Attrition-enhanced deracemization and absolute asymmetric synthesis of flavanones from prochiral precursors

Article abstract of DOI:10.1021/acs.cgd.0c00955

Seven racemic 5,7-dimethoxyflavanones afforded conglomerate crystals upon recrystallization from a solvent. Three methodologies were investigated to achieve asymmetric transformation based on dynamic crystallization of the chiral conglomerate system. The first was chiral symmetry breaking of racemic flavanones by attrition-enhanced deracemization. Continuous suspension of racemic flavanones in a small amount of propanol in the presence of a base (1,8-diazabicyclo[5.4.0]undec-7-ene (DBU)) and glass beads promoted chiral symmetry breaking and converted the flavanones to crystals of (+)- or (-)-enantiomers with 78 to 99% ee. The second method involved cyclization of the intermediate aldol product to give optically active flavanone with 90% ee involving a reversible oxa-Michael addition reaction with attrition-enhanced deracemization. The third was a reaction starting from prochiral 2-hydroxy-4,6-dimethoxyacetophenone and 2-naphthaldehyde under basic conditions, which gave the corresponding flavanone in 89% ee.

Full text of DOI:10.1021/acs.cgd.0c00955

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Communication
Attrition-Enhanced Deracemization and Absolute Asymmetric
Synthesis of Flavanones from Prochiral Precursors
Waku Shimizu, Naohiro Uemura, Yasushi Yoshida, Takashi Mino, Yoshio Kasashima, and Masami Sakamoto
Cryst. Growth Des., Just Accepted Manuscript • DOI: 10.1021/acs.cgd.0c00955 • Publication Date (Web): 10 Aug 2020
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Crystal Growth & Design
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Attrition-Enhanced Deracemization and Absolute Asymmetric Syn-
thesis of Flavanones from Prochiral Precursors
Waku Shimizu,† Naohiro Uemura,† Yasushi Yoshida,†,‡ Takashi Mino,†,‡ Yoshio Kasashima,§ and
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Masami Sakamoto*,†,‡
† Department of Applied Chemistry and Biotechnology, Graduate School of Engineering
Chiba University, Yayoi-cho, Inage-ku, Chiba 263-8522, Japan
‡ Molecular Chirality Research Center, Chiba University, Yayoi-cho, Inage-ku, Chiba 263-8522, Japan
§ Education Center, Faculty of Creative Engineering, Chiba Institute of Technology
Shibazono, Narashino, Chiba 275-0023, Japan
KEYWORDS. chiral symmetry breaking • flavanone • attrition-enhanced deracemization • absolute asymmetric synthesis •
conglomerate
ABSTRACT: Seven racemic 5,7-dimethoxyflavanones afforded conglomerate crystals upon recrystallization from a solvent. Three
methodologies were investigated to achieve asymmetric transformation based on dynamic crystallization of chiral conglomerate sys-
tem. The first was chiral symmetry breaking of racemic flavanones by attrition-enhanced deracemization. Continuous suspension of
racemic flavanones in a small amount of propanol in the presence of a base (DBU) and glass beads promoted chiral symmetry breaking,
and converted the flavanones to crystals of (+)- or (-)-enantiomers with 78 to 99% ee. The second method involved cyclization of the
intermediate aldol product to give optically active flavanone with 90% ee involving a reversible oxa-Michael addition reaction with
attrition-enhanced deracemization. The third was a reaction starting from prochiral 2-hydroxy-4,6-dimethoxyacetophenone and 2-
naphthaldehyde under basic conditions, which gave the corresponding flavanone in 89% ee.
Flavanones (I) are among the most prevalent and valuable
natural products, and their derivatives are widespread in many
plants, fruits, vegetables, and pharmaceutical materials (Figure
1, II-IX).1-7 Many flavanones with hydroxy or methoxy groups
at the 5 and 7 positions show bioactivities, including antibacte-
rial, antimalarial, anti-inflammatory, antipyretic, antiarrhyth-
mic, antiasthmatic, anti-ulcerative, antineoplastic, and HIV-1
IN inhibitory effects.8-14
Since flavanones exist in optically active forms in nature
(Figure 1), there have been many asymmetric syntheses re-
ported by several groups.15 These can be divided into three main
categories in which excellent asymmetric catalysts and isomer-
ases have been developed: (1) asymmetric reduction of C2-C3
double bonds,16-18 (2) asymmetric conjugate addition of a nucle-
ophile to chromone,19,20 and (3) intramolecular oxa-Michael ad-
dition of 2-hydroxychalcone.21-26 We aimed to develop a novel
asymmetric synthesis method for valuable flavanones without
Figure 1. Flavanone (I) and examples of derivatives (II-IX) in nature.
using chiral sources such as asymmetric catalysts or general op-
tical resolution.
In recent years, asymmetric transformations using naturally
designed a new reaction protocol for the absolute asymmetric
generated crystal chirality have provided chiral symmetry
synthesis of flavanones, as shown in Figure 2, in which fla-
vanone 4 can be obtained by aldol condensation of an achiral 2-
hydroxyacetophenone 1 and an aromatic aldehyde 2, followed
by intramolecular oxa-Michael addition. In the solution phase,
flavanone 4 is expected to racemize through a ring-opening and
–closing process via the aldol product 3, and finally, crystals of
the (R) or (S) enantiomer can be selectively obtained by derac-
emization via dynamic crystallization of the conglomerate. We
breaking of racemic mixtures by dynamic crystallization,27-29
and absolute asymmetric synthesis from a prochiral substrate to
form an asymmetric center that racemizes into a product with
high enantiomeric purity.30-36 Some novel examples have been
demonstrated, such as an asymmetric aza-Michael addition in-
volving the racemization of the products leading to enantiomor-
phic crystals.37-39 Products with very high enantiomeric purity
were successfully obtained from prochiral materials. Here, we
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Crystal Growth & Design
also describe a novel asymmetric transformation of racemic fla-
vanones by attrition-enhanced deracemization and asymmetric
synthesis from prochiral starting materials by combining the re-
action for generating chiral centers and the dynamic crystalliza-
tion in a one-pot manner.
Page 2 of 7
monoclinic P21 with a chiral scaffold.40,41 It is known that con-
glomerate crystals are formed at a lower proportion in racemic
materials, which is a bottleneck to exploring conglomerate crys-
tals for use in spontaneous preferential crystallization.42-46 Suc-
cessful examples are limited and it is still a challenging topic.
Therefore, it is remarkable that the majority of these flavanones
(7 of 13) formed chiral conglomerate crystals.
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Another prerequisite for asymmetric amplification using dy-
namic crystallization is that fast racemization must proceed in
solution under the crystallization conditions. To assess the ap-
parent racemization of 4 in solution by the ring-opening and -
closing process via 3,47,48 the decay of the enantiomeric excess
of almost enantiomerically pure 4m was followed by HPLC us-
ing a chiral column.
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The rate of racemization was greatly affected by the base,
solvent, and reaction temperature (Figure 4). Racemization of
4m in alcohol did not occur under neutral or acidic conditions
at room temperature, but slow racemization was observed by
increasing the temperature. On the other hand, racemization
proceeded smoothly under basic conditions in an alcoholic sol-
vent. While the racemization did not occur in toluene in the
presence of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) at
90 °C (Figure 4, black solid line), racemization was confirmed
under basic conditions in propanol at 90 °C, with a half-life of
12 minutes using 1.5 eq. of DBU (red dotted line) and a 0.8
minute half-life using 1.5 eq. of sodium hydroxide (blue dashed
line). However, the use of sodium hydroxide tilted the equilib-
rium toward opened-form 3m, so the use of DBU was consid-
ered to be the optimum base for synthesizing 4m. These results
indicated that the ring-opening and -closing process occurred
fast enough to adapt to dynamic crystallization.
Figure 2. Asymmetric synthesis of flavanones 4 from achiral materials involv-
ing dynamic crystallization.
To achieve the proposed asymmetric synthesis of flavanones in-
volving generation and amplification of chirality, the substrate
must form conglomerates. Flavanones 4 were synthesized from
2-hydroxy-4,6-dimethoxyacetophenone 1 and various aromatic
aldehydes 2 with a base in an alcoholic solvent. The first aldol
condensation reaction afforded adduct 3, which, after cycliza-
tion by an intramolecular oxa-Michael addition reaction,
formed flavanones 4 with an asymmetric center (Figure 3). In
the second step, cyclization proceeded efficiently by the use of
pyridine as a base with heating. The structures of the products
were determined by 1H NMR, 13C NMR, IR and MS spectros-
copies. Finally, a single-crystal X-ray structural analysis une-
quivocally established their molecular structures, crystal pack-
ing, and space groups.
Figure 4. Time-dependent change of ee value for 4m at 90 °C via reversible
oxa-Michael addition monitored by HPLC analysis.
Next, chiral symmetry breaking via attrition-enhanced derac-
emization (Viedma ripening) starting from racemic flavanones
was investigated. This method was developed in the deracemi-
zation of inorganic NaClO3 crystals involving a dynamic pro-
cess of crystal dissolution and growth enhanced by attrition,
leading to convergence to a one-handed enantiomorphic crystal
by attrition with glass beads.49 Much effort has been devoted to
the development of new systems of chiral symmetry breaking
using crystalline chirality, and successful examples of derace-
mization have been reported.50-58 In this method, it is possible
to achieve deracemization with high enantiomeric purity, even
in a reaction with a relatively low racemization rate.
Figure 3. Synthesis of flavanones 4a-4m and their space groups.
X-ray crystallographic analysis of all the crystals obtained by
recrystallization of the racemic mixtures revealed that 4a, 4c,
4h, 4j, 4k, and 4m formed conglomerates of the orthorhombic
P212121 crystal system and 4l afforded a crystal space group of
Racemic 4m (223 mg, 0.67 mmol), DBU (0.5 eq.) as a base,
glass beads, and 1-propanol (1.2 mL) as a solvent in a sealed
glass tube were stirred and suspended at 90 °C for several days
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Crystal Growth & Design
[a] The solids of racemic 4 were suspended in propanol in the pres-
(Figures 5 and 6). The enantiomeric purity of the solid of 4m
was monitored by HPLC analysis. After six days, deracemiza-
tion started and the enantiomeric purity was successfully in-
creased to 98% ee (74% of solid recovery by filtration) after 11
days (Figure 4, red dotted line). The deracemization period
could be reduced by increasing the amount of DBU to 1.0 eq.,
whereupon the enantiomeric purity increased on the 3rd day,
reaching 98% ee (70% of solid recovery) at the 6th day (Figure
4, red solid line). From these results, it was confirmed that the
acceleration of the racemization rate by DBU greatly affected
the reduction of the period of chiral amplification by attrition-
enhanced deracemization. The plot of enantiomeric purity ver-
sus time showed a non-linear curve and this sigmoid-like in-
crease in enantiomeric purity is typical for Viedma ripening.59,60
ence of DBU with heating. [b] Solid recovery by filtration. [c] Enan-
tiomeric purity was determined by HPLC using CHIRALPAK IB
column.
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When the racemic solids of 4a (Ar = C6H5) were suspended
in a small amount of propanol in the presence of 0.5 equiv of
DBU using glass beads and a stir bar at 60 °C, the enantiomeric
purity successfully started to increase at the 6th day and reached
91% ee (65% of solid recovery) after 14 days (Figure 6, yellow
line and Table 1, entry 1).
9
In the case of 4c (Ar = p-MeC6H4), the racemic solids in pro-
panol with 0.5 equivalent of DBU were suspended with stirring
at 80 °C. After 2 days, the enantiomeric purity started to in-
crease, reaching 83% ee (68% of solid recovery) in 5 days (Fig-
ure 6, green line and Table 1, entry 2).
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In the case of 4h (Ar = p-FC6H4), 0.2 equiv of DBU was used
due to the relatively high solubility of 4h. The racemic solids
were suspended in propanol at 80 °C as in the case of other de-
rivatives. After 6 days, the enantiomeric purity was successfully
increased to 78% ee (46% of solid recovery) (Figure 6, purple
line and Table 1, entry 3).
Figure 5. Attrition-enhanced deracemization from racemic flavanones 4.
When solids of racemic 4l (Ar = 1-naphthyl), 0.4 equivalent
of DBU as a base and 1-propanol as a solvent were suspended
at 80 °C, the enantiomeric purity of the solid was successfully
increased to 99% ee (68% of solid recovery) after 5 days (Fig-
ure 6, blue line and Table 1, entry 4).
Based on the results for the deracemization of 4m to an en-
antiomeric form, attrition-enhanced deracemization of other
conglomerates was investigated. As in the case of 4m, racemic
solids of 4 with a catalytic amount of DBU in a small amount
of alcohol were suspended with glass beads and a stir bar in a
sealed glass tube for several days while tracking the change in
the ee value for the solid of 4 (Table 1, Figures 5 and 6).
Flavanones 4j (Ar = p-ClC6H4) and 4k (Ar = p-BrC6H4) were
not suitable for deracemization by crystallization, despite the
conglomerate of the P212121 space group. Their suspensions in
propanol converged to the ring-opened 3j and 3k due to their
low solubility compared to starting flavanones 4j and 4k. We
examined the deracemization in various solvents. However, the
crystallinity of the ring-opened product was high, and no suita-
ble solvent was found for the deracemization of 4j and 4k.61,62
In all substrates, which of the two enantiomers is amplified
predominantly is random, and it is not possible to obtain one
enantiomer selectively. An additional ten deracemizations of 4
confirmed that the enantioselectivity in these deracemizations
was random. An additional ten deracemizations were performed
at optimized conditions for 4a, 4c, 4h, 4l, and 4m. The ratios of
times that each enantiomer, (+)-form or (−)-form, was obtained
were 5:5 for 4a, 4:6 for 4c, 5:5 for 4h, 6:4 for 4l, and 6:4 for 4m.
However, handedness could be controlled by starting Viedma
ripening from low ee (5% ee). Deracemization was immediately
initiated and the crystals with the same handedness as the
slightly excess stereoisomer was efficiently obtained after 4
days in all cases.
Figure 6. Attrition-enhanced deracemization from racemic flavanones 4.
Table 1: Attrition-enhanced deracemization of racemic fla-
vanones 4.[a]
Next, an asymmetric synthesis method combining the asym-
metric expression reaction and deracemization by Viedma rip-
ening was investigated. Absolute asymmetric synthesis using
prochiral precursor 3m as a starting material was investigated.
When the solids of 3m were suspended with stirring at 600 rpm
in a small amount of propanol in the presence of DBU (1.0
equiv) at 90 °C, the enantiomeric purity of the solid was in-
creased to 90% after 10 days (72% yield as the solid) (Figure 7).
Entry
4
DBU
(eq)
Temp
(℃)
60
Time
(day)
14
Recovery
(%)[b]
Ee
(%)[c]
1
2
3
4
5
6
4a
4c
4h
4l
0.5 eq
0.5 eq
0.2 eq
0.4 eq
0.5 eq
1.0 eq
65
68
46
68
74
70
91
83
78
99
98
98
80
80
80
90
90
5
6
5
4m
4m
11
6
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Figure 7. Absolute asymmetric synthesis of flavanone from the prochiral start-
ing material 3m.
in a small amount of alcohol with heating, deracemization pro-
ceeded efficiently and asymmetric amplification was achieved
leading to 78%-99% ee. Second, we developed a one-pot asym-
metric synthesis by a cyclization reaction and deracemization
from a prochiral 2-hydroxychalcone derivative, which is a pre-
cursor to the cyclization of flavanone. When crystals of the 2-
hydroxychalcone derivative were suspended and stirred in alco-
hol in the presence of DBU at 90 °C, the crystals gradually
transformed into flavanone crystals. The flavanone converged
to 90% ee of enantiomorphic crystals by linking the synthesis
with deracemization. Third, we examined the synthesis of opti-
cally active flavanones in a two-step one-pot operation: aldol
reaction and oxa-Michael addition reaction under deracemiza-
tion conditions. The reaction starting from prochiral 4,6-di-
methoxy-2-hydroxyacetophenone and 2-naphthaldehyde gave
enantiomorphic flavanone crystals with 89% ee.
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Finally, we investigated the one-pot asymmetric flavanone syn-
thesis (Figure 8). When a methanol solution of equal amounts
of 4,6-dimethoxy-2-hydroxyacetophenone 1 and 2-naphthalde-
hyde 2m was reacted in the presence of DBU (1.5 equiv) in a
sealed glass tube at room temperature for 24 h, 3m by the aldol
condensation was precipitated. To remove the produced water,
the solvent was evaporated off, thus promoting crystallization.
Thereafter, the solids were suspended with stirring at 600 rpm
in propanol with glass beads at 90 °C for several days. As a
result, the enantiomeric purity started to increase after 5 days,
and reached 89% ee (32% yield as the solid) after 29 days.
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Absolute asymmetric synthesis is a phenomenon that is of
great interest in many research fields because it is closely re-
lated to homochirality and the origin of life on Earth.63-68 It is
significant to realize the absolute asymmetric reaction of fla-
vanones that are widespread in natural plants and important in
the pharmaceutical field.
Figure 8. Absolute asymmetric synthesis of flavanones 4m from 2-hydroxy-
acetophenone 1 and 2m.
Acknowledgments
This work was supported by a Grant-in-Aid for Scientific Research
(No. 19H02708) from the Ministry of Education, Culture, Sports,
Science, and Technology (MEXT) of the Japanese Government.
Mr. Uemura acknowledges financial support from the Frontier Sci-
ence Program of Graduate School of Science and Engineering,
Chiba University.
There are two plausible reasons for the longer time required
for asymmetric amplification compared to the case of using ra-
cemic 4m or prochiral precursor 3m as starting materials. First,
when the adduct 3m is formed from the starting materials 1 and
2 by the aldol reaction, 1.0 equiv of water is formed. The water
prevents both crystallization of 4m and deracemization, which
does not proceed in aqueous alcohol. Second, the remained
starting materials and the byproducts in the reaction system may
reduce the crystallinity of the product, resulting in a delayed
asymmetric amplification. When racemic 4m or prochiral 3m
was used as the starting material, the reverse aldol reaction did
not occur because water did not exist in the reaction system.
Regardless, we succeeded in the absolute asymmetric flavanone
synthesis from prochiral starting materials without an external
chiral source.
ASSOCIATED CONTENT
Supporting Information. Experimental procedure, X-ray struc-
ture analysis, and spectroscopic data for synthesized compounds.
“This material is available free of charge via the Internet at
http://pubs.acs.org.”
AUTHOR INFORMATION
Corresponding Author
Masami Sakamoto; E-mail: sakamotom@faculty.chiba-u.jp
ORCID
Conclusion
Yasushi Yoshida: 0000-0002-3498-3696
Takashi Mino: 0000-0003-1588-1202
Masami Sakamoto: 0000-0001-9489-2641
We have developed chiral symmetry breaking of racemic fla-
vanones by attrition-enhanced deracemization and asymmetric
synthesis of flavanones from prochiral precursors without an
external chiral source by utilizing the property of conglomerates.
Flavanones naturally exist as optically active compounds and
are an important group as pharmaceuticals. Thirteen different
derivatives of 5,7-dimethoxyflavanone with various substitu-
ents on the 2-phenyl group were synthesized from 4,6-di-
methoxy-2-hydroxyacetophenone and the corresponding aro-
matic aldehydes. Single crystal X-ray structural analysis re-
vealed that seven substrates formed conglomerates. Although
the flavanones did not racemize at room temperature, it was re-
vealed that racemization proceeded efficiently in the presence
of DBU as a base at high temperature by a reversible oxa-Mi-
chael reaction.
Author Contributions
The manuscript was written through contributions by all authors.
ACKNOWLEDGMENT
This study was supported by a Grants-in-Aid for Scientific Re-
search from MEXT, Japan. (No. 19H02708). Dr. Uemura acknowl-
edges financial support from Frontier Science Program of Graduate
School of Science and Engineering, Chiba University.
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Table of Contents
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Attrition-Enhanced Deracemization and Absolute Asymmetric Synthesis of Flavanones from
Prochiral Precursors
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Waku Shimizu, Naohiro Uemura, Yasushi Yoshida, Takashi Mino, Yoshio Kasashima, and
Masami Sakamoto*
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Abstract: Seven racemic 5,7-dimethoxyflavanones afforded conglomerate crystals by recrystallization
from a solvent. Viedma ripening of racemic flavanones in propanol with a base promoted chiral symmetry
breaking and converted to enantiomer crystals with 78 to 99% ee. Furthermore, prochiral 2-hydroxyace-
tophenone and aldehyde under basic conditions gave the chiral flavanone crystals with 89% ee in a two-
step one-pot operation under deracemization conditions.
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