Semisynthesis of prunetin, a bioactive O-methylated isoflavone from naringenin, by the sequential deacetylation of chalcone intermediates and oxidative rearrangement

Article abstract of DOI:10.1093/bbb/zbaa021

Prunetin (4′,5-dihydroxy-7-methoxyisoflavone) was semisynthesized in 8 steps from readily available naringenin in 26% total yield. The key reaction was chemoenzymatic sequential deacetylation to 6′-acetoxy-2′,4″-dihydroxy-4′-methoxychalcone, the in situ-formed precursor for thallium(III) nitrate-mediated oxidative rearrangement.

Full text of DOI:10.1093/bbb/zbaa021

Bioscience, Biotechnology, and Biochemistry, 2021, Vol. 85, No. 1, 143-147
doi: 10.1093/bbb/zbaa021
Advance access publication date: 7 January 2021
REGULAR PAPER
REGULAR PAPER
Semisynthesis of prunetin, a bioactive O-methylated
isoflavone from naringenin, by the sequential
deacetylation of chalcone intermediates
and oxidative rearrangement
Takeshi Sugai ,1,∗ Kengo Hanaya, and Shuhei Higashibayashi1
1
1Department of Pharmaceutical Sciences, Faculty of Pharmacy, Keio University, Tokyo, Japan
∗
Correspondence: Takeshi Sugai, sugai-tk@pha.keio.ac.jp
ABSTRACT
ꢀ
Prunetin (4 ,5-dihydroxy-7-methoxyisoflavone) was semisynthesized in 8 steps from readily available naringenin in 26%
total yield. The key reaction was chemoenzymatic sequential deacetylation to
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
6
-acetoxy-2 ,4 -dihydroxy-4 -methoxychalcone, the in situ-formed precursor for thallium(III) nitrate-mediated oxidative
rearrangement.
Graphical Abstract
Prunetin was semisynthesized from naringenin in 8 steps, based on stepwise deacetylation and subsequent
thallium(III)-mediated oxidative rearrangement of a 2’-hydroxychalcone.
Keywords: O-methylated isoflavone, naringenin, chalcone, deacetylation, oxidative rearrangement
Prunetin (1a; Figure 1) is secreted from the roots of pea
plants and attracts zoospores of the phytopathogenic fun-
gus Aphanomyces euteiches (Yokosawa et al. 1986). Prunetin
has been isolated from many plants, such as Prunus
emarginata (Finnemore 1910), Pterocarpus angolensis (King
and Jurd 1952), and Crotalaria lachnophora (Awouafack et al.
genistein (1b) methylated at the C-7 position (King and
Jurd 1952). Prunetin exhibits several biological activities in
the human body, including as phytoestrogenic (Andres
et al. 2015; Hillerns et al. 2005) and has bone-regeneration (Khan
et al. 2015) anti-inflammatory (Yang et al. 2013), vasorelaxation,
(Kim et al. 2018) and anti-osteoarthritis (Nam et al. 2016)
properties.
a
2011), and its structure was elucidated as a derivative of
Received: 19 July 2020; Accepted: 17 August 2020
The Author(s) 2021. Published by Oxford University Press on behalf of Japan Society for Bioscience, Biotechnology, and Agrochemistry.
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©
143

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Bioscience, Biotechnology, and Biochemistry, 2021, Vol. 85, No. 1
the isolation of 3e by leaving over-methylated by-products such
as 3d intact. Chromatographic purification and subsequent crys-
tallization from diethyl ether furnished the desired 3e in 80%
yield from 2a in 3 steps (Scheme 2).
Next, we attempted to deacetylate one of the two acetyl
ꢀ
ꢀ
groups at C-2 and C-6 located adjacent to the aromatic carbonyl
group by activating with a Lewis acid, boron trifluoride-diethyl
ether complex [BF3·OEt2] (Narender et al. 2008; Tsunekawa
ꢀ
et al. 2018) and subsequently treating with water. The desired 2 -
hydroxychalcone 3a was obtained only in 22% yield because the
product was susceptible to over-deacetylation. Moreover, chro-
matographically purified 3a contained undesired flavanones
due to 3b being prone to spontaneous cyclization as suggested
in Scheme 1, even under neutral conditions. Similar behavior
Figure. 1. Prunetin (1a), related isoflavones (1b, 1c), and naringenin (2a).
Prunetin (1a) can be prepared simply by methylating genis-
tein (1b; Figure 1, Li et al. 2006), but genistein isolated from nat-
ural resources is expensive, prompting many researchers to de-
velop general chemical synthetic routes for isoflavones (Lévai,
ꢀ
ꢀ
was observed with the closely related compound 6 -acetoxy-2 -
hydroxychalcone (Shimokoriyama, 1949).
2
004). For example, prunetin has been synthesized by site-
Then, the solution of in situ-formed 3a in 1,4-dioxane
was submitted to TTN-mediated oxidative rearrangement in
methanol. Contrary to a previous report (Taylor et al. 1976),
oxidative rearrangement of the substrate in methanol was
faster than in a mixture of methanol and trimethyl orthofor-
mate. Hydrolytic cleavage of the dimethyl acetal moiety and
the remaining acetyl group under acidic conditions, followed
by neutralization, provided the desired 1a as a crude mixture.
However, purification from the highly polar inorganic debris
and by-products was difficult due to the low solubility of 1a in
organic solvents. The crude material was thus site-selectively
acetylated and isolated as the corresponding monoacetate 1d
in 33% yield from 3e in 4 steps. Forcing the acidic cleavage us-
ing a prolonged reaction time and subsequent workup omitting
the neutralization step resulted only in the undesired forma-
tion of a nitrated by-product. Its structure was determined to
be 4 after acetylation (Scheme 2). An alternative approach using
phenyliodine (III) bis(trifluoroacetate) (PIFA)-mediated oxidative
rearrangement (Miki et al. 1994) provided only a trace amount of
the desired isoflavone being detected in the crude product due to
the predominant formation of flavanones through spontaneous
cyclization of the chalcone intermediates.
selective demethylation at the C-5 position of the chemically
synthesized 5,7-di-O-methylated precursor (1c) (Iyer et al. 1951;
Sekizaki and Yokosawa, 1988). Our ongoing studies on the trans-
formation of naturally occurring flavonoids (Kurahayashi et al.
2018; Kurahayashi et al. 2020; Tsunekawa et al. 2018) prompted us
to synthesize 1a from readily available naringenin (2a; Figure 1),
a hydrolysate of naturally abundant and inexpensive naringin
(
Kurahayashi et al. 2018), and retaining the carbon atoms in the
original skeleton.
We envisioned the oxidative rearrangement of 2 -
hydroxychalcone (3a) mediated by thallium(III) nirate (TTN)
ꢀ
(
Farkas et al. 1974; Sekizaki and Yokosawa, 1988; Thakkar and
Cushman, 1995) as the key reaction for the transformation
Scheme 1). In 3a, the electron-rich property is advantageous
(
for the higher migrating property of aromatic ring (Thakkar and
Cushman, 1995) from initial intermediate (X) to the following
ꢀꢀ
oxonium ion (Y), and thus the oxygen function at the C-4 posi-
tion should be a free hydroxy group rather than protected form
with an electron-withdrawing group. The addition of methanol
provides an acetal (Z), and the treatment under acidic condi-
tions deprotects both of dimethyl acetal and phenolic acetate
to furnish 1a. Through this transformation, only one phenolic
hydroxy group should be temporarily protected, between the
hydroxy groups at the C-2 and C-6 positions, for efficient
oxidative rearrangement. If both of phenolic hydroxy groups
are over-deprotected to 3b, it would spontaneously cyclize to
undesired flavanone by-product 2b.
Finally, the acetyl group in the thus-obtained 1d was removed
by applying above-mentioned C. antarctica lipase B-mediated
transesterification (Fujita et al. 2019; Hanamura et al. 2016;
Kobayashi et al. 2013; Tsunekawa et al. 2018) to give prunetin 1a in
ꢀ
ꢀ
1
13
quantitative yield (Scheme 2). The H- and C-NMR spectra of 1a
were in accordance with those reported previously (Awouafack
et al. 2011). In the present case, high reactivity in the lipase-
ꢀ
catalyzed deacetylation at C-4 was in good accordance with
Results and discussion
those observed in chalcone (Tsunekawa et al. 2018), flavanone
(Kobayashi et al. 2013), and flavone (Fujita et al. 2019; Hanamura
et al. 2016) derivatives.
The first step of the present synthesis involved the directed in-
troduction of a methyl group at the most acidic C-7 hydroxy
group of naringenin (2a) (Kim et al. 2007; Oyama and Kondo,
2
004). The methylation at C-7 was driven to completion by treat-
Conclusion
ing 2a with a slight excess (1.1 equivalent) of dimethyl sulfate.
However, the desired product 2b was contaminated with over-
methylated byproducts such as 2c. Without isolating each com-
ponent, direct acetylation of the mixture at high temperature
In this way, we achieved the semisynthesis of prunetin (1a) in 8
steps and a total yield of 26% from naringenin (2a), retaining all
the original carbon atoms.
(
Fujise and Sasaki, 1938; Shimokoriyama, 1949) furnished a mix-
ture of chalcone acetates 3c and 3d, which behaved similarly
during chromatographic purification.
Experimental
To synthesize the key intermediate 3a, the two acetyl pro-
General
ꢀꢀ
ꢀ
tective groups at C-4 and C-2 were deprotected by the comple-
mentary use of lipase and a Lewis acid in a stepwise manner.
First, the mixture of 3c and 3d was subjected to Candida antarc-
tica lipase B (Novozym 435)-catalyzed deacetylation (Fujita et al.
Candida antarctica lipase B (Novozym 435) was purchased from
Novozymes Japan. Naringenin was prepared from commercially
available naringin (N0073 Tokyo Chemical Industry Co., Ltd.),
according to the reported procedure (Kurahayashi et al. 2018).
Column chromatography was performed with silica gel (Kanto
2
019; Hanamura et al. 2016; Kobayashi et al. 2013; Tsunekawa et al.
ꢀꢀ
2018) to liberate the C-4 position as a free hydroxy group, aiding

Semisynthesis of prunetin from naringenin
145
Scheme 1. Synthetic plan of prunetin (1a) from chalcone precursor (3a) by TTN-mediated oxidation, showing intermediates (X, Y, and Z).
Scheme 2. Chemoenzymatic semisynthesis of prunetin (1a) from naringenin (2a).
Chemical Co. Silica Gel 60 N 37 563-84, spherical and neutral, 40-
was gradually raised. At between 90 and 100 °C, acetone was dis-
tilled off. Then the temperature was further raised to reflux and
the mixture was stirred for 1 h, the formed acetic acid was dis-
tilled off. After acetic anhydride (5 mL) was added and the mix-
ture was stirred and heated at 170 °C for 1 h, while distilling of
acetic acid. Finally, acetic anhydride (5 mL) was further added
and the heating was continued for 1 h with distilling off acetic
acid. After cooling, the mixture was diluted with water and the
organic materials were extracted with dichloromethane. The ex-
tract was washed with aqueous solution of sodium bicarbon-
ate and brine, dried over anhydrous sodium sulfate, and con-
centrated in vacuo to give pale-yellow amorphous solid (4.15 g).
Crude product contained 3c as the major product, judged by its
5
0 μm). Melting points were measured on Mitamura Riken Ko-
1
gyo MELTEMP and are uncorrected. H-NMR spectra were mea-
sured at 400 MHz on a VARIAN 400-MR or at 500 MHz on a Bruker
spectrometer (ascend TM) and C-NMR spectra were measured
at 100 MHz on a VARIAN 400-MR or at 125 MHz on a Bruker
spectrometer (ascend TM). DMSO-d6 and CDCl3 were used as a
solvent and the residual peaks were used as an internal stan-
13
1
13
dard ( H-NMR: DMSO-d6 2.48 ppm, CDCl3 7.26 ppm; C-NMR:
DMSO-d6 39.9 ppm, CDCl3 77.0 ppm). IR spectra were measured
as ATR on a Jasco FT/IR-4700 FT-IR spectrometer. High-resolution
mass spectra (HRMS) were measured by a on Jeol JMS-T100LP
AccuTOF.
1
1
H-NMR spectrum. H-NMR (400 MHz, CDCl3) δ: 2.15 (6H, s), 2.31
ꢀ
ꢀ ꢀ ꢀ
,6 -Diacetoxy-4 -hydroxy-4 -methoxychalcone (3e)
(3H, s), 3.84 (3H, s), 6.62 (2H, s), 6.87 (1H, d, J = 16.0 Hz), 7.12 (2H,
d, J = 8.4 Hz), 7.40 (1H, d, J = 16.0 Hz), 7.55 (2H, d, J = 8.4 Hz).
The minor signals for other acetates (δ: 2.10 to 2.32) and other
methyl ethers (δ: 3.82 to 2.86) were due to the presence of insep-
arable over-methylated contaminants. This crude product was
employed for the next step without further purification.
2
To a suspension of 2a (naringenin, 2.72 g, 10.0 mmol), potassium
carbonate (1.39 g), and anhydrous sodium sulfate (1.5 g) in ace-
tone (100 mL) was added dimethyl sulfate (1.06 mL, 1.40 g, 1.1
eq.) and the mixture was stirred and heated under reflux for 3 h.
After cooling, acetic anhydride (20 mL) was added a sodium ac-
etate (8.60 g) and the mixture was stirred and the temperature
To a solution of the above-mentioned product in a mixture
of 2-propanol (15 mL) and tetrahydrofuran (THF, 30 mL), which

146
Bioscience, Biotechnology, and Biochemistry, 2021, Vol. 85, No. 1
ꢀ
tral data, its structure was supposed to be the diacetate of 3 -
nitro (1530, 1355 νmax cm ) derivative with a 1,3,4-trisubstituted
aromatic ring.
was pre-dried over anhydrous sodium sulfate at room temper-
ature overnight, was added an immobilized form of C. antarc-
tica lipase B (Novozymes, Novozym 435, 500 mg) and anhydrous
sodium sulfate (500 mg). The mixture was stirred for 30 h at 30 °C.
The mixture was filtered to remove insoluble materials with a
–
1
ꢀ
4
,5-Dihydroxy-7-methoxyisoflavone (prunetin, 1a)
®
pad of Celite . The precipitates were washed with ethyl acetate.
The combined filtrate and washings were concentrated in vacuo.
In a similar manner as described above, a suspension of 1d
The residue was purified by silica gel column chromatography
(32.6 mg, 0.10 mmol) in a pre-dried mixture of 2-propanol
(45 g). Elution with dichloromethane-diethyl ether (20 : 1 to 2 : 1)
(0.66 mL) and THF (1.34 mL) was treated with C. antarctica lipase
gave amorphous solid. Recrystallization from diethyl ether fur-
nished 3e (2.96 g, 80% from 2a) as pale-yellow hexagonal plates.
Melting point was 158.5-159.0 °C. H-NMR (400 MHz, CDCl3) δ:
B (35 mg). The mixture was stirred for 18 h at 24 °C. Accompanied
with the progress of the deacetylation, the suspension of the
substrate turned to be homogeneous. The mixture was filtered
1
2.14 (6H, s), 3.84 (3H, s), 5.58 (1H, broad s), 6.62 (2H, s), 6.78 (1H,
®
to remove insoluble materials with a pad of Celite . The precip-
d, J = 16.0 Hz), 6.81 (2H, d, J = 8.4 Hz), 7.37 (1H, d, J = 16.0 Hz),
itates were washed with THF. The combined filtrate and wash-
ings were concentrated in vacuo to give 1a (30.1 mg, quantita-
tive yield) as pale-yellow solids. Melting point was 238.0-238.5°C
13
7
5
1
1
.40 (2H, d, J = 8.4 Hz). C-NMR (100 MHz, CDCl3) δ: 20.9 (2C),
5.8, 106.9 (2C), 116.1 (2C), 119.4, 124.1, 126.4, 130.6 (2C), 146.7,
49.6 (2C), 159.1, 161.5, 169.2, 190.9 (2C). IR νmax cm– : 3415, 1760,
1
lit. (Awouafack et al. 2011) melting point 246-248°C]. 1H-NMR
[
(
732, 1577, 1568, 1515, 1195, 1172, 1141, 1059, 894, 833. HR-MS
400 MHz, DMSO-d6) δ: 3.85 (3H, s), 6.40 (1H, d, J = 2.4 Hz), 6.65 (1H,
+
[
3
ESI+, (M + Na) ]: calculated for C20H18NaO7, 393.0950; found,
d, J = 2.4 Hz), 6.81 (2H, d, J = 8.8 Hz), 7.38 (2H, d, J = 8.8 Hz), 8.40 (1H,
93.0963.
13
s), 9.58 (1H, s), 12.95 (1H, s). C-NMR (100 MHz, DMSO-d6) δ: 56.5,
9
2.8, 93.5, 105.8, 115.5 (2C), 121.5, 123.0, 130.6 (2C), 154.8, 157.9
1
13
ꢀ
(2C), 162.2, 165.7, 180.9. H- and C-NMR spectra were in good
4
-Acetoxy-5-hydroxy-7-methoxyisoflavone (1d)
accordance with those reported previously. (Awouafack et al.
–
1
To a solution of 3e (741 mg, 2.0 mmol) in anhydrous 1,4-dioxane
12 mL) were added BF3·OEt2 (0.4 mL, 3.2 mmol) and the mixture
2011) IR νmax cm : 3365, 2957, 1660, 1611, 1568, 1505, 1534, 1190,
+
(
1153, 1051. HR-MS [ESI+, (M + Na) ]: calculated for C16H12NaO5,
was stirred for 2 h at 80 °C. After cooling, the mixture was di-
luted with methanol (133 mL) and TTN (1.96 g, 7.4 mmol) was
added. The mixture was stirred for 1 h at room temperature.
Then, hydrochloric acid (3 M, 6.8 mL) was added and the mix-
ture was stirred and heated at reflux for 4.5 h. The mixture
was neutralized by a portion-wise addition of sodium hydroxide
307.0582; found, 307.0570.
Acknowledgments
T.S. thanks Emeritus Professor Shigeru Nishiyama of Keio Uni-
versity for his valuable advices on TTN-mediated oxidation. T.S.
also thanks the late Emeritus Professor Kenji Mori of University
of Tokyo for his encouragement throughout this study.
(
3.4 g), and evaporated to dryness in vacuo below 40 °C. The
residue was suspended in a mixture of acetic anhydride (5 mL)
and pyridine (5 mL) and the resulted mixture was stirred for 36 h
at room temperature. The mixture was poured into ice, and the
precipitates were collected by filtration and washed with wa-
ter. The solid was extracted twice with hot acetone. The acetone
solution was dried over anhydrous sodium sulfate and concen-
trated in vacuo. The residue was suspended with chloroform. The
chloroform solution was filtered to remove insoluble materials
Author contribution
T.S designed this study and carried out the experiments; K.H.
contributed to analytical works; T.S. wrote the manuscript with
assistance from all authors; and S.H. supervised the research.
®
with a pad of Celite . The precipitates were washed with chlo-
Funding
roform. The combined filtrate and washings were concentrated
in vacuo. The residue was purified by silica gel column chro-
matography (20 g). Elution with chloroform–ethyl acetate (10 : 1)
gave yellow amorphous solid. Recrystallization from ethanol fur-
nished 1d (215 mg, 33% from 3e) as pale-yellow fine needles.
This work was supported by JSPS KAKENHI (19K05849) to T.S. and
is gratefully acknowledged with thanks.
Disclosure statement
1
Melting point was 184.0-185.0 °C. H-NMR (500 MHz, CDCl3) δ:
2
.32 (3H, s), 3.88 (3H, s), 6.40 (1H, d, J = 2.0 Hz), 6.42 (1H, d,
The authors declare that they have no conflict of interest regard-
ing this article.
J = 2.0 Hz), 7.18 (2H, d, J = 9.0 Hz), 7.55 (2H, d, J = 9.0 Hz), 7.90 (1H,
s), 12.77 (1H, s). 13C-NMR (125 MHz, CDCl3) δ: 21.3, 55.9, 92.6, 98.5,
1
1
1
06.1, 121.9 (2C), 123.3, 128.5, 130.1 (2C), 150.9, 153.4, 158.0, 162.9,
References
65.8, 169.5, 180.6. IR νmax cm– : 3094, 1739, 1660, 1622, 1576, 1506,
1
+
441, 1420, 1220, 1194, 828, 785. HR-MS [ESI+, (M + Na) ]: calcu-
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1
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6
.81 (1H, d, J = 2.3 Hz), 7.28 (1H, d, J = 8.5 Hz), 7.82 (1H, dd,
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lonchocarpan,
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