Synthesis of (R)-6,7-dihydro-5-HETE lactone and (S)-6,7-dihydro-5-HETE lactone by using novel yeast reduction as a key reaction

Article abstract of DOI:10.1039/b206843p

Novel yeast reduction which gave (1R,2S)-hydroxy ester 10 and (1S,5S)-lactone 11 from racemic ketoester 12 was discovered. After 10 and 11 were converted to lactone 15 and 17, enantiomeric excesses were determined as 99% and 95%, respectively. This novel

Full text of DOI:10.1039/b206843p

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Synthesis of (R)-6,7-dihydro-5-HETE lactone and (S )-6,7-
dihydro-5-HETE lactone by using novel yeast reduction as a key
reaction
1
Satoshi Yamauchi,* Kenji Takeda, Makoto Ganaha and Yoshiro Kinoshita
College of Agriculture, Ehime University, Tarumi 3-5-7, Matsuyama, Ehime, 790-8566, Japan.
E-mail: syamauch@agr.ehime-u.ac.jp; Fax: ϩ81-89-977-4364
Received (in Cambridge, UK) 12th July 2002, Accepted 6th August 2002
First published as an Advance Article on the web 30th August 2002
Novel yeast reduction which gave (1R,2S )-hydroxy ester 10 and (1S,5S )-lactone 11 from racemic ketoester 12 was
discovered. After 10 and 11 were converted to lactone 15 and 17, enantiomeric excesses were determined as 99% and
95%, respectively. This novel yeast reduction was applied to synthetic study of metabolites of 5-oxo-ETE 1. (R)-6,7-
Dihydro-5-HETE lactone 5 and (S )-6,7-dihydro-5-HETE lactone 6 were synthesized from 15 and 17, respectively.
Introduction
The metabolites of polyunsaturated fatty acid (PUFA) play an
important role in organisms. However, their isolation is very
difficult because they are present in very small quantities. Syn-
thetic studies of PUFA metabolite are important for biological
research and many synthetic efforts of PUFA have been carried
out.1
5-Oxo-ETE 1 is a metabolite of arachidonic acid and has a
potent chemotactic agent for human neutrophiles. 5-Oxo-ETE
1 is reduced to (R) and (S )-6,7-dihydro-5-HETE 3 and 4 via
6,7-dihydro-5-oxo-ETE 2 (Scheme 1). Though the synthesis and
Scheme 2 Retrosynthetic analysis of (R)-6,7-dihydro-5-HETE lactone
5 and (S )-6,7-dihydro-5-HETE lactone 6.
7.2 This aldehyde 8 would be obtained from lactone 9 by one
carbon homologation. Hydroxy ester 10 could be converted to
lactone 9 by oxidation to the ketone followed by Baeyer–
Villiger oxidation, that proceeds with retention of configur-
ation. In this way the stereogenic center at position 5 could be
introduced stereospecifically. The planned starting materials for
the two enantiomers are (1R,2S )-hydroxy ester 10 and (1S,5S )-
Scheme 1 Biosynthesis of (R)-6,7-dihydro-5-HETE 3 and (S )-6,7-
lactone 11, obtained by a novel yeast reduction of racemic
ketoester 12. The stereogenic center at C5 of (R)-5 or (S )-6
derives from C1 carbon of 10 or from C5 carbon of 11. There-
fore, it is necessary to obtain these adducts in high enantiomeric
excess. As an example of bioreduction of cyclopentanone bear-
ing a carboxylate group, the reduction of ethyl 2-oxocyclo-
pentanecarboxylate has been previously reported.5 Our
substrate has a longer carboxylate bearing side chain.
dihydro-5-HETE 4.
biological activity of 6,7-dihydro-5-oxo-ETE 2 has been
reported,2 there is no report about 6,7-dihydro-5-HETE 3 and
4. The synthetic study of both enantiomers is valuable for bio-
logical research and the construction of the one chiral center is
interesting for synthetic research. A microbiological reduction
is one of the effective methods to construct the chiral center.3,4
This report describes the synthesis of (R)-6,7-dihydro-5-HETE
lactone 5 and (S )-6,7-dihydro-5-HETE lactone 6 using a new
yeast reduction as a key reaction.
Results and discussion
Scheme 2 shows the retrosynthetic analysis of (R)-6,7-
At first, the yeast reduction of racemic ketoester 12 was exam-
ined in the preparation of the two optically active reductive
products, which were expected to be the starting materials
for this project. The incubation of racemic substrate 12 with
dihydro-5-HETE lactone
5 and (S )-6,7-dihydro-5-HETE
lactone 6. Aldehyde 8 could be converted to target compound 5
by employing cis selective Wittig reaction with Wittig reagent
2156
J. Chem. Soc., Perkin Trans. 1, 2002, 2156–2160
This journal is © The Royal Society of Chemistry 2002
DOI: 10.1039/b206843p

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baker’s yeast gave (1R,2S )-hydroxy ester 106 (36%) and
(1S,5S )-latone 117 (27%). It is worth noting that two optically
active products were obtained in this yeast reduction using
our substrate. The enantiomeric excess was determined after
Baeyer–Villiger oxidation. The yeast reductions of the sub-
strates with longer side chain, 3-(2-oxocyclopentyl)propionic
acid, 2-(2-methoxy/ethoxycarbonylethyl)cyclopentanone, did
not proceed, recovering racemic substrates.
After LiAlH4 reduction of 10, the primary hydroxy group of
the resulting diol was selectively protected as TBDPS ether by
8
using TBDPSCl, Et3N, and 4-DMAP in CH2Cl2 to give 13 in
69% yield. This alcohol 13 was subjected to subsequent PCC
oxidation (99%) and Baeyer–Villiger oxidation with MCPBA in
CHCl3 and phosphate buffer pH 89 to give (R)-lactone 15 in
84% yield (Scheme 3). By the same procedure, (1S,5S )-lactone
11 was transformed to (S )-lactone 17.
Scheme 4 Determination of enantiomeric excess of 15 and 17.
As the synthetic study of the metabolites of 5-oxo-ETE 1,
(R)-6,7-dihydro-5-HETE lactone 5 and (S )-6,7-dihydro-5-
HETE lactone 6 were synthesized. A new yeast reduction which
gave (1R,2S )-hydroxyester 10 and (1S,5S )-lactone 11 from
racemic ketoester 12 was discovered in this project. These com-
pounds 10 and 11 were transformed to lactone 15 and 17, which
were 99% ee and 95% ee, respectively.
(R)-6,7-Dihydro-5-HETE lactone 5 and (S )-6,7-dihydro-5-
HETE lactone 6 were synthesized from lactone 15 and 17,
respectively.
Experimental
Melting-point (mp) data are uncorrected. NMR data were
measured by a JNM-EX 400 spectrometer. FABMS data
were measured with JEOL HX-110 spectrometers and optical
rotations were evaluated with Horiba SEPA-200, [α]D-values are
in units of 10Ϫ1 deg cm2 gϪ1. The silica gel used was Wakogel
C-300 (Wako, 200–300 mesh). HPLC analysis was performed
by Shimadzu LC-6AD and SPD-6AV.
Scheme 3 Reagents and conditions (yields): (a) i) LiAlH4, diethyl
ether, Ϫ10 ЊC, 1 h; ii) TBDPSCl, Et3N, 4-DMAP, CH2Cl2, rt, 2 h (69%);
(b) PCC, AcONa, CH2Cl2, Ϫ10 ЊC, 17 h (99%); (c) MCPBA, phosphate
buffer pH 8, CHCl3, 0 ЊC, 17 h (84%).
Yeast reduction of racemic ketoester 12
To determine the enantiomeric excess, (R)-lactone 15 was
converted to 18 by subsequent ethanolysis and reaction with
(Ϫ)-menthyl chloroformate. HPLC analysis showed that
diastereomeric excess was 99%. Diastereomeric excess of
(S )-lactone 17 was also determined as 95% by the same
method. These facts indicate that the 1 position of 10 and the 5
position of 11, which are the new yeast reductive products of
12, had high enantiomeric purity (Scheme 4).
A mixture of ( )-ketoester 12 (4.69 g, 0.030 mol), sucrose
(30 g), baker’s yeast (14 g) in H2O (250 ml) was shaken at 30 ЊC
for 48 h. After the mixture was filtered, the filtrate was extracted
with diethyl ether. The ether solution was washed with brine,
dried (Na2SO4) and evaporated. The residue was purified with
silica gel column chromatography (10% EtOAc in benzene) to
give (1R,2S )-hydroxy ester 10 (1.69 g, 36%) as a colorless oil
and (1S,5S )-lactone 11 as a colorless oil (1.02 g, 27%). 10: [α]2D0
= ϩ40.6, c 3.23, MeOH (lit.,6 [α]2D3 = ϩ43.1, c 1.08, MeOH). 11:
[α]2D0 = Ϫ59.4, c 4.90, MeOH (lit.,7 [α]2D5 = Ϫ59.0, c 1.00, MeOH).
Since desilylation of 15 gave many by-products, the lactone
ring was opened at this stage. The lactone ring of 15 was
reduced by subsequent DIBAL-H and NaBH4 reductions,
giving diol 20 in 96% yield. After the primary and secondary
hydroxy groups were protected as trityl ethers by using trityl
chloride in pyridine (89%) and MOM ether by using MOMCl
and iso-Pr2NEt (88%), respectively, the silyl ether of the result-
ing fully protected compound 22 was cleaved by n-Bu4NF in
100% yield. The resulting alcohol 23 was treated with TsCl and
KOH in diethyl ether to give tosylate 24 in 92% yield, and then
conversion to nitrile 25 by using NaCN in DMF was performed
in 100% yield. DIBAL-H reduction of nitrile 25 in ether gave
aldehyde 26 in 76% yield. This resulting aldehyde 26 was sub-
jected to cis-selective Wittig reaction with Wittig reagent 7 by
using LHMDS and HMPA,2 giving triene 27 in 68% yield.
Cleavage of trityl ether in HCO2H–diethyl ether (71%) follow-
ing Swern and NaClO2 oxidations gave carboxylic acid 29 in
73% yield. Finally, cleavage of MOM ether in acidic condition
gave (R)-6,7-dihydro-5-HETE lactone 5 in 92% yield (Scheme
5). By the same procedure, (S )-6,7-dihydro-5-HETE lactone 6
was synthesized from lactone 17.
(1S,2R)-2-[2-(tert-Butyldiphenylsilyloxy)ethyl]cyclopentanol
13. To a suspension of LiAlH4 (3.80 g, 0.10 mol) in diethyl ether
(50 ml) was added a solution of (1R,2S )-hydroxy ester 10 (17.2
g, 0.11 mol) in diethyl ether (50 ml) at Ϫ10 ЊC. After stirring at
Ϫ10 ЊC for 1 h, sat. aq. MgSO4 (ca. 3 ml) and K2CO3 (0.1 g)
were added. The mixture was stirred at room temperature for
1 h and filtered. The filtrate was concentrated to give crude diol.
To a solution of the crude diol, Et3N (17.1 ml, 0.12 mol), and
4-DMAP (0.50 g, 0.0041 mol) in CH2Cl2 (10 ml) was added
TBDPSCl (26.5 ml, 0.10 mol). The resulting reaction solution
was stirred at room temperature for 2 h before additions of H2O
and CH2Cl2. The organic solution was separated, washed with
brine, and dried (Na2SO4). After concentration, the residue was
applied to silica gel column chromatography (10% EtOAc–
hexane) to give silyl ether 13 (28.1 g, 0.076 mol, 69%) as a
colorless oil. [α]2D0 = ϩ21.9 (c 1.56, CHCl3); νmax(CHCl3)/cmϪ1
3428, 2876, 1472, 1429, 1113, 1076, 1015; δH(CDCl3) 1.06 (9H,
s, C(CH3 )3), 1.18 (1H, m, CHHCH2OTBDPS), 1.58–1.72 (5H,
J. Chem. Soc., Perkin Trans. 1, 2002, 2156–2160
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Scheme 5 Reagents and conditions (yields): (a) i) DIBAL-H, CH2Cl2, Ϫ75 ЊC, 30 min; ii) NaBH4, EtOH, 0 ЊC, 30 min (96%); (b) TrCl, pyridine, rt, 2
h (89%); (c) MOMCl, DIPEA, CH2Cl2, rt, 16 h (88%); (d) n-Bu4NF, THF, 0 ЊC, 1 h (100%); (e) TsCl, KOH, diethyl ether, rt, 2.5 h (92%); (f ) NaCN,
DMF, 50 ЊC, 2 h (100%); (g) DIBAL-H, ether, Ϫ10 ЊC, 1 h (76%); (h) 7, LHMDS, HMPA, THF, from Ϫ75 ЊC (30 min) to rt (30 min) (68%);
(i) HCO2H, diethyl ether, 0 ЊC, 30 min (71%); (j) i) (COCl)2, DMSO, CH2Cl2, Ϫ45 ЊC, 1 h, and then Et3N, 0 ЊC, 1 h; ii) 2-methylbut-2-ene, NaH2PO4,
NaClO2, aq. tert-BuOH, rt, 1 h (73%); (k) 6 M aq. HCl, THF, rt, 2 h (92%).
m, 3-H2, 4-H2, CHHCH2OTBDPS), 1.72–1.86 (2H, m, 5-H2),
1.97 (1H, m, 2-H), 3.31 (1H, s, OH), 3.73–3.80 (2H, m,
CH2OTBDPS), 3.82 (1H, m, 1-H), 7.38–7.44 (6H, m, ArH),
7.67–7.68 (4H, m, ArH); δC(CDCl3) 19.1, 21.3, 26.8, 30.8, 33.7,
36.6, 47.1, 64.2, 78.9, 127.7, 129.8, 133.2, 135.6 (Found: C,
74.77; H, 8.98. C23H32O2Si requires C, 74.95; H, 8.75%).
ArH); δC(CDCl3) 19.2, 20.8, 26.8, 29.7, 32.5, 37.9, 46.3, 62.1,
127.6, 129.6, 133.8, 135.5, 221.3 (Found: C, 75.27; H, 8.48.
C23H30O2Si requires C, 75.36; H, 8.25%). (S )-isomer: [α]2D0
Ϫ59.6 (c 1.34, CHCl3).
=
(R)-7-(tert-Butyldiphenylsilyloxy)heptan-5-olide 15. To an
ice-cooled mixture of ketone 14 (24.6 g, 0.067 mol) in CHCl3
(50 ml) and phosphate buffer pH 8 (100 ml) was added MCPBA
(23.3 g, 0.14 mol) in CHCl3 (50 ml). The resulting reaction
mixture was stirred in an ice-bath for 17 h before additions of
sat. aq. sodium thiosulfate and sat. aq. NaHCO3 soln. After
the mixture was filtered, the organic solution was separated
from the filtrate, washed with brine, and dried (Na2SO4). After
concentration, the residue was applied to silica gel column
chromatography (EtOAc–hexane 1 : 8) to give lactone 15 (21.5
g, 0.056 mol, 84%) as a colorless oil, [α]2D0 = Ϫ28.2 (c 1.70,
CHCl3); νmax(CHCl3)/cmϪ1 2932, 1727, 1429, 1246, 1113, 1094,
1057; δH(CDCl3) 1.05 (9H, s, C(CH3)3), 1.53 (1H, 6-HH),
1.77–1.98 (5H, m, 3-H2, 4-H2, 6-HH), 2.42 (1H, ddd, J 17.6,
8.3, 8.3 Hz, 2-HH), 2.56 (1H, ddd, J 17.6, 7.3, 7.3 Hz,
2-HH), 3.78 (1H, ddd, J 10.3, 5.9, 5.9 Hz, 7-HH), 3.90
(1H, ddd, J 10.3, 7.1, 4.9 Hz, 7-HH), 4.52 (1H, m, 5-H),
7.36–7.44 (6H, m, ArH), 7.63–7.67 (4H, m, ArH); δC(CDCl3)
18.5, 19.2, 26.9, 27.9, 29.4, 38.6, 59.6, 77.4, 127.7, 129.7, 133.5,
133.7, 135.5, 171.8 (Found: C, 71.86; H, 8.04. C23H30O3Si
requires C, 72.21; H, 7.90%). (S )-isomer 17: [α]2D0 = ϩ28.3
(c 1.10, CHCl3).
(1S,2S )-2-[2-(tert-Butyldiphenylsilyloxy)ethyl]cyclopentanol
16. To a suspension of LiAlH4 (3.0 0 g, 0.079 mol) in diethyl
ether (50 ml) was added a solution of (1S,5S )-lactone 11
(11.1 g, 0.079 mol) in diethyl ether (50 ml) at Ϫ10 ЊC. After
stirring at Ϫ10 ЊC for 1 h, sat. aq. MgSO4 (ca. 2 ml) and K2CO3
(0.1 g) were added. The mixture was stirred at room temper-
ature for 1 h and filtered. The filtrate was concentrated to give
crude diol. To a solution of the crude diol, Et3N (13.2 ml, 0.095
mol), and 4-DMAP (0.39 g, 0.0032 mol) in CH2Cl2 (10 ml) was
added TBDPSCl (20.6 ml, 0.079 mol). The resulting reaction
mixture was stirred at room temperature for 2 h before addi-
tions of H2O and CH2Cl2. The organic solution was separated,
washed with brine, and dried (Na2SO4). After concentration,
the residue was applied to silica gel column chromatography
(10% EtOAc–hexane) to give silyl ether 16 (23.7 g, 0.064 mol,
81%) as a colorless oil. [α]2D0 = ϩ8.73 (c 1.03, CHCl3);
νmax(CHCl3)/cmϪ1 3460, 2934, 1472, 1429, 1113, 1084, 1035,
990; δH(CDCl3) 1.06 (9H, s, C(CH3)3), 1.41 (1H, m, CHHCH2-
OTBDPS), 1.52 (1H, m, CHHCH2OTBDPS), 1.61–1.74 (3H,
m), 1.76–1.92 (4H, m), 2.51 (1H, s, OH), 3.67 (1H, m,
CHHOTBDPS), 3.76 (1H, m, CHHOTBDPS), 4.28 (1H, m,
1-H), 7.39–7.44 (6H, m, ArH), 7.66–7.69 (4H, m, ArH);
δC(CDCl3) 19.0, 22.4, 26.8, 29.9, 32.0, 34.4, 44.8, 64.2, 74.1,
127.7, 129.7, 133.2, 133.3, 135.6 (Found: C, 75.13; H, 8.96.
C23H32O2Si requires C, 74.95; H, 8.75%).
Determination of enantiomeric excess
A reaction mixture of lactone 15 (50 mg, 0.13 mmol) and
K2CO3 (18 mg, 0.13 mmol) in EtOH (5 ml) was stirred at room
temperature for 2 h before additions of H2O and EtOAc. The
organic solution was separated, washed with brine, and dried
(Na2SO4). Evaporation gave crude ethyl ester. To an ice-cooled
solution of the crude ethyl ester in pyridine (0.2 ml) was
added (Ϫ)-menthyl chloroformate (0.030 ml, 0.14 mmol). The
resulting reaction solution was stirred at room temperature
for 2 h before addition of H2O and EtOAc. The organic solu-
tion was separated, washed with brine, dried (Na2SO4), and
concentrated to give crude 18, which was applied to HPLC
(LiChrospher Si 60 of Cica-MERK, 3% EtOAc in hexane, 2 ml
minϪ1, detected at 270 nm): retention time was 12.3 min,
diastereomeric excess was 99%. Lactone 17 was converted to 19
by the same procedure and applied to HPLC: retention time
was 11.1 min, diastereomeric excess was 95%.
(R)-2-[(2-tert-Butyldiphenylsilyloxy)ethyl]cyclopentanone 14.
A reaction mixture of alcohol 13 (27.0 g, 0.073 mol), PCC (19.1
g, 0.089 mol), CH3CO2Na (6.65 g, 0.081 mol) in CH2Cl2 (200
ml) was stirred at Ϫ10 ЊC for 17 h. After addition of dry diethyl
ether, the mixture was filtered. The filtrate was concentrated.
The residue was applied to silica gel column chromatography
(EtOAc–hexane 1 : 10) to give ketone 14 (26.4 g, 0.072 mol,
99%) as a colorless oil, [α]2D0 = ϩ59.4 (c 1.01, CHCl3);
νmax(CHCl3)/cmϪ1 2934, 1732, 1429, 1111; δH(CDCl3) 1.04 (9H,
s, C(CH3)3), 1.41–1.52 (2H, m, CH2CH2OTBDPS), 1.75 (1H,
m), 1.98 (1H, m), 2.07–2.33 (5H, m), 3.69 (1H, ddd, J 10.3, 7.6,
5.6 Hz, CHHOTBDPS), 3.77 (1H, ddd, J 10.3, 6.4, 6.4 Hz,
CHHOTBDPS), 7.36–7.44 (6H, m, ArH), 7.65–7.67 (4H, m,
2158
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(R)-7-(tert-Butyldiphenylsilyloxy)heptane-1,5-diol 20. To a
solution of lactone 15 (10.0 g, 0.026 mol) in CH2Cl2 (150 ml)
was added DIBAL-H (1 M in toluene, 44.6 ml, 0.045 mol) at
Ϫ75 ЊC. After the reaction solution was stirred at Ϫ75 ЊC for
30 min, 6 M aq. HCl soln. was added. The organic solution was
separated, washed with sat. aq. NaHCO3 and brine, dried
(Na2SO4), and evaporated to give crude hemiacetal. To an ice-
cooled solution of the hemiacetal in EtOH (150 ml) was added
NaBH4 (0.75 g, 0.020 mol). The reaction mixture was stirred in
an ice-bath for 30 min before addition of 6 M aq. HCl solution.
After neutralization with sat. aq. NaHCO3, the mixture was
concentrated. The residue was dissolved in H2O and EtOAc.
The organic solution was separated, washed with brine, dried
(Na2SO4), and concentrated. The residue was applied to silica
gel column chromatography (EtOAc–hexane 1 : 1) to give diol
20 (9.59 g, 0.025 mol, 96%) as colorless crystals, mp 88–89 ЊC
(iso-Pr2O), [α]2D0 = ϩ5.3 (c 0.75, CHCl3); νmax(CHCl3)/cmϪ1 3500,
2934, 1429, 1113, 1078; δH(CDCl3) 1.05 (9H, s, C(CH3)3), 1.46–
1.59 (6H, m, 2-H2, 3-H2, 4-H2), 1.60–1.69 (2H, m, 6-H2), 3.34
(2H, br s, OH × 2), 3.64–3.67 (2H, m, 1-H2), 3.84–3.89 (3H, m,
5-H, 7-H2), 7.40–7.44 (6H, m, ArH), 7.66–7.68 (4H, m, ArH);
δC(CDCl3) 19.0, 21.7, 26.8, 32.7, 37.1, 38.3, 62.8, 63.6, 71.8,
127.8, 129.8, 132.9, 135.5 (Found: C, 71.23; H, 8.74. C23H34O3Si
requires C, 71.46; H, 8.86%). (S )-isomer: [α]2D0 = Ϫ5.3 (c 1.12,
CHCl3).
(80 ml) was added n-Bu4NF (1 M THF, 15.4 ml, 0.015 mol).
The resulting reaction solution was stirred in an ice-bath for 1 h
before additions of sat. aq. NH4Cl and EtOAc. The organic
solution was separated, washed with brine, dried (Na2SO4), and
evaporated. The residue was applied to silica gel column
chromatography (EtOAc–hexane 1 : 7) to give alcohol 23
(6.00 g, 0.014 mol, 100%) as a colorless oil, [α]2D0 = Ϫ28.0 (c 1.07,
CHCl3); νmax(CHCl3)/cmϪ1 3500, 2943, 1491, 1449, 1151, 1090,
1075, 1032, 920; δH(CDCl3) 1.37–1.49 (3H, m, 4-HH, 5-H2),
1.51–1.70 (4H, m, 2-HH, 4-HH, 6-H2), 1.80 (1H, m, 2-HH),
2.37 (1H, br s, OH), 3.06 (2H, t, J 6.3 Hz, 7-H2), 3.38 (3H, s,
OCH3), 3.60–3.83 (3H, m, 1-H2, 3-H), 4.63 (1H, d, J 6.8 Hz,
OCHHOCH3), 4.66 (1H, d, J 6.8 Hz, OCHHOCH3), 7.20–7.31
(9H, m, ArH), 7.42–7.44 (6H, m, ArH); δC(CDCl3) 22.0, 30.1,
34.4, 36.6, 55.8, 59.9, 63.3, 76.4, 86.3, 95.9, 126.8, 127.7, 128.7,
144.4 (Found: C, 77.57; H, 8.03. C28H34O4 requires C, 77.39; H,
7.89%). (S )-isomer: [α]2D0 = ϩ28.0 (c 1.00, CHCl3).
(R)-3-Methoxymethoxy-1-( p-tolylsulfonyloxy)-7-trityloxy-
heptane 24. A reaction mixture of alcohol 23 (5.15 g, 0.012
mol), TsCl (2.71 g, 0.014 mol), and pulverized KOH (1.33 g,
0.024 mol) in diethyl ether (50 ml) was stirred at room temper-
ature for 2.5 h before addition of H2O. The organic solution
was separated, washed with brine, and dried (Na2SO4). After
concentration, the residue was applied to silica gel column
chromatography (EtOAc–hexane 1 : 5) to give tosylate 24 (6.67
g, 0.011 mol, 92%) as a colorless oil, [α]2D0 = Ϫ7.9 (c 1.01,
CHCl3); νmax(CHCl3)/cmϪ1 3063, 2942, 1599, 1491, 1449, 1360,
1190, 1177, 1098, 1036, 960, 920; δH(CDCl3) 1.30–1.41 (3H, m,
5-H2, 4-HH), 1.45 (1H, m, 4-HH), 1.55–1.62 (2H, m, 6-H2),
1.77 (1H, m, 2-HH), 1.84 (1H, m, 2-HH), 2.42 (3H, s, OSO2-
C6H4CH3), 3.04 (2H, t, J 6.8 Hz, 7-H2), 3.26 (3H, s, OCH3),
3.57 (1H, m, 3-H), 4.08–4.18 (2H, m, 1-H2), 4.50 (1H, d, J 6.8
Hz, OCHHOCH3), 4.53 (1H, d, J 6.8 Hz, OCHHOCH3), 7.20–
7.33 (11H, m, ArH), 7.41–7.44 (6H, m, ArH), 7.78 (2H, d, J 8.3
Hz, ArH); δC(CDCl3) 21.6, 21.7, 30.0, 33.8, 34.3, 55.6, 63.3,
67.5, 74.1, 86.3, 95.8, 126.8, 127.7, 127.9, 128.6, 129.8, 133.2,
144.4, 144.7 (Found: C, 71.23; H, 7.02. C35H40O6S requires C,
71.40; H, 6.85%). (S )-isomer: [α]2D0 = ϩ7.9 (c 1.00, CHCl3).
(R)-1-(tert-Butyldiphenylsilyloxy)-7-trityloxyheptan-3-ol 21.
A solution of diol 20 (6.77 g, 0.018 mol) and TrCl (4.90 g,
0.018 mol) in pyridine (10 ml) was stirred at room temperature
for 2 h before additions of H2O and EtOAc. The organic solu-
tion was separated, washed with sat. aq. CuSO4, NaHCO3, and
brine, dried (Na2SO4), and evaporated. The residue was purified
with silica gel column chromatography (5% EtOAc–hexane) to
give trityl ether 21 (10.1 g, 0.016 mol, 89%) as a colorless oil,
[α]2D0 = ϩ3.5 (c 1.14, CHCl3); νmax(CHCl3)/cmϪ1 3500, 3073,
2934, 1449, 1429, 1113, 1078; δH(CDCl3) 1.05 (9H, s, C(CH3)3),
1.38–1.42 (2H, m, 5-H2), 1.45–1.57 (2H, m, 4-H2), 1.63–1.74
(4H, m, 2-H2, 6-H2), 3.06 (2H, t, J 6.6 Hz, 7-H2), 3.18 (1H, s,
OH), 3.82–3.88 (3H, m, 1-H2, 3-H), 7.19–7.29 (9H, m, ArH),
7.37–7.45 (12H, m, ArH), 7.66–7.68 (4H, m, ArH); δC(CDCl3)
19.0, 22.3, 26.8, 30.1, 37.4, 38.3, 63.6, 71.7, 86.3, 126.8, 127.7,
127.8, 129.8, 133.1, 135.5, 135.6, 144.5 (Found: C, 79.97; H,
7.92. C42H48O3Si requires C, 80.21; H, 7.69%). (S )-isomer:
[α]2D0 = Ϫ3.6 (c 1.10, CHCl3).
(R)-4-Methoxymethoxy-8-trityloxyoctanenitrile 25. A reac-
tion mixture of tosylate 24 (6.67 g, 0.011 mol) and NaCN
(1.67 g, 0.034 mol) in DMSO (5 ml) was heated at 50 ЊC for 2 h
before additions of EtOAc and H2O. The organic solution was
separated, washed with brine, and dried (Na2SO4). Evaporation
and silica gel column chromatography (EtOAc–hexane 1 : 5)
(R)-1-(tert-Butyldiphenylsilyloxy)-3-methoxymethoxy-7-
trityloxyheptane 22. To a mixture of alcohol 21 (10.1 g, 0.016
mol) and DIPEA (11.2 ml, 0.064 mol) in CH2Cl2 (10 ml) was
added MOMCl (2.44 ml, 0.032 mol). After the reaction mixture
was stirred at room temperature for 16 h, MeOH and CH2Cl2
were added. The organic solution was separated, washed with
6 M aq. HCl, NaHCO3, and brine, dried (Na2SO4), and evapor-
ated. The residue was purified with silica gel column chrom-
atography (5% EtOAc–hexane) to give MOM ether 22 (9.40 g,
0.014 mol, 88%) as a colorless oil, [α]2D0 = Ϫ2.8 (c 1.08, CHCl3);
νmax(CHCl3)/cmϪ1 3071, 2934, 1491, 1474, 1462, 1449, 1429,
1111, 1090, 1036; δH(CDCl3) 1.04 (9H, s, C(CH3)3), 1.30–1.50
(4H, m, 4-H2, 5-H2), 1.59–1.64 (2H, m, 6-H2), 1.68–1.73 (2H, m,
2-H2), 3.04 (2H, t, J 6.6 Hz, 7-H2), 3.28 (3H, s, OCH3), 3.68–
3.78 (3H, m, 1-H2, 3-H), 4.56 (1H, d, J 6.8 Hz, OCHHOCH3),
4.59 (1H, d, J 6.8 Hz, OCHHOCH3), 7.19–7.30 (9H, m, ArH),
7.34–7.40 (6H, m, ArH), 7.43–7.45 (6H, m, ArH), 7.63–7.66
(4H, m, ArH); δC(CDCl3) 19.2, 22.0, 26.9, 30.2, 34.6, 37.3, 55.4,
60.6, 63.5, 74.7, 86.3, 95.6, 126.8, 127.6, 127.7, 128.7, 129.6,
133.9, 135.5, 144.5 (Found: C, 78.70; H, 8.01. C44H52O4Si
requires C, 78.53; H, 7.79%). (S )-isomer: [α]2D0 = ϩ2.8 (c 2.58,
CHCl3).
gave nitrile 25 (4.68 g, 0.011 mol, 100%) as a colorless oil, [α]2D0
=
Ϫ20.6 (c 1.07, CHCl3); νmax(CHCl3)/cmϪ1 3063, 2940, 1491,
1449, 1219, 1152, 1090, 1076, 1036; δH(CDCl3) 1.35–1.46 (3H,
m, 5-HH, 6-H2), 1.50–1.58 (1H, m, 5-HH), 1.59–1.66 (2H, m,
7-H2), 1.77 (1H, m, 3-HH), 1.87 (1H, m, 3-HH), 2.41 (2H, t,
J 7.8 Hz, 2-H2), 3.06 (2H, t, J 6.6 Hz, 8-H2), 3.36 (3H, s, OCH3),
3.60 (1H, m, 4-H), 4.60 (1H, d, J 6.8 Hz, OCHHOCH3), 4.64
(1H, d, J 6.8 Hz, OCHHOCH3), 7.20–7.31 (9H, m, ArH), 7.42–
7.44 (6H, m, ArH); δC(CDCl3) 13.2, 21.8, 30.0, 30.1, 33.7, 55.8,
63.1, 75.8, 86.4, 95.8, 119.8, 126.9, 127.7, 128.6, 144.4 (Found:
C, 78.55; H, 7.65; N, 2.87. C29H33O3N requires C, 78.52; H,
7.50; N, 3.16%). (S )-isomer: [α]2D0 = ϩ20.5 (c 1.12, CHCl3).
(R)-4-Methoxymethoxy-8-trityloxyoctanal 26. To a solution
of nitrile 25 (3.23 g, 7.28 mmol) in diethyl ether (10 ml) was
added DIBAL-H (1 M toluene, 16.7 ml, 16.7 mmol) at Ϫ10 ЊC.
After stirring at Ϫ10 ЊC for 1 h, MeOH (2 ml), a few drops of
H2O, and toluene (3 ml) were added, and then the mixture was
stirred at room temperature for 30 min before filtration. The
filtrate was concentrated. The residue was applied to silica gel
column chromatography (EtOAc–hexane 1 : 5) to give aldehyde
26 (2.48 g, 5.55 mmol, 76%) as a colorless oil, [α]2D0 = Ϫ19.9
(c 1.01, CHCl3); νmax(CHCl3)/cmϪ1 3063, 2940, 1725, 1491,
1449, 1152, 1090, 1076, 1036; δH(CDCl3) 1.35–1.48 (3H, m,
(R)-3-Methoxymethoxy-7-trityloxyheptan-1-ol 23. To an ice-
cooled solution of silyl ether 22 (9.40 g, 0.014 mol) in THF
J. Chem. Soc., Perkin Trans. 1, 2002, 2156–2160
2159

View Article Online
5-HH, 6-H2), 1.48–1.57 (1H, m, 5-HH), 1.58–1.68 (2H, m,
7-H2), 1.75 (1H, m, 3-HH), 1.88 (1H, m, 3-HH), 2.49 (2H, t,
J 7.3 Hz, 2-H2), 3.06 (2H, t, J 6.3 Hz, 8-H2), 3.34 (3H, s, OCH3),
3.55 (1H, m, 4-H), 4.59 (2H, s, OCH2OCH3), 7.20–7.36 (9H, m,
ArH), 7.42–7.44 (6H, m, ArH), 9.76 (1H, s, CHO); δC(CDCl3)
22.0, 26.5, 30.0, 34.1, 39.8, 55.7, 63.3, 76.5, 86.3, 95.5, 126.8,
127.7, 128.7, 144.4, 202.2 (Found: C, 77.88; H, 7.82. C29H34O4
requires C, 78.00; H, 7.67%). (S )-isomer: [α]2D0 = ϩ20.0 (c 0.90,
CHCl3).
trated to give crude aldehyde. A reaction mixture of the crude
aldehyde, 2-methylbut-2-ene (0.47 ml, 4.44 mmol), NaH2-
PO4ؒ2H2O (0.16 g, 1.01 mmol), and NaClO2 (0.31 g, 3.44
mmol) in tert-BuOH (2 ml) and H2O (0.5 ml) was stirred at
room temperature for 1 h before additions of sat. aq. NH4Cl
and EtOAc. The organic solution was separated, washed with
brine, and dried (Na2SO4). After evaporation, the residue was
purified with silica gel column chromatography (EtOAc–hexane
1 : 3) to give carboxylic acid 29 (0.27 g, 0.74 mmol, 73%) as a
colorless oil, [α]2D0 = ϩ7.7 (c 1.55, CHCl3); νmax(CHCl3)/cmϪ1
3510, 2930, 1709, 1456, 1148, 1102, 1036; δH(CDCl3) 0.89 (3H,
t, J 6.4 Hz, 20-H3), 1.25–1.40 (6H, m, 17-H2, 18-H2, 19-H2),
1.51–1.62 (4H, m, 4-H2, 6-H2), 1.65–1.80 (2H, m, 3-H2), 2.00–
2.08 (2H, m, 16-H2), 2.08–2.18 (2H, m, 7-H2), 2.38 (2H, t, J 7.3
Hz, 2-H2), 2.77–2.83 (4H, m, 10-H2, 13-H2), 3.38 (3H, s, OCH3),
3.57 (1H, m, 5-H), 4.65 (2H, s, OCH2OCH3), 5.28–5.43 (6H, m,
8-H, 9-H, 11-H, 12-H, 14-H, 15-H); δC(CDCl3) 14.0, 20.5, 22.5,
23.1, 25.6, 27.2, 28.3, 29.3, 31.5, 33.6, 33.8, 34.2, 55.6, 77.2,
95.6, 127.6, 128.0, 128.3, 128.5, 129.5, 130.5, 178.2; m/z (FAB)
389 (M ϩ Naϩ, 100), 365 (79) [Found (HRMS): M ϩ Naϩ,
389.2670. C22H38O4Na requires M ϩ Naϩ, 389.2668]. (S )-
isomer: [α]2D0 = Ϫ7.6 (c 1.06, CHCl3).
(6Z,9Z,12Z,16R)-16-Methoxymethoxy-20-trityloxyicosa-
6,9,12-triene 27. To a solution of Wittig reagent 7 (6.82 g, 13.4
mmol) in THF (120 ml) was added LHMDS (1 M THF, 9.00
ml, 9.00 mmol) at Ϫ75 ЊC, and then the reaction solution was
stirred at Ϫ75 ЊC for 2 h before additions of HMPA (7 ml) and
aldehyde 26 (2.00 g, 4.48 mmol) in THF (50 ml). The reaction
solution was stirred at Ϫ75 ЊC for 30 min and gradually
warmed to room temperature. After stirring at rt for 30 min,
THF–H2O (1 : 1) and CHCl3 were added. The organic solution
was separated, washed with brine, and dried (Na2SO4). Evapor-
ation and silica gel column chromatography (5% EtOAc–
hexane) gave triene 27 (1.82 g, 3.06 mmol, 68%) as a colorless
oil, [α]2D0 = Ϫ4.6 (c 1.09, CHCl3); νmax(CHCl3)/cmϪ1 2932, 1491,
1449, 1150, 1090, 1075, 1038; δH(CDCl3) 0.88 (3H, t, J 6.8 Hz,
1-H3), 1.22–1.40 (6H, m, 2-H2, 3-H2, 4-H2), 1.40–1.58 (4H, m,
17-H2, 18-H2), 1.50–1.58 (2H, m, 15-H2), 1.60–1.67 (2H, m,
19-H2), 2.02–2.07 (2H, m, 5-H2), 2.09–2.13 (2H, m, 14-H2),
2.77–2.83 (4H, m, 8-H2, 11-H2), 3.06 (2H, t, J 6.3 Hz, 20-H2),
3.35 (3H, s, OCH3), 3.53 (1H, m, 16-H), 4.64 (2H, s,
OCH2OCH3), 5.34–5.37 (6H, m, 6-H, 7-H, 9-H, 10-H, 12-H,
13-H), 7.19–7.30 (9H, m, ArH), 7.42–7.44 (6H, m, ArH);
δC(CDCl3) 14.1, 22.1, 22.6, 23.1, 25.6, 27.2, 29.3, 30.2, 31.5,
34.2, 34.3, 55.5, 63.5, 77.1, 86.3, 95.5, 126.8, 127.6, 127.7, 128.1,
128.5, 128.7, 129.8, 130.5, 144.5 (Found: C, 82.45; H, 9.08.
C41H54O3 requires C, 82.78; H, 9.15%). (S )-isomer: [α]2D0 = ϩ4.7
(c 1.07, CHCl3).
(5R,8Z,11Z,14Z )-Icosa-8,11,14-trien-5-olide
((R)-6,7-
dihydro-5-HETE lactone) 5. A reaction solution of MOM ether
29 (43 mg, 0.12 mmol) in THF (3 ml) and 6 M aq. HCl (3 ml)
was stirred at room temperature for 2 h. After additions of H2O
and EtOAc, the organic solution was separated, washed with
sat. aq. NaHCO3 and brine, and dried (Na2SO4). After concen-
tration, the residue was applied to silica gel column chromato-
graphy (EtOAc–hexane 1 : 5) to give lactone 5 (33 mg, 0.11
mmol, 92%) as a colorless oil, [α]2D0 = Ϫ36.0 (c 0.75, CHCl3);
νmax(CHCl3)/cmϪ1 2930, 1728, 1464, 1445, 1375, 1345, 1329,
1248, 1178, 1053, 909; δH(CDCl3) 0.89 (3H, t, J 6.8 Hz, 20-H3),
1.24–1.40 (6H, m, 17-H2, 18-H2, 19-H2), 1.54 (1H, m, 4-HH),
1.63 (1H, m, 4-HH), 1.75–1.86 (2H, m, 6-H2), 1.87–1.93 (2H, m,
3-H2), 2.03–2.08 (2H, m, 16-H2), 2.21–2.26 (2H, m, 7-H2), 2.44
(1H, ddd, J 17.6, 8.8, 6.8 Hz, 2-HH), 2.58 (1H, m, 2-HH),
2.79–2.84 (4H, m, 10-H2, 13-H2), 4.29 (1H, m, 5-H), 5.30–5.45
(6H, m, 8-H, 9-H, 11-H, 12-H, 14-H, 15-H); δC(CDCl3) 14.0,
18.5, 22.5, 22.7, 25.6, 27.2, 27.8, 29.3, 29.4, 31.5, 35.6, 79.7,
127.5, 127.8, 128.5, 128.6, 129.1, 130.5, 171.6; m/z (FAB)
327 (M ϩ Naϩ, 100), 305 (90) [Found (HRMS): M ϩ Naϩ,
327.2301. C20H32O2Na requires M ϩ Naϩ, 327.2300]. (S )-
isomer 6: [α]2D0 = ϩ36.0 (c 1.03, CHCl3).
(5R,8Z,11Z,14Z )-5-Methoxymethoxyicosa-8,11,14-trien-1-ol
28. To an ice-cooled solution of trityl ether 27 (0.85 g, 1.43
mmol) in diethyl ether (20 ml) was added HCO2H (15 ml). After
the reaction solution was stirred in an ice-bath for 30 min,
diethyl ether and H2O were added. The organic solution was
separated, washed with sat. aq. NaHCO3 and brine, dried
(Na2SO4), and evaporated. The residue was purified with silica
gel column (EtOAc–hexane 1 : 4) to give alcohol 28 (0.36 g, 1.02
mmol, 71%) as a colorless oil, [α]2D0 = Ϫ6.9 (c 1.16, CHCl3);
νmax(CHCl3)/cmϪ1 3715, 2874, 1460, 1453, 1148, 1100, 1038;
δH(CDCl3) 0.89 (3H, t, J 6.8 Hz, 20-H3), 1.24–1.40 (6H, m, 17-
H2, 18-H2, 19-H2), 1.40–1.47 (3H, m, 3-H2, 4-HH), 1.50–1.62
(5H, m, 2-H2, 4-HH, 6-H2), 2.03–2.08 (2H, m, 16-H2), 2.12–2.15
(2H, m, 7-H2), 2.77–2.83 (4H, m, 10-H2, 13-H2), 3.39 (3H, s,
OCH3), 3.56 (1H, m, 5-H), 3.65 (2H, t, J 6.6 Hz, 1-H2), 4.66
(2H, s, OCH2OCH3), 5.33–5.43 (6H, m, 8-H, 9-H, 11-H, 12-H,
14-H, 15-H); δC(CDCl3) 14.0, 21.4, 22.5, 23.1, 25.6, 27.2, 29.3,
31.5, 32.8, 34.1, 34.3, 55.5, 62.8, 77.2, 95.6, 127.6, 128.0, 128.2,
128.5, 129.7, 130.5; m/z (FAB) 375 (M ϩ Naϩ, 100), 173 (53)
[Found (HRMS): M ϩ Naϩ, 375.2869. C22H40O3Na requires M
ϩ Naϩ, 375.2875]. (S )-isomer: [α]2D0 = Ϫ7.0 (c 1.01, CHCl3).
Acknowledgements
We measured the 400 MHz NMR data at the Advanced
Instrumentation Center for Chemical Analysis, Ehime Uni-
versity. We thank the staff of NMR and MS Operation Center
in Faculty of Pharmaceutical Science at Fukuoka University
for FABMS measurements. We are grateful to Marutomo Co.
for financial support.
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and then stirred for 1 h before addition of Et3N (1.03 ml, 7.39
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J. Chem. Soc., Perkin Trans. 1, 2002, 2156–2160