Organocatalytic asymmetric Michael-Michael cascade for the construction of highly functionalized N-fused piperidinoindoline derivatives

Article abstract of DOI:10.1021/ol5008185

Application of indolin-3-one derivatives in a cascade reaction for efficient assembly of complex molecules is a much less explored research area. It is demonstrated that structurally interesting polysubstituted piperidino[1,2-a]indoline compounds containi

Full text of DOI:10.1021/ol5008185

Letter
pubs.acs.org/OrgLett
Organocatalytic Asymmetric Michael−Michael Cascade for the
Construction of Highly Functionalized N‑Fused Piperidinoindoline
Derivatives
Yong-Long Zhao, Yao Wang, Jian Cao, Yong-Min Liang,* and Peng-Fei Xu*
State Key Laboratory of Applied Organic Chemistry, and College of Chemistry and Chemical Engineering, Lanzhou University,
Lanzhou 730000, P. R. China
S
* Supporting Information
ABSTRACT: Application of indolin-3-one derivatives in a
cascade reaction for efficient assembly of complex molecules is
a much less explored research area. It is demonstrated that
structurally interesting polysubstituted piperidino[1,2-a]-
indoline compounds containing four contiguous stereocenters
including one tetrasubstituted carbon center can be readily
obtained with good yields (up to 94% yield) and excellent
enantioselectivities (up to >99% ee) by employing indolin-3-
one derivatives as substrates via bifunctional catalysis.
iperidino[1,2-a]indoline represents an important class of
structural motifs that is frequently found in a large family
based on metal-catalyzed racemic syntheses and asymmetric
catalytic versions are challenging and generally lacking.2i,j
Therefore, the development of efficient and concise catalytic
approaches for the enantioselective construction of highly
functionalized piperidino[1,2-a]indoline derivatives is highly
desired.
P
of natural products and biologically active molecules (Figure
1).1 For example, indole alkaloids mersicarpine, secoleuconox-
The research area involving the use of 2-oxindole derivatives
has attracted a great deal of attention from the synthetic
community.3 This class of compounds has been extensively
used as privileged substrates and demonstrated to be very
reliable for the construction of a large number of
pharmaceutical candidates and natural products. However,
contrary to the significant progress in the development of 2-
oxindole chemistry, indolin-3-one derivatives, which could also
potentially serve as good substrates for developing a diverse
array of reactions, have received very little attention.4
Therefore, it is highly desirable to apply these substrates in
asymmetric catalysis as a complement to the current 2-oxindole
chemistry. We have worked in this area for a while and
developed several asymmetric catalytic reactions using this
scaffold.4a−c
Figure 1. Representative natural products containing a piperidino[1,2-
a]indoline scaffold.
The development of asymmetric organocatalytic cascade
reactions has served as a powerful tool for the quick
construction of complex molecules with multiple chiral
centers.5,6 Again, the application of indolin-3-one derivatives
in cascade reactions for the efficient assembly of complex
molecules is still an underdeveloped research area.4g With our
ongoing interest in the design and development of catalytic
cascade reactions6 and indolin-3-one chemistry,4a−c we would
like to further expand the scope of indolin-3-one reactivity to
cascade reactions for quickly assembling some interesting
ine, and leuconoxine were isolated from the Kopsia species.1a
Strychine, brucine, and vomicin are representative examples of
Strychnos alkaloids.1b Mangochinine is a main component of the
traditional Chinese medicine plant Manglietia chingii Dandy
(Magnoliaceae) which has antiulcer, muscle relaxant, and
antibacterial effects.1c Because of its interesting structure and
biological activity, the piperidino[1,2-a]indoline scaffold has
attracted extensive attention from both synthetic and medicinal
chemists. A few elegant methods have been developed for the
synthesis of the piperidino[1,2-a]indoline core structure in the
past several years.2 However, despite these significant advances,
it should be noted that most of these established methods are
Received: March 19, 2014
Published: April 15, 2014
© 2014 American Chemical Society
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dx.doi.org/10.1021/ol5008185 | Org. Lett. 2014, 16, 2438−2441

Organic Letters
Letter
a
scaffolds. We envisaged that piperidino[1,2-a]indoline skel-
etons possessing four contiguous stereocenters including one
chiral tetrasubstituted carbon center could be created via a
single Michael−Michael cascade sequence between indolin-3-
one derivatives 1 and nitroolefins 2 (Scheme 1).
Table 1. Optimization of Reaction Conditions
Scheme 1. Organocatalytic Asymmetric Michael−Michael
Cascade To Form Complex Polysubstituted Piperidino[1,2-
a]indoline Derivatives
b
c
d
entry
cat.
solvent
time (h) % yield
dr
% ee
1
A
CH2Cl2
THF
48
48
48
48
48
48
48
72
48
48
72
48
48
80
48
48
48
72
100
87
<20
<20
75
3.6:1.9:1
nd
97
nd
nd
93
94
96
nd
nd
82
nd
nd
98
97
nd
98
98
98
99
>99
Initially, a feasibility study of our hypothesis revealed that
indolin-3-one derivatives 1a and nitroolefin 2a reacted
smoothly in the presence of catalyst A (10 mol %) in
CH2Cl2 at room temperature to furnish the desired product 3a
in 87% yield, 3.6:1.9:1 dr, and 93% ee (Table 1, entry 1). Then,
different solvents such as CH3CN, THF, i-PrOH, toluene, and
dioxane were tested to see how they would affect this cascade
reaction (Table 1, entries 2−6). The results showed that
CH2Cl2 was the optimal choice (Table 1, entry 1). However, in
the absence of catalyst, the cascade process did not proceed
even in CH2Cl2 (Table 1, entry 7). Next, several bifunctional
catalysts were investigated, and bifunctional catalyst F was
found to be the most promising catalyst for this cascade
reaction (Table 1, entry 12). For catalyst E and H, no expected
product was obtained (Table 1, entries 11 and 14). Finally, we
examined the temperature effect on this cascade reaction and
found it could affect the diastereoselectivities significantly. By
lowering the temperature, the diastereoselectivities were
improved. (Table 1, entries 12 and 15−19). When the reaction
temperature was dropped to −60 °C, the desired product was
obtained with high yield and stereoselectivity (89% yield,
43.4:9.2:1 dr and 99% ee) (Table 1, entry 18).
With the reaction conditions optimized, the substrate scope
was then investigated to show the generality of this cascade
reaction (Table 2). In most cases, the reactions afforded the
corresponding polysubstituted piperidino[1,2-a]indoline prod-
ucts with moderate to excellent yields (49−94%), moderate to
good diastereoselectivities(8.2:3.9:1 to 37.8:2.7:1), and ex-
cellent enantioselectivities (up to >99% ee). The structural
variation of nitroalkenes 2 could be well tolerated in this
reaction irrespective of the electronic nature or position of the
substituents on the aromatic ring. Compared with the electron-
donating nitroalkenes (3c−e), the electron-withdrawing nitro-
alkenes (3l,m) gave higher yields and required shorter reaction
time. Generally speaking, due to the steric effect of the ortho
substituents, the ratio of the two major diastereomers increased
significantly in 3e, 3h, 3k, and 3r vs 3a. It is noteworthy that
this cascade process could also be successfully extended to an
aliphatic substituted nitroalkene 3o, albeit with lower
2
A
3
A
dioxane
i-PrOH
CH3CN
toluene
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
nd
4
A
2.2:1.5:1
4.0:2.7:1
3.6:1.5:1
nd
5
A
82
6
A
69
7
none
B
trace
70
8
1.2:2.7:1
1.2:2.4:1
2.8:3.2:1
nd
9
C
D
E
82
10
11
12
13
14
83
trace
89
F
4.6:1.8:1
2.4:1.1:1
nd
G
H
F
36
trace
87
e
15
7.8:2.9:1
26.4:7.2:1
35.9:8.8:1
43.4:9.2:1
6.1:1
f
16
F
87
g
17
F
85
h
18
F
89
i
19
F
54
a
Unless otherwise specified, all reactions were carried out with catalyst
(10 mol %), 1a (0.10 mmol), and 2a (0.20 mmol) in the indicated
b
solvent (1.0 mL) at room temperature. Combined yields of all
c
diastereomers after flash column chromatography. Determined by 1H
d
NMR analysis of the crude products. ee value of major compound 3a;
determined by chiral-phase HPLC analysis (OD-H column). Reaction
performed at 0 °C. Reaction performed at −40 °C. Reaction
performed at −50 °C. Reaction performed at −60 °C. Reaction
performed at −70 °C.
e
f
g
h
i
selectivities. The variation on the indolin-3-one scaffold could
also be tolerated in this cascade reaction and afforded the
desired products 3p−r with good results. The only exception
was 2-furyl-substituted nitroalkene; under the optimal reaction
conditions, the reaction using it (3n) as a substrate was not
successful and resulted in a complex mixture.
The absolute configuration of the major products in this
Michael−Michael cascade reaction was determined by X-ray
crystal diffraction of compound 3q (Figure 2).7 As shown in
Scheme 2, a possible reaction mechanism was also proposed.
The electrophilicity of nitroolefin 2 is enhanced by the
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dx.doi.org/10.1021/ol5008185 | Org. Lett. 2014, 16, 2438−2441

Organic Letters
Letter
a
Table 2. Substrate Scope of Michael−Michael Cascade
Scheme 2. Proposed Mechanism for Michael−Michael
Cascade
b
c
d
entry
1
R1
R2
C6H5
% yield
dr
% ee
H
89 (3a)
78 (3b)
72 (3c)
51 (3d)
64 (3e)
91 (3f)
89 (3g)
92 (3h)
86 (3i)
89 (3j)
94 (3k)
87 (3l)
92 (3m)
nd (3n)
71 (3o)
76 (3p)
49 (3q)
69 (3r)
43.4:9.2:1
17.6:5.3:1
29.3:8.5:1
8.2:3.9:1
99/nd
>99/90
99/>99
99/>99
99/nd
f
2
H
2-naphthyl
4-MeC6H4
4-MeOC6H4
2-MeOC6H4
4-FC6H4
4-ClC6H4
2-ClC6H4
4-BrC6H4
3-BrC6H4
2-BrC6H4
4-NO2C6H4
4-CF3C6H4
2-furyl
g
3
H
g
4
H
g
5
H
14.7:2.5:1
14.8:5.2:1
17.8:6.2:1
39.7:4.3:1
19.2:6.9:1
39.5:9.4:1
37.8:2.7:1
18.0:6.3:1
33.7:11.5:1
g
e
6
H
99/nd
Michael−Micheal cascade. The complex polysubstituted
piperidino[1,2-a]indoline derivatives containing four contigu-
ous stereocenters, including one chiral tetrasubstituted carbon
center were obtained with good yields, good diastereoselectiv-
ities, and excellent enantioselectivities. This work not only
provides a new method for the synthesis of chiral N-fused
piperidinoindoline derivatives but also is an important
complement to existing oxindole chemistry. Further inves-
tigation and application of activated indolin-3-one derivatives
are ongoing in our laboratories.
g
7
H
>99/99
99/nd
8
H
9
H
99/>99
>99/>99
99/nd
10
11
12
13
H
H
e
H
98/nd
e
H
98/nd
g
14
H
complex
nd
f
15
H
n-propyl
4.2:1.8:1
25.4:7.1:1
11.2:4.4:1
26.2:3.9:1
88/59
98/>99
16
17
18
6-Cl
5-Br
5-Br
C6H5
e
C6H5
99/nd
ASSOCIATED CONTENT
* Supporting Information
■
2-BrC6H4
99/>99
S
a
Unless otherwise specified, all reactions were carried out with catalyst
F (10 mol %), 1 (0.10 mmol), and 2 (0.20 mmol) in CH2Cl2 (1.0 mL)
at −60 °C, and the reaction time was determined by TLC (see the
Additional optimization of reaction parameters, experimental
procedure, and characterization data for all new compounds, X-
ray crystal structure data (CIF) for compound 3q. This material
is available free of charge via the Internet at http://pubs.acs.org.
b
Supporting Information). Combined yields of all diastereomers after
c
1
flash column chromatography. Determined by H NMR analysis of
d
the crude products. ee values of major compound 3 and major minor
AUTHOR INFORMATION
Corresponding Authors
diastereomer ; determined by chiral-phase HPLC analysis (AD-H and
■
e
OD-H column). The major minor diastereomer could not be
f
separated by chiral-phase HPLC analysis. Reaction performed at −40
*E-mail: xupf@lzu.edu.cn.
*E-mail: liangym@lzu.edu.cn.
g
°C. Reaction performed at −50 °C.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are grateful to the NSFC (21372105, 21032005,
21172097), PCSIRT (IRT1138), the International S&T
Cooperation Program of China (2013DFR70580), the National
Basic Research Program of China (No. 2010CB833203), and
the“111” program from MOE of P.R. China.
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