Synthesis of â-Difluoromethylated Materials
TABLE 5. Asymmetric Hydrolysis with Novozym 435, Lipase PS, or Lipase QL
compd. no
R
time (h)
lipasea
conversionb (%)
compd 7 (% ee)c
[R]D (c, CHCl3)e
7a
Ph
120
120
120
3
120
120
3
120
120
3
120
120
3
Novozym 435
lipase PS
66
77
46
78
63
68
69
61
61
63
52
58
55
53
71
88 (97)
88 (99)
97
+
-42.1 (c, 0.226)
lipase QL
-
+
7b
7c
7d
7e
PhCH2CH2
Novozym 435
lipase PS
lipase QL
Novozym 435
lipase PS
lipase QL
Novozym 435
lipase PS
lipase QL
Novozym 435
lipase PS
lipase QL
43
63 (92)
80
24
-2.60 (c, 1.062)
-
d
C5H11
-
67 (79)
65 (89)
55
+
+3.10 (c, 1.092)
d
C6H13
-
+
56
60
+ 2.35 (c, 0.974)
d
C8H17
52
-
120
120
58 (88)
68 (85)
+3.16 (c, 1.312)
+
a Novozym 435 (Candida antarctica, Novo Nordisk Co. Ltd.), lipase PS (Pseudomonas cepacia, Amano Enzyme Inc.), lipase QL (Alcaligenes
sp., Meito Sangyo Co. Ltd.). b Determined by 19F NMR. c Determined by HPLC analysis (Daicel chiralcel OD or chiralpac AD, n-hexane/
2-propanol: 99.7/0.3, 1.0 mL/min). % ee in parentheses was obtained from the enzymatic resolution of chiral material derived from the
second cycle. d Optical purities were determined by HPLC analysis after converting to benzyl esters. e [R]D are the values of % ee in
parentheses.
ature, it was quenched with H2O. Oily materials were ex-
tracted with a mixture of hexanes-ethyl acetate, and the
extract was dried over MgSO4. On removal of the solvent, the
yield was determined by 19F NMR integral intensities. 1H NMR
(CDCl3) δ 1.20 (t, J ) 7.14 Hz), 3.39 (2 H, J ) 2.2 Hz), 4.12 (2
H, q, J ) 7.14 Hz), 7.24-7.62 (Ar-H). 13C NMR (CDCl3) δ 13.9,
33.8 (d, J ) 2.29 Hz), 60.9, 87.1 (m), 127.3, 127.7 (t, J ) 3.43
Hz), 128.3, 132.8, 154.6 (dd, J ) 288.6, 288.3 Hz), 169.8. 19F
NMR (CDCl3) δ 72.5 (d, J ) 35.3 Hz), 73.8 (dt, J ) 35.3, 2.58
Hz) ppm from internal C6F6. Anal. Calcd for C12H12F2O2: C,
64.01 H; 5.62. Found: C, 63.71; H, 5.35.
temperature. After the solution was stirred for 120 h at room
temperature, it was filtered over a Celite pad in vacuo. The
organic materials were extracted with diethyl ether, and then
the extract was dried over anhydrous MgSO4. On removal of
the solvent, the residues were purified by column chromatog-
raphy on silica gel, eluting with a mixture of hexanes-ethyl
acetate, giving ethyl 4,4-difluoro-3-phenylbutanoate 7a (88%
ee) and 4,4-difluoro-3-phenylbutanoic acid 8a. Optical purity
was determined by HPLC analysis (Daicel Chiralpac AD,
n-hexane-isopropyl alcohol 99.7:0.3; flow speed 1.0 mL/mim;
tR (major), 12.6 min; tR (minor), 11.4 min).
Second cycle: (a) A mixture of chiral ethyl 4,4-difluoro-3-
phenylbutanoate 7a (70 mg, 0.31 mmol, 88% ee) and Novozym
435 (70 mg) in phosphate pH 7.4 buffer (1 mL) was stirred at
room temperature. After the solution was stirred for hours at
room temperature, and worked up similar to the above,
optically pure ethyl 4,4-difluoro-3-phenylbutanoate 7a (97%
ee) was obtained.
To a solution of ethyl 4,4-difluoro-3-phenylbutanoate 7a (114
mg, 0.5 mmol) in phosphate buffer (2 mL, pH 7.4) was added
lipase QL (171 mg, Alcaligenes sp., Meito Sangyo Co. Ltd.) at
room temperature. After the solution was stirred for 120 h at
room temperature, it was filtered with a Celite pad in vacuo.
The solution was diluted with ethyl acetate and then the
separated aqueous phase was extracted twice with ethyl
acetate and the combined organic layers were washed with
brine, dried over anhydrous MgSO4, and concentrated. The
conversion ratio of crude oil was determined by 19F NMR
analysis. The residual was subjected to column chromatogra-
phy (hexane/ethyl acetate). The opitical purity of ethyl 4,4-
difluoro-3-phenylbutanoate 7a (97% ee, 43% yield) was deter-
mined by HPLC, using a chiral column (Daicel Chiralpac AD,
n-hexane-isopropyl alcohol 99.7:0.3; flow speed 1.0 mL/mim;
tR (major), 11.4 min; tR (minor), 12.6 min).
(E)-Ethyl 4,4-difluoro-3-phenyl-2-butenoate 5a: A mix-
ture of ethyl 4,4-difluoro-3-phenyl-3-butenoate 4a (226 mg, 1
mmol) in DMF (2 mL)-fluoride ion [tetra-n-butylammonium
fluoride (TBAF)] (1.2 equiv, 1.2 mL; 1 M in THF) was stirred
at 12-14 °C. After the solution was stirred for 40 min at that
temperature, it was quenched with aq NH4Cl. Oily materials
were extracted with a mixture of hexanes-ethyl acetate, and
the extract was dried over MgSO4. On removal of the solvent,
the resultant crude product was purified by column chroma-
tography on silica gel, using a mixture of hexane and ethyl
1
acetate in 72% yield. H NMR (CDCl3) δ 1.07 (3 H, J ) 7.14
Hz), 4.04 (2 H, q, J ) 7.14 Hz), 6.24 (1 H, td, J ) 55.2, 0.55
Hz), 6.35 (1 H, t, J ) 2.20 Hz), 7.24-7.50 (Ar-H). 13C NMR
(CDCl3) δ 13.7, 60.7, 114.1 (t, J ) 242 Hz), 122.8 (t, J ) 8.88
Hz), 128.1, 128.1, 128.7, 132.3, 146.6 (t, J ) 20.3 Hz), 164.5.
19F NMR (CDCl3) δ 45.5 (dd, J ) 55.2, 2.58 Hz) ppm from
internal C6F6. Anal. Calcd for C12H12F2O2: C, 63.54; H, 5.52.
Found: C, 63.71; H, 5.35.
Ethyl 4,4-difluoro-3-phenylbutanoate 7a: To a MeOH
(3.3 mL) solution of ester 4a (226 mg, 1 mmol) was added 137
mg (0.13 mmol) of 10% Pd/C and the mixture was stirred under
hydrogen at 490 kPa pressure for 3 h. On removal of the
solvent, the resultant crude product was purified by column
chromatography on silica gel, using a mixture of hexane and
ethyl acetate, in 80% yield as an oily material. 1H NMR
(CDCl3) δ 1.15 (3 H, t, J ) 7.14 Hz), 2.78 (1 H, dd, J ) 16.2,
9.06 Hz), 2.96 (1 H, dd, J ) 16.2, 5.77 Hz), 3.55-3.71 (1 H,
m), 4.07 (2 H, qd, J ) 7.14, 2.47 Hz), 5.94 (1 H, td, J ) 56.6,
3.67 Hz), 7.26-7.38 (Ar-H). 13C NMR (CDCl3) δ 14.0, 33.5 (dd,
J ) 5.15, 3.73 Hz), 45.8 (t, J ) 20.3 Hz), 60.7, 116.8 (t, J )
245 Hz), 127.7, 128.5, 128.5, 135.6, 170.7. 19F NMR (CDCl3) δ
38.1 (dd, J ) 278, 18.1 Hz), 42.3 (dd, J ) 278, 13.8 Hz) ppm
from internal C6F6. IR γ 1736 (CdO) cm-1. Anal. Calcd for
C12H14F2O2: C, 63.13; H, 6.21. Found: C, 63.15; H, 6.18.
Asymmetric Hydrolysis. First cycle: A mixture of ethyl
4,4-difluoro-3-phenyl-butanoate 7a (114 mg, 0.5 mmol) and
Novozym 435 (0.228 g, Candida antarctica, Novo Nordisk Co.
Ltd.) in phosphate pH 7.4 buffer (1.5 mL) was stirred at room
4,4-Difluoro-3-phenylbutanoic acid 8a:1H NMR(CDCl3)-
δ 2.81 (1 H, dd, J ) 16.8, 8.79 Hz), 3.16 (1 H, dd, J ) 16.8,
5.76 Hz), 3.51-3.67 (1 H, m), 5.91 (1 H, td, J ) 56.3, 3.30 Hz),
7.26-7.38 (Ar-H). 13C NMR (CDCl3) δ 33.2, 45.5 (t, J ) 20.3
Hz), 116.7 (t, J ) 245 Hz), 127.9, 128.5, 128.7, 135.2, 177.3.19F
NMR (CDCl3) δ 37.7 (ddd, J ) 278, 56.0, 18.1 Hz), 42.5 (ddd,
J ) 278, 56.0, 13.8 Hz) ppm from internal C6F6. IR γ 1728
(CdO) cm-1. Anal. Calcd for C10H10F2O2: C, 60.38; H, 5.50.
Found: C, 60.00 H, 5.04.
Supporting Information Available: NMR spectra for all
isolated products. This material is available free of charge via
JO050634U
J. Org. Chem, Vol. 70, No. 15, 2005 5915