Absolute Asymmetric Synthesis of an Aspartic Acid Derivative from Prochiral Maleic Acid and Pyridine under Achiral Conditions

Article abstract of DOI:10.1002/asia.201901324

The asymmetric synthesis of an aspartic acid derivative, N-succinopyridine, from prochiral starting materials involving dynamic enantioselective crystallization was accomplished without using any external chiral source. The aza-Michael addition reaction of prochiral maleic acid and pyridine afforded racemic conglomerate N-succinopyridine in water. Continuous stirring of the suspension of the reaction mixture with acetic acid promoted gradual deracemization to afford a crystal with an excellent optical purity of 99 % in 71 % yield.

Full text of DOI:10.1002/asia.201901324

DOI: 10.1002/asia.201901324
Communication
Absolute Asymmetric Synthesis of an Aspartic Acid Derivative
from Prochiral Maleic Acid and Pyridine under Achiral Conditions
[
a]
[a]
[a]
[a, b]
[a, b]
Naohiro Uemura, Kento Sano, Arisa Matsumoto, Yasushi Yoshida,
Takashi Mino,
[a, b]
and Masami Sakamoto*
Abstract: The asymmetric synthesis of an aspartic acid de-
rivative, N-succinopyridine, from prochiral starting materi-
als involving dynamic enantioselective crystallization was
accomplished without using any external chiral source.
The aza-Michael addition reaction of prochiral maleic acid
and pyridine afforded racemic conglomerate N-succino-
pyridine in water. Continuous stirring of the suspension of
the reaction mixture with acetic acid promoted gradual
deracemization to afford a crystal with an excellent optical
purity of 99% in 71% yield.
Scheme 1. Asymmetric synthesis involving dynamic crystallization from pro-
chiral starting materials under achiral conditions.
namic crystallization and either a reverse reaction or a direct
[15]
racemization of the generated chiral center of the product.
Here, we describe the asymmetric synthesis of amino acid
derivatives using this methodology. The basic requirements
are: (1) a racemic conglomerate crystal and (2) fast racemiza-
tion under crystallization conditions. So far, most essential
[16]
[17]
Reactions in which optically active products are obtained from
prochiral starting materials without using chiral sources, i.e.,
absolute asymmetric synthesis, have been linked to the homo-
chirality of living matter and the origin of life, and are of inter-
amino acids except asparagine
and glutamic acid
have
either not given conglomerate crystals, or gave a conglomer-
[18]
ate as one of multiple polymorphs. It is not easy to control
polymorphism in dynamic crystallization. We focused on one
aspartic acid derivative, N-succinopyridine, synthesized by Mi-
chael addition of pyridine to maleic acid, crystallized as a con-
[
1]
est in many research fields. To date, absolute asymmetric syn-
thesis has been limited to the application of physical chiral
[
2]
[19]
forces such as circularly polarized light and chiral magnetic
glomerate in a chiral space group of P2 2 2 . Therefore, we
1
1 1
[
3]
[4]
fields. The Soai reaction and asymmetric synthesis using the
chirality of crystals generated by the crystallization of prochiral
materials are also considered to be methods for absolute
investigated the asymmetric synthesis of N-succcinopyridine
from prochiral starting materials and the conditions for its de-
racemization. N-Succinopyridine can be converted to aspartic
[
5,6]
[20]
asymmetric synthesis.
Recently, an asymmetric synthetic
acid, and is also a useful second-order nonlinear optical ma-
[21]
methodology has been developed that combines the genera-
tion of a chiral center from prochiral materials with deracemi-
zation via dynamic crystallization (Scheme 1). Some valuable
terial.
N-Succinopyridine 2 was effectively obtained by aza-Michael
addition of maleic acid 1 and pyridine in a water solution
(Scheme 2). The aza-Michael addition is a well-established re-
versible reaction, and it has been suggested that racemization
[7]
examples have been reported for the Mannich reaction, aldol
[
8]
reaction, desymmetrization from meso compounds via stereo-
[
9]
[10]
[10]
isomerization, aza-Michael addition reaction, Strecker reac-
may possibly occur through the reverse reaction. It is also
[
11]
tion, photoisomerization followed by ring-closing and ring-
plausible that racemization is promoted through the enol form
or enolate anion, because the acidity of the a-position of the
protonated amino acid is relatively high, and it is easily depro-
tonated under acidic and basic conditions. Therefore, this reac-
tion system is suitable for dynamic crystallization using a con-
glomerate crystal.
[
12]
[13]
opening reactions, photodimerization reaction, and Diels–
[
14]
Alder reaction. All processes involved deracemization by dy-
[
a] N. Uemura, K. Sano, A. Matsumoto, Dr. Y. Yoshida, Prof. Dr. T. Mino,
Prof. Dr. M. Sakamoto
Department of Applied Chemistry and Biotechnology
Graduate School of Engineering
Chiba University
A single crystal obtained from a water/methanol solution by
the vapor diffusion method was used for the XRD and high-
performance liquid chromatography (HPLC) analysis. The per-
spective view in Figure S1(a) shows that the space group is
Yayoi-cho, Inage-ku, Chiba 263-8522 (Japan)
E-mail: sakamotom@faculty.chiba-u.jp
[
b] Dr. Y. Yoshida, Prof. Dr. T. Mino, Prof. Dr. M. Sakamoto
Molecular Chirality Research Center
Chiba University
[19]
P2 2 2 , which is the same as that previously reported. The
1
1 1
packing diagram indicates that the carboxylic acid close to the
pyridinium ion has a deprotonated structure. Carboxylic
acid and carboxylate ions form intermolecular hydrogen
bonds(OHÀO, 1.695 ꢀ) along the b-axis to produce a column
as seen in Figure S1(b).
Yayoi-cho, Inage-ku, Chiba, 263-8522 (Japan)
Supporting information and the ORCID identification number(s) for the au-
thor(s) of this article can be found under:
https://doi.org/10.1002/asia.201901324.
th
This manuscript is part of a special collection celebrating the 100 Annual
The space group was chiral P2 2 2 which indicated that the
Meeting of the Chemical Society of Japan (CSJ). Click here to see the Table
of Contents of the special collection.
1 1 1
crystal was a conglomerate. However, the crystal data also indi-
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Figure 1. Time course for the deuterium labelling experiment of suc-cinopyr-
idine in D O at 908C.
2
pathway were observed. Even after almost all the starting suc-
cinopyridine (2 ) was consumed, less than 6% of the reverse
H
reaction products were formed. This indicates that racemiza-
tion occurred by a deprotonation mechanism as the major
pathway. Although succinopyridine has two types of a-pro-
tons, only the chiral carbon was deuterated, because there was
very little exchange of methylene protons with deuterium.
These results closely correlate with the racemization mecha-
nism that was involved in the deprotonation process.
Scheme 2. Aza-Michael addition of pyridine to maleic acid followed by dera-
cemization via dynamic crystallization.
cated that the crystal was twinned and the HPLC analysis of
the single crystal showed that it was composed of a 73:27 mix-
ture of enantiomers (Figure S2).
Next, we explored the conditions under which faster racemi-
zation is promoted. Racemization of enantiopure succinopyri-
dine in water or mixed solvent in the presence of various acids
was studied (Figure 2). In water without an additive, the half-
Next, we analyzed the crystal structure by powder XRD to
elucidate the possibility of polymorphic crystal systems. The
powdered crystalline 2 was produced by two methods. The
first was crystallization by slow evaporation of water at 908C.
The other solid sample was produced by the suspension of
crystalline succinopyridine in water at 908C for seven days.
Powder XRD analysis of both crystals showed the same spectra
as the pattern simulated by single-crystal XRD analysis. These
results suggest that N-succinopyridine is not polymorphic
under these conditions (Figure S3).
Targeted deracemization requires fast racemization under
the crystallization conditions. We examined the rate of racemi-
zation of succinopyridine in solution. There are two possible
pathways for racemization: deprotonation at the chiral center
of the a-position of the carbonyl group, or a reversible reac-
tion (Scheme 2). To analyze the racemization pathway, a deute-
rium labeling experiment was carried out (Scheme 3). Succino-
pyridine (2 ) was dissolved in D O and the time course of the
Figure 2. Time course for racemization of optically active succinopyridine at
908C in H O in the presence of acetic acid, trifluoroacetic acid, or trifluoro-
2
methanesulfonic acid.
H
2
change in the deuterated ratio at 908C was monitored by nu-
clear magnetic resonance (NMR) spectroscopy (Figure 1). After
life for racemization at 908C was 115 min. An investigation of
different acids revealed that acetic acid was the most suitable
catalyst for racemization. The half-life for racemization was re-
duced to 20 min in 10% (v/v) aqueous acetic acid at 908C. On
the other hand, the strong acids TFA (trifluoroacetic acid) and
TfOH (trifluoromethanesulfonic acid) reduced the racemization
rate, and the half-life using 10% (v/v) water was 501 min and
9
0 min, around half of the starting succinopyridine (2 ) was
H
deuterated at the chiral center. Very small amounts of maleic
acid 1D and fumaric acid 3D formed by the reverse reaction
1400 min, respectively. Using a base such as aqueous sodium
hydroxide or 1,8-diazabicycloundec-7-ene (DBU), decomposi-
tion of succinopyridine occurred along with racemization.
These results strongly suggested the possibility of applying
dynamic enantioselective crystallization to these systems as
shown in Scheme 2. We could easily obtain a few millimeter
Scheme 3. Investigation of racemization pathways by the deuterium label-
ling reaction in D O.
2
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square crystals by the usual recrystallization method from hot
water; however, the ee value was quite low since it was a twin-
ned crystal. In contrast, the ee values for small single crystals
were high. By regulating the crystal size to be relatively small,
the possibility of convergence to a crystal with high optical
purity is expected.
yield still needed improvement. Finally, ethanol (1.0 mL) was
added as a poor solvent to promote precipitation during dera-
cemization, and the continuous suspension gave 99% ee for
the solid in 71% chemical yield after filtration.
The experiment was repeated several times, and it was con-
firmed that the probability of tilting to either enantiomer was
about 1:1 and that the directionality of the asymmetric amplifi-
cation could be controlled by adding a small amount of enan-
tiomorphic crystals during attrition-enhanced deracemization.
In conclusion, we developed the first example of asymmetric
synthesis of an aspartic acid derivative from prochiral starting
materials involving dynamic enantioselective crystallization
with excellent optical purity of 99% ee without using any ex-
ternal chiral source. This reaction system is an absolute asym-
metric synthesis and will be of interest to many researchers be-
cause the reaction is strongly linked to homochirality on Earth.
Furthermore, this reaction process involving a chemical reac-
tion generating a chiral center followed by deracemization via
dynamic crystallization is simple and applicable to industrializa-
tion.
We examined the asymmetric synthesis of 2 involving attri-
[
22,23]
tion-enhanced deracemization (Viedma ripening).
When an
aqueous solution of maleic acid (0.595 g, 5.12 mmol) and pyri-
dine (0.405 g, 5.12 mmol) was stirred at 908C for 1 h, 2 precipi-
tated by the aza-Michael addition reaction. Subsequently,
acetic acid and glass beads (0.5 g) were added, and the solu-
tion was kept in suspension with stirring at the same tempera-
ture for several days. The change in the ee value for 2 for both
the crystalline phase and the mother liquor was analyzed by
HPLC using CHIRALPAK ZWIX(+) (Figure 3).
Experimental Section
General: NMR spectra were recorded in D O solutions on a
2
1
BRUKER 300 operating at 300 and 75 MHz, respectively, for H- and
13
C-NMR spectroscopy. Chemical shifts are reported in parts per
million (ppm). IR spectra were recorded on a JASCO FT/IR-230
spectrometer. HPLC analyses were performed on a JASCO HPLC
system (JASCO PU-1580 pump, DG-1580-53, LG-2080-02, MD-2015,
and CD-2095 detector). X-ray single crystallographic analysis was
conducted using a SMART APEX II ULTRA (Bruker AXS). Powder
XRD analysis was conducted using a D8 ADVANCE (Bruker AXS).
Figure 3. Asymmetric synthesis of 2 from prochiral maleic acid and pyridine
involving attrition-enhanced deracemization in aqueous acetic acid at 908C.
Using a mixed solvent of water and acetic acid in a ratio of
Asymmetric synthesis of N-succinopyridine via attrition-en-
hanced deracemization: A solution of maleic acid (1) (595 mg,
1
:3 by volume (water 0.25 mL: acetic acid 0.75 mL), deracemi-
zation began after 3 days and the ee value increased to 80%
ee after 6 days (Figure 3, red line). The analyzed sample includ-
ed both crystalline and dissolved compound in the mother
liquor. On the other hand, the filtered solid of 2 was obtained
in 22% chemical yield with 99% ee.
5.12 mmol) and 1.0 equiv. of pyridine (405 mg, 5.12 mmol) in H O
2
(0.25 or 0.40 mL) was stirred using an oval magnetic stirring bar
with or without glass beads (12.0 mm, 500 mg) in a sealed tube
at 908C. After crystalline 2 appeared, acetic acid (0.75 or 0.60 mL)
was added. The solution was kept in suspension with stirring at
the same temperature for several days.
To increase the chemical yield and the ee value, the ratio of
acetic acid was reduced, because acetic acid is the good dis-
solving solvent. Following the addition reaction in water, the
ratio was adjusted to 1:1.5 water (0.4 mL) and acetic acid
The ee value of 2 was monitored by HPLC using a chiral column,
CHIRALPAK ZWIX(+) (Daicel Ind.): eluent: MeOH/MeCN/H O/formic
2
acid/diethyl amine=490/490/20/1.9/2.6 (v/v/v/v/v).
Enantioselectivity of asymmetric reaction: Ten experiments were
(0.6 mL), whereupon the deracemization rate became a little
performed at optimized conditions (H O : AcOH=1:1.5, with glass
2
slower. The ee value started to increase at the ninth day and
reached 93% after 16 days (Figure 3, blue line). In this case,
the yield of the solid product after filtration was improved to
beads) in order to examine the probability of tilting to either enan-
tiomer. As the result, 6 times (À)-2 and 4 times (+)-2 were ob-
tained.
4
7% yield with 99% ee.
Control of chirality by seeding: We also attempted to control
chirality of dynamic crystallization by adding seed crystals. Maleic
acid (0.595 g), pyridine (0.405 g) and water (0.4 mL) were added to
a sealed tube, and the aqueous solution was stirred at 908C. After
crystalline N-succinopyridine 2 was appeared, acetic acid (0.6 mL),
glass beads (12.0 mm, 500 mg), and powdered seed crystal of
A control experiment was carried out to confirm the effect
of the glass beads. Under the same conditions as the blue line
using the solvent (water:acetic acid=1:1.5), asymmetric syn-
thesis followed by deracemization was examined without glass
beads. The rate of deracemization became slower and 28 days
were required to reach 91% ee. The solid succinopyridine after
filtration was obtained in 51% yield with 99% ee (Figure 3,
purple line).
(
À)-form (ca. <5 mg) were added. Next day, the ee value of sus-
pended solution increased to 14% ee (À) form, and ee value
reached 89% ee (À) form after 4 days.
Single-crystal X-ray structure analysis of N-succinopyridine 2 :
3
Asymmetric synthesis of the aspartic acid derivative with
very high optical purity was performed; however, the chemical
Colourless prism (0.20ꢂ0.10ꢂ0.10 mm ), orthorhombic space
group P2
2
1
2
1
, a=7.7020(2) ꢀ, b=7.7485(2) ꢀ, c=14.8933(5) ꢀ, V=
1
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3
À3
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0
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1 2
3
2
1
2
2
0
1
[
.070, H-atom parameters constrained. CCDC 1952557 contains the
3
supplementary crystallographic data for this paper. CCDC 1952557
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This work was supported by Grants-in-Aid for Scientific Re-
search (Nos. 19H02708, 17K19114, and 16H04144) from the
Ministry of Education, Culture, Sports, Science, and Technology
[
[
[
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School of Science and Engineering, Chiba University.
Conflict of interest
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The authors declare no conflict of interest.
Keywords: amino acids · asymmetric synthesis · attrition-
enhanced deracemization · conglomerate · Michael addition
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Version of record online: && &&, 0000
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Communication
COMMUNICATION
The asymmetric synthesis of an aspart-
ic acid derivative involving dynamic
enantioselective crystallization was ac-
complished without using any external
chiral source. The aza-Michael addition
reaction of prochiral maleic acid and
pyridine afforded a racemic conglomer-
ate. Continuous stirring of the suspen-
sion of the reaction mixture with acetic
acid promoted gradual deracemization
to afford a crystal with 99% ee in 71%
chemical yield.
Naohiro Uemura, Kento Sano,
Arisa Matsumoto, Yasushi Yoshida,
Takashi Mino, Masami Sakamoto*
&& – &&
Absolute Asymmetric Synthesis of an
Aspartic Acid Derivative from
Prochiral Maleic Acid and Pyridine
under Achiral Conditions
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These are not the final page numbers! ÞÞ