Asymmetric Synthesis of an Amino Acid Derivative from Achiral Aroyl Acrylamide by Reversible Michael Addition and Preferential Crystallization

Article abstract of DOI:10.1002/chem.201604207

Single-handed α-amino acid derivatives were generated from achiral precursors without an external chiral source. Conjugate addition of phenethylamine to an achiral aroyl acrylamide under homogeneous conditions gave the α-amino amides in quantitative yields, which crystallized as a conglomerate of a P2₁crystal system. Dynamic preferential crystallization or attrition-enhanced deracemization resulted in the formation of enantiomorphic crystals of 99 % ee.

Full text of DOI:10.1002/chem.201604207

A Journal of
Accepted Article
Title: Asymmetric Synthesis of Amino Acid Derivative from Achiral Aroylacrylamide
by Reversible Michael Addition and Preferential Crystallization
Authors: Yuki Kaji; Naohiro Uemura; Yoshio Kasashima; Hiroki Ishikawa; Yasushi
Yoshida; Takashi Mino; Masami Sakamoto
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COMMUNICATION
Asymmetric Synthesis of Amino Acid Derivative from Achiral
Aroylacrylamide by Reversible Michael Addition and Preferential
Crystallization
Yuki Kaji,[a] Naohiro Uemura,[a] Yoshio Kasashima,[b] Hiroki Ishikawa,[a] Yasushi Yoshida,[a] Takashi
Mino,[a] and Masami Sakamoto*[a]
Abstract: Single-handed -amino acid derivatives were generated
from achiral precursors without an external chiral source. Conjugate
addition of phenethylamine to an achiral aroylacrylamide under
homogeneous conditions gave the -amino amides in quantitative
yields, which crystallized as a conglomerate of a P21 crystal system.
examples demonstrate that the combined methodology of a
chemical reaction to generate chiral center and
a
deracemization by the reverse reaction is quite effective in
creating chiral materials under absolutely achiral conditions. In
our study, asymmetric synthesis of -amino acid derivatives
under absolutely achiral conditions was targeted. To achieve this
asymmetric reaction, the combination of a Michael addition of
achiral amines to -unsaturated amides and dynamic
crystallization of the racemic conglomerate crystal was proposed
(Figure 1). A chiral crystal in the starting precursor or external
optically active source is not required for the asymmetric
synthesis, but the key feature of this method is the racemic
conglomerate crystals as the product.
Dynamic
preferential
crystallization
or
attrition-enhanced
deracemization resulted in the formation of enantiomorphic crystals
of 99% ee.
Chiral materials are essential for biological, pharmaceutical, and
industrial purposes, and new methodologies for their generation
are in high demand. Many effective methods for producing chiral
materials have been developed, such as those involving
catalytic asymmetric reaction and optical resolution. On the
other hand, the synthesis of chiral molecules of single-
handedness from achiral reactants under achiral conditions, i.e.,
absolute asymmetric synthesis, is still a widely attractive and
challenging topic. This premise is central to the hypothesis for
the origin of homochirality on prebiotic Earth.[1] Absolute
asymmetric synthesis using only the chirality of crystals without
an external chiral source has been investigated by many
interesting methods, such as solid-state photochemical
reactions,[2] asymmetric reactions using frozen chirality,[3] and
dynamic preferential crystallization.[4] Pioneering work in
dynamic preferential crystallization using racemic conglomerate
crystals was reported by Havinga.[5] Furthermore, many
examples of axially chiral materials,[6] amino acids,[7] and
pharmaceutical materials[8],[9] were found to provide single-
handed molecules selectively. Herein, we report the
development of a new absolute asymmetric synthesis involving
a combined methodology to generate chiral centers from achiral
materials with deracemization by dynamic crystallization.
Recently, an asymmetric transformation of achiral meso-2,3-
diphenylsuccinimides to the chiral trans-isomers followed by
dynamic preferential crystallization was demonstrated in high
ees under absolutely achiral conditions.[10] Furthermore, aza-
Michael addition to an enone leading to an optically active
aminoketone[11] and Strecker reaction[12] were also reported by
deracemization involving dynamic crystallization. All these
Figure 1. Asymmetric synthesis using a combined methodology
To create single-handed chirality of an amino acid derivative, we
first demonstrated the reversible Michael addition of alkylamines
to aroylacrylamides (Scheme 1).[13] We found that 2 synthesized
by Michael addition of 2-phenethylamine to 2-benzoyl-N-(p-
tolyl)acrylamide 1 afforded a conglomerate crystal of the P21
crystal system (Figure S1).[14] In the crystal, an intermolecular
hydrogen bond between the amide carbonyl and the hydrogen
atom of the phenethylamino group was found with a distance of
3.15 Å (between the oxygen and the nitrogen atoms), promoting
the formation of a 21 helix along the b-axis (Figure S2). When a
racemic mixture of 2 was crystallized from solution, each single
crystal obtained was composed of a single-handed enantiomer.
[a]
[b]
Mr. Y. Kaji, Mr. N. Uemura, Mr. H. Ishikawa, Prof. Y. Yoshida, Prof.
T. Mino, Prof. M. Sakamoto
Department of Applied Chemistry and Biotechnology, Graduate
School of Engineering, Chiba University, Yayoi-cho, Inage-ku, Chiba
263-8522, Japan
E-mail: sakamotom@faculty.chiba-.jp
Prof. Y. Kasashima
Education Center, Faculty of Engineering, Chiba Institute of
Technology, Shibazono, Narashino, Chiba 275-0023, Japan
Supporting information for this article is given via a link at the end of
the document.
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rapidly occurred in solution to give both enantiomers of the
adduct in equal amounts. Gradually evaporating the solvent
caused the solution to become saturated and the poorly soluble
adduct started to precipitate. The first generated crystal
functioned as a seed crystal for subsequent crystallization and
was amplified by dynamic racemization by reverse Michael
addition in solution. Finally, the balance between the rates of
racemization and crystallization decided the enantiomeric purity
based on the amount of each enantiomorphic crystal.
Scheme 1. Reversible Michael addition of amine to benzoylacrylamide 1.
Next, we examined conjugate addition followed by attrition-
ripening).[16]
Preferential crystallization can be applied to racemic
conglomerate crystals, yielding single crystals composed of
single-handed enantiomers.[4] Furthermore, through the
racemization process promoted during the crystallization, single-
handed enantiomers can be obtained by dynamic crystallization
from racemic mixtures. It is well-known that the Michael addition
of amines to conjugated carbonyl compounds is reversible. In
fact, when 2 was allowed to stand at room temperature
overnight in CD3OD, the reverse reaction was promoted and
eliminated substrate 1 and the methanol adduct 3 were formed
in the ratio of 2 : 1 : 3 = 33 : 11 : 56 as a stationary state
(Scheme S1). The MeOH adduct 3 was apparently generated in
solution; however, it was not observed in the solidified crude
mixture after evaporation. The stereocenter of the Michael
adduct 2 was stable and did not racemize under aprotic
conditions; however, racemization was certainly promoted in a
protic solvent by a reversible path.
enhanced
deracemization
(Viedma’s
Arolyacrylamide 1 was reacted with 1.5 eq of phenethylamine in
EtOH with or without glass beads (Figure 3). The cycloaddition
reaction proceeded smoothly and the solid of adduct amino
amide 2 appeared immediately. The reaction mixture was
continuously stirred over several days while monitoring the ee
value. In solution, the racemization proceeded by reverse
conjugate addition reaction and deracemization by Viedma’s
ripening.
We demonstrated three methods for chirality generation and
amplification by using this reversible Michael addition and
crystallization. The first involved deracemization by dynamic
preferential crystallization by evaporating solvent to accelerate
crystallization. The second method was a combination of
racemization by reversible reaction and attrition-enhanced
deracemization. The last one was the combined methodology of
both methods.
Figure 2. Asymmetric synthesis of -amino amide 2 by reversible conjugate
addition and dynamic preferential crystallization.
First, we demonstrated the conjugate addition followed by
dynamic
preferential
crystallization
while
promoting
When we used glass beads with a stir bar, the ee value started
to increase after 14 days, reaching 95% ee after 22 days (Figure
4, blue squares). The ee was measured for both the mother
liquor and the solid. The ee value of the solid after 22 days was
99%, while that of the mother liquor was nearly racemic. Without
glass beads and with only a stir bar, the starting time was
delayed to 25 days; furthermore, the rate of deracemization
became slow and took as many as 45 days to reach a stationary
state (Figure 4, red circles) with the same ee value as that
obtained with glass beads. Thus, the use of glass beads was
effective in accelerating the rate of deracemization. This
reversible reaction was also efficiently accelerated by DBU in
aprotic solvent; however, DBU in protic solvent was not as
effective.[17] When DBU (0.5 eq) was added to the reaction
system (Figure 4, green triangles), some effect appeared on the
starting point of deracemization; however, the inclination of the
line of deracemization was almost the same. This reaction
afforded the asymmetric synthesis of an amino acid derivative
by reversible Michael addition.
crystallization by evaporating the solvent.[4] After 2-benzoyl-N-(p-
tolyl)acrylamide 1 and phenethylamine (1.3 eq) were dissolved
in a mixed solvent of EtOH and heptane, the reaction mixture
was warmed at 60 °C with grinding by using a magnetic stir bar
in open air until all the solvent was removed (Figure 2). The
addition of amine occurred immediately and solids of adduct 2
gradually appeared and grew. Finally, a quantitative amount of 2
was obtained and deracemization solidification gradually
occurred over 2 days to form optically active enantiomorphic
crystals. Due to the slow racemization, the ee of the produced
adduct 2 was only 45% even under optimized conditions. The
optimum amount of phenethylamine was 1.3 eq, because the
addition reaction occurred with an excess amount of amine;
however, the use of a large amount of amine prevented
crystallization. The racemization involving the back reaction
occurred faster in alcoholic solvent than in aprotic solvent. Thus,
we used ethanol as the major solvent. However, the
racemization rate was still slow compared to the rate of
crystallization even in ethanol at 60 °C. Therefore, the ee value
of the generated crystals was moderate. In these procedures,
both enantiomers appeared randomly in each crystallization
batch with almost the same probability.[15] The addition reaction
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COMMUNICATION
in a short period of time. First, benzoylacrylamide 1 and
phenethylamine (1.3 eq) were reacted in a mixed solvent of
MeOH and hexane, and the reaction mixture was vigorously
stirred while evaporating solvent at 40 °C. It took about a half
day to remove all the solvent. The ee value of the solid of adduct
2 was around 15%. To the solid, ethanol as a solvent, DBU (0.5
eq), and glass beads were added, and the suspended mixture
was stirred vigorously. The changes in ee values for the reaction
mixture (including both mother liquor and crystals) were plotted.
Deracemization began in a short time and the ee increased to
95% in only 8 or 9 days (Figure 5). In all cases the final ee value
of the separated solid was 99%. Thus, we shortened the
reaction time significantly by dynamic preferential crystallization
followed by Viedma’s ripening. The handedness of the chirality
of the crystal was determined by the first generated enantiomer
by dynamic preferential crystallization. When we started from
15% ee of (+)-(R)-2 crystals, the deracemization produced 95%
ee of (+)-(R)-2 [Figure 5-(a)]. When a small excess of (-)-(S)-2
(16% ee) was obtained by evaporating the solvent, the second
deracemization was amplified to (-)-(S)-2 [Figure 5-(b)], and
nearly enantiopure crystals of (-)-(S)-2 were obtained.
Figure 3. Asymmetric synthesis of -amino amide by conjugate addition and
attrition-enhanced deracemization.
In these procedures, both enantiomers appeared randomly in
each batch at almost the same probability.[15] Once the achiral
substrates, 1 and phenethylamine, were suspended in solution,
the reaction occurred to give both enantiomers of the product in
equal amounts. As the reaction progressed, the solution became
saturated with the poorly soluble product, and both enantiomers
of the product precipitated in equal amounts as racemic
conglomerate crystals. The solid of 1 was gradually replaced
with the solid of product 2. The initial symmetry of this solid state
was broken due to either local statistical fluctuations in ee or a
local difference in crystal size distribution between the
enantiomers. Subsequently, grinding of the crystals in
combination with solution-phase racemization (Viedma ripening)
caused complete deracemization of the solids. The reaction
proceeded quantitatively, and the yield of the filtered solid
product was 90% with 99% ee.
Figure 5. Chiral generation and amplification using the combined methodology
of dynamic preferential crystallization and Viedma’s ripening. (a) Viedma’s
ripening was started from 15% ee of (+)-2. (b) Viedma’s ripening was started
from 16% ee of ()-2.
In conclusion, asymmetric synthesis of an -amino amide was
performed under absolutely achiral conditions involving
deracemization. The conjugate addition of phenethylamine to
benzoylacrylamide efficiently proceeded to give an -amino
Figure 4. Chiral generation and amplification using Viedma’s ripening.
amide
which
crystallized
as
conglomerate
crystals.
Deracemization proceeded via a reversible reaction and gave
optically active adduct crystals via dynamic preferential
crystallization at 45% ee. Reversible addition reaction followed
by Viedma’s ripening using glass beads gave 99% ee for the
solid by slow deracemization over several days. We were able to
reduce the reaction time by the combination of dynamic
preferential crystallization followed by attrition-enhanced
deracemization. We achieved the absolute asymmetric
synthesis of an -amino acid derivative under absolute achiral
As described above, moderate chiral induction of 45% ee was
achieved in a couple of days by conjugate addition followed by
the dynamic preferential crystallization method. On the other
hand, a considerably higher ee value was obtained with the
second method by using Viedma’s ripening, although several
days were required for effective deracemization even in the
presence of DBU. Therefore, we examined combining the
methodology of both procedures to obtain optically pure crystals
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This work was supported by Grants-in-Aid for Scientific
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Ministry of Education, Culture, Sports, Science and Technology
(MEXT) of the Japanese Government.
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Keywords: Michael addition • asymmetric synthesis •
deracemization • dynamic preferential crystallization • amino
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COMMUNICATION
Entry for the Table of Contents (Please choose one layout)
Layout 1:
COMMUNICATION
Single-handed
-amino
acid
Yuki Kaji, Naohiro Uemura, Yoshio
derivatives were generated from
achiral precursors without an external
chiral source. Conjugate addition of
Kasashima, Hiroki Ishikawa, Yasushi
Yoshida, Takashi Mino, Masami
Sakamoto*
phenethylamine
to
an
achiral
aroylacrylamide under homogeneous
Page No. – Page No.
conditions gave the -amino amides
in
quantitative
yields,
which
Asymmetric Synthesis of Amino Acid
Derivative from Achiral
Aroylacrylamide by Reversible
Michael Addition and Preferential
Crystallization
crystallized as a conglomerate of a
P21 crystal system. Dynamic
preferential crystallization or attrition-
enhanced deracemization resulted in
the formation of enantiomorphic
crystals of 99% ee.
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