Effects of ionic liquids for lipase-catalyzed chiral 1,1′-binaphthyl- 2- yl(phenyl)methanone O-acetyl oxime synthesis

Article abstract of DOI:10.2174/157017809788489864

The resolution of 1,1'-binaphthyl-2-yl(phenyl)methanone O-acetyl oxime catalyzed by lipase in three different ionic liquids, 1-butyl-3- methylimidazolium hexafluoride-phosphate, [bmim][PF₆], 1-butyl-3-methylimidazolium tetrafluoroborate, [bmim][BF₄] and N-butyl-pyridium hexafluorophosphate, [BuPy][PF₆] and organic solvents was studied. The lipase shows low activity in ionic liquids and organic solvent with ionic liquids as the additive, while the lipase coated with ionic liquids gives the best enantioselectivity as high as 95 %.

Full text of DOI:10.2174/157017809788489864

Letters in Organic Chemistry, 2009, 6, 297-300
297
Effects of Ionic Liquids for Lipase-Catalyzed Chiral 1,1`-binaphthyl-2-
yl(phenyl)methanone O-acetyl Oxime Synthesis
Yongchang Zhou*,a,b, Motohiro Takahashia,b, Naoto Aoyagia, Chunlei Lia, Tatsuro Kijimaa and
Taeko Izumia
aChemistry and Chemical Engineering, Graduate School of science and engineering, Yamagata University, Jonan 4-3-
16, Yonezawa 992-8510, Japan
bTechnology Department, Yonezawa Hamari Chemicals, Ltd. Hachimanpara 2-4300-18, Yonezawa 992-1128, Japan
Received May 21, 2008: Revised March 17, 2009: Accepted March 26, 2009
Abstract: The resolution of 1,1'-binaphthyl-2-yl(phenyl)methanone O-acetyl oxime catalyzed by lipase in three different
ionic liquids, 1-butyl-3-methylimidazolium hexafluoride-phosphate, [bmim][PF6], 1-butyl-3-methylimidazolium tetra-
fluoroborate, [bmim][BF4] and N-butyl-pyridium hexafluorophosphate, [BuPy][PF6] and organic solvents was studied.
The lipase shows low activity in ionic liquids and organic solvent with ionic liquids as the additive, while the lipase
coated with ionic liquids gives the best enantioselectivity as high as 95 %
Keywords: Ionic liquids, Lipase-catalyzed, Chiral, O-acetyl oxime, Synthesis, Resolution.
INTRODUCTION
the application of ionic liquids on this reaction. Therefore, it
is necessary to study ionic liquids as alternative solvents for
biotransformations using lipase for synthesis of chiral oxime
1 and 2.
Room-temperature ionic liquids (RTILs) are known as
green solvents used as reaction media in the separation
process and electrochemistry and have attracted much
attention in recent years because of their negligible vapor
pressures. The application of ionic liquids on organic
synthesis has been well documented in the reviews.
Moreover, bio-catalysis in ionic liquids has also been
In this paper, the effect of ionic liquids on lipase-
catalyzed resolution of 1,1'-binaphthyl-2- yl(phenyl)meth-
anone O-acetyl oxime was examined.
Ph
Ph
lipase
Ph
+
N
N
N
OH
OAc
OAc
(Z)-(S)-1
(Z)-(R)-2
(Z)-(±)-1
Scheme 1. Lipase-catalyzed hydrolysis of (Z)-(±)-1
investigated in many chemical reactions, such as transesteri-
fication, synthesis, conversion, alcoholysis, ammoniolysis,
hydrolysis, epoxidation, resolution, oxidation, reduction,
deracemization etc. Unlike the conventional organic solv-
ents, the use of enzymes and substrates in ionic liquids can
enhance the activity, selectivity, and stability of catalysts [1-
11].
RESULTS AND DISCUSSION
We reported before that the optimal condition of enzyme-
resolution was carried out at 60 ˚C, so we wanted to find a
suitable ionic liquid, whose melting point is above 60 ˚C.
N-butyl-pyridium hexafluoride phosphate ([Bupy][PF6]) is
the suitable one since its melting point is 68 ˚C.
The successful approach involved the enzymatic resolu-
tion of (±)-1 under hydrolysis condition, using lipase prepa-
rations according to Scheme 1.
Lipase-catalyzed resolution of title compound has been
reported for the synthesis of chiral oxime, but the enatioex-
cess is not good enough [12]. No research was conducted on
In order to compare the effect of ionic liquids, we do the
lipase-catalyzed resolution with methyl tertiary-butyl ether
(MTBE) as a solvent only at the very beginning. As shown
in Table 1, entry 1, 36% yield is obtained for (Z)-(R)-2 and
83% yield for enatio-excess (ee) after 22 h reaction.
*Address correspondence to this author at the Technology Department,
Yonezawa Hamari Chemicals, Ltd. 2-4300-18, Hachimanpara, Yonezawa-
city 992-1128, Yamagata, Japan; Tel: +81-238-28-3809;
E-mail:yczhou97@hotmail.com
1570-1786/09 $55.00+.00
© 2009 Bentham Science Publishers Ltd.

298 Letters in Organic Chemistry, 2009, Vol. 6, No. 4
Zhou et al.
Table 1. Resolution of (Z)-(±)-1 by Lipase Catalyst
Ketoxime
O-acetyl ketoxime
Yield % d e.e. % e
Entrya
Ionic liquids
Type b
Ratio c
Time (h)
E f
Yield % d
e.e. % e
1
2
-
MTBE
IL
-
22
24
26
27
24
32
22
117
22
22
24
36
1
83
-
64
54
19
-
[BMIM][PF6]
[BMIM][PF6]
[HMIM][BF4]
[BuPy][Tf2N]
[Bupy][PF6]
[Bupy][PF6]
[Bupy][PF6]
[Bupy][PF6]
[Bupy][PF6]
[Bupy][PF6]
-
99
98
0
0
3
additive
additive
additive
ILCE
1:5
2
87
93
-
-
4
1:1
7
93
8
3
5
1:1
-
recovery
88
-
-
6
1:10
1:7.5
1:7.5
1:5
12
22
31
21
9
91
95
82
81
57
-
7
23
47
15
12
4
7
ILCE
78
28
40
21
3
8
ILCE
69
9
ILCE
79
10
11
ILCE
1:2.5
1:7.5
91
ILCE
-
recovery
-
-
aEntry 1~10 were carried out by Novozym 435, entry 11 was carried out by Novozym 525L. The temperature of entry 8 was 55 ˚C, and the others were 60 ˚C.
bAdditive means that the ionic liquids were added as co-solvent for lipase-catalyzed reaction; IL= ionic liquids; ILCE=ionic liquids coated Lipase.
cThe ratio is the mass ratio of lipase and ionic liquids.
dDetermined by internal standard method of HPLC using ODS-2(254nm, 0.8mL/min, CH3CN:H2O=8:2).
eDetermined by HPLC using Chiralcel OG (254nm, 0.5mL/min, n-Hexane:IPA=8:2).
f
see ref [16].
ꢁ
ꢃ
ꢁ
ꢃ
E = ln (eep (1 ꢀ eeS )) (eep + eeS ) ln (eep (1 + eeS )) (eep + eeS )
ꢂ
ꢄ
ꢂ
ꢄ
Then the lipase-catalyzed hydrolysis of (Z)-(±)-1 is
carried out in ionic liquids, but only 1 % of product of
(Z)-(±)-2 is detected with no ee. The reason may be that the
active point of the enzyme 435 was covered by ionic liquid.
On the contrary, the added ionic liquid changes from 7.5
times to 5.0 and 2.5 times, the yield also becomes lower
from 22% to 21% and 9% respectively (entries 7,9 and 10).
Enantioselectivity has the same trend. The reason may be
that when the weight of ionic liquid is 7.5 times greater than
that of lipase, the activity point was covered by ionic liquid.
The coating effect is insignificant if the weight of IL is less
than 7.5 times in the case where Novozym 435 is used. If
Novozym 525L is used instead, there is no reaction when IL
is 7.5 times the weight of lipase.
Then ionic liquids as a co-solvent in the lipase-catalyzed
hydrolysis of (Z)-(±)-1 are carried out for three kinds of
ionic liquids. The results show that the reaction rate is very
slow (entries 3 and 4) because of the high viscosity of ionic
liquids, but it is still better than that of in ionic liquids only
(entry 1). No reaction with [Bupy][Tf2N] as co-solvent
(entry 5) proceed.
The effect of temperature is also examined. The results
show that the temperature can affect the yield and enantio-
selectivity as shown in Fig. (2). The hydrolysis of (Z)-(±)-1
at 60 ˚C proceeded to 22 % yield after 22 h (entry 7), while
for the reaction carried out at 55 ˚C, 31% yield was obtained
after 117 h with enantio-selectivity of 82% (entry 8). When
the reaction temperature is at 65 ˚C (at the melting point of
ionic liquid), no reaction take place. So the [BuPy] anion is
prohibited at liquid state for hydrolysis of substrate (Z)-(±)-1
(entries 5, 10 and 11).
We investigated the activity of Ionic liquid-coated
enzyme at different ratio of lipase and ionic liquids. The
preparation of ionic liquids coated with Lipase/ enzyme
(ILCE) is similar to known procedure [13]. It is said that the
amount of ionic liquids varied depending upon the type of
enzyme used, but it is preferably between 5 and 20 g per 1g
of enzyme according to the reference [13].
We examine wide varieties of weight of ionic liquid per 1
g of enzyme as shown in Table 1.
The ILCE-catalyzed hydrolysis of 1 proceeded with
better enantioselectivity than that catalyzed by enzyme 435
only. The catalytic activity of ILCE varied with different
weight ratio of lipase to ionic liquids. The activity is chang-
ing with the weight ratio from 1:2.5 to 1:10. The ratio of
1:7.5 give the most effective selectivity for hydrolysis
(entries 6~10). Although the activity of hydrolysis reaction
catalyzed by ILCE proceeded at a slight yield, the
enantioselectivity is relatively high (95% ee, 22% yield,
entry 7) as shown in Fig. (1).
CONCLUSION
In summary, both the added quantities of ionic liquid per
weight of enzyme and reaction temperature have an effect on
the ionic liquids coated lipase catalyzed hydrolysis reactions
of O-acetyl binaphthyl ketoximes. The optimum condition is
7.5 g of ionic liquid per gram of enzyme 435, and the best
reaction temperature is at 60 ˚C.
ACKNOWLEDGEMENT
When adding more ionic liquid into the 1 g of enzyme,
for example, 10g of ionic liquid, the yield and enantioselec-
tivity become relatively low (91% ee, 12% yield, entry 6).
This research was financially supported by the Sasakawa
Scientific Research Grant from The Japan Science Society
under grant number 19-314.

Effects of Ionic Liquids for Lipase-Catalyzed Chiral
Fig. (1). The effect of ionic liquid on reactions.
Fig. (2). The effect of temperature.
Letters in Organic Chemistry, 2009, Vol. 6, No. 4
299
EXPERIMENTAL SECTION
cooled to 0°C in an ice bath. Potassium hexafluorophosphate
(1.1 eq) was added slowly with rapid stirring. The resulting
biphasic mixture was stirred for 2 h, then the upper layer,
aqueous phase was decanted. The lower layer, ionic liquid
phase was washed with water, and then extracted with di-
chloromethane (400 mL). The organic phase was dried over
MgSO4, filtered, the solvent was removed under reduced
pressure and the ionic liquid dried for 6 h at 70°C in vacuum.
85% yield is obtained.
A colorless solids; mp 65-67 ˚C;1H-NMR(400MHz,
CDCl3):ꢀ0.94-0.98(3H,t,CH3), 1.38-1.47(2H,m,CH2), 2.00-
2.08(2H,m,CH2),4.99-5.03 (2H, t,N-CH2), 8.15-8.23 (2H,m,
ArH), 8.52-8.57(1H,d, ArH), 9.54-9.5(2H,d,ArH); 13C-NMR
(400MHz, CDCl3): ꢀ=13.6, 19.4, 33.9, 61.9, 128.6, 145.2
Analytical-grade solvents and all chemicals were
1
purchased from TCI Ltd. H- and 13C-NMR spectrum were
measured with a JNM-ECS400 NMR spectrometer at 400
megahertz by using TMS as an internal standard (CDCl3 as
solvent). The melting point was determined by MFB-595-
030G digital thermometer apparatus.
Racemic mixtures of 1,1'-binaphthyl-2-yl(phenyl)meth-
anone O-acetyl oxime (Z)-(±)-1 were prepared according to
known literature.4 The ionic liquids were synthesized by
known scheme and the preparation of Ionic liquid-coated
enzyme (ILCE) is illustrated as Scheme 2 [13].
Bromobutane
benzene
reflux,5h
KPF6
H2O
Preparation of IL-Coated Enzyme [13]
Br
PF6
N
N
N
Ionic liquids [Bupy][PF6] (1 g) was heated above 75 °C
in a flask to get a liquid phase, and then a fixed quantity of
lipase is added. The resulting heterogeneous solution is
stirred for 30 min and then cooled to room temperature to
yield ILCE in a solidified solution. The solid ILCE is
crushed with a mortar and used for enzyme reaction.
n-Bu
n-Bu
Scheme 2. Synthesis of N-butylpyridinium hexafluorophosphate.
Synthesis of N-butylpyridinium hexafluorophosphate
[14,15]
Mixtures of 1-bromobutane and pyridine in a molar ratio
1:1.1 were heated for 3 h at 150°C. The wax-like solids were
recrystallized once in ether-ethanol (5:1) and three times in
acetone and finally dried under vacuum for 48 h at 105°C.
The resulting off-white solid was dissolved in H2O and then
General Procedure of Lipase Catalyzed Resolution
In a typical experiment, Novozym 435 (40 mg) and
n-butanol (0.0672 mmol) were added to a solution of
O-acetylketoxime (Z)-(±)-1 (28 mg, 0.0672 mmol)] and

300 Letters in Organic Chemistry, 2009, Vol. 6, No. 4
Zhou et al.
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