An organocatalytic Michael-aldol cascade: Formal [3+2] annulation to construct enantioenriched spirocyclic oxindole derivatives

Article abstract of DOI:10.1039/c2cc30931a

An efficient organocatalytic Michael-aldol cascade reaction for the asymmetric synthesis of spirocyclic oxindole derivatives fused with tetrahydrothiophenes has been developed through a formal [3+2] annulation strategy.

Full text of DOI:10.1039/c2cc30931a

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An organocatalytic Michael-aldol cascade: formal [3+2] annulation to
construct enantioenriched spirocyclic oxindole derivativeswz
Shu-Wen Duan, Yang Li, Yi-Yin Liu, You-Quan Zou, De-Qing Shi and Wen-Jing Xiao*
Received 9th February 2012, Accepted 5th March 2012
DOI: 10.1039/c2cc30931a
An efficient organocatalytic Michael-aldol cascade reaction for
the asymmetric synthesis of spirocyclic oxindole derivatives
fused with tetrahydrothiophenes has been developed through a
formal [3+2] annulation strategy.
On the other hand, a literature survey showed that the simple
and commercially available 1,4-dithiane-2,5-diol (the dimer of
mercaptoacetaldehyde) has proved to be an attractive synthon
for construction of thiophene and tetrahydrothiophene
derivatives.13 However, highly stereoselective incorporation
of 1,4-dithiane-2,5-diol into the tetrahydrothiophenes scaffold
has been largely unexplored.14 Also, as part of our ongoing
program on the development of carbon- and heterocycle-
oriented methodologies,15 we described herein a Michael-aldol
cascade between 3-ylideneoxindoles and 1,4-dithiane-2,5-diol,
which provided an efficient access to a new family of tetra-
hydrothiophene-fused spirooxindoles bearing three consecutive
stereogenic centers.
Spirocyclic oxindoles have emerged as attractive synthetic targets
in chemical science due to their prevalence in a wide range
of bioactive alkaloids and pharmacologically important
compounds.1 Moreover, the three dimensional structural proper-
ties of spirooxindoles have evoked immense interest from the
synthetic standpoint. Accordingly, great impressive advances
have been documented for the stereoselective synthesis of
spirocyclic oxindoles fused with pyrrolidines,2 piperidines,3
pyrans,4 tetrahydropyrans,5 tetrahydrofurans,6 cyclopropanes,7
and other five-8 or six-membered carbocycles.9 For example,
Barbas and coworkers developed an elegant organocatalytic
asymmetric cascade Michael-aldol reaction, providing excellent
stereocontrol of the newly formed spirocycle.8f This recent
achievement paves the way for the development of a novel
organocatalytic strategy for construction of spirocyclic oxindole
derivatives. In this context, however, successful examples
for assembly of optically active spirocyclic oxindoles bearing
biologically and synthetically important tetrahydrothiophene
motifs are still unknown to date. Furthermore, considering the
correlation between the potential bioactivities and their mole-
cular diversities, the development of new and general approaches
to chiral spirooxindole–tetrahydrothiophenes with functional
diversity is still highly desirable.
At the outset of our investigation, a series of organocatalysts
were evaluated in the selected reaction of (E)-ethyl 2-(1-methyl-
2-oxoindolin-3-ylidene)acetate 1a16 and 2 in dichloromethane at
room temperature (Fig. 1). As shown in Table 1, despite short
reaction time and good chemical yields, the cinchona alkaloid I
and thiourea-tertiary amine catalysts II–IV could only give the
desired cycloadduct 3a with up to 23% ee (entries 1–4). Further
optimizations showed that a substantial increase of enantio-
selectivity was observed by employing cinchona-based squaramide
V as the H-bond donor17 (entry 5). Moreover, the reaction could
afford the opposite enantiomer of 3a with similar stereoselectivity
by changing the cinchonidine-derived squaramide V to its quinidine
Pioneered by Jørgensen et al.10 and Wang et al.,11 diversely
substituted tetrahydrothiophenes12 can be efficiently obtained
in high yield and stereoselectivity utilizing the secondary
amine as the imine–enamine cycle promoter. However, these
reactions are generally limited to the unsaturated aldehydes.
Key Laboratory of Pesticide & Chemical Biology, Ministry of
Education, College of Chemistry, Central China Normal University,
152 Luoyu Road, Wuhan, Hubei 430079, China.
E-mail: wxiao@mail.ccnu.edu.cn; Fax: +86 27 67862041;
Tel: +86 27 67862041
w This article is part of the joint ChemComm–Organic & Biomolecular
Chemistry ‘Organocatalysis’ web themed issue.
z Electronic supplementary information (ESI) available: Experimental
procedures and compound characterisation data, including X-ray
crystal structure for 3a. CCDC 861216. For ESI and crystallographic
data in CIF or other electronic format see DOI: 10.1039/c2cc30931a
Fig. 1 The organocatalysts tested in this study.
c
5160 Chem. Commun., 2012, 48, 5160–5162
This journal is The Royal Society of Chemistry 2012

Table 1 Condition optimizationsa
Table 2 Organocatalytic asymmetric Michael-aldol cascade reaction
of 3-ylideneoxindoles 1 and 1,4-dithiane-2,5-diol 2 catalyzed by V or VIa
Entry
Cat.
Solvent
Time
Yield (%)b
drc
ee (%)d
Entry
R
R0
Product Time Yield (%)b drc
ee (%)d
1
2
3
4
5
6
7
8
I
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
PhMe
Et2O
THF
CHCl3
CH2Cl2
CH2Cl2
1 h
1 h
1 h
0.5 h
1 h
2 h
10 h
10 h
0.5 h
1 h
80
80
89
92
95
94
98
92
95
98
97
92
5 : 1
4 : 1
10 : 1
10 : 1
419 : 1
419 : 1
419 : 1
419 : 1
419 : 1
419 : 1
419 : 1
419 : 1
23
ꢀ7
ꢀ18
ꢀ13
79
II
III
IV
V
VI
V
V
V
V
V
1
2
3
4
5
6
7
8
H Me 3a
5-Me Me 3b
5-OMe Me 3c
5-F
5-Br
7 h
12 h 96
10 h 96
4 h
3 h
92
419 : 1
17 : 1
13 : 1
11 : 1
4 : 1
84
83
84
85
83
86
85
86
87
83
86
87
Me 3d
Me 3e
92
83
ꢀ80
68
55
5-OCF3 Me 3f
10 h 74
6 : 1
8 : 1
7 : 1
5 : 1
15 : 1
419 : 1
419 : 1
6-Cl
6-Br
7-F
Me 3g
Me 3h
Me 3i
4 h
5 h
87
89
9
69
76
79
84
10
11e
12f
9
10 h 81
10 h 94
0.5 h
7 h
10
11
12
13e
14e
15e
5,7-Me2 Me 3j
V
H
H
H
H
H
Bn
Allyl 3l
Me ent-3a
Bn ent-3k
Allyl ent-3l
3k
6 h
6 h
95
94
a
Unless otherwise specified, all reactions were carried out with
1a (0.3 mmol), 2 (0.18 mmol), cat. (10 mol%), MgSO4 (36 mg) in
12 h 96
11 h 94
11 h 93
419 : 1 ꢀ87
419 : 1 ꢀ90
419 : 1 ꢀ91
b
c
the solvent (1 mL) at 15 1C. Isolated yield. Determined by
1H NMR of the reaction mixture. Determined by chiral HPLC
d
a
e
f
Unless otherwise specified, all reactions were carried out with
1 (0.5 mmol), 2 (0.3 mmol), V (1 mol%), MgSO4 (60 mg) in DCM
analysis. The reaction was conducted with 0.3 mmol of 2. The
reaction was conducted with 1 mol% of V in CH2Cl2 (10 mL).
(10 mL) at 15 1C. Isolated yield. Determined by 1H NMR of crude
products. Determined by chiral HPLC analysis. The reaction was
conducted with 1 mol% of VI.
b
c
d
e
analogue VI (entry 6). Subsequent screening of the solvents
indicated a slight variation in diastereoselectivity but significant
solvent-dependence in enantioselectivity (entries 7–10). The
increasing loading of 1,4-dithiane-2,5-diol had little impact on
the efficiency of the reaction (entry 11). Importantly, when the
catalyst loading was reduced from 10 to 1 mol% cycloadduct 3a
still maintained the high yield and enantioselectivity while with
a slightly prolonged reaction time (entry 12).
Then, this Michael-aldol cascade reaction was extended to a
variety of other 3-ylideneoxindoles in the presence of 1 mol%
squaramide V under the optimized conditions. The results are
summarized in Table 2. It was found that most reactions with
different substituents at C5–C7 positions were completed
within 12 h, affording the corresponding products in excellent
yields and good enantioselectivities (entries 2–12). The results
indicated that the position and electronic property of the
substituents had a reasonable effect on the diastereoselectivity
(4 : 1 dr to 419 : 1 dr). The 3-ylideneoxindoles with benzyl and
allyl groups on the nitrogen atom were also well tolerated to
give the cycloadducts in excellent yields and diastereoselectivities
with good ee values (entries 11 and 12). Perhaps more importantly,
this strategy readily provided a facile access to the enantiomers
simply by changing the cinchonidine-based squaramide V to its
quinidine analogue VI. Slightly higher enantioselectivities were
observed within the similar reaction time (entries 13–15). To
determine the absolute configuration of the cycloadducts,
single crystals suitable for X-ray crystallographic analysis were
fortunately obtained from 3a that bears a sulfur atom. As shown
in Scheme 1, it contains a (C8R, C10R, C12S) configuration.
According to the above experimental results and previously
reported dual activation model,17a,d,f,i both the substrates
involved in the transition state are activated by squaramide
V as proposed in Scheme 1. The Michael acceptor is assumed
Scheme 1 Proposed transition state and the X-ray structure of 3a.
to be activated and oriented by the hydrogen bonds of the
squaramide, while the tertiary amine of the catalyst would
provide suitable basicity to enhance the nucleophilicity of the
mercaptoacetaldehyde. The well-defined orientation facilitates
the Si attack on the activated olefin, which favors the formation
of the C12S stereocenter. Subsequent intramolecular aldol
reaction through the attack from the Re face of the aldehyde
afforded the major C8R, C10R-configured product.
In conclusion, we have demonstrated herein an efficient organo-
catalytic Michael-aldol cascade for construction of enantio-
enriched spirocyclic oxindoles fused with tetrahydrothiophenes.
c
This journal is The Royal Society of Chemistry 2012
Chem. Commun., 2012, 48, 5160–5162 5161

The present method provided a facile access to a new family of
heavily functionalized spirooxindole derivatives bearing three
consecutive stereogenic centers in a highly stereoselective
fashion. Further applications of the current strategy to synthesis
of other types of polysubstituted dihydrothiophenes are underway
in our laboratory.
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We are grateful to the National Science Foundation of China
(21072069 and 21002036) and the National Basic Research
Program of China (2011CB808603) for support of this research.
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c
5162 Chem. Commun., 2012, 48, 5160–5162
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