8060 J . Org. Chem., Vol. 63, No. 22, 1998
Notes
Calcd for C9H12F2O4: C, 48.65; H, 5.44. Found: C, 48.69; H,
5.51.
genolysis of the corresponding ester with Pd-C/H2
produced the synthetic intermediate (S)-(-)-10 (>95%
ee), and then the lactonization was achieved by pyri-
dinium p-toluenesulfonate. Finally, the methylene group
was introduced into the lactone ring, giving (S)-(+)-3-
methylene-5-(difluoromethyl)propionate ((S)-(+)-2b, >98%
ee by GLC).
(R)-Met h yl
5,5-d iflu or o-4-h yd r oxy-2-m et h ylen ep en -
ta n oa te ((R)-3b): 1H NMR (CDCl3) δ 2.54 (1 H, dd, J ) 9.0,
14.4 Hz), 2.72 (1 H, dd, J ) 3.4, 14.4 Hz), 2.98 (1 H, d, J ) 5.1
Hz), 3.81 (3 H, s), 3.89-3.99 (1 H, m), 5.70 (1 H, dt, J ) 3.7,
55.7 Hz), 5.80 (1 H, dd, J ) 1.0, 2.2 Hz), 6.36 (1H, d, J ) 1.0
Hz); 13C NMR (CDCl3) δ 33.14 (t, J ) 3.8 Hz), 52.40, 70.00 (t, J
) 23.7 Hz), 115.95 (t, J ) 244.2 Hz), 129.31, 135.46, 168.25; 19
F
NMR (CDCl3) δ -131.0 (1 F, ddd, J ) 10.7, 54.9, 285.3 Hz),
-136.8 (1 F, ddd, J ) 10.7, 54.9, 285.3 Hz). Anal. Calcd for
C7H10F2O3: C, 46.67; H, 5.59. Found: C, 46.68; H, 5.59.
Asym m etr ic Hyd r olysis. A solution of methyl 5,5,5-trif-
luoro-4-acetoxy-2-methylenepentanoate (4a ) (0.85 g, 3.54 mmol)
and lipase MY (0.95 g; C. rugosa, Meito Sangyo Co., Ltd. 8000
unit/mol) in 35 mL of phosphate buffer (0.01 M, pH 7) was stirred
at 30 °C. The reaction was monitored by gas chromatography.
The acetylation stopped at a conversion of 47%, and the mixture
was diluted with diethyl ether. After the solid materials were
filtered, the solvent was removed in vacuo. The residue was
purified by column chromatography on silica gel, eluting with a
Exp er im en ta l Section
Gen er a l Meth od s. All commercially available reagents were
used without further purification. Chemical shift of 1H (500
MHz) and 13C NMR spectra were recorded in ppm (δ) downfield
from the following internal standards (Me4Si, δ 0.00, or CHCl3,
δ 7.24). The 19F (470 MHz) NMR spectra were recorded in ppm
downfield from external C6F6 in CDCl3 using a VXR 500
instrument. Gas-liquid chromatography (GLC) was performed
using silicone GE ULBON HR-20M on Chromosorb W, 30 m ×
3 mm. The optical purities of the materials were determined
by GLC.
25
mixture of hexane-diethyl ether (4:1-1:1) to give (R)-3a ([R]D
4-H yd r oxy-2-m et h ylen e-5,5,5-t r iflu or op en t a n oic Acid
(1a ). To a stirred solution of ethyl trifluoroacetate (0.35 mL,
9.0 mmol) and zinc powder (0.705 g, 10.8 mmol) in diethyl ether
(12 mL) at -78 °C was added LiAlH4 (1.0 M solution in THF,
9.0 mL, 9.0 mmol) for 10 min under an argon. The mixture was
stirred for 2 h at -30 °C, and then methyl (bromomethyl)acrylate
(1.19 mL, 9.9 mmol) in THF (10 mL) was added dropwise to the
above solution at 0 °C. The mixture was stirred at 60 °C for 30
min and then allowed to cool to room temperature over 8 h, and
the mixture was quenched with 15 mL of 1 N HCl. The organic
layer was separated and extracted with ethyl acetate. The
organic layer was washed with brine and dried over MgSO4.
After the solvent was removed, THF (10 mL) was added to the
residue. To this mixture solution at 0 °C were successively
added 2.0 N NaOH (4.0 mL) and EtOH (4.0 mL). The mixture
was stirred at room temperature for 4 h. The mixture was
diluted with water and was then acidified with 6.0 N HCl. The
mixture was extracted with CH2Cl2 and concentrated in vacuo.
The residue was purified by column chromatography on silica
gel, eluting with hexane/ether (1:1 to 0:1) to give 1.20 g (72%) of
4-hydroxy-2-methylene-5,5,5-trifluoropentanoic acid (1a ): 1H
NMR (CDCl3) δ 2.61 (1 H, ddd, J ) 0.7, 9.8, 14.4 Hz), 2.80 (1 H,
ddd, J ) 0.7, 3.2, 14.4 Hz),4.19 (1 H, ddq, J ) 3.2, 9.8, 6.6 Hz),
6.53 (1 H, d, J ) 0.7 Hz), 5.95 (1 H, d, J )0.7 Hz); 13C NMR
(CDCl3) δ 32.72, 69.37 (q, J ) 31.1 Hz), 124.91 (q, J ) 281.8
Hz), 132,53, 134.11, 172.32; 19F NMR (CDCl3) δ -80.9 (d, J )
+26.2 (c 0.90, CHCl3), 97% ee) (34% yield) and (S)-4a ([R]25
D
+18.1 (c 0.79, CHCl3), 95% ee) (65% yield). (S)-Methyl 5,5,5-
trifluoro-4-acetoxy-2-methylene-pentanoate ((S)-4a ): 1H NMR
(CDCl3) δ 2.09 (3 H, s), 2.94 (1 H, ddd, J ) 0.8, 3.2, 14.2 Hz),
2.57 (1 H, ddd, J ) 0.7, 10.5, 14.4 Hz), 3.80 (3 H, s), 5.56 (1 H,
ddq, J ) 3.2, 9.8, 6.6 Hz), 5.69 (1 H, d, J ) 1.0 Hz), 6.28 (1 H,
d, J ) 0.7 Hz); 13C NMR (CDCl3) δ 20.34, 31.62 (q, J ) 3.6 Hz),
52.27, 68.04 (q, J ) 24.5 Hz), 123.66 (q, J ) 244.6 Hz), 129.30,
134.05, 166.34, 169.17; 19F NMR (CDCl3) δ -78.3 (d, J ) 7.6
Hz). Anal. Calcd for C9H11F3O4: C, 45.01; H, 4.62. Found: C,
45.28; H, 4.84.
(R)-Met h yl 5,5,5-t r iflu or o-4-h yd r oxy-2-m et h ylen ep en -
ta n oa te ((R)-3a ): 1H NMR (CDCl3) δ 2.62 (1 H, dd, J ) 9.5,
14.4 Hz), 2.78 (1 H, ddd, J ) 1.0, 2.9, 14.4 Hz), 3.37 (1 H, d, J
)5.86 Hz), 3.82 (3 H, s), 4.10-4.18 (1 H, m), 5.83 (1 H, d, J )
0.7 Hz), 6.36 (1 H, d, J ) 0.5 Hz); 13C NMR (CDCl3) δ 33.26,
52.52, 69.46 (q, J ) 31.1 Hz), 124.97 (q, J ) 282.2 Hz), 130.01,
134.75, 168.30; 19F NMR (CDCl3) δ -80.9 (d, J ) 6.1 Hz). Anal.
Calcd for C7H9F3O3: C, 42.43; H, 4.58. Found: C, 42.02; H, 4.69.
Asym m etr ic La cton iza tion : (a ) P r ep a r a tion of (R)-2a .
A mixture of (R)-methyl 5,5,5-trifluoro-4-hydroxy-2-methylene-
pentanoate ((R)-3a ) (0.28 g, 1.41 mmol, 97% ee) and Novozym
435 (1.61 g, 8000 unit/mol; C. antarctica, Novo Nordisk Co., Ltd.)
in hexane (15 mL) was stirred at 30 °C overnight. The mixture
was diluted with diethyl ether. After the solid materials were
filtered, the solvent was removed in vacuo. The residue was
purified by column chromatography on silica gel, eluting with a
mixture solution of hexane-diethyl ether (2:1) to give (R)-2-
methylene-4-(trifluoromethyl)-4-butanolide ((R)-2a ) ([R]25D -20.9
(c 0.73, CHCl3), 96% ee): 1H NMR (CDCl3) δ 3.05 (1 H, ddt, J )
4.4, 17.8, 2.7 Hz), 3.19 (1 H, ddt, J ) 9.0, 17.8, 2.9 Hz), 4.81 (1
H, ddq, J ) 4.4, 6.1, 9.0 Hz), 5.81 (1 H, t, J ) 2.7 Hz) 6.38 (1 H,
t, J ) 2.9 Hz); 13C NMR (CDCl3) δ 27.61 (q, J ) 2.0 Hz), 72.61
(q, J ) 34.8 Hz), 123.82 (q, J ) 280.0 Hz), 125.25, 130.86 168.85;
19F NMR (CDCl3) δ -81.2 (d, J ) 6.0 Hz); IR (neat) ν 1665, 1724
6.1 Hz); IR (neat) ν 1634, 1699, 3450 cm-1
.
4-Hyd r oxy-2-m eth ylen e-5,5-d iflu or op en ta n oic a cid (1b):
1H NMR (CDCl3) δ 2.54 (1 H, dd, J ) 9.3, 14.4 Hz), 2.73 (1 H,
dd, J ) 3.4, 14.7 Hz), 3.94-4.02 (1 H, m), 5.71 (1 H, dt, J ) 3.7,
55.9 Hz), 5.91 (1 H, d, J ) 1.0 Hz), 6.49 (1 H, d, J ) 1.0 Hz); 19
F
NMR (CDCl3) δ -131.0 (1 F, ddd, J ) 10.7, 54.9, 286.9 Hz),
-132.3 (1 F, ddd, J )10.2, 56.5, 286.9 Hz); IR (neat) ν 1630,
1698, 2980 cm-1
.
Asym m etr ic Ester ifica tion . A mixture solution of methyl
5,5-difluoro-4-hydroxy-2-methylenepentanoate (3b) (1.10 g, 6.10
mmol), lipase PS (1.62 g; P. cepacia, Amano Pharmaceutical Co.,
Ltd. 8000 unit/mol), and vinyl acetate (5.62 mL, 61 mmol) in
hexane (61 mL) was stirred at 30 °C. The progress of the
reaction was readily followed by gas chromatography. The
acetylation stopped at a conversion of 36%, and the mixture was
diluted with diethyl ether. After the solid materials were
filtered, the solvent was removed in vacuo. The residue was
purified by column chromatography on silica gel, eluting with a
mixture solution of hexane-diethyl ether (3:1-1:1) to give (S)-
4b ([R]20D +8.68 (c 0.78, CHCl3), 93% ee) (34% yield) and (R)-3b
(46% ee, 64% yield). (S)-Methyl 5,5-difluoro-4-acetoxy-2-meth-
ylenepentanoate (S)-4b: 1H NMR (CDCl3) δ 2.07 (3 H, s), 2.55
(1 H, dd, J ) 9.5, 14.4 Hz), 2.86 (1 H, ddd, J ) 0.7, 3.7, 14.4
Hz), 3.79 (3 H, s), 5.24-5.33 (1 H, m), 5.68 (1 H, dd, J ) 1.2, 2.2
Hz), 5.80 (1 H, ddd, J ) 2.9, 54.4, 55.4 Hz), 6.27 (1 H, d, J ) 1.2
Hz); 13C NMR (CDCl3) δ 20.57, 30.71 (t, J )4.2 Hz), 52.18, 69.68
(t, J ) 24.6 Hz), 113.77 (t, J ) 254.0 Hz), 120.78, 134.75, 166.63,
169.82; 19F NMR (CDCl3) δ -129.5 (1 F, ddd, J ) 10.9, 54.9,
289.2 Hz), -132.0 (1 F, ddd, J ) 13.7, 56.4, 289.9 Hz). Anal.
cm-1
.
(b) P r ep a r a tion of (S)-2a . In the above reaction, (S)-methyl
5,5,5-trifluoro-4-acetoxy-2-methylenepentanoate (S)-4a (95% ee)
was used, and worked up similarly, giving 2-methylene-4-
(trifluoromethyl)-4-butanolide (S)-2a ([R]25D +19.6 (c 0.67, MeOH),
97% ee).
(R)-2-Met h ylen e-4-(d iflu or om et h yl)-4-b u t a n olid e ((R)-
2b): [R]20 -23.10 (c 0.93, MeOH), 97% ee; 1H NMR (CDCl3): δ
D
3.05-3.09 (2 H, m), 4.69 (1 H, dddt, J ) 2.7, 5.6, 7.8, 17.1 Hz),
5.77 (1 H, t, J ) 2.4 Hz), 5.92 (1 H, ddd, J ) 2.7, 54.0, 56.1 Hz),
6.34 (1 H, t, J ) 2.9 Hz); 13C NMR (CDCl3) δ 25.95 (dd, J ) 2.7,
7.1 Hz), 73.37 (dd, J ) 25.6, 30.2 Hz), 113.18 (dd, J ) 243.4,
246.2 Hz), 123.88, 131.57, 168.80; 19F NMR (CDCl3) δ -131.0
(1 F, ddd, J ) 6.1, 53.4, 296.0 Hz), -136.8 (1 F, ddd, J )16.8,
56.5, 296.0 Hz); IR (neat) ν 1668, 1772 cm-1
.
(S)-2-Met h ylen e-4-(d iflu or om et h yl)-4-b u t a n olid e ((S)-
2b): [R]20 +21.36 (c 0.99, MeOH), 98% ee.
D
P r ep a r a tion of (R)-(-)-2-Meth ylen e-4-(tr iflu or om eth yl)-
4-bu ta n olid e (2a ). (a ) (R)-(+)-4-Hyd r oxy-5,5,5-tr iflu or o-
p en ta n itir ile (6a ). To a solution of (R)-ethyl 3-(tert-butyldim-