Catalytic asymmetric hydroxylation of oxindoles by molecular oxygen using a phase-transfer catalyst

Article abstract of DOI:10.1021/ol800260r

The highly enantioselective catalytic hydroxylation of 3-substituted oxindoles was achieved by using a phase-transfer catalyst with molecular oxygen as an oxidant. The product then was converted to an optically active compound 8, which was a synthetic precursor of alkaloid CPC-1.

Full text of DOI:10.1021/ol800260r

ORGANIC
LETTERS
2008
Vol. 10, No. 8
1593-1595
Catalytic Asymmetric Hydroxylation of
Oxindoles by Molecular Oxygen Using a
Phase-Transfer Catalyst
Daisuke Sano, Kazuhiro Nagata, and Takashi Itoh*
School of Pharmaceutical Sciences, Showa UniVersity, 1-5-8 Hatanodai,
Shinagawa-ku, Tokyo 142-8555, Japan
itoh-t@pharm.showa-u.ac.jp
Received February 5, 2008
ABSTRACT
The highly enantioselective catalytic hydroxylation of 3-substituted oxindoles was achieved by using a phase-transfer catalyst with molecular
oxygen as an oxidant. The product then was converted to an optically active compound 8, which was a synthetic precursor of alkaloid CPC-1.
A number of oxindole alkaloids having a hydroxyl substituent
at their C-3 position possess various bioactivities.1 In the
field of medicinal chemistry, chiral 3-substituted-3-hydroxy-
2-oxindoles have been targets of synthesis, because they are
promising drug candidates.2 Furthermore, they are used as
starting materials and/or intermediates for the synthesis of
natural products.3 The reported methods for the synthesis of
chiral 3-substituted-3-hydroxy-2-oxindoles are an asymmetric
nucleophilic addition to isatins4 and asymmetric hydroxy-
lation of 3-substituted-2-oxindoles.5 In the latter case, a chiral
hydroxylation reagent was used, thus a stoichiometric amount
of the chiral source was required. Recently, the first catalytic
enantioselective hydroxylation of oxindoles with an oxaziri-
dine as an oxidant in the presence of chiral Zn(II) complex
was reported.6 The oxidant resulted in the formation of a
benzisothiazole derivative in the reaction mixture, and it
seems to be a drawback compared to the hydroxylation with
molecular oxygen as an oxidant.7 The use of O2 as an oxidant
is a paramount process, because it is inexpensive and
(1) (a) Tang, Y.-Q.; Sattler, I.; Thiericke, R.; Grabley, S.; Feng, X.-Z.
Eur. J. Org. Chem. 2001, 261. (b) Fre´chard, A.; Fabre, N.; Pe´an, C.;
Montaut, S.; Fauvel, M.-T.; Rollin, P.; Fouraste, I. Tetrahedron Lett. 2001,
42, 9015. (c) Koguchi, Y.; Kohno, J.; Nishino, M.; Takahashi, K.; Okuda,
T.; Ohnuki, T.; Komatsubara, S. J. Antibiot. 2000, 53, 105. (d) Codding, P.
W.; Lee, T. A.; Richardson, J. F. J. Med. Chem. 1984, 27, 649.
(2) (a) Tokunaga, T.; Hume, W. E.; Nagamine, J.; Kawamura, T.; Taiji,
M.; Nagata, R. Bioorg. Med. Chem. Lett. 2005, 15, 1789. (b) Tokunaga,
T.; Hume, W. E.; Umezome, T.; Okazaki, K.; Ueki, Y.; Kumagai, K.;
Hourai, S.; Nagamine, J.; Seki, H.; Taiji, M.; Noguchi, H.; Nagata, R. J.
Med. Chem. 2001, 44, 4641. (c) Hawawasam, P.; Erway, M.; Moon, S. L.;
Knipe, J.; Weiner, H.; Boissard, C. G.; Post-Munson, D. J.; Gao, Q.; Huang,
S;, Gribkoff, V. K.; Meanwell, N. A. J. Med. Chem. 2002, 45, 1487.
(3) (a) Kitajima, M.; Mori, I.; Arai, K.; Kogure, N.; Takayama, H.
Tetrahedron Lett. 2006, 47, 3199. (b) Sua´rez-Castillo, O. R.; Sa´nchez-
Zavala, M.; Mele´ndez-Rodr´ıguez, M.; Castela´n-Duarte, L. E.; Morales-R´ıos,
M. S.; Joseph-Nathan, P. Tetrahedron 2006, 62, 3040. (c) Kawasaki, T.;
Nagaoka, M.; Satoh, T.; Okamoto, A.; Ukon, R.; Ogawa, A. Tetrahedron
2004, 62, 3040.
(5) (a) Hewawasam, P.; Meanwell, N. A.; Gribkoff, V. K.; Dworetzky,
S. I.; Biossard, C. G. Bioorg. Med. Chem. Lett. 1997, 7, 1255. (b)
Hewawasam, P.; Erway, M.; Moon, S. L.; Knipe, J.; Weiner, H.; Boissard,
C. G.; Post-Munson, D. J.; Gao, Q.; Huang, S.; Gribkoff, V. K.; Meanwell,
N. A. J. Med. Chem. 2002, 45, 1487.
(6) Ishimaru, T.; Shibata, N.; Nagi, J.; Nakamura, S.; Toru, T.; Kanemasa,
S. J. Am. Chem. Soc. 2006, 128, 16488.
(7) There are some examples concerning racemic hydroxylation using
molecular oxygen, see: (a) Christoffer, J.; Baro, A.; Werner, T. AdV. Synth.
Catal. 2004, 346, 143. (b) Christoffer, J.; Werner, T.; Frey, W.; Baro, A.
Chem. Eur. J. 2004, 10, 1042. There are three examples concerning the
catalytic enantioselective hydroxylation of tetralone and indanone derivatives
using molecular oxygen, see: (c) Dehmlow, E. V.; Wagner, S.; Mu¨lller,
A. Tetrahedron 1999, 55, 6335. (d) De Vries, E. F. J.; Ploeg, L.; Colao,
M.; Brussee, J.; Van der Gen, A. Tetrahedron: Asymmetry 1995, 6, 1123.
(e) Masui, M.; Ando, A.; Shioiri, T. Tetrahedron Lett. 1988, 29, 2835.
(4) (a) Shintani, R.; Inoue, M.; Hayashi, T. Angew. Chem., Int. Ed. 2006,
45, 3353. (b) Toullec, P. Y.; Jagt, R. B. C.; de Vries, J. G.; Feringa, B. L.;
Minnaard, A. J. Org. Lett. 2006, 8. 2715. (c) Nakamura, T.; Shirokawa, S.;
Hosokawa, S.; Nakazaki, A.; Kobayashi, S. Org. Lett. 2006, 8. 677. (d)
Luppi, G.; Cozzi, P. G.; Monari, M.; Kaptein, B.; Broxterman, Q. B.;
Tomasini, C. J. Org. Chem. 2005, 70, 7418.
10.1021/ol800260r CCC: $40.75
© 2008 American Chemical Society
Published on Web 03/19/2008

environmentally benign. In the course of our investigation
of the synthesis of chiral 3,3-disubstituted oxindoles,8 we
have found that 3-substituted oxindoles react with molecular
oxygen in the presence of a base to give the corresponding
3-hydroxy derivatives quantitatively. The result prompted us
to investigate an asymmetric version of the hydroxylation
reaction using chiral phase-transfer catalyst (CPTC). In this
paper, we describe these results.
In the initial study, CPTCs were screened for the reaction
of 3-allyl-2-oxindole 4a with molecular oxygen. Although
the reaction with solid KOH proceeded without catalyst in
toluene to give 3-allyl-3-hydroxy-2-oxindole 5a, no product
was obtained when the reaction was run in toluene/50% KOH
aq solution. Thus the screening of CPTC was carried out in
the two-phase system (Table 1), and it was found that
moderate to good enantioselectivities were obtained. When
the hydroxyl group of 1b was converted to allyl ether,13 the
ee of the reaction lowered.
Using the selected catalyst 1b, we next carried out the
optimization of the solvent (Table 2). While ethereal
Table 2. Optimization of the Conditions for the Asymmetric
Hydroxylation of 4a14
catalyst (EtO)3P
time yield
ee
entry
(mol %)
(equiv)
solvent
(h)
(%)
(%)
Table 1. Catalyst Screening for the Asymmetric Hydroxylation
Reaction
1
2
3
4
5
6
7
8
9
20
20
20
20
20
20
20
20
20
10
5
0
2
2
2
2
2
2
4
10
4
toluene
toluene
xylene
mesitylene
Et2O
4
4
4
4
4
4
4
2.5
2.5
7.5
12
72
71
86
74
89
51
0
78
98
97
85
93
16
56
83
73
50
3
iPr2O
MeOt-Bu
toluene
toluene
toluene
toluene
toluene
4
85
85
80
74
31
10
11
12
4
4
1
Table 3. Catalytic Asymmetric Phase-Tranfer Hydroxylation
of 4
yield
(%)
ee
(%)
time
(h)
yield
(%)
ee
(%)
entry
PTC
entry
R
product
1
2
3
4
5
1a
1b
1c
2
96
86
quant
88
93
49
83
20
22
38
1
2
3
4
5
6
7
8
CH2CHdCH2
CH2Ph
CH2CtCH
CH2CH2CH3
CH2(CH2)4CH3
CH2CHdC(CH3)2
CH2Ph(4-OMe)
CH2(CH2)2CO2Et
5a
5b
5c
5d
5e
5f
2.5
2.5
24
6.0
48
2.5
48
75
98
95
92
97
quant
91
97
85
86
93
67
92
84
91
82
3
5g
5h
quant
spirobinaphthyl quaternary ammonium salt9 3 and tartrate-
derived bis-ammonium salt10 2 gave high chemical yields,
but low enantioselectivities. When cinchonidine derived
CPTC 1a11 or 1b12 was used, high chemical yields and
solvents gave low enantioselectivities, aromatic hydrocarbon
afforded good enantioselectivity, and toluene was found to
(8) Nagata, K.; Sano, D.; Itoh, T. Synlett 2007, 547.
(9) (a) Ooi, T.; Takeuch, M.; Kameda, K.; Maruoka, K. J. Am. Chem.
Soc. 2000, 122, 5228. (b) Ooi, T.; Kameda, K.; Maruoka, K. J. Am. Chem.
Soc. 2003, 125, 5139.
(10) Shibuguchi, T.; Fukuta, Y.; Akachi, Y.; Sekine, A.; Ohshima, T.;
Shibasaki, M. Tetrahedron Lett. 2002, 43, 9539.
(11) Dolling, U.-H.; Davis, P.; Grabowski, E. J. J. Am. Chem. Soc. 1984,
106, 446.
(12) Lygo, B.; Wainwright, P. G. Tetrahedron Lett. 1997, 38, 8595.
(13) Corey, E. J.; Xu, F.; Noe, M. C. J. Am. Chem. Soc. 1997, 119,
12414.
(14) We also carried out the hydroxylation reaction toward other
substrates, which have a benzyl or Boc protecting group, under the same
condition as that of entry 8 in Table 2. But the reaction of the oxindole
having a benzyl protecting group resulted in 49% yield and 61% ee. In the
case of the oxindole having a Boc protecting group, corresponding
hydroxylated product was not obtained probably due to the instability of
the product under the conditions.
1594
Org. Lett., Vol. 10, No. 8, 2008

give the best result (entries 2-7). On further optimization
of reaction conditions, it was found that using 4 equiv of
3-hydroxyindolin-2-one (8), which was reported to be a
synthetic precursor of alkaloid CPC-1.3a Absolute configu-
ration of 8 at the 3-position was determined to be R by
comparing the specific rotation of 8 with the reported one
(for (S)-83a, [R]26 -10 (c 1.3, MeOH)).
D
Scheme 1. Transformation of 5 into 8
We then investigated the asymmetric hydroxylation
using 2-oxindoles having various substituents at the 3-posi-
tion (Table 3). It was found that alkyl-, alkenyl-, and
alkynyl-substituted oxindoles were hydroxylated in high
yields and with high enantioselectivities.15 Even in the
presence of the ester group, enantioselective hydroxy-
lation was performed in high yield without hydrolysis
(entry 8).
In conclusion, we have shown that the catalytic en-
antioselective hydroxylation reaction of 3-substituted-2-
oxindoles with molecular oxygen was established, and high
enantioselectivity was achieved using cinchonidine-derived
CPTC. The reaction is operationally simple and environ-
mentally benign in that an organocatalyst from a natural
source and molecular oxygen are used. 3-Hydroxy-2-oxin-
doles obtained in the present reaction are thought to be useful
intermediates to synthesize the natural products which have
bioactivities. Application of the present method for the
synthesis of natural and bioactive compounds is under
investigation.
Acknowledgment. This work was supported in part by
a Grant-in-Aid for the High-Technology Research Center
Project from the Ministry of Education, Culture, Sports,
Science and Technology, Japan.
triethyl phosphite gave the highest yield. The absolute
configuration of 5 was confirmed to be R by chemical
correlation with 3-allyl-3-hydroxy-indolin-2-one (8) (Scheme
1). Acetylation of the hydroxyl group of 5 followed by CAN
oxidation in the presence of 2,6-pyridinecarboxylic acid
N-oxide gave compound 7. Then hydrolysis of 7 gave 3-allyl-
Supporting Information Available: Experimental pro-
cedures and full spectroscopic date for all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(15) The present reaction is thought to proceed via radical intermediate.
The detailed mechanism, which involves an asymmetric process, however,
is not cleared and the mechanistic consideration is now under investigation.
OL800260R
Org. Lett., Vol. 10, No. 8, 2008
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