Efficient construction of highly functionalized spiro[γ- butyrolactone-pyrrolidin-3,3′-oxindole] tricyclic skeletons via an organocatalytic 1,3-dipolar cycloaddition

Article abstract of DOI:10.1039/c3cc40669e

Highly functionalized spiro[γ-butyrolactone-pyrrolidin-3,3′- oxindole] tricyclic skeletons were delivered successfully with high optical purity using an effective yet simple procedure.

Full text of DOI:10.1039/c3cc40669e

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Efficient construction of highly functionalized
spiro[c-butyrolactone-pyrrolidin-3,30-oxindole]
tricyclic skeletons via an organocatalytic
1,3-dipolar cycloaddition†
Cite this: Chem. Commun., 2013,
49, 3458
Received 26th January 2013,
Accepted 28th February 2013h
a
a
Long Wang,z Xiao-Mei Shi,z Wei-Ping Dong,a Li-Ping Zhua and Rui Wang*ab
DOI: 10.1039/c3cc40669e
www.rsc.org/chemcomm
Highly functionalized spiro[c-butyrolactone-pyrrolidin-3,30-oxindole]
tricyclic skeletons were delivered successfully with high optical purity
using an effective yet simple procedure.
The specificity of biological activities found in natural compounds is
generally in connection with the characteristic structural complexity
and well-defined stereo-architecture.1 In this context, much attention
has been paid to asymmetric synthetic strategies for assembling
challenging scaffolds widespread in natural compounds. The
spiro[pyrrolidin-3,30-oxindole] ring is featured in a myriad
of naturally occuring alkaloids and medicinally relevant com-
pounds.2 Inspired by the varied and significant biological
activities, different synthetic approaches have been developed
in pursuit of the structurally diversified and stereocontrolled
spiro-oxindole skeletons over the past few decades.3 Albeit the
outstanding progress in this field, the construction of highly
functionalized polycyclic skeletons, particularly those containing
multiple spiro-quaternary carbon centers, still poses a great
synthetic problem.4 In this work, we report the first construction
of spiro[g-butyrolactone-pyrrolidin-3,30-oxindole] tricyclic skele-
tons via a tertiary amine thiourea mediated formal 1,3-dipolar
cycloaddition (Scheme 1). A series of spirotricyclic skeletons were
delivered successfully with excellent levels of stereocontrol over
four contiguous stereocenters, two of which are spiro-quaternary
carbon centers.
Scheme 1 Strategy for direct construction of spirotricyclic skeletons.
Since the pioneering work by Grigg and Allway,6 many efforts have
been made using chiral metal catalysts, and elegant studies have
been reported in this research field.7 In sharp contrast to the well-
documented methods based on metal complexes, organocatalytic
approaches are still far from being fully disclosed.8 Recently, chiral
proline derivatives have been applied in this transformation by
Cordova et al. and other groups.8a,c,i,j However, these methods did
´
not include dipolarophiles other than unsaturated aldehydes.
Several Brønsted acid mediated 1,3-dipolar cycloaddition reactions
of azomethine ylides have been presented by Gong et al.,8b,e–g
including the process for the first construction of chiral spiro-
[pyrrolidin-3,30-oxindole] derivatives.8f Therefore, the development
of more versatile and environmentally benign variants of this
transformation is still in great demand.
Recently, homoserine lactone derived imino esters have emerged
as useful reactants for assembling spirocyclic compounds. Grigg and
co-workers reported their utility in the synthesis of spiro-pyrrolidine
derivatives.9a,b Wang et al. extended their utility to asymmetric
construction of spiro-butyrolactone skeletons through CuI catalyzed
cascade processes.7d,10 Despite these, the versatility of this synthon is
still far from being fully explored. Therefore, we envisioned that the
desired spirotricyclic skeleton could be constructed by a 1,3-dipolar
cycloaddition of cyclic imino esters with methyleneindolinones via a
bifunctional strategy (Scheme 1). Herein, we present the successful
implementation of this strategy to provide a series of infrequent
spirocyclic skeletons with high enantiopurity and significant
opportunities for structural diversification.
The asymmetric 1,3-dipolar cycloaddition of azomethine
ylides with electron-deficient alkenes is one of the highly
powerful methods for the facile assembly of various pyrrolidines.5
a Key Laboratory of Preclinical Study for New Drugs of Gansu Province, State Key
Laboratory of Applied Organic Chemistry, School of Life Sciences, School of Basic
Medical Science, Lanzhou University, Lanzhou 730000, China.
E-mail: wangrui@lzu.edu.cn
b Department of Applied Biology and Chemical Technology, The Hong Kong
Polytechnic University, Kowloon, Hong Kong, China.
E-mail: bcrwang@polyu.edu.hk
† Electronic supplementary information (ESI) available. CCDC 906655. For ESI
and crystallographic data in CIF or other electronic format see DOI: 10.1039/
c3cc40669e
We recently developed a series of rosin-derived tertiary amine
thiourea bifunctional catalysts, which have been successfully
‡ These authors contributed equally to this work.
c
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Table 1 Optimization of the 1,3-dipolar cycloaddition of cyclic imino ester 2a
with methyleneindolinone 3aa
Table 2 Optimization of the 1,3-dipolar cycloaddition of cyclic imino esters 2a–
2n with methyleneindolinone 3aa
Entry
R1
Product
Yieldb (%)
d.r.c
eed (%)
1
2
3
4
5
6
C6H5
4a
4b
4c
4d
4e
4f
92
95
89
95
92
86
>20 : 1
16 : 1
14 : 1
15 : 1
>20 : 1
>20 : 1
95
92
90
95
94
97
4-ClC6H4
3-BrC6H4
4-MeC6H4
3-MeC6H4
2-MeC6H4
7
4g
95
>20 : 1
92
Entry
Cat.
Solvent
Yieldb (%)
d.r.c
18 : 1
14 : 1
13 : 1
10 : 1
>20 : 1
12 : 1
eed (%)
8
9
10
11
2-Naphthyl
2-Furanyl
2-Thionyl
Cyclohexyl
4h
4i
4j
95
91
97
90
>20 : 1
15 : 1
>20 : 1
>20 : 1
90
92
91
90
1
2
3
4
5
6
7
8
1a
1b
1c
1d
1b
1b
1b
1b
Tol
Tol
Tol
Tol
92
91
94
90
85
94
89
92
ꢀ67
87
ꢀ86
ꢀ23
89
83
70
4k
a
The reaction was conducted with 2 (0.11 mmol) and 3a (0.10 mmol)
Et2O
CH2Cl2
THF
Tol : Et2O = 1 : 1
b
in 1.0 mL solvent at room temperature for 24 h. Isolated yield.
c
d
Determined by 1H NMR spectroscopy. The ee values were deter-
14 : 1
>20 : 1
mined by HPLC.
95
a
The reaction was conducted with 2a (0.11 mmol) and 3a (0.10 mmol)
b
Interestingly, ortho-methyl-substituted imino esters 2f gave ee
values up to 97% without losing both yields and diastereos-
electivities (entry 6). Cyclic imino esters 2h–2j derived from
naphthaldehyde and heteroaromatic aldehyde also worked well
in 1.0 mL solvent at room temperature for 24 h. Isolated yield.
c
d
Determined by 1H NMR spectroscopy. The ee values were deter-
mined by HPLC.
applied to several asymmetric transformation processes.3e,f,11 in this transformation to provide the corresponding products
Our initial investigation began with studying these thiourea 4h–4j with satisfactory results (entries 8–10). A comparable
catalysts (10 mol% catalyst loading) in the reaction of a cyclic outcome was also achieved for the less reactive imino ester
imino ester (2a) with methyleneindolinone (3a) at room tempera- 2k, derived from aliphatic cyclohexanecarbaldehyde (90% yield,
ture in toluene, and the representative results are summarized in >20 : 1 d.r., 90% ee, entry 11).
Table 1. Gratifyingly, the screened catalysts 1a–1d all worked well
To further expand the synthetic utility of this transformation, a
and gave the desired product in satisfactory isolated yields (entries variety of substituted methyleneoxindoles were also examined
1–4). Among them, tertiary amine 1b with a pyrrolidine group under the optimal reaction conditions (Table 3). As expected,
afforded the best stereoselectivity result (87% ee, 14 : 1 d.r., 91% various cycloaddition products were obtained in good to excellent
yield, entry 2). The catalyst 1c, as the diastereomer of 1b, provided yields and stereoselectivities (83–94% yields, 14 : 1–>20 : 1 d.r.,
a slightly higher yield but a relatively lower selectivity (86% ee, 90–>99% ee). Minimal impact on efficiencies and stereo-
13 : 1 d.r., 94% yield, entry 3). Quinine derived thiourea catalyst 1d selectivities was observed, regardless of the electronic nature
could also promote such a transformation, while resulting in or positions of the substituents. Furthermore, methyleneindoli-
low ee values (23% ee, 10 : 1 d.r., 90% yield, entry 4). Screening nones with different ester substituents or N-protecting groups
of solvents revealed a mixture of toluene and ether (volume were also examined. The ester group of the dipolarophile has
ratio = 1 : 1) to be optimal among those tried in terms of both little impact on the reaction yield and stereoselectivity as well.
yields and selectivities (entries 5–8). It is worth noting that Satisfactory outcomes were also achieved for the dipolarophiles
reducing the catalyst loading to 5 mol% gave the same excellent with different N-protecting groups. An X-ray analysis of the
results, but 36 h were needed for completion of the reaction crystal of product 4c revealed the relative and absolute configu-
(not indicated in Table 1). Catalyst 1b at a 10 mol% loading was ration of the spirotricyclic skeleton (see the ESI†). The absolute
selected for further studies in terms of reaction efficiency.
With the optimized reaction conditions in hand, we next
configurations of all other products were assigned by analogy.
In summary, we have reported the first 1,3-dipolar cycloaddition
explored the generality of the reaction. A wide range of cyclic imino reaction of homoserine lactone derived cyclic imino esters with
esters 2a–2k, derived from various aromatic or aliphatic aldehydes, methyleneindolinones to provide a series of spiro[g-butyrolactone-
reacted smoothly with methyleneoxindole 3a to afford the corres- pyrrolidin-3,30-oxindole] tricyclic skeletons via a bifunctional
ponding products 4a–4k in good to excellent yields and stereo- organocatalytic strategy. Simple precursors were used under
selectivities (86–97% yields, 90–97% ee, 14 : 1–>20 : 1 d.r., Table 2). mild conditions to construct the desired products with excellent
Both electron-donating and electron-withdrawing substituents at levels of stereocontrol over four contiguous stereocenters, two
different positions on the aromatic ring were tolerated (entries 1–7). of which are spiro quaternary stereocenters. This new method
c
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Table 3 The cycloaddition reaction of homoserine lactone derived imino ester
2a with methyleneindolinones 3a
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Entry R2
R3
R4
Product Yieldb (%) d.r.c
eed (%)
1
2
3
5-Br
5-Cl
5-F
Et
Et
Et
Et
Et
Et
Et
H
H
H
H
H
H
H
H
H
H
4l
89
87
86
90
90
94
90
92
94
83
87
87
>20 : 1
>20 : 1
14 : 1
92
90
90
92
93
90
93
94
90
92
93
4m
4n
4o
4p
4q
4r
4s
4t
4u
6 P. Allway and R. Grigg, Tetrahedron Lett., 1991, 32, 5817.
4
5
6
6-Br
6-Cl
7-F
>20 : 1
>20 : 1
>20 : 1
>20 : 1
>20 : 1
>20 : 1
>20 : 1
>20 : 1
´
7 Selected examples: (a) J. Hernandez-Toribio, S. Padilla, J. Adrio and
J. C. Carretero, Angew. Chem., Int. Ed., 2012, 51, 8854; (b) A. Awata
´
and T. Arai, Chem.–Eur. J., 2012, 18, 8278; (c) M. Gonzalez-
7
8
5-Me
5-OMe Et
Esguevillas, J. Adrio and J. C. Carretero, Chem. Commun., 2012,
48, 2149; (d) T.-L. Liu, Z.-L. He, H.-Y. Tao and C.-J. Wang,
9
H
H
H
H
Me
tBu
Et
´
´
Chem.–Eur. J., 2012, 18, 8042; (e) M. M. Rodrıguez, C. Najera,
10
11
12
´
´
J. M. Sansano, A. de Cozar and F. P. Cossıo, Chem.–Eur. J., 2011,
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Me 4v
Bn 4w
Et
>20 : 1 >99
a
The reaction was conducted with 2a (0.11 mmol) and 3 (0.10 mmol)
b
in 1.0 mL solvent at room temperature for 24 h. Isolated yield.
c
d
Determined by 1H NMR spectroscopy. The ee values were deter-
mined by HPLC.
provides straightforward access to a series of highly functionalized
polycyclic compounds, and should be useful in the synthesis of
corresponding natural compounds and exploration of novel
therapeutic agents.
We gratefully acknowledge the financial support from the
National Natural Science Foundation of China (no. 91213302,
20932003 and 21272102), the Key National S&T Program ‘‘Major
New Drug Development’’ of the Ministry of Science and Technology
of China (2012ZX09504001-003).
´
8 Selected examples: (a) S. Reboredo, E. Reyes, J. L. Vicario, D. Badıa,
´
´
L. Carrillo, A. de Cozar and F. P. Cossıo, Chem.–Eur. J., 2012,
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´
J.-L. Sun and A. Cordova, Angew. Chem., Int. Ed., 2011, 50, 7624;
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c
3460 Chem. Commun., 2013, 49, 3458--3460
This journal is The Royal Society of Chemistry 2013