T. Ito et al. / Tetrahedron: Asymmetry 14 (2003) 3525–3531
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mL), 2% aqueous NaHCO3 solution (300 mL), water
(200 mL), 0.2 N HCl (200 mL) and water (2×200 mL),
and concentrated under reduced pressure. The residue
was triturated with n-hexane (40 mL) and AcOEt (2 mL).
The resulting crystals were collected by filtration and
washed with n-hexane (3×20 mL), and dried under
reduced pressure to give 7 (18.4 g, 59%, E/Z=99/1) as
added water (200 mL) and the mixture extracted with
AcOEt (2×450 mL). The organic layers were combined
and washed successively with water (3×300 mL), and
concentrated under reduced pressure to give rac-8 (172
g, purity 99.3%) as a colorless liquid, which was used in
further reactions without purification. An analytically
pure sample of rac-8 was obtained by crystallization
from isopropylether as a white crystalline powder. Mp
100.3–100.8°C; 1H NMR (CDCl3); l 1.10–1.20 (m, 1H),
1.35–1.45 (m, 1H), 1.62–1.75 (m, 2H), 2.10–2.38 (m, 7H),
3.59 (br, 6H), 3.84 (s, 3H), 4.72(br, 1H), 5.65(s, 1H), 6.69
(d, 2H, J=8.4 Hz), 7.07 (d, 2H, J=8.4 Hz), 7.42–7.49
(m, 2H), 7.96–8.07 (m, 2H); 13C NMR (CDCl3): l 13.5,
25.3, 27.9, 31.9, 33.9, 412, 51.5, 61.3, 62.0, 115.0, 122.2,
122.7, 125.4, 125.7, 127.0, 127.2, 127.8, 128.4, 133.7,
136.3, 150.5, 150.8, 153.7, 174.5; IR (KBr): 3353, 1731,
1513 cm−1; EIMS: m/z 422 (M+). Anal. calcd for
C26H30O5: C, 73.91; H, 7.16. Found: C, 73.95; H, 7.23%.
1
a white crystalline powder. Mp 85.2–86.0°C; H NMR
(CDCl3); l 1.84–1.95 (m, 2H), 2.35–2.41 (m, 3H), 2.49
(t, 2H, J=7.5 Hz), 3.80(s, 3H), 3.86 (s, 3H), 6.18–6.26
(m, 1H), 6.53 (d, 1H, J=16.1 Hz), 7.43–7.49 (m, 2H),
8.02–8.10 (m, 2H), 10.80 (br, 1H); 13C NMR (CDCl3):
l 13.7, 24.4, 33.2, 33.4, 60.7, 61.3, 122.0, 122.5, 124.9,
125.5, 125.9, 126.0, 127.5, 127.7, 127.9, 135.7, 149.9,
150.0, 179.6; IR (KBr): 3510, 1708, 1351 cm−1; EIMS:
m/z 314 (M+). Anal. calcd for C19H22O4: C, 72.59; H,
7.05. Found: C, 72.47; H, 7.18%.
4.5. rac-6-(1,4-Dimethoxy-3-methyl-2-naphthyl)-6-(4-
hydroxyphenyl)hexanoic acid, rac-2
4.7. rac-Methyl 6-(1,4-dimethoxy-3-methyl-2-naphthyl)-
6-(4-(propionyloxy)phenyl) hexanoate, rac-9b
To a solution of 7 (34.6 g, 110 mmol) and phenol (28.2
g, 300 mmol) in toluene (300 mL) was added dropwise
BF3–Et2O (25.2 mL, 200 mmol) at 0°C. The resulting
mixture was stirred for 3 h at 40°C and cooled to 20°C.
Cold water (1 L) and AcOEt (1 L) were added and the
organic layer was separated. The organic layer was
extracted with a 10% aqueous Na2CO3 solution (4×300
mL). The aqueous layers were combined and washed
with isopropylether/AcOEt (1/1, 100 mL). The aqueous
layer was treated with 6N HCl until the pH was adjusted
to 3 and extracted using AcOEt (2×400 mL). The organic
layers were combined and washed successively with water
(2×200 mL), and concentrated under reduced pressure.
The residue was triturated with toluene (80 mL). The
resulting crystals were collected by filtration, washed
with toluene (2×20 mL), and dried under reduced pres-
sure to give crude rac-2 (36.4 g) as a white crystalline
powder. To a solution of the crude rac-2 (36.4 g) in
AcOEt (80 mL) was added toluene (160 mL) at 60°C. The
resulting mixture was stirred for 6 h at rt. The resulting
crystals were collected by filtration, washed with toluene
(2×20 mL), and dried under reduced pressure to give
rac-2 (30.8 g, 69%, purity 98.8%) as a white crystalline
To a solution of rac-8 (172 g) and triethylamine (61.4 mL,
441 mmol) in THF (750 mL) was added propionyl
chloride (38.4 mL, 441 mmol) at 0°C. The resulting
mixture was stirred for 1.5 h at 0°C. After addition of
water (300 mL), the whole mixture was concentrated
under reduced pressure To the residue was added water
(300 mL) and the mixture extracted with AcOEt (2×450
mL). The organic layers were combined and washed
successively with water (3×300 mL), 0.1N HCl (2×200
mL), water (200 mL), saturated aqueous NaHCO3 solu-
tion (100 mL) and water (100 mL), and then concentrated
under reduced pressure. To the residue in isopropylether
(1 L) was added activated charcoal (15 g) with the
resulting mixture was stirred for 0.5 h at rt. The charcoal
was filtered off and washed with isopropylether (200
mL). The filtrate and washings were combined and
concentrated under reduced pressure. The residue was
triturated with isopropylether (200 mL) and to the
resulting suspension was added n-hexane (750 mL). The
mixture was stirred for 2 h at rt. The resulting crystals
were collected by filtration, washed with n-hexane (10
mL), and dried under reduced pressure to give rac-9b
(117.8 g, 83% from rac-2, purity 99.3%) as a white
crystalline powder. Mp 71.0–71.5°C; 1H NMR (CDCl3);
l 1.10–1.30 (m, 4H), 1.35–1.50 (m, 1H), 1.55–1.80 (m,
2H), 2.00–2.50 (m, 7H), 2.54 (q, 2H, J=7.5 Hz), 3.59 (br,
6H), 3.84 (s, 3H), 4.80 (br, 1H), 6.97 (d, 2H, J=8.5 Hz),
7.25 (d, 2H, J=8.5 Hz), 7.40–7.55 (m, 2H), 7.90–8.10 (m,
2H); 13C NMR (CDCl3): l 9.1, 13.6, 25.2, 27.7, 27.9, 31.9,
33.9, 41.5, 51.4, 61.3, 62.0, 121.1, 122.3, 122.7, 125.4,
125.8, 126.8, 127.3, 128.0, 128.3, 133.3, 142.0, 148.6,
150.7, 150.8, 173.0, 174.0; IR (KBr); 1760, 1737, 1506
cm−1; EIMS: m/z 478 (M+). Anal. calcd for C29H34O6: C,
72.78; H, 7.16. Found: C, 72.83; H, 7.15%.
1
powder. Mp 121.5–123.5°C; H NMR (DMSO-d6); l
1.10–1.26 (m, 1H), 1.28–1.48 (m, 1H), 1.49–1.72 (m, 2H),
2.02–2.40 (m, 7H), 3.64 (br, 3H), 3.76 (s, 3H), 4.68 (br,
1H), 6.69 (d, 2H, J=8.5 Hz), 7.04 (d, 2H, J=8.5 Hz),
7.49–7.52 (m, 2H), 7.97–8.01 (m, 2H), 9.18 (br, 1H), 11.9
(br, 1H); 13C NMR (DMSO-d6): l 13.9, 25.7, 28.5, 32.3,
34.4, 41.6, 61.7, 62.7, 115.8, 122.8, 123.4, 126.1, 126.4,
126.1, 127.4, 127.5, 128.0, 128.9, 134.7, 134.9, 150.9,
156.0, 175.3; IR (KBr): 3350, 1698, 1513 cm−1; EIMS:
m/z 408 (M+). Anal. calcd for C25H28O5: C, 73.51; H,
6.91. Found: C, 73.70; H, 6.92%.
4.6. rac-Methyl 6-(1,4-dimethoxy-3-methyl-2-naphthyl)-
6-(4-hydroxyphenyl) hexanoate, rac-8
4.8. (R)-(+)-Methyl 6-(1,4-dimethoxy-3-methyl-2-naph-
thyl)-6-(4-(propionyloxy)phenyl) hexanoate, (R)-9b (using
SO3-pyr)
To a solution of rac-2 (121.5 g, 297 mmol) in MeOH
(1050 mL) was added concentrated HCl (22.5 mL) at
0°C. The resulting mixture was stirred for 3 h at rt and
concentrated under reduced pressure To the residue was
To a solution of rac-9b (110 g, 230 mmol) and EtOH
(19.8 mL) in MTBE (1100 mL) was added lipase (LIP™,