T. R. Hoo6er, S. R. Hitchcock / Tetrahedron: Asymmetry 14 (2003) 3233–3241
3237
0.85 (d, 3H, J=6.9 Hz), 3.00 (s, 3H), 3.39–3.45 (m,
1H), 4.64 (d, 1H, J=17.9 Hz), 4.68 (d, 1H, J=2.2 Hz),
4.75 (d, 1H, J=17.9 Hz), 6.03 (d, 1H, J=4.0 Hz),
7.28–7.44 (m, 10H). 13C NMR (CDCl3): 12.3, 43.3,
56.8, 71.3, 73.3, 77.6, 124.9, 127.9, 128.2, 128.3, 128.4,
128.7, 135.2, 137.2, 148.4, 170.8. IR (neat): 1786, 1732,
1202, 1136, 738, 699 cm−1. HRMS calcd for
C20H23N2O4: 355.1658. Found: 355.1659.
(40:60, hexanes:EtOAc, Rf=0.27, column dimensions=
3×40 cm) to yield 8b (88%) as an oil. [h]2D5=−1.4 (c
2.22, methanol). 1H NMR (CDCl3): l 0.80 (d, 3H,
J=6.96 Hz), 2.96 (s, 3H), 3.40–3.46 (m, 1H), 5.41 (s,
1H), 6.01 (d, 1H, J=2.20 Hz), 6.08 (d, 1H, J=4.04
Hz), 6.74–7.55 (m, 14H). 13C NMR (CDCl3): 11.8, 42.8,
56.3, 72.9, 77.8, 81.8, 115.7, 122.1, 124.6, 127.6, 128.1,
128.2, 128.6, 129.3, 133.2, 134.9, 138.5, 148.9, 157.1,
169.2. IR (neat): 3438, 3064, 1700, 1598, 1134 cm−1.
HRMS calcd for C26H26N2O5Cl: 481.1530. Found:
481.1532.
4.3. Procedure for the synthesis of (2%S,3%R,4R,5S,6R)-
3,4,5,6-tetrahydro-3-(3-hydroxy-2-phenoxy-3-phenylpro-
pionyl)-4,5-dimethyl-6-phenyl-2H-1,3,4-oxadiazin-2-one
8a
4.4.2.
(2%S,3%R,4R,5S,6R)-3,4,5,6-Tetrahydro-3-[3-
hydroxy-3-(4-methoxyphenyl)-2-phenoxypropionyl]-4,5-
dimethyl-6-phenyl-2H-1,3,4-oxadiazin-one 8c. Yellow oil
purified by column chromatography on silica gel (40
hexanes: 60 EtOAc, Rf=0.24, column dimensions=3×
40 cm) to yield 8c (79%) as an oil. [h]2D5=−20.8 (c 2.29,
In a nitrogen-purged, flame-dried 100 mL, round bot-
tomed flask was placed 4 (0.75 g, 2.20 mmol), freshly
distilled THF (6.60 mL), and titanium tetrachloride
(0.25 mL, 2.3 mmol). The solution was stirred for 25
min and was then cooled to −78°C for 15 min. Triethyl-
amine (0.61 mL, 4.4 mmol) was then added, and the
reaction was brought to 0°C over a period of 15 min.
The reaction mixture was again cooled to −78°C and
benzaldehyde (0.44 mL, 4.4 mmol) was added. The
reaction stirred for 4 h and was quenched by the
addition of a saturated solution of ammonium chloride
(50 mL). The resulting mixture was then extracted with
EtOAc (3×50 mL), washed with a saturated solution of
brine, dried over MgSO4, and the solvent was removed
via rotary evaporation. This process afforded a yellow
oil purified by column chromatography on silica gel
(40:60, hexanes:EtOAc, Rf=0.27, column dimensions=
3×40 cm) to yield 8a (70%) as an oil. [h]2D5=−6.0 (c
2.46, methanol). 1H NMR (CDCl3): l 0.79 (d, 3H,
J=6.9 Hz), 2.91 (s, 3H), 3.38–3.44 (m, 1H), 5.41 (d,
1H, J=2.2 Hz), 6.05 (d, 1H, J=3.6 Hz), 6.10 (d, 1H,
J=2.6 Hz), 6.77–7.60 (m, 15H). 13C NMR (CDCl3):
11.9, 42.9, 56.5, 73.8, 77.8, 82.1, 115.9, 122.1, 124.7,
126.3, 127.8, 128.1, 128.2, 128.7, 129.3, 135.0, 139.7,
148.8, 157.3, 169.5. IR (neat): 3460, 3063, 1716, 1599,
1186, 732, 700 cm−1. HRMS calcd for C26H27N2O5:
447.1920. Found: 447.1922.
1
methanol). H NMR (CDCl3): l 0.74 (d, 3H, J=6.9
Hz), 2.74 (s, 3H), 3.31–3.37 (m, 1H), 3.49 (d, 1H,
J=7.3 Hz), 3.72 (s, 3H), 5.33 (d, 1H, J=4.0 Hz), 5.95
(d, 1H, J=4.03 Hz), 6.09 (d, 1H, J=2.9 Hz), 6.78–7.50
(m, 14H). 13C NMR (CDCl3): 11.7, 42.6, 54.9, 56.3,
73.5, 77.7, 81.9, 113.4, 115.7, 121.8, 124.6, 127.6, 128.1,
128.5, 129.2, 131.7, 135.0, 148.7, 157.3, 159.0, 169.4. IR
(neat): 3455, 2936, 1717, 1599, 740, 700 cm−1. HRMS
calcd for C27H29N2O5: 477.2026. Found: 477.2026.
4.4.3.
(2%S,3%R,4R,5S,6R)-3,4,5,6-Tetrahydro-3-(3-
hydroxy-3-naphthalen-2-yl-2-phenoxypropionyl)-4,5-di-
methyl-6-phenyl-2H-1,3,4-oxadiazin-2-one 8d. Yellow
oil purified by column chromatography on silica gel
(50:50, hexanes:EtOAc, Rf=0.19, column dimensions=
3×40 cm) to yield 8d (43%) as an oil. [h]2D5 +10.3 (c 2.00,
1
methanol). H NMR (CDCl3): l 0.79 (d, 3H, J=6.6
Hz), 2.87 (s, 3H), 3.32 (d, 1H, J=6.6 Hz), 3.36–3.42 (m,
1H), 5.59 (s, 1H), 5.99 (d, 1H, J=3.7 Hz), 6.20 (d, 1H,
J=2.7 Hz), 6.76–8.01 (m, 17H). 13C NMR (CDCl3):
11.9, 42.8, 56.4, 73.8, 77.7, 82.0, 115.8, 122.0, 124.2,
124.7, 125.3, 125.8, 125.9, 127.5, 127.9, 128.0, 128.2,
128.6, 129.3, 132.8, 132.9, 135.0, 137.3, 148.9, 157.3,
169.5. IR (neat): 3446, 3013, 1716, 1600, 751 cm−1.
HRMS calcd for C30H29N2O5: 497.2076. Found:
497.2070.
4.4. General procedure for the preparation of 8b–e
In a nitrogen-purged, flame-dried 100 mL, round bot-
tomed flask was placed 4 (1.00 g, 2.93 mmol), freshly
distilled tetrahydrofuran (8.80 mL), and the appropri-
ate aldehyde (5.86 mmol). The solution was then cooled
to −78°C for 10 min. To this solution was added
titanium tetrachloride (0.34 mL, 3.1 mmol) and the
reaction stirred for 15 min. Triethylamine (0.81 mL,
5.86 mmol) was then added. The reaction was allowed
to run for 4 h and was quenched by the addition of a
saturated solution of sodium bicarbonate (50 mL) at
25°C. The resulting mixture was then extracted with
EtOAc (3×50 mL), washed with a saturated solution of
brine, dried over MgSO4, and the solvent was removed
via rotary evaporation.
4.4.4.
(2%S,3%R,4R,5S,6R)-3,4,5,6-Tetrahydro-3-(3-
hydroxy-2-phenoxy-3-m-tolylpropionyl)-4,5-dimethyl-6-
phenyl-2H-1,3,4-oxadiazin-2-one 8e. Yellow oil purified
by column chromatography on silica gel (40:60, hex-
anes:EtOAc, Rf=0.30, column dimensions=3×40 cm)
to yield 8e (57%) as an oil. [h]2D5=−6.0 (c 1.28,
1
methanol). H NMR (CDCl3): l 0.79 (d, 3H, J=6.9
Hz), 2.34 (s, 3H), 2.84 (s, 3H), 3.22 (d, 1H, J=7.7 Hz),
3.35–3.41 (m, 1H), 5.37 (d, 1H, J=5.5 Hz), 6.00 (d, 1H,
J=4.0 Hz), 6.10 (d, 1H, J=2.6 Hz), 6.77–7.43 (m,
14H). 13C NMR (CDCl3): 11.8, 21.3, 42.7, 56.4, 73.8,
77.7, 82.0, 115.8, 121.9, 123.3, 124.6, 127.0, 128.0,
128.1, 128.4, 128.6, 129.2, 135.0, 137.6, 139.5, 148.7,
157.3, 169.4. IR (neat): 3464, 2976, 1718, 1239, 788, 752
cm−1. HRMS calcd for C27H29N2O5: 461.2076. Found:
461.2074.
4.4.1.
(2%S,3%R,4R,5S,6R)-3-[3-(4-Chlorophenyl)-3-
hydroxy-2-phenoxypropionyl]-3,4,5,6-tetrahydro-4,5-di-
methyl-6-phenyl-2H-1,3,4-oxadiazin-2-one 8b. Yellow
oil purified by column chromatography on silica gel