N. Matsunaga et al. / Tetrahedron: Asymmetry 15 (2004) 2021–2028
2027
Flack parameter20 of )0.05(11). Further details of the X-
ray structure data are available on request from the
Cambridge Crystallographic Data Centre (deposition
number CCDC 235615).
mmol) with ice-cooling and stirring continued for 1 h.
2,6-Lutidine (1.3 mL, 11.0 mmol) and trimethylsilyl tri-
fluoromethanesulfonate (1.3 mL, 7.0 mmol) were then
additionally added, and the reaction mixture stirred for
a further 0.5 h. The mixture was diluted with 1 M HCl
and extracted with AcOEt. The extract was washed with
4.9. (3S)-3-(6,7-Dimethoxy-2-naphthyl)-3-hydroxy-4-
methylpentan-2-one 22
water and aqueous NaHCO3, dried over MgSO4, and
cmÀ1: 2959, 1734, 1510,
KBr
max
concentrated to give 24; IR m
1
1489, 1256, 843. H NMR (CDCl3) d: 0.23 (9H, s), 0.93
(3H, d, J ¼ 6:8 Hz), 0.97 (3H, d, J ¼ 6:8 Hz), 2.86 (1H,
septet, J ¼ 6:8 Hz), 4.00 (3H, s), 4.02 (3H, s), 4.28 (2H,
s), 7.10 (2H, s), 7.30 (1H, dd, J ¼ 8:8, 2.2 Hz), 7.64–7.70
(2H, m). Compound 24 was dissolved in THF (4 mL)
and cooled to )15 ꢁC. Saturated NH3 solution in
methanol(23 mL) and formamidine acetate (1.83 g,
17.6 mmol) were added, and the mixture was stirred at
)15 ꢁC for 15 min and at room temperature for 39 h.
After removalof the solvent, the residue was partitioned
between AcOEt and brine. After separation of the lay-
ers, the organic phase was extracted with 1 M HCl
(2 · 100 mL). The combined aqueous HClalyers were
made alkaline by the addition of 2 M NaOH (150 mL)
and then extracted with AcOEt. The extract was washed
with brine, dried over MgSO4, and concentrated. The
residue was chromatographed on silica gel using
CH2Cl2–MeOH (50:1 to 20:1) as an eluent to give 2 as
an amorphous solid (2.90 g, 58% from 22). The enan-
tiomeric excess was determined to be 98.4% by HPLC
[Chiralcelꢂ OJ-R 0.46 · 15 cm column; CH3CN-10 mM
(pH 7) phosphate buffer (30:70) as an eluent; flow rate
To a solution of oxalyl chloride (8.7 mL, 100 mmol) in
CH2Cl2 (150 mL) was added DMSO (15.5 mL,
200 mmol) below )50 ꢁC and the mixture stirred at
)70 ꢁC for 0.5 h. A solution of 21 (15.00 g, 49.3 mmol) in
CH2Cl2 (100 mL) was added, the mixture stirred at
)40 ꢁC for 0.5 h and then cooled to )60 ꢁC. Triethyl-
amine (45.0 mL, 323 mmol) was added, and the mixture
allowed to warm to 10 ꢁC, stirred for an additional0.5 h,
and diluted with aqueous NH4Cl. After separation of
the layers, the aqueous phase was further extracted with
CH2Cl2. The combined organic layers were washed with
water, dried over MgSO4, and concentrated. The residue
was crystallized from 2-propanol to give 22 as colorless
prisms (13.64 g, 92%). The % ee was determined to be
98% ee by HPLC [Chiralpakꢂ AD 0.46 · 25 cm column;
n-hexane–EtOH (85:15) as an eluent; flow rate 0.8 mL/
20
D
min]. Mp 132.5–134.5 ꢁC. ½a ¼ þ10:7 (c 0.99, MeOH).
KBr
max
IR m
cmÀ1: 3461, 2976, 1692, 1510, 1493, 1260, 1219,
1167, 1140, 1005, 856. 1H NMR (CDCl3) d: 0.94 (3H, d,
J ¼ 6:6 Hz), 0.95 (3H, d, J ¼ 6:6 Hz), 2.17 (3H, s), 2.92
(1H, septet, J ¼ 6:6 Hz), 4.00 (6H, s), 4.57 (1H, s), 7.11
(1H, s), 7.14 (1H, s), 7.48 (1H, dd, J ¼ 8:4, 1.8 Hz),
7.70 (1H, d, J ¼ 8:4 Hz), 7.89 (1H, d, J ¼ 1:8 Hz). Anal.
Calcd for C18H22O4: C, 71.50; H, 7.33. Found: C, 71.41;
H, 7.39.
20
KBr
0.5 mL/min]. ½a ¼ À45:3 (c 1.00, MeOH). IR m
D
max
cmÀ1: 2971, 1510, 1489, 1254, 1163, 1005, 855, 731.
1H NMR (CDCl3) d: 0.81 (3H, d, J ¼ 6:8 Hz), 1.01 (3H,
d, J ¼ 6:8 Hz), 2.70 (1H, septet, J ¼ 6:8 Hz), 3.98 (6H,
s), 7.00 (1H, s), 7.08 (1H, s), 7.12 (1H, s), 7.47 (1H, dd,
J ¼ 8:4, 1.8 Hz), 7.51 (1H, s), 7.62 (1H, d, J ¼ 8:4 Hz),
7.90 (1H, d, J ¼ 1:8 Hz).
4.10. (3S)-1-Bromo-3-(6,7-dimethoxy-2-naphthyl)-3-
hydroxy-4-methylpentan-2-one (23)
To a solution of 22 (13.00 g, 43.0 mmol) in THF
(280 mL) was added pyridinium tribromide (15.13 g,
47.3 mmol) with ice-cooling. The mixture was stirred at
room temperature for 42 h, diluted with aqueous
Na2S2O3, and extracted with AcOEt. The extract was
washed with aqueous citric acid and aqueous NaHCO3,
dried over MgSO4, and concentrated. The residue was
chromatographed on silica gel using hexane–acetone
(15:1 to 4:1) as an eluent to give 23 as crystals (con-
taining a small amount of 22, 13.16 g, 71% yield). IR
mKmBaxr cmÀ1: 2969, 1721, 1508, 1489, 1256, 1167, 1009, 855.
1H NMR (CDCl3) d: 0.84 (3H, d, J ¼ 7:2 Hz), 1.04 (3H,
d, J ¼ 7:2 Hz), 2.95 (1H, septet, J ¼ 7:2 Hz), 4.00 (6H,
s), 4.20 (2H, s), 7.11 (1H, s), 7.14 (1H, s), 7.43 (1H, dd,
J ¼ 8:4, 1.8 Hz), 7.70 (1H, d, J ¼ 8:4 Hz), 7.87 (1H, d,
J ¼ 1:8 Hz).
4.12. (1S)-1-(6,7-Dimethoxy-2-naphthyl)-1-(1H-imidazol-
4-yl)-2-methylpropan-1-ol fumarate [fumarate of 2]
To a solution of 2 (2.78 g, 8.5 mmol) in methanol
(10 mL) was added fumaric acid (1.00 g, 8.6 mmol). The
solvent was removed to about a half volume and the
residualmixture then diluted with AcOEt (10 mL). After
5 days, the crystals that had separated out of the solu-
tion were collected by filtration, washed with AcOEt,
and dried to give the fumarate of 2 (2.61 g). The enan-
tiomeric excess was determined to be >99.9% by HPLC
[Chiralcelꢂ OJ-R 0.46 · 15 cm column; CH3CN-10 mM
(pH 7) phosphate buffer (30:70) as an eluent; flow rate
0.5 mL/min]. Mp 117–120 ꢁC [lit.2 mp 116–120 ꢁC].
20
20
½a ¼ À34:4 (c 1.00, MeOH) {lit.2 ½a ¼ À35:3 (c 1.01,
D
D
KBr
max
MeOH)}. IR m
cmÀ1: 3669, 3279, 3125, 2965, 1698,
1
1512, 1262, 1208, 1165, 849, 646. H NMR (DMSO-d6)
d: 0.66 (3H, d, J ¼ 5:4 Hz), 0.84 (3H, d, J ¼ 5:4 Hz),
2.60–2.80 (1H, m), 3.86 (6H, s), 5.10–5.30 (1H, br), 6.61
(2H, s), 7.00 (1H, s), 7.20–7.22 (2H, m), 7.54 (1H, d,
J ¼ 8:8 Hz), 7.61 (1H, d, J ¼ 8:8 Hz), 7.67 (1H, s), 7.90
(1H, s). Anal. Calcd for C19H22N2O3ÆC4H4O4Æ0.5H2O:
C, 61.19; H, 6.03; N, 6.20. Found: C, 61.05; H, 6.00; N,
6.37.
4.11. (1S)-1-(6,7-Dimethoxy-2-naphthyl)-1-(1H-imidazol-
4-yl)-2-methylpropan-1-ol 2
To a mixture of 23 (4.19 g, 11.0 mmol) and 2,6-lutidine
(2.6 mL, 22.0 mmol) in THF (40 mL) was added tri-
methylsilyl trifluoromethanesulfonate (2.6 mL, 14.3