PyBidine-Cu(OTf)2-catalyzed asymmetric [3+2] cycloaddition with imino esters: Harmony of Cu-lewis acid and imidazolidine-NH hydrogen bonding in concerto catalysis

Article abstract of DOI:10.1002/anie.201410782

A bis(imidazolidine)pyridine (PyBidine)-Cu(OTf)₂ complex catalyzing the endo-selective [3+2] cycloaddition of nitroalkenes with imino esters was applied to the reaction of methyleneindolinones with imino esters to afford spiro[pyrrolidin-3, 3′-

Full text of DOI:10.1002/anie.201410782

Angewandte
Chemie
DOI: 10.1002/anie.201410782
Asymmetric Catalysis
PyBidine–Cu(OTf)2-Catalyzed Asymmetric [3+2] Cycloaddition with
Imino Esters: Harmony of Cu–Lewis Acid and Imidazolidine-NH
Hydrogen Bonding in Concerto Catalysis**
Takayoshi Arai,* Hiroki Ogawa, Atsuko Awata, Makoto Sato, Megumi Watabe, and
Masahiro Yamanaka*
Abstract: A bis(imidazolidine)pyridine (PyBidine)–Cu(OTf)2
complex catalyzing the endo-selective [3+2] cycloaddition of
nitroalkenes with imino esters was applied to the reaction of
methyleneindolinones with imino esters to afford spiro[pyrro-
lidin-3,3’-oxindole]s in up to 98% ee. X-ray crystallographic
analysis of the PyBidine–Cu(OTf)2 complex and DFT calcu-
lations suggested that an intermediate Cu enolate of the imino
ester reacts with nitroalkenes or methyleneindolinones, which
are activated by NH-hydrogen bonding with the PyBidine–
Cu(OTf)2 catalyst.
a three-component [3+2] cycloaddition with a chiral Brønsted
acid catalyst.[5a] Simultaneously, Waldmann and co-workers
reported a Lewis acidic CuI-catalyzed [3+2] cycloaddition of
methyleneindolinones and imino esters,[5b,c] and the group of
Wang reported a AgI-catalyzed [3+2] cycloaddition.[5d] The
pioneering work on these [3+2] cycloaddition reactions has
been successfully applied not only to the synthesis of natural
products, but also in the screening of a new generation of
biologically active compounds in biology-oriented synthesis
(BIOS).[4b]
In our efforts toward diversity-oriented asymmetric
catalysis (DOAC),[6g,7g,8] we have developed the chiral imida-
zoline-aminophenol (IAP) ligand[6] and the bis(imidazolidi-
ne)pyridine (PyBidine) ligand[7] for the [3+2] cycloaddition of
nitroalkenes with imino esters. The IAP–nickel catalyst
provided the first general methodology for exo’-selective
cycloaddition reactions (Figure 1a).[6d,9,10]
D
iverse optically active pyrrolidines are widely observed in
biologically significant compounds. Since Grigg’s pioneering
work on Co catalysis,[1] efficient catalytic asymmetric [3+2]
cycloaddition reactions have been widely investigated for the
stereoselective construction of highly substituted pyrrolidine
rings.[2] Among these, the reaction of imino esters with
nitroalkenes is particularly important in the construction of
fully functionalized pyrrolidine rings.[3] With regard to the
significance of pyrrolidines in pharmaceutical research
directed toward the development of drug candidates, some
practical and useful [3+2] cycloaddition reactions have been
applied to the synthesis of more complex molecules.[4] For
example, in combination with the indole skeleton, several
unique families of spiro[pyrrolidin-3,3’-oxindole] scaffolds
have been conventionally constructed using the [3+2] cyclo-
addition of 2-oxoindolin-3-ylidene derivatives.[5] The first
catalytic asymmetric route to spiro[pyrrolidin-3,3’-oxindole]
was shown by Gong and co-workers in 2009, who employed
[*] Prof. Dr. T. Arai, H. Ogawa, Dr. A. Awata
Department of Chemistry, Graduate School of Science
Chiba University
1-33 Yayoi, Inage-ku, Chiba 263-8522 (Japan)
E-mail: tarai@faculty.chiba-u.jp
Homepage: http://synthesis.chem.chiba-u.jp/index.html
Dr. M. Sato, M. Watabe, Prof. Dr. M. Yamanaka
Department of Chemistry, Rikkyo University
3-34-1 Nishi-Ikebukuro, Toshima-ku, Tokyo 171-8501 (Japan)
E-mail: myamanak@rikkyo.ac.jp
[**] This work was supported by a Grant-in-Aid for Scientific Research on
Innovative Areas “Advanced Molecular Transformations by Orga-
nocatalysts” from the Ministry of Education, Culture, Sports,
Science and Technology (Japan), MEXT-Supported Program for the
Strategic Research Foundation at Private Universities, and by the
Workshop on Chirality at Chiba University (WCCU).
Figure 1. Classification of the stereochemical output of the [3+2]
cycloaddition using the IAP–Ni(OAc)2 catalyst and the PyBidine–Cu-
(OTf)2 catalyst.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201410782.
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The IAP–nickel catalyst system has also been successfully
applied to the [3+2] cycloaddition of imino esters with
methyleneindolinones to construct novel diastereomers of
spiro[pyrrolidin-3,3’-oxindole] with exo’-orientation (Fig-
ure 1b).[6e] In contrast, the bis(imidazolidine)pyridine (PyBi-
dine)–Cu(OTf)2 complex catalyzed an endo-selective [3+2]
reaction of imino esters with nitroalkenes to give adducts in
up to 99% ee (Figure 1c).[7a] The excellent endo-selectivity
observed using the PyBidine–Cu-catalyzed [3+2] cycloaddi-
tion prompted us to apply the PyBidine–metal catalyst to the
stereoselective construction of spiro[pyrrolidin-3,3’-oxindole]
(Figure 1d). Herein, the role of the PyBidine–metal catalyst
in controlling the stereoselective [3+2] cycloaddition reaction
is also examined in detail using DFT calculations.
reaction catalyzed by the PyBidine–Cu(OTf)2 complex, the
use of 2.0 equiv of imino ester improved the chemical yield,
and the reaction at 108C gave the product in 86% yield with
a diastereoselectivity of up to 94:6 (entry 8).
Under the optimized reaction conditions (Table 1,
entry 8), the generality of the PyBidine–Cu(OTf)2-catalyzed
asymmetric [3+2] cycloaddition of methyleneindolinones
with various imino esters was examined (Table 2). For b-
Table 2: PyBidine–Cu(OTf)2-catalyzed asymmetric [3+2] cycloaddition
of methyleneindolinones with various imino esters.
The study began with an exploration of the most
appropriate PyBidine–metal system for the reaction of b-
phenyl methyleneindolinone 1a with imino ester 2a (Table 1).
Table 1: Optimization of reaction conditions for the PyBidine–metal-
catalyzed [3+2] cycloaddition of an imino ester with methyleneindoli-
none.
Entry
Metal salt
x
Yield
[%]
d.r.
3a/3b
ee of 3a
[%]
1
2
3
4
5
6
7
Cu(OTf)2
Ni(OAc)2
NiCl2
1.1
1.1
1.1
1.1
1.1
1.1
2.0
2.0
2.0
49
80
55
75
54
36
78
86
91
87:13
69:31
61:39
79:21
73:27
94:6
89:11
94:6
90:10
97
13
44
12
44
72
91
96
93
CoCl2
Ni(OTf)2
Zn(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
8[a]
9[a,b]
[a] The reaction was performed at 108C. [b] With 5 mol% Cu(OTf)2 and
5.5 mol% PyBidine for 47 h.
aryl methyleneindolinones, both electron-deficient and elec-
tron-rich aryl groups were compatible, giving the product with
high enantioselectivities ranging from 90–98% ee. 2-Furyl
methyleneindolinone was converted to the product in 92%
yield with 85% ee (83:17 d.r.). A b-alkyl methyleneindoli-
none, n-propyl methyleneindolinone, was quantitatively
transformed to the product with 91% ee (87:7:6 d.r.).
The PyBidine–Cu(OTf)2 was able to generate an array of
variously functionalized spiro[pyrrolidin-3,3’-oxindole]s. For
understanding the role of the catalyst PyBidine–Cu(OTf)2,
the following three points (1–3) are worth mentioning.
1) Enantioface selection mode: Using an (S,S)-diphenyl-
ethylene diamine-derived PyBidine–Cu(OTf)2 catalyst, meth-
When 10 mol% PyBidine–Cu(OTf)2 catalyst was used in the
reaction of 1a with 1.1 equiv of 2a under the reaction
conditions optimized for the previous reaction using nitro-
alkenes,[7a] the spirooxindole compound 3 was obtained in
49% yield with 87:13 diastereoselectivity. The major isomer
3a had an ee of 97% (entry 1). The PyBidine–metal-salt
catalysts with Ni(OAc)2, NiCl2, and CoCl2, which had
previously been shown to be effective, gave the product in
moderate to low enantiomeric excess (entries 2–4). Among
the triflate salts of first-row transition metals that we
examined, the PyBidine–Cu(OTf)2 complex showed the best
catalytic activity for this [3+2] cycloaddition reaction. For the
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yl(2S,3R,4S,5S)-4-nitro-3,5-diphenylpyrrolidine-2-carboxyl-
ate, known as the endo-product, was obtained as the major
product in the reaction of imino ester with nitrostyrene. In the
reaction of imino ester with b-phenyl methyleneindolinone,
the major product was methyl (2’S,3R,4’S,5’S)-2-oxo-2’,4’-
diphenylspiro[indoline-3,3’-pyrrolidine]-5’-carboxylate (3a).
The mode of enantioface selection is the same for the endo-
selective [3+2] cycloaddition using nitroalkenes (Figure 2).
Figure 3. X-ray structure of PyBidine–Cu(OTf)2–H2O complex.
and the imidazolidines of PyBidine coordinate to the Cu,
keeping the protons (marked in orange) at the nitrogen
atoms. Apparently there are hydrogen bonds between one of
the oxygen atoms in each triflate anion and the imidazolidine-
NH atoms, with distances of 2.322 and 2.236 ꢀ.
Figure 2. Enantioface selection mode of PyBidine–Cu(OTf)2-catalyzed
asymmetric [3+2] cycloaddition.
With considering these points, DFT calculations[13] were
performed for the PyBidine–Cu(OTf)2-catalyzed [3+2] cyclo-
additions shown in Eq. (1) and (2) (Figure 1).[14] There are two
possibilities for the activation of substrates by Cu2+ and
Brønsted acidic sites. One scenario is that a Cu-bound enolate
of the imino ester nucleophilically attacks the electrophili-
cally activated nitroalkene on the imidazolidine-NH moiety
(TS1). The other possibility is that the enolate anion
coordinates to the imidazolidine-NH moiety and the nitro-
alkene is electrophilically activated on the Lewis acidic Cu2+
center (TS2). Four transition states (TSs) corresponding to
two activation modes (TS1, TS2) and two facial selectivities of
the nitroalkene (exo-TS, endo-TS) were compared (Figure 4).
2) Comparison of catalyst activity: The catalytic activity of
PyBidine–Cu(OTf)2 was compared with those of the well-
known pyridinebisimidazoline (pybim)[11] and pyridinebisox-
azoline (pybox) complexes with Cu(OTf)2,[12] and the results
are shown in Table 3. In both reaction systems, the use of the
Cu(OTf)2 catalysts pybim and pybox resulted in only trace
amounts of product under our conditions.
3) Structure of PyBidine–Cu(OTf)2: The structure of
PyBidine–Cu(OTf)2 was determined by X-ray crystallo-
graphic analysis and is provided in Figure 3. In the first
report on PyBidine, the X-ray structure was reported with
omission of the counter anions and protons for clarity.[7a]
However, two triflate anions occupy the apical positions,
Table 3: Comparison of the catalyst activity of PyBidine–Cu(OTf)2 with
pybim–Cu(OTf)2 and pybox–Cu(OTf)2.
Figure 4. Two types of activation mode in endo and exo TSs. The
relative energies are given in kcalmolÀ1
.
Entry
Product
Ligand
Yield
[%]
d.r.
ee
[%]
In both activation modes, the endo-TS is energetically more
favored than the exo-TS. The lowest-energy TS is endo-TS1,
in which a bidentate coordination of the imino ester enolate
on the Cu2+ cation and hydrogen bonding interactions
between the nitroalkene and the imidazolidine-NH distinctly
define the positions of both substrates to provide a high level
of stereocontrol (see details in the Supporting Information,
SI).
1[a]
2[a]
3[a]
PyBidine
pybim
pybox
96
trace
trace
99:1
–
–
97
–
–
4[b]
5[b]
6[b]
PyBidine
pybim
pybox
86
trace
trace
94:6
–
–
96
–
–
Next, to elucidate the origin of the high enantioselectiv-
ities observed experimentally, the realistic diastereomeric TSs
(TSa and TSb) were explored based on the ideal transition
state model endo-TS1. In the [3+2] cycloaddition of the imino
ester with the nitroalkene (TS3), endo-TS3b is 8.1 kcalmolÀ1
higher in energy than endo-TS3a (Figure 5).
[a] The reaction was performed using ligand (5.5 mol%) and Cu(OTf)2
(5 mol%) with Cs2CO3 (10 mol%) in dioxane at rt for 21–24 h. [b] The
reaction was performed using ligand (11 mol%) and Cu(OTf)2
(10 mol%) with Cs2CO3 (10 mol%) in dioxane at 108C for 27 h (entry 4)
and 15 h (entries 5 and 6).
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up the possibility to develop divergent metal catalysts using
variably functionalized chiral secondary amine ligands.
Received: November 5, 2014
Published online: && &&, &&&&
Keywords: asymmetric catalysis · asymmetric synthesis ·
.
cycloaddition · heterocycles · indoles
Figure 5. 3D structures of a) endo-TS3a and b) endo-TS3b for the
[3+2] cycloaddition of imino ester with nitroalkene.
[1] P. Allway, R. Grigg, Tetrahedron Lett. 1991, 32, 5817.
[2] Recent reviews of catalytic asymmetric [3+2] cycloaddition: a) J.
Adrio, J. C. Carretero, Chem. Commun. 2011, 47, 6784; b) A.
Moyano, R. Rios, Chem. Rev. 2011, 111, 4703; c) Ł. Albrecht, H.
Jiang, K. A. Jørgensen, Angew. Chem. Int. Ed. 2011, 50, 8492;
Angew. Chem. 2011, 123, 8642; d) E. E. Maroto, M. Izquierdo, S.
Reboredo, J. Marco-Martꢁnez, S. Filippone, N. Martꢁn, Acc.
Chem. Res. 2014, 47, 2660.
[3] Representative examples: a) S. Cabrera, R. G. Arrayꢂs, J. C.
Carretero, J. Am. Chem. Soc. 2005, 127, 16394; b) X.-X. Yan, Q.
Peng, Y. Zhang, K. Zhang, W. Hong, X.-L. Hou, Y.-D. Wu,
Angew. Chem. Int. Ed. 2006, 45, 2828; Angew. Chem. 2006, 118,
2894; c) J. Xie, K. Yoshida, K. Takasu, Y. Takemoto, Tetrahedron
Lett. 2008, 49, 6910; d) C. Guo, M.-X. Xue, M.-K. Zhu, L.-Z.
Gong, Angew. Chem. Int. Ed. 2008, 47, 3414; Angew. Chem.
2008, 120, 3462; e) Y.-K. Liu, H. Liu, W. Du, L. Yue, Y.-C. Chen,
Chem. Eur. J. 2008, 14, 9873; f) J.-W. Xie, L.-P. Fan, H. Su, X.-S.
Li, D.-C. Xu, Org. Biomol. Chem. 2010, 8, 2117; g) K. Imae, T.
Konno, K. Ogata, S. Fukuzawa, Org. Lett. 2012, 14, 4410; h) E.
Conde, D. Bello, A. de Cꢃzar, M. Sꢂnchez, M. A. Vꢂzquez, F. P.
Cossꢁo, Chem. Sci. 2012, 3, 1486.
In the energetically favored endo-TS3a, both substrates
are located in the empty chiral pocket and avoid steric
repulsion (Figure 5a). The energetically disfavored endo-
TS3b exhibits significant repulsive steric interactions with the
imidazolidine ring (left purple curves in Figure 5b) and its Ph
group (right purple curves in Figure 5b). Whereas the Ph
group of the imino ester is deformed and twisted by the
former steric interaction, a ring flip occurs in the imidazoli-
dine ring (right) due to the latter interaction. These repulsive
steric interactions destabilize endo-TS3b.
Similar structural features to TS3 are found in the [3+2]
cycloaddition of the imino ester with methyleneindolinone
(TS4). Both substrates are appropriately oriented for the
chiral reaction space in endo-TS4a (Figure 6a). In contrast,
[4] a) J. Yu, F. Shi, L.-Z. Gong, Acc. Chem. Res. 2011, 44, 1156; b) R.
Narayan, M. Potowski, Z.-J. Jia, A. P. Antonchick, H. Wald-
mann, Acc. Chem. Res. 2014, 47, 1296.
[5] a) X.-H. Chen, Q. Wei, S.-W. Luo, H. Xiao, L.-Z. Gong, J. Am.
Chem. Soc. 2009, 131, 13819; b) P. A. Antonchick, C. Gerfing-
Reimers, M. Catarinella, M. Schꢄrmann, H. Preut, S. Ziegler, D.
Rauh, H. Waldmann, Nat. Chem. 2010, 2, 735; c) P. A. Anton-
chick, H. Schuster, H. Bruss, M. Schꢄrmann, H. Preut, D. Rauh,
H. Waldmann, Tetrahedron 2011, 67, 10195; d) T.-L. Liu, Z.-Y.
Xue, H.-Y. Tao, C.-J. Wang, Org. Biomol. Chem. 2011, 9, 1980;
e) M.-N. Cheng, H. Wang, L.-Z. Gong, Org. Lett. 2011, 13, 2418;
f) F. Shi, Z.-L. Tao, S.-W. Luo, S.-J. Tu, L.-Z. Gong, Chem. Eur. J.
2012, 18, 6885; g) L. Wang, X.-M. Shi, W.-P. Dong, L.-P. Zhu, R.
Wang, Chem. Commun. 2013, 49, 3458; h) F. Salahi, M. J.
Taghizadeh, H. Arvinnezhad, M. Moemeni, K. Jadidi, B.
Notash, Tetrahedron Lett. 2014, 55, 1515; i) J.-A. Xiao, Q. Liu,
J.-W. Ren, J. Liu, R. G. Carter, X.-Q. Chen, H. Yang, Eur. J. Org.
Chem. 2014, 5700.
[6] a) T. Arai, N. Yokoyama, A. Yanagisawa, Chem. Eur. J. 2008, 14,
2052; b) T. Arai, N. Yokoyama, Angew. Chem. Int. Ed. 2008, 47,
4989; Angew. Chem. 2008, 120, 5067; c) N. Yokoyama, T. Arai,
Chem. Commun. 2009, 3285; d) T. Arai, N. Yokoyama, A.
Mishiro, H. Sato, Angew. Chem. Int. Ed. 2010, 49, 7895; Angew.
Chem. 2010, 122, 8067; e) A. Awata, T. Arai, Chem. Eur. J. 2012,
18, 8278; f) A. Awata, M. Wasai, H. Masu, S. Kado, T. Arai,
Chem. Eur. J. 2014, 20, 2470; g) T. Arai, Y. Yamamoto, Org. Lett.
2014, 16, 1700.
Figure 6. 3D structures of a) endo-TS4a and b) endo-TS4b for the
[3+2] cycloaddition of imino ester with methyleneindolinone.
the sterically hindered imidazolidine rings exert undesired
structural impact on endo-TS4b (Figure 6b). The endo-TS4b
is 12.4 kcalmolÀ1 higher in energy than endo-TS4a. These
computational results offer a rational explanation of the high
enantioselectivities observed in the experiments.
The electronic and structural properties of PyBidine–
Cu(OTf)2 are summarized in the multiple interactions oper-
ating in concert and the deep asymmetric reaction space using
imidazolidine as the “chiral fences”. (In the PyBidine–Cu-
(OTf)2 complex, two imidazolidine rings stand perpendicular
(ca. 938) to the equatorial terdentate coordination plane.) The
synergistic action of the Cu2+ cation and the imidazolidine-
NH not only activates both substrates but also controls their
relative orientation.
[7] a) T. Arai, A. Mishiro, N. Yokoyama, K. Suzuki, H. Sato, J. Am.
Chem. Soc. 2010, 132, 5338; b) T. Arai, Y. Ogino, Molecules 2012,
17, 6170; c) T. Arai, S. Kajikawa, E. Matsumura, Synlett 2013, 24,
2045; d) T. Arai, A. Mishiro, E. Matsumura, A. Awata, M.
Shirasugi, Chem. Eur. J. 2012, 18, 11219; e) T. Arai, E.
Matsumura, Synlett 2014, 25, 1776; f) T. Arai, E. Matsumura,
H. Masu, Org. Lett. 2014, 16, 2768; g) A. Awata, T. Arai, Angew.
Chem. Int. Ed. 2014, 53, 10462; Angew. Chem. 2014, 126, 10630.
In summary, PyBidine–Cu(OTf)2 demonstrates that imi-
dazolidine-NH can harmonize with the Cu2+ cation for
constructing a new dual activation system.[15,16] This opens
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[8] R. A. Stavenger, S. L. Schreiber, Angew. Chem. Int. Ed. 2001, 40,
3417; Angew. Chem. 2001, 113, 3525. See also ref. [6g,7g].
[9] Examples of enantioselective exo’-selective cyclization: a) S.
Filippone, E. E. Maroto, A. Martin-Domenech, M. Suarez, N.
Martin, Nat. Chem. 2009, 1, 578; b) Q.-H. Li, L. Wei, X. Chen,
C.-J. Wang, Chem. Commun. 2013, 49, 6277; c) R. Narayan, J. O.
Bauer, C. Strohmann, A. P. Antonchick, H. Waldmann, Angew.
Chem. Int. Ed. 2013, 52, 12892; Angew. Chem. 2013, 125, 13130.
[10] For the [3+2] cycloaddition of imino esters and nitroalkenes, the
stereochemistry is depicted by a Cossioꢅs classification, see:
a) M. Ayerbe, A. Arrieta, F. P. Cossio, J. Org. Chem. 1998, 63,
1795; b) L. M. Castellꢃ, C. Nꢂjera, J. M. Sansano, O. LarraÇaga,
A. de Cꢃzar, F. P. Cossꢁo, Org. Lett. 2013, 15, 2902.
[14] The ESI-MS analysis indicated that the catalyst structure
remained unchanged under the reaction conditions.
[15] a) J.-X. Gao, T. Ikariya, R. Noyori, Organometallics 1996, 15,
1087; b) Y. Jiang, Q. Jiang, X. Zhang, J. Am. Chem. Soc. 1998,
120, 3817; c) T. Ikariya, K. Murata, R. Noyori, Org. Biomol.
Chem. 2006, 4, 393; d) W. Zeng, G.-Y. Chen, Y.-G. Zhou, Y.-X.
Li, J. Am. Chem. Soc. 2007, 129, 750; e) T. Ikariya, I. D. Gridnev,
Chem. Rec. 2009, 9, 106; f) M. Wang, C.-J. Wang, Z. Lin,
Organometallics 2012, 31, 7870. See also Ref. [5b].
[16] The previously studied IAP–Ni(OAc)2 complex catalyzed the
reaction in exo’ manner, after the anti-selective Michael
addition, because the neutral Ni center cannot allow strong
coordination of both, the nitro functionality and the imino ester,
and the Ni atom would smoothly flip to the nitronate for opening
the strained cyclic intermediate. Before the subsequent Mannich
[11] S. Bhor, G. Anilkumar, M. K. Tse, M. Klawonn, C. Dçbler, B.
Bitterlich, A. Grotevendt, M. Beller, Org. Lett. 2005, 7, 3393.
[12] H. Nishiyama, H. Sakaguchi, T. Nakamura, M. Horihata, M.
Kondo, K. Itoh, Organometallics 1989, 8, 846.
À
reaction, the C N single bond must rotate to give the exo’-
isomer via the most stable transition state. See Ref. [6d].
[13] Gaussian09, Revision B.01., M. J. Frisch, et al. Gaussian, Inc.:
Wallingford CT, 2010. Computational details were described in
the SI.
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Communications
Asymmetric Catalysis
Dual activation system: A bis(imidazoli-
dine)pyridine (PyBidine)–Cu(OTf)2 com-
plex catalyzes the endo-selective [3+2]
cycloaddition of methyleneindolinones
with imino esters to afford spiro[pyrroli-
din-3,3’-oxindole]s in up to 98% ee. X-ray
analysis and DFT calculations suggest
that an intermediate Cu enolate of the
imino ester reacts with the methylenein-
dolinone, which is activated by NH-
hydrogen bonding with the PyBidine–
Cu(OTf)2 catalyst.
T. Arai,* H. Ogawa, A. Awata, M. Sato,
M. Watabe,
M. Yamanaka*
&&&& — &&&&
PyBidine–Cu(OTf)2-Catalyzed
Asymmetric [3+2] Cycloaddition with
Imino Esters: Harmony of Cu–Lewis Acid
and Imidazolidine-NH Hydrogen
Bonding in Concerto Catalysis
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