Efficient synthesis of polyoxygenated flavones from naturally occurring flavanones

Article abstract of DOI:10.1211/jpp.59.12.0012

Flavonoids are constituents of the human diet (they are present in many beverages and food), and in organisms they are responsible for several biological functions, including that of antioxidant. Because of the increasing interest in these molecules, methods for their synthesis and structural modification are of great importance; studies on the biological activities of many of these compounds are insufficient because of their scarcity and/or high cost. We have developed an expeditious synthesis of polyoxygenated flavones, starting from available and inexpensive flavanones, using a bromination- methoxylation procedure. A series of flavonoids that are not otherwise accessible can be prepared using this method. As an example, 3′-demethoxysudachitin, a limited flavone possessing antimicrobial activity against methicillin-resistant Staphylococcus aureus and Helicobacter pylori and acting as a 2,2-diphenyl-1-picrylhydrazyl (DPPH) scavenger, was prepared in fairly satisfactory yield.

Full text of DOI:10.1211/jpp.59.12.0012

JPP 2007, 59: 1697–1701
© 2007 The Authors
Received February 19, 2007
Accepted June 15, 2007
DOI 10.1211/jpp.59.12.0012
ISSN 0022-3573
Efficient synthesis of polyoxygenated flavones from
naturally occurring flavanones
Paolo Bovicelli, Vittoria D’Angelo, Daniela Collalto, Antonio Verzina,
Nicola D’Antona and Daniela Lambusta
Abstract
Flavonoids are constituents of the human diet (they are present in many beverages and food), and in
organisms they are responsible for several biological functions, including that of antioxidant. Because
of the increasing interest in these molecules, methods for their synthesis and structural modification
are of great importance; studies on the biological activities of many of these compounds are insuffi-
cient because of their scarcity and/or high cost. We have developed an expeditious synthesis of polyox-
ygenated flavones, starting from available and inexpensive flavanones, using a bromination–
methoxylation procedure. A series of flavonoids that are not otherwise accessible can be prepared
using this method. As an example, 3′-demethoxysudachitin, a limited flavone possessing antimicrobial
activity against methicillin-resistant Staphylococcus aureus and Helicobacter pylori and acting as a 2,2-
diphenyl-1-picrylhydrazyl (DPPH) scavenger, was prepared in fairly satisfactory yield.
Introduction
C.N.R. Instituto di Chimica
Biomolecolare, Sezione di Roma,
c/o Dipartimento di Chimica,
Università di Roma ‘La Sapienza’,
p.le A. Moro 5, I-00185 Roma,
Italy
Natural antioxidants have been isolated from various plants. They are usually polyphenols,
the most important of which are flavonoids, having a benzopyrane skeleton. Flavones,
which have an unsaturated C-ring, and flavanones, possessing a saturated C-ring, represent
typical examples of this class of compounds.
Flavonoids occur widely in the plant kingdom, especially in fruits and vegetables, and
they are the most abundant polyphenols in the human diet. Many flavonoids, including sev-
eral hydroxyflavones and flavanones, have been shown to possess free-radical scavenger
properties (Cotelle et al 1996), and are therefore possible candidates for the treatment of dis-
eases that involve oxidation processes.
Methoxylated flavones that exhibit interesting biological activities have recently been
isolated from plants, for example nevadensin (5,7-dihydroxy-6,8,4′-trimethoxyflavone),
which has antimycobacterial activity, and isothymusin (6,7-dimethoxy-5,8,4′-trihydroxyfla-
vone), which has antioxidant activity (Aroonrerk et al 2003). A semisynthetic analogue of
fumagillin (TNP-470) has been prepared and has been shown to inhibit endothelial cell pro-
liferation by interfering with endothelial cell DNA synthesis (Bernsen & van der Kogel
1999). Similarly, flavopiridol, a semisynthetic flavone analogue of natural rohitukine,
inhibits several cyclin-dependent kinases (CDKs) and is the first CDK inhibitor to be tested
in human clinical trials for the treatment of cancer and proliferative disorders (Senderowicz
1999, 2001).
Paolo Bovicelli, Vittoria
D’Angelo, Daniela Collalto,
Antonio Verzina
C.N.R. Istituto di Chimica
Biomolecolare, Sezione di
Catania, Via del Santuario 110,
I-95028 Valverde CT, Italy
Nicola D’Antona, Daniela
Lambusta
Correspondence: Paolo
Bovicelli, C.N.R. Instituto di
Chimica Biomolecolare, Sezione
di Roma, c/o Dipartimento di
Chimica, Università di Roma ‘La
Sapienza’, p.le A. Moro 5,
Despite the biological importance evident for this class of natural compounds, extensive
investigation into the activities of most of them is limited because of their scarcity. Moreover,
the synthesis and/or structural modification of these polyphenols is often complex, low yield-
ing and expensive (Stermitz etal 1975; Sanicanin & Tabakovic 1986; Matuyama etal 1989).
I-00185 Roma 62, Italy. E-mail:
paolo.bovicelli@uniroma1.it
Acknowledgement: The
financial support from the Italian
Ministry for University and
Research, General Management
for Strategies and Development
of Internationalization of
Scientific and Technological
Research is gratefully
Material and Methods
Each synthetic step was repeated in triplicate or until results were reproduced with a max-
imum deviation of 5% with respect to that reported in the experimental procedures.
acknowledged
1697

1698
Paolo Bovicelli etal
General procedure for the bromination
of flavanones
6,8-Dibromo-5,7,4¢-trihydroxyflavanone (17)
We used 250 mg (0.92 mmol) naringenin, 204 mg (2 mmol)
NaBr and 1.48 g (1.2 mmol) oxone. After 30 min, a non-crys-
tallizable yellow solid separated. The filtered product
To a 0.01 M solution of the appropriate flavanone and NaBr
(1 equivalent for every bromine atom to be introduced in
the substrate) in a 1:1 mixture of acetone and water, oxone
was added in small portions until consumption of the sub-
strate (usually 1.4 eq.); the course of the reaction was mon-
itored by thin-layer chromatography (TLC) (hexane/EtOAc
1:1). Na2S2O3 was added to reduce the excess of oxone,
until no reaction of a NaI solution occurred. The mixture
was then extracted twice with EtOAc. The organic extracts
were washed with a saturated aqueous NaCl solution, dried
over anhydrous Na2SO4 and the solvent evaporated in
vacuum.
1
(336 mg, 85%) was shown to be pure by NMR analysis. H-
NMR (acetone-d6) d(ppm): 2.95 (1H, dd, J = 12.2, 17.1 Hz),
3.33 (1H, dd, J = 3.4, 17.1 Hz), 5.66 (1H, dd, J = 3.4, 12.7 Hz),
6.91 (2H, d, J=8.8Hz), 7.43 (2H, d, J=8.8Hz), 13.01 (1H, s).
13C-NMR (acetone-d6) d(ppm): 80.6, 90.1, 91.1, 103.8, 116.3,
128.9, 130.0, 158.9, 159.2, 160.1, 160.2, 197.4. Anal. calcd for
C15H10Br2O5: C, 41.89; H, 2.34. Found: C, 41.65; H, 2.15.
Typical procedure for the oxidation of
flavanones to flavones
The appropriate flavanone (0.45 mmol) was dissolved in
DMSO (1 mL) and the solution heated to 100°C. To the warm
solution were added catalytic amounts of I2 (10 mg,
0.05 mmol) and concentrated H2SO4 (1 drop), and the reac-
tion was monitored by TLC (hexane/EtOAc). When the sub-
strate was completely consumed, the mixture was quenched
with ice and a 0.1 M aqueous solution of Na2S2O3 added to
destroy the I2 residue. The mixture was extracted with EtOAc
(3 × 10 mL) and the reunited organic phases washed with a
saturated aqueous NaCl solution (2 × 5 mL). The organic
solution was then dried over anhydrous Na2SO4 and the sol-
vent evaporated under vacuum. Products that did not need
any further chromatographic purification were obtained in
good yields (73% to > 95%, Table 1).
6,8-Dibromo-5-methoxyflavanone (2)
We used 250 mg (1 mmol) 5-methoxyflavanone, 204 mg
(2 mmol) NaBr and 1.85 g (1.5 mmol) oxone, and the reaction
was complete in 30 min. After flash chromatography (hexane/
EtOAc 8:2), 410 mg (90%) of product were obtained as
brown oil. 1H-NMR (CDCl3) d(ppm): 3.02 (1H, d, J = 4.5 Hz),
3.06 (1H, d, J = 11.3 Hz), 3.90 (3H, s), 5.56 (1H, dd, J = 4.5,
11.3 Hz), 7.43 (5H, m), 7.92 (1H, s). 13C-NMR (CDCl3)
d(ppm): 44.9, 61.7, 79.3, 107.4, 110.7, 117.1, 125.8, 128.8,
128.9, 137.7, 137.6, 141.2, 156.7, 158.1, 188.6. Anal. calcd
for C16H12Br2O3: C, 46.64; H, 2.94. Found: C, 46.40; H, 2.82.
6-Bromoflavanone (10)
The product was obtained by the above procedure from fla-
vone in 96% yield. Physical data were in accordance with that
reported in literature (Ramadas & Krupadanam 2004).
Data for compounds 6 (Moon et al 2005), 8 (Shen et al
1993), 9 (Rho et al 2002), 11 (Marder et al 1996) and 13
(Khan & Goswami 2005) were in accordance with that
reported in literature.
8-Bromo-5,7,4¢-trimethoxyflavanone (12)
6,8-Dibromo-5-methoxyflavone (3)
185 mg (0.45 mmol) of 6,8-bromo-5-methoxyflavanone gave
135 mg (73%) of product as a brown oil. H-NMR (CDCl3)
d(ppm): 3.98 (3H, s), 6.81 (1H, s), 7.54–7.57 (3H, m), 7.97–
8.02 (2H, m), 8.11 (1H, s). 13C-NMR (CDCl3) d(ppm): 62.0,
105.7, 107.4, 108.3, 114.6, 129.2, 132.0, 132.7, 139.5, 155.8,
161.9, 176.2. Anal. calcd for C16H10Br2O3: C, 46.86; H, 2.46.
Found: C, 46.50; H, 2.2.
We used 200 mg (0.64 mmol) naringenin trimethyl ether,
144 mg (1.4 mmol) NaBr and 1.23 g (1 mmol) oxone. After
45 min the mixture was extracted as usual and the product
purified by flash chromatography (hexane/EtOAc 8:2) to
yield a yellow–brown oil. 1H-NMR (CDCl3) d(ppm): 2.93
(1H, d, J = 4.0 Hz), 2.99 (1H, d, J = 11.3 Hz), 3.81 (3H, s),
3.94 (3H, s), 3.96 (3H, s), 5.48 (1H, dd, J = 4.0, 11.3 Hz), 6.15
(1H, s), 6.93 (1H, d, J = 8.8 Hz), 7.42 (1H, d, J = 8.8 Hz). 13C-
NMR (CDCl3) d(ppm): 44.9, 55.3, 56.2, 56.4, 78.8, 89.4,
91.7, 106.4, 114.1, 127.3, 130.5, 159.8, 160.1, 161.6, 161.9,
189.1. Anal. calcd for C18H17BrO5: C, 54.98; H, 4.36. Found:
C, 54.65; H, 4.25.
1
6,8-Bromo-5,7,4¢-trihydroxyflavone (18)
300 mg of 17 (0.7 mmol) gave 275 mg (92%) of a yellow
solid that was difficult to manipulate because of its low
Table 1 Oxidation of flavanones to flavones
Substrate
Time (min)
Product
Yield (%)
6-OMe-flavone (1)
6,8-Br-5-OMe-flavanone (2)
Flavanone (5)
Naringenin (7)
6-Br-flavanone (10)
8-Br-5,7,4′-OMe-flavanone (12)
6,8-Br-5,7,4′-OH-flavanone (17)
20
40
15
90
30
50
60
6-OMe-flavone (9)
6,8-Br-5-OMe-flavone (3)
Flavone (6)
Apigenin (8)
6-Br-flavone (11)
8-Br-5,7,4′-OMe-flavone (13)
6,8-Br-5,7,4′-OH-flavone (18)
92
73
95
95
90
90
92

Synthesis of polyoxygenated flavones
1699
solubility in most solvents. It was characterized as triacetate. this reaction is rarely used in synthesis and is not considered a
Crude product (275 mg) was treated with 1 mL pyridine and general route for the poly-oxygenation of aromatics. While
1 mL acetic anhydride and left overnight. The mixture was trying to improve the experimental procedure, we found a
quenched with a 1 M solution of HCl, the solution extracted protocol that proved highly successful for many of the sub-
with EtOAc (3 × 10 mL) and the organic solution washed to strates we used (Bovicelli et al 2005). Unfortunately, how-
neutrality with a saturated aqueous NaCl solution. The solu- ever, the reaction failed when sensitive compounds such as
tion was then dried over anhydrous Na2SO4 and the solvent flavones were submitted to the transformation. Pursuing our
evaporated under vacuum. A yellow-brown oil was obtained. objective of introducing oxygenated functionalities into fla-
1H-NMR (CDCl3) d(ppm): 2.33 (3H, s), 2.47 (3H, s), 2.49 vonoids, we tried to improve the method further and suc-
(3H, s), 6.70 (1H, s), 7.26 (1H, d, J = 8.8 Hz), 7.96 (1H, d, ceeded in designing a protocol that, so far, seems to be
J = 8.8 Hz). 13C-NMR (CDCl3) d(ppm): 20.4, 20.8, 21.1, completely successful.
105.8, 108.1, 110.9, 116.7, 122.5, 127.8, 147.1, 150.7, 153.2,
In the original procedure, a mixture of the catalyst and a
153.7, 161.8, 166.1, 167.9, 168.7, 175.0, 183.4. Anal. calcd solution of sodium methoxide in DMF were heated at 130°C
for C21H14Br2O8: C, 45.52; H, 2.55. Found: C, 45.30; H, and the substrate added in one portion. In improving the pro-
2.22.
cedure, we found both the nature of the catalyst, CuBr, which
has to be carefully recrystallized before use, and the composi-
tion of the solvent, which must contain a small percentage of
water to work well, to be of paramount importance.
Our protocol was improved as follows. We observed that a
blue mixture formed when NaOMe and CuBr were mixed in
DMF before the addition of the substrate and assumed the
formation of a reactive complex. At 130°C, DMF rapidly
decomposes; most probably some of the decomposition prod-
ucts interfere in some way in the process to reduce yields. To
avoid this, in the new protocol, the blue complex is prepared
separately and added to the warm solution of the substrate in
DMF.
In the light of this new procedure, the selective bromina-
tion of flavonoids, together with many other polyphenols,
becomes more attractive, since the products are not only
appealing as new ones but also as intermediates for higher
oxygenated species.
The bromination reaction carried out on flavones led to the
decomposition of the starting material because of the lability
of the enonic double bond on the C ring. To overcome this
problem it is necessary to work on flavanones and to put off
the introduction of the double bond into ring C by an oxida-
tive step. This oxidation, previously reported for a single case
(Fatma et al 1984), was successful mainly for bromo-fla-
vanones and proved ineffective in the case of most methoxy
derivatives.
Typical procedure for bromo-flavones
methanolysis
The protocol was improved with respect to that previously
reported (Bovicelli et al 2006). A 25% solution of MeONa in
MeOH (7.94 mL, 35 mmol, 4 eq. for every bromine atom to
substitute) was mixed at room temperature with CuBr
(125 mg, 0.87 mmol) and DMF (0.8 mL). After a few min-
utes’ stirring, a blue solution was formed, which was added
dropwise over 1 h to a solution of dibromoflavanone
(4.37 mmol) in DMF (6.7 mL) stirred at 120°C. The mixture
was then quenched with ice and extracted with EtOAc
(3 × 50 mL). The organic layers were dried over anhydrous
Na2SO4 and the solvent evaporated.
5,6,8-Trimethoxyflavone (4)
410 mg (1 mmol) of 5-methoxy-6,8-dibromoflavone 3 gave
278 mg (89%) of 4 as a colourless oil. Physical data were in
accordance with that reported by Iinuma et al (1980).
3¢-Demethoxysudachitin (19)
500 mg (1.14mmol) of 6,8-dibromoapigenin 18 gave 300 mg
(80%) of pure product as a colourless oil. 1H-NMR (acetone-
d6) d: 3.87 (3H, s), 3.96 (3H, s), 6.65 (1H, s), 7.04 (2H, d,
J=8.8Hz), 7.97 (2H, d, J=8.8Hz), 12.92 (1H, s). 13C-NMR
(acetone-d6) d: 60.8, 61.8, 103.6, 104.6, 116.5, 117.0, 123.4,
129.2, 132.4, 146.7, 149.8, 151.3, 162.0, 165.0, 183.7. Anal.
calcld for C17H14O7: C, 61.82; H, 4.27. Found: C, 61.9; H, 4.5.
Thus the correct sequence for obtaining a polymethoxy-
lated flavone is initial bromination of the flavanone, fol-
lowed by oxidation to the flavone, and finally methanolysis
(Figure 1). The same strategy was adopted for the prepara-
tion of 3′-demethoxysudachitin. In this case, a product with
alternated hydroxy and methoxy groups was obtained
(Figure 2).
Results and Discussion
This pathway is often found in natural antioxidants, and
the synthesis reported herein is just one example, the
approach being extendible to many other compounds. In all
cases, highly oxygenated and potentially bioactive products
(antioxidants, antibacterial, etc.) can be obtained.
3′-Demethoxysudachitin (19) is well known and is widely
present in several plant extracts, including that of Baccharis
grisebachii (Asteraceae) used in Argentinean traditional med-
icine as a digestive and to relieve ulcers. It exhibited the high-
est activity in inhibition of erythrocyte lipoperoxidation
compared with other hydroxylated flavonoids (Tapia et al
2004). Flavone 19 was also found to possess antimicrobial
Recently, we optimized a method for introducing oxygenated
moieties into activated aromatic rings, convenient to prepare
polyphenols starting from inexpensive and easily available
natural compounds. A selective bromination (Bovicelli et al
2001, 2002), followed by a methanolysis promoted by the
system MeO−/CuBr, allowed the synthesis of complex com-
pounds such as ubiquinones (Bovicelli et al 2005), bioactive
biphenols (Bovicelli etal 2006) and hydroxytyrosol (Bovicelli
et al 2007). The methanolysis step is already known, but the
procedures reported in the literature (Bacon & Rennison
1969) showed poor reproducibility, which is probably why

1700
Paolo Bovicelli etal
Br
B
O
O
NaBr, oxone
A
C
acetone, r.t., 90%
Br
OMe O
OMe O
1
2
I2, H2SO4
DMSO, 100°C
40min, 73%
Br
OMe
O
O
MeONa, CuBr
DMF, 120°C,
1 h, 89%
Br
MeO
OMe O
OMe O
4
3
Figure 1 Synthesis of 5,6,7-trimethoxyflavone.
OH
OH
Br
HO
O
HO
O
NaBr, oxone
acetone, H2O, r.t., 2 h, 85%
Br
OH
O
OH
O
16
17
I2,H2SO4
DMSO
100°C
1 h, 92%
OH
OH
OMe
Br
HO
MeO
O
O
HO
Br
O
MeONa, CuBr
DMF, 130°C, 1 h, 80%
OH
OH
O
19
18
Figure 2 Synthesis of 6,8-dimethoxyapigenin.
activity against methicillin-resistant Staphylococcus aureus brominated flavonoids have been found to have biological
and Helicobacter pylori (Nakagawa et al 2006) and acts as a properties, but the difficulties experienced in preparing deriv-
2,2-diphenyl-1-picrylhydrazyl (DPPH) scavenger (Tapia et al atives of a large number of natural compounds has, to date,
2004).
limited investigation. Polyoxygenated flavonoids were like-
wise not easily available until now. In this paper, we propose
an efficient and easy transformation of simple and available
flavanones into higher oxygenated flavones not easily obtain-
Conclusions
Investigations into the beneficial properties of flavonoids able by other methods. In particular, flavones highly oxygen-
require a practical and easy method to prepare many ated in ring A could be easily obtained, and many others can
compounds with many different functional groups. Some presumably be prepared by the same way.

Synthesis of polyoxygenated flavones
1701
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Kor. Chem. Soc. 26: 603–608
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