New method for synthesizing the intermediates to 5-HETE from yeast-mediated reduction products by employing Baeyer-Villiger oxidation with complete retention of enantiomeric excess.

Article abstract of DOI:10.1271/bbb.67.1959

(R) and (S)-Aldehydes 2, which are intermediates for the synthesis of (5R) and (5S)-HETE, were respectively synthesized from the yeast-mediated reductive products, hydroxy ester 3 and cis-lactone 4, through Baeyer-Villiger oxidation with complete retention of enantiomeric excess.

Full text of DOI:10.1271/bbb.67.1959

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New Method for Synthesizing the Intermediates to
5-HETE from Yeast-mediated Reduction Products by
Employing Baeyer-Villiger Oxidation with Complete
Retention of Enantiomeric Excess
Satoshi YAMAUCHIa, Yoshihiro KINOSHITAa & Yoshiro KINOSHITAa
a Faculty of Agriculture, Ehime UniversityTarumi 3-5-7, Matsuyama, Ehime 790-8566,
Japan
Published online: 22 May 2014.
To cite this article: Satoshi YAMAUCHI, Yoshihiro KINOSHITA & Yoshiro KINOSHITA (2003) New Method for Synthesizing
the Intermediates to 5-HETE from Yeast-mediated Reduction Products by Employing Baeyer-Villiger Oxidation with
Complete Retention of Enantiomeric Excess, Bioscience, Biotechnology, and Biochemistry, 67:9, 1959-1969, DOI: 10.1271/
bbb.67.1959
To link to this article: http://dx.doi.org/10.1271/bbb.67.1959
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Biosci. Biotechnol. Biochem., 67 (9), 1959–1969, 2003
New Method for Synthesizing the Intermediates to 5-HETE from
Yeast-mediated Reduction Products by Employing Baeyer-Villiger
Oxidation with Complete Retention of Enantiomeric Excess
Satoshi YAMAUCHI,† Yoshihiro KINOSHITA, and Yoshiro KINOSHITA
Faculty of Agriculture, Ehime University, Tarumi 3-5-7, Matsuyama, Ehime 790-8566, Japan
Received April 17, 2003; Accepted May 21, 2003
(
R
) and (
S
)-Aldehydes 2, which are intermediates for
) and (5 )-HETE, were respectively
The retrosynthetic analysis is shown in Scheme 2.
the synthesis of (5
R
S
＋
( )-(
R)-Aldehyde 2 could be obtained from glycol 5
synthesized from the yeast-mediated reductive products,
hydroxy ester 3 and cis-lactone 4, through Baeyer-
Villiger oxidation with complete retention of enantio-
meric excess.
by oxidative cleavage. Lactone 6 would be converted
to glycol 5. This lactone 6 could be obtained by
Baeyer-Villiger oxidation of ketone 7. The most
important reaction in this experiment is the Baeyer-
Villiger oxidation of cyclopentanone derivative 7.
The complete retention of enantiomeric excess is
required in this project. Hydroxy ester 3 would be
converted to cyclopentanone derivative 7 in a few
Key words: 5-HETE; yeast reduction
(5S)-HETE 1 is a precursor of the potent in‰am-
matory mediator, 5-oxo-ETE, but has less activity
steps involving
a
-hydroxylation. According to the
than that of 5-oxo-ETE.1) It has recently been report-
same process, ( )-(
S
)-aldehyde 2 could be obtained
－
ed that (5
S
)-HETE stimulated DNA synthesis which
from cis-lactone 4.
induced expression of the basic ˆbroblast growth fac-
tor.2) Fatty acid metabolites play important roles in
the living body, although their amounts are very
small. This is the reason why synthetic studies of fat-
ty acid metabolites have been continued and the syn-
Results and Discussion
After the hydroxy group of hydroxy ester 3 was
protected as a benzoate by treatment with benzoyl
theses of (5
R
) and (5
S
)-HETE have been reported.3–9)
z
chloride and triethylamine in 93 yield, a-hydroxy-
In previous work using aldehyde 2 as an intermediate
lation was tried. Exposure of ester 8 to MoOPH11)
and lithium diisopropylamide gave alcohol 9 in 54
for the synthesis of 5-HETE,7) the lower optical puri-
z
＋
ty of ( )-(
excess (95
HETE 1 (99
tive transformation of yeast-mediated reduction
products 3 and 410) to (
)-( )-2 and ( )-( )-2 by
R
)-2 resulted in a lower enantiomeric
ee) of (5 )-HETE 1 than that of (5 )-
ee). In this present study, the respec-
yield as a 3:2 mixture of diastereomers. Methoxy-
methylation by using chloromethyl methyl ether
z
R
S
z
and
methoxy ether 10 in 83
reduction (66 yield) and selective protection of the
resulting primary hydroxy group by using tert
butylchlorodiphenylsilane, triethylamine, and 4-
dimethylaminopyridine12) gave (2
)-cyclopentanol
N
,
N
-diisopropylethylamine aŠorded methoxy-
z
yield. Subsequent LiAlH4
＋
R
－
S
z
employing Baeyer-Viliiger oxidation with complete
retention of the enantiomeric excess is described
(Schemes 1 and 2).
-
S
Scheme 1.
81-89-977-4364; E-mail: syamauch agr.ehime-u.ac.jp
＠
†
To whom correspondence should be addressed. Fax:
＋

1960
S. YAMAUCHI et al.
Scheme 2. Retrosynthetic Analysis of (
)-(R) and ( )-(S)-Aldehyde 2.
＋ －
derivative 12 in 81
z
yield. This (2
S
)-cyclopentanol
derivative 13 by pyridinium chlorochromate oxida-
tion in 93 yield. At this stage, all preparations of
derivative 12 was converted to (2
R
)-cyclopentanone
z
derivative 13 by pyridinium chlorochromate oxida-
tion in 88 yield.
Since direct
the substrates for the Baeyer-Villiger oxidation,
which is the key reaction in this project, had been
accomplished (Scheme 3).
z
a
-hydroxylation to cis-lactone 4
proved unproductive, this lactone ring was opened to
alcohol 16. LiAlH4 reduction of cis-lactone 4, and
subsequent selective protection of the resulting pri-
mary hydroxy group as a trityl ether by treatment
with trityl chloride and pyridine gave trityl ether 14 in
Baeyer-Villiger oxidation of (2
-chloroperbenzoic acid in a phosphate buŠer at
pH 814) and CHCl3 aŠorded (5
,6 )-heptanolide 20
(52 yield) and (5 ,6 )-heptanolide 20 (35 yield).
Treatment of (5 ,6 ) and (5 ,6 )-heptanolide 20
R)-13 by using
m
R
R
z
R
S
z
R
R
R S
69
present in 14 was converted to a benzoate by using
benzoyl chloride and triethylamine in 84 yield,
z
yield. After the secondary hydroxy group
with K2CO3 in ethanol produced corresponding
unstable hydroxy ethyl esters, respectively. Subse-
quent exposure to benzoyl chloride and pyridine gave
z
cleavage of the trityl ether was carried out in re‰ux-
ing methanol containing a catalytic amount of
(5
R
,6
R
)-ester 21 (82
z
yield) and (5R,6S)-ester 21
(92
z
yield), respectively.
pyridinium
p
-toluenesulfonate in 92
z
yield. To
The absolute conˆgurations of (5
R,6R) and
achieve hydroxylation, this alcohol 16 was subjected
to pyridinium chlorochromate oxidation to give an
unstable corresponding aldehyde, which was convert-
ed to a triisopropylsilyl enol ether by employing
triisopropylsilyl tri‰ate, 1,8-diazabicyclo[5.4.0]un-
dec-7-ene, and 4-dimethylaminopyridine.13) Subse-
quent osmium oxidation and treatment with silica gel
(5R,6S)-21 were proven by a comparison with those
compounds derived from 2-deoxyribose.15) The enan-
tiomeric excesses of (5
each determined to be 99
chromatography.
R
,6
R
) and (5
R,6S)-21 were
z
ee by using chiralpak
Desilylation of (5
ment with (
-Bu)4NF in the presence of acetic acid16)
was successful to give (5 ,6 )-alcohol 22 (98 yield)
and (5 ,6 )-alcohol 22 (92 yield), respectively.
Cleavage of the methoxymethyl ethers of (5 ,6
and (5 ,6
)-22 by using trimethylsilyl bromide17)
R,6R) and (5R,6S)-21 by treat-
n
resulted in a polymer of
was exposed to NaBH4 reduction to give desired
glycol 17 as a 2:3 mixture of diastereomers in 31
yield from alcohol 16. tert-Butyldiphenylsilyl protec-
tion of the primary hydroxy group (100 yield) fol-
lowed by methoxymethyl protection of the secondary
a
-hydroxy aldehyde, which
R
R
z
R
S
z
z
R R)
R
S
z
provided corresponding glycols, which underwent
oxidative cleavage by periodate to give (R)-aldehyde
20＝＋
hydroxy group (91
z
yield) gave fully protected com-
2 ([
tively. The [
a
]
48.3) in 76
z
and 74 yields, respec-
z
D
pound 19. The benzoate function was then cleaved
a
]2D0 value of synthesized (
R)-2 was higher
7)
20＝＋
through the action of diisobutylaluminum hydride,
than that in the literature ([
a
]
35).
(
S
)-Alde-
)-
)- and
D
20＝－
providing (2
R
)-cyclopentanol derivative 12 in 88
z
hyde 2 ([
a
]
48.3) was also obtained from (2
,6
S
D
yield, which was transformed to (2
S
)-cyclopentanone
cyclopentanone derivative 13 via (5
S
S

Synthetic Study of 5-HETE
1961
Scheme 3. Conversion to (2
(a) BzCl, Et3N, CH2Cl2, r.t., 18 h (93
CH2Cl2, r.t., 18 h (83 yield). (d) LiAlH4, ether,
(f) PCC, NaOAc, MS 4A, CH2Cl2, 0 C, 18 h (88
yield, 2 steps). (h) BzCl, Et3N, CH2Cl2, r.t., 18 h (84
CH2Cl2, r.t., 18 h; (2) TIPSOTf, DBU, DMAP, 0 C, 1 h; (3) OsO4, NMO, aq. tert-BuOH, acetone, r.t., 18 h; (4) silica gel; (5) NaBH4,
EtOH, r.t., 3 h (31 yield, 5 steps). (k) TBDPSCl, Et3N, DMAP, CH2Cl2, r.t., 1 h (100 yield). (l) MOMCl, -(iso-Pr)2NEt,
yield). (m) DIBAL, toluene, 75 C, 30 min (88 yield). (n) PCC, NaOAc, MS 4A, CH2Cl2, 0 C, 18 h (93
R
) and (2
S
)-Ketone 13.
). (b) LDA, MoOPH, THF,
10 C, 3.5 h (66
yield). (g) (1) LiAlH4, ether,
). (i) PPTS, MeOH, re‰ux, 1 h (92
－
23
C, 20 min (54
yield). (c) MOMCl,
N
,
N
-(iso-Pr)2NEt,
z
9
z
－
z
yield). (e) TBDPSCl, Et3N, DMAP, CH2Cl2, r.t., 3 h (81
10 C, 30 min; (2) TrCl, pyridine, r.t., 2.5 h (69
yield). (j) (1) PCC, NaOAc, MS 4A,
z
9
z
z
yield).
－
9
9
z
z
z
9
z
z
N, N
CH2Cl2, r.t., 18 h (91
yield).
z
－
9
z
9
z
(5
excesses of (5
determined to be 99
matography (Scheme 4).
S
,6
R
)-ester 21, respectively. The enantiomeric
,6 )- and (5 ,6 )-ester 21 were each
ee by chiralpak chro-
hydroxy ester 3 and cis-lactone 4, in 12 and 18 steps
with 10 and 7 overall yields, respectively. In this
synthesis, the stereogenic centers of ( ) and ( )-alde-
S
S
S
R
z
z
z
R
S
hyde 2 were respectively introduced from yeast
reductive products 3 and 4 and Baeyer-Villiger oxida-
To examine the retention of enantiomeric excess in
the Baeyer-Villiger oxidation, a diŠerent substrate,
tion with (2
as substrates resulted in complete retention of the
enantiomeric excess, giving optically pure (5 ,6 ),
)-21. This synthetic
R) and (2S)-cyclopentanone derivative 13
(2
subjected to Baeyer-Villiger oxidation. Lactone 24
was obtained in a lower yield (44 ) as a diastereo-
meric mixture (1:1). (2 )-23 was recovered in 37
yield. After conversion to benzoate 25 and separation
of (5 ,6 ) and (5 ,6 ) isomers, the enantiomeric
excesses were determined as 83 ee and 96 ee,
R)-23 ( a diastereomeric mixture of 1:1), was
R
R
z
(5R,6S), (5S,6S) and (5S,6R
R
z
process demonstrates a new applicatipon of yeast
reductive products 3 and 4.
R
R
R S
z
z
Experiment
respectively (Scheme 5). This fact showed that the
trityl group had reduced the yield of the Baeyer-
Villiger oxidation products and their enantiomeric
excess. When the trityl group was present, the enan-
tiomeric excess of the erythro isomer was higher than
NMR data were measured by a JNM-EX400
spectrometer, IR spectra were determined with a
Shimadzu FTIR-8100 spectrophotometer, FABMS
data were measured with a JMS-MS700V spectrome-
ter, and optical rotation values were evaluated with a
HORIBA SEPA-200 instrument. The silica gel used
was Wakogel C-300 (Wako, 200–300 mesh). HPLC
analysis was performed by Shimadzu LC-6AD and
SPD-6AV instruments.
that of threo isomer. In this experiment, the tert
-
butyldiphenylsilyl group was better than the trityl
group to achieve complete retention of the enantio-
meric excess in the Baeyer-Villiger oxidation.
(R) and (S)-Aldehydes 2, which were intermedi-
ates for the synthesis of 5-HETE, were synthesized
from the yeast-mediated reduction products,

1962
S. YAMAUCHI et al.
Scheme 4. Conversion to (
)-(R) and ( )-(S)-2.
＋ －
(a) MCPBA, phosphate buŠer, pH 8, CHCl3, 0
(2) BzCl, pyridine, r.t., 18 h [(5 ,6 ): 82 yield, 2 steps; (5
98 yield; (5 ,6 ): 92 yield]. (d) (1) TMSBr, CH2Cl2, 0 C, 1 h; (2) NaIO4, MeOH, r.t., 2 h [from (5
(5 ,6 ): 74 yield, 2 steps].
9
C, 18 h [(5R,6
R
): 52
z
z
yield; (5
yield, 2 steps]. (c) (
R
,6
S
): 35
-Bu)4NF, AcOH, THF, r.t., 60 h [(5
,6 ): 76 yield, 2 steps; from
z
yield]. (b) (1) K2CO3, EtOH, r.t., 18 h;
R
R
z
R
,6S): 92
n
R R
,6 ):
z
R
R
z
S
z
9
R
R
z
S
Scheme 5. Baeyer-Villiger Oxidation of Cyclopentanone Derivative 23.
(a) MCPBA, phosphate buŠer, pH 8, CHCl3, 0 C, 18 h (44 yield). (b) (1) K2CO3, EtOH, r.t., 18 h; (2) BzCl, pyridine, r.t., 18 h
[(5 ,6 ): 31 yield, 2 steps; (5 ,6 ): 35 yield, 2 steps].
9
z
R
R
z
R
S
z
Methyl [(1R,2S)-2-Benzoyloxycyclopentyl]acetate
(R S)-Methyl [(1R,2S)-2-benzoyloxycyclopentyl]-
W
(
8
). To an ice-cooled solution of hydroxy ester 3
(hydroxy)acetate (
9). To a solution of LDA (0.029
(9.53 g, 0.055 mol) and Et3N (9.24 ml, 0.066 mol) in
CH2Cl2 (10 ml) was added BzCl (7.69 ml, 0.066 mol).
After the reaction mixture was stirred at room
temperature for 18 h, sat. aq. NaHCO3 solution
and CH2Cl2 were added. The organic solution was
separated, washed with brine, and dried (Na2SO4).
Concentration followed by silica gel column chro-
mol) in THF (150 ml) was added a solution of ester 8
－
(6.76 g, 0.026 mol) in THF (50 ml) at 75
the mixture was stirred at 75 C for 30 min,
MoOPH (16.8 g, 0.039 mol) was added. The reaction
9C. After
－
9
－
mixture was stirred at 23
sat. aq Na2SO3 solution and EtOAc were added. The
organic solution was separated, washed with 10 aq.
9C for 20 min, and then
z
matography (1
z
EtOAc benzene) gave benzoyl ester
HCl solution, sat. aq. NaHCO3 solution, and brine,
and dried (Na2SO4). Concentration followed by silica
W
20
＝
) as a colorless oil. [a]
8 (13.3 g, 0.051 mol, 93
z
D
＋
＝
gel column chromatography (EtOAc hexane 1 6,
W W
58.0 (
c
1.00, CHCl3). NMR
d
H (CDCl3): 1.34 (1H,
m), 1.70–1.85 (3H, m), 2.04–2.20 (2H, m), 2.35 (1H,
1 4 and 1 3) gave a diastereomeric mixture of
W W
＝
dd,
J
14.7, 8.3 Hz, C
CH2CO2Me), 2.61 (1H, dd,
CO2Me), 3.63 (3H, s, OCH3), 5.05 (1H, m,
OBz), 7.41–7.45 (2H, m, ArH), 7.55 (1H, m,
H
HCO2Me), 2.54 (1H, m,
hydroxy ester 9 (3.90 g, 0.014 mol, 54z) as a
＝
C
H
J
14.7, 5.9 Hz,
colorless oil. NMR dH (CDCl3): 1.50–1.68
CH
H
H
(1H, m), 1.70–1.86 (4H, m), 1.93–2.10 (1H, m), 2.51
C
(0.6H, m, CHCH(OH)CO2Me), 2.58 (0.4H, m,
ArH), 8.01–8.03 (2H, m, ArH). NMR dC (CDCl3):
22.5, 30.1, 31.6, 37.7, 42.2, 51.5, 80.7, 128.3, 129.5,
129.6, 130.4, 132.8, 132.9, 166.4, 172.9. IR nmax
CHCH(OH)CO2Me), 3.04 (0.6H, br. s, OH),
3.30 (0.4H, br. s, OH), 3.70 (1.2H, s, OCH3),
3.75 (1.8H, s, OCH3), 4.24 (0.4H, br. d,
＝
H
(CHCl3): 2955, 1732, 1713, 1453, 1439, 1316, 1279,
J
C
4.4 Hz, C
(OH)CO2Me), 5.33 (0.4H, m, C
(0.6H, m, C OBz), 7.41–7.46 (2H, m, ArH),
H
(OH)CO2Me), 4.54 (0.6H, br. s,
1202, 1177, 1119 cm－
.
Anal. Found: C, 68.81; H,
H
OBz), 5.37
1
7.08
z
. Calcd. for C15 H18O4: C, 68.68; H, 6.92
z
.
H

Synthetic Study of 5-HETE
1963
7.54–7.55 (1H, m, ArH), 7.98–8.04 (2H, m, ArH).
3.98 (0.6H, m, C
H
OMOM), 4.11 (0.4H, m, C
H
OM-
＝
NMR dC (CDCl3): 23.5, 24.3, 27.6, 32.7, 32.9, 49.4,
52.5, 70.4, 71.2, 78.5, 127.9, 128.3, 129.5, 130.3,
130.4, 132.9, 166.3, 166.6, 174.5, 174.8. IR nmax
OM), 4.66 (0.6H, d,
J
6.8 Hz, OC
6.8 Hz, OCH
6.8 Hz, OC HOMe), 4.81 (0.4H, d,
H
HOMe), 4.71
＝
(0.4H, d,
J
H
OMe), 4.76 (0.6H, d,
J
＝
＝
H
J
6.8 Hz,
(CHCl3): 3525, 2959, 1732, 1713, 1279, 1316, 1119,
OCHHOMe). NMR dC (CDCl3): 21.7, 21.8, 26.6,
922, 897 cm－
.
Anal. Found: C, 64.94; H, 6.73
z.
27.6, 33.8, 34.8, 49.0, 50.2, 55.6, 55.8, 64.35, 64.39,
1
Calcd. for C15H18O5: C, 64.74; H, 6.52
z.
75.1, 76.0, 83.0, 85.2, 96.90, 96.93. IR
n
max (CHCl3):
Anal. Found: C, 56.61;
. Calcd. for C9H18O4: C, 56.82; H, 9.54
3425, 2961, 1034, 909 cm－
H, 9.36
.
1
(R S)-Methyl [(1S,2S)-2-benzoyloxycyclopentyl]-
z
z.
W
(methoxymethoxy)acetate (10). To a solution of
alcohol 9 (3.35 g, 0.012 mol) and
N
,
N
-(iso-Pr)2NEt
(1S,2S)-2-[(1R S)-2-(tert-Butyldiphenylsilyloxy)-
W
(16.7 ml, 0.096 mol) in CH2Cl2 (5 ml) was added
MOMCl (3.65 ml, 0.048 mol). After the reaction
mixture was stirred at room temperature for 18 h,
MeOH and CH2Cl2 were added. The organic solution
1-(methoxymethoxy)ethyl]cyclopentanol ((2S)-12).
To an ice-cooled solution of diol 11 (1.69 g, 8.88
mmol), Et3N (1.49 ml, 10.7 mmol), and 4-DMAP
(43 mg, 0.35 mmol) in CH2Cl2 (10 ml) was added
TBDPSCl (2.31 ml, 8.88 mmol). After the reaction
mixture was stirred at room temperature for 3 h, sat.
aq. NaHCO3 solution and CH2Cl2 were added. The
organic solution was separated, washed with brine,
and dried (Na2SO4). Concentration followed by silica
was separated, washed with 1
M
aq. HCl solution,
sat. aq. NaHCO3 solution, and brine, and dried
(Na2SO4). Concentration followed by silica gel
＝
column chromatography (EtOAc hexane 1 5)
W
W
gave a diastereomeric mixture of MOM ether 10
(3.31 g, 0.010 mol, 83 ) as a colorless oil. NMR dH
＝
gel column chromatography (EtOAc hexane 1 9)
W W
z
(CDCl3): 1.57 (0.4H, m), 1.66–1.90 (4.6H, m),
1.97 (0.4H, m), 2.08 (0.6H, m), 2.58 (0.4H, m,
gave (2
S
)-cyclopentanol derivative 12 (3.10 g,
) as a colorless oil. NMR dH
7.23 mmol, 81
z
C
C
H
H
CH(OMOM)CO2Me),
2.64
(0.6H,
m,
(CDCl3): 1.06 (9H, s, tBu), 1.41 (0.6H, m), 1.50–1.74
(3.8H, m), 1.82 (0.6H, m), 1.90–2.00 (2H, m), 2.85
(0.6H, br. s, OH), 3.02 (0.4H, br. s, OH), 3.29
(1.8H, s, OCH3), 3.39 (1.2H, s, OCH3), 3.57–3.79
CH(OMOM)CO2Me), 3.38 (1.8H, s, OCH3),
3.40 (1.2H, s, OCH3), 3.67 (1.8H, s, OCH3),
＝
＝
＝
3.68 (1.2H, s, OCH3), 4.15 (0.6H, d,
J
J
J
5.4 Hz,
4.9 Hz,
7.1 Hz,
C
C
H
H
H
(OMOM)CO2Me), 4.38 (0.4H, d,
(OMOM)CO2Me), 4.65 (0.6H, d,
(3H, m, 1-H, CH2OSi), 4.04 (1H, m, C
H
OMOM),
＝
4.49 (0.6H, d,
d, 6.8 Hz, OC
6.8 Hz, OCH
OCH
J
6.8 Hz, OC
H
HOMe), 4.60 (0.6H,
OC
HOMe), 4.68 (0.6H, d,
J
＝
7.1 Hz, OC
7.1 Hz, OCH OMe), 4.73
7.1 Hz, OCH OMe), 5.29 (0.4H, m,
OBz), 5.41 (0.6H, m, C OBz), 7.40–7.46 (2H,
m, ArH), 7.55 (1H, m, ArH), 7.99–8.04 (2H, m,
ArH). NMR C (CDCl3): 23.2, 23.4, 25.4, 27.2, 32.6,
H
HO-
J
＝
H
HOMe), 4.63 (0.4H, d, J
＝
＝
＝
6.8 Hz,
Me), 4.70 (0.4H, d,
J
H
H
OMe), 4.86 (0.4H, d,
J
＝
(0.4H, d,
J
H
H
OMe), 7.37–7.43 (6H, m, ArH), 7.65–7.69
C
H
H
(4H, m, ArH). NMR dC (CDCl3): 19.1, 19.2, 21.5,
21.7, 26.2, 26.79, 26.81, 27.5, 33.5, 34.1, 48.8, 50.7,
55.7, 55.9, 65.6, 65.8, 75.0, 79.5, 82.2, 96.3, 96.5,
127.69, 127.71, 127.74, 129.73, 129.75, 129.8, 133.0,
d
32.9, 48.0, 48.3, 51.9, 56.2, 56.3, 75.6, 76.5, 77.4,
78.1, 96.46, 96.52, 128.2, 128.3, 129.49, 129.53,
130.3, 130.5, 132.7, 132.9, 165.9, 166.3, 172.1,
133.19, 133.24, 135.57, 135.59, 135.63. IR nmax
(CHCl3): 3500, 2961, 1146, 1113, 1030 cm－
. Anal.
1
172.3. IR
n
max (CHCl3): 2955, 1748, 1713, 1279, 914,
Anal. Found: C, 63.34; H, 6.89 . Calcd.
for C17H22O6: C, 63.34; H, 6.88
Found: C, 70.08; H, 8.49
C, 70.05; H, 8.47
z. Calcd. for C25H36O4Si:
903 cm－
.
z
z
.
1
z
.
(1S,2S)-2-(2-Trityloxyethyl)cyclopentanol (14). To
a suspension of LiAlH4 (2.85 g, 0.075 mol) in ether
(40 ml) was added a solution of cis lactone 4 (9.45 g,
(1S,2S)-2-[(1R
S)-2-Hydroxy-1-(methoxymeth-
W
oxy)ethyl]cyclopentanol(11).Toanice-cooledsuspen-
sion of LiAlH4 (0.43 g, 0.011 mol) in ether (10 ml)
was added a solution of ester 10 (3.31 g, 0.010 mol)
in ether (20 ml). The reaction mixture was stirred at
0.075 mol) in ether (80 ml) at
－
10
9
C. The reaction
－
mixture was stirred at 10
9
C for 30 min before addi-
tions of sat. aq. MgSO4 and K2CO3. The mixture was
stirred at room temperature for 30 min and then
ˆltered. The ˆltrate was concentrated to give a crude
diol. To a solution of this crude diol in pyridine
(20 ml) was added TrCl (20.9 g, 0.075 mol) in pyri-
dine (20 ml). The reaction mixture was stirred at
room temperature for 2.5 h before additions of H2O
and EtOAc. The organic solution was separated,
washed with sat. aq. CuSO4, sat. aq. NaHCO3, and
brine, and dried (Na2SO4). Concentration followed
9
0 C for 3.5 h before additions of sat. aq. MgSO4 so-
lution and K2CO3. The mixture was stirred at room
temperature for 30 min and ˆltered. The ˆltrate was
concentrated. The residue was applied to silica gel
＝
column chromatography (EtOAc hexane 1 1 and
W
W
3 1) to give diol 11 (1.26 g, 6.62 mmol, 66
z
) as a
W
colorless oil. NMR
dH (CDCl3): 1.32 (0.4H, m), 1.44
(0.6H, m), 1.53–1.63 (2H, m), 1.67–1.77 (1H, m),
1.80–2.00 (3H, m), 3.42 (1.8H, s, OCH3), 3.45
(1.2H, s, OCH3), 3.50–3.58 (1.4H, m, C
H
OH and
2OH),
by silica gel column chromatography (EtOAc hexane
W
＝
1 9) gave trityl ether 14 (19.3 g, 0.052 mol, 69 )
z
W
C
H
2OH), 3.67–3.75 (1.6H, m, C OH and C
H
H

1964
S. YAMAUCHI et al.
20＝－
as a colorless oil. [
a
]
21.0 (
c
1.02, CHCl3).
NaOAc (5.24 g, 0.064 mol), and MS 4A (3 g) in
CH2Cl2 (200 m) was stirred at room temperature for
18 h before addition of dry ether. After the mixture
was ˆltered, the ˆltrate was concentrated. The
residue was applied to silica gel column chro-
D
NMR dH (CDCl3): 1.35 (1H, m), 1.49 (1H, m),
1.60–1.85 (7H, m), 2.11 (1H, s, OH), 3.07 (1H, m,
C
C
H
H
HOTr), 3.31 (1H, m, CHHOTr), 4.11 (1H, m,
OH), 7.20–7.31 (9H, m), 7.42–7.44 (6H, m).
＝
matography (EtOAc hexane 1 5) to give an unsta-
W W
NMR dC (CDCl3): 22.1, 29.50, 29.52, 34.4, 44.3,
63.5, 74.2, 87.2, 126.9, 127.8, 128.6, 144.1. IR nmax
ble aldehyde (10.5 g, 0.045 mol, 78
(CDCl3): 1.57 (1H, m), 1.71 (1H, m), 1.80–2.10 (5H,
m), 2.40–2.57 (2H, m, C 2CHO), 5.47 (1H, m,
OBz), 7.43–7.46 (2H, m, ArH), 7.55 (1H, m,
z). NMR dH
(CHCl3): 3500, 2936, 1493, 1449, 1071, 1032, 1003,
982, 909 cm－
.
Anal. Found: C, 83.35; H, 7.64
z.
H
1
Calcd. for C26H28O2: C, 83.83; H, 7.58
z
.
CH
＝
7.8 Hz, ArH), 9.84 (1H,
ArH), 7.99–8.01 (2H, d,
J
(1S,2S)-2-(2-Trityloxyethyl)cyclopentyl benzoate
15). To an ice-cooled solution of alcohol 14 (29.7 g,
s, CHO). NMR dC (CDCl3): 22.1, 29.8, 32.4, 38.2,
(
44.1, 78.2, 128.35, 128.40, 129.5, 129.6, 132.9,
0.080 mol) and Et3N (29.7 ml, 0.21 mol) in CH2Cl2
(25 ml) was added a solution of BzCl (10.2 ml, 0.088
mol). After the reaction mixture was stirred at room
temperature for 18 h, sat. aq. NaHCO3 solution and
CH2Cl2 were added. The organic solution was
separated, washed with brine, and dried (Na2SO4).
Concentration followed by silica gel column chro-
133.0, 166.0, 201.4. IR nmax (CHCl3): 2963, 1717,
1277, 1117 cm－
.
1
To an ice-cooled solution of the resulting aldehyde
(10.5 g, 0.045 mol), DBU (14.8 ml, 0.099 mol), and
4-DMAP (4.89 g, 0.040 mol) in CH2Cl2 (150 ml) was
added TIPSOTf (13.4 ml, 0.050 mol). After the
9
reaction solution was stirred at 0 C for 1 h, sat. aq.
matography (3
z
EtOAc hexane) gave benzoate 15
NaHCO3 solution was added. The organic solution
was separated, washed with brine, and dried
(Na2SO4). Concentration followed by silica gel
W
20
＝
) as a colorless oil. [a]
(31.9 g, 0.067 mol, 84
z
D
＋
30.9 (
c
1.03, CHCl3). NMR dH (CDCl3): 1.46 (1H,
m), 1.58–1.72 (2H, m), 1.74–1.88 (3H, m), 1.94–2.03
column chromatography (3z EtOAc hexane) gave
W
(2H, m), 2.09 (1H, m), 3.07–3.15 (2H, m, C
5.30 (1H, m, C OBz), 7.16–7.33 (11H, m, ArH),
7.40–7.42 (6H, m, ArH), 7.54 (1H, dd,
7.3 Hz, ArH), 7.99 (2H, d, 7.9 Hz). NMR dC
H
2OTr),
an unstable TIPS enol ether (9.98 g, 0.033 mol, 74
as a colorless oil.
z
)
H
＝
J
7.3,
The reaction solution of the resulting silyl enol
ether (9.98 g, 0.026 mol), NMO (3.87 g, 0.033 mol)
and OsO4 (2z in H2O, 2 ml) in acetone (100 ml),
tert-BuOH (25 ml) and H2O (25 ml) was stirred at
room temperature for 18 h before addition of
Na2S2O3. After the mixture was concentrated, the
residue was dissolved in EtOAc and H2O. The organ-
ic solution was separated, washed with brine, and
dried (Na2SO4). Concentration followed by silica gel
J
＝
(CDCl3): 22.1, 29.75, 29.82, 32.6, 41.6, 62.5, 78.8,
86.4, 126.8, 127.2, 127.7, 127.89, 127.91, 128.3,
128.4, 128.6, 129.5, 130.9, 132.7, 144.3, 146.9,
166.0. IR
1279, 1119, 1071, 1028 cm－
H, 6.84 . Calcd. for C33H32O3: C, 83.16; H, 6.77
nmax (CHCl3): 2961, 1709, 1491, 1449, 1316,
1
.
Anal. Found: C, 83.08;
z
z.
＝
(1S,2S)-2-(2-Hydroxyethyl)cyclopentyl benzoate
16). A reaction solution of trityl ether 15 (28.8 g,
column chromatography (EtOAc hexane 1 1) gave
W
W
(
polymer of
a
-hydroxy aldehyde (7.96 g).
0.060 mol) and PPTS (20 mg, 0.080 mmol) in MeOH
(500 ml) was heated under re‰ux for 1 h. After addi-
tion of a few drops of Et3N, the mixture was concen-
trated. The residue was applied to silica gel column
To an ice-cooled solution of this polymer (7.96 g)
in EtOH (150 ml) was added NaBH4 (1.25 g, 0.033
mol). The reaction mixture was stirred at room
temperature for 3 h before addition of 1
M
aq. HCl
＝
chromatography (EtOAc hexane 1 5) to give
solution. After neutralized with sat. aq. NaHCO3
solution, the mixture was concentrated. The residue
was dissolved in EtOAc and H2O. The organic solu-
tion was separated, washed with brine, and dried
(Na2SO4). Concentration followed by silica gel
W
alcohol 16 (13.0 g, 0.055 mol, 92
20＝＋
1.55–1.60 (2H, m), 1.60–1.72 (2H, m), 1.79–1.97
(3H, m), 2.02 (1H, m), 2.10 (1H, m), 3.64–3.75 (2H,
W
z
) as a colorless oil.
[
a
]
64.2 (
c
1.93, CHCl3). NMR dH (CDCl3):
D
＝
column chromatography (EtOAc hexane 1 2) gave
W W
m, C
H
2OH), 5.46 (1H, m, C
H
OBz), 7.43 (2H, dd,
7.3, 7.3 Hz,
7.8 Hz, ArH). NMR dC
J
＝
7.8, 7.3 Hz, ArH), 7.55 (1H, dd,
J
＝
a diastereomeric mixture of glycol 17 (3.50 g, 0.014
mol, 54 from TIPS ether) as a colorless oil. NMR
dH (CDCl3): 1.48 (0.6H, m), 1.60–2.20 (6.4H, m),
＝
ArH), 8.02 (2H, d,
J
z
(CDCl3): 22.0, 29.8, 32.4, 32.6, 41.4, 62.0, 78.6,
×
128.3, 129.5, 130.7, 132.8, 166.3. IR nmax (CHCl3):
2.37–2.90 (2H, br., OH 2), 3.47–3.55 (1H, m,
HOH), 3.63 (0.4H, m, C OH), 3.66–3.72 (1H,
m, CH OH), 3.90 (0.6H, m, C OH), 5.42 (0.4H,
m, C OBz), 5.60 (0.6H, m, C OBz), 7.41–7.46
3500, 2948, 1709, 1279, 1119 cm－
.
Anal. Found: C,
C
H
H
1
71.83; H, 7.71
7.74
z
. Calcd. for C14H18O3: C, 71.77; H,
H
H
H
H
z.
(2H, m, ArH), 7.57 (1H, m, ArH), 7.97–8.02 (2H,
m, ArH). NMR dC (CDCl3): 21.9, 22.0, 25.0, 26.6,
31.9, 33.3, 46.6, 49.2, 65.3, 65.6, 71.3, 72.4, 77.9,
78.5, 128.3, 128.4, 129.4, 129.6, 129.7, 129.8, 130.4,
(1S,2S)-2-[(1R S)-1,2-Dihydroxyethyl]cyclopentyl
W
benzoate (17). A reaction mixture of alcohol 16
(13.6 g, 0.058 mol), PCC (13.8 g, 0.064 mol),

Synthetic Study of 5-HETE
1965
133.0, 133.3, 166.0, 167.6. IR nmax (CHCl3): 3313,
NMR dC (CDCl3): 19.3, 21.8, 21.9, 26.1, 26.5, 26.8,
26.9, 28.0, 32.3, 33.3, 45.8, 46.8, 55.6, 55.7, 65.35,
65.44, 77.5, 77.8, 78.8, 96.1, 96.4, 127.56, 127.64,
127.67, 127.69, 128.3, 128.4, 129.4, 129.5, 129.56,
129.61, 129.7, 130.6, 132.7, 132.9, 133.1, 133.2,
133.4, 134.8, 135.49, 135.53, 135.6, 135.7, 165.8. IR
2971, 1709, 1283, 1121 cm－
H, 7.43 . Calcd. for C14H18 O4: C, 67.18; H, 7.25
.
Anal. Found: C, 66.89;
1
z
z
.
(1S,2S)-2-[(1R S)-2-(tert-Butyldiphenylsilyloxy)-
W
1-hydroxyethyl]cyclopentyl benzoate (18). To an ice-
cooled solution of glycol 17 (2.52 g, 0.010 mol), Et3N
(1.68 ml, 0.012 mol) and 4-DMAP (0.049 g,
0.40 mmol) in CH2Cl2 (10 ml) was added TBDPSCl
(2.62 ml, 0.010 mol). The reaction mixture was
stirred at room temperature for 1 h before additions
of sat. aq. NaHCO3 and CH2Cl2. The organic
solution was separated, washed with brine, and dried
(Na2SO4). Concentration followed by silica gel
nmax (CHCl3): 2946, 1711, 1279, 1115, 1036, 1028,
909 cm－
.
Anal. Found: C, 72.43; H, 7.87
z
. Calcd.
1
for C32H40O5Si: C, 72.14; H, 7.57
z.
(1S,2R)-2-[(1R S)-2-(tert-Butyldiphenylsilyloxy)-
W
1-(methoxymethoxy)ethyl]cyclopentanol ((2R)-12).
To a solution of benzoate 19 (5.33 g, 10.0 mmol) in
toluene (80 ml) was added DIBAL (18.9 ml, 1
toluene, 18.9 mmol) at 75 C. After the reaction so-
C for 30 min, 1 aq. HCl
M
in
column chromatography (EtOAc hexane
＝
1 9) gave
－
9
W
W
－
a diastereomeric mixture of silyl ether 18 (4.89 g,
0.010 mol, 100
lution was stirred at 75
9
M
z
) as a colorless oil. NMR dH
solution was added. The organic solution was sepa-
rated washed with sat. aq. NaHCO3 solution and
brine, and dried (Na2SO4). Concentration followed
(CDCl3): 1.02 (5.4H, s, tBu), 1.05 (3.6H, s, tBu),
1.41 (0.4H, m), 1.58–1.75 (1.6H, m), 1.80–2.00 (3H,
m), 2.00–2.19 (2H, m), 2.64 (0.6H, d,
J
＝
3.9 Hz,
3.9 Hz, OH), 3.56–3.60 (1H,
HOSi), 3.70 (0.4H, m, C OH), 3.74–3.80
(1H, m, CH OSi), 3.97 (0.6H, m, C OH), 5.22
(0.6H, m, C OBz), 5.65 (0.4H, m, C OBz),
by silica gel column chromatography (EtOAc hexane
W
＝
＝
1 9) gave (2
OH), 2.93 (0.4H, d,
m, C
J
z
R)-12 (3.77 g, 8.80 mmol, 88 ) as a
W
H
H
colorless oil. NMR dH (CDCl3): 1.05 (5.4H, s, tBu),
1.06 (3.6H, s, tBu), 1.35–1.46 (1H, m), 1.50–1.60
(1H, m), 1.61–1.76 (3H, m), 1.76–1.92 (2H, m), 2.85
(0.4H, br. s, OH), 3.30 (1.2H, s, OCH3), 3.44 (1.8H,
s, OCH3), 3.54 (0.6H, br. s, OH), 3.63–3.78 (2.6H,
H
H
H
H
7.17–7.20 (1H, m), 7.28–7.45 (8H, m), 7.53–7.68
(4H, m), 7.94–8.01 (2H, m). NMR dC (CDCl3):
19.18, 19.24, 21.9, 22.2, 25.4, 26.8, 26.9, 27.0, 32.2,
33.3, 46.6, 48.2, 66.8, 67.1, 71.4, 72.2, 77.5, 77.8,
127.65, 127.69, 127.71, 127.75, 128.2, 128.3, 128.4,
129.5, 129.6, 129.71, 129.72, 129.74, 129.8, 130.5,
130.7, 132.75, 132.82, 132.9, 133.0, 133.1, 133.2,
＝
6.4,
m, C
6.4, 4.9 Hz,
OH), 4.58 (0.4H, d,
4.67 (0.4H, d, 6.8 Hz, OC
OMe), 4.99 (0.6H, d,
OMe), 7.36–7.44 (6H, m, ArH), 7.66–7.70
(4H, m, ArH). NMR C (CDCl3): 19.06, 19.14, 21.9,
H
2OSi, C
H
OMOM), 3.91 (0.4H, ddd,
J
C
H
OMOM), 4.30–4.37 (1H, m,
＝
C
H
J
6.8 Hz, OC
H HOMe),
J
＝
H HOMe), 4.70 (0.6H,
＝
H
＝
6.8 Hz,
d,
J
6.8 Hz, CH
H
J
134.8, 135.3, 135.4, 135.5, 135.6, 165.7. IR nmax
OCH
(CHCl3): 2878, 1713, 1279, 1115 cm－
.
Anal. Found:
d
1
C, 73.79; H, 7.70
73.73; H, 7.42
z
. Calcd. for C30H36O4Si: C,
22.7, 25.7, 26.0, 26.8, 33.3, 34.8, 47.7, 49.0, 55.7,
55.9, 65.3, 66.5, 67.1, 73.1, 74.1, 79.1, 81.1, 96.5,
98.3, 126.9, 127.7, 127.8, 128.5, 129.68, 129.72,
z
.
(1S,2R)-2-[(1R S)-2-(tert-Butyldiphenylsilyloxy)-
129.9, 132.8, 133.3, 135.5, 135.6. IR nmax (CHCl3):
W
3500, 2934, 1429, 1113, 1073, 1030 cm－
.
Anal.
1
1-(methoxymethoxy)ethyl]cyclopentyl benzoate (19).
A reaction mixture of alcohol 18 (5.21 g, 0.011 mol),
Found: C, 69.83; H, 8.73
C, 70.05; H, 8.47
z. Calcd. for C25H36O4Si:
N
,
N
-(iso-Pr)2NEt (14.9 ml, 0.086 mol) and MOMCl
z
.
(3.24 ml, 0.043 mol) in CH2Cl2 (15 ml) was stirred at
room temperature for 18 h before additions of
MeOH and CH2Cl2. The organic solution was
(2R)-2-[(1R
S)-2-(tert-Butyldiphenylsilyloxy)-1-
W
(methoxymethoxy)ethyl]cyclopentanone
(13).
A
washed with 1
M
HCl solution, sat. aq. NaHCO3
reaction mixture of (2S)-cyclopentanol derivative
solution, and brine, and dried (Na2SO4). Concentra-
tion followed by silica gel column chromatography
12 (3.87 g, 9.03 mmol), PCC (2.14 g, 9.93 mmol),
NaOAc (0.81 g, 9.87 mmol) and MS 4A (1.5 g) in
＝
(EtOAc hexane 1 9) gave a diastereomeric mixture
CH2Cl2 (80 ml) was stirred at 09C for 18 h before
W
W
of MOM ether 19 (5.53 g, 0.010 mol, 91
z
) as a
addition of dry ether. After the mixture was ˆltered,
the ˆltrate was concentrated. The residue was applied
colorless oil. NMR dH (CDCl3): 1.00 (5.4H, s, tBu),
1.07 (3.6H, s, tBu), 1.55–2.09 (5.4H, m), 2.13 (0.6H,
m), 2.28–2.38 (1H, m), 3.10 (1.2H, s, OCH3), 3.37
(1.8H, s, OCH3), 3.64–3.85 (2H, m), 3.85–3.90 (1H,
to silica gel column chromatography (3
benzene) to give a diastereomeric mixture of (2
cyclopentanone derivative 13 (3.39 g, 7.95 mmol,
88 ) as a colorless oil. NMR dH (CDCl3): 1.03
z EtOAc
W
)-
R
m), 4.49 (0.4H, d,
J
＝
6.8 Hz, OC
6.8 Hz, OCH OMe), 4.83 (0.6H, d,
HOMe), 5.34 (0.6H, m, C OBz), 5.53
(0.4H, m, C OBz), 7.20–7.24 (1H, m, ArH),
H
HOMe), 4.64
z
＝
＝
(1H, d,
J
H
J
(3.6H, s, tBu), 1.04 (5.4H, s, tBu), 1.65–1.79 (1H,
m), 1.81–2.35 (5H, m), 2.43–2.54 (1H, m), 3.20
(1.8H, s, OCH3), 3.29 (1.2H, s, OCH3), 3.55 (0.6H,
6.8 Hz, OC
H
H
H
＝
7.31–7.45 (6H, m, ArH), 7.52–7.64 (4H, m, ArH),
7.68–7.70 (2H, m, ArH), 7.97–8.01 (2H, m ArH).
dd,
J
10.3, 7.3 Hz, C
H
HOSi), 3.76–3.85 (1.4H, m,
5.9, 5.9, 3.4 Hz,
CH2OSi), 4.00 (0.6H, ddd,
J
＝

1966
S. YAMAUCHI et al.
＝
＝
＝
H), 3.83 (1H, dd, J
C
C
H
H
OMOM), 4.20 (0.4H, ddd,
J
5.9, 5.9, 2.4 Hz,
dd,
J
10.7, 6.6 Hz, 7-
H
10.7,
＝
OMOM), 4.55 (0.6H, d,
J
6.3 Hz, OC
6.3 Hz, OCH OMe), 4.61
6.3 Hz, OC HOMe), 4.69 (0.4H, d,
6.3 Hz, OCH OMe), 7.37–7.45 (6H, m, ArH),
H
HO-
5.4 Hz, 7-H
H
), 3.88 (1H, m, C
H
OMOM), 4.58 (1H,
＝
＝
＝
10.3, 3.9, 3.9 Hz, 5-H), 4.63 (1H, d, J
Me), 4.57 (0.6H, d,
J
H
ddd,
6.6 Hz, OC
OCH OMe), 7.36–7.46 (6H, m, ArH), 7.64–7.66
J
＝
＝
6.6 Hz,
(0.4H, d,
＝
J
H
J
H
HOMe), 4.66 (1H, d,
J
H
H
7.65–7.68 (4H, m, ArH). NMR dC (CDCl3): 19.1,
19.2, 20.87, 20.94, 23.0, 25.7, 26.7, 26.8, 39.0, 39.1,
50.2, 50.5, 55.5, 55.6, 64.1, 64.5, 76.2, 77.9, 96.7,
97.1, 127.67, 127.70, 129.66, 129.72, 133.21, 133.24,
(4H, m, ArH). NMR dC (CDCl3): 18.4, 19.2, 22.0,
26.8, 29.8, 55.7, 62.6, 78.2, 79.8, 96.8, 127.78,
127.80, 129.9, 133.0, 133.1, 135.53, 135.55, 135.60,
171.3. IR
nmax (CHCl3): 2948, 1728, 1244, 1113, 1107,
1
133.28, 133.33, 135.5, 135.6, 217.9, 220.0. IR nmax
1053, 1030, 911 cm－
. Anal. Found: C, 68.07; H,
(CHCl3): 2932, 1736, 1113, 1036, 909 cm－
.
Anal.
7.92
(5 ,6
CHCl3). (5
0.42, CHCl3).
z
. Calcd. for C25H34O5Si: C, 67.84; H, 7.74z.
1
20＝＋
Found: C, 70.61; H, 8.14
z
. Calcd. for C25H34 O4Si:
S
S
)-heptanolide 20,
,6
[
a
]
19.5
(
c
0.20,
D
20＝＋
C, 70.38; H, 8.03 2S-13: 93
z
.
z
yield. NMR dH
S
R
)-heptanolide 20, [
a
]
16.6 (c
D
(CDCl3): 1.03 (5.4H, s, tBu), 1.04 (3.6H, s, tBu),
1.65–1.79 (1H, m), 1.81–2.35 (5H, m), 2.43–2.54
(1H, m), 3.20 (1.2H, s, OCH3), 3.29 (1.8H, s,
(5R,6R) and (5R,6S)-Ethyl 5-benzoyloxy-7-(tert-
butyldiphenylsilyloxy)-6-(methoxymethoxy)heptano-
ate (21). A reaction mixture of (5R,6R)-heptanolide
＝
OCH3), 3.55 (0.4H, dd,
3.76–3.85 (1.6H, m, CH2OSi), 4.00 (0.4H, ddd,
5.9, 5.9, 3.4 Hz, C OMOM), 4.20 (0.6H, ddd,
5.9, 5.9, 2.4 Hz, C OMOM), 4.55 (0.4H, d,
Hz, OC HOMe), 4.57 (0.4H, d,
OCH OMe), 4.61 (0.6H, d,
Me), 4.69 (0.6H, d,
J
10.3, 7.3 Hz, C
H
HOSi),
＝
＝
J
J
＝
H
H
20 (1.03 g, 2.33 mmol) and K2CO3 (0.32 g,
2.32 mmol) in EtOH (10 ml) was stirred at room tem-
perature for 18 h before its concentration. The
residue was dissolved in H2O and EtOAc. The organ-
ic solution was separated, washed with brine, and
dried (Na2SO4). Concentration gave a crude unstable
hydroxy ester. To an ice-cooled solution of this
hydroxy ester in pyridine (10 ml) was added BzCl
(0.30 ml, 2.58 mmol). The reaction mixture was
stirred at room temperature for 18 h before additions
of sat. aq. NaHCO3 solution and CH2Cl2. The organ-
ic solution was separated, washed with brine, and
dried (Na2SO4). Concentration followed by silica gel
J
6.3
6.3 Hz,
6.3 Hz, OC HO-
6.3 Hz, OCH OMe),
＝
J
H
＝
H
J
H
＝
J
H
7.37–7.45 (6H, m, ArH), 7.65–7.68 (4H, m, ArH).
(5R,6R) and (5R,6S)-7-(tert-Butyldiphenylsilyl-
oxy)-6-(methoxymethoxy)-5-heptanolide (20). A reac-
tion mixture of (2R)-cyclopentanone derivative 13
(2.92 g, 6.84 mmol), MCPBA (2.06 g, 11.9 mmol) in
a phosphate buŠer at pH 8 (50 ml) and CHCl3 (50 ml)
9
was stirred at 0 C for 18 h before addition of
Na2S2O3. The organic solution was separated,
washed with sat. aq. NaHCO3 solution and brine,
and dried (Na2SO4). Concentration followed by silica
column chromatography (1z EtOAc toluene) gave
W
(5
R
,6
R
)-ester 21 (1.14 g, 1.92 mmol, 82
20＝－
9.3 (c 1.18, CHCl3). NMR dH
z
) as a
colorless oil. [
a
]
D
gel column chromatography (10
z
EtOAc benzene)
(CDCl3): 1.03 (9H, s, tBu), 1.21 (3H, t,
OCH2C 3), 1.69–1.77 (3H, m), 1.89 (1H, m),
J 6.8 Hz,
＝
W
gave (5
52
R
,6
R
)-heptanolide 20 (1.58 g, 3.57 mmol,
H
20＝－
z
) as a colorless oil, [
a
]
D
19.5 (
c
0.36,
2.26–2.38 (2H, m, 2-H2), 3.30 (3H, s, OCH3),
3.75–3.82 (2H, m, 7-H2), 3.87 (1H, m, 6-H), 4.09
CHCl3), and (5
2.37 mmol, 35
0.30, CHCl3). (5
(CDCl3): 1.05 (9H, s, tBu), 1.71–1.98 (4H, m, 3-H2,
R
,6
S
)-heptanolide 20 (1.05 g,
20＝－
＝
＝
J
z
) as a colorless oil, [
a
]
16.6
(2H, q,
6.6 Hz, OC
OCH OMe), 5.40 (1H, ddd,
5-H), 7.22 (2H, d,
m, ArH), 7.55 (1H, dd,
J
6.8 Hz, OC
H
2CH3), 4.67 (1H, d,
6.6 Hz,
7.8, 4.4, 4.4 Hz,
7.3 Hz, ArH), 7.30–7.43 (6H,
7.3, 7.3 Hz, ArH), 7.60
D
(
c
R
,6
R
)-heptanolide 20. NMR dH
H
HOMe), 4.73 (1H, d, J
＝
＝
J
H
＝
＝
J
4-H2), 2.42 (1H, ddd,
2.58 (1H, ddd, 18.1, 5.4, 5.4 Hz, 2-H
(3H, s, OCH3), 3.68 (1H, m, 6-H), 3.80 (1H, dd,
10.7, 4.9 Hz, 7- H), 3.89 (1H, dd, 10.7, 5.4 Hz,
7-H ), 4.57 (1H, ddd, 11.2, 3.9, 3.9 Hz, 5-H),
4.64 (1H, d, HOMe), 4.70 (1H, d,
6.8 Hz, OCH OMe), 7.37–7.43 (6H, m, ArH),
J
18.1, 8.3, 7.3 Hz, 2-
H
H),
J
＝
H
), 3.33
J
＝
＝
＝
＝
7.8 Hz, ArH),
7.3 Hz, ArH). NMR dC (CDCl3):
J
(2H, d,
J
7.8 Hz), 7.66 (2H, d,
J
H
J
＝
8.00 (2H, d, J
＝
＝
H
H
J
14.2, 19.1, 21.0, 26.7, 29.6, 34.0, 55.8, 60.2, 63.2,
73.3, 78.2, 96.8, 127.6, 127.7, 128.3, 129.6, 129.69,
129.72, 130.2, 132.9, 133.0, 133.20, 135.5, 165.9,
＝
J
6.8 Hz, OC
J
＝
H
7.65–7.69 (4H, m, ArH). NMR dC (CDCl3): 18.6,
19.2, 24.0, 26.8, 29.6, 55.8, 62.7, 78.6, 79.4, 96.8,
127.7, 129.8, 133.0, 133.2, 135.5, 135.6, 171.1. IR
173.2. IR
nmax (CHCl3): 2934, 1720, 1717, 1275, 1113,
1036, 1026 cm－
.
Anal. Found: C, 69.06; H, 7.66z.
1
Calcd. for C34H44O7Si: C, 68.89; H, 7.48
z
. (5R,6S)-
20＝＋
9.9 (c 1.00, CHCl3).
nmax (CHCl3): 2948, 1728, 1244, 1107, 1053, 1030,
ester 21, 92
NMR
7.3 Hz, OCH2CH
z
yield, [
a
]
D
911 cm－
.
Anal. Found: C, 67.74; H, 7.91
z
R
. Calcd.
,6 )-hep-
tanolide 20. NMR dH (CDCl3): 1.05 (9H, s, tBu),
d
H (CDCl3): 1.05 (9H, s, tBu), 1.21 (3H, t,
J
＝
1
for C25H34O5Si: C, 67.84; H, 7.74
z. (5
S
3), 1.68–1.85 (4H, m, 3-H2, 4-H2),
2.28–2.35 (2H, m, 2-H2), 3.30 (3H, s, OCH3),
3.75–3.82 (2H, m, 7-H2), 3.97 (1H, m, 6-H), 4.09
＝
J
1.72–1.85 (3H, m), 1.91 (1H, m), 2.42 (1H, ddd,
＝
＝
＝
J
16.0, 9.3, 6.8 Hz, 2-
H
H), 2.58 (1H, ddd,
J
16.0,
(2H, q,
J
7.3 Hz, OC
H
2CH3), 4.67 (1H, d,
6.6 Hz,
6.0, 5.4 Hz, 2-H ), 3.29 (3H, s, OCH3), 3.67 (1H,
H
6.6 Hz, OC
H
HOMe), 4.72 (1H, d, J
＝

Synthetic Study of 5-HETE
1967
＝
OCH
5-H), 7.31–7.44 (8H, m, ArH), 7.55 (1H, dd,
7.3 Hz, ArH), 7.64–7.70 (4H, m, ArH), 8.00 (2H, d,
H
OMe), 5.39 (1H, ddd,
J
8.8, 3.4, 3.4 Hz,
5.28 (1H, m, 5-H), 7.43–7.47 (2H, m, ArH), 7.58
(1H, m, ArH), 8.03–8.04 (2H, m, ArH). NMR dC
(CDCl3): 14.2, 20.8, 29.7, 33.8, 55.9, 60.3, 62.0,
73.0, 81.3, 97.0, 128.4, 129.7, 129.8, 133.2, 166.2,
＝
J
7.3,
＝
J
7.3 Hz, ArH). NMR dC (CDCl3): 14.2, 19.1, 21.1,
26.7, 29.0, 34.0, 55.7, 60.2, 63.4, 73.8, 78.2, 96.4,
127.69, 127.73, 128.3, 129.65, 129.69, 129.8, 130.3,
132.9, 133.1, 133.2, 135.59, 135.62, 165.9, 173.2. IR
173.1. IR
nmax (CHCl3): 3503, 2896, 1721, 1273, 1115,
1026 cm－
.
Anal. Found: C, 61.17; H, 7.53
z
.
1
Calcd. for C18H26 O7: C, 61.00; H, 7.39
cohol 22, [
cohol 22, [
z. (5
S
,6
S
)-al-
)-al-
20＝－
nmax (CHCl3): 2934, 1721, 1717, 1273, 1113, 1034,
a
a
]
34.2 (
c
1.00, CHCl3). (5
20＝＋
9.7 (c, 1.54, CHCl3).
S
,6
R
D
1028 cm－
.
Anal. Found: C, 69.11; H, 7.65
z
S S)-
)-ester
.
]
1
D
Calcd. for C34H44O7Si: C, 68.89; H, 7.48
z
. (5
,6
20＝＋
ester 21, [
a
]
9.3 (
c
1.09, CHCl3). (5
1.02, CHCl3).
S
,6
R
(5R)-Ethyl 5-benzoyloxy-5-formylpentanoate (
2).
D
20＝－
21, [
a
]
9.9 (
c
To an ice-cooled solution of (5 ,6 )-alcohol 22
R R
D
(0.60 g, 1.69 mmol) in CH2Cl2 (20 ml) was added
TMSBr (0.24 ml, 1.82 mmol). After the reaction
solution was stirred at 0 C for 1 h, sat. aq. NaHCO3
9
Determination of the enantiomeric excess of
(5S,6S), (5S,6R), (5R,6R) and (5R,6S)-ester 21. The
enantiomeric excess was determined by using DICEL
solution was added. The organic solution was sepa-
rated, washed with brine, and dried (Na2SO4). Con-
centration gave crude glycol. The reaction mixture of
the crude glycol and NaIO4 (0.39 g, 1.82 mmol) in
MeOH (15 ml) was stirred at room temperature for
2 h before concentration. The residue was dissolved
in EtOAc and H2O. The organic solution was sepa-
rated, washed with brine, and dried (Na2SO4).
Concentration followed by silica gel column chro-
CHIRALPAC AD-H [(5
S
,6
,6
R
S
) and (5
) and (5
R
,6
R
)-ester 21,
2
2
z
z
EtOH hexane, (5
S
R
,6
S
)-ester 21,
W
2-propanol hexane, 1.0 ml min, detected at 254
W
W
nm]. (5
S
,6
)-ester 21, retention time 6.5 min, 99
)-ester 21, retention time 6.9 min, 99
)-ester 21, retention time 9.8 min, 99
S
)-ester 21, retention time 5.9 min, 99
z
z
z
ee.
ee
ee
ee
(5
(5
(5
S
,6
R
R
R
,5
,6
R
S
z
(5R,6R) and (5R,6S)-Ethyl 5-benzoyloxy-7-
hydroxy-6-(methoxymethoxy)heptanoate (22). To an
matography (10
z
EtOAc toluene) gave (5
R
)-alde-
W
hyde 2 (0.36 g, 1.29 mmol, 76
z
) as a colorless oil.
ice-cooled solution of (5
0.88 mmol) and AcOH (56
(10 ml) was added (
R
,6
R
m
)-silyl ether 21 (0.52 g,
l, 0.98 mmol) in THF
-Bu)4NF (0.88 ml, 1
From (5
R
,6
S
)-alcohol 22, (5
R)-aldehyde 2 was also
obtained in 74
z
yield. [
a
]
2D0＝＋48.3 (
c
0.15, CHCl3),
7)
M
in THF,
[
a
]
20＝＋
7.3 Hz, OCH2C
35 in lit. NMR dH (CDCl3): 1.25 (3H, t, J
＝
n
D
0.88 mmol). The reaction solution was stirred at
room temperature for 60 h before additions of sat.
aq. NaHCO3 solution and EtOAc. The organic solu-
tion was separated, washed with brine, and dried
(Na2SO4). Concentration followed by silica gel
H3), 1.83–1.92 (2H, m), 1.92–2.04
＝
(2H, m), 2.40 (2H, t,
J
7.3 Hz, 2-H2), 4.13 (2H, q,
＝
＝
8.1,
J
7.3 Hz, OC
H
2CH3), 5.24 (1H, dd,
J
4.7 Hz, 5-H), 7.46–7.50 (2H, m, ArH), 7.62 (1H, m,
ArH), 8.09–8.11 (2H, m, ArH), 9.64 (1H, s, CHO).
NMR dC (CDCl3): 14.2, 20.5, 28.2, 33.6, 60.5, 78.3,
128.5, 129.0, 129.8, 129.9, 133.6, 166.1, 172.8,
column chromatography (5
z
EtOAc toluene) gave
W
)-alcohol 22 (0.31 g, 0.87 mmol, 98
(5
R
,6
R
z
) as a
20＝＋
colorless oil. [
a
]
34.2 (
c
0.15, CHCl3). NMR dH
7.3 Hz, OCH2C 3),
198.1. IR
n
max (CHCl3): 3031, 2988, 2932, 1725, 1271,
D
(CDCl3): 1.23 (3H, t,
J
＝
H
1113, 1098, 1071, 1026, 909 cm－1. HRMS (FAB) m z
W
(M＋ H): Calcd. for C15H19O5, 279.1232; found,
＋
1.68–1.77 (2H, m), 1.80–1.86 (2H, m), 2.33–2.36
(2H, m, 2-H2), 3.05 (1H, dd,
J
＝
6.8, 6.8 Hz, OH),
279.1236. (5
CHCl3), [
S
)-aldehyde 2, [a] c 0.35,
2D0＝－48.3 (
15)
20＝－
46 in lit.
3.41 (3H, s, OCH3), 3.66–3.71 (2H, m, 7-H2), 3.77
a
]
D
＝
(1H, m, 6-H), 4.11 (2H, q,
4.71 (1H, d, 6.8 Hz, OC
6.8 Hz, OCH
J
H
7.3 Hz, OC
H2CH3),
J
＝
HOMe), 4.76 (1H, dd,
Baeyer-Villiger oxidation of (2R)-cyclohexanone
＝
J
H
OMe), 5.33 (1H, m, 5-H),
derivative 23 and determination of the enantiomeric
7.43–7.47 (2H, m, ArH), 7.58 (1H, m, ArH),
8.05–8.07 (2H, m, ArH). NMR dC (CDCl3): 14.2,
21.0, 29.6, 33.8, 55.9, 60.3, 62.0, 73.4, 81.5, 97.5,
excess. A reaction mixture of (2R)-cyclopentanone
derivative 23 (1.08 g, 2.52 mmol, a diastereomeric
mixture of 1:1), MCPBA (0.87 g, 5.04 mmol) in a
phosphate buŠer at pH 8 (10 ml) and CHCl3 (10 ml)
127.7, 128.4, 129.8, 133.2, 166.5, 173.1. IR nmax
(CHCl3): 3500, 2955, 1721, 1275, 1113, 1026 cm－
.
was stirred at 09C for 18 h before addition of
1
Anal. Found: C, 61.50; H, 7.63
z
. Calcd. for
)-alcohol 22,
0.21, CHCl3). NMR dH
7.3 Hz, OCH2C 3),
Na2S2O3. The organic solution was separated,
washed with sat. aq. NaHCO3 solution and brine,
and dried (Na2SO4). Concentration followed by silica
C18H26O7: C, 61.00; H, 7.39
z
. (5R,6S
20＝－
9.7 (c
92
z
yield. [
a
]
D
(CDCl3): 1.23 (3H, t,
J
＝
H
gel column chromatography (EtOAc hexane 1 3)
＝
W W
1.65–1.89 (4H, m, 3-H2, 4-H2), 2.33–2.36 (2H, m,
2-H2), 2.90 (1H, m, OH), 3.42 (3H, s, OCH3), 3.68
(1H, m, 5-H), 3.75–3.80 (2H, m, 7-H2), 4.11 (2H, q,
gave recovered 22 (0.40 g, 0.93 mmol, 37
(5 ,6R S)-24 (0.50 g, 1.12 mmol, 44 , a diastereo-
meric mixture of 1:1) as a colorless oil. Anal. Found:
C, 75.23; H, 7.65 . Calcd. for C28H30O5: C, 75.31;
H, 6.77 . A reaction mixture of (5 ,6R S)-24
z) and
R
z
W
＝
OC
＝
H
J
7.3 Hz, OC
H
2CH3), 4.74 (1H, d,
J
6.8 Hz,
OMe),
z
H
HOMe), 4.77 (1H, d,
J
＝
6.8 Hz, OCH
z
R
W

1968
S. YAMAUCHI et al.
2) Zeng, Z.-Z., Yellaturu, C. R., Neeli, I., and Rao, G.
N., 5( )-Hydroxyeicosatetraenoic acid stimulates
DNA synthesis in human microvascular endothelial
(0.50 g, 1.12 mmol) and K2CO3 (0.19 g, 1.37 mmol)
in EtOH (10 ml) was stirred at room temperature for
18 h before concentration. The residue was dissolved
in H2O and EtOAc. The organic solution was
separated, washed with brine, and dried (Na2SO4).
Concentration gave a crude unstable hydroxy ester.
To an ice-cooled solution of this hydroxy ester
in pyridine (10 ml) was added BzCl (0.16 ml,
1.38 mmol). The reaction mixture was stirred at
room temperature for 18 h before additions of sat.
aq. NaHCO3 solution and CH2Cl2. The organic
solution was separated, washed with brine, and dried
(Na2SO4). Concentration followed by silica gel
S
cells via activation of jak STAT and phos-
W
phatidylinositol 3-kinase akt signaling, leading to
W
induction of expression of basic ˆbroblast growth
factor 2. J. Biol. Chem., 277, 41213–41219 (2002).
3) Gueugnot, S., Alami, M., Linstrumelle, G., Mambu,
L., Petit, Y., and Larcheveque, M., An e‹cient total
synthesis of 5-(
6635–6646 (1996).
S
)-HETE. Tetrahedron
,
52,
4) Tao, C., and Donaldson, W. A., Reactivity of tricar-
bonyl(pentadienyl)iron(1 ) cations: enantioselective
＋
synthesis of 5-HETE methyl ester. J. Org. Chem., 58,
2134–2143 (1993).
5) Shimazaki, T., Kobayashi, Y., and Sato, F.,
Stereospeciˆc total synthesis of dimorphecolic acid,
＝
column chromatography (EtOAc hexane 1 3) gave
W
W
(5
oil and (5
colorless oil. (5
R
,6
R
)-25 (0.21 g, 0.35 mmol, 31
z
) as a colorless
R
,6
S
)-25 (0.23 g, 0.39 mmol, 35
,6
7.3 Hz, OCH2C
3-H2, 4-H2), 2.21–2.31 (2H, m, 2-H2), 3.23 (1H, dd,
z
) as a
5(
S)-HETE, and 12(S)-HETE. Chem. Lett.,
R
R
)-25. NMR dH (CDCl3): 1.20
3), 1.57–1.72 (4H, m,
1785–1788 (1988).
＝
(3H, t,
J
H
6) Nicolaou, K. C., Ladduwahetty, T., TaŠer, I. M.,
and Zipkin, R. E., A general strategy for the synthesis
of monohydroxyeicosatetraenoic acids. Total synthe-
J
＝
(1H, dd,
4.07 (2H, q,
6.8 Hz, OC
10.3, 5.9 Hz, 7-
H
H), 3.31 (3H, s, OCH3), 3.33
＝
J
10.3, 4.9 Hz, 7-H
H
), 3.91 (1H, m, 6-H),
sis of 5(
S
)-hydroxy-6(
E
),8,11,14(
Z
)-eicosatetraenoic
),10( )-
＝
＝
J
7.3 Hz, OC
H
2CH3), 4.70 (1H, d,
J
acid (5-HETE) and 12(
S
)-hydroxy-5,8,14(
Z
E
＝
6.8 Hz,
eicosatetraenoic acid (12-HETE). Synthesis, 344–347
(1986).
H
HOCH3), 4.76 (1H, d,
J
OCHHOCH3), 5.39 (1H, m, 5-H), 7.16–7.26 (11H,
7) Zamboni, R., and Rokach, J., Stereospeciˆc synthe-
m, ArH), 7.38–7.44 (6H, m, ArH), 7.55 (1H, m,
sis of 5
to 5-(
(1983).
8) Corey, E. J., and Hashimoto, S., A practical process
for large-scale synthesis of ( )-5-hydroxy-6-trans
S-HETE, 5R-HETE, and their transformation
ArH), 7.93–7.95 (2H, m, ArH). Anal. Found: C,
±
)-HPETE. Tetrahedron Lett., 24, 999–1002
74.58; H, 7.77
6.76 . 83
AD-H, 1.0 ml min, detected at 254 nm, 5
z. Calcd. for C37H40O7: C, 74.47; H,
z
z
ee determined by DICEL CHIRALPAC
2-PrOH
)-25. NMR dH (CDCl3): 1.20 (3H, t,
7.3 Hz, OCH2C 3), 1.54–1.63 (4H, m, 3-H2,
4-H2), 2.25–2.28 (2H, m, 2-H2), 3.26 (1H, dd,
4.9, 3.7 Hz, 7- H), 3.30–3.33 (1H, m, 7-H ), 3.32
(3H, s, OCH3), 4.03–4.10 (3H, m, OC 2CH3, 6-H),
4.67 (1H, d, 6.6 Hz, OC HOCH3), 4.74 (1H, d,
6.6 Hz, OCH OCH3), 5.37 (1H, m, 5-H),
z
W
S
-
hexane. (5R,6S
W
8,11,14-cis-eicosatetraenoic acid (5-HETE). Tetrahe-
dron Lett., 22, 299–302 (1981).
＝
J
H
＝
J
9) Corey, E. J., Albright, J. O., Barton, A. E., and
Hashimoto, S., Chemical and enzymic syntheses of 5-
HPETE, a key biological precursor of slow-reacting
substance of anaphylaxis (SRS), and 5-HETE. J. Am.
Chem. Soc., 102, 1435–1436 (1980).
H
H
H
J
＝
H
＝
J
H
10) Yamauchi, S., Takeda, K., Ganaha, M., and
7.18–7.28 (11H, m, ArH), 7.38–7.44 (6H, m, ArH),
Kinoshita, Y., Synthesis of (
R
)-6,7-dihydro-5-HETE
7.53 (1H, m, ArH), 7.91–7.93 (2H, m, ArH). Anal.
lactone and
(
S)-6,7-dihydro-5-HETE lactone by
Found: C, 74.27; H, 7.60
74.47; H, 6.76 . 96
CHIRALPAC AD-H, 1.0 ml min, detected at
z
. Calcd. for C37H40O7: C,
using novel yeast reduction as a key reaction. J.
Chem. Soc. Perkin Trans. 1, 2156–2160 (2002).
z
z
ee determined by DICEL
W
11) Vedejs, E., and Larsen, S., Hydroxylation of enolates
with oxodiperoxymolybdenum(pyridine)(hexamethyl-
254 nm, 5
z 2-PrOH hexane.
W
･
･
phosphoric triamide), MoO5 Py HMPA (MoOPH):
3-hydroxy-1,7,7-trimethylbicyclo[2.2.1]heptan-2-
one. Org. Synth., Coll. Vol. VII, 277–282 (1990).
12) Chaudhary, S. K., and Hernandez, O., 4-
Dimethylaminopyridine: an e‹cient and selective
catalyst for the silylation of alcohols. Tetrahedron
Lett., 99–102 (1979).
Acknowledgments
We measured the 400 MHz NMR data in
Advanced Instrumentation Center For Chemical
Analysis Ehime University. We thank the staŠ of this
center for the FAB measurements. We are grateful to
Marutomo Co. for ˆnancial support.
13) Kusama, H., Hara, R., Kawahara, S., Nishimori, T.,
Kashima, H., Nakamura, N., Morihira, K., and
Kuwajima, I., Enantioselective total synthesis of
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