Asymmetric Synthesis Involving Reversible Photodimerization of a Prochiral Flavonoid Followed by Crystallization

Article abstract of DOI:10.1002/ejoc.201701457

Asymmetric synthesis involving photochemical dimerization of a prochiral flavonoid derivative in solution without any chiral source was achieved. Irradiation of ethyl 6-bromochromonecarboxylate in solution efficiently gave a C₂-chiral anti-head-to-head dimer in excellent chemical yield with good quantum efficiency (Φ₃₆₅ = 0.15). X-ray crystallographic analysis revealed that the dimer crystallized as a conglomerate of C2 space group. The crystalline dimer precipitated upon irradiation of the monomer in solution, and indirect racemization of the dimer through a reversible photoreaction in solution and selective crystallization simultaneously occurred to give the C₂-chiral dimer in optically active form with up to 80 % ee. Optically active photoproducts could be obtained by simply irradiating achiral materials in solution without an external chiral source.

Full text of DOI:10.1002/ejoc.201701457

DOI: 10.1002/ejoc.201701457
Communication
Asymmetric Synthesis
Asymmetric Synthesis Involving Reversible Photodimerization
of a Prochiral Flavonoid Followed by Crystallization
Hiroki Ishikawa,[a] Naohiro Uemura,[a] Fumitoshi Yagishita,[b] Nozomi Baba,[a]
Yasushi Yoshida,[a] Takashi Mino,[a] Yoshio Kasashima,[c] and Masami Sakamoto*[a]
Abstract: Asymmetric synthesis involving photochemical di- diation of the monomer in solution, and indirect racemization
merization of a prochiral flavonoid derivative in solution with- of the dimer through a reversible photoreaction in solution and
out any chiral source was achieved. Irradiation of ethyl 6- selective crystallization simultaneously occurred to give the C2-
bromochromonecarboxylate in solution efficiently gave a C2- chiral dimer in optically active form with up to 80 % ee. Opti-
chiral anti-head-to-head dimer in excellent chemical yield with cally active photoproducts could be obtained by simply irradiat-
good quantum efficiency (Φ365 = 0.15). X-ray crystallographic ing achiral materials in solution without an external chiral
analysis revealed that the dimer crystallized as a conglomerate source.
of C2 space group. The crystalline dimer precipitated upon irra-
Introduction
Since Havinga discovered the first example of dynamic selective
crystallization by using racemic conglomerate crystals,[1] many
valuable examples of total optical resolution by deracemization,
selectively leading to single-handed molecules, have been re-
ported.[2,3] This concept is closely linked to homochirality of
living matter and the origin of life, which is of wide interest in
prominent research fields.[4–6]
Asymmetric synthesis from prochiral starting materials by us-
ing only crystal chirality under absolutely achiral conditions,
that is, absolute asymmetric synthesis,[7] has been investigated
by many methods, including solid-state photochemical reac-
tions[8] and asymmetric reactions by using frozen chirality.[9] Re-
cently, elegant examples of asymmetric synthesis have been
demonstrated by combining chemical reactions providing
asymmetric centers with dynamic selective crystallization, and
products with high ee values without an external chiral source
have been obtained.[10] In such cases, the dynamic crystalliza-
tion process involves an enolate anion under basic condi-
tions[10,11] and a reversible reaction by thermal racemization.[12]
Figure 1. Three types of asymmetric reactions involving dynamic crystalliza-
tion.
This process has been named the TT-type (thermal reaction and
thermal racemization) absolute asymmetric reaction (Figure 1).
[a] Department of Applied Chemistry and Biotechnology, Graduate School of
Engineering, and Molecular Chirality Research Center, Chiba University,
Yayoi-cho, Inage-ku, Chiba 263-8522, Japan
E-mail: sakamotom@faculty.chiba-u.jp
Another example involves the photochemical isomerization
reaction of aroylacrylamide followed by intramolecular cycliza-
tion and racemization through thermally promoted ring-open-
ing and ring-closing reactions.[13] In this case, a nearly enantio-
merically pure product was obtained by irradiating a solution of
the prochiral aroylacrylamide with sunlight followed by gradual
solidification by evaporation of the solvent outdoors. The reac-
tion was triggered by photoisomerization of the alkenyl group;
however, racemization of the cyclization product involved ther-
mal ring-opening and ring-closing reactions. This is called a PT-
http://chem.tf.chiba-u.jp/gacb06/
[b] Department of Applied Chemistry, Graduate school of Science and
Technology, Tokushima University,
Minami-josanjima-cho, Tokushima 770-8506, Japan
[c] Education Center, Faculty of Creative Engineering, Chiba Institute of
Technology,
Shibazono, Narashino, Chiba 275-0023, Japan
Supporting information and ORCID(s) from the author(s) for this article are
available on the WWW under https://doi.org/10.1002/ejoc.201701457.
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Communication
type (photoreaction and thermal racemization) absolute
asymmetric reaction. Herein, we focused on developing a new
asymmetric synthetic system by simple irradiation of achiral
materials in solution, involving a photochemical process both
for generating chiral centers and for reversible racemization, a
PP-type (photochemical reaction and photochemical racemiza-
tion) asymmetric reaction.
Figure 2. Perspective view of (S,S,S,S)-(+)-2 showing thermal ellipsoids at 50 %
probability.
Results and Discussion
To achieve PP-type asymmetric induction, the photochemical
dimerization reaction of chromone was selected.[14] Chromone
(benzo-γ-pyrone) is the parent of a large number of naturally
occurring compounds such as flavonoids and plant pigments
and is also found in many pharmaceutical materials.[15] Re-
cently, the photolysis of such chromonecarboxylic acid deriva-
tives in fluid media was explored to give C2-symmetric anti-
head-to-head (anti-HH) dimers effectively and in excellent
chemical yields from the triplet excited state. In this photo-
reaction, formation of four dimers was possible; however, only
the C2-symmetric anti-HH dimers were exclusively produced
(Scheme 1).[14]
atmosphere, the photodimerization reaction proceeded effi-
ciently, and a single dimer was obtained exclusively (81 % con-
version). The quantum yield (Φ) for the dimerization by using
a 365 nm line was 0.15 at 0.05
M concentration. The dimeriza-
tion was also effectively sensitized by benzophenone as a trip-
let sensitizer. In this case, the photosensitized dimerization reac-
tion reached 91 % conversion and the chemical yield was 99 %
(on the basis of consumed monomer).
Next, we examined another important requirement, that is,
whether racemization of the dimer occurred upon irradiation.
Figure 3 shows the UV spectra of monomer 1 (red line) and
anti-HH photodimer 2 (blue line). The dimer has 2-alkoxyphen-
one chromophores and absorbs in a longer wavelength region
than the monomer. Even under these conditions, the conver-
sion reached 81 % in the photostationary state, because the
dimer might also serve as a triplet sensitizer for the dimeriza-
tion of 1.
Scheme 1. Stereoselective and product-selective photochemical dimerization
reaction of 2-chromonecarboxylic esters and amides.
If the photodimerization of achiral chromone gives a con-
glomerate dimer and the reverse reaction occurs photochemi-
cally, we can perform the PP-type asymmetric reaction involv-
ing dynamic crystallization (Figure 1). We analyzed the crystal
structures of several dimers by X-ray structural analysis and
HPLC analysis by using a chiral column to determine whether
they were conglomerates, and we found that brominated deriv-
ative
2 afforded a monoclinic C2-racemic conglomerate
Figure 3. Absorption spectra of monomer 1 (red line) and dimer 2 (blue line)
in MeCN, each at a concentration of 1.0 × 10–4
M.
(Scheme 2). The structure of crystalline dimer 2 was also estab-
lished to have the anti-HH stereochemistry. The absolute struc-
ture was determined by X-ray crystallography as the (S,S,S,S)
configuration for (+)-2 (Figure 2).[16] We then applied this pho-
todimerization to the proposed absolute asymmetric synthesis
involving dynamic crystallization.
Furthermore, irradiation of a low concentration (0.005
M) of
dimer 2 in MeCN regenerated monomer 1 quantitatively at
25 % reaction conversion. This is considered the photostation-
ary state under these conditions. Eventually, it was confirmed
that the reverse photoreaction proceeded and the achiral
monomer was regenerated, which is equivalent to the photo-
racemization of the primary produced dimer (Figure 4). Upon
irradiating 1 in solution, racemic C2-symmetric dimer 2 was
generated at the early stage of the reaction. According to the
progress of the photoreaction, the crystalline dimer precipi-
tated, and the process involved selective crystallization. In the
mother liquor, the reverse photoreaction occurred, which is not
a direct photoracemization, but a process equivalent to racemi-
zation involving a reverse reaction. From this reversible photo-
Scheme 2. Photochemical dimerization of 1 from the triplet excited state.
Upon irradiation of ethyl 6-bromochromone-2-carboxylate chemical system combined with selective crystallization, we
(1) in MeCN with a high-pressure mercury lamp under an argon could anticipate obtaining optically active photoproducts by
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simple irradiation of an achiral starting material under abso- to dissolve the precipitate, and the ee value of the generated
lutely achiral conditions.
dimer was analyzed by HPLC.
For method A, upon irradiating a 0.04
M acetonitrile solution
at 20 °C by evaporating the solvent gradually, the residual crys-
talline dimer was obtained as nearly a racemate (Table 1, en-
try 1). A high 0.04
in acceleration of the crystallization and a low ee value. Upon
decreasing the concentration to 0.01 to suppress the rate of
M concentration of the monomer resulted
M
dimerization against the reverse reaction, the optically active
dimer was obtained as expected; however, it had a maximum
ee value of 29 % (Table 1, entry 2). Seeding of a small amount
of dimer crystal was effective in raising the ee value to 50 %
(Table 1, entry 3). In this case, the product possessed the same
handedness of chirality as the seed crystal.
Figure 4. Asymmetric photochemical reaction involving dynamic selective
crystallization by racemization by photoreversible reaction (PP-type reaction).
To promote crystallization in method B, the reaction temper-
ature was decreased to –40 °C instead of evaporating the sol-
vent. If a concentration of 0.01
M was used, decreasing the tem-
Three procedures were examined for the asymmetric synthe-
sis involving reversible photodimerization followed by crystalli-
zation (Table 1). A double glass tube was used for the photo-
reaction with an artificial light source for methods A and B. An
acetonitrile solution of monomer 1 was irradiated with a
365 nm line from a 350 W high-pressure mercury lamp by using
a light guide while stirring magnetically. A cooling apparatus
was used for the low-temperature experiment.
perature to –40 °C accelerated the crystallization and gave bet-
ter results. We obtained the optically active product without
seeding with up to 38 % ee (Table 1, entry 4). Finally, irradiation
of 1 involving dynamic crystallization by seeding a tiny piece of
single crystal controlled the handedness of chirality to achieve
a higher ee value of up to 80 % (Table 1, entry 5).
Both monomer 1 and dimer 2 absorb longer wavelengths in
the UV region, and dimerization by method C proceeded by
the use of natural sunlight. An acetonitrile solution of 1 was
irradiated with natural sunlight at 10–20 °C on the roof of the
chemistry building of Chiba University on a sunny day. The so-
lution was continuously stirred until all of the solvent had evap-
orated, which took 6 h. The remaining colorless solid was ana-
lyzed by HPLC. With no seeding, crystallization was promoted
spontaneously, and a low ee or a racemic dimer was obtained
(0–8 % ee; Table 1, entry 6). On the other hand, by seeding a
small amount of powdered crystal during irradiation, we ob-
tained the dimer with 15–30 % ee possessing the same chirality
as the seed crystal (Table 1, entry 7).
Table 1. Asymmetric synthesis involving reversible photodimerization fol-
lowed by crystallization.
Entry
Method
Conc. [
M]
Temp [°C]
Seeding
ee[a] [%]
1
2
3
4
5
6
7
A
A
A
B
B
C
C
0.04
0.01
0.01
0.01
0.01
0.02
0.02
20
20
20
–40
–40
10–20
10–20
no
no
yes
no
yes
no
yes
0–2
0–29
32–50[b]
0–38
55–80[b]
0–8
15–30[b]
[a] The ee value was determined by HPLC by using a CHIRALCEL OD-H col-
umn. Crystallization was examined five times each. The major stereoisomer
randomly appeared. [b] The product had the same chirality as the seed crys-
tal.
We obtained optically active materials simply by irradiating
prochiral materials in solution under absolutely achiral condi-
tions. This reaction is an example of absolute asymmetric syn-
thesis by using the properties of crystal chirality. Generation of
chirality and spontaneous breaking of symmetry are closely
linked to homochirality of living matter and the origin of life,
which is of wide interest in prominent research fields.
For method A, an acetonitrile solution of 1 was irradiated,
and the solvent was gradually evaporated by slow introduction
of nitrogen. After all the solvent was evaporated, the remaining
solid of dimer 2 was analyzed by HPLC by using a CHIRALCEL
OD-H column.
For method B, an acetonitrile solution of 1 was irradiated at
–40 °C to promote crystallization of the produced dimer. After
irradiation, CHCl3 was added to the reaction mixture to dissolve
the crystalline dimer, and the ee value of the entire amount of
dimer (both in the crystal and the mother liquor) was deter-
mined by HPLC analysis.
For method C, an acetonitrile solution of monomer 1 in a vial
was irradiated with natural sunlight under open air by gradually
evaporating the solvent with stirring magnetically. In all cases,
according to the progress of the photodimerization reaction,
crystalline dimer 2 precipitated as a colorless powder.
Conclusions
We achieved an asymmetric photodimerization reaction by irra-
diating prochiral materials in solution with a reversible photore-
action and selective crystallization. Three important require-
ments are needed to achieve this asymmetric photoreaction:
(1) the structure of the product must be chiral; (2) the dimer
must crystallize as a conglomerate; (3) racemization of the
dimer must occur effectively by a reverse photoreaction. This
reaction provides not only the first example of asymmetric syn-
Except for method B, the solvent was removed by evapora- thesis by combining a reversible photochemical reaction with
tion during irradiation, and the solid dimer remained at the crystallization but also introduces the useful asymmetric syn-
bottom of the glass tube. After the reaction, CHCl3 was added thesis of a pharmaceutically important flavonoid derivative.
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Acknowledgments
This work was supported by the Ministry of Education, Culture,
Sports, Science and Technology (MEXT) of the Japanese Gov-
ernment through Grants-in-Aid for Scientific Research (Nos.
25288017, 26410124, and 16H04144). N. U. acknowledges finan-
cial support from the Frontier Science Program of Graduate
School of Science and Engineering, Chiba University.
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Keywords: Asymmetric amplification · Photochemistry ·
Dimerization · Crystallization · Reversible reactions
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Received: October 19, 2017
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Communication
Asymmetric Synthesis
H. Ishikawa, N. Uemura, F. Yagishita,
N. Baba, Y. Yoshida, T. Mino,
Y. Kasashima, M. Sakamoto* .......... 1–5
Asymmetric Synthesis Involving Re-
versible Photodimerization of a Pro-
chiral Flavonoid Followed by Crys-
tallization
Asymmetric photodimerization is indirect racemization of the dimer
achieved by irradiating a prochiral through a reversible photoreaction in
flavonoid derivative in solution under solution and selective crystallization
absolutely achiral conditions. The crys- occur simultaneously to give the C2-
talline dimer precipitates upon irradia- chiral dimer.
tion of the monomer in solution, and
DOI: 10.1002/ejoc.201701457
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