Asymmetric synthesis of 5,6-dehydrosenedigitalene using lipase-catalyzed highly enantioselective transesterification of a primary alcohol with vinyl 3-(4-trifluoromethylphenyl)propanoate

Article abstract of DOI:10.1016/j.tetasy.2005.10.041

The highly enantioselective kinetic resolution of a racemic primary alcohol by lipase-catalyzed transesterification with vinyl 3-(4-trifluoromethylphenyl) propanoate afforded an enantiomerically pure primary alcohol. The versatility of this approach is sh

Full text of DOI:10.1016/j.tetasy.2005.10.041

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 16 (2005) 4065–4072
Asymmetric synthesis of 5,6-dehydrosenedigitalene using
lipase-catalyzed highly enantioselective transesterification of
a primary alcohol with vinyl 3-(4-trifluoromethylphenyl)propanoate
Masashi Kawasaki,a,* Yuko Hayashi,b Hiroko Kakuda,c Naoki Toyooka,d Akira Tanaka,b
Michimasa Goto,e Shigeki Kawabataa and Tadashi Kometanie
aDepartment of Liberal Arts and Sciences, Faculty of Engineering, Toyama Prefectural University, 5180 Kurokawa, Kosugi-Machi,
Toyama-Ken 939-0398, Japan
bDepartment of Bioresources Science, College of Technology, Toyama Prefectural University, 5180 Kurokawa, Kosugi-Machi,
Toyama-Ken 939-0398, Japan
cLaboratory of Chemistry, University of Toyama, 2630 Sugitani, Toyama 930-0194, Japan
dFaculty of Pharmaceutical Sciences, University of Toyama, 2630 Sugitani, Toyama 930-0194, Japan
eDepartment of Chemical and Biochemical Engineering, Toyama National College of Technology, 13 Hongo, Toyama 939-8630, Japan
Received 21 October 2005; accepted 28 October 2005
Abstract—The highly enantioselective kinetic resolution of a racemic primary alcohol by lipase-catalyzed transesterification with
vinyl 3-(4-trifluoromethylphenyl)propanoate afforded an enantiomerically pure primary alcohol. The versatility of this approach
is shown in the asymmetric synthesis of 5,6-dehydrosenedigitalene (R)-1.
ꢀ 2005 Elsevier Ltd. All rights reserved.
1. Introduction
the acylated lipase reacts with an alcohol, it is possible,
in principle, to achieve highly enantioselective transeste-
rification by the selection of suitable acyl donors.2
Lipase-catalyzed reactions play an important role in the
resolution of the racemates of alcohols.1 The lipase-cat-
alyzed transesterification in organic solvents is particu-
larly important in this field. In the presence of an acyl
donor, one enantiomer of a racemic alcohol can be selec-
tively transformed into the corresponding ester, while
the other remains unreacted in an enantiomerically pure
form. Although lipases can accept a wide range of alco-
hols, they do not always show a high enantioselectivity
in the resolution. Secondary alcohols are frequently
good targets, whereas the resolution of chiral primary
alcohols is more difficult to achieve.1
On the basis of this assumption, several studies have
previously shown that the moderately enantioselective
transesterifications of racemic alcohols with vinyl ace-
tate, which is used most frequently as an acyl donor,
were improved upon by using other vinyl esters.3–7
Recently, we reported the highly enantioselective trans-
esterification of 2-phenyl-1-propanol with a lipase (Amano
PS from Burkholderia cepacia, formerly Pseudomonas
cepacia) and vinyl 3-arylpropanoates.3,5 Although the
E-value8 with vinyl acetate was 5, the value was 116
for vinyl 3-(4-iodophenyl)propanoate and 138 for vinyl
3-(4-trifluoromethylphenyl)propanoate.3 This is the first
example that shows the utility of vinyl esters having
a bulky substituent for lipase-catalyzed transesterifica-
tion. In the same paper, we also reported that vinyl
3-phenylpropanoate is an efficient reagent for the
lipase-catalyzed transesterification of several 2-phenyl-
1-alkanols.3 In order to demonstrate the efficiency of
vinyl 3-arylpropanoates for the lipase-catalyzed trans-
esterification of 2-phenyl-1-alkanols, we applied this
During the transesterification, a lipase is initially acyl-
ated by an acyl donor such as a vinyl alkanoate and
the acylated lipase then reacts enantioselectively with
an alcohol.2 Chen and Sih have proposed that because
the acyl group of the acylated lipase exerts steric and/
or stereoelectronic effects on the process during which
*
Corresponding author. E-mail: kawasaki@pu-toyama.ac.jp
0957-4166/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2005.10.041

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M. Kawasaki et al. / Tetrahedron: Asymmetry 16 (2005) 4065–4072
method to the asymmetric synthesis of 5,6-dehydrosene-
digitalene (R)-1,9 a member of the norsesquiterpenes.
Lipase-catalyzed hydrolysis has been used for the
asymmetric syntheses of sesquiterpenes such as elvirol
(R)-210 and curcuphenol (R)-3;11,12 the chiral primary
alcohols, which were the synthetic intermediates, have
been prepared by lipase-catalyzed hydrolysis.
available (Scheme 1). Deprotonation of ethyl (4-methyl-
phenyl)acetate with LDA and the addition of 5-bromo-
1-pentene provided ethyl 2-(4-methylphenyl)-6-hepteno-
ate ( )-5 in 77% yield. Treatment of ( )-5 with LiAlH4
produced the racemic primary alcohol, 2-(4-methylphe-
nyl)-6-heptene-1-ol ( )-6, in 89% yield.
OH
OH
(R)-1
(R)-2
(R)-3
(R)-4
Compound (R)-1 was isolated from the aerial parts of
the South African Senecio digitalifolius by Bohlmann
and Zdero in 19789 and is structurally related to (R)-3
and a-curcumene (R)-4, constituents of a large number
of essential oils.13 It has been reported that (R)-3 exhib-
its weak antibacterial activities against Staphylococcus
aureus and Vibrio anguillarum,14 while the (S)-enantio-
mer has potent antimicrobial activities against Candida
albicans et al.15 and inhibits the activity of gastric H+,
K+-ATPase.16 There are many reports on the asymmet-
ric syntheses of 4, which is quite structurally related to
(R)-1. Chemical methods using stoichiometric chiral
materials such as chiral sulfoximine,17 citronellal,18,19
1,1-binaphthalene-8,8-diol,20 t-leucinol,21 zingiberene
isolated from ginger,22 chiral 5-trimethylsilyl-2-cyclo-
hexenone,23 chiral N,N-dimethyllactamide,24 and D-man-
nitol25 have been reported. Catalytic procedures, which
are more practical, using asymmetric hydrovinylation,26
reductive esterification,27 boron reduction,28 bakerÕs
yeast-mediated reduction,29,30 Sharpless epoxida-
tion,31,32 cinchonidine-catalyzed Michael addition,33
and Grignard cross-coupling34 have also been reported.
However, several reports of the catalytic procedures do
not describe any enantiomeric excesses (ees) of 4 and the
ee from the bakerÕs yeast-mediated reduction approach,
the most efficient procedure for achieving high enantio-
meric excess in the final product, is 95%.29 Although
(R)-1 is an analogue of (R)-4, there is no report on the
asymmetric synthesis of (R)-1.35 In addition, the abso-
lute stereochemistry of (R)-1 has not yet been confirmed
by physical or chemical methods.
The most important point of the present synthesis is to
prepare 6 in an optically active form. We successfully
achieved this by using the Amano PS-catalyzed trans-
esterification of ( )-6 with vinyl 3-arylpropanoates. Ini-
tially, ( )-6 was subjected to screening experiments
(Table 1). While the lipase-catalyzed transesterification
of ( )-6 with vinyl acetate 7a in cyclohexane had an
E-value of 26 (entry 1), the reaction with vinyl 3-phenyl-
propanoate 7b had a higher enantioselectivity (E = 145,
entry 2). This result is consistent with our previous
report on the resolution of 2-phenyl-1-propanol.3,5 The
absolute configuration of the enantiomer preferentially
esterified by the lipase was thought to have the (S)-con-
figuration on the basis of the empirical rule for the enan-
tiopreference of the lipase.36 We then investigated the
effects of solvents on the enantioselectivity of the lipase
(entries 2–8), because the enantioselectivity of the lipase
was found to depend on the nature of the solvent.37 As a
result of the screening of solvents, we found that hexane
was the most suitable regarding the enantioselectivity
(E = 235) and reaction rate (entry 3). Finally, we tried
vinyl 3-(4-trifluoromethylphenyl)propanoate 7c, which
is a very efficient acyl donor for the lipase-catalyzed
transesterification of 2-phenyl-1-propanol, and obtained
the best result (E = 331, entry 9).
On the basis of these results, we conducted a large scale
resolution of ( )-6 with the lipase PS as the asymmetric
catalyst and 7c as the acyl donor in hexane. As we wanted
to obtain (R)-6 with an ee as high as possible, we con-
trolled the conversion of the reaction to exceed at least
34% (entry 9). With a rise of the conversion of the transe-
sterification, the ee of (R)-6 becomes higher theoretically,
Herein, we report the asymmetric synthesis of (R)-and
(S)-1 from the chiral primary alcohols prepared by
lipase PS-catalyzed transesterification with vinyl 3-(4-tri-
fluoromethylphenyl)propanoate in a highly optically
pure form (>99% ee).
while the ee of (S)-8 becomes lower.8 Thus, we obtained
24
(R)-6 with >99% ee {½aꢀD ¼ ꢁ12:6 (c 0.8, CHCl3)} in
40% yield and (S)-8c with 79% ee in 49% yield.
The enantiomerically pure (R)-6 obtained above was
converted to the corresponding methanesulfonate (R)-9
2. Results and discussion
1H NMR spectra data of (S)-8c showed that (S)-8c was contaminated
by 7c. The yields described here was estimated from the 1H NMR
analysis.
The first step in the sequence leading to (R)-1 was the
introduction of the 4-pentenyl group into the a-position
of ethyl (4-methylphenyl)acetate, which is commercially

M. Kawasaki et al. / Tetrahedron: Asymmetry 16 (2005) 4065–4072
4067
EtO
O
EtO
O
Br
LDA, HMPA
THF, -78oC
+
( )-5
(77%)
HO
LiAlH4
Et2O, reflux
( )-6
(89%)
Scheme 1.
Table 1. Lipase-catalyzed kinetic resolution of ( )-6a
HO
R
O
HO
O
Lipase PS
solvent, rt
O
+
+
O
R
( )-6
7a : R=Me
7b : R=CH2CH2C6H5
7c : R=CH2CH2C6H4-4-CF3
(S)-8
8a: R=Me
8b: R=CH2CH2C6H5
8c: R=CH2CH2C6H4-4-CF3
(R)-6
Entry
Acyl donor
Solvent
Cyclohexane
Cyclohexane
Hexane
Isooctane
Toluene
Acetone
THF
1,4-Dioxane
Hexane
Time (h)
Conversion (%)b
50
(S)-8 ee (%)
82
(R)-6 ee (%)
Eb
1
2
3
4
7ac
7b
7b
7b
7b
7b
7b
7b
7c
5.5
3.5
4.5
83
99
94
99
81
50
70
—
51
26
145
235
69
123
163
138
—
52
49
54
46
34
42
<1e
34
93
97
86
96
98
97
—
99
1.5
5
23.5
18.5
21
4.5
4.5
6d
7d
8
9
331
a Conditions: Lipase PS (20 mg/ml), ( )-6 (60 mM), acyl donor (60 mM), room temperature. All the solvents except isooctane were dried.
b Calculated from ees of (S)-8 and (R)-6.
c 7a (300 mM).
d Lipase PS (40 mg/ml).
e Determined by GC analysis.
with methanesulfonyl chloride and triethylamine in 84%
yield (Scheme 2). The synthesis of (R)-1 was finally
The 1H NMR spectroscopic data were identical to those
of the natural product isolated by Bohlmann and Zdero.9
accomplished by the reaction of (R)-9 with LiAlH4 in
23
81% yield and >99% ee {½aꢀD ¼ ꢁ21:6 (c 1.2, CHCl3)}.à
The absolute configuration of (R)-1 was determined
according to Scheme 3. Compound (R)-1 was hydroge-
nated with a catalytic amountof PtO2 at 1 atm of hydrogen
à Bohlmann and Zdero did not mention the value of the specific rotation
of (R)-1 in their paper. However, they stated that they assumed the
absolute configuration of (R)-1 by the comparison of the specific
rotation of (R)-1 with that of (R)-4. They also assumed the absolute
configuration of a structurally closely related norsesquiterpene having
an (R)-configuration by a similar method. The norsesquiterpene had a
specific rotation of ꢁ32.6 (c 1.38, CHCl3).9 Therefore, we judged that
(R)-1 had a specific rotation with a negative sign.
to give (R)-10. The treatment of (R)-10 with RuCl3 and
23
H5IO6 gave (R)-11 with >99% ee {½aꢀD ¼ ꢁ14:9 (c 1.2,
EtOH), Lit.:38 [a]D = ꢁ15.6 (c 0.55, EtOH), 93% ee (R)}.
We also synthesized (S)-1, not a natural product, from
(S)-8c according to Scheme 4. As (S)-8c did not have
an enantiomeric excess high enough for use, (S)-8c was

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M. Kawasaki et al. / Tetrahedron: Asymmetry 16 (2005) 4065–4072
hydrolyzed to (S)-6 with NaOH and (S)-6 again sub-
HO
MsO
jected to the lipase-catalyzed transesterification to
increase the ee. The obtained ester (S)-8c was then
MsCl, Et3N
CH2Cl2, 0oC
hydrolyzed in a similar manner to give (S)-6 with
24
>99% ee {½aꢀD ¼ þ16:0 (c 1.1, CHCl3)} and (S)-6 was
24
converted to (S)-1 with >99% ee {½aꢀD ¼ þ23:0 (c 1.1,
CHCl3)} according to the same route we used to prepare
(R)-6
(R)-9
(R)-1.
(84%)
3. Conclusion
LiAlH4
We have been able to synthesize optically active 5,6-
dehydrosenedigitalene (R)-1 and its enantiomer, not a
natural product, from the chiral intermediates obtained
via the lipase-catalyzed transesterification of ( )-6 with
7c. We firmly believe in the utility of vinyl 3-arylpropan-
oates in the lipase-catalyzed kinetic resolution of 2-aryl-
1-alkanols and are now synthesizing other natural prod-
ucts from chiral primary alcohols prepared via our
method.
Et2O, rt
(R)-1
(81%, >99% ee)
[α]23 = -21.6 (c 1.2, CHCl )
˚
D
3
Scheme 2.
H
2, PtO2
4. Experimental
4.1. General
EtOH, rt
All commercially available reagent chemicals were
obtained from Aldrich, Nacalai Tesque, Tokyo Kasei,
and Wako Chemicals, and generally used without further
purification. Compounds 7b and 7c were prepared
according to the reported procedure.3 Ether, benzene,
1,4-dioxane, and THF were distilled from Na/benzophe-
none under Ar. Cyclohexane, hexane, toluene, dichloro-
methane, pyridine, triethylamine, and diisopropylamine
were distilled from CaH2. Acetone and vinyl acetate were
(R)-1
(R)-10
(82%)
H5IO6, RuCl3
CO2H
H2O, CH3CN, CCl4, rt
˚
distilled from molecular sieves 3 A. HMPA was distilled
(R)-11
from CaH2 under reduced pressure (70.1–72.1 ꢁC/0.5
(42%, >99% ee)
mmHg). Lipase PS was purchased from Amano Enzyme,
1
Scheme 3.
Inc., and dried over P2O5. The H NMR spectra were
F3C
O
HO
1) NaOH / EtOH-H2O, rt
2)7c, Lipase PS / hexane, rt
O
3) NaOH / EtOH-H2O, rt
(S)-8c
(79% ee)
(S)-6
(73%, >99% ee)
(S)-1
(63% in two steps, >99% ee)
[α]24D = +23.0 (c 1.1, CHCl3)
˚
Scheme 4.

M. Kawasaki et al. / Tetrahedron: Asymmetry 16 (2005) 4065–4072
4069
recorded using a Jeol JNM-LA 400 spectrometer for
solution in CDCl3 with TMS as the internal standard,
and the J values are given in hertz. The IR spectra were
obtained using a Jasco FT/IR-410 spectrometer. The
mass spectra (MS) were obtained using a Jeol JMS-
GCmate spectrometer. The high-resolution mass spectra
(HRMS) were obtained using a Jeol JMS-AX505HAD
spectrometer and the electron ionization method. The
optical rotations were measured with a Horiba SEPA-
300 polarimeter. The gas chromatograms were recorded
on a Shimazu GC-14B with GAMMA DEXTM 120
capillary column (Supelco), 30 m · 0.25 mm and OV
101 bonded capillary column (GL Sciences), 17 m ·
0.25 mm. The HPLC analyses were carried out on a Hit-
achi L-6250 intelligent pump with a Hitachi L-4000 UV
detector using a Chiralcel OJ (Daicel), 250 · 4.6 mm.
4.96 (1H, dd, J = 17.1, J = 1.4), 4.91 (1H, dd,
J = 10.3, J = 1.2), 3.66–3.77 (2H, m), 2.71–2.78 (1H,
m), 2.33 (3H, s), 1.97–2.07 (2H, m), 1.65–1.73 (1H, m),
1.51–1.61 (1H, m), 1.26–1.37 (2H, m); IR (neat): 3350,
1640, 994, 910 cmꢁ1; MS (m/z) 204 (M+); HRMS calcd
for C14H20O (M+), 204.1514. Found: 204.1528.
4.4. 2-(4-Methylphenyl)-6-hepten-1-yl acetate ( )-8a
Compound ( )-8a was prepared as an authentic sample.
To a solution of ( )-6 (0.104 g, 0.509 mmol) and dry
pyridine (0.243 g, 3.07 mmol) in dry benzene (10 ml) at
0 ꢁC, acetyl chloride (0.138 g, 1.76 mmol) was slowly
added. The reaction mixture was stirred overnight at
room temperature and quenched at 0 ꢁC with 1 M HCl
(10 ml). The resulting mixture was extracted with ethyl
acetate. The organic phase was washed with deionized
water, a saturated sodium hydrogen carbonate solution,
and a saturated sodium chloride solution, then dried
over sodium sulfate. After removal of the solvents, the
residue was chromatographed (silica gel, hexane–ethyl
acetate 5:1 (v/v)) to give ( )-8a as a colorless oil
4.2. Ethyl 2-(4-methylphenyl)-6-heptenoate ( )-5
Anhydrous THF (15 ml) and anhydrous diisopropyl-
amine (2.532 g, 25.02 mmol) were added to a three-
necked, round-bottomed flask and maintained under
an Ar atmosphere. After cooling the mixture to 0 ꢁC,
n-butyl lithium in hexane solution (16 ml of 1.6 M,
26 mmol) was added via a syringe over a period of
10 min. The mixture was stirred for 15 min at 0 ꢁC and
cooled to ꢁ78 ꢁC. Ethyl 2-(4-methylphenyl)acetate
(4.453 g, 24.99 mmol) was added via a syringe over a per-
iod of 10 min. After stirring for 45 min, 5-bromo-1-pen-
tene (3.720 g, 24.96 mmol) dissolved in dry HMPA
(4.467 g, 24.93 mmol) was added over the period of
15 min at ꢁ78 ꢁC. After stirring overnight at room tem-
perature, the mixture was treated with 1 M HCl (50 ml)
at 0 ꢁC and extracted three times with ether. The ether
solution was washed with deionized water, saturated
aqueous sodium chloride, and dried with sodium sulfate.
The solvent was evaporated and the residue was chro-
matographed (silica gel, hexane–acetone 10:1 (v/v)) to
1
(0.107 g, 86%); H NMR: 7.12 (2H, d, J = 8.0), 7.07
(2H, d, J = 8.3), 5.73 (1H, ddt, J = 17.1, J = 10.2,
J = 6.6), 4.95 (1H, dd, J = 17.2, J = 2.1), 4.91 (1H, dd,
J = 10.3, J = 1.9), 4.12–4.21 (2H, m), 2.83–2.90 (1H,
m), 2.33 (3H, s), 1.99 (3H, s), 1.96–2.05 (2H, m), 1.68–
1.77 (1H, m), 1.53–1.63 (1H, m), 1.25–1.32 (2H, m);
IR (neat): 1741, 1640, 990, 911 cmꢁ1; MS (m/z) 246
(M+); HRMS calcd for C16H22O2 (M+), 246.1620.
Found: 246.1487.
4.5. 2-(4-Methylphenyl)-6-hepten-1-yl 3-phenylpro-
panoate ( )-8b
Compound ( )-8b was prepared as an authentic sample.
To a solution of ( )-6 (0.100 g, 0.489 mmol), 3-phenyl-
propanoic acid (0.076 g, 0.51 mmol), and 4-dimethyl-
aminopyridine (0.059 g, 0.48 mmol) in dry dichloro-
methane (10 ml) at 0 ꢁC, N,N0-dicyclohexylcarbodiimide
(0.102 g, 0.494 mmol) was slowly added. The reaction
mixture was stirred overnight at room temperature
and filtered. The filtrate was washed with 0.5 M HCl
(two times), and a saturated sodium hydrogen carbonate
solution (two times), and then dried over sodium sulfate.
After removal of the solvents, the residue was chromato-
graphed [silica gel, hexane–ethyl acetate 5:1 (v/v)] to give
1
give ( )-5 as a colorless oil (4.698 g, 77%); H NMR:
7.19 (2H, d, J = 8.0), 7.12 (2H, d, J = 8.3), 5.76 (1H,
ddt, J = 16.8, J = 10.3, J = 6.7), 4.98 (1H, dd,
J = 17.2, J = 1.6), 4.93 (1H, dd, J = 10.1, J = 1.3),
4.03–4.18 (2H, m), 3.48 (1H, t, J = 7.7), 2.32 (3H, s),
2.05 (2H, q, J = 7.7), 2.01–2.10 (1H, m), 1.71–1.80 (1H,
m), 1.29–1.41 (2H, m), 1.20 (3H, t, J = 7.1); IR (neat):
1640, 1732, 993, 911 cmꢁ1; MS (m/z) 246 (M+); HRMS
calcd for C16H22O2 (M+), 246.1620. Found: 246.1602.
1
( )-8b as a colorless oil (0.113 g, 69%); H NMR: 7.12–
4.3. 2-(4-Methylphenyl)-6-heptene-1-ol ( )-6
7.30 (5H, m), 7.10 (2H, d, J = 7.8), 7.04 (2H, d, J = 8.0),
5.72 (1H, ddt, J = 17.1, J = 10.2, J = 6.8), 4.99–4.98
(2H, m), 4.16 (2H, dd, J = 7.0, J = 3.3), 2.88 (2H, t,
J = 7.8), 2.82–2.90 (1H, m), 2.57 (2H, t, J = 7.9), 2.32
(3H, s), 1.96–2.03 (2H, m), 1.63–1.70 (1H, m), 1.53–
1.60 (1H, m), 1.23–1.31 (2H, m); IR (neat): 1736,
1639, 992, 911 cmꢁ1; MS (m/z) 336 (M+); HRMS calcd
for C23H28O2 (M+), 336.2089. Found: 336.2074.
To a suspension of LiAlH4 (0.720 g, 19.0 mmol) in dry
ether (25 ml) at room temperature under an Ar atmo-
sphere was slowly added a solution of ( )-5 (4.615 g,
18.73 mmol) in dry ether (35 ml). The reaction mixture
was refluxed overnight and quenched at 0 ꢁC with 6 M
HCl (20 ml). The resulting mixture was extracted three
times with ether. The organic phase was washed with a
saturated sodium chloride solution and dried over
sodium sulfate. After removal of the solvents, the residue
was chromatographed (silica gel, hexane–ethyl acetate
2:1 (v/v)) to give ( )-6 as a colorless oil (3.417 g,
89%); 1H NMR: 7.15 (2H, d, J = 8.3), 7.10 (2H, d,
J = 8.0), 5.74 (1H, ddt, J = 17.1, J = 10.1, J = 6.8),
4.6. 2-(4-Methylphenyl)-6-hepten-1-yl 3-(4-trifluorometh-
ylphenyl)propanoate ( )-8c
Compound ( )-8c as an authentic sample was prepared
from ( )-6 (0.094 g, 0.46 mmol), 3-(4-trifluoromethyl-
phenyl)propanoic acid (0.121 g, 0.555 mmol) with 4-

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M. Kawasaki et al. / Tetrahedron: Asymmetry 16 (2005) 4065–4072
dimethylaminopyridine (0.046 g, 0.38 mmol), and N,N0-
dicyclohexylcarbodiimide (0.094 g, 0.46 mmol) in dry
dichloromethane (5 ml) according to the procedure for
the preparation of ( )-8b. Chromatography [silica gel,
hexane–ethyl acetate 5:1 (v/v)] of the crude product pro-
room temperature. After removal of the solvent, the resi-
due was extracted three times with ether. The organic
layer was washed with brine, then dried over sodium
sulfate, and concentrated. The residue was chromato-
graphed (silica gel, hexane–ethyl acetate 5:1 (v/v))
1
1
vided ( )-8c as a colorless oil (0.096 g, 49%); H NMR:
to give (S)-6 (1.609 g, 98%) as a yellow oil. H NMR
7.51 (2H, d, J = 8.3), 7.23 (2H, d, J = 8.1), 7.11 (2H, d,
J = 7.8), 7.03 (2H, d, J = 8.0), 5.72 (1H, ddt, J = 17.1,
J = 10.2, J = 6.8), 4.89–4.98 (2H, m), 4.17 (2H, dd,
J = 7.0, J = 3.3), 2.92 (2H, t, J = 76), 2.82–2.86 (1H,
m), 2.58 (2H, t, J = 7.6), 2.32 (3H, s), 1.96–2.03 (2H,
m), 1.62–1.69 (1H, m), 1.50–1.60 (1H, m), 1.23–1.31
spectra data of this sample were identical to those of
( )-6.
According to the procedures described above, the (S)-6
obtained here was again subjected to the lipase PS-catal-
yzed transesterification with 7c to give the enantiomeri-
cally pure (S)-8c: lipase PS (1.250 g), (S)-6 (1.581 g,
7.739 mmol), 7c (2.861 g, 11.72 mmol), dry hexane
(125 ml), reaction time (24.5 h), yield of (S)-8c
(2.372 g, 76%). Compound (S)-8c was accompanied by
1.031 g of 7c.
(2H, m); IR (neat): 1737, 1640, 1326, 993, 912 cmꢁ1
;
MS (m/z) 404 (M+); HRMS calcd for C24H27F3O2
(M+), 404.1963. Found: 404.1978.
4.7. Resolution of ( )-6 (screening experiments)
In a typical run, lipase PS (20 mg) was placed in a vial
containing a 1 ml solution of ( )-6 (60 lmol) and vinyl
ester (60 lmol). The resulting suspension was then mag-
netically stirred at room temperature. Samples were
withdrawn from the vial and analyzed by gas chroma-
tography (OV 101). The reaction was stopped by the
filtration of the lipase at about a 40% conversion, and
the filtrate concentrated under reduced pressure. The
residue was chromatographed (silica gel, hexane–ethyl
acetate 10:1–5:1 (v/v)) with a short column (10 mm ·
80 mm) to give (R)-6 and (S)-8. The E-value and the
conversion of the reaction were calculated from the ees
of (R)-6 and (S)-8.8 As the ee of (S)-8b could not be
determined by either GC or HPLC, (S)-8b was hydro-
lyzed to (S)-6 according to the procedure in Section 4.8.
Thus, the obtained enantiomerically pure (S)-8c was
again hydrolyzed with NaOH to give (S)-6: (S)-8c
(2.359 g, 5.832 mmol) accompanied by 7c (1.026 g),
6 M NaOH (3.5 ml), ethanol (15 ml), reaction time 1 h,
24
yield of (S)-6 {1.158 g, 97%, >99% ee, ½aꢀD ¼ þ16:0 (c
1.1, CHCl3)}. 1H NMR spectra data of this sample were
identical to those of ( )-6.
4.9. (R)-2-(4-Methylphenyl)-6-hepten-1-yl methanesul-
fonate (R)-9
To a solution of (R)-6 (1.335 g, 6.535 mmol) and dry
Et3N (1.872 g, 18.50 mmol) in dry CH2Cl2 (20 ml) at
0 ꢁC was slowly added methanesulfonyl chloride
(0.959 g, 8.37 mmol). The reaction mixture was stirred
overnight at room temperature and quenched at 0 ꢁC
with 1 M HCl (20 ml). The resulting mixture was then
extracted twice with ether. The organic phase was
washed with deionized water, a saturated sodium hydro-
gen carbonate solution, and a saturated sodium chloride
solution in this order, then dried over sodium sulfate.
After removal of the solvents, the residue was chromato-
graphed [silica gel, hexane–ethyl acetate 2:1 (v/v)] to give
Conditions for the determination of the ee of (R)-6, (S)-
8a, and (S)-8c are as follows. Compound (R)-6: HPLC
(Chiralcel OJ), hexane–2-propanol = 10:1 (v/v); (S)-8a:
HPLC (Chiralcel OJ), hexane–2-propanol = 10:1 (v/v);
(S)-8c: HPLC (Chiralcel OJ), hexane–2-propanol = 30:1
(v/v).
1
4.8. Preparative resolution of ( )-6
(R)-8 as a colorless oil (1.540 g, 84%); H NMR: 7.14
(2H, d, J = 8.0), 7.08 (2H, d, J = 8.3), 5.72 (1H, ddt,
J = 16.8, J = 10.2, J = 6.8), 4.90–4.98 (2H, m), 4.28
(2H, d, J = 6.8), 2.91–2.98 (1H, m), 2.76 (3H, s), 2.32
(3H, s), 1.95–2.09 (2H, m), 1.74–1.83 (1H, m), 1.57–
1.67 (1H, m), 1.24–1.34 (2H, m); IR (neat): 1640,
1356, 1175, 974 cmꢁ1; MS (m/z) 282 (M+); HRMS calcd
for C15H22O3S (M+), 282.1290. Found: 282.1306.
Lipase PS (5.699 g) was added to a solution of ( )-6
(3.417 g, 16.73 mmol) and 7c (4.090 g, 16.75 mmol) in
dry hexane (280 ml). The mixture was stirred for 29 h
at room temperature. The reaction was quenched by fil-
tration and the filtrate was concentrated under reduced
pressure. The residue was chromatographed (silica gel,
hexane–ethyl acetate 5:1–2:1 (v/v)) to give (S)-8c and
(R)-6 as colorless oils.
4.10. 5,6-Dehydrosenedigitalene [(R)-6-(4-Methylphenyl)-
1-heptene] (R)-1
Compound (S)-8c: yield 3.304 g (49%), accompanied by
1
7c of 0.52 g; ee = 79%; H NMR spectra data of this
To a suspension of LiAlH4 (1.280 g, 33.73 mol) in dry
ether (45 ml) at room temperature under an Ar atmo-
sphere was slowly added a solution of (R)-8 (1.460 g,
5.170 mmol) in dry ether (14 ml). The reaction mixture
was stirred overnight at room temperature and quenched
at 0 ꢁC with 2 M HCl (70 ml). The resulting mixture was
extracted three times with ether. The organic phase was
washed with a saturated sodium hydrogen carbonate
solution and a saturated sodium chloride solution, then
dried over sodium sulfate. After removal of the solvents,
sample were identical with those of ( )-8c.
Compound (R)-6: yield 1.355 g (40%); ee >99%;
24
1
½aꢀD ¼ ꢁ12:6 (c 0.8, CHCl3); H NMR spectra data of
this sample were identical to those of ( )-6.
NaOH (6 M, 3 ml) was added to a solution of (S)-8c
(3.276 g, 8.100 mmol) accompanied by 7c (0.514 g) in
ethanol (15 ml). The mixture was stirred overnight at

M. Kawasaki et al. / Tetrahedron: Asymmetry 16 (2005) 4065–4072
4071
the residue was chromatographed (silica gel, hexane) to
give (R)-1 as a colorless oil (0.785 g, 81%, >99% ee);
Acknowledgments
23
1
½aꢀD ¼ ꢁ21:6 (c 1.2, CHCl3); H NMR: 7.10 (2H, d,
J = 8.0), 7.07 (2H, d, J = 8.3), 5.76 (1H, ddt, J = 17.1,
J = 10.2, J = 6.8), 4.96 (1H, dd, J = 17.1, J = 2.2), 4.91
(1H, dd, J = 10.2, J = 1.5), 2.64 (1H, sextet, J = 7.1),
2.32 (3H, s), 2.01 (2H, dt, J = 7.3, J = 6.8), 1.53–1.59
(2H, m), 1.24–1.39 (2H, m), 1.21 (3H, d, J = 7.1); IR
(neat): 1640, 995, 909 cmꢁ1; MS (m/z) 188 (M+); HRMS
calcd for C14H20 (M+), 188.1565. Found: 188.1547. The
enantiomeric excess was determined by GC analysis on a
GAMMA DEXTM 120 capillary column (95 ꢁC).
The authors thank the researchers at the Biotechnology
Research Center, Toyama Prefectural University, for
their generous support with the NMR spectroscopic
and optical rotation measurements.
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