Syntheses and odor properties of optically active dimethyl octenone and its analogs

Article abstract of DOI:10.1016/j.tetasy.2016.02.002

The optically active isomers of dimethyl octenone, which is used in citrus accords, and its analogs, were synthesized from a common chiral intermediate prepared by the lipase-catalyzed desymmetrization of prochiral diol. The results of an olfactory evaluation of the prepared isomers are also reported.

Full text of DOI:10.1016/j.tetasy.2016.02.002

Tetrahedron: Asymmetry xxx (2016) xxx–xxx
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Syntheses and odor properties of optically active dimethyl octenone
and its analogs
b
c
d
e
Masashi Kawasaki a, , Momo Shimizu , Saki Kuroyanagi , Yoshiaki Shishido , Tsuyoshi Komiyama ,
⇑
Naoki Toyooka c,f
a Department of Liberal Arts and Sciences, Faculty of Engineering, Toyama Prefectural University, 5180 Kurokawa, Imizu, Toyama-ken 939-0398, Japan
b Department of Life Sciences and Bioengineering, Faculty of Engineering, University of Toyama, 3190 Gofuku, Toyama 930-8555, Japan
c Graduate School of Science and Technology, University of Toyama, 3190 Gofuku, Toyama 930-8555, Japan
d Fragrance Creation, Givaudan Japan KK, 3014-1 Shinohara-cho, Kohoku-ku, Yokohama 222-0026, Japan
e Quality Control Team, Operations Flavours, Givaudan Japan KK, 3056 Kuno, Fukuroi, Shizuoka-ken 437-0061, Japan
f Graduate School of Innovation Life Science, University of Toyama, 3190 Gofuku, Toyama 930-8555, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
The optically active isomers of dimethyl octenone, which is used in citrus accords, and its analogs, were
synthesized from a common chiral intermediate prepared by the lipase-catalyzed desymmetrization of
prochiral diol. The results of an olfactory evaluation of the prepared isomers are also reported.
Ó 2016 Elsevier Ltd. All rights reserved.
Received 7 December 2015
Accepted 2 February 2016
Available online xxxx
1. Introduction
O
OH
O
Essential oils obtained from citrus fruits, called citrus oils, such
as bergamot, grapefruit, lemon, lime, mandarin, orange, and tan-
gerine are important raw materials for citrus flavors.1 Citrus flavors
are popular in beverages as well as in sweet products, such as con-
fectionery, cookies and desserts.2 Moreover, they have become
popular in sauces and dressings. As a result, the citrus oil industry
produces the oils in large quantities. In 2007, for example, the
amount of the oils that were produced from oranges, lemons,
limes, and mandarin oranges were assumed to reach 51,000 t,
9,200 t, 1,800 t, and 460 t, respectively.1
Citrus oils are also used in perfumes, eau de toilettes, cosmetic
products, toiletry and household products to give freshness and
lightness.1 A certain women’s perfume, which is maybe the world’s
most famous, utilizes lemon and bergamot oils.3 Synthetic ingredi-
ents as well as citrus oils are also used in fragrances. 2,6-Dimethyl-
7-octen-2-ol (dihydromyrcenol) is a synthetic ingredient used in
the fragrances for a citrus note (Fig. 1).3 Some acetals and nitriles
also possess a citrus character, for example, citronellal dimethyl
acetal and citronellyl nitrile.4 The racemic 4,7-dimethyl-6-octen-
3-one (dimethyl octenone) 1b has a citrus odor and is used in fra-
grance material to give a fresh top note.5–8
2,6-dimethyl-7-octen-2-ol
citronellal dimethyl acetal
O
CN
R
citronellyl nitrile
1a: R = Me
1b
: R = Et (dimethyl octenone)
1c: R = n-Pr
1d: R = n-Bu
1e: R = n-C5H11
Figure 1. Synthetic ingredients with citrus odor.
as specific enantiomers, and the aroma of such specific enan-
tiomers can be distinctive and characteristic.10 For example, (R)-
(+)-limonene, present in citrus peel oils, has an orange odor, while
(S)-(-)-limonene, found in oils from Mentha species, has a harsh
odor.10,11 The syntheses of both enantiomers of fragrance ingredi-
ents in highly enantiomerically pure form and the evaluation of the
odor properties of both enantiomers are accordingly of great inter-
est.12–36
We recently reported the syntheses of both enantiomers of Ros-
aphenÒ (2-methyl-5-phenyl-1-pentanol), valuable for adding floral
notes in soaps and domestic fragrances,37,38 and showed that the
odors of the enantiomers are distinctive.39 Moreover, we reported
The enantiomers of many chemical compounds are perceived
differently as odorants by the human nose; in plain terms, they
smell differently.9 Many natural aroma chemicals occur in Nature
⇑
Corresponding author. Tel.: +81 766 56 7500; fax: +81 766 56 6117.
E-mail address: kawasaki@pu-toyama.ac.jp (M. Kawasaki).
http://dx.doi.org/10.1016/j.tetasy.2016.02.002
0957-4166/Ó 2016 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Kawasaki, M.; et al. Tetrahedron: Asymmetry (2016), http://dx.doi.org/10.1016/j.tetasy.2016.02.002

2
M. Kawasaki et al. / Tetrahedron: Asymmetry xxx (2016) xxx–xxx
CO2Et
NaH
CO2Et
CO2Et
2 (58%)
+
THF, rt
Br
CO2Et
LiAlH4
OH
OH
THF, rt
3 (86%)
Scheme 1. Synthesis of prochiral diol 3.
O
O
n-C3H7
OH
O
(R)-4
Amano PS
OH
OH
+
O
n-C3H7
solvent, rt
+
O
3
O
n-C3H7
n-C3H7
O
O
5
Scheme 2. Enantioselective transesterification of prochiral diol 3.
Table 1
Effect of organic solvents on the enantioselective transesterification of 3
the syntheses of both enantiomers of cyclamen aldehyde
{2-methyl-3-(4-(1-methylethyl)phenyl)propanal}, an important
component for obtaining special blossom notes in perfume
composition,40 and the differences in the odors between the
enantiomers.41
Recently, Clarke et al. reported the asymmetric synthesis of
(S)-1b.42 However, this method required stoichiometric enan-
tiomerically pure compounds to synthesize (S)-1b, and the abso-
lute configuration was not determined. In addition, the
enantiomeric excess was moderate (89%), and no evaluation of
the odor profile of the synthesized (S)-1b was reported. We there-
fore became interested in developing a catalytic route to both
enantiomers of 1b and their odor profiles.
Entry
Solvent
Time (h)
3c (%)
(R)-4c (%)
ee (%)
5c (%)
1
1,4-Dioxane
Acetonitrile
Acetone
THF
Et2O
CH2Cl2
4.5
2.0
7.0
4.5
1.8
1.8
1.0
1.8
3
4
6
8
2
15
0
9
95
94
93
91
96
85
94
89
94
94
92
92
92
94
95
92
2
2
1
1
2
0
6
2
2a
3
4
5a
6
7a
8b
i-Pr2O
Toluene
Conditions: PS 20 mg/mL, diol 3 100 mM, vinyl butyrate 500 mM, rt.
a
PS 50 mg/mL.
PS 5 mg/mL, vinyl butyrate 200 mM.
The molar ratio was determined on the basis of the ratio of the peak areas of 3,
b
c
Herein we report the flexible syntheses of both enantiomers of
1b and its analogs 1a, 1c–e and the evaluation of their odor
profiles.
(R)-4 and 5.
ee) was achieved with diisopropyl ether (entry 7). The absolute
configuration of (R)-4 was thought to be (R) on the basis of the
empirical rule for the enantiopreference of the lipase.44 Although
we tried to use other esterification reagents such as vinyl acetate
or propionate, we could not achieve an ee of more than 95%. On
the basis of these results, we conducted a large scale desym-
metrization of 3 in diisopropyl ether and obtained (R)-4 with 95%
2. Results and discussion
2.1. Syntheses of the (S)-enantiomers of dimethyl octenone and
its analogs
Prochiral diol 3 was easily prepared by the alkylation of diethyl
malonate with 1-bromo-3-methyl-2-butene followed by LiAlH4
reduction (Scheme 1).
ee {[a]
22 = +14.2 (c 0.9, CHCl3)} in 93% yield.
D
The optically active monoester (R)-4 obtained above was con-
verted into the corresponding methanesulfonate (S)-6 with
methanesulfonyl chloride (MsCl) (Scheme 3). The methanesul-
fonate (S)-6 was then treated with LiAlH4 to give a mixture of
the desired primary alcohol (S)-7 and 1-butanol generated by the
reduction of the butyrate moiety. Since no separation of the two
alcohols occurred with thin layer chromatography, we abandoned
the separation of the two alcohols with silica-gel chromatography.
Evaporation for a long time did remove the 1-butanol from the
In a previous study, we succeeded in the desymmetrization of
two prochiral 2-substituted 1,3-propanediols by the lipase (Amano
PS)-catalyzed transesterification with vinyl esters in a highly enan-
tioselective manner.39,41 We found vinyl butyrate to be the best
acylation reagent for the enantioselective transesterification of 2-
hydroxymethyl-5-phenyl-1-pentanol.39 We therefore chose vinyl
butyrate as an acylation reagent (Scheme 2). The prochiral selectiv-
ity of lipases has been found to depend on the nature of the sol-
vent.43 We therefore performed reaction solvent screening
experiments (Table 1) and the highest prochiral selectivity (95%
mixture to afford (S)-7 with 95% ee {[
a
]
19 = À4.3 (c 1.0, CH2Cl2),
D
lit.45
[a]
D = À4.4 (c 3.8, CH2Cl2), (S), 95% ee}. However, this resulted
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M. Kawasaki et al. / Tetrahedron: Asymmetry xxx (2016) xxx–xxx
3
O
O
MsCl, pyridine
O
n-C3H7
O
n-C3H7
CH2Cl2, 0 o
C
OMs
OH
(R)-4 (95% ee)
(S)-6 (87%)
LiAlH4
Et2O, reflux
Dess-Martin
CH2Cl2, rt
CHO
OH
7
(S)- (66%, 95% ee)
(S)-8 (37-48%)
[α]D19 = -4.3 (c 1.0, CH2Cl2),
Lit.45 [α]D = -4.4 {c 3.8, CH2Cl2, (S), 95% ee}
OH
O
1) RMgI/Et2O, rt
2) NH4Cl aq., 0 o
Dess-Martin
CH2Cl2, rt
R
R
C
(S)-1a (42%, 95% ee)
(S)-1b (64%, 95% ee)
(S)-1c (71%, 95% ee)
(S)-1d (83%, 95% ee)
(S)-1e (75%, 95% ee)
9a:
(S)-
R = Me (77%)
(S)-9b: R = Et (68%)
(S)-9c: R = n -Pr (69%)
9d:
(S)-
R = n -Bu (79%)
(S)-9e: R = n -C5H11 (70%)
Scheme 3. Syntheses of the (S)-isomers of dimethyl octenone and its analogs.
in a slightly low yield of (S)-7 (66%). The ee of (S)-7 was the same as
that of the intermediate (R)-4, which indicates that no racemiza-
tion occurred during the transformation from (R)-4 to (S)-7. The
optically active primary alcohol (S)-7 was then oxidized with
Dess–Martin periodinane to give the corresponding aldehyde
(S)-8. The yield of (S)-8 was considerably low because of the
volatilization loss of (S)-8 in the evaporation of solvents. The addi-
tion of Grignard reagents prepared from iodoalkanes I(CH2)n-1CH3
(n = 1–5) to aldehyde (S)-8 gave a mixture of diastereomers
(S)-9a-e. The syntheses of (S)-1a-e were finally accomplished by
Dess–Martin oxidation of (S)-9a-e. The ees of (S)-1a-e were the
same as that of the intermediate (S)-7, which indicates that no
racemization occurred during the transformation from (S)-7 to
(S)-1a-e.
2.2. Syntheses of the (R)-enantiomers of dimethyl octenone and
its analogs
We synthesized (R)-1 from the common intermediate (R)-4
shown in Scheme 3. At first, the hydroxyl group of (R)-4 was pro-
tected with tert-butyldimethylsilyl trifluoromethanesulfonate
(TBDMSOTf) to give (S)-10 (Scheme 4). The ester moiety of (S)-10
was hydrolyzed with NaOH to give the corresponding alcohol (S)-
11, which was converted into the corresponding methanesulfonate
(R)-12 with MsCl. Treatment of (R)-12 with LiAlH4 gave the pri-
mary alcohol (R)-7 with 95% ee {[a]
19 = +4.2 (c 0.9, CH2Cl2), lit.45
D
[
a
]
D = À4.4 (c 3.8, CH2Cl2), (S), 95% ee}, which was produced by
the reduction of both methanesulfonic acid ester and TBDMS
ether moieties. The syntheses of (R)-1a-e were accomplished from
O
O
TBDMSOTf, pyridine
CH2Cl2, 0 o
O
n-C3H7
O
n-C3H7
C
OH
OTBDMS
(R)-4 (95% ee)
(S)-10 (92%)
MsCl
CH2Cl2, 0 o
NaOH
OH
OMs
H2O, EtOH, rt
C
OTBDMS
(S)-11 (86%)
OTBDMS
(R)-12 (95%)
OH
1) Dess-Martin/CH2Cl2, rt
2) RMgI/Et2O, rt
O
LiAlH4
OH
R
Et2O, reflux
3) NH4Cl aq., 0 o
4) Dess-Martin/CH2Cl2, rt
C
1a
(R)- (9%, 95% ee)
7
(R)- (87%, 95% ee)
[α]D19 = +4.2 (c 0.9, CH2Cl2)
Lit.45 [α]D = -4.4 {c 3.8, CH2Cl2, (S), 95% ee}
1b
(R)- (15%, 95% ee)
1c
(R)- (25%, 95% ee)
1d
(R)- (21%, 95% ee)
1e
(R)- (20%, 95% ee)
Scheme 4. Syntheses of the (R)-isomers of dimethyl octenone and its analogs.
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M. Kawasaki et al. / Tetrahedron: Asymmetry xxx (2016) xxx–xxx
(R)-7 according to the same procedures as those for (S)-1a-e; we
obtained the (R)-enantiomer of dimethyl octenone and its analogs
in optically active form (95% ee).
obtained using a Jeol MStation JMS-700 instrument. Optical rota-
tions were recorded on a Jasco P-1300 polarimeter. Gas chro-
matograms were recorded on
a
Shimadzu GC-2014 gas
chromatograph with Cyclodextrine-b-236M-19 capillary column
(Agilent Technologies, 25 m  0.25 mm /) or GAMMA DEXTM 120
capillary column (Supelco, 30 m  0.25 mm /) to follow the
lipase-catalyzed reactions and determine the enantiomeric
excesses (ees) of the products.
2.3. Odor profiles
The odor profiles of the obtained optically active ketones {(R)-
and (S)-1} were evaluated by three skilled perfumers (Givaudan
Japan KK). The following descriptions were obtained.
4.2. Syntheses of the (S)-enantiomers
(R)-1a: stronger than (S)-1a, grapefruit-like, herbal-green, peel-
like, slightly perilla-like.
4.2.1. Ethyl 2-ethoxycarbonyl-5-methyl-4-hexenoate 2
(S)-1a: clean, grapefruit-like, lighter than racemic dimethyl
octenone (RS)-1b.
(R)-1b: vetiveryl acetate-like, woody, racemic dimethyl octe-
none (RS)-1b-like.
(S)-1b: clean, sharp, grapefruit-like, less herbal-woody than
(R)-1b.
(R)-1c: grapefruit-like, slightly fruity, slightly heavy, carrot
seed-like.
(S)-1c: fruitier than racemic dimethyl octenone (RS)-1b, green.
(R)-1d: green-fruity, herbal, slightly powdery-woody.
(S)-1d: clean, fruity, grapefruit-like, slightly heavy.
(R)-1e: herbal-green, woody-powdery, slightly fatty.
(S)-1e: heavy, fruity, pear-like.
A solution of diethyl malonate (8.066 g, 50.36 mmol) in dry THF
(5 mL) was added dropwise to a suspension of 60% sodium hydride
(2.052 g, 51.30 mmol) in dry THF (10 mL) at room temperature.
After stirring for 30 min at room temperature, a solution of 1-
bromo-3-methyl-2-butene (5.031 g, 33.76 mmol) in dry THF
(5 mL) was added dropwise to the suspension. The reaction mix-
ture was stirred overnight at room temperature under an argon
atmosphere. After cooling to 0 °C, the mixture was acidified with
3 mol/L HCl (20 mL) and extracted three times with ether. The
organic layer was washed with a saturated sodium chloride solu-
tion, then dried over Na2SO4 and concentrated under reduced pres-
sure. The residue was chromatographed (silica gel, hexane/ethyl
acetate = 5/1) to give ethyl 2-ethoxycarbonyl-5-methyl-4-buteno-
ate 2 as a colorless oil (4.447 g, 58%). The 1H NMR spectra were
identical to those reported in the literature.47
Although it has been reported that the fruity odor of simple pri-
mary alcohols (C6–C12) becomes weaker and weaker and the fatty
odor becomes stronger and stronger with an increase in the num-
ber of the carbon atoms in the molecule,46 the change of the odors
with the regularity by the numerical increase in the carbon atoms
was not observed herein. The odors of (R)-enantiomers are greener,
more herbal, and woodier than those of the (S)-enantiomers, and
the odors of the (S)-enantiomers are fruitier, cleaner, and more
grapefruit-like than those of the (R)-enantiomers but weaker.
Therefore, the odors of the (S)-enantiomers are roughly more
citrus-like than those of the (R)-enantiomers.
4.2.2. 2-Hydroxymethyl-5-methyl-4-hexen-1-ol 3
A solution of ethyl 2-ethoxycarbonyl-5-methyl-4-butenoate 2
(4.139 g, 18.13 mmol) in dry THF (20 mL) was slowly added to a
suspension of LiAlH4 (1.392 g, 36.68 mmol) in dry THF (20 mL) at
0 °C. The reaction mixture was stirred overnight at room tempera-
ture under an argon atmosphere. The reaction mixture was
quenched at 0 °C with deionized water, and 6 mol/L HCl (25 mL)
was added to the mixture. The resulting mixture was extracted
three times with ether. The organic phase was washed with a sat-
urated sodium chloride solution and dried over Na2SO4. After
removal of the solvents, the residue was chromatographed (silica
gel, hexane/acetone = 1/1) to give 2-hydroxymethyl-5-methyl-4-
hexen-1-ol 3 as a colorless viscous oil (2.223 g, 86%); 1H NMR: d
5.14 (1H, t, J = 7.4), 3.81 (2H, dd, J = 4.0, J = 10.8), 3.67 (2H, dd,
J = 7.4, J = 10.6), 1.98 (2H, t, J = 7.4), 1.78–1.87 (1H, m), 1.71 (3H,
s), 1.61 (3H, 3); 13C NMR: d 133.43, 121.81, 66.23, 42.81, 26.60,
25.78, 17.75; IR (neat): 3331, 1031 cmÀ1; HRMS (FAB) calcd for
C8H17O2 (M++H), 145.1229. Found: 145.1228.
3. Conclusion
The syntheses of both enantiomers of dimethyl octenone and its
analogs from the common chiral intermediate obtained via the
lipase-catalyzed desymmetrization of the prochiral diol have been
achieved. In addition, the evaluation of the odor profiles of the chi-
ral ketones {(R)- and (S)-1} indicates that the odors of the (S)-enan-
tiomers are roughly more citrus-like than those of the (R)-
enantiomers.
4.2.3. 2-Hydroxymethyl-5-methyl-4-hexen-1-yl butanoate (RS)-
4 and 2-butanoyloxymethyl-5-methyl-4-hexen-1-yl butanoate
5
4. Experimental
4.1. General
2-Hydroxymethyl-5-methyl-4-hexen-1-yl butanoate (RS)-4 and
2-butanoyloxymethyl-5-methyl-4-hexen-1-yl butanoate 5 were
prepared as authentic samples. Butyryl chloride (0.083 g,
0.78 mmol) was then slowly added to a solution of 2-hydrox-
ymethyl-5-methyl-4-hexen-1-ol 3 (0.103 g, 0.71 mmol) and dry
pyridine (0.145 g, 1.83 mmol) in dry CH2Cl2 (2 mL) at 0 °C. The
reaction mixture was stirred for 1 h at room temperature and
quenched at 0 °C with deionized water. The resulting mixture
was extracted with ether. The organic phase was washed with a
saturated sodium hydrogen carbonate solution, and a saturated
sodium chloride solution, successively, and then dried over sodium
sulfate. After the removal of the solvents, the residue was chro-
matographed (silica gel, hexane/ethyl acetate = 2:1–1:1) to give
(RS)-4 (0.079 g, 52%) and 5 (0.040 g, 20%) as a colorless oil. (RS)-
4: 1H NMR: d 5.13 (1H, t, J = 7.4), 4.21 (1H, dd, J = 4.4, J = 11.2),
4.07 (1H, dd, J = 6.4, J = 11.2), 3.59 (1H, dd, J = 4.8, J = 11.2), 3.51
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. Ether used for Grignard reaction was distilled
from Na/benzophenone under an argon atmosphere. Lipase
(Amano PS) was purchased from Amano Enzyme, Inc., and dried
over P2O5 for three days at room temperature. Racemic 4,7-
dimethyl-6-octen-3-one (dimethyl octanone) (RS)-1b was pro-
vided by Givaudan Japan KK. The NMR spectra were recorded using
a Bruker Advance II 400 (400 MHz 1H, 100 MHz 13C) spectrometer
for solution in CDCl3 with TMS as the internal standard, and the J
values are given in hertz. IR spectra were recorded on a Jasco
FT/IR-410 spectrometer using KBr plates. HRMS spectra were
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M. Kawasaki et al. / Tetrahedron: Asymmetry xxx (2016) xxx–xxx
5
(1H, dd, J = 6.4, J = 11.2), 2.32 (2H, t, J = 7.4), 2.04 (2H, t, J = 7.2),
1.81–1.90 (1H, m), 1.71 (3H, s), 1.66 (2H, sextet, J = 7.3), 1.62
(3H, s), 0.96 (3H, t, J = 7.4); 13C NMR: d 174.34, 133.82, 121.38,
64.19, 62.80, 41.31, 36.23, 26.67, 25.81, 18.49, 17.73, 13.70; IR
(neat): 3443, 1737, 1184, 1040 cmÀ1; HRMS (FAB) calcd for
J = 7.5), 0.96 (3H, t, J = 7.4); 13C NMR: d 173.48, 135.01, 119.93,
69.01, 62.96, 38.47, 37.25, 36.10, 26.33, 25.81, 18.41, 17.80,
13.69; IR (neat): 1733, 1357, 1177 cmÀ1; HRMS (FAB) calcd for
24
C
13H25O5S (M++H), 293.1423. Found: 293.1424; [
a
]
À1.75 (c
D
0.5, CH2Cl2).
C
12H23O3 (M++H), 215.1647. Found: 215.1649. 5: 1H NMR: d 5.10
(1H, t, J = 7.4), 4.07 (2H, dd, J = 5.0, J = 11.0), 4.02 (2H, dd, J = 6.0,
J = 11.2), 2.29 (4H, t, J = 7.6), 2.00–2.10 (3H, m), 1.70 (3H, s), 1.65
(4H, sextet, J = 7.5), 1.59 (3H, s), 0.95 (6H, t, J = 7.4); 13C NMR: d
173.66, 134.18, 120.71, 63.85, 38.01, 36.19, 26.79, 25.79, 18.45,
17.69, 13.68; IR (neat): 1739, 1176 cmÀ1; HRMS (FAB) calcd for
4.2.7. (S)-2,5-Dimethyl-4-hexen-1-ol (S)-7
A solution of (S)-6 (3.377 g, 11.55 mmol) in dry ether (20 mL)
was slowly added to a suspension of LiAlH4 (0.878 g, 23.14 mmol)
in dry ether (20 mL). The reaction mixture was refluxed for 7 h
under an argon atmosphere. The reaction mixture was quenched
at 0 °C with deionized water, and 3 mol/L HCl (30 mL) was added
to the mixture. The resulting mixture was extracted three times
with ether. The organic phase was washed with deionized water,
and a saturated sodium chloride solution, successively, and dried
over Na2SO4. After removal of the solvents, the residue was chro-
matographed (silica gel, hexane/acetone = 2/1) to give a mixture
of (S)-2,5-dimethyl-4-buten-1-ol (S)-7 and 1-butanol, which was
generated by the reduction of the butyrate. Evaporation of the mix-
ture for 10 h to remove the 1-butanol gave (S)-7 as a colorless oil
(0.975 g, 66%). The 1H NMR spectra were identical to those
reported in the literature45; Ee: 95% (GAMMA DEXTM 120 capillary
C
16H29O4 (M++H), 285.2066. Found: 285.2065.
4.2.4. Lipase-catalyzed desymmetrization of 2-hydroxymethyl-
5-methyl-4-hexen-1-ol 3 (screening experiments)
In a typical run, a 1,4-dioxane solution (1 mL) containing diol 3
(0.1 mmol) and vinyl butanoate (0.5 mmol) was added to a vial in
which Amano PS (20 mg) was placed. The resulting suspension was
then stirred at room temperature. The time-courses of the reaction
were monitored by gas chromatography analysis (Cyclodextrin-b-
236M-19 capillary column, 190 °C). When the ratio of the peak
area of monoester (R)-4 in a gas chromatogram to the total of
the peak areas of 3, (R)-4 and diester 5 reached approximately
90%, the ee of (R)-4 was determined by gas chromatography anal-
ysis (cyclodextrin-b-236M-19 capillary column, starting at 125 °C
for 58 min and then raising the temperature by 10 °C/min until
200 °C). The peak areas of the three compounds were corrected
on the basis of the number of carbon atoms.48
column, 80 °C); [
CH2Cl2), (S), 95% ee}.
a
]
19 = À4.3 (c 1.0, CH2Cl2), {Lit.45
[
a]
D = À4.4 (c 3.8,
D
4.2.8. (2RS,3S)-3,6-Dimethyl-5-hepten-2-o1 (S)-9a
A solution of (S)-7 (0.604 g, 4.71 mmol) in dry CH2Cl2 (3 mL)
was slowly added to a suspension of 95% Dess–Martin periodinane
(2.535 g, 5.68 mmol) in dry CH2Cl2 (9 mL) at room temperature.
The reaction mixture was stirred for 1 h and then quenched with
ether (15 mL) and a saturated sodium hydrogen carbonate solution
(20 mL) containing Na2S2O3 (2.5 g). The resulting mixture was
extracted with ether. The organic phase was washed with a satu-
rated sodium chloride solution, and then dried over Na2SO4. After
removal of the solvents, the residue was chromatographed (silica
gel, hexane/acetone = 5:1) to give 2,5-dimethyl-4-butenal (S)-8 as
a colorless oil (0.259 g, 44%), which was immediately used for
the next step. The 1H NMR spectra were identical to those of (S)-
8 in the literature.49
Next, Mg shavings (0.247 g, 10.16 mmol) were placed in a
three-necked flask. The shavings were covered with approximately
1 mL of a solution of distilled (44.5 °C) iodomethane (1.310 g,
9.23 mmol) in dry ether (6 mL) under an argon atmosphere. When
the reaction was started, the remainder of the solution was slowly
added. The mixture was gently refluxed with a mantle heater for
30 min to give methylmagnesium iodide. After cooling to room
temperature, a solution of (S)-8 (0.244 g, 1.93 mmol) in dry ether
(3 mL) was slowly added to a solution of the methylmagnesium
iodide at room temperature. The reaction mixture was stirred
overnight under an argon atmosphere. After cooling the mixture
to 0 °C, a saturated ammonium chloride solution was added. The
mixture was extracted three times with ether. The extract was
washed with a saturated sodium chloride solution, then dried over
Na2SO4 and concentrated under reduced pressure. The residue was
chromatographed (silica gel, hexane/acetone = 5:1) to give a mix-
ture of diastereomers (S)-9a (0.211 g, 77%) as a colorless oil. The
1H NMR spectra were identical to those reported in the literature.49
4.2.5. (R)-2-Hydroxymethyl-5-methyl-4-hexen-1-yl butanoate
(R)-4 (preparative desymmetrization of 3)
Amano PS (2.007 g) was added to a solution of diol 3 (1.751 g,
12.14 mmol) and vinyl butyrate (2.772 g, 24.29 mmol) in dry diiso-
propyl ether (115 mL). The resulting suspension was stirred at
room temperature. Samples were withdrawn from the reaction
mixture and analyzed by GC (Cyclodextrin-b-236M-19 capillary
column, 190 °C) to calculate the ratio of the peak area of the pro-
duced monoester (R)-4 in the gas chromatogram to the total of
the peak areas of 3, (R)-4 and diester 5; the peak areas of the three
compounds were corrected on the basis of the number of carbon
atoms.48 When the ratio of the peak area of (R)-4 in the gas chro-
matogram to the total of the peak areas of 3, (R)-4 and 5 reached
92% (approximately 2.5 h), the lipase was filtered off with suction.
The filtrate was concentrated under reduced pressure. The residue
was chromatographed (silica gel, hexane/ethyl acetate = 1:1) to
give (R)-4 as a colorless oil (2.417 g, 93%). The 1H NMR spectra
were identical to those of (RS)-4; Ee: 95% (Cyclodextrin-b-236M-
19 capillary column, 125 °C, (R)-4: 52.8 min, (S)-4: 54.2 min);
[a]
22 = +14.2 (c 0.9, CHCl3).
D
4.2.6. (S)-2-Methanesulfonyloxymethyl-5-methyl-4-hexen-1-yl
butanoate (S)-6
Methanesulfonyl chloride (3.127 g, 27.30 mmol) was slowly
added to a solution of (R)-4 (2.992 g, 13.64 mmol) and dry pyridine
(3.241 g, 40.97 mmol) in dry CH2Cl2 (25 mL) at 0 °C. The reaction
mixture was stirred overnight at room temperature and quenched
at 0 °C with deionized water. The resulting mixture was then
extracted with ether. The organic phase was washed with a satu-
rated sodium hydrogen carbonate solution (twice), and a saturated
sodium chloride solution, successively, and then dried over Na2-
SO4. After removal of the solvents, the residue was chro-
matographed (silica gel, hexane/ethyl acetate = 1:1) to give (S)-6
as a colorless oil (3.434 g, 87%); 1H NMR: d 5.09 (1H, t, J = 7.2),
4.22 (1H, dd, J = 5.0, J = 9.8), 4.18 (1H, dd, J = 5.6, J = 9.6), 4.13
(1H, dd, J = 4.4, J = 11.2), 4.04 (1H, J = 6.4, J = 11.2), 3.01 (3H, s),
2.31 (2H, t, J = 7.4), 2.09–2.15 (3H, m), 1.71 (3H, s), 1.66 (2H, sextet,
4.2.9. (S)-3,6-Dimethyl-5-hepten-2-one (S)-1a
A solution of (S)-9a (0.199 g, 1.40 mmol) in dry CH2Cl2 (3 mL)
was slowly added to a suspension of 95% Dess–Martin periodinane
(0.766 g, 1.72 mmol) in dry CH2Cl2 (4.5 mL) at room temperature.
The reaction mixture was stirred for 2 h and quenched with ether
(10 mL) and a saturated sodium hydrogen carbonate solution
(20 mL) containing Na2S2O3 of 2.5 g. The resulting mixture was
extracted with ether. The organic phase was washed with a
Please cite this article in press as: Kawasaki, M.; et al. Tetrahedron: Asymmetry (2016), http://dx.doi.org/10.1016/j.tetasy.2016.02.002

6
M. Kawasaki et al. / Tetrahedron: Asymmetry xxx (2016) xxx–xxx
saturated sodium chloride solution, and then dried over Na2SO4.
After removal of the solvents, the residue was chromatographed
(silica gel, hexane/acetone = 5:1) to give a colorless oil, which
was distilled (122–140 °C/31.5 mmHg) to give (S)-1a as a colorless
oil (0.082 g, 42%). The 1H NMR spectra were identical to those of
(RS)-1a;50 Ee: 95% (Cyclodextrine-b-236M-19 capillary column,
2.26–2.33 (1H, m), 2.00–2.08 (1H, m), 1.68 (3H, s), 1.60 (3H, s),
1.59 (2H, sextet, J = 7.4), 1.05 (3H, d, J = 7.2), 0.90 (3H, t, J = 7.4);
13C NMR: d 214.68, 133.48, 121.56, 46.58, 43.34, 31.51, 25.77,
17.79, 17.08, 16.04, 13.81; IR (neat): 1712 cmÀ1; HRMS (EI) calcd
for C11H20O (M+), 168.1514. Found: 168.1515; Ee: 95% (GAMMA
DEXTM 120 capillary column, 75 °C); [ 24 = +34.6 (c 0.5, CHCl3).
a]
D
80 °C); [a]
24 = +29.0 (c 0.5, CHCl3).
D
4.2.14. (5RS, 6S)-6,9-Dimethyl-8-decen-5-o1 (S)-9d
4.2.10. (3RS, 4S)-4,7-Dimethyl-6-octen-3-o1 (S)-9b
n-Butylmagnesium iodide was prepared from 1-iodobutane
(1.660 g, 9.02 mmol) and Mg (0.240 g, 9.87 mmol) according to
the procedure described in Section 4.2.8. Compound (S)-8 was pre-
pared in 42% yield from (S)-7 (0.508 g, 3.96 mmol) and 95% Dess–
Martin periodinane (2.131 g, 4.77 mmol) according to the proce-
dure described in Section 4.2.8. Compound (S)-9d was prepared
in 79% yield from the n-butylmagnesium iodide and (S)-8
(0.196 g, 1.55 mmol)) according to the procedure described in Sec-
tion 4.2.8; 1H NMR: mixture of diastereomers: d 5.12–5.19 (1H, m),
3.51–3.55 (0.6H, m), 3.42–3.46 (0.4H, m), 2.06–2.17 (1H, m), 1.85–
1.95 (1H, m), 1.71 (3H, s), 1.62 (3H, s), 1.25–1.60 (7H, m), 0.91 (3H,
t, J = 7.0), 0.88 (0.6 Â 3H, d, J = 6.0), 0.86 (0.4 Â 3H, d, J = 6.0); 13C
NMR: mixture of diastereomers, all visible signals are listed: d
132.56, 132.48, 123.17, 123.15, 75.95, 74.85, 39.60, 38.84, 34.34,
33.43, 32.12, 30.88, 28.50, 28.20, 25.86, 22.81, 17.84, 15.67,
Ethylmagnesium iodide was prepared from distilled (74.5 °C)
iodoethane (1.387 g, 8.89 mmol) and Mg (0.236 g, 9.91 mmol)
according to the procedure described in Section 4.2.8. Compound
(S)-8 was prepared in 44% yield from (S)-7 (0.580 g, 4.52 mmol)
and 95% Dess–Martin periodinane (2.627 g, 5.88 mmol) according
to the procedure described in Section 4.2.8. Compound (S)-9b
was prepared in 68% yield from the ethylmagnesium iodide and
(S)-8 (0.240 g, 1.90 mmol) according to the procedure described
in Section 4.2.8; 1H NMR: mixture of diastereomers: d 5.12–5.19
(1H, m), 3.42–3.46 (0.6H, m), 3.33–3.38 (0.4H, m), 2.06–2.18 (1H,
m), 1.85–1.95 (1H, m), 1.71 (3H, s), 1.62 (3H, s), 1.33–1.59 (3H,
m), 0.97 (0.4 Â 3H, t, J = 7.4), 0.95 (0.6 Â 3H, t, J = 7.4), 0.88
(0.6 Â 3H, d, J = 4.8), 0.86 (0.4 Â 3H, d, J = 4.8); 13C NMR: mixture
of diastereomers, all visible signals are listed: d 132.53, 132.47,
123.20, 123.18, 77.36, 76.35, 39.28, 38.49, 32.16, 30.88, 27.43,
26.56, 25.86, 17.83, 15.71, 13.36, 10.64, 10.27; IR (neat):
3372 cmÀ1; HRMS (FAB) calcd for C10H21O (M++H), 157.1592.
Found: 157.1594.
14.11, 13.41; IR (neat): 3371 cmÀ1; HRMS (EI) calcd for C12H24
(M+), 184.1827. Found: 184.1825.
O
4.2.15. (S)-6,9-Dimethyl-8-decen-5-one (S)-1d
(S)-6,9-Dimethyl-8-decen-5-one (S)-1d was prepared from (S)-
9d (0.190 g, 1.03 mmol) and 95% Dess–Martin periodinane
(0.550 g, 1.24 mmol) in 83% yield according to the procedure
described in Section 4.2.9; B.p.: 152–160 °C/19 mmHg; 1H NMR:
d 5.04 (1H, t, J = 7.4), 2.54 (1H, sextet, J = 7.0), 2.42 (2H, t, J = 7.2),
2.25–2.32 (1H, m), 2.00–2.07 (1H, m), 1.68 (3H, s), 1.60 (3H, s),
1.54 (2H, quintet, J = 7.5), 1.30 (2H, sextet, J = 7.4), 1.05 (3H, d,
J = 6.8), 0.90 (3H, t, J = 7.4); 13C NMR: d 214.80, 133.47, 121.58,
46.59, 41.17, 31.56, 25.79, 25.77, 22.41, 17.79, 16.09, 13.91; IR
(neat): 1714 cmÀ1; HRMS (EI) calcd for C12H22O (M+), 182.1671.
Found: 182.1667; Ee: 95% (GAMMA DEXTM 120 capillary column,
4.2.11. (S)-4,7-Dimethyl-6-octen-3-one (S)-1b
(S)-4,7-Dimethyl-6-octen-3-one (S)-1b was prepared from (S)-
9b (0.192 g, 1.23 mmol) and 95% Dess–Martin periodinane
(0.656 g, 1.47 mmol) in 64% yield according to the procedure
described in Section 4.2.9; B.p.: 125–135 °C/18.5 mmHg; 1H
NMR: d 5.03 (1H, t, J = 7.4), 2.55 (1H, sextet, J = 6.9), 2.45 (2H, q,
J = 7.3), 2.25–2.32 (1H, m), 2.01–2.09 (1H, m), 1.68 (3H, s), 1.60
(3H, s), 1.06 (3H, d, J = 7.2), 1.04 (3H, t, J = 7.2). The spectra data
were identical to those of (RS)-1b from Givaudan; Ee: 95%
(GAMMA DEXTM 120 capillary column, 70 °C); [ 19 = +34.0 (c 1.2,
CHCl3).
a]
D
80 °C); [a]
19 = +33.8 (c 0.8, CHCl3).
D
4.2.12. (4RS, 5S)-5,8-Dimethyl-7-nonen-4-o1 (S)-9c
4.2.16. (5S,6RS)-2,5-Dimethyl-2-undecen-6-o1 (S)-9e
n-Propylmagnesium iodide was prepared from distilled
(102.5 °C) 1-iodoproane (1.399 g, 8.23 mmol) and Mg (0.240 g,
9.87 mmol) according to the procedure described in Section 4.2.8.
Compound (S)-8 was prepared in 48% yield from (S)-7 (0.551 g,
4.30 mmol) and 95% Dess–Martin periodinane (2.629 g,
5.89 mmol) according to the procedure described in Section 4.2.8.
Compound (S)-9c was prepared in 69% yield from the n-propyl-
magnesium iodide and (S)-8 (0.243 g, 1.93 mmol)) according to
the procedure described in Section 4.2.8; 1H NMR: mixture of
diastereomers: d 5.12–5.19 (1H, m), 3.52–3.56 (0.6H, m), 3.44–
3.48 (0.4H, m), 2.07–2.16 (1H, m), 1.87–1.95 (1H, m), 1.71 (3H,
s), 1.62 (3H, s), 1.29–1.58 (5H, m), 0.93 (3H, t, J = 7.2), 0.88
(0.6 Â 3H, d, J = 6.0), 0.86 (0.4 Â 3H, d, J = 6.0); 13C NMR: mixture
of diastereomers, all visible signals are listed: d 132.56, 132.47,
123.16, 75.66, 74.58, 39.65, 38.90, 36.83, 35.92, 32.09, 30.89,
25.86, 19.46, 19.18, 17.84, 15.63, 14.18, 14.17, 13.43; IR (neat):
3370 cmÀ1; HRMS (EI) calcd for C11H22O (M+), 170.1671. Found:
170.1667.
n-Pentylmagnesium iodide was prepared from 1-iodopentane
(0.488 g, 2.46 mmol) and Mg (0.065 g, 2.67 mmol) according to
the procedure described in Section 4.2.8. Compound (S)-8 was pre-
pared in 37% yield from (S)-7 (0.333 g, 2.60 mmol) and 95% Dess–
Martin periodinane (1.401 g, 3.14 mmol) according to the proce-
dure described in Section 4.2.8. Compound (S)-9e was prepared
in 70% yield from the n-pentylmagnesium iodide and (S)-8
(0.101 g, 0.80 mmol) according to the procedure described in Sec-
tion 4.2.8, but with the proviso that the mixture of hexane and
ethyl acetate (5:1) was used as the developing solvent for the silica
gel column chromatography; 1H NMR: mixture of diastereomers: d
5.12–5.18 (1H, m), 3.50–3.55 (0.6H, m), 3.42–3.47 (0.4H, m), 2.06–
2.16 (1H, m), 1.85–1.95 (1H, m), 1.71 (3H, s), 1.62 (3H, s), 1.25–1.59
(9H, m), 0.90 (3H, t, J = 6.8), 0.88 (0.6 Â 3H, d, J = 6.0), 0.86
(0.4 Â 3H, d, J = 6.0); 13C NMR: mixture of diastereomers, all visible
signals are listed: d 132.57, 132.49, 123.15, 75.98, 74.89, 39.60,
38.84, 34.62, 33.71, 32.12, 31.99, 31.97, 30.88, 25.97, 25.85,
25.67, 22.68, 17.84, 15.67, 14.07, 13.41; IR (neat): 3363 cmÀ1
HRMS (EI) calcd for C13H26O (M+), 198.1984. Found: 198.1984.
.
4.2.13. (S)-5,8-Dimethyl-7-nonen-4-one (S)-1c
(S)-5,8-Dimethyl-7-nonen-4-one (S)-1c was prepared from (S)-
9c (0.166 g, 0.97 mmol) and 95% Dess–Martin periodinane
(0.530 g, 1.19 mmol) in 71% yield according to the procedure
described in Section 4.2.9; B.p.: 115–125 °C/14 mmHg; 1H NMR:
d 5.04 (1H, t, J = 7.2), 2.53 (1H, sextet, J = 7.0), 2.40 (2H, t, J = 7.2),
4.2.17. (S)-2,5-Dimethyl-2-undecen-6-one (S)-1e
(S)-2,5-Dimethyl-2-undecen-6-one (S)-1e was prepared from
(S)-9e (0.098 g, 0.49 mmol) and 95% Dess–Martin periodinane
(0.266 g, 0.60 mmol) in 75% yield according to the procedure
described in Section 4.2.9, but with the proviso that the mixture
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M. Kawasaki et al. / Tetrahedron: Asymmetry xxx (2016) xxx–xxx
7
of hexane and acetone (20:1) was used as the developing solvent
for the silica gel column chromatography; B.p.: 157–187 °-
C/31 mmHg; 1H NMR: d 5.04 (1H, t, J = 7.2), 2.53 (1H, sextet,
J = 7.0), 2.41 (2H, t, J = 7.4), 2.25–2.32 (1H, m), 2.00–2.07 (1H, m),
1.68 (3H, s), 1.60 (3H, s), 1.55 (2H, quintet, J = 7.5), 1.20–1.36
(4H, m), 1.05 (3H, d, J = 6.8), 0.89 (3H, t, J = 7.2); 13C NMR: d
214.86, 133.47, 121.58, 46.58, 41.42, 31.56, 31.50, 25.77, 23.36,
22.51, 17.79, 16.09, 13.95; IR (neat): 1712 cmÀ1; HRMS (EI) calcd
for C13H24O (M+), 196.1827. Found: 196.1831; Ee: 95% (Cyclodex-
chromatographed (silica gel, hexane/acetone = 5:1) to give (R)-12
as a colorless oil (3.530 g, 95%); 1H NMR: d 5.09 (1H, t, J = 7.4),
4.22 (2H, d, J = 5.6), 3.63 (1H, dd, J = 4.6, J = 10.2), 3.55 (1H, dd,
J = 6.2, J = 10.2), 2.99 (3H, s), 2.05 (2H, t, J = 7.4), 1.85–1.94 (1H,
m), 1.71 (3H, s), 1.61 (3H, s), 0.89 (9H, s), 0.05 (6H, s); 13C NMR:
d 134.12, 120.92, 69.92, 61.60, 41.45, 36.92, 26.01, 25.86, 25.80,
18.24, 17.84, À5.51, À5.53; IR (neat): 1360, 1253, 1178,
838 cmÀ1; HRMS (FAB) calcd for C15H33O4SSi (M++H), 337.1869.
Found: 337.1873; [
a]
18 = À2.5 (c 1.1, CH3Cl).
D
trin-b-236M-19 capillary column, 90 °C); [a]
22 = +32.7 (c 0.5,
D
CHCl3).
4.3.4. (R)-2,5-Dimethyl-4-hexen-1-ol (R)-7
A solution of (R)-12 (3.443 g, 10.23 mmol) in dry ether (20 mL)
was slowly added to a suspension of LiAlH4 (0.768 g, 20.24 mmol)
in dry ether (18 mL) at room temperature. The reaction mixture
was gently refluxed for 14 h under an argon atmosphere. After
cooling to 0 °C, deionized water was added to the mixture, and
extraction was performed three times with ether. The organic layer
was washed with deionized water and a saturated sodium chloride
solution in this order and then dried over Na2SO4. After removal of
the solvents, the residue was chromatographed (silica gel, hexane/
ethyl acetate = 2:1) to give (R)-7 as a colorless oil (1.130 g, 87%).
The 1H NMR spectra were identical to those of (S)-7; Ee: 95%
4.3. Syntheses of the (R)-enantiomers
4.3.1. (S)-2-tert-Butyldimethylsiloxymethyl-5-methyl-4-buten-
1-yl butanoate (S)-10
tert-Butyldimethylsilyl trifluoromethanesulfonate (5.888 g,
22.27 mmol) was slowly added to a solution of (R)-4 (2.386 g,
11.13 mmol) and dry pyridine (2.644 g, 33.43 mmol) in dry CH2Cl2
(25 mL) at 0 °C. The reaction mixture was stirred overnight at room
temperature and quenched at 0 °C with deionized water. The
resulting mixture was then extracted with ether. The organic phase
was washed with deionized water and a saturated sodium chloride
solution, successively, and then dried over Na2SO4. After removal
of the solvents, the residue was chromatographed (silica gel, hex-
ane/ethyl acetate = 10:1) to give (S)-10 as a colorless oil (3.361 g,
92%); 1H NMR: d 5.11 (1H, t, J = 7.4), 4.04 (1H, d, J = 6.0), 3.57
(1H, dd, J = 5.4, J = 13.4), 3.55 (1H, dd, J = 5.4, J = 13.4), 2.28 (2H, t,
J = 7.4), 2.04–2.11 (1H, m), 1.95–2.02 (1H, m), 1.77–1.86 (1H, m),
1.70 (3H, s), 1.65 (2H, sextet, J = 7.5), 1.59 (3H, s), 0.95 (3H, t,
J = 7.4), 0.89 (9H, s), 0.03 (6H, s); 13C NMR: d 173.74, 133.24,
121.78, 64.19, 62.48, 41.08, 36.30, 26.48, 25.88, 25.80, 18.48,
18.28, 17.72, 13.73, À5.53; IR (neat) 1736, 1257, 835 cmÀ1; HRMS
(GAMMA DEXTM 120 capillary column, 80 °C); [
a]
19 = +4.2 (c 0.9,
D
CH2Cl2), {Lit.45
[a]D = À4.4 (c 3.8, CH2Cl2), (S), 95% ee}.
4.3.5. (2RS,3R)-3,6-Dimethyl-5-hepten-2-o1 (R)-9a
Methylmagnesium iodide was prepared from distilled (44.5 °C)
iodomethane (1.302 g, 9.18 mmol) and Mg (0.245 g, 10.08 mmol)
according to the procedure described in Section 4.2.8. Compound
(R)-8 was prepared in 47% yield from (R)-7 (0.553 g, 4.31 mmol)
and 95% Dess–Martin periodinane (2.338 g, 5.24 mmol) according
to the procedure described in Section 4.2.8. Compound (R)-9a
was prepared in 52% yield from the methylmagnesium iodide
and (R)-8 (0.254 g, 2.12 mmol) according to the procedure
described in Section 4.2.8. The 1H NMR spectra were identical to
those of (S)-9a.
(FAB) calcd for C18H37O3Si (M++H), 329.2512. Found: 329.2516; [
a]
17
À3.1 (c 0.7, CH3Cl).
D
4.3.2. (S)-2-tert-Butyldimethylsiloxymethyl-5-methyl-4-buten-
1-ol (S)-11
4.3.6. (R)-3,6-Dimethyl-5-hepten-2-one (R)-1a
At first, 6 mol/L NaOH (2.4 mL, 14 mmol) was added to a solu-
tion of (S)-10 (3.352 g, 10.20 mmol) in EtOH (14 mL). The ethanol
was removed under reduced pressure after 3 h, after which deion-
ized water was added to the residue. The residue was extracted
three times with ether. The organic layer was washed with a satu-
rated sodium chloride solution, then dried over Na2SO4 and con-
centrated. The residue was chromatographed (silica gel, hexane/
acetone = 5:1) to give (S)-11 (2.260 g, 86%) as a colorless oil; 1H
NMR: d 5.12 (1H, t, J = 7.4), 3.78 (1H, dd, J = 4.1, J = 9.9), 3.72 (1H,
ddd, J = 3.7, J = 6.9, J = 10.8), 3.62 (1H, ddd, J = 4.3, J = 7.0, J = 10.8),
3.60 (1H, dd, J = 7.4, J = 9.8), 1.94 (2H, t, J = 7.2), 1.74–1.82 (1H,
m), 1.70 (3H, s), 1.60 (3H, s), 0.90 (9H, s), 0.07 (6H, s); 13C NMR:
d 133.14, 122.06, 66.99, 66.57, 42.82, 26.49, 25.86, 25.77, 18.17,
17.77, À5.56, À5.61; IR (neat) 3355, 1256, 837 cmÀ1; HRMS (FAB)
(R)-3,6-Dimethyl-5-hepten-2-one (R)-1a was prepared from
(R)-9a (0.142 g, 1.00 mmol) and 95% Dess–Martin periodinane
(0.535 g, 1.20 mmol) in 33% yield according to the procedure
described in Section 4.2.9. The 1H NMR spectra were identical to
those of (S)-1a; B.p.: 110–117 °C/18.5 mmHg; Ee: 95% (Cyclodex-
trin-b-236M-19 capillary column, 70 °C); [
CHCl3).
a]
24 = À27.6 (c 0.50,
D
4.3.7. (3RS,4R)-4,7-Dimethyl-6-octen-3-o1 (R)-9b
Ethylmagnesium iodide was prepared from distilled (74.5 °C)
iodoethane (1.389 g, 8.90 mmol) and Mg (0.258 g, 10.62 mmol)
according to the procedure described in Section 4.2.8. Compound
(R)-8 was prepared in 49% yield from (R)-7 (0.581 g, 4.53 mmol)
and 95% Dess–Martin periodinane (2.472 g, 5.54 mmol) according
to the procedure described in Section 4.2.8. Compound (R)-9b
was prepared in 58% yield from the ethylmagnesium iodide and
(R)-8 (0.248 g, 1.97 mmol) according to the procedure described
in Section 4.2.8. The 1H NMR spectra were identical to those of
(S)-9b.
calcd for
C
14H31O2Si (M++H), 259.2093. Found: 259.2092;
[
a]
D
18 = À9.9 (c 1.2, CH3Cl).
4.3.3. (R)-2-tert-Butyldimethylsiloxymethyl-5-methyl-4-buten-
1-yl methanesulfonate (R)-12
Methanesulfonyl chloride (2.553 g, 22.29 mmol) was slowly
added to a solution of (S)-11 (2.878 g, 11.13 mmol) and dry pyri-
dine (2.657 g, 33.59 mmol) in dry CH2Cl2 (15 mL) at 0 °C. The reac-
tion mixture was stirred overnight at room temperature and then
quenched at 0 °C with deionized water. The resulting mixture was
then extracted with ether. The organic phase was washed with a
saturated sodium hydrogen carbonate solution (twice) and a satu-
rated sodium chloride solution in this order, and then dried over
Na2SO4. After removal of the solvents, the residue was
4.3.8. (R)-4,7-Dimethyl-6-octen-3-one (R)-1b
(R)-4,7-Dimethyl-6-octen-3-one (R)-1b was prepared from (R)-
9b (0.137 g, 0.88 mmol) and 95% Dess–Martin periodinane
(0.515 g, 1.15 mmol) in 50% yield according to the procedure
described in Section 4.2.9. The 1H NMR spectra were identical to
those of (S)-1b; B.p.: 100–106 °C/12 mmHg; Ee 95% (GAMMA
DEXTM 120 capillary column, 70 °C); [
a
]
D
19 = À37.4 (c 1.1, CHCl3).
Please cite this article in press as: Kawasaki, M.; et al. Tetrahedron: Asymmetry (2016), http://dx.doi.org/10.1016/j.tetasy.2016.02.002

8
M. Kawasaki et al. / Tetrahedron: Asymmetry xxx (2016) xxx–xxx
4.3.9. (4RS,5R)-5,8-Dimethyl-7-nonen-4-o1 (R)-9c
Acknowledgements
n-Propylmagnesium iodide was prepared from distilled
(102.5 °C) 1-iodopropane (1.538 g, 9.05 mmol) and Mg (0.245 g,
10.08 mmol) according to the procedure described in Section 4.2.8.
Compound (R)-8 was prepared in 47% yield from (R)-7
(0.507 g, 3.95 mmol) and 95% Dess–Martin periodinane (2.127 g,
4.76 mmol) according to the procedure described in Section 4.2.8.
Compound (R)-9c was prepared in 72% yield from the n-propyl-
magnesium iodide and (S)-8 (0.220 g, 1.74 mmol) according to
the procedure described in Section 4.2.8. The 1H NMR spectra were
identical to those of (S)-9c.
We are grateful to the researchers at the Department of
Biotechnology, Faculty of Engineering, Toyama Prefectural Univer-
sity, for their generous support with the NMR spectroscopic and
optical rotation measurements.
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(R)-6,9-Dimethyl-8-decen-5-one (R)-1d was prepared from (R)-
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