI:10.1016/S0957-4166(02)00009-5

A series of novel lipoxygenase substrates carrying a spacing modifier with a non-ionic hydroxyl terminus have been synthesized in an enantioselective fashion. One of the methylene hydrogens (flanked by the cis,cis-pentadienyl moiety) is replaced by alkyl,

Full text of DOI:10.1016/S0957-4166(02)00009-5

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 12 (2001) 3223–3234
Novel chiral lipoxygenase substrates: design and synthesis.
Part 2
J. S. Yadav* and S. Nanda
Organic Division, Indian Institute of Chemical Technology, Hyderabad 500007, India
Received 5 October 2001; accepted 28 December 2001
Abstract—A series of novel lipoxygenase substrates carrying a spacing modifier with a non-ionic hydroxyl terminus have been
synthesized in an enantioselective fashion. One of the methylene hydrogens (flanked by the cis,cis-pentadienyl moiety) is replaced
by alkyl, aryl and hydroxyl groups. The key steps in the synthesis involved enzymatic transesterification of 1,3-propanediol
derivatives and two consecutive cis-selective Wittig olefinations. © 2002 Elsevier Science Ltd. All rights reserved.
modifiers with a non-ionic hydroxyl terminus are well
1. Introduction
recognized by soybean lipoxygenase (Scheme 1).3 The
stereospecificity of lipoxygenase is characterized by the
stereoselective removal of pro-(S) hydrogen from the
prochiral methylene center.4 In our earlier
communication5 we described the synthesis of some
useful intermediates, which can lead to the total synthe-
sis of novel lipoxygenase substrates where pro-(R) and
pro-(S) hydrogens are replaced by a hydroxyl group.
As a continuation of our previous study, we wish to
report herein the asymmetric synthesis of some lipoxy-
genase substrates where the pro-(R) and pro-(S) hydro-
gens are replaced by several groups (Scheme 2). At the
prochiral methylene center we introduced different
alkyl, aryl and hydroxyl groups in an enantioselective
fashion.
The lipoxygenases constitute a family of lipid peroxidiz-
ing enzymes, which are involved in the biosynthesis of
inflammatory mediators in cell differentiation and
atherogenesis.1 They catalyze the stereospecific and
regiospecific incorporation of molecular oxygen into the
(1Z,4Z)-pentadienyl moiety of polyunsaturated fatty
acids.2 Previous studies reveal that substrates with a
single v-6-(1Z,4Z)-pentadienyl moiety carrying spacing
2. Results and discussion
2.1. Retrosynthesis
Careful retrosynthetic analysis of 1a–i reveals (Scheme
2) that (Z,Z)-dienols 9a–i serve as very good intermedi-
ates and are in turn easily accessible from 2-substituted
1,3-propanediol derivatives. First of all our main aim is
to construct the 2-substituted 1,3-propanediol deriva-
tives in an asymmetric fashion. For this we adopted
enzymatic transesterification of racemic 1,3-propanediol
derivatives. Secondly, to construct the (Z,Z)-diene moi-
ety we adopted a cis-selective Wittig olefination strat-
egy. Finally the attachment of a hydroxy protected acid
as a prosthetic modifier completes the synthesis.
Scheme 1. Substrate recognition by SBLO.
* Corresponding author. Fax: +91-40-7160512; e-mail: yadav@
iict.ap.nic.in
0957-4166/01/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(02)00009-5

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J. S. Yada6, S. Nanda / Tetrahedron: Asymmetry 12 (2001) 3223–3234
Scheme 2. Substrates 1a–j.
2.2. Enzymatic transesterification of 2-substituted 1,3-
propanediols
mers of 2a–i can be obtained by hydrolysis of the
acetates 3a–i.
To introduce chirality at the 2-position we adopted an
enzymatic transesterification of racemic 1,3-propanediol
derivatives. The corresponding meso-1,3-diols were eas-
ily available from monoalkylated diethyl malonate
derivatives. Enzymatic transesterification of 2-substi-
tuted meso-1,3-propanediol in organic solvents is well
documented in the literature.6 However, we have
monoprotected the diols as their mono PMB ethers
(4-methoxybenzyloxy). When these monoprotected
diols were subjected to transesterification (Scheme 3)
the acetates 3a–i and the unreacted alcohols 2a–i rich in
the (R)-form were obtained. The corresponding (S)-iso-
The transesterification of racemic 2-substituted 1,3-
propanediol derivatives deserves some comment. It was
already known that the (S)-isomer of the alcohol will
undergo faster acetylation7,8 to form the acetate than
the corresponding (R)-isomer. Regarding the selection
of lipases, CRL (lipase from Candida rugosa) gave
better result when compared to PPL (lipase from
porcine pancreas) and PSL (lipase from Pseudomonas
species). The enantioselectivity of the acetate and the
unreacted alcohols ranged from 70 to 95% (Table 1).
The absolute configuration of the acetates and the
alcohols were determined as follows: Deprotection of
Scheme 3. Desymmetrization of 2-substituted 1,3-propanediol derivatives. Reagents and conditions: (a) NaH, PMB-Br, rt; (b)
,
CRL, vinyl acetate, MS (4 A), rt; (c) K2CO3, MeOH, rt; (d) DDQ, DCM:H2O (18:1), rt.
Table 1. Transesterification of 2a–i with CRL and vinyl acetate
Entry
R
Time (h)
Conversion (c)
(R)-Acetate
Yield (%)
(R)-Alcohol
Eb
a
E.e.p
E.e.s
Yield (%)
1
2
3
4
5
6
7
8
9
Me
Et
10
9
12
8
8
15
7
48
49
47
47
47.5
49.5
47
52
50
96
95
90
98
88
92
96
70
91
48
40
43
46
41
39
42
43
38
90
91
82
88
80
90
85
75
90
40
38
30
39
35
42
44
31
42
145
125
50
282
40
70
134
14
n-Pr
n-Bu
i-Bu
t-Bu
Allyl
Ph
8
9
PhCH2
68
a E.e.s were calculated by chiral HPLC (Diacel, Chiral OD column, hexane-iso-propanol, 8.5:1).
b Enantioselectivities of the reaction (E)13 were determined using the following equation: E=ln[1−c(1+e.e.p)]/ln[1−c(1−e.e.p)], where e.e.p=pdt.
e.e.; c=e.e.s/(e.e.s+e.e.p).

J. S. Yada6, S. Nanda / Tetrahedron: Asymmetry 12 (2001) 3223–3234
3225
the PMB (4-methoxybenzyl) group with DDQ afforded
2.3. Synthesis of the (Z,Z)-diene moiety
the monoacetates, which have identical specific rotation
values to those reported earlier.7 The enantiomeric
excess (e.e.) of each of the products was calculated by
chiral HPLC and from NMR analysis by the Heun-
mann method (Scheme 4).9 In this way the monopro-
tected diols were derivatized as their esters with
(S)-FAC acid (fluoroaryllactic acid). As the esters are
Our next target was to construct the (Z,Z)-diene moi-
ety. It was evident that we need (R)-2a–i for synthesis
of 1a–i having pro-(S) hydrogen whereas (S)-2a–i will
be the precursor for 1a–i having pro-(R) hydrogen.
Compounds (R)-2a–i were subjected to Swern
oxidation10 to give the aldehydes 4a–i. Stereoselective
cis-Wittig olefination of 4a–i with n-hexyltriphenyl-
phosphonium iodide in the presence of t-BuOK
yielded the (Z)-olefins 5a–i in 60% yield. Deprotection
of the PMB ether functionality with DDQ11 furnished
the (Z)-alkenol 6a–i in good yield. Oxidation of 6a–i
under Swern conditions afforded the aldehyde 7a–i. A
second Wittig olefination with PMBO(CH2)3Ph3P+I− in
the presence of t-BuOK in THF yielded the (Z,Z)-
diene 8a–i. Subsequent removal of the PMB ether
group furnished the (Z,Z)-dienol 9a–i (Scheme 5).
1
diastereomeric in nature, their H NMR spectrum will
be of different pattern. Mainly by comparing the inte-
gration of the Me-doublet signal (coming from FAC
acid) at l 1.6 ppm we can predict their relative ratios
and hence the e.e.
Diisopropyl ether seems to be the best solvent to carry
out the transesterification reaction. We have also con-
ducted the same transesterification reaction in different
organic solvents and the results are summarized in
Table 2.
Scheme 4. Synthesis of FAC esters.
Table 2. Transesterification of 2-methyl-monoprotected 1,3-propane diol 2a
Entry
Solvent
Time (h)
Conversion
(R)-Acetate
Yield (%)
(R)-Alcohol
E
E.e.p
E.e.s
Yield (%)
1
2
3
4
5
6
7
8
Hexane
Et2O
i-Pr2O
t-BuOMe
THF
Cyclohexane
Toluene
Dioxan
16
12
10
14
15
20
18
22
44
46
48
48
49
49
49
49
90
80
96
85
60
68
72
78
39
30
48
28
30
35
31
32
72
70
90
80
58
65
70
75
32
34
48
25
21
30
28
30
40
19
145
30
7
11
13
18
Scheme 5. Synthesis of (Z,Z)-dienol. Reagents and conditions: (a) Me2S+ClCl−, TEA, −78°C; (b) KOt-Bu, n-C6H13PPh3P+I−,
THF, 0°C; (c) DDQ, DCM:H2O (18:1), rt; (d) same as (a); (e) KOt-Bu, PMBO(CH2)3PPh3P+I−, THF; (f) same as (c).

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2.4. Total synthesis of 1a–i
Our main intention was to study the effect of different
groups present in 1a–j, e.g. alkyl, aryl, hydroxyl in
asymmetric hydroxylation with soybean lipoxygenase.
In the first step of lipoxygenase-catalyzed asymmetric
hydroxylation the pro-(S) hydrogen was removed to
give a radical which undergoes resonance with the diene
to form the conjugated double bond. The presence of
different groups governs the course of the reaction,
particularly phenyl and allyl because these groups can
take part in conjugation with the generated radical (due
to the presence of an extra double bond). Currently we
are actively engaged in a detailed mechanistic investiga-
tion for the soybean lipoxygenase-catalyzed asymmetric
hydroxylation of these novel substrates.
After successful construction of the (Z,Z)-diene moiety
our next target was to attach the prosthetic modifier.
The (Z,Z)-dienols 9a–i were coupled with 5-(4-
methoxybenzyloxy)pentanoic3e acid in the presence of
DCC and DMAP to afford the esters 10a–i. Removal
of the PMB ether functionality furnished 1a–i in good
yield (Scheme 6). The enantiomers of 1a–i having pro-
(R) hydrogen were also prepared starting from (S)-2a–i
by the same synthetic route.
2.5. Total synthesis of 1j
Our next target was compound 1j, where one of the
methylene hydrogens (flanked by the (Z,Z)-diene moi-
ety) was replaced by a hydroxyl group. A logical retro-
synthesis (Scheme 7) revealed that 1j could be prepared
from the bis-acetylenic diol 11 by attaching the pros-
thetic modifier. Compound 11 can be easily constructed
from 12, which is readily prepared by enzymatic trans-
esterification.5
3. Conclusion
An efficient asymmetric synthesis of a series of novel
lipoxygenase substrates has been described. Com-
pounds where the pro-(S) hydrogen is present should
act as substrates for lipoxygenase, whereas compounds
lacking the pro-(S) hydrogen may act as suitable sub-
strate analogue inhibitors of lipoxygenase, which are of
tremendous biological interest.
Starting the synthesis of 1j from compound 12, the
acetate functionality was removed using K2CO3/
MeOH. The secondary hydroxyl group was then pro-
tected as its PMB ether with PMB imidate12 in the
presence of catalytic CSA to yield 13. Deprotection of
the TBDPS group with TBAF afforded 11 and attach-
ment of the prosthetic modifier yielded the coupled
ester 14 in good yield. Removal of the PMB ether
group in the presence of DDQ gave diacetylenic diol
15. Controlled hydrogenation of 15 with Lindlar cata-
lyst yielded 1j in good yield (Scheme 8). The enan-
tiomer of 1j was also prepared starting from the
enantiomer of 12 following the same synthetic route.
4. Experimental
4.1. General
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
Scheme 6. Total synthesis of 1a–i. Reagents and conditions: (a) PMBO(CH2)4CO2H, DCC, DMAP, rt; (b) DDQ, DCM:H2O
(18:1).
Scheme 7. Retrosynthetic analysis of 1j.

J. S. Yada6, S. Nanda / Tetrahedron: Asymmetry 12 (2001) 3223–3234
3227
Scheme 8. Total synthesis of 1j. Reagents and conditions: (a) K2CO3, MeOH, PMBO(CꢀN)CCl3, CSA, rt; (b) TBAF, THF, rt; (c)
PMBO(CH2)4CO2H, DCC, DMAP; (d) DDQ, DCM:H2O (18:1), rt; (e) H2, Lindlar catalyst.
,
and stored over 3 A molecular sieves. Dichloromethane
Purification by means of column chromatography gave
(DCM) was distilled from calcium hydride. Lipase
(from Candida rugosa, type VII, 1440 units/mg of
protein), lipase (from porcine pancreas, type II, 66
units/mg of protein) and lipase (from Pseudomonas
species, type XIII, 60 units/mg of protein) were
obtained from SIGMA Co. (USA) and used as
obtained. Reactions were monitored by thin-layer chro-
matography (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 develop-
ing agents. Silica gel 100–200 mesh was used for
column chromatography. Yields refer to chromato-
graphically and spectroscopically homogeneous materi-
als unless otherwise stated. NMR spectra were recorded
on 200 MHz spectrometers at rt in CDCl3 using tetra-
methylsilane as internal standard and the chemical
shifts are shown in l. 13C NMR spectra were recorded
with a complete proton decoupling instrument. Infrared
spectra were recorded on a Perkin–Elmer 1420 spec-
trometer. For enzymatic reactions the solvents
the product in 80% yield.
1H NMR data:
R=Me 2a: 0.95 (d, J=6.5 Hz, 3H), 1.75 (m, 1H),
3.4–3.6 (m, 4H), 3.9 (s, 3H), 4.45 (s, 2H), 6.8 (d,
J=6.0 Hz, 2H), 7.2 (d, J=6.0 Hz, 2H). EIMS (m/z):
210 (M+).
R=Et 2b: 0.9 (t, J=7.5 Hz, 3H), 1.3 (m, 2H), 1.75
(m, 1H), 3.3–3.7 (m, 4H), 3.9 (s, 3H), 4.45 (s, 2H), 6.8
(d, J=6.0 Hz, 2H), 7.2 (d, J=6.0 Hz, 2H). EIMS
(m/z): 224 (M+).
R=n-Pr 2c: 0.9 (t, J=7.0 Hz, 3H), 1.3 (m, 4H), 1.8
(m, 1H), 2.5 (brs, 1H, -OH), 3.4 (m, 1H), 3.55 (m,
2H), 3.7 (m, 1H), 3.8 (s, 3H), 4.4 (ABq, J=6.0 Hz,
2H), 6.8 (d, J=6.0 Hz, 2H), 7.2 (d, J=6.0 Hz, 2H).
EIMS (m/z): 238 (M+).
R=n-Bu 2d: 0.9 (t, J=7.2 Hz, 3H), 1.2–1.4 (m, 6H),
1.8 (m, 1H), 3.4 (m, 1H), 3.6 (m, 2H), 3.7 (m, 1H),
3.8 (s, 3H), 4.45 (ABq, J=6.0 Hz, 2H), 6.8 (d, J=6.0
Hz, 2H), 7.2 (d, J=6.0 Hz, 2H). EIMS (m/z): 252
(M+).
R=i-butyl 2e: 0.95 (m, 6H), 1.5 (m, 2H), 1.8 (m, 2H),
3.45–3.8 (m, 4H), 3.9 (s, 3H), 4.45 (s, 2H), 6.8 (d,
J=6.0 Hz, 2H), 7.2 (d, J=6.0 Hz, 2H). EIMS (m/z):
252 (M+).
R=t-Bu 2f: 0.9 (m, 9H), 1.75 (m, 1H), 3.4–3.7 (m,
4H), 3.8 (s, 3H), 4.4 (ABq, J=6.0 Hz, 2H), 6.8 (d,
J=6.0 Hz, 2H), 7.2 (d, J=6.0 Hz, 2H). EIMS (m/z):
252 (M+).
R=allyl 2g: 1.9 (m, 1H), 2.0 (m, 2H), 3.4–3.7 (m,
4H), 3.9 (s, 3H), 4.45 (s, 2H), 5.0 (m, 2H), 5.7 (m,
1H), 6.8 (d, J=6.0 Hz, 2H), 7.2 (d, J=6.0 Hz, 2H).
EIMS (m/z): 236 (M+).
R=Ph 2h: 2.4 (brs, 1H), 3.2 (m, 1H), 3.7–4.0 (m,
7H), 4.45 (s, 2H), 6.8 (d, J=6.0 Hz, 2H), 7.2 (m, 7H).
EIMS (m/z): 272 (M+).
,
employed were desiccated over 4 A molecular sieve
powder for 50 h prior to use. Optical rotations were
measured on a JASCO Dip 360 digital polarimeter. The
abbreviation TF denotes thin film.
4.2. 3-(4-Methoxybenzyloxy)-2-substituted-1-propanol
2a–i
The appropriate 2-substituted 1,3-propanediol (1
mmol) was dissolved in dry THF (5 mL) and NaH
(60% dispersion in mineral oil, 1 mmol) was added to
the solution portionwise at 0°C. The reaction mixture
was stirred at 0°C for 1 h under a nitrogen atmosphere.
Tetrabutylammonium iodide (catalytic) was added to
the mixture, followed by the addition of 4-methoxyben-
zyl bromide (0.24 g, 1.2 mmol). The mixture was stirred
for a further 2 h at rt. Water was added to the reaction
mixture and extracted with EtOAc. The reaction mix-
ture was then washed with brine and dried (Na2SO4).
R=PhCH2 2i: 1.9 (m, 1H), 2.6 (d, J=8.0 Hz, 2H),
3.4–3.7 (m, 4H), 3.8 (s, 3H), 4.4 (s, 2H), 6.8 (d,
J=6.0 Hz, 2H), 7.2 (m, 7H). EIMS (m/z): 286 (M+).

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J. S. Yada6, S. Nanda / Tetrahedron: Asymmetry 12 (2001) 3223–3234
4.3. (R)-3-(4-Methoxybenzyloxy)-2-substituted propyl
acetate 3a–i
column chromatography gave the alcohol in 80%
yield.
R=Me: [h]2D5=−15.2 (c 1.2, CHCl3);
R=Et: [h]2D5=−12.8 (c 1.0, CHCl3);
R=n-Pr: [h]2D5=−14.0 (c 1.1, CHCl3);
R=n-Bu: [h]2D5=−10.2 (c 1.5, CHCl3);
R=i-Bu: [h]2D5=−21.2 (c 1.2, CHCl3);
R=t-Bu: [h]2D5=−5.2 (c 1.1, CHCl3);
R=allyl: [h]2D5=−13.8 (c 1.2, CHCl3);
R=Ph: [h]2D5=+40.3 (c 0.8, CHCl3);
R=benzyl: [h]2D5=−28.9 (c 1.0, CHCl3).
In a typical resolution experiment a solution of the
monoprotected diol (1 g) in dry diisopropyl ether (50
mL) was stirred with vinyl acetate (3 mol equiv.),
followed by addition of CRL (1 g). The reaction mix-
ture was agitated in an orbit shaker at 250 rpm at rt
for the time shown in the table. After 50% conversion
(by GC analysis), the reaction mixture was filtered
through Celite and evaporated to dryness. The (R)-
alcohol and (R)-acetate were separated by column
chromatography.
4.5. (R)-3-(4-Methoxybenzyloxy)-2-substituted propanal
4a–i
1H NMR data:
A solution of the (R)-alcohol (1 mmol) in DCM (5
mL) was added to oxalyl chloride (1 mmol) and
DMSO (2 mmol) in DCM at −78°C. The temperature
was maintained at −78°C for a further 1 h. Triethyl-
amine (5 mmol) was then added and after stirring for
5 min the mixture was allowed to warm to 25°C and
stirred for a further 30 min at the same temperature.
Water was added to the solution and the mixture was
extracted with DCM. The organic extract was washed
with water, brine and dried (Na2SO4). The organic
extract was evaporated and purified by column chro-
matography to afford the aldehyde in 85% yield.
R=Me 3a: 0.95 (d, J=6.5 Hz, 3H), 1.7 (m, 1H), 2.0
(s, 3H), 3.4 (d, J=6.0 Hz, 2H), 3.9 (s, 3H), 4.1 (d,
J=6.0 Hz, 2H), 4.45 (s, 2H), 6.8 (d, J=6.0 Hz, 2H),
7.2 (d, J=6.0 Hz, 2H).
R=Et 3b: 0.9 (t, J=7.5 Hz, 3H), 1.4 (m, 2H), 1.75
(m, 1H), 2.0 (s, 3H), 3.3 (d, J=6.0 Hz, 2H), 3.9 (s,
3H), 4.05 (d, J=6.0 Hz, 2H), 4.45 (s, 2H), 6.8 (d,
J=6.0 Hz, 2H), 7.2 (d, J=6.0 Hz, 2H).
R=n-Pr 3c: 0.9 (m, 3H), 1.3 (m, 4H), 1.9 (m, 1H),
2.0 (s, 3H), 3.35 (d, J=7.0 Hz, 2H), 3.9 (s, 3H), 4.05
(d, J=7.0 Hz, 2H), 4.4 (s, 2H), 6.8 (d, J=6.0 Hz,
2H), 7.2 (d, J=6.0 Hz, 2H).
R=n-Bu 3d: 0.9 (m, 3H), 1.2–1.4 (m, 6H), 1.8 (m,
1H), 2.0 (s, 3H), 3.4 (d, J=6.8 Hz, 2H), 3.8 (s, 3H),
4.0 (d, J=6.8 Hz, 2H), 4.4 (s, 2H), 6.8 (d, J=6.0 Hz,
2H), 7.2 (d, J=6.0 Hz, 2H).
R=i-Bu 3e: 0.95 (m, 6H), 1.5 (m, 2H), 1.8 (m, 2H),
2.0 (s, 3H), 3.45 (d, J=6.8 Hz, 2H), 3.8 (s, 3H), 4.0
(d, J=6.8 Hz, 2H), 4.4 (s, 2H), 6.8 (d, J=6.0 Hz,
2H), 7.2 (d, J=6.0 Hz, 2H).
R=t-Bu 3f: 0.9 (m, 9H), 1.85 (m, 1H), 2.0 (s, 3H),
3.45 (d, J=6.8 Hz, 2H), 3.8 (s, 3H), 4.0 (d, J=6.8
Hz, 2H), 4.4 (s, 2H), 6.8 (d, J=6.0 Hz, 2H), 7.2 (d,
J=6.0 Hz, 2H).
R=allyl 3g: 1.9 (m, 1H), 2.0 (s, 3H), 2.1 (m, 2H), 3.4
(d, J=6.8 Hz, 2H), 3.8 (s, 3H), 4.2 (d, J=6.8 Hz,
2H), 4.4 (s, 2H), 5.0 (m, 2H), 5.6–5.8 (m, 1H), 6.8 (d,
J=6.0 Hz, 2H), 7.2 (d, J=6.0 Hz, 2H).
R=Ph 3h: 1.9 (s, 3H), 3.2 (m, 1H), 3.6 (d, J=6.8 Hz,
2H), 3.8 (s, 3H), 4.3 (m, 2H), 4.4 (s, 2H), 6.8 (d,
J=6.0 Hz, 2H), 7.2 (m, 7H).
R=PhCH2 3i: 2.0 (s, 3H), 2.2 (m, 1H), 2.65 (m, 2H),
3.3 (d, J=6.8 Hz, 2H), 3.85 (s, 3H), 4.1 (d, J=6.8
Hz, 2H), 4.4 (s, 2H), 6.8 (d, J=6.0 Hz, 2H), 7.2 (m,
7H).
1H NMR data:
R=Me 4a: 1.1 (d, J=6.7 Hz, 3H), 2.6 (m, 1H), 3.6
(m, 2H), 3.9 (s, 3H), 4.4 (s, 2H), 6.8 (d, J=6.0 Hz,
2H), 7.2 (d, J=6.0 Hz, 2H), 9.6 (s, 1H).
R=Et 4b: 0.9 (t, J=7.0 Hz, 3H), 1.4–1.8 (m, 2H), 2.4
(m, 1H), 3.6 (m, 2H), 3.8 (s, 3H), 4.4 (s, 2H), 6.8 (d,
J=6.0 Hz, 2H), 7.2 (d, J=6.0 Hz, 2H), 9.6 (s, 1H).
R=n-Pr 4c: 0.9 (t, J=7.0 Hz, 3H), 1.2–1.5 (m, 4H),
2.45 (m, 1H), 3.55 (m, 2H), 3.8 (s, 3H), 4.4 (s, 2H),
6.8 (d, J=6.2 Hz, 2H), 7.2 (d, J=6.2 Hz, 2H), 9.6 (s,
1H).
R=n-Bu 4d: 0.9 (t, J=7.0 Hz, 3H), 1.2–1.6 (m, 6H),
2.5 (m, 1H), 3.6 (m, 2H), 3.8 (s, 3H), 4.4 (s, 2H), 6.8
(d, J=6.2 Hz, 2H), 7.2 (d, J=6.2 Hz, 2H), 9.6 (s,
1H).
R=i-Bu 4e: 0.9 (m, 6H), 1.3 (m, 1H), 1.5 (m, 1H),
1.8 (m, 1H), 2.5 (m, 1H), 3.6–3.7 (m, 2H), 3.8 (s, 3H),
4.4 (s, 2H), 6.8 (d, J=6.2 Hz, 2H), 7.2 (d, J=6.2 Hz,
2H), 9.7 (s, 1H).
R=t-Bu 4f: 1.0 (s, 9H), 2.4 (m, 1H), 3.6–4.0 (m, 2H),
3.9 (s, 3H), 4.4 (s, 2H), 6.8 (d, J=6.0 Hz, 2H), 7.2 (d,
J=6.0 Hz, 2H), 9.55 (s, 1H).
R=allyl 4g: 2.2 (m, 1H), 2.4 (m, 1H), 2.6 (m, 1H),
3.8 (d, J=6.0 Hz, 2H), 3.9 (s, 3H), 4.4 (s, 2H), 5.0
(m, 2H), 5.75 (m, 1H), 6.8 (d, J=6.0 Hz, 2H), 7.2 (d,
J=6.0 Hz, 2H), 9.5 (s, 1H).
4.4. (S)-3-(4-Methoxybenzyloxy)-2-substituted-1-
propanol 2a–i
To
a solution of the (R)-acetate (1 mmol) in
R=Ph 4h: 3.75 (m, 1H), 3.8 (m, 1H), 3.9 (s, 3H), 4.1
(m, 1H), 4.4 (s, 2H), 6.8 (d, J=6.0 Hz, 2H), 7.2 (m,
7H), 9.6 (s, 1H).
R=PhCH2 4i: 2.5 (m, 1H), 2.6 (d, J=8.0 Hz, 2H),
3.6 (m, 2H), 3.8 (s, 3H), 4.4 (s, 2H), 6.8 (d, J=6.2
Hz, 2H), 7.2–7.4 (m, 7H), 9.7 (s, 1H).
methanol was added K2CO3 (0.414 g, 3 mmol) and
the mixture was stirred at rt for 1 h. The reaction
mixture was then filtered through Celite. After evapo-
ration of methanol, the remaining solid mass was
taken up in water, extracted with DCM, washed with
water, brine and dried (Na2SO4). Purification by

J. S. Yada6, S. Nanda / Tetrahedron: Asymmetry 12 (2001) 3223–3234
3229
4.7. 2-Substituted (Z)-3-nonen-1-ol 6a–i
4.6. 1-Methoxy-4-[2-substituted-(Z)-3-nonenyloxy-
methyl]benzene 5a–i
Olefinic compound 5a–i (0.5 mmol) was dissolved in
dichloromethane:water (19:1, 3 mL). DDQ (0.75 mmol)
was added and the solution was 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 the
alkenol in 80% yield.
n-Hexyltriphenylphosphonium iodide (1 mmol) was
taken up in THF:HMPA (6:1, 6 mL). t-BuOK (1.2
mmol) was added to the mixture at 0°C. The orange–
red colored solution was stirred at the same tempera-
ture for 0.5 h. Aldehyde 4a–i (0.3 mmol) in THF was
added and the reaction mixture was stirred for a further
6 h at rt. This was then quenched with satd NH4Cl,
extracted with ether, washed with water, brine and
dried (Na2SO4). The crude olefin was purified by
column chromatography.
1H NMR data:
R=Me 6a: 0.9 (t, J=7.2 Hz, 3H), 1.0 (d, J=6.8
Hz, 3H), 1.2–1.4 (m, 6H), 2.0 (m, 1H), 2.3 (m,
1H), 2.6 (m, 1H), 3.3 (m, 2H), 5.2 (m, 1H), 5.4 (m,
1H). EIMS (m/z): 157 (M+).
1H NMR data:
R=Et 6b: 0.9 (m, 6H), 1.15–1.55 (m, 8H), 2.0 (m,
2H), 2.45 (m, 1H), 3.3 (m, 1H), 3.55 (m, 1H), 5.1
(m, 1H), 5.6 (m, 1H). EIMS (m/z): 171 (M+).
R=n-Pr 6c: 0.95 (t, J=7.2 Hz, 6H), 1.2–1.6 (m,
10H), 2.0 (m, 2H), 2.6 (m, 1H), 3.2–3.5 (m, 2H),
5.0 (m, 1H), 5.4 (m, 1H). EIMS (m/z): 185 (M+).
R=n-Bu 6d: 0.9 (m, 6H), 1.2–1.5 (m, 12H), 2.0 (m,
2H), 2.55 (m, 1H), 3.35 (t, J=7.0 Hz, 2H), 5.1–5.5
(m, 2H). EIMS (m/z): 199 (M+).
R=i-Bu 6e: 0.9 (m, 9H), 1.2–1.5 (m, 9H), 2.0 (m,
2H), 2.4 (m, 1H), 3.2 (m, 1H), 3.55 (m, 1H), 5.0
(m, 1H), 5.5 (m, 1H).
R=t-Bu 6f: 0.9–1.0 (m, 12H), 1.2–1.5 (m, 6H), 2.0
(m, 2H), 2.3 (m, 1H), 3.2 (m, 1H), 3.5 (m, 1H),
5.2–5.5 (m, 2H).
R=allyl 6g: 0.85 (t, J=6.8 Hz, 3H), 1.2 (m, 6H),
1.8–2.0 (m, 4H), 2.5 (m, 1H), 3.2 (m, 1H), 3.4 (m,
1H), 4.8–5.0 (m, 3H), 5.4 (m, 1H), 5.6 (m, 1H).
EIMS (m/z): 183 (M+).
R=Ph 6h: 0.9 (t, J=7.0 Hz, 3H), 1.2–1.7 (m, 6H),
2.3 (m, 1H), 2.6 (t, J=7.6 Hz, 2H), 3.8 (d, J=7.0
Hz, 2H), 6.58 (d, J=10.5 Hz, 1H), 7.0–7.3 (m,
5H), 7.85 (dd, J=14.0 Hz, 10.5 Hz, 1H). EIMS
(m/z): 220 (M+).
R=PhCH2 6i: 0.9 (m, 3H), 1.2–1.6 (m, 6H), 1.9
(m, 2H), 2.35 (m, 1H), 2.8 (m, 2H), 3.4 (m, 1H),
3.55 (m, 1H), 5.2 (m, 1H), 5.55 (m, 1H), 7.1–7.3
(m, 5H). EIMS (m/z): 234 (M+).
R=Me 5a: 0.9 (t, J=7.2 Hz, 3H), 1.0 (d, J=6.8
Hz, 3H), 1.2–1.4 (m, 6H), 2.0 (m, 2H), 2.4 (m,
1H), 3.3 (m, 2H), 3.9 (s, 3H), 4.4 (s, 2H), 5.2 (m,
1H), 5.4 (m, 1H), 6.8 (d, J=6.0 Hz, 2H), 7.2 (d,
J=6.0 Hz, 2H). EIMS (m/z): 276 (M+).
R=Et 5b: 0.9 (m, 6H), 1.15–1.55 (m, 8H), 2.0 (m,
2H), 2.45 (m, 1H), 3.3 (m, 1H), 3.55 (m, 1H), 3.8
(s, 3H), 4.4 (s, 2H), 5.1 (m, 1H), 5.6 (m, 1H), 6.8
(d, J=6.0 Hz, 2H), 7.2 (d, J=6.0 Hz, 2H). EIMS
(m/z): 290 (M+).
R=n-Pr 5c: 0.95 (t, J=7.2 Hz, 6H), 1.2–1.6 (m,
10H), 2.0 (m, 2H), 2.35 (m, 1H), 3.2 (d, J=7.0 Hz,
2H), 3.85 (s, 3H), 4.35 (s, 2H), 5.0 (m, 1H), 5.4 (m,
1H), 6.8 (d, J=6.0 Hz, 2H), 7.2 (d, J=6.0 Hz,
2H). EIMS (m/z): 304 (M+).
R=n-Bu 5d: 0.9 (m, 6H), 1.2–1.5 (m, 12H), 2.0 (m,
2H), 2.2 (m, 1H), 3.35 (m, 2H), 3.8 (s, 3H), 4.4 (s,
2H), 5.1–5.5 (m, 2H), 6.8 (d, J=6.0 Hz, 2H), 7.2
(d, J=6.0 Hz, 2H). EIMS (m/z): 318 (M+).
R=i-Bu 5e: 0.9–1.0 (m, 9H), 1.4–1.6 (m, 8H), 1.8
(m, 1H), 2.0 (m, 2H), 2.45 (m, 1H), 3.4 (m, 2H),
3.8 (s, 3H), 4.4 (s, 2H), 5.2 (m, 1H), 5.5 (m, 1H),
6.8 (d, J=6.0 Hz, 2H), 7.2 (d, J=6.0 Hz, 2H).
EIMS (m/z): 318 (M+).
R=t-Bu 5f: 0.9–1.0 (m, 12H), 1.2–1.5 (m, 6H), 2.0
(m, 2H), 2.4 (m, 1H), 3.2 (m, 1H), 3.5 (m, 1H), 3.8
(s, 3H), 4.35 (s, 3H), 5.2–5.5 (m, 2H), 6.8 (d, J=
6.0 Hz, 2H), 7.2 (d, J=6.0 Hz, 2H). EIMS (m/z):
318 (M+).
4.8. 2-Substituted (Z)-3-nonenal 7a–i
R=allyl 5g: 0.9 (m, 3H), 1.2–1.5 (m, 6H), 2.0 (m,
2H), 2.2 (m, 2H), 2.75 (m, 1H), 3.3 (d, J=7.0 Hz,
2H), 3.85 (s, 3H), 4.5 (s, 2H), 4.9–5.2 (m, 3H), 5.4
(m, 1H), 5.65 (m, 1H), 6.8 (d, J=6.0 Hz, 2H), 7.2
(d, J=6.0 Hz, 2H). EIMS (m/z): 302 (M+).
R=Ph 5h: 0.9 (t, J=7.0 Hz, 3H), 1.2–1.7 (m, 6H),
2.3 (m, 1H), 2.6 (t, J=7.6 Hz, 2H), 3.8 (d, J=7.0
Hz, 2H), 3.9 (s, 3H), 4.4 (s, 2H), 6.58 (d, J=10.5
Hz, 1H), 6.8–7.0 (m, 5H), 7.45 (m, 4H), 7.85 (dd,
J=14 Hz, 10.5 Hz, 1H). EIMS (m/z): 338 (M+).
R=PhCH2 5i: 0.9 (m, 3H), 1.2–1.6 (m, 6H), 1.9
(m, 2H), 2.35 (m, 1H), 2.8 (m, 2H), 3.4 (m, 1H),
3.55 (m, 1H), 3.8 (s, 3H), 4.4 (s, 2H), 5.2 (m, 1H),
5.55 (m, 1H), 6.8 (d, J=6.0 Hz, 2H), 7.2 (m, 7H).
EIMS (m/z): 352 (M+).
The reaction conditions are the same as described in
Section 4.4.
1H NMR data:
R=Me 7a: 0.9 (t, J=7.0 Hz, 3H), 1.15 (d, J=6.8
Hz, 3H), 1.2–1.5 (m, 6H), 2.2 (m, 2H), 3.35 (m,
1H), 5.2 (m, 1H), 5.6 (m, 1H), 9.5 (s, 1H).
R=Et 7b: 0.9 (m, 6H), 1.2–1.8 (m, 8H), 2.1 (m,
2H), 3.18 (m, 1H), 5.2 (m, 1H), 5.55 (m, 1H), 9.5
(s, 1H).
R=n-Pr 7c: 0.9 (m, 6H), 1.2–1.5 (m, 10H), 2.1 (m,
2H), 3.2 (m, 1H), 5.2 (m, 1H), 5.7 (m, 1H), 9.4 (s,
1H).

3230
J. S. Yada6, S. Nanda / Tetrahedron: Asymmetry 12 (2001) 3223–3234
R=n-Bu 7d: 0.9 (m, 6H), 1.2–1.6 (m, 12H), 2.0 (m,
2H), 3.0 (m, 1H), 5.2 (m, 1H), 5.6 (m, 1H), 9.5 (s,
1H).
4.4 (s, 2H), 4.8–5.4 (m, 6H), 5.8 (m, 1H), 6.8 (d,
J=6.0 Hz, 2H), 7.2 (d, J=6.0 Hz, 2H). FABMS
(m/z): 342 (M+).
R=i-Bu 7e: 0.9 (m, 9H), 1.1–1.6 (m, 8H), 1.9 (m,
1H), 2.1 (m, 2H), 3.1 (m, 1H), 5.25 (m, 1H), 5.7 (m,
1H), 9.4 (s, 1H).
R=t-Bu 7f: 0.9–1.0 (m, 12H), 1.2–1.5 (m, 6H), 2.1
(m, 2H), 3.2 (m, 1H), 5.2 (m, 1H), 5.6 (m, 1H), 9.4 (s,
1H).
R=Ph 8h: 0.9 (t, J=7.0 Hz, 3H), 1.2–1.7 (m, 6H),
2.2–2.5 (m, 4H), 3.48 (m, 3H), 3.8 (s, 3H), 4.4 (s, 2H),
5.6–5.8 (m, 2H), 6.58 (d, J=10.5 Hz, 1H), 6.8 (d,
J=6.2 Hz, 2H), 7.0–7.3 (m, 5H), 7.2 (d, J=6.2 Hz,
2H), 7.85 (dd, J=14.0 Hz, 10.5 Hz, 1H). FABMS
(m/z): 378 (M+).
R=allyl 7g: 0.9 (m, 3H), 1.2–1.5 (m, 6H), 2.0–2.2 (m,
4H), 3.3 (m, 1H), 5.0–5.2 (m, 3H), 5.7 (m, 2H), 9.5 (s,
1H).
R=Ph 7h: 0.9 (t, J=7.0 Hz, 3H), 1.2–1.7 (m, 6H),
2.6 (t, J=7.6 Hz, 2H), 3.3 (m, 1H), 6.58 (d, J=10.5
Hz, 1H), 7.0–7.3 (m, 5H), 7.85 (dd, J=14.0 Hz, 10.5
Hz, 1H), 9.6 (s, 1H).
R=PhCH2 7i: 0.9 (t, J=7.0 Hz, 3H), 1.1–1.6 (m,
6H), 1.9 (m, 2H), 2.6 (m, 1H), 3.1 (m, 1H), 3.5 (m,
1H), 5.2 (m, 1H), 5.6 (m, 1H), 7.0–7.3 (m, 5H), 9.6 (s,
1H).
R=PhCH2 8i: 0.9 (m, 3H), 1.2–1.4 (m, 6H), 1.9 (m,
2H), 2.3 (m, 2H), 2.6 (d, J=8.0 Hz, 2H), 3.15–3.3 (m,
2H), 3.6 (m, 1H), 3.8 (s, 3H), 4.4 (s, 2H), 5.2–5.4 (m,
4H), 6.8 (d, J=6.0 Hz, 2H), 7.2 (m, 7H). FABMS
(m/z): 392 (M+).
4.10. 5-Substituted-(3Z,6Z)-3,6-dodecadien-1-ol 9a–i
Deprotection of the PMB ether group was done by
DDQ as described in Section 4.6.
1H NMR data:
4.9. Methoxy-4-[5-substituted-(3Z,6Z)-3,6-dodecadienyl-
oxymethyl]benzene 8a–i
R=Me 9a: 0.9 (t, J=7.0 Hz, 3H), 1.0 (d, J=6.8 Hz,
3H), 1.2–1.5 (m, 6H), 2.1 (m, 2H), 2.4 (m, 2H), 3.4
(m, 3H), 5.2–5.4 (m, 4H). EIMS (m/z): 197 (M+).
R=Et 9b: 0.9 (m, 6H), 1.2–1.4 (m, 8H), 2.0 (m, 2H),
2.3 (q, J=7.2 Hz, 2H), 3.2 (m, 1H), 3.6 (t, J=7.2 Hz,
2H), 5.0–5.4 (m, 4H). EIMS (m/z): 211 (M+).
R=n-Pr 9c: 0.9 (m, 6H), 1.2–1.5 (m, 10H), 2.0 (m,
2H), 2.4 (m, 2H), 3.2 (m, 1H), 3.4 (m, 2H), 5.1–5.4
(m, 4H). EIMS (m/z): 225 (M+).
The reaction conditions were the same as described in
Section 4.5. Instead of n-hexyltriphenylphosphonium
iodide, here we used 1-(3-triphenylphosphonium
iodopropoxymethyl)-4-methoxybenzene.
1H NMR data:
R=n-Bu 9d: 0.9 (m, 6H), 1.2–1.5 (m, 12H), 2.0 (m,
2H), 2.4 (m, 2H), 3.4 (m, 3H), 5.1–5.4 (m, 4H). EIMS
(m/z): 239 (M+).
R=i-Bu 9e: 0.9–1.0 (m, 9H), 1.2–1.6 (m, 8H), 1.75
(m, 1H), 2.0 (m, 2H), 2.4 (m, 2H), 3.15 (m, 1H), 3.4
(m, 2H), 5.15–5.4 (m, 4H).
R=t-Bu 9f: 0.9 (s, 12H), 1.3 (m, 6H), 2.0 (m, 2H),
2.4 (m, 2H), 3.15 (m, 1H), 3.4 (t, J=7.0 Hz, 2H),
5.15–5.4 (m, 4H).
R=allyl 9g: 0.9 (t, J=6.8 Hz, 3H), 1.4 (m, 6H), 2.1
(m, 4H), 2.4 (m, 2H), 3.4 (m, 1H), 3.6 (t, J=7.0 Hz,
2H), 5.0 (m, 2H), 5.2 (m, 1H), 5.4 (m, 3H), 5.7 (m,
1H). EIMS (m/z): 223 (M+).
R=Ph 9h: 0.9 (t, J=7.0 Hz, 3H), 1.2–1.7 (m, 6H),
2.2–2.5 (m, 4H), 3.48 (m, 1H), 3.6 (t, J=7.0 Hz, 2H),
5.6–5.8 (m, 2H), 6.58 (d, J=10.5 Hz, 1H), 7.0–7.3
(m, 5H), 7.85 (dd, J=14.0 Hz, 10.5 Hz, 1H). EIMS
(m/z): 260 (M+).
R=PhCH2 9i: 0.9 (m, 3H), 1.2–1.4 (m, 6H), 1.9 (m,
2H), 2.3 (m, 2H), 2.6 (d, J=8.0 Hz, 2H), 3.15–3.3 (m,
2H), 3.6 (m, 1H), 5.2–5.4 (m, 4H), 7.1–7.3 (m, 5H).
EIMS (m/z): 274 (M+).
R=Me 8a: 0.9 (t, J=7.0 Hz, 3H), 1.0 (d, J=7.0 Hz,
3H), 1.2–1.4 (m, 6H), 2.0 (m, 2H), 2.4 (m, 2H), 2.9
(m, 1H), 3.4 (t, J=7.0 Hz, 2H), 3.8 (s, 3H), 4.4 (s,
2H), 5.2–5.4 (m, 4H), 6.8 (d, J=6.0 Hz, 2H), 7.2 (d,
J=6.0 Hz, 2H). FABMS (m/z): 316 (M+).
R=Et 8b: 0.9 (m, 6H), 1.2–1.4 (m, 8H), 2.0 (m, 2H),
2.3 (m, 2H), 3.15 (m, 1H), 3.35 (t, J=7.2 Hz, 2H),
3.8 (s, 3H), 4.4 (s, 2H), 5.0–5.4 (m, 4H), 6.8 (d,
J=6.0 Hz, 2H), 7.2 (d, J=6.0 Hz, 2H). FABMS
(m/z): 330 (M+).
R=n-Pr 8c: 0.9 (m, 6H), 1.2–1.5 (m, 10H), 2.0 (m,
2H), 2.4 (m, 2H), 3.15 (m, 1H), 3.4 (m, 2H), 3.9 (s,
3H), 4.4 (s, 2H), 5.1–5.4 (m, 4H), 6.8 (d, J=6.0 Hz,
2H), 7.2 (d, J=6.0 Hz, 2H). FABMS (m/z): 344
(M+).
R=n-Bu 8d: 0.9 (m, 6H), 1.2–1.5 (m, 12H), 2.0 (m,
2H), 2.4 (m, 2H), 3.4 (m, 3H), 3.8 (s, 3H), 4.4 (s, 2H),
5.1–5.4 (m, 4H), 6.8 (d, J=6.0 Hz, 2H), 7.2 (d,
J=6.0 Hz, 2H). FABMS (m/z): 358 (M+).
R=i-Bu 8e: 0.9–1.0 (m, 9H), 1.2–1.6 (m, 8H), 1.75
(m, 1H), 2.0 (m, 2H), 2.4 (m, 2H), 3.15 (m, 1H), 3.4
(m, 2H), 3.8 (s, 3H), 4.4 (s, 2H), 5.15–5.4 (m, 4H), 6.8
(d, J=6.0 Hz, 2H), 7.2 (d, J=6.0 Hz, 2H). FABMS
(m/z): 358 (M+).
R=t-Bu 8f: 0.9 (s, 12H), 1.3 (m, 6H), 2.2 (m, 2H),
2.4 (m, 2H), 3.15 (m, 1H), 3.4 (t, J=7.0 Hz, 2H), 3.9
(s, 3H), 4.4 (s, 2H), 5.15–5.4 (m, 4H), 6.8 (d, J=6.0
Hz, 2H), 7.2 (d, J=6.0 Hz, 2H). FABMS (m/z): 358
(M+).
4.11. 5-Substituted-(3Z,6Z)-3,6-dodecadienyl-5-(4-
methoxybenzyloxy)pentanoate 10a–i
5-(4-Methoxybenzyloxy)pentanoic acid (0.25 mmol)
was dissolved in dichloromethane (2 mL). DCC (0.25
mmol) was added to the solution, followed by the
addition of DMAP (10 mol%) at 0°C. The reaction
mixture was stirred for 5 min and a solution of 5-substi-
R=allyl 8g: 0.9 (t, J=7.0 Hz, 3H), 1.2–1.4 (m, 6H),
2.1 (m, 4H), 2.35 (m, 2H), 3.4 (m, 3H), 3.8 (s, 3H),

J. S. Yada6, S. Nanda / Tetrahedron: Asymmetry 12 (2001) 3223–3234
3231
4.12. 5-Substituted-(3Z,6Z)-3,6-dodecadienyl-5-hydroxy-
pentanoate 1a–i
tuted (3Z,6Z)-3,6-dodecadiene-1-ol (0.25 mmol) in
dichloromethane was then added dropwise. The mix-
ture was stirred for a further 3 h at rt. Dicyclohexylurea
was filtered off, and the filtrate was washed with water,
brine and dried (Na2SO4). After chromatographic sepa-
ration the product was obtained in 60% yield.
The deprotection of the PMB ether was completed as
described in Section 4.6.
1H NMR data:
1H NMR data:
R=Me 1a: 0.9 (m, 3H), 1.0 (d, J=7.0 Hz, 3H),
1.2–1.4 (m, 6H), 1.6–1.8 (m, 4H), 2.0 (m, 2H), 2.2–2.4
(m, 4H), 3.4 (m, 3H), 4.0 (t, J=7.0 Hz, 2H), 5.2–5.4
(m, 4H). FABMS (m/z): 296 (M+). [h]D25=+2.9 (c 1.0,
CHCl3). Anal. calcd for C18H32O3: C, 72.93; H,
10.88. Found: C, 72.91; H, 10.94%.
R=Et 1b: 0.9 (m, 6H), 1.2–1.4 (m, 8H), 1.6–1.8 (m,
4H), 2.0 (m, 2H), 2.3 (q, J=7.2 Hz, 2H), 2.4 (m, 2H),
3.15 (m, 1H), 3.45 (t, J=7.2 Hz, 2H), 4.1 (t, J=7.0
Hz, 2H), 5.0–5.4 (m, 4H). FABMS (m/z): 310 (M+).
[h]2D5=+11.0 (c 1.2, CHCl3). Anal. calcd for
C19H34O3: C, 73.50; H, 11.04. Found: C, 73.55; H,
11.02%.
R=Me 10a: 0.9 (m, 3H), 1.0 (d, J=7.0 Hz, 3H),
1.2–1.4 (m, 6H), 1.6–1.8 (m, 4H), 2.0 (m, 2H), 2.2–2.4
(m, 4H), 3.4 (m, 3H), 3.8 (s, 3H), 4.0 (t, J=7.0 Hz,
2H), 4.4 (s, 2H), 5.2–5.4 (m, 4H), 6.8 (d, J=6.0 Hz,
2H), 7.2 (d, J=6.0 Hz, 2H). FABMS (m/z): 416
(M+).
R=Et 10b: 0.9 (m, 6H), 1.2–1.4 (m, 8H), 1.6–1.8 (m,
4H), 2.0 (m, 2H), 2.3 (q, J=7.2 Hz, 2H), 2.4 (m, 2H),
3.15 (m, 1H), 3.4 (t, J=7.2 Hz, 2H), 3.8 (s, 3H), 4.1
(t, J=7.0 Hz, 2H), 4.4 (s, 2H), 5.0–5.4 (m, 4H). 6.8
(d, J=6.0 Hz, 2H), 7.2 (d, J=6.0 Hz, 2H). FABMS
(m/z): 430 (M+).
R=n-Pr 1c: 0.9 (m, 6H), 1.2–1.4 (m, 10H), 1.6 (m,
4H), 2.0 (m, 2H), 2.4 (m, 4H), 3.2 (m, 1H), 3.4 (t,
J=7.0 Hz, 2H), 4.0 (t, J=7.0 Hz, 2H), 5.0–5.4 (m,
4H). FABMS (m/z): 324 (M+). [h]D25=+5.2 (c 1.0,
CHCl3). Anal. calcd for C20H36O3: C, 74.03; H,
11.18. Found: C, 74.08; H, 11.14%.
R=n-Bu 1d: 0.9 (m, 6H), 1.2–1.4 (m, 12H), 1.6 (m,
4H), 2.0 (m, 2H), 2.4 (m, 4H), 3.2 (m, 1H), 3.4 (t,
J=7.0 Hz, 2H), 4.0 (t, J=7.0 Hz, 2H), 5.0–5.4 (m,
4H). FABMS (m/z): 338 (M+). [h]D25=+9.8 (c 1.0,
CHCl3). Anal. calcd for C21H38O3: C, 74.51; H,
11.31. Found: C, 74.49; H, 11.26%.
R=i-Bu 1e: 0.9 (m, 9H), 1.35 (m, 6H), 1.5–1.8 (m,
7H), 2.0 (m, 2H), 2.2–2.45 (m, 4H), 3.19 (m, 1H), 3.4
(t, J=7.0 Hz, 2H), 4.1 (t, J=7.0 Hz, 2H), 5.35 (m,
4H). [h]2D5=+6.2 (c 1.1, CHCl3). FABMS (m/z): 338
(M+).
R=t-Bu 1f: 0.9 (s, 12H), 1.35 (m, 6H), 1.6–2.0 (m,
4H), 2.0 (m, 2H), 2.4 (m, 4H), 3.1 (m, 1H), 3.4 (t,
J=7.0 Hz, 2H), 4.0 (t, J=7.0 Hz, 2H), 5.2–5.4 (m,
4H). [h]2D5=+1.9 (c 1.1, CHCl3). FABMS (m/z): 338
(M+).
R=allyl 1g: 0.9 (t, J=7.0 Hz, 3H), 1.3 (m, 6H), 1.7
(m, 4H), 2.0 (m, 4H), 2.2–2.4 (m, 4H), 3.2 (m, 1H),
3.4 (t, J=7.2 Hz, 2H), 4.0 (t, J=7.2 Hz, 2H), 4.9–5.4
(m, 5H), 5.6–5.8 (m, 2H). FABMS (m/z): 322 (M+).
[h]2D5=+10.1 (c 1.0, CHCl3). Anal. calcd for
C20H34O3: C, 74.49; H, 10.63. Found: C, 74.53; H,
10.68%.
R=Ph 1h: 0.9 (t, J=7.0 Hz, 3H), 1.2–1.8 (m, 10H),
2.2–2.5 (m, 6H), 3.48 (m, 1H), 3.6 (t, J=7.0 Hz, 2H),
4.1 (t, J=7.0 Hz, 2H), 5.6–5.8 (m, 2H), 6.58 (d,
J=10.5 Hz, 1H), 7.0–7.3 (m, 5H), 7.85 (dd, J=14.0
Hz, 10.5 Hz, 1H). FABMS (m/z): 358 (M+). [h]D25=
−19.2 (c 1.0, CHCl3). Anal. calcd for C23H34O3: C,
77.05; H, 9.56. Found: C, 76.81; H, 9.87%.
R=n-Pr 10c: 0.9 (m, 6H), 1.2–1.4 (m, 10H), 1.6 (m,
4H), 2.0 (m, 2H), 2.3 (m, 4H), 3.2 (m, 1H), 3.4 (t,
J=7.0 Hz, 2H), 3.8 (s, 2H), 4.0 (t, J=7.0 Hz, 2H),
4.4 (s, 2H), 5.0–5.4 (m, 4H), 6.8 (d, J=6.0 Hz, 2H),
7.2 (d, J=6.0 Hz, 2H). FABMS (m/z): 444 (M+).
R=n-Bu 10d: 0.9 (m, 6H), 1.2–1.4 (m, 12H), 1.6 (m,
4H), 2.0 (m, 2H), 2.4 (m, 4H), 3.2 (m, 1H), 3.4 (t,
J=7.0 Hz, 2H), 3.8 (s, 3H), 4.0 (t, J=7.0 Hz, 2H),
4.4 (s, 2H), 5.0–5.4 (m, 4H), 6.8 (d, J=6.0 Hz, 2H),
7.2 (d, J=6.0 Hz, 2H). FABMS (m/z): 458 (M+).
R=i-Bu 10e: 0.9 (m, 9H), 1.35 (m, 6H), 1.5–1.8 (m,
7H), 2.0 (m, 2H), 2.2–2.45 (m, 4H), 3.1 (m, 1H), 3.4
(t, J=7.0 Hz, 2H), 3.8 (s, 3H), 4.1 (t, J=7.0 Hz, 2H),
4.4 (s, 2H), 5.35 (m, 4H), 6.8 (d, J=6.0 Hz, 2H), 7.2
(d, J=6.0 Hz, 2H). FABMS (m/z): 458 (M+).
R=t-Bu 10f: 0.9 (s, 12H), 1.35 (m, 6H), 1.6–1.9 (m,
4H), 2.0 (m, 2H), 2.3 (m, 4H), 3.1 (m, 1H), 3.4 (t,
J=7.0 Hz, 2H), 3.9 (s, 3H), 4.0 (t, J=7.0 Hz, 2H),
4.4 (s, 2H), 5.2–5.4 (m, 4H), 6.8 (d, J=6.0 Hz, 2H),
7.2 (d, J=6.0 Hz, 2H). FABMS (m/z): 458 (M+).
R=allyl 10g: 0.9 (t, J=7.0 Hz, 3H), 1.3 (m, 6H), 1.6
(m, 4H), 2.0 (m, 4H), 2.4 (m, 4H), 3.2 (m, 1H), 3.4 (t,
J=7.2 Hz, 2H), 3.9 (s, 3H), 4.0 (t, J=7.2 Hz, 2H),
4.4 (s, 2H), 4.9–5.4 (m, 5H), 5.6–5.8 (m, 2H), 6.8 (d,
J=6.0 Hz, 2H), 7.2 (d, J=6.0 Hz, 2H). FABMS
(m/z): 442 (M+).
R=Ph 10h: 0.9 (t, J=7.0 Hz, 3H), 1.2–1.8 (m, 10H),
2.2–2.5 (m, 6H), 3.48 (m, 1H), 3.6 (t, J=7.0 Hz, 2H),
3.8 (s, 3H), 4.1 (t, J=7.0 Hz, 2H), 4.4 (s, 2H), 5.6–5.8
(m, 2H), 6.58 (d, J=10.5 Hz, 1H), 6.8 (d, J=6.2 Hz,
2H), 7.0–7.3 (m, 5H), 7.2 (d, J=6.2 Hz, 2H), 7.85
(dd, J=14.0 Hz, 10.5 Hz, 1H). FABMS (m/z): 468
(M+).
R=PhCH2 10i: 0.9 (m, 3H), 1.2 (m, 6H), 1.6 (m,
4H), 1.9 (m, 2H), 2.1–2.35 (m, 4H), 2.6 (d, J=8.0 Hz,
2H), 3.4 (t, J=7.0 Hz, 2H), 3.45 (m, 1H), 3.8 (s, 3H),
3.85 (m, 2H), 4.4 (s, 2H), 5.15–5.4 (m, 4H), 6.8 (d,
J=6.0 Hz, 2H), 7.2 (m, 7H). FABMS (m/z): 482
(M+).
R=PhCH2 1i: 0.9 (m, 3H), 1.2 (m, 6H), 1.6 (m, 4H),
1.9 (m, 2H), 2.1–2.35 (m, 4H), 2.6 (d, J=8.0 Hz, 2H),
3.4 (t, J=7.0 Hz, 2H), 3.45 (m, 1H), 3.85 (m, 2H),

3232
J. S. Yada6, S. Nanda / Tetrahedron: Asymmetry 12 (2001) 3223–3234
5.15–5.4 (m, 4H), 2H), 7.2 (m, 5H). FABMS (m/z):
R=i-Bu: 0.9 (m, 6H), 1.5 (m, 2H), 1.6 (d, J=7.2 Hz,
3H), 1.8 (m, 2H), 3.3–3.4 (m, 2H), 3.8 (s, 3H), 4.1–4.2
(m, 2H), 4.4 (s, 2H), 4.75 (q, J=7.2 Hz, 1H), 6.8 (d,
J=6.0 Hz, 2H), 6.9–7.1 (m, 4H), 7.2 (d, J=6.2 Hz,
2H).
372 (M+). [h]D25=+12.4 (c 1.0, CHCl3). Anal. calcd for
C24H36O3: C, 77.38; H, 9.74. Found: C, 77.21; H,
10.02%.
R=t-Bu: 0.9 (m, 9H), 1.6 (d, J=7.2 Hz, 3H), 1.75
(m, 1H), 3.4 (m, 2H), 3.8 (s, 3H), 4.1 (m, 2H), 4.4 (s,
2H), 4.75 (q, J=7.2 Hz, 1H), 6.8 (d, J=6.0 Hz, 2H),
7.0–7.2 (m, 6H).
R=allyl: 1.6 (d, J=7.2 Hz, 3H), 2.0 (m, 3H), 3.3 (m,
2H), 3.8 (s, 3H), 4.15 (m, 2H), 4.45 (s, 2H), 4.75 (q,
J=7.2 Hz, 1H), 5.0 (m, 2H), 5.7 (m, 1H), 6.8 (d,
J=6.0 Hz, 2H), 6.9–7.2 (m, 6H).
R=Ph: 1.55 (d, J=7.2 Hz, 3H), 3.2 (m, 1H), 3.6 (m,
2H), 3.8 (s, 3H), 4.4 (ABd, J=6.0 Hz, 2H), 4.5 (m,
2H), 4.7 (q, J=7.2 Hz, 1H), 6.8 (d, J=6.0 Hz, 2H),
6.9–7.3 (m, 11H).
R=PhCH2: 1.6 (d, J=7.2 Hz, 3H), 1.9 (m, 1H), 2.6
(d, J=8.0 Hz, 2H), 3.4 (m, 2H), 3.8 (s, 3H), 4.15 (m,
2H), 4.4 (s, 2H), 4.72 (q, J=7.2 Hz, 1H), 6.8 (d,
J=6.0 Hz, 2H), 6.9–7.2 (m, 11H).
4.13. Preparation of FAC acid [2-(fluorophenoxy)-(2S)-
propanoic acid]
A solution of DIAD (0.05 mol) in THF (35 mL) was
added dropwise to a mixture of (S)-ethyl lactate (0.05
mol), 2-fluorophenol (0.05 mol) and TPP (0.05 mol) in
THF (75 mL). The mixture was stirred overnight at rt.
After evaporation of THF, a mixture of hexane:ether
(1:1, 125 mL) was added to the viscous residue and
stirring was continued until a crystalline precipitate had
separated (1 h). The precipitate was filtered off, and the
filtrate washed with 1N NaOH (2×50 mL), brine and
water. After evaporation of the solvent, the crude
product was directly hydrolyzed in methanol (200 mL)
with 2N aq. NaOH (50 mL). Methanol was evaporated
with minimum heat, and water (50 mL) was added.
Extraction with ether (3×50 mL) eliminates most of the
impurities. After cooling in an ice bath, the aq. layer
was neutralized with conc. HCL (10 mL). The free acid
was extracted with ether (3×50 mL). After drying
4.15. 1-(4-O-tert-Butyldiphenylsilyl-1-butynyl)-(1R)-2-
octynylalcohol 12
1
(Na2SO4) it was recrystallized from hexane. H NMR:
Deprotection of the acetate group was completed as
1
described in Section 2.3. IR (TF): 3390, 3010 cm−1. H
1.55 (d, J=7.5 Hz, 3H), 4.7 (q, J=7.5 Hz, 1H), 6.9–7.0
(m, 4H), 9.5 (brs, 1H). [h]2D5=+31.6 (c 1.15, CHCl3).
EIMS (m/z): 184 (M+).
NMR: 0.85 (t, J=7.0 Hz, 3H), 1.0 (s, 9H), 1.2–1.5 (m,
6H), 2.25 (t, J=7.0 Hz, 2H), 2.5 (t, J=7.0 Hz, 2H), 3.7
(t, J=7.0 Hz, 2H), 5.0 (s, 1H), 7.35–7.7 (m, 10H).
FABMS (m/z): 433 (M+1). [h]2D5=+9.2 (c 1.2, CHCl3).
4.14. Coupling of FAC acid with alcohols
DCC (1 mmol), the chiral alcohol (1 mmol) and FAC
acid (1 mmol) were dissolved in anhydrous THF. A few
crystals of DMAP were added. The clear solution
rapidly became cloudy on stirring. After stirring
overnight the mixture was filtered. Solvent was evapo-
rated without heating and the product was purified
using column chromatography.
4.16. 1-Methoxy-4[1-(4-O-tert-butyldiphenylsilyl-1-
butynyl-(1R)-2-octynyloxymethyl]benzene 13
A solution of the PMB alcohol (37.6 mmol) in ether (35
mL) was added to sodium hydride (60% suspension in
oil, 5 mmol) in ether (40 mL) at rt. The resulting
mixture was stirred at rt for 0.5 h and cooled to 0°C.
Trichloroacetonitrile (37.6 mmol) was added, and the
reaction mixture was allowed to warm slowly to rt over
4 h. The solution was concentrated to an orange syrup,
which was dissolved in dry petroleum ether (50 mL)
containing MeOH (0.2 mL). This suspension was
shaken vigorously and filtered through Celite, and the
filtrate was concentrated to a yellow syrup. The crude
imidate (0.784 g, 2.7 mmol) was dissolved in cyclohex-
ane (15 mL) and a solution of alcohol (1 g, 2.3 mmol)
in DCM (8 mL) was added. The resulting solution was
cooled to 0°C and treated with CSA (10 mol%). The
reaction mixture was warmed to rt and stirred
overnight; slowly, a white precipitate developed. The
solution was filtered and then washed with DCM. The
filtrate washed with satd NaHCO3, brine and dried
(Na2SO4). Purification by means of column chromatog-
1H NMR data:
R=Me: 0.9 (d, J=7.0 Hz, 3H), 1.64 (d, J=7.2 Hz,
3H), 1.8 (m, 1H), 3.2 (m, 2H), 3.8 (s, 3H), 4.2 (m,
2H), 4.4 (s, 2H), 4.89 (q, J=7.2 Hz, 1H), 6.8 (d,
J=6.2 Hz, 2H), 6.9–7.1 (m, 4H), 7.2 (d, J=6.2 Hz,
2H).
R=Et: 0.9 (t, J=7.0 Hz, 3H), 1.2–1.4 (m, 2H), 1.6
(d, J=7.0 Hz, 3H), 1.8 (m, 1H), 3.2 (m, 2H), 3.8 (s,
3H), 4.15 (m, 2H), 4.35 (s, 2H), 4.7 (q, J=7.0 Hz,
1H), 6.8 (d, J=6.2 Hz, 2H), 6.9–7.1 (m, 4H), 7.2 (d,
J=6.2 Hz, 2H).
R=n-Pr: 0.9 (t, J=7.0 Hz, 3H), 1.2–1.4 (m, 4H), 1.6
(d, J=7.2 Hz, 3H), 1.9 (m, 1H), 3.3 (m, 2H), 3.8 (s,
3H), 4.1–4.2 (m, 2H), 4.4 (s, 2H), 4.85 (q, J=7.2 Hz,
1H), 6.8 (d, J=6.2 Hz, 2H), 6.9–7.1 (m, 4H), 7.2 (d,
J=6.2 Hz, 2H).
R=n-Bu: 0.9 (t, J=7.0 Hz, 3H), 1.2 (m, 6H), 1.6 (d,
J=7.2 Hz, 3H), 1.8 (m, 1H), 3.3 (d, J=6.8 Hz, 2H),
3.9 (s, 3H), 4.2 (m, 2H), 4.45 (s, 2H), 4.75 (q, J=7.2
Hz, 1H), 6.8 (d, J=6.0 Hz, 2H), 6.9–7.2 (m, 6H).
1
raphy afforded the title product (1.1 g, 86%). H NMR:
0.9 (t, J=6.9 Hz, 3H), 1.1 (s, 9H), 1.2–1.4 (m, 6H), 2.2
(t, J=6.9 Hz, 2H), 2.5 (t, J=6.9 Hz, 2H), 3.8 (m, 5H),
4.5 (s, 2H), 4.8 (s, 1H), 6.8 (d, J=6.2 Hz, 2H), 7.2 (d,
J=6.2 Hz, 2H), 7.3 (m, 5H), 7.6 (m, 5H). FABMS
(m/z): 552 (M+). [h]D25=+32.5 (c 1.0, CHCl3).

J. S. Yada6, S. Nanda / Tetrahedron: Asymmetry 12 (2001) 3223–3234
3233
4.17. 5-(4-Methoxybenzyloxy)-(5R)-3,6-dodecadiyn-1-ol
11
4.20. 5-Hydroxy-(3Z,5R,6Z)-3,6-dodecadienyl-5-
hydroxypentanoate 1j
The compound obtained in the previous step (1.1 g, 2
mmol) was taken up in dry THF (25 mL). At 0°C a
solution of TBAF (1 M in THF, 3.8 mL, 4 mmol) was
added. The resulting solution was stirred for 2 h at rt.
After completion of the reaction, satd NH4Cl was
added and the mixture was extracted with EtOAc. The
organic extract was washed with water, brine and dried
(Na2SO4). The residue was purified by column chro-
The diacetylenic alcohol (350 mg) in absolute ethanol
(10 mL) was taken up in a small round-bottomed flask.
Lindlar catalyst (35 mg, Pd on CaCO3) and a few drops
of quinoline were added. Hydrogen was supplied from
balloons. The reaction was monitored by TLC (visual-
ization was done by dipping the plates in Eckerts
reagent and heating it at 120°C), where the olefinic
product moves a little faster than the starting material.
After completion of the reaction, it was filtered to
remove the catalyst. Ethanol was removed on a rotary
evaporator. Dichloromethane was added to the residue
and it was then washed with 5% aq. HCl, brine and
dried (Na2SO4). The product was purified by column
1
matography to afford the product (600 mg, 95%). H
NMR: 0.9 (t, J=7.0 Hz, 3H), 1.2–1.4 (m, 6H), 2.2 (t,
J=7.0 Hz, 2H), 2.5 (t, J=7.0 Hz, 2H), 3.6 (t, J=7.0
Hz, 2H), 3.8 (s, 3H), 4.5 (s, 2H), 4.9 (s, 1H), 6.8 (d,
J=6.0 Hz, 2H), 7.2 (d, J=6.0 Hz, 2H). 13C NMR:
159.41, 129.9, 129.4, 113.82, 86.35, 82.13, 78.12, 75.69,
68.73, 60.8, 57.94, 55.24, 31.04, 28.06, 23.16, 22.1,
18.69, 13.9. FABMS (m/z): 314 (M+). [h]D25=+19.1 (c
1.1, CHCl3). Anal. calcd for C20H26O3: C, 76.40; H,
8.33. Found: C, 76.48; H, 8.28%.
1
chromatography to afford 1j in 96% yield. H NMR:
0.9 (t, J=6.9 Hz, 3H), 1.2–1.4 (m, 6H), 1.5–1.8 (m,
4H), 2.2 (m, 2H), 2.4 (t, J=6.9 Hz, 2H), 2.6 (m, 2H),
3.6 (t, J=6.9 Hz, 2H), 4.1 (m, 2H), 5.2 (t, J=8 Hz,
1H), 5.4–5.7 (m, 4H). 13C NMR: 170.9, 132.12, 132.01,
128.58, 128.46, 81.0, 64.0, 62.11, 33.82, 31.42, 29.22,
27.72, 22.25, 22.48, 21.1, 19.8, 13.9. FABMS (m/z): 296
(M+). [h]D25=+13.4 (c 1.0, CHCl3). Anal. calcd for
C17H30O4: C, 68.42; H, 10.13. Found: C, 68.36; H,
10.16%.
4.18. 5-(4-Methoxybenzyloxy)-(5R)-3,6-dodecadienyl-5-
(4-methoxybenzyloxy)pentanoate 14
5-(4-Methoxybenzyloxy)pentanoic acid (460 mg, 2.0
mmol) was taken up in dichloromethane (8 mL). DCC
(452 mg, 2.0 mmol) was added followed by the addition
of DMAP (10 mg) at 0°C. The reaction mixture was
stirred for 5 min, and a solution of 5-(4-methoxybenzyl-
oxy)-(5R)-3,6-dodecadiyn-1-ol (600 mg, 1.9 mmol) in
dichloromethane (5 mL) was added dropwise. The mix-
ture was stirred for a further 3 h at rt. Dicyclohexylurea
was filtered off and the filtrate was washed with water,
brine and dried (Na2SO4). After chromatographic sepa-
ration, the coupled ester was obtained (800 mg, 78%).
1H NMR: 0.9 (t, J=6.8 Hz, 3H), 1.2–1.8 (m, 10H),
2.1–2.4 (m, 4H), 2.55 (t, J=6.8 Hz, 2H), 3.4 (t, J=6.8
Hz, 2H), 3.8 (s, 6H), 4.1 (t, J=6.8 Hz, 2H), 4.35 (s,
2H), 4.5 (s, 2H), 5.09 (s, 1H), 6.8 (d, J=6 Hz, 4H), 7.2
(d, J=6 Hz, 4H). FABMS (m/z): 534 (M+). [h]D25=+4.8
(c 0.9, CHCl3). Anal. calcd for C33H42O6: C, 74.13; H,
7.92. Found: C, 74.26; H, 7.99%.
Acknowledgements
One of the authors (S.N.) is thankful to the Council of
Scientific and Industrial Research (CSIR, New Delhi)
for the award of a research fellowship.
References
1. Brash, A. R. J. Biol. Chem. 1999, 274, 23679.
2. (a) Veldink, G. A.; Vliegenthart, J. F. G. Substrates and
products of lipoxygenase catalysis. In Studies in Natural
Products Chemistry; Amsterdam: Elsevier Science BV,
1991; Vol. 9: Structure and Chemistry (Part B), pp.
559–589; (b) Gardner, H. W. Biochim. Biophys. Acta
1991, 1084, 221; (c) Funk, C. D. Biochim. Biophys. Acta
1996, 1304, 65.
4.19. 5-Hydroxy-(5R)-3,6-dodecadienyl-5-hydroxypen-
3. (a) Datcheva, V. K.; Kiss, K.; Solomon, K.; Kyler, K. S.
J. Am. Chem. Soc. 1991, 113, 270; (b) Zhang, P.; Kyler,
K. S. J. Am. Chem. Soc. 1989, 111, 9241; (c) Novak, M.
J. Bioorg. Med. Chem. Lett. 1999, 9, 31; (d) Yadav, J. S.;
Nanda, S.; Rao, A. B. Synlett 2001, 787; (e) Yadav, J. S.;
Nanda, S.; Rao, A. B. Tetrahedron: Asymmetry 2001, 12,
2129.
tanoate 15
The compound obtained in the previous reaction (800
mg, 1.5 mmol) was taken up in dichloromethane:water
(19:1, 15 mL). DDQ (1.1 g, 4.5 mmol) was added and
the solution stirred for 1 h at rt. The reaction mixture
was filtered off, and the filtrate was washed with 5% aq.
NaHCO3 solution, brine and dried (Na2SO4). Chro-
matographic purification gave the desired product (350
4. Harmut, K.; Schewe, T.; Repoport, S. M. Adv. Enzymol.
1986, 58, 273.
5. Yadav, J. S.; Nanda, S.; Rao, A. B. Tetrahedron: Asym-
metry 2001, 12, 53.
1
mg, 80%). H NMR: 0.95 (t, J=7.0 Hz, 3H), 1.2–1.8
(m, 10H), 2.2 (t, J=7.0 Hz, 2H), 2.4 (t, J=7.0 Hz, 2H),
2.6 (t, J=7.0 Hz, 2H), 3.7 (t, J=7.0 Hz, 2H), 4.2 (t,
J=7.0 Hz, 2H), 5.1 (s, 1H). 13C NMR: 173.48, 80.14,
63.852, 62.168, 61.91, 60.72, 60.37, 52.17, 33.88, 31.0,
28.02, 22.1, 21.22, 21.12, 19.3, 18.62, 13.85. FABMS
(m/z): 294 (M+). [h]D25=+11.1 (c 1.0, CHCl3).
6. (a) Ramos Tombo, G. M.; Schar, H. P.; Busquets, X. F.;
Ghisalba, O. Tetrahedron 1986, 42, 507; (b) Di Dier, E.;
Loubinoux, B.; Ramos Tombo, G. M.; Rihs, G. Tetra-
hedron 1991, 47, 4941; (c) Bunnemann, S.; Crout, D. H.
G.; Dalton, H.; Hutchinson, D. W. Biocatalysis 1992, 5,
297.

3234
J. S. Yada6, S. Nanda / Tetrahedron: Asymmetry 12 (2001) 3223–3234
10. Mancuso, A. J.; Brownfain, D. S.; Swern, D. J. Org. Chem.
7. (a) Tsuji, K.; Terao, Y.; Achiwa, K. Tetrahedron Lett. 1989,
1979, 44, 4148.
30, 6189 (R=Me, allyl and benzyl); (b) Ramos Tambo, G.
M.; Schar, H.-P.; Fernandez, X.; Busquets, I.; Ghisalba,
O. Tetrahedron Lett. 1986, 27, 5707 (R=Ph); (c) Wang,
Y.-F.; Sih, C. J. Tetrahedron Lett. 1984, 25, 4999 (R=allyl).
11. Horita, K.; Yoshioka, T.; Tanaka, T.; Olikawa, Y.; Yone-
mitsu, O. Tetrahedron 1986, 42, 3021.
12. (a) Audia, J. E.; Boisvert, L.; Patten, A. D.; Villalobos, A.;
Danishefsky, S. J. J. Org. Chem. 1989, 54, 3378; (b)
Amouroux, R.; Gerin, B.; Chastrette, M. Tetrahedron 1985,
41, 5321.
13. Chen, C. S.; Fujimoto, Y.; Girdaukas, G.; Sih, C. J. J. Am.
Chem. Soc. 1982, 104, 7294.
8. Fadel, A.; Arzel, P. Tetrahedron: Asymmetry 1997, 8, 283.
9. (a) Grass, J. L.; Soto, T.; Heunmann, A. Eur. J. Org. Chem.
2000, 837; (b) Heunmann, A.; Loutfi, A.; Ortiz, B. Tetra-
hedron: Asymmetry 1995, 1073; (c) Heunmann, A.; Faure,
R. J. Org. Chem. 1993, 58, 1276.