Synthesis of chalcones bearing 2-hydroperoxy-3-methyl-3-butenyl or 2-hydroxy-3-methyl-3-butenyl group from prenylated chalcones

Article abstract of DOI:10.1080/00397911.2020.1745242

Chalcones bearing 2-hydroperoxy-3-methyl-3-butenyl or 2-hydroxy-3-methyl-3-butenyl groups, such as xanthoangelol E (1a), xanthoangelol D (2a), psorachalcone A (2 b), xanthohumol D (2c), and related derivatives were first synthesized by using the ene react

Full text of DOI:10.1080/00397911.2020.1745242

Synthetic Communications
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Synthesis of chalcones bearing 2-hydroperoxy-3-
methyl-3-butenyl or 2-hydroxy-3-methyl-3-butenyl
group from prenylated chalcones
Kazuhiro Sugamoto, Toru Yoshifuji, Shuhei Soejima & Yoshihiro Honda
To cite this article: Kazuhiro Sugamoto, Toru Yoshifuji, Shuhei Soejima & Yoshihiro Honda
(2020): Synthesis of chalcones bearing 2-hydroperoxy-3-methyl-3-butenyl or 2-hydroxy-3-
methyl-3-butenyl group from prenylated chalcones, Synthetic Communications, DOI:
10.1080/00397911.2020.1745242
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https://doi.org/10.1080/00397911.2020.1745242
Synthesis of chalcones bearing 2-hydroperoxy-3-methyl-3-
butenyl or 2-hydroxy-3-methyl-3-butenyl group from
prenylated chalcones
Kazuhiro Sugamoto, Toru Yoshifuji, Shuhei Soejima, and Yoshihiro Honda
Faculty of Engineering, University of Miyazaki, Miyazaki, Japan
ABSTRACT
ARTICLE HISTORY
Received 18 January 2020
Chalcones bearing 2-hydroperoxy-3-methyl-3-butenyl or 2-hydroxy-3-
methyl-3-butenyl groups, such as xanthoangelol E (1a), xanthoange-
lol D (2a), psorachalcone A (2 b), xanthohumol D (2c), and related
derivatives were first synthesized by using the ene reaction of preny-
lated chalcones with singlet oxygen.
KEYWORDS
word; xanthoangelol E;
xanthoangelol D;
psorachalcone A;
xanthohumol D;
singlet oxygen
GRAPHICAL ABSTRACT
Chalcones bearing 2-hydroperoxy-3-methyl-3-butenyl or 2-hydroxy-3-methyl-3-butenyl
groups, such as xanthoangelol E (1a), xanthoangelol D (2a), psorachalcone A (2 b), and
xanthohumol D (2c) were isolated from extracts of plants as biologically active
compounds (Supplementary Figure 1). Compounds 1a and 2a were isolated from
Angelica keiskei.[1] The hydroperoxide 1a showed to inhibit the production of thromb-
oxane B2 and 12-hydroxy-5,8,10-heptadecatrienoic acid from exogenous arachidonic
acid in platelets[2] and to inhibit phenylephrine-induced vasoconstriction through
endothelium-dependent production of EDRF/NO and/or thorough the reduction of the
[Ca2þ]i induced by phenylephrine.[3] The alcohol 2a was reported to inhibit endothelin-
1 production through the suppression of nuclear factor-jB,[4] to inhibit inflammatory-
induced plasminogen activator inhibitor production,[5] and to inhibit influenza virus
neuraminidase.[6] The alcohol 2 b was reported to be isolated from Maclura tinctoria[7]
and Psoralea corylifolia.[8] The alcohol 2c was isolated from Humulus lupulus,[9] exhib-
ited potent inhibitory activity of nitric oxide production.[10] Recently, F. Sang et al.
reported the synthesis of chalcones bearing 2-hydroxy-3-methyl-3-butenyl groups, such
as xanthoangelol D (2a), angusticornin A, and paratocarpin E with ene reaction using
CONTACT Kazuhiro Sugamoto
sugamoto@cc.miyazaki-u.ac.jp
Faculty of Engineering, University of Miyazaki,
Miyazaki, Japan
Supplemental data for this article can be accessed on the publisher’s website.
ß 2020 Taylor & Francis Group, LLC

2
K. SUGAMOTO ET AL.
Table 1. Photooxygenation of 3a under various conditions and lifetime of 1Dg
in solvent.
Photosensitizer
OOH
h
υ
OH O
OH O
O2 (1 atm)
Solvent, 15 ºC
MeO
OH
MeO
OH
1a
Time
3a
Conditions
Yield
(%)a
Lifetime of
Entry
Photosensitizer
Solvent
(h)
1Dg (ls)b
1
2
3
4
5
6
TPP
CH2Cl2
MeOH
MeOH
2-PrOH
Acetone
CH3CN
0.5
10
10
10
1
40
38
32
44
49
57
82.9
10.4
10.4
22.1
50.5
58.3
Rose bengal
Methylene blue
Methylene blue
Methylene blue
Methylene blue
1
aIsolated yield.
bThese data are taken from reference 14.
tetraphenylporphin (TPP) as the photosensitizer followed by reduction with triphenyl-
phosphine.[11] However , no work has been done on the synthesis of chalcones bearing
2-hydroperoxy-3-methyl-3-butenyl groups. In this paper, we report the synthesis of
these chalcone 1a, 2a-c and their related derivatives from prenylated chalcones.
Prenylated chalcones, such as 4-hydroxyderricin (3a), isobavachalcone (3b), derricin
(3d), were prepared according to our previous report.[12] Xanthohumol (3c) was synthe-
sized according to the literature.[13] Helesbeux et al. reported the ene reaction of ortho-
prenylphenol derivatives with singlet oxygen (1Dg) using tetraphenylporphin (TPP) as
the photosensitizer followed by a reduction with PPh3 to give ortho-(2-hydroxy-3-
methyl-3-butenyl)phenol derivatives.[14] Although the intermediately produced unstable
1
1
hydroperoxide was detected by H-NMR, it was not isolated. The ene reaction of Dg
with 4-hydroxyderricin (3a) was first attempted in the presence of TPP as the photosen-
sitizer (Table 1, entry 1). Xanthoangelol E (1a) with unstable hydroperoxy moiety was
first synthesized by this method in 40% yield, along with inseparable by-products.
However, compound 1a was difficult to separate from tpp by SiO2 column chromatog-
1
raphy. Rodgers was reported the natural lifetime of Dg in many solvent systems.[15]
1
Table 1 shows the photooxygenation of 3a under various conditions and lifetime of Dg
in each solvents. Although the reaction of 3a in MeOH using rose bengal (RB) or
methylene blue (MB) as photosensitizer were slow, the yield of 1a was moderate. MB
was the easiest to separate from 1a by SiO2 column chromatography. Entries 4–6 shows
the effect of solvent on the photooxygenation using MB. In the case of using MB as
photosensitizer, the reaction time on the photooxygenation of 3a is dependent on life-
1
time of Dg in each solvent. The yield of 1a increase with an increase in the lifetime of
1Dg. The reaction conditions in entry 6 gave the best result.
The conditions of the photooxygenation using MB in CH3CN was applied to several
prenylated chalcones (Table 2). The photooxygenatio of 1b–1d gave the corresponding
chalcones bearing 2-hydroperoxy-3-methyl-3-butenyl group in moderate yields
(entries 2–4).
Next, we tried the one-pot synthesis of chalcones bearing 2-hydroxy-3-methyl-3-
butenyl groups from the prenyled chalcones. Table 3 shows the photooxygenation of
prenylated chalcones in the presence of MB in CH3CN followed by reduction with

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3
Table 2. Photooxygenation of prenylated chalcones (3a-d) in the presence of methylene blue as
photosensitizer.
OOH
OH O
Methylene blue
OH O
h
υ
O2 (1 atm)
3 CH3CN,
R1
R2
R
R1
R2
R3
1h, 15 °C
3a: R1=OMe, R2=H, R3=OH
3b: R1=R3=OH, R2=H
3c: R1=R3=OH, R2=OMe
3d: R1=OMe, R2=R3=H
1a: R1=OMe, R2=H, R3=OH
1b: R1=R3=OH, R2=H
1c: R1=R3=OH, R2=OMe
1d: R1=OMe, R2=R3=H
Entry
Substrate
Product
Yield (%)
1
2
3
4
3a
3b
3c
3d
1a
1b
1c
1d
57
42
12
37
Bold values represent compound numbers.
Table 3. Synthesis chlcones bearing 2-hydroxy-3-methyl-3-butenyl group (2a–d) from prenylated
chalcones (3a–d).
Methylene blue
OH O
hυ
(CH3O)3P (1.3 eq.)
C, 3 h
O2 (1 atm)
R3
CH3CN,
R1
1
R2
2
0
°
3
3a
: R =OMe, R =H, R =OH
15 °C, 1 h
1
3
2
3b
: R =R =OH, R =H
1
3
2
3c
: R =R =OH,R =OMe
1
2
3
3d
: R =OMe, R =R =H
OH
OH O
R1
R2
R3
2a: R1=OMe, R2=H, R3=OH
2b: R1=R3=OH, R2=H
2c: R1=R3=OH,R2=OMe
2d: R1=OMe, R2=R3=H
Entry
Substrate
Product
Yield (%)
1
2
3
4
3a
3b
3c
3d
2a
2b
2c
2d
56
47
39
52
Bold values represent compound numbers.
trimethylphosphite. Thus chalcones bearing 2-hydroxy-3-methyl-3-butenyl group such
as xanthoangelol D (2a), psorachalcone A (2b), and xanthohumol D (2c) could be syn-
thesized from corresponding prenylated chalcones in 56, 47, and 39% yield, respectively
(entries 1–3).
In summary, the present method allowed for the synthesis of chalcones bearing
2-hydroperoxy-3-methyl-3-butenyl or 2-hydroxy-3-methyl-3-butenyl groups, such as
xanthoangelol E (1a), xanthoangelol D (2a), psorachalcone A (2b), xanthohumol D
(2c), and related derivatives from prenylated chalcones.

4
K. SUGAMOTO ET AL.
General procedure for the synthesis of chalcones bearing 2-hydroperoxy-3-
methyl-3-butenyl (1a–d)
Oxygen was bubbled trough a CH3CN solution (30 cm3) of prenylated chalcone (30 mg)
and methylene blue (3 mg) as photosensitizer. The reaction mixture was water-cooled at
15 ꢀC and irradiated with a halogen lamp (500 W) for 1 h. The reaction was terminated
when the substrate was completely consumed by checking on TLC. After removing the
solvent under reduced pressure, the residue was purified by silica gel column chroma-
tography with hexane-ethyl acetate.
General procedure for the synthesis of chalcones bearing 2-hydroxy-3-methyl-3-
butenyl (2a–d)
Oxygen was bubbled trough a CH3CN solution (30 cm3) of prenylated chalcone (30 mg)
and methylene blue (3 mg) as photosensitizer. The reaction mixture was water-cooled at
15 ꢀC and irradiated with a halogen lamp (500 W) for 1 h. The reaction was terminated
when the substrate was completely consumed by checking on TLC. To this reaction
solution was added 1.3 equiv. of trimethylphosphite at 0 ꢀC, and the mixture was stirred
for 3 h. After removing the solvent under reduced pressure, the residue was purified by
silica gel column chromatography with hexane-ethyl acetate.
References
[1] Baba, K.; Nakata, K.; Taniguchi, M.; Kido, T.; Kozawa, M. Chalcones from Angelica keis-
kei. Phytochemistry 1990, 29, 3907–3910. DOI: 10.1016/0031-9422(90)85357-L.
[2] Fujita, T.; Sakuma, S.; Sumiya, T.; Nishida, H.; Fujimoto, Y.; Baba, K.; Kozawa, M. The
Effects of Xanthoangelol E on Arachidonic Acid Metabolism in the Gastric Antral Mucosa
and Platelet of the Rabbit. Res. Commun. Chem. Pathol. Pharmacol 1992, 77, 227–240.
[3] Matsuura, M.; Kimura, Y.; Nakata, K.; Baba, K.; Okuda, H. Artery Relaxation by
Chalcones Isolated from the Roots of Angelica keiskei. Planta Med. 2001, 67, 230–235.
DOI: 10.1055/s-2001-12011.
[4] Sugii, M.; Ohkita, M.; Taniguchi, M.; Baba, K.; Kawai, Y.; Tahara, C.; Takaoka, M.;
Matsumura, Y. Xanthoangelol D Isolated from the Roots of Angelica keiskei Inhibits
Endothelin-1 Production through the Suppression of Nuclear Factor-jB. Biol. Pharm.
Bull. 2005, 28, 607–610. DOI: 10.1248/bpb.28.607.
[5] Ohkura, N.; Nakakuki, Y.; Taniguchi, M.; Kanai, S.; Nakayama, A.; Ohnishi, K.; Sakata, T.;
Nohira, T.; Matsuda, J.; Baba, K.; et al. Xanthoangelols Isolated from Angelica keiskei
Inhibit Inflammatory-Induced Plasminogen Activator Inhibitor 1 (PAI-1) Production.
BioFactors 2011, 37, 455–461. DOI: 10.1002/biof.187.
[6] Park, J. Y.; Jeong, H. J.; Kim, Y. M.; Park, S.-J.; Rho, M.-C.; Park, K. H.; Ryu, Y. B.; Lee,
W. S. Characteristic of Alkylated Chalcones from Angelica keiskei on Influenza Virus
Neuraminidase Inhibition. Bioorg. Med. Chem. Lett. 2011, 21, 5602–5604. DOI: 10.1016/j.
bmcl.2011.06.130.
[7] ElSohly, H. N.; Joshi, A. S.; Nimrod, A. C.; Walker, L. A.; Clark, A. M. Antifungal
Chalcones from Maclura tinctoria. Planta Med. 2001, 67, 87–89. DOI: 10.1055/s-2001-
10621.
[8] Yu, L.-L.; Chen, Y.-G.; Liu, J.-C.; Lu, Y.-O.; Gui, S.-H. Polish J. Chem. 2005, 79,
1173–1177.
[9] Tevens, J. F.; Taylor, A. W.; Nickerson, G. B.; Ivancic, M.; Henning, J.; Haunold, A.;
Deinzer, M. L. Prenylflavonoid Variation in Humulus lupulus: Distribution and

R
SYNTHETIC COMMUNICATIONSV
5
Taxonomic Significance of Xanthogalenol and 40-O-Methylxanthohumol. Phytochemistry
2000, 53, 759–775. DOI: 10.1016/s0031-9422(00)00005-4.
[10] Zhao, F.; Watanabe, Y.; Nozawa, H.; Daikonnya, A.; Kondo, K.; Kitanaka, S.
Prenylflavonoids and Phloroglucinol Derivatives from Hops (Humulus lupulus). J. Nat.
Prod. 2005, 68, 43–49. DOI: 10.1021/np0499113.
[11] Li, Y.; Sun, B.; Zhai, J.; Fu, L.; Zhang, S.; Zhang, J.; Liu, H.; Xie, W.; Deng, H.; Chen, Z.;
Sang, F. Tetrahedron Lett. 2019, 60, 1511156.
[12] Sugamoto, K.; Matsusita, Y-i.; Matsui, K.; Kurogi, C.; Matsui, T. Synthesis and
Antibacterial Activity of Chalcones Bearing Prenyl or Geranyl Groups from Angelica keis-
kei. Tetrahedron 2011, 67, 5346–5359. DOI: 10.1016/j.tet.2011.04.104.
[13] Khupse, R. S.; Erhardt, P. W. Total Synthesis of Xanthohumol. J. Nat. Prod. 2007, 70,
1507–1509. DOI: 10.1021/np070158y.
[14] Helesbeux, J.-J.; Duval, O.; Guilet, D.; Seraphin, D.; Rondeau, D.; Richomme, P.
Regioselectivity in the Ene Reaction of Singlet Oxygen with Ortho-Prenylphenol
Derivatives. Tetrahedron 2003, 59, 5091–5104. DOI: 10.1016/S0040-4020(03)00733-6.
[15] Rodgers, M. A. J. J. Am. Chem. Soc. 1983, 105, 6210–6205.