Synthesis of coumestrol and aureol

Article abstract of DOI:10.1021/acs.jnatprod.6b00510

A total synthesis of coumestrol (1) and aureol (2) is described. The Perkin condensation of 2-bromo-4-hydroxylphenylacetic acid (6) and o-hydroxybenzaldehydes (7) gave the corresponding 2′-bromo-3-arylcoumarins (9). A copper-catalyzed consecutive hydroxylation and aerobic oxidative coupling of 9 under microwave conditions facilitated the total synthesis of 1 and 2, respectively, with spectroscopic data highly similar to those of natural products.

Full text of DOI:10.1021/acs.jnatprod.6b00510

Note
pubs.acs.org/jnp
Synthesis of Coumestrol and Aureol
Jianfei Sheng,†,§,∥ Tianlong Xu,‡,§,∥ Ensheng Zhang,‡,§ Xuejing Zhang,†,§,⊥ Wentao Wei,†,§
and Yong Zou*,†,§,⊥
†School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, 510006, People’s Republic of China
‡Guangzhou Institute of Chemistry, Chinese Academy of Sciences, Guangzhou, 510650, People’s Republic of China
§Zhongshan WanYuan New Drug R&D Co., Ltd., Zhongshan City, 528451, People’s Republic of China
⊥Guangdong Provincial Key Laboratory of Brain Function and Disease, Sun Yat-sen University, Guangzhou, 510080, People’s
Republic of China
S
* Supporting Information
ABSTRACT: A total synthesis of coumestrol (1) and aureol
(2) is described. The Perkin condensation of 2-bromo-4-
hydroxylphenylacetic acid (6) and o-hydroxybenzaldehydes
(7) gave the corresponding 2′-bromo-3-arylcoumarins (9). A
copper-catalyzed consecutive hydroxylation and aerobic
oxidative coupling of 9 under microwave conditions facilitated
the total synthesis of 1 and 2, respectively, with spectroscopic
data highly similar to those of natural products.
oumestans are an important class of naturally occurring
through oxidative radical coupling,26 electrochemical or
Ctetracyclic lactones that are characterized by the presence enzymatic oxidation and addition27 (affording coumestans
of a fused ring system comprising coumarin and benzofuran
constituent units.1 These compounds have been isolated from a
variety of plant species belonging to botanical families such as
the Leguminosae, Fabaceae, and Asteraceae2 and have shown
antioxidative,1d,2b,3 anticarcinogenic,4 phytoestrogenic,5 anti-
bacterial,6 antifungal,7 immunomodulatory,8 neuroprotective,9
anti-snake-venom,10 antiosteoporsis,11 and antihepatotoxic
effects.12
with catechol moieties), oxidative cycloaddition between 4-
hydroxycoumarins and vinyl sulfides,28 vinyl lithiation,29 and
PtCl2-catalyzed cycloisomerization reactions.30 Among these,
the FeCl3-mediated direct intramolecular oxidative annulation
of 4-hydroxy-3-arylcoumarins, the di-tert-butyl peroxide
(DTBP) or oxygen-involved CDC reaction between β-
ketoesters and phenols, and the palladium-catalyzed ring-
closure reaction of 3-arylcoumarins were relatively more
efficient and straightforward. However, many of the reported
methods still suffer from disadvantages such as harsh reaction
conditions, the use of transition-metal catalysts, the necessity of
complicated substrates, multistep processes, and atom-
economic problems. Thus, a practical and effective route to
obtain coumestan natural products is still in high demand. We
recently disclosed a consecutive Cu-catalyzed hydroxylation/
aerobic oxidative cycloetherification approach for the assembly
of 2-arylbenzofurans.32 Ongoing interest in the synthesis of
natural products with C6−C2−C6 and C6−C3−C6 frame-
works33 prompted the development of a facile and practical
route to the total synthesis of 1 and 2 via the combination of a
Perkin condensation and a Cu(II)-catalyzed hydroxylation/
aerobic oxidative coupling process.
Coumestrol (1) and aureol (2) are representative members
in the coumestan family and were first isolated respectively
from ladino clover, strawberry clover, and alfalfa by Bickoff in
19575a and from Phaseolus aureus Roxb. by O’Neill in 1983.13
Coumestrol has proved to be a phytoalexin, phytoestrogen
(ERβ selective),14 antioxidant,3 HIF-1α inhibitor,4 α-glucosi-
c
dase inhibitor,2c and mitochondrial biogenesis inducer.8b The
coumestan aureol (2) was found to be an immunosuppressant
and neuroprotectant.9b,15 Owing to the wide variety of
pharmacological activities, many synthetic approaches have
been developed to construct the tetracyclic scaffold of
coumestans.11b,12,16−31 General strategies included arylcoumar-
in-based cyclization,16 palladium-catalyzed carbonylative annu-
lation (CO insertion),11b,12,17 α- or β-keto ester-based
annulation,18 [3,3]-sigmatropic rearrangement-based cycliza-
tion and elimination,19 iodonium ylide-based intramolecular
Heck reaction,20 flavylium salts-based oxidation and lactoniza-
tion,21 DreM-carbamoyl migration−transition-metal-catalyzed
cross-coupling,22 arylboronic acid-involved Pd-catalyzed C−S
activation for [3 + 3] annulation,23 aerobic iron-based cross-
dehydrogenative coupling (CDC),24 and tandem demethyla-
tion/annulation/oxidation of 2,3-bis(2-methoxyphenyl)-3-oxo-
propanals.25 Certain coumestans could also be synthesized
RESULTS AND DISCUSSION
■
On the basis of previous findings, the synthesis of coumestrol
(1) and aureol (2) could be realized through the consecutive
hydroxylation and aerobic oxidative coupling of 3-(2-bromo-4-
Received: June 4, 2016
© XXXX American Chemical Society and
American Society of Pharmacognosy
A
DOI: 10.1021/acs.jnatprod.6b00510
J. Nat. Prod. XXXX, XXX, XXX−XXX

Journal of Natural Products
Note
Deacetylation in hot NaOH solution followed by acidification
with diluted HCl afforded 2′-bromo-3-arylcoumarins 9a and 9b
in 92% and 86% yields, respectively.
With the 2′-bromo-3-arylcoumarins 9 in hand, all that
remained was to facilitate a consecutive Cu-catalyzed
hydroxylation and aerobic oxidative cyclization to assemble
the framework of coumestans. Although the established
protocol that employed Cu(OAc)2/1,10-phen in DMSO/
H2O (1:1) under microwave conditions could facilitate the
hydroxylation and aerobic oxidative coupling processes,32 the 3-
arylcoumarin 9a did not undergo analogous transformation to
give coumestrol (1) in acceptable yield. However, when the
reaction was performed at elevated temperature (120 °C) in
anhydrous DMSO under microwave conditions for 3 h,
coumestrol (1) was obtained in 68% yield. Likewise, using 9b
as the reactant, aureol (2) was obtained in 54% yield under the
same reaction conditions. The physical data of coumestrol (1)
and aureol (2) were in good agreement with reported data2a,c
(Table 1). This is the first total synthesis of aureol (2).
In conclusion, we have developed a facile and efficient
method to synthesize coumestrol (1) and aureol (2) based on
Perkin condensation, copper-catalyzed consecutive hydroxyla-
tion, and aerobic oxidative coupling. This result paved the way
for the straightforward synthesis of coumestan derivatives.
Further investigations to optimize the reaction sequence and
extend the substrate scope of this methodology are ongoing.
Figure 1. Structures of coumestrol (1) and aureol (2).
hydroxyphenyl)-7-hydroxycoumarins (9), which could be
obtained through Perkin reaction between an ortho-hydrox-
ybenzaldehyde (7) and 2-bromo-4-hydroxyphenylacetic acid
(6). Intermediate 6 could be readily obtained via reduction of
2-bromo-4-hydroxymandelic acid (5), which could further be
traced back to the commercially available starting materials m-
bromophenol (3) and glyoxylic acid (4) (Scheme 1).
Scheme 1. Retrosynthetic Analysis of Coumestrol (1) and
Aureol (2)
EXPERIMENTAL SECTION
■
General Experimental Procedures. Melting points were
recorded on a Thiele apparatus and are uncorrected. IR spectra
were recorded on an Analect RFX-65A IR spectrometer as KBr disks.
1H and 13C NMR spectra were obtained on a Bruker Avance 400 MHz
spectrometer (400 MHz for 1H NMR and 100 MHz for 13C NMR) at
295 K using DMSO-d6 as the solvent. Tetramethylsilane was used as
the internal standard, and chemical shift (δ) values were given in parts
per million (ppm). HRMS data were recorded on an LC-Q-TOF
(ESI) apparatus. Column chromatography was performed on silica gel
(300−400 mesh) using EtOAc/petroleum ether (60−90 °C) as the
eluent. Microwave reactions were carried out with a scientific WBFY
microwave reactor in a long-neck flask connected with a condenser.
The temperatures of the microwave reactions were recorded using an
infrared thermometer, and the ramp time (approximately 0.5 min) was
included as part of the reaction time. Reagents were obtained
commercially and used throughout without further purification unless
otherwise stated.
Initially, 2-bromo-4-hydroxymandelic acid (5) was success-
fully obtained through nucleophilic addition of m-bromophenol
(3) to glyoxylic acid (4) in aqueous NaOH (Scheme 2).
Subsequent reduction of 5 in the presence of SnCl2/HCl
afforded 2-bromo-4-hydroxyphenylacetic acid (6). Perkin
condensation between 6 and the commercially available o-
hydroxybenzaldehydes (7) in the presence of Ac2O/Et3N
smoothly gave acetylated 2′-bromo-3-arylcoumarins (8).
Synthesis. 2-(2-Bromo-4-hydroxyphenyl)-2-hydroxyacetic Acid
(5). 3-Bromophenol (8.65 g, 0.05 mol) was added to a three-necked,
round-bottom flask equipped with a condenser and a mechanical
stirrer. When the reaction temperature was raised to 40 °C, a 50%
aqueous solution of glyoxylic acid (0.05 mol) and an 8% aqueous
NaOH (0.075 mol) solution were added simultaneously through two
constant-pressure funnels over 1 h. The mixture was stirred for 8 h.
After the reaction was complete (monitored by TLC), the mixture was
cooled to room temperature and acidified to pH 1−2 with 2 M HCl.
The aqueous solution was washed with toluene (2 × 50 mL), and the
product was extracted with EtOAc (2 × 50 mL). The organic layer was
separated, washed with brine, dried over anhydrous Na2SO4, and
Scheme 2. Synthesis of Coumestrol (1) and Aureol (2)
1
concentrated in vacuo to give a yellow oil (9.25 g, 75.2% yield): H
NMR (DMSO-d6, 400 MHz, ppm) δ 12.50 (s, 1H), 9.90 (s, 1H), 7.25
(d, J = 8.4 Hz 1H), 6.96 (d, J = 2.4 Hz 1H), 6.77 (dd, J = 2.4, 2.4 Hz
1H), 5.19 (s, 1H), 7.25 (d, J = 8.4 Hz 1H), 1.97 (s, 1H).
2-(2-Bromo-4-hydroxyphenyl)acetic Acid (6). 2-(2-Bromo-4-hy-
droxyphenyl)-2-hydroxyacetic acid (5) (9.9 g, 0.04 mol), SnCl2·2H2O
(10.2 g, 0.045 mol), and concentrated HCl (20 mL) were added into a
round-bottom flask equipped with a condenser, and the mixture was
stirred at 80 °C for 3 h. After completion of the reaction as indicated
by TLC, H2O (40 mL) was added and the mixture was heated to
B
DOI: 10.1021/acs.jnatprod.6b00510
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Journal of Natural Products
Note
Table 1. NMR Data for Synthetic and Natural Coumestrol and Aureol in DMSO-d6
reflux until a clear solution was obtained. The resulting mixture was
cooled to room temperature, whereupon compound 6 recrystallized to
Coumestrol (1). 3-(2-Bromo-4-hydroxyphenyl)-7-hydroxycoumarin
(9a, 0.3331 g, 1 mmol), Cu(OAc)2 (36 mg, 0.2 mmol, 20 mol %),
1,10-phen (36 mg, 0.2 mmol, 20 mol %), KOH (0.56 g, 10 mmol),
and DMSO (10 mL) were added to a flask equipped with a condenser.
The flask was placed in a microwave reactor and irradiated under air
(240 W). The mixture was stirred at 120 °C for 3 h. After completion
of the reaction (monitored by TLC), the mixture was cooled to room
temperature and the copper-containing solid was filtered off. The
filtrate was poured into H2O (50 mL) and acidified to pH 4−5 with 2
M HCl. The product was extrated with EtOAc (20 mL), washed with
H2O, dried over anhydrous MgSO4, and evaporated in vacuo. The
crude product was purified by flash column chromatography (EtOAc/
petroleum ether, 1:4) to afford coumestrol 1 as a white solid (0.18 g,
1
afford a white solid (7.2 g, 77% yield): mp 176−178 °C; H NMR
(400 MHz, DMSO-d6, ppm) δ 12.35 (s, 1H), 9.80 (s, 1H), 7.15 (d, J =
8.4 Hz, 1H), 6.97 (d, J = 2.4 Hz, 1H), 6.72 (dd, J1 = 8.4 Hz, J2 = 2.4
Hz, 1H), 3.57 (s, 2H).
3-(2-Bromo-4-hydroxyphenyl)-7-hydroxycoumarin (9a). A mix-
ture of 2-bromo-4-hydroxyphenylacetic acid (6, 2.31 g, 10 mmol), 2,4-
dihydroxylbenzaldehyde (7a, 1.38g, 10 mmol), Ac2O (4.73 mL, 50
mmol), and Et3N (4.16 mL, 30 mmol) was added to a 25 mL round-
bottom flask equipped with a condenser. The mixture was stirred at
110 °C for 6 h. After completion of the reaction (monitored by TLC),
the hot mixture was poured into ice water and washed thoroughly
while stirring. A brown solid was obtained and collected by filtration.
The solid was dissolved in 10% aqueous NaOH, and the resulting
aqueous solution was washed with EtOAc (2 × 50 mL). The aqueous
layer was acidified with concentrated HCl to pH 3−4. The precipitated
crude product was collected by filtration and recrystallized from EtOH
to afford 9a (3.06 g, 92%) as a white solid: mp 337−340 °C; 1H NMR
(DMSO-d6, 400 MHz, ppm) δ 10.38 (s, OH), 9.94 (s, OH), 7.89 (s,
1H), 7.57 (d, J = 8.8 Hz, 1H), 7.26 (d, J = 8.4 Hz, 1H), 7.11 (d, J = 2.0
Hz, 1H), 6.86 (dd, J = 2.0, 8.8 Hz, 1H), 6.83 (dd, J = 2.0, 8.4 Hz, 1H),
6.78 (d, J = 2.0 Hz, 1H); 13C NMR (DMSO-d6, 100 MHz, ppm) δ
161.3, 159.6, 158.2, 155.2, 143.0, 132.5, 129.9, 126.9, 123.6, 123.4,
118.9, 114.8, 113.4, 111.4, 102.0; IR (neat) 3346, 3118, 2829, 1678,
1608, 1573, 1495, 1463, 1426, 1285, 1259, 1206, 1125, 1030, 863, 621
cm−1; HRMS m/z 354.9583 [M + Na]+ (calcd for C15H979BrO4Na,
354.9582).
3-(2-Bromo-4-hydroxyphenyl)-5,7-dihydroxycoumarin (9b). The
experimental procedure to synthesize 9b is the same as that of 9a:
white solid (3.0 g, 86% yield); mp 278−281 °C; 1H NMR (DMSO-d6,
400 MHz, ppm) δ 10.75 (s, OH), 10.46 (s, OH), 10.05 (s, OH), 7.78
(s, 1H), 7.24 (d, J = 8.4 Hz, 1H), 7.08 (d, J = 2.4 Hz, 1H), 6.83 (dd, J
= 2.4, 8.4 Hz, 1H), 6.29 (d, J = 2.0 Hz, 1H), 6.24 (d, J = 2.0 Hz, 1H);
13C NMR (DMSO-d6, 100 MHz, ppm) δ 162.1, 159.8, 158.1, 156.1,
156.1, 137.9, 132.5, 127.2, 123.6, 120.7, 118.9, 114.8, 101.6, 98.4, 93.9;
IR (neat) 3336, 3175, 1690, 1601, 1579, 1505, 1436, 1373, 1272, 1222,
1160, 1080,801, 585 cm−1; HRMS m/z 370.9528 [M + Na]+ (calcd for
C15H979BrO5Na, 370.9526).
1
68%): mp 361−364 °C; H NMR (DMSO-d6, 400 MHz, ppm) δ
10.71 (s, OH), 10.04 (s, OH), 7.85 (d, J = 8.4 Hz, 1H), 7.69 (d, J = 8.4
Hz, 1H), 7.16 (d, J = 2.0 Hz, 1H), 6.90−6.96 (m, 3H); 13C NMR
(DMSO-d6, 100 MHz, ppm) δ 161.2, 159.5, 157.6, 157.0, 155.9, 154.6,
122.7, 120.6, 114.6, 114.0, 113.7, 104.2, 103.0, 102.0, 98.7; IR (neat)
3417, 3269, 1719, 1633, 1607, 1512, 1437, 1379, 1297, 1264, 1237,
1091, 839, 807, 627 cm−1; HRMS m/z 291.0259 [M + Na]+ (calcd for
C15H8O5Na, 291.0264).
Aureol (2). The experimental procedure for the synthesis of 2 is the
1
same as for 1: white solid (0.53 g, 54% yield); mp 339−342 °C; H
NMR (DMSO-d6, 400 MHz, ppm) δ 10.92 (s, OH), 10.50 (s, OH),
9.96 (s, OH), 7.67 (d, J = 8.4 Hz, 1H), 7.14 (d, J = 1.6 Hz, 1H), 6.93
(dd, J = 2.0, 8.4 Hz, 1H), 6.41 (d, J = 2.0 Hz, 1H), 6.38 (d, J = 2.0 Hz,
1H); 13C NMR (DMSO-d6, 100 MHz, ppm) δ 161.4, 159.8, 157.7,
156.6, 155.8, 155.6, 155.2, 120.2, 114.4, 113.8, 100.7, 99.1, 98.6, 95.2,
94.9; IR (neat) 3374, 3192, 2959, 1710, 1626, 1581, 1488, 1445, 1379,
1297, 1262, 1162, 1083, 807, 623 cm−1; HRMS m/z 307.0215 [M +
Na]+ (calcd for C15H8O6Na, 307.0213).
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.jnat-
prod.6b00510.
1H and 13C NMR spectra for the compounds (PDF)
C
DOI: 10.1021/acs.jnatprod.6b00510
J. Nat. Prod. XXXX, XXX, XXX−XXX

Journal of Natural Products
Note
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(b) Yao, T.; Yue, D.; Larock, R. C. J. Org. Chem. 2005, 70, 9985−9989.
(12) Li, C. C.; Xie, Z. X.; Zhang, Y. D.; Chen, J. H.; Yang, Z. J. Org.
Chem. 2003, 68, 8500−8504.
AUTHOR INFORMATION
Corresponding Author
*E-mail: zou_jinan@163.com (Y. Zou).
■
(13) O’Neill, M. J. J. Biosci. 1983, 38, 698−700.
Author Contributions
∥J. Sheng and T. Xu contributed equally to this work.
(14) Wang, C.; Li, C.; Zhou, H.; Huang, J. J. Biomol. Screening 2014,
19, 253−258.
Notes
(15) It is worth mentioning that a meroterpenoid isolated from
marine sponges has also been named “aureol”; for references on this
marine sponge-derived natural product, see: (a) Ciminiello, P.;
Dell’Aversano, C.; Fattorusso, E.; Magno, S.; Pansini, M. J. Nat.
Prod. 2000, 63, 263−266. (b) Djura, P.; Stierle, D. B.; Sullivan, B.;
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Pepper, H. P.; Bloch, W. M.; George, J. H. Org. Lett. 2012, 14, 4710−
4713. (d) Rosales, A.; Munoz-Bascon, J.; Roldan-Molina, E.; Rivas-
Bascon, N.; Padial, N. M.; Rodriguez-Maecker, R.; Rodriguez-Garcia,
I.; Oltra, J. E. J. Org. Chem. 2015, 80, 1866−1870.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This project was supported by the National Key Research and
Development Project of China (2016YFA0602900), the
National Natural Science Foundation of China (21272280),
the Key Project of Guangdong Natural Science Foundation
(2016A030311033), the Science and Technology Programe of
Guangzhou City (201505041557046), and the Innovative
Scientific Research Team Introducing Project of Zhongshan
City (2015-224). We are also thankful to Prof. A. S. C. Chan at
Sun Yat-sen University for guidance and help.
(16) (a) Pandit, S. B.; Gadre, S. Y. Synth. Commun. 1988, 18, 157−
166. (b) Chang, C. F.; Yang, L. Y.; Chang, S. W.; Fang, Y. T.; Lee, Y. J.
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M. J. Am. Chem. Soc. 1958, 80, 4381−4383. (d) Gong, D. H.; Li, C. Z.;
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