Catalytic asymmetric synthesis of spirooxindoles by a Mannich-type reaction of isothiocyanato oxindoles

Article abstract of DOI:10.1002/anie.201203005

Easy access: A strontium/Schiff base complex as catalyst for the title reaction provided straightforward access to enantiomerically enriched spiro[imidazolidine-4,3'-oxindole] compounds, as well as a spiro[imidazoline-4, 3'-oxindole] through a two-step conversion from the Mannich adduct. Copyright

Full text of DOI:10.1002/anie.201203005

Angewandte
Chemie
DOI: 10.1002/anie.201203005
Asymmetric Catalysis
Catalytic Asymmetric Synthesis of Spirooxindoles by a Mannich-Type
Reaction of Isothiocyanato Oxindoles**
Shota Kato, Tatsuhiko Yoshino, Masakatsu Shibasaki, Motomu Kanai,* and Shigeki Matsunaga*
Spirooxindoles are privileged structural motifs found in many
alkaloids and unnatural biologically active compounds.[1]
Inspired by these important scaffolds, various synthetic
methods for producing chiral spirooxindoles, especially
applications to natural product synthesis, have been inves-
tigated over the last decade.[2] As a state-of-the-art method,
catalytic asymmetric one-step construction of spirooxindoles
has also been intensively studied.[3–5] However, most of the
studies reported to date have focused on the catalytic
asymmetric synthesis of spirooxindoles bearing an all-
carbon quaternary stereocenter at the C3ꢀ position of the
oxindole, such as in a spirocycloalkaneoxindole core[4] and
a spiro[pyrrolidin-3,3’-oxindole] core.[5] On the other hand,
catalytic asymmetric methods for spirooxindoles bearing
a nitrogen atom at the C3’ position of the oxindole unit are
still limited,[6,7] despite their importance for the design of
medicinally important compounds (Figure 1), such as
a CRTH2 antagonist with good oral bioavailability,[8] a selec-
Figure 1. Spirooxindoles bearing a nitrogen atom at the C3’ position of
the oxindole unit; a CRTH2 antagonist with good oral bioavailability,
an antituberculous agent, an antimalarial agent, and an inhibitor of
tive inhibitor of Mycobacterium tuberculosis protein tyrosine
phosphatase B,[9] a potent antimalarial agent,[10] and an
inhibitor of the interaction between the tumor suppressor
p53 and its negative regulator Hdm2.[11] Thus, expansion of
the scope of available chiral spirooxindole cores is in high
demand. Herein, we report a highly diastereo- and enantio-
selective synthesis of a spiro[imidazolidine-4,3’-oxindole]
core by an asymmetric Mannich-type reaction of isothiocya-
nato oxindoles catalyzed by a strontium/Schiff base complex
1 (Figure 2). The transformation of a Mannich adduct into
a spiro[imidazoline-4,3’-oxindole] core is also described.
As part of our ongoing investigation of the synthesis of
chiral oxindoles[12] and asymmetric reactions with isothiocya-
p53/Hdm2 interaction.
[*] S. Kato, T. Yoshino, Prof. Dr. M. Kanai, Dr. S. Matsunaga
Graduate School of Pharmaceutical Sciences
The University of Tokyo, Hongo
Figure 2. Structures of Schiff bases (R)-1a–g. Bn=benzyl.
Bunkyo-ku, Tokyo 113-0033 (Japan)
E-mail: kanai@mol.f.u-tokyo.ac.jp
smatsuna@mol.f.u-tokyo.ac.jp
Homepage: http://www.f.u-tokyo.ac.jp/~kanai/e_index.html
Prof. Dr. M. Kanai, Dr. S. Matsunaga
Kanai Life Science Catalysis Project
ERATO (Japan) Science and Technology Agency
Hongo, Bunkyo-ku, Tokyo 113-0033 (Japan)
nato esters as donors[13,14] under bifunctional metal/Schiff
base catalysis,[15] we studied the reaction of imine 2a and 3-
isothiocyanato oxindole 3a. Initial screenings of various
metal/Schiff base catalysts developed in our group showed
promising results, in particular with group 2 metal/Schiff base
1a (Figure 2). The optimization studies are summarized in
Table 1. Bu2Mg/Schiff base 1a, which was suitable for
reactions using isothiocyanato esters as donors,[13a] promoted
the reaction with high diastereoselectivity (Table 1, entry 1,
98:2 d.r.), but with only poor enantioselectivity (5% ee).
Among the group 2 metals screened (Table 1, entries 1–4),
Sr(OiPr)2 afforded the best enantioselectivity (93% ee;
entry 3). Enantioselectivity was much poorer when using
Prof. Dr. M. Shibasaki
Institute of Microbial Chemistry, Tokyo Kamiosaki
Shinagawa-ku, Tokyo 141-0021 (Japan)
[**] This work was supported by ERATO from JST, a Grant-in-Aid for
Young Scientists (A) from JSPS, the Naito Foundation, and the
Inoue Science Foundation.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201203005.
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Table 1: Optimization of the catalytic asymmetric Mannich-type reaction.
Table 2: Sr-catalyzed asymmetric Mannich-type reaction of isothiocya-
nato oxindoles.[a]
Entry
Metal source
1
T
Yield [%][a]
d.r.[a]
ee [%][b]
[8C]
1
2
3
4
5
6
7
8
Bu2Mg
1a
1a
1a
1a
1a
1a
1b
1c
1d
1e
1 f
À40
À40
À40
À40
À40
À40
À40
À40
À40
À40
À40
À40
À60
60
96
95
62
92
99
68
90
91
92
87
95
88[d]
98:2
87:13
91:9
91:9
55:45
91:9
76:24
76:24
71:29
89:11
84:16
97:3
5
1
93
9
30
10
1
3
5
76
89
95
97
Ca(OiPr)2
Sr(OiPr)2
Ba(OiPr)2
Al(OiPr)3
Ni(OAc)2
Sr(OiPr)2
Sr(OiPr)2
Sr(OiPr)2
Sr(OiPr)2
Sr(OiPr)2
Sr(OiPr)2
Sr(OiPr)2
R
2
3
x[b]
4
T
t
Yield d.r.[d]
[8C] [h] [%][c]
ee
[%][e]
1
4-Me-C6H4
2a 3a 10 4aa À60 12 88 98:2
97
97
96
2[f] 3-Me-C6H4
3[f] 2-Me-C6H4
2b 3a 10 4ba À60
2c 3a 10 4ca À60
9
9
98 92:8
95 94:6
4[g] 4-MeO-C6H4 2d 3a 10 4da À20 12 92 81:19 93
9
5[f] Ph
2e 3a 10 4ea À60
9
99 96:4
98
97
95
10
11
12
13[c]
6
7
Ph
Ph
2e 3a
5
4ea À60 24 96 95:5
2e 3a 2.5 4ea À60 48 96 95:5
1g
1g
8[f] 4-F-C6H4
2 f 3a 10 4 fa À60
8
95 87:13 99
98:2
9
3-F-C6H4
2g 3a 10 4ga À60 12 98 98:2
99
97
97
98
[a] Determined by 1H NMR spectroscopic analysis of the crude mixture.
[b] Determined by chiral stationary phase HPLC analysis. [c] Reaction
was run for 12 h. [d] Yield of isolated 4aa after purification by silica gel
column chromatography.
10 4-Cl-C6H4
11 4-Cl-C6H4
12 4-Br-C6H4
13[f] 3-thienyl
14[g] 2-furyl
2h 3b 10 4hb À60 11 87 97:3
2h 3c 10 4hc À60
2i 3a 10 4ia À60
2j 3a 10 4ja À60
2k 3d 10 4kd À40
9
9
9
9
93 97:3
99 97:3
98 83:17 94
88 89:11 98
15[g] 4-Me-C6H4
2a 3d 10 4ad À40 12 90 98:2
94
[a] Unless otherwise noted, reactions were run in THF (0.17m) using
imine 2 (0.20 mmol), isothiocyanato oxindole 3 (1.5 equiv), Sr(OiPr)2
(10 mol%), and (R)-1g with 5 ꢀ molecular sieves (40 mg). [b] x=mol%
of catalyst used. [c] Yield of isolated 4 after purification by silica gel
column chromatography. [d] Determined by 1H NMR spectroscopic
analysis of the crude mixture. [e] Determined by chiral stationary phase
HPLC analysis. [f] Schiff base (S)-1g was used instead of (R)-1g, and ent-
4 was obtained as the major product. [g] Schiff base (S)-1a was used
instead of (R)-1g, and ent-4 was obtained as the major product.
other metal sources, such as Al(OiPr)3 and Ni(OAc)2
(entries 5 and 6). To improve the diastereoselectivity with
Sr(OiPr)2, several Schiff bases were investigated (entries 7–
12). Schiff bases 1b–1d, which lack an ortho-MeO substitu-
ent, resulted in poor diastereo- and enantioselectivity, thus
suggesting the importance of the MeO-group. Electronic
tuning of the ligands using 1e and 1 f resulted in less
satisfactory selectivity (entries 10 and 11). Modification of
the diamine backbone was effective, and Schiff base 1g, which
bears a 2,2’-biphenyldiamine backbone, gave product 4aa in
97:3 d.r. and 95% ee at À408C (entry 12). After further
optimization of the reaction temperature and the reaction
time with Schiff base 1g, product 4aa was isolated in 88%
yield, 98:2 d.r., and 97% ee after 12 h at À608C (entry 13).
The substrate scope of the Mannich-type reaction under
optimized reaction conditions is summarized in Table 2.[16]
Substituents at the para-, meta-, and even the sterically
hindered ortho-positions on the aromatic ring of imines 2a–2c
were compatible, and the products were obtained in 97–96%
ee and 98:2–92:8 d.r. (Table 2, entries 1–3). In the case of the
less reactive 4-MeO-substituted imine 2d, Schiff base 1a with
the binaphthyl backbone showed better reactivity, and
product 4da was obtained in 92% yield and 93% ee at
À208C, albeit with only moderate diastereoselectivity (81:19
d.r.; entry 4). Catalyst loading was successfully reduced to
5 mol% and then to 2.5 mol% with imine 2e. Although
a longer reaction time was required with reduced catalyst
loading, high diastereoselectivity and enantioselectivity were
observed (entries 6 and 7). Imines 2 f–2I, which bear electron-
withdrawing substituents, also resulted in high selectivity, 99–
97% ee and 98:2–87:13 d.r. (entries 8–12). Aside from 3a, the
oxindole donors Cl-substituted oxindole 3b and Me-substi-
tuted oxindole 3c also gave the respective products in
excellent diastereo- and enantioselectivity (entries 10 and
11). For N-allyl protected oxindole donor 3d, Schiff base 1a
had better reactivity and stereoselectivity, and the Mannich
adducts were obtained in comparably good yield, diastereo-
selectivity, and enantioselectivity with N-Me oxindole donors
3a–3c (entries 14 and 15). These results with a removable
N-protecting group on the oxindole unit are important for
future synthetic applications using the present method.
To demonstrate the synthetic utility of the products, we
transformed the spiro[imidazolidine-4,3’-oxindole] core in
4aa into a spiro[imidazoline-4,3’-oxindole] core (Scheme 1).
After benzoylation of 4aa (94% yield), 5aa was subjected to
Pd-catalyzed desulfurative cross-coupling conditions.[17]
Removal of a diphenylphosphinoyl group and cross-coupling
with PhB(OH)2 proceeded simultaneously at 508C in THF,
and the spiro[imidazoline-4,3’-oxindole] product 6aa was
obtained in 63% yield. Product 6aa has a cis-diaryl relation-
ship, and can be regarded as a hybrid of two species:
1) Nutlin,[18] an imidozoline-based inhibitor of p53/E3-ubiq-
uitin ligase Mdm2 interaction, and 2) MI-219,[19] a spiro[pyr-
rolidin-3,3’-oxindole]-based p53/Mdm2 inhibitor. Because of
this, the present method would be useful in the field of
2
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Scheme 1. Transformation of Mannich adduct 4aa into spiro(imidazo-
line-4,3’-oxindole) 6aa. Reagents and conditions: a) Benzoyl chloride
(1.5 equiv), Et3N (1.5 equiv), DMAP (10 mol%), CH2Cl2, RT, 4 h.
b) PhB(OH)2 (2 equiv), CuTC (3 equiv), Pd(PPh3)4 (10 mol%), THF,
508C, 1 h. DMAP=N,N-dimethyl-4-aminopyridine, TC=thiophen-2-
carboxylate.
medicinal chemistry for the design and synthesis of new
potent anti-tumor agents.[20]
In summary, we have developed an asymmetric Mannich-
type reaction of isothiocyanato oxindoles catalyzed by a Sr/
Schiff base complex, which provides concise access to
enantiomerically enriched spiro[imidazolidine-4,3’-oxindole]
compounds, as well as a spiro[imidazoline-4,3’-oxindole]
through a two-step conversion from the Mannich adduct. In
an effort to develop a new anti-tumor agent, library syntheses
of divergent spiro[imidazoline-4,3’-oxindole] compounds is
ongoing and will be reported together with the biological
activity of the products in due course.
[8] The introduction of a heteroatom at the C3’ position of an
oxindole unit played a key role in improving the stability of
human plasma and the oral bioavailability of a CRTH2 antag-
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bell, V. Colovray, M. Missotten, Y. Humbert, C. Cleva, J.-F.
Arrighi, M. Gaudet, Z. Johnson, P. Ferro, A. Chollet, ACS Med.
Chem. Lett. 2011, 2, 644.
Received: April 19, 2012
Published online: && &&, &&&&
Keywords: asymmetric catalysis · asymmetric synthesis ·
Mannich reaction · oxindoles · salen
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Asymmetric Catalysis
S. Kato, T. Yoshino, M. Shibasaki,
M. Kanai,*
S. Matsunaga*
&&&& — &&&&
Catalytic Asymmetric Synthesis of
Spirooxindoles by a Mannich-Type
Reaction of Isothiocyanato Oxindoles
Easy access: A strontium/Schiff base
complex as catalyst for the title reaction
provided straightforward access to enan-
tiomerically enriched spiro[imidazolidine-
4,3’-oxindole] compounds, as well as
a spiro[imidazoline-4,3’-oxindole]
through a two-step conversion from the
Mannich adduct.
Angew. Chem. Int. Ed. 2012, 51, 1 – 5
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
These are not the final page numbers!