H8-BINOL chiral imidodiphosphoric acids catalyzed cyclization reactions of β,γ-unsaturated α-ketoesters, arylamines and 1,3-dicarbonyl compounds: enantioselective synthesis of 1,4-dihydropyridines

Article abstract of DOI:10.1016/j.tetasy.2015.06.019

Abstract Penta-substituted 1,4-dihydropyridines were synthesized via catalytic enantioselective cyclization reactions of β,γ-unsaturated α-ketoesters, arylamines and acetylacetone for the first time. H₈-BINOL-type chiral imidodiphosphoric acid

Full text of DOI:10.1016/j.tetasy.2015.06.019

Tetrahedron: Asymmetry 26 (2015) 897–906
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
H8-BINOL chiral imidodiphosphoric acids catalyzed cyclization
reactions of b,c-unsaturated a-ketoesters, arylamines and
1,3-dicarbonyl compounds: enantioselective synthesis of
1,4-dihydropyridines
Dong An a, Ziqian Zhu a, Guangliang Zhang a, Yang Gao a, Jigang Gao a, Xu Han a, Liangyu Zheng b,
,
⇑
Suoqin Zhang a,
⇑
a College of Chemistry, Jilin University, 2699 Qianjin Street, Changchun 130012, China
b College of Life Sciences, Key Laboratory for Molecular Enzymology and Engineering of Ministry of Education, Jilin University, 2699 Qianjin Street, Changchun 130012, China
a r t i c l e i n f o
a b s t r a c t
Article history:
Penta-substituted 1,4-dihydropyridines were synthesized via catalytic enantioselective cyclization reac-
tions of b,c-unsaturated a-ketoesters, arylamines and acetylacetone for the first time. H8-BINOL-type chi-
ral imidodiphosphoric acid 4c was a suitable catalyst and exhibited high catalytic and stereocontrolling
abilities in these enone-type reactions. Under the optimized conditions, these 1,4-dihydropyridines were
obtained with excellent enantioselectivities (up to 97% ee). In addition, the typical product 8ba was con-
verted into the corresponding substituted piperidine with high yield (87%) and excellent enantioselectiv-
ity (95% ee) in a single-step reduction.
Received 16 May 2015
Accepted 26 June 2015
Available online 29 July 2015
Ó 2015 Elsevier Ltd. All rights reserved.
1. Introduction
CH2OH
HOH2C
R2
Over the last five decades, 1,4-dihydropyridines have been
extensively researched due to their significant pharmacological
and biological activities. As a class of calcium channel blockers,
drugs containing 4-aryl-1,4-dihydropyridines, such as nicardipine,
nimodipine, nilvadipine and amlodipine (Fig. 1, A), are widely used
in the treatment of hypertension and other cardiovascular dis-
eases.1 Further research on 1,4-dihydropyridines has revealed their
bioactivities including anticancer, antioxidant, antidiabetic and
antitumour activities (Fig. 1, B).2 With the increasingly widespread
biological applications, chiral 1,4-dihydropyridines have received
much attention and have been shown to have a significant effect
on the biochemical properties.3 For example, the (À)-isomer of
mebudipine exhibited more than 1000 times higher activity than
the (+)-isomer in the L-type Ca2+ channel assay (Fig. 1, C).3e The
Cl
N
R1
N
R1
C2H5OOC
H3C
COOCH3
R2
CH2OH
HOH2C
O
N
H
NH2
R1 = 2,4-diOCH3, R2 = Bn
A: Amlodipine
B: antitumour compound
O2N
CF3
t-BuOOC
H3C
COOMe
CH3
MeOOC
H3C
NO2
N
H
N
H
CH3
C:
D:
(R)-(+)-Bay K 8644
(S)-(-)-isomer of mebudipine
best-known (R)-(+)-Bay
K 8644 even showed an opposite
biological effect compared with its enantiomer (Fig. 1, D).3a
Chiral 1,4-dihydropyridines also act as important building blocks
in the synthesis of many natural products and alkaloids, and as
NADH models in asymmetric reductions.4
Figure 1. 4-Aryl-1,4-dihydropyridines and their derivatives with biological
activities.
Despite plenty of reports for the preparation of symmetrical or
racemic 1,4-dihydropyridines,5 methods to obtain chiral 1,4-dihy-
dropyridines were not enough. Compared with most reports for
chiral auxiliaries and resolutions,3,6 few examples of catalytic
⇑
Corresponding authors.
E-mail addresses: lyzheng@jlu.edu.cn (L. Zheng), suoqin@jlu.edu.cn (S. Zhang).
http://dx.doi.org/10.1016/j.tetasy.2015.06.019
0957-4166/Ó 2015 Elsevier Ltd. All rights reserved.

898
D. An et al. / Tetrahedron: Asymmetry 26 (2015) 897–906
enantioselective syntheses are currently available.7–11 Besides
chiral phosphoric acids catalytic enantioselective Hantzsch
reactions7 and YCl3 together with chiral silver phosphate catalytic
asymmetric aza-Diels–Alder reactions,8 enantioselective cycliza-
R
R
O
P
O
P
O
O
O
O
OH
OH
tion reactions of
a,b-unsaturated aldehydes, primary amines and
R
R
1,3-dicarbonyl compounds could effectively produce chiral 1,4-di-
hydropyridines. In 2008, Jørgensen et al. successfully used the
pyrrolidine catalyst in this reaction and obtained chiral 1,4-dihy-
dropyridines with moderate yields and high enantioselectivities.9
At the same time, chiral phosphoric acids were applied in this
reaction by Gong et al. and moderate to good yields and high
enantioselectivities were obtained.10 Not long after, chiral
thiourea–ammonium salts and pyrrolidine were used in cycliza-
1a
: R = 1-naphthyl
2a: R = 1-naphthyl
: R = 3,5-(CF3)2-phenyl
1b: R = phenyl
2b
1c: R = 3,5-(CF 3)2-phenyl
R
R
O
O
OH
P
O
O
3a: R = 1-naphthyl
: R = 2-naphthyl
P
N
3b
O
tion reactions of
a,b-unsaturated aldehydes and b-enamino
R
R
R
R
esters.11 These enantioselective cyclization reactions are limited
to
a,b-unsaturated aldehyde and only give 1,2,3,4-tetra-
substituted 1,4-dihydropyridines (Fig. 2).9–11
O
O
OH
4a: R = 1-naphthyl
4b: R = 2-naphthyl
O
O
P
N
P
O
4c
: R = phenyl
Previous work
CHO
O
R1
R
R
4
O
O
3
2
R3
∗
5
6
R2 NH2
Figure 3. BINOL- and H8-BINOL-based chiral phosphoric acids and imidodiphos-
+
+
R3
R4
R1
1
N
R2
phoric acids.
R4
enals
This work
O
Table 1
Screening of BINOL- and H8-BINOL-based chiral phosphoric acids and imidodiphos-
O
R1
phoric acidsa
R5
4
O
O
3
2
R3
∗
5
+
R2 NH2
+
NO2
R3
R4
R1
1
O
R4
N
6
R5
enones
O
R2
O
O
NH2
cat
(5 mol%)
Figure 2. Comparison of enals and enones in the cyclization reactions.
O
O
+
+
O
toluene
N
O
50 o
C
The substituents at the C-2 and C-6 positions of 1,4-dihydropy-
ridines make a crucial contribution to their conformation and are
very important for their biological activities.1a,c Enones could
O
O
NO2
introduce
1,2,3,4,6-penta-substituted
a
substituent at C-6 position directly and afford
chiral 1,4-dihydropyridines.
6a
8aa
5a
7
Nevertheless, because of the sterically hindered effect and
electronic effect, the enone might exhibit relatively low activity
and difficult to stereocontrol by chiral catalysts. To the best of
our knowledge, enones have never been used in these
enantioselective cyclization reactions.
Chiral imidodiphosphoric acids have proven to be particularly
powerful in several enantioselective reactions since their first
report in 2012.12 In order to further expand upon the structural
diversity and application scope of this new type of catalysts, we
developed H8-BINOL derived chiral imidodi-phosphoric acids not
long ago.13 Herein, we report the first organocatalytic enantiose-
Entry
Catalyst
t (d)
Yieldb (%)
eec (%)
1
2
3
4
5
6
7
8
9
10
1a
1b
1c
2a
2b
3a
3b
4a
4b
4c
4
4
4
3
3
3
2
2
2
2
32
39
19
43
46
22
36
44
43
54
29
40
16
51
34
65
61
38
86
88
a
Reaction conditions: 5a (0.1 mmol, 1.0 equiv), 6a (0.12 mmol, 1.2 equiv), 7
(0.2 mmol, 2 equiv), catalyst (5 mol %), toluene (1 mL), 50 °C.
lective cyclization of b,c-unsaturated a-ketoesters, arylamines
and acetylacetone to obtain 1,2,3,4,6-five-substituted chiral 1,4-
dihydropyridines.
b
Isolated yield after flash chromatography.
Determined by HPLC analysis with Daicel ChiralPak AD-H column.
c
2. Results and discussion
comparison that the H8-BINOL scaffold might be more effective
for this reaction. The screening of BINOL-based imidodiphosphoric
acids 3a–b revealed low yields but enantioselectivities were
increased to 61–65% ee (Table 1, entries 6 and 7). Varying the
BINOL scaffold to H8-BINOL provided better yields and enantiose-
lectivities (Table 1, entries 8–10). Among the H8-BINOL-based imi-
dodiphosphoric acids, 4c with phenyl substituents was found to be
the best catalyst for the reaction, affording 54% yield and 88% ee
(Table 1, entry 10).
As shown in Figure 3, BINOL- and H8-BINOL-based chiral phos-
phoric acids and imidodiphosphoric acids were screened in the
cyclization of b,c-unsaturated a-ketoester 5a, m-methoxyaniline
6a and acetylacetone 7 (Table 1). The reaction was performed in
the presence of 5 mol % catalyst in toluene at 50 °C. The BINOL-
phosphoric acids 1a–c were tested and afforded low yields and
enantioselectivities (Table 1, entries 1–3). H8-BINOL phosphoric
2a–b gave slightly improved yields and enantioselectivities
(Table 1, entries 4 and 5); this could be inferred from the
Further screening of solvents showed that benzene afforded
approximately the same yield and enantioselectivity with a long

D. An et al. / Tetrahedron: Asymmetry 26 (2015) 897–906
899
Table 2
Table 3
Scope of ester groups of b,
Optimization of the reaction conditions with catalyst 4ca
c-unsaturated
a
-ketoesters and arylaminesa
NO2
NO2
R1
O
O
O
O
O
O
O
O
NH2
NH2
4c
(5 mol%)
O
O
O
O
4c
+
+
+
+
O
toluene
O
solvent
N
N
R1
50 oC, 48 h
R2
O
O
O
O
NO2
NO2
R2
6
7
8
5
6a
8aa
5a
7
Yieldb
(%)
eec
(%)
Entry
R1
R2
8
Yieldb (%)
eec (%)
Entry
Solvent
4c
(mol %)
T
(°C)
t
(d)
1
2
3
4
5
6
7
8
Methyl
Ethyl
Isopropyl
Benzyl
Isopropyl
Isopropyl
Isopropyl
Isopropyl
Isopropyl
Isopropyl
Isopropyl
3-OCH3
3-OCH3
3-OCH3
3-OCH3
3-Cl
4-Cl
3-Br
3-F
4-F
8aa
8ab
8ac
8ad
8ae
8af
8ag
8ah
8ai
54
61
54
51
53
52
54
58
53
55
58
88
85
90
89
91
89
88
94
87
83
75
1
2
3
4
5
6
7
8
Toluene
Benzene
Trimethyl-benzene
Cyclo-hexane
CH2Cl2
Isopropyl ester
Dioxane
THF
Ethanol
Toluene
Toluene
Toluene
5
5
5
5
5
5
5
5
5
5
5
5
2
8
50
50
50
50
50
50
50
50
50
25
40
60
50
50
2
3
2
3
2
3
2
4
4
7
4
1
3
2
54
53
48
49
28
43
50
—
88
87
80
82
77
88
71
—
9
10
11
3-CH3
4-CH3
8aj
8ak
9
—
—
10
11
12
13
14
24
46
55
38
47
90
89
83
83
86
a
Reaction conditions:
(0.2 mmol, 2 equiv), catalyst 4c (5 mol %), toluene (1 mL), 50 °C, 48 h.
5 (0.1 mmol, 1.0 equiv), 6 (0.12 mmol, 1.2 equiv), 7
Toluene
Toluene
b
Isolated yield after flash chromatography.
Determined by HPLC analysis with Daicel ChiralPak AD-H column.
c
a
Reaction conditions: 5a (0.1 mmol, 1.0 equiv), 6a (0.12 mmol, 1.2 equiv), 7
(0.2 mmol, 2 equiv), solvent (1 mL).
b
Isolated yield after flash chromatography.
Determined by HPLC analysis with Daicel ChiralPak AD-H column.
Table 4
Scope of b,
c
c
-unsaturated a
-ketoestersa
R1
R2
O
reaction time (Table 2, entry 2). The isopropyl ester also gave 88%
ee value but the yield decreased to 43% (Table 2, entry 6). We then
tested the temperature and catalyst loading. The best 90% ee was
achieved when performing the reaction at 25 °C, however the yield
and reaction rate decreased dramatically (Table 2, entry 10). In
addition, reducing the catalyst loading to 2 mol % led to a decrease
in both the yield and enantioselectivity, while increasing the cata-
lyst loading did not improve the catalytic performance (Table 2,
entries 13 and 14). Taking all these factors into consideration,
5 mol % 4c in toluene at 50 °C were selected as the reaction condi-
tions for further studies. It should be mentioned that high catalyst
loadings (from 10 to 20 mol %) were required in previous reports
for the enantioselective synthesis of 1,4-dihydropyridines.7–11
O
O
O
NH2
4c
(5 mol%)
O
O
+
+
O
toluene
N
R2
50 oC, 48 h
R3
O
R1
R3
5
7
6
8
Entry
R1
R2
R3
8
Yieldb (%)
eec (%)
1
2
3
4
5
6
7
8
4-NO2
4-NO2
4-Br
Benzyl
Benzyl
3-Cl
3-Br
3-Cl
3-Br
3-Cl
3-Cl
3-Br
3-Br
3-Cl
3-Cl
3-Cl
3-Br
3-Br
3-Br
3-Br
3-F
8ba
8bb
8bc
8bd
8be
8bf
8bg
8bh
8bi
54
56
54
58
41
56
51
55
53
55
55
54
55
48
43
34
46
52
94
94
92
91
93
95
94
91
91
95
93
94
92
90
94
97
96
96
Isopropyl
Isopropyl
Methyl
Isopropyl
Isopropyl
Ethyl
4-Br
3-Br
Under the optimized conditions, b,c-unsaturated a-ketoesters
with different ester groups were examined (Table 3, entries 1–4).
An enone with an ethyl ester group slightly decreased the enantios-
electivity, but afforded the best yield (61%; Table 3, entry 2).
Replacing the ester group with isopropyl and benzyl gave products
with higher enantioselectivities (89–90% ee; Table 3, entries 3 and
4). We next investigated arylamines with different substituents.
The meta- and para-substituted arylamines bearing either
electron-donating or electron-withdrawing groups smoothly
underwent the reaction with moderate yields and high enantiose-
lectivities. However ortho-substituted arylamines were found to
have very low reactivity and did not generate the products. The
meta-substituted arylamines afforded higher enantioselectivities
than the para-substituted arylamines. The p-nitroaniline and
1-naphthylamine were also tested, but the corresponding products
were not obtained.
4-CN
4-CN
4-F
9
4-CF3
Ethyl
10
11
12
13
14
15
16d
17d
18d
3,4-2-Cl
3,4-2-Cl
3,4-2-Cl
3,4-2-Cl
4-CH3
3-NO2
4-NO2
4-CN
3,4-2-Cl
Methyl
Isopropyl
Methyl
Ethyl
Isopropyl
Methyl
Benzyl
8bj
8bk
8bl
8bm
8bn
8bo
8bp
8bq
8br
Isopropyl
Methyl
3-Cl
3-Cl
a
Reaction conditions:
(0.2 mmol, 2 equiv), catalyst 4c (5 mol %), toluene (1 mL), 50 °C, 48 h.
5 (0.1 mmol, 1.0 equiv), 6 (0.12 mmol, 1.2 equiv), 7
b
Isolated yield after flash chromatography.
Determined by HPLC analysis with Daicel ChiralPak AD-H column.
The reaction was carried out at 40 °C for 4 d.
c
d
The scope of b,c-unsaturated a-ketoesters was subsequently
investigated. High enantioselectivities were achieved when enones
with electron-withdrawing groups on the aromatic ring were used
in the reaction. Notably, para-NO2 and para-CN substituted enones
formed 1,4-dihydropyridines with excellent enantioselectivities
(94–95% ee; Table 4, entries 1, 2, 6 and 7). Enones with meta-

900
D. An et al. / Tetrahedron: Asymmetry 26 (2015) 897–906
substituents were also tested, giving slightly lower yields with
high enantioselectivities (Table 4, entries 5 and 15). However the
reaction of enones with ortho-substituents progressed very slowly
and hardly generated the products. The reaction of 3,4-2-Cl substi-
tuted enones with different ester groups gave 1,4-dihydropyridines
with 92–95% ee (Table 4, entries 10–13). We also examined enones
with electron-rich substituents, obtaining 48% yield and 90% ee
(Table 4, entry 14). The enantioselectivities could be further
improved (96–97% ee) upon when the reaction temperature
was decreased to 40 °C, but with a slight reduction in the yield
Chiral multisubstituted 1,4-dihydropyridines can be trans-
formed into chiral piperidines and tetrahydropyridines, which
are important components of some drugs and natural products.4a,c
For example, a single-step reduction of the cyclization product 8ba
produced chiral multisubstituted piperidine 11 in 87% yield and
with 95% ee in the presence of NaBH4 and acetic acid (Scheme 1).
The absolute configuration of 11 was established by X-ray
crystallography. Accordingly, the stereogenic center at the C-4
position in 8ba was not affected by the reduction, thus 8ba was
determined to have an (R)-configuration.
(Table 4, entries 16–18). The reaction of
was also tested, but it did not occur under the same conditions.
In the cyclization reaction of b, -unsaturated -ketoester 5a,
a,b-unsaturated ketone
NO2
c
a
NO2
m-methoxyaniline 6a and acetylacetone 7 (Table 2, entry 1), two
by-products, 3-arylaminopyrroline-2-one 9 with 29% yield and 2-
arylquinoline-4-carboxylate 10 with 11% yield, were observed
(Fig. 4). Compound 9 might be produced through aza-Michael
NaBH4
O
O
AcOH
CH2Cl2, r.t.
addition of arylamine 6a and b,c-unsaturated
a-iminoester, which
O
O
N
was formed by b, -unsaturated
c
a-ketoester 5a and another ary-
N
O
lamine. The intramolecular cyclization of the intermediate gave
O
CH2Ph
CH2Ph
compound 9.14 The formation of compound 10 was via Michael
Cl
addition and intramolecular cyclization of b,c-unsaturated
Cl
a-ketoester 5a and arylamine 6a. The generation of these by-prod-
8ba
11
ucts is a reason for the moderate yields of 1,4-dihydropyridines.
Scheme 1. Reduction of product 8ba and the absolute configuration of 11.
A plausible mechanism for the cyclization reaction of b,
urated -ketoester, arylamine and acetylacetone is shown in
Scheme 2. At the beginning, dehydration condensation of b, -un-
saturated -ketoester and arylamine produces b, -unsaturated
-iminoester. The anti-isomer of the iminoester is activated by
c-unsat-
H
N
O
O
a
c
O
O
O
a
c
N
NO2
a
O
N
forming
a
hydrogen bond with imidodiphosphoric acid.
NO2
Meanwhile, the enol form of acetylacetone interacts with imi-
dodiphosphoric acid by forming another hydrogen bond with
P@O bond to give transition state I. The Michael addition then
takes place to form intermediate II. Subsequently, the amino group
attacked the activated C@O bond of acetylacetone to give cycliza-
tion intermediate III. Finally, chiral 1,4-dihydropyridines are
generated via dehydration of intermediate III.
9
10
Figure 4. By-products of the cyclization reaction.
R3
R
R
R
R
R2
O
O
O
O
O
N
P
P
R2
R3
O
O
O
NH2
O
O
O
N
O
O
cat
H
-H2O
O
H
O
+
+
O
N
R3
R2
R1
O
R1
R1
I
R1
R1
R
R
R
R
O
O
O
O
N
O
P
P
O
O
O
O
∗
H
∗
-H2O
-cat
O
O
R2
O
N
HO
N
R2
O
NH
O
R1
R3
O
R3
R2
R3
O
III
II
Scheme 2. A plausible mechanism for the cyclization reaction in the presence of imidodiphosphoric acids.

D. An et al. / Tetrahedron: Asymmetry 26 (2015) 897–906
901
O
O
O
O
PPh3
NH2
N
N3
O
N
O2N
(i) NaNO2, HCl
C2H5OH, NaN3
(ii) PPh3
5b
THF, reflux
(iii) THF, reflux
O
O
O
O
O2N
syn : anti = 29:71
12
13
6a
14
Scheme 3. Synthesis of b,
c
-unsaturated a-iminoester 12.
Next, b,
c
-unsaturated
a
-iminoester 12 was synthesized to confirm
acids. By using enones, 1,4-dihydropyridines substituted at the C-
6 position were obtained with excellent enantioselectivities. The
reduction of these products then gave the chiral multisubstituted
piperidine in a single-step reaction. Further applications of the
H8-BINOL type chiral imidodiphosphoric acids are currently in
progress in our laboratory.
the plausible mechanism (Scheme 3). The 1-azido-3-methoxybenzene
13 could be easily achieved by azidation of 3- methoxyaniline 6a.15 The
arylazides 13 then interacted with triphenylphosphine to give N-aryl
triphenylphoshazenes 14. Subsequently, Wittig-type condensation of
N-aryl triphenyl-phoshazenes 14 with b,
c-unsaturated
a-ketoester
5b afforded the b,c-unsaturated a-iminoester 12 as an syn/anti mixture
(29:71).16
4. Experimental
On the basis of the plausible mechanism, b,
-iminoester 12 was used in the cyclization reaction with acety-
lacetone 7 (Scheme 4). Initially, under a nitrogen atmosphere,
0.1 mmol b, -unsaturated -iminoester 12 and 5 mol % catalyst
c-unsaturated
a
4.1. General methods
c
a
All reagents were used without purification. All solvents were
purified and dried according to standard methods. The reaction
products were purified by flash column chromatography on
200–300 mesh silica gel. The melting point was recorded on a
melting point apparatus (MPA100, Stanford Research Systems,
Inc.). Optical rotations were measured with a Jasco-P-2000 digital
polarimeter at 25 °C and concentrations (c) are given in
4c were dissolved in 1 mL of toluene and stirred at 25 °C for
10 min, after which 0.2 mmol acetylacetone was added, and the
reaction mixture was stirred at 50 °C. After 12 h, product 8ab
was obtained with 41% yield and 89% ee. We also tried to recover
the iminoester 12 after the reaction was carried out for 8 h and
found that the recovered iminoester was mainly the syn-isomer,
while the anti-isomer had almost disappeared. The syn-isomer
was independently used in the reaction, but this did not give
product 8ab, which is another reason for the moderate yields of
1,4-dihydropyridines. These results strongly support the existence
g  (100 mL)À1
.
1H and 13C NMR spectra were recorded with
Bruker 400 MHz spectrometers (400 MHz for 1H NMR, 101 MHz
for 13C NMR) and Bruker 300 MHz spectrometers (300 MHz for
1H NMR, 75 MHz for 13C NMR); chemical shifts (d) are given in
ppm. High-resolution mass spectrometry analysis (HRMS) data
were measured on a Bruker ApexII mass spectrometer by means
of the ESI technique. Analytical HPLC was recorded on a HPLC
machine equipped with Agilent 1100 series or Ichrom 5100 series
quaternary pump with a UV diode array detector. Enantiomeric
excess values were measured by analytical HPLC with Daicel
ChiralPak AD-H or Daicel Chiralcel OD-H column.
of b,c-unsaturated a-iminoester intermediate in the three-compo-
nent cyclization reaction and the formation of the iminoester
intermediate is most probably the rate-determining step. This also
indicated that the anti-isomer of b,c-unsaturated a-iminoester 12
was more suitable for generating 1,4-dihydropyridines.
NO2
O
4.2. Synthesis of catalyst 4c
O
Catalyst 4c was prepared according to our previous work.13 NaH
(80% in oil, 2 mmol) was added to a stirred solution of H8-BINOL-
type phosphoryl chloride (1.3 mmol) in dry DMF (10 ml) under a
nitrogen atmosphere at room temperature. After stirring for
5 min, H8-BINOL-type phosphoramide (1 mmol) was added and
the mixture was stirred for another 1 h. After the reaction was
completed, 30 ml of CH2Cl2 was added to the flask and the mixture
was washed with saturated brine (50 ml  5). The organic layer
was dried over Na2SO4 and concentrated under reduced pressure.
The crude product was purified with silica gel column chromatog-
raphy. The product was dissolved in CH2Cl2, acidified with 4 M HCl
(10 ml), washed with brine (20 ml  2), dried over Na2SO4 and
concentrated in vacuo to give catalyst 4c.
O
N
O
O
O
4c
+
O
toluene
N
50 oC, 12 h
O
O
NO2
8ab
12
7
41% yield
89% ee
Scheme 4. Cyclization reaction of b,
c
-unsaturated a-iminoester 12 and acetylace-
tone 7.
3. Conclusions
4.2.1. H8-BINOL-type chiral imidodiphosphoric acid catalyst 4c
White solid; 82% yield; mp 343–345 °C; [
a]
20 = À334.8 (c 1,
D
In conclusion, the enantioselective cyclization of b,
c-unsatu-
CHCl3); 1H NMR (300 MHz, CDCl3) d 7.37–7.35 (m, 4H), 7.29–
7.24 (m, 5H), 7.22–7.19 (m, 2H), 7.16 (s, 2H), 7.05–6.98 (m, 11H),
3.00–2.97 (m, 4H), 2.87–2.65 (m, 8H), 2.57–2.51 (m, 2H), 2.38–
2.33 (m, 2H), 2.00–1.97 (m, 4H), 1.91–1.78 (m, 10H), 1.67–1.60
(m, 2H); 13C NMR (75 MHz, CDCl3) d 143.8, 143.3, 137.2, 136.6,
134.4, 134.3, 132.2, 131.5, 130.6, 130.4, 129.6, 128.2, 127.7,
rated -ketoesters, arylamines and acetylacetone enabled the
a
highly enantioselective synthesis of penta-substituted chiral 4-
aryl-1,4-dihydropyridines. In these enone-type reactions, H8-
BINOL type chiral imidodiphosphoric acids showed high catalytic
and stereocontrolling abilities in comparison to chiral phosphoric

902
D. An et al. / Tetrahedron: Asymmetry 26 (2015) 897–906
127.3, 126.8, 126.7, 29.5, 29.2, 27.9, 22.9, 22.8, 22.7, 22.6; 31P NMR
(162 MHz, DMSO-d6) d 7.66; HRMS (ESI) m/z calcd for C64H58NO6P2
([M+H]+): 998.3734, found: 998.3725.
(minor) = 32.33 min, t (major) = 34.95 min]; [a]
25 = +179.8 (c
D
0.502, EtOAc). 1H NMR (400 MHz, DMSO) d 8.26 (d, J = 8.4 Hz,
2H), 7.60 (d, J = 8.8 Hz, 2H), 7.32–7.28 (m, 4H), 7.09–7.07 (m,
2H), 6.96 (dd, J = 2.4, 8.4 Hz, 1H), 6.76–6.74 (m, 2H), 6.11 (d,
J = 6.8 Hz, 1H), 4.89 (s, 2H), 4.88 (d, J = 6.8 Hz, 1H), 3.70 (s, 3H),
2.14 (s, 3H), 2.11 (s, 3H). 13C NMR (101 MHz, DMSO) d 198.18,
162.87, 159.88, 153.43, 149.85, 146.78, 142.25, 135.68, 133.52,
130.22, 128.82, 128.79, 128.63, 128.49, 124.72, 121.68, 117.92,
115.91, 114.31, 110.62, 66.90, 55.72, 39.67, 30.72, 19.26.
HRMS(ESI) m/z calcd for C29H27N2O6 ([M+H]+): 499.1864, found:
499.1865.
4.3. General procedure for the enantioselective three-
component cyclization reaction
A solution of b,c-unsaturated a-ketoester (0.1 mmol), ary-
lamine (0.12 mmol), and catalyst 4c (5 mol %, 0.005 mmol) in
toluene (1 mL) was stirred at 25 °C for 10 min, then acetylacetone
(0.2 mmol) was added. The reaction mixture was stirred at 50 °C
for 48 h (reaction progress monitored by TLC). Next, EtOAc and sil-
ica gel were added and, after removal of the solvent, the residue
was purified by flash column chromatography on silica gel (ethyl
acetate/petroleum ether, 1:5 to 1:2) to afford the pure products.
4.3.5. (R)-Isopropyl-5-acetyl-1-(3-chlorophenyl)-6-methyl-4-(4-
nitrophenyl)-1,4-dihydropyridine-2-carboxylate 8ae
Colorless oil, 53% yield, 91% ee [Daicel Chiralcel AD-H column,
n-hexane/i-PrOH = 70:30, 1.0 ml/min, k = 254 nm,
t
(min-
4.3.1. (R)-Methyl-5-acetyl-1-(3-methoxyphenyl)-6-methyl-4-(4-
nitrophenyl)-1,4-dihydropyridine-2-carboxylate 8aa
or) = 7.27 min, (major) = 11.03 min];
t
[a]
D
25 = +226.7 (c 0.486,
EtOAc). 1H NMR (400 MHz, CDCl3) d 8.25 (d, J = 8.8 Hz, 2H), 7.49
(d, J = 8.4 Hz, 2H), 7.38–7.32 (m, 2H), 7.22 (t, J = 2.0 Hz, 1H), 7.07
(dt, J = 1.6, 7.2 Hz, 1H), 6.05 (d, J = 6.4 Hz, 1H), 4.84 (d, J = 6.8 Hz,
1H), 4.83–4.77 (m, 1H), 2.16 (s, 3H), 2.15 (s, 3H), 1.03 (d,
J = 6.0 Hz, 3H), 0.94 (d, J = 6.4 Hz, 3H). 13C NMR (101 MHz, CDCl3)
d 198.68, 162.29, 152.27, 148.81, 146.93, 142.60, 134.46, 133.78,
130.14, 129.86, 128.49, 128.12, 127.70, 124.37, 117.25, 111.27,
69.34, 40.48, 30.33, 21.31, 21.14, 19.26. HRMS(ESI) m/z calcd for
Colorless oil, 54% yield, 88% ee [Daicel Chiralcel AD-H column,
n-hexane/i-PrOH = 70:30, 1.0 ml/min, k = 254 nm,
t
(min-
or) = 16.05 min, t (major) = 19.88 min]; [
a
]
D
20 = +143.4 (c 0.456,
EtOAc). 1H NMR (400 MHz, CDCl3) d 8.23 (d, J = 8.4 Hz, 2H), 7.50
(d, J = 8.8 Hz, 2H), 7.28 (t, J = 8.4 Hz, 1H), 6.89 (dd, J = 2.4, 8.4 Hz,
1H), 6.77 (dd, J = 1.2, 8.0 Hz, 1H), 6.70 (t, J = 2.4 Hz, 1H), 6.07 (d,
J = 6.8 Hz, 1H), 4.84 (d, J = 6.4 Hz, 1H), 3.79 (s, 3H), 3.50 (s, 3H),
2.18 (s, 3H), 2.17 (s, 3H). 13C NMR (75 MHz, CDCl3) d 198.38,
163.17, 159.89, 152.57, 150.04, 146.82, 142.07, 133.50, 129.48,
128.07, 124.25, 121.74, 117.14, 115.56, 113.61, 110.73, 55.37,
52.11, 40.18, 30.42, 19.34. HRMS(ESI) m/z calcd for C23H23N2O6
([M+H]+): 423.1551, found: 423.1544.
C
24H24ClN2O5 ([M+H]+): 455.1368, found: 455.1360.
4.3.6. (R)-Isopropyl-5-acetyl-1-(4-chlorophenyl)-6-methyl-4-(4-
nitrophenyl)-1,4-dihydropyridine-2-carboxylate 8af
Colorless oil, 52% yield, 89% ee [Daicel Chiralcel AD-H column,
n-hexane/i-PrOH = 80:20, 1.0 ml/min, k = 254 nm,
t
(min-
4.3.2. (R)-Ethyl-5-acetyl-1-(3-methoxyphenyl)-6-methyl-4-(4-ni-
trophenyl)-1,4-dihydropyridine-2-carboxylate 8ab
or) = 14.95 min, t (major) = 22.19 min]; [
a]
D
25 = +226.5 (c 0.476,
EtOAc). 1H NMR (400 MHz, CDCl3) d 8.24 (d, J = 8.8 Hz, 2H), 7.48
(d, J = 8.4 Hz, 2H), 7.36 (d, J = 8.8 Hz, 2H), 7.12 (d, J = 8.8 Hz, 2H),
6.05 (d, J = 6.4 Hz, 1H), 4.83 (d, J = 6.4 Hz, 1H), 4.81–4.75 (m, 1H),
2.15 (s, 6H), 1.03 (d, J = 6.4 Hz, 3H), 0.97 (d, J = 6.4 Hz, 3H). 13C
NMR (101 MHz, CDCl3) d 198.57, 162.27, 152.32, 149.23, 146.90,
139.86, 134.12, 133.80, 130.84, 129.11, 128.08, 124.35, 117.19,
111.05, 69.34, 40.39, 30.31, 21.33, 21.19, 19.25. HRMS(ESI) m/z
calcd for C24H24ClN2O5 ([M+H]+): 455.1368, found: 455.1363.
Colorless oil, 61% yield, 85% ee [Daicel Chiralcel AD-H column, n-
hexane/i-PrOH = 70:30, 1.0 ml/min, k = 254 nm, t (minor) = 13.75
min, t (major) = 20.48 min]; [a]
25 = +145.2 (c 0.566, EtOAc). 1H
D
NMR (300 MHz, CDCl3) d 8.23 (d, J = 8.7 Hz, 2H), 7.50 (d, J = 9.0 Hz,
2H), 7.28 (t, J = 7.8 Hz, 1H), 6.89 (dd, J = 2.4, 8.4 Hz, 1H), 6.78 (dd,
J = 2.1, 7.5 Hz, 1H), 6.71 (t, J = 2.1 Hz, 1H), 6.04 (d, J = 6.6 Hz, 1H),
4.84 (d, J = 6.6 Hz, 1H), 3.96–3.79 (m, 2H), 3.79 (s, 3H), 2.19 (s, 3H),
2.17 (s, 3H), 1.01 (t, J = 7.2 Hz, 3H). 13C NMR (101 MHz, CDCl3) d
198.47, 162.93, 159.92, 152.66, 149.83, 146.85, 142.23, 133.89,
129.49, 128.12, 124.26, 121.72, 116.69, 115.61, 113.60, 110.77,
61.28, 55.39, 40.32, 30.39, 19.35, 13.69. HRMS(ESI) m/z calcd for
4.3.7. (R)-Isopropyl-5-acetyl-1-(3-bromophenyl)-6-methyl-4-(4-
nitrophenyl)-1,4-dihydropyridine-2-carboxylate 8ag
Colorless oil, 54% yield, 88% ee [Daicel Chiralcel AD-H column,
C
24H25N2O6 ([M+H]+): 437.1707, found: 437.1707.
n-hexane/i-PrOH = 80:20, 1.0 ml/min, k = 254 nm,
t
(min-
or) = 10.97 min, t (major) = 18.21 min]; [
a
]
D
25 = +240.6 (c 0.271,
4.3.3. (R)-Isopropyl-5-acetyl-1-(3-methoxyphenyl)-6-methyl-4-
(4-nitrophenyl)-1,4-dihydropyridine-2-carboxylate 8ac
Colorless oil, 54% yield, 90% ee [Daicel Chiralcel AD-H column,
EtOAc). 1H NMR (400 MHz, CDCl3) d 8.25 (d, J = 8.8 Hz, 2H), 7.51–
7.47 (m, 3H), 7.37 (t, J = 1.6 Hz, 1H), 7.28–7.24 (m, 1H), 7.13–7.11
(m, 1H), 6.05 (d, J = 6.4 Hz, 1H), 4.84 (d, J = 6.4 Hz, 1H), 4.81–4.73
(m, 1H), 2.16 (s, 3H), 2.15 (s, 3H), 1.03 (d, J = 6.4 Hz, 3H), 0.94 (d,
J = 6.4 Hz, 3H). 13C NMR (101 MHz, CDCl3) d 198.67, 162.28,
152.26, 148.78, 146.92, 142.74, 133.79, 132.97, 131.38, 130.12,
128.20, 128.13, 124.36, 122.21, 117.25, 111.30, 69.35, 40.47,
30.32, 21.31, 21.15, 19.26. HRMS(ESI) m/z calcd for C24H24BrN2O5
([M+H]+): 499.0863, found: 499.0846.
n-hexane/i-PrOH = 70:30, 1.0 ml/min, k = 254 nm,
t
(min-
or) = 9.45 min, (major) = 15.42 min];
t
[a]
D
25 = +238.0 (c 0.484,
EtOAc). 1H NMR (400 MHz, CDCl3) d 8.23 (d, J = 8.8 Hz, 2H), 7.50
(d, J = 8.8 Hz, 2H), 7.28 (t, J = 8.0 Hz, 1H), 6.88 (dd, J = 2.4, 8.4 Hz,
1H), 6.77 (dd, J = 1.2, 8.0 Hz, 1H), 6.71 (t, J = 2.0 Hz, 1H), 5.99 (d,
J = 6.8 Hz, 1H), 4.83 (d, J = 6.4 Hz, 1H), 4.79–4.73 (m, 1H), 3.79 (s,
3H), 2.20 (s, 3H), 2.16 (s, 3H), 1.01 (d, J = 6.4 Hz, 3H), 0.92 (d,
J = 6.4 Hz, 3H). 13C NMR (101 MHz, CDCl3) d 198.52, 162.62,
159.92, 152.72, 149.69, 146.83, 142.33, 134.21, 129.49, 128.13,
124.26, 121.66, 116.37, 115.61, 113.57, 110.75, 69.10, 55.40,
40.41, 30.37, 21.29, 21.10, 19.37. HRMS(ESI) m/z calcd for
4.3.8. (R)-Isopropyl-5-acetyl-1-(3-fluorophenyl)-6-methyl-4-(4-
nitrophenyl)-1,4-dihydropyridine-2-carboxylate 8ah
Colorless oil, 58% yield, 94% ee [Daicel Chiralcel AD-H column,
n-hexane/i-PrOH = 80:20, 1.0 ml/min, k = 254 nm,
or) = 11.54 min, t (major) = 22.66 min]; [
t
(min-
a]
25 = +248.0 (c 0.508,
D
C
25H27N2O6 ([M+H]+): 451.1864, found: 451.1862.
EtOAc). 1H NMR (400 MHz, CDCl3) d 8.25 (d, J = 8.8 Hz, 2H), 7.49
(d, J = 8.8 Hz, 2H), 7.38–7.32 (m, 1H), 7.10–7.06 (m, 1H), 6.97–
6.95 (m, 2H), 6.05 (d, J = 6.4 Hz, 1H), 4.83 (d, J = 6.4 Hz, 1H),
4.81–4.73 (m, 1H), 2.18 (s, 3H), 2.15 (s, 3H), 1.02 (d, J = 6.4 Hz,
3H), 0.95 (d, J = 6.0 Hz, 3H). 13C NMR (101 MHz, CDCl3) d 198.67,
4.3.4. (R)-Benzyl-5-acetyl-1-(3-methoxyphenyl)-6-methyl-4-(4-
nitrophenyl)-1,4-dihydropyridine-2-carboxylate 8ad
Colorless oil, 51% yield, 89% ee [Daicel Chiralcel AD-H column,
n-hexane/i-PrOH = 70:30,
1.0 ml/min,
k = 254 nm,
t

D. An et al. / Tetrahedron: Asymmetry 26 (2015) 897–906
903
163.67, 162.31, 161.19, 152.30, 148.91, 146.90, 142.91, 133.80,
130.05, 128.10, 125.16, 124.35, 117.24, 115.31, 111.21, 69.28,
40.44, 30.34, 21.29, 21.13, 19.23. HRMS(ESI) m/z calcd for
4.3.13. (R)-Benzyl-5-acetyl-1-(3-bromophenyl)-6-methyl-4-(4-
nitrophenyl)-1,4-dihydropyridine-2-carboxylate 8bb
Colorless oil, 56% yield, 94% ee [Daicel Chiralcel AD-H column, n-
hexane/i-PrOH = 80:20, 1.0 ml/min, k = 254 nm, t (minor) = 25.74 -
C
24H24FN2O5 ([M+H]+): 439.1664, found: 439.1658.
min, t (major) = 31.56 min]; [a]
25 = +193.5 (c 0.307, EtOAc). 1H
D
4.3.9. (R)-Isopropyl-5-acetyl-1-(4-fluorophenyl)-6-methyl-4-(4-
nitrophenyl)-1,4-dihydropyridine-2-carboxylate 8ai
NMR (400 MHz, CDCl3) d 8.24 (d, J = 8.8 Hz, 2H), 7.47 (d, J = 8.4 Hz,
2H), 7.43 (d, J = 8.0 Hz, 1H), 7.32–7.30 (m, 4H), 7.17 (t, J = 8.0 Hz,
1H), 7.12–7.09 (m, 3H), 6.14 (d, J = 8.4 Hz, 1H), 4.97 (d, J = 12.0 Hz,
1H), 4.88 (d, J = 12.0 Hz, 1H), 4.83 (d, J = 6.8 Hz, 1H), 2.15 (s, 3H),
2.13 (s, 3H). 13C NMR (101 MHz, CDCl3) d 198.58, 162.44, 152.07,
148.97, 146.95, 142.41, 134.72, 133.22, 132.60, 131.51, 130.06,
128.57, 128.52, 128.45, 128.37, 128.12, 124.37, 122.29, 118.16,
111.40, 67.24, 40.38, 30.35, 19.25. HRMS(ESI) m/z calcd for
Colorless oil, 53% yield, 87% ee [Daicel Chiralcel AD-H column,
n-hexane/i-PrOH = 80:20, 1.0 ml/min, k = 254 nm,
t
(min-
or) = 12.97 min, t (major) = 22.22 min]; [
a
]
D
25 = +303.4 (c 0.470,
EtOAc). 1H NMR (400 MHz, CDCl3) d 8.24 (d, J = 8.4 Hz, 2H), 7.49
(d, J = 8.4 Hz, 2H), 7.18–7.15 (m, 2H), 7.09–7.05 (m, 2H), 6.03 (d,
J = 6.8 Hz, 1H), 4.83 (d, J = 6.4 Hz, 1H), 4.81–4.73 (m, 1H), 2.15 (s,
3H), 2.15 (s, 3H), 1.03 (d, J = 6.4 Hz, 3H), 0.97 (d, J = 6.0 Hz, 3H).
13C NMR (101 MHz, CDCl3) d 198.53, 163.19, 162.39, 160.71,
152.44, 149.58, 146.86, 137.13, 134.00, 131.36, 128.07, 124.34,
116.77, 115.94, 115.71, 110.90, 69.28, 40.34, 30.32, 21.33, 21.20,
19.24. HRMS(ESI) m/z calcd for C24H24FN2O5 ([M+H]+): 439.1664,
found: 439.1669.
C
28H24BrN2O5 ([M+H]+): 547.0863, found: 547.0838.
4.3.14. (R)-Isopropyl-5-acetyl-4-(4-bromophenyl)-1-(3-chloro-
phenyl)-6-methyl-1,4-dihydropyridine-2-carboxylate 8bc
Colorless oil, 54% yield, 92% ee [Daicel Chiralcel AD-H column,
n-hexane/i-PrOH = 90:10, 1.0 ml/min, k = 254 nm,
t
(min-
or) = 10.03 min, t (major) = 17.29 min]; [
a]
25 = +417.2 (c 0.494,
D
4.3.10. (R)-Isopropyl-5-acetyl-6-methyl-4-(3-nitrophenyl)-1-(m-
tolyl)-1,4-dihydropyridine-2-carboxylate 8aj
EtOAc). 1H NMR (400 MHz, CDCl3) d 7.51 (d, J = 8.4 Hz, 2H), 7.34–
7.28 (m, 2H), 7.22–7.18 (m, 3H), 7.08 (dt, J = 2.0, 6.8 Hz, 1H), 6.07
(d, J = 6.4 Hz, 1H), 4.81–4.72 (m, 1H), 4.66 (d, J = 6.4 Hz, 1H), 2.13
(s, 3H), 2.08 (s, 3H), 1.02 (d, J = 6.4 Hz, 3H), 0.94 (d, J = 6.4 Hz,
3H). 13C NMR (101 MHz, CDCl3) d 199.44, 162.47, 148.36, 144.12,
143.01, 134.32, 132.99, 132.17, 130.13, 129.73, 129.04, 128.25,
127.81, 120.95, 118.71, 111.34, 69.08, 40.27, 29.92, 21.32, 21.16,
Colorless oil, 55% yield, 83% ee [Daicel Chiralcel AD-H column,
n-hexane/i-PrOH = 80:20, 1.0 ml/min, k = 254 nm,
t
(min-
or) = 9.41 min, (major) = 14.22 min];
t
[a]
D
25 = +117.4 (c 0.301,
EtOAc). 1H NMR (400 MHz, CDCl3) d 8.16 (d, J = 8.4 Hz, 2H), 7.43
(d, J = 8.4 Hz, 2H), 7.23–7.13 (m, 1H), 7.07 (d, J = 7.1 Hz, 1H), 6.91
(s, 2H), 5.90 (d, J = 6.4 Hz, 1H), 4.76 (d, J = 6.4 Hz, 1H), 4.72–4.57
(m, 1H), 2.28 (s, 3H), 2.10 (s, 3H), 2.08 (s, 3H), 0.92 (d, J = 6.4 Hz,
3H), 0.88 (d, J = 6.4 Hz, 3H). 13C NMR (101 MHz, CDCl3) d 198.12,
162.39, 152.47, 149.61, 146.50, 140.82, 138.59, 133.99, 129.67,
128.60, 128.34, 127.82, 126.13, 123.94, 115.83, 110.18, 68.74,
40.12, 30.04, 29.34, 20.93, 20.72, 19.13. HRMS(ESI) m/z calcd for
19.00. HRMS(ESI) m/z calcd for
488.0623, found: 488.0636.
C
24H24BrClNO3 ([M+H]+):
4.3.15. (R)-Isopropyl-5-acetyl-1-(3-bromophenyl)-4-(4-bromo-
phenyl)-6-methyl-1,4-dihydropyridine-2-carboxylate 8bd
Colorless oil, 58% yield, 91% ee [Daicel Chiralcel AD-H column, n-
hexane/i-PrOH = 90:10, 1.0 ml/min, k = 254 nm, t (minor) = 10.13
C
25H27N2O5 ([M+H]+): 435.1914, found: 435.1921.
min, t (major) = 16.63 min]; [a]
25 = +160.9 (c 0.307, EtOAc). 1H
D
4.3.11. (R)-Isopropyl-5-acetyl-6-methyl-4-(3-nitrophenyl)-1-(p-
tolyl)-1,4-dihydropyridine-2-carboxylate 8ak
NMR (400 MHz, CDCl3) d 7.50 (d, J = 8.4 Hz, 2H), 7.49–7.46 (m, 1H),
7.37 (t, J = 1.6 Hz, 1H), 7.24–7.22 (m, 1H), 7.19 (d, J = 8.4 Hz, 2H),
7.14–7.12 (m, 1H), 6.06 (d, J = 6.4 Hz, 1H), 4.81–4.72 (m, 1H), 4.66
(d, J = 6.4 Hz, 1H), 2.12 (s, 3H), 2.08 (s, 3H), 1.02 (d, J = 6.0 Hz, 3H),
0.94 (d, J = 6.0 Hz, 3H). 13C NMR (101 MHz, CDCl3) d 199.45,
162.48, 148.21, 144.13, 143.17, 133.00, 132.97, 132.16, 131.13,
129.99, 129.05, 128.31, 122.09, 120.94, 118.67, 111.41, 69.09,
40.27, 29.94, 21.33, 21.17, 18.97. HRMS(ESI) m/z calcd for
Colorless oil, 58% yield, 75% ee [Daicel Chiralcel AD-H column,
n-hexane/i-PrOH = 80:20, 1.0 ml/min, k = 254 nm,
t
(min-
or) = 11.39 min, t (major) = 16.75 min]; [
a
]
D
25 = +102.2 (c 0.256,
EtOAc). 1H NMR (400 MHz, CDCl3) d 8.25 (d, J = 8.5 Hz, 2H), 7.52
(d, J = 8.5 Hz, 2H), 7.19 (d, J = 8.0 Hz, 2H), 7.07 (d, J = 8.0 Hz, 2H),
6.00 (d, J = 6.6 Hz, 1H), 4.84 (d, J = 6.6 Hz, 1H), 4.77 (dt, J = 12.3,
6.2 Hz, 1H), 2.39 (s, 3H), 2.19 (s, 3H), 2.18 (s, 3H), 1.02 (d,
J = 6.2 Hz, 3H), 0.94 (d, J = 6.2 Hz, 3H). 13C NMR (101 MHz, CDCl3)
d 198.39, 162.67, 152.81, 150.30, 146.84, 138.55, 138.25, 134.33,
129.51, 129.22, 128.14, 124.29, 116.27, 110.50, 69.13, 40.38,
30.40, 29.70, 21.33, 21.13, 19.43. HRMS(ESI) m/z calcd for
C
24H24Br2NO3 ([M+H]+): 532.0117, found: 532.0128.
4.3.16. (R)-Methyl-5-acetyl-4-(3-bromophenyl)-1-(3-chlorophe-
nyl)-6-methyl-1,4-dihydropyridine-2-carboxylate 8be
Colorless oil, 41% yield, 93% ee [Daicel Chiralcel AD-H column,
C
25H27N2O5 ([M+H]+): 435.1914, found: 435.1928.
n-hexane/i-PrOH = 90:10, 1.0 ml/min, k = 254 nm,
t
(min-
or) = 11.59 min, (major) = 17.78 min];
t
[a]
D
25 = +217 (c 0.203,
EtOAc). 1H NMR (400 MHz, CDCl3) d 7.45 (s, 1H), 7.40 (dt, J = 2.4,
6.8 Hz, 1H), 7.34–7.31 (m, 2H), 7.24–7.21 (m, 2H), 7.21 (s, 1H),
7.15–7.12 (m, 1H), 6.17 (d, J = 6.4 Hz, 1H), 4.68 (d, J = 6.4 Hz, 1H),
3.51 (s, 3H), 2.13 (s, 3H), 2.12 (s, 3H). 13C NMR (101 MHz, CDCl3)
d 199.12, 163.00, 147.20, 142.63, 134.40, 132.31, 130.69, 130.34,
130.25, 130.13, 129.88, 129.66, 128.48, 128.18, 125.86, 123.32,
119.55, 111.11, 52.12, 40.32, 30.09, 19.04. HRMS(ESI) m/z calcd
for C22H20BrClNO3 ([M+H]+): 460.0310, found: 460.0310.
4.3.12. (R)-Benzyl-5-acetyl-1-(3-chlorophenyl)-6-methyl-4-(4-
nitrophenyl)-1,4-dihydropyridine-2-carboxylate 8ba
Colorless oil, 54% yield, 94% ee [Daicel Chiralcel AD-H column,
n-hexane/i-PrOH = 90:10, 1.0 ml/min, k = 254 nm,
t
(min-
or) = 53.96 min, t (major) = 66.14 min]; [
a
]
D
25 = +189.2 (c 0.446,
EtOAc). 1H NMR (400 MHz, CDCl3) d 8.24 (d, J = 8.8 Hz, 2H), 7.47
(d, J = 8.8 Hz, 2H), 7.32–7.29 (m, 3H), 7.28–7.27 (m, 1H), 7.23 (t,
J = 8.0 Hz, 1H), 7.15 (t, J = 1.6 Hz, 1H), 7.13–7.10 (m, 2H), 7.05–
7.03 (m, 1H), 6.14 (d, J = 6.8 Hz, 1H), 4.64 (d, J = 12.0 Hz, 1H),
4.87 (d, J = 12.0 Hz, 1H), 4.83 (d, J = 6.4 Hz, 1H), 2.15 (s, 3H), 2.13
(s, 3H). 13C NMR (101 MHz, CDCl3) d 198.57, 162.44, 152.08,
148.97, 146.95, 142.27, 134.72, 134.50, 133.21, 129.81, 128.61,
128.55, 128.51, 128.45, 128.11, 127.82, 124.36, 118.13, 111.35,
67.23, 40.38, 30.34, 19.23. HRMS(ESI) m/z calcd for C28H24ClN2O5
([M+H]+): 503.1368, found: 503.1364.
4.3.17. (R)-Isopropyl-5-acetyl-1-(3-chlorophenyl)-4-(4-cyano-
phenyl)-6-methyl-1,4-dihydropyridine-2-carboxylate 8bf
Colorless oil, 56% yield, 95% ee [Daicel Chiralcel AD-H column,
n-hexane/i-PrOH = 80:20, 1.0 ml/min, k = 254 nm,
t
(min-
or) = 10.82 min, (major) = 17.16 min];
t
[a]
D
25 = +704 (c 0.486,

904
D. An et al. / Tetrahedron: Asymmetry 26 (2015) 897–906
EtOAc). 1H NMR (400 MHz, CDCl3) d 7.68 (d, J = 8.4 Hz, 2H), 7.43 (d,
J = 8.0 Hz, 2H), 7.36–7.31 (m, 2H), 7.20 (t, J = 1.6 Hz, 1H), 7.06 (dt,
J = 1.6, 7.2 Hz, 1H), 6.05 (d, J = 6.4 Hz, 1H), 4.81–4.74 (m, 2H),
2.15 (s, 3H), 2.13 (s, 3H), 1.03 (d, J = 6.4 Hz, 3H), 0.94 (d,
J = 6.4 Hz, 3H). 13C NMR (101 MHz, CDCl3) d 198.80, 162.31,
150.29, 148.72, 142.65, 134.40, 133.61, 132.90, 130.09, 129.81,
128.42, 128.08, 127.72, 118.74, 117.52, 111.15, 110.85, 69.28,
40.67, 30.24, 21.30, 21.12, 19.19. HRMS(ESI) m/z calcd for
198.83, 162.92, 148.95, 145.22, 142.46, 134.43, 133.15, 132.54,
131.11, 130.99, 129.87, 129.71, 129.19, 128.56, 128.07, 126.55,
118.78, 111.15, 52.16, 39.71, 30.23, 19.12. HRMS(ESI) m/z calcd
for C22H19Cl3NO3 ([M+H]+): 450.0425, found: 450.0418.
4.3.22. (R)-Isopropyl-5-acetyl-1-(3-chlorophenyl)-4-(3,4-dichlo-
rophenyl)-6-methyl-1,4-dihydropyridine-2-carboxylate 8bk
Colorless oil, 55% yield, 93% ee [Daicel Chiralcel AD-H column,
C
25H24ClN2O3 ([M+H]+): 435.1470, found: 435.1464.
n-hexane/i-PrOH = 90:10, 1.0 ml/min, k = 254 nm,
t
(min-
[a]
25 = +191.6 (c 0.262,
D
or) = 8.13 min, (major) = 11.54 min];
t
EtOAc). 1H NMR (400 MHz, CDCl3) d 7.45 (d, J = 8.0 Hz, 1H), 7.38
(d, J = 2.0 Hz, 1H), 7.35–7.29 (m, 2H), 7.23 (s, 1H), 7.15 (dd,
J = 2.0, 6.4 Hz, 1H), 7.09 (dt, J = 2.0, 6.8 Hz, 1H), 6.04 (d, J = 6.8 Hz,
1H), 4.82–4.73 (m, 1H), 4.67 (d, J = 6.4 Hz, 1H), 2.14 (s, 3H), 2.12
(s, 3H), 1.03 (d, J = 6.4 Hz, 3H), 0.95 (d, J = 6.4 Hz, 3H). 13C NMR
4.3.18. (R)-Isopropyl-5-acetyl-4-(4-cyanophenyl)-1-(3-fluoroph-
enyl)-6-methyl-1,4-dihydropyridine-2-carboxylate 8bg
Colorless oil, 51% yield, 94% ee [Daicel Chiralcel AD-H column,
n-hexane/i-PrOH = 80:20, 1.0 ml/min, k = 254 nm,
t
(min-
or) = 11.39 min, t (major) = 19.98 min]; [
a
]
D
25 = +249.9 (c 0.214,
EtOAc). 1H NMR (400 MHz, CDCl3) d 7.68 (d, J = 8.4 Hz, 2H), 7.43
(d, J = 8.0 Hz, 2H), 7.37–7.32 (m, 1H), 7.10–7.05 (m, 1H), 6.97–
6.93 (m, 2H), 6.04 (d, J = 6.8 Hz, 1H), 4.82–4.73 (m, 2H), 2.16 (s,
3H), 2.13 (s, 3H), 1.02 (d, J = 6.0 Hz, 3H), 0.94 (d, J = 6.0 Hz, 3H).
13C NMR (101 MHz, CDCl3) d 198.81, 162.35, 150.34, 148.80,
142.98, 133.66, 132.90, 130.00, 128.07, 125.14, 118.74, 117.46,
117.22, 115.46, 115.25, 111.12, 110.83, 69.24, 40.66, 30.25, 21.29,
21.12, 19.16. HRMS(ESI) m/z calcd for C25H24FN2O3 ([M+H]+):
419.1765, found: 419.1767.
(101 MHz, CDCl3)
d 198.97, 162.36, 148.63, 145.37, 142.77,
134.40, 133.33, 133.12, 131.06, 130.98, 130.16, 129.79, 129.27,
128.37, 127.78, 126.63, 118.02, 111.19, 69.22, 39.91, 30.17, 21.33,
21.16, 19.11. HRMS(ESI) m/z calcd for C24H23Cl3NO3 ([M+H]+):
478.0738, found: 478.0747.
4.3.23. (R)-Methyl-5-acetyl-1-(3-bromophenyl)-4-(3,4-dichloro-
phenyl)-6-methyl-1,4-dihydropyridine-2-carboxylate 8bl
Colorless oil, 54% yield, 94% ee [Daicel Chiralcel AD-H column,
n-hexane/i-PrOH = 80:20, 1.0 ml/min, k = 254 nm,
t
(min-
or) = 8.01 min, (major) = 10.94 min];
t
[a]
D
25 = +201.5 (c 0.271,
4.3.19. (R)-Ethyl-5-acetyl-1-(3-bromophenyl)-4-(4-fluorophen-
yl)-6-methyl-1,4-dihydropyridine-2-carboxylate 8bh
EtOAc). 1H NMR (400 MHz, DMSO) d 7.66 (d, J = 8.4 Hz, 1H), 7.59
(d, J = 8.0 Hz, 1H), 7.55 (d, J = 1.6 Hz, 1H), 7.42 (s, 1H), 7.39 (t,
J = 8.0 Hz, 1H), 7.30 (dd, J = 1.6, 8.0 Hz, 1H), 7.21 (d, J = 8.0 Hz,
1H), 6.17 (d, J = 6.8 Hz, 1H), 4.77 (d, J = 6.8 Hz, 1H), 3.43 (s, 3H),
2.10 (s, 3H), 2.08 (s, 3H). 13C NMR (101 MHz, DMSO) d 198.60,
163.07, 148.91, 146.81, 142.92, 132.85, 132.61, 131.94, 131.72,
131.66, 131.26, 129.87, 129.48, 129.00, 127.93, 121.68, 119.16,
111.10, 52.60, 38.89, 30.62, 19.07. HRMS(ESI) m/z calcd for
Colorless oil, 55% yield, 91% ee [Daicel Chiralcel AD-H column,
n-hexane/i-PrOH = 80:20, 1.0 ml/min, k = 254 nm,
t
(min-
or) = 7.98 min, (major) = 14.21 min];
t
[a]
D
25 = +213.1 (c 0.502,
EtOAc). 1H NMR (400 MHz, CDCl3) d 7.47 (d, J = 8.0 Hz, 1H), 7.36
(t, J = 2.0 Hz, 1H), 7.29–7.23 (m, 3H), 7.16 (d, J = 8.0 Hz, 1H), 7.07
(t, J = 8.4 Hz, 2H), 6.13 (d, J = 6.4 Hz, 1H), 4.69 (d, J = 6.4 Hz, 1H),
4.00–3.86 (m, 2H), 2.11 (s, 3H), 2.09 (s, 3H), 1.05 (t, J = 6.8 Hz,
3H). 13C NMR (101 MHz, CDCl3) d 199.65, 162.89, 160.64, 148.04,
143.14, 140.89, 132.83, 132.44, 131.18, 129.92, 128.87, 128.79,
128.51, 122.09, 119.44, 116.01, 115.80, 111.79, 61.23, 40.00,
C
22H19BrCl2NO3 ([M+H]+): 493.9920, found: 493.9920.
4.3.24. (R)-Ethyl-5-acetyl-1-(3-bromophenyl)-4-(3,4-dichloro-
phenyl)-6-methyl-1,4-dihydropyridine-2-carboxylate 8bm
Colorless oil, 55% yield, 92% ee [Daicel Chiralcel AD-H column,
29.89, 18.93, 13.73. HRMS(ESI) m/z calcd for
C23H22BrFNO3
([M+H]+): 458.0762, found: 458.0767.
n-hexane/i-PrOH = 90:10, 1.0 ml/min, k = 254 nm,
t
(min-
or) = 10.06 min, t (major) = 16.03 min]; [a]
25 = +179.5 (c 0.507,
D
EtOAc). 1H NMR (400 MHz, CDCl3) d 7.49 (d, J = 8.0 Hz, 1H), 7.45
(d, J = 8.0 Hz, 1H), 7.38 (d, J = 8.8 Hz, 2H), 7.28–7.24 (m, 1H), 7.15
(d, J = 8.0 Hz, 2H), 6.09 (d, J = 6.4 Hz, 1H), 4.68 (d, J = 6.8 Hz, 1H),
4.01–3.88 (m, 2H), 2.13 (s, 6H), 1.05 (t, J = 7.2 Hz, 3H). 13C NMR
4.3.20. (R)-Ethyl-5-acetyl-1-(3-chlorophenyl)-6-methyl-4-(4-
(trifluoromethyl)phenyl)-1,4-dihydropyridine-2-carboxylate 8bi
Colorless oil, 53% yield, 91% ee [Daicel Chiralcel AD-H column,
n-hexane/i-PrOH = 90:10, 1.0 ml/min, k = 254 nm,
t
(min-
25 = +205.7 (c 0.244,
(101 MHz, CDCl3)
d 198.88, 162.66, 148.73, 145.29, 142.76,
or) = 8.80 min, (major) = 15.17 min];
t
[a]
D
EtOAc). 1H NMR (400 MHz, CDCl3) d 7.64 (d, J = 8.0 Hz, 2H), 7.44
(d, J = 8.4 Hz, 2H), 7.35–7.29 (m, 2H), 7.21 (s, 1H), 7.10 (dt, J = 2.0,
6.8 Hz, 1H), 6.12 (d, J = 6.4 Hz, 1H), 4.79 (d, J = 6.4 Hz, 1H), 4.00–
3.87 (m, 2H), 2.14 (s, 3H), 2.11 (s, 3H), 1.03 (t, J = 6.8 Hz, 3H). 13C
NMR (101 MHz, CDCl3) d 199.13, 162.75, 148.97, 148.59, 142.77,
134.39, 132.97, 130.05, 129.74, 128.43, 127.94, 127.66, 126.10,
126.06, 118.51, 111.32, 61.33, 40.56, 30.12, 19.06, 13.72.
133.14, 132.96, 132.84, 131.36, 131.10, 130.98, 130.00, 129.24,
128.46, 126.61, 122.17, 118.36, 111.25, 61.37, 39.83, 30.20, 19.13,
13.74. HRMS(ESI) m/z calcd for
C
23H21BrCl2NO3 ([M+H]+):
508.0076, found: 508.0076.
4.3.25. (R)-Isopropyl-5-acetyl-1-(3-bromophenyl)-6-methyl-4-
(p-tolyl)-1,4-dihydropyridine-2-carboxylate 8bn
HRMS(ESI) m/z calcd for
found: 464.1254.
C
24H22ClF3NO3 ([M+H]+): 464.1235,
Colorless oil, 48% yield, 90% ee [Daicel Chiralcel AD-H column,
n-hexane/i-PrOH = 90:10, 1.0 ml/min, k = 254 nm,
t
(min-
or) = 8.53 min, (major) = 12.93 min];
t
[a]
D
25 = +195.6 (c 0.226,
EtOAc). 1H NMR (400 MHz, CDCl3) d 7.45 (d, J = 8.0 Hz, 1H), 7.38
(t, J = 1.6 Hz, 1H), 7.25–7.16 (m, 6H), 6.12 (d, J = 6.4 Hz, 1H),
4.80–4.71 (m, 1H), 4.64 (d, J = 6.4 Hz, 1H), 2.35 (s, 3H), 2.12 (s,
3H), 2.05 (s, 3H), 1.01 (d, J = 6.4 Hz, 3H), 0.93 (d, J = 6.4 Hz, 3H).
13C NMR (101 MHz, CDCl3) d 200.04, 162.65, 147.76, 143.55,
142.18, 136.72, 133.00, 132.50, 130.92, 129.87, 129.79, 128.48,
127.28, 122.01, 119.91, 111.78, 68.86, 40.57, 29.82, 21.35, 21.20,
21.04, 18.81. HRMS(ESI) m/z calcd for C25H27BrNO3 ([M+H]+):
468.1169, found: 468.1175.
4.3.21. (R)-Methyl-5-acetyl-1-(3-chlorophenyl)-4-(3,4-dichloro-
phenyl)-6-methyl-1,4-dihydropyridine-2-carboxylate 8bj
Colorless oil, 55% yield, 95% ee [Daicel Chiralcel AD-H column,
n-hexane/i-PrOH = 80:20, 1.0 ml/min, k = 254 nm,
t
(min-
t (major) = 11.01 min]; [a]
25 = +240.0 (c 0.490,
D
or) = 7.78 min,
EtOAc). 1H NMR (400 MHz, DMSO) d 7.66 (d, J = 8.4 Hz, 1H), 7.55
(d, J = 2.0 Hz, 1H), 7.47–7.42 (m, 2H), 7.32–7.28 (m, 2H), 7.16–
7.13 (m, 1H), 6.16 (d, J = 6.8 Hz, 1H), 4.77 (d, J = 6.8 Hz, 1H), 3.42
(s, 3H), 2.09 (s, 3H), 2.08 (s, 3H). 13C NMR (101 MHz, CDCl3) d

D. An et al. / Tetrahedron: Asymmetry 26 (2015) 897–906
905
4.3.26. (R)-Methyl-5-acetyl-1-(3-bromophenyl)-6-methyl-4-(3-
nitrophenyl)-1,4-dihydropyridine-2-carboxylate 8bo
4.4.1. (2S,4S,5S,6S)-Benzyl-5-acetyl-1-(3-chlorophenyl)-6-meth-
yl-4-(4-nitrophenyl)piperidine-2-carboxylate 11
Colorless oil, 43% yield, 94% ee [Daicel Chiralcel AD-H column, n-
hexane/i-PrOH = 90:10, 1.0 ml/min, k = 254 nm, t (minor) = 10.78
White solid, 87% yield, 95% ee [Daicel Chiralcel OD-H column,
n-hexane/i-PrOH = 70:30, 1.0 ml/min, k = 254 nm,
30.16 min, (minor) = 38.10 min]; mp 157.3–158.1 °C;
[a]
25 = +83.2 (c 0.149, EtOAc). 1H NMR (400 MHz, CDCl3) d 8.19
D
t (major) =
min, t (major) = 12.21 min]; [a D
]
25 = +273.4 (c 0.237, EtOAc). 1H NMR
t
(400 MHz, CDCl3) d 8.20 (s, 1H), 8.13 (d, J = 8 Hz, 1H), 7.69–7.67
(m, 1H), 7.57–7.49 (m, 2H), 7.40 (s, 1H), 7.30–7.23 (m, 2H), 6.18 (d,
J = 4.0 Hz, 1H), 4.83 (d, J = 4.0 Hz, 1H), 3.53 (s, 3H), 2.19 (s, 3H), 2.15
(s, 3H). 13C NMR (101 MHz, CDCl3) d 198.44, 162.88, 149.32, 147.26,
145.14, 142.37, 133.46, 132.93, 132.82, 131.62, 130.07, 129.90,
128.62, 125.63, 122.23, 122.13, 118.45, 111.57, 52.23, 40.02, 30.51,
19.38. HRMS(ESI) m/z calcd for C22H20BrN2O5 ([M+H]+): 471.0550,
found: 471.0540.
(d, J = 8.8 Hz, 2H), 7.39 (d, J = 8.8 Hz, 2H), 7.31–7.28 (m, 3H), 7.21
(s, 1H), 7.19–7.13 (m, 2H), 7.11–7.07 (m, 3H), 4.95 (d, J = 12.0 Hz,
1H), 4.90 (d, J = 12.0 Hz, 1H), 3.95 (dd, J = 2.8, 11.2 Hz, 1H), 3.31–
3.27 (m, 2H), 3.18 (t, J = 4.0 Hz, 1H), 3.02 (dd, J = 12.8, 24.4 Hz,
1H), 2.14–2.10 (m, 1H), 2.09 (s, 3H), 0.87 (d, J = 6.8 Hz, 3H). 13C
NMR (101 MHz, CDCl3) d 207.95, 171.25, 149.70, 148.70, 146.92,
135.17, 134.40, 129.85, 128.48, 128.23, 128.15, 128.03, 127.14,
126.74, 125.46, 123.84, 67.19, 66.70, 59.09, 58.57, 43.03, 34.75,
29.51, 19.28. HRMS(ESI) m/z calcd for C28H28ClN2O5 ([M+H]+):
507.1681, found: 507.1688. CCDC 1045862 for compound 11 con-
tains the supplementary crystallographic data for this paper. These
data can be obtained from the Cambridge Crystallographic Data
Centre via www.ccdc.cam.ac.uk/data_request/cif.
4.3.27. (R)-Benzyl-5-acetyl-1-(3-fluorophenyl)-6-methyl-4-(4-
nitrophenyl)-1,4-dihydropyridine-2-carboxylate 8bp
Colorless oil, 34% yield, 97% ee [Daicel Chiralcel AD-H column,
n-hexane/i-PrOH = 70:30, 1.0 ml/min, k = 254 nm,
t (minor) =
23.64 min, t (major) = 26.25 min]; [
a
]
D
25 = +251.5 (c 0.334, EtOAc).
1H NMR (400 MHz, DMSO) d 8.25 (d, J = 8.8 Hz, 2H), 7.60 (d,
J = 8.4 Hz, 2H), 7.44–7.38 (m, 1H), 7.29–7.28 (m, 3H), 7.23–7.15
(m, 2H), 7.11–7.09 (m, 2H), 7.00 (d, J = 8.0 Hz, 1H), 6.17 (d,
J = 6.8 Hz, 1H), 4.94–4.87 (m, 3H), 2.11 (s, 3H), 2.10 (s, 3H). 13C
NMR (101 MHz, DMSO) d 198.38, 162.61, 153.13, 149.09, 146.81,
142.71, 135.62, 133.05, 130.96, 128.86, 128.82, 128.66, 128.52,
125.72, 124.73, 118.61, 117.68, 115.91, 110.99, 66.95, 40.32,
30.68, 19.12. HRMS(ESI) m/z calcd for C28H24FN2O5 ([M+H]+):
487.1664, found: 487.1651.
4.5. General procedure for b,c-unsaturated a-iminoester 12
3-Methoxyaniline (1 g, 8.13 mmol) was suspended in 50 mL of
hydrochloric acid (17%) at room temperature. The solution was
cooled to 0 °C and NaNO2 (0.8415 g, 12.20 mmol) was added in small
portions. After stirring at 0 °C for 15–30 min, NaN3 (0.7930 g,
12.20 mmol) was slowly added and the mixture was stirred for an
additional 2 h at room temperature. The reaction mixture was
extracted with diethyl ether (40 mL Â 3) and the combined organic
fractions were washed with saturated NaHCO3 solution (30 mL Â 3)
and with brine (30 mL). After drying over MgSO4, the ether was
4.3.28. 1-(3-Methoxyphenyl)-3-((3-methoxyphenyl)amino)-5-
(4-nitrophenyl)-1H-pyrrol-2(5H)-one 9
removed
under
reduced
pressure
and
the
desired
White solid, 29% yield, mp 135.5–136.4 °C; 1H NMR (300 MHz,
CDCl3) d 8.15 (d, J = 11.6 Hz, 2H), 7.35 (d, J = 11.6 Hz, 2H), 7.24–
7.16 (m, 3H), 7.00 (dd, J = 2.8, 10.8 Hz, 1H), 6.68–6.64 (m, 3H),
6.61 (t, J = 2.8 Hz, 1H), 6.53 (dd, J = 2.8, 10.8 Hz, 1H), 6.03 (d,
J = 3.6 Hz, 1H), 5.77 (d, J = 3.2 Hz, 1H), 3.79 (s, 3H), 3.76 (s, 3H).
13C NMR (101 MHz, CDCl3) d 166.92, 160.64, 160.14, 147.72,
145.19, 142.08, 137.83, 132.68, 130.26, 129.84, 127.48, 124.39,
113.30, 110.68, 109.63, 107.65, 106.59, 103.31, 63.40, 55.28,
29.69. HRMS(ESI) m/z calcd for C24H22N3O5 ([M+H]+): 432.1554,
found: 432.1542.
1-azido-3-methoxybenzene was obtained without further purifica-
tion. A solution of triphenylphosphine (0.6295 g, 2.40 mmol) in dry
THF (7 mL) was added dropwise to a solution of the 1-azido-3-
methoxybenzene (0.3590 g, 2.40 mmol) in dry THF (5 mL) under
argon over 30 min. The reaction mixture was stirred at room tem-
perature for 2 h and then heated at reflux for 30 min then the reac-
tion mixture was allowed to cool to room temperature, whereupon
(E)-ethyl 4-(4-nitrophenyl)-2-oxobut-3-enoate (0.2988 g, 1.20 mm
ol) was added. The mixture was heated at reflux for 4 h and cooled
to room temperature. The solvent was removed in vacuo. The crude
product was purified by silica gel column chromatography to afford
4.3.29. Methyl-7-methoxy-2-(4-nitrophenyl)quinoline-4-carbox-
ylate 10
b,c-unsaturated a-iminoester 12 as a yellow oil in 84% yield.
White solid, 11% yield, mp 197.6–198.3 °C; 1H NMR (400 MHz,
CDCl3) d 8.43 (d, J = 8.4 Hz, 2H), 8.05 (s, 1H), 7.83 (s, 1H), 7.74–
7.70 (m, 3H), 7.32 (dd, J = 2.4, 9.2 Hz, 1H), 4.12 (s, 3H), 4.01 (s,
3H). 13C NMR (101 MHz, CDCl3) d 165.65, 161.50, 149.95, 148.12,
147.49, 147.18, 144.09, 130.51, 125.85, 123.95, 123.07, 122.36,
119.25, 108.65, 55.88, 53.36. HRMS(ESI) m/z calcd for C18H15N2O5
([M+H]+): 339.0975, found: 339.0989.
4.5.1. (3E)-Ethyl 2-((3-methoxyphenyl)imino)-4-(4-nitro-phen-
yl)but-3-enoate 12
Yellow oil, 84% yield, syn:anti = 29:71; 1H NMR (400 MHz,
DMSO) d 8.26 and 8.21 (d, J = 8.8 Hz, and d, J = 8.8 Hz, 2H), 8.03
and 7.77 (d, J = 8.8 Hz, and d, J = 8.8 Hz, 2H), 7.49–7.30 (m, 2H),
7.29 and 7.04 (t, J = 8.4 Hz, and t, J = 8.4 Hz, 1H), 6.84–6.75 (m,
1H), 6.49–6.31 (m, 2H), 4.42 and 4.16 (q, J = 6.8 Hz, and q,
J = 6.8 Hz, 2H), 3.76 and 3.75 (s, 3H), 1.36 and 1.00 (t, J = 6.8 Hz,
and t, J = 6.8 Hz, 3H). 13C NMR (101 MHz, DMSO) d (major + minor)
13C NMR (101 MHz, DMSO) d 164.85, 164.02, 160.96, 160.85,
160.49, 160.21, 151.19, 149.84, 148.32, 148.24, 141.73, 141.64,
140.27, 139.57, 130.62, 130.37, 130.28, 129.69, 129.50, 129.41,
124.56, 124.47, 112.27, 111.96, 111.59, 111.43, 105.80, 105.59,
62.43, 62.01, 55.63, 55.28, 14.54, 14.02. HRMS(ESI) m/z calcd for
4.4. General procedure for chiral multisubstituted piperidine 11
Glacial acid (0.2 ml) was added to a stirred solution of 4-aryl-
1,4-dihydropyridine 8ba (0.0177 g, 0.035 mmol) in dry CH2Cl2
(1 ml) at room temperature. Next, a solution of NaBH4 (0.0067 g,
0.177 mmol) in dry CH2Cl2 (0.5 mL) was added gradually over
30 min after which the mixture was stirred for 12 h at room tem-
perature. After the reaction was completed, 10 ml of CH2Cl2 were
added and the mixture was washed with 10 ml of saturated aque-
ous sodium hydrogen carbonate. The organic layer was dried over
Na2SO4 and concentrated under reduced pressure. The crude pro-
duct was purified with silica gel column chromatography to give
chiral multisubstituted piperidine 11 in 87% yield.
C
19H19N2O5 ([M+H]+): 355.1288, found: 355.1289.
4.6. General procedure for the enantioselective cyclization of
b, -unsaturated -iminoester 12 and acetyl-acetone
c
a
A solution of b,c-unsaturated a-iminoester 12 (0.1 mmol) and
catalyst 4c (5 mol %, 0.005 mmol) in toluene (1 mL) under a

906
D. An et al. / Tetrahedron: Asymmetry 26 (2015) 897–906
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Acknowledgments
The authors are grateful for the financial support provided by
the National Natural Science Foundation of China (Nos. 21372098
and 20802025), Jilin Provincial Science and Technology
Sustentation Program (Nos. 20140307004GX, 201215033 and
20110436).
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