An easy route to exotic 9-epimers of 9-amino-(9-deoxy) cinchona alkaloids with (8S, 9R) and (8R, 9S)-configurations through two inversions of configuration

Article abstract of DOI:10.1016/j.cclet.2013.12.008

Four exotic chiral organocatalysts, 9-amino-(9-deoxy) cinchona alkaloids with (8S, 9R) and (8R, 9S)-configurations, were conveniently synthesized for the first time in 27-72% total yields through two conversions of configuration at the 9-stereogenic centers of commercially available cinchona alkaloids.

Full text of DOI:10.1016/j.cclet.2013.12.008

Chinese Chemical Letters 25 (2014) 557–560
Contents lists available at ScienceDirect
Chinese Chemical Letters
journal homepage: www.elsevier.com/locate/cclet
Original article
An easy route to exotic 9-epimers of 9-amino-(9-deoxy) cinchona
alkaloids with (8S, 9R) and (8R, 9S)-configurations through two
inversions of configuration
*
*
Jing-Wei Wan, Xue-Bing Ma , Rong-Xing He, Ming Li
College of Chemistry and Chemical Engineering, Southwest University, Chongqing 400715, China
A R T I C L E I N F O
A B S T R A C T
Article history:
Four exotic chiral organocatalysts, 9-amino-(9-deoxy) cinchona alkaloids with (8S, 9R) and (8R, 9S)-
configurations, were conveniently synthesized for the first time in 27–72% total yields through two
conversions of configuration at the 9-stereogenic centers of commercially available cinchona alkaloids.
ß 2013 Xue-Bing Ma and Ming Li. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All
rights reserved.
Received 8 October 2013
Received in revised form 25 November 2013
Accepted 28 November 2013
Available online 7 December 2013
Keywords:
Cinchona alkaloids
9-Amino-(9-deoxy) cinchona alkaloids
Synthesis
Inversion of configuration
1. Introduction
and (8R, 9S)-9-amino-(9-deoxy) cinchona alkaloids possibly play
the different and unthinkable role in determining the spatial
Recent years have witnessed an unthinkable upsurge in
potential utility of asymmetric organocatalysis as a tool for the
synthesis of enantiopure molecules under mild, environmentally
benign conditions [1]. Readily, available cinchona alkaloids,
namely cinchonidine (CD), cinchonine (CN), quinine (QN) and
quinidine (QD), enjoyed much interest as privileged organocata-
lysts effective in numerous mechanistically diverse enantioselec-
tive transformations [2]. The resulting (8S, 9S) and (8R, 9R)-9-
amino-(9-deoxy) cinchona alkaloids are employed as attractive
and efficient organocatalysts with excellent catalytic properties in
asymmetric Aldol addition [3], Diels–Alder reaction [4], Friedel–
Crafts reaction [5], Henry reaction [6], Mannich reaction [7],
Michael addition [8], hydrogenation [9], epoxidation [10], 1,3-
dipolar cycloaddition [11], decarboxylation [12] and methanolytic
desymmetrization [13]. In the aforementioned organocatalytic
asymmetric reactions, the stereochemistry of catalytic products, to
a great extent, generally depended on the configurations of the 8-
and 9-stereogenic centers in 9-amino-(9-deoxy) cinchona alka-
loids, although the experimental observations occasionally
revealed the unexpected hint of enantioselectivity [14].
Considering the influence of stereochemical diversity of the
organocatalyst on the stereochemistry of the products, (8S, 9R)
structures of catalytic products. However, until now, (8S, 9R) and
(8R, 9S)-9-amino-(9-deoxy) cinchona alkaloids have not been
developed or received considerable attention. Based on the
Mitsunobu reaction, in this report, four exotic pseudoenantiomers
of (8S, 9R) and (8R, 9S)-9-amino-(9-deoxy) cinchona alkaloids were
conveniently synthesized for the first time through the two
conversions of the configurations at the 9-stereogenic centers in
commercially available cinchona alkaloids (Scheme 1).
2. Experimental
General procedure for 9-amino(9-deoxy) cinchona alkaloids:
The epi-cinchona alkaloids (epi-CD, CN, QN and QD) (1.63 mmol)
and triphenylphosphine (520 mg, 1.95 mmol) were dissolved in
6 mL of anhydrous THF under an argon atmosphere and added
dropwise 2 mL of diisopropyl azidocarboxylate (DIAD) (0.38 mL,
1.95 mmol) and 1 mL THF solution of diphenylphosphoryl azide
(DPPA) (0.42 mL, 1.95 mmol) at 0 8C. The reaction mixture was
stirred at room temperature for 12 h and 50 8C for 2 h and then
triphenylphosphine (563 mg, 2.12 mmol) added in one portion.
After the gas evolution had ceased (about 2 h), the reaction mixture
was cooled to room temperature, added 0.3 mL of water, stirred for
another 3 h and evaporated under reduced pressure. The residue
was dissolved in 10 mL of CH2Cl2 and added 5 mL of diluted
hydrochloric acid (10%). The aqueous phase was washed with
CH2Cl2 (3 ꢀ 10 mL), alkalinized with an excess of concentrated
*
Corresponding authors.
E-mail addresses: zcj123@swu.edu.cn (X.-B. Ma), Liming@swu.edu.cn (M. Li).
1001-8417/$ – see front matter ß 2013 Xue-Bing Ma and Ming Li. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
http://dx.doi.org/10.1016/j.cclet.2013.12.008

558
J.-W. Wan et al. / Chinese Chemical Letters 25 (2014) 557–560
H
H
H
R
R
S
H
HO
H
N
N
R
S
H2N
H
HO
R
H
H
N
R1
R1
CN: R1=H
QD:
H
epi-CN
epi-QD
R1
R1=OCH3
CN-NH2
QD-NH2
N
N
(1) PPh3, DIAD, DPPA / T H F , 12 h
(3) H2O, 3 h
(1) PNBA, DEAD, PPh3, THF
(2) LiOH, H2O
N
10
4
11
H
H
3
(2) PPh3, 2 h
H
7
H
H
8
2
HO
H
H
R
H
5
N
N
H
The second
conversion
The first
conversion
9
S
S
N
S
6
HO
R
11'
R1
S
5'
4'
R1
H2N
9'
epi-CD
epi-QN
3'
2'
CD: R1=H
QN: R1=OCH3
R1
6'
7'
CD-NH2
QN-NH2
51% - 83%
53% - 87%
N
N
10'
8'
N
Scheme 1. The synthetic route to 9-amino-(9-deoxy) cinchona alkaloids through the two inversions of configuration.
ammonia and extracted with CH2Cl2 (3 ꢀ 30 mL). The organic
phase was dried over anhydrous Na2SO4. The concentrated organic
phase was purified by silica gel column chromatography using
CHCl3–MeOH (40:1, v/v) as an eluent to afford the title compounds
as yellowish viscous oils.
53.4 (C-9), 41.8 (C-6), 39.6 (C-3), 27.7 (C-7), 27.6 (C-4), 26.4 (C-5).
Anal. Calcd. for C19H23N3: C, 77.78; H, 7.90; N, 14.32. Found: C,
77.72; H, 9.98; N, 14.29. MS: m/z 293.7 [M+H]+.
QN-NH2: Yellowish viscous oil, ½a D20
ꢁ
= ꢂ42.3 (c 1.76, EtOH). 1H-
NMR (300 MHz, CDCl3, Me4Si): d
8.74 (d, 1 H, 3J = 6.0 Hz, H-20), 8.02
CN-NH2: Yellowish viscous oil, ½a D20
ꢁ
= ꢂ56.0 (c 0.30, EtOH). 1H
(d, 1 H, 3J = 12.0 Hz, H-80), 7.44 (d, 1 H, 3J = 3.0 Hz, H-50), 7.38 (1 H, d,
3J = 3.0 Hz, H-70), 7.35 (d, 1 H, 3J = 6.0 Hz, H-30), 5.87–5.99 (1 H, m, H-
10), 5.03–5.09 (m, 2 H, H-11), 4.63 (d, 1 H, 3J = 9.0 Hz, H-9), 3.96 (s, 3
NMR (300 MHz, CDCl3, Me4Si): d
8.89 (d, 1 H, 3J = 6.0 Hz, H-20), 8.21
(d, 1 H, 3J = 6.0 Hz, H-50), 8.12 (d, 1 H, 3J = 6.0 Hz, H-80), 7.70 (t, 1 H,
3
3J = 6.0 Hz, H-70), 7.57 (t, 1 H, J = 6.0 Hz, H-60), 7.41 (d, 1 H,
H, H-110), 3.21(q, 1 H, 3J = 9.0 Hz, H-8), 2.95–3.07(m, 2 H, H-6
exo), 2.66 (d, 1 H, 3J = 12.0 Hz, H-6 ), 2.56 (1 H, td, 3J1 = 12.0 Hz,
3J2 = 3.0 Hz, H-2-endo), 2.28 (s, 1 H, H-3), 2.15 (td, 1 H, 3J1 = 9.0 Hz
3J2 = 3.0 Hz, H-4), 1.90 (s, 3 H, NH2, H-7 ,), 1.67 (td, 1 H, 3J1 = 15.0 Hz,
3J2 = 3.0 Hz, H-7 ), 1.52 (2 q, H, 3J = 9.0 Hz, H-5). 13C NMR (75 MHz,
CDCl3):
157.7 (C-60), 149.2 (C-20), 147.8 (C-100), 144.7 (C-10), 141.8
a, H-2-
3J = 3.0 Hz, H-30), 5.93–6.05 (m, 1 H, H-10), 5.12 (d, 1 H, 3J = 6.0 Hz,
b
H-11
9), 3.18 (q, 1 H, 3J = 9.0 Hz, H-8), 2.66–2.88 (m, 4 H, H-6
H-6
, H-2-endo), 2.25 (q, 1 H, 3J = 9.0 Hz, H-3), 1.90–1.95 (m, 3 H,
NH2, H-4), 1.80 (d, 2 H, 3J = 9.0 Hz, H-7
, H-7 ), 1.62 (q, 2 H,
3J = 9.0 Hz, H-5). 13C NMR (75 MHz, CDCl3): 150.0 (C-20), 148.3 (C-
a b
), 5.08 (d, 1 H, 3J = 6.0 Hz, H-11 ), 4.81 (d, 1 H, 3J = 9.0 Hz, H-
a
, H-2-exo,
b
b
a
a
b
d
d
(C-40), 131.9 (C-80), 127.6 (C-90), 121.1 (C-30), 118.3 (C-70), 114.4 (C-
11), 101.1 (C-50), 60.5 (C-8), 56.1 (C-2), 55.6 (C-110), 53.7 (C-9), 41.9
(C-6), 39.6 (C-3), 27.8 (C-7), 27.7 (C-4), 26.5 (C-5). Anal. Calcd. for
100), 139.3 (C-40), 130.2 (C-10), 129.1 (C-70), 128.8 (C-80), 126.5 (C-
90), 126.3 (C-60), 122.6 (C-50), 117.6 (C-30), 114.9 (C-11), 60.4 (C-8),
52.1 (C-9), 49.1 (C-2), 48.1 (C-6), 38.8 (C-3), 29.4 (C-7), 27.5 (C-4),
25.6 (C-5). Anal. Calcd. for C19H23N3: C, 77.78; H, 7.90; N, 14.32.
Found: C, 77.75; H, 9.93; N, 14.27. MS: m/z 293.8 [M+H]+.
C
20H25N3O: C, 74.27; H, 7.79; N, 12.99; O, 4.95. Found: C, 74.32; H,
7.80; N, 12.97; O, 4.98. MS: m/z 324.9 [M+H]+.
QD-NH2: Yellowish viscous oil, ½a D20
ꢁ
= ꢂ106.7 (c 0.79, EtOH). 1H
3. Results and discussion
NMR (300 MHz, CDCl3, Me4Si): d
8.72 (d, 1 H, 3J = 6.0 Hz, H-20), 8.01
(d, 1 H, 3J = 9.0 Hz, H-80), 7.42 (s, 1 H, H-50), 7.31–7.37 (m, 2 H, H-70,
H-30), 5.93–6.04 (m, 1 H, H-10), 5.04–5.12 (m, 2 H, H-11), 4.73 (d, 1
H, 3J = 9.0 Hz, H-9), 3.95 (s, 3 H, H-110), 3.13 (q, 1 H, 3J = 9.0 Hz, H-8),
The first conversion of cinchona alkaloids to 9-epimers of
cinchona alkaloids was achieved through one-pot inversion of
Mitsunobu esterification–saponification [15]. Four cinchona alka-
loids (CD, CN, QN and QD) were esterified with 4-nitrobenzoic acid
(NBA) and subsequently treated in situ with aqueous lithium
hydroxide solution. The corresponding 9-epi-cinchona alkaloids
(epi-CD, CN, QN and QD) were easily purified by flash column
chromatography using CHCl3/t-BuOMe (3:1, v/v) as an eluent to
remove Ph3PO and diethyl hydrazine-1,2-dicarboxylate, and then
CHCl3/MeOH/Et3N (40:1:1, v/v/v) to obtain the target compounds
of analytical purity in 51%–83% yield, which were identified by
2.65–2.92 (m, 4 H, H-6
3J = 9.0 Hz, H-3), 2.13 (s, 2 H, NH2), 1.86 (s, 1 H, H-4), 1.77 (q, 2 H,
3J = 6.0 Hz, H-7 ), 1.60 (q, 2 H, 3J = 9.0 Hz, H-5). 13C NMR
, H-7
(75 MHz, CDCl3):
157.5 (C-60), 149.3 (C-20), 147.6 (C-100), 144.4
a, H-2-exo, H-6b, H-2-endo), 2.24 (q, 1 H,
a
b
d
(C-10), 140.2 (C-40), 131.6 (C-80), 127.6 (C-90), 121.2 (C-30), 118.0
(C-70), 114.5 (C-11), 101.0 (C-50), 60.6 (C-8), 55.4 (C-2), 52.8 (C-110),
49.3 (C-9), 48.4 (C-6), 39.2 (C-3), 27.7 (C-7), 26.1 (C-5), 25.2 (C-4).
Anal. Calcd. for C20H25N3O: C, 74.27; H, 7.79; N, 12.99; O, 4.95.
Found: C, 74.34; H, 7.81; N, 12.96; O, 4.96. MS: m/z 324.7 [M+H]+.
1H- NMR, 13C NMR, ½a D20
ꢁ
and Rf (Table 1).
According to the reported synthetic procedure [16], four (8S, 9R)
and (8R, 9S)-9-amino(9-deoxy) cinchona alkaloids (CD-NH2,
CD-NH2: Yellowish viscous oil, ½a D20
ꢁ
= ꢂ55.6 (c 1.63, EtOH). 1H
NMR (300 MHz, CDCl3, Me4Si): d
8.89 (d, 1 H, 3J = 6.0 Hz, H-20), 8.22
(d, 1 H, 3J = 6.0 Hz, H-50), 8.13 (d, 1 H, 3J = 9.0 Hz, H-80), 7.70 (t, 1 H,
3
3J = 6.0 Hz, H-70), 7.57 (t, 1 H, J = 6.0 Hz, H-60), 7.42 (1 d, H,
Table 1
3J = 6.0 Hz, H-30), 5.86–5.98 (m, 1 H, H-10), 5.03–5.09 (m, 2 H, H-
11), 4.76 (d, 1 H, 3J = 9.0 Hz, H-9), 3.23 (q, 1 H, 3J = 9.0 Hz, H-8),
Inversion of cinchona alkaloids by Mitsunobu esterification/saponification.a
Entry
epi-Alkaloid
(Rf)b
½
a 2D0
ꢁ
(c, EtOH)
Yield (%)
2.96–3.07 (m, 2 H, H-6
2.55 (td, 1 H, 3J1 = 12.0 Hz, 3J2 = 6.0 Hz, H-2-endo), 2.28 (s, 3 H, NH2,
H-3), 2.16 (m, 1 H, H-4), 1.90 (d, 1 H, H-7 ), 1.68 (td, 1 H,
3J1 = 12.0 Hz, 3J2 = 3.0 Hz, H-7 ), 1.50–1.56 (q, 2 H, 3J = 9.0 Hz, H-5).
13C NMR (75 MHz, CDCl3): 150.3 (C-20), 148.6 (C-100), 141.7 (C-
a b),
, H-2-exo), 2.66 (d, 1 H, 3J = 15.0 Hz, H-6
1
2
3
4
epi-CD
epi-QN
epi-CN
epi-QD
0.611
0.575
0.602
0.584
+56.4 (0.86)
+38.8 (0.81)
68
83
51
78
b
+112.6 (1.47)
+94.2 (1.23)
a
d
a
Reaction conditions: NBA (1.1 equiv.), DEAD (1.2 equiv.), Ph3P, (1.3 equiv.), then
40), 130.5 (C-10), 129.3 (C-70), 128.9 (C-80), 126.6 (C-90), 126.5 (C-
60), 122.6 (C-50), 118.0 (C-30), 114.5 (C-11), 60.6 (C-8), 56.1 (C-2),
LiOH (5 equiv.).
b
Eluent: CHCl3–MeOH (10:1, v/v).

J.-W. Wan et al. / Chinese Chemical Letters 25 (2014) 557–560
559
Table 2
and C9–C8 bonds from their minimum energy structures, in which
Inversion of epi-cinchona alkaloids to 9-amino(9-deoxy) cinchona alkaloids by
0
0
the H5 –H9 and H3 –H8 pairs of atoms showed close NOE
interactions with the closed conformations [18]. Furthermore,
1H NMR and 13C NMR spectra of (8S, 9R)-CD-NH2 differed from that
of (8S, 9S)-9-amino-(9-deoxy) cinchona alkaloids (epi-CD-NH2)
because of their opposite configurations of carbon atoms at
C9-position. The mixture of 50 wt% (8S, 9R)-CD-NH2 and 50 wt%
(8S, 9S)-epi-CD-NH2 showed the more sophisticated 1H NMR and
13C NMR spectra than their own shown in the Supporting
information, which provided the indirect evidence to elucidate
the different configurations at the C9-position between (8S, 9R)-
CD-NH2 and (8S, 9S)-epi-CD-NH2.
Mitsunobu reaction.
Entry
Amino-alkaloid
(Rf)a
½
a 2D0
ꢁ
(c, EtOH)
Yield (%)b
1
2
3
4
CD-NH2
QN-NH2
CN-NH2
QD-NH2
0.16
0.20
0.17
0.19
ꢂ55.6 (1.63)
ꢂ42.3 (1.76)
ꢂ56.0 (0.30)
81
87
53
75
ꢂ106.7 (0.79)
a
Eluent: CHCl3–MeOH (10:1, v/v).
Isolated yield.
b
CN-NH2, QN-NH2, QD-NH2) were conveniently prepared in good
yields (53%–87%) [17]. The key step was the Mitsunobu reaction
that led to the C9-azido compound by an SN2 mechanism. The
reduction is performed in situ by adding triphenylphosphane.
Hydrolysis of the intermediate aminophosphorane yielded free
amine. The pure 9-amino(9-deoxy) cinchona alkaloids (CD-NH2,
CN-NH2, QN-NH2 and QD-NH2) were easily separated by silica gel
flash column chromatography using CHCl3/MeOH (40:1, v/v) as an
eluent to afford yellowish viscous oils, whose structures were
identified by 1H NMR, 13C NMR, 1H COSY 2D NMR, 1H NOESY 2D
4. Conclusion
In summary, four exotic (8S, 9R) and (8R, 9S)-9-amino(9-deoxy)
cinchona alkaloids were conveniently synthesized for the first time
through the two conversions of the configurations at the 9-
stereogenic centers of commercially available cinchona alkaloids.
Their catalytic performances in various asymmetric reactions are
under investigation.
NMR, ½a 2D0
ꢁ
and Rf (Table 2). It is noteworthy that the ½a D20
ꢁ
values of
CD-NH2, CN-NH2, QN-NH2 and QD-NH2 were converted from
positive to negative due to the inversions of the configurations at
the 9-hydroxyl groups of epi-CD, CN, QN and QD.
Acknowledgments
Research support from the National Science Foundation of
China (No. 21071116) and Chongqing Scientific Foundation, China
(No. 2010BB4126).
Herein, we provided the direct evidence for conformational
preference of 9-amino(9-deoxy) cinchona alkaloids (CD-NH2, CN-
NH2, QN-NH2 and QD-NH2) through a combination of 1H NOESY 2D
NMR and computational methods. Full geometric optimization
calculations were performed in chloroform using the polarized
continuum model (PCM) with B3LYP functional and 6-31G(d) basis
set, and their minimum energy structures were shown in the
Supporting information. For the identification of conformers, the
interring NOEs between the quinoline and quinuclidine protons
and NOEs involving H8 and H9 are most useful. Pointedly, four 9-
amino(9-deoxy) cinchona alkaloids appeared to exhibit the
Appendix A. Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.cclet.2013.12.008.
References
0
hindered rotations around the C4 –C9 and C9–C8 bonds and to
[1] (a) J. Seayad, B. List, Asymmetric organocatalysis, Org. Biomol. Chem. 3 (2005)
719–724;
favor only a narrow range of the available conformational space of
the molecule. The 1H NOESY 2D NMR of CN-NH2 displayed only
three cross-peaks related to aromatic hydrogen, indicating close
interactions between the H5 –H9, H5 –H8, and H3 –H6 pairs of
atoms. These data mainly supported the minimum energy
conformation of CN-NH2, and elucidated that CN-NH2 favored
the open conformation (Fig. 1). Although the NOESY spectrum of
CD-NH2, QN-NH2 and QD-NH2 did not directly support their
minimum energy conformations, but the favored conformations
(b) C.F. Barbas III, Organocatalysis lost: modern chemistry, ancient chemistry,
and an unseen biosynthetic apparatus, Angew. Chem. Int. Ed. 47 (2008) 42–47;
(c) W. Notz, F. Tanaka, C.F. Barbas III, Enamine-based organocatalysis with
proline and diamines: the development of direct catalytic asymmetric Aldol,
Mannich, Michael, and Diels–Alder reactions, Acc. Chem. Res. 37 (2004) 580–591;
(d) H. Chen, R. Jiang, Q.F. Wang, et al., Synthesis of chiral dihydrofuran com-
0
0
0
pounds by thiourea derivatives-catalyzed ‘‘interrupted’’ Feist–Benary reaction,
Chin. Chem. Lett. 21 (2010) 167–170.
´
[2] (a) S.K. Tian, Y.G. Chen, J.F. Hang, et al., Asymmetric organic catalysis with
modified cinchona alkaloids, Acc. Chem. Res. 37 (2004) 621–631;
(b) S.J. Connon, Asymmetric catalysis with bifunctional cinchona alkaloid-based
urea and thiourea organocatalysts, Chem. Commun. (2008) 2499–2510;
(c) T. Marcelli, H. Hiemstra, Cinchona alkaloids in asymmetric organocatalysis,
Synthesis 8 (2010) 1229–1279.
0
could be obtained through molecular rotations around the C4 –C9
[3] (a) J. Zhou, V. Wakchaure, P. Kraft, B. List, Primary-amine-catalyzed enantiose-
lective intramolecular aldolizations, Angew. Chem. Int. Ed. 47 (2008) 7656–7658;
(b) B.L. Zheng, Q.Z. Liu, C.S. Guo, X.L. Wang, L. He, Highly enantioselective direct
Aldol reaction catalyzed by cinchona derived primary amines, Org. Biomol. Chem.
5 (2007) 2913–2915;
(c) J.Q. Zhou, J.W. Wan, X.B. Ma, W. Wang, Copolymer-supported heterogeneous
organocatalyst for asymmetric Aldol addition in aqueous medium, Org. Biomol.
Chem. 10 (2012) 4179–4185;
(d) W. Wang, X.B. Ma, J.W. Wan, J. Cao, Q. Tang, Preparation and confinement effect
of a heterogeneous 9-amino-9-deoxy-epi-cinchonidine organocatalyst for asym-
metric Aldol addition in aqueous medium, Dalton Trans. 41 (2012) 5715–5726.
[4] R.P. Singh, K. Bartelson, Y. Wang, et al., Enantioselective Diels–Alder reaction of
simple a,b-unsaturated ketones with a cinchona alkaloid catalyst, J. Am. Chem.
Soc. 130 (2008) 2422–2423.
[5] (a) H.M. Li, Y.Q. Wang, L. Deng, Enantioselective Friedel–Crafts reaction of indoles
with carbonyl compounds catalyzed by bifunctional cinchona alkaloids, Org. Lett.
8 (2006) 4063–4065;
(b) G. Bartoli, M. Bosco, A. Carlone, et al., Organocatalytic asymmetric Friedel–
Crafts alkylation of indoles with simple a,b-unsaturated ketones, Org. Lett. 9
(2007) 1403–1405.
[6] P. Hammar, T. Marcelli, H. Hiemstra, F. Himo, Density functional theory study of
the Cinchona thiourea-catalyzed Henry reaction: mechanism and enantioselec-
tivity, Adv. Synth. Catal. 349 (2007) 2537–2548.
Fig. 1. 1H NOESY 2D NMR and minimum energy conformation of CN-NH2.

560
J.-W. Wan et al. / Chinese Chemical Letters 25 (2014) 557–560
[7] T.Y. Liu, H.L. Cui, J. Long, et al., Organocatalytic and highly stereoselective direct
[12] H. Brunner, M.A. Baur, a-Amino acid derivatives by enantioselective decarboxyl-
ation, Eur. J. Org. Chem. (2003) 2854–2862.
[13] (a) S.H. Oh, H.S. Rho, J.W. Lee, et al., A highly reactive and enantioselective
bifunctional organocatalyst for the methanolytic desymmetrization of cyclic
anhydrides: prevention of catalyst aggregation, Angew. Chem. Int. Ed. 47
(2008) 7872–7875;
vinylogous Mannich reaction, J. Am. Chem. Soc. 129 (2007) 1878–1879.
[8] (a) P.F. Li, Y.C. Wang, X.M. Liang, J.X. Ye, Asymmetric multifunctional organoca-
talytic Michael addition of nitroalkanes to a,b-unsaturated ketones, Chem.
Commun. 28 (2008) 3302–3304;
(b) B. Vakulya, S. Varga, A. Csa´mpai, T. Soo´s, Highly enantioselective conjugate
addition of nitromethane to chalcones using bifunctional cinchona organocata-
lysts, Org. Lett. 7 (2005) 1967–1969;
(b) H.S. Rho, S.H. Oh, J.W. Lee, et al., Bifunctional organocatalyst for methanolytic
desymmetrization of cyclic anhydrides: increasing enantioselectivity by catalyst
dilution, Chem. Commun. (2008) 1208–1210.
(c) J.P. Malerich, K. Hagihara, V.H. Rawal, Chiral squaramide derivatives are excel-
lent hydrogen bond donor catalysts, J. Am. Chem. Soc. 130 (2008) 14416–14417.
[9] H.Y. Jiang, C.F. Yang, C. Li, et al., Heterogeneous enantioselective hydrogenation of
aromatic ketones catalyzed by cinchona- and phosphine-modified iridium cat-
alysts, J. Angew. Chem. Int. Ed. 47 (2008) 9240–9244.
[14] M. Barto´k, Unexpected inversions in asymmetric reactions: reactions with chiral
metal complexes, chiral organocatalysts, and heterogeneous chiral catalysts,
Chem. Rev. 110 (2010) 1663–1705.
[15] Ł. Sidorowicz, J. Skarz˙ ewski, Easy access to 9-epimers of cinchona alkaloids: one-
pot inversion by Mitsunobu esterification–saponification, Synthesis 5 (2011)
708–710.
[10] (a) X.W. Wang, C.M. Reisinger, B. List, Catalytic asymmetric epoxidation of cyclic
enones, J. Am. Chem. Soc. 130 (2008) 6070–6071;
(b) X.J. Lu, Y. Liu, B.F. Sun, B. Cindric, L. Deng, Catalytic enantioselective peroxi-
dation of a,b-unsaturated ketones, J. Am. Chem. Soc. 130 (2008) 8134–8135;
(c) Q.F. Wang, H. Chen, P. Liu, et al., Asymmetric epoxidation of alpha, beta-
enones catalyzed by chiral amine salts, Chin. J. Org. Chem. 29 (2009) 1617–1620;
(d) X.D. Liu, X.L. Bai, X.P. Qiu, L.X. Gao, Asymmetric phase-transfer mediated
epoxidation of alpha, beta-enones using dendritic catalysts derived from cincho-
na alkaloids, Chin. Chem. Lett. 16 (2005) 975–978.
[16] H. Brunner, J. Bu¨gler, B. Nuber, Enantioselective catalysis 98. Preparation of 9-
amino(9-deoxy)cinchona alkaloids, Tetrahedron: Asymmetry 6 (1995) 1699–
1702.
[17] C.G. Oliva, A.M.S. Silva, D.I.S.P. Resende, F.A.A. Paz, J.A.S. Cavaleiro, Highly enan-
tioselective 1,4-Michael additions of nucleophiles to unsaturated aryl ketones
with organocatalysis by bifunctional cinchona alkaloids, Eur. J. Org. Chem. (2010)
3449–3458.
[11] W. Chen, W. Du, Y.Z. Duan, et al., Enantioselective 1,3-dipolar cycloaddition of
cyclic enones catalyzed by multifunctional primary amines: beneficial effects of
hydrogen bonding, Angew. Chem. Int. Ed. 46 (2007) 7667–7670.
[18] H. Brunner, P. Schmidt, M. Prommesberger, Enantioselective catalysis. Part 133:
Conformational analysis of amides of 9-amino(9-deoxy)epicinchonine, Tetrahe-
dron: Asymmetry 11 (2000) 1501–1502.