Highly enantioselective synthesis of chiral 3-substituted indolines by catalytic asymmetric hydrogenation of indoles

Article abstract of DOI:10.1021/ol049317k

N-Tosyl 3-substituted indoles were hydrogenated with high enantioselectivities (95-98% ee) by use of a trans-chelating chiral bisphosphine, (S,S)-(R,R)-PhTRAP ligand. The chiral catalyst, which was generated in situ from [Rh(nbd)₂]SbF6, PhTRAP, and Cs ₂CO₃, is useful for enantioselectively synthesizing a range of diverse optically active indolines possessing a chiral carbon at the 3-position.

Full text of DOI:10.1021/ol049317k

ORGANIC
LETTERS
2004
Vol. 6, No. 13
2213-2215
Highly Enantioselective Synthesis of
Chiral 3-Substituted Indolines by
Catalytic Asymmetric Hydrogenation of
Indoles
,†
Ryoichi Kuwano,* Kohei Kaneda,† Takashi Ito,‡ Koji Sato,‡
,‡
Takashi Kurokawa,‡ and Yoshihiko Ito*
Department of Chemistry, Graduate School of Sciences, Kyushu UniVersity, 6-10-1
Hakozaki, Higashi-ku, Fukuoka 812-8581, Japan, and Department of Synthetic
Chemistry & Biological Chemistry, Graduate School of Engineering, Kyoto UniVersity,
Sakyo-ku, Kyoto 606-8501, Japan
rkuwascc@mbox.nc.kyushu-u.ac.jp
Received April 14, 2004
ABSTRACT
N-Tosyl 3-substituted indoles were hydrogenated with high enantioselectivities (95−98% ee) by use of a trans-chelating chiral bisphosphine,
(S,S)-(R,R)-PhTRAP ligand. The chiral catalyst, which was generated in situ from [Rh(nbd)2]SbF6, PhTRAP, and Cs2CO , is useful for
3
enantioselectively synthesizing a range of diverse optically active indolines possessing a chiral carbon at the 3-position.
The highly enantioselective hydrogenation of heteroaromatics
could offer a straightforward approach to a wide range of
optically active heterocycles if it could be performed
successfully on a routine basis. However, the heteroaromatic
substrates applicable to asymmetric reduction have so far
been limited to 2-methylquinoxaline,1 2-substituted quino-
lines,2,3 and 2-substituted indoles.4
selective formation of a chiral center at the 3-position have
been scarce. Recently, Groth and Bailey reported the ster-
eoselective syntheses of chiral 3-substituted indolines by
asymmetric intramolecular carbolithiation.7-9 This methodol-
ogy suffers several disadvantages in that it requires an excess
of chiral agent to deliver chiral products that never exceed
90% ee.
Notwithstanding 3-substituted indolines being important
chiral constituents of a number of biologically active com-
pounds (e.g., the Duocarmycins),5,6 methods for the enantio-
Recently, we reported the first highly enantioselective
hydrogenation of 2-substituted N-acetylindoles.4 A rhodium
complex bearing a trans-chelating chiral bisphosphine
PhTRAP10-12 (Figure 1) was the most enantioselective cat-
alyst. It afforded optically active indolines bearing a chiral
† Kyushu University.
‡ Kyoto University.
(1) Bianchini, C.; Barbaro, P.; Scapacci, G.; Farnetti, E.; Graziani, M.
Organometallics 1998, 17, 3308-3310.
(2) Wang, W.-B.; Lu, S.-M.; Yang, P.-Y.; Han, X.-W.; Zhou, Y.-G. J.
Am. Chem. Soc. 2003, 125, 10536-10537.
(3) Yang, P.-Y.; Zhou, Y.-G. Tetrahedron: Asymmetry 2004, 15, 1145-
1149.
(6) Yamada, K.; Kurokawa, T.; Tokuyama, H.; Fukuyama, T. J. Am.
Chem. Soc. 2003, 125, 6630-6631.
(7) Gil, G. S.; Groth, U. M. J. Am. Chem. Soc. 2000, 122, 6789-6790.
(8) Bailey, W. F.; Mealy, M. J. J. Am. Chem. Soc. 2000, 122, 6787-
6788.
(4) Kuwano, R.; Sato, K.; Kurokawa, T.; Karube, D.; Ito, Y. J. Am. Chem.
Soc. 2000, 122, 7614-7615.
(5) Boger, D. L.; Boyce, C. W.; Garbaccio, R. M.; Goldberg, J. A. Chem.
ReV. 1997, 97, 787-828.
(9) Bailey, W. F.; Luderer, M. R.; Mealy, M. J. Tetrahedron Lett. 2003,
44, 5303-5305.
(10) (S,S)-(R,R)-PhTRAP ) (R,R)-2,2′′-bis[(S)-1-(diphenylphosphino)-
ethyl]-1,1′′-biferrocene.
10.1021/ol049317k CCC: $27.50 © 2004 American Chemical Society
Published on Web 05/20/2004

of 2b was found to be only 16% (entry 2). We then dis-
covered that hydrogenation of N-sulfonylindoles 1c-e
proceeded with high enantioselectivity and acceptable reac-
tion rates (entries 3-6). In particular, the reaction of N-tos-
ylamide 1c produced 98% ee of (S)-3-methyl-N-tosylindoline
(2c) in 96% isolated yield after 24 h with no formation of 3
(entry 4).13 Similarly, when the (R,R)-(S,S)-PhTRAP ligand
was used, the antipode (R)-2c was obtained with 98% ee.
The N-tosyl group of 2c was removable by reduction using
sodium bis(2-methoxyethoxy)aluminum dihydride without
the loss of enantiopurity.14 It is noteworthy that no hydro-
genation occurred in the presence of rhodium complexes
generated from other phosphine ligands, e.g., PPh3 and cis-
chelating bisphosphine BINAP.15
Figure 1. Structure of (S,S)-(R,R)-PhTRAP.
carbon at the 2-position with up to 95% ee. In this paper we
now describe a new highly enantioselective synthesis of
3-substituted indolines that also proceeds by asymmetric
hydrogenation with the PhTRAP-rhodium catalyst. The
enantiomeric excesses of the products were between 93 and
98%.
As seen from Table 2, a variety of 3-substituted N-
tosylindolines could be obtained with high enantiomeric
First, we attempted the asymmetric hydrogenation of
N-acetyl-3-methylindole (1a) in 2-propanol at 50 atm of
hydrogen pressure in the presence of the (S,S)-(R,R)-
PhTRAP-[Rh(nbd)2]SbF6-Cs2CO3 (nbd ) 2,5-norbornadiene)
catalyst, which is the most effective for achieving the
asymmetric hydrogenation of 2-substituted indoles.4 Through
this reaction, it was possible to obtain 3-methylindoline (S)-
2a with 84% ee in 24% yield. However, the majority (58%)
of 1a that remained underwent undesirable alcoholysis of
the N-acetyl group under these conditions. Thus, our initial
effort focused on controlling the undesirable solvolysis. The
use of weak or insoluble bases (Et3N, Na2CO3, etc.) did
suppress this side reaction, but the ee values of the resulting
products were lower than 10%. No hydrogenation occurred
in MeCN, THF, or toluene. Next, we evaluated a variety of
protective groups on the nitrogen of 1 (Table 1). Although
Table 2. Catalytic Asymmetric Hydrogenation of 3-Substituted
Indolesa
entry
R (1)
yield (2), %
ee, %
1d
2e
3
4
5
i-Pr (1f)
Ph (1g)
CH2CH2OTBS (1h )
CH2CH2CO2(t-Bu) (1i)
CH2CH2NHBoc (1j)
94 (2f)
93 (2g)
94 (2h )
93 (2i)
71 (2j)
97
96
98
97
95
a Reactions were conducted at 80 °C and 50 atm of H2 in 2-propanol
(2.0 mL) for 24 h. 1 (0.5 mmol)/[Rh(nbd)2]SbF6/(S,S)-(R,R)-PhTRAP/
Cs2CO3 was 100/1.0/1.0/10 unless otherwise specified. b Isolated yield.
c Determined by chiral HPLC analysis. d Reaction was conducted in
2-propanol (1.0 mL) for 48 h. e Performed with 2 mol % PhTRAP-Rh
catalyst.
Table 1. Catalytic Asymmetric Hydrogenation of
3-Methylindolesa
excesses and high yields by asymmetric hydrogenation with
the PhTRAP-rhodium catalyst. The indoles 1f and 1g
bearing bulky substituents at the 3-position underwent highly
enantioselective hydrogenation (entries 1 and 2). Silyl ether,
ester, and carbamate groups did not cause a significant
deterioration in stereoselectivity (entries 3-5). No hydro-
genation of tert-butyl (3-indolyl)acetate occurred by means
of the present catalyst system. Its enolizable hydrogens may
cause deactivation of the catalyst.
Next, we applied our enantioselective hydrogenation meth-
od to the catalytic asymmetric synthesis of chiral indoline 4
(Scheme 1). This compound is Wierenga’s synthetic inter-
mediate for the left-hand segment of the antitumor agent (+)-
conversion, %b
yield, %b
ee, %c
entry
R (1)
1
2
3
2
1
2d
3
4e
5e
6e
Ac (1a )
Boc (1b)
Ts (1c)
Ts (1c)
Ms (1d )
Tf (1e)
82
14
31
100
95
100
24
14
31
100 (96)
92 (83)
100 (93)
58
0
0
0
3
84
16
97
98
94
94
0
a Reactions were conducted at 80 °C and 50 atm of H2 in 2-propanol (2
mL) for 2 h unless otherwise specified. 1 (0.5 mmol)/[Rh(nbd)2]SbF6/(S,S)-
(R,R)-PhTRAP/Cs2CO3 was 100/1.0/1.0/10. b Determined by 1H NMR
analysis. Isolated yields are given in parentheses. c Determined by chiral
HPLC analysis. d Reaction was conducted at 100 atm of H2. e Reactions
were conducted for 24 h.
(11) Sawamura, M.; Hamashima, H.; Ito, Y. Tetrahedron: Asymmetry
1991, 2, 593-596.
(12) Sawamura, M.; Hamashima, H.; Sugawara, M.; Kuwano, R.; Ito,
Y. Organometallics 1995, 14, 4549-4558.
(13) See Supporting Information for assignment of absolute configuration
of 2c.
no solvolysis of the tert-butoxycarbonyl group of 1b was
observed in the presence of Cs2CO3, the enantiomeric excess
(14) Gold, E. H.; Babad, E. J. Org. Chem. 1972, 37, 2208-2210.
(15) BINAP ) 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl
2214
Org. Lett., Vol. 6, No. 13, 2004

lacetylene 7,18 and it was transformed into the indole having
a trimethylsilyl group at the 2-position. The 2-silyl group of
the indole was removed selectively by exposure to Bu4NCl
and KOAc in DMF at 100 °C. The indole 8 was reduced to
the chiral indoline 9 in 93% ee using the present catalytic
asymmetric hydrogenation method with (S,S)-(R,R)-PhTRAP.
After changing the TIPS protection of 9 into the acetate, the
desired indoline 4 was obtained in optically active form.
In summary, we have developed a new highly enantiose-
lective approach to chiral 3-substituted indolines by way of
catalytic asymmetric reduction of indoles. The use of the
trans-chelating chiral diphosphine PhTRAP is essential for
the occurrence of hydrogenation, as well as for achieving
high enantioselectivity. This methodology is applicable to
the preparation of a wide range of optically active indolines
having a chiral center at the 3-position.
Scheme 1. Catalytic Asymmetric Synthesis of 4
Acknowledgment. This work was supported by Kyushu
University Foundation, the Naito Foundation, and a Grant-
in-Aid for Young Scientists (B) (No. 14750681) from
MEXT.
Supporting Information Available: Experimental pro-
cedures and characterization data for all new compounds
(PDF). This material is available free of charge via the
Internet at http://pubs.acs.org.
CC-1065, although the compound was previously synthesized
in racemic form.16 After N-mesylation of 2-iodo-5-meth-
oxyaniline (5),17 the resulting sulfonamide 6 was subjected
to palladium-catalyzed intermolecular annulation with sily-
OL049317K
(16) Wierenga, W. J. Am. Chem. Soc. 1981, 103, 5621-5623.
(17) Ma, C.; Liu, X.; Li, X.; Flippen-Anderson, J.; Yu, S.; Cook, J. M.
J. Org. Chem. 2001, 66, 4525-4542.
(18) Larock, R. C.; Yum, E. K.; Refvik, M. D. J. Org. Chem. 1998, 63,
7652-7662.
Org. Lett., Vol. 6, No. 13, 2004
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