2-Azanorbornane-Based Amino Alcohol Organocatalysts for Asymmetric Michael Reaction of β-Keto Esters with Nitroolefins

Article abstract of DOI:10.1002/ejoc.201900308

New optically active 2-azanorbornane-based amino alcohol organocatalysts were designed and synthesized, and these catalysts were successfully employed in the asymmetric Michael reaction of β-keto esters with nitroolefins to obtain the corresponding chiral

Full text of DOI:10.1002/ejoc.201900308

A Journal of
Accepted Article
Title: 2-Azanorbornane-Based Amino Alcohol Organocatalysts for
Asymmetric Michael Reaction of β-Keto Esters with Nitroolefins
Authors: Rei Togashi, Madhu Chennapuram, Chigusa Seki, Yuko
Okuyama, Eunsang Kwon, Koji Uwai, Michio Tokiwa,
Mitsuhiro Takeshita, and Hiroto Nakano
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201900308
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10.1002/ejoc.201900308
European Journal of Organic Chemistry
FULL PAPER
2-Azanorbornane-Based Amino Alcohol Organocatalysts for
Asymmetric Michael Reaction of β-Keto Esters with Nitroolefins
Rei Togashi,[a] Madhu Chennapuram,[a] Chigusa Seki,[a] Yuko Okuyama,[b] Eunsang Kwon,*[c] Koji
Uwai,[a] Michio Tokiwa,[d] Mitsuhiro Takeshita,[d] Hiroto Nakano*[a]
[a]Division of Sustainable and Environmental Engineering, Graduate School of Engineering, Muroran Institute of Technology, 27-1
Mizumoto, Muroran 050-8585, Japan
[b]Tohoku Medical and Pharmaceutical University, 4-4-1 Komatsushima, Aoba-Ku, Sendai 981-8558, Japan
[c]Research and Analytical Center for Giant Molecules, Graduate School of Sciences, Tohoku University, 6-3 Aoba, Aramaki, Aoba-Ku,
Sendai 980-8578, Japan
[d]Tokiwakai Group, 62 Numajiri Tsuduri-chou Uchigo Iwaki 973-8053, Japan
Abstract: New optically active 2-azanorbornane-based amino
alcohol organocatalysts were designed and synthesized, and these
catalysts were successfully employed in the asymmetric Michael
reaction of β-keto esters with nitroolefins to obtain the corresponding
chiral Michael adducts with both high chemical yields (up to 99%)
and high stereoselectivities (up to dr = 91:9, up to 91% ee).
organocatalyst for asymmetric aldol and Michael reactions
respectively.[2a,e] Especially, to the best of our knowledge, the
successfully use of 2-azanorbornanes
B
with mono-
phenylmethanol moiety at 3-position as organocatalyst has not
been reported until now.
The Michael reaction is widely used as one of the most well-
known versatile carbon-carbon bond-forming reactions. This
reaction is especially useful for the construction of chiral building
blocks containing quaternary stereocenters, which are key chiral
intermediates for the synthesis of biologically active complex
compounds and synthetic drug candidates.[3] Therefore,
intensive efforts have been made in recent years to develop an
efficient organocatalyst for this reaction. However, despite its
great synthetic potential, only a few successful catalysts that
show satisfactory activity to substrates in a wide range of
applications have been reported.[5]
Introduction
The development of new organocatalysts has attracted
considerable interest in the field of synthetic organic chemistry
over the past 10 years. Efficient covalent and non-covalent
organocatalysts have been explored for proceeding successfully
a wide range of reactions.[1] 2-Azanorbornane A having cage
structure is prepared by the hetero Diels-Alder (HDA) reaction of
cyclopentadiene with chiral imino dienophile, and the cage
compound works as useful synthetic intermediate for converting
to various biologically active compounds such as anti-tumor
drugs (Scheme 1).[2] 2-Azanorbornane-based amino alcohol B,
that is derived from the DA adduct A, has bulky 2-
azanorbornane backbone and the cage structure contains
nitrogen atom acting as a Brønsted basic site. Furthermore, the
compound B has the side chain at 3-position on the 2-
azanorbornane skeleton, which might show strong electronic
and steric effects for controlling stereoselectivity in the course of
reaction. Considering these structurally properties, it is expected
that the cage type amino alcohol B might show an efficient
functionality as an organocatalyst for enantioselective reactions.
However, till now only a few successful studies were reported by
using the compound B containing with di-phenylmethanol moiety
at 3-position and thiourea derived azanorbornanes as
Ph
N
+
CO2Et
Hetero
Diels-Alder
reaction
cyclopentadiene
imino dienophile
hydrogen
bonding
site
basic site
Ph
R
N
OH
H
N
COOEt
R
steric influence
2-azanorbornane A
2-azanorbornane-based
cage compound B
O
O
asymmetric
Michael reaction
O
O
∗
OR
NO2
+
∗
R'
NO2
OR
R'
chiral
Michael adducts E
β-keto esters C
nitroolefines D
Scheme 1. Functional of 2-azanorbornanes and its use in Michael addition
Against this background, we explore the optically active 2-
azanorbornane organocatalysts B for this reaction using β-keto
esters C with nitroolefins D (Scheme 1).
[a] Rei Togashi, Dr. Madhu Chennapuram, Dr. Chigusa Seki, Dr. Koji Uwai, Prof. Hiroto
Nakano. Department of Bioengineering, Graduate School of Engineering, Muroran Institute
of Technology.
27-1 Mizumoto, Muroran 050-8585, Japan
We describe that the 2-azanorbornane-based amino alcohol
organocatalysts B prepared here showed efficient catalytic
activity in the Michael addition of β-keto esters C with various
nitroolefins D to obtain chiral Michael adducts E at satisfactory
chemical yields and stereoselectivities (up to 99%, dr = 91:9,
91% ee).
E-mail: catanaka@mmm.muroran-it.ac.jp
http://www3.muroran-it.ac.jp/hnakano/
[b] Dr. Yuko Okuyama, Tohoku Medicinal and Pharmaceutical University,
4-4-1 Komatsushima, Aoba-ku, Sendai 981-8585, Japan
[c] Dr. Eunsang Kwon, Research 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
www.kiki.chem.tohoku.ac.jp/kwon/index.html
[d] Michio Tokiwa, Mitsuhiro Takeshita, Tokiwakai Group, 62 Numajiri Tsuduri-chou Uchigo
Iwaki 973-8053, Japan
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10.1002/ejoc.201900308
European Journal of Organic Chemistry
FULL PAPER
Me
H
N
Results and Discussion
PhMgBr
6
7
O
2-Azanorbornanes with a phenylmethanol moiety as the side
chain organocatalyst 5, 7–15 were derived from the DA adduct 3
by the following reactions (Scheme 2).[4] First, 2-azanorbornanes
3 having an ethoxycarbonyl group as the side chain at the 3-
position were prepared by the HDA reaction of cyclopentadiene
with a chiral imino dienophile, which was afforded
X
H
PhMgBr
Fig. 1. Direction of attack of PhMgBr on aldehyde 6
First, we carried out the Michael addition of methyl 2-oxo-
cyclopentanecarboxylate 16a as a Michael donor and nitro-
styrene 17 as a Michael acceptor with 10 mol% of our explored
2-azanorbornanes with mono-(S)-phenylmethanol moiety
organocatalysts 5, 7–12 in toluene at room temperature (entries
1–4, Table 1). All catalysts 5, 7–12 showed catalytic activities in
this reaction and afforded the Michael adduct 18a. In particular,
the bulkiest N-(S)-phenylethylated 2-azanorbornanes 7 with a
mono-(S)-phenylmethanol moiety afforded the adduct 18a at
good chemical yield and stereoselectivities (70%, dr = 82:18,
86% ee, entry 2). In addition, the catalytic activities of our
EtO2
C
Ph
H2
CO2Et
CHO
1
N
MS 4ꢀ
+
CO2Et
N
Ph
CH2Cl2
CF3CO2
BF3 • Et2
-50 °C to rt, 16 h
46%
H
O
5% Pd-C
K2CO3
EtOH
rt, 1 h
61%
NH2
0 ꢁ,1 h
Ph
[S]-2
3
N
CO2Et
(COCl)2
DMSO
Et3N
OH
OH
N
Ph
N
N
4
1-NaphMgBr
H
LiAlH4
CHO
1-Naph
CH2Cl2
-78 °C to rt,
3 h
ether
-78 °C to rt,
20 h
THF
reflux, 3 h
94%
Ph
Ph
Ph
5
6
11
21%
81%
CeCl3
THF
PhMgBr
CH3
I
OH
-78 °C to rt, 20 h
84%
N
H
DA adduct 4
CH3CN
reflux, 12 h
67%
Ph
9
OH
OH
N
H
H2
OH
Ph
NH
H
3
N
Ph
20% Pd(OH)2
EtOH
rt, 96 h
Ph
2
Ph
Ph
8
R
OH
7
13-15
N
72%
H
previously explored 2-azanorbornanes 13–15 with
a
di-
PhCH2Br
CH2Cl2
Ph
CH2Cl2
-30 ºC to rt, 24 h
67 %
13: R = Me
14: R = (S)-Ph(Me)CH2
15: R = H
TMSOTf
Et3N
Ph
10
phenylmethanol moiety were also examined (entries 8–10).
However, these catalysts did not show satisfactory catalytic
activities in this reaction, in contrast to 2-azanorbornane with a
mono-phenylmethanol moiety. The absolute configuration and
Et3
N
0 ºC to rt, 12 h
41%
OTMS
N
H
Ph
Ph
12
diastereoselectivity of 18a were identified based on
comparison with literature data.[5]
a
Scheme 2. Preparations of 2-azanorbornane-based organocatalysts
Table 1. Asymmetric Michael additions of b-keto esters 16a,b with trans-b-
nitrostyrene 17 using organocatalysts 5,7-15
by the condensation of aldehydes 1 with chiral amines 2. The
catalytic hydrogenation of the DA adduct 3 resulted in the
hydrogenated compound 4. Furthermore, the reduction using
LiAlH4 of 4 afforded 2-azanorbornylmethanol 5 and then the
alcohol 5 was converted to aldehyde 6 by Swern oxidation. The
O
O
O
O
catalysts 5,7-15
(10 mol%)
R
R
O
O
NO2
O
O
+
R
toluene
rt, 24 h
O
NO2
NO2
Ph
Ph
16a: R = Me
16b: R = Et
17
[2R,3S]-18a,b
[2S,3S]-18a',b'
Grignard reaction of the obtained product
magnesium bromide gave 2-azanorbornane with mono-(S)-
phenylmethanol at the side chain, followed by catalytic
6 with phenyl
yield
dr
(18:18')[b]
63:37
82:18
63:37
58:42
50:50
84:16
88:12
57:43
88:12
55:45
91:9
ee (%)[c]
entry
16
product
catalyst
(%)[a]
60
70
37
38
27
54
99
42
71
42
90
18
55
86
-56
58
rac
33
4
18'
rac
8
-16
5
16
rac
rac
17
rac
-33
rac
7
1
2
3
4
5
6
7
8
9
16a
16a
16a
16a
16a
16a
16a
16a
16a
16a
16b
18a
18a
18a
18a
18a
18a
18a
18a
18a
18a
18b
5
7
8
reduction with palladium hydroxide in an H2 stream of 7 affording
the N-unsubstituted compound 8 at good yield. Compound 8
was also converted to N-methylated 9 and N-benzylated 10
products. In addition, the Grignard reaction of aldehyde 6 with 1-
naphthyl magnesium bromide gave the bulkier 2-azanorbornane
11 with a mono-(S)-1-naphthylmethanol moiety as the side chain.
9
10
11
12
13
14
15
7
7
rac
-44
23
2-Azanorbornyl-trimethylsilylphenylether 12 having
a
TMS
10
11
(trimethylsilyl)-protected hydroxyl group was obtained by the
reaction of 7 with TMSOTf at moderate yield. Moreover, 2-
azanorbornanes 13–15 with a di-phenylmethanol moiety as the
side chain were also easily prepared by our previously reported
method,[4f] along with 2-azanorbornanes with a mono-(S)-phenyl-
methanol moiety. The (S)-absolute configuration of the
secondary chiral center at the side chain in 2-azanorbornane
with mono-phenylmethanol 7 was confirmed, in accordance with
previous reports.[4d,f] Thus, when the Grignard reaction of
aldehyde 6 with PhMgBr proceeds, a phenyl nucleophile may
attack from the less sterically hindered side, which is not
influenced by the bulky phenyl ethyl group on the amino nitrogen
atom in the 2-azanorbornane backbone to afford compound 7
having the (S)-configuration on a side chain (Fig. 1).
aIsolated yield. bDiastereoselectivity was determined by 1H-NMR.
cThe ee of isomer was determined by HPLC using CHIRALCEL OD-H column
(hexane:2-propanol = 90:10).
To further improve the enantioselectivity of this organocatalytic
reaction, we evaluated the effects of various solvents, molar
ratios, temperatures, and reaction times using superior catalyst
7 (entries 1–24, Table 2). First, we examined the solvent
screening in different non-polar aromatic (entries 1, 2), aliphatic
(entry 3), ethereal (entries 4–7), chlorinated (entry 8), polar
protic (entries 9–13), and special hexafluorobenzene (entry 14)
solvents in the presence of 10 mol% of catalyst 7 for 24 h. As a
result, toluene, i-Pr2O, and CH2Cl2 afforded the Michael adduct
18a at good chemical yields and stereoselectivities. Based on
these results, the reactions were carried out at 0, −30, and
−50 °C in these solvents, respectively (entries 15–21). The best
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10.1002/ejoc.201900308
European Journal of Organic Chemistry
FULL PAPER
results for the chemical yield (80%) and enantioselectivity (91%
ee) were obtained in i-Pr2O at 0 °C with good diastereoselectivity
(84:16) (entry 16). Furthermore, the effects of catalyst loading
(20 mol% and 5 mol%, entries 22–24) were examined in
superior i-Pr2O solvent. However, the reactions under both
catalytic loadings did not afford better results than the use of 10
mol%. These results showed that catalyst loading at 10 mol% in
i-Pr2O as a solvent at 0 °C was the best reaction conditions to
dr
ee (%)[c]
entry
catalyst
yield (%)[a]
(18a:18a')[b]
54:46
18a
18a'
1
2
3
19
20
9
39
68
29
11
21
85
30
10
14
82:18
62:38
aIsolated yield. bDiastereoselectivity was determined by 1H-NMR.
cThe ee of isomer was determined by HPLC using CHIRALCEL OD-H
column (hexane:2-propanol = 90:10).
afford
product
18a
at
satisfactory
chemical
yield,
in our identified superior i-Pr2O solvent (entries 1 and 2, Table 3).
However, neither catalyst 19 nor catalyst 20 showed better
catalytic activities than our 2-azanorbornane catalyst 7. In
addition, not only N-(S)-phenylethylated 7 but also N-methylated
2-azanorbornane 9 with a mono-phenylmethanol moiety showed
better catalytic activity than both catalysts 19 and 20 in i-Pr2O
(entry 3). In contrast with proline-based 19, 2-azanorbornanes 7
did not work well in hexafluorobenzene (entry 12, Table 2).
diastereoselectivity, and enantioselectivity as the optimized
conditions (entry 16).
Table 2. Asymmetric Michael additions of b-keto ester 16a with trans-b-
nitrostyrene 17 using organocatalyst 7
O
O
Me
OH
N
O
H
catalyst 7
+
16a
17
Ph
solvent
temp., 24 h
NO2
Ph
After optimization of the reaction conditions, the asymmetric
Michael addition was extended to various nitroolefins 21a–i with
b-keto ester 16a using catalyst 7 (Table 4).[5][7]
Ph
7
[2R,3S]-18a
ee (%)[c]
temp.
(℃)
catalyst
(mol%)
yield
dr[b]
(18a:18a')
Table 4. Asymmetric Michael additions of b-keto ester 16a with trans-b-
nitroolefins 21a-i using organocatalyst 7
entry
solvent
(%)[a]
18a
18a'
1
2
3
4
5
toluene
benzene
hexane
Et2O
THF
i-Pr2O
10
10
10
10
10
rt
rt
rt
rt
rt
70
78
22
77
53
82:12
84:16
74:26
82:18
63:37
86
79
82
64
71
8
11
rac
9
4
8
O
O
catalyst 7
(10 mol%)
Me
O
O
O
NO2
+
Me
R''
6
10
rt
82
81:19
85
i-Pr2O
0 °C, 24 h
O
NO2
7
8
9
10
11
12
13
14
1,4-dioxane
CH2Cl2
CH3CN
MeOH
acetone
C6F6
10
10
10
10
10
10
10
10
rt
rt
rt
rt
rt
rt
rt
rt
35
62
21
36
68
68
51
41
75:25
81:19
53:47
50:50
77:23
79:21
64:36
71:29
36
79
53
8
51
34
50
54
7
R''
11
12
rac
34
rac
rac
8
16a
21a-i
R'' = aryl, alkyl
[2R,3S]-22-30
dr[b]
entry
1
21a-i
products
yield (%)[a]
ee (%)[c]
35
water
brine
NO2
O
15
16
17
18
19
20
21
22
23
24
toluene
i-Pr2O
CH2Cl2
toluene
i-Pr2O
toluene
i-Pr2O
i-Pr2O
i-Pr2O
i-Pr2O
10
10
10
10
10
10
10
20
15
5
0
0
0
-30
-30
-50
-50
0
0
0
65
80
85
70
75
70
82
68
70
70
76:24
84:16
86:14
84:16
86:14
88:12
88:12
84:16
77:23
78:22
63
91
59
88
75
44
40
86
86
57
23
rac
5
5
4
rac
rac
27
17
6
NO2
F
Cl
Br
97
91:9
O
F
O
O
O
21a
22
NO2
O
O
O
NO2
2
3
4
5
6
7
99
99
74
83
93
94
90:10
89:11
89:11
89:11
88:12
89:11
35
49
20
31
59
30
O
Cl
21b
23
aIsolated yield. bDiastereoselectivity was determined by 1H-NMR.
cThe ee of isomer was determined by HPLC using CHIRALCEL OD-H column
(hexane:2-propanol = 90:10).
NO2
NO2
O
Br
It is well known that proline-based amino alcohol organo-
catalyst 19 showed excellent catalytic activity to the reaction of
16a with 17 in special hexafluorobenzene as a solvent.[5g]
However, the use of this solvent might be limited by its higher
cost than other typical organic solvents, and it also shows
toxicity such as serious eye damage. We thus examined this
reaction using catalyst 19[6] with a di-phenylmethanol moiety and
related catalyst 20[6] with a mono-phenylmethanol moiety,
24
21c
21d
21e
NO2
NO2
Me
O
Me
O
25
NO2
O
NO2
OMe
O
OMe
O
26
NO2
O
NO2
Table 3. Asymmetric Michael additions of b-keto ester 16a with 17 using
organocatalysts 9,19,20
O
Br
Br
O
21f
27
NO2
O
catalyst 9,19,20
(10 mol%)
O
O
NO2
+
+
16a
17
[2R,3S]-18a [2S,3S]-18a'
O
i-Pr2O
rt, 24 h
O
28
21g
Ph
H
N
N
Ph
Ph
N
2R
Ph
2R
3S
OH
OH
OH
H
9
[2R]-19
[2R,3S]-20
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10.1002/ejoc.201900308
European Journal of Organic Chemistry
FULL PAPER
conditions (i-Pr2O, 0 °C, 24 h)(Scheme 3). However, catalyst 7
did not show catalytic activity in their reactions to afford the
corresponding Michael adducts. And also, the uses of acyclic b-
keto esters 31d or 31e instead of cyclic b-keto esters were
examined (Scheme 3). The reaction of 17 with simple 31d
afforded the corresponding Michael adduct 32 with good
chemical yield and diastereoselectivity (68%, dr = 53:47), but
racemate. On the other hand, the use of bulkier 31e gave only
trace amount of the corresponding adduct. Unfortunately,
catalyst 7 did not show catalytic activity to some substrates 21i
and 31a-c,e. It might be that substrates do not coordinate with
catalyst 7 due to steric interaction between them, given the
bulkiness of this catalyst, although the actual reason remains
unclear.
NO2
O
S
S
NO2
8
86
-
91:9
70
O
O
21h
29
NO2
NO2
O
-
-
9
O
O
21i
30
aIsolated yield. bDiastereoselectivity was determined by 1H-NMR.
cThe ee of isomer was determined by HPLC using CHIRALCEL OD-H,
CHIRALPAK IC (hexane:2-propanol = 90:10, hexane:EtOH = 90:10).
As summarized in Table 4, in most cases, the desired Michael
adducts 22–29 were obtained at good yields and
stereoselectivities. The reactions of substrate 16a with p-
halogenated nitrostyrenes 21a–c also proceeded at good
chemical yields and diastereoselectivities, but with low to
moderate enantioselectivities (22: 97%, dr = 91:9, 35% ee; 23:
99%, dr 90:10, 35% ee; 24: 99%, dr = 89:11, 49% ee) (entries
1–3). Although the reaction using p-methylated nitrostyrene 21d
also afforded the corresponding Michael adduct 25, the
enantioselectivity was substantially reduced (74%, dr = 89:11,
20% ee) (entry 4). Similarly, the use of p-methoxynitrostyrene
21e also afforded the corresponding adduct 25 at good chemical
yield and diastereoselectivity, but with low enantioselectivity
Considering both the good enantioselectivity (91% ee) of the
chiral Michael adduct [2R,3S]-18a that was obtained in the
reaction of 16a with 17 using catalyst 7 and the results of its
calculation studies (Fig. 2–5), an enantioselective reaction
course is proposed as follows (Scheme 3).
First, the frontier orbital DFT calculation between 16a and 17
was examined for consideration of the regioselectivity of the
reaction between 16a and 17 (Fig. 2). For the DFT calculation,
(83%, dr
=
89:11, 31% ee) (entry 5). When bulkier o-
Michael acceptor,
bromonitrostyrene 21f was used as
a
enantioselectivity was increased to a moderate level with good
chemical yield and diastereoselectivity (93%, dr = 88:12, 59%
ee) to afford the corresponding adduct 27 (entry 6). Furthermore,
the reaction using heterocyclic 2-1-(2-furyl)-2-nitroethylene 21g
was also carried out and adduct 28 was obtained at good
chemical yield with low enantioselectivity (94%, dr = 89:11, 30%
ee) (entry 7). On the other hand, the use of similar heterocyclic
2-[(E)-2-nitrovinyl]thiophene 21h afforded the adduct 29 at good
chemical yield and stereoselectivity (86%, dr = 91:9, 70% ee)
(entry 8). In a similar manner, the reaction is also examined with
aliphatic nitroolefin 21i with 16a in superior reaction conditions
(i-Pr2O, 0 °C, 24 h). However, the reaction did not proceed under
these conditions (entry 9).
Fig. 2. The frontier orbitals between 16a and 17 obtained by DFT calculations
at the 6-31 G(d) level using a B3LYP exchange-correction functional (the blue
and red dotted lines in the square expressed an interactions between the
molecular orbitals of 16a and 17).
catalyst
(10 mol%)
7
31a-e
+
17
Michael adducts
O
i-Pr2O
0 ºC, 24 h
O
O
O
O
O
O
O
O
31a: no reaction
31c: no reaction
31b: no reaction
O
O
32
O
O
O
O
68% yield
dr=53:47
racemate
Fig. 3. The scan of total energies for 16a-anion
O
O
O
NO2
Ph
the conformation of 16a-anion moiety was assumed by using
the scan of total energy analysis (Fig. 3). The energy levels of
the orbitals indicated the dominant interaction between the
HOMO of 16a and the LUMO of 17, and their orbital phase and
the coefficient of the orbital clearly showed matching in favor of
overlapping to afford the observed configuration of major adduct
18a (Fig. 2).
31d
31e: trace
Scheme 3. Asymmetric Michael additions of cyclic or acyclic b-keto esters
31a-e with 17 using organocatalyst 7
Moreover, we also examined the reactions of six membered
2-methoxycarbonylcyclohexanone 31a, seven membered 2-
methoxy-carbonylcycloheptanone 31b and 2-methoxycarbonyl-
indanone 31c with 17, respectively, in the superior reaction
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10.1002/ejoc.201900308
European Journal of Organic Chemistry
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Moreover, the conformational analysis of catalyst 7 was carried
out using the scan of total energy of catalyst 7-cation for
estimation of the enantioselective reaction course (Fig. 4).
species than those of Ts-2-4, which have a larger steric
interaction among substrates 16a, 17, and the ammonium
catalyst species (Scheme 4).
O
O
NO2
+
O
16a
17
OH
N
H
Ph
Ph
catalyst 7
O
O
O
O
O
O
N
O
O
O
O
O
O
O
N
N
O
O
O
O
N
H
N
O
H
H
N
H
H
O
O
H
H
O
H
O
N
O
N
O
H
H
H
H
H
H
H
H
Ts-1
Ts-2
Ts-4
Ts-3
91% ee
Fig. 4. The scan of total energies for 7
O
O
O
O
O
O
O
O
Based on the calculation results, the structure of catalyst 7-
cation might be fixed by the intramolecular hydrogen bonding
interaction between amino nitrogen atom and the hydroxyl
hydrogen atom at the side chain; thereby, 7-cation might have a
conformation with less steric interaction between the bulky 2-
azanorbornane skeleton and the phenyl group on the (S)-
phenylethyl substituent at the nitrogen atom.
In addition, in the electrostatic potential maps of 7-cation, 16a-
anion, and 17 based on the Mulliken charge distribution, the
positive charges were observed around both the amino nitrogen
atom and the hydroxyl hydrogen atom in the catalyst 7-cation,
and the negative charges were observed around both the nitro
oxygen atoms in nitrostyrene 17 and the ester oxygen atoms in
the β-keto ester moiety 16a-anion (Fig. 5).
O
O
O
O
NO2
NO2
NO2
NO2
Ph
Ph
Ph
Ph
[2R,3S]-18a
[2R,3R]-18a'
[2S,3S]-18a'
[2S,3R]-18a
Scheme 4. Plausible reaction course
In this reaction, 2-azanorbornane
7
with
a
mono-
phenylmethanol moiety and 2-azanorbornane 14 with a di-
phenylmethanol moiety showed a great difference in catalytic
activities; namely, the reaction using catalyst 7 afforded the
chiral Michael adduct 18a at good enantioselectivity (91% ee)
(entry 16, Table 2), while that using catalyst 14 only afforded
racemate 18a (entry 9, Table 1). This might depend on the steric
influences of the bulky structures of catalysts 7 and 14 (Scheme
5).
OH
N
H
O
Ph
91% ee
Ph
7
O
O
O
N
18a
H
H
O
N
O
H
H
Michael
addition
Ts-A
+
16a
17
O
O
N
O
H
O
racemic
O
rac-18a
H
O
N
OH
N
Ph
Ph
H
Ph
14
Scheme 5. Differences of enantioselectivities by catalysts 7 and 14
Thus, less bulky catalyst 7 might fix both substrates 16a and 17
by the hydrogen bonding interaction to afford high
enantioselectivity (91% ee). On the other hand, catalyst 14 that
is bulkier than catalyst 7 might be difficult to fix with substrate 17
for the steric influence of the phenyl group on the side chain.
Fig. 5. The electrostatic potential maps of 7-cation, 16a-anion and 17
Considering the above calculation results, the reaction might
proceed through any proposed Ts-1-4, in which substrate 16a
fixes with the ammonium hydrogen atom and 17 fixes with the
hydrogen atom that is formed by the intramolecular hydrogen
bonding interaction between amino nitrogen atom and the
hydroxyl hydrogen atom on the ammonium catalyst species. In
the proposed Ts-1-4, the reaction might proceed through Ts-2,
which has smaller steric interactions both between substrates
16a and 17 and between 16a and the ammonium catalyst
Conclusions
Newly designed optically active 2-azanorbornane-based amino
alcohol organocatalysts were developed based on a new design
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10.1002/ejoc.201900308
European Journal of Organic Chemistry
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NMR (500 MHz, CDCl3) δ 7.51-7.45 (m, 2H), 7.42-7.35 (m, 2H), 7.33-
7.27 (m, 1H), 7.16-7.02 (m, 3H), 6.73-6.66 (m, 2H), 3.67 (s, 1H), 3.59 (s,
1H), 3.47 (q, J = 6.5 Hz, 1H), 2.28-2.19 (m, 2H), 2.00 (s, 1H), 1.97-1.88
(m, 1H), 1.43 (m, 1H), 1.37 (d, J = 6.6 Hz, 3H), 1.33-1.24 (m, 1H), 1.09 (d,
J = 8.6 Hz, 1H), 0.97-0.91 (m, 1H), -0.01-0.04 (m, 9H). 13C-NMR (500
MHz, CDCl3) δ 146.76, 144.9, 129.08, 128.32, 127.55, 127.45, 126.14,
125.93, 76.74, 76.02, 62.01, 58.27, 37.02, 36.42, 29.76, 23.12, 22.79,
0.62. Ms m/z: 380 [M+H]. HRMS (EI) calcd for (C24H34NOSi): 379.6104,
found: 380.2405.
concept and their catalytic activities were examined in the
asymmetric Michael addition of various b-keto esters with
nitroolefins. All catalysts showed activities as catalysts in this
reaction. In particular, N-(S)-phenylethylated 2-azanorbornane 7
with a mono-phenylmethanol moiety showed the best catalytic
performance and the corresponding chiral Michael adducts
having a quaternary chiral carbon center were obtained with
good to excellent chemical yields (up to 99%),
diastereoselectivities (up to 91:9), and enantioselectivities (up to
91% ee). The modification of 2-azanorbornane-based amino
alcohol organocatalysts, the application to other substrates, and
detailed mechanistic study are underway.
General Procedure for Catalytic Asymmetric Michael addition of β-
Keto Ester 16a to Nitroolefins 21a-i
To the solution of catalyst 7 (10 mol%) in dry i-Pr2O (2 mL) were added
nitroolefines 21a-i (0.2 mmol) and b-keto ester 16a (0.4 mmol) and the
solution was stirred at 0 °C for 24 h, after completion of the reaction the
solvent was removed under reduced pressure and the residue was
purified by flash chromatography on silica gel (n-hexane/AcOEt = 10/1) to
give the chiral Michael adducts 22-30. The compounds 18a and 23-32
are the known compounds and the structures were identified by spectral
data which were in good agreement with those reported.[5]
Experimental Section
General
All reactions were performed under argon atmosphere in flame dried
glassware. Thin layer chromatography was performed on silica gel 60
F254, and the analytes were detected under UV light and coloration of
TLC performed in ninhydrin and iodine vapor. Column chromatography
was performed on silica gel 60N (40-100 µm), and PLC was performed
on silica gel 60 F254. Infrared (IR) spectra were measured with a FT-IR
Spectro-photometer (JASCO FT/IR-400). Optical rotations were
measured on JASCO DIP-360 digital polarimeter. 1H NMR (500 MHz)
and 13C NMR (125 MHz) spectra were measured using JEOL JNM-ECS
500 instrument and chemical shifts (d) are expressed in ppm down-field
from internal TMS. Diastereomeric ratio was determined by 1H-NMR of
crude reaction mixture and enantiomeric excess was determined by high
performance liquid chromatography (HPLC) with DAICEL CHIRALPAK
OD-H and CHIRALPAK IC columns. HRMS data were collected in
electron impact (EI) mode using Hitachi RMG-GMG sector instrument.
Acknowledgments
A part of this research is partially supported by the Adaptable
& Seam-less Technology Transfer Program through Target-
driven R&D from Japan Science and Technology Agency (JST)
(AS231Z01382G).
Keywords: organocatalyst・amino alcohol・2-
azanorbornane・Michael addition・asymmetric reaction
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to give 9 (36 mg, 67%). [a]D = 15.00 (c = 0.2, CH2Cl2); IR (neat) cm-1:
3510, 3315, 2975, 1450. 1H-NMR (500 MHz, CDCl3) δ 7.40-7.21 (m, 5H),
4.60 (d, J = 4.9 Hz, 1H), 3.29 (s, 1H), 2.28 (s, 3H), 2.03 (m, 2H), 1.92-
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10.1002/ejoc.201900308
European Journal of Organic Chemistry
FULL PAPER
Entry for the Table of Contents (Please choose one layout)
Layout 1:
A highly enantioselective Michael
addition of b-keto esters to
nitroolefins was carried out using
newly designed optically active
Key Topic *Asymmetric
Organocatalysis
R1
OH
R2
N
Ph
N
+
R2
(R1 : alkyl, H, R2 : Ph, H)
2-azanorbornane-based
amino alochol organocatalyst
Rei Togashi,[a] Madhu Chennapuram,[a]
Chigusa Seki,[a] Yuko Okuyama,[b]
Eunsang Kwon,*[c] Koji Uwai,[a] Michio
Tokiwa,[d] Mitsuhiro Takeshita,[d] Hiroto
Nakano*[a]
CO2Et
imino dienophile
cyclopentadiene
2-azanorbornane-based
amino
alcohol organocatalysts to produce
the corresponding chiral Michael
adducts in good chemical yields (up
to 99%) and stereoselectivities (up
to dr = 91:9, up to 91% ee).
O
O
asymmetric
Michael addition
O
O
∗
OR
NO2
+
∗
R'
NO2
OR
R'
chiral
Michael adducts
(up to 99% yield
dr = 91:9, 91% ee)
β-keto esters
nitroolefins
Page No. – Page No.
2-Azanorbornane-Based Amino
Alcohol Organocatalysts for
Asymmetric Michael Reaction of β-
Keto Esters with Nitroolefins
*Organocatalyst, 2-Azanorbornane-based amino alcohols, Asymmetric Michael Addition
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