Catalytic asymmetric hydrogenation of indoles using a rhodium complex with a chiral bisphosphine ligand PhTRAP

Article abstract of DOI:10.1016/j.tetasy.2006.01.016

Highly enantioselective hydrogenation of N-protected indoles was successfully developed by use of the rhodium catalyst generated in situ from [Rh(nbd)₂]SbF₆ and the chiral bisphosphine PhTRAP, which can form a trans-chelate complex with a transition metal atom. The PhTRAP-rhodium catalyst required a base (e.g., Cs₂CO₃) for the achievement of high enantioselectivity. Various 2-substituted N-acetylindoles were converted into the corresponding chiral indolines with up to 95% ee. The hydrogenations of 3-substituted N-tosylindoles yielded indolines possessing a stereogenic center at the 3-position with high enantiomeric excesses (up to 98% ee).

Full text of DOI:10.1016/j.tetasy.2006.01.016

Tetrahedron: Asymmetry 17 (2006) 521–535
Catalytic asymmetric hydrogenation of indoles using a
rhodium complex with a chiral bisphosphine ligand PhTRAP
Ryoichi Kuwano,a,* Manabu Kashiwabara,a Koji Sato,b Takashi Ito,b
Kohei Kanedaa and Yoshihiko Itob,
aDepartment of Chemistry, Graduate School of Sciences, Kyushu University, 6-10-1 Hakozaki, Higashi-ku, Fukuoka 812-8581, Japan
bDepartment of Synthetic Chemistry and Biological Chemistry, Graduate School of Engineering, Kyoto University, Sakyo-ku,
Kyoto 606-8501, Japanà
Received 6 December 2005; accepted 10 January 2006
Available online 21 February 2006
This paper is dedicated to Professor Jack Halpern on the occasion of his 80th birthday
Abstract—Highly enantioselective hydrogenation of N-protected indoles was successfully developed by use of the rhodium catalyst
generated in situ from [Rh(nbd)2]SbF6 and the chiral bisphosphine PhTRAP, which can form a trans-chelate complex with a tran-
sition metal atom. The PhTRAP–rhodium catalyst required a base (e.g., Cs2CO3) for the achievement of high enantioselectivity.
Various 2-substituted N-acetylindoles were converted into the corresponding chiral indolines with up to 95% ee. The hydrogenations
of 3-substituted N-tosylindoles yielded indolines possessing a stereogenic center at the 3-position with high enantiomeric excesses (up
to 98% ee).
ꢀ 2006 Elsevier Ltd. All rights reserved.
1. Introduction
In 1998, Bianchini reported the iridium-catalyzed asym-
metric hydrogenation of 2-methylquinoxaline, which
was converted into 1,2,3,4-tetrahydro-2-methylquinoxa-
line with 90% ee.5 To the best of our knowledge, this is
the first example of highly enantioselective hydrogena-
tion of aromatic functionality, but the asymmetric catal-
ysis was proven effective for the hydrogenation of 2-
methylquinoxaline only. Furthermore, the yield of the
chiral heterocyclic product was not satisfactory. In a
preliminary communication, we reported the rhodium-
catalyzed asymmetric hydrogenation of 2-substituted in-
doles.6 Characteristically, the asymmetric reaction pro-
ceeded with high enantioselectivity only when trans-
chelate chiral bisphosphine PhTRAP7 (Fig. 1) was used
as a chiral ligand. A wide range of indoles, including 3-
substituted ones,8 were transformed into chiral indolines
with high ee values by the PhTRAP–rhodium catalyst.
Subsequently, 2-substituted quinolines9 and N-iminopy-
ridinium ylides10 were successfully hydrogenated with
high stereoselectivity by means of asymmetric cataly-
sis.11 Herein, we report the asymmetric hydrogenation
of 2- and 3-substituted indoles catalyzed by PhTRAP–
rhodium catalyst. Previously, we reported that the
hydrogenation of N-acyl indoles was promoted with
high efficiency by a rhodium catalyst generated from
Rh(acac)(cod) and triphenylphosphine.12 The present
Catalytic asymmetric hydrogenation of prochiral unsat-
urated compounds is regarded as a versatile method in
synthetic organic chemistry.1 The enantioselective
hydrogenations of olefins, ketones, and imines have
been intensively studied and are widely utilized for pre-
paring optically active compounds in industrial produc-
tion as well as on a laboratory scale. Meanwhile,
catalytic asymmetric hydrogenation of aromatic func-
tionality is expected to be useful for organic synthesis.2,3
In particular, the asymmetric reduction of heteroaro-
matics could offer a straightforward approach to various
optically active heterocycles, if it could be conducted
successfully on a routine basis. Chiral heterocyclic skel-
etons are often found in biologically active compounds.4
However, such an asymmetric hydrogenation has been
rare despite its potential usefulness.
*
Corresponding author. Tel.: +81 92 642 2572; fax: +81 92 642
2607; e-mail: rkuwascc@mbox.nc.kyushu-u.ac.jp
Present address: Department of Molecular Science and Technology,
Faculty of Engineering, Doshisha University, Kyotanabe, Kyoto 610-
0394, Japan.
à The graduate school has moved to the following address: Katsura,
Saikyo-ku, Kyoto 615-8510, Japan.
0957-4166/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2006.01.016

522
R. Kuwano et al. / Tetrahedron: Asymmetry 17 (2006) 521–535
Table 2 summarizes the effects of the rhodium catalyst
H
H
Ph2P
Me
Fe
PPh2
(S,S)-(R,R)-PhTRAP
Figure 1. Structure of PhTRAP.
Me
Fe
Ph2P
(R,R)-(S,S)-PhTRAP
PPh2
precursor and additive on the hydrogenation of 1a using
the (S,S)-(R,R)-PhTRAP ligand. When [Rh(nbd)2]SbF6
and [RhCl(cod)]2 were used as a catalyst precursor with
no additives, the hydrogenation of 1a scarcely proceeded
to give a small amount of 2a with very low enantioselec-
tivity (entries 1 and 2). In contrast, (hydroxo)rhodium
complex produced (R)-2a with a good ee value as well
as Rh(acac)(cod) did (entry 3). These findings suggest
that the basicity of the hydroxo or acetylacetonato
ligand might be essential for achieving a high level of
asymmetric induction as well as the catalytic activity
of PhTRAP–rhodium catalyst. The ee values of 2a were
enhanced to 93% when the catalytic hydrogenation was
conducted in the presence of 10% cesium carbonate and
PhTRAP–Rh(acac)(cod) catalyst (entry 4). In the pres-
ence of a base, [Rh(diene)2]+ and [RhCl(diene)]2 worked
as good catalyst precursors, and gave 2a with high enan-
tiomeric excess (entries 5–8). 2,5-Norbornadiene-ligated
rhodium complexes exhibited somewhat higher catalytic
activity than 1,5-cyclooctadiene-ligated ones, whereas
the diene ligand scarcely influenced the enantioselectiv-
ity. Cesium carbonate merely acted as a base because
the PhTRAP–rhodium catalyst gave 2a with 92–94%
ee in the presence of other bases, including tertiary
amines (entries 9, 11, and 12). However, the use of
potassium carbonate or diisopropylamine resulted in
lower enantioselectivities (entries 10 and 13). It is possi-
ble that the insolubility of potassium carbonate
obstructed the generation of the catalyst species. The
active hydrogen of the secondary amine might cause
the formation of an undesirable rhodium species in the
latter case. No consumption of 1a was observed during
hydrogenation using pyridines as an additive (entries 14
and 15). The tight coordination of pyridine to rhodium
Fe
Fe
Me
Me
H
H
asymmetric hydrogenation of indoles is based on the
Rh(acac)(cod)–PPh3 catalyst.
2. Results and discussion
2.1. Development of asymmetric catalysis for hydro-
genation of indoles
Toward the development of highly enantioselective
hydrogenation of indoles, we evaluated a broad range
of chiral bidentate phosphine ligands for the asymmetric
hydrogenation of N-acetyl-2-butylindole 1a by using
Rh(acac)(cod). The evaluation of chiral ligands was
conducted with 1 mol % rhodium at 60 ꢁC for 2 h. The
representative results are shown in Table 1. The hydro-
genation of 1a quantitatively gave 2-butylindoline 2a by
use of various commercially available chiral phosphines,
but the product was almost racemic in every case
(entries 1–6). However, only the (S,S)-(R,R)-PhTRAP
ligand, able to form a trans-chelate metal complex,
was found to exhibit high enantioselectivity (entry 7).
Table 1. Evaluation of chiral ligands for the hydrogenation of 2-butylindole 1a
Rh(acac)(cod) (1.0 mol%)
Chiral Ligand (1.05 mol%)
Bu
Bu
+ H2
N
N
Ac
2-propanol, 60 C, 2 h
˚
(50 atm)
Ac
1a
2a
NMe2
Me
Me
Me
PPh2
PPh2
PPh2
PPh2
Fe PPh2
PPh2
(2S,3S)-Chiraphos
(R)-(S)-BPPFA
Me
Me
(R)-BINAP
Ph2P
P
P
O
O
Me
Me
PPh2
PPh2
N
PPh2
Me
Me
Boc
(2R,3R)-DIOP
(R,R)-Me-DuPHOS
(2S,4S)-BPPM
Entry
Chiral ligand
Yield (%)a
ee (%)b
1
2
3
4
5
6
7
(R)-BINAP
(2S,3S)-Chiraphos
(R)-(S)-BPPFA
(ꢀ)-(2R,3R)-DIOP
(R,R)-Me-DuPHOS
(2S,4S)-BPPM
100
100
100
100
100
100
77
1 (S)
1 (S)
0
0
0
0
(S,S)-(R,R)-PhTRAP
85 (R)
a Yields were determined by 1H NMR spectra of crude mixture.
b ees were determined by chiral HPLC. Absolute configurations are given in parentheses.

R. Kuwano et al. / Tetrahedron: Asymmetry 17 (2006) 521–535
Table 2. Effects of rhodium catalyst precursor and additive
523
[Rh] (1.0 mol%)
(S,S)-(R,R)-PhTRAP (1.05 mol%)
Bu
Bu
+ H2
N
N
Ac
additive
2-propanol, 60 C, 2 h
(50 atm)
Ac
1a
2a
˚
Entry
[Rh]
Additivea
Yield (%)b
ee (%)c
1
2
3
4
5
6
7
8
[Rh(nbd)]2SbF6
[RhCl(cod)]2
[Rh(OH)(cod)]2
Rh(acac)(cod)
[RhCl(cod)]2
—
—
—
<5
9
53
100
68
86
7 (S)
33 (R)
85 (R)
93 (R)
94 (R)
95 (R)
94 (R)
94 (R)
93 (R)
76 (R)
94 (R)
92 (R)
78 (R)
—
Cs2CO3 (10)
Cs2CO3 (10)
Cs2CO3 (10)
Cs2CO3 (10)
Cs2CO3 (10)
K3PO4 (10)
K2CO3 (10)
Et3N (10)
i-Pr2NEt (10)
i-Pr2NH (10)
Pyridine (10)
DMAP (10)
Cs2CO3 (20)
Cs2CO3 (5)
Cs2CO3 (1)
[RhCl(nbd)]2
[Rh(cod)2]BF4
[Rh(nbd)2]SbF6
[Rh(nbd)2]SbF6
[Rh(nbd)2]SbF6
[Rh(nbd)2]SbF6
[Rh(nbd)2]SbF6
[Rh(nbd)2]SbF6
[Rh(nbd)2]SbF6
[Rh(nbd)2]SbF6
[Rh(nbd)2]SbF6
[Rh(nbd)2]SbF6
[Rh(nbd)2]SbF6
55
100 (94)
100
44
100
100
99
0
0
100
100
100
9
10
11
12
13
14
15
16
17
18
—
94 (R)
95 (R)
94 (R)
a Equivalents of additive to rhodium are given in parentheses.
b Yields were determined by 1H NMR spectra of crude mixture. Isolated yield is shown in parentheses.
c ees were determined by chiral HPLC. Absolute configurations are given in parentheses.
might prohibit the indole substrate from interacting with
the rhodium. The ratio of base to rhodium was not
essential for high enantioselectivity (entries 16–18).
successfully improved to 95% ee by using triethylamine
in place of cesium carbonate (entry 5). The ee values
of 2 were scarcely affected by the steric and electronic
properties of the substituent on the fused aromatic ring
of 1 (entries 6–9).
The hydrogenation of 1a proceeded in solvents other
than 2-propanol, but the use of toluene, 1,2-dichloroeth-
ane, or THF diminished slightly the enantiomeric excess
of 2a (Table 3, entries 1–3). No hydrogenation occurred
in methanol, which caused the alcoholysis of N-acetyl
group in 1a (entry 4). The catalytic hydrogenation of
1a can be conducted at a lower hydrogen pressure
(10 atm) without any significant loss of reaction rate
and enantioselectivity (entry 5). The catalyst loading
was successfully reduced to 0.1 mol % when the hydro-
genation was conduced at 100 atm of hydrogen pressure
(entry 6).
The protective group on the nitrogen of 1 was crucial for
high enantioselection by the PhTRAP–rhodium cata-
lyst. When 2-alkylindole protected by p-toluenesulfonyl
or tert-butoxycarbonyl group was used as a substrate,
the asymmetric hydrogenation yielded the correspond-
ing N-protected 2-alkylindoline with 77–78% ee (entries
10 and 11). A sulfonyl group on the nitrogen seemed to
cause diminution of the reaction rate.
2.3. Catalytic asymmetric hydrogenation of 3-substituted
indoles
2.2. Catalytic asymmetric hydrogenation of 2-substituted
indoles
Next, we challenged the catalytic asymmetric hydroge-
nation of 3-substituted indoles. The hydrogenation of
N-acetyl-3-methylindole 3a was conducted in 2-propa-
nol at 80 ꢁC for 2 h by means of the (S,S)-(R,R)-
PhTRAP–[Rh(nbd)2]SbF6–Cs2CO3 catalyst system,
which is the most effective for the reaction of 2-substi-
tuted indoles. The chiral rhodium catalyst promoted
the hydrogenation of 3a with good enantioselectivity
(Scheme 1). However, the hydrogenation competed with
undesirable alcoholysis of the N-acetyl group, which
gave 3-methylindole 5 in 58% yield. Therefore, our ini-
tial effort was focused on suppressing the solvolysis of
the N-protecting group. The undesired reaction can be
suppressed by the use of organic or insoluble bases (tri-
ethylamine, potassium carbonate, etc.), but the ee values
As shown in Table 4, various 2-substituted indoles 1
were subjected to asymmetric hydrogenation with the
PhTRAP–rhodium–Cs2CO3 catalyst system. Indole 1b
possessing a b-branched primary alkyl group was hydro-
genated into indoline 2b with high enantiomeric excess
(entry 1). However, the secondary alkyl group at the
2-position of 1c hindered the catalytic hydrogenation,
and the product 2c was obtained with low ee value (en-
try 2). The reactions of 1d and 1e proceeded with 87%
and 79% ee, respectively (entries 3 and 4). In the case
of 1e, a higher temperature and hydrogen pressure
(100 ꢁC, 100 atm) were favorable to achieving higher
enantioselectivity. Moreover, the enantioselectivity was

524
R. Kuwano et al. / Tetrahedron: Asymmetry 17 (2006) 521–535
Table 3. Effect of reaction conditions
[Rh(nbd)2]SbF6 (1.0 mol%)
(S,S)-(R,R)-PhTRAP (1.05 mol%)
Bu
Bu
+ H2
N
N
Ac
Cs2CO3 (10 mol%)
Ac
1a
2a
solvent, 60 C, 2 h
˚
Entry
Solvent
Toluene
ClCH2CH2Cl
THF
H2 pressure (atm)
Yield (%)a
ee (%)b
1
2
3
4
50
50
50
92
53
52
0
91 (R)
87 (R)
84 (R)
—
MeOH
50
5
6c
i-PrOH
i-PrOH
10
100
100 (94)
100 (92)
92 (R)
93 (R)
a Yields were determined by 1H NMR spectra of crude mixture. Isolated yields are given in parentheses.
b ees were determined by chiral HPLC. Absolute configurations are given in parentheses.
c The reaction was conducted in the presence of 0.1 mol % PhTRAP–rhodium catalyst.
Table 4. Catalytic asymmetric hydrogenation of 2-substituted indoles 1
R2
R2
[Rh(nbd)2]SbF6 (1.0 mol%)
(S,S)-(R,R)-PhTRAP (1.05 mol%)
5
5
R1
R1
+ H2
6
6
N
PG
N
Cs2CO3 (10 mol%)
(50 atm)
PG
1
2
2-propanol, 60 C
˚
Entry
Substrate
Time (h)
Product
R1
R2
PG
1
2
Yield (%)a
ee (%)b
1
2
3
4
5c
6
7
8
i-Bu
c-C6H11
Ph
CO2Me
CO2Me
Bu
Bu
Bu
Bu
Me
H
H
H
H
H
5-Me
5-CF3
6-CF3
6-MeO
H
Ac
Ac
Ac
Ac
Ac
Ac
Ac
Ac
Ac
Ts
1b
1c
1d
1e
1e
1f
2
3
1
2
0.5
2
2
2
2
2b
2c
2d
2e
2e
2f
91
(27)
91
86
95
94
84
83
98
45
94
91
19
87
79 (S)
95 (S)
94
92
92
1g
1h
1i
2g
2h
2i
9
10
11
94
78 (R)
77d (R)
1j
1k
2
2
2j
2k
Bu
H
Boc
a Isolated yield. Yield in parentheses was estimated by 1H NMR spectrum of the crude reaction mixture.
b ees were determined by chiral HPLC.
c The reaction was conducted at 100 ꢁC and 100 atm. Triethylamine was used in place of cesium carbonate.
d The enantiomeric excess was determined by HPLC analysis of 2a derived from the hydrogenation product 2k.
[Rh(nbd)2]SbF6 (1.0 mol%)
(S,S)-(R,R)-PhTRAP (1.0 mol%)
Me
Me
Me
+
Cs2CO3 (10 mol%), H2 (50 atm)
N
Ac
N
Ac
N
H
2-propanol, 80 C, 2 h
˚
4a
5
3a
24% yield
58% yield
84% ee (S)
Scheme 1. Hydrogenation of N-acetyl-3-methylindole 3a.
of the resulting products were lower than 10% ee. No
hydrogenation occurred in aprotic solvent such as aceto-
nitrile, THF, toluene, and so on. When indole 3b pro-
tected by tert-butoxycarbonyl was employed as a
substrate, no deprotection of the N-protective group
was observed even in the presence of cesium carbonate
but the enantiomeric excess of indoline 4b was only
16% (Table 5, entry 1). The use of sulfonyl protective
groups dramatically improved the enantiomeric excess
as well as the yield of the desired product. Tosyl-pro-
tected 3-methylindole 3c was converted into (S)-3-
methyl-N-tosylindoline 4c with 97% ee in 31% yield after
2 h, with no formation of 5 (entry 2). Furthermore, the
yield of 4c was improved to 96% without the loss of the
ee value by prolonging the reaction time to 24 h (entry
3). The antipode (R)-4c was obtained with 98% ee when

R. Kuwano et al. / Tetrahedron: Asymmetry 17 (2006) 521–535
Table 5. Hydrogenation of 3-methylindoles 3
525
[Rh(nbd)2]SbF6 (1.0 mol%)
Me
Me
(S,S)-(R,R)-PhTRAP (1.0 mol%)
+ H2
Cs2CO3 (10 mol%)
N
N
(50 atm)
2-propanol, 80 C
˚
PG
PG
3
4
Entry
PG (3)
Time (h)
Product
Yield (%)a
ee (%)b
1
2
3
4c
5
Boc (3b)
Ts (3c)
Ts (3c)
Ts (3c)
Ms (3d)
Tf (3e)
2
2
24
24
24
24
4b
4c
4c
4c
4d
4e
14
31
100 (96)
100 (98)
92 (83)
100 (93)
16
97 (S)
98 (S)
98 (R)
94
6
94
a Yields were determined by 1H NMR spectra of crude mixture. Isolated yields are given in parentheses.
b ees were determined by chiral HPLC. Absolute configurations are given in parentheses.
c (R,R)-(S,S)-PhTRAP was used.
(R,R)-(S,S)-PhTRAP was used as a chiral ligand (entry
4). Indoles 3d and 3e protected with other sulfonyl
groups were also transformed into the corresponding
indolines with high enantiomeric excesses by using the
PhTRAP–rhodium catalyst (entries 5 and 6). In contrast
to the hydrogenation of 2-substituted indoles 1, no
hydrogenation of 3c occurred in the presence of the rho-
dium catalysts generated from other phosphine ligands,
for example, triphenylphosphine and cis-chelating bis-
phosphine ligand BINAP.
product in 34% yield. This undesirable side reaction
may deactivate the PhTRAP–rhodium catalyst, because
no hydrogenation product of the isopropyl ester 3k0 was
detected by 1H NMR analysis of the crude reaction mix-
ture. (Indol-3-yl)acetate 3l was converted into 4l with
moderate enantiomeric excess in low yield (entry 7).
The enolizable hydrogens of 3l might cause a decrease
in enantioselectivity as well as catalyst turnover number.
When 3-acetyl-N-tosylindole was used as a substrate,
the PhTRAP–rhodium catalyst reduced the ketone car-
bonyl as well as the indole ring to give 1-(N-tosylindo-
lin-3-yl)ethanol quantitatively. The hydrogenation
product was obtained as a mixture of two diastereomers
(73:27), which were racemic.
As shown in Table 6, the hydrogenations of various 3-
substituted N-tosylindoles were attempted by means of
the (S,S)-(R,R)-PhTRAP–rhodium catalyst. The indoles
3f and 3g possessing a bulky substituent at the 3-posi-
tion underwent highly enantioselective hydrogenation
(entries 1 and 2). The catalytic asymmetric hydrogena-
tion was compatible with a silyl-protected alcohol,
Boc-protected amine, and tert-butyl ester (entries 3–5).
Although the hydrogenation of methyl ester 3k pro-
ceeded with 97% ee, the product 4k was obtained in
low yield (entry 6). The reaction was accompanied by
ester exchange of 3k with 2-propanol, and isopropyl 3-
(N-tosylindol-3-yl)propionate 3k0 was formed as a side
2.4. Stereochemistry in the catalytic asymmetric hydro-
genation of indoles
The absolute configurations of the hydrogenation prod-
ucts (ꢀ)-2a and (ꢀ)-2e were assigned by comparison
with the chiral HPLC data of their authentic samples.
The authentic samples were prepared from commer-
cially available (S)-indoline-2-carboxylic acid 6 (Scheme
2). The esterification of 6 with methanol and thionyl
Table 6. Catalytic asymmetric hydrogenation of 3-substituted indoles 3
[Rh(nbd)2]SbF6 (1.0 mol%)
(S,S)-(R,R)-PhTRAP (1.0 mol%)
R
R
+ H2
Cs2CO3 (10 mol%)
N
Ts
N
Ts
(50 atm)
2-propanol, 80 C, 24 h
˚
3
4
Entry
R (3)
Product
Yield (%)a
ee (%)b
1c
2d
3
4
5
i-Pr (3f)
Ph (3g)
CH2CH2OTBS (3h)
CH2CH2NHBoc (3i)
CH2CH2CO2(t-Bu) (3j)
CH2CH2CO2Me (3k)
CH2CO2(t-Bu) (3l)
4f
4g
4h
4i
94
93
94
71
93
(32)
(29)
97
96
98
95
97
97
62
4j
6
7d
4k
4l
a Isolated yield. Yields in parentheses were estimated by 1H NMR spectrum of the crude reaction mixture.
b ees were determined by chiral HPLC.
c The reaction was conducted for 48 h.
d The reactions were conducted with 2 mol % catalyst.

526
R. Kuwano et al. / Tetrahedron: Asymmetry 17 (2006) 521–535
SOCl2
MeOH
Ac2O
Et3N
CO2Me
CO2H
CO2Me
N
Ac
(S)-2e
N
N
H
99%
86%
• HCl
H
6
7
1. DMSO, (COCl)2, Et3N
2. Ph3P=CHEt
OH
Et
LiBH4
74%
N
Ac
N
Ac
2%
8
9
H2, cat. 5% Pd/C
Bu
N
Ac
(R)-2a
Scheme 2. Transformation of 6 to authentic (S)-2e and (R)-2a.
chloride gave a-amino ester 7 quantitatively. Authentic
(S)-2e was obtained by the N-acetylation of 7 in 86%
yield. The ester group of (S)-2e was reduced with LiBH4.
The resulting primary alcohol 8 was subjected to Swern
oxidation followed by Wittig olefination. Although the
productivity of these processes was very low, 2-substi-
tuted indoline 9 was successfully obtained in an amount
large enough for HPLC analysis. The hydrogenation of
9 yielded authentic (R)-2a. The retention times of the
authentic (R)-2a and (S)-2e in HPLC analysis revealed
the configurations of (ꢀ)-2a and (ꢀ)-2e produced by
the (S,S)-(R,R)-PhTRAP–rhodium catalyst to be R
and S, respectively.
reacting with hydrogen was opposite to that of the 2-
substituted indoles 1. Although the mechanism of the
asymmetric hydrogenation remains to be further investi-
gated, the reaction pathway of the reduction of 3-substi-
tuted indoles may be different from that of 2-substituted
ones.
3. Conclusion
The highly enantioselective hydrogenation of indoles
was successfully developed by using a trans-chelating
chiral bisphosphine PhTRAP ligand. The rhodium com-
plex generated in situ from [Rh(nbd)2]SbF6 and
PhTRAP in the presence of Cs2CO3 was the best cata-
lyst for the asymmetric hydrogenation of indoles. A
wide range of 2- and 3-substituted indoles were con-
verted with high enantioselectivities into the indolines
possessing a chiral center at their 2- or 3-position. The
use of PhTRAP was crucial for achieving the high
enantioselectivity in the hydrogenation of indoles. The
hydrogenation of 2-substituted indoles 1 proceeded with
no stereoselectivity when other chiral bisphosphine
ligands were used in place of PhTRAP. In the case of
3-substituted indoles 3, no hydrogenation occurred in
the presence of rhodium complexes modified with other
phosphine ligands. To our surprise, the enantiofaces of 1
and 3 reacting with hydrogen were opposite to each
other. The observation suggests that the asymmetric
hydrogenation of 3 may proceed through a different
reaction pathway from that of 1.
The absolute configuration of (+)-2j, which was ob-
tained from the (S,S)-(R,R)-PhTRAP–rhodium-cata-
lyzed hydrogenation of N-tosyl-protected indole 1j,
was determined by means of an HPLC analysis as men-
tioned above. An authentic sample of (R)-2j was pre-
pared by the removal of the Boc group from (R)-N-
Boc-2-methylindoline13 followed by the reaction of the
resulting secondary amine with tosyl chloride. The
retention time of the authentic (R)-2j in HPLC analysis
indicated the configuration of (+)-2j to be R. These ste-
reochemistries of the hydrogenation products 2 indicate
that the prochiral face of the indole reacting with hydro-
gen was not inverted by the N-protecting group or by
the substituent at the 2-position of 1.
In order to determine the stereochemistry of the asym-
metric hydrogenation of 3-substituted indoles, the
hydrogenation product 4c was transformed into N-benz-
yl-3-methylindoline, whose correlation between the
absolute configuration and specific rotation had been
established by Groth.14 The N-tosyl group of (+)-4c,
which was yielded by the (S,S)-(R,R)-PhTRAP–rho-
dium catalyst, was removed by treatment with sodium
bis(methoxyethoxy)aluminum dihydride. Optically ac-
tive 3-methylindoline was obtained with no racemiza-
tion at the 3-position.15 The chiral indoline in hand
was alkylated with benzyl chloride to give (+)-N-benz-
yl-3-methylindoline. The sign of the specific rotation
indicates that the configuration at the 3-position of
(+)-4c is S. It is noteworthy that the enantioface of 3c
At this stage, the enantioselectivity was significantly
affected by the substituent on the nitrogen of the sub-
strate. Acetyl and tosyl groups were the protecting
groups of choice for the reaction of 2- and 3-substituted
indoles, respectively. However, removal of these protect-
ing groups from the indoline products 2 and 4 usually
requires harsh reaction conditions, which is disadvan-
tage for the application of the present hydrogenation
to organic synthesis of complex molecules. We will
direct our interest to the development of the highly enan-
tioselective hydrogenation of indoles protected with Boc
group, which is removable under mild acidic conditions.

R. Kuwano et al. / Tetrahedron: Asymmetry 17 (2006) 521–535
527
4. Experimental
for 24 h. The mixture was then allowed to cool to room
temperature. After the resulting precipitate was filtered
off, the filtrate was evaporated. The residue was purified
with a flash column chromatography on silica gel
(EtOAc/hexane) to give 1e (3.27 g, 85%): pink solid;
1H NMR (200 MHz, CDCl3, TMS) d 2.62 (s, 3H),
3.95 (s, 3H), 7.29 (ddd, J = 1.0, 7.1, 7.8 Hz, 1H), 7.33
(d, J = 0.7 Hz, 1H), 7.45 (ddd, J = 1.4, 7.1, 8.5 Hz,
1H), 7.63 (ddd, J = 0.7, 1.4, 7.8 Hz, 1H), 8.13 (dd,
J = 1.0, 8.5 Hz, 1H).
4.1. General
Optical rotations were measured with a JASCO P-1020
polarimeter. NMR spectra were measured with Varian
GEMINI-2000 (7.0 T magnet), VXR-200 (4.7 T
magnet), or Bruker AVANCE 400 (9.4 T magnet) spec-
trometer. Flash column chromatographies and prepara-
tive TLCs were performed with silica gel 60 (230–
400 mesh, Merck) and silica gel 60 PF254 (Merck),
respectively.
4.3. 2-Methyl-N-tosylindole 1j
The N-tosylations of indoles were carried out by a mod-
ified Wenkert procedure.19 Aqueous sodium hydroxide
solution (50%, 7.2 g, 90 mmol) was added to a solution
of 2-methylindole (459 mg, 3.5 mmol) and tetrabutylam-
monium hydrogensulfate (119 mg, 0.35 mmol) in dichlo-
romethane (17.5 ml). A solution of p-toluenesulfonyl
chloride (1.17 g, 6.1 mmol) in dichloromethane (2.8 ml)
was added dropwise to the reaction mixture for
30 min. The two-phase solution was stirred vigorously
at room temperature for 5 h, and was poured into water.
The resulting mixture was extracted five times with
EtOAc. The combined organic layer was washed with
brine, dried over Na2SO4, and evaporated. The residue
was purified by MPLC (EtOAc/hexane) after passing
through a short column on silica gel (EtOAc/hexane =
All reactions were conducted under a nitrogen atmo-
sphere unless otherwise noted. Methanol was dried with
Mg(OMe)2. Dichloromethane, N,N-dimethylacetamide
(DMA), N,N-dimethylformamide (DMF), and 2-propa-
nol were dried with CaH2. Diethyl ether, 1,4-dioxane,
tetrahydrofuran (THF), and toluene were dried with
sodium-benzophenone ketyl. These dry solvents were
distilled under a nitrogen atmosphere before use.
N-Acetyl-2-substituted indoles 1a–1d, 1f–1i were pre-
pared from the gold-catalyzed cyclizations of N-acetyl-
2-(1-alkynyl)anilines.16 PhTRAP,7b [Rh(nbd)2]SbF6,17
N-Boc-indoles 1k and 3b18 were prepared by the litera-
ture procedure. Other materials were commercially
available and were used without further purification.
1
1/5), giving 1j (372 mg, 37%): pale pink oil; H NMR
4.2. Methyl N-acetylindole-2-carboxylate 1e
(400 MHz, CDCl3, TMS) d 2.34 (s, 3H), 2.60 (s, 3H),
6.34 (s, 1H), 7.17–7.27 (m, 4H), 7.39 (d, J = 7.6 Hz,
1H), 7.66 (d, J = 8.4 Hz, 2H), 8.15 (d, J = 8.3 Hz, 1H).
Thionyl chloride (21.2 g, 0.18 mol) was added dropwise
to dry methanol (50 ml) at 0 ꢁC for 20 min. After
10 min, racemic indoline-2-carboxylic acid (8.16 g,
50 mmol) was added carefully to the solution in small
portions for 5 min. The mixture was stirred at room
temperature for 21 h, and then evaporated. The residue
was crystallized in diethyl ether to give methyl indoline-
2-carboxylate hydrochloride (9.75 g, 91%): colorless
crystals; 1H NMR (200 MHz, CD3OD) d 3.51 (dd,
J = 7.6, 16.4 Hz, 1H), 3.71 (dd, J = 9.4, 16.4 Hz, 1H),
3.89 (s, 3H), 5.09 (dd, J = 7.6, 9.4 Hz, 1H), 7.37–7.54
(m, 4H). Triethylamine (4.65 g, 46 mmol) was added to
a suspension of methyl indoline-2-carboxylate hydro-
chloride (4.27 g, 20 mmol) in dry THF (20 ml) at room
temperature. After 10 min, acetic anhydride (2.46 g,
24 mmol) and 4-(N,N-dimethylamino)pyridine (24.4
mg, 0.20 mmol) were added to the suspension. The mix-
ture was stirred at room temperature for 10 h, and then
at 40 ꢁC for 3 h. Water was added to the mixture, and
then the mixture was extracted with EtOAc. The organic
layer was washed with 10% citric acid aq, with saturated
Na2CO3 aq, then with brine, dried over Na2SO4, and
was evaporated. The residue was recrystallized from
hexane–EtOAc to give methyl N-acetylindoline-2-car-
boxylate (3.89 g, 89%): colorless crystals; 1H NMR
(200 MHz, CDCl3, TMS) d 2.18 and 2.49 (a pair of br
s, 3H), 3.00–3.67 (br m, 2H), 3.77 and 3.74 (a pair of
br s, 3H), 4.84–4.98 and 5.10–5.23 (a pair of br m,
1H), 7.03 (t, J = 7.9 Hz, 1H), 7.09–7.31 (m, 2H), 8.22
(br d, J = 7.8 Hz, 1H). A mixture of methyl N-acetylind-
oline-2-carboxylate (3.89 g, 18 mmol) and DDQ (6.03 g,
27 mmol) in dry toluene (90 ml) was stirred under reflux
4.4. 3-Methyl-N-(p-toluenesulfonyl)indole 3c (typical
procedure of N-tosylation of 3-substituted indoles)
Aqueous potassium hydroxide solution (50%, 10.0 g,
89 mmol) was added dropwise for 20 min to a solution
of 3-methylindole (1.31 g, 10.0 mmol), p-toluenesulfonyl
chloride (2.10 g, 11.0 mmol), and tetrabutylammonium
hydrogensulfate (340 mg, 1.0 mmol) in benzene
(30 ml). The two-phase solution was stirred vigorously
at room temperature for 1 h, and then was poured into
water. The resulting mixture was extracted three times
with EtOAc. The combined organic layer was washed
with brine, dried with Na2SO4, and evaporated. The res-
idue was purified by a flash column chromatography on
silica gel (EtOAc/hexane), giving 3c (2.15 g, 75%): pale
brown solid; 1H NMR (400 MHz, CDCl3, TMS) d
2.24 (d, J = 1.2 Hz, 3H), 2.32 (s, 3H), 7.19 (d, J =
8.3 Hz, 2H), 7.20–7.26 (m, 1H), 7.28–7.33 (m, 2H),
7.44 (d, J = 7.6 Hz, 1H), 7.74 (d, J = 8.3 Hz, 2H), 7.98
(d, J = 8.2 Hz, 1H).
4.5. 3-(2-Propyl)-N-(p-toluenesulfonyl)indole 3f
The procedure for the preparation of 3c was carried out
with 3-(2-propyl)indole20 (768 mg, 4.8 mmol). The crude
product was purified by a flash column chromatography
on silica gel (EtOAc/hexane) and recrystallization from
EtOAc/hexane, giving 3f (574 mg, 38%): colorless crys-
tal; 1H NMR (400 MHz, CDCl3, TMS) d 1.32 (d,

528
R. Kuwano et al. / Tetrahedron: Asymmetry 17 (2006) 521–535
J = 6.9 Hz, 6H), 2.33 (s, 3H), 3.08 (septet, J = 6.9 Hz,
1H), 7.18–7.31 (m, 5H), 7.52 (d, J = 7.7 Hz, 1H), 7.74
(d, J = 8.4 Hz, 2H), 7.96 (d, J = 8.2 Hz, 1H).
or three times). The resulting mixture was diluted with
water, and extracted three times with EtOAc. The com-
bined organic layer was washed with saturated Na2CO3
aq, with brine, dried over MgSO4, and evaporated. The
residue was purified by a flash column chromatography
on silica gel (EtOAc/hexane), giving 3h (2.34 g, 91%): 1H
NMR (200 MHz, CDCl3, TMS) d –0.02 (s, 6H), 0.87 (s,
9H), 2.33 (s, 3H), 2.87 (t, J = 6.8 Hz, 2H), 3.86 (t,
J = 6.8 Hz, 2H), 7.16–7.36 (m, 4H), 7.39 (s, 1H), 7.49
(dd, J = 1.1, 6.7 Hz, 1H), 7.75 (d, J = 8.4 Hz, 2H),
7.98 (d, J = 7.2 Hz, 1H).
4.6. 3-Phenyl-N-(p-toluenesulfonyl)indole 3g
A
mixture of 3-bromo-N-triisopropylsilylindole21
(3.51 g, 10 mmol), phenylboronic acid (1.46 g,
12 mmol), cesium carbonate (10.8 g, 33 mmol), Pd(dba)2
(115 mg, 0.20 mmol), and tri(tert-butyl)phosphonium
tetrafluoroborate22 (139 mg, 0.48 mmol) in dry THF
(20 ml) was stirred under reflux for 18 h. The mixture
was diluted with water, and then extracted three times
with EtOAc. The combined organic layer was washed
with brine, dried over Na2SO4, and evaporated. Tetra-
butylammonium fluoride (1.0 M in THF solution,
10 ml, 10 mmol) was added at 0 ꢁC to a solution of the
residue in dry THF (30 ml). The reaction mixture was
stirred at 0 ꢁC for 20 min and at room temperature for
50 min. The mixture was diluted with water, and then
extracted three times with EtOAc. The combined organ-
ic layer was washed with brine, dried over Na2SO4, and
evaporated. The residue was purified by a flash column
chromatography on silica gel (EtOAc/hexane), giving 3-
phenylindole (1.74 g, 90%) as a colorless solid. The pro-
cedure for the preparation of 3c was followed with
3-phenylindole (1.70 g, 8.8 mmol) to give 3g (2.90 g,
95%): colorless crystal; 1H NMR (400 MHz, CDCl3,
TMS) d 2.34 (s, 3H), 7.23 (d, J = 8.3 Hz, 2H), 7.25–
7.31 (m, 1H), 7.34–7.39 (m, 2H), 7.43–7.49 (m, 2H),
7.58–7.62 (m, 2H), 7.69 (s, 1H), 7.76–7.83 (m, 3H),
8.06 (d, J = 8.3 Hz, 1H).
4.8. 3-[2-(tert-Butoxycarbonylamino)ethyl]-N-(p-toluene-
sulfonyl)indole 3i
(Boc)2O (12.1 g, 55 mmol) was added to a solution of
tryptamine (8.01 g, 50 mmol) and triethylamine
(13.9 ml, 100 mmol) in dry 1,4-dioxane (80 ml). The
reaction mixture was stirred at room temperature for
4 h, and then evaporated. After water was added to
the residue, the mixture was extracted three times with
EtOAc. The combined organic layer was washed with
1
brine, dried over Na2SO4, and evaporated. H NMR
spectrum indicated that the residue was almost pure
3-[2-(tert-butoxycarbonylamino)ethyl]indole
(13.0 g,
1
100%): H NMR (200 MHz, CDCl3, TMS) d 1.44 (s,
9H), 2.95 (t, J = 6.8 Hz, 2H), 3.46 (br q, J = 6.4 Hz,
2H), 4.55–4.72 (br, 1H), 7.01 (s, 1H), 7.07–7.26 (m,
2H), 7.36 (d, J = 7.6 Hz, 1H), 7.61 (d, J = 7.8 Hz, 1H),
8.04–8.30 (br, 1H). The procedure for the preparation
of 3c was followed with the Boc-protected amine
(5.28 g, 20 mmol) to give 3i (7.99 g, 95%): 1H NMR
(200 MHz, CDCl3, TMS) d 1.45 (s, 9H), 2.33 (s, 3H),
2.86 (t, J = 6.9 Hz, 2H), 3.41 (q, J = 6.6 Hz, 2H),
4.49–4.66 (br, 1H), 7.16–7.38 (m, 5H), 7.46–7.52
(m, 1H), 7.75 (d, J = 8.4 Hz, 2H), 7.98 (d, J = 7.8 Hz,
1H).
4.7. 3-[2-(tert-Butyldimethylsilyloxy)ethyl]-N-(p-toluene-
sulfonyl)indole 3h
tert-Butyldimethylchlorosilane (1.24 g, 8.2 mmol) was
added at 0 ꢁC to a solution of 3-(2-hydroxyethyl)indole
(1.12 g, 7.0 mmol) and imidazole (1.18 g, 17.3 mmol) in
dry DMF (3.0 ml). The solution was stirred for 19 h at
room temperature, and then poured into water. The
resulting mixture was extracted twice with EtOAc. The
combined organic layer was washed with brine, dried
4.9. tert-Butyl 3-[N-(p-toluenesulfonyl)indol-3-yl]propio-
nate 3j
2-Bromo-2-methylpropane (21.4 g, 156 mmol) was
added at 55 ꢁC to a suspension of 3-(3-indolyl)propionic
acid (757 mg, 4.0 mmol), benzyltriethylammonium chlo-
ride (910 mg, 4.0 mmol), and potassium carbonate
(14.4 g, 104 mmol) in dry DMA (31 ml). After the mix-
ture was stirred at 55 ꢁC for 5 h, water was added to the
mixture. The resulting mixture was extracted three times
with EtOAc. The combined organic layer was washed
with brine, dried over Na2SO4, and then evaporated.
The residue was purified by a flash column chromato-
graphy on silica gel (EtOAc/hexane), giving tert-butyl
1
over MgSO4, and evaporated. H NMR spectrum indi-
cated that the residue was almost pure 3-[2-(tert-butyl-
1
dimethylsilyloxy)ethyl]indole (1.92 g, 100%): H NMR
(200 MHz, CDCl3, TMS) d 0.00 (s, 6H), 0.87 (s, 9H),
2.96 (t, J = 7.5 Hz, 2H), 3.85 (t, J = 7.5 Hz, 2H), 6.98
(d, J = 2.2 Hz, 1H), 7.03–7.19 (m, 2H), 7.27–7.34 (m,
1H), 7.54–7.61 (m, 1H), 7.96–8.16 (br, 1H). A solution
of the silyl-protected compound (1.65 g, 6.0 mmol) in
dry THF (12 ml) was added at 0 ꢁC to a suspension of
sodium hydride (60% in oil, 299 mg, 7.5 mmol) in dry
THF (36 ml). After the mixture was stirred at room tem-
perature for 1 h, a solution of p-toluenesulfonyl chloride
(1.21 g, 6.4 mmol) in dry THF (12 ml) was added at
room temperature to the reaction mixture. After 24 h,
1
3-(3-indolyl)propionate (643 mg, 65% yield): H NMR
(200 MHz, CDCl3, TMS) d 1.42 (s, 9H), 2.62 (t, J =
7.8 Hz, 2H), 3.05 (t, J = 7.8 Hz, 2H), 6.92 (d, J = 2.4
Hz, 1H), 7.04–7.21 (m, 2H), 7.29 (d, J = 7.2 Hz, 1H),
7.60 (d, J = 7.6 Hz, 1H), 7.94–8.16 (br, 1H). The proce-
dure for the preparation of 3c was followed with the
tert-butyl ester (594 mg, 2.4 mmol) to give 3j (593 mg,
61%): 1H NMR (200 MHz, CDCl3, TMS) d 1.43 (s,
9H), 2.32 (s, 3H), 2.60 (t, J = 7.5 Hz, 2H), 2.95 (d,
J = 7.5 Hz, 2H), 7.14–7.37 (m, 5H), 7.49 (d, J =
1
the mixture was monitored by TLC and H NMR anal-
ysis. Until no unreacted starting material was detected in
the mixture, addition of sodium hydride and p-toluene-
sulfonyl chloride as mentioned above was repeated (two

R. Kuwano et al. / Tetrahedron: Asymmetry 17 (2006) 521–535
529
7.4 Hz, 1H), 7.73 (d, J = 8.2 Hz, 2H), 7.97 (d, J =
4.12. 3-Acetyl-N-(p-toluenesulfonyl)indole
8.2 Hz, 1H).
The procedure for the preparation of 3c was followed
4.10. Methyl 3-[N-(p-toluenesulfonyl)indol-3-yl]propio-
nate 3k
with 3-acetylindole (955 mg, 6.0 mmol) to give the
desired compound (1.83 g, 97%): H NMR (300 MHz,
1
CDCl3, TMS) d 2.37 (s, 3H), 2.57 (s, 3H), 7.24–7.43
(m, 4H), 7.79–7.98 (m, 3H), 8.20 (s, 1H), 8.28–8.39 (m,
1H).
A suspension of 3-(3-indolyl)propionic acid (3.69 g,
19.5 mmol) and Amberlyst 15 (H+ form) (3.94 g) in
methanol (39 ml) was stirred at room temperature for
16 h. The mixture was filtered through a Celite pad,
and then the filtrate evaporated. 1H NMR spectrum
indicates that the residue was almost pure methyl 3-(3-
4.13. General procedure for asymmetric hydrogenation of
2-substituted indoles 1
1
indolyl)propionate (3.85 g, 97%): H NMR (200 MHz,
A mixture of [Rh(nbd)2]SbF6 (2.6 mg, 5.0 lmol) and
(S,S)-(R,R)-PhTRAP (4.2 mg, 5.3 lmol) in dry 2-propa-
nol (2.0 ml) was stirred at room temperature for 10 min.
The resulting orange suspension was transferred by a
cannula to a mixture of 1 (0.50 mmol) and Cs2CO3
(16.2 mg, 50 lmol). The mixture was moved into a nitro-
gen-filled 50 ml stainless steel autoclave. Hydrogen was
introduced into the autoclave until the pressure gauge
indicated over 50 atm, and then the pressure was care-
fully released to 1 atm. This procedure was repeated
twice, and finally the inside of the autoclave was pressur-
ized with hydrogen to 50 atm. The reaction mixture was
stirred at 60 ꢁC for 2 h. The resulting mixture was con-
centrated under reduced pressure. The residue was puri-
fied by a flash column chromatography on silica gel
(EtOAc/hexane) to give 2. The enantiomeric excess of
2 was determined by chiral HPLC analysis.
CDCl3, TMS) d 2.72 (t, J = 7.6 Hz, 2H), 3.10 (t,
J = 7.6 Hz, 2H), 3.66 (s, 3H), 6.96 (d, J = 2.0 Hz, 1H),
7.06–7.23 (m, 2H), 7.32 (d, J = 7.2 Hz, 1H), 7.59
(dd, J = 0.9, 7.5 Hz, 1H), 7.91–8.12 (br, 1H). The
procedure for the preparation of 3c was followed with
the methyl ester (2.03 g, 10 mmol) to give 3k (2.88 g,
81%): 1H NMR (200 MHz, CDCl3, TMS) d 2.33
(s, 3H), 2.69 (t, J = 7.6 Hz, 2H), 3.00 (t, J = 7.6 Hz,
2H), 3.67 (s, 3H), 7.14–7.39 (m, 5H), 7.48 (d, J =
7.8 Hz, 1H), 7.73 (d, J = 8.4 Hz, 2H), 7.97 (d,
J = 7.6 Hz, 1H).
4.11. tert-Butyl [N-(p-toluenesulfonyl)indol-3-yl]acetate 3l
A suspension of (3-indolyl)acetic acid (17.5 g, 100 mmol)
and Amberlyst 15 (H+ form) (20.0 g) in methanol
(200 ml) was stirred at room temperature for 16 h. The
mixture was filtered through a Celite pad, and then the
4.13.1. (R)-N-Acetyl-2-butylindoline 2a (Table 2, entry
8). The general procedure was followed with N-acetyl-
1
filtrate evaporated. H NMR spectrum indicated that
the residue was almost pure methyl (3-indolyl)acetate
(18.7 g, 99%): 1H NMR (200 MHz, CDCl3, TMS) d
3.70 (s, 3H), 3.79 (s, 2H), 7.08–7.26 (m, 3H), 7.36 (d,
J = 7.0 Hz, 1H), 7.62 (d, J = 7.6 Hz, 1H), 7.91–8.25
(m, 1H). The procedure for the preparation of 3c was fol-
lowed with the methyl ester (3.79 g, 20 mmol). The reac-
tion mixture was washed three times with EtOAc. The
aqueous layer was acidified with 10% HCl aq, and then
was extracted three times with EtOAc. The combined or-
ganic layer was washed with brine, dried over Na2SO4,
and evaporated. The residue was purified by a flash col-
umn chromatography on silica gel (EtOAc/hexane), giv-
ing [N-(p-toluenesulfonyl)indol-3-yl]acetic acid (1.75 g,
26%): 1H NMR (200 MHz, CDCl3, TMS) d 2.32 (s,
3H), 3.73 (s, 2H), 7.14–7.38 (m, 4H), 7.45–7.52 (m,
1H), 7.58 (s, 1H), 7.76 (d, J = 8.4 Hz, 2H), 7.97 (d,
J = 7.6 Hz, 1H). 2-Bromo-2-methylpropane (39.2 g,
286 mmol) was added at 55 ꢁC to a suspension of the car-
boxylic acid (1.97 g, 6.0 mmol), benzyltriethylammo-
nium chloride (1.36 g, 6.0 mmol), and potassium
carbonate (21.4 g, 155 mmol) in dry DMA (46 ml). After
the mixture was stirred at 55 ꢁC for 4 h, water was added
to the mixture. The resulting mixture was extracted three
times with EtOAc. The combined organic layer was
washed with brine, dried over Na2SO4, and evaporated.
The residue was purified by a flash column chromatogra-
phy on silica gel (EtOAc/hexane), giving 3l (2.04 g, 89%
yield): 1H NMR (200 MHz, CDCl3, TMS) d 1.41 (s, 9H),
2.33 (s, 3H), 3.58 (s, 2H), 7.14–7.36 (m, 4H), 7.45–7.55
(m, 2H), 7.75 (d, J = 8.4 Hz, 2H), 7.97 (d, J = 7.6 Hz,
1H).
2-butylindole 1a (108 mg, 0.50 mmol) to give (R)-2a
20
(102 mg, 94%): pale yellow oil; ½aꢁD ¼ ꢀ94:0 (c 1.00,
CHCl3); 1H NMR (300 MHz, CDCl3, TMS) d 0.80–
0.99 (br, 3H), 1.19–1.41 (br, 4H), 1.51–1.79 (br, 2H),
2.28 and 2.38 (a pair of br s, 3H), 2.57–2.88 (br m,
1H), 3.12–3.40 (br m, 1H), 4.16–4.41 and 4.63–4.90 (a
pair of br, 1H), 7.02 (t, J = 7.5 Hz, 1H), 7.05–7.28 (m,
2H), 8.14 (br d, J = 6.9 Hz, 1H); 13C {1H} NMR
(75 MHz, CDCl3) d 13.9, 22.5, 23.3, and 24.3 (a pair
of s), 27.2, 33.8, and 32.7 (a pair of s), 35.0, 60.6, and
59.8 (a pair of s), 117.8 and 115.1 (a pair of s), 123.8,
124.7, and 126.0 (a pair of s), 127.4, 130.6, and 133.4
(a pair of s), 142.4 and 141.4 (a pair of s), 168.4; Anal.
Calcd for C14H19NO: C, 77.38; H, 8.81; N, 6.45. Found:
C, 77.38; H, 8.93; N, 6.24. The enantiomeric excess of 2a
was determined to be 94% ee by HPLC analysis with
CHIRALPAK AD (4.6 mm B · 250 mm): 4% 2-propa-
nol in hexane, 0.5 ml/min flow, at 35 ꢁC, UV 254 nm
detection, (R) t1 = 24.8 min, (S) t2 = 27.0 min.
4.13.2.
(ꢀ)-N-Acetyl-2-(2-methylpropyl)indoline
2b
(Table 4, entry 1). The general procedure was followed
with N-acetyl-2-(2-methylpropyl)indole 1b (108 mg,
0.50 mmol) to give 2b (99 mg, 91%): pale yellow oil;
20
½aꢁD ¼ ꢀ79:5 (c 1.00, CHCl3); 1H NMR (300 MHz,
CDCl3, TMS) d 0.94 (d, J = 6.3 Hz, 3H), 1.01 (br d,
J = 6.3 Hz, 3H), 1.18–1.80 (br m, 3H), 2.27 and 2.37
(a pair of br s, 3H), 2.56–2.88 (br m, 1H), 3.11–3.40
(br m, 1H), 4.23–4.46 and 4.73–5.01 (a pair of br, 1H),
7.02 (t, J = 7.4 Hz, 1H), 7.14–7.36 (m, 2H), 8.14 (br d,
J = 6.9 Hz, 1H); 13C {1H} NMR (75 MHz, CDCl3) d

530
R. Kuwano et al. / Tetrahedron: Asymmetry 17 (2006) 521–535
21.3, 23.3, 23.7, 24.6, 33.7, and 32.9 (a pair of s), 43.9
and 42.7 (a pair of s), 59.1 and 58.4 (a pair of s), 117.8
and 115.3 (a pair of s), 123.7, 124.9, and 126.0 (a pair
of s), 127.4, 130.4, and 133.4 (a pair of s), 142.2 and
141.5 (a pair of s), 168.1; Anal. Calcd for C14H19NO:
C, 77.38; H, 8.81; N, 6.45. Found: C, 77.39; H, 8.96;
N, 6.50. The enantiomeric excess of 2b was determined
to be 91% ee by HPLC analysis with CHIRALCEL
OD-H (4.6 mm B · 250 mm): 4% 2-propanol in hexane,
0.5 ml/min flow, at 35 ꢁC, UV 254 nm detection, (+)
t1 = 18.1 min, (ꢀ) t2 = 29.0 min.
mined to be 95% ee by HPLC analysis with CHIR-
ALPAK AS (4.6 mm B · 250 mm): 20% 2-propanol in
hexane, 0.5 ml/min flow, at 35 ꢁC, UV 254 nm detection,
(R) t1 = 22.1 min, (S) t2 = 25.3 min.
4.13.6. (ꢀ)-N-Acetyl-2-butyl-5-methylindoline 2f (Table
4, entry 6). The general procedure was followed with
N-acetyl-2-butyl-5-methylindole 1f (115 mg, 0.50 mmol)
20
to give 2f (109 mg, 94%): pale yellow oil; ½aꢁD ¼ ꢀ98:2
1
(c 1.00, CHCl3); H NMR (300 MHz, CDCl3, TMS) d
0.77–0.97 (br, 3H), 1.17–1.76 (br m, 6H), 2.26 and
2.37 (a pair of br s, 3H), 2.30 (s, 3H), 2.52–2.80 (br m,
1H), 3.08–3.35 (br m, 1H), 4.18–4.32 and 4.67–4.82 (a
pair of br, 1H), 6.88–7.06 (m, 2H), 8.01 (br d,
J = 8.1 Hz, 1H); 13C {1H} NMR (75 MHz, CDCl3) d
13.8, 20.9, 22.5, 23.1, and 24.2 (a pair of s), 27.1, 33.7,
and 32.5 (a pair of s), 34.9 and 33.4 (a pair of s), 60.7
and 59.8 (a pair of s), 117.4 and 114.8 (a pair of s),
125.4 and 126.7 (a pair of s), 127.8, 130.7, 133.4,
140.0, and 139.2 (a pair of s), 168.0; Anal. Calcd for
C15H21NO: C, 77.88; H, 9.15; N, 6.05. Found: C,
77.65; H, 9.37; N, 6.05. The enantiomeric excess of 2f
was determined to be 94% ee by HPLC analysis with
CHIRALPAK AD (4.6 mm B · 250 mm): 20% 2-pro-
panol in hexane, 0.5 ml/min flow, at 35 ꢁC, UV
254 nm detection, (ꢀ) t1 = 13.9 min, (+) t2 = 21.6 min.
4.13.3. N-Acetyl-2-cyclohexylindoline 2c (Table 4, entry
2). The general procedure was followed with N-acetyl-
2-cyclohexylindole 1c (121 mg, 0.50 mmol). 1H NMR
analysis of the resulting reaction mixture indicated that
2c was formed in 27%. The enantiomeric excess of 2e
was determined to be 19% ee by HPLC analysis of the
crude mixture with CHIRALCEL OD-H (4.6 mm
B · 250 mm): 4% 2-propanol in hexane, 0.5 ml/min
flow, at 35 ꢁC, UV 254 nm detection, t1 = 19.1 min,
t2 = 23.5 min.
4.13.4. (ꢀ)-N-Acetyl-2-phenylindoline 2d (Table 4, entry
3). The general procedure was followed with N-acetyl-
2-phenylindole 1d (117 mg, 0.50 mmol) to give 2d
20
(108 mg, 91%): pale yellow oil; ½aꢁD ¼ ꢀ148:1 (c 1.00,
1
CHCl3); H NMR (300 MHz, CDCl3, TMS, at 50 ꢁC)
4.13.7. (ꢀ)-N-Acetyl-2-butyl-5-(trifluoromethyl)indoline
2g (Table 4, entry 7). The general procedure was fol-
lowed with N-acetyl-2-butyl-5-(trifluoromethyl)indole
d 1.57–2.40 (br, 3H), 2.96 (br d, J = 16.0 Hz, 1H), 3.76
(br dd, J = 10.2, 16.0 Hz, 1H), 5.14–5.64 (br, 1H), 7.03
(t, J = 7.5 Hz, 1H), 7.08–7.45 (m, 7H), 8.02–8.51 (br,
1H); 13C {1H} NMR (75 MHz, CDCl3, at 50 ꢁC) d
24.0, 38.8, 63.5, 117.0, 124.0, 124.9, 125.1, 127.8,
129.1, 143.3, 143.4, 169.4; Anal. Calcd for C16H15NO:
C, 80.98; H, 6.37; N, 5.90. Found: C, 80.69; H, 6.25;
N, 5.82. The enantiomeric excess of 2d was determined
to be 87% ee by HPLC analysis with CHIRALPAK
AD (4.6 mm B · 250 mm): 10% 2-propanol in hexane,
0.5 ml/min flow, at 35 ꢁC, UV 254 nm detection, (ꢀ)
t1 = 16.9 min, (+) t2 = 19.4 min.
1g (142 mg, 0.50 mmol) to give 2g (119 mg, 84%): pale
20
yellow oil; ½aꢁD ¼ ꢀ61:6 (c 1.00, CHCl3); 1H NMR
(300 MHz, CDCl3, TMS, at 50 ꢁC) d 0.90 (br t,
J = 6.6 Hz, 3H), 1.21–1.46 (br, 4H), 1.46–1.74 (br,
2H), 2.31 (s, 3H), 2.83 (br d, J = 16.0 Hz, 1H), 3.34
(br dd, J = 9.0, 16.0 Hz, 1H), 4.15–4.74 (br, 1H), 7.41
(s, 1H), 7.46 (d, J = 8.4 Hz, 1H), 7.76–8.52 (br, 1H);
13C {1H} NMR (75 MHz, CDCl3, at 50 ꢁC) d 13.8,
22.4, 23.3, 27.0, 33.4, 34.9, 60.9, 117.3, 121.9, 124.4 (q,
J = 272 Hz), 125.2, 125.7 (q, J = 32 Hz), 131.3, 145.2,
168.8; Anal. Calcd for C15H18NOF3: C, 63.15; H, 6.36;
N, 4.91. Found: C, 63.29; H, 6.36; N, 4.92. The enantio-
meric excess of 2g was determined to be 92% ee by
HPLC analysis with CHIRALPAK AD (4.6 mm
B · 250 mm): 20% 2-propanol in hexane, 0.5 ml/min
flow, at 35 ꢁC, UV 254 nm detection, (ꢀ)
t1 = 16.5 min, (+) t2 = 30.3 min.
4.13.5. Methyl (S)-N-acetylindoline-2-carboxylate 2e
(Table 4, entry 5). The general procedure was followed
with methyl N-acetylindole-2-carboxylate 1e (109 mg,
0.50 mmol). Triethylamine was used as an additive in
place of Cs2CO3 and the hydrogenation was conducted
at 100 ꢁC and 100 atm of hydrogen pressure for
30 min. The reaction gave 2e (104 mg, 95%): colorless
20
solid; ½aꢁD ¼ ꢀ126:1 (c 1.00, CHCl3); 1H NMR
4.13.8. (ꢀ)-N-Acetyl-2-butyl-6-(trifluoromethyl)indoline
2h (Table 4, entry 8). The general procedure was fol-
lowed with N-acetyl-2-butyl-6-(trifluoromethyl)indole
(300 MHz, CDCl3, TMS) d 2.18 and 2.49 (a pair of s,
3H), 3.27 and 3.11 (a pair of br d, J = 17.1 Hz and
16.5 Hz, 1H), 3.38–3.69 (br m, 1H), 3.77 and 3.74 (a pair
of s, 3H), 4.92 and 5.17 (a pair of br d, J = 10.5 Hz and
7.8 Hz, 1H), 7.03 (t, J = 7.7 Hz, 1H), 7.10–7.32 (m, 2H),
8.23 (br d, J = 8.1 Hz, 1H); 13C {1H} NMR (75 MHz,
CDCl3) d 23.5 and 24.4 (a pair of s), 33.4 and 31.4 (a
pair of s), 52.8 and 52.3 (a pair of s), 61.3 and 60.1 (a
pair of s), 117.3 and 113.8 (a pair of s), 124.0 and
123.4 (a pair of s), 124.2 and 125.7 (a pair of s), 127.9,
128.4, and 130.8 (a pair of s), 142.6 and 141.3 (a pair
of s), 168.9 and 168.5 (a pair of s), 171.9; HRMS
(FAB) Calcd for C12H13NO3: 219.0895. Found:
219.0892 (M+). The enantiomeric excess of 2e was deter-
1h (141 mg, 0.50 mmol) to give 2h (118 mg, 83%): pale
20
yellow oil; ½aꢁD ¼ ꢀ45:0 (c 1.01, CHCl3); 1H NMR
(300 MHz, CDCl3, TMS, at 50 ꢁC) d 0.90 (br t,
J = 6.8 Hz, 3H), 1.15–1.46 (br m, 4H), 1.46–1.74 (br,
2H), 2.30 (s, 3H), 2.83 (br d, J = 15.8 Hz, 1H), 3.34 (br
dd, J = 8.9, 15.8 Hz, 1H), 4.16–4.66 (br, 1H), 7.17–7.36
(m, 2H), 8.11–8.66 (br, 1H); 13C {1H} NMR (75 MHz,
CDCl3, at 50 ꢁC) d 13.8, 22.4, 23.2, 27.0, 33.7, 35.0,
60.9, 114.6, 120.8, 124.3 (q, J = 273 Hz), 124.9, 129.9
(q, J = 32 Hz), 134.6, 142.8, 168.7; Anal. Calcd for
C15H18NOF3: C, 63.15; H, 6.36; N, 4.91. Found: C,
63.22; H, 6.40; N, 4.93. The enantiomeric excess of 2h

R. Kuwano et al. / Tetrahedron: Asymmetry 17 (2006) 521–535
531
was determined to be 92% ee by HPLC analysis with
CHIRALPAK AD (4.6 mm B · 250 mm): 4% 2-propa-
nol in hexane, 0.5 ml/min flow, at 35 ꢁC, UV 254 nm
detection, (+) t1 = 16.1 min, (ꢀ) t2 = 17.9 min.
(3.6 ml). The mixture was stirred at room temperature
for 1 h, and then was evaporated. After the residue and
(N,N-dimethylamino)pyridine (1.2 mg, 10 lmol) were
dissolved in CH2Cl2 (0.2 ml), acetic anhydride
(12.3 mg, 0.12 mmol) and triethylamine (40.5 mg,
0.40 mmol) were added to the resulting solution at
0 ꢁC. The mixture was stirred for 1 h, and then diluted
with EtOAc. The mixture was washed with 3 M HCl
aq, with saturated NaHCO3 aq, and with water. The
organic layer was dried over Na2SO4, and then evapo-
rated. The residue was purified by a flash column chro-
matography on silica gel (EtOAc/hexane), giving 2a.
4.13.9. (ꢀ)-N-Acetyl-2-butyl-6-methoxyindoline 2i (Table
4, entry 9). The general procedure was followed
with N-acetyl-2-butyl-6-methoxyindole 1i (123 mg,
0.50 mmol) to give 2i (121 mg, 98%): pale yellow oil;
20
½aꢁD ¼ ꢀ54:8 (c 1.01, CHCl3); 1H NMR (300 MHz,
CDCl3, TMS) d 0.79–0.95 (br, 3H), 1.17–1.40 (br, 4H),
1.51–1.74 (br, 2H), 2.27 (br s, 3H), 2.72 (br d,
J = 14.7 Hz, 1H), 3.05–3.32 (br m, 1H), 3.80 (s, 3H),
4.18–4.39 (br, 1H), 6.58 (br dd, J = 2.0, 7.9 Hz, 1H),
7.05 (br d, J = 7.9 Hz, 1H), 7.77–7.90 (br, 1H); 13C
{1H} NMR (75 MHz, CDCl3) d 13.9, 22.5, 23.3, 27.2,
33.0, 35.0, 55.5, 61.5, 103.7, 110.1, 122.4, 124.8, 143.5,
159.4, 168.5; Anal. Calcd for C15H21NO2: C, 72.84; H,
8.56; N, 5.66. Found: C, 72.58; H, 8.64; N, 5.68. The
enantiomeric excess of 2i was determined to be 92% ee
by HPLC analysis with CHIRALPAK AD (4.6 mm
B · 250 mm): 20% 2-propanol in hexane, 0.5 ml/min
flow, at 35 ꢁC, UV 254 nm detection, (+) t1 =
13.5 min, (ꢀ) t2 = 19.0 min.
4.14. General procedure for asymmetric hydrogenation of
3-substituted indoles 3
A mixture of [Rh(nbd)2]SbF6 (2.6 mg, 5.0 lmol) and
(S,S)-(R,R)-PhTRAP (4.0 mg, 5.0 lmol) in dry 2-propa-
nol (2.0 ml) was stirred at room temperature for 10 min.
The resulting orange suspension was transferred by can-
nula to a mixture of 3 (0.50 mmol) and Cs2CO3
(16.2 mg, 50 lmol). The mixture was moved into a nitro-
gen-filled 50 ml stainless steel autoclave. Hydrogen was
introduced into the autoclave until the pressure gauge
indicated over 50 atm. The pressure was then carefully
released to 1 atm. This procedure was repeated twice,
and finally the inside of the autoclave pressurized with
hydrogen to 50 atm. The reaction mixture was stirred
at 80 ꢁC for 24 h. The resulting mixture was concen-
trated under reduced pressure. The residue was purified
by a flash column chromatography on silica gel (EtOAc/
hexane) to give 4. The enantiomeric excess of 4 was
determined by chiral HPLC analysis.
4.13.10. (R)-2-Methyl-N-(p-toluenesulfonyl)indoline 2j
(Table 4, entry 10). The general procedure was fol-
lowed with 2-methyl-N-(p-toluenesulfonyl)indole 1j
(143 mg, 0.50 mmol) to give 2j (50 mg, 45%): pale yel-
27
low oil; ½aꢁD ¼ þ206:8 (c 0.99, CHCl3); 1H NMR
(400 MHz, CDCl3, TMS) d 1.42 (d, J = 6.5 Hz, 3H),
2.34 (s, 3H), 2.43 (dd, J = 2.2, 16.0 Hz, 1H), 2.89 (dd,
J = 9.4, 16.0 Hz, 1H), 4.30–4.39 (m, 1H), 6.98–7.06
(m, 2H), 7.13–7.27 (m, 3H), 7.55 (d, J = 8.1 Hz, 2H),
7.65 (d, J = 8.0 Hz, 1H); 13C {1H} NMR (100.5 MHz,
CDCl3) d 21.5, 23.3, 36.2, 58.4, 117.1, 124.4, 125.2,
126.9, 127.6, 129.5, 131.6, 135.3, 141.0, 143.7. The
enantiomeric excess of 2j was determined to be 78% ee
by HPLC analysis with CHIRALPAK AD-H (4.6 mm
B · 250 mm): 4% 2-propanol in hexane, 0.5 ml/min
flow, at 35 ꢁC, UV 254 nm detection, (S) t1 = 25.5 min,
(R) t2 = 32.0 min.
4.14.1. (S)-3-Methyl-N-(p-toluenesulfonyl)indoline 4c
(Table 5, entry 3). The general procedure was followed
with 3-methyl-N-(p-toluenesulfonyl)indole 3c (143 mg,
0.50 mmol) to give (S)-4c (138 mg, 96%): colorless solid;
20
½aꢁD ¼ þ29:4 (c 1.06, CHCl3); 1H NMR (300 MHz,
CDCl3, TMS) d 1.11 (d, J = 7.0 Hz, 3H), 2.36 (s, 3H),
3.19 (double quintet, J = 8.6, 7.0 Hz, 1H), 3.42 (dd,
J = 7.0, 10.4 Hz, 1H), 4.08 (dd, J = 8.6, 10.4 Hz, 1H),
6.96–7.08 (m, 2H), 7.16–7.26 (m, 3H), 7.64 (d,
J = 8.4 Hz, 1H), 7.68 (d, J = 8.4 Hz, 2H); 13C {1H}
NMR (75 MHz, CDCl3) d 19.4, 21.4, 34.6, 57.5, 114.9,
123.8, 124.0, 127.4, 127.9, 129.7, 134.1, 136.9, 141.6,
144.1; Anal. Calcd for C16H17NO2S: C, 66.87; H, 5.96;
N, 4.87. Found: C, 66.84; H, 5.96; N, 4.73. The enantio-
meric excess of 4c was determined to be 98% ee by
HPLC analysis with CHIRALCEL OD-H (4.6 mm
B · 250 mm): 4% 2-propanol in hexane, 0.5 ml/min
flow, at 35 ꢁC, UV 254 nm detection, (S) t1 = 22.4 min,
(R) t2 = 25.8 min.
4.13.11. (R)-N-(tert-Butoxycarbonyl)-2-butylindoline 2k
(Table 4, entry 11). The general procedure was
followed with N-(tert-butoxycarbonyl)-2-butylindole
1k (139 mg, 0.51 mmol) to give 2k (131 mg, 94%): color-
26
less oil; ½aꢁD ¼ ꢀ46:3 (c 1.04, CHCl3); 1H NMR
(400 MHz, CDCl3, TMS) d 0.90 (t, J = 6.9 Hz, 3H),
1.23–1.41 (m, 4H), 1.46–1.62 (m, 1H), 1.56 (s, 9H),
1.71–1.81 (m, 1H), 2.72 (dd, J = 2.1, 16.0 Hz, 1H),
3.26 (dd, J = 9.7, 16.0 Hz, 1H), 4.37 (br, 1H), 6.92
(t, J = 7.4 Hz, 1H), 7.10–7.17 (m, 2H), 7.40–7.88 (br,
1H); 13C {1H} NMR (100.5 MHz, CDCl3) d 14.1,
22.6, 27.2, 28.5, 33.3, 34.3, 59.4, 80.6, 115.3, 122.2,
124.8, 127.2, 130.5, 142.2, 152.4; Anal. Calcd for
C17H25NO2: C, 74.14; H, 9.15; N, 6.45. Found: C,
77.39; H, 8.96; N, 6.50. The enantiomeric excess of 2k
was determined to be 77% ee by HPLC analysis of 2a
derived from 2k with CHIRALPAK AD (4.6 mm
B · 250 mm). The procedure of the transformation is
as follows: trifluoroacetic acid (0.4 ml) was added at
0 ꢁC to a solution of 2k (23.5 mg, 0.10 mmol) in CH2Cl2
4.14.2. (R)-3-Methyl-N-(p-toluenesulfonyl)indoline 4c
(Table 5, entry 4). The general procedure was followed
with 3-methyl-N-(p-toluenesulfonyl)indole 3c (285 mg,
1.00 mmol) and (R,R)-(S,S)-PhTRAP to give (R)-4c
25
(280 mg, 98%): colorless solid; ½aꢁD ¼ ꢀ32:4 (c 1.54,
CHCl3). The enantiomeric excess of 4c was determined
to be 98% ee by HPLC analysis with CHIRALCEL
OD-H (4.6 mm B · 250 mm).

532
R. Kuwano et al. / Tetrahedron: Asymmetry 17 (2006) 521–535
4.14.3. (+)-3-(2-Propyl)-N-(p-toluenesulfonyl)indoline 4f
(Table 6, entry 1). The general procedure was followed
with the exception of amount of solvent (1 ml) and reac-
tion time (48 h), with 3-(2-propyl)-N-(p-toluenesulfon-
yl)indole 3f (157 mg, 0.50 mmol) to give 4f (152 mg,
50 ꢁC, UV 254 nm detection, (ꢀ) t1 = 54.1 min, (+)
t2 = 58.0 min.
4.14.6. (+)-3-[2-{N-(tert-Butoxycarbonyl)amino}ethyl]-
N-(p-toluenesulfonyl)indoline 4i (Table 6, entry 4).
The general procedure was followed with 3-[2-{N-(tert-
butoxycarbonyl)amino}ethyl]-N-(p-toluenesulfonyl)-
indole 3i (208 mg, 0.50 mmol) to give 4i (148 mg,
20
1
94%): colorless oil; ½aꢁD ¼ ꢀ19:1 (c 1.06, CHCl3); H
NMR (400 MHz, CDCl3, TMS) d 0.63 (d, J = 6.8 Hz,
3H), 0.88 (d, J = 6.8 Hz, 3H), 1.87 (double septet,
J = 4.8, 6.8 Hz, 1H), 2.37 (s, 3H), 3.11 (dt, J = 10.5,
5.2 Hz, 1H), 3.73 (dd, J = 5.5, 10.5 Hz, 1H), 3.81 (dd,
J = 10.0, 10.5 Hz, 1H), 6.96 (t, J = 7.5 Hz, 1H), 7.06
(d, J = 7.5 Hz, 1H), 7.19 (t, J = 8.0 Hz, 1H), 7.23 (d,
J = 8.0 Hz, 2H), 7.64 (d, J = 8.0 Hz, 1H), 7.71 (d,
J = 8.0 Hz, 2H); 13C {1H} NMR (100.5 MHz, CDCl3)
d 17.3, 20.0, 21.5, 31.3, 45.8, 51.7, 114.1, 123.2, 125.0,
127.3, 127.9, 129.6, 133.9 (2C), 142.2, 144.0; Anal. Calcd
for C18H21NO2S: C, 68.54; H, 6.71; N, 4.44. Found: C,
68.47; H, 6.70; N, 4.39. The enantiomeric excess of 4f
was determined to be 97% ee by HPLC analysis with
CHIRALCEL OD-H (4.6 mm B · 250 mm), 20% 2-
propanol in hexane, 0.5 ml/min flow, at 35 ꢁC, UV
254 nm detection, (+) t1 = 17.3 min, (ꢀ) t2 = 19.3 min.
20
1
71%): colorless solid; ½aꢁD ¼ þ9:0 (c 1.02, CHCl3); H
NMR (300 MHz, CDCl3, TMS) d 1.32–1.55 (m, 1H),
1.44 (s, 9H), 1.67–1.80 (m, 1H), 2.37 (s, 3H), 3.05–3.20
(m, 3H), 3.61 (dd, J = 5.9, 10.6 Hz, 1H), 4.00 (dd,
J = 9.2, 10.6 Hz, 1H), 4.48 (br s, 1H), 6.99 (t,
J = 7.4 Hz, 1H), 7.08 (d, J = 7.4 Hz, 1H), 7.17–7.26
(m, 3H), 7.65 (d, J = 8.1 Hz, 1H), 7.69 (d, J = 8.4 Hz,
2H); 13C {1H} NMR (75 MHz, CDCl3) d 21.4, 28.3,
29.6, 35.3, 37.6, 38.2, 55.4, 114.9, 123.8, 124.4, 127.4,
128.2, 129.7, 133.9, 134.9, 141.7, 144.2, 155.9; Anal.
Calcd for C22H28N2O4S: C, 63.44; H, 6.78; N, 6.73.
Found: C, 63.71; H, 6.83; N, 6.60. The enantiomeric
excess of 4i was determined to be 95% ee by HPLC
analysis with CHIRALCEL OC (4.6 mm B ·
250 mm), 20% 2-propanol in hexane, 0.5 ml/min flow,
at 35 ꢁC, UV 254 nm detection, (+) t1 = 31.6 min, (ꢀ)
t2 = 38.8 min.
4.14.4. (+)-3-Phenyl-N-(p-toluenesulfonyl)indoline 4g
(Table 6, entry 2). The general procedure was followed
with 3-phenyl-N-(p-toluenesulfonyl)indole 3g (174 mg,
0.50 mmol), [Rh(nbd)2]SbF6 (5.2 mg, 10 lmol), and
4.14.7. tert-Butyl (+)-3-[N-(p-toluenesulfonyl)indolin-3-
yl]propionate 4j (Table 6, entry 5). The general proce-
dure was followed with tert-butyl 3-[N-(p-toluenesulfon-
(S,S)-(R,R)-PhTRAP (8.3 mg, 10.5 lmol) to give
25
4g (163 mg, 93%): colorless solid; ½aꢁD ¼ þ88:9 (c 1.01,
yl)indol-3-yl]propionate 3j (201 mg, 0.50 mmol) to
1
CHCl3); H NMR (400 MHz, CDCl3, TMS) d 2.39 (s,
20
give 4j (187 mg, 93%): colorless solid; ½aꢁD ¼ þ15:6 (c
3H), 3.74–3.82 (m, 1H), 4.31–4.38 (m, 2H), 6.84–6.89
(m, 3H), 6.97 (t, J = 7.5 Hz, 1H), 7.17–7.28 (m, 6H),
7.68 (d, J = 8.0 Hz, 2H), 7.74 (d, J = 8.0 Hz, 1H); 13C
{1H} NMR (100.5 MHz, CDCl3) d 21.6, 46.2, 58.5,
114.9, 124.0, 125.6, 127.1, 127.4, 127.7, 128.3, 128.7,
129.7, 133.8, 134.8, 142.1, 142.4, 144.1; Anal. Calcd
for C21H19NO2S: C, 72.18; H, 5.48; N, 4.01. Found:
C, 71.96; H, 5.46; N, 3.90. The enantiomeric excess of
4g was determined to be 96% ee by HPLC analysis with
CHIRALCEL OD-H (4.6 mm B · 25 cm): 20% 2-pro-
panol in hexane, 0.5 ml/min flow, at 35 ꢁC, UV
254 nm detection, (+) t1 = 26.4 min, (ꢀ) t2 = 31.6 min.
1.06, CHCl3); 1H NMR (300 MHz, CDCl3, TMS) d
1.43 (s, 9H), 1.47–1.60 (m, 1H), 1.79–1.92 (m, 1H),
2.16 (t, J = 7.7 Hz, 2H), 2.36 (s, 3H), 3.08–3.20 (m,
1H), 3.58 (dd, J = 5.9, 10.4 Hz, 1H), 3.97 (dd, J = 9.0,
10.4 Hz, 1H), 6.99 (dt, J = 0.9, 7.5 Hz, 1H), 7.09 (d,
J = 7.5 Hz, 1H), 7.18–7.26 (m, 3H), 7.65 (d,
J = 8.4 Hz, 1H), 7.69 (d, J = 8.1 Hz, 2H); 13C {1H}
NMR (75 MHz, CDCl3) d 21.4, 28.0, 29.7, 32.5, 39.0,
55.2, 80.6, 114.8, 123.7, 124.6, 127.3, 128.2, 129.7,
133.8, 134.7, 141.7, 144.2, 172.2; Anal. Calcd for
C22H27NO4S: C, 65.81; H, 6.78; N, 3.49. Found: C,
66.03; H, 6.82; N, 3.50. The enantiomeric excess of 4j
was determined to be 97% ee by HPLC analysis with
CHIRALPAK AD (4.6 mm B · 250 mm), 4% 2-propa-
nol in hexane, 0.5 ml/min flow, at 35 ꢁC, UV 254 nm
detection, (+) t1 = 37.7 min, (ꢀ) t2 = 41.6 min.
4.14.5.
(+)-3-[2-(tert-Butyldimethylsilyloxy)ethyl]-N-
(p-toluenesulfonyl)indoline 4h (Table 6, entry 3). The
general procedure was followed with 3-[2-(tert-butyl-
dimethylsilyloxy)ethyl]-N-(p-toluenesulfonyl)indole 3h
(215 mg, 0.50 mmol) to give 4h (202 mg, 94%): colorless
4.14.8. Methyl 3-[N-(p-toluenesulfonyl)indolin-3-yl]propi-
onate 4k (Table 6, entry 6). The general procedure was
followed with methyl 3-[N-(p-toluenesulfonyl)indol-3-
20
solid; ½aꢁD ¼ þ9:7 (c 1.18, CHCl3); 1H NMR (300 MHz,
CDCl3, TMS) d 0.05 (s, 6H), 0.90 (s, 9H), 1.32–1.45 (m,
1H), 1.70–1.82 (m, 1H), 2.32 (s, 3H), 3.14–3.27 (m, 1H),
3.57 (dd, J = 6.6, 10.8 Hz, 1H), 3.58 (t, J = 6.0 Hz, 2H),
3.99 (dd, J = 9.0, 10.8, 1H), 6.94 (dt, J = 0.8, 7.4 Hz,
1H), 7.02 (d, J = 7.4 Hz, 1H), 7.12–7.21 (m, 3H), 7.58–
7.66 (m, 3H); 13C {1H} NMR (75 MHz, CDCl3) d
ꢀ5.5, 18.1, 21.4, 25.8, 37.2, 37.5, 56.0, 60.7, 114.9,
123.7, 124.4, 127.4, 128.0, 129.7, 134.1, 135.7, 141.8,
144.0; Anal. Calcd for C23H33NO3SSi: C, 64.00; H,
7.71; N, 3.24. Found: C, 64.27; H, 7.86; N, 3.33. The
enantiomeric excess of 4h was determined to be 98%
ee by HPLC analysis with Ceramospher RU-1
(4.6 mm B · 250 mm), methanol, 0.08 ml/min flow, at
1
yl]propionate 3k (179 mg, 0.50 mmol). H NMR analy-
sis of the resulting reaction mixture indicated that 4k
was formed in 32%. The enantiomeric excess of 4k was
determined to be 97% ee by HPLC analysis with CHIR-
ALPAK AS (4.6 mm B · 250 mm), 30% 2-propanol in
hexane, 0.5 ml/min flow, at 35 ꢁC, UV 254 nm detection,
t1 = 23.3 min, t2 = 28.0 min.
4.14.9. tert-Butyl [N-(p-toluenesulfonyl)indolin-3-yl]ace-
tate 4l (Table 6, entry 7). The general procedure was
followed with tert-butyl [N-(p-toluenesulfonyl)indol-3-
1
yl]acetate 3l (98 mg, 0.25 mmol). H NMR analysis of

R. Kuwano et al. / Tetrahedron: Asymmetry 17 (2006) 521–535
533
the resulting reaction mixture indicated that 4l was
formed in 29%. The enantiomeric excess of 4l was deter-
mined to be 62% ee by HPLC analysis with CHIR-
ALPAK AS (4.6 mm B · 250 mm), 4% 2-propanol in
hexane, 0.5 ml/min flow, at 35 ꢁC, UV 254 nm detection,
t1 = 18.7 min, t2 = 25.8 min.
methane (0.25 ml) was added dropwise to a solution
of oxalyl chloride (70 mg, 0.55 mmol) in dry dichloro-
methane (0.5 ml) at ꢀ60 ꢁC for 30 min. After 5 min, a
solution of (S)-8 (95.6 mg, 0.50 mmol) in dry
dichloromethane (0.25 ml) was added dropwise to the
reaction mixture for 5 min. After 15 min, triethylamine
(250 mg, 2.5 mmol) was added. After 5 min, the mixture
was warmed to room temperature, and stirred for
10 min. The mixture was diluted with water, and ex-
tracted three times with EtOAc. The combined organic
layer was washed with brine, dried over Na2SO4, and
evaporated. The residue was dissolved in dry diethyl
ether (1.5 ml). A suspension of the phosphonium ylide,
which was prepared by mixing triphenylpropylphospho-
nium bromide (202 mg, 0.52 mmol) and potassium tert-
butoxide (73 mg, 0.65 mmol) in dry diethyl ether
(1.5 ml) at 0 ꢁC for 2.5 h was added to the solution of
the residue at ꢀ78 ꢁC. After 1 h, the resulting mixture
was warmed to room temperature and stirred for 24 h.
After the mixture was diluted with Et2O, the colorless
precipitate was filtered off. The filtrate was evaporated.
The residue was purified by a preparative TLC
4.15. Assignment of the absolute configuration of 2a and
2e
4.15.1. Methyl (S)-indoline-2-carboxylate hydrochloride
7. Thionyl chloride (2.6 ml, 36 mmol) was added care-
fully to dry methanol (10 ml) at ꢀ10 ꢁC. After the mix-
ture was stirred for 10 min, (S)-indoline-2-carboxylic
acid 6 (1.63 g, 10.0 mmol) was added to the resulting
solution. The mixture was stirred at room temperature
for 53 h, and then evaporated. The residue was crystal-
lized in Et2O, giving (S)-7 (2.12 g, 99%): colorless crys-
1
tals; H NMR (200 MHz, CD3OD) d 3.51 (dd, J = 7.6,
16.4 Hz, 1H), 3.71 (dd, J = 9.4, 16.4 Hz, 1H), 3.89 (s,
3H), 5.09 (dd, J = 7.6, 9.4 Hz, 1H), 7.37–7.54 (m, 4H).
1
4.15.2.
Methyl
(S)-N-acetylindoline-2-carboxylate
(EtOAc/hexane), giving (S)-9 (1.6 mg, 1.5%): H NMR
2e. Triethylamine (2.54 g, 25 mmol) was added at
room temperature to a suspension of (S)-7 (2.12 g,
9.9 mmol) in dry THF (10 ml). After 30 min, acetic
anhydride (1.19 g, 12 mmol) was added to the resulting
mixture at 0 ꢁC. The mixture was stirred at 0 ꢁC for
10 min and then at room temperature for 17 h. The mix-
ture was diluted with water, and then extracted with
EtOAc. The organic layer was washed with 10% HCl
aq, then with saturated Na2CO3 aq, followed by brine,
dried over Na2SO4, and then evaporated. The residue
was purified by a flash column chromatography on silica
gel (EtOAc/hexane), giving (S)-2e (1.86 g, 86%): color-
(200 MHz, CDCl3, TMS) d 1.06 (t, J = 7.5 Hz, 3H),
2.08–2.32 (br, 5H), 2.79 (br d, J = 15.4 Hz, 1H), 3.56
(br dd, J = 10.4, 15.4 Hz, 1H), 5.00–5.18 (br, 1H),
5.36–5.56 (m, 2H), 7.02 (dt, J = 0.9, 7.5 Hz, 1H), 7.11–
7.29 (m, 2H), 8.20 (br d, J = 7.6 Hz, 1H).
4.15.5. (R)-N-Acetyl-2-butylindoline 2a. A mixture of
(S)-9 (1.6 mg, 7.4 lmol) and palladium on carbon (5%)
(1.3 mg) in dry methanol (1.0 ml) was stirred at room
temperature and 50 atm of hydrogen pressure for 3 h.
The catalyst was filtered off through Celite, and then
the filtrate was evaporated. The residue was passing
through a short column on silica gel (EtOAc/hex-
ane = 1/1), giving (R)-2a. The retention time of the
authentic (R)-2a in chiral HPLC analysis with CHIR-
ALPAK AD revealed the absolute configuration of
(ꢀ)-2a obtained from the asymmetric hydrogenation
of 1a using (S,S)-(R,R)-PhTRAP to be R.
1
less solid; H NMR (200 MHz, CDCl3, TMS) d 2.18
and 2.49 (a pair of br s, 3H), 3.00–3.67 (br m, 2H),
3.77 and 3.74 (a pair of s, 3H), 4.84–4.98 and 5.10–
5.23 (a pair of br m, 1H), 7.03 (t, J = 7.9 Hz, 1H),
7.09–7.31 (m, 2H), 8.22 (br d, J = 7.8 Hz, 1H). The
retention time of the authentic (S)-2e in HPLC analysis
with CHIRALPAK AS revealed the absolute configura-
tion of (ꢀ)-2e obtained from the asymmetric hydrogena-
tion of 1e using (S,S)-(R,R)-PhTRAP to be S.
4.16. Assignment of the absolute configuration of 2j
Trifluoroacetic acid (2.4 ml) was added at 0 ꢁC to a solu-
tion of (R)–N-(tert-butoxycarbonyl)-3-methyl indoline13
(145 mg, 0.62 mmol) in dry dichloromethane (21.6 ml).
The reaction mixture was stirred at room temperature
for 1 h, and then evaporated. The residue was regarded
as 3-methylindoline trifluoroacetic acid salt (153.8 mg).
The residue (26.3 mg, 0.11 mmol) and triethylamine
(43.2 mg, 0.43 mmol) were added at 0 ꢁC to a solution
of p-toluenesulfonyl chloride (38.4 mg, 0.20 mmol) and
4-(N,N-dimethylamino)pyridine (1.2 mg, 10 lmol) in
dry dichloromethane (0.1 ml). The reaction mixture
was stirred at room temperature for 24 h. After water
was added, the resulting mixture was extracted four
times with EtOAc. The combined organic layer was
washed with 3 M HCl aq, with saturated NaHCO3 aq,
dried over Na2SO4, and then evaporated. The residue
was purified by flash column chromatography on
silica gel (EtOAc/hexane), giving the authentic sample
of (R)-2j (10.5 mg, 43%). The retention time of the
4.15.3. (S)-N-Acetyl-2-(hydroxymethyl)indoline 8. Lith-
ium borohydride (205 mg, 9.4 mmol) was added to a
solution of (S)-2e (1.37 g, 6.2 mmol) in dry THF
(6.2 ml) at room temperature. After the mixture was stir-
red for 5 h, 10% HCl aq was carefully added to the reac-
tion mixture. The mixture was extracted twice with
EtOAc. The combined organic layer was washed with
saturated Na2CO3 aq, with brine, dried with Na2SO4,
and then evaporated. The residue was purified by a flash
column chromatography on silica gel (EtOAc/hexane),
giving 890 mg (74%) of (S)-8: 1H NMR (200 MHz,
CDCl3, TMS) d 2.18–2.54 (br s, 3H), 2.54–2.96 (br m,
1H), 3.34 (dd, J = 9.5, 16.5 Hz, 1H), 3.43–3.85 (m,
2H), 4.35–4.67 and 4.81–5.09 (a pair of br, 1H), 7.04
(t, J = 7.5 Hz, 1H), 7.11–7.34 and 7.92–8.12 (br, 3H).
4.15.4. (S)-N-Acetyl-2-(1-butenyl)indoline 9. A solution
of dimethyl sulfoxide (78 mg, 1.0 mmol) in dry dichloro-

534
R. Kuwano et al. / Tetrahedron: Asymmetry 17 (2006) 521–535
Catal. 1997, 170, 254–264; (b) Besson, M.; Gallezot, P.;
Neto, S.; Pinel, C. Chem. Commun. 1998, 1431–1432; (c)
Besson, M.; Delbecq, F.; Gallezot, P.; Neto, S.; Pinel, C.
Chem. Eur. J. 2000, 6, 949–958; (d) Ranade, V. S.; Prins,
R. J. Catal. 1999, 185, 479–486; (e) Ranade, V. S.;
Consiglio, G.; Prins, R. Catal. Lett. 1999, 58, 71–74; (f)
authentic (R)-2j in chiral HPLC analysis with CHIR-
ALPAK AD-H revealed the absolute configuration of
(+)-2j obtained from the asymmetric hydrogenation of
1j using (S,S)-(R,R)-PhTRAP to be R.
4.17. Assignment of the absolute configuration of 4c
´
´
´
Hegedus, L.; Hada, V.; Tungler, A.; Mathe, T.; Szepesy,
L. Appl. Catal. A 2000, 201, 107–114; (g) Kukula, P.;
Prins, R. J. Catal. 2002, 208, 404–411; (h) Douja, N.;
Besson, M.; Gallezot, P.; Pinel, C. J. Mol. Catal. A: Chem.
2002, 186, 145–151; (i) Douja, N.; Malacea, R.; Banciu,
M.; Besson, M.; Pinel, C. Tetrahedron Lett. 2003, 44,
6991–6993; (j) Barbosa, L. A. M. M.; Sautet, P. J. Catal.
2003, 217, 23–29.
Compound (+)-4c (72.5 mg, 0.25 mmol), which was ob-
tained from the asymmetric hydrogenation of 3c using
(S,S)-(R,R)-PhTRAP, was dissolved in dry toluene
(0.5 ml). Sodium bis(2-methoxyethoxy)aluminum dihy-
dride (ca. 70% in toluene) (340 mg, 1.18 mmol) was
added to the solution of 4c. The mixture was stirred un-
der reflux for 16 h. After water was carefully added to
the mixture, the resulting suspension was diluted with
EtOAc, and then filtered through Celite. The filtrate
was extracted three times with EtOAc. The combined
organic layer was dried with Na2SO4, and evaporated.
To a suspension of the residue, K2CO3 (57 mg,
0.41 mmol), and KI (4.5 mg, 27 lmol) in dry DMF
(0.5 ml) was added benzyl chloride (48 mg, 0.38mmol).
After 5 h of stirring at 100 ꢁC, water was added to the
resulting mixture. The mixture was extracted ten times
with hexanes. The combined organic layer was washed
with water, dried with Na2SO4, and evaporated. After
passing through a column on silica gel, the residue was
purified by medium-pressure liquid chromatography
(EtOAc/hexane) with C.I.G. pre-packed column CPS-
223L-1 (Kusano, Tokyo, Japan), giving (+)-N-benzyl-
3-methylindoline (26 mg, 46 %) as pale yellow oil:
3. Recently, Glorius reported the highly stereoselective
hydrogenation of pyridines modified with a chiral oxazo-
lidinone, see: (a) Glorius, F.; Spielkamp, N.; Holle, S.;
Goddard, R.; Lehmann, C. W. Angew. Chem., Int. Ed.
2004, 43, 2850–2852; (b) Scheiper, B.; Glorius, F.; Leitner,
A.; Furstner, A. Proc. Natl. Acad. Sci. U.S.A. 2004, 101,
¨
11960–11965; (c) Glorius, F. Org. Biomol. Chem. 2005, 3,
4171–4175.
4. Comprehensive Natural Products Chemistry; Barton, D.,
Nakanish, K., Meth-Cohn, O., Eds.; Elsevier: Oxford,
1999; Vols. 1–9.
5. (a) Bianchini, C.; Barbaro, P.; Scapacci, G.; Farnetti, E.;
Graziani, M. Organometallics 1998, 17, 3308–3310; (b)
Henschke, J. P.; Burk, M. J.; Malan, C. G.; Herzberg, D.;
Peterson, J. A.; Wildsmith, A. J.; Cobley, C. J.; Casy, G.
Adv. Synth. Catal. 2003, 345, 300–307.
6. Kuwano, R.; Sato, K.; Kurokawa, T.; Karube, D.; Ito, Y.
J. Am. Chem. Soc. 2000, 122, 7614–7615.
7. (a) Sawamura, M.; Hamashima, H.; Ito, Y. Tetrahedron:
Asymmetry 1991, 2, 593–596; (b) Sawamura, M.; Hama-
shima, H.; Sugawara, M.; Kuwano, R.; Ito, Y. Organo-
metallics 1995, 14, 4549–4558.
26
20
½aꢁD ¼ þ59:0 (c 0.51, CH2Cl2), lit.14 ½aꢁD ¼ ꢀ49:7 (c 1,
1
CH2Cl2) for 87% ee (R); H NMR (400 MHz, CDCl3,
TMS) d 1.30 (d, J = 6.5 Hz, 3H), 2.83 (t, J = 8.5 Hz,
1H), 3.30 (sextet, J = 7.5 Hz, 1H), 3.50 (t, J = 8.5 Hz,
1H), 4.11 (d, J = 15.1 Hz, 1H), 4.36 (d, J = 15.1 Hz,
1H), 6.51 (d, J = 8.0 Hz, 1H), 6.70 (t, J = 7.5 Hz, 1H),
7.06 (t, J = 7.0 Hz, 2H), 7.24–7.36 (m, 5H); 13C {1H}
NMR (100.5 MHz, CDCl3) d 18.6, 35.2, 53.4, 61.6,
107.0, 117.7, 123.2, 127.0, 127.4, 127.9, 128.4, 135.0,
138.5, 152.1.
8. Kuwano, R.; Kaneda, K.; Ito, T.; Sato, K.; Kurokawa, T.;
Ito, Y. Org. Lett. 2004, 6, 2213–2215.
9. (a) Wang, W.-B.; Lu, S.-M.; Yang, P.-Y.; Han, X.-W.;
Zhou, Y.-G. J. Am. Chem. Soc. 2003, 125, 10536–10537;
(b) Yang, P.-Y.; Zhou, Y.-G. Tetrahedron: Asymmetry
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G. Adv. Synth. Catal. 2004, 346, 909–912; (d) Xu, L.; Lam,
K. H.; Ji, J.; Wu, J.; Fan, Q.-H.; Lo, W.-H.; Chan, A. S.
C. Chem. Commun. 2005, 1390–1392.
10. Legault, C. Y.; Charette, A. B. J. Am. Chem. Soc. 2005,
127, 8966–8967.
Acknowledgements
11. Catalytic asymmetric hydrogenations of pyridines and
furans have been reported but were low enantioselective,
see: (a) Blaser, H.-U.; Ho¨ning, H.; Studer, M.; Wede-
meyer-Exl, C. J. Mol. Catal. A: Chem. 1999, 139, 253–257;
(b) Raynor, S. A.; Thomas, J. M.; Raja, R.; Johnson, B. F.
G.; Bell, R. G.; Mantle, M. D. Chem. Commun. 2000,
1925–1926; (c) Studer, M.; Wedemeyer, C.; Spindler, F.;
Blaser, H.-U. Monatsh. Chem. 2000, 131, 1335–1343.
12. Kuwano, R.; Sato, K.; Ito, Y. Chem. Lett. 2000, 428–
429.
13. Gross, K. M. B.; Jun, Y. M.; Beak, P. J. Org. Chem. 1997,
62, 7679–7689.
14. Gil, G. S.; Groth, U. M. J. Am. Chem. Soc. 2000, 122,
6789–6790.
15. The enantiomeric excess of 3-methylindoline was deter-
mined by chiral HPLC analysis of its acetamido deriva-
tive, which was prepared by the treatment with acetic
anhydride.
This work was supported by Kyushu University Foun-
dation, the Naito Foundation, and Grant-in-Aids for
Scientific Research on Priority Area 17035062 from
MEXT.
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