Lewis acid-catalyzed enantioselective hydroxylation reactions of oxindoles and β-keto esters using DBFOX ligand

Article abstract of DOI:10.1021/ja0668825

The first catalytic enantioselective hydroxylation reaction of both 3-aryl and 3-alkyl-2-oxindoles using the DBFOX-Zn(II) complex, leading to pharmaceutically important chiral 3-hydroxy-2-oxindoles was described. The structure of oxidant was found to play

Full text of DOI:10.1021/ja0668825

Published on Web 12/08/2006
Lewis Acid-Catalyzed Enantioselective Hydroxylation Reactions of Oxindoles
and â-Keto Esters Using DBFOX Ligand
Takehisa Ishimaru, Norio Shibata,* Jun Nagai, Shuichi Nakamura, Takeshi Toru,* and
Shuji Kanemasa
Department of Applied Chemistry, Graduate School of Engineering, Nagoya Institute of Technology, Gokiso,
Showa-ku, Nagoya 466-8555, Japan, and Institute for Materials Chemistry and Engineering, Kyushu UniVersity,
6-1 Kasugakoen, Kasuga 816-8580, Japan
Received September 25, 2006; E-mail: nozshiba@nitech.ac.jp; toru@nitech.ac.jp
Table 1. Optimization Studies for Enantioselective Hydroxylation
of 3-Phenyl-2-oxindole 1a to 3-Hydroxy-3-phenyl-2-oxindole 2aa
3-Hydroxy-2-oxindoles are key structural functionalities through-
out natural products and drug candidates.1,2 Chiral 3-aryl-3-hydroxy-
2-oxindoles2 are particularly promising molecules in the field of
medicinal chemistry represented by SM-130686.2b Probably the
most direct approach to enantioselective synthesis of 3-aryl-3-
hydroxy-2-oxindoles is through both asymmetric nucleophilic
arylation of isatins3 and enantioselective electrophilic hydroxylation
of 3-aryl-2-oxindoles.2a,c Although several examples of the catalytic
asymmetric preparation of 3-aryl or alkyl-3-hydroxy-2-oxindoles
have been reported,3a-e the asymmetric synthesis of these com-
pounds by way of direct catalytic asymmetric hydroxylation reaction
of oxindoles is rare. One report detailed the application of Davis’
chiral oxaziridine4 as asymmetric hydroxylating reagent for sto-
ichiometric approach to the synthesis of chiral 3-aryl-3-hydroxy-
2-oxindoles;2a,c however, to the best of our knowledge, there is no
catalytic enantioselective hydroxylation of oxindoles dealing with
asymmetric catalysis. Recently, our group has demonstrated the
DBFOX-Ni(II)-catalyzed enantioselective fluorination and chlo-
rination of â-keto esters as well as oxindoles.5a As a part of our
ongoing research program directed to the development of new
methodology leading to biologically active indole compounds,5 we
herein describe the first example of catalytic enantioselective
hydroxylation reaction of 2-oxindoles 1 using the DBFOX-Zn(II)
catalyst with oxaziridine 3 as oxidant. The extension of the method
to the Ni(II)-catalyzed enantioselective hydroxylation reaction of
â-keto esters 4 using DBFOX ligand is also described (Figure 1).
yield
(%)
ee
run
oxidant 3
Lewis acid
solvent
(%)
1
Ni(OAc)2·4H2O
CH2Cl2
97
11
2
3
4
5
6
7
8
9
3b
3b
3b
3b
3b
3b
3b
3b
3b
3a
3a
Zn(ClO4)2
Zn(SbF6)2
Mg(SbF6)2
Ni(SbF6)2
AgSbF6
Zn(SbF6)2
Zn(SbF6)2
Zn(SbF6)2
Zn(OAc)2
Zn(SbF6)2
Zn(OAc)2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
toluene
ether
EtOH
CH2Cl2
EtOH
41
57
78
68
65
59
62
37
81
54
82
2
74
16
65
2
13
25
85
39
12
93
10
11
12
CH2Cl2
a 1a (1.0 equiv), oxaziridine 3 (1.2 equiv), DBFOX (11 mol %), and
Lewis acid (10 mol %) were reacted in solvent in the presence of MS4A at
rt for 1-2 h. Enantioselectivity was determined by chiral HPLC analysis.
conditions gave good ee of 85%, the conversion was rather low
(37%, run 9). On further optimization of the reaction conditions,
we found that the racemic oxaziridine 3a4 was much more effective
than 3b for the enantioselective hydroxylation in the presence of
Zn(OAc)2 in CH2Cl2 (run 12). Thus, the use of oxaziridine 3a (1.2
equiv), DBFOX (11 mol %), and Zn(OAc)2 (10 mol %) in the
presence of 4 Å molecular sieves (MS4A) in CH2Cl2 at room
temperature became the standard conditions for our catalytic
enantioselective hydroxylation reaction of oxindoles 2.
The scope of the hydroxylation reaction of a series of 3-aryl-2-
oxindoles 1 was investigated; we found that the DBFOX/Zn(OAc)2
catalyst exhibits excellent enantioselectivity in the level of >90%
ee with high yields (90-97% ee, Table 2, entries 1-8). It is
interesting to note that the method is effective not only for the
synthesis of chiral 3-aryl-3-hydroxy-2-oxindoles 2a-h but also for
chiral 3-alkyl-3-hydroxy-2-oxindoles 2i-m (entries 9-13, 83-86%
ee). More than 83% ee of products was observed for 3-alkyl-3-
hydroxy-2-oxindoles in high yields independent of the substituents
at C-3, except the case of 3-perfluorophenyl-2-oxindole 2n (entry
14). The absolute configuration of 2a was determined by comparing
the optical rotation of the NH derivative of 2a with that of the
known 3-hydroxy-3-phenyl-2-oxindole, and the stereochemistry of
other oxindoles 2 was tentatively assumed by analogy (see the
Supporting Information, SI, for details). Very recently, an excellent
but different procedure for chiral 3-aryl-3-hydroxy-2-oxindoles
using rhodium-catalyzed asymmetric addition of arylboronic acids
Figure 1. Lewis acid-catalyzed enantioselective hydroxylations of oxindoles
and â-keto esters using DBFOX with oxaziridine.
Our studies on the DBFOX-catalyzed enantioselective hydroxy-
lation of oxindoles 1 are summarized in Table 1. We first attempted
the reaction of N-Boc-3-phenyl-2-oxindole 1a5a,6 using racemic
oxaziridine 3b4 [3-(4-nitrophenyl)-2-(phenylsulfonyl)-1,2-oxaziri-
dine, 4-NO2-C6H4-CH(O)N-Ph] under the previously reported
conditions for enantioselective fluorination/chlorination of oxindoles,5a
Ni(OAc)2‚4H2O in CH2Cl2. The 3-hydroxy-3-phenyl-2-oxindole 2a
was obtained in 97% yield, but the enantioselectivity was only 11%
(run 1). Optimization of the Lewis acid and solvent revealed that
both chemical yield and enantioselectivity were largely dependent
on this combination. When the reaction was performed in the
presence of Ni(SbF6)2 in CH2Cl2, the hydroxylation proceeded in
68% yield with 65% ee (run 5). While Zn(SbF6)2 in EtOH
9
16488
J. AM. CHEM. SOC. 2006, 128, 16488-16489
10.1021/ja0668825 CCC: $33.50 © 2006 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Enantioselective Hydroxylation of 3-Aryl- and
3-Alkyl-2-oxindoles 1a-na
ochemistry of 5 was tentatively determined to be S, as shown in
Figure 1 (see the SI).
In conclusion, we have described the first catalytic enantiose-
lective hydroxylation reaction of both 3-aryl- and 3-alkyl-2-
oxindoles using the DBFOX-Zn(II) complex, leading to pharma-
ceutically important chiral 3-aryl-3-hydroxy-2-oxindoles. The structure
of oxaziridine 3 was found to play an important role to increase
the enantioselectivity. The methodology has been applied to the
highly enantioselective hydroxylation11 of â-keto esters using the
DBFOX-Ni(II) complex.
T
yield
(%)
ee
entry
1
R
X
(h)
2
(%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
1a
1b
1c
1d
1e
1f
1g
1h
1i
Ph
p-Tol
H
H
H
6
2a
82
93
94
91
93
90
90
97
91
84b
15 2b
15 2c
13 2d
2
1
3
1
19 2i
48 2j
14 2k
19 2l
84
77
76
91
92
95
88
68b
p-F-C6H4
Acknowledgment. Support was provided by JSPS KAKENHI
(17350047, 17590087). T.I. is grateful for Research Fellowships
of JSPS for Young Scientists.
p-Tol
Ph
Me
Me
Me
MeO
MeO
H
2e
2f
2g
2h
p-F-C6H4
Ph
Supporting Information Available: Experimental procedures and
characterization of new compounds. This material is available free of
charge via the Internet at http://pubs.acs.org.
p-F-C6H4
Me
1j
1k
1l
i-Pr
H
H
H
H
43(83)c 83
97
91
p- Br-C6H4CH2
p-Cl-C6H4CH2
86
86
85
36
References
1m p-MeO-C6H4CH2
1n
28 2m 90
2n 60
C6F5
H
3
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substrate 4
(X H)
time
(h)
product 5
(X OH)
yield
(%)
ee
entry
)
)
(%)
1
4a: n ) 1, R ) tBu
4b: n ) 1, R ) Ad
4b: n ) 1, R ) Ad
4c: n ) 2, R ) tBu
4d: n ) 2, R ) Ad
4e: n ) 1
2
0.5
0.5
7
18
1
5a
5b
5b
5c
5d
5e
5f
96
97
96
91b
94
96
97
95
93
2
85
3b
4
81b
84
5
6
97
82
7
4f: n ) 2
18
50
83
8c
4g
5g
27(55)d
a 4 (1.0 equiv), 3a (1.2 equiv), DBFOX (11 mol %), and Ni(ClO4)2‚6H2O
(10 mol %) were reacted in CH2Cl2 in the presence of MS4A at rt.
b Oxaziridine 3b was used instead of 3a. c The reaction was carried out at
40 °C. d Based on recovered starting material.
to isatins was reported,3a and our method was slightly more
enantioselective than the reported procedure.
To demonstrate the further synthetic utility of this DBFOX-
catalyzed hydroxylation system, we tested other substrates, â-keto
esters. The R-hydroxy-â-dicarbonyl functional unit is an important
structural motif found in many bioactive molecules.7 Examples
include the antibacterial kjellmanianone7a and tetracycline antibiotic
doxycycline.7bA few successful examples of catalytic enantiose-
lective R-hydroxylation of â-keto esters8-10 have appeared; how-
ever, the scope of the reaction is not broad. After optimization of
the reaction conditions, solvent, Lewis acid, and oxidant (see SI
for details), the combination of oxaziridine 3a, DBFOX, and Ni-
(ClO4)2‚6H2O in the presence of MS4A in CH2Cl2 afforded the
best results in both chemical yield and enantioselectivity. The results
are shown in Table 3, and excellent enantioselectivities, 93-97%
ee, were obtained. In most cases, our hydroxylation was more
enantioselective than the reported procedures for the catalytic
asymmetric hydroxylation of â-keto esters.8,9 The absolute stere-
JA0668825
9
J. AM. CHEM. SOC. VOL. 128, NO. 51, 2006 16489