Enantioselective cyanoethoxycarbonylation of isatins promoted by a Lewis base-Bronsted acid cooperative catalyst

Article abstract of DOI:10.1002/anie.201303572

Teaming up to make it happen: In the title reaction, the Lewis basic site of the catalyst activated ethyl cyanoformate, and the deep and flexible Bronsted acidic cavity stabilized and selectively recognized the key reaction intermediate to promote asymmet

Full text of DOI:10.1002/anie.201303572

Angewandte
Chemie
DOI: 10.1002/anie.201303572
Asymmetric Catalysis
Enantioselective Cyanoethoxycarbonylation of Isatins Promoted by
a Lewis Base–Brønsted Acid Cooperative Catalyst**
Yoshihiro Ogura, Matsujiro Akakura, Akira Sakakura,* and Kazuaki Ishihara*
Oxindole is an important core structure found in many
natural and synthetic bioactive compounds.[1] For the chem-
ical synthesis of these useful bioactive compounds, much
attention has been devoted to the development of stereo-
selective carbon–carbon bond-forming reactions at the C3
carbonyl carbon atom of isatins, and many enantioselective
methods have been reported.[2] However, the enantioselective
cyanation of isatins has not yet been reported. Enantioselec-
tive cyanation affords the corresponding cyanohydrin or its
equivalent, which would be a useful chiral building block for
the synthesis of these bioactive compounds.
The asymmetric cyanation of carbonyl compounds is an
important reaction for the construction of tetrasubstituted
carbon stereocenters.[3] Representative cyanation methods
include hydrocyanation with hydrogen cyanide and silylcya-
nation with a silyl cyanide.[4] Although many chiral catalysts
Scheme 1. Organocatalytic enantioselective cyanoethoxycarbonylation
have been developed for asymmetric hydrocyanation and
silylcyanation, these methods require a highly toxic cyanation
reagent, and the corresponding cyanation products are rather
unstable. In contrast, cyanocarbonylation with a less toxic acyl
cyanide or alkyl cyanoformate[5] is also useful for the
cyanation of carbonyl compounds, and the products are
rather stable.
In 2001, Deng and Tian reported the first enantioselective
cyanocarbonylation with (DHQ)2AQN as a chiral nucleo-
philic-base catalyst.[6,7] Although this pioneering method is
highly efficient for the reaction of ketones, (DHQ)2AQN gave
poor results in the reaction of N-methylisatin in our study,
of isatins.
probably because N-methylisatin is much less reactive than
ketones (Scheme 1). We envisioned that acid–base coopera-
tive catalysts,[8] which have a Lewis basic site and a Brønsted
acidic site, may be able to promote the enantioselective
cyanocarbonylation of isatins. The Lewis basic site would
activate the cyanocarbonylation reagent, and the Brønsted
acidic site would simultaneously activate the carbonyl group
of the isatin through hydrogen bonding to promote the
reaction. We report herein the enantioselective cyanoethoxy-
carbonylation of isatins with acid–base cooperative organo-
catalysts.
On the basis of the findings of the Deng research group
and our preliminary experiments, we chose the chiral
quinuclidine moiety B1 derived from cinchonidine as the
Lewis basic site B in the acid–base cooperative catalyst 1, and
optimized the Brønsted acidic site A (Table 1). The reaction
of N-methylisatin (R = Me) was conducted with ethyl cyano-
formate (1.1 equiv) in CH2Cl2 in the presence of 1 (10 mol%)
at ambient temperature. Catalyst 1a containing sulfonamide
A1 as the Brønsted acidic site did not give any products,
whereas the use of thiourea A2 gave the desired product in
moderate yield with moderate enantioselectivity (Table 1,
entries 1 and 2). Upon further investigation of the Brønsted
acidic site in catalyst 1, we found that the introduction of
a third Brønsted acid (in A3)[9,10] successfully improved both
the yield and enantioselectivity to 73% and 65% ee (Table 1,
entry 3). In contrast, the use of the diastereomeric chiral
Lewis base B2 and/or the enantiomeric chiral Brønsted acid
A4 led to decreased both yields and enantioselectivity
(Table 1, entries 4–6). Therefore, we concluded that catalyst
1c with the Lewis basic site B1 and Brønsted acidic site A3
was the optimal catalyst.
[*] Y. Ogura, Prof. Dr. K. Ishihara
Graduate School of Engineering, Nagoya University
Furo-cho, Chikusa, Nagoya 464-8603 (Japan)
E-mail: ishihara@cc.nagoya-u.ac.jp
Homepage: http://www.ishihara-lab.net
Prof. Dr. M. Akakura
Department of Chemistry, Aichi University of Education
Igaya-cho, Kariya, Aichi 448-8542 (Japan)
Prof. Dr. A. Sakakura
Graduate School of Natural Science and Technology
Okayama University
3-1-1 Tsushima-naka, Kita-ku, Okayama 700-8530 (Japan)
E-mail: sakakura@okayama-u.ac.jp
Prof. Dr. M. Akakura, Prof. Dr. K. Ishihara
JST, CREST
Furo-cho, Chikusa, Nagoya 464-8603 (Japan)
[**] Financial support for this project was partially provided by the JSPS
KAKENHI Program (23350039) and the Program for Leading
Graduate Schools “Integrative Graduate Education and Research in
Green Natural Sciences” of MEXT (Japan).
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201303572.
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Table 1: Catalytic activity of catalysts 1 (B–A).[a]
The protocol of the present reaction was very simple: the
substrate, reagent, and catalyst were stirred together at
ambient temperature in simple glassware. Thus, this reaction
could be applied to a large-scale synthesis without any
difficulties. When the reaction of N-PNB-protected isatin
(1.4 g, 5 mmol) was conducted in the presence of 1c (5 mol%)
under the optimized reaction conditions, 1.8 g of the product
was obtained (94% yield; Table 1, entry 12).[12]
Under the optimized reaction conditions, isatin deriva-
tives bearing a variety of substituents were converted into the
corresponding products in high yields with excellent enantio-
selectivity (Table 2). For example, isatin derivatives with
electron-donating methyl, methoxy, and trifluoromethoxy
groups and electron-withdrawing nitro, fluoro, chloro,
Table 2: Exploration of the generality of the cyanoethoxycarbonylation
catalyzed by 1c.[a]
Entry
1 (B–A)
R
Yield [%][b]
ee [%]
1
2
3
4
5
6
7
8
9
1a (B1–A1)
1b (B1–A2)
1c (B1–A3)
1d (B1–A4)
1e (B2–A3)
1 f (B2–A4)
1c (B1–A3)
1c (B1–A3)
1c (B1–A3)
1c (B1–A3)
1c (B1–A3)
1c (B1–A3)
Me
Me
Me
Me
Me
Me
Bn
0
34
73
30
22
42
71
41
59
87
98
94
–
33
65
20
Entry
R
Yield [%][b]
ee [%]
À18[c]
À55[c]
72
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
5-Me
5,7-Me2
5-MeO
5,6-(MeO)2
5-CF3O
5-NO2
5-F
5-Cl
5-I
5-Br
4-Br
96
70
88
61
97
85
96
97
94
98
96
91
87
67
94
95
94
95
88
96
98
96
97
97
96
99
95
94
96
95
p-methoxybenzyl
p-nitrobenzyl (PNB)
p-nitrobenzyl (PNB)
p-nitrobenzyl (PNB)
p-nitrobenzyl (PNB)
61
82
95
95
10[d]
11[d,e]
12[e,f]
95
[a] Reaction conditions: N-protected isatin (0.50 mmol), EtOCOCN
(1.1 equiv), 1 (10 mol%), CH2Cl2, ambient temperature, 48 h. [b] Yield of
the isolated product. [c] The negative values indicate that the major
enantiomer had the S configuration. [d] The reaction was conducted with
EtOCOCN (2.2 equiv) in the presence of 1c (5 mol%) in CHCl3 for 6 h.
[e] The reaction was conducted with MeOH (50 mol%). [f] The reaction
was conducted on a 5 mmol scale with EtOCOCN (2.2 equiv) in the
presence of 1c (5 mol%) in CHCl3 for 24 h. Bn=benzyl.
6-Br
7-Br
5,7-Br2
7-CF3
[a] Reaction conditions: N-PNB-isatin (0.5 mmol), ethyl cyanoformate
(2.0 equiv), 1c (5 mol%), MeOH (50 mol%), CHCl3 (2.5 mL), ambient
temperature, 9 h. [b] Yield of the isolated product.
With this optimized catalyst in hand, we turned our focus
to the protecting group of the amide group of isatin. We found
that the use of a benzyl group improved the enantioselectivity
(Table 1, entry 7). Interestingly, the use of a benzyl group
substituted with an electron-donating methoxy group led to
a decrease in enantioselectivity (Table 1, entry 8), whereas
the introduction of an electron-withdrawing p-nitrobenzyl
(PNB) substituent led to an increase in enantioselectivity, and
the product was obtained with 82% ee (entry 9). During
further optimization of the reaction conditions, we found that
the use of chloroform as the solvent and 2.2 equivalents of
ethyl cyanoformate improved both the reactivity and the
enantioselectivity (87% yield, 95% ee; Table 1, entry 10).
Furthermore, the addition of MeOH (50 mol%) improved
the reactivity remarkably: the reaction reached completion in
only 2 h under the optimized conditions (Table 1, entry 11).
The results of 1H NMR spectroscopic analysis suggested that
catalyst 1c largely existed as a less active oligomeric species in
CHCl3. The addition of MeOH might dissociate the oligomer
to give the active monomer[11] and thus promote the reaction.
bromo, and iodo groups at the 5-position were converted
into the corresponding products in up to 98% yield with 88–
98 ee (Table 2, entries 1–10). Furthermore, reactions of isatins
bearing a bromine substituent proceeded with excellent
enantioselectivity regardless of the position of the bromine
substituent (Table 2, entries 10–13). The absolute configura-
tion of the 5-brominated product was determined to be R by
X-ray single-crystal analysis.[13,14]
A proposed mechanism for the enantioselective cyano-
ethoxycarbonylation of isatins is shown in Scheme 2. The
cyanoethoxycarbonylation is a two-step reaction: the first
step is a reversible cyanation of the carbonyl group, and the
second step is the irreversible acylation of the cyanohydrin
alkoxide intermediate. Kinetic studies of the present 1c-
catalyzed cyanoethoxycarbonylation of isatins showed that
the initial reaction rate did not depend on the concentration
of the substrate or EtOCOCN.[14] Furthermore, the ee value of
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conceivable
that
when
a
Lewis base such as
(DHQ)2AQN is used as
a catalyst for the cyanoe-
thoxycarbonylation of isa-
tins, the first-step equilibri-
um greatly favors the start-
ing materials, in contrast to
the 1c-catalyzed reaction,
and that the (DHQ)2AQN-
catalyzed cyanoethoxycar-
bonylation
of
isatins
showed poor reactivity for
this reason (Scheme 1).
We next investigated the
removal of the PNB group
in the products. Since the
carbonate moiety is rather
unstable under strongly
Scheme 2. Proposed mechanism for the 1c-catalyzed cyanoethoxycarbonylation of isatins.
the product was completely independent of the conversion of
the reaction.[14,15] These results suggested that the first
cyanation step was a rapid equilibrium and the second
acylation step was rate-determining.
acidic and basic conditions, deprotection should be conducted
under weakly acidic or basic conditions. Therefore, we
attempted deprotection by DDQ oxidation, which is gener-
ally conducted under nearly neutral mild conditions. Since
electron-deficient benzyl groups are less reactive toward
oxidation with DDQ, we had to convert the electron-with-
drawing nitro group into an electron-donating group to make
the benzyl group electron-rich. We first selectively reduced
the PNB nitro group with tin(II) chloride to an electron-
donating amino group (Scheme 3). Subsequent DDQ oxida-
tion of the electron-rich p-aminobenzyl group successfully
gave the deprotected compound 4 in 78% yield.
Deng and Tian reported that asymmetric induction in the
Lewis base catalyzed cyanoethoxycarbonylation of ketones
arose from kinetic resolution of the cyanohydrin alkoxy anion
intermediates through asymmetric acylation, since the ee val-
ues of the cyanohydrin intermediates were much lower than
those of the cyanoethyoxycarbonylation products.[6] In con-
trast, in the present 1c-catalyzed cyanoethoxycarbonylation
of isatins, a theoretical calculation showed that ion pair 2 of
the R alkoxy anion (Figure 1) was 3 kcalmolÀ1 more stable
than ion pair 3 of the S alkoxy anion.[14,16] In ion pair 2, the
three acidic hydrogen atoms of 1c act as an “oxyanion
hole”[17,18] and stabilize the oxyanion through three hydrogen-
bonding interactions. These results implied that asymmetric
induction would arise not only from the kinetic resolution of
the cyanohydrin alkoxy anion intermediate in the second step,
but also from the cyanation of the isatin in the first step.[19] It is
Scheme 3. Removal of PNB protection. DDQ=2,3-dichloro-5,6-
dicyano-1,4-benzoquinone, DMF=N,N-dimethylformamide.
The spiro-fused compound 6 was obtained by the selective
reduction of the cyano group of 5, which was obtained from 4
by benzylation of the amide group (Scheme 4). Reduction of
the cyano group with cobalt(II) chloride and sodium boro-
hydride[20] gave the corresponding primary amine, which
underwent simultaneous cyclization with the carbonate
moiety to give cyclic carbamate 6 without any loss of optical
purity. Removal of the benzyl group under Birch conditions
gave 7 in 52% yield. Compound 7 is a promising chiral
building block for the synthesis of various bioactive oxindoles.
In conclusion, we have developed the first enantioselec-
tive cyanoethoxycarbonylation of isatins by using the Lewis
base–Brønsted acid cooperative catalyst 1c. The Lewis basic
site of 1c caused nucleophilic activation of ethyl cyanofor-
mate, and the Brønsted acidic, deep, and flexible cavity
simultaneously stabilized and selectively recognized the R
Figure 1. Optimized geometry (B3LYP/6-31G(d)) of ion pair 2
(R=PNB) of the R alkoxy anion intermediate.[21,22] Hydrogen atoms,
except for those in the thiourea and sulfonamide groups, are omitted
for clarity.
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Liu, X. Zhou, X. Feng, Tetrahedron 2007, 63, 7935; e) Y. N.
Belokonꢀ, W. Clegg, R. W. Harrington, C. Young, M. North,
Tetrahedron 2007, 63, 5287; f) W. Wang, S. Gou, X. Liu, X. Feng,
Synlett 2007, 2875; g) S.-K. Chen, D. Peng, H. Zhou, L.-W. Wang,
F.-X. Chen, X.-M. Feng, Eur. J. Org. Chem. 2007, 639; h) S. Gou,
J. Wang, X. Liu, W. Wang, F.-X. Chen, X. Feng, Adv. Synth.
Catal. 2007, 349, 343; and Ref. [3c].
[6] a) S.-K. Tian, L. Deng, Tetrahedron 2006, 62, 11320; b) S.-K.
Tian, L. Deng, J. Am. Chem. Soc. 2001, 123, 6195.
Scheme 4. Synthesis of the spiro-fused compound 7.
[7] Catalysis with quaternary ammonium salts is another strategy;
see: a) R. Chinchilla, C. Nꢁjera, F. J. Ortega, A. Tarꢂ, Tetrahe-
dron: Asymmetry 2009, 20, 2279; b) R. Chinchilla, C. Nꢁjera, F. J.
Ortega, Tetrahedron: Asymmetry 2008, 19, 265; c) D. Peng, H.
Zhou, X. Liu, L. Wang, S. Chen, X. Feng, Synlett 2007, 2448.
[8] a) M. Shibasaki, M. Kanai, S. Matsunaga, N. Kumagai, Acc.
Chem. Res. 2009, 42, 1117; b) K. Ishihara, Proc. Jpn. Acad. Ser. B
2009, 85, 290; c) K. Ishihara, A. Sakakura, M. Hatano, Synlett
2007, 686; d) H. Li, Y. Wang, L. Tang, L. Deng, J. Am. Chem.
Soc. 2004, 126, 9906; e) M. Kanai, N. Kato, E. Ichikawa, M.
Shibasaki, Synlett 2005, 1491.
alkoxy anion intermediate to promote asymmetric acylation.
Furthermore, the use of a p-nitrobenzyl protecting group
successfully improved the enantioselectivity. The protocol
was very simple, all the reagents could be used without
purification, and the reaction could be readily applied to
a large-scale synthesis without any difficulties.
Received: April 26, 2013
[9] a) M.-X. Zhao, T.-L. Dai, R. Liu, D.-K. Wei, H. Zhou, F.-H. Ji,
M. Shi, Org. Biomol. Chem. 2012, 10, 7970; b) W. Li, W. Wu, F.
Yu, H. Huang, X. Liang, J. Ye, Org. Biomol. Chem. 2011, 9, 2505.
[10] For catalysis of chiral bifunctional amine-thioureas bearing
multiple hydrogen-bonding donors, see: a) X.-F. Wang, Q.-L.
Hua, Y. Cheng, X.-L. An, Q.-Q. Yang, J.-R. Chen, W.-J. Xiao,
Angew. Chem. 2010, 122, 8557; Angew. Chem. Int. Ed. 2010, 49,
8379; b) C.-J. Wang, X.-Q. Dong, Z.-H. Zhang, Z.-Y. Xue, H.-L.
Teng, J. Am. Chem. Soc. 2008, 130, 8606; c) C.-J. Wang, Z.-H.
Zhang, X.-Q. Dong, X.-J. Wu, Chem. Commun. 2008, 44, 1431.
[11] Since a linear relationship was observed between the optical
purity of 1c and the ee value of the product, monomeric 1c
should be the active catalytic species (see the Supporting
Information); see also: a) J.-S. Oh, J.-W. Lee, T. H. Ryu, J. H.
Lee, C. E. Song, Org. Biomol. Chem. 2012, 10, 1052; b) H. B.
Jang, H. S. Rho, J. S. Oh, E. H. Nam, S. E. Park, H. Y. Bae, C. E.
Song, Org. Biomol. Chem. 2010, 8, 3918; c) W. Kaminsky, D.
Responte, D. Daranciang, J. B. Gallegos, B.-C. Tran, T.-A. Pham,
Molecules 2010, 15, 554; d) H. S. Rho, S. H. Oh, J. W. Lee, J. Y.
Lee, J. Chin, C. E. Song, Chem. Commun. 2008, 1208; e) M. S.
Taylor, E. N. Jacobsen, Angew. Chem. 2006, 118, 1550; Angew.
Chem. Int. Ed. 2006, 45, 1520.
Published online: July 3, 2013
Keywords: asymmetric catalysis · Brønsted acids · isatins ·
.
Lewis bases · synthetic methods
[1] For selected reviews on isatin derivatives, see: a) G. S. Singh,
Z. Y. Desta, Chem. Rev. 2012, 112, 6104; b) N. Lashgari, G. M.
Ziarani, Arkivoc 2012, 277; c) K. Shen, X. Liu, L. Lin, X. Feng,
Chem. Sci. 2012, 3, 327; d) R. Dalpozzo, G. Bartoli, G.
Bencivenni, Chem. Soc. Rev. 2012, 41, 7247; e) C. Marti, E. M.
Carreira, Eur. J. Org. Chem. 2003, 2209; f) B. M. Trost, K. B.
Brennan, Synthesis 2009, 3003.
[2] For selected recent studies, see: a) L. Hong, R. Wang, Adv.
Synth. Catal. 2013, 355, 1023; b) D. Wang, J. Liang, J. Feng, K.
Wang, Q. Sun, L. Zhao, D. Li, W. Yan, R. Wang, Adv. Synth.
Catal. 2013, 355, 548; c) Y.-L. Liu, J. Zhou, Chem. Commun.
2013, 49, 4421; d) A. A. Esmaeili, S. A. Ghalandarabad, M.
Zangouei, Tetrahedron Lett. 2012, 53, 5605; e) N. V. Hanhan,
N. R. Ball-Jones, N. T. Tran, A. K. Franz, Angew. Chem. 2012,
124, 1013; Angew. Chem. Int. Ed. 2012, 51, 989; f) L.-H. Sun, L.-
T. Shen, S. Ye, Chem. Commun. 2011, 47, 10136; g) A. Sacchetti,
A. Silvani, F. G. Gatti, G. Lesma, T. Pilati, B. Trucchi, Org.
Biomol. Chem. 2011, 9, 5515; h) Y.-L. Liu, F. Zhou, J.-J. Cao, C.-
B. Ji, M. Ding, J. Zhou, Org. Biomol. Chem. 2010, 8, 3847.
[3] For selected reviews on the cyanation of carbonyl and imino
compounds, see: a) J. Wang, X. Liu, X. Feng, Chem. Rev. 2011,
111, 6947; b) S. Kobayashi, Y. Mori, J. S. Fossey, M. M. Salter,
Chem. Rev. 2011, 111, 2626; c) J. Wang, W. T. Wang, W. Li, X. L.
Hu, K. Shen, C. Tan, X. H. Liu, X. M. Feng, Chem. Eur. J. 2009,
15, 11642; d) M. North, D. L. Usanov, C. Young, Chem. Rev.
2008, 108, 5146; e) A. G. Doyle, E. N. Jacobsen, Chem. Rev.
2007, 107, 5713; f) H. Grçger, Chem. Rev. 2003, 103, 2795; g) S.
Kobayashi, H. Ishitani, Chem. Rev. 1999, 99, 1069.
[4] For selected recent reviews on enantioselective silylcyanation,
see: a) J. Gawronski, N. Wascinska, J. Gajewy, Chem. Rev. 2008,
108, 5227; b) N. H. Khan, R. I. Kureshy, S. H. R. Abdi, S.
Agrawal, R. V. Jasra, Coord. Chem. Rev. 2008, 252, 593; and
Ref. [3c – e].
[5] For recent studies on enantioselective cyanoethoxycarbonyla-
tion with chiral metal catalysts, see: a) N. H. Khan, S. Agrawal,
R. I. Kureshy, S. H. R. Abdi, K. Pathak, H. C. Bajaj, Chirality
2010, 22, 153; b) N. H. Khan, S. Agrawal, R. I. Kureshy, S. H. R.
Abdi, K. J. Prathap, R. V. Jasra, Eur. J. Org. Chem. 2008, 4511;
c) Y. N. Belokonꢀ, W. Clegg, R. W. Harrington, E. Ishibashi, H.
Nomura, M. North, Tetrahedron 2007, 63, 9724; d) S. Gou, X.
[12] The catalyst was recovered in 98% yield after flash column
chromatography.
[13] CCDC 925315 contains the supplementary crystallographic data
for this paper. These data can be obtained free of charge from
The Cambridge Crystallographic Data Centre via www.ccdc.
cam.ac.uk/data_request/cif.
[14] See the Supporting Information for details.
[15] Deng and Tian also observed that the ee value of the product
only depended slightly on the conversion in the Lewis base
catalyzed cyanoethyoxycarbonylation of ketones.[6]
[16] The present cyanoethoxycarbonylation of isatins did not give
any cyanohydrin intermediates, which suggested that the cyano-
hydrin alkoxy anion intermediates were highly unstable.
[17] For oxyanion holes in enzyme-catalyzed processes, see: a) W.
Childs, S. G. Boxer, Biochemistry 2010, 49, 2725; b) P. A. Sigala,
D. A. Kraut, J. M. M. Caaveiro, B. Pybus, E. A. Ruben, D. Ringe,
G. A. Petsko, D. Herschlag, J. Am. Chem. Soc. 2008, 130, 13696;
c) Y. Zhang, J. Kua, J. A. McCammon, J. Am. Chem. Soc. 2002,
124, 10572; d) A. K. Whiting, W. L. Peticolas, Biochemistry 1994,
33, 552.
[18] For oxyanion-hole mimics in chemical processes, see: a) E. V.
Beletskiy, J. Schmidt, X.-B. Wang, S. R. Kass, J. Am. Chem. Soc.
2012, 134, 18534; b) M. B. Jimꢃnez, V. Alcꢁzar, R. Pelꢁez, F.
Sanz, ꢄ. L. F. de Arriba, M. C. Caballero, Org. Biomol. Chem.
2012, 10, 1181; c) F. M. MuÇiz, V. Alcꢁzar, F. Sanz, L. Simꢅn,
8302 www.angewandte.org
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Angewandte
Chemie
ꢄ. L. F. de Arriba, C. Raposo, J. R. Morꢁn, Eur. J. Org. Chem.
2010, 6179; d) R. R. Knowles, E. N. Jacobsen, Proc. Natl. Acad.
Sci. USA 2010, 107, 20678; e) M. Kotke, P. R. Schreiner,
Synthesis 2007, 779; f) S. Kondo, T. Harada, R. Tanaka, M.
Unno, Org. Lett. 2006, 8, 4621.
Duwenhorst, W. Schmidt, T. Borrmann, W.-D. Stohrer, F.-P.
Montforts, Chem. Eur. J. 2007, 13, 6595; b) H. Ducatel, A. N. V.
Nhien, D. Postel, Tetrahedron: Asymmetry 2008, 19, 67.
[21] a) M. J. Frisch et al., Gaussian03, RevisionE.01, Gaussian, Inc.,
Wallingford, CT, 2004; b) M. J. Frisch et al., Gaussian09,
RevisionC.01, Gaussian, Inc., Wallingford, CT, 2009.
[19] We could not exclude the possibility that asymmetric induction
arose solely from the first cyanation step.
[20] For selected reports on the selective reduction of the nitrile
group with CoCl2 and NaBH4, see: a) T. Kçnekamp, A. Ruiz, J.
[22] All optimized structures of complexes and calculation data are
described in the Supporting Information.
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