The asymmetric addition of dioxindoles to nitroolefins was
developed. Two factors are central to the successful implementa-
tion of the chemistry: the reactivity of dioxindole, and the ability
of A to catalyse the reaction through the cooperation of multiple
weak attractive interactions with the substrates.
Research support from the Institute of Chemical Research
of Catalonia (ICIQ) Foundation and from MICINN (grant
CTQ2010-15513) is gratefully acknowledged.
Notes and references
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2 For reviews, see: (a) K. Shen, X. Liu, L. Lin and X. Feng, Chem.
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Synth. Catal., 2010, 352, 1381. For our contributions:;
(c) P. Galzerano, G. Bencivenni, F. Pesciaioli, A. Mazzanti,
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3 (a) C. Marti and E. M. Carreira, Eur. J. Org. Chem., 2003, 2209;
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4 T. Bui, S. Syed and C. F. Barbas III, J. Am. Chem. Soc., 2009,
131, 8756.
Scheme 1 Catalyst structure/reactivity and stereoselectivity correlation
studies. Reaction conditions: 20 mol% of the catalyst, 1.5 equiv. of 1c,
[2]0 = 0.05 M in DCM, 25 1C, 16 hours reaction time.
The straightforward preparation of compound 4—which
bears the hexahydropyrrolo[2,3-b]indole unit found in many
natural molecules—through standard manipulations of
compound 3m testifies to the potential synthetic usefulness
of this previously unexplored reactivity (eqn (3)).
5 Y. Kato, M. Yurutachi, Z. Chen, H. Mitsunuma, S. Matsunaga
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7 M. Ding, F. Zhou, Y.-L. Liu, C.-H. Wang, X.-L. Zhao and
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(3)
8 Classic catalytic asymmetric approaches to 3-substituted 3-hydroxy-
oxindoles mainly relied on: (i) additions to isatins, (a) R. Shintani,
M. Inoue and T. Hayashi, Angew. Chem., Int. Ed., 2006, 45, 3353;
(b) N. V. Hanhan, A. H. Sahin, T. W. Chang and A. K. Franz,
Angew. Chem., Int. Ed., 2010, 49, 744. (ii) Intramolecular arylation
reactions,; (c) Y.-X. Jia, J. M. Hillgren, E. M. Watson, S. P. Marsden
and E. P. Kundig, Chem. Commun., 2008, 4040. (iii) Direct hydroxy-
lation of 3-alkyl substituted oxindoles, ; (d) T. Bui, N. R. Candeias
and C. F. Barbas III, J. Am. Chem. Soc., 2010, 132, 5574.
9 A defined three-dimensional spatial arrangement of 3-substituted
3-hydroxyoxindoles greatly influences the biological activity, see:
J. J. Badillo, N. Hanhan and A. K. Franz, Curr. Opin. Drug
Discovery Dev., 2010, 13, 758.
10 In parallel to the present research, we investigated the reactivity of
dioxindole using covalent modes of catalysis. For our recent
achievement in the asymmetric conjugate addition to enals under
iminium ion catalysis, see: G. Bergonzini and P. Melchiorre,
Angew. Chem., Int. Ed., 2012, 51, 971.
11 The tetrahydropyranyl ether of dioxindole (THP-O protected 1a)
was successfully reacted with ethyl acrylate in the presence of alkali
alcoholates: P. L. Julian, E. E. Dailey, H. C. Printy, H. L. Cohen
and S. Hamashige, J. Am. Chem. Soc., 1956, 78, 3503.
We then focused on extensive structure/stereoselectivity
correlation studies in order to understand the importance of
the structural and stereochemical elements of the organo-
catalyst A in dictating the selectivity of the reaction. We
investigated the addition of dioxindole 1c to 2 in DCM using
modified thiourea derivatives. Selected results are reported in
Scheme 1, with an in depth discussion detailed in Fig. S3 in the
ESI.z The amido-moiety and the primary amine were soon
recognised as essential elements for catalysis, since their
absence dramatically affected the outcome of the reaction
(catalysts E–F). It appeared that only a well-defined relative
spatial arrangement of the catalytic moieties, as dictated by the
absolute configurations of the three stereocentres, brought
about an effective catalysis. The stereochemistry and the
nature of the substituent within the amino acid part were both
important for securing high stereoselectivity, while a specific
stereochemistry of the diaminocyclohexane backbone was
required (A against I). Surprisingly, replacing the primary
amine in A with the corresponding N,N-dimethyl tertiary
amine (K) caused an inversion of the diastereoselectivity
together with a complete loss of enantiocontrol. This suggests
an uncommon mechanistic scenario where the primary amino
moiety is not operating as a Brønsted base. It is plausible that
the primary amine-thiourea catalyst A stabilises the enol
form16 of the dioxindole through hydrogen bonding instead
of promoting the formation of an enolate intermediate. A
mechanistic model to reconcile the catalyst structure/reactivity
and stereoselectivity correlation studies is proposed in Fig. S4
of the ESI.z
12 O. Tomotaka, Y. Hoashi and Y. Takemoto, J. Am. Chem. Soc.,
2003, 125, 12672.
13 (a) G. A. Russell, C. L. Myers, P. Bruni, F. A. Neugebauer and
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T. Kappe and R. Salvador, Monatsh. Chem., 1963, 94, 453;
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pathway leading to isatide are discussed in Fig. S7 and S8 (ESIz).
14 (a) H. Huang and E. N. Jacobsen, J. Am. Chem. Soc., 2006,
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15 This phenomenon is not uncommon for bifunctional thiourea-based
catalysts, see: H. B. Jang, H. S. Rho, J. S. Oh, E. H. Nam, S. E. Park,
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16 The potential of primary amine-thiourea catalyst to operate
through enol-based chemistry has already been demonstrated:
D. A. Yalalov, S. V. Tsogoeva, T. E. Shubina, I. M. Martynova
and T. Clark, Angew. Chem., Int. Ed., 2008, 47, 6624.
c
3338 Chem. Commun., 2012, 48, 3336–3338
This journal is The Royal Society of Chemistry 2012