The first total synthesis of sophoflavescenol, flavenochromane C, and citrusinol

Article abstract of DOI:10.1002/ejoc.201403689

The first total syntheses of sophoflavescenol (1), flavenochromane C (2), and citrusinol (3) were achieved. These three naturally occurring prenylated or prenyl-cyclized flavonoids have important biological activities such as cytotoxicity against some can

Full text of DOI:10.1002/ejoc.201403689

Job/Unit: O43689
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Date: 16-02-15 13:19:42
Pages: 7
FULL PAPER
DOI: 10.1002/ejoc.201403689
The First Total Synthesis of Sophoflavescenol, Flavenochromane C, and
Citrusinol
Van-Son Nguyen,[a,b] Lin-Pei Dong,[a] Sheng-Chun Wang,[a] and Qiuan Wang*[a]
Keywords: Total synthesis / Natural products / Sigmatropic rearrangement / Cyclization / Fused-ring systems / Oxygen
heterocycles
The first total syntheses of sophoflavescenol (1), flaveno-
chromane C (2), and citrusinol (3) were achieved. These
three naturally occurring prenylated or prenyl-cyclized
flavonoids have important biological activities such as cyto-
dioxirane, O-prenylation, microwave-assisted Claisen re-
arrangement, deprotection, cyclization of the prenyl group,
and dehydrogenation with 2,3-dichloro-5,6-dicyano-1,4-
benzoquinone. The overall yields of 1, 2, and 3 were 23, 17,
toxicity against some cancer cell lines, or are lead com- and 16%, respectively. All compounds were characterized by
pounds for the treatment of erectile dysfunction. Starting
1H and 13C NMR spectroscopy and MS. The key step of the
from 2,4,6-trihydroxyacetophenone and substituted benzal- synthetic route was a regioselective microwave-assisted
dehydes, the synthesis involved methoxymethyl protection,
aldol condensation, cyclization, oxidation with dimethyl-
Claisen rearrangement to form an 8-prenylated flavonoid
from a 5-O-prenylflavonoid.
activity against lung carcinoma (A549), ovarian carcinoma
(1A9), and breast adenocarcinoma (MCF-7) cell lines with
IC50 values of 1.7–3.6 μm.[7] Citrusinol (3), the dimethyl
pyrano derivative of C-8-prenylkaempferol, isolated from
the stems and leaves of Desmodium caudatum, has been
shown to have antibacterial and antifungal activities.[8] It
has also shown cytotoxicity against KB cells and the
HepG2 cell line.[9]
Introduction
Prenylated flavonoids are a unique class of naturally oc-
curring flavonoids characterised by the presence of a pren-
ylated side-chain on the flavonoid skeleton. C-Prenylation
of flavonoids can enhance their binding affinity toward P-
glycoprotein, and can remarkably improve the biological
activity of the flavonoids.[1] Over the past few decades, an
impressive number of biological activities and pharmaco-
logical effects have been demonstrated for C-prenylated
flavonoids, including antitumor, anti-inflammatory, and
antiosteoporosis activities, enzyme inhibition, and vascular-
protective and estrogen regulation activities.[2,3]
Sophoflavescenol (1), a C-8-prenylated flavonoid isolated
from S. flavescens, was the most potent and selective inhibi-
tor of CGMP phosphodiesterase 5 (PDE5; IC50 0.013 μm),
and so it was considered as a lead structure for the treat-
ment of erectile dysfunction.[4] Sophoflavescenol (1) also
showed inhibitory activity against HL-60, LLC, and A549
tumor cells.[5] Flavenochromane C (2) is a prenyl-cyclized
derivative of sophoflavescenol, and it showed potent cyto-
toxicity against a panel of five human tumour cell lines with
IC50 values of 1.0–3.6 μm.[6] It also showed strong cytotoxic
Sophoflavescenol (1), flavenochromane C (2), and cit-
rusinol (3) only occur at low levels in natural plants, and
this has negatively influenced further evaluation of their
biological activity. Therefore, the chemical synthesis of 1, 2,
and 3 would be a very important way of addressing the
problem of their availability. In this paper, we describe the
first total synthesis of sophoflavescenol (1), flavenochrom-
ane C (2), and citrusinol (3) in 10–11 steps, starting from
commercially available 2,4,6-trihydroxyacetophenone and
MOM-protected 4-hydroxybenzaldehyde. The key step is a
regioselective microwave-assisted Claisen rearrangement to
form an 8-prenylated flavonoid from a 5-O-prenylflavonoid.
1
All the compounds synthesized were characterized by H
and 13C NMR spectroscopy and MS. The synthetic route
to sophoflavescenol (1), flavenochromane C (2), and cit-
rusinol (3) is shown in Schemes 1 and 2.
[a] College of Chemistry and Chemical Engineering,
Hunan University,
Changsha 410082, P. R. China
Results and Discussion
E-mail: wangqa@hnu.edu.cn
http://cc.hnu.cn
Starting material 2,4,6-trihydroxyacetophenone is com-
mercially available. 2-Hydroxy-4,6-bis(methoxymethoxy)-
acetophenone (4) and 4-(methoxymethoxy)benzaldehyde
[b] Faculty of Chemical Engineering,
Industry University of Hochiminh City,
Vietnam
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201403689.
were prepared according to literature procedures.[10,11]
A
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V.-S. Nguyen, L.-P. Dong, S.-C. Wang, Q. Wang
FULL PAPER
Scheme 1. Synthesis of 11 by aldol condensation, cyclization, oxidation with dimethyldioxirane (DMDO), selective 5-demethoxymethyl
protection, O-prenylation, and microwave-assisted Claisen rearrangement. Reagents and conditions: (a) CH3OCH2Cl, K2CO3, acetone,
room temp., 83–90%; (b) 4-MOMO-benzaldehyde, KOH, EtOH, reflux, 85%; (c) I2, DMSO, reflux, 8 h, 70%; (d) oxone, acetone, CH2Cl2/
NaHCO3/Na2CO3, r.t.; then p-toluenesulfonic acid, r.t., 76%; (e) dilute HCl (aq.), EtOH, r.t., 89%; (f) prenyl bromide, K2CO3, acetone,
reflux, 95%; (g) microwave, PhNEt2, reflux, 82%.
Scheme 2. The last steps in the total synthesis of sophoflavescenol (1), flavenochromane C (2), and citrusinol (3): 5-O-methylation,
deprotection, cyclization of the prenyl group, and dehydrogenation with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ). Reagents
and conditions: (h) (Me)2SO4, NaOH, r.t., 80%; (i) HCl (aq.), EtOH, r.t., 96%; (j) H2SO4 (20% aq.), CH3OH, reflux, 86%; (k) DDQ,
1,4-dioxane, reflux, 76%.
methoxymethyl (MOM) group was chosen to protect the a 3-OH group was introduced by treatment with dimethyl-
hydroxy group because it is stable under the basic condi- dioxirane (DMDO), generated in situ from Oxone and acet-
tions, and is easily removed by acidic treatment. Base-cata- one[13] at low temperature, followed by opening of the re-
lysed aldol condensation of 4 with 4-(methoxymethoxy)- sulting epoxide with catalytic p-toluenesulfonic acid to give
benzaldehyde gave chalcone 5 in 85% yield after a simple flavonol 7 in 76% yield.
purification. Chalcone 5 was cyclized in the presence of
catalytic iodine in dimethyl sulfoxide at 140 °C to give moved by a catalytic amount of dilute HCl in EtOH at
MOM-protected flavone 6 in high yield. room temperature to give compound 8. Treatment of 8 with
The oxidation of the flavone to the flavonol was achieved chloromethyl methyl ether and K2CO3 in acetone give the
by following our previously published procedures.[12] Thus, intermediate
3,7,4Ј-tri-O-(methoxymethoxyl)kaempferol
The MOM protecting group of 5-OH was selectively re-
2
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Sophoflavescenol, Flavenochromane C, and Citrusinol
(9). O-Prenylation of the free 5-hydroxy group of 9 using for the entire 10-step sequence from 2,4,6-trihydroxyaceto-
prenyl bromide as the electrophile gave 10. phenone was 16%. The NMR spectroscopic data of the nat-
Once prenyl ether 10 was available, our attention was fo- ural and synthetic flavonoids 1, 2, and 3 are shown in
cussed on the formation of an 8-prenylated flavonoid from Tables 1, 2, and 3.
the 5-O-prenylflavonoid. A microwave-assisted Claisen re-
arrangement was the key step of our synthetic strategy. O-
Prenylated Claisen precursor 10 was subjected to micro-
wave-assisted Claisen rearrangement in N,N-diethylaniline Table 1. Comparison of the NMR spectroscopic data of natural
and synthetic flavonoid 1.
to give the desired C-prenylated flavonoid (i.e., 11). The ef-
fects of microwave irradiation versus conventional heating
on the regioselectivity of the Claisen rearrangement and the
reactivity of 10 in the reaction were investigated. Using con-
ventional heating, the ortho-rearranged product was found
to be the major product (70% yield) in N,N-diethylaniline
at 190 °C, and only 15% of the para-rearranged product
(i.e., 11) was obtained. However, using microwave irradia-
tion, the para-rearranged product (i.e., 11) was obtained se-
lectively in 82% yield under otherwise identical conditions,
and it was the only product observed in the 1H NMR spec-
trum of the crude reaction mixture [signals for the –CH2–
CH=C(CH3)2 group in 11 at δ = 3.04 (d, 2 H) ppm, and
loss of H-8 (C-8 position)]. These results also show that
microwave irradiation can greatly accelerate the reaction
rate of the Claisen rearrangement. The reaction rates under
microwave irradiation (700 W) are 72 times higher than
those using conventional heating at 190 °C. Thus, we con-
firmed that the microwave-assisted procedure was suitable
for the synthesis of MOM-protected 8-prenylflavonoids.
The next step involved the introduction of the desired
methyl functionality onto the reexposed 5-hydroxy group in
11. This was accomplished by using dimethyl sulfate in the
presence of potassium carbonate to produce 12. Removal
of the MOM protecting groups was achieved by stirring 12
in HCl (3 m) and EtOH for 2 h, carefully monitoring the
Position Synthesized Natural
compound compound
Synthesized Natural
compound compound
δH [ppm]
δH [ppm]
δC [ppm]
δC [ppm]
2
3
4
4a
5
–
–
145.4
136.3
175.6
104.4
159.5
56.8
141.6
136.8
171.2
105.2
157.9
55.7
9.52 (s)
8.57 (s)
–
–
–
–
–
–
5-OMe 3.87 (s)
3.80
6
6.46 (d)
10.23 (s)
–
6.45 (s)
10.53 (s)
–
96.2
95.4
7
8
160.5
106.0
155.6
122.0
129.5
114.5
158.7
–
159.5
106.8
155.4
122.3
128.6
115.4
158.5
–
8a
1Ј
2Ј
3Ј
4Ј
–
–
–
–
8.05 (d)
7.06 (d)
–
7.99 (d)
6.92 (d)
–
4Ј-OH
5Ј
6Ј
1ЈЈ
2ЈЈ
3ЈЈ
4ЈЈ
5ЈЈ
10.69 (s)
7.06 (d)
8.05 (d)
3.46 (d)
5.18 (t)
–
9.94 (s)
6.92 (d)
7.99 (d)
3.46 (d)
5.18 (t)
–
114.5
129.5
21.6
115.4
128.6
21.4
123.0
131.4
25.8
122.7
130.9
25.4
1.63 (s)
1.75 (s)
1.63 (s)
1.76 (s)
18.3
17.8
reaction by TLC to avoid concomitant cyclization to 2. In- Table 2. Comparison of the NMR spectroscopic data of natural
and synthetic flavonoid 2.
deed, heating 12 at pH 3–5 largely resulted in the cyclized
product. Alternatively, lowering the pH to slightly less than
1 and avoiding elevated temperature by stirring at room
temperature for 2 h allowed the gradual removal of the
MOM groups without cyclization. After aqueous work-up
and purification by silica gel flash column chromatography,
we obtained sophoflavescenol (1). The optimized yield for
this step was 72%, and the overall yield for the entire 10-
step synthesis became about 23%. The prenyl group in com-
pound 1 underwent cyclization with the neighbouring
hydroxy group upon treatment with H2SO4 (20% aq.) in
CH3OH to give flavenochromane C (2) as shown by the
characteristic NMR signals at δ = 1.83 and 2.82 (2 t, 4 H,
J = 6.7 Hz, –CH2–), and 1.33 [s, 6 H, (CH3)2C=] ppm. Re-
moval of the MOM protecting group of 11 to give 8-prenyl-
kaempferol (13) was achieved using same conditions as
were used for the synthesis of 1 from 12. Compound 13
underwent acid-catalysed cyclization to give 14, under the
same conditions as were used for the conversion of 1 into
2. Compound 14 was subjected to dehydrogenation with
DDQ to give another natural product, citrusinol (3). The
spectra and melting point of synthetic 3 were identical to
those of 3 obtained from Citrus nobilis.[14] The overall yield
Position Synthesized Natural
compound compound
Synthesized Natural
compound compound
δH [ppm]
δH [ppm]
δC [ppm]
δC [ppm]
2
3
4
4a
5
–
–
–
–
–
145.9
141.8
137.3
171.1
105.7
158.1
55.9
8.70 (s, OH) 136.8
–
–
–
175.1
105.2
159.3
56.6 (s)
98.8
5-OMe 3.83 (s)
3.81 (s)
6.33 (s)
–
6
6.28 (s)
–
96.2
7
159.9
102.5
153.8
122.6
128.1
115.3
157.3
–
157.8
100.9
154.9
122.2
128.6
115.5
158.5
–
8
8a
1Ј
–
–
–
–
–
–
2Ј
3Ј
4Ј
8.02 (d)
6.96 (d)
–
8.04 (d)
6.94 (d)
–
4Ј-OH
5Ј
6Ј
1ЈЈ
2ЈЈ
3ЈЈ
4ЈЈ
5ЈЈ
10.23 (s)
6.96 (d)
8.02 (d)
2.82 (t)
1.83 (t)
–
9.97 (s)
6.94 (d)
8.04 (d)
2.87 (t)
1.88 (t)
–
115.3
128.1
16.8
115.5
128.6
16.0
32.4
77.6
31.1
75.9
1.33 (s)
1.33 (s)
1.35 (s)
1.35 (s)
25.6
25.6
26.3
26.3
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V.-S. Nguyen, L.-P. Dong, S.-C. Wang, Q. Wang
FULL PAPER
for 48 h. The reaction mixture was cooled to 0 °C (ice-water bath)
and acidified with HCl (10% aq.). A yellow precipitate formed,
which was collected by filtration, and washed with HCl (10% aq.).
The yellow solid was recrystallized from petroleum ether/EtOAc to
give chalcone 5 (5.36 g, 85%), m.p. 83–85 °C. 1H NMR (400 MHz,
CDCl3): δ = 13.85 (s, 1 H, 2Ј-OH), 7.83 (d, J = 15.2 Hz, 1 H, β-
CH=), 7.71 (d, J = 15.2 Hz, 1 H, α-CH=), 7.46 (d, J = 8.5 Hz, 2
H, 2-H and 6-H), 6.96 (d, J = 8.5 Hz, 2 H, 3Ј-H and 6Ј-H), 6.31
(d, J = 2.1 Hz, 1 H, 3Ј-H), 6.26 (d, J = 2.1 Hz, 1 H, 5Ј-H), 5.28,
5.26, 5.18 (3 s, each 2 H, 3 OCH2O), 3.52, 3.48, 3.42 (3 s, each 3
H, 3 OCH3) ppm. 13C NMR (100 MHz, CDCl3): δ = 192.2, 165.2,
163.5, 161.2, 159.7, 142.2, 129.3, 125.5, 124.8, 115.4, 107.7, 97.2,
95.6, 94.7, 94.3, 94.2, 56.8, 56.5, 56.2 ppm. MS (EI): m/z = 405 [M
+ 1]+.
Table 3. Comparison of the NMR spectroscopic data of natural
and synthetic flavonoid 3.
Position Synthesized Natural
compound compound
Synthesized Natural
compound compound
δH [ppm]
δH [ppm]
δC [ppm]
δC [ppm]
2
3
4
4a
5
5-OH
6
7
8
8a
1Ј
2Ј
3Ј
4Ј-OH
4Ј
5Ј
–
–
–
–
–
–
–
–
146.6
136.3
175.4
103.7
159.2
–
146.3
136.0
175.6
101.2
160.8
–
–
–
12.96 (s)
6.13 (s)
–
–
–
12.30 (s)
6.25 (s)
–
–
–
98.6
98.8
161.8
101.1
151.8
121.5
129.1
115.5
–
158.7
115.5
129.1
114.2
127.1
77.8
159.5
103.8
150.9
122.5
129.6
115.6
–
159.3
115.6
129.6
114.5
127.5
78.1
5,4Ј,7-Trimethoxymethylflavone (6):
A solution of 5 (5.0 g,
–
–
12.37 mmol) and I2 (1.9 g) in DMSO (60 mL) was stirred at reflux
for 24 h. The reaction mixture was cooled to room temperature,
then poured into cold water. Saturated aqueous Na2S2O3 was
added, and the mixture was extracted with dichloromethane. The
organic layer was dried with anhydrous Na2SO4, and the solvent
was removed under reduced pressure. The solid residue was re
8.11 (d)
6.95 (d)
10.53 (s)
–
6.95 (d)
8.11 (d)
6.72 (d)
5.56 (d)
–
8.22 (d)
7.06 (d)
9.14 (s)
–
7.06 (d)
8.22 (d)
6.63 (d)
5.79 (d)
–
6Ј
1ЈЈ
2ЈЈ
3ЈЈ
4ЈЈ
5ЈЈ
crystallized from dichloromethane/petroleum ether to give
6
(3.48 g, 70%) as yellow crystals, m.p. 124–126 °C. 1H NMR
(400 MHz, CDCl3): δ = 7.74 (d, J = 8.8 Hz, 2 H, 2Ј-H and 6Ј-H),
7.05 (d, J = 8.8 Hz, 2 H, 3Ј-H and 5Ј-H), 6.78 (d, J = 2.1 Hz, 1 H,
8-H), 6.67 (d, J = 2.1 Hz, 1 H, 3-H), 6.50 (s, 1 H, 6-H), 5.26, 5.18,
5.16 (3 s, each 2 H, 3 OCH2O), 3.49, 3.44, 3.42 (3 s, each 3 H, 3
OCH3) ppm. 13C NMR (100 MHz, CDCl3): δ = 177.4, 161.2, 160.8,
159.7, 159.3, 158.1, 127.6, 124.8, 116.4, 110.6, 107.7, 101.1, 97.2,
95.6, 94.2, 56.6, 56.5, 56.3 ppm. HRMS (EI): calcd. for C21H22O8
[M]+ 402.1309; found 402.1322.
1.41 (s)
1.41 (s)
1.49 (s)
1.49 (s)
26.9
26.9
28.4
28.4
Conclusion
Sophoflavescenol (1), flavenochromane C (2), and cit-
rusinol (3) are three structurally similar naturally occurring
flavonoids. They have excellent biological activities such as
3-Hydroxy-5,4Ј,7-trimethoxymethylflavone (7): A solution of 6
antitumor, antibacterial, and antifungal properties, or are (3.5 g, 8.70 mmol) in acetone/ CH2Cl2 (3:4; 210 mL) was mixed
with a solution of Na2CO3 (14 g) and NaHCO3 (7 g) in water
(100 mL), and the mixture was vigorously stirred at 0 °C. Then a
solution of Oxone (60 g) in water (200 mL) was added dropwise
over 5 h, and after the addition was complete, the pH of the reac-
tion mixture was adjusted to pH 9. Then the reaction mixture was
stirred for a further 24 h, after which the mixture was extracted
with dichloromethane (3ϫ 30 mL). The combined organic extracts
were washed with saturated NaCl (aq.) and saturated Na2S2O3
(aq.), and dried with anhydrous sodium sulfate, and the solvent
was removed under reduced pressure.
lead compounds for the treatment of erectile dysfunction.
We report here the first total synthesis of these compounds
in 10–11 linear steps and in 16–23% overall yield, starting
from 2,4,6-trihydroxyacetophenone. The assembly of the
8-prenylated flavonoid carbon skeleton was achieved via a
5-O-prenylflavonoid intermediate using a regioselective mi-
crowave-assisted Claisen rearrangement.
Experimental Section
A solution of p-toluensulfonic acid (15 mg) in dry acetone (30 mL)
was added to solid residue, and the resulting mixture was stirred at
room temperature for 30 min. The solvent was removed under re-
duced pressure, and the solid residue was purified by silica gel col-
umn chromatography (petroleum ether/EtOAc, 3:1) to give 7
(2.76 g, 76%) as a yellow solid, m.p. 143–145 °C. 1H NMR
(400 MHz, CDCl3): δ = 8.04 (d, J = 8.6 Hz, 2 H, 2Ј-H and 6Ј-H),
7.02 (d, J = 8.6 Hz, 2 H, 3Ј-H and 5Ј-H), 6.81 (d, J = 1.7 Hz, 1 H,
8-H), 6.73 (d, J = 1.7 Hz, 1 H, 6-H), 5.35, 5.25, 5.20 (3 s, each 2
H, 3 OCH2O), 3.56, 3.51, 3.19 (3 s, each 3 H, 3 OCH3) ppm. 13C
NMR (100 MHz, CDCl3): δ = 172.1, 162.4, 161.2, 158.4, 158.2,
146.1, 137.5, 130.5, 123.7, 114.4, 103.5, 97.6, 96.8, 95.5, 94.4, 92.7,
57.6, 56.5, 55.4 ppm. MS (EI): m/z = 419 [M + 1]+.
General Remarks: Melting points were determined with a XRC-1
1
apparatus. H and 13C NMR spectra were recorded with a Bruker
AV400 instrument, using tetramethylsilane as internal standard.
Chemical shifts (δ) are reported in ppm, and coupling constants
(J) in Hertz (Hz). Mass spectra (MS) and high-resolution mass
spectrometry (HRMS) were determined with VG Autospec-3000
and Mat 95 XP spectrometers using the EI method. For microwave-
assisted synthesis, an XH-MC-1 instrument with power (50–900 W,
2450 MHz) was used. Column chromatography was carried out on
silica gel (200–300 mesh). Commercially available AR grade or
chemically pure reagents were used. Anhydrous solvents were dried
and redistilled. 2-Hydroxy-4,6-bis(methoxymethoxy)acetophenone
(4) was synthesized according to a literature procedure.[10,11]
3,5-Hydroxy-4Ј,7-dimethoxymethylflavone (8):
A solution of 7
2Ј-Hydroxy-4,4Ј,6Ј-trimethoxymethoxylchalcone (5): Potassium (2.5 g, 5.98 mmol) and HCl (3 n aq.; 3 mL) in EtOH (20 mL) was
hydroxide (20% aq.; 20 mL) was added to a stirred solution of 2- stirred at room temperature for 30 min. The mixture was poured
hydroxy-4,6-bis(methoxymethoxy)acetophenone (4.0 g, 15.62 mmol) into ice-water, and extracted with EtOAc (3ϫ 20 mL). The com-
and 4-methoxymethoxybenzaldehyde (2.5 g, 15.62 mmol) in ethanol
(30 mL), and the reaction mixture was stirred at room temperature
bined organic layers were dried with anhydrous Na2SO4, and the
solvent was removed under reduced pressure. The residue was
4
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Sophoflavescenol, Flavenochromane C, and Citrusinol
recrystallized from EtOAc/petroleum ether to give 8 (2.0 g, 89%)
96.8, 94.6, 94.1, 93.6, 56.6, 55.3, 55.2, 25.4, 21.8, 19.4 ppm. MS
1
as a yellow solid, m.p. 154–155 °C. H NMR (400 MHz, CDCl3): (EI): m/z = 487 [M + 1]+. HRMS (EI): calcd. for C26H30O9 [M]+
δ = 11.85 (s, 1 H, 5-OH), 8.07 (d, J = 8.6 Hz, 2 H, 2Ј-H and 6Ј- 486.1890; found 486.1892.
H), 7.12 (d, J = 8.6 Hz, 2 H, 3Ј-H and 5Ј-H), 6.68 (d, J = 1.7 Hz,
7,8-(2,2-Dimethyl-2H-pyran)-5,4Ј-dihydroxyflavonol (12): (CH3)2-
1 H, 8-H), 6.48 (s, 1 H, 6-H), 5.26, 5.18 (3 s, each 2 H, 3 OCH2O),
SO4 (10.53 mmol, 1.0 mL) was added dropwise to a stirred solution
3.51, 3.21 (2 s, 9 H, 3 OCH3) ppm. 13C NMR (100 MHz, CDCl3):
of 11 (500 mg, 1.02 mmol) in NaOH (5% aq.; 15 mL). The reaction
δ = 175.6, 163.3, 161.1, 160.4, 156.7, 146.2, 136.7, 129.8, 123.5,
mixture was stirred at room temperature, and maintained at pH 9–
114.4, 105.1, 98.8, 94.7, 94.4, 93.3, 56.3, 55.6 ppm. MS (EI): m/z =
10 for 5 h. After this time, the reaction mixture was adjusted to pH
375 [M + 1]+.
6 using HCl (2% aq.), and then the mixture was extracted with
ethyl acetate (3ϫ 20 mL). The organic phase was dried with
anhydrous sodium sulfate, and the solvent was removed in vacuo.
The residue was purified by silica gel column chromatography (pe-
troleum ether/EtOAc, 5:1) to give 12 (400 mg, 80%) as a white
3,4Ј,7-Tris-O-methoxymethylkaempferol (9): A solution of 8 (1.5 g,
4.0 mmol) and anhydrous K2CO3 (5 g, 36.2 mmol) in dry acetone
(50 mL) was stirred for 30 min at room temperature. Chloromethyl
methyl ether (0.6 mL, 4.5 mmol) was then added dropwise, and the
reaction mixture was stirred at room temperature for 2 h. The or-
ganic phase was filtered, and the K2CO3 solid residue was washed
with acetone. The solvent was removed under reduced pressure,
and the residue was purified by silica gel column chromatography
(petroleum ether/EtOAc, 7:1) to give 9 (1.38 g, 83%) as a white
1
solid, m.p. 107–109 °C. H NMR (400 MHz, CDCl3): δ = 8.04 (d,
J = 8.7 Hz, 2 H, 2Ј-H and 6Ј-H), 7.01 (d, J = 8.7 Hz, 2 H, 3Ј-H
and 5Ј-H), 6.35 (s, 1 H, 6-H), 5.41 (t, J = 5.5 Hz, 1 H, 2ЈЈ-H), 5.35,
5.25, 5.20 (3 s, each 2 H, 3 OCH2O), 3.79 (s, 3 H, 5-OCH3), 3.56,
3.51, 3.19 (3 s, each 3 H, 3 OCH3), 3.11 (d, J = 5.3 Hz, 1 H, 1ЈЈ-
H), 1.72 (s, 3 H, 4ЈЈ-CH3), 1.63 (s, 3 H, 5ЈЈ-CH3) ppm. 13C NMR
(100 MHz, CDCl3): δ = 176.2, 163.4, 161.8, 159.6, 158.5, 146.1,
137.5, 130.5, 128.6, 123.2, 120.3, 113.7, 108.8, 104.6, 97.6, 96.9,
95.9, 94.4, 57.8, 56.7, 56.4, 55.8, 25.7, 22.4, 19.0 ppm. MS (EI): m/z
= 501 [M + 1]+. HRMS (EI): calcd. for C27H32O9 [M]+ 500.2042;
found 500.2046.
1
powder, m.p. 112–115 °C. H NMR (400 MHz, CDCl3): δ = 12.55
(s, 1 H, 5-OH), 8.02 (d, J = 8.8 Hz, 2 H, 2Ј-H and 6Ј-H), 7.15 (d,
J = 8.8 Hz, 2 H, 3Ј-H and 5Ј-H), 6.62 (d, J = 2.0 Hz, 1 H, 8-H),
6.46 (d, J = 2.0 Hz, 1 H, 6-H), 5.25, 5.23, 5.18 (3 s, each 2 H, 3
OCH2O), 3.51, 3.49, 3.21 (3 s, each 3 H, 3 OCH3) ppm. 13C NMR
(100 MHz, CDCl3): δ = 177.9, 164.2, 161.8, 158.6, 158.4, 146.7,
136.5, 131.4, 124.2, 116.2, 105.5, 101.6, 98.8, 95.8, 94.3, 94.2, 56.8,
56.5, 54.5 ppm. MS (EI): m/z = 419 [M + 1]+.
Sophoflavescenol (1): Compound 12 (250 mg, 0.51 mmol) was dis-
solved in EtOH (15 mL) and HCl (3 m aq.; 2.5 mL), and the reac-
tion mixture was stirred for 2 h. Then the mixture was poured into
ice-water, and extracted with EtOAc (3ϫ 20 mL). The combined
organic phases were dried with anhydrous Na2SO4, and the solvent
was evaporated in vacuo. The solid residue was recrystallized from
EtOAc/petroleum ether to give 1 (181 mg, 96%) as yellow needles,
m.p. 272–274 °C (ref.[15] 273–275 °C). 1H NMR (400 MHz, [D6]-
DMSO): δ = 10.69 (s, 1 H, 4Ј-OH), 10.23 (s, 1 H, 7-OH), 9.52 (s,
1 H, 3-OH), 8.05 (d, J = 8.5 Hz, 2 H, 2Ј-H and 6Ј-H), 7.06 (d, J =
8.6 Hz, 2 H, 3Ј-H and 5Ј-H), 6.46 (d, J = 2.2 Hz, 1 H, 6-H), 5.18
(t, J = 6.2 Hz, 1 H, 2ЈЈ-H), 3.87 (s, 3 H, 5-OCH3), 3.46 (d, J =
6.1 Hz, 2 H, 1ЈЈ-H), 1.75 (s, 3 H, 4ЈЈ-CH3), 1.63 (s, 3 H, 5ЈЈ-CH3)
ppm. 13C NMR (100 MHz, [D6]DMSO): δ = 175.6, 160.5, 159.5,
158.7, 155.6, 145.4, 136.3, 131.4, 129.5, 123.0, 122.0, 114.5, 106.0,
104.4, 96.2, 56.8, 25.8, 21.6, 18.3 ppm. MS (EI): m/z = 369 [M +
1]+. HRMS (EI): calcd. for C21H20O6 [M]+ 368.1262; found
368.1254.
5-O-Prenyl-3,4Ј,7-tris-O-methoxymethylkaempferol (10): A solution
of 9 (1.2 g, 2.87 mmol) and anhydrous K2CO3 (5 g, 36.2 mmol) in
dry acetone (50 mL) was stirred at room temperature for 1 h, then
prenyl bromide (0.5 mL, 6.99 mmol) was added dropwise. The mix-
ture was stirred at 50 °C for 5 h. After this time, the mixture was
cooled to room temperature, and filtered. The filter residue was
washed with acetone, and the solvent was evaporated from the
combined filtrates. The crude product was purified by silica gel
column chromatography (petroleum ether/EtOAc, 3:1) to give 10
(1.33 g, 95%) as a white solid, m.p. 67–69 °C. 1H NMR (400 MHz,
CDCl3): δ = 7.75 (d, J = 8.5 Hz, 2 H, 2Ј-H and 6Ј-H), 7.63 (d, J =
8.5 Hz, 2 H, 3Ј-H and 5Ј-H), 6.56 (d, J = 1.9 Hz, 1 H, 8-H), 6.36
(d, J = 1.9 Hz, 1 H, 6-H), 5.48 (t, J = 6.1 Hz, 1 H, 2ЈЈ-H), 5.17,
5.15, 5.11 (3 s, each 2 H, 3 OCH2O), 4.63 (d, J = 6.1 Hz, 2 H, 1ЈЈ-
H), 3.46, 3.44, 3.15 (3 s, each 3 H, 3 OCH3), 1.71 (s, 3 H, 4ЈЈ-CH3),
1.65 (s, 3 H, 5Ј-CH3) ppm. 13C NMR (100 MHz, CDCl3): δ =
175.2, 163.5, 162.3, 160.4, 156.0, 145.4, 138.0, 136.3, 129.9, 127.8,
121.8, 116.7, 111.0, 98.9, 96.6, 94.6, 94.1, 93.3, 66.5, 56.5, 55.4,
55.3, 26.5, 19.9 ppm. MS (EI): m/z = 487 [M + 1]+.
8-Prenylkaempferol (13): A solution of 11 (300 mg, 0.6 mmol) and
HCl (3 m aq.; 3 mL) in CH3OH (20 mL) was stirred at reflux for
2 h. After this time, the mixture was cooled to room temperature,
and poured into ice-water. A yellow precipitate was formed, which
was collected by filtration. The yellow solid was recrystallized from
petroleum ether/EtOAc to give 13 (203 mg, 96%) as a pale yellow
5-Hydroxy-8-prenyl-3,4Ј,7-tris-O-methoxymethylkaempferol (11): A
solution of 10 (1.0 g, 2.05 mmol) in dry N,N-diethylaniline (15 mL)
was stirred under microwave irradiation (700 W) under a nitrogen
atmosphere at 190 °C for 45 min. After this time, the reaction mix-
ture was cooled to room temperature and acidified with HCl (1 m
aq.; 15 mL). The mixture was extracted with dichloromethane, the
organic phase was dried with anhydrous Na2SO4, and the solvent
was evaporated. The solid residue was purified by silica gel
chromatography (petroleum ether/EtOAc, 7:1) to give 11 (0.82 g,
82%) as a white solid, m.p. 115–117 °C. 1H NMR (400 MHz,
CDCl3): δ = 11.96 (s, 1 H, 5-OH), 7.82 (d, J = 8.5 Hz, 2 H, 2Ј-H
and 6Ј-H), 7.63 (d, J = 8.5 Hz, 1 H, 3Ј-H and 5Ј-H), 6.36 (s, 1 H,
1
solid, m.p. 224–225 °C (ref.[16] 226 °C). H NMR (400 MHz, [D6]-
DMSO): δ = 12.48 (s, 1 H, 5-OH), 10.68 (s, 1 H, 4Ј-OH), 10.54 (s,
1 H, 7-OH), 9.59 (s, 1 H, 3-OH), 8.16 (d, J = 8.6 Hz, 2 H, 2Ј-H
and 6Ј-H), 7.14 (d, J = 8.6 Hz, 2 H, 3Ј-H and 5Ј-H), 6.25 (s, 1 H,
6-H), 5.21 (t, J = 5.6 Hz, 1 H, 2ЈЈ-H), 3.45 (d, J = 5.5 Hz, 2 H, 1ЈЈ-
H), 1.73 (s, 3 H, 4ЈЈ-CH3), 1.63 (s, 3 H, 5ЈЈ-CH3) ppm. 13C NMR
(100 MHz, [D6]DMSO): δ = 176.5, 164.3, 161.8, 160.6, 157.7,
146.2, 136.1, 131.9, 128.9, 123.4, 121.6, 116.4, 108.9, 105.1, 99.3,
25.5, 21.7, 19.2 ppm. MS (EI): m/z = 355 [M + 1]+.
6-H), 5.52 (t, J = 6.2 Hz, 1 H, 2ЈЈ-H), 5.24, 5.18, 5.15 (3 s, each 2 Flavenochromane C (2): A solution of 1 (150 mg, 0.40 mmol) in
H, 3 OCH2O), 3.52, 3.48, 3.44 (3 s, each 3 H, 3 OCH3), 3.04 (d, J H2SO4 (20% aq.; 10 mL) and CH3OH (40 mL) was stirred at reflux
= 6.1 Hz, 2 H, 1ЈЈ-H), 1.73 (s, 3 H, 4ЈЈ-CH3), 1.65 (s, 3 H, 5ЈЈ-CH3) for 2 h, then the mixture was poured into ice-water and extracted
ppm. 13C NMR (100 MHz, CDCl3): δ = 176.7, 164.2, 160.2, 159.7,
with EtOAc (3ϫ 20 mL). The combined organic phases were dried
158.6, 146.9, 136.9, 131.6, 128.5, 123.6, 121.6, 114.5, 108.8, 103.5,
with anhydrous Na2SO4, and the solvent was removed in vacuo.
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Job/Unit: O43689
/KAP1
Date: 16-02-15 13:19:42
Pages: 7
V.-S. Nguyen, L.-P. Dong, S.-C. Wang, Q. Wang
FULL PAPER
The residue was purified by silica gel column chromatography (pe- MS (EI): m/z = 353 [M + 1]+. HRMS (EI): calcd. for C20H16O6,
troleum ether/EtOAc, 10:1) to give 2 (126 mg, 86%) as yellow need- [M]+ 352.0947; found 352.0946.
les, m.p. 266–268 °C (ref.[7] 268–270 °C). 1H NMR (400 MHz,
CDCl3): δ = 10.23 (s, 1 H, 4Ј-OH), 8.02 (d, J = 8.9 Hz, 2 H, 2Ј-H
and 6Ј-H), 6.96 (d, J = 8.9 Hz, 2 H, 3Ј-H and 5Ј-H), 6.28 (s, 1 H,
Acknowledgments
6-H), 3.83 (s, 3 H, 5-OCH3), 2.82 (t, J = 6.2 Hz, 2 H, CH2-1ЈЈ),
The authors thank the National Natural Science Foundation of
1.83 (t, J = 6.2 Hz, 2 H, CH2-2ЈЈ), 1.33 (s, 6 H, 4ЈЈ-CH3 and 5ЈЈ-
China (NSFC) (grant numbers J1210040, 21342015) and the Hu-
CH3) ppm. 13C NMR (100 MHz, CDCl3): δ = 175.1, 159.9, 159.3,
nan Provincial Natural Science Foundation of China (grant
157.3, 153.8, 145.9, 136.8, 128.1, 122.6, 115.3, 105.2, 102.5, 98.8,
number 14JJ2048) for financial support.
77.6, 56.6, 32.4, 25.6, 16.8 ppm. MS (EI): m/z = 369 [M + 1]+.
HRMS (EI): calcd. for C21H20O6 [M]+ 368.1261; found 368.1254.
[1] P. Basabe, M. de Román, S. I. Marcos, D. Diez, A. Blanco, O.
4Ј-Desmethyl-β-anhydroicaritin (14): A solution of 13 (180 mg,
0.50 mmol) in H2SO4 (20% aq.; 15 mL) and MeOH (45 mL) was
stirred at reflux for 2 h. Then the mixture was poured into ice-
water, and extracted with EtOAc (3ϫ 20 mL). The combined or-
ganic phases were washed with water, and dried with anhydrous
Na2SO4, and the solvent was removed. The solid residue was puri-
fied by silica gel column chromatography (petroleum ether/EtOAc,
5:1) to give 14 (152 mg, 86%) as yellow needles, m.p. 207–209 °C
Boder, F. Mollinedo, G. B. Sierra, G. J. Urones, Eur. J. Med.
Chem. 2010, 45, 4258–4269.
[2] P. Tiziana, F. Silvia, G. Fravcesca, M. Alberto, G. Giovanni,
L. Grazia, Eur. J. Pharmacol. 2009, 620, 120–130.
[3] X. Dong, Y. Fan, L. Yu, Y. Hu, Arch. Pharmacol. Res. 2007,
340, 372–376.
[4] T. H. Shin, J. K. Kim, H. J. Kwak, O. H. Chun, H. J. Kim, H.
Park, H. D. Kim, S. Y. Lee, Bioorg. Med. Chem. Lett. 2002, 12,
2313–2316.
1
(ref.[17] 209–210 °C). H NMR (400 MHz, [D6]DMSO): δ = 12.93
[5] A. H. Jung, E. S. Jin, J. R. Choi, T. H. Manh, S. Y. Kim, S. B.
Min, K. Y. Son, R. B. Ahn, W. B. Kim, S. S. Sohn, S. J. Choi,
Arch. Pharmacol. Res. 2011, 34, 2087–2099.
(s, 1 H, 5-OH), 10.35 (s, 1 H, 4-OH), 8.03 (d, J = 8.8 Hz, 2 H, 2Ј-
H and 6Ј-H), 6.77 (d, J = 8.8 Hz, 2 H, 3Ј-H and 5Ј-H), 6.24 (s, 1
H, 6-H), 2.84 (t, J = 6.1 Hz, 2 H, 1ЈЈ-H), 1.84 (t, J = 6.1 Hz, 2 H,
2ЈЈ-H), 1.36 (s, 6 H, 4ЈЈ-CH3 and 5ЈЈ-CH3) ppm. 13C NMR
(100 MHz, [D6]DMSO): δ = 174.1, 159.6, 158.3, 157.3, 152.8,
145.0, 136.2, 128.2, 122.6, 115.6, 104.9, 103.2, 96.8, 78.2, 30.7, 26.3,
16.7 ppm. MS (EI): m/z = 355 [M + 1]+. HRMS (EI): calcd. for
C20H18O6 [M]+ 354.1098; found 354.1096.
[6] X. Zhang, Curr. Drug Targets: CNS Neurol. Disord. 2004, 3,
137–152.
[7] P. Ding, F. D. Chen, F. K. Bastow, K. A. Nyarko, X. Wang,
H. K. Lee, Helv. Chim. Acta 2004, 87, 2574–2580.
[8] H. Sasaki, H. Shibata, K. Imabay, Y. Takaishi, Y. Kashiwada,
J. Agric. Food Chem. 2014, 62, 6345–6353.
[9] C. C. Shen, T. S. Wang, Y. S. Tsai, H. C. Yang, J. B. Shieh,
C. C. Chen, J. Nat. Prod. 2005, 68, 791–793.
[10] S. R. Khupse, W. P. Erhardt, J. Nat. Prod. 2007, 70, 1507–1509.
[11] A. Detsi, M. Majdalani, A. K. Kontogiorgis, D. Hadjipavlou-
Litina, P. Kefalas, Bioorg. Med. Chem. 2009, 17, 8073–8085.
[12] Z. Wu, L. S. Cai, J. W. Fan, Q. A. Wang, Chin. J. Org. Chem.
2012, 32, 1296–1302.
[13] J. Yu, J. Cui, C. Zhang, Eur. J. Org. Chem. 2010, 36, 7020–
7026.
[14] S. T. Wu, Phytochemistry 1987, 26, 3094–3095.
[15] R. E. Woo, H. J. Kwak, J. H. Kim, H. Park, J. Nat. Prod. 1998,
61, 1552–1554.
Citrusinol (3): A solution of 14 (120 mg, 0.33 mmol) and DDQ
(110 mg) in dry 1,4-dioxane (15 mL) was heated at 110 °C and
stirred under a nitrogen atmosphere for 24 h. Then the mixture
was cooled to room temperature, and filtered, and the solvent was
removed under reduced pressure. The resulting solid residue was
purified by silica gel chromatography (petroleum ether/EtOAc, 6:1)
to give 3 (88 mg, 76%) as a yellow solid, m.p. 251–253 °C (ref.[14]
1
253–254 °C). H NMR (400 MHz, [D6]DMSO): δ = 12.96 (s, 1 H,
5-OH), 10.53 (s, 1 H, 4Ј-OH), 8.11 (d, J = 8.6 Hz, 2 H, 2Ј-H and
6Ј-H), 6.95 (d, J = 8.6 Hz, 2 H, 3Ј-H and 5Ј-H), 6.72 (d, J = 10 Hz,
1 H, 1ЈЈ-H), 6.13 (s, 1 H, 6-H), 5.56 (d, J = 10 Hz, 1 H, 2ЈЈ-H),
1.41 (s, 6 H, 4ЈЈ-CH3 and 5ЈЈ-CH3) ppm. 13C NMR (100 MHz,
[D6]DMSO): δ = 175.4, 161.8, 159.2, 158.7, 151.8, 146.6, 136.3,
129.1, 127.1, 121.5, 115.5, 114.2, 103.7, 101.1, 98.6, 77.8, 26.9 ppm.
[16] M. Komatsu, T. Tomimori, K. Hatayama, N. Mikuriya, Yaku-
gaku Zasshi 1970, 90, 463–468.
[17] H. X. Zheng, Y. L. Kong, Zhongcaoyao 2002, 33, 964–967.
Received: December 27, 2014
Published Online: ᭿
6
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© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O43689
/KAP1
Date: 16-02-15 13:19:42
Pages: 7
Sophoflavescenol, Flavenochromane C, and Citrusinol
Flavonoids
V.-S. Nguyen, L.-P. Dong, S.-C. Wang,
Q. Wang* .......................................... 1–7
The First Total Synthesis of Sophoflaves-
cenol, Flavenochromane C, and Citrusinol
Keywords: Total synthesis / Natural prod-
ucts / Sigmatropic rearrangement / Cycli-
zation
/ Fused-ring systems / Oxygen
heterocycles
The first total syntheses of sophoflaves-
cenol, flavenochromane C, and citrusinol
were achieved in 23, 17, and 16% yields,
respectively, starting from 2,4,6-trihydroxy-
acetophenone and substituted benzalde-
hydes. The key step was a regioselective
microwave-assisted Claisen rearrangement
to form an 8-prenylated flavonoid from a
5-O-prenylflavonoid.
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
7