Efficient synthesis of scutellarein

Article abstract of DOI:10.1080/14786419.2011.566224

Scutellarein is a component of Scutellaria, recently known as a potent cytotoxic agent on human leukaemia cells. The aim of this study was the synthesis of scutellarein and its methylated derivative. The new features are the innovating method to afford flavones from flavanones and the A-ring regioselective bromination step that lead to the target molecule by a facile and high-yielding pathway.

Full text of DOI:10.1080/14786419.2011.566224

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Natural Product Research: Formerly
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Efficient synthesis of scutellarein
Giuliana Righi a , Ilaria Proietti Silvestri b , Maurizio Barontini c
, Fernanda Crisante b , Andrea Di Manno b , Romina Pelagalli b &
Paolo Bovicelli d
a C.N.R. Institute of Biomolecular Chemistry (ICB), Unity of Rome,
c/o Department of Chemistry , Sapienza University of Rome , p.le
A. Moro 5 , 00185 Rome , Italy
b Department of Chemistry , Sapienza University of Rome , p.le A.
Moro 5 , 00185 Rome , Italy
c CRA-ING , via della Pascolare 16, Monterotondo Scalo 00016
Rome , Italy
d C.N.R. ICB-Unity of Sassari, Traversa La Crucca 3 , Baldanica
07040 Sassari , Italy
Published online: 19 Oct 2011.
To cite this article: Giuliana Righi , Ilaria Proietti Silvestri , Maurizio Barontini , Fernanda
Crisante , Andrea Di Manno , Romina Pelagalli & Paolo Bovicelli (2012) Efficient synthesis of
scutellarein, Natural Product Research: Formerly Natural Product Letters, 26:14, 1278-1284, DOI:
10.1080/14786419.2011.566224
To link to this article: http://dx.doi.org/10.1080/14786419.2011.566224
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Natural Product Research
Vol. 26, No. 14, July 2012, 1278–1284
Efficient synthesis of scutellarein
c
Giuliana Righia, Ilaria Proietti Silvestrib , Maurizio Barontini ,
*
Fernanda Crisanteb, Andrea Di Mannob, Romina Pelagallib and Paolo Bovicellid
aC.N.R. Institute of Biomolecular Chemistry (ICB), Unity of Rome, c/o Department of
Chemistry, Sapienza University of Rome, p.le A. Moro 5, 00185 Rome, Italy; bDepartment of
Chemistry, Sapienza University of Rome, p.le A. Moro 5, 00185 Rome, Italy; CRA-ING,
c
d
via della Pascolare 16, Monterotondo Scalo 00016 Rome, Italy; C.N.R. ICB-Unity of
Sassari, Traversa La Crucca 3, Baldanica 07040 Sassari, Italy
(Received 14 January 2011; final version received 22 February 2011)
Scutellarein is a component of Scutellaria, recently known as a potent
cytotoxic agent on human leukaemia cells. The aim of this study was the
synthesis of scutellarein and its methylated derivative. The new features are
the innovating method to afford flavones from flavanones and the A-ring
regioselective bromination step that lead to the target molecule by a facile
and high-yielding pathway.
Keywords: scutellarein; flavonoids; methanolysis; polyphenols
1. Introduction
Flavonoids are a group of plant-derived compound that can be found in considerable
quantities in fruits and vegetables (Beecher, 2003; Ross & Kasum, 2002). They exert
antioxidant and biological activities due to their aromatic moieties and the presence
of oxygenated groups (Fernandez-Bolanos, Felizon, Brenes, Guillen, & Heredia,
1998). The increasing interest in this kind of molecules is justified also by their low
toxicity, which allows their use as drugs or food preservatives. Moreover, flavonoids
have been shown to possess anticancer activity and flavonoid-based anticancer
therapies are under development (Galati & O’Brien, 2004). Recently, scutellarein
(Figure 1), a flavone extract from Scutellaria, became noteworthy due to its
interesting biological activities reported by different research groups like cytotoxic
activity on human leukaemia cells (Plochmann et al., 2007) and inhibitory activity
towards 17ꢀ-HSD (Brozic et al., 2009) and human salivary ꢁ-amylase (Lo Piparo
et al., 2008). It is also known to be an antagonist of tromboxane A2 receptor
˜
(Navarro-Nunez et al., 2009) leading to the formulation of new drugs involved in the
thrombotic diseases. To the best of our knowledge, no synthesis of scutellarein was
reported until now for preparative purposes (Gao & Kawabata, 2004). Therefore, we
investigated a practical and high-yielding synthesis of scutellarein and its methylated
derivatives in order to make them available to a deeper inspection.
*Corresponding author. Email: ilaria.proietti@tiscali.it
ISSN 1478–6419 print/ISSN 1478–6427 online
ß 2012 Taylor & Francis
http://dx.doi.org/10.1080/14786419.2011.566224
http://www.tandfonline.com

Natural Product Research
1279
OH
OCH3
i
HO
O
O
H3CO
O
O
OH
OH
1
Naringenin
ii
OCH3
Br
O
H3CO
OCH3
OH
O
H3CO
O
O
iii
3
OCH3
OH
2
H3CO
Br
O
O
OH
4
iv
OCH3
OH
H3CO
H3CO
O
HO
HO
O
O
v
OH
O
OH
6
5
Scutellarein
Figure 1. Convergent synthesis of scutellarein: (i) acetone, K2CO3, (CH3O)2SO2; (ii) NMO,
IBX, DMSO; (iii) TBATB, CHCl3; (iv) CuBr, MeONa, DMF and (v) HBr, AcOH. Overall
yield is 62% from naringenin.
2. Results and discussion
Our approach to the synthesis of scutellarein consisted in finding out a new and
easily reproducible way to prepare it starting from inexpensive compounds.
Referring to our previous work (Righi et al., 2010), in which crysin was converted
to baicalein using a bromination/methanolysis protocol, the dimethylated apigenin
(2) was chosen as starting material. Apigenin being very expensive and scarcely
available in nature, our first goal was to convert naringenin, the flavanone precursor,
into the above corresponding flavone. It is well known in literature that flavones

1280
G. Righi et al.
have enhanced biological activities than flavanones (Ares et al., 1996; Farkas, Jakus
& Heberger, 2004; Park, 2004; Tapas, Sakarkar & Kakde, 2008). The oxidation step
was carried out with the complex N-methylmorpholine-N-oxide (NMO) ꢀ 2-iodox-
ybenzoic acid (IBX) in DMSO at room temperature (RT; Figure 1). This procedure,
reported few years ago by Nicolau, Montagnon, and Baran (2002), was recently
applied on similar substrates (Barontini, Bernini, Crisante, & Fabrizi, 2010). To
convert naringenin into 2, the previous methylation of hydroxyl groups (Jurd, 1962)
was necessary to avoid chemoselective issues arising from the presence of free
hydroxyl groups since it is known that IBX can oxidise the B ring by introducing a
second hydroxy group (Selenski & Pettus, 2006). The following bromination step led
to a mixture of regioisomer, i.e. 6-bromo-5-hydroxy-7-methoxyflavone 3 and
8-bromo-5-hydroxy-7-methoxyflavone 4, in accordance with our previous work.
Tetrabutylammonium tribromide (TBATB) demonstrated to have a perfect
regioselectivity towards the A ring since no bromination occurred on B ring. The
mixture of monobromoflavones was directly converted to 6,7,40-trimethoxyflavone
(5) with copper bromide and sodium methoxide in DMF. A Wessely–Moser
rearrangement occurs in basic media during the methanolysis step, as reported for
crysin (Righi et al., 2010). The final selective demethylation steps led to scutellarein
(6) passing through the methyl derivatives. The proposed synthesis occurred in 62%
overall yield, allowing preparation of the target compound for drug uses and for
extensive biological studies.
3. Experimental
3.1. General
NMR spectra were recorded on a Varian Mercury 3000 instrument (1H 300 MHz,
13C 75 MHz). Chemical shifts were calculated from the residual solvent signals of
chloroform-d (1H-NMR ꢂ ¼ 7.26 ppm, 13C-NMR ꢂ ¼ 77.0 ppm) and DMSO-d6
(1H-NMR ꢂ ¼ 2.50 ppm, 13C-NMR ꢂ ¼ 77.0 ppm). Melting points were measured
on a Mettler FP80 instrument and were uncorrected. HRMS were performed on a
Q-TOF MICRO spectrometer (Micromass, now Water, Manchester, UK) equipped
with an ESI source. All chromatographic purifications were performed on silica gel
(100–200 mesh from E. Merck, Germany). Thin-layer chromatography was per-
formed on precoated silica gel 60 F254 aluminium sheets (Merck Italia) and spots
were visualised under UV torch. All reagents used were of analytical grade and were
purchased from Aldrich Chemical Co. Organic solvents used for the chemical
synthesis and for chromatography acquired from Merck Italia were of analytical
grade.
3.1.1. 7,40-Dimethylnaringenin (1)
Potassium carbonate (507 mg, 3.67 mmol) and dimethyl sulphate (0.35 mL,
3.67 mmol) were added to a solution of naringenin (500 mg, 1.84 mmol) in acetone
(15 mL). The reaction mixture was stirred at 50ꢁC overnight, and then aqueous NH3
(3 mL) was added to quench the reaction. The acetone was evaporated under vacuum
and HCl 2N was added in order to obtain an acidic solution. The resulting aqueous
phase was extracted with ethyl acetate (3 ꢂ 10 mL). The combined organic layer was

Natural Product Research
1281
washed with brine (3 ꢂ 10 mL) and dried over anhydrous Na2SO4 and the solvent
was evaporated to obtain a yellow powder. The crude product was purified over
silica gel (eluent: hexane/ethyl acetate 7/3) to afford 1 (498 mg, 1.66 mmol, 90%
yield) as yellow needles, m.p. 113.8–114.5ꢁC (literature 114–115ꢁC) (Oyama &
1
Kondo, 2004). H-NMR (chloroform-d1) ꢂ (ppm): 2.774 (dd, 1H, C3–H, J ¼ 3 Hz,
J ¼ 17.1 Hz), 3.096 (dd, 1H, C3–H, J ¼ 12.9 Hz, J ¼ 17.1 Hz), 3.797 (s, 3H, CH3),
3.828 (s, 3H, CH3), 5.355 (dd, 1H, C2–H, J ¼ 12.9 Hz, J ¼ 3 Hz), 6.035 (d, 1H, CH,
J ¼ 2.4 Hz), 6.064 (d, 1H, CH, J ¼ 2.4 Hz), 6.950 (d, 2H, CH, J ¼ 8.7 Hz), 7.378 (d,
2H, CH, J ¼ 8.7 Hz) and 12.040 (s, 1H, OH); 13C-NMR (chloroform-d1) ꢂ (ppm):
43.1 (CH2), 55.3 (OCH3), 55.6 (OCH3), 79.0, 94.2, 95.0, 103.1, 114.2, 127.7, 130.4,
160.0, 162.9, 164.1, 167.9 and 195.9 (C¼O). HRMS: calcd for C17H16O5Naþ
(M þ Naþ) 323.0890; found 323.0873.
3.1.2. 7,40-Dimethylapigenin (2)
N-methylmorpholine-N-oxide (123 mg, 1.09 mmol) was added to a solution of IBX
(222 mg, 1.09 mmol) in DMSO (0.8 mL). When a clear solution was obtained (about
15 min), 1 (100 mg, 0.33 mmol) was added and the reaction mixture was stirred for
48 h at RT. The mixture was then diluted with ethyl acetate (5 mL) and the organic
layer was sequentially washed with NaHCO3 saturated solution (2 ꢂ 3 mL) and brine
(3 mL) and dried over anhydrous Na2SO4. The solvent was evaporated under
reduced pressure to give a yellow powder. The crude product was purified over silica
gel (eluent: hexane/ethyl acetate 8/2) to afford 2 (89 mg, 0.30 mmol, 92% yield) as
yellow needles, m.p. 169.1–172.2ꢁC, (literature 167–170ꢁC) (Areche, Schmeda-
1
Hirschmann, Theoduloz, & Rodriguez, 2009). H-NMR (chloroform-d1) ꢂ (ppm):
3.852 (s, 3H, OCH3), 3.866 (s, 3H, OCH3), 6.323 (d, 1H, CH, J ¼ 2.4 Hz), 6.434 (d,
1H, CH, J ¼ 2.4 Hz), 6.523 (s, 1H, C3–H), 6.973 (d, 2H, CH, J ¼ 9 Hz), 7.790 (d, 2H,
CH, J ¼ 9 Hz) and 12.783 (s, 1H, OH); 13C-NMR (chloroform-d1) ꢂ (ppm): 55.7
(OCH3), 55.9 (OCH3), 92.8, 98.2, 104.5, 105.7, 114.7, 128.2, 157.9, 162.4, 162.8,
164.2, 165.6 and 182.6 (C¼O). HRMS: calcd for C17H14O5Naþ (M þ Naþ) 321.0733;
found 321.0758.
3.1.3. 6-Bromo-5-hydroxy-7,40-dimethoxyflavone (3) and 8-Bromo-5-hydroxy-7,
40-dimethoxyflavone (4)
TBATB (133 mg, 0.30 mmol) was added to a solution of 2 (89 mg, 0.30 mmol) in
chloroform (3 mL). The solution was stirred for 80 min at RT and then the reaction
was diluted with ethyl acetate (6 mL). The organic layer was washed with brine
(3 ꢂ 5 mL) and dried over anhydrous Na2SO4 and the solvent was removed under
reduced pressure to afford a 2:1 mixture of 3 and 4 (105 mg, 0.28 mmol, 94% yield).
The mixture was used in the following step without any further purification.
Compounds 3 and 4 were characterised after column chromatography on silica gel
(eluent: hexane/ethyl acetate 8/2). Compound
3 (61 mg, 0.16 mmol) m.p.
248.1–249.5ꢁC (recrystallised from acetone). 1H-NMR (chloroform-d1) ꢂ (ppm):
3.872 (s, 3H, OCH3), 4.001 (s, 3H, OCH3), 6.549 (s, 1H), 6.614 (s, 1H), 7.019 (d, 2H,
CH, J ¼ 6.6 Hz), 7.820 (d, 2H, CH, J ¼ 6.6 Hz) and 12.357 (s, 1H, OH). 13C-NMR
(chloroform-d1) ꢂ (ppm): 55.5 (OCH3), 56.8 (OCH3), 90.7, 95.9, 104.2, 105.8, 114.5,

1282
G. Righi et al.
123.0, 123.2, 128.3, 128.4, 153.2, 158.2, 161.5, 162.7, 164.1 and 181.7 (C¼O); HRMS:
calcd for C17H13BrO5Naþ (M þ Naþ) 398.9839; found 398.9868.
Compound 4 (24 mg, 0.06 mmol) m.p. 248.3–249.7ꢁC, (literature 249–250ꢁC)
(D.J. Donnelly, J.A. Donnelly, & Philbin, 1972). 1H-NMR (chloroform-d1) ꢂ (ppm):
3.904 (s, 3H, OCH3), 3.979 (s, 3H, OCH3), 6.432 (s, 1H), 6.607 (s, 1H), 7.002 (d, 2H,
CH, Jꢁ¼ꢁ6.6ꢁHz), 7.933 (d, 2H, CH, Jꢁ¼ꢁ6.6ꢁHz) and 12.145 (s, 1H, OH); 13C-NMR
(chloroform-d1) ꢂ (ppm): 55.5 (OCH3), 56.7 (OCH3), 88.0, 94.2, 103.5, 103.6, 114.7,
122.9, 123.1, 128.0, 128.4, 156.5, 161.3, 161.6, 162.8, 164.2 and 182.2 (C¼O); HRMS:
calcd for C17H13BrO5Naþ (MꢁþꢁNaþ) 398.9839; found 398.9882.
3.1.4. 6,7,40-Trimethylscutellarein (5)
DMF (0.7 mL) was added to a suspension of CuBr (30 mg, 0.21 mmol) in a 25%
solution of sodium methoxide in methanol (1.89 mL, 8.32 mmol) and left under
stirring at RT until a bright blue colour appeared (about 1 h). The mixture was added
to a solution of 3 and 4 (96 mg, 0.26 mmol) dissolved in DMF (2.1 mL) at 120ꢁC in
0.5 mL portion. The mixture was left stirring for 5 h and then cooled down to RT and
washed with cold HCl 2N (3 mL). The reaction mixture was extracted with diethyl
ether (3 ꢂ 10 mL) and the combined organic layer was washed with brine (3 ꢂ 10 mL)
and dried over anhydrous Na2SO4 and the solvent removed under reduced pressure.
The crude product was purified over silica gel (eluent: hexane/ethyl acetate 8/2) to
afford 5 (70 mg, 0.21 mmol, 82% yield) as pale yellow needles, m.p. 180.3–181.1ꢁC,
1
(literature 180ꢁC) (Achari, Chaudhuri, Saha, Dutta, & Pakrashi, 1990). H-NMR
(chloroform-d1) ꢂ (ppm): 3.866 (s, 3H, OCH3), 3.901 (s, 3H, OCH3), 3.948 (s, 3H,
OCH3), 6.525 (s, 1H), 6.577 (s, 1H), 6.980 (d, 2H, CH, J ¼ 8.1 Hz), 7.809 (d, 2H, CH,
J ¼ 8.1 Hz) and 12.325 (s, 1H, OH); 13C-NMR (chloroform-d1) ꢂ (ppm): 55.5
(OCH3), 56.3 (OCH3), 60.8 (OCH3), 90.6, 104.2, 106.2, 114.5, 123.6, 128.0, 132.7,
153.1, 153.2, 158.7, 162.6, 164.0 and 182.7 (C¼O). HRMS calcd for C18H16O6Naþ
(M þ Naþ) 351.0839; found 351.0798.
3.1.5. Scutellarein (6)
A solution of bromidic acid in water 47% (2.5 mL) was added to a solution of 5
(70 mg, 0.21 mmol) in glacial acetic acid (5.1 mL) at reflux. The solution was stirred
for 72 h and then quenched with ice (100 g). The yellow precipitate was collected after
filtration under vacuum and dried in oven (60ꢁC) overnight. Compound 6 (58 mg,
0.20 mmol, 97% yield) was obtained as a yellow powder. Analytical data agreed with
those reported in literature (Gao & Kawabata, 2004).
4. Conclusions
In this study, scutellarein and its 6,7,40-methylated derivate were synthesised with an
easy and high-yielding route by applying our previous procedure. These results
highlighted the versatility of our semi-synthesis approach to the preparation of
flavonoids. The presence of an activated B ring will allow further modification,
which will be the next goal of our research group.

Natural Product Research
1283
Acknowledgement
The financial support from the Italian Ministry for Education, University and Research,
General Management for International Research is gratefully acknowledged.
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