Organocatalyzed asymmetric 1,4-addition of azlactones to α,β-unsaturated trichloromethyl ketones: Synthesis of α,α-disubstituted α-amino acid derivatives

Article abstract of DOI:10.1002/ejoc.201403158

The first asymmetric 1,4-addition of azlactones to α,β-unsaturated trichloromethyl ketones catalyzed by cinchona alkaloid derived bifunctional thiourea catalysts was developed. A series of α,α-disubstituted α-amino acid derivatives bearing a quaternary stereocenter at the α-position were obtained in high yields with excellent diastereo- and enantioselectivities (up to -20:1 dr and 99% ee). In addition, the trichloromethyl moiety in these adducts was identified as a good leaving group.

Full text of DOI:10.1002/ejoc.201403158

SHORT COMMUNICATION
DOI: 10.1002/ejoc.201403158
Organocatalyzed Asymmetric 1,4-Addition of Azlactones to α,β-Unsaturated
Trichloromethyl Ketones: Synthesis of α,α-Disubstituted α-Amino Acid
Derivatives
Jinlong Zhang,[a] Xihong Liu,[a] Chongyang Wu,[a] Panpan Zhang,[a] Jianbo Chen,[a] and
Rui Wang*[a,b]
Keywords: Organocatalysis / Amino acids / Alkaloids / Nitrogen heterocycles / Ketones
The first asymmetric 1,4-addition of azlactones to α,β-unsatu-
rated trichloromethyl ketones catalyzed by cinchona alkaloid
derived bifunctional thiourea catalysts was developed. A
series of α,α-disubstituted α-amino acid derivatives bearing
a quaternary stereocenter at the α-position were obtained in
high yields with excellent diastereo- and enantioselectivities
(up to Ͼ20:1dr and 99%ee). In addition, the trichloromethyl
moiety in these adducts was identified as a good leaving
group.
Mannich-type reaction,[9] cycloaddition,[10] Steglich re-
arrangement,[11] allylation,[12] benzylation,[13] and kinetic
resolution.[14] Among these methodologies, the catalytic
asymmetric conjugate addition to different α,β-unsaturated
ketones could be regarded as a straightforward strategy,
partially because organocatalysis can serve as a powerful
tool for stereochemical control in the reaction pro-
cess.[7a–7c,7e]
Introduction
The catalytic asymmetric synthesis of α,α-disubstituted
α-amino acids and their derivatives has attracted consider-
able attention in bioorganic chemistry, as they constitute an
important class of non-natural amino acids.[1] The proper-
ties of peptides and proteins possessing an α-quaternary
amino acid component, for example, resistance against
chemical and enzymatic degradation, can be dramatically
enforced owing to the stability and restricted conforma-
tional flexibility of such a moiety.[2] Furthermore, α,α-di-
substituted α-amino acids are also present in a variety of
pharmaceuticals and antibiotics.[3] Owing to their signifi-
cance from biological and medicinal points of view, intense
effort has been focused on the development of various easy
and efficient synthetic methods to gain access to a structur-
ally diverse family of these optically active amino acids.[4]
In recent years, as versatile masked and reactive amino acid
equivalents, azlactones[5] (pKa ≈ 9) have been recognized to
be one of the most valuable reagents for the asymmetric
synthesis of α-amino acid derivatives containing a hetero-
quaternary carbon stereocenter,[6] and a variety of catalytic
transformations for their preparation have been established,
including the Michael reaction,[7] Aldol-type reaction,[8]
Peters and co-workers[7b,7c,7e] reported very elegant
Michael additions of azlactones to enones with a mono- or
bispalladiumcycle catalyst, and excellent results were ob-
tained [Scheme 1, Equation (1)]. Thereafter, the Amarante
group[7a] developed a (Ϯ)-camphorsulfonic acid catalyzed
protocol for this transformation with high diastereoselectiv-
ity [Scheme 1, Equation (2)]. In the above two cases, the
products were only anti isomers.
Given that part of our research program is directed at
the asymmetric synthesis of bioactive chemical compounds,
especially non-natural amino acid derivatives, we decided to
conduct a reaction between azlactones and α,β-unsaturated
ketones in the presence of a bifunctional organocatalyst.
However, if the R4 group was methyl or phenyl, the reaction
did not take place. It was reasoned that the activation of
unsaturated ketones by the catalyst was insufficient for this
pathway, and more chemically reactive substrates were
needed. In this respect, α,β-unsaturated trichloromethyl
ketones[15] were synthesized, in which the trichloromethyl
motif is a good electron-withdrawing group. Excitingly, af-
ter a series of optimization attempts, this reaction pro-
ceeded well with a quinine-derived bifunctional thiourea
catalyst[16] and provided syn products in good yields with
high to excellent diastereo- and enantioselectivities. More
importantly, the trichloromethyl group turned out to be an
attractive ester and amide synthetic equivalent.
[a] School of Life Sciences, Institute of Biochemistry and
Molecular Biology, Lanzhou University, Lanzhou 730000, P. R.
China
E-mail: wangrui@lzu.edu.cn
http://lifesc.lzu.edu.cn/
[b] State Key Laboratory of Chiroscience, Department of Applied
Biology and Chemical Technology, The Hong Kong Polytechnic
University,
Kowloon, Hong Kong, P. R. China
E-mail: bcrwang@polyu.edu.hk
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201403158.
7104
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2014, 7104–7108

Synthesis of α,α-Disubstituted α-Amino Acid Derivatives
Table 1. Screening of the reaction conditions.[a]
Entry Cat.
R4
Solvent
Yield[b] [%] dr[c]
ee[d] [%]
1
2
3
4
5
6
7
8
9
II
II
II
I
III
IV
V
VI
VII
VIII
VIII
VIII
VIII
VIII
VIII
Me
Ph
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
CH2Cl2
MTBE[e]
xylene
–
–
–
–
6:1
5:1
8:1
5:1
4:1
5:1
15:1
6:1
11:1
Ͼ20:1
13:1
Ͼ20:1
Ͼ20:1
–
–
Scheme 1. Michael additions between azlactones and ketones; Ts =
p-tolylsulfonyl, CSA = camphorsulfonic acid.
CCl3
CCl3
CCl3
CCl3
CCl3
CCl3
CCl3
CCl3
CCl3
CCl3
CCl3
CCl3
CCl3
75
32
76
69
51
80
78
72
85
62
74
81
78
50
43
61
47
80
60
20
82
35
80
88
90
97[f]
Results and Discussion
Initial investigation of the reaction conditions was set out
for the model reaction between azlactone 1a and α,β-unsat- 10
11
12
13
14
urated trichloromethyl ketone 2a with cyclohexanediamine-
derived thioureas I–IV in toluene at room temperature. For-
tunately, C4 addition product 3a was obtained with moder-
ate yield albeit low diastereoselectivity (Table 1, entries 3–
6). No improvement in the enantioselectivity was observed
if cyclohexanediamine-derived organocatalysts V–VI were
added to the reaction mixture (Table 1, entries 7 and 8).
Next, quinine-derived catalysts were applied to the transfor-
mation, and the best result was gained by using thiourea
VIII as a catalyst, with which the diastereo- and enantio-
mesitylene
mesitylene
15
[a] Performed with 1a (0.13 mmol), ketone (0.10 mmol), and cata-
lyst (15 mol-%) in solvent (0.3 mL) at room temperature for 10 h.
[b] Yield of isolated product. [c] Determined by 1H NMR spec-
troscopy. [d] Determined by HPLC on a chiral stationary phase.
[e] MTBE = methyl tert-butyl ether. [f] Conducted at 0 °C.
selectivity were increased to 6:1 and 82%, respectively α,β-unsaturated trichloromethyl ketone with a chloro sub-
(Table 1, entries 9 and 10). A screening of the solvents indi- stituent in the ortho position of the aromatic ring proceeded
cated that aromatic solvents appeared to be the best reac- smoothly to provide the product in moderate yield with
tion media, and xylene gave the products with 88%ee and high diastereoselectivity (up to Ͼ20:1) but with low enan-
13:1dr (Table 1, entries 11–13). Clearly, further optimi- tiomeric excess (Table 2, see compound 3g). However, start-
zation of the reaction conditions was still desired, and ing material methylated at the β-position of 2 could also be
mesitylene was used to promote the process. As expected, applied, and both diastereomers were obtained as a mixture
a high yield and excellent chemical stereoselectivity were with 80 and 82%ee, respectively (Table 2, see compound
achieved (Table 1, entry 14). Finally, the influence of reac- 3h).
tion temperature on this transformation was estimated, and
0 °C was selected for further studies in terms of both reac- and various azlactones under the optimized conditions was
tivity and selectivity (Table 1, entry 15). also studied, and the results are shown in Table 3. The reac-
The reaction scope of the Michael addition between 2a
With the optimized reaction conditions established, the tion was performed with a substituted aromatic group at
substrate scope of the 1,4-addition between azlactone 1a R2, and the high yields and excellent stereoselectivities were
and different α,β-unsaturated trichloromethyl ketones was similar to those obtained with a phenyl substituent (Table 3,
investigated in the presence of catalyst VIII (15 mol-%). As see compounds 3i–l). Subsequently, azlactones derived from
the results show (Table 2), both electron-donating and elec- alanine, leucine, allylglycine, and methionine were tested in
tron-withdrawing substituents in the para position of the this reaction, and their additions to α,β-unsaturated tri-
phenyl ring in substrate 2 were adaptable to the optimal chloromethyl ketone 2a took place in good yields, and the
reaction conditions, and the products were obtained in high enantioselectivities ranged from 83 to 95% (Table 3, see
yields with excellent stereoselectivity (Table 2, see com- compounds 3m–p). Only in the case of isoleucine-derived
pounds 3a–f). Moreover, we found that the reaction of an azlactone 2n was a low 3:1 diastereomeric ratio afforded.
Eur. J. Org. Chem. 2014, 7104–7108
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
7105

J. Zhang, X. Liu, C. Wu, P. Zhang, J. Chen, R. Wang
SHORT COMMUNICATION
Table 2. Scope for the asymmetric addition of azlactone 1a to tri-
Table 3. Scope for the asymmetric addition of azlactones to tri-
chloromethyl ketones.[a]
chloromethyl ketone 2a.[a]
[a] Performed with 1 (0.26 mmol), 2 (0.20 mmol), and catalyst VIII
(15 mol-%) in mesitylene (0.6 mL) for 10 h. [b] Yield of isolated
product. [c] Determined by 1H NMR spectroscopy. [d] Determined
by HPLC on a chiral stationary phase. [e] Conducted with 1
(0.20 mmol), 2 (0.30 mmol), and catalyst VIII (20 mol-%) in mesit-
ylene (0.6 mL) for 30 h.
[a] Performed with 1 (0.26 mmol), 2 (0.20 mmol), and catalyst VIII
(15 mol-%) in mesitylene (0.6 mL) for 10 h. [b] Yield of isolated
product. [c] Determined by 1H NMR spectroscopy. [d] Determined
by HPLC on a chiral stationary phase. [e] Absolute stereochemistry
of 3f was determined by X-ray crystallography and that of the other
products was assigned by analogy.
Encouraged by these results, quinidine-derived thiourea
IX was synthesized and used to catalyze this reaction under
the same conditions. Adduct 4a was obtained in 75% yield
with acceptable 73%ee and 6:1dr; this adduct is the
enantiomer of compound 3a (Scheme 2).
The absolute configuration of the two sequential
stereocenters of 3f was determined as (S,R) by X-ray crys-
tallography and that of the other products was assigned by
analogy.[17] On the basis of the absolute configuration, a
plausible mechanism is outlined in Scheme 3. The acti-
vation of two substrates through hydrogen bonds attached
to the catalyst followed by nucleophilic addition of the eno-
lized electrophilic partner to α,β-unsaturated ketone 2f from
the Si face gives rise to 1,2-syn isomer 3f.
Scheme 2. Synthesis of enantiomer 4a with a quinidine-derived
thiourea.
The practical utility of this reaction was demonstrated in
a further step by the transformation shown in Scheme 4.
Highly optically active 3a was easily converted into esteri-
fied products 3aa and 3ab in a THF/MeOH mixed solvent
with the addition of NaHCO3 and TMSCl, respectively.
Upon using a strong nucleophile such as NaOMe, the reac-
tion was complete within 30 min and afforded diesterified
ring-opened product 3ac. Amide 4ab was also easily ob-
tained from the corresponding amine in acetonitrile.
Furthermore, reduction of the trichloromethyl group to a
Scheme 3. Stereochemical structure of enantiopure 3f and mechan-
dichloromethyl group was achieved by using Pt/C as a cata- istic consideration for the approach.
7106 Eur. J. Org. Chem. 2014, 7104–7108
www.eurjoc.org
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Synthesis of α,α-Disubstituted α-Amino Acid Derivatives
lyst under a hydrogen atmosphere. These compounds are
important protected non-natural quaternary α-amino acids.
Acknowledgments
The authors are grateful for grants from the National Natural Sci-
ence Foundation of China (NSFC) (grant numbers 91213302 and
21272102), the Key National S&T Program “Major New Drug De-
velopment” of the Ministry of Science and Technology of China
(2012ZX09504001-003), and the Program for Changjiang Scholars
and Innovative Research Team in University (PCSIRT: IRT1137).
[1] a) H. Vogt, S. Bräse, Org. Biomol. Chem. 2007, 5, 406–430; b)
C. Cativiela, M. D. Díaz-de-Villegas, Tetrahedron: Asymmetry
2007, 18, 569–632; c) J. Venkatraman, S. C. Shankaramma, P.
Balaram, Chem. Rev. 2001, 101, 3131–3152.
[2] a) M. Tanaka, Chem. Pharm. Bull. 2007, 55, 349–358; b) S. J.
O’Connor, Z. Liu, Synlett 2003, 2135–2138; c) A. Giannis, T.
Kolter, Angew. Chem. Int. Ed. Engl. 1993, 32, 1244–1267; An-
gew. Chem. 1993, 105, 1303–1326; d) M. C. Khosla, K. Sta-
chowiak, R. R. Smeby, F. Piriou, K. Lintner, S. Fermandjian,
Proc. Natl. Acad. Sci. USA 1981, 78, 757–760.
Scheme 4. Different transformations of product 3a; Bz = benzoyl.
[3] a) T. Kan, Y. Kawamoto, T. Asakawa, T. Furuta, T. Fukuyama,
Org. Lett. 2008, 10, 169–171; b) A. Takahashi, H. Naganawa,
D. Ikeda, Y. Okami, Tetrahedron 1991, 47, 3621–3632.
[4] For reviews on the synthesis of α,α-disubstituted α-amino ac-
ids, see: a) R. A. Mosey, J. S. Fisk, J. J. Tepe, Tetrahedron:
Asymmetry 2008, 19, 2765–2762; b) C. Cativiela, M. D. Díaz-
de-Villegas, Tetrahedron: Asymmetry 2007, 18, 569–623; c) C.
Nájera, J. M. Sansano, Chem. Rev. 2007, 107, 4581–4671; d) Y.
Ohfune, T. Shinada, Eur. J. Org. Chem. 2005, 5127–5143; e) H.
Vogt, S. Bräse, Org. Biomol. Chem. 2007, 5, 406–430; f) M.
Tanaka, Chem. Pharm. Bull. 2007, 55, 349–358; g) J. Venkatra-
man, S. C. Shankaramma, P. Balaram, Chem. Rev. 2001, 101,
3131–3152; h) C. Cativiela, M. D. Díaz-de-Villegas, Tetrahe-
dron: Asymmetry 2000, 11, 645–732; i) C. Cativiela, M. D.
Díaz-de-Villegas, Tetrahedron: Asymmetry 1998, 9, 3517–3599;
j) M. C. Khosla, K. Stachowiak, R. R. Smeby, F. Piriou, K.
Lintner, S. Fermandjian, Proc. Natl. Acad. Sci. USA 1981, 78,
757–760.
Conclusions
In summary, we developed the first catalytic asymmetric
Michael addition of azlactones to α,β-unsaturated tri-
chloromethyl ketones in high yields with excellent stereose-
lectivities by using a commercially available quinine-derived
thiourea catalyst. Alkyl and aromatic substituents on both
substrates were explored under the optimized reaction con-
ditions, and the corresponding products were obtained in
all cases. More importantly, quinidine-derived thiourea was
able to catalyze this reaction, by which the enantiomer of
the former adduct was obtained with moderate stereoselec-
tivity. Additional derivations for protected non-natural
amino acids were also presented.
[5] For reviews on the diverse chemistry of azlactones, see: a) A.-
N. R. Alba, R. Rios, Chem. Asian J. 2011, 6, 720–734; b) J. S.
Fisk, R. A. Mosey, J. J. Tepe, Chem. Soc. Rev. 2007, 36, 1432–
1440.
[6] For reviews on the synthesis of quaternary stereocenters, see:
a) B. Wang, Y.-Q. Tu, Acc. Chem. Res. 2011, 44, 1207–1222; b)
P. G. Cozzi, R. Hilgraf, N. Zimmermann, Eur. J. Org. Chem.
2007, 5969–5994; c) J. T. Mohr, B. M. Stoltz, Chem. Asian J.
2007, 2, 1476–1491; d) B. M. Trost, C. Jiang, Synthesis 2006,
369–396; e) J. Christoffers, A. Baro, Adv. Synth. Catal. 2005,
347, 1473–1482; f) C. J. Douglas, L. E. Overman, Proc. Natl.
Acad. Sci. USA 2004, 101, 5363–5367; g) I. Denissova, L. Bar-
riault, Tetrahedron 2003, 59, 10105–10146.
[7] For selected examples of Michael additions of azlactones, see:
a) E. P. Ávila, A. C. de Mello, R. Diniz, G. W. Amarante, Eur.
J. Org. Chem. 2013, 1881–1883; b) M. Weber, S. Jautze, W.
Frey, R. Peters, Chem. Eur. J. 2012, 18, 14792–14804; c) M.
Weber, R. Peters, J. Org. Chem. 2012, 77, 10846–10855; d) H.
Jiang, M. W. Paixão, D. Monge, K. A. Jørgensen, J. Am. Chem.
Soc. 2010, 132, 2775–2783; e) M. Weber, S. Jautze, W. Frey, R.
Peters, J. Am. Chem. Soc. 2010, 132, 12222–12225; f) A.-N. R.
Alba, G. Valero, T. Calbet, M. Font-Bardía, A. Moyano, R.
Rios, Chem. Eur. J. 2010, 16, 9884–9889; g) S. Cabrera, E.
Reyes, J. Alemán, A. Milelli, S. Kobbelgaard, K. A. Jørgensen,
J. Am. Chem. Soc. 2008, 130, 12031–12037; h) J. Alemán, A.
Milelli, S. Cabrera, E. Reyes, K. A. Jørgensen, Chem. Eur. J.
2008, 14, 10958–10966; i) D. Uraguchi, Y. Ueki, T. Ooi, Science
2009, 326, 120–123; j) A.-N. R. Alba, X. Companyó, G. Valero,
A. Moyano, R. Rios, Chem. Eur. J. 2010, 16, 5354–5361; for
examples of additions to alkynyl carbonyl substrates, see: k) D.
Uraguchi, Y. Ueki, A. Sugiyama, T. Ooi, Chem. Sci. 2013, 4,
Experimental Section
General Procedure for the Addition of Azlactones to α,β-Unsaturated
Trichloromethyl Ketones: Azlactone 1 (0.26 mmol) and α,β-unsatu-
rated trichloromethyl ketone 2 (0.2 mmol) were added to a flask
and cooled to 0 °C. After 10 min, a solution of catalyst VIII
(15 mol-%) in mesitylene (0.6 mL, cooled to 0 °C) was added in
one portion. The mixture was then stirred for another 10 h at this
temperature (monitored by TLC). The crude residue was purified
by column chromatography to afford compound 3.
Procedure for the Addition of Azlactones to α,β-Unsaturated Tri-
chloromethyl Ketones: Azlactone 1 (0.20 mmol) and α,β-unsatu-
rated trichloromethyl ketone 2 (0.30 mmol) were added to a flask
and cooled to 0 °C. After 10 min, a solution of catalyst VIII
(15 mol-%) in mesitylene (0.6 mL, cooled to 0 °C) was added in
one portion. The mixture was then stirred for another 30 h at this
temperature (monitored by TLC). The crude residue was purified
by column chromatography to afford compound 3.
Supporting Information (see footnote on the first page of this arti-
cle): Experimental details, analytical data, and copies of the
1H NMR and 13C NMR spectra of all key intermediates and final
products.
Eur. J. Org. Chem. 2014, 7104–7108
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
7107

J. Zhang, X. Liu, C. Wu, P. Zhang, J. Chen, R. Wang
SHORT COMMUNICATION
1308–1311; l) T. Misaki, K. Kawano, T. Sugimura, J. Am. [13] B. M. Trost, L. C. Czabaniuk, Chem. Eur. J. 2013, 19, 15210–
Chem. Soc. 2011, 133, 5695–5697.
M. Terada, H. Tanaka, K. Sorimachi, J. Am. Chem. Soc. 2009,
131, 3430–3431.
a) W.-Q. Zhang, L.-F. Cheng, J. Yu, L.-Z. Gong, Angew. Chem.
Int. Ed. 2012, 51, 4085–4088; Angew. Chem. 2012, 124, 4161–
4164; b) D. Uraguchi, K. Koshimoto, T. Ooi, Chem. Commun.
2010, 46, 300–302; c) D. Uraguchi, Y. Ueki, T. Ooi, J. Am.
Chem. Soc. 2008, 130, 14088–14089; d) X. Liu, L. Deng, X.
Jiang, W. Yan, C. Liu, R. Wang, Org. Lett. 2010, 12, 876–879.
15218.
[14] For selected examples of dynamic kinetic resolutions, see: a) C.
Quigley, Z. Rodríguez-Docampo, S. J. Connon, Chem. Com-
mun. 2012, 48, 1443–1445; b) J.-S. Oh, J.-W. Lee, T. H. Ryu,
J. H. Lee, C. E. Song, Org. Biomol. Chem. 2012, 10, 1052–1055;
c) G. Lu, V. B. Birman, Org. Lett. 2011, 13, 356–358; d) D. G.
Blackmond, N. S. Hodnett, G. C. Lloyd-Jones, J. Am. Chem.
Soc. 2006, 128, 7450–7451; e) A. Berkessel, S. Mukherjee, F.
Cleemann, T. N. Müller, J. Lex, Chem. Commun. 2005, 1898–
1900; for other selected examples, see: f) B. Qiao, X. Liu, S.
Duan, L. Yan, Z. Jiang, Org. Lett. 2014, 16, 672–675; g) P.
Finkbeiner, N. M. Weckenmann, B. J. Nachtsheim, Org. Lett.
2014, 16, 1326–1329; h) Y.-L. Yang, C.-K. Pei, M. Shi, Org.
Biomol. Chem. 2011, 9, 3349–3358; i) M. Terada, K. Moriya,
K. Kanomata, K. Sorimachi, Angew. Chem. Int. Ed. 2011, 50,
12586–12590; Angew. Chem. 2011, 123, 12794–12798; j) D. Ur-
aguchi, Y. Asai, T. Ooi, Angew. Chem. Int. Ed. 2009, 48, 733–
737; Angew. Chem. 2009, 121, 747–751; k) E. Busto, V. Gotor-
Fernández, V. Gotor, Adv. Synth. Catal. 2006, 348, 2626–2632.
[15] For the direct use of α,β-unsaturated trichloromethyl ketones
in Michael reactions, see: a) C. Zheng, Y. Li, Y. Yang, H. Wang,
H. Cui, J. Zhang, G. Zhao, Adv. Synth. Catal. 2009, 351, 1685–
1691; b) H. Morimoto, S. H. Wiedemann, A. Yamaguchi, S.
Harada, Z. Chen, S. Matsunaga, M. Shibasaki, Angew. Chem.
Int. Ed. 2006, 45, 3146–3150; Angew. Chem. 2006, 118, 3218–
3222.
[8]
[9]
[10] a) F. Esteban, R. Alfaro, F. Yuste, A. Parra, J. L. G. Ruano, J.
Alemán, Eur. J. Org. Chem. 2014, 1395–1400; b) W. Sun, G.
Zhu, C. Wu, G. Li, L. Hong, R. Wang, Angew. Chem. Int. Ed.
2013, 52, 8633–8637; Angew. Chem. 2013, 125, 8795–8799; c)
M. Weber, W. Frey, R. Peters, Angew. Chem. Int. Ed. 2013, 52,
13223–13227; Angew. Chem. 2013, 125, 13465–13469; d) M.
Martín-Rodríguez, C. Nájera, J. M. Sansano, Synlett 2012, 23,
62–65; e) M. Terada, H. Nii, Chem. Eur. J. 2011, 17, 1760–
1763; f) A. D. Melhado, G. W. Amarante, Z. J. Wang, M. Lupa-
ria, F. D. Toste, J. Am. Chem. Soc. 2011, 133, 3517–3527; g) Y.
Ying, Z. Chai, H.-F. Wang, P. Li, C.-W. Zheng, G. Zhou, Y.-P.
Cai, Tetrahedron 2011, 67, 3337–3342; h) S. Dong, X. Liu, X.
Chen, F. Mei, Y. Zhang, B. Gao, L. Lin, X. Feng, J. Am. Chem.
Soc. 2010, 132, 10650–10651; i) J. Jiang, J. Qing, L.-Z. Gong,
Chem. Eur. J. 2009, 15, 7031–7034; j) S. A. Shaw, P. Aleman,
E. Vedejs, J. Am. Chem. Soc. 2003, 125, 13368–13369.
[11] a) C. K. De, N. Mittal, D. Seidel, J. Am. Chem. Soc. 2011, 133,
16802–16805; b) D. Uraguchi, K. Koshimoto, S. Miyake, T.
Ooi, Angew. Chem. Int. Ed. 2010, 49, 5567–5569; Angew. Chem.
2010, 122, 5699–5710; c) C. Joannesse, C. P. Johnston, C. Con-
cellón, C. Simal, D. Philp, A. D. Smith, Angew. Chem. Int. Ed.
2009, 48, 8914–8918; Angew. Chem. 2009, 121, 9076–9080; d)
S. A. Shaw, P. Aleman, J. Christy, J. W. Kampf, P. Va, E. Vedejs,
J. Am. Chem. Soc. 2006, 128, 925–934; e) H. V. Nguyen,
D. C. D. Butler, C. J. Richards, Org. Lett. 2006, 8, 769–772; f)
J. G. Seitzberg, C. Dissing, I. Søtofte, P.-O. Norrby, M.
Johannsen, J. Org. Chem. 2005, 70, 8332–8337; g) S. A. Shaw,
P. Aleman, E. Vedejs, J. Am. Chem. Soc. 2003, 125, 13368–
13369; h) J. C. Ruble, G. C. Fu, J. Am. Chem. Soc. 1998, 120,
11532–11533.
[16] For reviews on cinchona alkaloids, see: a) H. Martin, R.
Hoffmann, J. Frackenpohl, Eur. J. Org. Chem. 2004, 4293–
4312; b) S.-K. Tian, Y. Chen, J. Hang, L. Tang, P. Mcdaid, L.
Deng, Acc. Chem. Res. 2004, 37, 621–631; c) S. France, D. J.
Guerin, S. J. Miller, T. Lectka, Chem. Rev. 2003, 103, 2985–
3012; for reviews on bifunctional thiourea catalysis, see: d)
A. G. Doyle, E. N. Jacobsen, Chem. Rev. 2007, 107, 5713–5743;
e) M. S. Taylor, E. N. Jacobsen, Angew. Chem. Int. Ed. 2006,
45, 1520–1243; Angew. Chem. 2006, 118, 1550–1573; f) S. J.
Connon, Chem. Eur. J. 2006, 12, 5418–5427; g) Y. Takemoto,
Org. Biomol. Chem. 2005, 3, 4299–4306.
[17] CCDC-1014388 (for 3f) contains the supplementary crystallo-
graphic 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. See the Supporting In-
formation for details.
[12] a) B. M. Trost, C. Jäkel, B. Plietker, J. Am. Chem. Soc. 2003,
125, 4438–4439; b) B. M. Trost, K. Dogra, J. Am. Chem. Soc.
2002, 124, 7256–7257; c) B. M. Trost, X. Ariza, J. Am. Chem.
Soc. 1999, 121, 10727–10737.
Received: September 2, 2014
Published Online: October 9, 2014
7108
www.eurjoc.org
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2014, 7104–7108