Organocatalytic asymmetric multicomponent cascade reaction via 1,3-proton shift and [3+2] cycloaddition: An efficient strategy for the synthesis of oxindole derivatives

Article abstract of DOI:10.1039/c3cc43755h

An efficient and powerful organocatalytic cascade reaction was achieved for the synthesis of biologically important chiral spiro[pyrrolidin-3,2′- oxindoles] using very simple and readily available starting materials. Three C-C bonds and four contiguous stereogenic centers including one quaternary stereocenter were established in a single operation with reasonable yields and good stereoselectivity.

Full text of DOI:10.1039/c3cc43755h

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Organocatalytic asymmetric multicomponent cascade
reaction via 1,3-proton shift and [3+2] cycloaddition:
an efficient strategy for the synthesis of oxindole
derivatives†
Cite this: DOI: 10.1039/c3cc43755h
Received 18th May 2013,
Accepted 18th June 2013
DOI: 10.1039/c3cc43755h
Li Tian, Xiu-Qin Hu, Yun-Han Li and Peng-Fei Xu*
www.rsc.org/chemcomm
An efficient and powerful organocatalytic cascade reaction was synthesis of spiro[pyrrolidin-3,20-oxindoles] has been a challenge
achieved for the synthesis of biologically important chiral for a long time, since the established methods are either racemic
spiro[pyrrolidin-3,20-oxindoles] using very simple and readily avail- approaches or require enantiopure starting materials.1,2 Not
able starting materials. Three C–C bonds and four contiguous until 2012, Gong and co-workers reported the first asymmetric
stereogenic centers including one quaternary stereocenter were catalytic approach through 1,3-dipolar cycloadditions involving
established in a single operation with reasonable yields and good azomethine ylides generated in situ from unsymmetrical cyclic
stereoselectivity.
ketones.3a To date, only a few catalytic asymmetric synthetic
methods have been reported.3 As a consequence, it is still highly
The spiro[pyrrolidin-3,20-oxindoles] are privileged structural desired to explore novel catalytic approaches to generate this
motifs that can be found in a large number of clinical pharma- structurally rigid architecture, especially those using simple and
ceuticals and natural spirooxindole alkaloids possessing various readily available starting materials.
biological activities (Fig. 1) such as anti-microbial, anti-tumor,
Recently, the groups of Shi4 and Deng5 elegantly introduced
anti-diabetic, anti-inflammatory, anti-tubercular, and acetyl- an attractive strategy of cinchona alkaloid derivative catalyzed
cholinesterase (AChE) inhibitory activities.1 Due to the medicinal 1,3-proton shift of imines6 for the asymmetric synthesis of
significance of this structural core, it has drawn tremendous chiral a-amino acid derivatives7 and trifluoromethylated
attention from both synthetic and medicinal chemists. Despite amines.8 We reasoned that this efficient biomimetic transamina-
the importance of such compounds, the catalytic asymmetric tion could serve as a good starting point to design novel trans-
formations for the synthesis of a range of valuable compounds.
Additionally, organocatalytic cascade reactions have been con-
sidered as powerful synthetic tools for rapidly creating complex
molecules with multiple stereocenters.9 Thus, with our ongoing
interest in the development of bifunctional base–Brønsted acid-
catalyzed cascade reactions10 and inspired by the achievements
of enantioselective 1,3-proton shift of imines, we have developed
and report here a novel and efficient strategy for the construction
of a spiro[pyrrolidin-3,20-oxindole] scaffold with four contiguous
stereogenic centers including one quaternary stereocenter
through 1,3-proton shift and [3+2] cycloaddition catalyzed by a
bifunctional squaramide.
In our initial investigation,11 several bifunctional catalysts
were screened (Fig. 2) to evaluate their ability to promote the
cascade reaction of isatin 1a, benzylamine 2a and nitroalkene
3a in dichloromethane at 10 1C (Table 1). The results showed
that catalysts 5a–5i gave the desired product 4a with moderate
yield albeit with low enantioselectivity (Table 1, entries 1–9). 5j
could not catalyze the reaction without tertiary amine (Table 1,
entry 10). Cinchona-based squaramide 5i was then selected as
the promising catalyst for further screening (Table 1, entry 9).
To our delight, variation of the N-protecting group of the isatin
Fig. 1 Some biologically important compounds containing the spiro[pyrrolidin-
3,20-oxindoles] core.
State Key Laboratory of Applied Organic Chemistry, College of Chemistry and
Chemical Engineering, Lanzhou University, Lanzhou 730000, P. R. China.
E-mail: xupf@lzu.edu.cn
† Electronic supplementary information (ESI) available: Experimental procedures
and spectra of all new compounds. CCDC 936431. For ESI and crystallographic
data in CIF or other electronic format see DOI: 10.1039/c3cc43755h
c
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Table 2 Substrate scope of the cascade reactiona
Entry R1
R2
R3
Yieldb (%) d.r.c
eed (%)
1
2
3
4
H
H
H
H
H
H
H
H
H
H
H
H
H
H
5-Cl
5-Me
6-Cl
6-Br
H
H
H
H
H
H
H
H
H
Ph
75(4a)
76(4b)
77(4c)
73(4d)
73(4e)
65(4f)
68(4g)
70(4h)
63(4i)
58(4j)
64(4k)
67(4l)
75(4m)
76(4n)
67(4o)
71(4p)
69(4q)
73(4r)
o20(4s)
9 : 1
9 : 1
10 : 1 86
9 : 1 87
11 : 1 85
8 : 1
9 : 1
7 : 1
10 : 1 80
9 : 1 85
10 : 1 86
7 : 1
6 : 1
5 : 1
5 : 1
5 : 1
9 : 1
8 : 1
n.d.
86
84
4-MeC6H4
3,4-(Me)2C6H3
3-MeOC6H4
2-Naphthyl
4-BrC6H4
4-ClC6H4
2-Furyl
4-FC6H4
3-MeOC6H4
3-MeOC6H4
3-MeOC6H4
3-MeOC6H4
5
6e
82
80
78
Fig. 2 Bifunctional catalysts examined in this study.
Table 1 Optimization of reaction conditionsa
7f
8
9f
H
10f
11
12
13
14
15f
16
17
18
19e,f
2-F
4-F
4-Br
4-Me
86
81
77
80
82
81
83
n.d.
4-OMe 3-MeOC6H4
H
H
H
H
H
Ph
Ph
Ph
Ph
Entry
R
Cat. T (1C) Time (h) Yieldb (%) d.r.c eed (%)
n-Pr
a
1
2
3
4
5
6
7
8
H
H
H
H
H
H
H
H
H
H
Me
5a
5b
5c
5d
5e
5f
5g
5h
5i
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
36
36
36
36
36
36
36
36
36
36
12
24
12
12
12
12
43
61
60
62
59
65
63
63
66
n.d.
n.d.
n.d.
n.d.
n.d.
n.d.
n.d.
n.d.
5 : 1
n.d.
7 : 1
n.d.
8 : 1
11 : 1 74
5 : 1
n.d.
10 : 1 76
9 : 1 77
10 : 1 77
9 : 1
9 : 1
8
11
5
5
10
7
13
29
53
n.d.
55
n.d.
70
Unless otherwise specified, the reaction was carried out with 1
(0.2 mmol), 2 (0.2 mmol), 3 (1 mmol), 5i (5 mol%) and MgSO4 (120 mg)
b
in CH2Cl2 (0.5 mL) under reflux in 12 h. The yields are the combined
c
yields of the isolated diastereomers after flash chromatography. Deter-
mined by 1H NMR analysis of the crude products. Determined by chiral-
d
phase HPLC analysis. e The reaction time was 24 h. In the presence of
f
10 mol% 5i.
9
10
11
12
13
14
15e
16f
17
18g
19h
20i
5j
5i
o20
results, the optimal condition was found to be the use of
catalyst 5i (5 mol%) in CH2Cl2 under reflux.
65
Boc 5i
Allyl 5i
o20
70
73
51
39
76
72
70
74
Under the optimal reaction conditions, the substrate scope
of the reaction was also investigated. As shown in Table 2, in all
the cases, the reaction proceeded smoothly to afford the
corresponding oxindole derivatives in a generally moderate
yield and good diastereo- and enantioselectivity. The reaction
of nitroalkenes 3 with electron-donating substituents pro-
ceeded faster and gave better results than those with electron-
withdrawing substituents (Table 2, entries 2–5 vs. entries 6, 7
and 9). Nitroalkenes with a heteroaromatic group such as furan
(Table 2, entry 8) were also successfully converted into the
corresponding product with a slightly lower enantioselectivity.
In addition to aromatic groups, nitroalkenes with an aliphatic
group were also investigated, which gave a lower yield (Table 2,
entry 19). Compared with electron-donating substituents,
benzylamines 2 with electron-withdrawing substituents gave higher
Bn
Bn
Bn
Bn
Bn
Bn
Bn
5i
5i
5i
5i
5i
5i
5i
5i
71
18
Reflux
Reflux
10
Reflux
Reflux 12
1.5
5
4
5
81
86
21g,h,i,j Bn
75
a
Unless otherwise specified, the reaction was carried out with 1
(0.2 mmol), 2a (0.2 mmol), 3a (0.2 mmol) and an organocatalyst
b
(10 mol%) in CH2Cl2 (1.0 mL) at 10 1C. The yields are the combined
yields of the isolated diastereomers after flash chromatography.
c
d
Determined by 1H NMR analysis of the crude products. Determined
e
by chiral-phase HPLC analysis (AD-H column). 1.0 mL toluene was
added. 1.0 mL CH3CN was added. 5 mol% loading of catalyst. 120 mg
MgSO4 was added. 1 mmol 3a was added. Use of 0.5 mL CH2Cl2.
f
g
h
i
j
had a significant effect on the enantioselectivity and benzyl- selectivities but lower yields (Table 2, entries 10–12 vs. entries
protected isatin 1c was proven to be an optimal selection 13–14). However, different substituents of isatins 1 appeared to
(Table 1, entry 14). Further screening revealed that CH2Cl2 have only a slight effect on results except that lower diastereo-
was the solvent of choice (Table 1, entries 14–16). Better results selectivities were obtained with C5 substituted isatins (Table 2,
were obtained when the transformation was under reflux for entries 15–18). The absolute configuration of the product 4f was
a shorter time (Table 1, entry 17). Lower catalyst loading determined to be (20R, 30S, 40S, 50S) by X-ray crystallographic
(5 mol%) was appropriate for the reaction (Table 1, entry 18). analysis.12
Increasing the amount of 3a resulted in a significant improve-
A plausible catalytic cycle is outlined in Scheme 1. The
ment in the enantioselectivity (Table 1, entry 20) and the rest of reaction may be initiated by base catalyzed 1,3-proton shift to
the nitroalkene could be recycled easily when purifying the form intermediate 8. Intermediate 9 is then generated through
product through column chromatography. Based on the above synergistic activation of both 8 and nitroalkene 3a by the
c
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In summary, with very simple and readily available starting
materials, we have successfully established a catalytic enantio-
selective route to the biologically important spiro[pyrrolidin-
3,20-oxindole] scaffold with four contiguous stereogenic centers
including one quaternary stereocenter in good selectivity using
a bifunctional squaramide. Similarly importantly, it is a very
efficient strategy in which a single catalyst can be used to
catalyze both 1,3-proton shift and [3+2] cycloaddition. Further
investigation of this transformation and attempts to explore the
cascade reaction involving 1,3-proton shift are underway in
our group.
We are grateful to the NSFC (21032005, 21172097, 21202070),
the National Basic Research Program of China (no. 2010CB833203),
National Natural Science Foundation from Gansu Province of
China (no.1204WCGA015), and the ‘‘111’’ program from MOE of
P. R. China.
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Notes and references
1 (a) A. A. Raj, R. Raghunathan, M. R. SrideviKumari and N. Raman, 11 For details, see ESI†.
Bioorg. Med. Chem., 2003, 11, 407; (b) A. S. Girgis, Eur. J. Med. Chem., 12 CCDC 936431. See the ESI† for details.
c
This journal is The Royal Society of Chemistry 2013
Chem. Commun.