Enantioselective construction of spirooxindole derivatives through [3+2] annulation catalyzed by a bisthiourea as a multiple-hydrogen-bond donor

Article abstract of DOI:10.1002/chem.201202937

Anything between ureas? Spiro[isoxazolidine-3,3′-oxindole]s have been constructed by employing methyleneindolinones and nitrones as the starting materials through [3+2] annulation catalyzed by a bisthiourea. Products with three contiguous stereocenters, including one spiroquaternary stereocenter, are obtained in good yields with excellent enantio- and diastereoselectivity. The bisthiourea catalyst acts as a multiple-hydrogen-bond donor to simultaneously activate both substrates. Copyright

Full text of DOI:10.1002/chem.201202937

DOI: 10.1002/chem.201202937
Enantioselective Construction of Spirooxindole Derivatives through [3+2]
Annulation Catalyzed by a Bisthiourea as a Multiple-Hydrogen-Bond Donor
Yan Shi,[a] Aijun Lin,[a] Haibin Mao,[a] Zhijie Mao,[a] Weipeng Li,[a] Hongwen Hu,[a]
Chengjian Zhu,*[a, b] and Yixiang Cheng*[a]
Finding cost-effective and sustainable synthetic methods
to reproduce the rich structural diversity and complexity of
natural molecules has always captured the attention of
chemists, especially in relation to biologically active com-
pounds.[1] Particularly intriguing is the spirocyclic oxindole
core, which is featured in a number of natural products, as
well as medicinally relevant compounds.[2] The pharmaceuti-
cal value of these enantiomerically pure backbones have led
to a demand for efficient methods for their asymmetric syn-
thesis. Pioneered by the work of the groups of Overman[3]
and Trost,[4] impressive advances have been documented for
the stereoselective synthesis of spirocyclic oxindoles.[5,6]
However, little effort so far has been focused on enantio-
ACHTUNGTRENNUNGselective approaches to the potentially bioactive isoxazoli-
dine ring fused with an oxindole moiety.[7]
Bifunctional tertiary amine–thiourea catalysts have
emerged as a powerful acid–base catalyst for asymmetric
transformations.[8] In these strategies, the thiourea and ter-
ACHTUNGTRENNUNGtiary amine groups act as a hydrogen-bond donor and ac-
ceptor, respectively, to catalyze the reactions (Figure 1a).[9]
However, the bifunctional thiourea catalytic system still re-
mains to be explored.[10] Chen and co-workers[11] have re-
ported that the concerted hydrogen-bonding interaction of
the two reactants with two thiourea functional groups might
be responsible for the higher enantiocontrol in the Man-
nich-type reaction step (Figure 1b). Moreover, Barbas III
and co-workers[12] used a bisthiourea catalyst as a hydrogen-
bonding catalyst in the D–A reaction of 3-vinylindoles and
methyleneindolinones (Figure 1b). It has been found that
the multiple hydrogen-bonding interactions which exist in
these reactions may have a profound influence on the enan-
tioselectivity. Nevertheless, the exact catalytic mechanism
Figure 1. Different catalytic modes of bifunctional thioureas.
and reaction scope still need more investigation. Consider-
ing our continuous interest in developing new enantioselec-
tive synthetic methods,[13] we describe herein an unusually
efficient asymmetric [3+2] annulation, involving methy-
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
diastereoselectivities.
Initial experiments were carried out by using N-tert-butox-
ycarbonyl (N-Boc)-protected methyleneindolinone 1a and
nitrone 2a as the starting materials in the presence of cata-
lysts I–IV (20 mol%, Figure 2) in toluene at room tempera-
ture. Although the reactions proceeded smoothly, products
with moderate d.r. and low ee were obtained (Table 1, en-
tries 1–4). We realized that the catalysts I–IV could activate
1a through hydrogen-bonding interactions,[14] but had no
direct contact with 1,3-dipole 2a, resulting in the poor enan-
tiocontrol. Next, the reaction was attempted with catalysts
VI–VIII. To our delight, the reactivity and enantioselectivity
were dramatically improved (Table 1, entries 5 and 7). Bis-
thiourea catalyst VI, which can function as a multiple-hydro-
gen-bond donor, was the best catalyst for the reaction of hy-
drogen-bond acceptor substrates, like 1a and 2a (Fig-
[a] Y. Shi, A. Lin, H. Mao, Z. Mao, W. Li, Prof. Dr. H. Hu,
Prof. Dr. C. Zhu, Prof. Dr. Y. Cheng
School of Chemistry and Chemical Engineering
Nanjing University, Nanjing, 210093 (P. R. China)
Fax : (+86)25-83594886
E-mail: cjzhu@nju.edu.cn
yxcheng@nju.edu.cn
[b] Prof. Dr. C. Zhu
Shanghai Institute of Organic Chemistry
Chinese Academy of Sciences, Shanghai, 200032 (P. R. China)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201202937.
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Chem. Eur. J. 2013, 19, 1914 – 1918

COMMUNICATION
diastereo– (90:10 d.r.) and enantioselectivity (77% ee;
Table 1, entry 11). Other solvents, such as CH2Cl2, petro-
AHCTUNGTREGlNNUN eum ether, acetic ether, and pentane, furnished the product
in lower yields (Table 1, entries 9, 10, 12 and 13). Different
reaction temperatures were attempted, and À108C was
found to be optimal (Table 1, entries 14 and 15). Optimal re-
sults were obtained for the reaction performed in hexane
with 20 mol% of catalyst VI at À108C (Table 1, entry 14).
Under the optimized conditions, the scope of the reaction
was evaluated (Scheme 1). A wide range of methyleneindoli-
nones were tolerated. Excellent enantio- and diastereoselec-
tivities (up to 99% ee and 99:1 d.r.) were obtained. The
enantioselectivities were slightly affected when the steric
hindrance of substituents on the aromatic ring of methy-
AHCTUNGTREGlNNNU eneindolinones was increased (Scheme 1, 3e–3g). Further
exploration of the substrate scope focused on the 1,3-dipolar
nitrones (Scheme 1). The corresponding products were ob-
tained in good yields and enantioselectivities (3j–3q). We
have also tested N-methyl nitrone and the N-benzyl nitrone,
however, the reactivity was poor. Halogen substituents (F,
Cl, and Br, 3e–3o) can also be successfully incorporated
into the aromatic ring of the nitrone, which provides addi-
tional potential reaction sites for further synthetic transfor-
mations. The absolute configuration of the stereogenic cen-
ters of the product 3i was confirmed by X-ray crystallo-
graphic analysis (Figure 3).[15]
Figure 2. Screened catalysts (Ar=3,5-(CF3)2C6H3).
Table 1. Optimization of the reaction conditions.[a]
Entry
Cat.
T
[8C]
Solvent
Yield[b]
[%]
d.r.[c]
ee[d]
[%]
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
I
II
RT
RT
RT
RT
RT
RT
RT
RT
RT
RT
RT
RT
RT
À10
À20
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
CH2Cl2
petroleum ether
hexane
acetic ether
pentane
hexane
52
23
38
40
73
43
70
45
61
55
70
60
55
65
59
78:22
61:39
73:27
65:35
80:20
66:34
80:20
70:27
63:37
93:7
90:10
60:40
92:7
99:1
98:2
28
25
9
III
IV
VI
VII
VIII
V
VI
VI
VI
VI
VI
VI
VI
8
60
10
60
11
15
72
77
5
72
98
96
Figure 3. X-ray crystal structure of 3i.
hexane
[a] The reactions were performed with 1a (0.1 mmol) and 2a (0.1 mmol)
in the presence of the organocatalyst (20 mol%) in the solvent (1 mL).
1
[b] Yield of the isolated product. [c] The d.r. was determined by H NMR
Under the standard conditions, the reaction was carried
out on a gram scale (Scheme 2). Thus, 3 mmol of 1d and 2a
in 15 mL of hexane gave 1.2 g of the desired product (75%
yield, 95% ee, 98:2 d.r.), suggesting that this method is ame-
nable to large scale production.
The effects of the N-methyleneoxindole protecting group
were also taken into consideration. Under the standard con-
ditions, only Boc-protected 3-methyleneoxindole derivatives
provided the product stereoselectively, whereas the corre-
sponding benzyl (Bn)- or Me-protected products were not
detected (Figure 4a).[16] Further mechanistic studies were
spectroscopic analysis. [d] The ee of the major diastereoisomer was deter-
mined by HPLC analysis.
ure 1b). Additionally, a poor ee value was obtained with cat-
alyst V, which contains a free -OH group (Table 1, entry 8).
These results indicate that the bisthiourea functionality in
catalyst VI was essential.
Reactions catalyzed by VI were further optimized. The
asymmetric induction was sensitive to solvent (Table 1, en-
tries 5 and 9–13); of those tested, hexane provided the best
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1915

C. Zhu, Y. Cheng et al.
carried out with the help of MS
and NMR spectroscopy. When
catalyst VI was mixed with
methyleneindolinone 1a and
1,3-dipolar nitrone 2a, a new
species characterized by a base
peak at m/z=1171.08 was de-
tected and assigned to be VI+
1a+2a (Figure 4b). In 1H and
13C NMR
experiments,
the
spectra gave strong evidence of
catalyst interactions with both
substrates (see the Supporting
Information). On the basis of
the aforementioned clues, we
conclude that a synergistic in-
teraction between the catalyst
and the two reactants occurs, as
shown in Figure 4c. The process
was directed by multiple hydro-
gen-bonding interactions be-
tween the bisthiourea catalyst
and the two substrates.
In summary, the [3+2] annu-
lation of methyleneindolinone
with nitrones has been devel-
oped as a highly convenient
and practical approach to con-
struct enantioenriched spiro-
AHCTUNGTRENN[GUN isoxazolidine-3,3’-oxindole] de-
rivatives. The bisthiourea cata-
lyst was used as a multiple-hy-
drogen-bond donor to simulta-
neously activate the two
substrates. The products, with
three contiguous stereocenters
including one spiroquaternary
stereocenter, are obtained in
good yields with excellent enan-
tio- and diastereoselectivity.
This method would be suitable
for large-scale chemical produc-
tion because the reaction was
scalable. We believe that these
spiro[isoxazolidine-3,3’-oxin-
dole] derivatives will provide
promising candidates for chemi-
cal biology and drug discovery.
Experimental Section
General procedure: Methyleneindoli-
nones
1 (0.1 mmol) and nitrones 2
Scheme 1. Synthesis of spiro[isoxazolidine-3,3’-oxindole] derivatives. The reactions were performed with 1
(0.1 mmol) and 2 (0.1 mmol) in the presence of catalyst VI (20 mol%) in hexane (1 mL), the d.r. was deter-
mined by 1H NMR spectroscopic analysis, and the ee of the major diastereoisomer was determined by HPLC
analysis.
(0.1 mmol) were dissolved in hexane
(1.0 mL). When the mixture was
cooled to À108C, catalyst VI
(20 mol%) was added. After stirring
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Chem. Eur. J. 2013, 19, 1914 – 1918

Synthesis of Spirooxindole Derivatives
COMMUNICATION
for 48 h, the reaction mixture was directly subjected to flash column
chromatography on silica gel (petroleum ether/ethyl acetate) to afford
the corresponding pure products 3. The diastereomeric ratio (d.r.) was
1
determined by H NMR spectroscopic analysis of the crude reaction mix-
ture. HPLC analyses were performed on a chiral column (Daicel Chiral-
pak IA, AD-H column, Chromatography Interface 600 Series Link and
Series 200 pump) with a Series 200 UV/Vis detector at 238 nm. The race-
mic simples for HPLC analysis were prepared in toluene at room temper-
ature and catalyzed by the diphenylphosphate.
Scheme 2. Gram scale experiment.
Acknowledgements
We gratefully acknowledge the National Natural Science Foundation of
China (20832001, 20972065, 21074054, 21172106) and the National Basic
Research Program of China (2010CB923303) for their financial support.
Keywords: asymmetric synthesis · bisthioureas · hydrogen
bonds · spiro compounds · synthetic methods
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Received: August 17, 2012
Revised: November 23, 2012
Published online: December 23, 2012
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Chem. Eur. J. 2013, 19, 1914 – 1918