Stereocontrolled synthesis of (1S)-1-(1H-imidazol-4-yl)-1-(6-methoxy-2- naphthyl)-2-methylpropan-1-ol as a potent C17,20-lyase inhibitor

Article abstract of DOI:10.1016/j.tetasy.2004.02.035

An efficient stereocontrolled synthesis of the potent C_17,20- lyase inhibitor, (1S)-1-(1H-imidazol-4-yl)-1-(6-methoxy-2-naphthyl)-2-methyl-1- propanol 1, has been established. The stereogenic center of 1 was successfully constructed by a highly

Full text of DOI:10.1016/j.tetasy.2004.02.035

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 15 (2004) 1555–1559
Stereocontrolled synthesis of (1S)-1-(1H-imidazol-4-yl)-
1-(6-methoxy-2-naphthyl)-2-methylpropan-1-ol
as a potent C17;20-lyase inhibitor
Akio Ojida, Nobuyuki Matsunaga,* Tomohiro Kaku and Akihiro Tasaka
Medicinal Chemistry Research Laboratories, Pharmaceutical Research Division: Takeda Chemical Industries, Ltd,
17-85, Jusohonmachi 2-chome, Osaka, Yodogawa-ku 532-8686, Japan
Received 25 February 2004; accepted 25 March 2004
Available online 27 April 2004
Abstract—An efficient stereocontrolled synthesis of the potent C17;20-lyase inhibitor, (1S)-1-(1H-imidazol-4-yl)-1-(6-methoxy-2-
naphthyl)-2-methyl-1-propanol 1, has been established. The stereogenic center of 1 was successfully constructed by a highly dia-
stereoselective Grignard reaction of 2, while a subsequent imidazole ring annulation afforded 1 in an enantiomerically pure form.
The procedure enables a practical synthesis of 1 that can be conveniently carried out on a multigram scale.
Ó 2004 Elsevier Ltd. All rights reserved.
1. Introduction
Grignard alkylation of 2, while a subsequent imidazole
ring annulation would provide 1 in an enantiomerically
pure form (Fig. 1).
In our search for potential drugs for the treatment of
androgen-dependent prostate cancer, we have identified
(1S)-1-(1H-imidazol-4-yl)-1-(6-methoxy-2-naphthyl)-2-
O
OH
methyl-1-propanol 1 as a novel inhibitor of C17;20
-
N
O
lyase,1;2 a key enzyme involved in androgen biosynthe-
sis. Compound 1 showed potent enzyme inhibitory
activity for rat and human C17;20-lyase with IC50 values
of 21 and 28 nM, respectively, and markedly reduced the
serum testosterone concentration in animal models and
decreased the weights of androgen-dependent organs
such as prostate and seminal vesicles in rats.2 With the
identification of 1 as a potent C17;20-lyase inhibitor that
may serve as a therapeutically useful agent for prostate
cancer, an efficient stereocontrolled synthesis of 1 was
initiated. Several methods for the preparation of chiral
tertiary alcohols such as enantioselective Reformatsky
reactions,3 alkylzinc additions,4 and diastereoselective
Grignard reactions5;6 have been reported. We envisioned
that the stereogenic center of 1 bearing the two aromatic
rings could be constructed by a diastereoselective
O
NH
MeO
MeO
2
1
Figure 1.
2. Results and discussion
The synthetic approach that has been developed, sum-
marized in Scheme 1, starts from the optically active
ester 3, which is commercially available or can be readily
prepared from
D-mannitol in large quantities according
to the reported method.7 Ester 3 was converted into the
corresponding amide 4, which was treated with Grig-
nard reagent 5 prepared from 6-bromo-2-methoxy-
naphthalene, to give 2 without any loss of enantiomeric
excess (99% ee confirmed by HPLC analysis using a
Chiralcelâ OD-R).8 To set the benzylic stereocenter, a
Grignard reaction was investigated. Initially this process
was carried out using isopropylmagnesium bromide
according to the literature.5 Although treatment of 2
with isopropylmagnesium bromide gave the desired 7
(62%) as the major product, it also resulted in formation
* Corresponding author. Tel.: +81-6-6300-6706; fax: +81-6-6300-6306;
e-mail: matsunaga_nobuyuki@takeda.co.jp
Present address: Department of Chemistry and Biochemistry, Grad-
uate School of Engineering, Kyushu University, Fukuoka 812-8581,
Japan.
0957-4166/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2004.02.035

1556
A. Ojida et al. / Tetrahedron: Asymmetry 15 (2004) 1555–1559
MgBr
O
O
O
MeO
a
5
N
O
MeO
O
O
O
O
O
O
b
MeO
4
2
3
OH
OH
c
d
e
O
O
O
O
MeO
MeO
6
7
OH
OH
OH
O
f, g
h
OH
OTs
MeO
MeO
MeO
8
9
OH
OTMS
OTs
O
N
i
NH
MeO
10
1 (>99.5% ee)
O
OH
O
O
MeO
MeO
11
12
Scheme 1. Reagents and conditions: (a) morpholine, 90 °C, 71%; (b) 5, THF, ꢁ20 to 0 °C, 81%; (c) isopropenylmagnesium bromide, ꢁ10 to 0 °C,
THF; (d) H2, Pd/C, AcOEt, rt, 84%, two steps; (e) 1 M HCl, THF–EtOH, 60 °C, 93%; (f) TsCl, pyridine, CH2Cl2, rt; (g) DMSO, (COCl)2, Et3N,
CH2Cl2, ꢁ70 to ꢁ40 °C, 66%, two steps; (h) TMSCl, 2,6-lutidine, THF, rt; (i) formamidine acetate, saturated NH3–MeOH, rt, 73%, two steps.
of the corresponding diastereomer (6%) and alcohol 11
(20%). The formation of 11 was due to hydride transfer
from the Grignard reagent. During a survey of reaction
conditions and reagents, the best results were obtained
via a modified two-step procedure. Reaction of 2 with
RMgBr
Mg
O
O
H
O
MeO
2
isopropenylmagnesium bromide exclusively gave
6
(>99% de) without formation of the undesired diaste-
reomer and alcohol 11. After hydrogenation of 6, the
desired 7 was obtained in good yield (84% in two steps).
The absolute configuration of 7 was confirmed to be the
(1S,2R)-form by X-ray crystallographic analysis (Fig.
2). The diastereoselectivity observed above is consistent
with the prediction that the nucleophilic addition would
occur specifically under chelation control as shown in
Figure 3.
Figure 3.
The acid-catalyzed deprotection of 7 gave triol 8 in high
yield, which was selectively tosylated at the primary
hydroxyl group while subsequent Swern oxidation
afforded 9. Imidazole ring formation was carried out by
using 9 and formamidine acetate under the conditions
reported by Wong and Gluchowski9 (i.e., 45 °C in liquid
ammonia). However, this procedure gave only low
yields (ꢀ30%) of 1, with concomitant formation of
ketone 12 as a major product, which was presumably
formed via retro-benzoin condensation.10 We found that
the formation of 12 was effectively prevented by pro-
tection of the hydroxyl group of 9 with a trimethylsilyl
(TMS) group, and that imidazole ring annulation
occurred efficiently when saturated NH3–MeOH was
used as the solvent instead of liquid ammonia. Thus,
treatment of 9 with TMSOTf gave 10 quantitatively,
which without purification was reacted with formami-
dine in saturated NH3–MeOH to afford 1 in good yield
Figure 2. Crystal structure of 7.

A. Ojida et al. / Tetrahedron: Asymmetry 15 (2004) 1555–1559
1557
(73% from 9). The enantiomeric excess of 1 obtained by
this procedure was confirmed to be >99.5% ee by HPLC
tion of 5 in THF (250 mL), which was prepared from
2-bromo-6-methoxynaphthalene (80.2 g, 338 mmol) and
Mg (8.2 g, 338 mmol), while maintaining the tempera-
ture of the solution below ꢁ10 °C. After stirring for
20 min at ꢁ10 to 0 °C, the mixture was poured into 1 M
HCl. The organic phase was separated and the aqueous
phase extracted with AcOEt. The combined organic
layers were washed with brine, dried over MgSO4, and
concentrated in vacuo. The residue was dissolved in
AcOEt, and the insoluble material filtered off. The fil-
trate was concentrated, and the residue recrystallized
from diisopropyl ether to give 2 (65.3 g, 81%) as a col-
orless powder. The enantiomeric excess was determined
to be 99% by HPLC analysis using a Chiralcelâ OD-R:
analysis using a Chiralcelâ OD-R. Physical data of the
23
D
asymmetrically synthesized 1 {mp 178–180 °C, ½aꢂ
¼
ꢁ49:6 (c 0.5, MeOH)} were identical with those of the
chromatographically separated
1
{mp 179–181 °C,
23
D
½aꢂ ¼ ꢁ48:4 (c 0.5, MeOH)}.2
3. Conclusion
The stereocontrolled synthesis described above allows
the preparation of 1 in nine steps with 23% overall yield
from the commercially available ester 3, and is a prac-
tical and convenient procedure for the production of
multigram quantities of 1. Furthermore, the present
synthetic approach is adaptable and should enable the
preparation of a wide range of optically active analogues
of 1 for biological evaluation.
25
1
mp 116–117 °C; ½aꢂ ¼ ꢁ14:9 (c 1.0, MeOH); H NMR
D
(CDCl3) d: 1.46 (3H, s), 1.51 (3H, s), 3.95 (3H, s), 4.28–
4.43 (2H, m), 5.40 (1H, dd, J ¼ 6:2, 7.0 Hz), 7.14–7.26
(2H, m), 7.77 (1H, d, J ¼ 8:8 Hz), 7.86 (1H, d,
J ¼ 8:8 Hz), 8. 02 (1H, dd, J ¼ 1:7, 8.7 Hz), 8.48 (1H, s);
IR (KBr): 1690, 1624, 1277, 1246, 1061, 1013, 897, 835,
822 cmꢁ1. Anal. Calcd for C17H18O4: C, 71.31; H, 6.34.
Found: C, 71.38; H, 6.25.
4. Experimental
4.4. (1S)-1-[(4R)-2,2-Dimethyl-1,3-dioxolan-4-yl]-1-(6-
methoxy-2-naphthyl)-2-methyl-2-propen-1-ol 6
4.1. General methods
To a cooled (ꢁ20 °C) solution of 2 (75.0 g, 262 mmol) in
anhydrous THF (400 mL) was added dropwise a solu-
tion of isopropenylmagnesium bromide, which was
prepared from 2-bromopropene (41.9 g, 472 mmol) and
Mg (11.5 g, 472 mmol), while maintaining the tempera-
ture of the reaction mixture below ꢁ10 °C. The mixture
was stirred for a further 20 min at ꢁ10 to 0 °C and then
diluted with saturated NH4Cl, after which the organic
phase was separated, and the aqueous phase extracted
with AcOEt. The combined organic layers were washed
with brine, dried over MgSO4, and concentrated
in vacuo to give 6 as a pale yellow solid, which was used
in the next reaction without further purification. An
analytical sample was obtained by recrystallization from
All commercially available substrates and reagents were
used without purification. The melting points are
uncorrected. The H NMR chemical shifts (d) are re-
1
ported in parts per million (ppm) with tetramethylsilane
as an internal standard. Analytical thin-layer chroma-
tography (TLC) was performed with silica gel 60 F254 (E.
Merck). Chromatographic separations were carried out
on silica gel 60 (E. Merck, 70–230 mesh) and flash
chromatography carried out on silica gel 60 (E. Merck,
230–400 mesh). HPLC analysis was performed using the
following conditions: Chiralcelâ OD-R (250 ꢃ 4.6 mm),
mobile phase CH3CN/pH 7.0 phosphate buffer (45:55),
flow rate 0.5 mL/min, detection, UV (254 nm).
AcOEt–hexane (colorless prisms): mp 133–134 °C;
23
½aꢂ ¼ þ107:5 (c 1.0, MeOH); 1H NMR (CDCl3) d: 1.44
D
4.2. 4-{[(4R)-2,2-Dimethyl-1,3-dioxolan-4-yl]carbonyl}-
morpholine 4
(3H, s), 1.50 (3H, s), 1,62 (3H, s), 2.80 (1H, br s), 3.46
(1H, dd, J ¼ 6:6, 8.2 Hz), 3.73 (1H, dd, J ¼ 8:3, 8.2 Hz),
3.91 (3H, s), 4.89 (1H, dd, J ¼ 6:6, 8.2 Hz), 5.12 (1H, s),
5.40 (1H, s), 7.13–7.18 (2H, s), 7.43 (1H, dd, J ¼ 1:8,
8.6 Hz), 7.67–7.76 (2H, m), 7.87 (1H, s); IR (KBr): 3557,
A mixture of 36 (64.5 g, 400 mmol) and morpholine
(70 mL, 800 mmol) was heated at 90 °C for 16 h with
stirring. After concentration in vacuo, the residue was
purified by silica gel column chromatography (hexane–
2994, 2948, 1267, 1209, 1161, 1032, 897, 855, 812 cmꢁ1
.
Anal. Calcd for C20H24O4: C, 73.15; H, 7.37. Found: C,
73.30; H, 7.21.
AcOEt ¼ 4:1 to 1:1) to give 4 (60.8 g, 71%) as a pale
25
D
yellow oil: ½aꢂ ¼ ꢁ17:0 (c 1.8, MeOH); 1H NMR
(CDCl3) d: 1.40 (6H, s), 3.47–3.86 (8H, m), 4.13 (1H, dd,
J ¼ 6:8, 8.4 Hz), 4.48 (1H, dd, J ¼ 6:0, 8.6 Hz), 4.65
(1H, dd, J ¼ 6:0, 6.8 Hz); IR (KBr): 2986, 2859, 1651,
4.5. (1S)-1-[(4R)-2,2-Dimethyl-1,3-dioxolan-4-yl]-1-(6-
methoxy-2-naphthyl)-2-methylpropan-1-ol 7
1443, 1372, 1238, 1221, 1115, 1069, 847 cmꢁ1
.
A solution of 6 and 10% Pd–C (10 g) in AcOEt (400 mL)
was vigorously stirred for 24 h at room temperature
under an H2 atmosphere (1 atm). The resulting mixture
was filtered and concentrated in vacuo, the residue
passed through a silica gel plug (elution with hexane–
AcOEt ¼ 3:1), and the eluate concentrated to give a pale
yellow solid. The solid was recrystallized from hexane to
4.3. [(4R)-2,2-Dimethyl-1,3-dioxolan-4-yl](6-methoxy-2-
naphthyl)methanone 2
To a cooled (ꢁ20 °C) solution of 4 (60.8 g, 282 mmol) in
anhydrous THF (200 mL) was added dropwise a solu-

1558
A. Ojida et al. / Tetrahedron: Asymmetry 15 (2004) 1555–1559
afford 7 (64.8 g, 75%) as colorless needles. The mother
liquor was concentrated and the residue recrystallized
from hexane to give an additional quantity of 7 (7.67 g,
(47.6 mL, 588 mmol) and p-toluenesulfonyl chloride
(41.2 g, 216 mmol). After stirring for 12 h at room tem-
perature, the reaction mixture was successively washed
with 1 M HCl (ꢃ2), and saturated NaHCO3 followed by
drying over MgSO4. The solution was concentrated in
vacuo to give the tosylate as a pale yellow viscous oil,
which was used for the next reaction without further
purification.
25
9%) as colorless needles: mp 105–106 °C; ½aꢂ ¼ þ46:3
D
(c 1.0, MeOH); 1H NMR (CDCl3) d: 0.84 (3H, d,
J ¼ 6:8 Hz), 0.95 (3H, d, J ¼ 6:8 Hz), 1.44 (3H, s), 1.46
(3H, s), 2.11–2.28 (1H, m), 2.43 (1H, br s), 3.44–3.59
(2H, m), 3.91 (3H, s), 4.78 (1H, dd, J ¼ 6:5, 8.1 Hz),
7.13–7.18 (2H, m), 7.43 (1H, dd, J ¼ 1:8, 8.6 Hz), 7.67–
7.80 (3H, m); IR (KBr): 3548, 2984, 1607, 1466, 1381,
1368, 1265, 1221, 1177, 1067, 1038, 849 cmꢁ1. Anal.
Calcd for C20H26O4: C, 72.70; H, 7.93. Found: C, 72.69;
H, 7.83.
To a cooled (ꢁ70 °C) solution of oxalyl chloride
(34.2 mL, 392 mmol) in anhydrous CH2Cl2 (250 mL)
was added dropwise a solution of DMSO (55.6 mL,
784 mmol) in anhydrous CH2Cl2 (50 mL). After stirring
for 5 min, a solution of the tosylate in anhydrous
CH2Cl2 (200 mL) was added dropwise over 1 h, and the
reaction mixture stirred for 30 min at ꢁ50 to ꢁ40 °C.
After cooling to ꢁ70 °C, triethylamine (200 mL) was
added dropwise over 30 min, and the mixture then
allowed to warm to room temperature. The result-
ing mixture was diluted with water and extracted
with CH2Cl2 (ꢃ2). The combined organic layers were
washed with water and dried over MgSO4. After
removal of the solvent, the obtained solid was filtered
and washed with AcOEt. The filtrate was concentrated
and the residue passed through a silica gel plug (eluting
with CH2Cl2) after which the eluant was concentrated to
give a brown solid. The solids were combined and
recrystallized from AcOEt to give 9 (47.4 g, 55%) as a
colorless powder. The mother liquor was concentrated
and the residue purified by column chromatography on
silica gel (hexane–AcOEt ¼ 4:1) followed by recrystalli-
zation from AcOEt to give an additional amount of 9
4.6. Single-crystal X-ray analysis of 7
An analytical sample of 7 for X-ray analysis was ob-
tained by recrystallization from diisopropyl ether. X-ray
measurement was preformed on a Rigaku AFC5R dif-
fractometer with Cu-Ka radiation. Crystal data for 7:
C20H26O4, M ¼ 330:42, monoclinic, space group C2
ꢀ
ꢀ
ꢀ
(#5), a ¼ 20:478ð4Þ A, b ¼ 5:878ð4Þ A, c ¼ 15:359ð3Þ A,
b ¼ 92:76ð2Þ°, V ¼ 1846ð1Þ A , Dcalcd ¼ 1:188 g cmꢁ3
,
3
ꢀ
Z ¼ 4; final R-values were R1 ¼ 0:040 for 2337 reflec-
tions with Fo > 4r (Fo), wR2 ¼ 0:113 for all the 2759
reflections. The absolute configuration was supported
by the Flack parameter11 of ꢁ0.03(29). Further details
of the X-ray structure data are available on request from
the Cambridge Crystallographic Data Centre (deposi-
tion number CCDC 231491).
(9.43 g, 11%) as a colorless powder: mp 155–156 °C;
23
4.7. (2R,3S)-3-(6-Methoxy-2-naphthyl)-4-methylpentane-
1,2,3-triol 8
½aꢂ ¼ ꢁ125:3 (c 0.5, MeOH); 1H NMR (CDCl3) d: 0.72
D
(3H, d, J ¼ 6:8 Hz), 0.94 (3H, d, J ¼ 6:8 Hz), 2.34 (3H,
s), 2.78–2.92 (1H, m), 3.05 (1H, s), 3.93 (3H, s), 5.00
(2H, s), 7.10–7.21 (4H, m), 7.39 (1H, dd, J ¼ 1:9,
8.7 Hz), 7.62 (2H, d, J ¼ 8:2 Hz), 7.71 (2H, d,
J ¼ 8:6 Hz), 7.83 (1H, s); IR (KBr): 3555, 1736, 1406,
1362, 1260, 1190, 1175, 1034, 1017, 845, 814 cmꢁ1. Anal.
Calcd for C24H26O6S: C, 65.14; H, 5.92. Found: C,
65.02; H, 5.83.
A solution of 7 (72.0 g, 218 mmol) in 1 M HCl–THF–
EtOH (1:1:2, 480 mL) was heated at 60 °C for 2 h. After
removal of the solvent, the residue was diluted with
water, and the mixture extracted with AcOEt (ꢃ2). The
combined organic layers were washed with saturated
NaHCO3 and brine, followed by drying over MgSO4.
After removal of the solvent, the residue was recrystal-
lized from hexane–AcOEt (4:1) to give 8 (54.8 g, 87%) as
a colorless powder. The mother liquor was concentrated
and the residue recrystallized from diisopropyl ether to
4.9. (3S)-3-(6-Methoxy-2-naphthyl)-4-methyl-2-oxo-3-
[(trimethylsilyl)oxy]pentyl p-toluenesulfonate 10
give an additional quantity of 8 (3.98 g, 6%) as a col-
23
D
orless powder: mp 131–132 °C; ½aꢂ ¼ þ15:6 (c 1.0,
1
MeOH); H NMR (CDCl3) d: 0.78 (3H, d, J ¼ 6:8 Hz),
To a cooled (0 °C) solution of 9 (40.0 g, 90.4 mmol) and
2,6-lutidine (21.1 mL, 118 mmol) in anhydrous THF
(400 mL) was added dropwise trimethylsilyl trifluoro-
methanesulfonate (21.4 mL, 118 mmol) and the mixture
stirred for 30 min at 0 °C. After stirring for 3 h at room
temperature, the reaction was quenched with water and
the resulting mixture diluted with 1 M HCl, and
extracted with AcOEt (ꢃ2). The combined organic lay-
ers were successively washed with water, saturated
NaHCO3, and brine, followed by drying over MgSO4.
The solvent was removed in vacuo to give 10 as a pale
yellow solid, and this material was used for the next
reaction without further purification: 1H NMR (CDCl3)
d: 0.14 (9H, s), 0.89 (3H, d, J ¼ 6:8 Hz), 0.93 (3H, d,
J ¼ 6:8 Hz), 2.36 (3H, s), 2.76–2.89 (1H, m), 3.93 (3H,
0.93 (3H, d, J ¼ 6:8 Hz), 2.33–2.47 (1H, m), 3.09 (3H, br
s), 3.53 (2H, d, J ¼ 4:2 Hz), 3.92 (3H, s), 4.32 (1H, dd,
J ¼ 4:2, 4.2 Hz), 7.12–7.18 (2H, m), 7.36 (1H, dd,
J ¼ 8:7, 1.7 Hz), 7.66–7.79 (3H, m); IR (KBr): 3537,
3428, 2973, 2959, 1605, 1391, 1265, 1223, 1165, 1030,
883, 855 cmꢁ1. Anal. Calcd for C17H22O4: C, 70.32; H,
7.64. Found: C, 70.43; H, 7.51.
4.8. (3S)-3-Hydroxy-3-(6-methoxy-2-naphthyl)-4-methyl-
2-oxopentyl p-toluenesulfonate 9
To a cooled (0 °C) solution of 8 (57.0 g, 196 mmol) in
anhydrous CH2Cl2 (350 mL) were added pyridine

A. Ojida et al. / Tetrahedron: Asymmetry 15 (2004) 1555–1559
1559
s), 5.07 (2H, s), 7.11–7.20 (4H, m), 7.31 (1H, dd, J ¼ 1:9,
8.1 Hz), 7.64–7.71 (5H, m); IR (KBr): 1736, 1375, 1366,
1208, 1182, 1011, 851 cmꢁ1
Acknowledgements
.
We thank Drs. A. Miyake and T. Naka for helpful
discussions throughout this work and Mr. A. Fujishima
and Ms. K. Higashikawa for single-crystal X-ray anal-
ysis.
4.10. (1S)-1-(1H-Imidazol-4-yl)-1-(6-methoxy-2-naphth-
yl)-2-methylpropan-1-ol 1
References and notes
In a round bottomed flask, 10 and formamidine acetate
(14.2 g, 136 mmol) was dissolved in anhydrous THF
(40 mL), after which freshly prepared saturated NH3–
MeOH solution (200 mL) was added, and the reaction
mixture stirred for 60 h at room temperature. After
removal of the solvent, the residue was diluted with
water and extracted with AcOEt (ꢃ2) and the combined
organic layers washed with brine, dried over MgSO4
then concentrated in vacuo. The residue was purified by
1. Matsunaga, N.; Kaku, T; Itoh, F.; Tanaka, T.; Hara, T.;
Miki, H.; Iwasaki, M.; Aono, T.; Yamaoka, M.; Kusaka,
M.; Tasaka, A. Bioorg. Med. Chem. 2004, 12, 2251.
2. Matsunaga, N.; Kaku, T; Ojida, A; Tanaka, T.; Hara, T.;
Yamaoka, M.; Kusaka, M.; Tasaka, A. Bioorg. Med.
Chem. (in press).
3. (a) Ojida, A.; Yamano, T.; Taya, N.; Tasaka, A. Org. Lett.
2002, 4, 3051; (b) Soai, K.; Oshio, A.; Saito, T. J. Chem.
Soc., Chem. Commun. 1993, 811.
ꢁ
4. (a) Garcıa, C.; LaRochelle, L. K.; Walsh, P. J. J. Am.
Chem. Soc. 2002, 124, 10970; (b) Yus, M.; Ramon, D. J.;
silica
gel
column
chromatography
(CH2Cl2–
ꢁ
MeOH ¼ 20:1 to 10:1) to give a brown viscous oil which
was crystallized from AcOEt to give 1 (17.2 g, 64%) as a
pale yellow powder. The mother liquor was concen-
trated and the residue was purified by column silica gel
chromatography followed by recrystallization from
AcOEt to give an additional amount of 1 (2.52 g, 9%) as
a pale yellow powder. The enantiomeric excess of 1 was
Prieto, O. Tetrahedron: Asymmetry 2002, 13, 2291; (c)
Dosa, P. I.; Fu, G. C. J. Am. Chem. Soc. 1998, 120, 445.
ꢁ
5. Meric, R.; Vigneron, J.-P. Bull. Soc. Chim. Fr. 1973, 327.
6. Still, W. C.; McDonald, J. H., III. Tetrahedron Lett. 1980,
21, 1031.
7. (a) Chittenden, G. J. Carbohydr. Res. 1980, 84, 350; (b)
Schmid, C. R.; Bryant, J. D. Org. Synth. 1995, 72, 6; (c)
Lichtenthaler, F. W.; Jarglis, P.; Lorenz, K. Synthesis
1988, 790.
8. Tasaka, A.; Tamura, N.; Matsushita, Y.; Teranishi, K.;
Hayashi, R.; Okonogi, K.; Itoh, K. Chem. Pharm. Bull.
1993, 41, 1035.
9. (a) Wong, W. C.; Gluchowski, C. Synthesis 1995, 139; (b)
Grimmett, M. R. Imidazole and Benzimidazole Synthesis;
Academic, 1997.
>99.5% as determined by HPLC using a Chiralcelâ
23
OD-R: mp 178–180 °C; ½aꢂ ¼ ꢁ49:6 (c 0.5, MeOH);
D
1H NMR (CDCl3 þ CD3OD) d: 0.81 (3H, d,
J ¼ 6:8 Hz) 1.00 (3H, d, J ¼ 6:8 Hz), 2.78–2.64 (1H, m),
3.91 (3H, s), 7.00 (1H, d, J ¼ 1:0 Hz), 7.15–7.09 (2H, m),
7.56–7.51 (2H, m), 7.75–7.65 (2H, m), 7.91 (1H, d,
J ¼ 1:4 Hz); IR (KBr): 3140, 2984, 2957, 1464, 1222,
1028, 856, 806, 652 cmꢁ1. Anal. Calcd for C18H20N2O2:
C, 72.95; H, 6.80; N, 9.45. Found: C, 72.77; H, 6.79; N,
9.31.
10. Miyashita, A.; Suzuki, Y.; Okumura, Y.; Iwamoto, K.;
Higashino, T. Chem. Pharm. Bull. 1998, 46, 6.
11. Flack, H. D. Acta Cryst. 1983, A39, 876.