Highly enantioselective synthesis of bisoxindoles with two vicinal quaternary stereocenters via Lewis base mediated addition of oxindoles to isatin-derived ketimines

Article abstract of DOI:10.1039/c4ob01039f

A highly efficient asymmetric organocatalytic addition of 3-substituted oxindole to isatin-derived ketimine is reported with excellent stereocontrol (>99:1 dr, >99% ee) under mild conditions. This method provides access to the bisoxindole structure moiety

Full text of DOI:10.1039/c4ob01039f

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Highly enantioselective synthesis of bisoxindoles
with two vicinal quaternary stereocenters via
Lewis base mediated addition of oxindoles to
isatin-derived ketimines†
Cite this: Org. Biomol. Chem., 2014,
12, 6085
Received 20th May 2014,
Accepted 18th June 2014
Zhongkai Tang,‡a Yan Shi,‡a Haibin Mao,a Xuebin Zhu,a Weipeng Li,a Yixiang Cheng,a
DOI: 10.1039/c4ob01039f
www.rsc.org/obc
Wen-Hua Zheng*a and Chengjian Zhu*a,b
A highly efficient asymmetric organocatalytic addition of 3-substi-
tuted oxindole to isatin-derived ketimine is reported with excellent
stereocontrol (>99 : 1 dr, >99% ee) under mild conditions. This
method provides access to the bisoxindole structure moiety with
two vicinal quaternary stereogenic centers.
Enantioselective synthesis of chiral compounds bearing a
quaternary stereogenic center is one of the most challenging
research areas in asymmetric catalysis.1 In contrast, asym-
metric catalytic highly diastereoselective and enantioselective
construction of two vicinal quaternary centers is a much more
formidable problem in organic synthesis.2 Hence it is urgent
to develop a highly efficient asymmetric catalytic methodology
to meet this challenging task.
Oxindoles bearing a tetrasubstituted carbon stereocenter at
the 3-position are popularly found in many biologically impor-
tant natural products.3 In recent years, some elegant examples
of highly enantioselective construction of the 3,3-disubstituted
oxindole structure motif with different transition-metal cata-
lysts or organocatalysts are reported.4 There are two major
strategies to obtain chiral oxindole products. One is nucleo-
philic addition to isatin or isatin derived imines, which provides
access to a series of chiral 3-hydroxyloxindoles and 3-amino-
oxindoles. Another one is a reaction with 3-substituted oxi-
ndole as a nucleophile with a wide variety of electrophiles,
including alkylation, oxygenation, amination and halogena-
tion.5 Recently, natural alkaloids containing a bis-indole struc-
tural moiety and two vicinal chiral quaternary carbon centers
at the same time (Fig. 1) have been shown to have high bio-
Fig. 1 Isatin/oxindole basic structural motif and natural products
bearing a bis-indole moiety.
logical activity and hence have enormously attracted organic
synthetic chemists’ attention.6 Although there were many
excellent examples of synthesis of single chiral oxindoles,
bisoxindole containing two continuous chiral quaternary
carbon centers are still limited. To the best of our knowledge,
there are no examples of highly enantioselective addition of
3-substituted oxindoles to isatin derived imines.7 Herein, we
report a highly efficient protocol for synthesis of bisoxindoles
bearing two vicinal quaternary stereogenic centers.
We started to investigate the reaction of N-Boc ketimine 1a
with 3-subsititued-2-oxindole 2a in toluene in the presence of
10 mol% Lewis base catalysts. We are delighted to find that
the reaction works well under those known catalysts 4a–4c as
H-bond donors and 4d–4f as the Lewis base catalysts (Fig. 2)
(Table 1, entries 1–6). Based on the yield, diastereoselectivity
and enantioselectivity, the catalyst 4f is the best catalyst in this
reaction, affording the desired product in 81% yield, >99 : 1 dr
and 77% ee. Furthermore, solvent screening shows that polar
solvents (such as DMF and methanol) and DCM are less
suitable than ether type solvents (entries 7–13), and methyl
aState Key Laboratory of Coordination Chemistry, School of Chemistry and Chemical
Engineering, Nanjing University, Nanjing, 210093, P.R. China.
E-mail: cjzhu@nju.edu.cn, wzheng@nju.edu.cn
bState Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic
Chemistry, CAS, Shanghai, 200032, P.R. China
†Electronic supplementary information (ESI) available: Crystallographic data;
limited experimental and spectral data. CCDC 988539. For ESI and crystallo-
graphic data in CIF or other electronic format see DOI: 10.1039/c4ob01039f
‡Z. Tang and Y. Shi contributed equally to this work.
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reaction (25% ee), other substituents perform worse. Lowering
the reaction temperature did increase the enantioselectivity,
with erosion of the yield (entries 17–19). Considering the
balance between yield and ee, we selected 10 °C as the optimal
reaction temperature.
With the optimal condition in hand, the substrates’ scope
was then explored. As summarized, a wide variety of N-Boc
ketimines and 3-subsititued oxindoles were tolerated, the
corresponding products (3a–3q) were obtained in excellent
yield, excellent diastereoselectivity and excellent ee (Scheme 1).
In all cases the diastereoselectivity was >99 : 1. Substrates of
the imine bearing either electron-withdrawing or electron-
donating groups in ether 5 or 6 position of oxindoles all
afforded the corresponding products in good to excellent yield
Fig. 2 Structure of the catalysts.
Table 1 Optimization of the reaction conditionsa
Entry
R1
Cat.
Solvent
Yieldb (%)
drc
99 : 1
98 : 2
98 : 2
eed (%)
1
2
3
4
5
6
7
8
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Me
Et
4a
4b
4c
4d
4e
4f
4f
4f
4f
4f
4f
4f
4f
4f
4f
4f
4f
4f
4f
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
DMF
MeOH
DCM
Et2O
54
45
61
73
65
81
63
59
35
81
90
70
73
80
83
55
85
70
40
4
9
13
14
−35
77
8
10
15
85
87
7
21
81
85
25
93
95
96
96 : 4
>99 : 1
>99 : 1
98 : 2
98 : 2
9
>99 : 1
>99 : 1
>99 : 1
>99 : 1
96 : 4
>99 : 1
>99 : 1
>99 : 1
>99 : 1
>99 : 1
>99 : 1
10
11
12
13
14
15
16
17e
18f
19g
MTBE
THF
Hexane
MTBE
MTBE
MTBE
MTBE
MTBE
MTBE
Boc
Bn
Bn
Bn
a Unless otherwise noted, the reaction was carried out with 0.10 mmol
of 1, 0.12 mmol of 2, 10 mol% of catalyst 4 in the solvent (1 mL) for
24h. b Yield of the isolated product. c Determined by 1H NMR analysis
of the crude products. d ees of the major diastereoisomer were
determined by chiral HPLC analysis. e The reaction was carried out at
10 °C. f The reaction was carried out at 0 °C. g The reaction was carried
out at −10 °C.
tertbutyl ether (MTBE) is the best solvent (87% ee). Different
substituents on the nitrogen of 3-methyl oxindole are further
examined (entries 14–16), and the alkyl substituted substrates
show similar reactivity and enantioselectivity, but the Boc
protected 3-methyl oxindole is not a good substrate in this
Scheme 1 Scope of the reaction. For detail, see the ESI.† Yield of the
isolated product.
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preferably from the Re-face of the ketimine by oxindole to
obtain the highly enantioselective products. Nevertheless,
further studies are required to elucidate the mechanism.
Conclusions
Scheme 2 Addition of isatin with 2-oxindole.
In summary, we have developed a highly efficient method for
diastereoselective and enantioselective addition of 3-substi-
tuted-2-oxindoles to N-Boc ketimines catalyzed by a chiral
Lewis base catalyst. The new method provides a highly
enantioselective synthesis of bisoxindole with two chiral
vicinal quaternary carbon centers. Further application of
the methodology for the synthesis of natural and bioactive
compounds is currently underway and will be reported in due
course.
We gratefully acknowledge the National Natural Science
Foundation of China (21372114, 21172106, 21074054), the
National Basic Research Program of China (2010CB923303)
and the Research Fund for the Doctoral Program of Higher
Education of China (20120091110010) for their financial
support.
Fig. 3 X-ray crystal structure of product 3l.
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