A new class of flavonoids bearing macrocyclic polyethers by stereoselective photochemical cycloaddition reaction

Article abstract of DOI:10.1016/j.tet.2019.06.007

A new class of flavonoids bearing cyclic polyethers involving a phenyl ring was conveniently provided by the intramolecular photochemical dimerization of 2-chromonecarboxylic esters. Irradiation of 2-chromonecarboxylate with a polyether tethered at both ends promoted intramolecular [2 + 2] cyclobutane formation leading to 14- to 27-membered cyclic polyethers. The efficiency depended on the substituted position of the phenyl ring, with ortho- and meta-substituted derivatives giving cycloadducts in good chemical yields and quantum efficiencies, whereas the para-derivatives were inert toward photolysis. X-ray crystallographic analysis revealed that the stereochemistry of the macrocyclic cycloadducts exhibited C₂-symmetry.

Full text of DOI:10.1016/j.tet.2019.06.007

Tetrahedron xxx (xxxx) xxx
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
A new class of flavonoids bearing macrocyclic polyethers by
stereoselective photochemical cycloaddition reaction
,
b
Hiroki Ishikawa a, Naohiro Uemura a, Ryo Taira a, Kento Sano a, Yasushi Yoshida a
,
,
, b, *
Takashi Mino a b, Yoshio Kasashima c, Masami Sakamoto a
a Department of Applied Chemistry and Biotechnology, Graduate School of Engineering, Chiba University, Yayoi-cho, Inage-ku, Chiba, 263-8522, Japan
b Molecular Chirality Research Center, Chiba University, Yayoi-cho, Inage-ku, Chiba, 263-8522, Japan
c Education Center, Faculty of Creative Engineering, Chiba Institute of Technology, Shibazono, Narashino, Chiba, 275-0023, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
A new class of flavonoids bearing cyclic polyethers involving a phenyl ring was conveniently provided by
the intramolecular photochemical dimerization of 2-chromonecarboxylic esters. Irradiation of 2-
chromonecarboxylate with a polyether tethered at both ends promoted intramolecular [2 þ 2] cyclo-
butane formation leading to 14- to 27-membered cyclic polyethers. The efficiency depended on the
substituted position of the phenyl ring, with ortho- and meta-substituted derivatives giving cycloadducts
in good chemical yields and quantum efficiencies, whereas the para-derivatives were inert toward
photolysis. X-ray crystallographic analysis revealed that the stereochemistry of the macrocyclic cyclo-
adducts exhibited C2-symmetry.
Received 13 April 2019
Received in revised form
3 June 2019
Accepted 4 June 2019
Available online xxx
Keywords:
photochemical dimerization
Chromone
© 2019 Elsevier Ltd. All rights reserved.
Cyclic polyether
Cyclobutane
C2-symmetry
1. Introduction
If we can provide size-specific and stereo-controlled polyethers
fused with flavonoids efficiently and selectively such as by click
Chromone (benzo-
g
-pyrone) I is the mother structure of natu-
chemistry, this will provide a powerful tool for synthesizing mac-
rocycles with functionality.
rally occurring flavonoids. Most of their derivatives, e.g., flavonol
quercetin II [1e3], flavone luteolin III [4,5], and isoflavanone gen-
istein IV [6,7], are widely used for drugs with antibacterial, anti-
cancer, and antioxidant activities (Fig. 1) [8e10]. The hydroxyl
groups of the phenol moieties play many important roles, one of
which is the role of ionophore. We aimed to develop a new flavo-
noid analog having an ionophore by conversion of the hydroxy
groups and to create a synthetic route to new derivatives pos-
sessing polyether ionophores because cyclic polyethers are well
known to selectively incorporate alkali metals and organic cations
depending on their ring size [11e18].
Recently, we reported the photochemical cyclization of
covalently-linked chromonecarboxylic esters 1 leading to macro-
cyclic polyethers 2 (Scheme 1) [28]. The reaction selectively and
predominantly gave C2 symmetric products. Here, we introduce a
benzene ring with the polyether chain at o-, m-, and p-positions to
determine if the photochemical reactivity depends on the differ-
ence in the substituted positions and the stereochemistry of the
products, and also to provide new functional macrocycles.
2. Results and discussion
Many synthetic methods involving photochemical reactions
have been developed to cyclize polyether chains; however, it is not
easy to create desired polyether sizes [19e23]. Furthermore, the
stereochemistry cannot be controlled except in rare cases [24e27].
Nine starting materials 5a-i were prepared by esterification
reactions as shown in Scheme 2. When two equimolar amounts of
chromone-2-carbonyl acid chloride 3 were reacted with 4, with
three different lengths of polyethers and three positional ortho,
meta, and para isomers, nine acyclic polyethers covalently-linked
with two chromones were obtained in moderate yields. As the
length of the polyether chain increased, the solubility of 5
decreased and the handling became troublesome.
* Corresponding author. Department of Applied Chemistry and Biotechnology,
Graduate School of Engineering, Chiba University, Yayoi-cho, Inage-ku, Chiba, 263-
8522, Japan.
E-mail address: sakamotom@faculty.chiba-u.jp (M. Sakamoto).
https://doi.org/10.1016/j.tet.2019.06.007
0040-4020/© 2019 Elsevier Ltd. All rights reserved.
Please cite this article as: H. Ishikawa et al., A new class of flavonoids bearing macrocyclic polyethers by stereoselective photochemical
cycloaddition reaction, Tetrahedron, https://doi.org/10.1016/j.tet.2019.06.007

2
H. Ishikawa et al. / Tetrahedron xxx (xxxx) xxx
than 4.2 Å (Schmidt's rule) at which the photocycloaddition reac-
tion proceeds in the solid-state [29,30], such that the reaction of 5d
in the solid-state did not proceed [31e34]. All other chromones 5
were also inert toward the solid-state photoreaction.
Next, we examined the direct irradiation of 5 in solution using
the 365 nm line from a high pressure mercury lamp with uranium
glass filter. It is known that the photodimerization of chromone-
carboxylate proceeds from the triplet excited state. We also
examined the sensitization reaction using benzophenone
(ET ¼ 69 kcal molꢀ1) [26e28].
When
a MeCN solution of the ortho-isomer with dieth-
yleneglycol unit 5a was irradiated for 0.5 h, an effective cycload-
dition reaction was promoted and cyclic polyether 6a was obtained
in 77% yield at 74% conversion (Scheme 3 and Table 1, entry 1,
numbers in parentheses). The chemical yields were determined
based on consumed starting materials. Prolonged irradiation did
not give a better yield because 6a also absorbs light. Fig. S1 shows
the absorption spectra of 5a and 6a. The structure of 6a includes
two chromophore functions, thus the same concentration of
spectra indicates the decrease of absorption co-efficiency for one
chromone structure of 6a; however, the absorption spectrum
moved to the longer wavelength region due to the alkoxyphenone
chromophore.
Fig. 1. Examples of naturally occurring flavonoids with high pharmaceutical activity.
The triplet sensitization reaction using benzophenone as a
sensitizer resulted in better conversion and chemical yield. In the
case of 5a, the conversion rose to 80% and a better chemical yield of
82% was obtained (Table 1, entry 1). Irradiation of meta derivative
5b gave similar results; better yield and conversion were obtained
than in the reaction by direct irradiation, and 74% of 6b was isolated
(entry 2). The para isomer 5c was inert toward photolysis even in
the sensitization reaction (entry 3), likely due to steric demands
with the two chromones placed far away from each other.
When the chain length was expanded, diethyleneglycol and
triethyleneglycol gave similar results, and the corresponding cyclic
ethers (6d, 6e, 6g, and 6h) were obtained. In these derivatives, the
para isomers did not react and the starting materials were recov-
ered. In all cases, sensitization experiments gave better results for
conversion and chemical yield.
Scheme 1. Photochemical reaction of bischromones tethered with a polyethylene
chain.
The stereo-structure was unequivocally established by single
crystal X-ray analysis. The stereochemistry of the chromone dimer
was anti-head-to-head as in the case of the photoreaction of
aliphatic polyether-tethered materials 1 leading to 2 [28]. The
dimeric structure exhibited C2 symmetry and a C2 structure for the
hole crown ether with large molecules like 6 was formed (Fig. 3).
Materials with C2 symmetry are widely utilized as ligands in cata-
lytic asymmetric synthesis and functional materials [35e38]. Thus,
the development of a new reaction leading to C2-symmetric ma-
terials would be extremely useful. Most C2-symmetric polyethers
are produced from C2-symmetric units and polyethers. There are
Scheme 2. Synthesis of bischromones tethered with polyethers 5a-i.
Whereas most of the polyethers 5 gave colorless powders, only
5d gave a single crystal suitable for X-ray structural analysis. Its
perspective views are shown in Fig. 2. The crystal structure shows
that the molecule forms a spiral structure and the two chromones
at both ends are aligned in an anti-parallel fashion. The distance
between the two double bonds was about 7.07 Å, which is larger
Scheme 3. Intramolecular photocycloaddition of bischromones tethered with poly-
ethers 5 leading to crown ethers 6.
Fig. 2. Perspective views of 5d: (a) top view and (b) side view.
Please cite this article as: H. Ishikawa et al., A new class of flavonoids bearing macrocyclic polyethers by stereoselective photochemical
cycloaddition reaction, Tetrahedron, https://doi.org/10.1016/j.tet.2019.06.007

H. Ishikawa et al. / Tetrahedron xxx (xxxx) xxx
3
Table 1
Photochemical reaction of chromonecarboxylate tethered with polyethers.
4. Experimental section
Conv. of 5a
Yield of 6 (%)a
4.1. General information
Entry
5
n
position
1
2
3
4
5
6
7
8
9
5a
5b
5c
5d
5e
5f
5g
5h
5i
1
1
1
2
2
2
3
3
3
ortho
meta
para
ortho
meta
para
ortho
meta
para
80 (74)
77 (52)
0 (0)
71 (58)
73 (45)
0 (0)
76 (58)
66 (40)
0 (0)
82 (77)
74 (70)
0 (0)
77 (79)
65 (49)
0 (0)
76 (48)
61 (49)
0 (0)
NMR spectra were recorded in CDCl3 solution on Bruker 300
and JEOL ECA500 spectrometers for 1H- and 13C NMR. Chemical
shifts are reported in parts per million (ppm) relative to TMS as an
internal standard. IR spectra were recorded on a JASCO FT/IR-230
spectrometer. UV absorption spectra were recorded on a JASCO V-
570 spectrometer. High-resolution mass spectra (HRMS) were
performed on an Orbitrap ThermoFisher Exactive ion trap mass
spectrometer. X-ray single crystallographic analysis was conducted
using a SMART APEX II (Bruker AXS) and APEX II ULTRA (Bruker
AXS). Eikosya 500 W high pressure mercury lamp and SAN-EI super
cure UVF-352S were used as irradiation sources. Commercially
available reagents and solvents were used without further
purification.
a
The values in parentheses show conversion and chemical yields by direct irra-
diation for 0.5 h. Direct irradiation: isolated yield, sensitization reaction: determined
by 1H NMR using triphenylmethane as an internal standard.
4.2. Synthesis of polyethers 4a-i
The polyethers were synthesized according to the reported
procedure [39,40]. The corresponding benzenediol (0.5 g,
4.54 mmol) in acetonitrile (20 mL), the corresponding chloro-
ethylene glycol (3.0 eq., 13.62 mmol), potassium carbonate (1.88 g,
13.62 mmol), and lithium bromide (0.039 g, 0.45 mmol) were
mixed and the reaction was stirred at 90 ꢁC for 3 days. After
filtration of the precipitate, the solvent was removed under
reduced pressure, and the obtained residue was separated by silica
gel chromatography (hexane/ethyl acetate) to obtain the corre-
sponding polyethers in 40e73% yields.
4.3. Synthesis of polyethers with chromone groups 5a-5i
Fig. 3. Perspective view of (a) 6d and (b) 6e.
Chromonecarbonyl chloride was prepared by the reaction of
acid with thionyl chloride. After a toluene solution of 2-chromonic
carboxylic acid (1.4 g, 7.6 mmol) and thionyl chloride (1.1 g,
9.1 mmol) was stirred at 90 ꢁC for 2e3 h, thionyl chloride was
removed under reduced pressure. The toluene solution of the cor-
responding polyethers 4a-4c (0.5 g, 2.5 mmol) and chromone-
carbonyl chloride was stirred at 120 ꢁC overnight. After base
extraction, the solvent was removed under reduced pressure, and
the residue was separated by silica gel column chromatography
(hexane/ethyl acetate) to obtain the corresponding chromone de-
rivatives 5a-i in 30e92% yields.
few examples of synthesizing C2-symmetric units from linear ma-
terials with a polyethylene chain [24,25,28].
It is well documented that alkali cations are recognized by
polyethers. Thus, there is the potential to influence the reactivity of
the photoreaction. We examined the photoreaction of 5a, 5d, and
5g in the presence of Li, Na, and K cations. The photocyclization of
ortho and meta derivatives 5 leading to 6 proceeded effectively,
with or without metal cations. The para derivatives did not give any
photoproduct even in the presence of metal cations (Table S1). We
are continuing to explore the asymmetric photocycloaddition by
using chiral organic cations.
4.3.1. Photoreaction in solution
Chromone derivatives (0.004 M) were dissolved in a Pyrex test
tube using acetonitrile as a solvent and bubbled with argon for
15 min. Thereafter, light irradiation was performed using a 500 W
high pressure mercury lamp. After completion of the reaction, the
solvent was removed under reduced pressure, and the obtained
residue was separated by silica gel column chromatography (hex-
ane/ethyl acetate or chloroform/ethyl acetate) to isolate the cor-
responding chromone derivatives.
3. Conclusions
We developed a facile synthetic methodology for macrocyclic
polyethers by the stereoselective dimerization of chromone-
carboxylic esters connected by various polyether chains of differing
lengths and positions on the benzene rings. The reaction proceeded
effectively leading to 14- to 27-membered cyclic polyethers and the
structures were determined to have C2-symmetric stereochemistry.
C2-symmetric materials are very useful and widely found in syn-
thetic materials, especially ligands for catalytic asymmetric syn-
thesis and molecular recognition. Furthermore, the products
contain flavonoid structures, which exist in many plants and
pharmaceutical materials. This reaction provides a very efficient
method for imparting C2 symmetry to cyclic polyethers. The
products also possess modifiable functional groups such as a ke-
tone carbonyl group.
4.3.2. Sensitization reaction
A chromone derivative (0.004 M) was dissolved in a Pyrex test
tube using acetonitrile as a solvent. Benzophenone (5.0 eq.) was
added as a triplet sensitizer, and the solution was bubbled with
argon for 15 min then sealed. Thereafter, while rotating the test
tube in a merry-go-round, the reaction was irradiated with light of
365 nm from a 500 W high pressure mercury lamp. After comple-
tion of the reaction, triphenylmethane was added as an internal
standard, the solvent was removed under reduced pressure, and
the conversion and product yield were calculated by 1H NMR.
Please cite this article as: H. Ishikawa et al., A new class of flavonoids bearing macrocyclic polyethers by stereoselective photochemical
cycloaddition reaction, Tetrahedron, https://doi.org/10.1016/j.tet.2019.06.007

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H. Ishikawa et al. / Tetrahedron xxx (xxxx) xxx
4.3.3. Photoreaction of chromone derivatives 5 with alkali metal
salts
4.3.9. (((1,4-Phenylenebis(oxy))bis(ethane-2,1-diyl))bis(oxy))
bis(ethane-2,1-diyl)bis(4-oxo-4H-chromene-2-carboxylate) (5f)
Slightly yellow crystal; m.p. 95e97 ꢁC; 1H NMR (CDCl3)
Chromone derivatives 5a, 5d, 5g (0.005 M) were dissolved in a
Pyrex test tube with acetonitrile as a solvent. LiClO4, NaClO4, or
KClO4 as a metal cation (10.0 eq.) was added and the reaction was
bubbled with argon for 15 min and sealed. Thereafter, the four
samples were placed in a merry-go-round together with a sample
to which no metal salt was added, and light irradiation was carried
out using a 500 W high pressure mercury lamp while rotating the
test tubes. After the reaction, triphenylmethane was added as an
internal standard, the solvent was removed under reduced pres-
sure, and the conversion and product yields were calculated by 1H
NMR.
d
3.82e3.94 (m, 8H), 4.05e4.08 (m, 4H), 4.57e4.60 (m, 4H),
6.75e6.81 (m, 4H), 7.14 (s, 2H), 7.43e7.48 (m, 2H), 7.57e7.60 (m,
2H), 7.70e7.77 (m, 2H), 8.17e8.20 (m, 2H); 13C NMR (CDCl3)
66.0,
d
68.2, 69.0, 70.1, 115.2, 115.7, 119.0, 124.5, 125.9, 126.1, 134.9, 152.1,
153.1, 156.1, 160.7, 178.6; IR (cmꢀ1, neat) 1747, 1644; HRMS (ESI-MS)
m/z calcd for C34H30O12þNa 653.1629, found 653.1630.
4.3.10. (((((1,2-Phenylenebis(oxy))bis(ethane-2,1-diyl))bis(oxy))
bis(ethane-2,1-diyl))bis(oxy))bis(ethane-2,1-diyl) bis(4-oxo-4H-
chromene-2-carboxylate) (5g)
Slightly yellow oil; 1H NMR (CDCl3)
d 3.72e3.77 (m, 8H),
4.3.4. (1,2-Phenylenebis(oxy))bis(ethane-2,1-diyl)bis(4-oxo-4H-
chromene-2-carboxylate) (5a)
3.85e3.89 (m, 8H),4.14e4.17 (m, 4H), 4.53e4.56 (m, 4H), 6.84e6.91
(m, 4H), 7.13 (s, 2H), 7.41e7.47 (m, 2H), 7.58e7.60 (m, 2H), 7.70e7.76
Colorless solid; m.p. 138e140 ꢁC; 1H NMR (CDCl3)
d
4.39 (t,
(m, 2H), 8.16e8.19 (m, 2H); 13C NMR (CDCl3)
d 65.8, 68.7, 68.8, 69.9,
J ¼ 4.7 Hz, 4H), 4.76 (t, J ¼ 4.7 Hz, 4H), 6.99 (s, 4H), 7.10 (m, 2H),
70.8, 70.8, 114.8, 115.0, 118.8, 121.6, 124.4, 125.7, 125.9, 134.7, 148.9,
151.9,155.9,160.5,178.3; IR (cmꢀ1, neat) 1745,1653; HRMS (ESI-MS)
m/z calcd for C38H38O14þNa 741.2154, found 741.2129.
7.40e7.45 (m, 2H), 7.56e7.59 (m, 2H), 7.70e7.76 (m, 2H), 8.13e8.16
(m, 2H); 13C NMR (CDCl3)
d
65.4, 67.5, 115.3, 116.3, 119.0, 122.9,
124.6, 125.9, 126.1, 135.0, 148.9, 151.9, 156.1, 160.6, 178.5; IR (cmꢀ1
,
neat) 1742, 1654; HRMS (ESI-MS) m/z calcd for C30H22O10þNa
4.3.11. (((((1,3-Phenylenebis(oxy))bis(ethane-2,1-diyl))bis(oxy))
bis(ethane-2,1-diyl))bis(oxy))bis(ethane-2,1-diyl) bis(4-oxo-4H-
chromene-2-carboxylate) (5h)
565.1105, found 565.1099.
4.3.5. (1,3-Phenylenebis(oxy))bis(ethane-2,1-diyl)bis(4-oxo-4H-
chromene-2-carboxylate) (5b)
Slightly yellow oil; 1H NMR (CDCl3)
d 3.75e3.88 (m, 16H),
4.07e4.11 (m, 4H), 4.54e4.57 (m, 4H), 6.44e6.48 (m, 3H), 7.10e7.14
(m, 3H), 7.42e7.45 (m, 2H), 7.58e7.61 (m, 2H), 7.71e7.73 (m, 2H),
Colorless solid; m.p. 149e150 ꢁC; 1H NMR (CDCl3)
d 4.32 (t,
J ¼ 4.7 Hz, 4H), 4.75 (t, J ¼ 4.7 Hz, 4H), 6.56e6.60 (m, 3H), 7.13 (s,
8.17e8.20 (m, 2H); 13C NMR (CDCl3)
d 66.0, 67.4, 68.8, 69.9, 70.9,
2H), 7.20 (t,1H), 7.42e7.47 (m, 2H), 7.59e7.62 (m, 2H), 7.71e7.77 (m,
70.9, 101.7, 107.1, 115.1, 118.9, 124.5, 125.8, 126.0, 129.9, 134.9, 152.0,
156.1, 160.0, 160.1, 178.5; IR (cmꢀ1, neat) 1745, 1655; HRMS (ESI-MS)
m/z calcd for C38H38O14þNa 741.2154, found 741.2140.
2H), 8.17e8.20 (m, 2H); 13C NMR (CDCl3)
d 65.2, 65.7, 102.3, 107.7,
115.4, 119.0, 124.6, 126.0, 126.2, 130.5, 135.0, 151.9, 156.2, 160.0,
160.7, 178.5; IR (cmꢀ1, neat) 1744, 1644; HRMS (ESI-MS) m/z calcd
for C30H22O10þNa 565.1105, found 565.1090.
4.3.12. (((((1,4-Phenylenebis(oxy))bis(ethane-2,1-diyl))bis(oxy))
bis(ethane-2,1-diyl))bis(oxy))bis(ethane-2,1-diyl)bis(4-oxo-4H-
chromene-2-carboxylate) (5i)
4.3.6. (1,4-Phenylenebis(oxy))bis(ethane-2,1-diyl)bis(4-oxo-4H-
chromene-2-carboxylate) (5c)
Colorless crystal; m.p. 80e81 ꢁC; 1H NMR (CDCl3)
d 3.75e3.89
Slightly yellow solid; m.p. 148e149 ꢁC; 1H NMR (CDCl3)
d
4.29 (t,
(m, 16H), 4.04e4.07 (m, 4H), 4.54e4.57 (m, 4H), 6.79 (s, 4H), 7.13 (s,
2H), 7.42e7.47 (m, 2H), 7.58e7.60 (m, 2H), 7.70e7.76 (m, 2H),
J ¼ 4.7 Hz, 4H), 4.73 (t, J ¼ 4.7 Hz, 4H), 6.88e6.90 (m, 4H), 7.14 (s,
2H), 7.43e7.48 (m, 2H), 7.60e7.63 (m, 2H), 7.72e7.78 (m, 2H),
8.16e8.19 (m, 2H); 13C NMR (CDCl3)
d 65.9, 68.0, 68.7, 69.9, 70.8,
8.18e8.21 (m, 2H); 13C NMR (CDCl3)
d
65.4, 66.4, 115.4, 116.1, 119.0,
70.8, 115.0, 115.5, 118.8, 124.4, 125.7, 126.0, 134.8, 151.9, 153.0, 155.9,
160.5, 178.3; IR (cmꢀ1, neat) 1738, 1651; HRMS (ESI-MS) m/z calcd
for C38H38O14þNa 741.2154, found 741.2118.
124.6, 125.9, 126.2, 135.0, 151.9, 153.2, 156.2, 160.7, 178.6; IR (cmꢀ1
,
neat)1743, 1647; HRMS (ESI-MS) m/z calcd for C30H22O10þNa
565.1105, found 565.1093.
4.3.13. syn-6,7,15a,15b,24,25-Hexahydro-9H,22H-benzo[50,6']
[1,4,7,10]tetraoxacyclotetradecino[120,13':1,4]cyclobuta[1,2-b:4,3-b']
dichromene-9,15,16,22-tetraone (6a)
4.3.7. (((1,2-Phenylenebis(oxy))bis(ethane-2,1-diyl))bis(oxy))
bis(ethane-2,1-diyl)bis(4-oxo-4H-chromene-2-carboxylate) (5d)
Colorless crystal; m.p. 138e140 ꢁC; 1H NMR (CDCl3)
d
3.90e3.97
Colorless crystal; m.p. 219e221 ꢁC; 1H NMR (CDCl3)
d 4.26e4.29
(m, 8H), 4.17e4.20 (m, 4H), 4.56e4.59 (m, 4H), 6.46e6.90 (m, 4H),
7.11 (s, 2H), 7.41e7.46 (m, 2H), 7.56e7.59 (m, 2H), 7.70e7.75 (m,
(m, 2H), 4.26 (s, 2H), 4.42e4.47 (m, 4H), 4.81 (m, 2H), 6.75 (m, 2H),
7.06e7.13 (m, 6H), 7.44e7.49 (m, 2H), 7.88e7.92 (m, 2H); 13C NMR
2H), 8.15e8.19 (m, 2H); 13C NMR (CDCl3)
d
66.1, 69.0, 69.1, 70.1,
(CDCl3) d 43.2, 64.9, 69.4, 83.9, 117.0, 118.5, 119.5, 123.0, 123.6, 127.7,
114.9, 115.2, 119.0, 121.9, 124.6, 125.9, 126.1, 134.9, 148.9, 152.1, 156.1,
160.7, 178.5; IR (cmꢀ1, neat) 1746, 1659; HRMS (ESI-MS) m/z calcd
for C34H30O12þNa 653.1629, found 653.1619.
137.1, 150.0, 158.7, 165.3, 186.3; IR (cmꢀ1, neat) 1742, 1697; HRMS
(ESI-MS) m/z calcd for C30H23O10 543.1286, found 543.1274.
4.3.14. syn-15a,15b,111,111a,111b,112-Hexahydro-3,6,8,11-tetraoxa-
1(5a,5b)-cyclobuta[1,2-b:4,3-b']dichromene-7(1,3)-
benzenacyclododecaphane-111,112,2,12-tetraone (6b)
4.3.8. (((1,3-Phenylenebis(oxy))bis(ethane-2,1-diyl))bis(oxy))
bis(ethane-2,1-diyl)bis(4-oxo-4H-chromene-2-carboxylate) (5e)
Colorless solid; m.p. 79e81 ꢁC; 1H NMR (CDCl3)
d
3.88e3.94 (m,
Colorless crystal; m.p. 124e125 ꢁC; 1H NMR (CDCl3)
d 4.30 (s,
8H), 4.09e4.13 (m, 4H), 4.56e4.59 (m, 4H), 6.44e6.47 (m, 3H),
7.06e7.12 (m,1H), 7.13 (s, 2H), 7.42e7.47 (m, 2H), 7.57e7.60 (m, 2H),
2H), 4.30e4.33 (m, 2H), 4.48 (m, 4H), 4.64 (m, 2H), 6.55e6.58 (m,
2H), 6.69e6.72 (m, 2H), 7.06e7.11 (m, 2H), 7.26e7.28 (m, 2H), 7.45
7.71e7.76 (m, 2H), 8.17e8.20 (m, 2H); 13C NMR (CDCl3)
d
66.0, 67.6,
(m, 2H), 7.85e7.88 (m, 2H); 13C NMR (CDCl3)
d 44.9, 67.3, 68.5, 84.8,
69.0, 70.0, 101.9, 107.3, 115.2, 119.0, 124.6, 125.9, 126.1, 130.1, 134.9,
152.0, 156.1, 160.0, 160.7, 178.5; IR (cmꢀ1, neat) 1748, 1659; HRMS
(ESI-MS) m/z calcd for C34H31O12 631.1810, found 631.1794.
106.1, 112.0,118.0,119.4,123.3,127.4, 129.8,136.9,158.6,161.3,166.6,
187.6; IR (cmꢀ1, neat) 1741, 1697; HRMS (ESI-MS) m/z calcd for
C30H23O10 543.1286, found 543.1286.
Please cite this article as: H. Ishikawa et al., A new class of flavonoids bearing macrocyclic polyethers by stereoselective photochemical
cycloaddition reaction, Tetrahedron, https://doi.org/10.1016/j.tet.2019.06.007

H. Ishikawa et al. / Tetrahedron xxx (xxxx) xxx
5
4.3.15. syn-6,7,9,10,18a,18b,27,28,30,31-Decahydro-12H,25H-benzo
b
¼ 102.106(7) ꢁ, V ¼ 2908.0(2) Å3, Z ¼ 4,
l
(MoK
a
) ¼ 0.71073 Å,
[80,9'][1,4,7,10,13,16]hexaoxacycloicosino[180,19':1,4]cyclobuta[1,2-
b:4,3-b']dichromene-12,18,19,25-tetraone (6d)
r
¼ 1.440 g/cm3,
m
(MoK
a
) ¼ 0.110 cm, 16207 reflections measured
(T ¼ 173 K, 1.628ꢁ <
q
< 27.546ꢁ), nb of independent data collected:
Colorless crystal; m.p. 182e183 ꢁC; 1H NMR (CDCl3)
d
3.80 (m,
6591, nb of independent data used for refinement: 3991 in the final
least-squares refinement cycles on F [2], the model converged at
4H), 3.98e4.00 (m, 4H), 4.22e4.24 (m, 4H), 4.32 (s, 2H), 4.42 (m,
4H), 6.97e7.09 (m, 8H), 7.34e7.37 (m, 2H), 7.85e7.87 (m, 2H); 13C
R1 ¼0.0536, wR2 ¼ 0.1286 [I > 2 (I)], R1 ¼0.0980, wR2 ¼ 0.1607 (all
s
NMR (CDCl3)
d
45.7, 67.1, 69.2, 69.2 70.4, 85.2, 102.0, 114.8, 118.2,
data), and GOF ¼ 0.975, H-atom parameters constrained.
119.7, 122.0, 123.1, 127.2, 136.8, 149.1, 158.9, 167.3, 188.2; IR (cmꢀ1
,
(CCDC1902865).
neat) 1734, 1695; HRMS (ESI-MS) m/z calcd for C34H31O12 631.1810,
found 631.1796.
4.6. Single crystal X-Ray structure analysis of 6e
4.3.16. syn-15a,15b,111,111a,111b,112-Hexahydro-3,6,9,11,14,17-
hexaoxa-1(5a,5b)-cyclobuta[1,2-b:4,3-b']dichromene-10(1,3)-
benzenacyclooctadecaphane-111,112,2,18-tetraone (6e)
Colorless prism (0.30 ꢂ 0.30 ꢂ 0.20 mm3), monoclinic space
group P21/n, a ¼ 15.947(2) Å, b ¼ 11.4095(17) Å, c ¼ 16.328(3) Å,
b
¼ 99.592(3) ꢁ, V ¼ 2929.3(8) Å3, Z ¼ 4,
l
(MoK
a) ¼ 0.71073 Å,
Colorless crystal; m.p. 169e171 ꢁC; 1H NMR (CDCl3)
d 3.64e3.66
r
¼ 1.430 g/cm3,
m
(MoK
a
) ¼ 0.109 cm, 16430 reflections measured
(T ¼ 173 K, 1.653ꢁ <
q
< 27.455ꢁ), nb of independent data collected:
(m, 4H), 3.73e3.84 (m, 4H), 4.16e4.40 (m, 8H), 4.30 (s, 2H),
6.56e6.59 (m, 2H), 6.85e6.90 (m, 2H), 7.04e7.08 (m, 2H), 7.21e7.26
(m, 2H), 7.38e7.42 (m, 2H), 7.84e7.86 (m, 2H); 13C NMR (CDCl3)
6619, nb of independent data used for refinement: 2725 in the final
least-squares refinement cycles on F [2], the model converged at
d
46.2, 66.1, 68.2, 68.7, 69.4, 85.2, 103.4, 108.0, 118.0, 119.6, 122.7,
R1 ¼0.0626, wR2 ¼ 0.1430 [I > 2 (I)], R1 ¼0.1688, wR2 ¼ 0.2032 (all
s
126.8, 129.9, 136.4, 158.8, 160.1, 167.5, 188.4; IR (cmꢀ1, neat) 1735,
1691; HRMS (ESI-MS) m/z calcd for C34H30O12þNa 653.1629, found
653.1611.
data), and GOF ¼ 0.905, H-atom parameters constrained.
(CCDC1902866).
4.7. Single crystal X-Ray structure analysis of 6g
4.3.17. syn-6,7,9,10,12,13,21a,21b,30,31,33,34,36,37-
Tetradecahydro-15H,28H-benzo[110,12'][1,4,7,10,13,16,19,22]
octaoxacyclohexacosino[240,25':1,4]cyclobuta[1,2-b:4,3-b']
dichromene-15,21,22,28-tetraone (6g)
Colorless prism (0.50 ꢂ 0.50 ꢂ 0.30 mm3), orthorhombic space
group Pca21, a ¼ 22.787(3) Å, b ¼ 9.2042(12) Å, c ¼ 18.492(2) Å,
V ¼ 3878.4(9) Å3, Z ¼ 4,
l
(MoK
a
) ¼ 0.71073 Å,
r
¼ 1.382 g/cm3,
m
Colorless crystal; m.p. 77e78 ꢁC; 1H NMR (CDCl3)
d 3.647e3.75
(MoK
a
) ¼ 0.106 cm, 21372 reflections measured (T ¼ 173 K,
2.099ꢁ < < 27.587ꢁ), nb of independent data collected: 6308, nb of
q
(m, 8H), 3.80e3.83 (m, 4H), 3.92e3.94 (m, 4H), 4.18e4.21 (m, 4H),
4.26e4.38 (m, 2H), 4.32 (s, 2H), 4.39e4.41 (m, 2H), 6.93 (s, 4H),
7.04e7.26 (m, 4H), 7.45e7.50 (m, 2H), 7.87e7.89 (m, 2H); 13C NMR
independent data used for refinement: 5628 in the final least-
squares refinement cycles on F [2], the model converged at
(CDCl3)
d 45.4, 66.5, 68.8, 69.2, 70.0, 71.0, 71.0, 84.9, 114.3, 118.0,
R1 ¼0.0332, wR2 ¼ 0.0773 [I > 2 (I)], R1 ¼0.0396, wR2 ¼ 0.0809 (all
s
119.5, 121.5, 122.9, 127.1, 136.6, 149.0, 158.7, 166.9, 187.8; IR (cmꢀ1
,
data), and GOF ¼ 1.019, H-atom parameters constrained.
neat) 1737, 1699; HRMS (ESI-MS) m/z calcd for C38H38O14þNa
(CCDC1902867).
741.2154, found 741.2130.
Acknowledgements
4.3.18. syn-15a,15b,111,111a,111b,112-hexahydro-3,6,9,12,14,17,20,23-
octaoxa-1(5a,5b)-Cyclobuta[1,2-b:4,3-b']dichromene-13(1,3)-
benzenacyclotetracosaphane-111,112,2,24-tetraone (6h)
This work was supported by Grants-in-Aid for Scientific
Research (Nos. 17K19114, 26410124 and 16H04144) from the Min-
istry of Education, Culture, Sports, Science and Technology (MEXT)
of the Japanese Government. Mr. Uemura acknowledges financial
support from Frontier Science Program of Graduate School of Sci-
ence and Engineering, Chiba University.
Colorless crystal; m.p. 148e150 ꢁC; 1H NMR (CDCl3)
d 3.28 (m,
2H), 3.42 (m, 2H), 3.55 (m, 4H), 3.72 (m, 4H), 3.86e3.90 (m, 6H),
4.17e4.33 (m, 4H), 4.33 (s, 2H), 6.51 (m, 2H), 6.85 (m, 1H), 7.03e7.13
(m, 5H), 7.43e7.46 (m, 2H), 7.82e7.84 (m, 2H); 13C NMR (CDCl3)
d
46.7, 66.0, 67.7, 68.1, 69.9, 70.7, 70.9, 85.1, 101.5, 107.7, 118.2, 119.7,
122.9, 127.0, 129.7, 136.8, 159.1, 160.3, 166.4, 188.6; IR (cmꢀ1, neat)
1748, 1698; HRMS (ESI-MS) m/z calcd for C38H38O14þNa 741.2154,
found 741.2137.
Appendix A. Supplementary data
Supplementary data to this article can be found online at
https://doi.org/10.1016/j.tet.2019.06.007.
4.4. Single crystal X-Ray structure analysis of 5d
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cycloaddition reaction, Tetrahedron, https://doi.org/10.1016/j.tet.2019.06.007

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Please cite this article as: H. Ishikawa et al., A new class of flavonoids bearing macrocyclic polyethers by stereoselective photochemical
cycloaddition reaction, Tetrahedron, https://doi.org/10.1016/j.tet.2019.06.007