Combined Computational and Experimental Studies on the Asymmetric Michael Addition of α-Aminomaleimides to β-Nitrostyrenes Using an Organocatalyst Derived from Cinchona Alkaloid

Article abstract of DOI:10.1021/acs.orglett.1c01831

Maleimides are often used as electrophiles in conventional reactions; however, their application as nucleophiles is limited to only a few reactions, and reactions utilizing α-aminomaleimides as asymmetric Michael donors have not been reported to date. Thus, in this work, asymmetric Michael addition of α-aminomaleimides as Michael donors to β-nitrostyrenes was conducted for the first time using an organocatalyst derived from a Cinchona alkaloid. Density functional theory investigations were crucial to improve the enantioselectivity of the adduct.

Full text of DOI:10.1021/acs.orglett.1c01831

pubs.acs.org/OrgLett
Letter
Combined Computational and Experimental Studies on the
Asymmetric Michael Addition of α‑Aminomaleimides to
β‑Nitrostyrenes Using an Organocatalyst Derived from Cinchona
Alkaloid
Naoki Sakai, Kyohei Kawashima, Masashi Kajitani, Seiji Mori,* and Takeshi Oriyama*
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ABSTRACT: Maleimides are often used as electrophiles in
conventional reactions; however, their application as nucleophiles
is limited to only a few reactions, and reactions utilizing α-
aminomaleimides as asymmetric Michael donors have not been
reported to date. Thus, in this work, asymmetric Michael addition
of α-aminomaleimides as Michael donors to β-nitrostyrenes was
conducted for the first time using an organocatalyst derived from a
Cinchona alkaloid. Density functional theory investigations were
crucial to improve the enantioselectivity of the adduct.
he application of organocatalysts in highly enantiose-
lective reactions has been extensively investigated in
from a Cinchona alkaloid. To the best of our knowledge, this
is the first report of asymmetric Michael addition using α-
aminomaleimides as nucleophiles.
T
recent decades1 because of their various advantages, such as
low toxicity, requirement of mild reaction conditions, low
cost, easy manipulation, and excellent enantiomeric excess
(ee). Therefore, the development of more efficient reactions
employing organocatalysts is essential. Particularly, organo-
catalysts derived from Cinchona alkaloids are applied in
various asymmetric reactions, including Michael addition,2
Mannich,3 aldol,4 Morita−Baylis−Hillman,5 and dihydrox-
ylation6 reactions. The quinuclidine moiety of these organo-
catalysts plays a significant role as an activator of
nucleophiles.
Initially, we examined β-nitrostyrene (1a)1f,11 as a Michael
acceptor to optimize the organocatalyst (Table 1). Un-
expectedly, when unmodified natural quinine and cinchoni-
dine were used as organocatalysts, the Michael adduct 3aa
was acquired in moderate to good yields with moderate ee’s
(entries 1 and 2, respectively). In contrast, when benzoyl-
protected quinine and cinchonidine were used as organo-
catalysts, 3aa was obtained only in a trace amount or in 15%
yield with low enantioselectivity, respectively. As β-nitro-
styrene is well-controlled by urea-type organocatalysts,1d urea
and thiourea were introduced to improve the enantioselec-
tivity (entries 5−10). Consequently, 3aa was formed in 81%
yield with 73% ee using catalyst J derived from quinine
containing a 3,5-bis(trifluoromethyl)phenyl moiety; thus, J
was selected as an appropriate catalyst. However, the ee’s
acquired using J were not satisfactory. Therefore, we
performed density functional theory (DFT) calculations to
improve the enantioselectivity of the adduct.
Maleimide is a promising framework because its derivatives
have remarkable physical7 and biological8 properties (Scheme
1a). Furthermore, asymmetric Michael addition of maleimides
has been extensively investigated because maleimides act as
suitable Michael acceptors.9 However, the products obtained
by Michael addition to maleimides as Michael acceptors are
converted to succinimides. In a few reactions, maleimides
have been utilized as nucleophilic agents10 for the highly
effective construction of maleimide-containing compounds via
direct introduction of the maleimide moiety (Scheme 1b).
Although maleimides are often employed as electrophiles,
their application as nucleophiles is limited to only a few
reactions, and reactions utilizing α-aminomaleimides as
asymmetric Michael donors have not been reported to date.
Therefore, in this work, we conducted the asymmetric
Michael addition of α-aminomaleimides as Michael donors
to β-nitrostyrenes using a bifunctional organocatalyst derived
Received: June 2, 2021
Published: July 13, 2021
https://doi.org/10.1021/acs.orglett.1c01831
© 2021 American Chemical Society
Org. Lett. 2021, 23, 5714−5718
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a
Scheme 1. Asymmetric Michael Addition Reactions
Table 1. Optimization of the Organocatalyst
b
c
entry
organocatalyst
yield (%)
ee (%)
d
1
2
3
4
5
6
7
8
9
A
B
C
D
E
F
G
H
I
78
74
trace
15
63
58
43
36
57
81
−55
−72
−
d
d
We proposed a plausible catalytic cycle (Scheme 2).
Coordination of 1a to J leads to urea−nitro group complex I.
−13
67
68
55
59
73
Scheme 2. Plausible Mechanism of the Asymmetric
Michael Addition Reaction
10
J
73
a
Reaction conditions: 1a (0.1 mmol), 2a (0.1 mmol), catalyst (20
b
mol %), CHCl3 (0.5 mL), room temperature, 48 h, open air. Isolated
yields. Determined by HPLC with a chiral IA column. Negative ee
c
d
values indicate that the S enantiomer of 3aa was formed preferentially.
of 3aa, respectively. The lowest-energy R conformation (R-
TSMe6) and S conformation (S-TSMe1) at the B3LYP+D3BJ/
6-311++G**(SMD)//M06-2X/6-31G**(SMD) level are
shown in Scheme 3a. By comparing the two TSs, we
obtained a ΔΔG⧧ (the Gibbs free energy of the most stable
TS leading to the S product relative to the most stable TS
leading to the R product) of 6.7 kJ mol−1 and a ΔΔH⧧ (the
enthalpy of the most stable TS leading to the S product
relative to the most stable TS leading to the R product) of
16.9 kJ mol−1 at 298.15 K between R-TSMe6 and S-TSMe1 via
thermal corrections. On the basis of these results, we
speculated that ΔΔS⧧ between these TSs was a dominant
factor in ΔΔG⧧. To achieve a significantly smaller ΔΔS⧧, we
increased the size of the N substituent of the maleimide,
which demonstrated high flexibility in the TS. Among N-
substituted maleimides, the N-isobutylmaleimide acts as a
potential inhibitor of Leishmania donovani.8c Therefore, we
analyzed the TS achieved by substituting the N-Me group of
the α-aminomaleimide with an N-iBu group (Scheme 3b).
Consequently, ΔΔG⧧ between the lowest-energy R con-
formation of N-iBu (R-TSiBu6) and the lowest S con-
formation of N-iBu (S-TSiBu2) was 15.9 kJ mol−1 and ΔΔH⧧
Then the maleimide hydrogen is activated by the
quinuclidine in I, and Michael addition occurs via a transition
state (TS) to give II. This C−C bond formation step is the
enantioselectivity-determining step. Thereafter, proton trans-
fer to the nitrostyrene moiety takes place to regenerate the
maleimide moiety and J. Initially, we employed S and R
conformations of TS, which resulted in S and R enantiomers
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Letter
substituted Michael adduct to verify the validity of the
above-mentioned results (see the Supporting Information).
Furthermore, we conducted intrinsic reaction coordinate
(IRC) analysis of R-TSiBu6 to confirm the reaction
mechanism along with energy decomposition analysis
(EDA) and non-covalent interaction (NCI) analysis to
understand the enantioselectivity. The electronic circular
dichroism (ECD) spectrum of 3ab was measured and
computed by time-dependent DFT calculations to determine
the stereochemistry of 3ab (see the Supporting Information).
Next, using J and 2b, we tested the effect of the solvent on
the yield and ee of 3ab (Table 2). When a polar protic
Scheme 3. Comparison of Transition States in the
Enantioselection Step
a
Table 2. Examination of the Solvent Effect
b
c
entry
solvent
CHCl3
CH2Cl2
(CH2Cl)2
chlorobenzene
MeOH
DMSO
THF
Et2O
yield (%)
ee (%)
1
2
3
4
5
6
7
8
83
85
84
73
15
24
53
63
86
88
87
87
34
d
−3
84
85
a
Reaction conditions: 1a (0.1 mmol), 2b (0.1 mmol), catalyst J (20
b
mol %), solvent (0.5 mL), room temperature, 48 h, open air. Isolated
c
d
yields. Determined by HPLC with a chiral IA column. The negative
ee value indicates that the S enantiomer of 3ab was formed
preferentially.
solvent (methanol) and an aprotic solvent (dimethyl
sulfoxide) were used, 3ab was obtained in only 15% and
24% yield with 34% and −3% ee, respectively (entries 5 and
6). In contrast, when a halogenic solvent or an ether was
employed, 3ab was obtained with high enantioselectivity
(entries 1−4, 7, and 8), possibly because of the high
solubility of the substrate in the solvent. Consequently, we
chose dichloromethane as an optimal solvent because it
provided 3ab in 85% yield with 88% ee (entry 2).
Moreover, the reaction conditions were optimized (Table
3). The concentration of reactant did not affect the ee of 3ab
(entries 1−3). Satisfactorily, 3ab with 88% ee was obtained
even when the amount of the catalyst was reduced to 1 mol
% (entries 3−6). When the reaction temperature was
changed to 10 °C, 3ab was obtained in 86% yield with
90% ee (entry 8). When the reaction temperature was
lowered further, the solubility of the substrate and hence the
product yield were reduced. Thus, the optimal reaction
conditions were as follows: 0.1 mmol of β-nitrostyrene and
0.1 mmol of α-aminomaleimide in 0.3 mL of dichloro-
methane with a catalyst loading of 1 mol % at 10 °C.
With the optimized reaction conditions in hand, we
investigated the substrate scope of β-nitrostyrene derivatives
(Scheme 4). When the phenyl moiety of β-nitrostyrene was
substituted with an electron-withdrawing group, the resulting
Michael adduct decomposed, and p-NO2-, p-COOMe-, and
was 13.9 kJ mol−1, as expected. Using these theoretical
results, we conducted the asymmetric Michael addition of N-
isobutyl-α-aminomaleimide 2b to β-nitrostyrene, and the
result is shown in Scheme 3c. When 2b was used instead of
2a as the Michael donor, the ee increased from 73% to 86%.
We also performed DFT calculations for the N-Bn-
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a
p-CN-substituted maleimides were isolated in 61%, 6%, and
7% yield, respectively. β-Elimination possibly occurred at the
chiral center. When β-nitrostyrenes with o-, m-, and p-bromo-
substituted phenyl moieties were used, the corresponding
Michael adducts were obtained in appropriate yields with
high enantioselectivities (3eb−gb). However, when β-nitro-
styrene with a p-bromo-substituted phenyl group was
employed, the catalyst loading had to be increased from 1
to 5 mol % to execute the reaction (3eb). Furthermore, the
reactivity of the para electron-donating group of β-nitro-
styrene was lower than those of the other groups, and thus, a
higher catalyst loading was required. The Michael adduct was
obtained in 94% yield with 90% ee when the catalyst loading
was increased from 1 to 5 mol % (3ib). Naphthyl and thienyl
groups were appropriately tolerated, and the desired products
3jb and 3kb were obtained in moderate yields with high ee’s.
However, β-nitrostyrene with a pyridyl moiety did not react
at all (3ib)
Finally, we examined the tolerance of α-aminomaleimides.
α-Aminomaleimides with a halogen-substituted phenyl ring
provided the corresponding Michael adducts in suitable yields
with high enantioselectivities (3ad and 3ae). When α-
aminomaleimides with a phenyl group containing an
electron-donating group were employed, the desired products
were obtained in appropriate yields with high enantioselec-
tivities (3af and 3ag). Our attempt to synthesize α-
aminomaleimides with electron-withdrawing groups, such as
a p-nitro group, was unsuccessful. When α-aminomaleimides
with an aliphatic moiety at the α-amino position were used,
the desired Michael adducts were rarely obtained (3ah−ak).
In conclusion, we have performed the asymmetric Michael
addition of α-aminomaleimides to β-nitrostyrenes using an
organocatalyst derived from Cinchona alkaloid for the first
time to afford chiral maleimides with up to 92% ee. This
reaction provides a new route to various useful chiral
maleimide derivatives. Furthermore, DFT results guided the
improvement of the ee of the adduct and revealed the
reaction mechanism, including the stereochemistry of the
adduct.
Table 3. Optimization of the Reaction Conditions
b
c
entry
X (mol %)
Y (mL)
temp. (°C)
yield (%)
ee (%)
1
2
3
4
5
6
7
8
9
20
20
20
10
5
2.5
1
1
1
0.5
0.3
0.3
0.3
0.3
0.3
0.3
0.3
0.3
0.3
rt
rt
rt
rt
rt
rt
rt
10
0
−10
−20
86
85
85
85
84
85
86
86
66
79
56
88
88
88
88
88
89
88
90
90
91
92
1
5
20
10
11
a
b
Reaction conditions: 1a (0.1 mmol), 2b (0.1 mmol), 48 h, open air.
Isolated yields. Determined by HPLC with a chiral IA column.
c
a b c
, ,
Scheme 4. Substrate Scope
ASSOCIATED CONTENT
* Supporting Information
■
sı
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.1c01831.
General information, catalyst screening using N-iBu
maleimide, experimental procedure, characterization
data, fluorescence data, details and references of
computational study, IRC analysis, EDA analysis, NCI
analysis, ECD spectra, and copies of NMR and HPLC
spectra (PDF)
FAIR data, including the primary NMR FID files, for
compounds 2b, 2d−k, 3aa−ag, 3bb, and 3eb−kb
(ZIP)
AUTHOR INFORMATION
Corresponding Authors
■
a
Takeshi Oriyama − Department of Chemistry, Faculty of
Science, Ibaraki University, Mito, Ibaraki 310-8512, Japan;
Email: takeshi.oriyama.sci@vc.ibaraki.ac.jp
Seiji Mori − Department of Chemistry, Faculty of Science
and Institute of Quantum Beam Science, Ibaraki University,
Mito, Ibaraki 310-8512, Japan; Frontier Research Center
Reaction conditions: 1 (0.1 mmol), 2 (0.1 mmol), catalyst J (1 mol
b
%), CH2Cl2 (0.3 mL), 10 °C, 48 h, open air. Isolated yields are
shown. The enantiomeric excess was determined by HPLC with a
chiral IA column. Decomposition of the Michael adduct. The
catalyst loading was 5 mol %.
c
d
e
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for Applied Atomic Sciences, Ibaraki University, Tokai,
pubs.acs.org/OrgLett
Letter
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Authors
Naoki Sakai − Department of Chemistry, Faculty of Science,
Ibaraki University, Mito, Ibaraki 310-8512, Japan
Kyohei Kawashima − Institute of Quantum Beam Science,
Ibaraki University, Mito, Ibaraki 310-8512, Japan; Present
Address: Institute for Materials Chemistry and
Engineering, Kyushu University, 6-1 Kasugakoen,
Kasuga, Fukuoka 816-8580, Japan
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Masashi Kajitani − Department of Chemistry, Faculty of
Science, Ibaraki University, Mito, Ibaraki 310-8512, Japan
Complete contact information is available at:
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Author Contributions
M.K. and T.O. designed the project. N.S. conducted all of the
experiments. N.S. and K.K. performed all of the calculations.
N.S., S.M., and T.O. analyzed and discussed the data and
wrote the manuscript.
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Funding
This work was supported by Grants-in-Aid for Scientific
Research (C) (Japan Society for the Promotion of Science
KAKENHI Grants JP21K05016 to S.M. and JP21K05065 to
T.O.).
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Agents. Eur. J. Med. Chem. 2003, 38, 123−140. (b) Sivaprakasam,
P.; Xie, A.; Doerksen, R. J. Probing the Physicochemical and
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Chem. 2006, 14, 8210−8218. (c) Fan, Y.; Lu, Y.; Chen, X.;
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Activities of a Series of Maleimides: Synthesis, Biological Evaluation
and Structure-Activity Relationship. Molecules 2018, 23, 2878−2887.
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Asymmetric Organocatalytic Addition Reactions of Maleimides: A
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Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The generous allotment of computation time from the
Research Center for Computational Science, the National
Institutes of Natural Sciences, Japan, is gratefully acknowl-
edged.
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