Enantioselective synthesis of (S)-1-phenylethanol, a precursor to low-molecular-weight bioregulators

Article abstract of DOI:10.1134/S107036321613017X

A procedure has been proposed for the synthesis of (S)-(–)-1-phenylethanol, an important building block for the preparation of medicinal agents possessing antidiabetic, antidepressant, and antirabic activity, as well as of antifeedants and antiparasitic,

Full text of DOI:10.1134/S107036321613017X

ISSN 1070-3632, Russian Journal of General Chemistry, 2016, Vol. 86, No. 13, pp. 3021–3024. © Pleiades Publishing, Ltd., 2016.
Original Russian Text © A.R. Chanysheva, G.V. Yunusova, T.E. Vorobyoeva, V.V. Zorin, 2016, published in Ekologicheskaya Khimiya, 2017, Vol. 26, No. 1,
pp. 6–10.
Enantioselective Synthesis of (S)-1-Phenylethanol,
a Precursor to Low-Molecular-Weight Bioregulators
A. R. Chanysheva*, G. V. Yunusova, T. E. Vorobyova, and V. V. Zorin
Ufa State Petroleum Technological University, ul. Kosmonavtov 1, Bashkortostan, Ufa, 450062 Russia
*e-mail: aliyach@mail.ru
Received November 11, 2016
Abstract—A procedure has been proposed for the synthesis of (S)-(–)-1-phenylethanol, an important building
block for the preparation of medicinal agents possessing antidiabetic, antidepressant, and antirabic activity, as
well as of antifeedants and antiparasitic, antimicrobial, and antifungal metabolites, by enantioselective
bioreduction of acetophenone. Different exogenous reducing agents (propan-2-ol, ethanol, and glucose) were
tried to improve the yield of the target product and its enantiomeric purity.
Keywords: bioreduction, enantioselective biocatalysis, acetophenone, (S)-(–)-1-phenylethanol, environmentally
benign processes
DOI: 10.1134/S107036321613017X
Development of “green chemistry” involves design
of promising environmentally benign processes and
materials. Creation of modern highly efficient low
molecular weight bioregulators such as medicinal
agents (analogs of natural compounds with complex
structure due to the presence of double bonds and
chiral centers with definite configurations) for the
treatment of various diseases, including malignant
tumors and viral infections, insect behavior regulators
(pheromones and other species-specific attractants and
repellents), and their precursors requires stereo-
selective synthetic procedures. This problem is
especially important for the preparation of enantio-
merically pure biologically active compounds whose
optical purity is responsible for their efficiency and
selectivity of action. The most efficient approach to
enantioselective synthesis is based on the use of
biocatalysts (enzymes and cell catalysts) capable of
operating under mild conditions (temperature, pressure)
in both aqueous medium and organic solvents [1–8].
Zygosaccharomyces rouxii, and other yeasts [22] are
traditionally used as biocatalysts for the reduction of
carbonyl compounds. Procedures have been developed
for the preparation of optically pure alcohols (yield
>80%, >90% ee) as key building blocks for the
synthesis of a number of α- and β-adrenergic blockers
with the use of Saccharomyces bayanus, Pichia
Mexicana [23], Rhodotorula rubra [24], and Spingomonas
paucimobilis cells [25]. Asymmetric reduction of an
aryl phenyl ketone in the presence of Rhodotorula
pilimanae afforded the S enantiomer of the the
corresponding alcohol (>96% ee) used in the synthesis
of specific phosphodiesterase inhibitor for the treatment
of asthma [26]. Dormant or growing Kluyveromyces
marxianus cells successfully catalyzed diastereo- and
enantioselective reduction of ethyl 2-(4-chlorophen-
oxy)-3-oxobutyrate to ethyl 2-(4-chlorophenoxy)-3-
hydroxybutyrate, an analog of Clofibrate (hypo-
lipidemic drug) [27].
Organic solvents were found [28, 29] to con-
siderably increase the optical purity of products ob-
tained by reduction of carbonyl compounds with
Baker’s yeast. Ethyl acetoacetate, ethyl 3-oxo-5-phenyl-
pentanoate, and N-phenyl-3-oxobutanamide were
reduced with Baker’s yeast in petroleum ether with an
enantioselectivity of 99–100% (ee) and 69–82% yield
[30, 31]. Permeabilized cells of microorganisms were
also used to catalyze asymmetric reduction of carbonyl
Numerous examples have been reported to demon-
strate high synthetic potential of biocatalytic reactions.
The most efficient is enantioselective reduction of
ketones in the presence of microorganisms producing
enantioselective oxidoreductases which ensure forma-
tion of optically active alcohols with high yield and
optical purity [9–16]. Baker’s yeast (Saccharomyces
cerevisiae) [17–21], as well as Candida famata,
3021

3022
CHANYSHEVA et al.
Table 1. Yield and enantiomeric purity of (S)-(–)-1-
phenylethanol in the biocatalytic reduction of acetophenone
in water in the presence of propan-2-ola
Table 2. Yield and enantiomeric purity of (S)-(–)-1-
phenylethanol in the biocatalytic reduction of acetophenone
in water in the presence of ethanola
Concentration of
propan-2-ol, %
Yield,
%
Concentration of
ethanol, %
Yield,
%
Optical purity, % ee
Optical purity, % ee
0
1
75
75
95
65
75
53
–
97.0
98.2
97.0
97.5
98.3
98.0
–
0
1
75
77
55
55
45
35
–
97.0
60.0
60.0
55.0
55.0
53.0
–
2
2
3
3
4
4
5
5
10
15
10
15
–
–
–
–
a
a
Temperature 20–25°C; concentration of acetophenone 1.4 g/L.
Temperature 20–25°C; concentration of acetophenone 1.4 g/L.
compounds [32, 33]. The reduction of acetophenone
with an acetone powder of Geotrichum candidum in
propan-2-ol, pentan-2-ol, octan-2-ol, or cyclopentanol
using NADP+ and NAD+ as coenzymes afforded
(S)-(–)-1-phenylethanol with >99% ee and 86–97%
yield [34]. Analogous procedures were applied to
reduce simple and some functionally substituted
aliphatic ketones, aromatic ketones, and β-keto esters
to the corresponding S-configured alcohols (98–99% ee)
[34–36].
is known that enzymes capable of reducing various
carbonyl compounds utilize mainly endogenous reducing
agents, particularly reduced coenzymes (NADPH or
NADH) [26, 38] and that biocatalysts need to be
regenerated. Efficient procedures have been reported
for the regeneration of those coenzymes [39] with
inexpensive accessible exogenous reducing agents
such as ethanol, cyclopentanol, propan-2-ol, sucrose,
glucose, etc. [17, 18, 40].
In order to improve the procedure for the synthesis
of (S)-(–)-1-phenylethanol by reduction of aceto-
phenone with D. carota as biocatalyst, we examined
the transformation of acetophenone in the presence of
propan-2-ol, ethanol, and glucose at different con-
centrations. These compounds act as exogenous reducing
agents toward coenzymes [17, 18, 40], and they could
affect the enantioselectivity of acetophenone reduction
and the yield of the target alcohol.
Search for new highly efficient environmentally
benign enantioselective procedures for the reduction of
prochiral carbonyl compounds with accessible
catalysts attracts increased interest and is a promising
research line.
An important precursor to low-molecular-weight
bioregulators is (S)-(–)-1-phenylethanol. It is used in
the synthesis of medicinals possessing antidiabetic,
antidepressant, and antirabic activity, as well as of
antifeedants and antiparasitic, antimicrobial, and
antifungal agents [37]. Derivatives of (S)-(–)-1-phenyl-
ethanol are also used for the preparation of liquid
crystals and optically active polymers for the separa-
tion of racemic mixtures.
In fact, the yield of (S)-(–)-1-phenylethanol in-
creased to 95% (97% ee) in the presence of 2% of
propan-2-ol (Table 1). When ethanol was added as
exogenous reducing agent (2%), the maximum yield of
(S)-(–)-1-phenylethanol was 77% (97% ee), other
conditions being equal (Table 2). Presumably, this is
In this work we made an attempt to develop a
highly efficient procedure for the synthesis of optically
pure (S)-(–)-1-phenylethanol from acetophenone using
Daucus carota as biocatalyst (Scheme 1).
Scheme 1.
D. carota
We have found that the reduction of acetophenone
with D. sarota in water at room temperature (144 h)
yields 75% of (S)-(–)-1-phenylethanol with 97% ee. It
OH
O
(S)-(−)-1-Phenylethanol
Acetophenone
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 86 No. 13 2016

ENANTIOSELECTIVE SYNTHESIS OF (S)-1-PHENYLETHANOL
3023
related to the higher reducing ability of propan-2-ol
compared to ethanol. Raising the concentration of
propan-2-ol or ethanol to 5–30% resulted in a
considerable decrease of the yield of (S)-(–)-1-phenyl-
ethanol, presumably due to inhibition of oxido-
reductase responsible for the reduction process.
(S)-(–)-1-Phenylethanol. Acetophenone (0.1 g)
was added to a suspension of D. carota (15 g) in
70 mL of water, and the mixture was placed in an
orbital shaker (150 rpm) and shaken at room
temperature until a required substrate conversion was
attained. The mixture was filtered, and the biomass
was washed thrice with water. The filtrate was
combined with the washings and extracted with diethyl
ether (3 × 125 mL). The extracts were dried over
Na2SO4 and evaporated on a rotary film evaporator. 1H
NMR spectrum, δ, ppm: 1.42–1.49 d (3H, CH3), 2.6 s
(1H, OH), 4.2–4.4 q (1H, CH), 7.2–7.35 m (5H, Harom).
13C NMR spectrum, δC, ppm: 20.28 (CH3), 70.35 (CH),
125.27 (2C, CHarom), 127.35 (CHarom), 128.12 (2C,
CHarom), 145.8 (Carom). Mass spectrum, m/z (Irel, %):
105.1 (100), 77.1 (93.8), 51.1 (36.7), 120.1 (32.9),
79.1 (26.4), 107.1 (25.3), 43.0 (21.7), 78.1 (14.0), 50.1
(13.7), 122.2 (9.7).
We also tried to optimize the synthesis of optically
active (S)-(–)-1-phenylethanol by reduction of aceto-
phenone with D. sarota using glucose as endogenous
reducing agent. The reduction was carried out in water
at room temperature (144 h) in the presence of an
equimolar amount of glucose. In this case, the yield of
(S)-(–)-1-phenylethanol considerably increased (98%),
but its optical purity was poor (60% ee).
The progress of reactions was monitored by GLC
using a chiral Astec Chiraldexb-PM capillary column
(30 m × 0.25 mm; film thickness 0.12 μm) which
discriminated R and S enantiomers of 1-phenylethanol
from authentic racemic alcohol. The structure of
Racemic (RS)-1-phenylethanol was synthesized
according to the procedure described in [41].
1
(S)-(–)-1-phenylethanol was confirmed by H and 13C
NMR and GC/MS, and its configuration was identified
by polarimetry.
ACKNOWLEDGMENTS
This study was performed in the framework of a
state assignment of the Ministry of Education and
Science of the Russian Federation.
Thus, we have found conditions ensuring prepara-
tion of (S)-(–)-1-phenylethanol in 95% yield with 97%
ee by bioreduction of acetophenone in the presence of
biocatalyst based on D. carota and propan-2-ol (2%).
REFERENCES
1. Shakirov, A.N., Del’mukhametov, R.R., Petukhova, N.I.,
and Zorin, V.V., Bashk. Khim. Zh., 2015, vol. 22, no. 1,
p. 72.
EXPERIMENTAL
The H and 13C NMR spectra were recorded on
1
Bruker AM-300 and AMX-300 spectrometers at 300
and 75 MHz, respectively, using tetramethylsilane as
internal standard. The 13C NMR spectra were
measured with complete decoupling from protons and
with JMOD pulse sequence. The GC/MS data were
obtained on a Shimadzu GCMS-QP2010S instrument
(electron impact, 70 eV; a.m.u. range 33–500; HP-
1MS capillary column, 30 m × 0.25 mm, film thick-
ness 0.25 μm; injector temperature 280°C, ion source
temperature 200°C; oven temperature programming
from 100 to 280°C at a rate of 20 deg/min; carrier gas
helium, flow rate 1.1 mL/min).
2. Shakirov, A.N., Petukhova, N.I., and Zorin, V.V.,
Bashk. Khim. Zh., 2013, vol. 20, no. 3, p. 20.
3. Sharaeva, A.A., Petukhova, N.I., Shakirov, I.G., and
Zorin, V.V., Bashk. Khim. Zh., 2013, vol. 20, no. 4,
p. 49.
4. Shakirov, A.N., Petukhova, N.I., and Zorin, V.V.,
Bashk. Khim. Zh., 2013, vol. 20, no. 4, p. 59.
5. Shakirov, A.N., Del’mukhametov, R.R., Petukhova, N.I.,
Shakhmaev, R.N., and Zorin, V.V., Ekol. Khim., 2012,
vol. 21, no. 3, p. 187.
6. Shakirov, A.N., Petukhova, N.I., Del’mukhametov, R.R.,
Koreneva, S.V., and Zorin, V.V., Bashk. Khim. Zh.,
2012, vol. 19, no. 2, p. 71.
Polarimetric analysis was performed in chloroform
using an Optical Activity Limited Modeli AA-55
automated polarimeter with a halogen lamp (λ 589
nm). GLC analyses were obtained on a hardware–
software system based on a Khromatek-Kristall-5000.2
gas chromatograph equipped with a flame ionization
detector and an Astec Chiraldexb-PM chiral column
(30 m × 0.25 mm; film thickness 0.12 μm).
7. Zorin, V.V., Petukhova, N.I., and Shakhmaev, R.N.,
Ross. Khim. Zh., 2011, vol. 55, no. 1, p. 77.
8. Shakirov, A.N., Zorin, V.V., Petukhova, N.I., and
Vasilova, L.Ya., Bashk. Khim. Zh., 2011, vol. 18, no. 4,
p. 38.
9. Khalimova, L.Kh., Mubarakov, A.I., Ankudinova, N.V.,
Petukhova, N.I., and Zorin, V.V., Bashk. Khim. Zh.,
2010, vol. 17, no. 5, p. 21.
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 86 No. 13 2016

3024
CHANYSHEVA et al.
10. Vasilova, L.Ya., Shakirov, A.N., Petukhova, N.I.,
Shakhmaev, R.N., and Zorin, V.V., Bashk. Khim. Zh.,
2010, vol. 17, no. 5, p. 32.
26. Ishihara, K., Hamada, H., Hirata, T., and Nakajima, N.,
J. Mol. Catal. B: Enzym., 2003, vol. 23, p. 145.
27. Pawlowicz, P. and Siewinski, A., Phytochemistry, 1987,
11. Vasilova, L.Ya., Shakirov, A.N., Sharaeva, A.A.,
Petukhova, N.I., and Zorin, V.V., Bashk. Khim. Zh.,
2010, vol. 17, no. 5, p. 43.
12. Kalimullina, L.Ya., Petukhova, N.I., Khannanova, D.G.,
and Zorin, V.V., Bashk. Khim. Zh., 2009, vol. 16, no. 4,
p. 57.
vol. 26, p. 1001.
28. Patel, R., McNamee, C.G., Banerjee, A., Howell, J.M.,
Robison, R.S., and Szarka, L.J., Enzyme Microb.
Technol., 1992, vol. 14, p. 731.
29. Nakamura, K., Kondo, S., Nakajima, N., and Ohno, A.,
Tetrahedron, 1995, vol. 51, p. 687.
13. Kalimullina, L.Ya., Petukhova, N.I., and Zorin, V.V.,
30. Rotthaus, O., Krüger, D., Demuth, M., and Schaffner, K.,
Bashk. Khim. Zh., 2008, vol. 15, no. 1, p. 8.
Tetrahedron, 1997, vol. 53, p. 935.
14. Kalimullina, L.Ya., Khannanova, D.G., Petukhova, N.I.,
and Zorin, V.V., Bashk. Khim. Zh., 2007, vol. 14, no. 1,
p. 148.
31. Medson, C., Smallridge, A.J., and Trewhella, M.A.,
Tetrahedron: Asymmetry, 1997, vol. 8, p. 1049.
32. Athanasiou, N., Smallridge, A.J., and Trewhella, M.A.,
15. Kalimullina, L.Ya., Mukhitdinov, E.R., Petukhova, N.I.,
and Zorin, V.V., Bashk. Khim. Zh., 2007, vol. 14, no. 1,
p. 151.
16. Zorin, V.V., Petukhova, N.I., and Shakhmaev, R.N.,
Russ J. Gen. Chem., 2012, vol. 82, no. 5, p. 1013. doi
10.1134/S1070363212050362
17. Nakamura, K. and Matsuda, T., Tetrahedron, 1998,
vol. 54, p. 8393.
18. Matsuda, T., Harada, T., Nakajima, Y., Itoh, T., and
Nakamura, K., J. Org. Chem., 2000, vol. 65, p. 157.
19. Lappin, G.J., Stride, J.D., and Tampion, J.,
Phytochemistry, 1987, vol. 26, p. 995.
20. Hamada, H., Nakamura, N., Ito, S., Kawabe, S., and
J. Mol. Catal. B: Enzym., 2001, vol. 11, p. 893.
33. Hamada, H., Miura, T., Kumobayashi, H., Matsuda, T.,
Harada, T., and Nakamura, K., Biotechnol. Lett., 2001,
vol. 23, p. 1603.
34. Ishihara, K., Yamaguchi, H., Hamada, H., Nakajima, N.,
and Nakamura, K., J. Mol. Catal. B: Enzym., 2000,
vol. 10, p. 429.
35. Nakamura, K. and Matsuda, T., Tetrahedron, 1998,
vol. 54, p. 8393.
36. Matsuda, T., Harada, T., Nakajima, Y., Itoh, T., and
Nakamura, K., J. Org. Chem., 2000, vol. 65, p. 157.
37. Semenov, A.A., Ocherk khimii prirodnykh soedinenii
(Survey of the Chemistry of Natural Compounds),
Novosibirsk: Nauka, 2000.
Funamoto, T., Phytochemistry, 1988, vol. 27, p. 3807.
21. Hamada, H., Bull. Chem. Soc. Jpn., 1988, vol. 61,
38. Zarevucka, M., Wimmer, Z., Saman, D., Demnerova, K.,
and Mackova, M., Tetrahedron: Asymmetry, 2004,
vol. 15, p. 1325.
p. 869.
22. Yadav, J.S., Reddy, P.T., Nanda, S., and Rao, A.B.,
Tetrahedron: Asymmetry, 2001, vol. 12, p. 63.
39. Hirata, T., Hamda, H., Aoki, T., and Suga, T.,
23. Lee, Y.S., J. Sci. Hiroshima Univ., Ser. A: Phys. Chem.,
Phytochemistry, 1982, vol. 21, p. 2209.
1983, vol. 47, p. 21.
40. Matsuda, T., Nakajima, Y., Harada, T., and Nakamura, K.,
24. Suga, T., Hirata, T., and Lee, Y.S., Chem. Lett., 1982,
Tetrahedron: Asymmetry, 2002, vol. 13, p. 971.
vol. 11, no. 10, p. 1595.
25. Suga, T., Hirata, T., and Izumi, S., Phytochemistry,
41. Agronomov, A.E., Laboratornye raboty v organi-
cheskom praktikume (Laboratory Works in Organic
Practicum), Moscow: Khimiya, 1974.
1986, vol. 25, p. 2791.
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 86 No. 13 2016