Synthesis and odor properties of Phantolide analogues

Article abstract of DOI:10.1016/j.tet.2017.02.055

Phantolide analogues 1a–1d were newly synthesized to evaluate their odor profiles. The enantiomers of 1a and 1b were also synthesized. Both (S) enantiomers of 1a and 1b had musk odor although weakly, and but neither of the (R) enantiomers 1a and 1b had mu

Full text of DOI:10.1016/j.tet.2017.02.055

Accepted Manuscript
Synthesis and odor properties of Phantolide analogues
Masashi Kawasaki, Saki Kuroyanagi, Takuya Ito, Hiroyuki Morita, Yasuo Tanaka,
Naoki Toyooka
PII:
S0040-4020(17)30203-X
10.1016/j.tet.2017.02.055
TET 28496
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 25 January 2017
Revised Date: 23 February 2017
Accepted Date: 24 February 2017
Please cite this article as: Kawasaki M, Kuroyanagi S, Ito T, Morita H, Tanaka Y, Toyooka N, Synthesis
and odor properties of Phantolide analogues, Tetrahedron (2017), doi: 10.1016/j.tet.2017.02.055.
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ACCEPTED MANUSCRIPT

ACCEPTED MANUSCRIPT
Synthesis and odor properties of Phantolide analogues
Masashi Kawasakia,*, Saki Kuroyanagib, Takuya Itoc, Hiroyuki Moritac, Yasuo Tanakad,
Naoki Toyookab,e,*
aDepartment of Liberal Arts and Sciences, Faculty of Engineering, Toyama Prefectural
University, 5180 Kurokawa, Imizu, Toyama-ken 939-0398, Japan
bGraduate School of Science and Engineering, University of Toyama, 3190 Gofuku,
Toyama 930-8555, Japan
cDivision of Natural Products Chemistry, Institute of Natural Medicine, University of
Toyama, 2630 Sugitani, Toyama 930-0194, Japan
dTAIYO CORPORATION, 1-6-27 Higashiawaji, Yodogawa-ku, Osaka 533-0023, Japan
eGraduate School of Innovation Life Science, University of Toyama, 3190 Gofuku,
Toyama 930-8555, Japan
Abstract
Phantolide analogues 1a-1d were newly synthesized to evaluate their odor profiles.
The enantiomers of 1a and 1b were also synthesized.
1b had musk odor although weakly, and but neither of the (R) enantiomers 1a and 1b
had musk odor. During the investigations, we encountered the undesirable
Both (S) enantiomers of 1a and
racemization in Friedel-Crafts reaction of the intermediate (S)-5.
* Corresponding authors. E-mail address: kawasaki@pu-toyama.ac.jp (M. Kawasaki),
toyooka@eng.u-toyama.ac.jp (N. Toyooka)
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Keywords: Asymmetric synthesis; Friedel-Crafts reaction; Lipase; Phantolide;
Racemization
1. Introduction
Musk is secreted from the exocrine odor glands, called musk pods, of male musk
deer.1,2
Before 1979, when musk deer were protected from extinction by the
Convention on International Trade in Endangered Species of Wild Fauna and Flora,
musk tincture was used in the production of perfume.1
The musk pods were dried
and then opened to yield brownish grain from which the musk was extracted with
ethanol.1
Musk odor, although difficult to describe, is often likened to warm, sweet, powdery,
animal smells.3
was isolated in 1906, and the structure was elucidated in 1926.2
The most intense chemical component of musk, (R)-muscone (Fig. 1),
Because the
production of musk tincture from musk deer has been prohibited, and industrial
synthetic routes to (R)-muscone have not been developed until recently, synthetic musk
odor compounds have been used.4
Five main classes of musk odorants are known at
present: macrocyclic musks, nitro musks, polycyclic musks, linear musks and dienone
musks (Fig. 1).2,5
Compounds totally different from (R)-muscone in structure have
the musk odor. Kraft et al. have been studying the odor-structure relationship of
musk odorants to design new ones.5-8
Among the musk odorants, polycyclic aromatic
musks were inexpensively synthesized and consequently used in large quantities.4
The ease with which the 1,1,2,3,3-pentamethylindane skeleton can be constructed
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explains the attractive price of Galaxolide and Phantolide.2
The enantiomers of many chemical compounds are perceived differently as odorants
by the human nose; in plain terms, they smell differently.9
Many natural flavors and
fragrances occur in nature as specific enantiomers, and the aromas of such specific
enantiomers can be distinctive and characteristic.10
For example, (R)-carvone has a
herbaceous odor reminiscent of spearmint, while (S)-carvone has a herbaceous odor
reminiscent of caraway and dill seeds.10,11
The synthesis of the enantiomers of
fragrance ingredients in highly enantiomerically pure form and the evaluation of the
difference in the odor properties of the enantiomers are accordingly of great
interest.8,12-14
We have also been interested in the differences in the olfactory
properties of the enantiomers of fragrance ingredients and have reported the synthesis of
the enantiomers of floral odorants and citrus odorants.15-17
There are some reports on
the evaluation of the odors of the enantiomers of musk odorants.
(R)- and
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(S)-muscone show distinct differences in their odor.
(R)-muscone, naturally
occurring, is described as “a very nice musky note, rich and powerful”, whereas
(S)-muscone is “poor and less strong”.18
Felker et al. recently reported the
differences in the olfactory properties between the enantiomers of some Cashmeran
odorants.8
diastereomers of Galaxolide.19
Fráter et al. reported the differences in the olfactory properties of the four
We, therefore, have become interested in the
differences in the olfactory properties of the enantiomers of musk odorants.
We herein report the synthesis of racemic and optically active Phantolide analogues
1a-1d, which have never been synthesized before, and the evaluation of their odor
profiles (Fig. 2).
We also report the racemization which we encountered in the course
of the asymmetric synthesis of the Phantolide analogues 1a and 1b in Friedel-Crafts
reactions.
2. Results and Discussion
2.1. Synthesis and odor profiles of racemic Phantolide analogues 1a-1d
The syntheses of racemic Phantolide analogues 1a-1d are shown in Scheme 1.
The enolate that was generated in situ from ethyl (4-methylphenyl)acetate and LDA was
treated with 1-bromo-3-methyl-2-butene to give the desired ester 2 in 90% yield.
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Reduction of 2 with LiAlH4 provided the primary alcohol 3 in 83% yield, which was
converted to the corresponding iodide 4 using the Appel reaction in 83% yield. The
iodide 4 was then treated with LiAlH4 to give the desired aromatic hydrocarbon 5 in
84% yield.
Intramolecular Friedel-Crafts alkylation with AlCl3 as the catalyst in
No
benzene smoothly proceeded and gave the desired indane 6 in 62% yield.
reaction took place in CH2Cl2 instead of benzene as the solvent or with BF3·OEt2, ZnCl2,
SnCl2 in benzene, respectively. The syntheses of the racemic Phantolide analogs
1a-1d were accomplished by Friedel-Crafts acylation of 6 with acyl chlorides in the
presence of AlCl3, and 1a-1d were obtained in 57-75% yield as a single regioisomer.
The regioselectivity of the acylation was determined by the NOESY experiment of 1a
(Fig. 3), and those of the other derivatives 1b-1d were determined by the analogy of
their 1H NMR spectra to 1a.
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The odor profiles of the racemic Phantolide analogues 1a-1d were evaluated by two
skilled perfumers and two skilled flavorists (TAIYO CORPORATION).
following descriptions were obtained (Table 1).
The
Table 1. Odor profiles of racemic Phantolide analogues 1a-1d.
Compound
Odor profiles
1a
1b
1c
ambergris, dusty, tomato fiber, mixture of citrus and sandalwood
soap, ionone, sandalwood, plain
odor like unclear 1b, citrus, odor like 1b with unpleasant feeling
peach, p-t-butylcyclohexyl acetate-like, powdery, heavy,
organic solvent-like, odor like 1b with unpleasant feeling
1d
Although none of the Phantolide analogues 1a-1d had a musk odor, analogues 1a
and 1b received good evaluations like ambergris and ionone, respectively. We, therefore,
decided to synthesize the enantiomers of 1a and 1b and evaluate their odor.
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2.2. Synthesis and odor profiles of optically active Phantolide analogues 1a, 1b
We first tried to synthesize optically active intermediate (S)-6 for the
enantiodivergent synthesis of (S)-1a and (S)-1b according to Scheme 2.
The first step
in the sequence leading to (S)-6 is the ethoxycarbonylation of ethyl
(4-methylphenyl)acetate with LiHMDS and ethyl cyanoformate to give the diester 7 in
96% yield, and then the diester was reduced with LiAlH4 to the corresponding diol 8 in
79% yield.
We followed the preparation, porcine pancreatic lipase (PPL)-catalyzed
enantioselective acetylation of 8 with vinyl acetate, reported by Shishido et al.20 and
obtained (R)-9 in 90% yield and 99% enantiomeric excess (ee). The monoester (R)-9
on treatment with MOMCl and DIPEA afforded the ester (R)-10 in 96% yield.
Hydrolysis of the ester moiety of (R)-10 with K2CO3 quantitatively gave the alcohol
(S)-11.
Treatment of (S)-11 with TsCl and Et3N quantitatively afforded the
corresponding tosylate (R)-12. Reduction of (R)-12 with NaBH4 in DMSO afforded
the protected alcohol (R)-13 in 85% yield.
Deprotection of (R)-13 with HCl allowed
the formation of the primary alcohol (R)-1421 with 99% ee in 95% yield.
The ee of
(R)-14 was the same as that of the intermediate (R)-9, and this means that no
racemization occurred during the transformation from (R)-9 into (R)-14.
of (R)-14 afforded the corresponding iodide (R)-15 in 83% yield.
Iodination
The
cross-coupling reaction of (R)-15 gave the desired olefin (S)-16 in 71% yield.
Wacker oxidation of (S)-16 (59%) and subsequent Wittig reaction of the resulting
ketone (S)-17 (70%) gave the desired olefin (S)-524 with 99% ee.
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With the intermediate, olefin (S)-5, in hand, next we tried intramolecular
Friedel-Crafts alkylation of (S)-5 according to the same procedure as that for the
synthesis of racemic 6 and observed partial racemization in the cyclization with the ees
of the product (S)-6 (93% ee at the 1st run and 86% ee at the 2nd run) lower than that of
(S)-5 (99% ee). We mixed (S)-6 (99% ee) with AlCl3 under the same conditions to
confirm whether (S)-6 itself racemizes and found that the ee of recovered (S)-6 (98% ee)
decreased a little.
during the cyclization of (S)-5.
proposed in Scheme 3. The mechanism assumes that the initial step is the attack by
This suggests that the decrease of the ee of (S)-6 occurs mainly
A plausible mechanism of the racemization is
the hydrated form of AlCl3, H+[AlCl3OH]-, which was produced by the interaction of
AlCl3 with the trace of moisture, on the olefin moiety of (S)-5 with the formation of the
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intermediate complex 18.25
The next step would be the intramolecular attack of the
cation moiety of 18 on the aromatic ring to form the complex 19, and then the hydrogen
of the benzyl position, which was a chiral center eliminated to form a double bond 20
with the regeneration of H+[AlCl3OH]-.
The last step would be attack by the
H+[AlCl3OH]- on the olefin moiety of the cyclopentene ring of 20 with the formation of
the partially racemized intermediate complex 19’, which forms 6 with the regeneration
of H+[AlCl3OH]-.
To the best of our knowledge, there are no reports of racemization
on the benzyl position during intramolecular Friedel-Crafts alkylation.
As mentioned above, we encountered partial racemization in the intramolecular
Friedel-Crafts alkylation of (S)-5, so we examined an alternative route to obtain
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optically pure 1a and 1b (Scheme 4).
We planned to construct the indane skeleton 21
first and obtain the chiral intermediates (R)-22 and (S)-23 by resolution, after which
they would be transformed to optically pure final products, respectively.
OH
CO2Et
CO2Et
a
b
c
OH
OAc
+
( )-
( )-
OMs
O
d
e
f
R
( )-
( )-
( )-
( )- : R = Me
( )- : R = Et
OH
O
R
g, h, i
j, k, l
( )-
( )-
( )- : R = Me
( )- : R = Et
Synthesis of optically active Phantolid analogues
,
.
Reagents and conditions: (a) AlCl3, benzene, 0 C to rt, 87%; (b) LiAlH4,
THF, 0 C to rt, 95%; (c) PPL, vinyl acetate, THF, rt, ( )- : 44%, >99%
ee; ( )- : 56%, 76% ee; (d) MsCl, pyridine, CH2Cl2, 0 C to rt, 89%; (e)
LiAlH4, Et2O, 0 C to rt, 91%, >99% ee; (f) acyl chloride, CH2Cl2, 0 C to
rt, ( )- : 91%, >99% ee; ( )- : 89%, 99% ee; (g) 6
NaOH, EtOH, rt,
98%, 76% ee; (h)PPL, vinyl acetate, THF, rt, 54%, 99% ee; (i)6 NaOH,
EtOH, rt, 98%, 99% ee; (j) MsCl, pyridine, CH2Cl2, 0 C to rt, 96%; (k)
LiAlH4, Et2O, 0 C to rt, 96%, 99% ee; (l)acyl chloride, AlCl3, CH2Cl2, 0 C
to rt, ( )- : 71%, 98% ee; ( )- : 86%, 99% ee.
.
Ester 2 was first subjected to intramolecular Friedel-Crafts alkylation to give rise to
the cyclized product 21 in 87% yield, which was converted to the corresponding alcohol
22 in 95% yield.
The most important point of the present synthesis is to prepare (R)- and (S)-22 in
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highly optically active forms.
We achieved this by the optical resolution of 22
through the porcine pancreatic lipase (PPL)-catalyzed enantioselective acetylation of 22
with vinyl acetate. We initially investigated the effects of the reaction solvents on the
enantioselectivity of the PPL-catalyzed resolution (Table 2), because the
enantioselectivity of lipases was found to depend on the nature of reaction solvents.26
As a result of the screening of the solvent, we found that THF was the most suitable
solvent for this resolution (E22 = 49).
Table 2. PPL-catalyzed transesterification of 22.
Conversiona
(%)
ee of (R)-22
ee of (S)-23
Solvent
Time (h)
Ea
(%)
(%)
hexane
cyclohexane
toluene
0.2
20.5
5.5
88b
48
48
3b
-
-
-
80
80
-
85
87
-
30
35
-
CH2Cl2
19.5
2.3
diethyl ether
ethyl acetate
THF
49
49
49
48
48
48
86
86
87
83
81
79
89
88
89
89
89
86
48
43
49
45
43
32
3.5
6.3
acetone
3.5
acetonitrile
1,4-dioxane
4.0
4.3
Conditions: PPL (100 mg mL-1), 22 (45 mM), vinyl acetate (1 M), room temperature.
aCalculated from ees of (R)-22 and (S)-23.22 bDetermined by GC analysis.
On the basis of these results, we conducted a large-scale resolution of 22 in THF to
obtain (R)-22 with >99% ee in 44% yield and (S)-23 with 76% ee in 56% yield,
respectively.
Treatment of (R)-22 with MsCl afforded the corresponding mesylate
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(R)-24 in 89% yield. The mesylate (R)-24 was then treated with LiAlH4 to give the
desired aromatic hydrocarbon (R)-6 with >99% ee in 91% yield.
The synthesis of
(R)-1a and (R)-1b was accomplished by Friedel-Crafts acylation of (R)-6 with acyl
chlorides in the presence of AlCl3 in 91 and 89% yield, respectively.
The acetate (S)-23 did not have a sufficiently high ee for use in the initial resolution,
and we examined the preparation of (S)-23 with higher ee.
was hydrolyzed to the corresponding alcohol (S)-22, which was subjected to the
PPL-catalyzed transesterification again to obtain (S)-23 with 99% ee. The acetate
The initial acetate (S)-23
(S)-23 with high ee obtained above was converted to (S)-1a and (S)-1b in the same
manner as for (R)-1a and (R)-1b as shown in Scheme 3.
The odor profiles of the obtained optically pure Phantolide analogues (R)- and
(S)-1a and 1b were evaluated by two skilled perfumers and two skilled flavorists
(TAIYO CORPORATION).
The following descriptions were obtained (Table 3).
Table 3. Odor profiles of optically active Phantolide analogues 1a, 1b.
Compound
Odor profiles
powdery, chemical, weakly woody, the smell of burnt plastic,
artificial
(R)-1a
(S)-1a
(R)-1b
(S)-1b
powdery, weakly musky, woody, musk with a light floral note and
a metallic tone, mild sandalwood
very weakly woody, sweet like vanilla, odorless
weakly woody, (weakly) musky, powdery with chemical substance
note
It is very interesting that both the (S) enantiomers of 1a and 1b showed musk odor
although weakly, but neither of the (R) enantiomers showed musk odor.
As
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previously mentioned, neither racemic 1a nor 1b had a musk odor.
Therefore, it is
supposed that the musky odors of (S) enantiomers would be masked by (R) enantiomers.
In these substrates, the absolute configuration played a very important role in their odor
profiles.
3. Conclusions
We newly synthesized four racemic Phantolide analogues 1a-1d and evaluated their
odor profiles. Although none of them had a musk odor, 1a and 1b had a good odor
like ambergris and ionone, respectively.
musk odor although weakly, but neither of the (R) enantiomers 1a and 1b had a musk
odor. The absolute configuration in these substrates was very important for their
odor profiles.
During these investigations, we encountered the racemization in the Friedel-Crafts
reaction of (S)-5. To the best of our knowledge, there are no reports of racemization
Both (S) enantiomers of 1a and 1b had a
on the benzyl position during intramolecular Friedel-Crafts alkylation.
4. Experimental Section
4.1. General
All commercially available reagent chemicals were obtained from Aldrich, Kanto
Kagaku, Nacalai Tesque, Tokyo Kasei, and Wako Chemicals and generally used without
further purification, unless otherwise indicated.
Porcine pancreatic lipase was
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purchased from Sigma-Aldrich and dried over P2O5 for three days at room temperature.
NMR spectra were recorded on either a Bruker Advance II 400 spectrometer (1H 400
13
MHz, and C 100 MHz) or a Varian UNITY plus 500 spectrometer (1H 500 MHz, and
13C 125 MHz). Chemical shifts (δ) are reported in parts per million (ppm) and
referenced to TMS (δ = 0.00 ppm).
spectrometer. HRMS was performed on a Jeol MStation JMS-700 instrument.
Optical rotations were recorded on a Jasco P-1300 polarimeter. The melting point
was measured by a Yanaco MP-S3 micro-melting point apparatus. Gas
IR spectra were recorded on a Jasco FT/IR-410
chromatography (GC) analyses were performed on a Shimadzu GC-2014 gas
chromatograph equipped with a CP-Cyclodextrin-β-2,3,6-M-19 capillary column
(Agilent Technologies, 0.25 mm ϕ × 25 m) or InertCap 1 capillary column (GL Sciences,
0.25 mm ϕ × 30 m).
High performance liquid chromatography (HPLC) analyses
were performed on a Shimadzu LC-20AD intelligent pump with a Shimadzu SPD-20A
UV detector, using CHIRALCEL OB-H, CHIRALCEL OD-H, CHIRALCEL OJ-H, or
CHIRALPACK AS-H (all the columns from Dicel, 4.6 mm ϕ × 25 cm).
4.2. Ethyl 4-methyl-2-(4-methylphenyl)-4-pentenoate 2
LDA was prepared by the treatment of diisopropylamine (3.455 g, 34.14 mmol) with
n-BuLi (1.6 M solution in hexane, 21 mL, 34 mmol) in dry THF (50 mL) at 0 ºC for 30
min. To a solution of ethyl p-tolylacetate (5.043 g, 28.30 mmol) in dry THF (50 ml),
HMPA (7.612 g, 42.48 mmol) and the LDA were added at -78 ºC, and the mixture was
stirred at -78 ºC for 30 min. To the mixture was added 3-bromo-2-methyl-1-propene
(4.538 g, 33.62 mmol) at -78 ºC. The mixture was allowed to warm to 0 ºC for 20
min. Aqueous saturated NH4Cl was added at 0 ºC, and the aqueous mixture was
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extracted three times with EtOAc. The combined organic extracts were washed with
brine and then dried over Na2SO4.
After removal of the solvent, the residue was
purified by column chromatography using silica gel (hexane/EtOAc = 50/1 to 30/1) to
1
afford 2 as a colorless oil (5.913 g, 90%). IR (neat) 1733 cm-1; H NMR (500 MHz,
CDCl3) δ 1.20 (3H, t, J = 7.0 Hz), 1.72 (3H, s), 2.32 (3H, s), 2.41 (1H, dd, J = 6.5, 15.0
Hz), 2.82 (1H, dd, J = 9.3, 15.0), 3.76 (1H, dd, J = 6.5, 9.3 Hz), 4.03-4.17 (2H, m), 4.70
(1H, s), 4.75 (1H, s), 7.12 (2H, d, J = 7.8 Hz), 7.22 (2H, d, J = 7.8 Hz); 13C NMR (125
MHz, CDCl3) δ 14.01, 20.92, 22.51, 41.30, 49.56, 60.52, 111.90, 127.60, 129.14,
135.87, 136.68, 142.65, 173.58; HRMS (FAB) m/z calcd for C15H21O2 (M+H)+
233.1542, found 233.1553.
4.3. 4-Methyl-2-(4-methylphenyl)-4-penten-1-ol 3
To a suspension of LiAlH4 (1.704 g, 44.90 mmol) in dry THF (30 mL) was slowly
added a solution of ester 2 (5.210 g, 22.43 mmol) in dry THF (20 mL) at 0 ºC.
mixture was stirred at room temperature overnight. Water was added to the mixture
at 0 ºC, and then 6 M HCl was added to the mixture. The resulting mixture was
extracted three times with Et2O, and the combined organic extracts were washed with
brine and then dried over Na2SO4. After removal of the solvent, the residue was
The
purified by column chromatography using silica gel (hexane/acetone = 10/1) to afford 3
1
as a colorless oil (3.549 g, 83%). IR (neat) 3337, 1036 cm-1; H NMR (400 MHz,
CDCl3) δ 1.71 (3H, s), 2.32 (1H, dd, J = 8.0, 13.8 Hz), 2.33 (3H, s), 2.44 (1H, dd, J =
7.2, 13.8 Hz) 2.97-3.04 (1H, m), 3.66-3.71 (1H, m), 3.74-3.80 (1H, m), 4.67 (1H, s),
13
4.71 (1H, s), 7.12 (2H, d, J = 8.4 Hz), 7.14 (2H, d, J = 8.4 Hz); C NMR (100 MHz,
CDCl3) δ 20.91, 22.25, 40.57, 45.67, 67.19, 112.16, 127.72, 129.15, 136.06,
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138.91,143.37; HRMS (FAB) m/z calcd for C13H19O (M+H)+ 191.1436, found
191.1433.
4.4. 5-Iodo-2-methyl-4-(4-methylphenyl)-1-pentene 4
To a solution of the alcohol 3 (0.443 g, 2.33 mmol) in dry CH2Cl2 (7 ml) were added
imidazole (0.238 g, 3.50 mmol), triphenylphosphine (0.734 g, 2.80 mmol), and iodine
(0.888 g, 3.50 mmol) at 0 ºC.
After the mixture was stirred at room temperature for 1
The mixture was extracted with CH2Cl2,
h, aqueous saturated Na2S2O3 was added.
and the organic layers were dried over Na2SO4. After removal of the solvent, the
residue was purified by column chromatography using silica gel (hexane/EtOAc = 50/1
to 30/1) to afford 4 as a colorless oil (0.579 g, 83%). IR (neat) 668 cm-1; 1H NMR (500
MHz, CDCl3) δ 1.67 (3H, s), 2.33 (3H, s), 2.35 (1H, dd, J = 8.5, 13.8 Hz), 2.56 (1H, dd,
J = 7.0, 13.8 Hz), 2.98-3.04 (1H, m), 3.33 (1H, dd, J = 7.5, 10.0 Hz), 3.42 (1H, dd, J =
6.0, 10.0 Hz), 4.66 (1H, s), 4.73 (1H, s), 7.06 (2H, d, J = 7.8 Hz), 7.13 (2H, d, J = 7.8
13
Hz); C NMR (125 MHz, CDCl3) δ 13.97, 21.06, 22.20, 43.91, 45.33, 112.89, 127.14,
129.08, 136. 38, 139.62, 142.62; HRMS (FAB) (M+H)+ m/z calcd for C13H18I 301.0453,
found 301.0462.
4.5. 2-Methyl-4-(4-methylphenyl)-1-pentene 5
To a solution of 4 (2.000 g, 6.66 mmol) in dry THF (50 ml) was added LiAlH4
(0.763 g, 20.10 mmol) at 0 ºC. The mixture was stirred at room temperature for 3.5 h,
and 10% NaOH was added to the mixture at 0 ºC. The mixture was filtered off with
suction, and the resulting solution was dried over Na2SO4. After removal of the
solvent, the residue was purified by column chromatography using silica gel (hexane) to
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afford 5 as a colorless oil (0.978 g, 84%).
1H NMR spectra data were identical to
those reported in the literature.27
4.6. 1,3,3,5-Tetramethylindane 6
To a solution of 5 (0.300 g, 1.72 mmol) in dry benzene (6 ml) was added AlCl3 (0.045
g, 0.34 mmol) at 0 ºC. The solution was stirred at room temperature for 2 h.
Aqueous saturated NaHCO3 was added at 0 ºC, and the resulting mixture was extracted
twice with EtOAc. The combined organic layers were washed with water, and brine
in this order and then dried over Na2SO4. After removal of the solvent, the residue
was purified by column chromatography using silica gel (hexane) to give 6 as a
1
colorless oil (0.186 g, 62%). IR (neat) 3003, 812 cm-1; H NMR (500 MHz, CDCl3) δ
1.16 (3H, s), 1.28 (3H, d, J = 7.0 Hz), 1.34 (3H, s), 1.49 (1H, dd, J = 9.5, 12.0 Hz), 2.13
(1H, dd, J = 7.0, 12.0 Hz), 2.34 (3H, s), 3.16-3.23 (1H, m), 6.95 (1H, s), 7.00 (1H, d, J =
13
7.5 Hz), 7.05 (1H, d, J = 7.5 Hz); C NMR (100 MHz, CDCl3) δ 19.73, 21.38, 28.81,
29.21, 36.00, 42.66, 51.28, 122.59, 122.87, 127.14, 135.99, 144.26, 152.48; HRMS (EI)
m/z calcd for C13H18 M+ 174.1409, found 174.1407.
4.7. 1-(2,3-dihydro-1H-1,3,3,5-tetramethyl-6-indenyl)-1-ethanone 1a
To a solution of 6 (0.050 g, 0.29 mmol) in dry CH2Cl2 (1 ml) were added acetyl
chloride (0.051 g, 0.65 mmol) and AlCl3 (0.077 g, 0.58 mmol) at 0 ºC.
mixture was stirred at room temperature for 30 min. Aqueous saturated NaHCO3
was added at 0 ºC, and the mixture was filtered with suction. The filtrate was
extracted with CH2Cl2 and then dried over Na2SO4. After removal of the solvent,
The reaction
Kugelrohr distillation (115–166 ºC/1.5 mmHg) provided 1a as a white solid (0.038 g,
17

ACCEPTED MANUSCRIPT
1
61%). Mp 55-58 ºC; IR (KBr) 1672 cm-1; H NMR (500 MHz, CDCl3) δ 1.17 (3H, s),
1.32 (1H, d, J = 7.0 Hz), 1.35 (1H, s), 1.52 (2H, dd, J = 9.5, 12.3 Hz), 2.18 (1H, dd, J =
7.5, 12.3 Hz), 2.52 (3H, s), 2.58 (3H, s), 3.19-3.27 (1H, m), 6.98 (1H, s), 7.47 (1H, s);
13C NMR (125 MHz, CDCl3) δ 19.54, 21.81, 28.42, 28.81, 29.43, 35.86, 42.82, 50.94,
124.21, 125.41, 136.10, 137.19, 144.56, 156.17, 201.33; HRMS (EI) m/z calcd for
C15H20O M+ 216.1514, found 216.1512.
4.8. 1-(2,3-dihydro-1H-1,3,3,5-tetramethyl-6-indenyl)-1-propanone 1b
Compound 1b was synthesized from 6 (0.089 g, 0.51 mmol) and propionyl chloride
(0.102 g, 1.10 mmol) with AlCl3 (0.133 g, 1.00 mmol) in 57% yield according to the
procedure described in Section 4.7.
Kugelrohr distillation (120-160 ºC/1.5 mmHg)
provided 1b as a colorless oil. IR (neat) 1684 cm-1; 1H NMR (500 MHz, CDCl3) δ 1.17
(3H, s), 1.19 (3H, t, J = 7.2 Hz), 1.31 (3H, d, J = 7.0 Hz), 1.34 (3H, s), 1.52 (1H, dd, J =
9.5, 12.3 Hz), 2.17 (1H, dd, J = 7.5, 12.3 Hz), 2.48 (3H, s), 2.92 (2H, q, J = 7.2 Hz),
13
3.20-3.26 (1H, m), 6.98 (1H, s), 7.41 (1H, s); C NMR (125 MHz, CDCl3) δ 8.40,
19.57, 21.50, 28.49, 28.88, 34.53, 35.93, 42.83, 51.00, 123.14, 125.32, 136.58, 136.61,
144.53, 155.69, 204.86; HRMS (EI) m/z calcd for C16H22O M+ 230.1671, found
230.1672.
4.9. 1-(2,3-dihydro-1H-1,3,3,5-tetramethyl-6-indenyl)-1-butanone 1c
Compound 1c was synthesized from 6 (0.150 g, 0.86 mmol) and butyryl chloride
(0.203 g, 1.91 mmol) with AlCl3 (0.229 g, 1.72 mmol) in 75% yield according to the
procedure described in Section 4.7.
Kugelrohr distillation (140-190 ºC/1.5 mmHg)
provided 1c as a colorless oil. IR (neat) 1684 cm-1; 1H NMR (500 MHz, CDCl3) δ 0.99
18

ACCEPTED MANUSCRIPT
(3H, t, J = 7.3 Hz), 1.16 (3H, s), 1.31 (3H, d, J = 7.0 Hz), 1.34 (3H, s), 1.52 (1H, dd, J =
9.0, 12.2 Hz), 1.74 (2H, sextet, J = 7.3 Hz), 2.17 (1H, dd, J = 7.3, 12.2 Hz), 2.48 (3H, s),
13
2.87 (2H, t, J = 7.3 Hz), 3.20-3.26 (1H, m), 6.97 (1H, s), 7.39 (1H, s); C NMR (125
MHz, CDCl3) δ 13.77, 17.80, 19.56, 21.39, 28.46, 28.86, 35.90, 42.80, 43.34, 50.98,
123.11, 125.27, 136.52, 136.81, 144.47, 155.59, 204.47; HRMS (EI) m/z calcd for
C17H24O M+ 244.1827, found 244.1825.
4.10.
1-(2,3-dihydro-1H-1,3,3,5-tetramethyl-6-indenyl)-2-methyl-1-propanone 1d
Compound 1d was synthesized from 6 (0.089 g, 0.51 mmol) and isobutyryl chloride
(0.110 g, 1.03 mmol) with AlCl3 (0.133 g, 1.00 mmol) in 72% yield according to the
procedure described in Section 4.7.
Kugelrohr distillation (136-160 ºC/1.5 mmHg)
provided 1d as a colorless oil. IR (neat) 1684 cm-1; 1H NMR (500 MHz, CDCl3) δ 1.16
(3H, 3), 1.17 (6H, d, J = 7.0 Hz), 1.30 (3H, d, J = 6.5 Hz), 1.34 (3H, s), 1.51 (1H, dd, J
= 9.5, 12.3 Hz), 2.17 (1H, dd, J = 7.0, 12.3 Hz), 2.42 (3H, s), 3.18-3.25 (1H, m), 3.38
13
(1H, septet, J = 7.0 Hz), 6.97 (1H, s), 7.29 (1H, s); C NMR (125 MHz, CDCl3) δ
18.69, 18.75, 19.61, 29.99, 28.54, 28.95, 35.95, 38.45, 42.83, 51.03, 122.32, 125.10,
136.21, 136.94, 144.42, 155.22, 209.20; HRMS (EI) m/z calcd for C17H24O (M)+
244.1827, found 244.1833.
4.11.
Diethyl 2-(4-methylphenyl)malonate 7
LiHMDS was prepared by the treatment of HMDS (2.432 g, 15.07 mmol) with
n-BuLi (1.6 M solution in hexane, 9.4 mL, 15 mmol) in dry THF (30 mL) at 0 ºC for 30
min. To a solution of ethyl p-tolylacetate (1.778 g, 9.98 mmol) in dry THF (30 ml)
was added the LiHMDS at -78 ºC.
The mixture was stirred at -78 ºC for 30 min.
19

ACCEPTED MANUSCRIPT
To the mixture, ethyl cyanoformate (1.110 g, 11.20 mmol) was added at -78 ºC, and
then the mixture was allowed to warm to 0 ºC for 80 min.
10% HCl was added at 0
ºC, and the mixture was extracted twice with CH2Cl2. The combined organic extracts
were dried over Na2SO4. After removal of the solvent, the residue was purified by
column chromatography using silica gel (hexane/acetone = 25/1) to afford 7 as a
colorless oil (2.396 g, 96%).
the literature.28
1H NMR spectra data were identical to those reported in
4.12.
2-(4-Methylphenyl)-1,3-propanediol 8
Compound 8 was synthesized from 7 (5.930 g, 23.69 mmol) with LiAlH4 (1.800 g,
47.43 mmol) in 79% yield according to the procedure described in Section 4.3. The
crude product was purified by column chromatography using silica gel (hexane/acetone
= 3/1 to 1/1) to give 8 as a colorless oil.
1H NMR spectra data were identical to those
reported in the literature.28
4.13.
Diol 8 (2.900 g, 17.45 mmol) was dissolved in vinyl acetate (52 ml).
g) was added to the solution, and the resulting suspension was stirred at room
temperature for 3 h. The lipase was filtered off with suction. After removal of the
solvent, the residue was purified by column chromatography using silica gel
(R)-3-hydroxy-2-(4-methylphenyl)propyl acetate (R)-9
PPL (1.360
(hexane/EtOAc = 1/2) to afford (R)-9 (3.283 g, 90%).
1H NMR spectra data were
identical to those reported in the literature.28
The enantiomeric excess was
determined by HPLC (CHIRALCEL OD-H, hexane/2-propanol = 9/1) and found to be
99%. [α]D19 = +14.9 (c 0.75, CHCl3), Lit.28 [α]D = -16.2 (CHCl3), (S), 96% ee.
20

ACCEPTED MANUSCRIPT
4.14.
(R)-3-methoxymethoxy-2-(4-methylphenyl)propyl acetate (R)-10
To a solution of (R)-9 (1.790 g, 8.60 mmol) in dry CH2Cl2 (27ml) were added
DIPEA (1.780 g, 13.77 mmol) and MOMCl (1.039 g, 12.91 mmol) at 0 ºC. The
reaction mixture was stirred at room temperature overnight. After removal of the
solvent, the residue was purified by column chromatography using silica gel
(hexane/acetone = 3/2) to afford (R)-10 as a colorless oil (2.090 g, 96%). IR (neat) 1740,
1043 cm-1; 1H NMR (400 MHz, CDCl3) δ 2.01(3H, s), 2.33 (3H, s), 3.21 (1H, quintet, J
= 6.6 Hz), 3.28 (3H, s), 3.77 (2H, d, J = 6.6 Hz), 4.31 (1H, dd, J = 6.6, 11.1 Hz), 4.36
(1H, dd, J = 6.6, 11.1 Hz), 4.59 (2H, s), 7.13 (2H, d, J = 8.6), 7.15 (2H, d, J = 8.6); 13C
NMR (100 MHz, CDCl3) δ 20.53, 20.74, 44.20, 54.84, 65.15, 68.28, 96.17, 127.64,
128.92, 136.20, 136.27, 170.53; HRMS (FAB) m/z calcd for C14H21O4 (M+H)+
253.1440, found 253.1438; [α]D16 = -9.57 (c 0.40, CHCl3).
4.15.
To a solution of (R)-10 (2.090 g, 8.28 mmol) in MeOH (30 ml) was added K2CO3
(2.290 g, 16.57 mmol). The solution was stirred at room temperature for 2 h.
(S)-3-methoxymethoxy-2-(4-methylphenyl)-1-propanol (S)-11
CH2Cl2 was added, and the mixture was filtered with suction. After removal of the
solvent, the residue was purified by chromatography using silica gel (hexane/acetone =
5/1 to 3/1) to afford (S)-11 as a colorless oil (1.740 g, quant). IR (neat) 3421, 1042 cm-1;
1H NMR (500 MHz, CDCl3) δ 2.33 (3H, s), 3.14 (1H, quintet, J = 6.8 Hz), 3.35 (3H, s),
3.81-3.88 (3H, m), 3.97 (1H, dd, J = 6.8, 10.8 Hz), 4.64 (2H, s), 7.14 (4H, s); 13C NMR
(125 MHz, CDCl3) δ 20.81, 47.40, 55.05, 65.17, 69.83, 96.35, 127.72, 129.08, 136.29,
136.60; HRMS (FAB) m/z calcd for C12H19O3 (M+H)+ 211.1334, found 211.1333;
21

ACCEPTED MANUSCRIPT
[α]D16 = -20.74 (c 0.85, CHCl3).
4.16.
(R)-3-methoxymethoxy-2-(4-methylphenyl)propyl p-toluenesulfonate (R)-12
To a solution of alcohol (S)-11 (0.622 g, 2.96 mmol) in dry CH2Cl2 (9 ml) were
added Et3N (0.539 g, 5.33 mmol), TsCl (0.904 g, 4.74 mmol), and DMAP (0.072 g, 0.59
mmol) at 0 ºC. The reaction mixture was stirred at room temperature for 2 h, and the
solvent was evaporated.
The residue was purified by chromatography using silica gel
(hexane/acetone = 10/1 to 7/1) to afford (R)-12 as a colorless oil (1.080 g, quant). IR
(neat) 1362, 1177, 1043 cm-1; 1H NMR (400 MHz, CDCl3) δ 2.31 (3H, s), 2.43 (3H, s),
3.17 (1H, quintet, J = 6.5 Hz), 3.24 (3H, s), 3.72 (2H, d, J = 6.5 Hz), 4.21 (1H, dd, J =
6.5, 9.8 Hz), 4.31 (1H, dd, J = 6.5, 9.8 Hz), 4.53 (2H, s), 7.03 (2H, d, J = 8.0 Hz), 7.07
(2H, d, J = 8.0 Hz), 7.27 (2H, d, J = 8.8), 7.67 (2H, d, J = 8.8 Hz); 13C NMR (100 MHz,
CDCl3) δ 20.83, 21.39, 44.40, 55.03, 67.51, 70.70, 96.29, 127.64, 127.69, 129.03,
129.55, 132.56, 134.87, 136.68, 144.48; HRMS (FAB) m/z calcd for C19H25O5S (M+H)+
365.1423, found 365.1421; [α]D18 = -6.02 (c 0.55, CHCl3).
4.17.
(R)-1-methoxymethoxy-2-(4-methylphenyl)propane (R)-13
To a solution of (R)-12 (1.080 g, 2.96 mmol) in DMSO (7 ml) was added NaBH4
(0.224 g, 5.92 mmol) at room temperature, and the reaction mixture was stirred at 60 ºC
for 5 h. Water was added at 0 ºC, and the mixture was extracted three times with
EtOAc. The combined organic extracts were dried over Na2SO4. After removal of the
solvent, the residue was purified by column chromatography using silica gel
(hexane/acetone = 20/1) to afford (R)-13 as a colorless oil (0.489 g, 85%). IR (neat)
1
1045 cm-1; H NMR (400 MHz, CDCl3) δ 1.28 (3H, d, J = 6.9 Hz), 2.32 (3H, s), 2.99
22

ACCEPTED MANUSCRIPT
(1H, sextet, J = 6.9 Hz), 3.29 (3H, s), 3.57 (1H, dd, J = 6.9, 9.5 Hz), 3.65 (1H, dd, J =
13
6.9, 9.5 Hz), 4.59 (2H, s), 7.13 (4H, s); C NMR (100 MHz, CDCl3) δ 18.50, 20.89,
39.49, 54.96, 73.31, 96.28, 127.04, 128.95, 135.67,141.20, HRMS (EI) m/z calcd for
C11H15O (M-OCH3)+ 163.1123, found 163.1119; [α]D17 = -14.27 (c 0.60, CHCl3).
4.18.
To a solution of (R)-13 (1.550 g, 7.98 mmol) in MeOH (24 ml) was added three
drops of concentrated hydrochloric acid. The mixture was refluxed for 3.5 h.
Aqueous saturated NaHCO3 was added, and the mixture was extracted with CH2Cl2.
The organic layer was dried over Na2SO4. After removal of the solvent, the residue
(R)-2-(4-methylphenyl)-1-propanol (R)-14
was purified by column chromatography using silica gel (hexane/acetone = 2/1) to
1H NMR spectra data were identical
afford (R)-14 as a colorless oil (1.142 g, 95%).
to those reported in the literature.29
The enantiomeric excess of (R)-14 was
determined by HPLC (CHIRALCEL OB-H, hexane/2-propanol = 95/5) and found to be
99%. [α]D21 = +16.05 (c 1.0, CHCl3), Lit.29 [α]D25 = +17.4 (c 1, CHCl3), (R), 97.5% ee.
4.19.
(R)-1-iodo-2-(4-methylphenyl)propane (R)-15
Compound (R)-15 was synthesized from (R)-14 (1.817 g, 12.10 mmol) and iodine
(4.291 g, 16.91 mmol) with imidazole (1.239 g, 17.68 mmol) and PPh3 (3.803 g, 14.50
mmol) in 83% yield according to the procedure described in Section 4.4.
The crude
product was purified by column chromatography using silica gel (hexane) to give
1H NMR spectra data were identical to those reported in the
(R)-15 as a colorless oil.
literature.29 [α]D25 = +33.59 (c 1.1, CHCl3), Lit.29 [a]D25 = +30.1 (c 1, CHCl3), (R).
23

ACCEPTED MANUSCRIPT
4.20.
(S)-4-(4-methylphenyl)-1-pentene (S)-16
The Gilman reagent was prepared by slow addition of MeLi (1.08 M solution in
hexane, 16 ml, 17 mmol) to tetravinyltin (0.946 g, 4.17 mmol) in dry Et2O (2.5 mL) at 0
ºC and then stirred for 30 min.
The solution was then transferred to a flask
containing CuI (1.600 g, 8.40 mmol) and dry Et2O (4 ml) at -78 ºC, and the reaction
mixture was allowed to warm to -35ºC for 30 min. The mixture was cooled to -78 ºC
and added to the solution of (R)-15 (0.550 g, 2.11 mmol) in dry Et2O (4 ml). The
reaction mixture was allowed to warm to 0 ºC for 1.5 h.
Aqueous saturated NH4Cl
The filtrate was
was added at 0 ºC, and the mixture was filtered with suction.
extracted with CH2Cl2, and the organic layer was dried over Na2SO4. After removal
of the solvent, the residue was purified by chromatography using silica gel (hexane) to
afford (S)-16 as a colorless oil (0.241 g, 71%).
1H NMR spectra data were identical
24
20
to those reported in the literature.30 [α]D = +21.65 (c 0.30, CHCl3), Lit.30 [a]D
=
+15.0 (c 1.0, CHCl3), 98% ee (S).
4.21.
(S)-4-(4-methylphenyl)-2-pentanone (S)-17
To a solution of (S)-16 (0.097 g, 0.61 mmol) in DMF (1.5 ml) and H2O (0.5 ml),
CuCl (0.060 g, 0.61 mmol) and PdCl2 (0.032 g, 0.18 mmol) were added, and the
resulting suspension was stirred at room temperature under an oxygen atmosphere
overnight.
Aqueous saturated NaHCO3 was added, and the mixture was extracted
three times with Et2O.
dried over Na2SO4.
The combined organic extracts were washed with brine and
After removal of the solvent, the residue was purified by
chromatography using silica gel (hexane/acetone = 50/1 to 30/1) to afford (S)-17 a
colorless oil (0.063 g, 59%).
1H NMR spectra data were identical to those reported in
24

ACCEPTED MANUSCRIPT
27
20
the literature.31 [α]D = +30.7 (c 0.15, CH2Cl2), Lit.32 [a]D = -30.0 (c 1.0, CH2Cl2),
89% ee, (R).
4.22.
(S)-2-methyl-4-(4-methylphenyl)-1-pentene (S)-5
To a solution of MePPh3Br (2.357 g, 6.60 mmol) in dry THF (6 ml) was added
n-BuLi (1.6 M solution in hexane, 3.9 mL, 6.2 mmol) at 0 ºC. The solution of (S)-17
(0.231 g, 1.31 mmol) in dry THF (6 ml) was added dropwise at room temperature, and
the mixture was stirred overnight.
Aqueous saturated NH4Cl was added at 0 ºC.
The mixture was extracted with EtOAc, and the organic layer was dried over Na2SO4.
After removal of the solvent, the residue was purified by chromatography using silica
gel (hexane) to afford (S)-5 a colorless oil (0.160 g, 70%).
1H NMR spectra were
identical to those of (±)-5.
The enantiomeric excess was determined by GC
25
(CP-Cyclodextrin-β-2,3,6-M-19 capillary column, 70 ºC) and found to be 99%. [α]D
-1.61 (c 1.35, CHCl3).
=
4.23.
Cyclialkylation of (S)-5
The alkene (S)-5 (0.053 g, 0.30 mmol) was treated with AlCl3 (0.008 g, 0.06 mmol)
in dry benzene (0.9 mL) at room temperature for 3 h according to the procedure
described in Section 4.6.
1H NMR spectra data of the product (S)-6 were identical to
those of (±)-6.
The enantiomeric excess was determined by GC
(CP-Cyclodextrin-β-2,3,6-M-19 capillary column, 100 ºC) and found to be 93%. The
cyclialkylation was conducted under the same conditions once again, and the ee of the
product (S)-6 was 86%.
25

ACCEPTED MANUSCRIPT
4.24.
Treatment of (S)-6 with AlCl3
To the solution of (S)-6 (0.052 g, 0.30 mmol) with 99% ee (See Section 4.34) in dry
benzene (0.9 ml), AlCl3 (0.008 g, 0.060 mmol) was added at 0 ºC, and the mixture was
stirred at room temperature for 3 h.
ºC, and the resulting precipitate was filtered off with suction.
extracted with EtOAc and then dried over Na2SO4. After removal of the solvent, the
residue was purified by chromatography using silica gel (hexane/EtOAc = 20/1) to
Aqueous saturated NaHCO3 was then added at 0
The filtrate was
recover (S)-6.
(±)-6.
1H NMR spectra data of the recovered (S)-6 were identical to those of
The enantiomeric excess was determined by GC
(CP-Cyclodextrin-β-2,3,6-M-19 capillary column, 100 ºC) and found to be 98%.
4.25.
Ethyl 3,3,5-trimethylindane-1-carboxylate 21
To the solution of 2 (2.637 g, 11.35 mmol) in dry benzene (34 ml), AlCl3 (3.800 g,
28.50 mmol) was added at 0 ºC. The mixture was stirred at room temperature for 3.5
h. Aqueous saturated NaHCO3 was added at 0 ºC, and the resulting precipitate was
filtered off with suction.
The filtrate was extracted with EtOAc, and the organic layer
was dried over Na2SO4. After removal of the solvent, the residue was purified by
chromatography using silica gel (hexane/EtOAc = 20/1) to afford 21 (2. 290 g, 87%). IR
(neat) 1737 cm-1; 1H MNR (400 MHz, CDCl3) δ 1.21 (3H, s), 1.30 (3H, t, J = 7.0 Hz),
1.36 (3H, s), 2.18 (1H, dd, J = 8.5, 12.6 Hz), 2.30 (1H, dd, J = 8.5, 12.6 Hz), 2.35 (3H,
s), 4.03 (1H, t, J = 8.5 Hz), 4.21 (2H, q, J = 7.0 Hz), 6.97 (1H, s), 7.01 (1H, d, J = 7.4
Hz), 7.23 (1H, d, J = 7.4 Hz); 13C NMR (100 MHz, CDCl3) δ 14.16, 21.23, 28.76, 29.35,
43.04, 44.25, 47.33, 60.50, 122.76, 124.30, 127.38, 136.27, 137.21, 152.29, 173.81;
HRMS (FAB) m/z calcd for C15H21O2 (M+H)+ 233.1542, found 233.1539.
26

ACCEPTED MANUSCRIPT
4.26.
2,3-dihydro-1H-3,3,5-trimethyl-1-indenylmethanol 22
Compound 22 was synthesized from 21 (1.248 g, 5.37 mmol) with LiAlH4 (0.306 g,
8.06 mmol ) in 95% yield according to the procedure described in Section 4.3. The
crude product was purified by chromatography using silica gel (hexane/EtOAc = 3/1).
IR (neat) 3344 cm-1; 1H NMR (400 MHz, CDCl3) δ 1.20 (3H, s), 1.35 (3H, s), 1.77 (1H,
dd, J = 8.4, 12.6 Hz), 2.12 (1H, dd, J = 7.6, 12.6 Hz), 2.35 (3H, s), 3.35-3.42 (1H, m),
3.82-3.39 (2H, m), 6.98 (1H, s), 7.01 (1H, d, J = 7.6 Hz), 7.14 (1H, d, J = 7.6 Hz); 13C
NMR (100 MHz, CDCl3) δ 21.27, 29.15, 29.79, 42.70, 44.39, 45.00, 60.04, 122.92,
+
123.40, 127.16, 136.66, 139.35, 153.24; HRMS (FAB) m/z calcd for C13H18O M
190.1358, found 190.1357.
4.27.
Lipase-catalyzed transesterification of 22 (screening experiments)
In a typical run, a dry THF solution (1 mL) containing racemic primary alcohol 22
(0.045 mmol) and vinyl acetate (1.0 mmol) was added to a vial in which Sigma PPL
(100 mg) was placed.
The time-courses of the reaction were monitored by GC using InertCap 1 capillary
column (220 °C). The reaction was stopped by the filtration of the lipase at a
The resulting suspension was then stirred at room temperature.
conversion of approximately 50%. The conversion was calculated from the ratio of
the peak area of ester 23 in gas chromatogram to the total of the peak areas of 22 and 23.
The peak areas of the two compounds were corrected on the basis of the number of
carbon atoms in the molecules.33
The filtrate was concentrated, and the residue was
purified by column chromatography on silica gel (hexane/EtOAc = 10/1 to 1/1) packed
in a short column (10 mm ϕ × 80 mm) to afford (R)-22 and (S)-23.
The enantiomeric
27

ACCEPTED MANUSCRIPT
excess of (R)-22 was determined by GC using CP-Cyclodextrin-β-2,3,6-M-19 capillary
column (150 °C).
The enantiomeric excess of (S)-23 was determined by HPLC using
the OJ-H column (hexane/2-propanol = 9/1).
The E-value and the conversion of the
reaction were calculated from the ee of (R)-22 and (S)-23.22
4.28.
Preparative kinetic resolution of 22 (preparation of (R)-22 and (S)-22)
PPL (11.12 g) was added to the solution of 22 (2.764 g, 14.53 mmol) and vinyl
acetate (25.00 g, 290.40 mmol) in dry THF (120 ml). The resulting suspension was
stirred at room temperature for 3.5 h.
stirring continued for a further 3.5 h.
PPL (1.700 g) was added to the mixture and
The conversion, which was calculated by GC
using InertCap 1 capillary column (220 °C), was then approximately 56%.
The lipase
was filtered off with suction. After removal of the solvent, the residue was purified
by chromatography using silica gel (hexane/EtOAc = 5/1 to 1/1) to afford (R)-22 (1.225
g, 44%) and (S)-23 (1.885 g, 56%) as colorless oils.
1
(R)-22: H NMR spectra data were identical to those of (±)-22.
The enantiomeric
excess was determined by GC (CP-Cyclodextrin-β-2,3,6-M-19 capillary column,
150 °C) and found to be >99%. [α]D19 = +8.55 (c 1.0, CHCl3).
1
(S)-23: IR (neat) 1741 cm-1; H NMR (400 MHz, CDCl3) δ 1.19 (3H, s), 1.34 (3H, s),
1.67 (1H, dd, J = 8.6, 12.7 Hz), 2.10 (3H, s), 2.14 (1H, dd, J = 7.6, 12.7 Hz), 2.35 (3H,
s), 3.45-3.52 (1H, m), 4.19 (1H, dd, J = 7.2, 10.8 Hz), 4.34 (1H, dd, J = 6.4, 10.8 Hz),
13
6.97 (1H, s), 6.99 (1H, d, J = 7.8 Hz), 7.14 (1H, d, J = 7.8 Hz) ; C NMR (100 MHz,
CDCl3) δ 21.03, 21.41, 29.22, 29.68, 41.18, 42.87, 45.58, 68.08, 122.99, 123.70, 127.35,
137.07, 139.11, 152.96, 171.22; HRMS (FAB) m/z calcd for C15H21O2 (M+H)+
233.1542, found 233.1543.
28