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ture for 2—5 h. Hexane was then added and the resulting mixture was fil-
tered through a chromatographic column of silica gel to remove polar sub-
stances. Evaporation of solvent gave the mixture of the diastereomers 8
and 9. These were separated by column chromatography on silica gel
(hexane/AcOEtꢀ4/1 or CHCl3/AcOEtꢀ95/5) to give the ester diastereomers
8a—e and 9a—e, respectively (the yields of each pair of the ester diastere-
omers were 52—77% in 2 steps).
Methyl 2-Fluoro-2-(4-phenoxyphenyl)propionate [(ꢅ)-4d]: Yellow oil. IR
(neat) cmꢁ1: 1744 (CꢀO). 1H-NMR (CDCl3) d: 1.91 (3H, d, Jꢀ22 Hz), 3.77
(3H, s), 6.93—7.03 (3H, m), 7.09—7.26 (3H, m), 7.30—7.38 (3H, m). 19F-
NMR (CDCl3) d: ꢁ151.85 (1F, q, Jꢀ22 Hz). MS m/z: 274 (Mꢂ), 255, 215.
HR-MS Calcd for C16H15FO3 (Mꢂ): 274.1006. Found: 274.0977.
Methyl 2-Fluoro-2-[3-(2-phenyl-1,3-dioxolan-2-yl)phenyl]propionate
1
[(ꢅ)-6]: Colorless oil. IR (neat) cmꢁ1: 1742 (CꢀO). H-NMR (CDCl3) d:
(1R,2R,3R,6S)-4-Hydroxy-4,7,7-trimethyl-bicyclo[4.1.0]hept-3-yl (2R)-
2-Fluoro-2-[4-(2-methylpropyl)phenyl]propionate (8a): Colorless oil. IR
(neat) cmꢁ1: 1739 (CꢀO), 3456 (OH). 1H-NMR (CDCl3) d: 0.64—0.76
(2H, m), 0.89 (6H, d, Jꢀ7 Hz), 0.97 (3H, s), 1.00 (3H, s), 1.16 (3H, s),
1.20—1.31 (1H, m), 1.58—1.70 (1H, m), 1.80—1.96 (2H, m), 1.94 (3H, d,
Jꢀ22 Hz), 2.15 (1H, dd, Jꢀ8, 15 Hz), 2.47 (2H, d, Jꢀ7 Hz), 4.55 (1H, dd,
Jꢀ8, 10 Hz), 7.16 (2H, d, Jꢀ8 Hz), 7.40 (2H, d, Jꢀ8 Hz). 19F-NMR (CDCl3)
d: ꢁ148.96 (1F, q, Jꢀ22 Hz). MS m/z: 376 (Mꢂ), 358. HR-MS Calcd for
C23H33FO3 (Mꢂ): 376.2414. Found: 376.2420.
1.91 (3H, d, Jꢀ22 Hz), 3.74 (3H, s), 4.06 (4H, s), 7.24—7.37 (4H, m),
7.40—7.52 (4H, m), 7.71 (1H, t, Jꢀ2Hz). 19F-NMR (CDCl3) d: ꢁ151.85
(1F, q, Jꢀ22 Hz). MS m/z: 330 (Mꢂ), 271. HR-MS Calcd for C19H19FO4
(Mꢂ): 330.1267. Found: 330.1265.
Preparation of Methyl 2-Fluoro-2-[3-(phenylcarbonyl)phenyl]propi-
onate [(ꢀ)-4e] Ten percent aqueous HCl (5 ml) was added to a solution of
2-fluorinated ester 6 (562 mg, 1.7 mmol) in MeOH (5 ml) and the mixture
was stirred at room temperature for 18 h. Saturated aqueous NaHCO3 was
added to the reaction mixture, the MeOH was evaporated and the aqueous
layer was extracted with AcOEt (20 mlꢄ3). The organic layer was washed
with brine and dried over Na2SO4. After the solvent was evaporated, the
residual oil was purified by column chromatography on silica gel
(hexane/AcOEtꢀ4/1) to give 2-fluorinated ester 4e in 93% yield. Colorless
(1R,2R,3R,6S)-4-Hydroxy-4,7,7-trimethyl-bicyclo[4.1.0]hept-3-yl (2S)-2-
Fluoro-2-[4-(2-methylpropyl)phenyl]propionate (9a): Colorless oil. IR (neat)
1
cmꢁ1: 1733 (CꢀO), 3436 (OH). H-NMR (CDCl3) d: 0.65—0.77 (2H, m),
0.89 (6H, d, Jꢀ7 Hz), 0.93 (3H, s), 0.96 (3H, s), 1.16—1.33 (1H, m), 1.20
(3H, s), 1.63—1.75 (1H, m), 1.82—2.01 (2H, m), 1.92 (3H, d, Jꢀ22 Hz),
2.11 (1H, dd, Jꢀ8, 15 Hz), 2.47 (2H, d, Jꢀ7 Hz), 4.58 (1H, dd, Jꢀ8, 10 Hz),
7.15 (2H, d, Jꢀ8 Hz), 7.38 (2H, d, Jꢀ8 Hz). 19F-NMR (CDCl3) d: ꢁ151.47
(1F, q, Jꢀ22 Hz). MS m/z: 376 (Mꢂ), 358. HR-MS Calcd for C23H33FO3
(Mꢂ): 376.2414. Found: 376.2401.
1
oil. IR (neat) cmꢁ1: 1661 (CꢀO), 1744 (CꢀO). H-NMR (CDCl3) d: 1.97
(3H, d, Jꢀ22 Hz), 3.78 (3H, s), 7.46—7.66 (4H, m), 7.73—7.81 (4H, m),
7.96 (1H, d, Jꢀ2 Hz). 19F-NMR (CDCl3) d: ꢁ152.43 (1F, q, Jꢀ22 Hz). MS
m/z: 330 (Mꢂ), 271. HR-MS Calcd for C19H19FO4 (Mꢂ): 330.1267. Found:
330.1265.
(1R,2R,3R,6S)-4-Hydroxy-4,7,7-trimethyl-bicyclo[4.1.0]hept-3-yl (2R)-2-
Fluoro-2-[6-methoxy(2-naphthyl)]propionate (8b): Colorless oil. IR (neat)
General Procedure for Preparation of 2-Aryl-2-fluoropropionic Acids
2a—e 1 M KOH (3 ml) was added to a solution of 2-fluorinated esters 4
(2.0 mmol) in MeOH (5 ml) and the mixture was stirred at room temperature
for 1—3 h. After evaporation of MeOH, the aqueous layer was washed with
ether (10 mlꢄ2), acidified with 10% HCl (pH 1) and extracted with CH2Cl2
(20 mlꢄ3). The organic layer was washed with brine and dried over MgSO4.
Evaporation of the solvent gave 2-aryl-2-fluoropropionic acids (ꢅ)-2a—e in
74—100% yields.
2-Fluoro-2-[4-(2-methylpropyl)phenyl]propionic Acid [(ꢅ)-2a]: Color-
less solid (from hexane/AcOEt). mp 68—70 °C. IR (KBr) cmꢁ1: 1715
(CꢀO), 3438 (OH). 1H-NMR (CDCl3) d: 0.89 (6H, d, Jꢀ7 Hz), 1.83—1.91
(1H, m), 1.87 (3H, d, Jꢀ22 Hz), 2.47 (2H, d, Jꢀ7 Hz), 7.14 (2H, d, Jꢀ8 Hz),
7.38 (2H, d, Jꢀ8 Hz). 19F-NMR (CDCl3) d: ꢁ149.46 (1F, q, Jꢀ22 Hz). MS
m/z: 224 (Mꢂ), 179. HR-MS Calcd for C13H17FO2 (Mꢂ): 224.1213. Found:
224.1180.
1
cmꢁ1: 1739 (CꢀO), 3511 (OH). H-NMR (CDCl3) d: 0.63—0.75 (2H, m),
0.96 (3H, s), 0.99 (3H, s), 1.17 (3H, s), 1.23—1.32 (1H, m), 1.58—1.69
(1H, m), 1.90—1.99 (1H, m), 2.03 (3H, d, Jꢀ22 Hz), 2.15 (1H, dd, Jꢀ8,
15 Hz), 3.92 (3H, s), 4.58 (1H, dd, Jꢀ7, 10 Hz), 7.12 (1H, d, Jꢀ2 Hz), 7.17
(1H, dd, Jꢀ2, 9 Hz), 7.52 (1H, dd, Jꢀ2, 9 Hz), 7.74 (1H, s), 7.77 (1H, s),
7.90 (1H, d, Jꢀ1 Hz). 19F-NMR (CDCl3) d: ꢁ149.20 (1F, q, Jꢀ22 Hz). MS
m/z: 400 (Mꢂ). HR-MS Calcd for C24H29FO4 (Mꢂ): 400.2050. Found:
400.2066.
(1R,2R,3R,6S)-4-Hydroxy-4,7,7-trimethyl-bicyclo[4.1.0]hept-3-yl (2S)-2-
Fluoro-2-[6-methoxy(2-naphthyl)]propionate (9b): Colorless prisms (from
hexane/CHCl3). mp 111—116 °C. IR (KBr) cmꢁ1: 1745 (CꢀO), 3506 (OH).
1H-NMR (CDCl3) d: 0.63—0.77 (2H, m), 0.96 (3H, s), 0.98 (3H, s), 1.20
(3H, s), 1.26—1.32 (1H, m), 1.62—1.74 (1H, m), 1.92—2.01 (1H, m), 2.02
(3H, d, Jꢀ22 Hz), 2.04—2.14 (1H, m), 3.93 (3H, s), 4.61 (1H, dd, Jꢀ8,
10 Hz), 7.12 (1H, d, Jꢀ2 Hz), 7.17 (1H, dd, Jꢀ2, 9 Hz), 7.54 (1H, dd, Jꢀ2,
9 Hz), 7.73 (1H, s), 7.76 (1H, s), 7.89 (1H, d, Jꢀ2 Hz). 19F-NMR (CDCl3) d:
ꢁ150.62 (1F, q, Jꢀ22 Hz). MS m/z: 400 (Mꢂ). HR-MS Calcd for C24H29FO4
(Mꢂ): 400.2050. Found: 400.2064.
2-Fluoro-2-[6-methoxy(2-naphthyl)]propionic Acid [(ꢅ)-2b]: Colorless
prisms (from hexane/AcOEt). mp 119—122 °C. IR (KBr) cmꢁ1: 1739
1
(CꢀO), 3445 (OH). H-NMR (CDCl3) d: 2.04 (3H, d, Jꢀ22 Hz), 3.91 (3H,
s), 7.11—7.18 (2H, m), 7.57 (1H, dd, Jꢀ2, 9 Hz), 7.73 (1H, s), 7.76 (1H, s),
7.92 (1H, d, Jꢀ1 Hz). 19F-NMR (CDCl3) d: ꢁ150.16 (1F, q, Jꢀ22 Hz). MS
m/z: 248 (Mꢂ), 203. HR-MS Calcd for C14H13FO3 (Mꢂ): 248.0849. Found:
248.0837.
Crystal Data: C24H29O4F, Mꢀ400.49, orthorhombic, P212121 (no 19),
aꢀ6.444 (2), bꢀ14.743 (6), cꢀ22.452 (8) Å, Vꢀ2132.9 (13) Å3, Zꢀ4, DCꢀ
1.291 g/cm3, m (MoKa)ꢀ0.93 cmꢁ1
, Tꢀ173 K, colorless prism (0.30ꢄ
2-Fluoro-2-(3-fluoro-4-phenylphenyl)propionic Acid [(ꢅ)-2c]: Colorless
solid (from hexane/MeOH). mp 97—100 °C. IR (KBr) cmꢁ1: 1618 (CꢀO),
0.20ꢄ0.20 mm), 31168 measured, 4881 unique, R1ꢀ0.032, wR2ꢀ0.075 for
all reflections (SIR 92 refinement).
1
3406 (OH). H-NMR (CD3OD) d: 1.86 (3H, d, Jꢀ22 Hz), 7.32—7.44 (6H,
m), 7.47—7.54 (2H, m). 19F-NMR (CD3OD) d: ꢁ118.71—ꢁ118.78 (1F,
m), ꢁ141.55 (1F, q, Jꢀ22 Hz). MS m/z: 262 (Mꢂ), 217. HR-MS Calcd for
C15H12F2O2 (Mꢂ): 262.0805. Found: 262.0798.
(1R,2R,3R,6S)-4-Hydroxy-4,7,7-trimethyl-bicyclo[4.1.0]hept-3-yl (2R)-2-
Fluoro-2-(3-fluoro-4-phenylphenyl)propionate (8c): Colorless prisms (from
hexane/AcOEt). mp 61—65 °C. IR (KBr) cmꢁ1: 1732 (CꢀO), 3444 (OH).
1H-NMR (CDCl3) d: 0.67—0.79 (2H, m), 1.01 (3H, s), 1.03 (3H, s), 1.16—
1.37 (1H, m), 1.25 (3H, s), 1.58—1.75 (1H, m), 1.86—2.05 (1H, m), 1.96
(3H, d, Jꢀ22 Hz), 2.16 (1H, dd, Jꢀ8, 14 Hz), 4.61 (1H, dd, Jꢀ8, 10 Hz),
7.31—7.56 (8H, m). 19F-NMR (CDCl3) d: ꢁ117.19—ꢁ117.27 (1F, m),
ꢁ151.22 (1F, q, Jꢀ22 Hz). MS m/z: 414 (Mꢂ), 396. HR-MS Calcd for
C25H28F2O3 (Mꢂ): 414.2007. Found: 414.1987.
Crystal Data: C25H28O3F2, Mꢀ414.49, monoclinic, C2 (no 5), aꢀ32.445
(9), bꢀ5.939 (2), cꢀ25.451 (8) Å, b=100.3712 (9)°, Vꢀ4824.0 (24) Å3,
Zꢀ8, DCꢀ1.141 g/cm3, m (MoKa)ꢀ0.84 cmꢁ1, Tꢀ173 K, colorless prism
(0.20ꢄ0.20ꢄ0.20 mm), 35780 measured, 10916 unique, R1ꢀ0.075, wR2ꢀ
0.083 for all reflections (SIR 92 refinement).
2-Fluoro-2-(4-phenoxyphenyl)propionic Acid [(ꢅ)-2d]: Colorless solid
(from hexane/AcOEt). mp 62—66 °C. IR (KBr) cmꢁ1: 1725 (CꢀO), 3074
(OH). 1H-NMR (CDCl3) d: 1.92 (3H, d, Jꢀ23 Hz), 6.70—7.37 (9H, m). 19F-
NMR (CDCl3) d: ꢁ151.70 (1F, q, Jꢀ23 Hz). MS m/z: 260 (Mꢂ), 240, 215.
HR-MS Calcd for C15H13FO3 (Mꢂ): 260.0849. Found: 260.0848.
2-Fluoro-2-[3-(phenylcarbonyl)phenyl]propionic Acid [(ꢅ)-2e]: Yellow
oil. IR (neat) cmꢁ1: 1660 (CꢀO), 1738 (CꢀO), 3066 (OH). 1H-NMR
(CDCl3) d: 2.00 (3H, d, Jꢀ22 Hz), 7.45—7.64 (4H, m), 7.76—7.81 (4H, m),
7.99 (1H, t, Jꢀ2 Hz). 19F-NMR (CDCl3) d: ꢁ152.50 (1F, q, Jꢀ22 Hz). MS
m/z: 272 (Mꢂ), 227. HR-MS Calcd for C16H13FO3 (Mꢂ): 272.0849. Found:
272.0823.
(1R,2R,3R,6S)-4-Hydroxy-4,7,7-trimethyl-bicyclo[4.1.0]hept-3-yl (2S)-2-
Fluoro-2-(3-fluoro-4-phenylphenyl)propionate (9c): Colorless oil. IR (neat)
General Procedure of Preparation of (1R,2R,3R,6S)-4-Hydroxy-4,7,7-
trimethyl-bicyclo[4.1.0]hept-3-yl 2-Aryl-2-fluoropropionates 8a—e and
9a—e (COCl)2 (8.0 mmol) was added to a solution of 2-aryl-2-fluoropro-
pionic acids 2 (4.0 mmol) and N,N-dimethylformamide (DMF, 0.4 mmol) in
dry THF (30 ml) at 0 °C and the mixture was stirred at room temperature for
2—5 h. After evaporation of the excess reagents and solvent, the residual oil
was dried well under vacuum. Then the crude product was solved in dry
THF (30 ml) and N,N-dimethylaminopyridine (DMAP, 0.4 mmol) and chiral
alcohol 7 (4.0 mmol) were added to this solution. Et3N (8.0 mmol) was then
added slowly to the reaction, and the mixture was stirred at room tempera-
1
cmꢁ1: 1741 (CꢀO), 3465 (OH). H-NMR (CDCl3) d: 0.67—0.78 (2H, m),
0.98 (3H, s), 1.01 (3H, s), 1.15—1.37 (1H, m), 1.25 (3H, s), 1.64—1.80
(1H, m), 1.88—2.05 (1H, m), 1.96 (3H, d, Jꢀ22 Hz), 2.14 (1H, dd, Jꢀ7,
14 Hz), 4.64 (1H, dd, Jꢀ7, 10 Hz), 7.30—7.56 (8H, m). 19F-NMR (CDCl3)
d: ꢁ117.20—ꢁ117.28 (1F, m), ꢁ151.83 (1F, q, Jꢀ22 Hz). MS m/z: 414
(Mꢂ), 396. HR-MS Calcd for C25H28F2O3 (Mꢂ): 414.2007. Found:
414.1991.
(1R,2R,3R,6S)-4-Hydroxy-4,7,7-trimethyl-bicyclo[4.1.0]hept-3-yl (2R)-2-