Asymmetric reduction of aromatic ketones by the baker's yeast in organic solvent systems

Article abstract of DOI:10.1081/SCC-100104064

The reduction of aromatic ketones to optically active alcohols, mediated by dried baker's yeast, proceeded in moderate conversion and good enantioselectivity (82 ～ 91% e.e.) in a number of organic solvents, including petroleum ether, toluene, chloroform, and tetrahydrofuran. A small amount of water (0.4 mL: g yeast) was required for the reaction to proceed. The water:yeast ratio and the solvent polarity were found to significantly influence the reactivity of the system.

Full text of DOI:10.1081/SCC-100104064

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ASYMMETRIC REDUCTION OF
AROMATIC KETONES BY THE
BAKER'S YEAST IN ORGANIC
SOLVENT SYSTEMS
Xiang Liu a , Tong-Sheng Zhu a , Pei-Dong Sun a &
Jian-He Xu b
a Department of Chemical Engineering , Wuxi
University of Light Industry , Wuxi, Jiangsu,
214036, P.R. China
b State Key Laboratory of Bioreactor Engineering ,
East China University of Science and Technology ,
Shanghai, 200237, P.R. China
Published online: 02 Aug 2010.
To cite this article: Xiang Liu , Tong-Sheng Zhu , Pei-Dong Sun & Jian-He Xu (2001)
ASYMMETRIC REDUCTION OF AROMATIC KETONES BY THE BAKER'S YEAST IN ORGANIC
SOLVENT SYSTEMS, Synthetic Communications: An International Journal for Rapid
Communication of Synthetic Organic Chemistry, 31:10, 1521-1526, DOI: 10.1081/
SCC-100104064
To link to this article: http://dx.doi.org/10.1081/SCC-100104064
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SYNTHETIC COMMUNICATIONS, 31(10), 1521–1526 (2001)
ASYMMETRIC REDUCTION OF
AROMATIC KETONES BY THE
BAKER’S YEAST IN ORGANIC
SOLVENT SYSTEMS
Xiang Liu,1, Tong-Sheng Zhu,1 Pei-Dong Sun,1
*
and Jian-He Xu2
1Department of Chemical Engineering,
Wuxi University of Light Industry, Wuxi,
Jiangsu 214036, P.R. China
2State Key Laboratory of Bioreactor Engineering,
East China University of Science and Technology,
Shanghai 200237, P.R. China
ABSTRACT
The reduction of aromatic ketones to optically active alco-
hols, mediated by dried baker’s yeast, proceeded in moderate
conversion and good enantioselectivity (82 ꢀ 91% e.e.) in a
number of organic solvents, including petroleum ether,
toluene, chloroform, and tetrahydrofuran. A small amount
of water (0.4 mL: g yeast) was required for the reaction to
proceed. The water:yeast ratio and the solvent polarity were
found to significantly influence the reactivity of the system.
*Corresponding author. E-mail: chend@wxuli.edu.cn
1521
Copyright & 2001 by Marcel Dekker, Inc.
www.dekker.com

1522
LIU ET AL.
Figure 1.
Yeast is often employed as a reducing agent in organic synthesis, such
as asymmetric reduction of prochiral b-ketoesters and aromatic ketones.1,2
One of the major drawbacks associated with yeast-mediated reduction
reactions has been the necessity for an aqueous reaction medium that
restricts the usefulness of the system for water-insoluble compounds or
compounds containing water labile functionality. A number of reports
have appeared recently that indicate that the reducing capability of yeast
could be preserved in an organic solvent if the yeast is first immobilized.3–5
Also, it has been reported that free (unimmobilized) yeast is capable of the
reduction of a-ketoesters6 in benzene and b-ketoesters7 in petroleum ether.
Our work was to perform the asymmetric reduction of aromatic ketones 1
by direct use of dried baker’s yeast in organic solvent systems (Fig. 1). We
have extended our investigation of the yeast-mediated reduction from the
medium of petroleum ether to a range of solvents with different polarity.
The influence of various water:yeast ratios on the reactivity of the biocata-
lytic system has also been examined.
EFFECT OF WATER ON REACTIVITY
No reaction was observed when aromatic ketones 1 were stirred in dry
petroleum ether in the presence of yeast (1 g:mmol-substrate) at room
temperature for 24 h. However, the addition of small amounts of water to
the reaction system greatly contributed to the increased reduction of 1. The
most suitable amount of water was 0.4 mL:g-yeast. Perhaps larger amounts
of water would improve the substrate conversion. Nevertheless, the amount
of 0.5 mL-water/g-yeast resulted in obvious swelling and adhesion of dried
baker’s yeast. As a result, the reaction proceeded hardly and the conversion
went contrary to our expectation. The same effect was also observed when
the reaction was carried out in chloroform and toluene (Fig. 2). A water:-
yeast ratio (mL:g) of 0.4 was thus considered to be the optimum ratio for the
yeast-mediated reduction of aromatic ketones 1 in these solvents.
The yeast-catalyzed reduction of carbonyl groups involves the
concomitant oxidation of the coenzyme NAD(P)H to NAD(P)þ. In aqueous

ASYMMETRIC KETONE REDUCTION
1523
Figure 2. Effect of water on the yeast-mediated reduction of acetophenone.
(5 mmol acetophenone, 5 g dried yeast, 100 mL solvent, room temperature, 24 h.
Conversion was calculated from GC ratio of substrate to product.)
systems, various metabolic pathways within the yeast continuously
recycle the NAD(P)þ back to NAD(P)H, ensuring a continuous supply
of the coenzyme. In completely anhydrous organic solvents, however,
regeneration of the coenzymes cannot occur and the extent of reduction
is limited by the amount of available NAD(P)H in the yeast. The yeast
is therefore providing both the catalyst (oxidoreductase enzyme(s)) and the
reagent (NAD(P)H) for the reaction. Small amounts of water enabled
the recycling of the coenzymes to satisfy the necessity of the reaction
process in our organic solvent systems.
From the above results, it is obvious that the water:yeast ratio indeed
affects the reaction significantly. It has been shown lately that an enzyme
molecule becomes fully hydrated when surrounded by a few layers of water
molecules.8,9 It is thought that this hydration layer acts as a micro-reactor
for the enzyme and protects it from any detrimental effects of the bulk
organic solvent. It therefore appears that 0.4 mL water:g yeast is the opti-
mum amount of water required to form this protective layer around the
yeast enzymes for the reduction of aromatic ketones 1.
EFFECT OF SOLVENT POLARITY ON REACTION
The extent of interaction between the organic solvent and the essential
water surrounding an enzyme depends on the nature of the solvent
employed. Hydrophilic solvents usually tend to remove or distort this

1524
LIU ET AL.
Table 1. Effect of Solvents on Conversion and Enantioselectivitya
Solvent
log P
Conversionb (%)
e.e.c (%)
Petroleum ether
Toluene
Chloroform
Tetrahydrofuran
Ethyl acetate
Ethanol
3.5
2.5
2.0
0.49
0.68
ꢁ0.24
6290
52
55
50
15
<5
86
91
85
/
/
a5 mmol acetophenone, 5 g dried yeast, 100 mL solvent, 2mL water, room tempera-
ture, 24 h;
bcalculated from GC ratio of substrate to product;
cdetermined by chiral HPLC analysis using a Daicel chiralcel OD column.
protective water layer and cause inactivation of the enzyme. While hydro-
phobic solvents are less able to interfere with the water and thus are
expected to be the most suitable nonaqueous media for enzymatic reactions.
Our results have also lead to the same conclusion (Table 1).
The partition coefficient of a solvent between water and n-octanol has
been proposed as a measure of the polarity of the solvent.10 The logarithm
of the partition coefficient (log P) has been shown to correlate reasonably
well with the reactivity of a variety of enzymes in organic solvents.8,11 As
expected, enzymes were more active in nonpolar solvents (log P>2) and the
results from the yeast-mediated reduction of acetophenone in variety of
solvents followed this trend (Table 1). In fact, the reaction proceeded
smoothly in the nonpolar solvents such as petroleum, ether, toluene, and
chloroform, while product of the reaction was hardly detected in solvents of
higher polarity. However, the activity of yeast in tetrahydrofuran was rather
surprising, given the low log Pvalue of this solvent. The higher-than-
expected activity of enzymes in diethyl ether has been previously noted.10
Tetrahydrofuran is similar to diethyl ether in many ways.
CONVERSION AND ENANTIOSELECTIVITY
In aqueous solvents, the yeast-mediated reduction of substituted
acetophenones afforded (S)-1-arylethanols in moderate yields and e.e. values
between 82% and 96%.1 In our organic solvent systems, the yeast-
mediated reduction of acetophenone proceeded in moderate conversion and
also resulted in the formation (>85% e.e. of (S)-1-phenylethanol (Table 1).
The other aromatic ketones had similar results (Table 2). No influence on the

ASYMMETRIC KETONE REDUCTION
1525
Table 2. The Results of Asymmetric Reduction of Several Aromatic Ketones
Entry
R1
R2
Conversionb (%)
e.e.c (%)
Configuration
S
1
2
3
4
5
6
ꢁH
ꢁCH3
ꢁC2H5
ꢁCH3
ꢁCH3
ꢁCH3
ꢁCH2Br
6290
59
6289
54
63
51
S
88
S
82S
90
85
ꢁH
ꢁCH3
ꢁOCH3
ꢁBr
S
R
ꢁH
aSee also Fig. 1. Conditions: 5 mmol substrate, 5 g dried yeast, 100 mL petroleum
ether, 2mL water; room temperature, 24 h;
bcalculated from GC ratio of substrate to product;
cdetermined by chiral HPLC analysis using a Daicel chiralcel OD column.
steric course of the reduction was observed when the group R1 and R2
of aromatic ketones 1 were changed, but there were some changes in the
conversion ratios of substrates and enantiomeric excesses of products.
The reduction of a-bromoacetophenone also had the same steric course as
the reduction of the other ketones although (R)-1-phenyl-2-bromoethanol
was obtained (Table 2, Entry 6).
GENERAL PROCEDURE FOR REDUCTION OF
AROMATIC KETONES12
In a 250-mL round-bottom flask was placed 0.60 g (5 mmol) aceto-
phenone, 100 mL petroleum ether, 2.5 mL water, and 5 g yeast, and the
reaction was stirred at room temperature. After 24 h, the reaction mixture
was filtered to remove the yeast. Being dried over anhydrous magnesium
sulfate, the filtrate was concentrated with a rotary evaporator under reduced
pressure. The oily residue was refined by silica gel column chromatography
using chloroform as an eluant. 1-Phenylethanol was finally obtained.
Enantiomeric excess of (S)-1-phenylethanol was 90%, determined by
chiral HPLC analysis using a Daicel chiracel OD column. Conversion,
calculated from GC ratio of substrate to product, was 62%.
ACKNOWLEDGMENTS
This work was supported by the National Natural Science Foundation
of China (No. 29776018) and the Open Project Program of the State Key

1526
LIU ET AL.
Laboratory of Bioreactor Engineering, East China University of Science
and Technology, Shanghai, China.
REFERENCES
1. Csuk, R.; Glanzer, B.I. Chem. Rev. 1991, 91, 49.
2. Santaniello, E.; Ferraboschi, P.; Grisenti, P.; Manzocchi, A. Chem.
Rev. 1992, 92, 1071.
3. Griffin, D.R.; Yang, F.X.; Carta, G.; Gainer, J.L. Biotechnol. Prog.
1998, 14, 588.
4. Izumi, T.; Satou, K.; Ono, K. J. Chem. Tech. Biotechnol. 1996, 66,
233.
5. Kanda, T.; Miyata, N.; Fukui, T.; Kawamoto, T.; Tanaka, A. Appl.
Microbiol. Biotechnol. 1998, 49, 377.
6. Nakamura, K.; Kondo, S.; Kawai, Y.; Ohno, A. Bull. Chem. Soc. Jpn.
1993, 66, 2738.
7. Jayasinghe, L.Y.; Smallridge, A.J.; Trewhella, M.A. Tetrahedron Lett.
1993, 34, 3949.
8. Dordick, J.S. Enzyme Microb. Technol. 1989, 11, 94.
9. Katiyar, S.S.; Tapas, K.D. Biochem. Int. 1990, 20, 1127.
10. Laane, C. Biocatalysis 1987, 1, 17.
11. Bornscheuer, U.; Herar, A.; Kreye, L.; Wendel, V.; Capewell, A.;
Meyer, H.H.; Scheper, T.; Kolisis, F.N. Tetrahedron Asymmetry
1993, 4, 1007.
12. Baker’s yeast was purchased from Oriental Yeast Co., Ltd., Japan.
Chemicals such as acetophenone and petroleum ether were purchased
from Shanghai Chemical Reagent Co., P.R. China. The enantiomeric
excesses of the products were determined by chiral HPLC analysis
using a chiralcel OD column (Daicel Chemical Industry, Ltd., Japan)
with hexane/propane-2-ol (98:2 ꢀ 95:5) as a mobile phase. Gas
chromatography was performed with a 25-m PEG-30M bonded
column at 90ꢂC.
Received in the UK May 23, 2000