Lipase-mediated preparation of optically active isomers of Rosaphen

Article abstract of DOI:10.1016/j.molcatb.2010.07.019

The optically active isomers of Rosaphen (RS)-1 were synthesized from the chiral intermediate prepared by lipase-catalyzed desymmetrization of prochiral diol. The results of an olfactory evaluation of the prepared isomers are reported.

Full text of DOI:10.1016/j.molcatb.2010.07.019

Journal of Molecular Catalysis B: Enzymatic 67 (2010) 135–142
Contents lists available at ScienceDirect
Journal of Molecular Catalysis B: Enzymatic
journal homepage: www.elsevier.com/locate/molcatb
Lipase-mediated preparation of optically active isomers of Rosaphen®
Masashi Kawasakia,∗, Naoki Toyookab, Tomoki Sakac, Michimasa Gotod,
Yuji Matsuyac, Tadashi Kometanid
a Department of Liberal Arts and Sciences, Faculty of Engineering, Toyama Prefectural University, 5180 Kurokawa, Imizu, Toyama-Ken 939-0398, Japan
b Graduate School of Science and Technology, University of Toyama, 3190 Gofuku, Toyama 930-8555, Japan
c Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, 2630 Sugitani, Toyama 930-0194, Japan
d Department of Chemical and Biochemical Engineering, Toyama National College of Technology, 13 Hongo, Toyama 939-8630, Japan
a r t i c l e i n f o
a b s t r a c t
The optically active isomers of Rosaphen® (RS)-1 were synthesized from the chiral intermediate prepared
by lipase-catalyzed desymmetrization of prochiral diol. The results of an olfactory evaluation of the
prepared isomers are reported.
Article history:
Received 1 June 2010
Received in revised form 6 July 2010
Accepted 27 July 2010
Available online 6 August 2010
© 2010 Elsevier B.V. All rights reserved.
Keywords:
Asymmetric synthesis
Fragrance
Lipase
1. Introduction
While asymmetric synthesis of (S)-1 has not been reported,
there are four reports on the synthesis of (R)-1. Santini et al. syn-
thesized (R)-1 from an optically active oxazolidinone derivative
Many organic compounds with odor occur in nature as a specific
enantiomer, and the odor of the specific enantiomer is distinctive
and characteristic [1]. Examples of the differences in odor descrip-
tion and in strength between enantiomers have been reported
[1–3]. For example, (R)-limonene has an orange odor, while (S)-
limonene has a harsh odor [1]. Accordingly, the synthesis of
fragrance ingredients in highly enantiomerically pure form and the
evaluation of their odor properties are of great interest, and many
reports on the asymmetric synthesis of fragrance ingredients have
been published [2–5].
Among many fragrances, floral notes are very much appre-
ciated and widely used [3b]. Recently, Matteoli et al. reported
the enantioselective synthesis of three fragrances displaying flo-
ral notes, Phenoxanol® 2a, Citralis® 2b and Citralis Nitrile® 2c
(Fig. 1) [3b]. Enantiopure samples of 2a, 2b and 2c were evaluated
for the odor profiles. Rosaphen® (RS)-1 {(RS)-2-methyl-5-phenyl-
1-pentanol}, an analogue of 2a, is valuable for adding floral note
in soaps and domestic fragrances [6,7]. (RS)-1 is used in racemic
form, so the odor profiles of the single enantiomers have not been
reported.
and used the (R)-1 for determining the absolute configuration
of the side chain of zarazonic acid C [8]. Abiko reported the
synthesis of a new chiral auxiliary and evaluated the utility of
the auxiliary by applying it to the synthesis of (R)-1 [9]. Other
reports presented the syntheses of (R)-1, which was used for
the synthesis of zarazonic acid C, with chiral auxiliary methods
[10,11]. However, those methods required stoichiometric optically
pure compounds to synthesize (R)-1, so we became interested in
developing an enantioselective catalytic route to (R)-1 and (S)-
1.
We have been studying lipase-catalyzed reactions in aqueous or
organic media and succeeded in the asymmetric synthesis of chro-
manones [12,13], flavanones [12–15], and a norsesquiterpene [16].
It is a characteristic of our method to obtain the chiral intermediates
for the synthesis of the target compounds by the lipase-catalyzed
reactions. Lipase-catalyzed reactions play an important role in the
optical resolutions of the racemates and in desymmetrizations of
prochiral substrates, and the obtained enantiopure substrates are
used for the further synthesis [17]. Many lipase-catalyzed prepa-
rations of enantiomerically enriched odorants have been reported
[2e–g,3c–f,5a–d].
Herein we report the asymmetric synthesis of (R)-1 and (S)-1
from a chiral primary alcohol prepared by lipase-catalyzed desym-
metrization of a prochiral diol and the evaluation of the odor
profiles of the optically active isomers.
∗
Corresponding author. Tel.: +81 766 56 7500; fax: +81 766 56 6117.
E-mail address: kawasaki@pu-toyama.ac.jp (M. Kawasaki).
1381-1177/$ – see front matter © 2010 Elsevier B.V. All rights reserved.
doi:10.1016/j.molcatb.2010.07.019

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M. Kawasaki et al. / Journal of Molecular Catalysis B: Enzymatic 67 (2010) 135–142
Scheme 1. Synthesis of 2-hydroxymethyl-5-phenyl-1-pentanol 4.
basis of the empirical rule for the enantiopreference of the lipase
[19].
We then investigated the effects of the acyl donors on the
prochiral selectivity of the lipase (Table 2), because the enantiose-
lectivity of lipases has been found to depend on the nature of the
acyl donors [20]. As a result of the screening of the vinyl esters,
we found that vinyl butanoate (Entry 3) was the most suitable
regarding the prochiral selectivity (97% ee).
Fig. 1. Compounds with floral fragrance.
On the basis of the results, we conducted the large scale desym-
metrization of 4 with 7c as the acyl donor in 1,4-dioxane and could
obtain (R)-5c with 96% ee in 85% yield.
The optically active (R)-5c (96% ee) obtained above was
converted to the corresponding methanesufonate (S)-8 with
methanesufonyl chloride (MsCl) and pyridine in 92% yield
(Scheme 3). The synthesis of (S)-1 was finally accomplished by
2. Results and discussion
2.1. Asymmetric synthesis of (S)-1
The first step in the sequence leading to (S)-1 is the alkylation
of diethyl malonate with 1-bromo-3-phenylpropane (Scheme 1).
The deprotonation of diethyl malonate with NaH and the addition
of 1-bromo-3-phenylpropane provided ethyl 2-ethoxycarbonyl-5-
phenylpentanoate 3 in 78% yield. The treatment of 3 with LiAlH4
produced the diol, 2-hydroxymethyl-5-phenyl-1-pentanol 4, in
83% yield.
24
the reduction of (S)-8 with LiAlH4 in 57% yield and 95% ee {[˛]D
−13.6◦ (c 1.1, EtOH); Lit. [8] [˛]D +11.2◦ (c 6.4, EtOH), (R)}. Because
the enantiomeric excess of (S)-1 could not be determined by either
GC or HPLC, (S)-1 was converted to the corresponding acetate (S)-12
with acetyl chloride and after that the ee was determined.
The most important point of the present synthesis is to pre-
pare a monoester of 4 in an optically active form. We successfully
achieved the preparation using lipase-catalyzed desymmetrization
of 4 (Scheme 2). Initially, we tested the enantioselectivity of 13
lipases (Amano AK, AY, PS, Meito ALC, MY, OF, PLC, QLM, ST, TL,
Novozym 435, Sigma CRL, PPL) in the acetylation of 4 with vinyl
acetate in 1,4-dioxane. Among the lipases investigated, lipase PS
proved to be the most enantioselective.
2.2. Asymmetric synthesis of (R)-1
We also synthesized (R)-1 from (R)-5c (97% ee) according to
Scheme 4. At first, the hydroxyl group of (R)-5c was protected with
tert-butyldimethylsilyl trifluoromethanesulfonate (TBDMSOTf)
and pyridine to obtain 2-tert-butyldimethylsiloxymethyl-
5-phenylpentyl butanoate (S)-9 in 97% yield. The ester
moiety of (S)-9 was hydrolyzed with NaOH to obtain 2-tert-
butyldimethylsiloxymethyl-5-phenyl-1-pentanl (S)-10 in 52%
yield. Deprotection slightly occurred during the hydrolysis,
which resulted in the formation of the diol, confirmed with TLC.
The chiral alcohol (S)-10 was converted to the corresponding
methanesufonate (R)-11 with methanesufonyl chloride (MsCl) and
pyridine in 93% yield (Scheme 3). The synthesis of (S)-1 was finally
accomplished by the reaction of (R)-11 with LiAlH4 in 54% yield
Next, diol
4 was subjected to reaction solvent screening
experiments (Table 1). The substrate specificity, enantioselectiv-
ity, prochiral selectivity, regioselectivity, and chemoselectivity of
enzymes have been found to depend on the nature of the solvent
[18]. It was observed in our present study that polar solvent sys-
tems are more efficient for the prochiral selectivity than nonpolar
solvent systems. Because the highest prochiral selectivity and rapid
reaction were achieved with 1,4-dioxane (Entry 1), the solvent was
chosen for further study. The absolute configuration of the pro-
duced monoester was thought to be the (R)-configuration on the
and 96% ee {[˛]D +12.6◦ (c 1.1, EtOH), Lit. [8] [˛]D +11.2◦ (c 6.4,
24
EtOH), (R)}. Reduction and deprotection took place at the same
time. The ee of (R)-1 was determined after it was converted to the
corresponding acetate (R)-12 with acetyl chloride.
Table 1
Effect of organic solvents on desymmetrization of 4 using lipase PS.
Table 2
Entry
Solvent
Time (h)
4:(R)-5a:6a
ee of (R)-5a (%)
Effect of vinyl esters 7 on desymmetrization of 4 using lipase PS.
1
2
3
4
5
6
1,4-Dioxane
Acetone
THF
Diisopropyl ether
Dichloromethane
Toluene
2.8
6.4
5.2
2.1
20.5
1.8
5:92:3
2:93:5
2:94:4
1:88:11
3:96:1
2:86:12
95
94
94
91
90
83
Entry
Vinyl ester 7 (R)
Time (h)
4: (R)-5: 6a
ee of (R)-5 (%)
1
2
3
4
CH3
CH2CH3
CH2CH2CH3
CH2(CH2)3CH3
2.8
2.7
3.0
3.1
5:92:3
3:93:4
1:90:9
1:90:9
95
96
97
84
Conditions: lipase PS (20 mg/mL), 4 (100 mmol/L), 7a (1 mol/L), rt.
Conditions: lipase PS (20 mg/mL), 4 (100 mmol/L), 7 (1 mol/L), rt.
a
a
Ratio of the peak areas of 4, (R)-5a and 6 in gas chromatogram.
Ratio of the peak areas of 4, (R)-5 and 6 in gas chromatogram.

M. Kawasaki et al. / Journal of Molecular Catalysis B: Enzymatic 67 (2010) 135–142
137
Scheme 2. Enantioselective esterification of 2-hydroxymethyl-5-phenyl-1-pentanol 4.
Scheme 3. Synthesis of (S)-2-methyl-5-phenyl-1-pentanol (S)-1.
Scheme 4. Synthesis of (R)-2-methyl-5-phenyl-1-pentanol (R)-1.

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M. Kawasaki et al. / Journal of Molecular Catalysis B: Enzymatic 67 (2010) 135–142
78%); 1H NMR: 7.26–7.29 (2H, m), 7.16–7.20 (3H, m), 4.19 (4H, q,
J = 7.1), 3.34 (1H, t, J = 7.6), 2.64 (2H, t, J = 7.8), 1.94 (2H, q, J = 7.7), 1.66
(2H, quintet, J = 7.8), 1.25 (6H, t, J = 7.0); 13C NMR: 169.43, 141.71,
128.36, 128.35, 125.87, 61.31, 51.92, 35.48, 29.10, 28.36, 14.07; IR
(neat): 1732 cm−1; MS (m/z) 278 (M+, base peak), 232, 186, 173,
158, 131, 117, 104, 91; HRMS calcd for C16H22O4 (M+), 278.1518.
Found: 278.1490.
The obtained optically active alcohols {(R)-1 and (S)-1} and the
corresponding racemate (RS)-1 which was synthesized according to
the procedure in Section 4.8 were submitted to the evaluation of the
odor profiles by skilled perfumers. The following descriptions were
obtained. (R)-1: green tea-like, fatty, slightly fruity, heavy, green
and citrus-like; (S)-1: slightly citrus-like, fruity, aldehydic, citrus
peel-like, pine terpene-like, powdery plum-like; (RS)-1: fruity, bril-
liant, rosy, wine-like, honey, tea-like, geranyl acetate-like, sweet
grapefruit-like.
4.3. 2-Hydroxymethyl-5-phenyl-1-pentanol 4
A solution of 3 (5.347 g, 19.21 mmol) in dry THF (12 mL) was
slowly added to a suspension of 80% LiAlH4 (2.013 g, 42 mmol) in
dry THF (10 mL) at 0 ◦C under an Ar atmosphere. The reaction mix-
ture was stirred for 21 h at room temperature and quenched at 0 ◦C
with 3 mol/L HCl (60 mL). The resulting mixture was extracted three
times with ether. The organic phase was washed with a saturated
sodium chloride solution and dried over Na2SO4. After removal of
the solvents, the residue was chromatographed (silica gel, ethyl
acetate) to give 4 as a colorless viscous oil, which turned to a white
solid a few days later (3.061 g, 83%); mp: 38.7–40.2 ◦C (lit. [21]
43–44 ◦C); 1H NMR: 7.26–7.30 (2H, m), 7.16–7.20 (3H, m), 3.81
(2H, dd, J = 3.8, J = 10.6), 3.65 (2H, dd, J = 7.4, J = 10.6), 2.62 (2H, t,
J = 7.8), 1.74–1.84 (1H, m), 1.67 (2H, quintet, J = 7.8), 1.27–1.33 (3H,
m); 13C NMR: 142.20, 128.37, 128.33, 125.79, 66.48, 41.87, 36.09,
29.05, 27.30; IR (CCl4): 3349 cm−1; MS (m/z) 194 (M+), 177 (base
peak), 176, 157, 145, 130, 115, 103, 91, 80, 71, 63, 51; HRMS calcd
for C12H18O2 (M+), 194.1307. Found: 194.1336.
3. Conclusion
We synthesized optically active Rosaphen® 1 (2-methyl-5-
phenyl-1-pentanol) from the chiral intermediates obtained via the
lipase-catalyzed desymmetrization of prochiral diol. We are now
synthesizing other optically active fragrance ingredients according
to the method described here.
4. Experimental
4.1. Materials and methods
All commercially available reagent chemicals were obtained
from Aldrich, Kanto Kagaku, Nacalai Tesque, Tokyo Kasei and
Wako Chemicals, and generally used without further purifica-
tion. Ether and THF were distilled from Na/benzophenone under
Ar. Dichloromethane, diisopropyl ether, 1,4-dioxane, toluene,
diisopropylamine and pyridine were distilled from CaH2 under
Ar. Acetone was distilled from molecular sieves 3A under
Ar. HMPA was distilled from CaH2 under reduced pressure
(70.1–72.1 ◦C/0.5 mm Hg). Vinyl acetate was distilled from molec-
ular sieves 4A under Ar. Amano AK, PS, Sigma CRL, PPL were
purchased from Amano Enzyme, Inc., and Sigma–Aldrich, Inc.
Amano AY, Meito ALC, MY, OF, PLC, QLM, ST, TL, Novozym 435
were provided by Amano Enzyme Inc., Meito Sangyo Co., Ltd., and
Novozymes Japan, Inc. All the lipases except Novozym 435 were
dried over P2O5. The NMR spectra were recorded using a Bruker
Advance II 400 (400 MHz 1H, 100 MHz 13C) spectrometer for solu-
tion 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 MS spectra were obtained using a Jeol JMS-
GCmate II spectrometer. The HRMS spectra 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 melting point was measured by a Yanaco
MP-S3 micro-melting point apparatus. The gas chromatograms
were recorded on a Shimadzu GC-14B with INTERCAP 1 capillary
column (GL Sciences, 30 m × 0.25 mm). The HPLC analyses were
carried out on a Hitachi L-6250 intelligent pump with a Hitachi
L-4000 UV detector and CHIRALCEL OJ, CHIRALCEL OB-H and CHI-
RALCEL OJ-H (all the columns from Daicel, 250 mm × 4.6 mm).
4.4. (RS)-2-hydroxymethyl-5-phenylpentyl acetate (RS)-5a and
2-acetoxymethyl-5-phenylpentyl acetate 6a
(RS)-2-Hydroxymethyl-5-phenylpentyl acetate (RS)-5a and 2-
acetoxymethyl-5-phenylpentyl acetate 6a were prepared as
authentic samples. Acetyl chloride (0.06 g, 0.8 mmol) was slowly
added to a solution of 4 (0.100 g, 0.515 mmol) and dry pyridine
(0.109 g, 1.38 mmol) in dry CH2Cl2 (4 mL) at 0 ◦C. The reaction mix-
ture was stirred for 2 h at room temperature and quenched at 0 ◦C
with 1 mol/L HCl (2 mL). The resulting mixture was extracted with
ether. The organic phase was washed with deionized water, a satu-
rated sodium hydrogen carbonate solution, and a saturated sodium
chloride solution in this order, and then dried over sodium sulfate.
After removal of the solvents, the residue was chromatographed
{silica gel, hexane/ethyl acetate = 1:1 (v/v)} to give (RS)-5a (0.059 g,
49%) and 6a (0.018 g, 13%) as colorless oils.
(RS)-5a: 1H NMR: 7.26–7.29 (2H, m), 7.16–7.20 (3H, m), 4.18
(1H, dd, J = 4.8, J = 11.2), 4.08 (1H, dd, J = 6.4, J = 11.2), 3.59 (1H, dd,
J = 4.6, J = 11.4), 3.51 (1H, dd, J = 6.6, J = 11.4), 2.62 (2H, t, J = 7.6), 2.05
(3H, s), 1.78–1.87 (1H, m), 1.68 (2H, quintet, J = 7.9), 1.29–1.45 (2H,
m); 13C NMR: 171.71, 142.14, 128.37, 128.34, 125.81, 64.56, 62.57,
40.35, 36.01, 28.78, 27.41, 20.92; IR (neat): 3448, 1738 cm−1; MS
(m/z) 236 (M+, base peak), 176, 157, 145, 130, 115, 103, 91, 80, 71,
61, 51; HRMS calcd for C14H20O3 (M+), 236.1413. Found: 236.1423.
6a: 1H NMR: 7.26–7.30 (2H, m), 7.16–7.20 (3H, m), 4.08 (2H, dd,
J = 5.2, J = 11.2), 4.02 (2H, dd, J = 6.4, J = 11.2), 2.62 (2H, t, J = 7.6), 2.04
(6H, s), 1.97–2.04 (1H, m), 1.68 (2H, quintet, J = 7.8), 1.37–1.43 (2H,
m); 13C NMR: 169.54, 140.40, 126.84, 126.82, 124.32, 62.63, 35.56,
34.32, 26.94, 26.13, 19.35; IR (neat): 1739 cm−1; MS (m/z) 278 (M+),
219 (base peak), 218, 176, 157, 145, 130, 115, 103, 91, 80, 71, 61,
51; HRMS calcd for C16H22O4 (M+), 278.1518. Found: 278.1554
4.2. Ethyl 2-ethoxycarbonyl-5-phenylpentanoate 3
A solution of diethyl malonate (6.010 g, 37.52 mmol) in dry THF
(9 mL) was added dropwise to a suspension of 60% sodium hydride
(1.282 g, 32 mmol) in dry THF (9 mL). After stirring for 20 min, a
solution of 1-bromo-3-phenylpropane (5.015 g, 25.19 mmol) in dry
THF (9 mL) added dropwise to the suspension. The reaction mix-
ture was refluxed for 16 h. After cooling to 0 ◦C, the mixture was
added acidified with 1 mol/L HCl (50 mL) and extracted three times
with ether. The organic layer was washed with a saturated sodium
chloride solution, then dried over Na2SO4 and concentrated under
reduced pressure. The residue was chromatographed {silica gel,
hexane/ethyl acetate = 5/1 (v/v)} to give 3 as a colorless oil (5.455 g,
4.5. (RS)-2-hydroxymethyl-5-phenylpentyl propanoate (RS)-5b
and 5-phenyl-2-propanoyloxymethylpentyl propanoate 6b
(RS)-2-Hydroxymethyl-5-phenylpentyl propanoate (RS)-5b and
5-phenyl-2-propanoyloxymethylpentyl propanoate 6b as authen-
tic samples were prepared from 4 (0.101 g, 0.520 mmol), propionyl

M. Kawasaki et al. / Journal of Molecular Catalysis B: Enzymatic 67 (2010) 135–142
139
chloride (0.07 g, 0.8 mmol), dry pyridine (0.108 g, 1.37 mmol)
and dry CH2Cl2 (3 mL) as a solvent according to the procedure
described in Section 4.4. Chromatography {silica gel, hexane/ethyl
acetate = 2:1 (v/v)} of the crude product afforded (RS)-5b (0.066 g,
51%) and 6b (0.028 g, 18%) as colorless oils.
(2H, t, J = 7.6), 1.78–1.87 (1H, m), 1.69 (2H, quintet, J = 7.8), 1.62 (2H,
quintet, J = 7.3), 1.25–1.45 (6H, m), 0.90 (3H, t, J = 6.9); 13C NMR:
174.50, 142.12, 128.36, 128.33, 125.80, 64.25, 62.66, 40.48, 36.02,
34.28, 31.30, 28.79, 27.42, 24.68, 22.29, 13.90; IR (neat): 3447,
1734 cm−1; MS (m/z) 292 (M+), 176 (base peak), 157, 145, 129, 117,
104, 91, 80, 71, 65, 55; HRMS calcd for C18H28O3 (M+), 292.2039.
Found: 292.2028.
(RS)-5b: 1H NMR: 7.26–7.29 (2H, m), 7.16–7.20 (3H, m), 4.20
(1H, dd, J = 4.4, J = 11.2), 4.09 (1H, dd, J = 6.6, J = 11.0), 3.58 (1H, dd,
J = 4.4, J = 11.2), 3.50 (1H, dd, J = 6.6, J = 11.4), 2.62 (2H, t, J = 7.6),
2.33 (2H, q, J = 7.6), 1.78–1.87 (1H, m), 1.69 (2H, quintet, J = 7.8),
1.29–1.45 (2H, m), 1.12 (3H, t, J = 7.6); 13C NMR: 175.10, 142.13,
128.37, 128.33, 125.80, 64.35, 62.63, 40.45, 36.01, 28.79, 27.58,
27.40, 9.17; IR (neat): 3446, 1737 cm−1; MS (m/z) 250 (M+), 232,
177 (base peak), 175, 157, 145, 130, 115, 103, 91, 80, 71, 65, 51;
HRMS calcd for C15H22O3 (M+), 250.1569. Found: 250.1603.
6b: 1H NMR: 7.26–7.29 (2H, m), 7.15–7.20 (3H, m), 4.08 (2H,
dd, J = 5.2, J = 11.2), 4.03 (2H, dd, J = 6.2, J = 11.0), 2.62 (2H, t, J = 7.6),
2.31 (4H, q, J = 7.5), 1.98–2.07 (1H, m), 1.69 (2H, quintet, J = 7.8),
1.37–1.43 (2H, m), 1.12 (6H, t, J = 7.4); 13C NMR: 174.43, 141.94,
128.36, 128.33, 125.83, 64.00, 37.22, 35.86, 28.47, 27.68, 27.52,
9.11; IR (neat): cm−1; MS (m/z) 306 (M+), 232 (base peak), 175,
159, 144, 129, 117, 104, 92, 65, 57; HRMS calcd for C18H26O4 (M+),
306.1831. Found: 306.1839
6d: 1H NMR: 7.26–7.29 (2H, m), 7.15–7.20 (3H, m), 4.08 (2H,
dd, J = 5.2, J = 11.2), 4.03 (2H, dd, J = 6.2, J = 11.0), 2.62 (2H, t, J = 7.6),
2.28 (4H, t, J = 7.4), 2.02 (1H, septet, J = 6.1), 1.68 (2H, quintet, J = 7.9),
1.60 (4H, quintet, J = 7.5), 1.24–1.42 (10H, m), 0.89 (6H, t, J = 6.9); 13
C
NMR: 173.97, 142.10, 128.50, 128.47, 125.97, 64.08, 37.35, 36.04,
34.38, 31.44, 28.64, 27.89, 24.77, 22.44, 14.05; IR (neat): 1738 cm−1
;
MS (m/z) 390 (M+), 275, 192 (base peak), 174, 158, 143, 129, 117,
104, 91, 80, 71, 65, 55; HRMS calcd for C24H38O4 (M+), 390.2770.
Found: 390.2771
4.8. 2-Methyl-5-phenyl-1-pentanol (Rosaphen®) (RS)-1
Racemic 2-methyl-5-phenyl-1-pentanol (Rosaphen®) (RS)-1
was prepared as an authentic sample. Dry THF (20 mL) and dry
diisopropylamine (5.125 g, 50.65 mmol) were added to a three-
necked, round-bottomed flask and maintained under an argon
atmosphere. After cooling the mixture to 0 ◦C, 2.6 mol/L n-butyl
lithium in hexane solution (19.5 mL, 51 mmol) was added via a
syringe over a period of 10 min. The mixture was stirred for 20 min
at 0 ◦C. A solution of propanoic acid (1.655 g, 22.34 mmol) in dry
THF (4.5 mL) was dropwise added over a period of 10 min. After
stirring for 10 min, dry HMPA (4.4 mL, 25 mmol) was introduced via
a syringe over a period of 10 min, and the mixture was stirred for
40 min at room temperature. 1-Bromo-3-phenylpropane (4.459 g,
22.40 mmol) dissolved in dry THF (4.467 g, 24.93 mmol) was drop-
wise added over the period of 15 min at 0 ◦C. After stirring overnight
at room temperature, the mixture was treated with 1 mol/L HCl
(60 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 chromatographed {silica gel, hex-
ane/acetone = 2:1 (v/v)} to give a colorless oil, which was distilled
(223–243 ◦C/0.9 mm Hg) to give 2-methyl-5-phenylpentanoic acid
(2.658 g, 62%); 1H NMR: 7.25–7.29 (2H, m), 7.16–7.19 (3H, m),
2.62 (2H, t, J = 7.6), 2.49 (1H, sextet, J = 6.9), 1.63–1.78 (3H, m),
1.44–1.53 (1H, m), 1.18 (3H, t, J = 6.8); 13C NMR: 182.92, 142.08,
128.37, 128.33, 125.80, 39.24, 35.74, 33.09, 28.95, 16.84; IR (neat):
1705 cm−1; MS (m/z) 192 (M+, base peak), 174, 131, 117, 104, 92, 87,
74, 65; HRMS calcd for C12H16O2 (M+), 192.1150. Found: 192.1149.
4.6. 2-Hydroxymethyl-5-phenylpentyl butanoate (RS)-5c and
2-butanoyloxymethyl-5-phenylpentyl butanoate 6c
(RS)-2-Hydroxymethyl-5-phenylpentyl butanoate (RS)-5c and
2-butanoyloxymethyl-5-phenylpentyl butanoate 6c as authentic
samples were prepared from 4 (0.102 g, 0.525 mmol), butyryl
chloride (0.09 g, 0.8 mmol), dry pyridine (0.135 g, 1.71 mmol)
and dry CH2Cl2 (3 mL) as a solvent according to the procedure
described in Section 4.4. Chromatography {silica gel, hexane/ethyl
acetate = 2:1–1:1 (v/v)} of the crude product afforded (RS)-5c
(0.072 g, 52%) and 6c (0.030 g, 17%) as colorless oils.
(RS)-5c: 1H NMR: 7.26–7.30 (2H, m), 7.16–7.20 (3H, m), 4.22
(1H, dd, J = 4.4, J = 11.2), 4.09 (1H, dd, J = 6.4, J = 11.2), 3.59 (1H, dd,
J = 4.6, J = 11.4), 3.50 (1H, dd, J = 6.6, J = 11.4), 2.62 (2H, t, J = 7.4), 2.30
(2H, t, J = 7.4), 1.78–1.87 (1H, m), 1.60–1.73 (4H, m), 1.29–1.45 (2H,
m), 0.94 (3H, t, J = 7.4); 13C NMR: 174.32, 142.12, 128.37, 128.33,
125.80, 64.22, 62.66, 40.47, 36.19, 36.01, 28.79, 27.39, 18.48, 13.68;
IR (neat): 3449, 1734 cm−1; MS (m/z) 264 (M+), 176 (base peak),
159, 144, 129, 117, 104, 92, 77, 65, 57; HRMS calcd for C16H24O3
(M+), 264.1726. Found: 264.1720.
6c: 1H NMR: 7.26–7.29 (2H, m), 7.15–7.20 (3H, m), 4.08 (2H, dd,
J = 5.2, J = 11.2), 4.03 (2H, dd, J = 6.4, J = 11.2), 2.62 (2H, t, J = 7.6), 2.27
(4H, t, J = 7.4), 1.97–2.06 (1H, m), 1.58–1.72 (6H, m), 1.37–1.42 (2H,
m), 0.94 (3H, t, J = 7.4); 13C NMR: 173.64, 141.94, 128.36, 128.33,
125.82, 63.89, 37.20, 36.15, 35.88, 28.48, 27.70, 18.43, 13.67; IR
(neat): 1738 cm−1; MS (m/z) 334 (M+), 246 (base peak), 175, 159,
144, 129, 117, 104, 91, 83, 65, 57; HRMS calcd for C20H30O4 (M+),
334.2144. Found: 334.2142
A
solution of 2-methyl-5-phenylpentanoic acid (2.570 g,
13.37 mmol) in dry THF (20 mL) was added to a suspension of 80%
LiAlH4 (0.669 g, 14 mmol) in dry THF (15 mL) at 0 ◦C under an argon
atmosphere. The reaction mixture was stirred overnight at room
temperature and quenched at 0 ◦C with 1 mol/L HCl (60 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 twice {silica gel, first: hexane/acetone = 2:1
(v/v), second: hexane/ethyl acetate = 2:1 (v/v)} to give a colorless
oil, which was distilled (187–208 ◦C/0.8 mm Hg) to give (RS)-1 as a
colorless oil (2.088 g, 88%). The 1H NMR spectra data were identical
to those in the literature [8].
4.7. 2-Hydroxymethyl-5-phenylpentyl hexanoate (RS)-5d and
2-hexanoyloxymethyl-5-phenylpentyl hexanoate 6d
(RS)-2-Hydroxymethyl-5-phenylpentyl hexanoate (RS)-5d and
2-hexanoyloxymethyl-5-phenylpentyl hexanoate 6d as authentic
samples were prepared from 4 (0.104 g, 0.535 mmol), hexanoyl
chloride (0.12 g, 0.89 mmol), dry pyridine (0.152 g, 1.92 mmol)
and dry CH2Cl2 (3 mL) as a solvent according to the procedure
described in Section 4.4. Chromatography {silica gel, hexane/ethyl
acetate = 2:1–1:1 (v/v)} of the crude product afforded (RS)-5d
(0.088 g, 57%) and 6d (0.066 g, 32%) as colorless oils.
4.9. 2-Methyl-5-phenylpentyl acetate (RS)-12
2-Methyl-5-phenylpentyl acetate (RS)-12 was prepared as an
authentic sample. Acetyl chloride (0.09 g, 1 mmol) was slowly
added to a solution of (RS)-1 (0.100 g, 0.561 mmol) and dry pyri-
dine (0.133 g, 1.68 mmol) in dry dichloromethane (5 mL) at 0 ◦C.
(RS)-5d: 1H NMR: 7.26–7.30 (2H, m), 7.16–7.20 (3H, m), 4.21
(1H, dd, J = 4.4, J = 11.2), 4.09 (1H, dd, J = 6.8, J = 11.2), 3.59 (1H, dd,
J = 4.6, J = 11.4), 3.50 (1H, dd, J = 6.6, J = 11.4), 2.62 (2H, t, J = 7.6), 2.31

140
M. Kawasaki et al. / Journal of Molecular Catalysis B: Enzymatic 67 (2010) 135–142
The reaction mixture was stirred overnight at room temperature
and quenched at 0 ◦C with 1 mol/L HCl (10 mL). The resulting mix-
ture was extracted with ether. The organic phase was washed
with a saturated sodium chloride solution, and then dried over
sodium sulfate. After removal of the solvents, the residue was chro-
matographed {silica gel, hexane/ethyl acetate = 5:1 (v/v)} to give
(RS)-12 as a colorless oil (0.114 g, 93%); 1H NMR: 7.26–7.29 (2H, m),
7.16–7.19 (3H, m), 3.94 (1H, dd, J = 6.2, J = 10.6), 3.85 (1H, dd, J = 6.8,
J = 10.8), 2.54–2.66 (2H, m), 2.04 (3H, s), 1.81 (1H, sextet, J = 6.6),
1.55–1.74 (2H, m), 1.39–1.47 (1H, m), 1.16–1.26 (1H, m), 0.90 (3H,
d, J = 6.8); 13C NMR: 171.27, 142.44, 128.37, 128.28, 125.71, 69.34,
36.06, 32.93, 32.40, 28.69, 20.96, 16.79; IR (neat): 1739 cm−1; MS
(m/z) 220 (M+), 161 (base peak), 160, 145, 132, 115, 103, 92, 82, 77,
65, 51; HRMS calcd for C14H20O2 (M+), 220.1463. Found: 220.1513.
NMR: 171.36, 139.57, 126.29, 126.27, 123.84, 66.92, 60.77, 35.63,
35.16, 33.96, 33.65, 26.27, 25.01, 16.29, 11.57; IR (neat): 1734, 1358,
1175 cm−1; MS (m/z) 342 (M+), 254 (base peak), 246, 175, 157, 145,
130, 115, 103, 91, 80, 71, 65, 55; HRMS calcd for C17H26O5S (M+),
342.1501. Found: 342.1477.
4.11.3. (S)-2-methyl-5-phenyl-1-pentanol (S)-1
A solution of (S)-8 (0.832 g, 2.43 mmol) in dry THF (5 mL) was
slowly added to a suspension of 80% LiAlH4 (0.130 g, 2.7 mmol)
in dry THF (6 mL) at 0 ◦C under an argon atmosphere. The reac-
tion mixture was stirred overnight at room temperature and
quenched at 0 ◦C with 0.5 mol/L HCl (40 mL). The resulting mix-
ture was extracted three times 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 chromatographed {silica gel, first:
hexane/acetone = 5:1 (v/v)} to give a colorless oil, which was
distilled twice (first time: 170–180 ◦C/0.7 mm Hg; second time:
4.10. Lipase-catalyzed desymmetrization of
2-hydroxymethyl-5-phenyl-1-pentanol 4 (screening experiments)
In a typical run, a 1,4-dioxane solution (1 mL) containing diol
4 (0.1 mmol) and vinyl acetate 7a (1 mmol) was added to a vial
in which lipase PS (20 mg) was placed. The resulting suspension
was then magnetically stirred at room temperature. Samples were
withdrawn from the vial and analyzed by gas chromatography. The
reaction was stopped by filtration of the lipase when the peak area
of optically active monoester (R)-5a in gas chromatogram reached
about 90% of the total of peak areas of 4, (R)-5a and diester 6a. The
filtrate was concentrated under reduced pressure. The residue was
chromatographed {silica gel, hexane/ethyl acetate = 2:1–1:1 (v/v)}
with a short column (10 mm × 80 mm) to give (R)-5a. The ee of (R)-
5a was determined by HPLC.
Conditions for the determination of the ees of (R)-5a, (R)-
5b, (R)-5c and (R)-5d were as follows. (R)-5a: Chiralcel OJ-H,
hexane/2-propanol = 5:1 (v/v); (R)-5b: Chiralcel OJ-H, hexane/2-
propanol = 5:1 (v/v); (R)-5c: Chiralcel OJ, hexane/2-propanol = 5:1
(v/v); (R)-5d: Chiralcel OJ, hexane/2-propanol = 5:1 (v/v).
160–178 ◦C/1.0 mm Hg) to give (S)-1 as a colorless oil (0.246 g, 57%);
24
[˛]D
−13.6◦ (c 1.1, EtOH), {Lit. [8] [˛]D +11.2◦ (c 6.4, EtOH),
(R)}; The 1H NMR spectra data were identical to those of (RS)-
1.
4.11.4. Determination of the ee of (S)-1
Acetyl chloride (7 drops) was slowly added to a solution of (S)-
1 (2 drops) and dry pyridine (9 drops) in CH2Cl2 (5 mL) at 0 ◦C.
The reaction mixture was stirred 2.5 h at room temperature and
quenched at 0 ◦C with 1 mol/L HCl. The resulting mixture was then
extracted with ether. The organic phase was washed with deion-
ized water, a saturated sodium hydrogen carbonate solution, and
a saturated sodium chloride solution in this order, then dried over
sodium sulfate. After removal of the solvents, the residue was chro-
matographed {silica gel, hexane/ethyl acetate = 10:1 (v/v)} with a
short column (80 mm × 10 mm) to give the corresponding acetate
(S)-12 as a colorless oil. The 1H NMR spectra data were identical to
those of the acetate of (RS)-12. The ee of (S)-12 was determined by
HPLC {Chiralcel OB-H, hexane:2-propanol = 75:1 (v/v)} and found
95%.
4.11. Synthesis of (S)-2-methyl-5-phenyl-1-pentanol (S)-1
4.11.1. (R)-2-hydroxymethyl-5-phenylpentyl butanoate (R)-5c
(preparative desymmetrization of 4)
Lipase PS (0.653 g) was added to a solution of 4 (0.658 g,
3.39 mmol) and 7c (3.873 g, 33.93 mmol) in dry 1,4-dioxane
(30 mL). The mixture was stirred for 2 h 45 min at room temper-
ature. The reaction was quenched by filtration and the filtrate
was concentrated under reduced pressure. The residue was chro-
matographed {silica gel, hexane/ethyl acetate = 2:1 (v/v)} to give
(R)-5c as colorless oil (0.754 g, 85%, 96% ee). The 1H NMR spectra
data were identical to those of (RS)-5c.
4.12. Synthesis of (R)-2-methyl-5-phenyl-1-pentanol (R)-1
4.12.1. (R)-2-hnydroxymethyl-5-phenylpentyl butanoate (R)-5c
(preparative desymmetrization of 4)
(R)-2-Hydroxymethyl-5-phenylpentyl butanoate (R)-5c with
97% ee for the synthesis of (R)-1 was newly prepared via the prepar-
ative desymmetrization of 4 in 89% yield according to the procedure
described in Section 4. 11. 1. The 1H NMR spectra data of (R)-5c
obtained here were identical to those of (RS)-5c.
4.11.2. (S)-2-methanesulfonyloxymethyl-5-phenylpentyl
butanoate (S)-8
4.12.2. (S)-2-tert-butyldimethylsiloxymethyl-5-phenylpentyl
butanoate (S)-9
Methanesulfonyl chloride (0.656 g, 5.73 mmol) was slowly
added to a solution of (R)-5c (0.744 g, 2.81 mmol) and dry pyri-
dine (0.676 g, 8.55 mmol) in dry CH2Cl2 (10 mL) at 0 ◦C. The reaction
mixture was stirred overnight at room temperature and quenched
at 0 ◦C with 1 mol/L HCl (20 mL). The resulting mixture was then
extracted with ether. The organic phase was washed with deion-
ized water, a saturated sodium hydrogen carbonate solution, and
a saturated sodium chloride solution in this order, then dried over
sodium sulfate. After removal of the solvents, the residue was chro-
matographed {silica gel, hexane/ethyl acetate = 2:1 (v/v)} to give
(S)-8 as a colorless oil (0.886 g, 92%): 1H NMR: 7.26–7.30 (2H, m),
7.16–7.21 (3H, m), 4.21 (1H, dd, J = 5.0, J = 9.8), 4.18 (1H, dd, J = 5.8,
J = 9.8), 4.14 (1H, dd, J = 4.6, J = 11.4), 4.04 (1H, dd, J = 6.8, J = 11.2),
2.98 (3H, s), 2.63 (2H, t, J = 7.4), 2.28 (2H, t, J = 7.4), 2.05–2.14 (1H,
m), 1.59–1.74 (4H, m), 1.36–1.50 (2H, m), 0.94 (3H, t, J = 7.4); 13C
Tert-butyldimethylsilyl trifluoromethanesulfonate (3.66 g,
13.8 mmol) was slowly added to a solution of (R)-5c (1.824 g,
6.900 mmol) and dry pyridine (1.66 g, 21.0 mmol) in dry CH2Cl2
(15 mL) at 0 ◦C. The reaction mixture was stirred overnight at room
temperature and quenched at 0 ◦C with deionized water (50 mL).
The resulting mixture was then extracted with ether. The organic
phase was washed with deionized water twice and dried over
sodium sulfate. After removal of the solvents, the residue was
chromatographed {silica gel, hexane/ethyl acetate = 5:1 (v/v)} to
give (S)-9 as a colorless oil (2.521 g, 97%); 1H NMR: 7.25–7.29 (2H,
m), 7.16–7.19 (3H, m), 4.06 (2H, d, J = 5.6), 3.52–3.60 (2H, m), 2.60
(2H, t, J = 7.6), 2.26 (2H, t, J = 7.4), 1.81 (1H, septet, J = 6), 1.61–1.70
(4H, m), 1.24–1.45 (2H, m), 0.94 (3H, t, J = 7.4), 0.87 (9H, s), 0.02
(6H, s); 13C NMR: 173.74, 142.35, 128.37, 128.27, 125.70, 64.27,

M. Kawasaki et al. / Journal of Molecular Catalysis B: Enzymatic 67 (2010) 135–142
141
62.56, 40.16, 36.27, 36.13, 28.77, 27.50, 25.86, 18.48, 18.26, 13.70,
Acknowledgements
−5.54; IR (neat): 1738, 1092 cm−1; MS (m/z) 378 (M+), 322 (base
peak), 321, 187, 163, 146, 131, 115, 104, 91, 81, 76, 59; HRMS calcd
for C22H38O3Si (M+), 378.2590. Found: 378.2574
We are grateful to the researchers at the Biotechnology Research
Center, Toyama Prefectural University, for their generous support
with the NMR spectroscopic and optical rotation measurements.
We are also grateful to Dr. Yasuo Tanaka, Taiyo Koryo Corporation
for the olfactory evaluation. Amano Enzyme Inc., Meito Sangyo Co.,
Ltd., and Novozymes Japan, Inc provided the lipases.
4.12.3.
(S)-2-tert-butyldimethylsiloxymethyl-5-phenyl-1-pentanol
(S)-10
Six mole per Litre NaOH (4 mL, 24 mmol) was added to a solu-
tion of (S)-9 (2.426 g, 6.408 mmol) in EtOH (24 mL). The mixture was
stirred overnight at room temperature. After removal of the solvent,
the residue was extracted three times with ether. The organic layer
was washed with brine, then dried over sodium sulfate and concen-
trated. The residue was chromatographed {silica gel, hexane/ethyl
acetate = 3:1 (v/v)} to give (S)-10 (1.028 g, 52%) as a colorless oil;
1H NMR: 7.26–7.30 (2H, m), 7.16–7.20 (3H, m), 3.80 (1H, dd, J = 4.0,
J = 9.6), 3.74 (1H, dd, J = 3.4, J = 10.6), 3.63 (1H, dd, J = 7.2, J = 10.8),
3.59 (1H, dd, J = 7.4, J = 9.8), 2.61 (2H, t, J = 7.6), 1.71–1.80 (1H, m),
References
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4.12.4. (R)-2-tert-butyldimethylsiloxymethyl-5-phenylpentyl
methanesulfonate (R)-11
Methanesulfonyl chloride (0.75 g, 6.5 mmol) was slowly added
to a solution of (S)-10 (0.990 g, 3.21 mmol) and dry pyridine (0.76 g,
9.6 mmol) in dry CH2Cl2 (10 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 (twice)
and a saturated sodium chloride solution in this order, then dried
over sodium sulfate. After removal of the solvents, the residue was
chromatographed {silica gel, hexane/ethyl acetate = 3:1 (v/v)} to
give (R)-11 as a colorless oil (1.146 g, 93%): 1H NMR: 7.26–7.30
(2H, m), 7.16–7.20 (3H, m), 4.22 (2H, d, J = 5.6), 3.64 (1H, dd, J = 4.4,
J = 10.0), 3.53 (1H, dd, J = 6.4, J = 10.0), 2.97 (3H, s), 2.62 (2H, t, J = 7.5),
1.84–1.92 (1H, m), 1.67 (2H, quintet, J = 7.8), 1.36–1.42 (2H, m),
0.88 (9H, s), 0.04 (6H, s); 13C NMR: 142.03, 128.38, 128.36, 125.84,
70.04, 61.53, 40.62, 36.93, 36.00, 28.70, 26.88, 25.84, 18.22, −5.50,
−5.55; IR (neat): 1359, 1177, 1094 cm−1; MS (m/z) 387 (M+ + H),
233 (base peak), 195, 171, 156, 145, 137, 130, 115, 101, 90, 81,
71, 60, 51; HRMS calcd for C19H34O4SSi (M+), 386.1947. Found:
386.1915.
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4.12.5. (R)-2-methyl-5-phenyl-1-pentanol (R)-1
A solution of (R)-11 (1.049 g, 2.713 mmol) in dry Et2O (10 mL)
was slowly added to a suspension of 80% LiAlH4 (0.148 g, 3.1 mmol)
in dry Et2O (8 mL) at room temperature. The reaction mixture
was refluxed for 6.5 h. 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 a saturated sodium
chloride solution, then dried over Na2SO4 and concentrated under
reduced pressure. The residue was chromatographed {silica gel,
hexane/ethyl acetate = 2/1 (v/v)} to give a colorless oil, which was
distilled (165–180 ◦C/1.0 mm Hg) to give (R)-1 as a colorless oil
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(0.246 g, 57%, 96% ee); [˛]D +12.6◦ (c 1.1, EtOH), {Lit. [8] [˛]D
24
+11.2◦ (c 6.4, EtOH), (R)}; The 1H NMR spectra data were identical
to those of (RS)-1; The ee was determined after (R)-1 was converted
to the corresponding acetate (R)-12 according to the procedure in
Section 4.11.4.

142
M. Kawasaki et al. / Journal of Molecular Catalysis B: Enzymatic 67 (2010) 135–142
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