Organocatalytic asymmetric desymmetrization: Efficient construction of spirocyclic oxindoles bearing a unique all-carbon quaternary stereogenic center via sulfa-Michael addition

Article abstract of DOI:10.1039/c3cc42587h

An unprecedented enantioselective desymmetrization of spiro cyclohexadienone oxindoles has been developed successfully via organocatalyzed asymmetric SMA, which provides facile access to spirocyclic oxindoles bearing a unique all-carbon quaternary stereogenic center with excellent levels of stereoselectivity.

Full text of DOI:10.1039/c3cc42587h

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Organocatalytic asymmetric desymmetrization:
efficient construction of spirocyclic oxindoles bearing
a unique all-carbon quaternary stereogenic center
via sulfa-Michael addition†
Cite this: DOI: 10.1039/c3cc42587h
Received 9th April 2013,
Accepted 15th May 2013
Lu Yao,ab Kang Liu,a Hai-Yan Tao,a Guo-Fu Qiu,c Xiang Zhoua and
Chun-Jiang Wang*ab
DOI: 10.1039/c3cc42587h
www.rsc.org/chemcomm
An unprecedented enantioselective desymmetrization of spiro quaternary and a contiguous sulfur-substituted tertiary stereogenic
cyclohexadienone oxindoles has been developed successfully via center remains not only a demand for biochemists and medicinal
organocatalyzed asymmetric SMA, which provides facile access to chemists, but also a challenge for synthetic organic chemists. We
spirocyclic oxindoles bearing
a unique all-carbon quaternary envisioned that excellent stereoselective control achieved in catalytic
stereogenic center with excellent levels of stereoselectivity.
asymmetric sulfur-Michael addition reactions rendered them well
suitable for the facile access to highly functionalized spirocyclic
Spirocyclic oxindoles widely occur in a large number of natural oxindoles containing a unique all-carbon stereogenic center via
products and biologically active molecules,1 especially those bearing enantio-selective desymmetrization of prochiral spiro-[cyclo-
a unique all-carbon quaternary stereogenic center at the C-3-position.2 hexadienone-oxindole] (Scheme 1). In this communication, we
With the development of asymmetric catalysis, the past decade has reported the first desymmetrical construction of chiral spiro-
witnessed great progress in the construction of the tetrasubstituted cyclic oxindoles bearing two contiguous stereogenic centers via a
carbon stereogenic center at the C-3 position of oxindoles, which was highly efficient asymmetric sulfa-Michael addition reaction.
popularly carried out through asymmetric addition reactions of
Considering the significant role of acid–base bifunctional organo-
3-substituted oxindoles employing various types of chiral metal catalysts9 in asymmetric catalysis, we reasoned that an amine–
catalysts3 and organocatalysts.4 Enantioselective desymmetrization thiourea catalyst could efficiently enhance the nucleophilicity of the
is an efficient and economical protocol to generate enantiomerically thiols and simultaneously activate the conjugated double bond in
enriched and highly functionalized compounds bearing multiple the prochiral spiro-[cyclohexadienone-oxindole] through hydrogen
stereogenic centers, and this strategy is effected by differentiation bonding interactions with the carbonyl group, and therefore generate
of two enantiotopic groups on the readily available symmetric or the two contiguous stereogenic centers with high stereoselective
prochiral molecules.5,6 Although impressive advances have been control. Hence, we initiated our study by evaluating the reaction of
made in the catalytic asymmetric synthesis of spirocyclic oxindoles, spiro-[cyclohexadienone-oxindole] 1a with thiophenol 2a in DCM at
to our knowledge, a desymmetrization strategy has never been applied room temperature with the fine-tunable amine–thiourea catalyst
in the synthesis of such motifs so far. Chiral sulfur-containing developed in the lab recently.10 To our gratification, the reaction
compounds also have important applications in many areas of was finished smoothly in less than 20 h with catalystI-a, affording the
chemistry and biology, for example, serving as antibiotics, ligands desired adduct 3aa as a single diastereomer (>20 : 1 dr) although
for metal-based catalysts, catalysts themselves, and chiral auxiliaries.7 the enantioselectivity is pretty low (Table 1, entry 1). Encouraged by
In sharp contrast to the well-documented approaches to access either the promising results, a series of fine-tunable bifunctional amine–
optically active oxindole compounds2 or chiral sulfur-containing thiourea catalysts I were subsequently screened. Among the tested
compounds,8 the development of an effective method for the bifunctional amine–thiourea catalysts, I-d was revealed to be the best
construction of spirocyclic oxindoles bearing a unique all-carbon
a College of Chemistry and Molecular Sciences, Wuhan University, Wuhan 430072,
China. E-mail: cjwang@whu.edu.cn; Fax: +86-27-68754067
b State Key Laboratory of Elemento-Organic Chemistry, Nankai University, Tianjin,
300071, China
c School of Pharmaceutical Sciences, Wuhan University, Wuhan 430072, China
† Electronic supplementary information (ESI) available: Experimental section.
Scheme 1 Enantioselective desymmetrization of prochiral spirocyclic oxindoles
via SMA.
CCDC 932106. For ESI and crystallographic data in CIF or other electronic format
see DOI: 10.1039/c3cc42587h
c
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Table 1 Screening studies of enantioselective desymmetrization of spiro cyclo-
hexadienone oxindole 1a via organocatalytic asymmetric SMAa
Table 2 Substrate scope of enantioselective desymmetrization of spiro cyclo-
hexadienone oxindoles via organocatalytic asymmetric SMAa
Yieldb (%)
eec (%)
1
Entry
Catal.
Solvent
T (1C)
Entry R1
R2
R3
3
Yieldb (%) eec (%)
1
2
3
4
5
6
7
8
I-a
I-b
I-c
I-d
II
III
IV
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
Et2O
THF
EtOAc
PhMe
CHCl3
CHCl3
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
À20
86
85
81
89
88
75
79
81
72
67
75
72
85
96
92
18
30
20
74
65
59
72
À61
À68
47
52
54
46
74
1
H
H
H
H
H
H
H
H
H
H
H
Me (1a) Ph (2a)
Me (1a) o-Me-C6H4 (2b)
Me (1a) p-Me-C6H4 (2c)
3aa 92
3ab 85
3ac 85
84
83
82
82
88
88
85
86
92
88
95
84
84
82
92
2d
3
4
Me (1a) m-Me-C6H4 (2d) 3ad 83
5d
6
Me (1a) o-F-C6H4 (2e)
Me (1a) p-F-C6H4 (2f)
Me (1a) m-F-C6H4 (2g)
Me (1a) p-Cl-C6H4 (2h)
Me (1a) 1-Naphthyl (2i)
Me (1a) 2-Naphthyl (2j)
Me (1a) 2-Thienyl (2k)
3ae 77
3af 85
3ag 84
3ah 95
3ai
3aj
3ak 83
3bj 85
3cj
3dj 81
3ej 82
V
VI
7
8
9
10
11
12
13
14
15
9
10
11
12
13
14
15d
I-d
I-d
I-d
I-d
I-d
I-d
86
89
MeO Me (1b) 2-Naphthyl (2j)
Cl
Me
H
Me (1c) 2-Naphthyl (2j)
Me (1d) 2-Naphthyl (2j)
Bn (1e) 2-Naphthyl (2j)
80
84
a
All reactions were carried out with 0.20 mmol of 1a and 0.22 mmol of
b
c
2a in 0.5 mL solvent in 10–18 h. Isolated yield. dr was determined by
a
All reactions were carried out with 0.20 mmol of 1 and 0.22 mmol of
crude 1H NMR and ee was determined by HPLC analysis. In 16 h.
d
b
c
2 in 0.5 mL CHCl3. Isolated yield. dr was determined by crude
1H NMR and ee was determined by HPLC analysis. In 48 h.
d
and electron-deficient substituents (entries 5–8) all worked well,
providing optically active adducts in high yields (77–95%) and good
to excellent enantioselectivities (82–88% ee). Remarkably, the sub-
stitution pattern of the arene had little effect on the stereoselectivity of
the reaction, and ortho-substituted thiols 2b and 2e underwent this
transformation leading to desired adducts 3ab and 3ae with 82% and
88% ee, respectively (entries 2 and 5). Heteroaromatic 2-thienyl thiol
2k was also a viable substrate as the condensed-ring thiol in this
transformation leading to the corresponding adducts in 95% ee
(entry 11). The scope of this SMA reaction with respect to the prochiral
electrophile partner was also explored. Spirocyclic oxindoles, which
bear electron-donating or electron-withdrawing groups on the phenyl
ring, proved to be excellent Michael acceptors for this reaction
catalyst in terms of diastereoselectivity and enantioselectivity providing high diastereoselectivity and good enantioselectivity
(entries 1À4). Other chiral bifunctional amine–thiourea catalysts (entries 12–14). To our delight, N-benzyl substituted spirocyclic
derived from 1,2-diaminocyclohexane or cinchona alkaloid11 were oxindole 1e can be well tolerated in this catalytic system and lead to
also tested in this transformation, producing the desired adducts the desired adduct 3ej in 82% yield and 92% ee (entry 15).
with a little lower ee (entries 5À9). Subsequent evaluation of solvent
To determine the relative and absolute configuration of
effects improved the enantioselectivity to 74% when chloroform was cycloadduct 3aj, the derived oximes 4 were synthesized in a
used as the solvent (entries 10–14). Reducing the temperature to 1 : 1 E/Z ratio via a simple condensation protocol. X-ray analysis
of the crystal of 4E revealed the (1R,6R) configuration for the
À20 1C led to full conversion with >20 : 1 dr and 84% ee for the
desymmetrical adduct within 16 h (entry 15).
spiro all-carbon quaternary stereogenic center and the adjacent
With the optimized desymmetrization reaction conditions in tertiary stereogenic center, and therefore also for the corre-
hand, a series of experiments was performed to investigate the sponding moieties in 3aj (Fig. 1).‡
substrate scope for this sulfa-Michael addition. As summarized in
The optically active adducts contain functional groups that are
Table 2, a wide array of aryl thiols reacted smoothly with spiro- amenable towards further transformations as exemplified in
[cyclohexadienone-oxindole] 1a to afford the expected adducts in high Scheme 2. Direct hydrogenation of the adduct 3aj with MeOH as
yields and excellent diastereoselectivities and good to high enantio- the solvent at room temperature in the presence of a catalytic amount
of Pd(OH)2/C afforded compound 5 in 92% yield without loss of
selectivities in the presence of 5 mol% of catalyst I-d. Aryl thiols
bearing electron-rich (Table 2, entries 2–4), electron-neutral (entries 1), diastereomeric and enantiomeric excess. Upon treatment with two
c
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and broad substrate scope. The ready availability of the starting
materials and the great importance of the chiral spirocyclic oxindole
derivatives make the current methodology particularly interesting in
synthetic chemistry. Further investigations of the scope and synthetic
applications of this desymmetrization methodology are ongoing.
This work is supported by the 973 program (2011CB808600),
NSFC (20972117, 21172176), NCET-10-0649, IRT1030, and the
Fundamental Research Funds for the Central Universities.
Fig. 1 X-ray structure of (1R,6R)-4E.
Notes and references
‡ For (1R,6R)-4E: C24H20N2O2S, Mr = 400.48, T = 296 K, orthorhombic,
space group P212121, a = 8.8678(9), b = 9.3161(9), c = 24.972(3) Å, V =
2063.0(4) Å3, Z = 4, 4277 reflections measured, 3493 unique (Rint
=
0.0363) which were used in all calculations. The final wR2 = 0.0851
(all data), flack w = 0.02(7). CCDC 932106 (4E).
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Scheme 2 Synthetic transformation and synthesis of compounds 7 and epi-7
via double SMA by switching the adding sequence of thiols.
equivalents of NaBH4 in THF at room temperature for 0.5 h, the
carbonyl group in 3aj was reduced successfully to afford the corre-
sponding alcohol 6 containing one quaternary and two tertiary
stereogenic centers in high yield and acceptable diastereoselectivity.
Meanwhile, the a,b-unsaturated carbonyl moiety can be used for
rapidly increasing the stereochemical and structural complexity of
the SMA adducts 3: subsequent achiral base-catalyzed SMA was
successfully implemented, which provided 7 and epi-7 with 2,6-trans
configuration through simply switching the adding sequence of the
two different thiols (see ESI† for more details).
In conclusion, we have developed the first catalytic asymmetric
synthesis of spirocyclic oxindoles bearing a unique all-carbon qua-
ternary and an adjacent tertiary stereogenic center via organocatalyzed
enantioselective desymmetrization. This catalytic system exhibited
high reactivity, excellent diastereo-selectivity, good enantioselectivity
c
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Chem. Commun.