Asymmetric Anisoin Synthesis Involving Benzoin Condensation Followed by Deracemization

Article abstract of DOI:10.1021/acs.cgd.1c00036

The highly enantioselective synthesis of p-anisoin was achieved via the benzoin condensation of a prochiral p-anisaldehyde using achiral NHC catalysts such as vitamin B1. In this reaction, p-anisoin crystallized as a conglomerate, and the deracemization of racemic p-anisoin under basic conditions was efficiently performed by Viedma ripening. Although the handedness of the enantioselective crystallization could not be controlled by spontaneous crystallization, it could be controlled by the coexistence of a catalytic amount of optically active valine. It was clarified that this is due to the asymmetric transformation of p-anisoin with enantiomeric valine in the mother liquor.

Full text of DOI:10.1021/acs.cgd.1c00036

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Article
Asymmetric Anisoin Synthesis Involving Benzoin Condensation
Followed by Deracemization
Aoi Washio, Momoka Hosaka, Naohiro Uemura, Yasushi Yoshida, Takashi Mino, Yoshio Kasashima,
and Masami Sakamoto*
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ABSTRACT: The highly enantioselective synthesis of p-anisoin was achieved via
the benzoin condensation of a prochiral p-anisaldehyde using achiral NHC
catalysts such as vitamin B1. In this reaction, p-anisoin crystallized as a
conglomerate, and the deracemization of racemic p-anisoin under basic conditions
was efficiently performed by Viedma ripening. Although the handedness of the
enantioselective crystallization could not be controlled by spontaneous
crystallization, it could be controlled by the coexistence of a catalytic amount of
optically active valine. It was clarified that this is due to the asymmetric
transformation of p-anisoin with enantiomeric valine in the mother liquor.
mization. When one enantiomer crystallizes, the opposite
isomers are present in excess in the mother liquor. However,
since racemization proceeds sufficiently fast, the racemic
balance can always be maintained. Finally, the racemic mixture
converges into one-handed enantiomeric crystals. This
asymmetric amplification method includes gradually growing
crystals from a supersaturated solution (crystallization-induced
enantiomer transformation)9−11 or attrition-enhanced dera-
cemization (Viedma ripening), which is performed by
suspending and stirring the crystals with glass beads in a
small amount of solvent.12 In either method, the products must
crystallize as a conglomerate, and rapid racemization must
proceed under the conditions of crystal growth. It has been
reported that the racemization of the products can be carried
out directly via an achiral intermediate, such as an enolate
anion,13−15 using a reversible reaction such as the Michael
addition reaction16−18 or the Diels−Alder reaction.19,20
Various new reaction systems are actively under develop-
ment.21−23
INTRODUCTION
■
Research on providing optically active materials with high
enantioselectivities without the use of an external asymmetric
source is related to the expression of the homochirality of
biomolecules.1−3 It is of interest in many academic fields. The
crystallization-induced dynamic optical resolution method
(CIDR), which utilizes the chirality of crystals, is an excellent
optical resolution method capable of generating a one-handed
enantiomer from a racemic mixture with a high optical purity
and simple filtration.4,5 Furthermore, a reaction that gives a
conglomerate-forming product in one pot from a prochiral
starting material combined with deracemization enables
asymmetric synthesis without the use of an external
asymmetric source (Figure 1).6−8 In this method, a racemic
mixture is generated in the reaction system, and one-handed
enantiomer crystals are preferentially crystallized with race-
We aimed to develop a new asymmetric reaction system that
fuses the benzoin condensation reaction, which uses N-
heterocyclic carbene (NHC) catalysts such as vitamin B1,
with deracemization via dynamic crystallization. The benzoin
condensation reaction is one of the fundamental reactions of
organic chemistry. It is a dimerization reaction that occurs by
the umpolung reaction of aromatic aldehydes catalyzed by
Received: January 12, 2021
Revised: March 10, 2021
Published: March 24, 2021
Figure 1. Asymmetric synthesis from prochiral starting materials via
deracemization involving the dynamic enantioselective crystallization
of conglomerates.
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cyanide ions (Scheme 1, reaction 1).24,25 The reaction has
been developed for various substrates using NHC catalysts
Scheme 1. Historical Benzoin Condensation and Our
Proposal for the Asymmetric Synthesis of Benzoin
Derivatives
modeled on vitamin B1 (Scheme 1, reaction 2).26−29 We
expected that benzoin derivatives could be asymmetrically
synthesized from prochiral aromatic aldehydes via deracemiza-
tion by dynamic crystallization because the substrates have an
enolizable acidic proton at the chiral center (Scheme 1,
reaction 3).
Figure 2. Perspective view and packing diagram along the a-axis of p-
anisoin 1.
The benzoin or acyloin structure exists widely in natural
products and pharmaceuticals and is one of the most critical
groups used as synthetic intermediates; thus, many asymmetric
catalytic reactions have been developed for its synthesis.28,29
We studied a method of providing optically active benzoins
using only crystal chirality as a chirality source. To employ
deracemization with dynamic crystallization, benzoin deriva-
tives must crystallize as conglomerates. A search of the CCDC
database revealed that the crystal structure of p-anisoin 1 had
been analyzed 35 years ago, and its crystal space group was
P212121.30 In this study, we reanalyzed the crystal structure of
p-anisoin 1 and then investigated deracemization by dynamic
crystallization from racemic p-anisoin 1, its one-pot asym-
metric synthesis from prochiral p-anisaldehyde, and the
addition of chiral amino acids to control the handedness for
enantiomeric crystallization.
α-position of the carbonyl group, sufficiently fast racemization
can be expected under basic crystallization conditions.
The stability of the asymmetric center is also crucial for
isolation. 1 hardly racemizes at room temperature regardless of
the solvent, but racemization occurs slowly when it is heated to
60 °C in ethanol, with a half-life of 54.7 h (ΔG‡ = 28 kcal
mol−1) (Table 1, entry 4). The asymmetric center is fairly
stable under neutral conditions; however, in the presence of a
catalytic amount of base, racemization via the enolate anion
proceeds at a considerable rate even at room temperature
(Scheme 2). When the racemization rate was measured in
various solvents and bases, the use of NaOH in ethanol was
found to be the most suitable. A sufficient racemization rate
was also shown with DBU (Table 1 and Figure 3).
Based on these results, the dynamic optical resolution from
racemic 1 was examined. We used EtOH as the solvent and
conducted experiments using three types of bases. To a sealed
glass tube (⌀20 mm) were added 1 (272 mg, 1.0 mmol),
EtOH (0.5 mL), base (0.10 mmol), and glass beads (⌀2 mm,
20 pieces), and the mixture was suspended with stirring at 600
rpm using a cross-shaped stirring bar (15 mm) at 60 °C.
Crystals obtained by filtration at regular intervals were
subjected to HPLC (CHIRALPAK OD-H) to determine the
enantiomeric purity. Asymmetric amplification was observed
from the second day onward, and a sigmoid curve was drawn
that eventually converged to 94−99% ee crystals (Figure 4a).
Finally, crystals were recovered by filtration in 90−91% yields
using any of the bases (Table 2). The rate of asymmetric
amplification appears to be related to the racemization speed,
reaching the boundary fastest in seven days with NaOH but
even converging in 10 days with K2CO3. It was also suggested
that deracemization progressed via first-order kinetics in the
initial stage regardless of the nature of the base, as shown in
Figure 4b. Thus, we discovered one of the ideal environ-
mentally friendly asymmetric amplification systems.
RESULTS AND DISCUSSION
■
The single-crystal X-ray structure analysis of p-anisoin 1 was
re-examined to confirm the absence of polymorphism. Indeed,
the crystals obtained by recrystallization from either EtOH or a
mixture of CHCl3/hexane exhibited the same crystal structure,
and polymorphism was not observed.31 The crystal space
group is P212121, and the crystal parameters are almost the
same as those from the previously reported data. It was thus
expected that the conglomerate could be used for dynamic
crystallization.
Since the hydroxyl group has an intramolecular hydrogen
bond with the carbonyl group’s oxygen atom (distance for
OHOC of 2.168 Å), the twist angle of O1−C1−C2-O2 is
small, 16.26°. The molecule also has an intermolecular
hydrogen bond with the MeO group of the neighboring
molecule (distance for OH−OMe of 2.304 Å), which forms a
C2 spiral along the a-axis (Figure 2).
Next, we investigated the rate of racemization, which is vital
for obtaining high enantiomeric crystals via dynamic
crystallization. Since the molecule has an acidic proton at the
This deracemization of 1 could be applied to a gram-scale
experiment. When p-anisoin 1 (2.2 g, 8.0 mmol) in EtOH (2.0
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a
Table 1. Thermodynamic Parameters for the Rate of Racemization of 1
entry
solvent
base
temperature (°C)
τ1/2 (min)
krac (s−1
)
ΔG‡ (kcal mol−1
)
1
2
3
4
5
6
toluene
MeCN
EtOH
EtOH
EtOH
EtOH
DBU
DBU
DBU
none
K2CO3
NaOH
25
25
25
60
25
25
39.4
20.5
14.7
3.28 × 103
33
1.5 × 10−4
2.8 × 10−4
3.9 × 10−4
1.7 × 10−6
1.7 × 10−4
5.8 × 10−4
22.7
22.3
22.1
28.3
22.6
21.7
9.9
a
The rate of racemization was measured under conditions of 1.0 × 10−2 mol L−1 1 in a solvent with base (10 mol %).
Scheme 2. Racemization Mechanism for 1 via an Enolate
Ion
Figure 3. Racemization of 1 under various conditions. Entry numbers
correspond to those in Table 1.
mL) was suspended with stirring at 600 rpm at 60 °C in a
sealed glass tube in the presence of DBU (122 mg, 0.8 mmol)
and glass beads, crystals were recovered by filtration in a 90%
yield with a 99% ee.
In all experiments, which of the two enantiomers is
predominantly amplified is random, and it is not possible to
selectively obtain one enantiomer. Additional deracemizations
of 1 confirmed that the enantioselectivity in these deracemiza-
tions was random (Figure S1). However, handedness could be
controlled by starting the Viedma ripening from a low ee (5%
ee) using NaOH or DBU as a base. Deracemization was
immediately initiated, and the crystals with the same
handedness as the slightly excess stereoisomer were efficiently
obtained after four days.
Figure 4. Time course of the deracemization of racemic 1 with
Viedma ripening using various bases at 60 °C shown as (a) ee (%) vs
time (days) and (b) ln(ee) vs time (days).
a
Table 2. Deracemization of 1 by Viedma Ripening
b
c
entry
solvent
base
recovery (%)
ee (%)
1
2
3
EtOH
EtOH
EtOH
NaOH
DBU
K2CO3
90
91
91
99
99
94
a
All experiments were performed in the presence of crystals of 1 (273
mg, 1.0 mmol), 0.5 mL of solvent, and a catalytic amount of base (10
b
c
mol %) at 60 °C. Crystals were recovered by filtration. One of the
two enantiomers predominantly amplified was random.
Next, we examined the asymmetric synthesis of 1 by
continuously performing benzoin condensation from prochiral
p-anisaldehyde and chiral amplification by dynamic crystal-
lization in one pot. C1, C2, and C3, all achiral NHC catalysts,
were used as catalysts for benzoin condensation (Scheme 3).
C1 is vitamin B1, a vital substance in vivo, and is commercially
available.26−29 The commercially available thiazolium salt C2
and the imidazolium salt C3, which are commonly used as
catalysts for the benzoin condensation reaction, were also
examined.32,33
aqueous sodium hydroxide solution (0.5 ml, 0.6 M), and glass
beads, and the mixture was stirred at room temperature for 24
h. A small amount of water was needed for its dissolution of
vitamin B1. After the condensation reaction was complete, the
solvent was evaporated under reduced pressure to remove the
water. To the crude racemic p-anisoin was added EtOH (0.5
mL), which was suspended with stirring at 600 rpm using a
cross-shaped stirring bar (15 mm) at 60 °C. A small amount of
the crystals obtained by filtration was subjected to HPLC
analysis every day to determine the enantiomeric purity.
Finally, crystals were filtered and washed with a small amount
To a sealed glass tube were added p-anisaldehyde (272 mg,
2.0 mmol), EtOH (0.5 mL), C1 (60 mg, 0.2 mmol), an
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finally obtained by filtration in a 75% yield with a 99% ee
(Table 3, entry 3, and Figure 5). In the reaction using C2 and
DBU, crystals were filtered and washed with a small amount of
cold ethanol to give a 50% yield of 1 with a 94% ee (Table 3,
entry 4, and Figure 5).
Scheme 3. One-Pot Asymmetric Synthesis of 1 By
Combining Benzoin Condensation Using Achiral NHC
Catalysts with Dynamic Crystallization
In the reaction using catalyst C3, it was also possible to carry
out the reaction simultaneously with the asymmetric
amplification. The use of NaOH as a base gave an 88% yield
of 1 in a 99% ee (Table 3, entry 5, and Figure 5). When using
DBU as a base, we could not obtain the crystalline 1 (Table 3,
entry 6).
As described above, the formation of racemic 1 by the
benzoin condensation of prochiral p-anisaldehyde was followed
by deracemization via Viedma ripening. It is plausible that
racemization is promoted through the enolate ion such as in
the case of the deracemization of anisoin shown in Table 2. On
the other hand, benzoin condensation is a well-established
reversible reaction, and it has also been suggested that
racemization possibly occurs through the reverse reaction.
Therefore, this reaction system is suitable for dynamic
crystallization using a conglomerate crystal.
It was possible to isolate a 99% ee of 1 by simple filtration
from the reaction mixture without using an external
asymmetric source. These crystals could be easily purified
into 100% ee by a recrystallization from chloroform/hexane. It
was possible to isolate 100% ee p-anisoin from prochiral p-
anisaldehyde simply by filtering the crystals twice.
Next, the control of the handedness of the chirality was
examined. In dynamic optical resolution by spontaneous
crystallization, it was impossible to predict which enantiomer
crystal would converge (Figure S1). In this case, it was possible
to control the handedness by starting from slightly enriched
crystals or adding enantiomer crystals as a seed; however, we
examined another approach to control the handedness of the
deracemization using optically active amino acids.
A catalytic amount of L- or D-valine crystals was added
during the Viedma ripening of racemic 1. In a sealed glass tube,
1 (272 mg, 1.0 mmol), EtOH (0.5 mL), DBU (15 mg, 0.10
mmol), glass beads, and L- or D-valine (12 mg, 0.1 mmol) were
suspended with stirring at 600 rpm using a cross-shaped
stirring bar at 60 °C. Deracemization began immediately and
reached an enantiomeric excess of 99% in just five days (Table
4, entries 1 and 2, and Figure S2). The configuration of the
obtained 1 matched that of the added valine. When L-valine
was used, (R)-1 was obtained, while the addition of D-valine
caused the handedness of the deracemization to converge to
(S)-1. The experiments were repeated five times each.
The same asymmetric control was observed when valine
coexisted in the benzoin condensation from p-anisaldehyde.
Deracemization proceeded efficiently and faster than that
without valine. (R)-Anisoin 1 was obtained in 68−70% yield
with a >99% ee by adding L-valine (Table 4, entry 3), while the
reaction in the presence of D-valine gave (S)-1 in all five
experiments (Table 4, entry 4).
of cold ethanol to give a 70% yield of p-anisoin with a 93% ee
(Table 3, entry 3, and Figure 5). When using DBU instead of
NaOH, the chemical yield of 1 was low, and solids were not
obtained for suspension (Table 3, entry 2).
Table 3. Asymmetric Synthesis of p-Anisoin from p-
Anisaldehyde Involving Benzoin Condensation and Viedma
a
Ripening
b
c
entry
catalyst
solvent
base
yield (%)
70
n.a.
ee (%)
93
d
1
C1
C1
C2
C2
C3
C3
EtOH/H2O
EtOH/H2O
EtOH
EtOH
EtOH
NaOH
DBU
NaOH
DBU
NaOH
DBU
e
2
3
4
5
6
75
50
88
99
94
99
e
EtOH
n.a.
a
All experiments were performed in the presence of p-anisaldehyde
(2.0 mmol), 0.5 mL of solvent, catalyst (10 mol %), and base (15 mol
b
%). The solution was suspended with stirring. Yield of crystallized 1
c
obtained by filtration. One of the two enantiomers predominantly
d
amplified was random. After the reaction at rt for 24 h, the solvent
was removed under reduced pressure. Next, EtOH (0.5 mL) was
e
added and suspended with stirring at 60 °C. Crystalline 1 was not
obtained.
Figure 5. Time course of the asymmetric synthesis of 1 involving
deracemization by Viedma ripening. Entry numbers correspond to
those in Table 3.
To clarify this phenomenon, we first investigated the crystal
growth of 1 in the presence of optically active valine. However,
a clear difference was not observed in the growth rate between
(R)-1 and (S)-1 in the presence of L-valine, and both
enantiomer crystals were grown.34 Additionally, to investigate
the possibility of forming mixed crystals with optically active
valine, the crystals obtained from recrystallization in the
presence of valine were analyzed by NMR spectroscopy. It was
found that valine was not included in the crystals of 1.35
In the case of the reaction using catalyst C2, we could use
EtOH as a solvent without water, and it was possible to carry
out the reaction and the asymmetric amplification at the same
time. In a sealed glass tube, p-anisaldehyde (272 mg, 2.0
mmol), EtOH (0.5 mL), C2 (0.2 mmol), powdered NaOH
(12 mg, 3.0 mmol), and glass beads were reacted At 60 °C.
Crystals of 1 immediately precipitated and were suspended
with stirring at the same temperature. The changing ee value of
the crystals was analyzed using the above method, and 1 was
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Table 4. Control of the Handedness of the Deracemization
of 1 in the presence of L- or D-Valine
AUTHOR INFORMATION
■
Corresponding Author
time
configuration of
Masami Sakamoto − Department of Applied Chemistry and
Biotechnology, Graduate School of Engineering and
Molecular Chirality Research Center, Chiba University,
Chiba 263-8522, Japan; orcid.org/0000-0001-9489-
2641; Email: sakamotom@faculty.chiba-u.jp
entry
material
( )-1
( )-1
p-anisaldehyde L-valine
p-anisaldehyde D-valine
additive
(days)
1
ee of 1
a
b
1
L-valine
D-valine
5
5
6
6
R
>99%
>99%
>99%
>99%
a
b
S
d
2
c
3
R
c
d
S
4
a
Authors
In a sealed glass tube (⌀20 mm), 1 (272 mg, 1.0 mmol), EtOH (0.5
Aoi Washio − Department of Applied Chemistry and
Biotechnology, Graduate School of Engineering, Chiba
University, Chiba 263-8522, Japan
Momoka Hosaka − Department of Applied Chemistry and
Biotechnology, Graduate School of Engineering, Chiba
University, Chiba 263-8522, Japan
Naohiro Uemura − Department of Applied Chemistry and
Biotechnology, Graduate School of Engineering, Chiba
University, Chiba 263-8522, Japan
Yasushi Yoshida − Department of Applied Chemistry and
Biotechnology, Graduate School of Engineering and
Molecular Chirality Research Center, Chiba University,
Chiba 263-8522, Japan; orcid.org/0000-0002-3498-
3696
Takashi Mino − Department of Applied Chemistry and
Biotechnology, Graduate School of Engineering and
Molecular Chirality Research Center, Chiba University,
Chiba 263-8522, Japan; orcid.org/0000-0003-1588-
1202
Yoshio Kasashima − Education Center, Faculty of Creative
Engineeing, Chiba Institute of Technology, Chiba 275-0023,
Japan
mL), DBU (15 mg, 0.10 mmol), glass beads (⌀2 mm, 20 pieces), and
L- or D-valine (12 mg, 0.1 mmol) were suspended with stirring at 600
b
rpm using a cross-shaped stirring bar at 60 °C. Crystals were
c
recovered in 89−91% yields in all five experiments. In a sealed glass
tube, p-anisaldehyde (272 mg, 2.0 mmol), EtOH (0.5 mL), C1 (60
mg, 0.2 mmol), a sodium hydroxide aqueous solution (0.5 mL, 0.6
M), and glass beads were combined, and the mixture was stirred at
room temperature for 24 h. After the solvent was evaporated under
reduced pressure, EtOH (0.5 mL) was added and suspended with
d
stirring at 600 rpm at 60 °C. Crystals were recovered in 68−70%
yields in all five experiments.
Next, we studied the asymmetric transformation of 1 with
chiral valine.36−38 When racemic 1 and L-valine (0.1 equiv)
were dissolved in ethanol with DBU (0.5 equiv) and left to
stand at rt for 24 h, it was observed that the racemic
equilibrium moved to the enrichment of (R)-1 in a 5% ee.
Similarly, the addition of D-valine under the same conditions
led to an asymmetric transformation to (S)-1 in a 5% ee. These
results indicate that chiral valine resulted in an asymmetric
equilibration in the basic solution of racemic anisoin. This bias
caused the dynamic crystallization to converge on the excess
enantiomeric crystals.
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.cgd.1c00036
CONCLUSION
■
Author Contributions
The manuscript was written through contributions by all
authors.
Efficient deracemization from racemic p-anisoin was achieved
by Viedma ripening in 99% ee. The asymmetric synthesis from
prochiral p-anisaldehyde in one pot by benzoin condensation
using an NHC catalyst, such as vitamin B1, followed by
deracemization via Viedma ripening afforded a 99% ee of the
product without the use of any external chiral source. We
succeeded in controlling the handedness of the asymmetric
amplification by adding a catalytic amount of optically active
valine. These results provide not only the asymmetric
transformation of p-anisoin, which is important as an
intermediate for medical and agrochemical products, but also
essential information deeply related to the expression of the
homochirality of biomolecules on Earth.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This study was supported by a Grants-in-Aid for Scientific
Research from MEXT, Japan (no. 19H02708). N.U. acknowl-
edges financial support from Frontier Science Program of
Graduate School of Science and Engineering, Chiba University.
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