Synthesis of optically active 2,2-difluorohomoallylalcohols by lipase-catalyzed transesterification

Article abstract of DOI:10.1016/S0957-4166(02)00612-2

Racemic 2,2-difluorohomoallylalcohols could be resolved into (R)-alcohols and (S)-acetates through Pseudomonas fluorescens lipase-catalyzed enantioselective transesterification. The utility of the resulting chiral, non-racemic 2,2-difluorohomoallylalcohol

Full text of DOI:10.1016/S0957-4166(02)00612-2

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 13 (2002) 2283–2289
Synthesis of optically active 2,2-difluorohomoallylalcohols by
lipase-catalyzed transesterification
a,
b
a
c
d
Masayuki Kirihara, * Masashi Kawasaki, Hiroki Katsumata, Hiroko Kakuda, Motoo Shiro and
b
Shigeki Kawabata
a
Department of Materials Science, Shizuoka Institute of Science and Technology, 2200-2 Toyosawa, Fukuroi,
Shizuoka 437-8555, Japan
b
Faculty of Engineering, Toyama Prefectural University, 5180 Kurokawa, Kosugi-Machi, Toyama 939-0398, Japan
c
Laboratory of Chemistry, Toyama Medical and Pharmaceutical University, 2630 Sugitani, Toyama 930-0194, Japan
d
Rigaku Corporation, 3-9-12 Matsubara, Akishima, Tokyo 196-8666, Japan
Received 25 September 2002; accepted 27 September 2002
Abstract—Racemic 2,2-difluorohomoallylalcohols could be resolved into (R)-alcohols and (S)-acetates through Pseudomonas
fluorescens lipase-catalyzed enantioselective transesterification. The utility of the resulting chiral, non-racemic 2,2-difluorohomo-
allylalcohols was demonstrated by conversion of one of the (S)-acetates into a synthetically important 2,2-difluoro-3-hydroxy-
carboxylate derivative. © 2002 Elsevier Science Ltd. All rights reserved.
2
1
. Introduction
2,2-difluoro-3-hydroxycarboxylates, which are versatile
intermediates for the synthesis of several biologically
important fluorinated peptides, might easily be
obtained from the targeted optically active 2,2-difluoro-
homoallylalcohols 1.
We have previously reported on the synthesis of 2,2-
difluorohomoallylalcohols of the type 1 from the reac-
tion of 3-bromo-3,3-difluoropropene and aldehydes in
the presence of indium (Scheme 1). This method is easy
1
and affords the desired products in high yields.
The hydroxyl moiety is also useful for further transfor-
mations of 1: Percy and co-workers prepared 2,2-
difluorohomoallylalcohols using our method and
synthesized racemic difluorinated dihydropyrans from
Optically active 2,2-difluorohomoallylalcohols 1 can be
considered very useful fluorine-containing chiral build-
ing blocks because they bear several different functional
groups, which gives great scope for further transforma-
tions. For example, oxidation the alkene moiety of 1
can lead to either an aldehyde, or carboxylic acid
derivatives. Using such a method, chiral, non-racemic
(
±)-1 by allylation of the hydroxyl moiety and subse-
3
quent ring closing metathesis. Therefore, optically
active difluorinated dihydropyrans, which are potential
precursors of fluorinated sugar mimetics, can be
obtained from the targeted optically active 2,2-difluoro-
homoallylalcohols 1 (Scheme 2).
The resolution of racemic alcohols through lipase-cata-
lyzed transesterification in organic solvents is now a
widely used methodology and has been successfully
4
applied to a wide variety of substrates. The lipase-cata-
lyzed reaction proceeds under very mild conditions and
many functional groups such as double bonds, triple
bonds, carbonyl groups, cyano groups and halogen
atoms are not affected by the reaction conditions. Opti-
cally active fluorinated alcohols have previously been
Scheme 1.
5
obtained using this method of resolution. As a result
of their synthetic potential, we planned to resolve com-
pounds 1 through lipase-catalyzed transesterification in
*
0
Corresponding author. Tel.: +81-538-45-0166; fax: +81-538-45-0110;
e-mail: kirihara@ms.sist.ac.jp
957-4166/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(02)00612-2

2
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M. Kirihara et al. / Tetrahedron: Asymmetry 13 (2002) 2283–2289
Scheme 2.
organic solvents and to utilize the optically active 1 as
a chiral fluorinated building block (Scheme 3).
agent in hexane solvent (Table 1). All of the lipases
tested here show the same enantiopreference, which is
expected to be for the S-configuration. The determina-
tion of the absolute configuration of the preferentially
transesterified enantiomers will be discussed later. From
this initial screening, lipase from Pseudomonas fluores-
cens (Amano AK) was selected and employed for fur-
ther studies, because it demonstrated high
2
. Results and discussion
2.1. Kinetic resolution of racemic fluorinated alcohols
6
We first screened eight commercially available lipases
Amano AK, Amano AY, Amano PPL, Amano PS,
enantioselectivity (E =82) and the best reactivity.
(
Meito ALC, Meito PLC, Novozym 435 and Toyobo
LIP) for their ability to mediate the transesterification
of (±)-1a smoothly and with good enantioselectivity. In
all reactions, vinyl acetate was used as the acylating
We next examined the effect of the organic solvents on
the enantioselectivity and the reactivity of Amano AK
lipase (Table 2). The lipase shows the highest enantio-
selectivity and reactivity in hexane. No correlation
Scheme 3.
Table 1.
Lipasea
Time (h)
Conversion (%)
Ee 2a (%)
Ee 1a (%)
E6
PCLb
PFL
1056
68
28
50
23
97
92
90
75
–
–
–
–
38
93
27
41
–
–
–
–
95
82
25
10
–
–
–
–
CAL
1061
981
768
114
115
114
b
AlsL
PAL
35
b
B9
B2
B0.6
0
b
AcsL
CRL
PPL
Conditions: lipase (20 mg), 1a (25 mmol), vinyl acetate (0.1 ml), hexane (1 ml).
a
PCL: Pseudomonas cepacia (Amano PS), PFL: P. fluorescens (Amano AK), CAL: Candida antarctica (Novozym 435), AlsL: Alcaligenes sp.
Meito PLC), PAL: Pseudomonas aeruginosa (Toyobo LIP), AcsL: Achromobacter sp. (Meito ALC), CRL: Candida rugosa (Amano AY), PPL:
(
Porcine pancrea (Amano PPL).
Lipase (10 mg).
b

M. Kirihara et al. / Tetrahedron: Asymmetry 13 (2002) 2283–2289
2285
Table 2.
Solvent
Time (h)
Conversion (%)
Ee 2a (%)
Ee 1a (%)
E6
Hexane
Isooctane
Diisopropyl ether
Acetonitrile
68
94
361
967
50
55
43
40
92
76
90
70
93
92
67
46
82
24
38
9
between the hydrophobicity of the solvents and the E
values was observed.
tion of 3 was then determined by X-ray crystallographic
analysis. The ORTEP plot (Scheme 4) shows the X-ray
structure of 3.
7
We then investigated whether a combination of Amano
AK and hexane as a reaction media could effectively
resolve the analogous alcohols 1b–1f. As shown in
Table 3 1a–1d could be resolved with good enantiose-
lectivity. It has been reported previously that many
secondary alcohols in which the stereogenic carbons are
attached to an aromatic group and an alkyl group
could be resolved highly enantioselectively via lipase-
The absolute structure of 3 shows that optically active
alcohol 1c has R-configuration, (which means that the
acetate product from the resolution reaction (com-
pound 2c) has S-configuration). Although the absolute
configuration of alcohols 1a, 1b and 1d–1f obtained
from the kinetic resolution of the racemic alcohols were
not determined, they were expected to have R-configu-
ration based on the case of 1c and the empirical rule for
8
catalyzed reactions. In contrast, moderate enantiose-
lectivity was observed for 1e and 1f, which have two
aliphatic groups attached to the stereogenic carbons.
9
the enantiopreference of lipases.
The lipase shows extremely high enantioselectivity (E>
2.3. Synthesis of optically active 2,2-difluoro-3-hydroxy-
1
00) toward all the para-substituted phenyl derivatives
carboxylate derivatives
1b–1d. In this study, the effect of the substituents on the
E values is not clear; it is meaningless to distinguish
between E values greater than 100 when we are dis-
cussing the enantioselectivity of lipase-catalyzed reac-
tions because the E values become increasingly sensitive
As was mentioned in the introduction to this paper,
optically
active
2,2-difluoro-3-hydroxycarboxylate
derivatives are important compounds. As a demonstra-
tion of the synthetic potential of the compounds 2, we
planned to convert the obtained (S)-2a into the 2,2-
difluoro-3-hydroxycarboxylate derivative 5. In practice,
this was effected in two steps: Ruthenium-catalyzed
6
to very small errors in the measurement of ee.
2.2. Determination of the absolute configurations
10
oxidation of the alkene function of (S)-2a provided
the carboxylic acid 4. The reaction of trimethylsilyldia-
zomethane with 4 then afforded the desired methyl
ester 5 in 41% overall yield (Scheme 5).
We synthesized ester 3 from optically active 1c
(
(
obtained from the kinetic resolution of (±)-1c) and
S)-(+)-O-acetylmandelic acid. The absolute configura-
Table 3.
Substrate
Time (h)
Conversion (%)
Ee (S)-2 (%)
Ee (R)-1 (%)
E6
82
142
146
303
43
1
1
1
1
1
1
a: R=C H5
b: R=p-CH O–C H
c: R=p-Br-C H4
d: R=p-NC–C H4
e: R=cyclohexyl
f: R=n-C H
68
47
48
57
47
48
50
43
43
50
49
46
92
97
97
98
88
76
93
72
74
97
86
65
6
3
6
4
6
6
14
9
19

2
286
M. Kirihara et al. / Tetrahedron: Asymmetry 13 (2002) 2283–2289
Scheme 4.
Scheme 5.
3
. Conclusion
Amano AY, Amano PPL and Amano PS were supplied
by Amano Enzyme, Inc. Meito ALC and Meito PLC
were supplied by Meito Sangyo Co., Ltd. Novozym 435
and Toyobo LIP were supplied by Novo Nordisk and
Toyobo Co., Ltd., respectively. The infrared spectra
(IR) were measured using a Jasco IR-8300 FT-IR spec-
The P. fluorescens lipase-catalyzed resolution of racemic
,2-difluorohomoallylalcohols effectively afforded the
R)-alcohols 1 and (S)-acetates 2. A 2,2-difluoro-3-
hydroxycarboxylate derivative 5 could be obtained
from the optically active 2. The resulting optically
active 2,2-difluorohomoallylalcohols and their deriva-
tives are expected to be useful chiral fluorinated build-
ing blocks.
2
(
1
19
trophotometer. The H and F NMR spectra were
obtained using a JEOL JNM-400 instrument with tetra-
1
methylsilane (for H) and chlorotrifluoromethane (for
19
F) as the internal standards. The mass spectra (MS)
and high-resolution mass spectra (HR-MS) were mea-
sured with a JEOL JMS D-200 spectrometer. Melting
points were measured with a Yanaco MP-S3 melting-
point apparatus. Optical rotations were measured with
a Perkin–Elmer 241 polarimeter. Gas chromatograms
were recorded on a Shimadzu GC-14B with an OV 101
bonded capillary column (Gasukuro Industry), 17 m×
0.25 mm, or a CP Cyclodextrin-B-236-M-19 capillary
4
. Experimental
4
.1. General
2
,2-Difluorohomoallylalcohols (1a and 1c) were pre-
pared according to the author’s method. Amano AK,
1

M. Kirihara et al. / Tetrahedron: Asymmetry 13 (2002) 2283–2289
2287
column (Chrompack), 25 m×0.25 mm, or a Gamma
DEX 120 capillary column (Supelco), 30 m×0.25 mm.
HPLC analyses were done on a Hitachi L-6250 intel-
ligent pump with a Hitachi L-4000 UV detector using
a chiral column CHIRALPAK AD-H (Daicel), 250
mm×4.6 mm. Column chromatography was per-
formed on silica gel (Wakogel C300).
(4H, m), 1.85ꢀ1.98 (2H, m), 3.48ꢀ3.55 (1H, m),
5.52 (1H, d, J=12 Hz), 5.72 (1H, d, J=12 Hz),
19
5.94ꢀ6.01 (1H, m); F NMR l: −104.38 (1F, dt,
JFF=250 Hz, JFH=12 Hz), −110.05 (1F, dd, JFF=
+
250 Hz, JFH=12 Hz); MS (m/z) 191 (M ). HRMS
+
calcd for C H F (M −H O), 169.0829. Found:
10
11
2
5
169.0831.
4
.2. Representative procedure for the preparation of
4.3.2. (±)-3,3-Difluorotridec-1-en-4-ol, 1f. Chemical
−1 1
racemic 2,2-difluorohomoallylalcohols, 1b, 1d–f
yield, 70%, a colorless oil. IR (neat) cm : 3398; H
NMR l: 0.88 (3H, t, J=7 Hz), 1.15ꢀ1.46 (16H, m),
3.76 (1H, q, J=9 Hz), 5.54 (1H, d, J=11 Hz), 5.71
A suspension containing p-anisaldehyde (340 mg, 2.50
mmol), 3-bromo-3,3-difluoropropene (0.38 ml, 3.57
mmol), powdered indium (430 mg, 3.57 mmol) and
DMF (5 ml) was stirred for 3 h at rt. The reaction
mixture was then quenched with 10% HCl and
extracted with ether (3×20 ml). The combined organic
extract was washed with brine, dried over anhydrous
magnesium sulfate and the solvent was removed in
vacuo. The residue was purified using chromatogra-
phy on silica gel (n-hexane:ethyl acetate=5:1) to give
19
(1H, d, J=18 Hz), 5.91ꢀ6.04 (1H, m); F NMR l:
−109.23 (1F, dt, JFF=244 Hz, JFH=11 Hz), −110.05
(1F, dt, JFF=244 Hz, JFH=11 Hz); MS (m/z) 233
+
+
(M −H). HRMS calcd for C H FO (M −F),
13
24
215.1812. Found: 215.1812.
4.4. Lipase-catalyzed transesterification of alcohols, 1
A typical experimental procedure is as follows: The
lipase (20 mg) was placed in a vial to which was
added the alcohol (25 mmol), vinyl acetate (0.1 ml)
and hexane (1 ml). The resulting suspension was then
stirred at 30°C. The reaction was quenched by filtra-
tion and the filtrate was concentrated under reduced
pressure. The residue was chromatographed on a sil-
ica gel column using hexane–ethyl acetate as the elu-
ent to afford an acetate (S)-2 and an unreacted
alcohol (R)-1. An aliquot of the combined fractions
containing the unreacted alcohol (R)-1 was analyzed
by HPLC or GC to determine the ee of the alcohol.
The ee of the produced ester was also determined as
mentioned above; 2e and 2g were hydrolyzed (1 M
NaOH, MeOH) into the corresponding alcohols, the
ees of which were determined as mentioned above.
The E value and the conversion of the reaction were
calculated from the ees of the unreacted alcohol and
512 mg (94%) of (±)-1b.
4
.2.1. (±)-2,2-Difluoro-1-(p-methoxyphenyl)but-3-en-1-
−
1
1
ol, 1b. Colorless oil. IR (neat) cm : 3410; H NMR
l: 2.55–2.63 (1H, br), 3.81 (3H, s), 4.85 (1H, t, J=10
Hz), 5.46 (1H, d, J=10 Hz), 5.59 (1H, d, J=18 Hz),
5
.79ꢀ5.92 (1H, m), 6.89 (2H, d, J=8 Hz), 7.34 (2H,
19
d, J=8 Hz); F NMR l: −108.72 (1F, dt, JFF=250
Hz, JFH=10 Hz), −110.05 (1F, dd, JFF=250 Hz,
JFH=10 Hz); MS (m/z) 214 (M ). HRMS calcd for
+
+
C H F O (M ), 214.0805. Found: 214.0813.
11
12
2
2
4
.3. (±)-1-(p-Cyanophenyl)-2,2-difluorobut-3-en-1-ol, 1d
Chemical yield, quant.: colorless crystals, mp 63–66°C
−
1
1
(
n-hexane). IR (neat) cm : 3427, 2230; H NMR l:
.83 (1H, s), 4.99 (1H, t, J=9 Hz), 5.48ꢀ5.60 (2H,
m), 5.77ꢀ5.91 (1H, m), 7.56 (2H, d, J=8 Hz), 7.66
2
6
the produced ester.
1
9
(
2H, d, J=8 Hz); F NMR l: −106.79 (1F, d, JFF=
2
2
2
50 Hz), −110.05 (1F, d, J =250 Hz); MS (m/z)
We also conducted preparative kinetic resolution of
all the alcohols using a combination of Amano AK
and hexane. From 1.5 to 11 mmol of the racemic
fluorinated alcohols were resolved (Table 4). The
experimental procedure of the preparative kinetic res-
olution is the same as that of the small scale resolu-
tion.
FF
+
+
10 (M +H). HRMS calcd for C H F NO (M ),
11
9 2
09.0652. Found: 209.0651.
4
.3.1. (±)-1-Cyclohexyl-2,2-difluorobut-3-en-1-ol, 1e.
−
1
Chemical yield, 58%: colorless oil. IR (neat) cm :
1
3
398; H NMR l: 1.10ꢀ1.25 (5H, m), 1.52ꢀ1.75
Table 4. Preparative kinetic resolution of (9)-1
Substrate Produced esters (S)-2
Recovered alcohol (R)-1
Yield (%)
Ee (%)
[h]D (CHCl3)
Yield (%)
Ee (%)
[h]D (CHCl3)
(9)-1a
(9)-1b
(9)-1c
(9)-1d
(9)-1e
(9)-1f
34
34
40
50
46
49
84
90
97
97
87
67
+52.2 (21°C, c 1.45)
+71.3 (23°C, c 1.14)
+53.8 (22°C, c 1.21)
+59.2 (30°C, c 1.09)
+5.3 (25°C, c 1.03)
−8.2 (25°C, c 1.05)
39
35
38
50
36
42
79
94
96
88
95
82
−14.7 (23°C, c 1.13)
−20.2 (23°C, c 1.01)
−14.3 (24°C, c 1.13)
−7.5 (31°C, c 1.07)
+20.5 (23°C, c 1.09)
+19.7 (25°C, c 1.10)

2
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M. Kirihara et al. / Tetrahedron: Asymmetry 13 (2002) 2283–2289
4
.4.1. (+)-(S)-4-Acetoxy-3,3-difluoro-4-phenylbut-1-ene,
(S)-(+)-O-acetylmandelic acid (627 mg, 3.23 mmol) and
N,N-dimethylaminopyridine (43 mg, 0.35 mmol) in
dichloromethane (5 ml) was added dicyclohexylcarbodi-
imide (6.44 mg, 3.12 mmol) at room temperature under
an inert atmosphere and stirred for 1.5 h. The reaction
mixture was diluted with ethyl acetate (10 ml) and
filtered with Celite. The filtrate was washed with water,
dried over anhydrous magnesium sulfate and evapo-
rated. The residue was purified using chromatography
on silica gel (n-hexane:ethyl acetate=10:1) to give 3 as
colorless crystals (1163 mg, 96%). mp 91–92°C (n-hex-
−
1
1
(
S)-2a. Colorless oil. IR (neat) cm : 1754; H NMR l:
.15 (3H, s), 5.48 (1H, d, J=11 Hz), 5.62 (1H, d, J=18
Hz), 5.78ꢀ5.91 (1H, m), 5.99 (1H, t, J=9 Hz), 7.34ꢀ
2
1
9
7
.42 (5H, m); F NMR l: −107.07 (1F, dd, JFF=250
Hz, JFH=12 Hz), −110.05 (1F, dt, JFF=250 Hz, JFH
1
=
+
2 Hz); MS (m/z) 226 (M ). HRMS calcd for
+
C H F O (M ), 226.0805. Found: 226.0806.
12
12
2
2
4
.4.2.
(+)-(S)-4-Acetoxy-3,3-difluoro-4-(p-methoxy-
−1
phenyl)but-1-ene, (S)-2b. Colorless oil. IR (neat) cm :
1
26
−1
1
752; H NMR l: 2.14 (3H, s), 3.81 (3H, s), 5.48 (1H,
ane). [h]D +29.0 (c 1.02, CHCl ). IR (neat) cm : 1751;
3
1
d, J=11 Hz), 5.62 (1H, d, J=17 Hz), 5.77ꢀ5.87 (1H,
m), 5.94 (1H, t, J=11 Hz), 6.88 (2H, d, J=9 Hz), 7.33
H NMR l: 2.19 (3H, s), 5.51 (1H, d, J=11 Hz), 5.63
(1H, d, J=18 Hz), 5.74ꢀ5.88 (2H, m), 6.04 (1H, s),
6.86 (2H, d, J=8 Hz), 7.31 (2H, d, J=8 Hz), 7.36ꢀ
1
9
(
2H, d, J=9 Hz); F NMR l: −107.37 (1F, dd,
19
JFF=256 Hz, JFH=11 Hz), −110.05 (1F, dt, JFF=256
Hz, JFH=11 Hz); MS (m/z) 256 (M ). HRMS calcd for
7.43 (5H, m); F NMR l: −106.23 (1F, d, JFF=245
Hz), −110.29 (1F, dd, J =245 Hz, J =28 Hz); MS
+
FF
81
FH
+
+
+
79
C H F O (M ), 256.0911. Found: 256.0910.
(m/z) 441 (M +H for Br) 439 (M +H for Br).
13
14
2
3
81 + 81
HRMS calcd for C H BrF O4 (M +H for Br),
20
18
2
4
.4.3. (+)-(S)-4-Acetoxy-4-(p-bromophenyl)-3,3-difluoro-
441.0339. Found: 441.0310.
−
1
but-1-ene, (S)-2c. Colorless oil. IR (neat) cm : 1749;
1
H NMR l: 2.15 (3H, s), 5.50 (1H, d, J=11 Hz), 5.62
4.6. X-Ray crystallographic data for 3
(
1H, d, J=17 Hz), 5.76ꢀ5.85 (1H, m), 5.90 (1H, t,
J=11 Hz), 7.27 (2H, d, J=10 Hz), 7.49 (2H, d, J=10
A colorless plate crystal of 3 was mounted on a glass
fiber. All measurements were made on a Rigaku
AFC7R diffractometer with graphite-monochromated
1
9
Hz); F NMR l: −107.37 (1F, dd, JFF=250 Hz,
JFH=11 Hz), −110.05 (1F, d, J =256 Hz); MS (m/z)
FF
79
+
81
+
3
06 (M for Br) 304 (M for Br). HRMS calcd for
Mo–Ka radiation (u=0.71073 A
,
) and a rotating anode
7
9
+
C H BrF O (M −2H), 303.9729. Found: 303.9736.
generator. The structure was solved by Patterson
12
9
2
2
11
methods (PATTY ), and the non-hydrogen atoms were
refined anisotropically except for those of the disor-
dered olefinic group.
4
.4.4. (+)-(S)-4-Acetoxy-4-(p-cyanophenyl)-3,3-difluoro-
−1
but-1-ene, (S)-2d. Colorless oil. IR (neat) cm : 2230,
1
1
752; H NMR l: 2.18 (3H, s), 5.54 (1H, d, J=11 Hz),
.64 (1H, d, J=17 Hz), 5.79ꢀ5.92 (1H, m), 5.99 (1H, t,
5
C H BrF O , M=439.25, monoclinic, space group
20
17
2
4
J=9 Hz), 7.52 (2H, d, J=8 Hz), 7.67 (2H, d, J=8 Hz);
P12 1, a=10.223(4), b=8.866(6), c=11.220(4) A
,
, i=
1
1
9
3
F NMR l: −105.77 (1F, dd, JFF=250 Hz, JFH=12
101.82(3)°, V=995.5(8) A
,
, Z=2, F(000)=444, v=
−
1
−3
Hz), −110.45 (1F, tt, JFF=256 Hz, JFH=12 Hz); MS
2.110 cm , D
=1.465 g cm . Final goodness of
calcd
+
+
(
m/z) 251 (M ). HRMS calcd for C H F NO (M ),
fit=1.095, R =0.0402, wR =0.1174.
1 2
1
3
11
2
2
2
51.0757. Found: 251.0757.
Crystallographic data (excluding structure factors) for
the structure of 3 have been deposited with the Cam-
bridge Crystallographic Data Centre as supplementary
publication number CCDC 193905. Copies of the data
can be obtained, free of charge, on application to
CCDC, 12 Union Road, Cambridge CB2 1EZ, UK
[fax: +44(0)-1223-336033 or e-mail: deposit@
ccdc.cam.ac.uk].
4
.4.5. (+)-(S)-4-Acetoxy-4-cyclohexyl-3,3-difluorobut-1-
−
1
1
ene, (S)-2e. Colorless oil. IR (neat) cm : 1750;
H
NMR l: 1.04ꢀ1.29 (6H, m), 1.71ꢀ1.82 (5H, m), 2.11
(
5
3H, s), 4.95ꢀ5.02 (1H, m), 5.50 (1H, d, J=11 Hz),
1
9
.70 (1H, d, J=18 Hz), 5.83ꢀ5.96 (1H, m); F NMR
l: −102.71 (1F, dd, JFF=250 Hz, JFH=12 Hz), −110.45
1F, tt, JFF=250 Hz, JFH=12 Hz). Anal. calcd for
C H F O : C, 62.05; H, 7.81. Found: C, 61.86; H,
(
12
18
2
2
7
.67%.
4.7. (+)-Methyl (S)-3-acetoxy-2,2-difluoro-3-phenyl-
propanoate, 5
4
.4.6. (−)-(S)-4-Acetoxy-3,3-difluorotridec-1-ene, (S)-2f.
−
1
1
Colorless oil. IR (neat) cm : 1749; H NMR l: 0.88
To a stirred solution of 2a (200 mg, 0.876 mmol) in
acetonitrile (4 ml) and carbon tetrachloride (4 ml) was
added an aqueous solution (4 ml) of sodium periodate
(1.53 g, 7.19 mmol) and ruthenium trichloride trihy-
drate (9 mg, 0.03 mmol). The reaction mixture was
(
5
3H, t, J=7 Hz), 1.14ꢀ1.39 (16H, m), 2.10 (3H, s),
.11ꢀ5.20 (1H, m), 5.52 (1H, d, J=11 Hz), 5.70 (1H,
19
d, J=18 Hz), 5.81ꢀ5.95 (1H, m); F NMR l: −107.21
(
1F, dd, JFF=250 Hz, JFH=12 Hz), −112.51 (1F, dt,
+
JFF=250 Hz, JFH=12 Hz); MS (m/z) 277 (M +H).
stirred at rt for 2.5
h
and extracted with
+
HRMS calcd for C H F O (M −H O); 257.1717.
dichloromethane (2×30 ml). The extract was washed
with water and dried over anhydrous magnesium sul-
fate and the solvent evaporated. The residue was
diluted with ether (50 ml) and extracted with saturated
aqueous sodium bicarbonate (3×30 ml). The aqueous
extract was acidified with hydrochloric acid to pH 1
and extracted with ether (3×30 ml). The combined
1
5
23
2
3
Found: 257.1718.
4
.5. (+)-[(R)-1-(p-Bromophenyl)-2,2-difluorobut-3-enyl]
(
S)-acetoxyphenylacetate, 3
To a stirred solution of 1c (730 mg, 2.77 mmol),

M. Kirihara et al. / Tetrahedron: Asymmetry 13 (2002) 2283–2289
2289
organic extract was washed with brine, dried over anhy-
drous magnesium sulfate and the solvent evaporated to
afford crude 4. The crude 4 was diluted with
dichloromethane and trimethylsilyldiazomethane (10%
in n-hexane, 0.4 ml) was added. The resulting mixture
was evaporated and the residue was purified using
chromatography on silica gel (n-hexane:ethyl acetate=
Kuroki, Y.; Asada, D.; Kobayashi, Y. Tetrahedron Lett.
1997, 38, 1447–1448; (b) Iseki, K.; Kuroki, Y.; Asada, D.;
Takahashi, M.; Kishimoto, S.; Kobayashi, Y. Tetra-
hedron 1997, 53, 10271–10280; (c) Kuroki, Y.; Asada, D.;
Iseki, K. Tetrahedron Lett. 2000, 41, 9853–9858.
. Percy, J. M.; Pintat, S. Chem. Commun. 2000, 607–608.
. For a review, see: Roberts, S. M. J. Chem. Soc., Perkin
Trans. 1 1999, 1–21.
3
4
28
1
2:1) to give 5 as a colorless oil (93 mg, 41%). [h]
D
−1 1
+
26.8 (c 1.09, CHCl ). IR (neat) cm : 1768; H NMR
3
5. Representative reports are cited as follows: (a) Takagi,
l: 2.08 (3H, s), 3.77 (3H, s), 6.16 (1H, q, J=19 Hz),
Y.; Kashiwagi, M.; Kihara, H.; Itoh, T. Tetrahedron Lett.
1
9
7
.31ꢀ7.37 (5H, m); F NMR l: −113.90 (1F, dd,
1
999, 40, 2801–2802; (b) Itoh, T.; Kudo, K.; Tanaka, N.;
Sakabe, K.; Takagi, Y.; Kihara, H. Tetrahedron Lett.
000, 41, 4591–4595; (c) Sakai, T.; Miki, Y.; Tsuboi, M.;
JFF=260 Hz, JFH=19 Hz), −117.38 (1F, dd, JFF=260
Hz, JFH=19 Hz); MS (m/z) 258 (M ). HRMS calcd for
+
2
+
C H F O (M ), 258.0704. Found: 258.0697.
12
12
2
4
Takeuchi, H.; Ema, T.; Uneyama, K.; Utaka, M. J. Org.
Chem. 2000, 65, 2740–2747; (d) Hamada, H.; Shiromoto,
M.; Funahashi, M.; Itoh, T.; Nakamura, K. J. Org.
Chem. 1996, 61, 2332–2336; (e) Kirihara, M.; Takuwa,
T.; Kawasaki, M.; Kakuda, H.; Hirokami, S.; Takahata,
H. Chem. Lett. 1999, 405–406.
Acknowledgements
The authors thank Amano Pharmaceutical Co., Ltd.,
Meito Sangyo Co., Ltd., Novo Nordisk Co., Ltd., and
Toyobo Co., Ltd., for kindly providing the lipases. The
authors also thank the researchers at the Biotechnology
Research Center, Toyama Prefectural University, for
their generous support during specific rotation
measurements.
6
7
8
9
. Chen, C.-S.; Fujimoto, Y.; Girdaukas, G.; Sih, C. J. J.
Am. Chem. Soc. 1982, 104, 7294–7299.
. For a review, see: Wescott, C. R.; Klibanov, A. M.
Biochim. Biophys. Acta 1994, 1206, 1–9.
. Nakamura, K.; Kawasaki, M.; Ohno, A. Bull. Chem. Soc.
Jpn. 1996, 69, 1079–1085.
. Cygler, M.; Grochulski, P.; Schrag, J. D. Can. J. Micro-
biol. 1995, 41, 289–296.
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