A. Tessier et al. / Journal of Fluorine Chemistry 130 (2009) 1140–1144
1143
3. Conclusion
dried over magnesium sulfate and concentrated over reduced
pressure. Purification of the crude mixture by flash chromatography
(cyclohexane/ethyl acetate: 90/10 to80/20) afforded298 mgof pure
anti diastereomer (Anti1)-2 as a white solid (66%), 42 mg of (Anti2)-2
(9%) and 42 mg of (Syn,R,R)-2 (9%).
In summary we demonstrated that the Fox chiral auxiliary is
suitable for aldol reactions. Although its performance does not
compete with oxazolidinone-type chiral auxiliaries, this chiral
auxiliary is efficiently separated from the chiral hydroxy acid
product by liquid/liquid extraction in basic medium. Further
investigations about synthetic applications of the Fox chiral
auxiliary are underway and will be reported in due course.
(Anti1)-2: White solid, 1H NMR(250 MHz, CDCl3):
d = 0.50 (3H,
d, 3J = 6.6 Hz), 2.6 (1H, quint., 3J = 6.6 Hz), 2.73 (1H, d, 3J = 1.9 Hz),
3.97 (1H, d, 2J = 8.7 Hz), 4.45 (1H, dd, 2J = 8.7 Hz, 3J = 6.2 Hz), 4.64
(1H, d, 3J = 6.2 Hz), 4.73 (1H, dd, 3J = 1.9 Hz, 3J = 6.6 Hz), 6.01 (1H, q,
3J = 5 Hz), 7.14–7.18 (2H, m), 7.26–7.37 (m, 8H); 13C NMR
(62.9 MHz, CDCl3):
d = 11.3, 48.3, 60.7, 75.9, 76.3, 84.8 (q,
4. Experimental
1
2J = 35.2 Hz), 123.0 (q, JC–F = 288.9 Hz), 125.9, 126.2, 128.5,
General: unless otherwise mentioned, all the reagents were
purchased from commercial source. THF was distilled under
nitrogen from sodium/benzophenone prior to use. 1H NMR
(400.00 MHz), 13C NMR (100.50 MHz) and 19F NMR
128.0, 128.8, 129.6, 141.6, 141.8, 175.6; 19F NMR (235.35 MHz,
3
CDCl3):
d
= À77.6 (3 F, JH–F = 5.0 Hz); EIMS(probe), m/z (rel. int.):
361(2), 273 (68), 241 (5), 204 (59), 186 (20), 148 (100), 120 (53),
105 (79), 91 (31), 77 (77), 57 (54).
(376.20 MHz) were measured on
Chemical shifts of 1H NMR were expressed in parts per million
downfield from tetramethylsilane ( = 0) in CDCl3. Chemical shifts
of 13C NMR were expressed in parts per million downfield from
CDCl3 as internal standard (
= 77.0). Chemical shifts of 19F NMR
were expressed in parts per million downfield from C6F6 as internal
standard (
= À164.9). Coupling constants are reported in hertz.
a
JEOL 400 spectrometer.
(Anti2)-2: White solid; 1H NMR (250 MHz, CDCl3):
d = 0.46 (3H,
3
d, JH–F = 6.8 Hz), 2.65 (1H, quint., 3J = 6.6 Hz), 3.3 (1H, bs), 3.95
(1H, dd, 2J = 8.5 Hz), 4.48 (1H, dd, 2J = 8.5 Hz, 3J = 6.92), 4.65 (1H, d,
3J = 6.9 Hz), 4.65 (1H, d, 3J = 6.6 Hz), 6.00 (1H, q, 3J = 5.1 Hz), 7.15–
d
d
7.50 (m, 10H); 13C NMR (62.9 MHz, CDCl3):
d
= 13.5, 47.0, 60.3,
1
2
76.3, 77.1, 84.7 (q, JC–F = 35.3 Hz), 122.8 (q, JC–F = 289.3 Hz),
125.5, 125.6, 127.6, 128.3, 128.5, 129.3, 141.6, 142.3, 175.3; 19F
NMR (235.35 MHz, CDCl3):
EIMS(probe), m/z (rel. int.): 361 (Mꢀ+: 4), 310 (1), 273 (100), 204
d
3
Column chromatography was performed on Merck Kieselgel 60
(0.040–0.063 mm), employing mixture of specified solvent as
eluent. Thin-layer chromatography (TLC) was performed on Merck
silica gel (Merck 60 PF254) plates. Silica TLC plates were visualized
under UV light, by a 10% solution of phosphomolybdic acid in
ethanol followed by heating. Mass spectra (MS) were obtained on a
GC/MS apparatus HP 5973 MSD with an HP 6890 Series GC.
Ionization was obtained by electronic impact (EI 70 eV). Infrared
d
= À77.11 (3 F, d, JH–F = 5.1 Hz);
(45), 186 (25), 148 (67), 120 (44), 105 (90), 91 (35), 77 (77), 57 (36).
4.2. [2S,4R(2R,3R)]-2-trifluoromethyl-3-[Syn-3-hydroxy-2-methyl-
3-phenylpropanoyl]-4-phenyloxazolidine ((Syn,R,R)-2)
2.0 equiv. of Bu2BOTf (Table 2, entry 1): To a stirred solution of
the amide 1 (0.190 g, 0.69 mmol) in dry diethylether (1.75 mL)
was added a Bu2BOTf solution (1M, 1.39 mL, 1.39 mmol) and the
diisopropylethylamine (0.13 mL, 0.764 mmol) at À10 8C under
argon. The reaction was stirred from À10 8C to 0 8C for 2 h and
cooled to À78 8C before the addition of benzaldehyde (0.092 mL,
0.9 mmol). The reaction mixture was stirred for two additional
hours at À78 8C, warmed up to ambient temperature over 2 h and
quenched with a buffer solution (15 mL), methanol (10 mL) and an
oxygen peroxide solution (30%, 8 mL). After extraction with
diethylether (1Â 5 mL) and dichloromethane (2Â 5 mL), com-
bined organic layers were dried over magnesium sulfate and
concentrated over reduced pressure. Purification of the crude
mixture by flash chromatography (cyclohexane/ethyl acetate: 90/
10 to 80/20) afforded 42 mg of pure syn diastereomer (Syn,R,R)-2
as a white solid (16%) and 95 mg of a mixture of (Syn,S,S)-2/(Anti2)-
2 (70/30).
¨
spectra (IR) were obtained by Fourier-transformation on BRUCKER
TENSOR 27, wavenumbers are given in cmÀ1. Elemental analyses
were performed by the CNRS analysis central service. Optical
rotations are reported as their specific rotations determined using
a JASCO DIP-370 polarimeter. Melting points were obtained on a
Bu¨chi apparatus and are uncorrected.
4.1. (2S,4R)-2-trifluoromethyl-3-[anti-3-hydroxy-2-methyl-3-
phenylpropanoyl]-4-phenyloxazolidine ((Anti1)-2, (Anti2)-2)
Li-enolate, (Table 1, entry 2): To
a stirred solution of
hexamethyldisilazane (HMDS, 0.315 g, 1.95 mmol) in dry tetra-
hydrofuran (6 mL) was added a n-butyllithium solution (2.17 M,
0.76 mL, 1.65 mmol) at 0 8C. The yellow solution was stirred
40 min at 0 8C and cooled down to À78 8C and a solution of the
amide 1 (0.325 g, 1.19 mmol) in dry tetrahydrofuran (3 mL) was
added. The orange solution was stirred for 1 h at this temperature
before the addition of benzaldehyde (0.286 mL, 2.25 mmol). The
reaction mixture was stirred for five additional hours at À78 8C,
quenched at this temperature with a saturated NH4Cl solution
(15 mL) and extracted with dichloromethane (3Â 30 mL). Com-
bined organic layers were dried over magnesium sulfate and
concentrated over reduced pressure. Purification of the crude
mixture by flash chromatography (cyclohexane/ethyl acetate: 90/
10 to 80/20) afforded 215 mg of pure anti diastereomer (Anti1)-2 as
a white solid (48%), 42 mg of pure anti diastereomer (Anti2)-2 (4%)
and 145 mg of a mixture of (Syn,R,R)-2/amide 1 (70/30).
Na-enolate, (Table 1, entry 3): To a stirred solution of the amide 1
(0.32 g, 1.19 mmol) in dry tetrahydrofuran was added a NaHMDS
solution (2 M in tetrahydrofuran, 0.79 mL, 1.57 mL) at À78 8C under
argon. The reaction was stirred at À78 8C for 1 h and benzaldehyde
(0.29 mL, 2.25 mmol) was added dropwise. The reaction mixture
was stirred for five additional hours at À78 8C, quenched at this
temperature with a saturated NH4Cl solution (15 mL) and extracted
with dichloromethane (3Â 30 mL). Combined organic layers were
1.1 equiv. of Bu2BOTf (Table 2, entry 2): To a stirred solution of
the amide 1 (0.32 g, 1.19 mmol) in dry dichloromethane was added
a Bu2BOTf solution (1M, 1.31 mL, 1.31 mmol) and the diisopropy-
lethylamine (0.24 mL, 1.43 mmol) at 0 8C under argon. The reaction
was stirred from 0 8C to ambient temperature for 2 h and cooled to
À78 8C before the addition of benzaldehyde (0.15 mL, 1.43 mmol).
The reaction mixture was stirred for one additional hour at À78 8C,
warmed up to ambient temperature over 2 h and quenched with a
buffer solution (15 mL), methanol (10 mL) and an oxygen peroxide
solution (30%, 8 mL). After extraction with dichloromethane (3Â
30 mL), combined organic layers were dried over magnesium
sulfate and concentrated over reduced pressure. Purification of the
crude mixture by flash chromatography (cyclohexane/ethyl
acetate: 90/10 to 80/20) afforded 332 mg of pure syn diastereomer
(Syn,R,R)-2 as a white solid (74%) and 70 mg of a mixture of
(Syn,S,S)-2/(Anti2)-2 (62/38).
(Syn,R,R)-2: White solid, 1H NMR (250 MHz, CDCl3):
d = 1.04
(3H, d, 3J = 7.2 Hz), 2.43 (1H, qd, 3J = 2.0 Hz, 3J = 7.2 Hz), 4.06 (1H, d,
2J = 8.8 Hz), 4.25 (1H, bs), 4.45 (1H, d, 3J = 2.0 Hz), 4.66 (1H, dd,