Organocatalytic enantioselective stereoablative hydroxylation of 3-halooxindoles: An effective method for the construction of enantioenriched 3-substituted 3-hydroxy-2-oxindoles

Article abstract of DOI:10.1002/chem.201201395

3-Substituted oxindoles as electrophilic partners: An unprecedented method for the construction of hydroxylated 3-substituted oxindoles in high yields and excellent enantioselectivities through stereoablative hydroxylation of 3-halooxindoles with an organocatalyst has been developed. This process not only differs from the common convention of using 3-substituted oxindoles as nucleophiles, but also provides a viable entry to optically active 3-substituted 3-hydroxy-2-oxindoles (see scheme).

Full text of DOI:10.1002/chem.201201395

COMMUNICATION
DOI: 10.1002/chem.201201395
Organocatalytic Enantioselective Stereoablative Hydroxylation of
3-Halooxindoles: An Effective Method for the Construction of
Enantioenriched 3-Substituted 3-Hydroxy-2-Oxindoles
Yu-Hua Liao,[a, c] Zhi-Jun Wu,[b] Wen-Yong Han,[a, c] Xiao-Mei Zhang,[a] and
Wei-Cheng Yuan*[a]
The highly efficient and stereoselective construction of
enantioenriched heterocyclic compounds has attracted con-
siderable attention in organic synthesis. In particular, the 3-
substituted 3-hydroxy-2-oxindole framework has emerged as
an attractive synthetic target, because of its prevalence in
a large number of alkaloid natural products and pharma-
ceutically relevant compounds.[1] Additionally, it has been
shown that both the defined substituent and the absolute
configuration of the tetrasubstituted stereogenic center at C-
3 of the 3-hydroxy-2-oxindoles greatly influence the biologi-
cal activity.[1,2] Accordingly, the importance of the 3-substi-
tuted 3-hydroxy-2-oxindole scaffold in synthetic and medici-
nal chemistry continues to encourage the development of
creative methods to access this relevant structural motif.[3]
Recent asymmetric synthetic methods for 3-substituted 3-hy-
droxy-2-oxindoles mainly include the nucleophilic addition
to isatins,[4] the hydroxylation of 3-monosubstituted oxin-
doles,[5] and other cyclization reactions.[6] However, the de-
velopment of an alternative and efficient strategy for the
construction of structurally diverse 3-substituted 3-hydroxy-
2-oxindoles is of great importance and highly desirable.
Herein, we report an unprecedented synthetic method for
the construction of optically active 3-substituted 3-hydroxy-
2-oxindoles in high yields and excellent enantioselectivities
with broad substrate scope.
preparation of oxindoles bearing a tetrasubstituted stereo-
genic center at C-3.[3,5,7] In sharp contrast, the process taking
advantage of the oxindole moiety as electrophilic partner to
build a tetrasubstituted stereocenter at C-3 of the oxindole
skeleton remains highly underdeveloped.[8] Consequently,
this prompted us to explore a more novel method by using
the 3-substituted oxindole moiety as an electrophile for gen-
erating optically active 3,3-disubstituted oxindole deriva-
tives. We envisioned that the realization of this concept
would open new avenues to access the important oxindole
framework containing a tetrasubstituted stereogenic center
at C-3 of the oxindole. Therefore, on the basis of some suc-
cesses in stereoablative reactions[8a,9] and as a continuation
of our investigations aimed at developing new strategies for
the synthesis of structurally diverse 3,3-disubstituted oxin-
dole derivatives,[10] we developed a new strategy for the
enantioselective synthesis of 3-substituted 3-hydroxy-2-oxin-
doles through stereoablative hydroxylation of 3-halooxin-
doles with environmentally benign organocatalysts and by
using oximes[11] as oxygen nucleophiles (Scheme 1). To the
The stereoselective functionalization of the 3-substituted
oxindole moiety, in which this unit serves as a nucleophile,
has proven to be the most commonly used method for the
Scheme 1. Stereoablative hydroxylation of 3-halooxindoles.
[a] Y.-H. Liao, W.-Y. Han, Prof. Dr. X.-M. Zhang, Prof. Dr. W.-C. Yuan
National Engineering Research Center of Chiral Drugs
Chengdu Institute of Organic Chemistry
Chinese Academy of Sciences
best of our knowledge, this represents the first example em-
ploying 3-substituted oxindoles as electrophilic partners for
the generation of enantioenriched 3-substituted 3-hydroxy-
2-oxindole derivatives.
Chengdu 610041 (P.R. China)
Our initial studies focused on the reaction between race-
mic 3-benzyl-3-bromooxindole (2a) and (E)-benzaldehyde
oxime (3a) by using a series of cinchona alkaloids 1a–i as
catalysts (Table 1). The reaction proceeded smoothly in
THF at room temperature without any chiral catalyst and
with only one equivalent of K2CO3 as base, giving product
4a in 83% yield (Table 1, entry 1). When adding 20 mol%
quinidine (1a) as chiral catalyst, 4a was produced in 88%
E-mail: yuanwc@cioc.ac.cn
[b] Dr. Z.-J. Wu
Chengdu Institute of Biology
Chinese Academy of Sciences
Chengdu 610041 (P.R. China)
[c] Y.-H. Liao, W.-Y. Han
Graduate School of Chinese Academy of Sciences
Beijing 100049 (P.R. China)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201201395.
yield, but surprisingly as
a racemic mixture (Table 1,
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Table 1. Screening of various conditions for the reaction between 3-
With the optimized conditions in hand, we turned our
focus on the substrate scope and generality of the reaction.
At first, a wide range of 3-substituted 3-bromooxindoles 2
were prepared[12] and reacted with (E)-benzaldehyde oxime
(3a) under the optimized conditions (Table 2). We were
benzyl-3-bromooxindole (2a) and (E)-benzaldehyde oxime (3a).[a]
Table 2. Substrate scope for the 1 f-catalyzed reaction of (E)-benzalde-
hyde oxime (3a) with various 3-substituted-3-bromooxindoles 2.[a]
Entry
1
Solvent
Base
Yield [%][b]
ee [%][c]
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
–
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
DCM
EtOAc
toluene
THF
THF
THF
THF
THF
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
Na2CO3
KHCO3
Et3N
83
88
93
93
88
90
88
86
87
83
90
88
89
60
83
64
69
89
–
0
1a
1b
1c
1d
1e
1 f
1g
1h
1i
1 f
1 f
1 f
1 f
1 f
1 f
1 f
1 f
55
93[d]
96[d]
96
99
97
38
0
97
95
86
96
99
96
92
99[e]
DIPEA
K2CO3
[a] Unless otherwise noted, reactions were carried out with 2a
(0.1 mmol), 3a (0.12 mmol), base (0.1 mmol), and 1 (0.02 mmol) in the
solvent (1.0 mL) at room temperature for 12 h. [b] Isolated yield. [c] De-
termined by chiral HPLC. [d] The opposite configuration of the product
was observed. [e] 0.08 mmolK2CO3 were used. Bn=benzyl; Bz=benzo-
yl; DIPEA=N,N-diisopropylethylamine.
[a] All reactions were performed by using 2 (0.1 mmol), 3a (0.12 mmol),
K2CO3 (0.08 mmol), and 1 f (0.02 mmol) in THF (1.0 mL) at room tem-
perature for 12 h. All yields refer to isolated yields of products. The ee
values were determined by chiral HPLC.
entry 2). However, the reaction with catalyst 1b bearing
À
a C6’ OH group gave 4a in 93% yield with 55% ee
(Table 1, entry 3). Encouraged by this promising lead, we
next examined the other catalysts under the same reaction
conditions (Table 1, entries 4–10). Catalyst 1 f was found to
be the most effective in comparison with catalysts 1a–e and
1g–i, giving 4a in 88% yield with 99% ee (Table 1, entry 7).
pleased to find that the introduction of electron-withdrawing
or -donating groups on both the oxindole core and the ben-
zene ring of the R’ group smoothly provided the corre-
sponding products in good yields (74–88%) with excellent
enantioselectivities (96–99% ee) (Table 2, 4b–i and 4m–o).
Nevertheless, oxindoles 2 bearing a heteroaromatic ring on
the R’ group were also viable substrates for the 1 f-catalyzed
enantioselective stereoablative hydroxylation reaction
(Table 2, 4j–k). Meanwhile, we also found that the bulkier
3-naphthalen-1-ylmethyl-3-bromooxindole could be readily
transformed into the desired product 4l in 87% yield with
98% ee. Notably, a functional group, such as methoxycarbo-
nylamide, incorporated into the substituent at C-3 of the ox-
indole core, was very well tolerated under the mild reaction
À
Notably, the pronounced effect of the C6’ OH (1b–h) or
À
C6’ OMe (1a and 1i) groups on the asymmetric induction
À
demonstrates that the C6’ OH group is of vital importance
for the enantioselectivity (Table 1, entries 3–9 vs. 2 and 10).
Afterwards, the screening of different solvents revealed
THF to be the most suitable solvent in terms of enantiose-
lectivity (Table 1, entry 7 vs. entries 11–13). Additionally,
the investigation of bases showed that the use of 0.8 equiva-
lents of K2CO3 was an optimum parameter for the reaction
(Table 1, entry 18 vs. entries 7 and 14–17).
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Enantioselective Stereoablative Hydroxylation of 3-Halooxindoles
COMMUNICATION
Table 4. Substrate scope for the 1 f-catalyzed reaction of 3-benzyl-3-
chlorooxindole (2b) with various oximes 3.[a]
conditions (Table 2, 4p). Even with a substrate bearing an
allyl substituent at C-3 of the oxindole core, a good yield
and enantioselectivity (89% yield, 88% ee) were obtained
(Table 2, 4q).
To further explore the substrate scope of the developed
methodology, we attempted to change the structure of
oximes 3. We prepared a library of aromatic aldehyde
oximes 3 and employed them in the reaction with 3-benzyl-
3-bromooxindole (2a) under the optimized reaction condi-
tions (Table 3). Gratifyingly, high yields and excellent enan-
Table 3. Substrate scope for the 1 f-catalyzed reaction of 3-benzyl-3-bro-
mooxindole (2a) with various oximes 3.[a]
[a] For details, see the footnote of Table 2.
these reactions also revealed that the variation of the elec-
tronic and steric properties of the functional groups at the
benzene ring of oximes 3 had no drastic effect on the reac-
tivity and enantioselectivity.
With product 4a as starting material, the 3-benzyl-3-hy-
droxy-2-oxindole 5 could be readily accessed by hydrogena-
tion with Pd/C/H2 in MeOH at room temperature for 20 h
without loss in enantiopurity (Scheme 2).[13] The product 4q
[a] For details, see the footnote of Table 2.
tioselectivities were obtained in all cases. Nevertheless, stud-
ies also showed that various functional groups incorporated
into the phenyl group of the oximes were well-tolerated
under the mild reaction conditions (Table 3, 4r–w), and
even an unprotected hydroxyl group could be used without
any difficulty (Table 3, 4x). Furthermore, a bulkier oxime,
such as (E)-1-naphthaldehyde oxime, gave the correspond-
ing product 4y with 99% ee. Heteroaromatic aldehyde
oximes could also be employed in this reaction to give the
expected products with excellent enantioselectivities
(Table 3, 4z and 4a’).
Furthermore, we also applied the newly developed enan-
tioselective stereoablative hydroxylation protocol to 3-
benzyl-3-chlorooxindole (2b). To our delight, the reactions
between 2b and some oximes 3 proceeded well to give the
desired products in good yields (60–66%) with high to ex-
cellent enantiomeric excesses ranging from 91 to 99% ee
under the standard reaction conditions (Table 4). Moreover,
Scheme 2. Transformations of the products and the potential synthetic
application.
is a potentially valuable building block for asymmetric syn-
thesis, as it is functionalized with an allyl group at C-3. As
shown in Scheme 2, 4q could be readily converted to a syn-
thetically important chiral 1,3-diol oxindole 6 in two steps.[13]
It is worth noting that 1,3-diol oxindole 6 is the precursor
for the asymmetric synthesis of chiral donaxaridine,[2d] CPC-
1, and
a half fragment of madindcline A and B
(Scheme 2).[14] By comparison of the optical rotation of 6
with that reported in the literature, we assigned the absolute
configuration as S.[14] As no reaction occurred at the stereo-
genic center in 4q during the transformations into 6, 4q was
thus assigned as S configured. The absolute configurations
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W.-C. Yuan et al.
K2CO3 (0.08 mmol) in THF (1 mL) was stirred at room temperature for
12 h. Then, the reaction mixture was subjected to flash column chroma-
tography on silica gel (petroleum ether/ethyl acetate) to give the corre-
sponding product 4.
of the remaining products shown in Tables 2–4 were tenta-
tively proposed by analogy.
Although a detailed mechanism has yet to be elucidated,
a plausible transition state model, based on the experimen-
tal results and previous studies,[8a,9] is proposed in Figure 1.
Acknowledgements
This work was supported by the National Basic Research Program of
China (973 Program, 2010CB833300), and Western Light Talent Culture
Project, and Sichuan Youth Science and Technology Foundation.
Keywords: alkaloids
·
asymmetric
catalysis
·
organocatalysis · oximes · oxindoles
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In conclusion, we have developed an unprecedented
method for the construction of enantioenriched 3,3-disubsti-
tuted oxindoles through a stereoablative hydroxylation of 3-
halooxindoles with a cinchona alkaloid derivative as catalyst
and by using aromatic oximes as hydroxylating agents. The
protocol is amenable to a wide variety of substrates, afford-
ing structurally diverse hydroxylated 3-substituted oxindoles
in high yields (up to 93%) and excellent enantioselectivities
(up to 99% ee) under mild conditions. Notably, the current
process that uses 3-substituted oxindoles as electrophilic
partners not only differs from the convention of commonly
using 3-substituted oxindoles as nucleophiles, but also pro-
vides a viable entry to optically active 3-substituted 3-hy-
droxy-2-oxindole derivatives. Further efforts will be devoted
to understanding the reaction mechanism, as well as devel-
oping more catalytic asymmetric systems to expand the ap-
plication of 3-halooxindoles as electrophiles.
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Enantioselective Stereoablative Hydroxylation of 3-Halooxindoles
COMMUNICATION
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[14] T. Itoh, H. Ishikawa, Y. Hayashi, Org. Lett. 2009, 11, 3854–5857.
[10] a) W.-B. Chen, Y.-H. Liao, X.-L. Du, X.-M. Zhang, W.-C. Yuan,
Green Chem. 2009, 11, 1465–1476; b) W.-B. Chen, X.-L. Du, L.-F.
Received: April 24, 2012
Published online: && &&, 0000
Chem. Eur. J. 2012, 00, 0 – 0
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
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W.-C. Yuan et al.
Asymmetric Synthesis
Y.-H. Liao, Z.-J. Wu, W.-Y. Han,
X.-M. Zhang, W.-C. Yuan* . &&&& — &&&&
Organocatalytic Enantioselective Ste-
reoablative Hydroxylation of 3-
Halooxindoles: An Effective Method
for the Construction of Enantioen-
riched 3-Substituted 3-Hydroxy-2-
Oxindoles
3-Substituted oxindoles as electrophilic
partners: An unprecedented method
for the construction of hydroxylated 3-
substituted oxindoles in high yields
and excellent enantioselectivities
lyst has been developed. This process
not only differs from the common con-
vention of using 3-substituted oxin-
doles as nucleophiles, but also provides
a viable entry to optically active 3-sub-
stituted 3-hydroxy-2-oxindoles (see
scheme).
through stereoablative hydroxylation
of 3-halooxindoles with an organocata-
&
6
&
www.chemeurj.org
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 0000, 00, 0 – 0
ÝÝ
These are not the final page numbers!