Efficient and practical synthesis of both enantiomers of 3-phenylcyclopentanol derivatives

Article abstract of DOI:10.1016/S0040-4020(02)01090-6

An efficient, multigram scale synthesis of the respective optical isomers of 3-(substituted-phenyl) cyclopentanols was achieved by a lipase-catalyzed transesterification (kinetic resolution) in organic medium. This enzymatic reaction proceeded with great

Full text of DOI:10.1016/S0040-4020(02)01090-6

Tetrahedron 58 (2002) 8729–8736
Efficient and practical synthesis of both enantiomers of
3-phenylcyclopentanol derivatives
Yoshiyuki Okumura,a Akemi Ando,a Rodney William Stevensa and Makoto Shimizub
,
*
aDepartment of Medicinal Chemistry, Pfizer Global Research and Development, Nagoya, 5-2 Taketoyo, Aichi 470-2393, Japan
bDepartment of Chemistry for Materials, Mie University, Tsu, Mie 514-8507, Japan
Received 29 July 2002; accepted 27 August 2002
Abstract—An efficient, multigram scale synthesis of the respective optical isomers of 3-(substituted-phenyl) cyclopentanols was achieved
by a lipase-catalyzed transesterification (kinetic resolution) in organic medium. This enzymatic reaction proceeded with great efficiency as
measured by chemical yield and enantioselectivity. The racemic cis-alcohol 3 was successfully resolved to yield (1R,3S)-acetate 7 and the
corresponding (1S,3R)-alcohol 3. The utility of this procedure was demonstrated by the practical syntheses of the biologically active
compounds. The (1R,3S)-acetate 7 and the (1S,3R)-alcohol 3 were converted into orally active 5-lipoxygenase inhibitors, respectively,
without loss of optical purity. q 2002 Published by Elsevier Science Ltd.
1. Introduction
exploiting an enzyme-catalyzed transesterification (kinetic
resolution) of 3-substituted phenyl cyclopentanol, employ-
ing porcine pancreas lipase (PPL).
5-Lipoxygenase,1 (5-LO) is an enzyme that metabolizes
arachidonic acid to a group of biologically active lipids
known as leukotrienes. The leukotrienes are extremely
potent substances that elicit a wide variety of biological
effects,2 often at nano-molar to pico-molar concentrations.
An agent that selectively inhibits the action of 5-LO is
expected to have therapeutic value for the treatment of acute
and chronic inflammatory conditions.3 Already, the thera-
peutic benefits of 5-LO inhibitors have been demonstrated
for asthma.4
2. Results and discussion
2.1. Diastereoselective reduction of the chiral
cyclopentenone 2
Many efforts have been devoted to the development of
efficient methodologies for the preparation of enantiomeri-
cally pure 3-arylcyclopentanones. A successful approach,
developed by Posner,6a utilizes a neighboring group effect to
direct the stereoselectivity at the anomeric center. An
efficient catalytic process has recently been reported by
Miyaura and Hayashi and involves the rhodium-catalyzed
1,4-addition of phenylboronic acid to 2-cyclopentene-1-one
with excellent enantioselectivity and in high yield.6a,c
Previously, we reported on a series of substituted N-
cyclopentyl-N-hydroxyureas, 1a and 1b (Fig. 1).5 These
compounds, prepared as racemates, exhibited good potency
as 5-LO inhibitors, both in vitro and in vivo. The
preliminary biological evaluations of each enantiomer,
isolated in small amounts (,20 mg) using chiral HPLC,
indicate that the (þ)-enantiomer is substantially more potent
than the corresponding (2)-enantiomer.
To prepare the desired 3-arylcyclopentanols, the diastereo-
selective reduction of optically active 3-arylcyclopentanone6
Further detailed investigations required an efficient, multi-
gram scale synthesis of each enantiomer. Optically active 3-
substituted phenyl cyclopentanols were chosen as the key
synthetic intermediates. We wish to report here the first
asymmetric synthesis of the respective optical isomers by
Keywords: 5-lipoxygenase inhibitors; kinetic resolution; lipase-catalyzed
transesterification; optically active-3-phenylcyclopentanol derivatives.
*
Corresponding author. Tel./fax: þ81-59-231-9413; e-mail:
mshimizu@chem.mie-u.ac.jp
Figure 1. 1,5-Lipoxygenase inhibitors.
0040–4020/02/$ - see front matter q 2002 Published by Elsevier Science Ltd.
PII: S0040-4020(02)01090-6

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Y. Okumura et al. / Tetrahedron 58 (2002) 8729–8736
The requisite cis-alcohol 3 was readily prepared from 3-
aryl-2-cyclopenten-1-one10 in four steps, as illustrated
below (Scheme 2). Thus, the chemoselective 1,2-
reduction11 of cyclopentenone 5 with NaBH4 –CeCl3
followed by immediate allylic alcohol. The direct hydro-
genation of the allylic alcohol was unsuccessful, however,
in constrast, silylation of the hydroxyl group provided the
formation of desired 6 in quantitative yield. Fluoride ion
mediated desilylation of 6 gave a 10:1 diastereomeric
mixture of cis-3 and trans-4, respectively. Pure cis-alcohol 3
was then obtained after column chromatography.
Scheme 1. Reagents: (a) DIBAL, toluene, 2788C or LiAl[OtBu]3H, THF,
2788C.
was initially investigated. Disappointingly, hydride reduction
of 3-phenylcyclopentanone,7 (2a) did not proceed with good
diastereoselectivity for either the cis or trans-alcohol. Even
when DIBAL or LiA1[OtBu]3H was used as the reducing
agent, at low temperature, the diastereoselectivity of the
reduction was not satisfactory (cis-3a: trans-4a¼,3:1)
(Scheme 1). Furthermore, it was difficult to obtain preparative
quantities of a single diastereomer from a ,3:1 mixture of 3a
and 4a by column chromatography.
For the transesterification of (^)-cis-3, stereoselectivity and
activity screening of several commercially available lipases
was carried out using vinyl acetate as an irreversible acyl
transfer reagent (vinyl alcohol undergoes irreversible
tautomerisation to acetaldehyde). The results are summar-
ized in Table 1. Among the lipases examined, Pseudomonas
cepacia lipase (Amano PS) and PPL exhibited good
stereoselectivity (entries 1, 2, 5, and 6), while Pseudomonas
fluorescens lipase (L 056P) gave unsatisfactory results
(entries 3 and 7). In the case of Candida rugosa lipase
(Amano AY), the transesterification did not progress and the
racemic starting material (^)-cis-3 was recovered (entries 4
and 8). In the PPL mediated transesterification, excellent
selectivity for both (^)-cis-3a and 3b was achieved.
Notably, PPL was superior to Amano PS since only the
favored antipode acetylated, while the unfavored antipode
showed almost no reaction during the 4 h incubation (entries
1 vs 2 and 5 vs 6). The resulting cis-acetates 7a (97% ee,
E¼134) and 7b (.98% ee, E¼298) were isolated in high
2.2. Enzymatic transesterification of the cis-3-arylcyclo-
pentan-1-o1 3
As an alternative approach, the lipase-catalyzed kinetic
resolution of pure cis-3-phenylcyclopentan-1-ol (3) was
explored. Biocatalysts are powerful tools for the preparation
of chiral compounds that are not obtained easily by
conventional chemical asymmetric synthesis.8 In particular,
lipase-catalyzed transesterification in organic media is
considered to be a practical method to prepare large
quantities of optically active alcohols.9
Table 1. Enzymatic resolution of (^)-cis-3
Entry
3
X
Lipase
Time
(h)
(þ)-7, % ee
(2)-3, % ee
(% yield)a
Eb
(% yield)a
1
2
3
4
5
6
7
8
a
a
a
a
b
b
b
b
a
b
a
H
H
H
H
F
F
F
F
H
F
Amano PS
PPL
L 056P
Amano AY
Amano PS
PPL
L 056P
Amano AY
PPL
PPL
PPL
4
4
4
4
4
4
4
4
83 (50)
97 (37)
90 (39)
(0)
93 (24)
.98 (29)
78 (34)
(0)
96 (39)
68 (51)
79 (44)
(93)
39 (64)
41 (63)
nd (32)
(95)
42
134
46
–
40
298
–
–
180
259
317
9
10
11c
24
24
24
95 (48)
96 (48)
.98 (30)
98 (42)
.98 (44)
47 (58)
H
a
Isolated yield.
E ¼ ln½1 2 cð1 þ eepÞ=ln½1 2 cðð1 2 eepÞ; c¼eea/eesþeep; cfs. Ref. 9b and 12.
b
c
Transesterification was performed without hexane.
Scheme 2. Reagents: (a) NaBH4, CeCl3, MeOH; (b) TBDMSCl, imidazole, DMF; (c) H2, Pd–C (5%), MeOH; (d) Bu4NF, THF; (e) column chromatography.

Y. Okumura et al. / Tetrahedron 58 (2002) 8729–8736
8731
Scheme 3. Reagents: (a) K2CO3, MeOH; (b) PCC, CH2Cl2.
relative stereochemistry (1R p,3S p) at C(1) and C(3) of 3-
phenylcyclopentanol (3a) was assigned by comparing the
1H and 13C NMR chemical shift data of 3a with those
reported in the literature.13 Next, (þ)-7a was converted to
2a (Scheme 3) and compared with known material to
determine the absolute configuration at C(3). The hydrolysis
of acetate (þ)-7a (78% ee) was easily carried out with
K2CO3 in methanol to give alcohol (þ)-3a. The secondary
hydroxyl group of alcohol (þ)-3a was then oxidized with
pyridinium chlorochromate (PCC) in dichloromethane to
generate the desired 3-phenylcyclopentanone (2a). The sign
of the optical rotation of the ketone 2a ([a]D¼261.48 (c
0.68, CHCl3)) was the same as the literature value for (3S)-
3-phenylcyclopentanone ([a]D¼284.98 (c 0.72, CHCl3)).14
Therefore, the acetylated product (þ)-7a had the (1R,3S)
configuration, and the stereogenic reaction center had a (1R)
configuration.
Figure 2. Key PNOESY experiments (_) of 3b and 4b in CDCl3.
yield (34 and 37%, respectively). Also, in the reaction
without hexane, the cis-acetate 7a (.98% ee, E¼317) was
obtained in 30% yield (entry 11). In 24 h reactions, both
(^)-cis-3a and 3b gave optically active cis-3a (98% ee,
E¼180) and 3b (.98% ee, E¼259) in high yield (42 and
44%, respectively). It seems that a prolonged reaction time
does not have a negative effect on the stereoselectivity and
the undesired acetate is scarcely observed, even after 24 h
(entries 9 and 10).
In the case of acetate (þ)-7b, the relative configuration of
the hydroxyl and p-fluorophenyl group in 3b was deter-
mined by a comparison of the phase sensitive NOESY
spectra of 3b with its diastereomer 4b. An NOE interaction
was observed between the protons at C(l) and C(3) of
cyclopentane ring for 3b and no such interaction was
observed for 4b (Fig. 2). Therefore, the alcohol 3b has the
cis-stereochemistry (1R p,3S p) at C(l) and C(3).
2.3. Determination of the stereochemistry of
cyclopentanols 3a and 3b
The absolute configuration of the stereogenic center C(1)
was determined by the application of the advanced
Mosher’s method, using MaNP [2-methoxy-2-(1-
naphthyl)propionic acid] as a chiral anisotropic reagent.15
The absolute configuration of the acetylated product (þ)-7a
was determined by the following two steps. First, the cis-
Figure 3. 1H NMR assignment of MaNP ester and chemical shift difference (dR2dS).
Scheme 4. Reagents: (a) PhCO2H, DEAD, PPh3, THF; (b) NaOH aq., MeOH; (c) HN(Boc)OBoc, DEAD, PPh3, THF; (d) trifluoroacetic acid, CH2Cl2;
(e) TMSNCO, THF.

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Y. Okumura et al. / Tetrahedron 58 (2002) 8729–8736
The requisite MaNP esters, were prepared by acylation of
(þ)-3b (obtained after hydrolysis of the acetate (þ)-7b)
with (R) and (S)-MaNP acid in the presence of DCC and
DMAP. Their proton chemical shifts were assigned by
COSY and phase sensitive NOESY, and the chemical shift
difference (dR2dS) for each corresponding proton was
calculated as shown in Fig. 3. Looking at the molecule from
MaNP direction, the chemical shift differences of the right-
hand side of MaNP plain are positive and those of the other
side are negative. Therefore the MaNP ester should have a
b-direction (R-configuration). Hence, the resolved stereo-
genic center C(1) of acetate (þ)-7b would also have a (1R)
configuration. In conjunction with the stereochemical
assignment of the cis-stereochemistry of 3b, these results
confirmed the (1R,3S) configuration of acetylated product
(þ)-7b. The absolute stereochemistry of (2)-3b was also
determined as (1S,3R) in the same manner, in which the
positive and negative sides to MaNP plain were opposite to
those in (þ)-3b case.
mediated synthesis provides an additional example of one of
the more powerful methods for the practical preparation of
optically pure chiral synthons for the construction of
biologically important molecules.
4. Experimental
4.1. General methods
Instruments. Proton nuclear magnetic resonance (1H NMR)
spectra were recorded on a JEOL JNM-LA 270 spec-
trometer system at 270 MHz. Carbon nuclear magnetic
resonance (13C NMR) spectra were recorded on a JEOL
JNM-LA 270 spectrometer system at 67.8 MHz. Chemical
shifts are reported as d values in ppm from tetramethylsilane
as internal standard. COSY and phase sensitive NOESY
spectra were recorded on a Bruker AVANCE 600 NMR
spectrometer system at 600 MHz with standard 5 mm probe
or 2.5 mm micro-probe. IR spectra were recorded on a
Shimadzu IR-470 infrared spectrometer. Low-resolution
mass spectra (ESI) were recorded on a Waters/Micromass
ZMD mass spectrometer. High resolution mass spectra (EI)
were recorded on a JEOL JMS-700 spectrometer (MStation)
with direct inlet mode, and reported in m/z. Optical rotations
were measured using a JASCO DIP-370 Digital Polari-
meter. All melting points were measured in open capillary
tubes with Bu¨ch 535 or 520 apparatus and are uncorrected.
Elemental analyses (CHN) were carried out on a Thermo
Finnigan elemental analyzer EA 1110.
2.4. Application to large scale synthesis
On large-scale, the simplicity of the reaction resulted in an
efficient resolution. Under optimized conditions, the kinetic
resolution of 55.8 g of cis-3-(4-fluorophenyl)cyclopentanol
(3b) for 4 h provided 26.6 g of (þ)-(1R,3S)-3-(4-fluorophe-
nyl)cyclopentyl acetate (7b), that showed excellent enan-
tiomeric purity (.98% ee). (1R,3S)-Acetate (þ)-7b was
easily hydrolyzed by means of K2CO3 in methanol to yield
21.7 g (39% from (^)-3b) of (1R,3S)-alcohol (þ)-3b. Re-
incubation of the recovered intact cis-alcohol 3b (32.1 g)
into the reaction medium, followed by 24 h of transester-
ification, afforded 25.4 g (46% from (^)-3b) of (1S,3R)-
alcohol (2)-3b, that showed excellent enantiomeric purity
(.98% ee).
Materials. Reactions were monitored by thin-layer chro-
matography carried out on 0.25 mm silica gel coated glass
plates 60 F254 (Merck, Art5719). For flash column
chromatography, Merck Silicagel 60 (230–400 mesh
ASTM) was used. C. rugosa lipase (Amano AY) and P.
cepacia lipase (Amano PS) were supplied by Amano
Pharmaceutical CO., Ltd. Porcine pancrease lipase (PPL)
(EC 3.1.1.3) was obtained from Sigma. P. fluorescens lipase
(L 056P) was obtained from BIOCATALYSTS LTD.
Anhydrous tetrahydrofuran (THF) and dichloromethane
(CH2Cl2) were purchased from Wako Pure Chemical
Industries, Ltd. All other materials were purchased from
Nacalai Tesque, Inc, Tokyo Kasei Kogyo Co, Ltd, Wako
Pure Chemical Industries, Ltd, and Aldrich Chemical Co,
Inc and were used as received.
2.5. Conversion to the biologically active compound
After having secured the requisite optically active inter-
mediate alcohols, elaboration to the respective target
compounds proved uneventful. Thus, double inversion of
(1R,3S)-alcohol (þ)-3 employing Mitsunobu’s procedure16
((1) PhCO2H, PPh3–DEAD (2) hydrolysis (3) HN(Boc)O-
Boc, PPh3 –DEAD)) gave an excellent yield of the
corresponding di-Boc protected hydroxylamine 8. Acid
hydrolysis of the tert-butoxycarbonyl functionality
(trifluoroacetic acid in CH2Cl2) and subsequent treatment
with trimethylsilylisocyanate furnished the desired
hydroxyurea (þ)-1. The corresponding (2)-enantiomer,
(2)-1, was synthesized in an analogous manner to prepare
hydroxyurea (þ)-1 from (1S,3R)-alcohol 3 (Scheme 4).
4.1.1. tert-Butyl[[cis-3-(4-fluorophenyl)cyclopentyl]oxy]-
dimethylsilane (6b). To a cooled (08C) mixture of 3-(4-
fluorophenyl)cyclopent-2-en-l-one10c (5b; 96 g, 546 mmol)
and cerium (III) chloride heptahydrate (208 g, 560 mmol) in
MeOH (2000 ml) was added NaBH4, (21.2 g, 560 mmol) in
small portions over a 30 min period. The mixture was
allowed to warm to room temperatue and stirred for 1 h. The
reaction was quenched by the addition of ice-cold water
(500 ml), and then the volatiles were removed under
reduced pressure. The residue was extracted with EtOAc
(1000 ml). The organic extracts were washed with brine
(300 ml), dried over Na2SO4, and concentrated in vacuo to
yield 97 g of the corresponding 3-(4-fluorophenyl)cyclo-
pent-2-en-l-ol as yellow solids.
3. Conclusion
Both enantiomers of cis-3-(substituted-phenyl)cyclopentan-
ols have been obtained in optically active form by a lipase-
catalyzed transesterification in organic medium. The
enzyme catalyst, PPL, is readily available, inexpensive,
and environmentally benign and can be used under mild
reaction conditions. Additionally, the derived cyclopentan-
ols can easily be transformed into the corresponding
cyclopentanones without loss of optical purity. This enzyme
To a cooled (08C) solution of the allylic alcohol (97 g) in

Y. Okumura et al. / Tetrahedron 58 (2002) 8729–8736
8733
anhydrous DMF (400 ml) was added successively imidazole
4.2. General procedure of lipase-catalyzed
transesterification
(38.1 g, 560 mmol) and tert-butyldimethylsilyl chloride
(84.4 g, 560 mmol). The mixture was stirred at room
temperature for 3 h. The reaction mixture was diluted with
EtOAc (1000 ml). The whole mixture was washed with
water (500 ml), 1N-HCl (500 ml), saturated aqueous
NaHCO3 (500 ml), and brine (300 ml). The organic phase
was dried over Na2SO4, and concentrated to afford 142 g of
the corresponding tert-buty1[[3-(4-fluorophenyl)cyclopent-
2-en-l-yl]oxy]dimethylsilane as a brown oil.
˚
A mixture of powdered 4 A molecular sieves (30 mg), (^)-
cis-cyclopentanol (3, 0.3 mmol), and vinyl acetate (2 ml) in
hexane (2 ml) was stirred at room temperature for 10 min.
To this mixture was added a powder of lipase (20 mg) in one
portion. The reaction mixture was stiffed vigorously at room
temperature. After an appropriate time, the reaction mixture
was filtered through a pad of celite, and the filtrate was
concentrated in vacuo to afford a crude mixture. The
mixture was separated by silica-gel column chromatography
to afford corresponding acetate (7) and unacetylated alcohol
(3).
A suspension of the silylated cyclopentenol and 5% Pd/C
(10 g) in EtOAc (400 ml) was stirred under H2 atmosphere
for 8 h. The catalyst was removed by filtration, and the
filtrate was concentrated under reduced pressure to afford
138.5 g (86% for three steps) of tert-butyl[[3-(4-fluorophe-
nyl)-cyclopentyl]oxy]dimethylsilane (6b) as a pale yellow
oil: 1H NMR (CDCl3) d 7.29–7.20 (m, 2H), 6.95 (t,
J¼8.8 Hz, 2H), 4.41–4.30 (m, 1H), 3.06–2.93 (m, 1H),
2.38–2.26 (m, 1H), 2.07–1.91 (m, 1H), 1.88–1.72 (m, 3H),
1.67–1.55 (m, 1H), 0.91 (s, 9H), 0.07 (s, 6H); HRMS (EI)
calcd for C17H26OFSi (M2H)þ 293.1737, found 293.1726.
4.2.1. (1)-(1R,3S)-3-(4-Fluorophenyl)cyclopentyl acetate
(7b) and (2)-(1S,3R)-3-(4-fluorophenyl)cyclopentanol
˚
(3b). A mixture of powdered 4 A molecular sieves
(33.6 g), (^)-cis-3-(4-fluorophenyl)cyclopentanol (3b;
55.8 g, 310 mmol), and vinyl acetate (2240 ml) in hexane
(2240 ml) was stirred for 10 min at room temperature. To
this mixture was added PPL, (Sigma, Lipase from Porcine
Pancreas; 22.4 g) in small portions. The reaction mixture
was stirred vigorously at room temperature. After 4 h, the
reaction mixture was filtered through a pad of celite, and the
filtrate was concentrated in vacuo to afford a crude mixture.
The mixture was separated by silica-gel column chroma-
tography (SiO2, 1700 g; hexane/EtOAc (10/1 and then 3/1))
to afford 26.6 g (39%) of optically pure (.98% ee) (þ)-
(1R,3S)-3-(4-fluorophenyl)cyclopentyl acetate (7b) as a
colorless oil and 32.1 g of an unreacted alcohol 3b. The
optical purity of the acetate 7b was determined by chiral
HPLC analysis (column, CHIRALCEL OJ-H; eluent,
hexane/2-propanol (95/5); flow rate, 0.5 ml/min; tR
13.0 min (1R,3S) and 14.6 min (1S,3R)): (þ)-(1R,3S)-7b
(.98% ee); [a]D¼þ16.68 (c 1.00, EtOH); 1H NMR
(CDCl3) d 7.24–7.15 (m, 2H), 6.98 (t, J¼8.8 Hz, 2H),
5.28–5.18 (m, 1H), 3.12–296 (m, 1H), 2.61–2.49 (m, 1H),
2.12–1.60 (m, 5H), 2.06 (s, 3H); HRMS (EI) calcd for
C13HI5O2F 222.1056, found 222.1062.
4.1.2. tert-Butyl[cis-3-phenylcyclopentyl)oxy]dimethyl-
silane (6a). tert-Butyl[(cis-3-phenylcyclopentyl)oxy]-
dimethylsilane (6a) was prepared from the corresponding
3-phenyl-2-cyclopenten-1-one10a,b (5a) in 86% yield as a
light brown oil in a similar manner as described for the
1
preparation of cis-6b: H NMR (CDCl3) d 7.34–7.10 (m,
5H), 4.41–4.26 (m, 1H), 3.07–2.94 (m, 1H), 2.34–2.20 (m,
1H), 2.17–1.56 (m, 5H), 0.90 (s, 9H), 0.08 (s, 6H); HRMS
(EI) calcd for C17H28OSi 276.1910, found 276.1910.
4.1.3. cis-3-(4-Fluorophenyl)cyclopentanol (3b). To a
cooled (08C) solution of tert-butyl[[3-(4-fluorophenyl)-
cyclopentyl]oxy]dimethylsilane (6b, 9.4 g, 30 mmol) in
THF (100 ml) was added a solution of n-Bu4NF (1 M
solution in THF, 40 ml). The reaction mixture was stirred
for 1 h at room temperature. The mixture was diluted with
EtOAc (100 ml). The whole mixture was washed with brine
(100 ml), dried over or MgSO4, and concentrated in vacuo.
Purification of the residue by column chromatography
(SiO2, 300 g, hexane/EtOAc (3/1)) afforded 4.5 g (83%) of
cis-3-(3-fluorophenyl)cyclopentan-1-ol (3b) as a colorless
oil and 615 mg (11%) of diastereomeric mixture
The recovered alcohol (32.1 g) was subjected to the above
mentioned reaction conditions for 24 h. An analogous work-
up and purification by silica-gel column chromatography
(SiO2, 800 g; hexane/EtOAc (2/1)) gave 25.4 g (46% from
racemate) of optically pure (.98% ee) (2)-(1S,3R)-3-(4-
fluorophenyl)cyclopentanol (3b) as a colorless oil and 7.2 g
(10%) of 97% ee (þ)-(1R,3S)-3-(4fluorophenyl)cyclopentyl
acetate (7b) as a colorless oil. Cyclopentanol 3b could not
be separated by chiral HPLC under a variety of conditions,
and hence the optical purity was determined from the
derived acetate 7b, that was obtained from 3b by the
treatment with Ac2O, pyridine, and DMAP in CH2Cl2: (2)-
1
(cis/trans¼1:1) of 3b: cis-3b; H NMR (CDCl3,) d 7.23
(dd J¼8.8, 5.4 Hz, 2H), 6.96 (t, J¼8.8 Hz, 2H), 4.50–4.38
(m, 1H), 3.52–2.94 (m, 1H), 2.52–2.37 (m, 1H), 2.08–1.77
(m, 4H), 1.68–1.53 (m, 2H); 13C NMR (CDCl3) d 161.2 (d,
J¼242 Hz), 141.3 (d, J¼3 Hz), 128.5 (d, J¼8 Hz), 115.0 (d,
J¼21 Hz), 73.5, 44.1, 43.5, 36.0, 32.8; HRMS (EI) calcd for
C11H13NOF 180.0950, found 180.0955.
1
4.1.4. cis-3-Phenylcyclopentanol (3a). cis-3-Phenylcyclo-
pentanol (3a) was prepared from the corresponding tert-
butyl[(cis-3-phenylcyclopentyl)oxy]dimethylsilane (6a) in
78% yield as a colorless oil in a similar manner as described
for the preparation of cis-3b: 1H NMR (CDCl3) d 7.38–7.13
(m, 5H), 4.51–4.40 (m, 1H), 3.13–2.99 (m, 1H), 2.52–2.40
(m, 1H), 2.11–1.60 (m, 6H); 13C NMR (CDCl3) d 145.65,
128.34, 127.13, 125.94, 73.65, 44.23, 44.00, 36.06, 32.63;
HRMS (EI) calcd for C11H13NOF 162.1045, found
162.1027.
(1S,3R)-3b (.98% ee); [a]D¼28.18 (c 1.00, EtOH); H
NMR (CDCl3) d 7.28–7.19 (m, 2H), 6.94 (t, J¼8.8 Hz, 2H),
4.50–4.39 (m, 1H), 3.12–2.96 (m, 1H), 2.62–2.48 (m, 1H),
2.10–1.54 (m, 6H).
4.2.2. MaNP esters of (1)-3b and (2)-3b. Cyclopentanol
(þ)-3b (0.50 mg, 2.8 mmol) was treated with 10 mmol of
(S)-MaNP [2-methoxy-2-(1-naphthyl)propionic acid],
10 mmol of DCC, and 10 mmol of DMAP in 2000 ml of
CH2Cl2, at room temperature, for 22 h. Purification by

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Y. Okumura et al. / Tetrahedron 58 (2002) 8729–8736
1
preparative TLC afforded the pure (S)-MaNP ester of (þ)-
3b (0.84 mg, 2.1 mmol): Rf¼0.55 (CHCl3); 1H NMR
(600 MHz, CDCl3) d 8.40 (1H, m), 7.85 (1H, br d,
J¼8.1 Hz), 7.82 (1H, m), 7.6), 6.81 (2H, t, J¼8.7 Hz),
6.64 (2H, dd, J¼8.6, 5.4 Hz), 5.23 (1H, m), 3.12 (3H, s), 6
(1H, dd, J¼7.2, 1.0 Hz), 7.52 (1H, dd, J¼8.1, 7.4 Hz), 7.45
(1H, m), 7.44 (1H, m), 2.84 (1H, m), 2.33 (1H, ddd, J¼14.7,
10.0, 6.3 Hz), 2.00 (3H, s), 1.60 (3H, m), 1.41 (1H dddd,
J¼12.6, 7.6, 2.7, 1.27 Hz), 0.68 (1H, m).
(2)-(1S,3R)-3a (98% ee); [a]D¼28.78 (c 1.00, EtOH); H
NMR (CDCl3) d 7.36–7.12 (m, 5H), 4.51–4.41 (m, 1H),
3.13–2.97 (m, 1H), 2.51–2.40 (m, 1H), 2.10–1.57 (m, 6H).
4.2.4. (2)-(S)-3-Phenylcyclopentanone (2a).14 To a solu-
tion of 78% ee (þ)-3-phenylcyclopentyl acetate (7a; 86 mg,
0.42 mmol) in MeOH (5 ml) was added K2CO3 (300 mg,
2.2 mmol) in one portion. The mixture was stirred at room
temperature for 3 h. The volatiles were removed under
reduced pressure, and the residue was diluted with 30 ml of
water. The aqueous mixture was extracted with EtOAc
(50 ml). The organic phase was washed with brine (30 ml),
dried over MgSO4, and concentrated in vacuo to afford
70 mg of crude (þ)-3-phenylcyclopentanol (3a).
The pure (R)-MaNP ester (0.88 mg, 2.2 mmol) was also
obtained from (þ)-3b in a similar manner as described for
1
the preparation of (S)-MaNP ester: Rf¼0.55 (CHCl3); H
NMR (600 MHz, CDCl3) d 8.41 (1H, m), 7.88 (1H br d,
J¼8.1 Hz), 7.87 (1H, m), 7.65 (1H, dd, J¼72, 1.0 Hz), 7.51
(1H, dd, J¼8.1, 7.4 Hz), 7.46 (1H, m), 7.45 (1H, m), 6.76
(2H, t, J¼8.7 Hz), 6.55 (2H, dd, J¼8.6, 5.4 Hz), 5.29 (1H,
tt, J¼6.5, 3.0 Hz), 3.10 (3H, s), 2.84 (1H, br pent.,
J¼8.1 Hz), 2.30 (1H ddd, J¼14.7, 9.6, 6.5 Hz), 2.00 (3H,
s), 1.84 (1H, m), 1.79 (1H, m), 1.74 (1H, m), 1.25 (1H, m),
1.13 (1H, dddd, J¼14.8, 8.4, 3.0, 1.4 Hz).
To a suspension of pyridinium chlorochromate (PCC)
(135 mg, 0.63 mmol) in dry CH2Cl2 (2 ml) was added a
solution of the alcohol (þ)-3a in dry CH2Cl2 (2 ml). The
mixture was stirred vigorously at room temperature for 2 h.
The reaction mixture was suspended in diethyl ether (50 ml)
and then passed through a short Florisil (Nacalai Tesque,
60–100 mesh) column. The solvent was removed from the
eluate to furnish 63 mg (94%) of 3-phenylcyclopentanone
The (S)-MaNP ester (0.89 mg, 2.3 mmol) and (R)-MaNP
ester (0.85 mg, 2.2 mmol) of (2)-3b were also prepared in a
similar manner. The 1H NMR spectrum of the MaNP esters
was perfectly identical to that of the corresponding
enantiomers.
1
(2a) as a colorless oil: [a]D¼261.48 (c 0.68, CHCl3); H
NMR (CDCl3) d 7.39–7.20 (m, 5H), 3.53–3.34 (m, 1H),
2.74–2.63 (m, 1H), 2.60–2.23 (m, 1H), 2.35–1.61 (m, 1H).
The spectral data are identical with those in the literature.14
4.2.3. (1)-(1R,3S)-3-Phenylcyclopentyl acetate (7a) and
(2)-(1S,3R)-3-phenylcyclopentanol (3a). A mixture of
4.2.5. (1)-(1S,3S)-3-(4-Fluorophenyl)cyclopentanol (4b).
To a solution of (þ)-(1R,3S)-3-(4-fluorophenyl)cyclopentyl
acetate (7b; 379 mg, 1.7 mmol) in MeOH (50 ml) was
added K2CO3 (1.2 g, 8.5 mmol). The reaction mixture was
stirred for 3 h at room temperature. The volatiles were
removed under reduced pressure, and the residue was
diluted with 100 ml of water. The aqueous mixture was
extracted with EtOAc (100 ml). The organic layer was
washed with brine (50 ml), dried over MgSO4, and
concentrated in vacuo to afford crude (þ)-(1R,3S)-3-(4-
fluorophenyl)cyclopentanol (3b).
˚
powdered 4 A molecular sieves (300 mg) and (^)-cis-3-
phenylcyclopentanol (3a; 400 mg, 2.5 mmol) in vinyl
acetate (20 ml) was stirred at room temperature for
10 min. To this mixture was added PPL (200 mg), and the
reaction mixture was stirred vigorpusly at room temperature
for 24 h (entry 11). The reaction mixture was then diluted
with chloroform (50 ml) and filtered through a pad of celite.
The filtrate was concentrated in vacuo to afford a crude
mixture. The mixture was separated by silica-gel column
chromatography (SiO2, 20 g; hexane/EtOAc (10/1 and then
3/1)) to afford 152 mg (30%) of optically pure (.98% ee)
(þ)-(1R,3S)-3-phenylcyclopentyl acetate (7a) as a colorless
oil (the optical purity of 7a was determined after hydrolysis
to 3a) and 232 mg (58%) of 47% ee (2)-(1S,3R)-
cyclopentanol 3a as a colorless oil. The optical purity of
the alcohol 3a was determined by chiral HPLC analysis
(column, CHIRALPAK AD-H; eluent, hexane/EtOH
(95/5); flow rate, 1.0 ml/min; tR 9.2 min (1R,3S) and
To a stirred solution of the alcohol (þ)-(1R,3S)-3b (299 mg,
1.7 mmol), benzoic acid (224 mg, 2.0 mmol), and triphe-
nylphosphine (525 mg, 2.0 mmol) in THF (25 ml) was
added dropwise diethyl azodicarboxylate (435 mg,
2.5 mmol) in THF (5 ml) at 08C under an argon atmosphere.
The mixture was stirred for 1 h at room temperature, and
then the volatiles were removed under reduced pressure.
The residue was suspended in Et2O, and insoluble material
was removed by filtration. The ether layer was concentrated
in vacuo to afford crude (1S,3S)-3-(4-fluorophenyl)cyclo-
pentyl benzoate.
10.4 min
(1R,3S)):
(þ)-(1R,3S)-7a
(.98%
ee):
1
[a]D¼þ19.08 (c 1.00, EtOH); H NMR (CDCl3) d 7.35–
7.22 (m, 5H), 5.30–5.18 (m, 1H), 3.22–2.99 (m, 1H), 2.63–
2.50 (m, 1H), 2.05 (s, 3H), 2.12–1.71 (m, 5H); HRMS (EI)
calcd for C13H16O2 204.1150, found 204.1133.
To a solution of the crude benzoate (1.2 g, 1.7 mmol) in
MeOH (30 ml) was added an aqueous solution of KOH
(560 mg in 5 ml of water). The mixture was stirred for 12 h
at room temperature. The volatiles were removed under
reduced pressure, and the residue was diluted with water
(50 ml). The aqueous mixture was extracted with EtOAc
(100 ml). The organic layer was washed with brine (50 ml),
dried over MgSO4, and concentrated in vacuo. The residual
oil was purified by flash chromatography (SiO2, 80 g;
hexane/EtOAc (2/1)) to afford 245 mg (80%) of (þ)-
(1S,3S)-3-(4-fluorophenyl)cyclopentanol (4b) as a colorless
˚
A mixture of powdered 4 A molecular sieves (150 mg), (^)-
cis-3a (200 mg, 1.2 mmol), and vinyl acetate (10 ml) in
hexane (10 ml) was stirred at room temperature for 10 min.
To this mixture was added PPL (100 mg), and the reaction
mixture was stirred vigorously at room temperature for 24 h
(entry 9). An analogous work-up and purification afforded
84 mg (42%) of 98% ee (2)-(1S,3R)-3-phenylcyclopenta-
nol (3a) as a colorless oil and 121 mg (48%) of 95% ee (þ)-
(1R,3S)-3-phenylcyclopentyl acetate (7a) as a colorless oil:

Y. Okumura et al. / Tetrahedron 58 (2002) 8729–8736
8735
oil. The optical purity, determined by HPLC analysis
(column, CHIRALPAK AS; eluent, hexane/2-propanol
(95/5); flow rate, 0.5 ml/min; tR 16.1 min (1S,3S) and
17.9 min (1R,3R)), was .98% ee: [a]D¼þ11.48 (c 1.00,
removed under reduced pressure, and the residue was
diluted with HtOAc (50 ml). The organic layer was washed
with water (30 ml), sat. aqueous NaHCO3 solution (30 ml),
and brine (50 ml). The organic layer was dried over MgSO4
and concentrated in vacuoto afford crude (1R,3S)-3-(4-
fluorophenyl)cyclopentylhydroxylamine as white solids.
1
EtOH); H NMR (CDCl3) d 7.18 (dd, J¼8.7, 5.4 Hz, 2H),
6.97 (t, J¼8.7 Hz, 2H), 4.56–4.50 (m, 1H), 3.45–3.30 (m,
1H), 2.31–2.12 (m, 2H), 2.12–2.02 (m, 1H), 1.85–1.47 (m,
4H); 13C NMR (CDCl3) d 161.2 (d, J¼242 Hz), 141.0 (d,
J¼3 Hz), 128.3 (d, J¼8 Hz), 115.0 (d, J¼20 Hz), 73.6, 44.4,
42.2, 35.6, 32.7; HRMS (EI) calcd for C11H13NOF
180.0950, found 180.0952.
To a solution of the crude hydroxylamine (234 mg,
1.2 mmol) in THF (10 ml) was added trimethylsilyl
isocyanate (0.3 ml, 2.0 mmol) at room temperature. The
reaction mixture was stirred for 30 min. Volatiles were
removed under reduced pressure, and the residue was
purified by silica gel column chromatography (SiO2, 30 g;
CHCl3/acetone (3/2)). Recrystallization from EtOAc
afforded 142 mg (50%) of (þ)-N-[(1R,3S)-3-(4-Fluorophe-
nyl)cyclopentyl]-N-hydroxyurea (1b) as a white powder.
The optical purity, determined by HPLC analysis (column,
CHIRALCEL OJ; eluent, hexane/2-propanol (90/10); flow
rate, 0.5 ml/min; tR 13.1 min (1S,3R) and 17.6 min (1R,3S),
was .98% ee: [a]D¼þ22.28 (c 0.5, EtOH); mp 139.2–
4.2.6. (1)-(1S,3S)-3-Phenylcyclopentanol (4a). (þ)-
(1S,3S)-3-Phenylcycloperntanol (4a) was prepared from
the corresponding (þ)-(1R,3S)-3-phenylcyclopentyl acetate
(7a) in 74% yield as a colorless oil in a similar manner as
described for the preparation of (þ)-(1S,3S)-4b. The optical
purity, determined by HPLC analysis (column, CHIRAL-
CEL OG; eluent, hexane/2-propanol (90/10); flow rate,
0.5 ml/min; tR 12.9 min (1S,3S) and 14.8 min (1R,3R), was
.98% ee: [a]D¼þ12.78 (c 1.00, EtOH); 1H NMR (CDCl3)
d 7.37–7.14 (m, 5H), 4.56–4.49 (m, 1H), 3.48–3.30 (m,
1H), 2.35–2.06 (m, 3H), 1.90–1.53 (m, 4H); 13C NMR
(CDCl3) d 145.49, 129.33, 127.02, 125.92, 73.70, 44.27,
42.90, 35.69, 32.61; HRMS (EI) calcd for C11H13NOF
162.1045, found 162.1042.
140.28C; IR (KBr)
n 3400, 3250, 1650, 1620,
1510,1400,1220, 840 cm21; H NMR (DMSO-d6) d 9.09
(s, 1H), 7.31–7.24 (m, 2H), 7.10 (t, J¼9.0 Hz, 2H), 6.28 (s,
2H), 4.73–4.60 (m, 1H), 3.04–2.88 (m, 1H), 2.11–1.53 (m,
6H); MS (ESI) m/z 239 (MHþ), 237 ([M2H]2); Anal. calcd
for C12H15N2O2F: C, 60.49; H, 6.35; N, 11.76. Found: C,
60.18; K 6.33; N, 11.69.
1
4.2.7. N,O-Bis(tert-butoxycarbonyl)-N-[(1R,3S)-3-(4-
fluorophenyl)cyclopentyl] hydroxylamine (8b). To a
stirred solution of (þ)-(1S,3S)-3-(4-fluorophenyl)cyclopen-
tanol (4b; 245 mg, 1.4 mmol), N,O-bis-(tert-butoxycarbon-
4.2.10. (2)-N-[(1S,3R)-3-(4-Fluorophenyl)cyclopentyl]-
N-hydroxyurea (1b). (2)-N-[(1S,3R)-3-(4-Fluorophenyl)-
cyclopenty1]-N-hydroxyurea (1b) was prepared from the
corresponding (2)-(1S,3R)-alcohol 3b as a white powder in
a similar manner as described for the ion of (þ)-(1R,3S)-1b.
The optical purity determined by HPLC analysis (column,
CMRALCEL OJ; eluent, hexane/2-propanol (90/10); flow
rate, 0.5 ml/min; tR 13.1 min (1S,3R) and 17.6 min (1R,3S)),
was .98% ee: [a]D¼222.48 (c 0.5, EtOH); mp 139.0–
140.48C; IR (KBr) n 3400, 3350, 1650, 1510, 1400, 1220,
950 cm21; 1H NMR (DMSO-d6) d 9.09 (s, 1H), 7.32–7.24
(m, 2H), 7.10 (m, 2H), 6.29 (br.s, 2H), 4.75–4.58 (m, 1H),
3.05–2.88 (m, 1H), 2.09–1.56 (m, 6H); MS (ESI) m/z 239
(MHþ), 237 ([M2H]2); Anal. calcd for C12H15N2O2F: C,
60.49; H, 6.35; N, 11.76. Found: C, 60.45; H, 6.50; N, 11.72.
yl)hydroxylamine
(400 mg,
1.7 mmol),
and
triphenylphosphine (450 mg, 1.7 mmol) in THF (25 ml)
was added dropwise diethyl azodicarboxylate (350 mg,
2.0 mmol) in THF (5 ml) at 08C under and argon
atmosphere. After completion of addition, the mixture was
stirred for 1 h at room temperature, an then the volatiles
were removed under reduced pressure. Chromatographic
removal of triphenylphosphine oxide provided 489 mg
(88%) of N,O-bis(tert-butoxycarbonyl)-N-[(1R,3S)-3-(4-
fluorophenyl)-cyclopentyl]hydroxylamine, (8b) as a pale
yellow oil: 1H NMR (CDCl3) d 7.24–7.16 (m, 2H), 6.97 (t,
J¼8.8 Hz, 2H), 4.81–4.62 (m, 1H), 3.09–2.88 (m, 1H),
2.42–2.22 (m, 1H), 2.10–1.35 (m, 23H). This material was
used for the next steps without further purification.
4.2.11. (1)-N-Hydroxy-N-[(1R,3S)-3-phenylcyclopentyl]
urea (1a). (þ)-N-Hydroxy-N-[(1R,3S)-3-phenylcyclo-
pentyl]urea (1a) was prepared from the corresponding N,O-
bis(tert-butoxycarbonyl)-N-[(1R,3S)-3-phenylcyclopentyl]hy-
droxylamine (8a) in 53% yield as a white powder in a similar
manner as described for the preparation of (þ)-(1R,3S)-1b.
The optical purity, determined by HPLC analysis (column,
CHIRALCEL OJ; eluent, hexanen/2-propanol (80/20); flow
rate, 1.0 ml/min; tR 7.0 min (1S,3R) and 12.0 min (1R,3S)),
was .98% ee: [a]D¼þ26.28 (c 0.5, EtOH); mp 126.1–
126.98C; IR (KBr) n 3480, 3350, 3300, 1810, 1580, 1450,
1150, 1070, 760, 700 cm21; 1H NMR (DMSO-d6) d 9.10 (s,
1H), 7.31–7.16 (m, 5H), 6.28 (s, 2H), 4.70–4.60 (m, 1H),
2.95–2.90 (m, 1H), 2.06–1.58 (m, 6H); MS (ESI) m/z 221
(MHþ), 219 ([M2H]2); Anal. calcd for C12Hl6N2O2: C,
65.43; H, 7.32; N, 12.72. Found: C, 65.18; M 7.41; N, 12.41.
4.2.8. N,O-Bis(tert-butoxycarbonyl)-N-[(1R,3S)-3-phe-
nylcyclopentyl]hydroxylamine(8a). N,O-Bis(tert-butoxy-
carbonyl)-N-[(1R,3S)-3-phenylcyclopentyl]-hydroxylamine
(8a) was prepared from the corresponding (þ)-(1S,3S)-3-
phenylcyclopentanol (4a) in 91% yield as yellow oil in a
1
similar manner as described for the preparation of 8b: H
NMR (CDCl3) d 7.38–7.17 (m, 5H), 4.80–4.65 (m, 1H),
3.12–2.93 (m, 1H), 2.53–2.28 (m, IH), 2.11–1.65 (m, 5H),
1.50–1.40 (m, 18H). This material was used for the next
steps without further purification.
4.2.9. (1)-N-[(1R,3S)-3-(4-Fluorophenyl)cyclopentyl]-N-
hydroxyurea (1b). To a stirred solution of N,O-bis(tert-
butoxycarbonyl)-N-[(1R,3S)-3-(4-fluorophenyl)-cyclopen-
tyl]hydroxylamine (8b; 489 mg, 1.2 mmol) in CH2Cl2
(10 ml) was added trifluoroacetic acid (4 ml). The mixture
was stirred for 1 h at room temperature. The volatiles were
4.2.12. (2)-N-Hydroxy-N-[(1S,3R)-3-phenylcyclopentyl]
urea (1a). (2)-N-Hydroxy-N-[(1S,3R)-3-phenylcyclopen-

8736
Y. Okumura et al. / Tetrahedron 58 (2002) 8729–8736
Y.; Ogasawara, M.; Hayashi, T. Tetrahedron Lett. 1999, 40,
6957. (d) Kuriyama, M.; Tomioka, K. Tetrahedron Lett. 2001,
42, 921. (e) Estevan, F.; Herbst, K.; Lahuerta, P.; Barberis, M.;
Perez-Prieto, J. Organometallics 2001, 20, 950. (f) Funk, R. L.;
Yang, G. Tetrahedron Lett. 1999, 40, 1073. (g) Wang, Y.;
Gladysz, J. A. J. Org. Chem. 1995, 60, 903. (h) Barnhart,
R. W.; Wang, X.; Noheda, P.; Bergens, S. H.; Whelan, J.;
Bosnich, B. J. Am. Chem. Soc. 1994, 116, 1821. (i)
Nakashima, H.; Sato, M.; Taniguchi, T.; Ogasawara, K.
Tetrahedron Lett. 2000, 41, 2639.
tyl]urea (1a) was prepared from the corresponding (2)-
(1S,3R) alcohol 3a as a white powder in a similar manner as
described for the preparation of (þ)-(1R,3S)-1a. The optical
purity, determined by HPLC analysis (column, CHIRAL-
CEL OJ; eluent, hexane/2-propanol (80/20); flow rate,
1.0 ml/min; tR 7.0 min (1R,3S) and 12.0 min (1R,3S)), was
.98% ee: [a]D¼227.28 (c 0.5, EtOH); mp 125.8–126.88C;
IR (KBr) n 3480, 3350, 3300, 1610, 1580, 1450, 1150, 1070,
760, 700 cm21; 1H NMR (DMSO-d6) d 9.12 (s, 1H), 7.31–
7.16 (m, 5H), 6.28 (s, 2H), 4.70–4.60 (m, 1H), 2.93–2.88
(m, 1H), 2.10–1.55 (m, 6H); MS (ESI) m/z 221 (MHþ), 219
([M2H]2); Anal. calcd for C12Hl6N2O2: C, 65.43; H, 7.32;
N, 12.72. Found: C, 65.24; H 7.41; N, 12.39.
7. Kolobielski, M.; Pines, H. J. Am. Chem. Soc. 1957, 79, 5820.
8. For recent reviews regarding the use of enzymes in organic
synthesis see: (a) Roberts, S. M. J. Chem. Soc., Perkin Trans. 1
1998, 157. (b) Schmid, R. D.; Verger, R. Angew. Chem., Int.
Ed. 1998, 37, 1608. (c) Bornscheuer, U. T.; Kazlauskas, R. J.
Hydrolases in Organic Synthesis. Wiley-VCH: Weinheim,
1999. (d) Roberts, S. M. Biocatalysts for Fine Chemicals
Synthesis. Wiley: Chichester, 1999. (e) Stereoselctive Bio-
catalysis. Patel, R. N., Ed.; Marcel Dekker: New York, 1999.
(f) Roberts, S. M. J. Chem. Soc., Perkin Trans. 1 1999, 1. (g)
Svendsen, A. Biochem. Biophys. Acta 2000, 223. (h) Roberts,
S. M. J. Chem. Soc., Perkin Trans. 1 2000, 611. (i) Theil, F.
Tetrahedron 2000, 56, 2905. (j) Roberts, S. M. J. Chem. Soc.,
Perkin Trans. 1 2001, 1475. (k) Drauz, K.; Waldmann, H.
Enzyme Catalysis in Organic Synthesis. 2nd ed. Wiley-VCH:
Weinheim, 2002.
Acknowledgements
We are grateful to Amano Pharmaceutical Co., Ltd. for the
generous gift of lipases. We also thank Hideo Hirai and
Shinichi Sakemi (Structural Sciences Department, PGRD
Nagoya Laboratories) for NMR experiments, and Yoko
Matsuoka (Pharmaceutical and Analytical R&D Depart-
ment, PGRD Nagoya Laboratories) for analytical support.
References
9. (a) Cambou, B.; Klibanov, A. M. J. Am. Chem. Soc. 1984, 106,
2687. (b) Chen, C.-S.; Sih, C. J. Angew. Chem., Int. Ed. Engl.
1989, 28, 695. (c) Klibanov, A. M. Acc. Chem. Res. 1990, 23,
114. (d) Burgess, K.; Jennings, L. D. J. Am. Chem. Soc. 1991,
112, 6129. (e) Fang, J.-M.; Wong, C.-H. Synlett 1994, 393. (f)
Carrea, G.; Riva, S. Angew. Chem., Int. Ed. 2000, 39, 2226.
10. (a) Farnum, D. G.; Mostashari, A.; Hagedo, A. A. J. Org.
Chem. 1971, 36, 699. (b) Borsche, W.; Menz, W. Ber. 1908,
41, 190. (c) Jefford, C. W.; Kohmoto, S.; Jaggi, D.; Timari, G.;
Rossier, J.-C.; Rudaz, M.; Barbuzzi, O.; Gerard, D.; Burger,
U.; Kamalaprija, P.; Mareda, J.; Bernardinelli, G.; Manznares,
I.; Canfield, C. J.; Flock, S. L.; Robinson, B. L.; Peters, W.
Helv. Chim. Acta 1995, 78, 647.
1. (a) Samuelsson, B. Science 1983, 220, 568. (b) Lewis, R. A.;
Austen, K. F.; Soberman, R. J. New Engl. J. Med. 1990, 323,
645.
2. Henderson, Jr. W. R. J. Allergy Clin. Immunol. 1987, 79, 543.
3. (a) Masamune, H.; Melvin, Jr. L. S. Annu. Rep. Med. Chem.
1989, 24, 71. (b) Jackson, W. T.; Fleisch, J. H. Prog. Drug Res.
1996, 46, 115.
4. (a) Israel, E.; Rubin, P.; Kemp, J. P.; Grossman, J.; Pierson,
W.; Siegel, S. C.; Tinkelman, D.; Murray, J. J.; Busse, W.;
Segal, A. T.; Fish, J.; Kaiser, H. B.; Ledford, D.; Wenzel, S.;
Rosenthal, R.; Cohn, J.; Lanni, C.; Pearlman, H.; Karahalios,
P.; Drazen, J. M. Ann. Int. Med. 1993, 119, 1059. (b) Israel, E.;
Fischer, A. R.; Rosenberg, M. W.; Lilly, C. M.; Callery, J. C.;
Shapiio, J.; Cohn, J.; Rubin, P.; Drazen, J. M. Am. Rev. Respir.
Dis. 1993, 148, 1447. (c) Israel, E. Ann. Allergy 1994, 72, 279.
(d) Brooks, C. D. W.; Summers, J. B. J. Med. Chem. 1996, 39,
2629.
11. Luche, J.-L. J. Am. Chem. Soc. 1978, 100, 2226.
12. Chen, C.-S.; Fujimoto, Y.; Girdaukas, G.; Sih, C. J. J. Am.
Chem. Soc. 1982, 104, 7294.
13. Janes, N. F.; Khambay, B. P. S. Magn. Reson. Chem. 1989, 27,
197.
5. (a) Ikeda, T.; Kawai, A.; Mano, T.; Okumura, Y.; Stevens,
R. W. PCT Int. Appl. 1992; WO 9209566. (b) Kawai, A.;
Ikeda T.; Stevens, R. W.; Mano, T.; Okumura, Y. Jpn. Kokai
Tokkyo Koho, 1993; JP 05170725. (c) Nakao, K.; Kawai, A.;
Stevens, R. W. PCT Int. Appl. 1993; WO 9321149.
6. (a) Posner, G. H.; Hulce, M. Tetrahedron Lett. 1984, 25, 379.
(b) Takaya, Y.; Ogasawara, M.; Hayashi, T.; Sakai, M.;
Miyaura, N. J. Am. Chem. Soc. 1998, 120, 5579. (c) Takaya,
14. Paquette, L. A.; Gilday, J. P.; Ra, C. S. J. Am. Chem. Soc.
1987, 109, 6858.
15. (a) Ohtani, I.; Kusumi, T.; Kashman, Y.; Kakisawa, H. J. Am.
Chem. Soc. 1991, 113, 4092. (b) Harada, N.; Watanabe, M.;
Kuwahara, S.; Sugio, A.; Kasai, Y.; Ichikawa, A. Tetrahedron:
Asymmetry 2000, 11, 1249. Erratum 2000 11, 2843.
16. Mitsunobu, O. Synthesis 1981, 1.