Organocatalytic asymmetric synthesis of trifluoromethyl-substituted diarylpyrrolines: Enantioselective conjugate cyanation of β-aryl-β- trifluoromethyl-disubstituted enones

Article abstract of DOI:10.1002/anie.201201278

Ether way: The cinchona-alkaloid-catalyzed title reaction was achieved in high yields with high to excellent ee values for the first time, and affords key intermediates for the biologically important 2 having a trifluoromethylated all-carbon quaternary chiral center. Ether-type catalysts (1) are more efficient in this transformation than the conventional hydroxy analogues. Copyright

Full text of DOI:10.1002/anie.201201278

Angewandte
Chemie
DOI: 10.1002/anie.201201278
Organocatalysis
Organocatalytic Asymmetric Synthesis of Trifluoromethyl-substituted
Diarylpyrrolines: Enantioselective Conjugate Cyanation of b-Aryl-b-
trifluoromethyl-disubstituted Enones**
Hiroyuki Kawai, Satoshi Okusu, Etsuko Tokunaga, Hiroyasu Sato, Motoo Shiro, and
Norio Shibata*
Trifluoromethylated dihydroazoles (1; Figure 1)[1,2] are an
important class of fluorinated heterocyclic compounds[3] with
remarkable biological activities, thus making their synthesis
a competitive area in life science industries.[1] Ever since the
first discovery of the structurally unique 3,5-diaryl-5-
1, that is 3,5-diaryl-5-(trifluoromethyl)-3,4-dihydro-2H-pyr-
roles or b-trifluoromethyl 3,5-diaryl-pyrrolines (2; X = CH2)
as a promising drug candidate such as an antiparasiticide.[2]
Since the first report of 2 in 2005[2a] more than 5000 analogues
of 2 in racemic form were reported within 19 patents.[2]
However, no example of the asymmetric synthesis of 2 has
appeared. The challenge for synthesizing 2 is the enantiose-
lective construction of sterically demanding trifluoromethy-
lated, all-carbon quaternary stereocenters.[7]
Construction of all-carbon quaternary chiral centers is
a particularly demanding task and a challenging topic in
organic chemistry.[8] The asymmetric conjugate addition of
cyanide to b,b-disubstituted-a,b-unsaturated carbonyl com-
pounds is an ideal strategy for this purpose. Several conjugate
additions of cyanide to b-monosubstituted substrates leading
to b-tertiary stereocenters have been reported,[9] however,
there are few reports of asymmetric conjugate cyanation of
b,b-disubstituted substrates resulting in high enatioselectivi-
ties.[9d,10] In 2008, the group of Jacobsen showed a single
example of asymmetric conjugate cyanation of b,b-disubsti-
tuted imide substrates with trimethylsilyl cyanide using
a dinuclear [{(salene)}Al] catalyst with high enantioselectivity
but low conversion.[9d] An organocatalytic conjugate addition
of cyanide to b,b-disubstituted nitroalkanes was investigated
by Ricci et al. and resulted in low to moderate enantioselec-
tivities.[10a] Shibasaki, Kanai, and co-workers dramatically
improved this type of reaction for the first time using
bifunctional catalysts derived from Sr(OiPr)2 and d-glucose-
based ligands, and trialkylsilyl cyanides.[10b] These methods,
however, were not applied to the synthesis of trifluoromethy-
lated all-carbon quaternary stereocenters.[10] We disclose
herein the first enantioselective conjugate addition of cyanide
to sterically demanding b-aryl-b-trifluoromethyl aryl-enones
(3) catalyzed by ammonium salts of cinchona alkaloids to
provide 4, having trifluoromethylated all-carbon quaternary
stereocenters, in high yields with high to excellent enantio-
selectivities. Product 4 serves as a precursor for 2, thus
achieving the asymmetric synthesis of 2 for the first time
(Scheme 1). Ether-type cinchona alkaloids are found to be
much more efficient than conventional hydroxy-type cin-
chona alkaloids. The fully saturated analogue 6 was also
accessed without any loss of enantiopurity of 4. The proce-
dure is operationally simple, and inexpensive acetone cyano-
hydrin and organocatalysts are used, which is an advantage
for industrial purposes.
Figure 1. Trifluoromethylated 2-isoxazolines 1 and pyrrolines 2.
(trifluoromethyl)-2-isoxazoline derivatives 1 (X = O) as pest
control agents in 2004,[1a] the search for new agrochemicals
and veterinary medicines has focused largely on this skel-
eton.[1] Thus far, more than 20000 compounds have been
registered,[1] and several promising drug candidates of type A
have been discovered (Figure 1). We recently reported the
catalytic asymmetric synthesis of 1 using chiral ammonium
salts of cinchona alkaloids to promote a hydroxylamine enone
cascade reaction involving a conjugate addition/cyclization/
dehydration sequence.[4] The expeditious synthesis of 1 based
on the direct introduction of a trifluoromethyl group into
aromatic isoxazoles was also disclosed.[5] As part of our
ongoing research programs directed at the development of
efficient methodologies for the construction of trifluoro-
methylated heterocyclic frameworks,[6] we became interested
in the catalytic, asymmetric synthesis of the carbon variant of
[*] H. Kawai, S. Okusu, E. Tokunaga, Prof. N. Shibata
Department of Frontier Materials, Graduate School of Engineering
Nagoya Institute of Technology
Gokiso, Showa-ku, Nagoya 466-8555 (Japan)
E-mail: nozshiba@nitech.ac.jp
H. Sato, Dr. M. Shiro
Rigaku Corporation
3-9-12 Mastubara-cho, Akishima, Tokyo 196-8666 (Japan)
[**] Support was provided by the Grants-in-Aid for Scientific Research
(21390030, 23915014, 22106515, Project No. 2105: Organic Syn-
thesis Based on Reaction Integration). We also thank the Asahi
Glass Foundation for support in part.
We first examined the reaction of (E)-4,4,4-trifluoro-1,3-
diphenylbut-2-en-1-one (3a) with acetone cyanohydrin in the
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201201278.
Angew. Chem. Int. Ed. 2012, 51, 1 – 5
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Table 1: Optimization of the reaction conditions.[a]
Entry
Base
Solvent
5
Yield [%]
ee [%][b]
1
2
3
4
5
6
7
8
K2CO3
K2CO3
K2CO3
K2CO3
Na2CO3
Cs2CO3
KOH
NaOEt
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
Cs2CO3
Cs2CO3
toluene/H2O (2:1)
toluene/H2O (2:1)
toluene
THF
THF
THF
THF
THF
Et2O
iPr2O
5a
5b
5b
5b
5b
5b
5b
5b
5b
5b
5b
5b
5b
5b
5b
5b
5c
5c
5c
22
93
85
99
25
94
38[f]
31[f]
98
81
54
24
84
90
99
99
76
97
90
rac
62
72
72
53
72
52[f]
70[f]
76
74
67
72
65
81
86
89
91
90
92
9
10
11
12
13
14[c]
15[d]
16[d]
17[d]
18[d]
19[d,e]
DME
Scheme 1. Enantioselective synthesis of b-trifluoromethyl D1-pyrrolines
2 through asymmetric conjugate cyanation.
mesitylene
CH2Cl2
Et2O
Et2O
iPr2O
iPr2O
iPr2O
iPr2O
presence of K2CO3 and a catalytic amount of a chiral phase-
transfer catalyst under conventional biphasic conditions
(toluene/H2O = 2:1) at ambient temperature (entry 1,
Table 1). N-3,5-Bis(trifluoromethylbenzyl) quinidinium bro-
mide (5a) was selected as the asymmetric catalyst as it is the
best catalyst for the enantioselective asymmetric hydroxyl-
amine enone cascade reaction of 3a as previously reported.[4]
Much to our disappointment, conjugate addition of cyanide to
3a did not proceed as anticipated. The desired conjugate
adduct 4a was obtained only in 22% yield with 0% ee
(entry 1). Indeed, the conjugate addition of cyanide to 3 had
not been examined thus far, not even in a racemic fashion.
This poor result led us to change the catalyst character
entirely. It is reported that the hydroxy group of cinchona
alkaloids often plays an important role both in reactivity and
in asymmetric induction, probably through hydrogen bonding
with substrates.[4,11] We therefore hypothesized that the
hydrogen bonding could be hindering the desired conjugate
addition, so a variety of OH-protected ether-type cinchona
alkaloids were synthesized (see Table S1 in the Supporting
Information).[12] Gratifyingly, when the reaction was carried
out using the methylether catalyst 5b, the desired 4a was
obtained in 93% with 62% ee (entry 2). Enantioselectivity
was further improved to 72% ee in toluene or THF (entries 3
and 4). A screen of different bases (entries 5–8) showed that
either K2CO3 or Cs2CO3 was the base of choice with regard to
both enantioselectivity and yield (entries 4 and 6). Interest-
ingly, when the reaction was carried out in the presence of
a stoichiometric amount of KOH or NaOEt, only the 1,2-
adduct was detected in low yield and moderate to good
enatioselectivity (entries 7 and 8).[13] Upon screening solvents,
we found that Et2O and iPr2O produced good results, with
ee values in the range of 74–76% (entries 9 and 10). Further
improvement was observed under high dilution (entries 14–
16), and 89% ee of 4a was obtained in iPr2O (0.017m,
entry 16). A second catalyst screening (see Table S2 in the
[a] The reaction of 3a with acetone cyanohydrine (3.0 equiv) was carried
out in the presence of 5 (10 mol%) and base (3.0 equiv) in solvent
(0.5 mL, 0.2m) at room temperature, unless otherwise noted.
[b] Determined by HPLC analysis using a chiral stationary phase.
[c] 3.0 mL of solvent was used (0.033m). [d] 6.0 mL of solvent was used
(0.017m). [e] The reaction was carried out at 08C; [f] Corresponding 1,2-
adduct was obtained instead. DME=dimethoxyethane.
Supporting Information) indicated that the use of structurally
new, N-2,5-bis(trifluoromethylbenzyl) O-methyl quinidinium
bromide (5c) displayed the highest enantioselectivity (91%
ee, entry 17). In particular, the use of 3.0 equivalents of
acetone cyanohydrin in the presence of 5c (10 mol%) and
Cs2CO3 (3.0 equiv) in iPr2O at 08C was the most effective
combination for the formation of 4a in 90% yield with
92% ee (entry 19).
With optimal reaction conditions in hand, the scope of the
enantioselective conjugate cyanation of a variety of b-aryl-b-
trifluoromethyl-substituted enones (3) in the presence of
a catalytic amount of 5c was explored to establish the
generality of the process. In all cases the reactions afforded
products in excellent yields and enantioselectivities (Table 2).
A series of trifluoromethylated enone derivatives (3a–f, 3h–
m) having a variety of substituents on their aromatic rings,
including methyl, methoxy, chloro, bromo, and nitro groups,
were nicely converted into the corresponding products 4a–f,
4h–m in excellent yields with 90–96% ee (entries 1–6 and 8–
13). The sterically demanding naphthyl-substituted enones 3g
and 3n were also compatible with the same reaction
conditions, thus affording products 4g and 4n, respectively,
in excellent yields with 90–94% ee (entries 7 and 14). It
should be noted that the multiply substituted substrates 3o
2
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Table 2: Substrate generality.[a]
Entry
3
Ar1
Ar2
4
Yield
[%]
ee
[%][b]
1
2
3
4
5
6
7
8
3a
3b
3c
3d
3e
3 f
3g
3h
3i
3j
3k
3l
3m
3n
3o
3p
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
4a
4b
4c
4d
4e
4 f
4g
4h
4i
4j
4k
4l
4m
4n
4o
4p
90
99
99
93
96
92
92
92
98
99
99
99
99
99
99
94
92
91
91
90
90
90
90
92
94
96
90
95
91
94
95
92
Scheme 2. Transformations of 4a to pyrolline 2a and pyrrolidine 6.
3-MeC6H4
4-MeC6H4
4-MeOC6H4
4-ClC6H4
4-BrC6H4
2-naphthyl
Ph
Ph
Ph
Ph
Ph
In summary, we have developed an operationally simple,
highly enantioselective conjugate cyanation of b-aryl-b-tri-
fluoromethyl-substituted enones (3) using acetone cyano-
hydrin and the simple cinchona alkaloid catalyst 5c to provide
conjugate addition adducts having trifluoromethylated all-
carbon quaternary stereocenters.[14] Ether-type cinchona
alkaloids are very effective for this transformation and
excellent chemical yields with enantioselectivities, over 90%
ee, were obtained for all cases. Complete 1,4-additon selec-
tivity over 1,2-addition is also achieved. Transformation to the
medicinally important trifluoromethylated arylpyrolline 2
and pyrrolidine derivative 6 were achieved from 4 for the
first time. The procedure is carried out using inexpensive
acetone cyanohydrin and organocatalysts, and is thus an
advantage for industrial purposes.
4-MeC6H4
4-MeOC6H4
4-ClC6H4
3-BrC6H4
4-BrC6H4
4-NO2C6H4
2-naphthyl
2-Me-3-BrC6H3
2-MeC6H4
9
10
11
12
13
14
15
16
Ph
Ph
3,5-Cl2C6H3
3,5-Cl2C6H3
[a] The reaction of 3 with acetone cyanohydrin (3.0 equiv) was carried out
in the presence of 5c (10 mol%) and Cs2CO3 (3.0 equiv) in iPr2O
(6.0 mL, 0.017m) at 08C. [b] Determined by HPLC analysis using a chiral
stationary phase.
Received: February 15, 2012
Published online: && &&, &&&&
and 3p were also smoothly converted into the desired 1,4-
adducts 4o and 4p with 95 and 92% ee, respectively
(entries 15 and 16). The absolute stereochemistry of (R)-4l
was clearly determined by X-ray analysis (Figure 2) and all
the other products were tentatively assigned by analogy with
(R)-4l.
Keywords: asymmetric catalysis · fluorine · heterocycles ·
.
organocatalysis · synthetic methods
[1] For examples, see: a) T. Mita, Y. Kudo, T. Mizukoshi, H. Hotta,
K. Maeda, S. Takii, WO2004018410, 2004; b) T. Mita, T. Kikuchi,
T. Mizukoshi, M. Yaosaka, M. Komoda, WO2005085216, 2005;
c) G. P. Lahm, W. L. Shoop, M. Xu, WO2007079162, 2007; d) M.
Yaosaka, T. Utsunomiya, Y. Moriyama, T. Matsumoto, K.
Matoba, WO2009001942, 2009; e) K. Matoba, WO
2009063910, 2009; f) J. K. Long, T. P. Selby, M. Xu,
WO2009045999, 2009; g) W. Zambach, P. Renold,
WO2009049846, 2009; h) P. Renold, W. Zambach, P. Maienfisch,
M. Muehlebach, WO2009080250, 2009; i) T. Murata, Y. Yoneta,
J. Mihara, K. Domon, M. Hatazawa, K. Araki, E. Shimojo, K.
Shibuya, T. Ichihara, U. Goergens, A. Voerste, A. Becker, E.
Franken, K. Mueller, WO2009112275, 2009; j) Y. Ozoe, M.
Asahi, F. Ozoe, K. Nakahira, T. Mita, Biochem. Biophys. Res.
Commun. 2010, 391, 744 – 749; k) N. P. Mulholland, E. God-
ineau, J. Y. Cassayre, P. Renold, M. El Qacemi, G. Revol,
WO2011104089, 2011; l) N. A. L. Chubb, T. M. Maddux, S. R.
Menon, WO2011124998, 2011.
[2] For examples, see: a) T. Mita, Y. Kudo, T. Mizukoshi, H. Hotta,
K. Maeda, S. Takii, JP2005272452, 2005; b) T. Mita, E. Ikeda, H.
Takahashi, M. Komoda, WO2009072621, 2009; c) U. Goergens,
Y. Yoneta, T. Murata, J. Mihara, K. Domon, E. Shimojo, K.
Shibuya, T. Ichihara, WO2009097992, 2009; d) J. Y. Cassayre, P.
Renold, T. Pitterna, V. Bobosik, M. El Qacemi, A. J. Dalencon,
W. Zambach, C. R. Godfrey, P. J. Jung, J. Pabba, WO2010020522,
2010; e) H. Ihara, K. Kumamoto, WO2010090344, 2010; f) T.
Murata, Y. Yoneta, H. Kishikawa, J. Mihara, D. Yamazaki, M.
Hatazawa, N. Sasaki, K. Domon, E. Shimojo, T. Ichihara, K.
Figure 2. X-ray crystallographic analysis of (R)-4l.[15] Thermal ellipsoids
are shown at 50% probability.
Finally, the one-step conversion of 4 into the partially
saturated target arylpyrroline 2 was carried out (Scheme2).
Treatment of 4a with Raney nickel in MeOH at ambient
temperature for 10 minutes led to 2a in 49%, without any loss
of enantiopurity in one step consisting of three sequential
reactions (cyano reduction/cyclization/dehydration). The
fully saturated pyrrolidine derivative 6 was also obtained
from 4a under a hydrogen atmosphere in 56% in one step
consisting of four sequential reactions (cyano reduction/
cyclization/dehydration/imine hydrogenation).
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.
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Shibuya, M. Ataka, U. Goergens, WO2010133336, 2010;
g) A. W. Moradi, T. N. Mueller, T. Murata, M. Hatazawa, P.
Bruechner, E. Shimojo, T. Ichihara, M. Ataka, K. Shibuya, U.
Goergens, WO2011128299, 2011; h) K. Araki, J. Mihara, N.
Sasaki, P. Bruechner, K. Domon, J.-R. Jansen, N. Lui,
WO2011141414, 2011.
1789; Angew. Chem. Int. Ed. 2008, 47, 1762 – 1765; e) I. Fujimori,
T. Mita, K. Maki, M. Shiro, A. Sato, S. Furusho, M. Kanai, M.
Shibasaki, Tetrahedron 2007, 63, 5820 – 5831; f) Y. Tanaka, M.
Kanai, M. Shibasaki, J. Am. Chem. Soc. 2008, 130, 6072 – 6073;
g) J. Wang, W. Li, Y. Liu, Y. Chu, L. Lin, X. Liu, X. Feng, Org.
Lett. 2010, 12, 1280 – 1283; h) P. Bernal, R. Fernꢀndez, J.
Lassaletta, Chem. Eur. J. 2010, 16, 7714 – 7718; i) N. Kurono, N.
Nii, Y. Sakaguchi, M. Uemura, T. Ohkuma, Angew. Chem. 2011,
123, 5655 – 5658; Angew. Chem. Int. Ed. 2011, 50, 5541 – 5544;
j) B. A. Provencher, K. J. Bartelson, Y. Liu, B. M. Foxman, L.
Deng, Angew. Chem. 2011, 123, 10753 – 10757; Angew. Chem.
Int. Ed. 2011, 50, 10565 – 10569.
[3] a) V. A. Petrov, Fluorinated Heterocyclic Compounds: Synthesis
Chemistry, and Applications, Wiley, Hoboken, 2009; b) P. Kirsch,
Modern Fluoroorganic Chemistry, Wiley-VCH, Weinheim, 2004;
c) “Biomedical Frontiers of Fluorine Chemistry”: I. Ojima, J. R.
MacCarthy, J. T. Welch, ACS Symp. Ser. 1996, 0, 0; d) R. Filler, Y.
Kobayashi, L. M. Yagupolskii, Organofluorine Compounds in
Medicinal Chemistry and Bio medical Applications, Elsevier,
Amsterdam, 1993; e) J. T. Welch, S. Eswarakrishman, Fluorine in
Bioorganic Chemistry, Wiley, New York, 1991; f) R. Filler, Y.
Kobayashi, Biomedicinal Aspects of Fluorine Chemistry, Elsevier
Biomedical Press and Kodansya Ltd, Amsterdam, 1982; g) V. M.
Muzalevskiy, A. V. Shastin, E. S. Balenkova, G. Haufe, V. G.
Nenajdenko, Synthesis 2009, 3905 – 3929; h) A. W. Erian, J.
Heterocycl. Chem. 2001, 38, 793 – 808; i) P. Lin, J. Jiang,
Tetrahedron 2000, 56, 3635 – 3671; j) M. J. Silvester, Adv. Heter-
ocycl. Chem. 1994, 59, 1 – 38; k) J. T. Welch, Tetrahedron 1987,
43, 3123 – 3197.
[4] K. Matoba, H. Kawai, T. Furukawa, A. Kusuda, E. Tokunaga, S.
Nakamura, M. Shiro, N. Shibata, Angew. Chem. 2010, 122, 5898 –
5902; Angew. Chem. Int. Ed. 2010, 49, 5762 – 5766.
[5] H. Kawai, K. Tachi, E. Tokunaga, M. Shiro, N. Shibata, Angew.
Chem. 2011, 123, 7949 – 7952; Angew. Chem. Int. Ed. 2011, 50,
7803 – 7806.
[6] a) N. Shibata, H. Fujimoto, S. Mizuta, S. Ogawa, Y. Ishiuchi, S.
Nakamura, T. Toru, Synlett 2006, 3484 – 3488; b) S. Ogawa, N.
Iida, E. Tokunaga, M. Shiro, N. Shibata, Chem. Eur. J. 2010, 16,
7090 – 7095; c) S. Ogawa, T. Nishimine, E. Tokunaga, N. Shibata,
Synthesis 2010, 3274 – 3281; d) Y. Huang, E. Tokunaga, S. Suzuki,
M. Shiro, N. Shibata, Org. Lett. 2010, 12, 1136 – 1138.
[7] a) Enantiocontrolled Synthesis of Fluoro-Organic Compounds
(Ed.: V. A. Soloshonok), Wiley, Chichester, 1999; b) J.-A. Ma, D.
Cahard, Chem. Rev. 2008, 108, PR1 – PR43; c) N. Shibata, S.
Mizuta, H. Kawai, Tetrahedron: Asymmetry 2008, 19, 2633 –
2644; d) J. Nie, H.-C. Guo, D. Cahard, J.-A. Ma, Chem. Rev.
2011, 111, 455 – 529.
[10] a) L. Bernandi, F. Fini, M. Fochi, A. Ricci, Synlett 2008, 1857 –
1861; b) Y. Tanaka, M. Kanai, M. Shibasaki, J. Am. Chem. Soc.
2010, 132, 8862 – 8863.
[11] a) Cinchona Alkaloids in Synthesis & Catalysis: Ligands, Immo-
bilization and Organocatalysis, (Ed.: C. E. Song), Wiley-VCH,
Weinheim, 2009; b) E. M. O. Yeboah, S. O. Yeboah, G. S. Singh,
Tetrahedron 2011, 67, 1725 – 1762.
[12] Although the reason of failure of the hydroxy cinchona
derivative 5a in promoting enantioselectivity remains obscure,
we propse that there is a reaction between the OH moiety and
acetone cyanohydrin based on the 1H NMR experiments. The
1H NMR spectra of OH-protected cinchona derivative 5c in
CDCl3 do not indicate any major change to the catalyst after
addition of acetone cyanohydrin. In contrast, there are differ-
ences observed in the 1H NMR spectrum of 5a compared to that
of 5a/acetone cyanohydrin. These results indicate that 5a in the
presence of acetone cyanohydrin might exist as an equilibrium
mixture of the OH form and an unstable cyanomethyl ether
form, which interrupts the catalysis of the 5a.
[13] This behavior is related to the nature of the base, not to its
amount. When a stoichiometric amount of Cs2CO3 was used,
a similarly high enantioselecticity of 4a was observed with
a slightly lower yield (iPr2O, 0 8C, 18 h, 67%, 90% ee). In
contrast, the reaction using NaCN (3.0 equiv) instead of acetone
cyanohydrin furnished the 1,2-additon product in 57% with
49% ee (THF, RT, 24 h). These results imply that the use of
a strong base such as KOH or NaOEt (entries 7 and 8, Table 1)
should provide a harder CN species than acetone cyanohydrin
and results 1,2-addition.
[8] a) E. J. Corey, A. Guzman-Perez, Angew. Chem. 1998, 110, 402 –
415; Angew. Chem. Int. Ed. 1998, 37, 388 – 401; b) J. Christoffers,
A. Mann, Angew. Chem. 2001, 113, 4725 – 4732; Angew. Chem.
Int. Ed. 2001, 40, 4591 – 4597; c) I. Denissova, L. Barriault,
Tetrahedron 2003, 59, 10105 – 10146; d) B. M. Trost, C. Jiang,
Synthesis 2006, 369 – 396; e) P. G. Cozzi, R. Hilgraf, N. Zimmer-
mann, Eur. J. Org. Chem. 2007, 5969 – 5994.
[9] a) G. N. Sammis, E. N. Jacobsen, J. Am. Chem. Soc. 2003, 125,
4442 – 4443; b) G. N. Sammis, H. Danjo, E. N. Jacobsen, J. Am.
Chem. Soc. 2004, 126, 9928 – 9929; c) T. Mita, K. Sasaki, M.
Kanai, M. Shibasaki, J. Am. Chem. Soc. 2005, 127, 514 – 515;
d) C. Mazet, E. N. Jacobsen, Angew. Chem. 2008, 120, 1786 –
[14] Less than one month before the submission of this manuscript,
an enantioselective conjugate addition of cyanide to b-aryl-b-
trifluoromethyl aryl enones using hydroxy-type cinchona alka-
loids appeared in SciFinderꢁ. However, the catalyst activity and
substrate generality were not satisfactory and only three
substates were examined. See, M. El Qacemi, H. Smits, J. Y.
Cassayre, N. P. Mulholland, P. Renold, E. Godineau, T. Pitterna,
WO 2011154555, 2011.
[15] CCDC 866122 (4l) 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.
4
www.angewandte.org
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2012, 51, 1 – 5
These are not the final page numbers!

Angewandte
Chemie
Communications
Organocatalysis
H. Kawai, S. Okusu, E. Tokunaga, H. Sato,
M. Shiro, N. Shibata*
&&&& — &&&&
Organocatalytic Asymmetric Synthesis of
Trifluoromethyl-substituted
Diarylpyrrolines: Enantioselective
Conjugate Cyanation of b-Aryl-b-
trifluoromethyl-disubstituted Enones
Ether way: The cinchona-alkaloid-cata-
lyzed title reaction was achieved in high
yields with high to excellent ee values for
the first time, and affords key intermedi-
ates for the biologically important 2
having a trifluoromethylated all-carbon
quaternary chiral center. Ether-type cata-
lysts (1) are more efficient in this trans-
formation than the conventional hydroxy
analogues.
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!