G. Chaume et al. / Journal of Fluorine Chemistry 129 (2008) 1104–1109
1107
25
cooled to 0 8C with an ice-bath. The resulting mixture was filtered
and toluene was evaporated. Purification by flash chromatography
(95:5 cyclohexane/ethyl acetate) gave 5.80 g (93%) of 1 (75:25
diastereomeric mixture).
[
a
]
À124.4 (c 0.26, CHCl3); IR (neat): 2360, 1763, 1725, 1226,
1H NMR (400 MHz, CDCl3):
= 2.34–2.48
D
1172, 1151, 701 cmÀ1
(m, 1H), 2.60–2.74 (m, 2H), 2.86–2.98 (m, 1H), 4.40 (dd, J = 11.5,
1.4 Hz, 1H), 5.05 (dd, J = 11.5, 4.1 Hz, 1H), 5.07 (dd, J = 4.1,
1.4 Hz, 1H), 7.04–7.08 (m, 2H), 7.27–7.40 (m, 3H); 13C NMR
;
d
4.2. (E)-1-Ethoxycarbonyl-2,2,2-trifluoroethylidene (1R)-2-
(100.5 MHz, CDCl3):
71.4, 124.3 (q, J = 288.9 Hz), 125.6, 128.5, 129.2, 138.2, 165.3,
174.8; 19F NMR (376.2 MHz, CDCl3):
d = 28.6, 29.2, 53.0, 66.6 (q, J = 29.7 Hz),
benzoyloxy-1-phenylethylamine (3)
d
= À76.67 (s); MS (EI) m/z
To a stirred solution of 200 mg of (R)-N-Bz-phenylglycinol
(0.83 mmol, 1.0 equiv.) in 10 mL of toluene at room temperature,
were added 23 mg of p-toluenesulfonic acid (0.12 mmol,
299 [M+Á], 230, 212, 104 (100), 91; Anal. Calcd for C14H12F3NO3:
C, 56.12; H, 4.04; N, 4.68. Found: C, 56.03; H, 4.06; N, 4.61. (R,R)-
25
7: colorless oil; Rf = 0.29 (7:3 cyclohexane/ethyl acetate); [a]
D
0.15 equiv.) and 110
m
L of ethyl trifluoropyruvate (0.83 mmol,
À1.6 (c 0.8, CHCl3); 1H NMR (400 MHz, CDCl3):
d = 2.40 (ddd,
1.0 equiv.). The mixture was warmed to 140 8C with a Dean–Stark
apparatus for 20 h, and then cooled to 0 8C with an ice-bath. The
resulting mixture was filtered and toluene was evaporated.
Purification by flash chromatography (9:1 cyclohexane/ethyl
acetate) gave 229 mg of imine 3 (71%). Colorless oil; [
J = 16.0, 9.2, 1.4 Hz, 1H), 2.60–2.78 (m, 2H), 2.87–2.92 (m, 1H),
4.49 (t, J = 12.8 Hz, 1H), 4.59 (ddd, J = 12.8, 6.9, 1.4 Hz, 1H), 5.04
(dd, J = 12.8, 6.9 Hz, 1H), 7.26–7.30 (m, 2H), 7.32–7.45 (m, 3H);
13C NMR (100.5 MHz, CDCl3):
d = 28.7, 28.8, 53.7, 66.3 (q,
20
a
]
D
J = 30.1 Hz), 68.8, 124.2 (q, J = 284.9 Hz), 127.2, 128.5, 129.1,
À3.05 (c 2.1, CHCl3); IR (neat): 2987, 1742, 1684, 1452, 1272,
134.8, 165.7, 176.6; 19F NMR (376.2 MHz, CDCl3):
MS (EI) m/z 299 [M+Á], 230, 212, 104 (100).
d
= À76.75 (s);
713 cmÀ1 1H NMR (400 MHz, CDCl3):
;
d
= 1.19 (t, J = 7.1 Hz, 3H),
4.17 (dq, J = 10.8, 7.1 Hz, 1H), 4.30 (dq, J = 10.8, 7.1 Hz, 1H), 4.50
(dd, J = 11.1, 9.3 Hz, 1H), 4.74 (dd, J = 11.1, 3.8 Hz, 1H), 5.33 (dd,
J = 9.3, 3.8 Hz, 1H), 7.37–7.47 (m, 8H), 8.02–7.99 (m, 2H); 13C NMR
4.5. (S)-a-Trifluoromethylpyroglutamic acid ((S)-6)
(100.5 MHz, CDCl3):
J = 279.0 Hz), 127.3, 128.4, 128.6, 128.9, 129.6, 133.2, 136.8,
150.2 (q, J = 36.4 Hz), 158.4, 166.0; 19F NMR (376.2 MHz, CDCl3):
d
= 13.8, 62.9, 66.3, 67.8, 118.1 (q,
To a solution of pure bicyclic diastereomer (R,S)-7 (372 mg,
1.04 mmol) in THF (6.3 mL) was slowly added at 0 8C, a 1 M
aqueous solution of LiOH (1.25 mL, 1.25 mmol, 1.2 equiv.). The
resulting mixture was vigorously stirred at 0 8C for 2 h, and then
diluted with ether (10 mL). The layers were separated and the
organic layer was washed with water (2Â 10 mL). The combined
aqueous layers were then acidified with 1N HCl until pH 2,
extracted with EtOAc (3Â 10 mL), dried over Na2SO4 and
concentrated to give 380 mg of crude acid directly used in the
next step without further purification.
d
= À72.9 (s); MS (EI) m/z 393 [M+Á], 271; 243, 198, 105 (100), 77;
Anal. Calcd for C20H18F3NO4: C, 61.07; H, 4.61; N, 3.56. Found: C,
61.01; H, 5.01; N, 3.45.
4.3.
a-Trifluoromethyl-5-hydroxynorvaline (5)
To a 75:25 diastereomeric mixture of hydroxymorpholinone
2 (207 mg, 0.68 mmol) in EtOH (20 mL) was added 380 mg of
20% Pd(OH)2/C. The reaction was stirred for 48 h under 1 bar
atmosphere pressure of hydrogen. The resulting mixture was
filtered and evaporated under reduced pressure. The crude
mixture was taken up with ether and water. The aqueous phase
was washed with ether and evaporated to afford 133 mg of 5
(97%) as white solid. 1H NMR (400 MHz, D2O):
1H), 1.34–1.49 (m, 1H), 1.80 (ddd, J = 16.7, 11.9, 5.0 Hz, 1H), 2.03
(ddd, J = 16.7, 11.9, 4.6 Hz, 1H), 3.39 (td, J = 6.0, 2.8 Hz, 2H); 13C
A solution of the above acid (1.04 mmol) in anhydrous THF
(25 mL) and absolute ethanol (2.5 mL) was added to an oven dried
three-neck round bottom flask charged with argon. The flask was
cooled to À40 8C bath, liquid NH3 (approximately 150 mL) was
condensed using an acetone/liquid nitrogen cold trap flask. Fresh
polished lithium flakes were added to the reactants at À40 8C until
the deep blue color was kept for 5 min. The reaction was quenched
by the addition of NH4Cl powder (2.7 g), and the reaction was left
in the hood until almost all the NH3 evaporated. The reaction
mixture was then diluted with EtOAc (15 mL) and water (15 mL).
The aqueous layer was washed with EtOAc (2Â 20 mL), acidified
with 1N HCl until pH 2 and extracted with EtOAc (3Â 20 mL). The
d = 1.21–1.33 (m,
NMR (100.5 MHz, D2O):
125.9 (q, J = 283.7 Hz), 169.3; 19F NMR (376.2 MHz, D2O):
= À76.2.
d = 27.7, 29.4, 63.1, 68.2 (q, J = 26.8 Hz),
d
combined organic layers were evaporated to afford 100 mg of pure
22
4.4. 8a-Trifluoromethyl-4-phenyltetrahydropyrrolo[2,1-
(S)-6 (49%). White solid; m.p.: 143–144 8C; [
a
]
D
À12.6 (c 2.2,
1H NMR
= 2.35–2.55 (m, 4H);1H NMR (400 MHz,
= 2.20–2.40 (m, 4H); 13C NMR (100.5 MHz, CD3OD):
= 26.9; 30.3; 69.0; 126.2 (q, J = 283.6 Hz), 170.2, 180.3; 13C
NMR (100.5 MHz, D2O): = 25.3, 29.0, 67.8 (q, J = 28.8 Hz), 124.2
(q, J = 283.6 Hz), 170.4, 181.3; 19F NMR (376.2 MHz, D2O):
c][1,4]oxazine-1,6-dione (7)
MeOH); IR (neat): 3139, 3049, 1670, 1402, 1155 cmÀ1
(400 MHz, CD3OD):
D2O):
;
d
To a stirred solution of 263 mg of a 75:25 diastereomeric
mixture of alcohol 2 (0.87 mmol, 1.0 equiv.) in 2.8 mL of acetone
d
d
was added dropwise at 0 8C 634
(2.74 M in 3.2:1 H2O/H2SO4 solution, 1.7 mmol, 2.0 equiv.). After
20 min at 0 8C, 250 L of solution of Jones reagent was added
m
L of solution of Jones reagent
d
d
À79.0
m
(s); MS (EI) m/z 152 (M+–CO2H) (100); Anal. Calcd for C6H6F3NO3:
once more and the reaction mixture was stirred for another
20 min at 0 8C. Finally, isopropanol was added until color turned
green and the resulting solution was diluted in 50 mL of diethyl
ether and 25 mL of water. The layers were separated and the
aqueous phase was extracted with AcOEt (3 mL Â 20 mL). The
combined organic extracts were washed with saturated aqueous
NaHCO3 solution, dried over MgSO4 and evaporated under
reduced pressure. Purification by flash chromatography (9:1
cyclohexane/ethyl acetate) gave 157 mg (61%) of the diaster-
C, 36.56; H, 3.07; N, 7.11. Found: C, 36.93; H, 3.10; N, 6.97.
4.6. (R)-a-Trifluoromethylpyroglutamic acid ((R)-6)
According to the procedure described for (S)-6, starting from
(R,R)-7 (551 mg, 1.84 mmol) in THF (11 mL) and 1 M aqueous
solution of LiOH (2.21 mL, 2.21 mmol, 1.2 equiv.), crude acid
(451 mg) was obtained. This acid was directly used in the next
reductive debenzylation step without further purification to
25
eomer (R,S)-7 as
a
white solid and 53 mg (20%) of the
afford 222 mg of pure (R)-6 (69%). White solid; [
a
]
+11.7 (c
D
diastereomer (R,R)-7 as a colorless oil. (R,S)-7: white solid;
m.p.: 189–190 8C; Rf = 0.41 (7:3 cyclohexane/ethyl acetate);
2.2, MeOH). The spectral data of (R)-6 were identical to those of
(S)-6.