Synthesis of fluorinated materials catalyzed by proline or antibody 38C2 in ionic liquid

Article abstract of DOI:10.1016/S0022-1139(03)00032-0

The utility of reusable ionic liquid-proline (or aldolase antibody 38C2) reaction system,proceeding the aldol reactions, is described. Further, obtained α-chloro-β-hydroxy compounds were transformed to the optically active α,β-epoxy carbonyl compounds. Th

Full text of DOI:10.1016/S0022-1139(03)00032-0

Journal of Fluorine Chemistry 121 (2003) 205–212
Synthesis of fluorinated materials catalyzed by
proline or antibody 38C2 in ionic liquid
*
Tomoya Kitazume , Zaiju Jiang, Kana Kasai, Yuma Mihara, Mamie Suzuki
Graduate School of Biosceince & Biotechnology, Tokyo Institute of Technology, 4259 Nagatsuta, Midori-ku, Yokohama 226-8501, Japan
Received 30 October 2002; received in revised form 17 January 2003; accepted 21 January 2003
Abstract
The utility of reusable ionic liquid–proline (or aldolase antibody 38C2) reaction system, proceeding the aldol reactions, is described.
Further, obtained a-chloro-b-hydroxy compounds were transformed to the optically active a,b-epoxy carbonyl compounds. The aldolase
antibody 38C2–ionic liquid system was able to reuse in Michael additions and the reaction of fluoromethylated imines.
#
2003 Elsevier Science B.V. All rights reserved.
Keywords: Aldolase antibody; Aldol reaction; Michael addition reaction
1
. Introduction
obtained materials to the optically active fluorinated a,b-
epoxy carbonyl compounds. Furthermore, we would like to
describe the aldol and the Michael addition reactions based
on the utility of aldolase antibody 38C2 (Aldrich) in an ionic
liquid.
While aldol reactions have been recognized to be useful in
organic synthesis, the reactions commonly employ organic
solvent and Lewis acid, and in many cases they are removed
from the final reaction mixture by water quench which leads
to an aqueous waste stream [1]. In synthetic chemistry,
replacement of toxic organic solvents and/or development
of molecular catalyst systems are one of the most important
issues. Their use in organic synthesis inevitably leads to
solvent emissions and/or waste. In recent investigations in
this field, the research regarding reusable media such as
fluorous fluids [2,3] and molten salts (ionic liquids) [4,5] is
focused on the reaction media. While carbon–carbon bond
forming reactions are carried out in polar organic solvents
2. Results and discussion
2.1. Proline promoted aldol reactions
The construction of carbon–carbon bond forming reac-
tions with complete control of the stereochemistry is most
important for organic synthesis. In chemical methods, the
control of stereochemistry has been accomplished though
the use of chiral starting materials, stoichiometric chiral
auxiliaries attached to the donor nucleophiles and/or chiral
auxiliaries [1].
(
such as THF, Et O, etc.) [6], synthetic value of ionic liquids
2
still appears to be grossly underestimated. Obviously, asym-
metric syntheses in ionic liquids remain a synthetic chal-
lenge.
Recently, the development of practical approach for the
asymmetric aldol reactions, L-proline–DMSO system includ-
ing non-metallic and enzyme-like system [7], attracted our
attention.
In our continuous research of the fluorinated materials in
ionic liquid–catalyst system [4], we examined the aldol
reaction of acetone derivatives with aldehydes in the reu-
sable ionic liquid–proline system and the transformation of
The reusable of chiral auxiliary in ionic liquids is of
considerable interest. Therefore, we examined the L-pro-
line–ionic liquid system as a reusable stereocontrolled reac-
tion for the carbon–carbon bond forming reaction. Initially,
we carried out the aldol reactions under the conditions (alde-
hyde, L- (or D-)proline, and acetone in an ionic liquid ([emi-
m][OTf])atroomtemperature). Inthereactionofacetonewith
benzaldehyde, compounds (PhCH(OH)CH COCH : 36%;
2 3
PhCH¼CHCOCH : 47%) were produced. Moreover, in the
3
cases of aliphatic and/or a,b-unsaturated aldehydes, the aldol
condensation (Knoevenagel) reaction proceeds to produce
unsaturated ketones [8,9] (C H CH¼CHCOCH : 42%;
*
Corresponding author. Fax: þ81-45-924-5780.
E-mail address: tkitazum@bio.titech.ac.jp (T. Kitazume).
6
13
3
0022-1139/03/$ – see front matter # 2003 Elsevier Science B.V. All rights reserved.
doi:10.1016/S0022-1139(03)00032-0

206
T. Kitazume et al. / Journal of Fluorine Chemistry 121 (2003) 205–212
Scheme 1. Aldol reactions in ionic liquid–proline reusable reaction system.
C H CH¼CHCOCH : 40%). In the case of ethyl methyl
recovered reaction system is possible to proceed the same
reaction.
4
9
3
ketone and/or hydroxyacetone, we have found that it is
possible to control the stereochemistry. To make clear the
utility of L-proline in this reaction system, we examined the
aldol reaction in various molar ratios of L-proline and
2.1.1. Epoxidation
Optically active epoxides have much attention during past
few years [10–12]. However, the oxidation reaction is
particularly troublesome in this respect as traditional meth-
ods commonly employ organic solvents and Lewis acid, and
in many cases they are removed from the final reaction
mixture by a water quench which leads to an aqueous waste
stream.
The target a,b-epoxy carbonyl compounds 3 were
obtained via the epoxidation of compound 1 (X ¼ Cl) with
triethylamine in ionic liquid [emim][OTf] at room tempera-
ture. For example, 3-chloro-4-hydroxy-4-phenylbutan-2-
one (diastereomeric ratio 81:19), prepared in L-proline–ionic
liquid system, was converted to the corresponding a,b-
epoxy carbonyl compound in ionic liquid [emim][OTf]-
4
-(trifluoromethyl)benzaldehyde. In the presence of L-pro-
line (50 mol% of aldehyde), successive reuse of the recov-
ered reaction system and in the same reaction yielded
amounts and stereoselectivity of product as high as in the
first cycle. In the case of D-proline (10 mol%), the reaction
proceeded smoothly to give (À)-4-hydroxy-3-methyl-4-{4-
(
(
trifluoromethyl)-phenyl}butan-2-one with 83% ee and
À)-5-hydroxy-5-{4-(trifluoromethyl)phenyl}pentan-3-
one with 92% ee. In the cases of 4-fluorobenzaldehyde,
chiral materials were not obtained, and then aliphatic
aldehyde (C H CHO) gave unsaturated ketone (23%
6
13
yield). In the case of fluoroacetone (entry 8), regio- and
stereoselectivities are poor. However, the reaction of chlor-
oacetone with aromatic aldehydes proceeded to give the
target material with high regioselectivity (>99%). However,
Et N system at room temperature in 69% yield. The product
3
was determined as trans-isomer based on the comparison of
the reported NMR spectra [11]. Further, the absolute con-
figuration (trans-(3R, 4S)-isomer) was also determined by
comparing the measured optical rotation with the reported
one [11]. From the above results, the absolute configuration
of 3-chloro-4-hydroxy-4-phenylbutan-2-one is anti-(3S,
4S)-isomer with 70% ee. In this epoxidation reaction, the
in the cases of aliphatic aldehydes (Me CHCHO and cyclo-
2
C H CHO) as a substrate, the yields were decreased (13
6
11
and 23%) (Scheme 1).
In view of ‘green chemistry’, reuse of the catalyst and
solvent are preferable. From the results from the reaction in
Table 1 (entries 3, 4 and/or 5, 6), successive reuse of the
Table 1
Aldol reactions in ionic liquid–proline system
a
b
d.r. of 1
c
Entry
RCHO
X
Proline (50 mol%)
Yield (%)
% ee
1
2
1
2
1
2
PhCHO
Cl
L
D
L
L
L
L
D
L
L
L
L
D
21
27
68
64
68
86
61
41
71
91
45
22
81:19
79:21
99:1
Cl
d
3
4-CF
3
C
6
H
4
CHO
Me
Me
Cl
29
39
88
86
>98
88
e
4
99:1
d
5
e
83:17
85:15
85:15
78:22
75:25
50:50
78:22
72:28
6
Cl
7
8
9
Cl
F
41
20
Ome
OH
Cl
1
1
1
0
1
2
6 4
4-CF H CHO
Cl
a
b
c
Isolated yield.
The diastereomeric ratio was determined by NMR spectra.
Optical purities were determined by NMR after converting to the corresponding MTPA-ester and/or by HPLC analysis: CHIRALPAK AD; hexane/i-
PrOH ¼ 98:2; flow rate, 1.25 ml/min. Other optical purities were determined by the comparison of the optical rotation.
d
First cycle.
e
Second cycle.

T. Kitazume et al. / Journal of Fluorine Chemistry 121 (2003) 205–212
207
Table 2
reactions in ionic liquids have not been studied in detail. As
it is known that aldol reactions catalyzed by aldolase anti-
body 38C2 in buffer solution are known to proceed at room
temperature [14], we carried out the aldol reaction catalyzed
by aldolase antibody 38C2 (Aldrich no. 48157-2) in an ionic
liquid. In the present reaction, we carried out the aldol
reaction of hydroxyacetone with 4- or 3-(trifluoromethyl)-
benzaldehyde (5 mmol) in the antibody aldolase 38C2
Epoxidation
a
Entry
X
Yield (%)
Optical
D 3
[a] (c, CHCl )
purity (% ee)
b
13
14
15
16
17
18
H
69
75
66
76
81
83
70
66
68
65
75
69
À73.4 (1.033)
þ67.9 (0.954)
À58.4 (1.031)
þ52.2 (1.054)
À58.2 (1.006)
þ52.6 (1.065)
F
CF
3
(
3
Aldrich no. 48157-2, 10 mg)–ionic liquid ([bmim][PF6],
g). After stirring for 14 days at room temperature, starting
a
CHIRALPAK AD, hexane/i-PrOH ¼ 98:2; flow rate, 1.25 ml/min;
materials and products were extracted with diethyl ether
(10Â 20 ml), and ionic liquid and antibody aldolase 32C2
were recovered. As shown in Table 3, the reaction of
hydroxyacetone with 4- or 3-(trifluoromethyl)benzaldehyde
in this system proceeded to produce the 3,4-dihydroxy-4-{4-
or 3-(trifluoromethyl)phenyl}butan-2-one. However, acet-
one, methyl ethyl ketone, methoxyacetone, fluoroacetone
and chloroacetone did not react in this system. Moreover, in
the cases of aliphatic and/or a,b-unsaturated aldehydes,
aldol reaction did not proceed. Successive reuse of the
recovered Ab32C2–ionic liquid system and in the same
reaction yielded amounts of product as higher than the first
cycle in the both cases of 3- and 4-(trifluoromethyl)benzal-
dehyde. In the third and fourth cycles, reuse of this system
recovered from the second cycle is possible to produce the
same alcohol in the same reaction (Scheme 3).
l ¼ 254 nm.
b
25
trans-(3S, 4R)-epoxy-4-phenylbutan-2-one: ½aꢀ þ96.5 (c 1.0,
D
3
CHCl ), 94% ee [12].
Scheme 2. Epoxidation in an ionic liquid.
produced epoxides are trans-isomer only, and cis-isomers
are not produced. The optical purities of trans-epoxides in
Table 2, were determined by HPLC (coloumn: Daicel Chi-
ralpak AD, hexane/i-PrOH ¼ 98:2, flow rate 1.25 ml/min,
l ¼ 254 nm) (Scheme 2).
2.3. Antibody aldolase promoted Michael reaction
2
.2. Aldolase antibody 38C2 promoted aldol reaction
In the next step, we examined the Michael addition
reaction of hydroxyacetone to 2-(phenyl)-ethyl-2-(trifluor-
omethyl)acrylate in the ionic liquid [emim][OTf]–aldolase
antibody 38C2 system. After stirring for 14 days at room
While the utility of enzyme in an ionic liquid has been
reported [13], the enzymatic carbon–carbon bond forming
Table 3
Antibody aldolase promoted aldol reaction in the reusable reaction system
a
Entry
RCHO
CHO
X
Ionic liquid
Conversion (%)
No reaction
d.r.
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
C
6
H
5
OH
OH
[bmim][PF
[bmim][PF
6
]
]
b
4-CF
3
C
6
H
4
CHO
6
21 (59)
c
89
37:63
42:58
36:64
35:65
69:31
d
66 (75)
e
46 (58)
OH
OMe
H
[emim][Otf]
56
No reaction
Trace
[bmim][PF
[bmim][PF
[bmim][PF
[bmim][PF
[bmim][PF
6
6
6
6
6
]
]
]
]
]
Cl
No reaction
No reaction
17 (33)
F
3-CF
3
3
C
6
6
H
H
4
CHO
CHO
OH
42:58
29:71
29:71
c
45 (95)
d
22 (40)
2-CF
C
4
CH
OH
3
[bmim][PF
[bmim][PF
6
]
]
No reaction
No reaction
6 5
C F CHO
6
a
b
c
d
e
Diastereomeric ratio was determined by NMR.
Conversion yield in parenthesis.
Second cycle.
Third cycle.
Fourth cycle.

208
T. Kitazume et al. / Journal of Fluorine Chemistry 121 (2003) 205–212
Scheme 3. Antibody 38C2 promoted aldol reaction.
temperature, products were extracted with diethyl ether
(
10Â 20 ml), and ionic liquid and antibody aldolase 32C2
were recovered. On removal of the solvent, the yield of
products (diastereomer) was determined by 19F NMR using
C H CF as an internal standard.
6
5
3
Products were purified by column chromatography on
silica gel using a mixture of hexane–ethyl acetate (3:1) as an
1
eluent. The structure of compound 6 was confirmed by H,
19F and 13
C NMR spectra. A proposed mechanism for this
reaction is shown in Scheme 4. Enamine 5, generated
from the reaction of hydroxyacetone and aldolase anti-
body 38C2, reacts with the activated methylene group in
2-(phenyl)ethyl-2-(trifluoromethyl)acrylate, resulting the
compound 6.
2.4. The reaction of fluoromethylated imines using
antibody aldolase 38C2–ionic liquid system
Scheme 4. Michael addition reaction.
We carried out the reaction of fluoromethylated imines
with hydroxyacetone in the antibody aldolase 38C2–ionic
liquid system. In this reaction system, the reaction did not
proceed in the absence of antibody aldolase 38C2. In the
presence of antibody aldolase 38C2, the reaction smoothly
proceeded, giving a fluoromethylated carbinol. Proposed
reaction mechanism is shown in Scheme 5. At first, reaction
intermediate 5 and H O were produced from the reaction of
2
hydroxyacetone and antibody 38C2 and then the produced
H O attacked on imine to produce the N,O-acetal 7. The
2
N,O-acetal was reacted with reaction intermediate 5, giving
the reaction intermediate 8. The intermediate 8 was converted
to the product 9 with small amount of water containing ionic
Scheme 5. Reaction paths of fluoromethylated imines with hydroxyacetone in antibody aldolase 38C2–ionic liquid.

T. Kitazume et al. / Journal of Fluorine Chemistry 121 (2003) 205–212
209
liquids [15]. To construct the fluorinated materials based on
the utility of aldolase antibody, we designed a facile syn-
(880 mg, 5 mmol), L-proline (1 g) and ethyl methyl ketone
(1 g) were added, and the mixture was stirred at room
temperature. After stirring 48 h of stirring, the product
was extracted with diethyl ether (10Â 20 ml). The organic
thetic reaction of N,O-acetal with CF group. Initially, we
3
carried out the reaction of trifluoroacetaldehyde N,O-acetal
with hydroxyacetone in ionic liquid ([emim][OTf]). After
7
layer was dried over anhydrous MgSO , and then concen-
4
stirring for 14 days at room temperature, the reaction
mixture was worked up similarly, giving 2-ethoxy-1,1,1-
trifluoro-3-hydroxypentan-4-one in 18% (conversion yield:
trated. Products were purified by column chromatography
on silica gel using a mixture of hexane–ethyl acetate (10:1).
4-Hydroxy-3-methyl-4-{4-(trifluoromethyl)phenyl}butan-2-
1
5
7%) yield.
In conclusion, the successful application of this combina-
one. H NMR (CDCl ): d 0.98 (3H, d, J ¼ 7:14 Hz), 2.22
3
(3H, s), 2.92 (1H, dq, J ¼ 7:42, 7.42 Hz), 3.16 (OH), 4.82
1
9
tion of environmentally friendly solvent and antibody cat-
alyst is exciting and is likely to open the door to the
development of similar reaction systems for other important
organic reactions.
(1H, d, J ¼ 8:24 Hz), 7.45–7.64 (Ar–H). F NMR (CDCl ):
3
1
3
d 99.15 (s). C NMR (CDCl ): d 13.801, 29.806, 53.407,
3
75.543, 123.887 (q, J ¼ 271:7 Hz), 125.040 (q, J ¼
3:72 Hz), 126.807, 129.475 (q, J ¼ 32:35 Hz), 145.901,
À1
20
D
2
(
12.879. IR: 3429 (OH), 1707 (C¼O) cm . ½aꢀ þ 32:0
2
D
1
c 1.009, CHCl ), 83% ee from L-proline. (½aꢀ À 31:9 (c
3
3
. Experimental
1.069, CHCl ), 83% ee from D-proline.)
3
5
-Hydroxy-5-{4-(trifluoromethyl)phenyl}pentan-3-one.
1
3
.1. General
H NMR (CDCl ): d 1.21 (3H, t, J ¼ 6:86 Hz), 2.82 (2H, d,
3
6
.04 Hz), 3.48 (2H, q, J ¼ 6:87 Hz), 5.23 (1H, t, J ¼
1
9
All commercially available reagents were used without
1
6:04 Hz), 7.45–7.64 (Ar–H). F NMR (CDCl ): d 99.17
3
13
further purification. Chemical shifts of H (300 MHz) and
1
(s). C NMR (CDCl ): d 7.519, 36.844, 50.448, 69.280,
3
3
C NMR (75 MHz) spectra were recorded in ppm (d)
downfield from the following internal standard (Me Si, d
125.300 (q, J ¼ 3:72 Hz), 125.756 (q, J ¼ 271:4 Hz),
4
125.768, 129.804 (q, J ¼ 66:42 Hz), 146.664, 211.335.
19
À1
21
IR: 3446 (OH), 1712 (C¼O) cm . ½aꢀ þ38.4 (c ¼
0
recorded in ppm downfield from internal standard C F in
.00) in CDCl . The F (282 MHz) NMR spectra were
3
D
2
D
0
6
6
0:580, CHCl ), >98% ee from L-proline. (½aꢀ À33.6
3
CDCl using a VXR 300 instrument.
3
(c 1.875, CHCl ), 92% ee from D-proline.)
3
Aldol reaction: Typical procedure is as follows:
3.4. 3-Chloro-4-hydroxy-4-
{4-(trifluoromethyl)phenyl}butan-2-one
3
.2. (3S, 4S)-3-Chloro-4-hydroxy-4-phenylbutan-2-one
In the 1-ethyl-3-methyl-1H-imidozolium trifluorometha-
nesulfonate ([emim][OTf], 2 g), benzaldehyde (530 mg,
In the above reaction, chloroacetone (1 g), 4-(trifluoro-
methyl)benzaldehyde (880 mg, 5 mmol), L-proline (1 g) and
1-ethyl-3-methylimidazolium trifluoromethanesulfonate
5 mmol), L-proline (1.0 g) and chloroacetone (0.92 g,
0 mmol) were added, and then the whole was stirred at
1
room temperature. After 48 h of stirring, the product was
[emim][OTf] (2 g) were used, and then worked up similarly.
1
H NMR (CDCl ): d 2.39 (3H, s), 3.25 (OH), 4.29 (1H, d,
3
extracted with diethyl ether (10Â 20 ml). The organic layer
J ¼ 7:96 Hz), 5.09 (1H, d, J ¼ 7:96 Hz), 7.50–7.66
1
9
13
was dried over anhydrous MgSO , and then the solvent was
4
(Ar–H). F NMR (CDCl ): d 99.04 (s). C NMR (CDCl ):
3
3
removed. Products were purified by column chromatogra-
phy on silica gel using a mixture of hexane–ethyl acetate
d 27.496, 63.923, 74.075, 123.755 (q, J ¼ 271:4 Hz),
125.065 (q, J ¼ 3:72 Hz), 126.580, 127.327, 130.091
(q ¼ 32:35 Hz), 203.008. IR: 3447 (OH), 1718 (C¼O)
(
10:1), giving (3S, 4S)-3-chloro-4-hydroxy-4-phenylbutan-
1
À1
1
2
-one. H NMR (CDCl ): d 2.35 (3H, s), 4.34 (1H, d,
cm . Diastereomer: H NMR (CDCl ): d 2.36 (3H, s),
3
3
J ¼ 7:97 Hz), 5.02 (1H, d, J ¼ 7:97 Hz), 7.26–7.50 (Ar–
3.09 (OH), 4.43 (1H, d, J ¼ 3:84 Hz), 5.36 (1H, d,
1
3
19
H). C NMR (CDCl ): d 27.140, 64.500, 74.599, 126.705,
J ¼ 3:82 Hz), 7.50–7.66 (Ar–H). F NMR (CDCl ): d
3
3
1
3
1
28.052, 128.245, 138.678, 202.954. IR: 3431 (OH), 1719
À1
99.07 (s). C NMR (CDCl ): d 28.179, 67.986, 72.463,
3
(
C¼O) cm . Diastereomer: 2.27 (3H, s), 4.44 (1H, d,
23.755 (q, J ¼ 271:4 Hz), 125.065 (q, J ¼ 3:72 Hz),
J ¼ 4:67 Hz), 5.23 (1H, d, J ¼ 4:67 Hz), 7.26–7.50 (Ar–
126.580, 127.327, 130.091 (q ¼ 32:35 Hz), 203.429.
1
3
H). C NMR (CDCl ): d 28.092, 68.453, 73.309, 126.098,
3
1
28.029, 129.668, 133.059, 203.095.
3.5. 3-Fluoro-4-hydroxy-4-{4-(trifluoromethyl)-
phenyl}butan-2-one and 1-fluoro-4-hydroxy-4-
{4-(trifluoromethyl)phenyl}butan-2-one
3
.3. 4-Hydroxy-3-methyl-4-{4-(trifluoromethyl)-
phenyl}butan-2-one and 5-hydroxy-5-{4-(trifluoromethyl)-
phenyl}pentan-3-one
In the above reaction, fluoroacetone (1 g), 4-(trifluoro-
methyl)benzaldehyde (880 mg, 5 mmol), L-proline (1 g)
and 1-ethyl-3-methylimidazolium trifluoromethanesulfonate
[emim][OTf] (2 g) were used, and then worked up similarly.
In 1-ethyl-3-methylimidazolium trifluoromethanesulfo-
nate [emim][OTf] (2 g), 4-trifluoro-methylbenzaldehyde

210
T. Kitazume et al. / Journal of Fluorine Chemistry 121 (2003) 205–212
3
-Fluoro-4-hydroxy-4-{4-(trifluoromethyl)phenyl}butan-
1
(CDCl ):d2.37(3H, s), 3.11(OH), 4.28(1H, d, J ¼ 8:24 Hz),
13
3
2
(
5
-one. H NMR (CDCl ): d 2.12 (3H, d, J ¼ 5:22 Hz), 4.83
5.02 (1H, d, J ¼ 8:24 Hz), 7.07–7.38 (Ar–H). C NMR
3
1H, dd, J ¼ 48:9, 5.22 Hz), 5.12 (1H, dd, J ¼ 15:1,
.22 Hz), 5.24 (1H, dd, J ¼ 25:8, 2.47 Hz), 7.18–7.70 (Ar–
H). Diastereomer: 2.32 (3H, d, J ¼ 4:94 Hz), 4.85 (1H, dd
(CDCl ): d 27.583, 64.344, 74.052, 115.171 (d, J ¼
3
21:47 Hz), 128.596 (d, J ¼ 21:47 Hz), 134.577 (d,
J ¼ 3:44 Hz), 162.419 (d, J ¼ 246:78 Hz), 203.121. 19F
NMR (CDCl ): d 48.67 (m) from ext. C F . IR: 3446
13
J ¼ 48:1, 3.02 Hz). C NMR (CDCl ): d 27.185, 73.089,
3
3
6 6
À1
1
9
(
6.377 (d, J ¼ 192:1 Hz), 125.182 (q, J ¼ 3:72 Hz), 125.316
(OH), 1720 (C¼O) cm . Diastereomer; H NMR (CDCl ):
3
q, J ¼ 270:9 Hz), 127.168, 130.436 (q, J ¼ 32:35 Hz),
d 2.29 (3H, s), 2.97 (OH), 4.39 (1H, d, J ¼ 4:67 Hz), 5.22
1
3
1
9
1
3
(
(
41.553, 206.887 (d, J ¼ 25:48 Hz), 27.439, 72.804,
6.743 (d, J ¼ 195:3 Hz), 123.811 (q, J ¼ 271:4 Hz),
25.227 (q, J ¼ 3:44 Hz), 126.595, 130.233 (q, J ¼
(1H, d, J ¼ 4:67 Hz), 7.07–7.38 (Ar–H). C NMR (CDCl ):
3
d 28.331, 68.164, 72.706, 115.224 (d, J ¼ 21:47 Hz),
128.038 (d, J ¼ 8:30 Hz), 134.420 (d, J ¼ 3:15 Hz),
19
19
2:64 Hz), 142.711, 207.481 (d, J ¼ 29:92 Hz). F NMR
162.273 (d, J ¼ 246:49 Hz), 203.150. F NMR (CDCl ):
3
CDCl ): d À33.92 (ddq, J ¼ 44:25, 15.26, 4.57 Hz), 99.28
d 48.43 (m) from ext. C F .
6 6
3
s) ppm from ext. C F .
6
6
Fluoro-4-hydroxy-4-{4-(trifluoromethyl)phenyl}butan-
1
3.8. trans-(3R, 4S)-Epoxy-4-phenylbutan-2-one [11]
2
(
0
-one. H NMR (CDCl ): d 2.90 (1H, dm, J ¼17.6 Hz), 3.03
3
1H, ddd, J ¼ 17:6, 8.79, 2.19 Hz), 4.85 (1H, dd, J ¼ 48:1,
A mixture of 3-chloro-4-hydroxy-4-phenylbutan-2-one
(186 mg, 0.94 mmol) derived from L-proline system and
triethylamine (1.22 g, 1.22 mmol) in ionic liquid [emi-
m][OTf] (2 g) was stirred for 48 h at room temperature.
The reaction mixture was diluted with diethyl ether (20 ml),
and then the whole was washed with 1N HCl and water. On
removal of the solvent, the crude material was purified by
flash column on silica gel, giving the target material in 69%
.55 Hz), 5.12 (1H, dd, J ¼ 15:4, 5.49 Hz), 5.31 (1H, dd,
13
3
J ¼ 8:79, 3.57 Hz), 7.45–7.70 (Ar–H). C NMR (CDCl ): d
4
1
6.939, 68.662 (d, J ¼ 1:72 Hz), 84.952 (d, J ¼ 184:9 Hz),
29.845 (q, J ¼ 32:35 Hz), 129.975, 146.364, 205.886 (d,
1
9
J ¼ 19:18 Hz). F NMR (CDCl ): d 99.14 (s), À46.61 (td,
3
J ¼ 52:8, 3.16 Hz) ppm from ext. C F .
6
6
3.6. 4-Hydroxy-3-methoxy-4-{4-(trifluoromethyl)-
phenyl}butan-2-one and 4-hydroxy-1-methoxy-4-
yield. 1H NMR (CDCl ): d 2.20 (3H, s), 3.50 (1H, d,
3
J ¼ 1:92 Hz), 4.01 (1H, d, J ¼ 1:92 Hz), 7.26–7.39 (Ar–
1
3
{
4-(trifluoromethyl)phenyl}butan-2-one
H). C (CDCl ): d 24.813, 57.676, 63.386, 125.467,
3
1
28.490, 128.821, 134.740, 203.923. IR: 1711 (C¼O)
À1
3
27
D
In the above reaction, methoxyacetone (1 g), 4-(trifluoro-
cm . ½aꢀ À73.4 (c 1.033, CHCl ).
methyl)benzaldehyde (880 mg, 5 mmol), L-proline (1 g) and
-ethyl-3-methylimidazolium trifluoro-methanesulfonate
emim][OTf] (2 g) were used, and then worked up similarly.
-Hydroxy-3-methoxy-4-{4-(trifluoromethyl)phenyl}bu-
1
[
3.9. trans-3,4-Epoxy-4-{4-(trifluoromethyl)phenyl}butan-
2-one
4
1
tan-2-one. H NMR (CDCl ): d 2.12, 3.32, 3.72 (d,
In the above reaction, 3-chloro-4-hydroxy-4-{4-(trifluoro-
methyl)phenyl}butan-2-one derived from L-proline system
3
J ¼ 6:04 Hz), 4.96 (d, J ¼ 6:32 Hz), 7.45–7.55; diastereo-
mer: 2.16, 3.36, 3.77 (d, J ¼ 4:20 Hz), 4.99 (d, J ¼ 5:49 Hz),
and triethylamine in ionic liquid [emim][OTf] were used,
1
1
3
7
8
1
2
.45–7.55. C NMR (CDCl ): d 26.646, 58.460, 73.058,
and then worked up similarly. H NMR (CDCl ): d 2.21 (3H,
3
3
9.853, 123.742 (q, J ¼ 271:4 Hz), 124.565 (m), 126.773,
29.393 (q, J ¼ 32:35 Hz), 144.088, 209.650; diastereomer:
7.048, 59.048, 73.165, 90.050, 124.615, 126.299, 129.322
s), 3.47 (1H, d, J ¼ 1:65 Hz), 4.08 (1H, d, J ¼ 1:65 Hz),
1
9
7.40–7.65 (Ar–H). F (CDCl ): d 99.03 (s) ppm from int.
3
1
3
C F . C (CDCl ): d 24.802 (d, J ¼ 1:14 Hz), 56.845,
6
6
3
1
9
(
from ext. C F .
q, J ¼ 32:07 Hz), 209.977. F NMR (CDCl ): d 99.2 ppm
63.280, 123.679 (q, J ¼ 271:7 Hz), 125.479 (q, J ¼
4:0 Hz), 125.494, 130.832 (q, J ¼ 32:64 Hz), 138.991 (q,
3
6
6
2
7
4
-Hydroxy-1-methoxy-4-{4-(trifluoromethyl)phenyl}bu-
1
J ¼ 0:86 Hz), 203.270. ½aꢀ À58.2 (c 1.006, CHCl ). Anal.
11 9 3 2
D
calc. for C H F O : C, 57.40; H, 3.94. Found. C, 57.15; H,
3
tan-2-one. H NMR (CDCl ): d 2.86–2.91 (2H, m), 3.42,
3
4
.03, 4.99 (OH, br), 5.27 (dd, J ¼ 7:70, 4.67 Hz), 7.45–7.55.
4.08.
1
3
C NMR (CDCl ): 47.383, 58.912, 68.756, 77.580, 123.806
3
(
q, J ¼ 271:69 Hz), 124.841 (q, J ¼ 3:72 Hz), 125.038 (q,
3.10. trans-3,4-Epoxy-4-{4-(fluoro)phenyl}butan-2-one
19
J ¼ 3:72 Hz), 146.963, 207.423. F NMR (CDCl ): d
3
9
9.2 ppm from ext. C F .
6
In the above reaction, 3-chloro-4-hydroxy-4-{4-(fluoro)-
phenyl}butan-2-one derived from L-proline system and
6
3
.7. 3-Chloro-4-hydroxy-4-{4-(fluoro)phenyl}butan-2-one
triethylamine in ionic liquid [emim][OTf] were used, and
1
then worked up similarly. H NMR (CDCl ): d 2.20 (3H, s),
3
In the above reaction, chloroacetone (1 g), 4-fluoroben-
zaldehyde (630 mg, 5 mmol), L-proline (1 g) and 1-ethyl-3-
3.46 (1H, d, J ¼ 1:64 Hz), 4.00 (1H, d, J ¼ 1:64 Hz), 7.06–
1
9
7.25 (Ar–H). F (CDCl ): d 49.48 (m) ppm from int. C F .
3
6 6
1
3
methylimidazolium trifluoromethanesulfonate [emim][OTf]
1
C (CDCl ): d 24.786, 57.077, 63.306, 115.554 (q, J ¼
3
(
2 g) were used, and then worked up similarly. H NMR
21:8 Hz), 127.296 (d, J ¼ 8:6 Hz), 130.616 (d, J ¼

T. Kitazume et al. / Journal of Fluorine Chemistry 121 (2003) 205–212
211
2
D
7
2
1
:87 Hz), 132.027 (d, J ¼ 9:73 Hz), 203.737. ½aꢀ À58.4 (c
d, J ¼ 4:67 Hz), 5.17 (1H, d,J ¼ 2:75 Hz), 7.7–8.15 (Ar–
À1
13
.031, CHCl ). IR: 1712 (C¼O) cm . Anal. calc. for
H). C NMR (CDCl ): d 27.519, 72.967, 74.250, 122.919
3
3
C H FO : C, 66.66; H, 5.03. Found. C, 66.35; H, 5.29.
2
(m), 124.470 (m), 128.632, 129.584, 123.812 (J ¼
1
0
9
1
9
2
71:69 Hz), 140.294, 141.117, 208.304. F NMR (CDCl ):
3
3
2
.11. 3,4-Dihydroxy-4-{4-(trifluoromethyl)phenyl}butan-
-one
d 99.13, and 99.18 ppm from ext. C F . Anal. calc. for
6
6
C H F O : C, 53.23; H, 4.47. Found: C, 53.56; H, 4.21.
1
1 11 3 3
(
A) First cycle: A mixture of 4-(trifluoromethyl)benzalde-
3.13. 2-(Phenyl)ethyl 4-hydroxy-5-oxo-2-
(trifluoromethyl)hexanate
hyde (870 mg, 5 mmol), hydroxyacetone (1 g) and antibody
aldolase 38C2 (Aldrich no. 48157-2, 10 mg) in 1-butyl-3-
methyl-1H-imidozolium hexafluorophosphate ([bmim][PF6],
(A) First cycle: In the above reaction, 2-(phenyl)ethyl-2-
(trifluoromethyl)acrylate (1.22 g, 5 mmol) and hydroxyace-
tone (1 g) were used, and then worked up similarly, giving 2-
3
g) was stirred at room temperature. After stirring of 14 days
at that temperature, organic materials were extracted with
diethyl ether (10Â 10 ml), and ionic liquid containing anti-
body was recovered. The organic layer was dried over anhy-
(phenyl)ethyl-4-hydroxy-5-oxo-2-(trifluoromethyl)hexanate.
1
Mixture of diastereomer— H NMR (CDCl ): d 2.10, 2.38
3
drous MgSO , and then the solvent was removed. 3,4-
4
(2H, m), 2.18, 2.23 (3H, s), 2.97 (2H, m), 3.50 (2H, m), 3.90,
4.22 (1H, m), 4.35, 4.47 (2H, m), 7.20–7.35 (Ar–H). 13C
Dihydroxy-4-{4-(trifluoromethyl)-phenyl}butan-2-one was
obtained by silica gel chromatography using a mixture of
hexane and ethyl acetate (10:1).
NMR (CDCl ): d 24.968, 25.109, 29.481 (q, J ¼ 2:0 Hz),
3
29.791 (q, J ¼ 2:29 Hz), 34.620, 34.742, 46.368 (q,
J ¼ 27:8 Hz), 46.552 (q, J ¼ 27:8 Hz), 66.334, 33.357,
73.243, 74.024, 124.324 (q, JCÀF ¼ 279:7 Hz), 124.458
(q, JCÀF ¼ 279:8 Hz), 126.488, 126.541, 128.316, 128.343,
128.362, 128.684, 136.967, 136.993, 166.954 (q, J ¼
3:43 Hz), 166.598 (q, J ¼ 2:86 Hz), 207.740, 207.759.
(
B) Second cycle: Into the recovered ionic liquid–aldolae
antibody medium ftom the above reaction, 4-(trifluoro-
methyl)benzaldehyde (870 mg, 5 mmol) and hydroxyace-
tone (1 g) were added, and then the mixture was stirred at
room temperature. After 14 days of stirring, organic materi-
als were extracted with diethyl ether (10Â 10 ml), and ionic
liquid containing antibody was recovered. The organic layer
1
9
F NMR (CDCl ): d 93.46 (d, JFÀH ¼ 8:62 Hz), 93.83
3
(d, J
¼ 7:75 Hz) ppm from ext. C F . Anal. calc. for
4
FÀH
6 6
was dried over anhydrous MgSO , and then the solvent was
4
C H F O : C 56.60; H, 5.38. Found: C, 56.31; H, 5.50.
15 17 3
removed. 3,4-Dihydroxy-4-{4-(trifluoromethyl)phenyl}bu-
tan-2-one was obtained by silica gel chromatography using
a mixture of hexane and ethyl acetate (10:1). The recovered
ionic liquid–aldolae antibody medium was used in the third
cycle—mixture of diastereomer.
(B) Second cycle: Into the recovered ionic liquid–aldolae
antibody medium from the above reaction, 2-(phenyl)ethyl-
2-(trifluoromethyl)acrylate (1.22 g, 5 mmol) and hydroxya-
cetone (1 g) were used, and then worked up similarly.
(C) Third and fourth cycles: In the third and/or fourth
cycles, the same manner using the recovered ionic liquid–
3.14. 1,1,1-Trifluoro-2,3-dihydroxypentan-4-one [14]
aldolase antibody medium was carried out.
1
In the above reaction, imine (RF ¼ CF , 5 mmol), hydro-
3
H NMR (CD COCD ): d 2.32, 4.39 (1H), 4.46 (1H, d,
xyacetone (1 g) and antibody aldolase 38C2 (Aldrich no.
48157-2, 10 mg) in 1-methyl-3-ethyl-1H-imidozolium tri-
fluoromethansulfonate ([emim][OTf], 3 g) were used, and
3
3
J ¼ 4:40 Hz), 5.05 (1H, d, J ¼ 4:12 Hz), 5.14 (1H),
7
2
.53–7.66 (Ar–H). 13C NMR (CD COCD ): d 24.939,
6.032, 72.106, 73.438, 79.682, 79.788, 123.317 (q,
3
3
then worked up similarly, giving 1,1,1-trifluoro-2,3-dihy-
1
J ¼ 270:82 Hz), 123.354 (q, J ¼ 270:83 Hz), 123.510
m), 123.527 (m), 125.108, 125.145, 125.961, 126.454,
44.744, 145.301, 204.866, 207.127, 207.608. 19F NMR
CD COCD ): d 99.23, 99.21 ppm from ext. C F . Anal.
droxypentan-4-one. H NMR (CDCl ): d 2.35 (3H, s), 4.35
3
1
9
(
1
(1H, qd, J ¼ 6:84, 1.23 Hz), 4.43 (1H, d, J ¼ 1:23 Hz).
F
13
NMR (CDCl ): d 84.9 (d, J ¼ 6:10 Hz). C NMR (CDCl ):
3
3
(
d 25.068, 69.273 (q, J ¼ 31:5 Hz), 74.423 (q, J ¼ 1:43 Hz),
3
3
6 6
calc. for C H F O : C 53.23; H, 4.47. Found: C. 52.51; H,
4
123.788 (q, J ¼ 282:9 Hz), 205.075. IR: 3418 (OH), 1719
1
1 11 3 3
À1
.39.
(C¼O) cm
.
3
2
.12. 3,4-Dihydroxy-4-{3-(trifluoromethyl)phenyl}butan-
-one
3.15. 1,1-Difluoro-2,3-dihydroxypentan-4-one [14]
In the above reaction, imine (RF ¼ CHF , 5 mmol)
2
In the above reaction, 3-(trifluoromethyl)benzaldehyde
and hydroxyacetone (1 g) were used, and then worked up
similarly, giving 1,1-difluoro-2,3-dihydroxypentan-4-one.
(
870 mg, 5 mmol), hydroxyacetone (1 g) and antibody aldo-
lase 38C2 (Aldrich no. 48157-2, 10 mg) in 1-butyl-3-methyl-
H-imidozolium hexafluorophosphate ([bmim][PF ], 3 g)
1
Main— H NMR (CDCl ): d 2.38 (3H, s), 4.18 (1H, m),
3
1
9
1
4.40 (1H, d,), 5.85 (1H, td, J ¼ 56:3, 6.04 Hz). F NMR
6
were used, and then worked up similarly.
1
(CDCl ): d 30.85 (ddd, J ¼ 292:1, 57.7, 10.3 Hz), 33.59
3
13
Mixture of diastereomer— H NMR (CDCl ): d 2.39, 4.41
(ddd, J ¼ 292:1, 55.2, 10.3 Hz). C NMR (CDCl ): d
3
3
(
1H, d, J ¼ 2:47 Hz), 4.46 (1H, d, J ¼ 4:67 Hz), 5.04 (1H,
25.220, 70.747 (dd, J ¼ 27:49, 23.19 Hz), 75.532,

212
T. Kitazume et al. / Journal of Fluorine Chemistry 121 (2003) 205–212
1
(
(
(
(
e) B. List, Synlett (2001) 1675–1686;
1
(
(
(
14.724 (t, J ¼ 243:3 Hz), 207.000. Minor— H NMR
f) B. Lost, P. Pojarliev, H.J. Martin, Org. Lett. 3 (2001) 2423–2424;
g) B. Lost, C. Castello, Synlett (2001) 1687–1689;
h) B. List, P. Pojarliev, W.T. Biller, H.J. Martin, J. Am. Chem. Soc.
CDCl ): d 2.39 (3H, s), 4.18 (1H, m), 4.38 (1H, d,), 5.90
3
19
1H, td, J ¼ 55:8, 4.39 Hz). F NMR (CDCl ): d 33.53
3
ddd, J ¼ 291:3, 54.3, 5.17 Hz), 28.23 (ddd, J ¼ 291:3,
1
24 (2002) 827–833.
[8] (a) S. Arai, H. Tsuge, M. Oku, M. Miura, T. Shioiri, Tetrahedron 58
2002) 1623–1630;
b) E.J. Corey, F.-Y. Zhang, Org. Lett. 1 (1999) 1287–1288.
1
3
5
6.0, 14.7 Hz). C NMR (CDCl ): d 26.620, 71.317 (dd,
3
(
J ¼ 25:19, 22.62 Hz), 75.612, 114.450 (t, J ¼ 243:3 Hz),
(
2
07.100.
[
9] (a) P.A. Bentley, S. Bergeron, M.W. Cappi, D.E. Hibbs, M.B.
Hursthouse, T.C. Nugent, R. Pulido, S.M. Roberts, L.E. Wu, Chem.
Commun. (1997) 739–740;
References
(
b) P.A. Bentley, M.W. Cappi, R.W. Flood, S.M. Roberts, J.A.
Smith, Tetrahedron Lett. 39 (1998) 9297–9298;
(c) R.W. Flood, T.P. Geller, S.A. Petty, S.M. Roberts, J. Skidmore,
M. Volk, Org. Lett. 3 (2001) 683–684.
[
1] B.M. Trost, in: I. Fleming (Eds.), Comprehensive Organic Synthesis,
vol. 2, Pergamon Press, Oxford, 1991.
[
2] A. Ogawa, D.P. Curran, J. Org. Chem. 62 (1997) 450–451.
3] (a) H. Nakano, T. Kitazume, Green Chem. 1 (1999) 21–22;
[10] E.N. Jacobsen, A. Pfaltz, H. Yamamoto (Eds.), Comprehensive
Asymmetric Catalysis, vol. 2, Springer, Berlin, 1999, p. 649.
[11] (a) M. Bougauchi, S. Watanabe, T. Arai, H. Sasai, M. Shibasaki, J.
Am. Chem. Soc. 119 (1997) 2329–2330;
[
(b) H. Nakano, T. Kitazume, Green Chem. 1 (1999) 179–182;
(c) T. Kitazume, T. Ishizuka, M. Takeda, K. Itoh, Green Chem. 1
(
1999) 221–224, and references cited therein.
4] (a) T. Kitazume, F. Zulfiqar, G. Tanaka, Green Chem. 2 (2000) 133–
37;
(b) S. Watanabe, Y. Kobayashi, T. Arai, H. Sasai, M. Bougauchi, M.
Shibasaki, Tetrahedron Lett. 39 (1998) 7353–7354;
(c) T. Nemoto, T. Ohshima, K. Yamaguchi, M. Shibasaki, J. Am.
Chem. Soc. 123 (2001) 2725–2726;
[
1
(
(
(
b) F. Zulfiqar, T. Kitazume, Green Chem. 2 (2000) 137–139;
c) T. Kitazume, K. Kasai, Green Chem. 3 (2000) 30–32;
d) T. Kitazume, G. Tanaka, J. Fluor. Chem. 106 (2000) 211–215.
(d) T. Nemoto, T. Ohshima, M. Shibasaki, J. Am. Chem. Soc. 123
(2001) 9474–9475.
[
5] (a) C.E. Song, E.J. Roh, Chem. Commun. (2000) 837–838;
b) J.N. Rosa, C.A.M. Afonsa, A.G. Santos, Tetrahedron 57 (2001)
189–4193;
c) R.M. Lau, F.V. Rantwijk, K.R. Seddon, R.M. Sheldon, Org. Lett.
(2000) 4189–4190;
d) C.L. Adams, M.J. Earle, G. Roberts, K.R. Seddon, Chem.
Commun. (1998) 2097–2098;
e) J.N. Rosa, C.A.M. Asonso, A.C. Santos, Tetrahedron 57 (2001)
189–4193.
[12] (a) K. Daikai, M. Kamaura, J. Inanaga, Tetrahedron Lett. 39 (1998)
7321–7322;
(
4
(b) R. Chen, C. Qian, J.G. de Vries, Tetrahedron Lett. 42 (2001)
6919–6921.
(
2
[13] (a) T. Itoh, E. Arasaki, K. Kudo, S. Shirakami, Chem. Lett. (2001)
262–263;
(
(b) S.H. Sch o¨ fer, N. Kaftzik, P. Wasserscheid, U. Kragl, Chem.
Commun. (2001) 425–426.
(
4
[14] (a) J. Wagner, R.A. Lerner, C.F. Barbas III, Science 270 (1995)
1797;
[
6] G. Wilkinson (Ed.), Comprehensive Organometallic Chemistry,
Pergamon Press, Oxford, 1982.
(b) C.F. Barbas III, A. Heine, G. Zhong, T. Hoffmann, S.
Gramatikova, R. Bj o¨ mestedt, B. List, J. Anderson, E.A. Stura, I.A.
Wilson, R.A. Lerner, Science 278 (1997) 2085–2092;
(c) B. List, R.A. Lerner, C.F. Barbas III, Org. Lett. 1 (1999) 59–61.
[15] T. Kitazume, K. Tamura, Z. Jiang, N. Miyake, I. Kawasaki, J. Fluor.
Chem. 115 (2002) 49–53.
[
7] (a) B. List, R.A. Lerner, C.F. Barbas III, J. Am. Chem. Soc. 122
(2000) 2395–2396;
(b) W. Notz, B. List, J. Am. Chem. Soc. 122 (2000) 7386–7387;
(c) B. List, J. Am. Chem. Soc. 122 (2000) 9336–9337;
(d) B. Lost, P. Pojarliev, C. Castello, Org. Lett. 3 (2001) 573–574;