Amino amide organocatalysts for asymmetric michael addition of β-Keto esters with β-nitroolefins

Article abstract of DOI:10.1246/bcsj.20180302

Asymmetric Michael addition of β-keto esters with trans-β-nitroolefins using chiral amino amide organocatalyst was tried and afforded synthetically useful chiral Michael adducts in both excellent chemical yields (up to 99%) and stereoselectivities (up to dr. 99:1, up to 98% ee).

Full text of DOI:10.1246/bcsj.20180302

Advance Publication Cover Page
Amino Amide Organocatalysts for Asymmetric Michael Addition of β-Keto Esters with
β-Nitroolefins
Isiaka Alade Owolabi, Madhu Chennapuram, Chigusa Seki, Yuko Okuyama, Eunsang Kwon,* Koji Uwai,
Michio Tokiwa, Mitsuhiro Takeshita, and Hiroto Nakano*
Advance Publication on the web January 11, 2019
doi:10.1246/bcsj.20180302
© 2019 The Chemical Society of Japan
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Publication manuscripts.

Amino Amide Organocatalysts for Asymmetric Michael Addition of β-Keto Esters
with β-Nitroolefins
Isiaka Alade Owolabi,1 Madhu Chennapuram,1 Chigusa Seki,1 Yuko Okuyama,2 Eunsang Kwon,*3 Koji Uwai,1
Michio Tokiwa,4 Mitsuhiro Takeshita,4 and Hiroto Nakano*1
1Division of Sustainable and Environmental Engineering, Graduate School of Engineering, Muroran Institute of Technology, 27-1 Mizumoto,
Muroran 050-8585, Japan.
2Tohoku Medical and Pharmaceutical University, 4-4-1 Komatsushima, Aoba-Ku, Sendai 981-8558, Japan
3Research and Analytical Center for Giant Molecules, Graduate School of Sciences, Tohoku University, 6-3 Aoba, Aramaki, Aoba-Ku, Sendai
980-8578, Japan, E-mail: ekwon@m.tohoku.ac.jp
4Tokiwakai Group, 62 Numajiri Tsuduri-chou Uchigo Iwaki 973-8053, Japan
E-mail: catanaka@mmm.muroran-it.ac.jp
Hiroto Nakano
Dr. Hiroto Nakano received his Ph.D. degree in 1989 from Tohoku Pharmaceutical University (at present: Tohoku Medical
and Pharmaceutical University). He joined the faculty of this university, as an assistant professor and then an associate
professor. During the period of 1997 to 1999, he also joined Professor Albert I. Meyers group at Colorado State University
in USA as a Postdoc. From 2010, he is a professor of Muroran Institute of Technology. His research interest is catalytic
asymmetric syntheses in the field of synthetic organic chemistry.
Abstract
sites, and also the amide group for hydrogen bonding site to the
substrate. In addition, the bulky flexible polycyclic aromatic ring
on the nitrogen atom of amide group in catalyst might be
shielded effectively the one enantiotopic face on the basis of a
steric factor to enhance the selectivity (Scheme 1).7,8
Asymmetric Michael addition of β-keto esters with trans-β-
nitroolefins using chiral amino amide organocatalyst was tried
and afforded synthetically useful chiral Michael adducts in both
excellent chemical yields (up to 99%) and stereoselectivities (up
to dr. 99:1, up to 98% ee).
steric influence
site
hydrogen
bonding
site
R
O
Keywords: Amino amide, Organocatalyst, Michael
addition
enamine
formation
or
basic
sites
HN
H
N
H
Ar
polycyclic
aromatic groups
amino amide
organocatalysts
hydrogen
bonding
site
X
O
O
1. Introduction
O
O
R
The Michael addition is widely recognized as one of the most
general and versatile method for the formation of carbon-carbon
bonds in the field of synthetic organic chemistry.1 Especially, the
reaction of tri-substituted carbon nucleophiles and electron-
deficient olefins to form the chiral Michael adducts containing
adjacent quaternary and tertiary stereocenters, which are the
valuable chiral building blocks for many synthetic intermediates
and biologically active natural products.2 For this reaction,
several efficient chiral organometallic catalysts and
organocatalysts have been investigated in recent years.3 For
examples, chiral bifunctional Co2-schiff based binaphthyl type
organometallic catalyst and both thiourea- and squaramide type
organocatalysts have been reported to achieve high levels of
stereoselectivities.4,5 However, there are still need to develop
more efficient and environmentally catalysts, especially,
organocatalysts that will enhance high stereoselectivities for this
reaction.
∗
∗
R
A
β-keto esters
NO2
R'
+
asymmetric
Michael addition
C
chiral
Michael adducts
NO2
R'
B
nitroolefins
up to 99%, up to dr. 99:1
up to 98% ee
Scheme 1. Catalyst’s concept and its use in Michael addition.
Herein, we describe that our explored amino amide
organocatalyst X showed a highly efficient catalytic activity in
asymmetric Michael addition of β-keto esters A with various
nitroolefins Bto afford the corresponding chiral Michael adducts
C in good to excellent chemical yields and stereoselectivities (up
to 99%, up to dr. 99:1, up to 98% ee), in the presence of eco-
friendly aqueous medium (Scheme 1).
2. Experimental
In the last decade, our research group has been extensively
exploring a series of novel multifunctional amino alcohol based
organocatalysts and its derivatives for asymmetric reactions.6
Most recently, we reported that a polycyclic aromatic
substituted primary amino amide type organocatalyst X for the
enantioselective crossed aldol reaction of ketones with isatins or
aromatic aldehydes.7,8 This catalyst X has the basic primary
amino group for the enamine formation and hydrogen bonding
2.1. General
Unless otherwise noted, the commercial reagents were used
without purification. All reactions were carried out using
flamed-dried glassware. Thin layer chromatography (TLC) was
performed on silica gel 60 F254 and analytes were detected by
UV light and by staining with ninhydrin solution. The flash
column chromatography was performed on silica gel 60N (40-
50 μm). NMR spectra were measured on JEOL JNM-ECA-500

1
MHz spectrometer. H NMR spectra referred to the TMS (δ =
and the organic layer was dried over anhydrous Na2SO4, filtered,
and concentrated under a reduced pressure. The residue was
purified by flash column chromatography on SiO2
(EtOAc/hexane = 10/1) to afford the corresponding chiral
Michael adducts 7a-l. The diastereomeric ratio was determined
by the 1H NMR analysis of the crude product. The compounds
7a-l were known compounds and were identified in accordance
with the previously reported methods.9
0.00 ppm). 13C NMR (125 MHz) referred to the residual solvent
(δ = 77.6 ppm) were measured in CDCl3. IR spectra measured
using JASCO-4100 spectrophotometer. Optical rotations values
were obtained using JASCO DIP-360 digital polarimeter. High-
resolution mass spectra (HRM) were measured by EI mode using
Hitachi RMG-6MG and JEOL-JNM-DX303 spectrometers. The
enantiomeric excess was obtained by using chiral HPLC using a
Chiralcel OD-H column.
3. Results and Discussion
2.1.1.General procedure for the synthesis of catalysts (4h,i).
To a vial contain amine 2d (0.36 mmol) and N-Boc amino
acids 1b,c (0.30 mmol) were added 1-hydroxybenzotriazole
(HOBt) (49 mg, 0.36 mmol) and 1-(3-dimethylaminopropyl)-3-
ethylcarbondiimide (EDC) (64 μL, 0.36 mmol) (EDC) in CH2Cl2
(3 mL) and the mixtures was stirred at 0 oC for 1 h. Subsequently,
the reaction mixture was stirred for 20 h. The crude reaction
mixture was washed with EtOAc, 0.1 N HCl, saturated NaHCO3
solution and brine. The organic layer was dried over anhydrous
Na2SO4 and evaporated under a reduced pressure. The residue
was dissolved in dry CH2Cl2 (1 mL) and CF3CO2H (0.4 mL) was
added at 0 oC. The reaction temperature was increased to r.t. and
stirred for 3 h. Upon the completion of the reaction (monitored
by TLC) in detail follow (Scheme 2). The residue 4h,i were
purified by flash column chromatography on SiO2
(EtOAc/hexane = 3/1).7,8
For an amino amide with polycyclic aromatic ring
organocatalysts for this reaction, amino amides having 1- or 4-
pyrenyl 4a-d, 1-anthracenyl 4e, and 1-naphthyl 4f-i groups were
selected (Scheme 2). The catalysts 4a-g showed good catalytic
activities in the aldol reactions using isatins and general ketones
such as cyclohexanone, respectively, in our previous reports.7,8
The catalysts 4a-i were easily prepared by the condensations of
the corresponding chiral N-Boc amino acids 1a-d with
polycyclic aromatic amines 2a-d, according to our previous
methods.7,8
R2-NH2
2a-d
HOBt, EDC
R1
HN
O
R1
O
R1
O
CF3CO2
H
CH2Cl2
rt., 3 h
HN R2
Boc
HN R2
HN
OH
H2
N
CH2Cl2
r.t., 20 h
Boc
1a-d
1a: R1 tBu, 1b: R1= Ph
1c: R1= Bn, 1d: iPr
4a-i
3a-i
=
HN
O
HN
O
HN
O
HN
O
H2
N
O
H2
N
H2
N
H2
N
4c: 63%
4a: 62%
4b: 52%
4d: 67%
2.2. The synthesis of the catalysts 4a-i
The organocatalysts 4a-g analytical data have been reported in
our recent works.7,8
O
O
O
O
N
H
H2
N
N
H
H2
N
N
H
N
H
N
H
H2N
H2N
H2
N
4e: 54%
4g: 66%
4h: 74%
4i: 59%
4f: 53%
2.2.1. (S)-2-Amino-N-(naphthalene-1-yl)-2-phenylethana-
mide (4h)
Scheme 2. Synthesis of amino amide organocatalysts 4a-i.
Brown oil, 74% yield. [α]D22 = -36.00 (c = 0.200, CH2Cl2). IR
(neat) 3288, 1681, 1526, 947, 858, 770,696, cm-1. 1H NMR (500
MHz, CDCl3): δ = 10.20 (br s, 1H, NH), 8.23-8.22 (d, J = 7.0
Hz,1H), 7.91-7.86 (m, 2H), 7.66-7.64 (d, J = 8.0 Hz, 1H), 7.56-
7.25 (m, 8H), 2.05 (br s, 2H, NH2), 1.14-1.13 (d, J = 6.0 Hz, 1H).
13C NMR (125 MHz, CDCl3): δ = 171.83,141.02, 134.16, 132,48,
129.02, 128.92, 128.26, 127.12, 126.37, 126.09, 126.03, 125.14,
120.57, 118.81, 77.69, 77.43, 77.18, 60.67. MS (EI): m/z = 276
[M+H]+. HRMS (EI): calcd. for C18H16N2O [M+H]+ 276.1263,
found 276.1263.
First, we carried out the Michael addition of methyl- 2-oxo-
cyclopentanecarboxylate 5a and trans-β-nitroolefin 6a with 10
mol% of our explored bulkiest organocatalysts 4a-d having
pyrenyl groups in the presence of H2O at room temperature
(Table 1), according to our previous reported aldol
Table 1. Asymmetric Michael additions of β-keto esters 5a with
trans-β-nitroolefin 6a using organocatalysts 4a-i.
O
2
O
OMe
catalyst 4a-i
3
R1
O
O
NO2
O
NO2
(10 mol%)
2.2.2. (S)-2-Amino-N-(naphthalene-1-yl)-3-phenylpropan-
amide (4i)
NH2 NHR2
4a-i
OMe
5a (2.0 equiv.)
H2O
rt., 48 h
6a (1.0 equiv.)
[2R,3S]-7a
Brown oil, 59% yield. [α]D20 = -17.34 (c = 0.64, CH2Cl2). IR
1
(neat) 3295, 2920, 1677, 1524, 1250, 771, 699 cm-1. H NMR
entrya catalyst 4
yield (%)b
drc
ee (%)d
77
69
64
72
59
84
69
72
(500 MHz, CDCl3): δ = 10.21 (br s, 1H, NH), 8.26-8.25 (d, J =
7.0 Hz,1H), 7.87-7.85 (m, 1H), 7.66-7.64 (t, J = 9.5 Hz, J = 5.0
Hz 1H), 7.67-7.65 (d, J = 8.5 Hz, 1H), 7.52-7.25 (m, 8H), 3.91
(m, 1H), 3.47-3.43 (dd, J = 13.5 Hz, J = 10.0 Hz 1H), 2.94-2.89
(m, 1H), 1.65 (br s, 2H, NH2). 13C NMR (125 MHz, CDCl3): δ =
172.96,137.81, 134.19, 132.60, 129.53, 128.98, 128.87, 127.09,
126.47, 126.27, 126.09, 125.04, 120.65, 118.69, 77.69, 77.45,
77.19, 57.21, 40.89. MS (EI): m/z = 290 [M+H]+. HRMS (EI):
calcd. for C19H18N2O [M+H]+ 290.1419, found 290.1418.
1
2
3
4
5
6
7
8
9
a
b
c
d
e
f
g
h
i
83
76
89
78
74
91
82
78
69
90:10
83:17
90:10
87:13
90:10
92:8
90:10
87:13
83:17
65
b
aThe reactions were carried out under suspension. Isolated
2.3. General procedure for the asymmetric Michael
addition of ß-keto esters to trans-β-nitroolefins
c
1
yields. The diastereomeric ratio (dr) was determined by H
d
NMR spectroscopy of the crude reaction mixture. The ee
To a stirred solution of trans-β-nitroolefins 6a-h (0.34 mmol,
50.00 mg) and organocatalysts 4a-i (0.03 mmol, 10 mol%) in
H2O (0.5 mL) were added β-keto esters 5a-e (0.67 mmol, 0.08
mL) at room temperature (r.t.). The crude reaction mixture was
stirred at r.t. until the reaction completed been monitored by TLC.
Afterwards, the mixture was extracted with CH2Cl2 (3x5 mL),
values were determined by HPLC with a Daicel Chiralcel OD-
H column.
reaction conditions.8 All catalysts 4a-d showed catalytic
activities in this reaction and afforded the chiral Michael adduct

7a as the main product with moderate to good chemical yields
and stereoselectivities, (up to 89%, up to dr. 90:10, up to 77%
ee). Especially, tert-butyl-catalyst 4a with 1-pyrenyl group
afforded the adduct 7a in good chemical yield and
stereoselectivities (83%, dr. 90:10, 77% ee, entry 1).
Furthermore, the same reaction using bulkier catalyst 4e with the
1-anthracenyl group also gave the adduct 7a in good chemical
yield and moderate stereoselectivities (74%, dr. 90:10, 59% ee,
entry 5). Moreover, the reaction using less bulky tert-butyl-
catalyst 4f with 1-naphthyl group was also examined and the best
result (91%, dr. 92:8, 84% ee, entry 6) was obtained by using
this catalyst. The determination of absolute configuration and
stereoselectivity of 7a were confirmed on comparison with the
previous data.9
In order to optimize the reaction conditions using the superior
catalyst 4f (Table 2), we next examined the molar ratio of the
catalyst, effects of solvents, and the reaction time (Table 2).
Firstly, the effect of catalyst loading was examined (entries 1-5).
Subsequently, 5 mol% of organocatalyst 4f showed the best
catalytic activity and afforded the corresponding chiral Michael
adduct 7a with good chemical yield with both excellent
diastereoselectivity and enantioselectivity (93%, dr. 99:1, 98%
ee, entry 3).
solvents, but better results than the use of water were not
obtained. Considering that the reaction using H2O was carried
out under suspension, H2O might be work as an additive but a
solvent, although the reasons are not clear. We also examined the
effect of the reaction time period (24 h and 12 h) in the presence
of best H2O (24 h: entry 20, 12h: entry 21). However, the
chemical yields and the enantioselectivities decreased than the
result of 48 h, although the reasons are not clear. Based on these
results, it was proved that 5 mol% of catalyst loading in the
presence of H2O at 48 h was the best reaction conditions to
obtain the chiral Michael adduct 7a in satisfactory chemical
yield and stereoselectivities (entry 3).
After optimization of the reaction conditions, we examined the
generality of superior catalyst 4f in the reactions of β-keto esters
5a,c-e with various trans-β-nitroolefins 6a-h (Scheme 3). All
reactions proceeded to afford the corresponding chiral Michael
adducts 7c-l. The reactions of substrate 5a with o- or p-
methylated nitrostyrenes 6b,c afforded the corresponding chiral
Michael adducts 7c,d in good to moderate chemical yields,
diastereoselectivities and good enantioselectivities (7c: 74%, dr.
98:2, 98% ee, 7d: 91%, dr. 93:7, 90% ee). The use of p-
methoxynitrostyrene 6d afforded the corresponding adduct 7e in
good chemical yield (86%) and stereoselectivities (dr. 97:3, 90%
ee). Also, the reactions using the p-halogenated nitrostyrenes
6e,f was also in accordance with this condition and resulted in
corresponding adducts 7f,g were obtained with satisfactory
results (7f: 81%, dr. 94:6, 97% ee, 7g: 91%, dr. 99:1, 92% ee).
The uses of both heterocyclic 2-furyl-nitroethylene 6g and
nitrovinyl-thiophene 6h afforded the adducts 7h and 7i,
respectively, in good chemical yields (7h: 86%, 7i: 79%) with
good stereoselectivities (7h: dr. 93:7, 93% ee, 7i: dr. 83:17, 91%
ee). Furthermore, 1-oxo-2-indanecarboxylate 5c with 6a also
afforded the corresponding adduct 7j in good chemical yield and
enantioselectivity (82%, 88% ee) with good diastereoselectivity
(dr. 85:15). Also, the uses of methyl 2-oxo-1-
Table 2. Optimization conditions of asymmetric Michael
additions of β-keto esters 5a,b with trans-β-nitroolefin 6a using
organocatalysts 4f.
catalyst 4f
(mol%)
solvent
r.t., 48 h
[2R,3S]-7a,b
5a,b
6a
(2.0 equiv.)
(1.0 equiv.)
entrya catalyst 4f
solvent
yield
(%)b
90
91
93
46
23
74
92
64
88
99
34
37
68
89
74
17
37
89
24
65
57
drc
ee
(%)d
80
84
98
91
90
94
88
62
68
43
83
76
49
51
69
64
90
51
88
95
92
(mol %)
1
2
3
20
10
5
H2O
H2O
H2O
H2O
H2O
90:10
98:2
99:1
90:10
99:1
96:4
90:10
81:19
86:14
88:12
84:16
89:11
88:12
80:20
84:16
80:20
77:23
80:20
82:18
99:1
cyclohexanecarboxylate
5d
and
2-oxo-1-
cycloheptanecarboxylate 5e also provided the corresponding
adducts 7k,l in good chemical yields and high level of
stereoselectivities (7k: 76%, dr. 90:10, 91% ee, 7l: 84%, dr.
86:14, 88% ee). In addition, the reaction of acyclic methyl 2-
methylacetoacetate, instead of cyclic b-keto esters, with 6a was
examined. However, only trace amount of the corresponding
Michael adduct was conformed in this reaction condition,
although the reason is not clear.
4
5
2.5
1
6e
7
5
5
H2O
toluene
benzene
hexane
CH2Cl2
CHCl3
Et2O
8
5
9
5
10
11
12
13
14
15
16
17
18
19
20f
21f
5
5
5
5
5
5
5
5
5
5
5
5
O
O
catalyst 4f
(5 mol%)
NO2
6a-h
(1.0 equiv.)
R
THF
+
[2R,3S]-7c-l
R'
O
H2O
rt., 48 h
1,4-dioxane
EtOAc
MeOH
DMF
DMSO
CH3CN
H2O
5a,c-e
(2.0 equiv.)
O
O
O
O
O
O
O
O
O
O
OMe
OMe
NO2
OMe
NO2
OMe
NO2
OMe
NO2
NO2
OMe
[2R,3S]-7e
86%, dr. 97:3,
90% ee
Cl
F
[2R,3S]-7c
74%, dr. 98:2,
98% ee
[2R,3S]-7d
91%, dr. 93:7,
90% ee
[2R,3S]-7f
81%, dr. 94:6,
97% ee
[2R,3S]-7g
91%, dr. 99:1,
92% ee
H2O
99:1
O
O
O
O
O
O
aThe reactions were carried out under suspension. bIsolated
O
O
O
O
OMe
OMe
NO2
OMe
NO2
OMe
NO2
OMe
NO2
c
1
NO2
yields. The diastereomeric ratio (dr) was determined by H
NMR spectroscopy of the crude reaction mixture. dThe ee values
were determined by HPLC with a Daicel Chiralcel OD-H
column. eThe use of ethyl ester 5b in entry 6. fThe reactions were
carried out at 24h and 12h, respectively.
O
S
[2R,3S]-7h
86%, dr. 93:7,
93% ee
[2R,3S]-7i
[2R,3S]-7j
82%, dr. 85:15,
88% ee
[2R,3S]-7k
[2R,3S]-7l
79%, dr. 83:17,
91% ee
76%, dr. 90:10,
91% ee
84%, dr. 86:14,
88% ee
Scheme 3. Generality of catalyst 4f in asymmetric Michael
additions of β-keto esters 5a,c-e with trans-β-nitroolefins 6a-h.
Furthermore, the use of ethyl ester 5b also afforded the
corresponding adduct 7b in good chemical yield and selectivities
(74%, dr. 96:4, 94% ee, entry 6). Next, the Michael addition was
examined in various solvents (entries 7-19) in the presence of 5
mol % of 4f for 48 h. Although all reactions proceeded in these
In view of the excellent enantioselectivity (98% ee) of the
Michael adduct [2R,3S]-7a that was obtained in the reaction of
5a with 6a using catalyst 4f, the results of its calculation studies

(Fig. 1-3), and based on the structure of catalyst 4a by our
previous study,8 an enantioselective reaction course is proposed
as follows (Scheme 4).
I-1
C-1
For the estimation of enantioselective reaction course, the
conformational analysis by using the scan of total energies for 4f
was firstly carried out and the result was indicated that the
conformation of I-1 was most stable as the conformation of 4f
(Fig. 1).
6a
5a
Figure 3. The electrostatic potential maps of 4f (C-1), 5a and 6a.
Moreover, we examined the reaction of amino amide 4f, that acts
as the best catalyst, with β-keto methyl ester under the same
reaction condition in Table 1. However, the formation of
enamine species was not observed in this reaction condition.
This result indicates that amino amide 4f may act as a basic
catalyst in this reaction.
Based on the calculation results of the scan total energy, the
structure of catalyst 4f might be fixed by the intramolecular
hydrogen bonding interaction between the amino hydrogen atom
and the amide oxygen atom, and thereby catalyst 4f might have
the conformation shape C-1 of which are having less steric
interaction between the tert-butyl substituent at the a-position
and the 1-naphthy substituent on amide group. Furthermore,
when the reaction proceeds, 4a acts as a base and then it might
be formed Ts-1-4 in which both substrates 5a and 6a fixed with
the ammonium hydrogen atom on the ammonium catalyst
species by the hydrogen bonding interactions. In the proposed
Ts-1-4, the reaction might be proceeding through Ts-1, based on
the frontier and the electrostatic potential map, that has a smaller
steric interaction both between substrates 5a and 6a and between
4f and the 1-naphthyl substituent at amide group on the
ammonium catalyst species than those of Ts-2-4 that have a
larger steric interaction between substrates 5a, 6a and the 1-
naphthyl substituent ammonium catalyst species.
Figure 1. The scan of total energies for 4f (conformations C-1
to C-4 generated).
Furthermore, to examine the regioselectivity of the reaction
between 5a and 6a more accurately, the calculation of the
energies and coefficients of their frontier orbitals was conducted.
The energy levels of the orbitals clearly showed the dominate the
interaction between the LUMO of 6a and the
O
O
NO2
OMe
6a
5a
O
N
O
H
O
MeO
O
O
O
H
NO2
+
OMe
O
LUMO
HOMO
HN
O
!0.*0238
!0.2232
HN
O
N
5a
6a
H
HN
NH2
HN
!0.0967
!0.2553
H
H
catalyst 4f
C-1
C-2
HOMO
LUMO
ꢈꢁ
ꢉꢁ
ꢈꢁ
O
O
O
O
N
ꢈꢁ
ꢈꢁ
N
O
H
O
N
O
N
O
H
H
O
O
N
H
N
H
N
N
O
N
H
H
H
H
H
H
N
O
O
H
N
H
H
O
O
H
O
N
O
MeO
O
O
H
OMe
H
OMe
O
H
H
OMe
H
ꢇꢃꢁ
ꢆꢃꢁ
Ts-1
Ts-2
Ts-3
Ts-4
“favor"
98% ee
ꢆꢃꢁ
ꢇꢃꢁ
O
O
O
O
O
O
O
O
The red and blue dotted lines:
the matching of orbital phase
between 5a and 6a
S
S
S
R
R
OMe
OMe
NO2
OMe
MeO
R
R
S
Ph
Ph
NO2
Ph
NO2
Ph
O2
N
[2S,3R]-7a,b
[2R,3R]-7a,c
[2S,3S]-7a,d
[2R,3S]-7a
Figure 2. The frontier orbitals between 5a and 6a obtained by
DFT calculations at the 6-31 G(d) level using a B3LYP
exchange-correction functional [the dotted lines (blue and red)
in the red square indicated an interactions between the molecular
orbitals of 6a and 5a].
Scheme 4. Plausible reaction course using catalyst 4f (the blue
dotted lines indicated the hydrogen bonds among the N+H
moiety of 4f, 6a and 5a. The red dotted lines indicated the
interactions between the molecular orbitals of 6a and 5a).
HOMO of 5a, and their orbital phase and the coefficient of the
orbital clearly demonstrated a matching in favor of overlapping
to afford the observed configuration of major adduct 7a (Fig. 2).
In addition, the positive charge was on the nitrogen atom of the
amino moiety in the catalyst 4f (C-1), and the negative charges
were both on the oxygen atoms of the nitro group in nitrostyrene
6a and on the oxygen atoms of the β-keto ester 5a (Fig. 3).
4. Conclusion
In conclusion, the new simple amino amide organocatalysts
4a-i were developed and examined based on a new catalyst
design concept in the asymmetric Michael addition of various β-
keto esters 5a-e with trans-b-nitroolefins 6a-h. Among the
optimized catalysts 4a-i, the catalyst 4f possessing with 1-
naphthyl group have showed a best catalytic activity in this
reaction and afforded the corresponding chiral Michael adducts
7a-l having quaternary chiral carbon centre with good to
excellent chemical yields (up to 99%), diastereoselectivities (up

to 99:1) and enantioselectivities (up to 98% ee). The
modification of amino amide catalysts and detailed mechanistic
study are in progress.
51, 7802–7804.
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5396–5409.
Acknowledgement
We thank Adaptable & Seamless Technology Transfer
Program through Target-driven R&D from Japan Science and
Technology Agency (JST) and Muroran Institute of Technology
for partial financial support to this study.
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Supporting Information
Supplementary data related to this article can be found at ---------.
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