Organocatalytic asymmetric synthesis of substituted 3-hydroxy-2-oxindoles via morita-baylis-hillman reaction

Article abstract of DOI:10.1021/ja107858z

We report a highly enantioselective Morita-Baylis-Hillman (MBH) reaction of isatins and acrolein to provide enantiomerically enriched 3-substituted 3-hydroxyoxindoles, which could serve as valuable synthetic building blocks. This is also the first time that a ketone has been used as the electrophile and acrolein as the nucleophile in a highly enantioselective catalytic asymmetric MBH reaction. Hatakeyama's catalyst, β-isocupreidine (1), turned out to be a powerful catalyst for this transformation.

Full text of DOI:10.1021/ja107858z

Published on Web 10/12/2010
Organocatalytic Asymmetric Synthesis of Substituted 3-Hydroxy-2-oxindoles
via Morita-Baylis-Hillman Reaction
Yun-Lin Liu, Bo-Lun Wang, Jun-Jie Cao, Long Chen, Yong-Xue Zhang, Chao Wang, and Jian Zhou*
Shanghai Key Laboratory of Green Chemistry and Chemical Processes, Department of Chemistry,
East China Normal UniVersity, 3663N Zhongshan Road, Shanghai 200062, China
Received September 10, 2010; E-mail: jzhou@chem.ecnu.edu.cn
Abstract: We report a highly enantioselective Morita-Baylis-
Hillman (MBH) reaction of isatins and acrolein to provide enan-
tiomerically enriched 3-substituted 3-hydroxyoxindoles, which
could serve as valuable synthetic building blocks. This is also
the first time that a ketone has been used as the electrophile
and acrolein as the nucleophile in a highly enantioselective
catalytic asymmetric MBH reaction. Hatakeyama’s catalyst, ꢀ-iso-
cupreidine (1), turned out to be a powerful catalyst for this
transformation.
The catalytic asymmetric construction of tetrasubstituted carbon
stereogenic centers is one of the major challenges in asymmetric
catalysis. Among the available methods, the catalytic asymmetric
addition of carbon nucleophiles to ketones is one of the most
Figure 1
including nucleophilic addition to isatins,9b-n hydroxylation of
efficient synthetic routes. Despite achievements, the synthesis of
3-substituted oxindoles,9o-q and intramolecular arylation reactions,9r,s
the synthesis of this subunit via a catalytic asymmetric MBH
reaction has not been reported.10
tertiary alcohols via the catalytic asymmetric Morita-Baylis-Hillman
(MBH) reaction has not been realized.1
Because of its versatility in the selective atom-economical synthesis
of highly functionalized allylic alcohols, which are valuable building
blocks in organic synthesis, the development of the catalytic asym-
metric MBH reaction received much attention.2 Since Hatakeyama
and co-workers discovered a powerful catalyst, ꢀ-isocupreidine (ꢀ-
ICD, 1),3 much progress has been made in this area, including the use
of multifunctional organocatalysts and chiral Lewis acids for the
addition of various activated alkenes to aldehydes4 or aldimines.5
However, to the best of our knowledge, the use of ketones as the
electrophilic reaction partner has not been reported.6 Remarkably, using
a ketone electrophile in the catalytic asymmetric MBH reaction
simultaneously forms a carbon skeleton and tetrasubstituted stereogenic
center and thus extends the potential of this reaction. Furthermore,
acrolein has not been used as the nucleophile in the catalytic
asymmetric MBH reaction, although the aldehyde group of the resulting
MBH adducts would be valuable for further transformation. Acrolein
as the nucleophile has been tried in some aza-MBH reactions5 and in
only one case afforded the product with excellent ee.5a In this
communication, we report the first example of a catalytic asymmetric
MBH reaction using a ketone, isatin, as the electrophile and acrolein
as the nucleophile; this reaction readily afforded 3-hydroxy-2-oxindoles
with excellent enantioselectivity.
In our efforts to synthesize 3,3-disubstituted oxindoles for
biological evaluation,11 we realized that isatins are highly reactive,
so we tried to develop an enantioselective MBH reaction employing
this type of activated ketone to prepare substituted 3-hydroxyox-
indoles. In view of the fact that the reaction of isatins and acrylate
esters catalyzed by DBACO proceeds very slowly even at room
temperature,10a we chose the more reactive nucleophile acrolein
to react with isatin for optimization (for details, see the Supporting
Information). Finally, ꢀ-ICD 1 turned out to be the most powerful
catalyst, and the optimal reaction conditions were determined to
be in air using CH2Cl2 in the presence of 10 mol % 1 at -20 °C
(eq 1).
The substrate scope is shown in Table 1. The protecting group
of isatin 2 (either methyl or benzyl) had little effect on the ee of
the corresponding MBH adducts. Furthermore, the N-methyl- and
N-benzyl-protected isatins 2b and 2c had good solubility in CH2Cl2,
and the corresponding products 4b and 4c were obtained in excellent
yield and ee (entries 2 and 3). This observation is very important,
because the solubility of substituted unprotected isatins in CH2Cl2
is generally very poor, and the use of unprotected isatins except
2a resulted in low conversion, although the ee of the corresponding
products was excellent. The use of N-methyl- or N-benzyl-protected
isatins 2d-w afforded the corresponding products 4d-w in good
to excellent yield with excellent enantioslectivity (entries 4-23).
3-Substituted 3-hydroxyoxindoles are encountered in a large
variety of natural and artificial bioactive compounds and can be
used for the total synthesis of natural products such as CPC-1 and
flustraminol (Figure 1).7 Structure-activity relationship studies have
revealed that the biological activities of these compounds are greatly
affected by the configuration of the hydroxy group and the
substituents at the C3 position of the oxindole.8 Accordingly, the
development of new synthetic methods for the synthesis of this
structural motif is of paramount importance. While a variety of
catalytic asymmetric methods have already been developed,9
9
15176 J. AM. CHEM. SOC. 2010, 132, 15176–15178
10.1021/ja107858z  2010 American Chemical Society

C O M M U N I C A T I O N S
Table 1. Substrate Scope
electrophile and acrolein as the nucleophile. A variety of isatins
worked well with acrolein to give the MBH adducts with
excellent ee. Experiments in our lab now aim to expand the
substrate scope of the catalytic asymmetric MBH reaction using
ketones as the electrophile.
entrya
isatin 2
4
yield (%)b
ee (%)c
Acknowledgment. We are grateful for the financial support
from the National Natural Science Foundation of China
(20902025), the Shanghai Pujiang Program (10PJ1403100),
Shanghai Talent Grooming Funding (2009015), and the 973
Program (2011CB808600).
1
2
3
4
5
6
7
8
2a: R, R1, R2, R3 ) H
4a
4b
4c
4d
4e
4f
4g
4h
4i
79
96
97
92
86
83
88
79
91
74
85
91
70
66
80
65
73
90
95
86
88
96
93
98
98
96
96
96
96
96
97
99
97
95
97
94
92
90
90
91
96
95
96
94
93
91
2b: R, R1, R2 ) H, R3 ) Me
2c: R, R1, R2 ) H, R3 ) Bn
2d: R ) F, R1, R2 ) H, R3 ) Me
2e: R ) F, R1, R2 ) H, R3 ) Bn
2f: R ) Cl, R1, R2 ) H, R3 ) Me
2g: R ) Cl, R1, R2 ) H, R3 ) Bn
2h: R ) Br, R1, R2 ) H, R3 ) Me
2i: R ) Br, R1, R2 ) H, R3 ) Bn
2j: R ) Me, R1, R2 ) H, R3 ) Me
2k: R ) Me, R1, R2 ) H, R3 ) Bn
2l: R ) MeO, R1, R2 ) H, R3 ) Me
Supporting Information Available: Experimental procedures,
compound characterization, NMR spectra, and crystallographic data
(CIF). This material is available free of charge via the Internet at http://
pubs.acs.org.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
4j
4k
4l
2m: R ) MeO, R1, R2 ) H, R3 ) Bn 4m
2n: R ) NO2, R1, R2 ) H, R3 ) Me
2o: R ) NO2, R1, R2 ) H, R3 ) Bn
2p: R ) CF3, R1, R2 ) H, R3 ) Me
2q: R ) CF3, R1, R2 ) H, R3 ) Bn
2r: R, R2 ) H, R1 ) Br, R3 ) Me
2s: R, R2 ) H, R1 ) Br, R3 ) Bn
2t: R, R1 ) H, R2 ) Cl, R3 ) Me
2u: R, R1 ) H, R2 ) Cl, R3 ) Bn
2v: R, R2 ) Br, R1 ) H, R3 ) Me
2w: R, R2 ) Br, R1 ) H, R3 ) Bn
4n
4o
4p
4q
4r
4s
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