Kinetic resolution of fluorinated propargyl alcohols by lipase-catalyzed enantioselective transesterification

Article abstract of DOI:10.1016/j.tetasy.2009.03.041

In order to obtain optically active fluorinated propargyl alcohols, a lipase-catalyzed kinetic resolution has been carried out. The effect of lipase types, organic solvents, reaction temperature, and acyl donors was examined in the lipase-catalyzed transe

Full text of DOI:10.1016/j.tetasy.2009.03.041

Tetrahedron: Asymmetry 20 (2009) 1109–1114
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Kinetic resolution of fluorinated propargyl alcohols by lipase-catalyzed
enantioselective transesterification
Sung-Jin Ko a,b, Jung Yun Lim a, Nan Young Jeon a, Keehoon Won c, Deok-Chan Ha b,
Bum Tae Kim a, Hyuk Lee a,
*
a Medicinal Chemistry Research Center, Korea Research Institute of Chemical Technology, Shinseong-No 19, Yuseong-Gu, Daejeon 305-600, Republic of Korea
b Department of Chemistry, Korea University, Anam-Dong, Seongbuk-Gu, Seoul 136-701, Republic of Korea
c Department of Chemical and Biochemical Engineering, Dongguk University, 26 Pil-dong 3-ga, Jung-gu, Seoul 100-715, Republic of Korea
a r t i c l e i n f o
a b s t r a c t
Article history:
In order to obtain optically active fluorinated propargyl alcohols, a lipase-catalyzed kinetic resolution has
been carried out. The effect of lipase types, organic solvents, reaction temperature, and acyl donors was
examined in the lipase-catalyzed transesterification of 1,1,1-trifluoro-4-phenyl-3-butyn-2-ol. Various
enantiomerically pure fluorinated propargyl alcohols have been successfully prepared in good enantio-
meric excess (>84%) by Novozym 435-catalyzed transesterification with vinyl butanoate at 60 °C in n-
hexane. In some cases, the enantiomeric purities were excellent (>99% ee).
Received 9 January 2009
Accepted 26 March 2009
Available online 22 May 2009
Ó 2009 Elsevier Ltd. All rights reserved.
1. Introduction
fluorinated propargyl alcohols has been performed by hydrolysis
of the corresponding esters so far, the enantiomeric purity was
Optically active propargyl alcohols are important building
blocks for various natural products and biologically active
compounds such as prostaglandins, steroids, and carotenoids.1
For example, 1-methyl propargyl alcohols are key intermediates
for (R)-(+)-N-[[5-(4-fluorophenoxy)furan-2-yl]-1-methyl-2-propy-
nyl]-N-hydroxyurea (A-79175), a second generation 5-lipoxyge-
nase inhibitor, which treats inflammatory and allergic disorders.2
Chiral propargyl alcohols have been prepared by various ap-
proaches including asymmetric reduction, asymmetric 1,2-addi-
tion, [2,3]-sigmatropic rearrangement, and kinetic resolution.3
Recently, fluorinated compounds have been attracting attention
in various areas, particularly in pharmaceutical research, due to
their interesting biological and physical properties. Nowadays,
fluoro-organic compounds are routinely synthesized in the
pharmaceutical industry.4 In this respect, a facile and efficient syn-
thesis of chiral fluorinated propargyl alcohols is becoming more
important. So far, several methods have been developed for the
synthesis of optically active fluorinated propargyl alcohols.5
Due to their excellent enantioselectivity, lipases have been
widely employed for the synthesis of various chiral compounds
including fluorinated alkanols.6 For example, we succeeded in pre-
paring enantiomerically pure alkyl lactates and halogenated phe-
nyl 2-hydroxypropanones in high yields and enantiopurities by
lipase-catalyzed transesterification in organic solvents.7 Although
the lipase-catalyzed kinetic resolution of optically active
low (less than 67% ee).8 Herein, we report on lipase-catalyzed
transesterification for the kinetic resolution of various fluorometh-
yl propargyl alcohols.
2. Results and discussion
First, we screened commercially available lipases for the transe-
sterification of 1,1,1-trifluoro-4-phenyl-3-butyn-2-ol rac-1a with
vinyl butanoate 2a in n-hexane at 30 °C for 12 h. This revealed that
the transesterification reaction occurred only for three different li-
pases. Lipozyme IM (immobilized lipase from Rhizomucor miehei)
and Lipase AK (free lipase from Pseudomonas fluorescence) showed
the catalytic activity (yields) but no stereoselectivity. Novozym
435 (immobilized lipase B from Candida antarctica), which was
successfully used for the kinetic resolution of racemic propargyl
alcohols,3c,d exhibited the highest reactivity for rac-1a. From these
results, Novozym 435 was chosen as a catalyst for the transesteri-
fication of fluorinated propargyl alcohols.
OH
CF3
OH
CF3
Ph
Ph
(R)-1a
(R)-1a
Novozym 435
O
+
+
ð1Þ
O
OH
CF3
OH
CF3
H2SO4
MeOH
n-Pr
O
n-Pr
O
2a
Ph
Ph
CF3
(S)-1a
(S)-1a
* Corresponding author. Tel.: +82 42 860 7019; fax: +82 42 861 0307.
E-mail address: leeh@krict.re.kr (H. Lee).
Ph
(S)-3a
0957-4166/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2009.03.041

1110
S.-J. Ko et al. / Tetrahedron: Asymmetry 20 (2009) 1109–1114
Table 1
Novozym 435-catalyzed transesterification of rac-1a in various organic solventsa
Entry
Solvent
Time (h)
GC yield (%) of the remaining 1a
% eec of the isolated 1a
(R)-1a
(S)-1ad
E
(R)-1a
(S)-1a
1
2
3
4
5
6
7
n-Hexane
Et2O
t-BuOMe
THF
1,4-Dioxane
CH2Cl2
Toluene
35b
66b
72b
72
49
49
49
50
50
50
49
0
0
0
43
37
13
0
>99
>99
>99
8
15
59
98
96
98
>99
>99
>99
95
>200
194
>200
>200
>200
>200
146
72
72
42b
>99
a
Reaction conditions: rac-1a (0.5 mmol), 2a (1 mmol), and Novozym 435 (25 mg) in various organic solvents (1 mL) were shaken at 30 °C.
The time required for a 50% conversion.
Determined by GC analysis.
Isolated after the hydrolysis of (S)-3a.
b
c
d
Novozym 435-catalyzed transesterification of rac-1a with 2a
As shown in Table 1, (S)-1a was preferably acylated, which fol-
lowed Kazlauskas’s rule.9 In the case of 1a, the trifluoromethyl
group was considered as a smaller part when compared with the
phenylethynyl group. To determine the absolute configuration of
1a, p-nitrobenzoylated 4 was synthesized from p-nitrobenzoyl
chloride and (R)-1a (Eq. 2), and characterized by X-ray crystallog-
raphy (Fig. 1). During the synthesis of 4, no racemization occurred,
which is supported by experimental results of the hydrolysis prod-
uct of 4 (>99% ee).
was then conducted in various organic solvents (Eq. 1 and Table
1). In n-hexane, diethyl ether, t-BuOMe and toluene, enzymatic
transesterification of rac-1a proceeded with excellent yields and
ees (entries 1, 2, 3, and 7). However, the time required for 50% con-
version in n-hexane (35 h) was shorter than in diethyl ether (66 h)
in t-BuOMe (72 h) and in toluene (42 h). When the other solvents
(THF, dioxane, and CH2Cl2) were used as a reaction medium, the
conversion did not reach 50% within 72 h, and consequently the
ee of (R)-1a was very low (entries 3–6).
O
OH
CF3
O
O
Et3N
Cl
+
ð2Þ
CF3
NO2
CH2Cl2
RT, 2 h
Ph
NO2
Ph
(R)-1a
4
It is known that Novozym 435 can be used at high temperatures
for many hours without any significant loss in activity.10 The reac-
tion temperature effect on the Novozym 435-catalyzed transesteri-
fication of rac-1a with vinyl butanoate in n-hexane was examined
(Table 2). When the temperature was increased from 30 to 60 °C,
the time taken to reach 50% conversion was shortened, indicating
that the reaction rate was enhanced. Furthermore, the reaction
Table 3
Novozym 435-catalyzed transesterification of rac-1a with various vinyl alkanoatesa
Entry
R
Timeb (h)
Isolated yield (%)
% eed
E
(R)-1a
(S)-1ac
(R)-1a
(S)-1a
1
2
3
Me 2b
Et 2c
n-Pr 2a
72
14
9
41
50
45
31
42
49
67
>99
>99
93
98
95
94
146
146
a
Reaction conditions: rac-1a (0.5 mmol), vinyl alkanoates
Novozym 435 (25 mg) in n-hexane (1 mL) were shaken at 60 °C.
2
(1 mmol), and
b
The time required for 50% conversion.
Isolated after the hydrolysis of (S)-3.
Determined by GC analysis.
c
d
Figure 1. ORTEP depiction of the solid-state molecular structure of 4.
Table 2
The temperature effect on the enzymatic transesterification of rac-1aa
Entry
Temp (°C)
Timeb (h)
Isolated yield (%)
% eec
E
(R)-1a
(S)-3a
(S)-1ac
(R)-1a
(S)-1ad
1
2
3
4
30
40
50
60
35
23
14
9
49
49
48
45
50
49
47
52
48
48
47
49
>99
>99
>99
>99
98
99
99
95
>200
>200
>200
146
a
Reaction conditions: rac-1a (0.5 mmol), 2 (1 mmol), and Novozym 435 (25 mg) in n-hexane (1 mL) were shaken at various temperatures.
The time required for 50% conversion.
Determined by GC analysis.
b
c
d
Isolated after the hydrolysis of (S)-3a.

S.-J. Ko et al. / Tetrahedron: Asymmetry 20 (2009) 1109–1114
1111
Table 4
The transesterification of various fluorinated propargyl alcohols rac-1 with vinyl butanoate catalyzed by Novozym 435a
Timeb (h)
GC area (%)
Isolated yield (%)
% ee
[a]
D
E
d
Entry
R
X
(ꢀ)-1
3
(ꢀ)-1
3
(+)-1c
(ꢀ)-1
98
98
(+)-1c
(ꢀ)-1
(+)-1
1
2
3
4
5
6
7
1ae
Ph
Ph
Ph
F
11
48
96
6
5
5
39
40
45
42
42
37
43
61
60
55
58
58
63
57
46
49
47
49
46
38
35
49
45
45
49
48
46
48
46
41
40
45
42
26
24
91
91
96
96
96
ꢀ6.8f
ꢀ18.0
ꢀ15.5
ꢀ1.9
7.2
14.6
17.3
2.7
3.6
2.3
67
67
1bg,h
1cg,h
1de
1ee
Cl
Br
F
F
F
84
194
194
194
>200
>200
Cyclohexyl
n-Hexyl
n-Butyl
n-Propyl
>99
>99
>99
97
ꢀ2.8
1fe
>99
98
ꢀ2.9
1ge
F
7
ꢀ2.3
2.2
a
Reaction conditions: rac-1 (5 mmol), vinyl butanoate (10 mmol), and Novozym 435 (250 mg) in n-hexane (3 mL) were shaken at 60 °C.
The time required for 50% conversion.
Isolated after hydrolysis of 3.
b
c
d
e
f
c = 0.02, methanol.
Determined by GC analysis (RtTM-bDEXcst column).
[
a
]
of (R)-1a was ꢀ6.8 unlike the literature.5a
D
g
h
Determined by LC analysis (Chiralcel OJ-H column).
Five hundred milligrams of Novozym 435 were used.
temperature had little effect on the enantioselectivity toward (R)-
1a, as shown in Table 2.
4. Experimental
4.1. General
In order to investigate the effects of the chain length of vinyl
alkanoates, Novozym 435-catalyzed transesterifications of rac-1a
were carried out with vinyl acetate 2b, propionate 2c, or butanoate
2a at 60 °C in n-hexane. Table 3 shows that increasing the chain
length of vinyl alkanoate from vinyl acetate to vinyl butanoate im-
proved the reaction rate and ee value of Novozym 435-catalyzed
transesterification. The enantioselectivity study of Novozym 435
revealed that the activity of the lipase increased when increasing
the acyl chain length from ethyl acetate (C2) to ethyl caproate
(C6) in the transesterification with butanol in cyclohexane.11
Finally, the kinetic resolution of various fluorinated propargyl
alcohols (rac-1) by Novozym 435 was conducted at 60 °C in n-hex-
ane (Eq. 3 and Table 4). The acylated products, (R)- and (S)-3 were
not successfully separated under various GC or HPLC conditions.
Therefore, the ee of 3 was determined by using the hydrolysis
products of 3. When the F atom was replaced with the larger Cl
and Br atoms, the time required to reach 50% conversion was con-
siderably prolonged (entries 1–3). The substitution of other groups
(cyclohexyl, n-hexyl, n-butyl, and n-propyl) for the phenyl group
decreased the reaction time from 11 h to 5–7 h and improved the
ee of the product from 91% to 96–>99% as shown in Table 4 (entries
1 and 4–7). Thus, we succeeded in obtaining enantiomerically pure
fluorinated propargyl alcohols (+)/(-)-1 in high ee (>91%) except
for (ꢀ)-1c.
All chemicals were purchased from Sigma, Aldrich, Fluka, and
TCI. The lipases screened were as follows: C. antarctica lipase B,
immobilized (Novozym 435, Novozymes); R. miehei lipase, immo-
bilized (Lipozyme IM, Novozymes); Aspergillus niger lipase, free (Li-
pase A, Amano); Burkholderia cepacia lipase, free (Lipase PS,
Amano); B. cepacia lipase, immobilized on ceramic (Lipase PS-C,
Amano); B. cepacia lipase, immobilized on diatomite (Lipase PS-
D, Amano); Candida rugosa lipase, free (Lipase AY, Amano); Mucor
javanicus lipase, free (Lipase M, Amano); Penicillium camembertii li-
pase, free (Lipase G, Amano); P. fluorescence lipase, free (Lipase AK,
Amano); Rhizopus oryzae lipase, free (Lipase F-AP 15, Amano); C.
rugosa lipase, free (Sigma); wheat germ lipase, free (Sigma); C. rug-
osa lipase, free (Lipase OF, Meito Sangyo). The conversion and ee of
the substrates 1 were analyzed by GC or HPLC. GC analysis was
conducted with a Young-Lin M600D equipped with a flame ioniza-
tion detector using RtTM-bDEXcst (30 m ꢁ 0.25 mm, Restek) and
nitrogen as a column and carrier gas, respectively. The injector
and detector temperatures were 210 °C and 230 °C, respectively.
HPLC analysis was performed with a Young-Lin M930 pump sys-
tem connected to a Young-Lin M720 absorbance detector. Separa-
tions were carried out over a Chiralcel OJ-H (250 mm ꢁ 4.6 mm,
Daicel Chemical Industries) using n-hexane/isopropyl alcohol
(10:1, v/v) at a flow rate of 0.6 mL/min and monitored at 254 nm.
1H NMR spectra and 13C NMR spectra were recorded in ppm (d)
OH
OH
CF2X
CF2X
on
a Varian Gemini 300 (300 MHz) and a Bruker AM-500
R
1
(-)-
(125 MHz) using CDCl3 as solvent, respectively. IR spectra and
Mass spectra were obtained on a Shimadzu IR-435 spectrometer
and a Varian GC/MS 1220L, respectively.
Novozym 435 (250 mg)
R
+
1
rac-
ð3Þ
O
n-Hexane (3 mL)
H2SO4
MeOH
OH
CF2X
+
60 oC, Shaking
n-Pr
O
2a
rt, 4 h
CF2X
R
stirring
R
4.2. Synthesis of the substrates (fluoromethyl propargyl
alcohols)
(+)-1
3
3. Conclusions
4.2.1. Typical procedure
The fluoromethyl propargyl alcohols were obtained by reducing
fluoroalkyl alkynyl ketones, which were synthesized by the reac-
tion of lithiated alkynes with alkyl fluoroacetate according to the
The kinetic resolution of various fluorinated propargyl alcohols
was performed by a lipase-catalyzed transesterification with vinyl
alkanoate in organic solvents. When the reaction was carried out
with vinyl butanoate in n-hexane at 60 °C using Novozym 435
(immobilized lipase B from C. antarctica), racemic fluorinated prop-
argyl alcohols were efficiently resolved in good enantiopurities
(>84% ee). In some cases, the enantiomeric purities were excellent
(>99% ee).
method by Kitazume and Sato.5c To
a mixture of alkyne
(10.0 mmol) and anhydrous THF (30 mL) at ꢀ78 °C was added n-
BuLi (10.0 mmol, 2.5 M solution) for 5 min. After 20 min stirring
at ꢀ78 °C, ethyl fluoroacetate (10.0 mmol), boron trifluoride
diethyl etherate (12.0 mmol), and anhydrous THF (20 mL) were
added. After an additional 2 h of stirring, the reaction was

1112
S.-J. Ko et al. / Tetrahedron: Asymmetry 20 (2009) 1109–1114
quenched with saturated NaCl solution (50 mL). The reaction med-
ium was extracted with ethyl acetate (3 ꢁ 50 mL), dried over
MgSO4, and then concentrated under reduced pressure. The result-
ing ketone was purified by silica gel chromatography (n-hexane/
ethyl acetate = 9:1). The ketone was dissolved in methanol
(10 mL). To the solution was added NaBH4 (10.0 mmol) slowly
and the reaction solution was stirred for 30 min at room tempera-
ture. The mixture was quenched by adding brine (50 mL) and ex-
tracted with ethyl acetate (3 ꢁ 50 mL). The organic layer was
dried over MgSO4 and concentrated under reduced pressure. Final-
ly, purification by silica gel chromatography (n-hexane/ethyl ace-
tate = 9:1) yielded the fluoromethyl propargyl alcohols.
J = 279.8 Hz), 93.6, 72.3, 62.7(q, CH, J = 35.9 Hz), 32.0, 29.0, 25.9,
24.8; IR (neat) mmax: 3370, 2933, 2858, 2240, 1450, 1352, 1273,
1163, 1055, 706 cmꢀ1; MS (relative intensity) 205 (M+,1), 188 (2),
137 (38), 122 (2), 119 (19), 107 (32), 99 (3), 83 (14), 19 (40).
4.2.6. 1,1,1-Trifluoro-3-decyn-2-ol 1e
A yield of 60% (2.5 g) was obtained from 1-octyne (2.95 mL,
20.0 mmol) and ethyl trifluoroacetate (2.38 mL, 20.0 mmol) by
using the typical procedure. The baseline separation was achieved
by GC analysis. The column temperature was maintained at 60 °C
for 5 min, raised to 100 °C at 5 °C/min, kept at 100 °C for 10 min,
and then increased to 200 °C at 5 °C/min. Under these conditions,
the retention times were 35.19 min for (ꢀ)-1e and 35.04 min for
(+)-1e. 1H NMR (CDCl3, 300 MHz): d 4.69–4.62 (m, 1H), 2.71 (br
s, 1H), 2.24 (t, 2H, J = 7.0 Hz), 1.56–1.51 (m, 2H), 1.38–1.27 (m,
6H), 0.89 (t, 3H, J = 6.7 Hz); 13C NMR (CDCl3, 125 MHz): d 123.1
(q, CF3, J = 279.9 Hz), 89.9, 72.3, 62.8(q, CH, J = 35.8 Hz), 31.4,
4.2.2. 1,1,1-Trifluoro-4-phenyl-3-butyn-2-ol 1a
A yield of 76% (1.5 g) was obtained from phenyl acetylene
(1.07 mL, 10.0 mmol) and ethyl trifluoroacetate (1.19 mL,
10.0 mmol) by using the typical procedure. The baseline separation
of rac-1a was achieved by gas chromatography. The column tem-
perature was maintained at 60 °C for 5 min, raised to 130 °C at
5 °C/min, kept at 130 °C for 30 min, and then increased to 180 °C
at 5 °C/min. Under these conditions, the retention times were
52.49 min for (R)-1a and 52.06 min for (S)-1a. 1H NMR (CDCl3,
300 MHz): d 7.50–7.47 (m, 2H), 7.42–7.31 (m, 3H), 4.96–4.87 (m,
1H), 2.48 (d, 1H, J = 8.37 Hz); 13C NMR (CDCl3, 125 MHz): d 132.2,
129.7, 128.6, 123.0 (q, CF3, J = 279.9 Hz), 121.0, 88.1, 80.5, 63.1
28.6, 28.2, 22.7, 18.7, 14.2; IR (neat)
mmax: 3370, 2957, 2934,
2862, 2240, 1468, 1354, 1274, 1053, 699 cmꢀ1; MS (relative inten-
sity) 209 (M+,1), 139 (8), 109 (18), 99 (4), 85 (1), 69 (68), 41 (100).
4.2.7. 1,1,1-Trifluoro-3-octyn-2-ol 1f
A yield of 50% (3.6 g) was obtained from 1-hexyne (4.60 mL,
40.0 mmol) and ethyl trifluoroacetate (4.76 mL, 40.0 mmol) by
using the typical procedure. The baseline separation was achieved
by GC analysis. The column temperature was maintained at 60 °C
for 5 min, raised to 100 °C at 5 °C/min, kept at 100 °C for 10 min,
and then increased to 200 °C at 5 °C/min. Under these conditions,
the retention times were 29.90 min for (ꢀ)-1f and 30.79 min for
(+)-1f. 1H NMR (CDCl3, 300 MHz): d 4.70–4.64 (m, 1H), 2.30–2.25
(m, 3H), 1.59–1.39 (m, 4H), 0.94 (t, 3H, J = 7.20 Hz); 13C NMR
(CDCl3, 125 MHz): d 122.8 (q, CF3, J = 279.8 Hz), 89.6, 72.1, 62.5
(q, CH, J = 36.0 Hz); IR (neat) mmax: 3370, 1273, 1187, 1077, 981,
838, 757, 690 cmꢀ1; MS (relative intensity) 200 (M+, 52), 183 (3),
169 (3), 149(4), 131 (100), 103 (50), 77 (48).
4.2.3. 1-Chloro-1,1-difluoro-4-phenyl-3-butyn-2-ol 1b
A yield of 71% (4.6 g) was obtained from phenyl acetylene
(3.29 mL, 30.0 mmol) and methyl chlorodifluoroacetate (3.16 mL,
30.0 mmol) by using the typical procedure. The baseline separation
was achieved by HPLC analysis. The retention times were
16.92 min for (ꢀ)-1b and 18.74 min for (+)-1b. 1H NMR (CDCl3,
300 MHz): d 7.51–7.46 (m, 2H), 7.39–7.28 (m, 3H), 4.94 (t, 1H,
J = 6.3 Hz), 3.04 (br s, 1H); 13C NMR (CDCl3, 125 MHz): d 132.1,
129.5, 128.5, 127.4 (t, CF2Cl, J = 295.0 Hz), 120.9, 88.2, 81.2, 69.8
(q, CH, J = 36.0 Hz), 30.0, 21.8, 18.2, 13.5; IR (neat)
mmax: 3370,
2962, 2938, 2876, 2240, 1354, 1274, 1056, 1042, 699 cmꢀ1; MS
(relative intensity) 179 (M+, 2), 165 (2), 147 (19), 111 (100), 93
(46), 81 (36), 71 (47), 55 (45).
4.2.8. 1,1,1-Trifluoro-3-heptyn-2-ol 1g
(t, CH, J = 31.5 Hz); IR (neat) mmax: 3370, 2238, 1491, 1201, 1177,
1011, 993, 952, 802, 690, 658 cmꢀ1; MS (relative intensity) 216
(M+, 10), 199 (1), 181 (1), 131 (100), 114 (4), 85 (15), 77 (44).
A yield of 59% (3.9 g) was obtained from 1-pentyne (3.94 mL,
40.0 mmol) and ethyl trifluoroacetate (4.76 mL, 40.0 mmol) by
using the typical procedure. The baseline separation was achieved
by GC analysis. The column temperature was maintained at 60 °C
for 5 min, raised to 100 °C at 5 °C/min, kept at 100 °C for 10 min,
and then increased to 200 °C at 5 °C/min. Under these conditions,
the retention times were 26.38 min for (ꢀ)-1g and 25.78 min for
(+)-1g. 1H NMR (CDCl3, 300 MHz): d 4.69–4.62 (m, 1H), 2.71 (br
s, 1H), 2.24 (t, 2H, J = 7.0 Hz), 1.56–1.51 (m, 2H), 1.38–1.27 (m,
6H), 0.89 (t, 3H, J = 6.7 Hz); 13C NMR (CDCl3, 125 MHz): d 122.9
(q, CF3, J = 279.8 Hz), 89.3, 72.2, 62.5 (q, CH, J = 35.4 Hz), 21.5,
4.2.4. 1-Bromo-1,1-difluoro-4-phenyl-3-butyn-2-ol 1c
A yield of 94% (3.6 g) was obtained from phenyl acetylene
(1.65 mL, 15.0 mmol) and ethyl bromodifluoroacetate (1.90 mL,
15.0 mmol) by using the typical procedure. The baseline separation
was achieved by HPLC analysis. The retention times were
22.84 min for (ꢀ)-1c and 24.39 min for (+)-1c. 1H NMR (CDCl3,
300 MHz): d 7.49–7.46 (m, 2H), 7.39–7.28 (m, 3H), 4.75 (t, 1H,
J = 6.5 Hz), 3.03 (br s, 1H); 13C NMR (CDCl3, 125 MHz): d 132.1,
129.3, 128.4, 122.1 (t, CF2Br, J = 309.5 Hz), 120.9, 88.4, 81.5, 69.1
20.5, 13.3; IR (neat)
mmax: 3370, 2970, 2240, 1356, 1275, 1160,
1056, 700 cmꢀ1; MS (relative intensity) 167 (M+, 40), 149 (100),
137 (4), 129 (10), 113 (17), 97 (90), 83 (60), 71 (41), 57 (56).
(t, CH, J = 29.5 Hz); IR (neat) mmax: 3368, 2237, 1490, 1194, 1167,
1125, 1077, 1034, 922, 795, 690, 609 cmꢀ1; MS (relative intensity)
260 (M+, 22), 164 (15), 149 (11), 131(100), 103 (60), 77 (55).
4.3. Synthesis of the products (fluoromethyl propargyl esters)
4.2.5. 4-Cyclohexyl-1,1,1-trifluoro-3-butyn-2-ol 1d
A yield of 64% (2.7 g) was obtained from cyclohexyl acetylene
(2.58 mL, 20.0 mmol) and ethyl trifluoroacetate (2.38 mL,
20.0 mmol) by using the typical procedure. The baseline separation
was achieved by GC analysis. The column temperature was main-
tained at 60 °C for 5 min, raised to 100 °C at 5 °C/min, kept at
100 °C for 40 min, and then increased to 180 °C at 5 °C/min. Under
these conditions, the retention times were 65.33 min for (ꢀ)-1d
and 65.10 min for (+)-1d. 1H NMR (CDCl3, 300 MHz): d 4.67–4.64
(m, 1H), 2.88 (br s, 1H), 2.45–2.43 (m, 1H), 1.82–1.67 (m, 4H),
1.52–1.29 (m, 6H); 13C NMR (CDCl3, 125 MHz): d 123.1 (q, CF3,
4.3.1. Typical procedure
A mixture of fluoromethyl propargyl alcohols (1.0 mmol) and
triethylamine (1.5 mmol) was dissolved in anhydrous CH2Cl2
(20 mL) at 0 °C. After 20 min stirring at 0 °C, butanoyl chloride
(2.0 mmol) was added in the solution, and the reaction mixture
was stirred for 30 min at room temperature. The reaction was
quenched with saturated NaCl solution (20 mL) and extracted with
ethyl acetate (3 ꢁ 50 mL). The extract was dried over MgSO4, con-
centrated under reduced pressure, and then purified by silica gel
chromatography (hexane/ethyl acetate = 9:1).

S.-J. Ko et al. / Tetrahedron: Asymmetry 20 (2009) 1109–1114
1113
4.3.2. 1,1,1-Trifluoro-4-phenylbut-3-yn-2-yl butanoate 3a
A yield of 99% (268 mg) was obtained from 1,1,1-trifluoro-4-
phenyl-3-butyn-2-ol (200 mg, 1.0 mmol). 1H NMR (CDCl3,
300 MHz): d 7.51–7.50 (m, 2H), 7.48–7.31 (m, 3H), 6.11 (q, CH,
J = 5.85 Hz), 2.45 (t, 2H, J = 7.35 Hz), 1.75 (h, 2H, J = 8.28 Hz), 0.99
(t, 3H, J = 7.38 Hz); 13C NMR (CDCl3, 125 MHz): d 171.4, 132.4,
129.8, 128.6, 123.2 (q, CF3, J = 278.8 Hz), 121.0, 88.1, 78.0, 61.8
5.83 (m, 1H), 2.40 (t, 2H, J = 7.38 Hz), 2.27–2.22 (m, 2H), 1.70 (h,
2H, J = 7.41 Hz), 1.55–1.35 (m, 4H), 0.97 (t, 3H, J = 7.44 Hz), 0.91
(t, 3H, J = 7.41 Hz); 13C NMR (CDCl3, 125 MHz): d 171.4, 122.2 (q,
CF3, J = 278.6 Hz), 90.0, 69.6, 61.6 (q, CH, J = 36.6 Hz), 35.8, 30.2,
22.0, 18.49, 18.47, 13.7, 13.6; IR (neat) mmax: 2964, 2939, 2877,
1763, 1360, 1274, 1245, 1140, 1102, 1013, 933 cmꢀ1; MS (relative
intensity) 250 (M+, 1), 179 (1), 163 (1), 123 (1), 111 (1), 99 (1), 81
(1), 71 (100), 69 (3), 57 (1).
(q, CH, J = 37.3 Hz), 35.8, 18.5, 13.6; IR (neat) mmax: 2970, 2940,
2240, 1763, 1361, 1274, 1256, 1101, 1053, 757, 690 cmꢀ1; MS (rel-
ative intensity) 270 (M+, 18), 241 (4), 228 (8), 133 (23), 85 (25), 71
(100).
4.3.8. 1,1,1-Trifluorohept-3-yn-2-yl butanoate 3g
A yield of 77% (109 mg) was obtained from 1,1,1-trifluoro-3-
heptyn-2-ol (100 mg, 0.6 mmol). 1H NMR (CDCl3, 300 MHz): d
5.85–5.83 (m, 1H), 2.40 (t, 2H, J = 7.35 Hz), 2.24–2.19 (m, 2H),
1.70 (h, 2H, J = 7.41 Hz), 1.59–1.52 (m, 2H), 0.98 (t, 3H,
J = 7.35 Hz), 0.97 (t, 3H, J = 7.38 Hz); 13C NMR (CDCl3, 125 MHz):
d 171.4, 122.2 (q, CF3, J = 278.3 Hz), 89.8, 69.8, 61.6 (q, CH,
4.3.3. 1-Chloro-1,1-difluoro-4-phenylbut-3-yn-2-yl butanoate
3b
A yield of 36% (61 mg) was obtained from 1-chloro-1,1-di-
fluoro-4-phenyl-3-butyn-2-ol (128 mg, 0.6 mmol). 1H NMR (CDCl3,
300 MHz): d 7.52–7.48 (m, 2H), 7.39–7.34 (m, 3H), 6.16 (t, 1H,
J = 7.0 Hz), 2.46 (t, 2H, J = 7.3 Hz), 1.74 (h, 2H, J = 7.4 Hz), 1.00 (t,
3H, J = 7.4 Hz); 13C NMR (CDCl3, 125 MHz): d 171.4, 132.4, 129.8,
128.6, 125.7 (t, CF2Cl, J = 294.5 Hz), 121.1, 88.3, 78.9, 66.4 (t, CH,
J = 37.0 Hz), 35.8, 21.6, 20.7, 18.5, 13.6, 13.4; IR (neat) mmax: 2969,
2941, 2879, 1763, 1361, 1273, 1245, 1140, 1010, 934 cmꢀ1; MS
(relative intensity) 236 (M+, 5), 216 (10), 207 (30), 194 (24), 165
(6), 149 (5), 127 (23), 120 (32), 101 (24), 71 (100).
J = 32.4 Hz), 35.9, 18.5, 13.6; IR (neat)
mmax: 2969, 2939, 2240,
1760, 1207, 1179, 1147, 1101, 1055, 959, 926, 757, 690 cmꢀ1; MS
(relative intensity) 286 (M+, 46), 251 (10), 216 (11), 198 (51),
164 (100), 131 (31), 105 (27), 71 (100).
4.4. Enzymatic transesterification of rac-1
To mixture of rac-1 (5 mmol) and vinyl butanoate (10 mmol) in
anhydrous n-hexane (3 mL) was added Novozym 435 (250 mg).
The reaction mixture was shaken at 200 rpm at 60 °C. During the
reaction, the samples were taken, and then subjected to GC/HPLC
analysis to monitor the reaction. When a 50% conversion was mon-
itored, the reaction mixture was filtered to remove Novozym 435.
The filtrate was concentrated in vacuum, and then purified by silica
gel chromatography (n-hexane/diethyl ether = 9:1) to provide the
remaining (ꢀ)-1 and 2. To 2 in methanol (10 mL) was added
H2SO4 (10.0 mmol) with stirring at room temperature for 4 h.
The reaction mixture was quenched and neutralized with 2 M
NaOH solution. The extraction with ethyl acetate, concentration,
and purification of the reaction mixture offered (+)-1. Using an
Auto Digital Polarimeter, the angle of rotation of 1 was measured
4.3.4. 1-Bromo-1,1-difluoro-4-phenylbut-3-yn-2-yl butanoate
3c
A yield of 53% (30 mg) was obtained from 1-bromo-1,1-di-
fluoro-4-phenyl-3-butyn-2-ol (44 mg, 0.17 mmol). 1H NMR (CDCl3,
300 MHz): d 7.52–7.49 (m, 2H), 7.39–7.32 (m, 3H), 6.14 (t, 1H,
J = 7.8 Hz), 2.46 (t, 2H, J = 7.3 Hz), 1.74 (h, 2H, J = 7.4 Hz), 1.00 (t,
3H, J = 7.4 Hz); 13C NMR (CDCl3, 125 MHz): d 171.3, 132.4, 129.8,
128.6, 121.1, 119.1 (t, CF2Br, J = 307.8 Hz), 88.5, 79.3, 67.7 (t, CH,
J = 29.9 Hz), 35.9, 18.4, 13.7; IR (neat)
mmax: 2968, 2938, 2238,
1760, 1243, 1198, 1102, 1078, 1052, 940, 922, 757, 690 cmꢀ1; MS
(relative intensity) 330 (M+, 4), 262 (6), 251 (43), 242 (9), 180
(20), 164 (71), 129 (12), 114 (18), 71 (100).
from which the specific rotation ½a D25
ꢂ
was obtained.
4.3.5. 4-Cyclohexyl-1,1,1-trifluorobut-3-yn-2-yl butanoate 3d
A yield of 28% (38 mg) was obtained from 4-cyclohexyl-1,1,1-
trifluoro-3-butyn-2-ol (103 mg, 0.5 mmol). 1H NMR (CDCl3,
4.5. Synthesis of compound 4
300 MHz):
d
5.91–5.87 (m, 1H), 2.47 (m, 1H), 2.43 (t, 2H,
Mixture of (R)-1a (0.38 mmol) and triethylamine (0.57 mmol)
was dissolved in anhydrous CH2Cl2 (1 mL). After 30 min stirring
at rt, p-nitrobenzoyl chloride (0.57 mmol) was added slowly into
the solution, and the reaction mixture was stirred for 2 h at room
temperature. The reaction was quenched with saturated NaCl solu-
tion (30 mL) and extracted with CH2Cl2 (3 ꢁ 20 mL). The extract
was washed with saturated NaHCO3 solution and dried over
MgSO4, concentrated under reduced pressure, and then purified
by silica gel chromatography (hexane/ethyl acetate = 9:1) to give
a yellowish solid 4 (103 mg) in a 73% yield. mp 78–79 °C,
J = 7.34 Hz), 1.81–1.78 (m, 2H), 1.78–1.69 (m, 2H), 1.51–1.36 (m,
4H), 1.36–1.34 (m, 4H), 1.00 (t, 3H, J = 7.38 Hz); 13C NMR (CDCl3,
125 MHz): d 171.2, 121.9 (q, CF3, J = 278.6 Hz), 93.4, 69.4, 61.4 (q,
CH, J = 37.3 Hz), 35.6, 31.8, 28.7, 25.7, 24.5, 18.2, 13.4; IR (neat)
m
max: 2936, 2858, 1763, 1358, 1274, 1244, 1164, 1142, 1096,
1015, 934 cmꢀ1; MS (relative intensity) 276 (M+, 3), 192 (3), 107
(3), 71 (100), 69 (6).
4.3.6. 1,1,1-Trifluorodec-3-yn-2-yl butanoate 3e
A yield of 42% (68 mg) was obtained from 1,1,1-trifluoro-3-de-
cyn-2-ol (125 mg, 0.6 mmol). 1H NMR (CDCl3, 300 MHz): d 5.79–
5.75 (m, 1H), 2.33 (t, 2H, J = 7.34 Hz), 2.18–2.15 (m, 2H), 1.63 (h,
2H, J = 7.39 Hz), 1.45 (p, 2H, J = 7.23 Hz), 1.32–1.28 (m, 2H), 1.27–
1.19 (m, 4H), 0.90 (t, 3H, J = 7.40 Hz), 0.82 (t, 3H, J = 6.86 Hz); 13C
NMR (CDCl3, 125 MHz): d 171.4, 122.2 (q, CF3, J = 278.5 Hz), 90.0,
69.6, 61.6 (q, CH, J = 37.3 Hz), 35.8, 31.4, 28.5, 28.1, 22.7, 18.8,
½
a 2D5
ꢂ
¼ þ45:9 (c 0.01, CH3OH), 1H NMR (CDCl3, 300 MHz): d 8.34–
8.32 (m, 5H), 7.53–7.50 (m, 2H), 6.39–6.32 (m, 1H); 13C NMR
(CDCl3, 125 MHz): d 162.5, 151.2, 133.5, 132.3, 131.4, 129.9,
128.5, 123.8, 121.8 (q, CF3, J = 278.9 Hz), 120.4, 89.0, 77.3, 63.2
(q, CF3, J = 37.6 Hz); IR (neat) mmax: 2924, 2853, 2239, 1745, 1608,
1530, 1497, 1349, 1252, 1192, 1143, 1088 cmꢀ1; MS (relative
intensity) 348.3 (M+), 320.3, 282.3, 242.0, 193.2.
18.5, 14.1, 13.6; IR (neat)
mmax: 2960, 2936, 2862, 1763, 1360,
1273, 1140, 1013 cmꢀ1; MS (relative intensity) 278 (M+, 6), 256
(4), 236 (3), 213 (2), 207 (4), 161 (6), 149 (18), 137 (11), 123 (9),
111 (15), 97 (26), 81 (38), 71 (100).
4.6. X-ray analysis of compound 4
Molecular formula: C17H10F3NO4, Mw = 349.26, Rhombohe-
dral, T = 296 K, space group R3, Z = 9, a = 30.9135(12) Å,
b = 30.9135(12) Å, c = 4.4600(2) Å, V = 3691.1(3) Å3, dcalcd = 1.414
),
Bruker SMART Apex II CCD diffractometer, h range 1.32–28.35°,
4.3.7. 1,1,1-Trifluorooct-3-yn-2-yl butanoate 3f
A yield of 91% (137 mg) was obtained from 1,1,1-trifluoro-3-oc-
g cmꢀ3, F(0 0 0) = 1602, k = 0.71073 Å (Mo K = 0.123 mmꢀ1
a l ,
tyn-2-ol (108 mg, 0.6 mmol). 1H NMR (CDCl3, 300 MHz): d 5.85–

1114
S.-J. Ko et al. / Tetrahedron: Asymmetry 20 (2009) 1109–1114
Tetrahedron: Asymmetry 2004, 15, 3117–3122; (d) Xu, D.; Li, Z.; Ma, S.
Tetrahedron Lett. 2003, 44, 6343–6346.
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22659 collected reflections, 4070 unique, full-matrix least-squares
on F2
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0.0951 all data), goodness of fit = 0.971. Further details on the crys-
tal structure are available on request from Cambridge Crystallo-
graphic Data Centre, 12 Union Road, Cambridge, UK on quoting
the depository number CCDC 715765.
(
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Acknowledgment
This work was supported by grants from the Ministry of Knowl-
edge Economy (Grant No. SI-0901) of the Republic of Korea and the
Korea Research Council for Industrial Science and Technology (SK-
0603).
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