A scalable synthesis of (R)-3-(2-aminopropyl)-7-benzyloxyindole via resolution

Article abstract of DOI:10.1016/S0957-4166(02)00004-6

(±)-3-(2-Aminopropyl)-7-benzyloxyindole 1, assembled from 7-benzyloxyindole 3 in 59% overall yield, is resolved with O,O′-di-p-toluoyl L-(2R,3R)-tartaric acid 7 into (R)-1, a key intermediate of AJ-9677 2 (selective adrenaline β₃-agonist) in 99

Full text of DOI:10.1016/S0957-4166(02)00004-6

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 12 (2001) 3235–3240
A scalable synthesis of (R)-3-(2-aminopropyl)-7-benzyloxyindole
via resolution
Akihito Fujii,a Yoshito Fujima,b Hiroshi Harada,a Masaya Ikunaka,b,* Toru Inoue,b Shiro Katoa
and Keisuke Matsuyamab
aChemistry Research Laboratories, Drug Research Division, Dainippon Pharmaceutical Co., Ltd., Enoki, 33-94, Suita,
Osaka 564-0053, Japan
bThe 1st Laboratories, Research & Development Center, Nagase & Co., Ltd., 2-2-3 Murotani, Nishi-ku, Kobe 651-2241, Japan
Received 17 October 2001; accepted 28 December 2001
Abstract—( )-3-(2-Aminopropyl)-7-benzyloxyindole 1, assembled from 7-benzyloxyindole 3 in 59% overall yield, is resolved with
O,O%-di-p-toluoyl -(2R,3R)-tartaric acid 7 into (R)-1, a key intermediate of AJ-9677 2 (selective adrenaline b3-agonist) in 99.5%
L
e.e. and 36% overall yield. The unwanted enantiomer (S)-1 (61.9% e.e.; recovered in 57% yield from the crystallization filtrate) can
be reused in another round of resolution after its enantiomeric purity is lowered to 3.7% by Raney Co treatment under a hydrogen
atmosphere. © 2002 Elsevier Science Ltd. All rights reserved.
1. Introduction
into (R)-1 via diastereomeric salt formation and mak-
ing the resolution process enantioconvergent by devel-
oping the method to recycle the unwanted enantiomer
(S)-1.
(R)-3-(2-Aminopropyl)-7-benzyloxyindole 1 is a key
chiral intermediate of AJ-9677 2,1 which, being a potent
and selective adrenaline b3-agonist, has been nominated
as a clinical candidate to treat obesity in those who are
suffering from diabetes (Fig. 1).2 In the stage of drug
discovery, (R)-1 was assembled enantioselectively by
the chiral pool method.1 However, this was plagued
with the following drawbacks from the practical per-
2. Results and discussion
2.1. Preparation of ( )-3-(2-Aminopropyl)-7-benzyloxy-
indole 1
spective: (1) relatively expensive N-Fmoc D-alanyl chlo-
ride, an unnatural a-amino acid derivative, was
employed as a chiral source; (2) cryogenic conditions
The starting point of our synthesis was 7-benzyloxyin-
dole 3, because it could be prepared either from 2-nitro-
phenol by Bartoli’s method3 or from 3-hydroxy-2-
nitrotoluene by Leimgruber-Batcho’s method.4 Vilsmeir
reaction (POCl3, DMF) of 3 gave indole-3-carboxalde-
hyde 4 in 99% yield,5 which on nitroaldol reaction
(EtNO2, AcONa, PhMe) provided nitroolefin 5 in 95%
yield (Scheme 1).
had to be applied to append the N-Fmoc
D-alanyl
group to the 3 position of 7-benzyloxyindole; (3) the
acylation proceeded with a reasonably high yield and
regioselectivity only in ethyl ether, a solvent of which
industrial use is limited due to its high flammability.
Hence, we explored more practical and easily scalable
processes for (R)-1, and succeeded in resolving ( )-1
OH
H
N
NH2
Me
Me
O
N
H
PhH2CO
N
H
O
Cl
OH
(R)-1
2
Figure 1. Structures of (R)-3-(2-aminopropyl)-7-benzyloxyindole 1 and AJ-9677 2.
* Corresponding author. Tel.: +81 78 992 3163; fax: +81 78 992 1050; e-mail: masaya.ikunaka@nagase.co.jp
0957-4166/01/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(02)00004-6

3236
A. Fujii et al. / Tetrahedron: Asymmetry 12 (2001) 3235–3240
CHO
a
b
PhH2CO
PhH2CO
N
H
N
H
3
4
NO2
Me
c
NO2
Me
PhH2CO
PhH2CO
N
H
N
H
6
5
d
NH2
Me
PhH2CO
N
H
(±)-1
Scheme 1. Preparation of ( )-3-(2-aminopropyl)-7-benzyloxyindole 1. Reagents and conditions: (a) POCl3, DMF, 99%; (b) EtNO2,
AcONH4, PhMe, 95%; (c) NaBH4, THF/MeOH (4:1), 79%; (d) H2 (1 atm), Raney Ni, PhMe, 50°C, 79%.
Conjugated nitroolefins such as 5 were reported to be
reduced by LiAlH4 directly to saturated primary
amines.5 However, from a practical viewpoint, the
LiAlH4-mediated reduction posed the following con-
cerns: (1) LiAlH4 is a rather expensive reagent; (2) it is
pyrophoric in its nature; (3) voluminous Al salts gener-
ated from the aqueous work-up make the product
isolation a tedious process; and (4) the Al salt disposal
entails considerable cost. Thus, we investigated syn-
thetic processes that could dispense with LiAlH4, and
eventually developed a two-step reduction protocol
comprising: (1) 1,4-hydride addition to the olefinic
bond in 5; and (2) hydrogenation of the nitro group in
6 to a primary amine function.
maximize both the yield and enantiomeric purity of the
resolved (R)-1. Under the optimized conditions, ( )-1
(1.0 equiv) was combined with 7 (0.5 equiv) in MeOH/
H2O (4:1), and the diastereomeric salt 8 was allowed to
crystallize preferentially in 41% yield based on the
whole amount of ( )-1. The (R)-configuration of the
Me
O
CO2H
O
O
HO2C
O
Me
7
When 5 was treated with NaBH4 in THF-MeOH,6 the
expected 1,4-reduction proceeded uneventfully provid-
ing 6 in 79% yield. It was then subjected to Raney
Ni-catalyzed hydrogenation to give ( )-1 in 79% yield
(4-step overall yield of 59% from 3), with its O-benzyl
group surviving the hydrogenolysis.
H
N
Me
OCH2Ph
Me
+H3N
-
CO2
2.2. Resolution of ( )-1
O
O
O
O
-O2C
+
With ample quantities of ( )-1 in hand, we explored a
commercially available library of optically active acids
for an agent that could resolve ( )-1 into (R)-1, which
NH3
Me
led to identification of O,O%-di-p-toluoyl L-(2R,3R)-tar-
PhH2CO
N
H
Me
taric acid 7 as the resolving agent of choice (Fig. 2).
8
Experimental parameters affecting the resolution
efficiency (a ratio of 7 to ( )-1, solvent species, solvent
volume, temperature, annealing, etc.) were examined to
Figure 2. Structures of O,O%-di-p-toluoyl
acid 7 and its diastereomeric salt 8.
L-(2R,3R)-tartaric

A. Fujii et al. / Tetrahedron: Asymmetry 12 (2001) 3235–3240
3237
amine contained in the salt was confirmed and its
3. Conclusion
enantiomeric purity was determined to be 94% by chi-
ral HPLC analysis on CHIRALPACK AD column
(Daicel) which employed the authentic (R)-1 assem-
Scalable processes for (R)-1, a key synthetic intermedi-
ate of AJ-9677 2, have been developed successfully
bled from N-Fmoc
D
-alanyl chloride1 as a reference
employing
resolution
of
the
racemate
via
compound. Single recrystallization from MeOH/H2O
(4:1) provided the purified salt 8 in 91% yield, which
contained (R)-1 of 99.5% e.e. as determined by the
chiral HPLC analysis. Finally, the recrystallized salt 8
was treated with aqueous NaOH solution to liberate
(R)-1 of 99.5% e.e. in 97% yield (36% overall yield
based on the whole amount of ( )-1) (Scheme 2).
diastereomeric salt formation. The features worth
mentioning are itemized as follows: (1) ( )-1 can be
prepared from 3 in four steps and 59% overall yield
without recourse to expensive intractable reagents and
chromatographic purification; (2) ( )-1 can be resolved
by O,O%-di-p-toluoyl
L
-(2R,3R)-tartaric acid 7 into
(R)-1 of 99.5% e.e. in 36% overall yield based on the
whole amount of ( )-1 after single recrystallization of
the diastereomeric salt 8; (3) (S)-1 of 61.9% e.e.
(recovered in 57% yield from the crystallization
filtrate) can be recycled for another round of resolu-
tion after it is treated with Raney Co catalyst and
hydrogen to lower the enantiomeric purity to 3.7%
and combined with (R)-1 of 45.1% e.e. (recovered in
4.4% yield from the recrystallization filtrate).
2.3. Racemization of the off-enantiomer (S)-1
For the above-discussed resolution process to be
industrially viable, the off-enantiomer (S)-1 needed to
be recouped and racemized for another round of reso-
lution, because preparation of ( )-1 was highly
demanding, whether Bartoli’s3 or Leimgruber–Batcho’s
method4 was employed.
Hence, racemization was attempted with (S)-1 that
was recovered in 62% e.e. and 57% yield from the
crystallization filtrate (Scheme 2). When a PhMe solu-
tion of (S)-1 was heated up to 135°C in the presence
of Raney Co under a hydrogen atmosphere at an
initial pressure of 2 kg/cm,7 racemization took place.
After the reaction time was prolonged to 25 h, the
enantiomeric purity of (S)-1 was lowered to 3.7%
(70% yield).
4. Experimental
4.1. General
Melting points were measured on an Electrothermal
1A8104 melting point apparatus and uncorrected. H
1
NMR spectra were recorded at 400 MHz on a Varian
UNITY-400 spectrometer in a CDCl3 solution with
tetramethylsilane as an internal standard. FT-IR spec-
tra were recorded on a Perkin-Elmer 1600 spectrome-
ter. Mass spectra were recorded on a Hitachi M-8000
spectrometer (ESI). Elemental analyses were per-
formed on an Elementar Vario EL analyzer. Optical
rotations were measured on a Horiba SEPA-200
polarimeter.
As far as this particular incomplete racemization is
concerned, no serious problem arises, because ( )-1
could be easily reconstituted by blending the (S)-1 of
3.7% e.e. (obtained in 40% overall yield from ( )-1)
with the (R)-1 of 45.1% e.e. (obtained in 4.4% yield
from the recrystallization filtrate) (Scheme 2).
(±)-1 (1.0 equiv)
Crystallization 7 (0.5 equiv)
Crystals
Filtrate
NaOH aq
8 (41%)
[(R)-1 of 94% e.e.]
(S)-1 of 62% e.e.
Recrystallization
Crystals
(57%)
Filtrate
H2 (2 kg/cm2)
8 (91%)
[(R)-1 of 99.5% e.e.]
NaOH aq
Raney Co
PhMe, 135°C
(70%)
(S)-1 of 45% e.e.
[4.4%% from (±)-1]
NaOH aq
(R)-1 of 99.5% e.e.
[36% from (±)-1]
(S)-1 of 3.7% e.e.
[40% from (±)-1]
Scheme 2. Resolution of ( )-1 and lowering the enantiomeric purity of (S)-1.

3238
A. Fujii et al. / Tetrahedron: Asymmetry 12 (2001) 3235–3240
4.2. 7-Benzyloxyindole-3-carboxaldehyde 4
maintaining the temperature between 39 and 40°C. The
mixture was stirred at the same temperature range for 1
h, it was neutralized by adding AcOH (3.5 g), and
concentrated in vacuo. The residue was dissolved in
PhMe (100 mL) and the solution was washed with H2O
(1×40 mL, 2×20 mL), dried (Na2SO4), and concentrated
in vacuo to give a viscous oil (16.7 g). MeOH (30 mL)
was added and the mixture was heated to 58–60°C
wherein it became homogeneous. To the solution was
added activated charcoal, and the mixture was filtered
while it was hot. The decolorized filtrate was ice-cooled,
and kept between 0 and 5°C for 1 h. The precipitated
solids were collected by filtration, washed with a mini-
mum volume of MeOH, and concentrated in vacuo to
give 6 (12.3 g, 79%): mp 88.1–90.1°C; IR n (KBr) 3431
(v.s), 3028 (s), 2902 (m), 2856 (m), 1578 (m), 1543 (v.s),
1500 (s), 1443 (s), 1261 (s), 1090 (s), 1055 (s), 779 (s),
To a stirred and ice-cooled DMF (73.1 g) was added
dropwise POCl3 (34.5 g, 0.22 mol) between 1 and 5°C
over 50 min. The mixture was stirred at the same
temperature range for 30 min and a solution of 3 (44.7
g, 0.20 mol) in DMF (50.0 mL) was added dropwise
between 3 and 8°C over 50 min. The reaction mixture
was gradually warmed to 35°C and stirring was contin-
ued at the same temperature for 60 min. To the reac-
tion mixture was added ice (75 g) such that the inner
temperature did not exceed 50°C. The mixture was
ice-cooled to 35°C and poured into a mixture of water
(25 g) and ice (50 g). To the mixture was added 32%
(w/w) NaOH aq. solution (93.7 g, 0.74 mol) dropwise
between 20 and 34°C. Further 32% (w/w) NaOH aq.
solution (187.3 g, 1.37 mol) was added dropwise
between 34 and 47°C and the stirred mixture was
heated to gentle reflux at 95°C. The mixture was
allowed to cool to 40°C and to 0–5°C by ice-cooling.
Stirring was continued with ice-cooling for 1 h and the
precipitated solids were collected by filtration, and sus-
pended in H2O (500 mL). The mixture was stirred at
ambient temperature for 3 h. The solids were filtered
off, washed with H2O (3×75 mL), and air-dried at 50°C
(oven temperature) to give 4 (49.9 g, 99%): mp 156.3–
157.3°C; IR n (KBr) 3120 (m), 3059 (m), 3028 (m), 2877
(m), 1635 (s), 1620 (v.s), 1403 (m), 1263 (m), 1232 (s),
1
737 (s) cm−1; H NMR d 1.54 (3H, d, J=6.8 Hz), 3.16
(1H, ddd, J=0.4, 6.8, 14.6 Hz), 3.45 (1H, ddd, J=0.4,
6.8, 14.6 Hz), 4.86 (1H, sextet, J=6.8 Hz), 5.16 (2H, s),
6.72 (1H, d, J=8.0 Hz), 6.95 (1H, d, J=2.4 Hz), 7.04
(1H, dd, J=8.0, 8.0 Hz), 7.18 (1H, d, J=8.0 Hz),
7.33–7.43 (3H, m), 7.43–7.48 (2H, m), 8.30 (1H, m); MS
m/z 311 {[M+H]+}.
4.5. ( )-3-(2-Aminopropyl)-7-benzyloxyindole 1
To a solution of 6 (3.10 g, 10.0 mmol) in PhMe (50 mL)
was added Raney Ni (NDHT-95, Kawaken Fine Chem-
icals Co., Ltd.; about 1.0 mL; washed with MeOH
followed by PhMe prior to use). The mixture was
stirred under H2 (atmospheric pressure) with heating
between 49 and 50°C for 13 h. The mixture was allowed
to cool to ambient temperature and the catalyst was
filtered off and washed with warmed PhMe. The com-
bined filtrate and washings were concentrated in vacuo
to give a syrupy residue (2.54 g), which was allowed to
crystallize after the addition of AcOEt (5.0 mL). The
precipitated solids were collected by filtration, washed
with AcOEt, and dried in vacuo to give ( )-1 (2.22 g) in
79.3% yield: mp 129.2–130.5°C; IR n (KBr) 3361 (m),
3303 (w), 3062 (m), 2951 (m), 2879 (m), 2867 (m), 1575
(m), 1464 (m), 1375 (m), 1621 (m), 1238 (s), 1020 (s),
1
1188 (m), 1128 (s), 783 (m) cm−1; H NMR d 5.26 (2H,
s), 6.93 (1H, d, J=7.6 Hz), 7.16 (1H, t, J=7.6 Hz),
7.34–7.42 (3H, m), 7.53–7.56 (2H, m), 7.83 (1H, d,
J=7.6 Hz), 8.12 (1H, s), 10.04 (1H, s), 11.46 (1H, s);
MS m/z 250 {[M-H]-}.
4.3. 7-Benzyloxy-3-(2-nitro-1-propenyl)indole 5
A stirred mixture of 4 (22.6 g, 90.0 mmol), EtNO2 (20.3
g, 270 mmol), AcONH4 (3.47 g, 45.0 mmol), and PhMe
(100 mL) was heated to 93–105°C and the mixture was
heated under reflux for 3 h to remove the generated
water azeotropically, during which time it became
homogeneous as the inner temperature reached 80°C.
The stirred mixture was allowed to cool to ambient
temperature, and crystallization was initiated. The mix-
ture was ice-cooled, and it was kept between 0 and 5°C
for 2 h. The precipitated solids were collected by filtra-
tion, washed with MeOH (2×20 mL), and dried in
vacuo to give 5 (25.2 g, 91%). A further amount of 5
(1.16 g) was obtained in 4% yield from the combined
filtrate and washings; a total yield of 5: 26.36 g (95%);
mp 147.6–148.5°C; IR n (KBr) 3410 (m), 3394 (m),
3277 (m), 2850 (w), 1625 (m), 1581 (m), 1475 (m), 1433
(m), 1308 (s), 1277 (s), 1228 (v.s), 1120 (m), 1093 (s),
1
891 (m), 806 (m), 733 (m), 712 (m), 692 (m) cm−1; H
NMR d 1.14 (3H, d, J=6.8 Hz), 1.36 (2H, br.s), 2.60
(1H, ddd, J=0.8, 6.8, 14.2 Hz), 2.83 (1H, ddd, J=0.8,
4.8, 14.2 Hz), 5.16 (2H, s), 6.70 (1H, d, J=7.8 Hz), 6.94
(1H, d, J=2.0 Hz), 7.00 (1H, dd, J=7.8, 7.8 Hz), 7.22
(1H, d, J=7.8 Hz), 7.33–7.43 (3H, m), 7.43–7.48 (2H,
d, J=7.2 Hz), 8.75 (1H, s); MS 281 {[M+H]+}.
4.6. Bis [(R)-2-(7-benzyloxy-3-indolyl)-1-methylethyl-
ammonium] O,O%-di-p-toluoyl -(2R,3R)-tartrate 8
L
1
980 (s) cm−1; H NMR d 2.51 (3H, s), 5.26 (2H, s), 6.90
(1H, d, J=8.0 Hz), 7.15 (1H, t, J=8.0 Hz), 7.32–7.46
(4H, m), 7.52–7.58 (2H, m), 7.85 (1H, s), 8.45 (1H, s),
11.46 (1H, s); MS m/z 307 {[M-H]-}.
4.6.1. Formation of the diastereomeric salt 8. A mixture
of ( )-1 (6.80 g, 24.3 mmol) and MeOH–H2O (4:1; 45
mL) was heated to 70°C wherein it became homoge-
neous. To the solution was added dropwise a solution
4.4. 7-Benzyloxy-3-(2-nitropropyl)indole 6
of di-p-toluoyl
L
-(2R,3R)-tartaric acid 7 (4.71 g, 12.2
mmol) in MeOH–H2O (4:1; 5.0 mL). After the addition
was complete, the dropping funnel used was rinsed with
MeOH–H2O (4:1; 8.0 mL). The mixture was allowed to
cool to 49°C, and seeded with 8 containing (R)-1 of
A stirred solution of 5 (15.4 g, 50.0 mmol) in 6:1
THF/MeOH (70 mL) was heated to 40°C and NaBH4
(1.89 g, 50.0 mmol) was added in portions over 6 h

A. Fujii et al. / Tetrahedron: Asymmetry 12 (2001) 3235–3240
3239
95.5% e.e. The stirred mixture was allowed to cool to
30°C, and heated to 45°C. The mixture was allowed to
cool to 25°C with stirring and the mixture was then
cooled and kept between 15 and 17°C for 1 h. The
precipitated solids were collected by filtration, washed
with MeOH–H2O (4:1; 2×10 mL), and dried in vacuo to
give 8 (4.71 g, 41% based on the whole amount of
( )-1), which was shown to contain (R)-1 of 94% e.e. by
the HPLC analysis described in Section 4.6.2.
in vacuo. The syrupy residue (7.5 g) was suspended in
H2O (20 mL), and 45% (w/w) NaOH aq. solution (2.60
g, 29.0 mmol) was added. The mixture was stirred at
ambient temperature for 1 h and the precipitated solids
were collected by filtration, washed with H2O, and
dried in vacuo to give crude (S)-1 (4.16 g). This was
suspended in AcOEt (10 mL), and the mixture was
stirred at ambient temperature for 15 min. Stirring was
continued with ice-cooling for 30 min and the precipi-
tated solids were collected by filtration, washed with
AcOEt, and dried in vacuo to give purified (S)-1 as
colorless solids (3.85 g, 56.6% overall yield from ( )-1),
the enantiomeric purity of which was determined to be
61.9% as determined by HPLC analysis described in
Section 4.6.2; all of the spectral data of (S)-1 were
identical to those of ( )-1 recorded in Section 4.5.
4.6.2. Recrystallization of the diastereomeric salt 8. To 8
(4.70 g; containing (R)-1 of 94% e.e.) was added
MeOH–H2O (4:1; 47 mL), and the mixture was stirred
and heated to 65°C wherein complete dissolution took
place. The stirred mixture was allowed to cool to 58°C,
and seeded with 8 containing (R)-1 of 99.0% e.e. The
stirred mixture was allowed to cool to 35°C, and heated
to 55°C. After the stirred mixture was kept at the same
temperature for 30 min, it was allowed to cool to 25°C.
Stirring was stopped and the mixture was left to stand
at ambient temperature overnight. The precipitated
solids were collected by filtration, washed with MeOH–
H2O (4:1; 2×5.0 mL) and air-dried at 50°C to give 8
(4.26 g, 91%), which was shown to contain (R)-1 of
99.5% e.e. by HPLC analysis [column, CHIRALPAK
AD (Daicel; ¥ 4.6 mm×25 cm); elution, hexane/2-
propanol/N,N-diethylamine (90:10:0.2); flow rate, 1.0
mL/min; detection, UV at 254 nm; 15% (w/w) NaOH
aq. solution (0.5 mL) was added to the recrystallized 8
(80 mg), and the precipitated solids were filtered off.
After a portion (about 2 mg) of the filtrate was diluted
with 2-propanol (2.0 mL), 1.0 mL of the 2-propanol
solution was injected; tR 23.7 min for (R)-1 (99.75%),
32.4 min for (S)-1 (0.25%)]; mp 166.6–168.2°C; [a]D20
−71.8 (c 0.50, MeOH); IR n (KBr) 3412 (s), 3034 (s),
2944 (s), 1715 (s), 1611 (v.s), 1578 (s), 1499 (m), 1443
(m), 1372 (s), 1266 (v.s), 1179 (s), 1096 (s), 1022 (m),
754 (s) cm−1. Anal. calcd for C56H58N4O10·2H2O: C,
68.4; H, 6.4; N, 5.7. Found: C, 68.8; H, 6.3; N, 5.6%.
4.9. (R)-3-(2-Aminopropyl)-7-benzyloxyindole 1 of
45.1% e.e.
The filtrate and washings generated in the course of the
recrystallization of 8 (as recorded in Section 4.6.2) were
combined, and the MeOH was removed by evaporation
in vacuo to give a syrupy residue (0.5 g) from which
(R)-1 (0.30 g) of 45.1% e.e. was obtained in 4.4%
overall yield from ( )-1 in the same manner as recorded
in Section 4.8; its enantiomeric purity was determined
by the HPLC analysis recorded in Section 4.6.2, and its
spectral data were identical to those of ( )-1 recorded
in Section 4.5.
4.10. Lowering the enantiomeric excess of (S)-1
Raney Co (about 1 mL; DFT-55, Kawaken Fine
Chemicals Co., Ltd.) was washed with H2O (2×6.0 mL),
MeOH (3×6.0 mL), 2-propanol (2×6.0 mL), and PhMe
(5×6.0 mL) and a portion (0.5 g) of the residue was
added to a solution of (S)-1 (61.9% e.e., 0.50 g) in
PhMe (40 mL). The mixture was stirred at 135°C under
an atmosphere of H2 (initial pressure: 2 kg/cm2) for 25
h. After the mixture was allowed to cool to ambient
temperature, the supernatant was decanted and filtered.
Acetone (20 mL) was added to the residue and the
mixture was well mixed by agitation. The mixture was
filtered and the filter cake was washed with acetone (5.0
mL). The filtered supernatant, the acetone filtrate and
washing were combined and the resulting solution was
concentrated in vacuo to give a residue, which was
suspended in AcOEt (2.5 mL). The mixture was stirred
at ambient temperature for 15 min, and the precipitated
solids were collected by filtration, and dried in vacuo to
give (S)-1 of 3.7% e.e. as colorless solids (0.35 g, 70%);
its enantiomeric purity was determined by the HPLC
analysis described in Section 4.6.2, and its spectral data
were identical to those of ( )-1 recorded in Section 4.5.
4.7. (R)-3-(2-Aminopropyl)-7-benzyloxyindole 1
To a suspension of the recrystallized 8 (4.00 g, 8.45
mmol) in H2O (20.0 mL) was added dropwise 45%
(w/w) NaOH aq. solution (1.65 g, 18.6 mmol) at ambi-
ent temperature. After stirring the mixture at ambient
temperature for 1 h, the precipitated solids were col-
lected by filtration, washed with H2O, and air-dried at
50°C to give (R)-1 (2.29 g, 96.6%), the enantiomeric
purity of which was determined to be 99.7% e.e. by the
HPLC analysis described in Section 4.6.2; mp 123.4–
1
135.3°C; [a]2D0 −17.8 (c 0.50, MeOH); the IR, H NMR
and MS data were identical with those of ( )-1
recorded in Section 4.5. Anal. calcd for C18H20N2O: C,
77.1; H, 7.2; N, 10.0. Found: C, 77.1; H, 7.2; N, 9.8%.
Acknowledgements
4.8. (S)-3-(2-Aminopropyl)-7-benzyloxyindole 1 of
61.9% e.e.
M.I. thanks Mr. Masafumi Moriwaki, Director of
Research & Development Center, Nagase & Co., Ltd.,
for his consistent encouragement throughout this syn-
thetic program.
The filtrate and washings generated in the course of
crystallization of 8 (as recorded in Section 4.6.1) were
combined and the MeOH was removed by evaporation

3240
A. Fujii et al. / Tetrahedron: Asymmetry 12 (2001) 3235–3240
4. (a) Batcho, A. D.; Leimgruber, W. Org. Synth. 1985, 63,
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