Facile total synthesis of xanthotoxol

Article abstract of DOI:10.1080/00397910601038616

Xanthotoxol, a biologically active linear furocoumarin, has been efficiently synthesized from 7-hydroxycoumarin in six steps. The key steps included two efficient rearrangements - Fries rearrangement and Claisen rearrangement - and a Baeyer-Villiger oxidation process. The overall yield of xanthotoxol was 29%. This approach also provided a new strategy to furnish easily furocoumarins with a hydroxyl group in the framework. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397910601038616

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Facile Total Synthesis of Xanthotoxol
a
b
b
a
a
Wei He , Bang‐Le Zhang , Si‐Yuan Zhou , Xiao‐Li Sun & Sheng‐Yong Zhang
a
Department of Chemistry, Fourth Military Medical University, Xi'an, Shaanxi, China
Department of Pharmacology, Fourth Military Medical University, Xi'an, Shaanxi, China
b
Published online: 06 Feb 2007.
To cite this article: Wei He , Bang‐Le Zhang , Si‐Yuan Zhou , Xiao‐Li Sun & Sheng‐Yong Zhang (2007): Facile Total Synthesis of
Xanthotoxol, Synthetic Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry,
37:3, 361-367
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Synthetic Communications , 37: 361–367, 2007
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910601038616
Facile Total Synthesis of Xanthotoxol
Wei He
Department of Chemistry, Fourth Military Medical University, Xi’an,
Shaanxi, China
Bang-Le Zhang and Si-Yuan Zhou
Department of Pharmacology, Fourth Military Medical University, Xi’an,
Shaanxi, China
Xiao-Li Sun and Sheng-Yong Zhang
Department of Chemistry, Fourth Military Medical University, Xi’an,
Shaanxi, China
Abstract: Xanthotoxol, a biologically active linear furocoumarin, has been efficiently
synthesized from 7-hydroxycoumarin in six steps. The key steps included two efficient
rearrangements—Fries rearrangement and Claisen rearrangement—and a Baeyer–
Villiger oxidation process. The overall yield of xanthotoxol was 29%. This approach
also provided a new strategy to furnish easily furocoumarins with a hydroxyl group
in the framework.
Keywords: Baeyer–Villiger oxidation, Claisen rearrangement, Fries rearrangement,
furocoumarins, total synthesis, xanthotoxol
INTRODUCTION
Xanthotoxol (1) is a natural furocoumarin that occurs in a large number of
[1]
plants. It exhibits a wide range of biological properties, such as antioxidative
[4]
[
activity, 5-HT antagonistic effect, and central nervous system activity.
2]
[3]
Received in Japan April 3, 2006
Address correspondence to Sheng-Yong Zhang, Department of Chemistry, Fourth
Military Medical University, Xi’an, Shaanxi 710032, China. E-mail: syzhang@
fmmu.edu.cn
3
61

3
62
W. He et al.
Recently, it was reported that xanthotoxol had a cytotoxic effect on transitional
[
cell carcinoma (TCTC) cells, and they could be used as biological probes to
5]
[6]
investigate the structure and function of nucleic acid in molecular biology.
Besides the isolation from natural sources, the preparation of xanthotoxol
was often established by a semisynthetic method from xanthotoxin (Fig. 1),
[7]
which is also a natural product usually isolated from some plants.
Although several approaches for the O-demethylation of xanthotoxin
[
6a]
[6b]
have been described in the literature, such as pyridine–HCl,
[
BBr3,
the difficulties obtaining natural xantho-
8a]
[8b]
[8c]
Mg/I2,
Me SiI,
3
and AlCl3,
toxin have limited the application of xanthotoxol. In the context of our conti-
nuing interest in the important biological properties of furocoumarins, we
report herein an efficient strategy for the total synthesis of xanthotoxol.
RESULTS AND DISCUSSION
The general approach to synthesize xanthotoxol is outlined in Scheme 1. At
first, commercially available 7-hydroxycoumarin was easily converted into
7-acetoxycoumarin 2 by acetylation in 98% yield. Acetyl migration was
carried out under Fries rearrangement with AlCl as usual to predominately
3
[9]
afford isomer 8-acetyl-7-hydroxycoumarin 3 in 72% yield.
When
refluxed overnight in acetone, compound 3 was then converted into the
desired allyl ether 4 in 96% yield by an allylation reaction with allyl
bromide in the presence of anhydrous K CO . The Claisen rearrangement
2
3
of 4 was performed in refluxing N,N-diethylaniline and allowed for
isolation of pure 5 in 73% yield. With 6-allyl derivative 5 in hand, the furo-
[
10]
coumarin 6
could be obtained through an oxidation reaction with
osmium tetroxide–potassium periodate and cyclization with a phosphoric
acid sequence in one pot in 71% yield.
It is well known that aryl ketone derivatives can be easily converted to
[9]
phenolic derivatives by the Baeyer–Villiger oxidation. When 6 is trans-
formed by the usual oxidation procedure, 30% H O in 2 M NaOH, the
2
2
desired title compound xanthotoxol 1 was isolated in 82% yield. All the
compounds mentioned previously were consistent with the structures
1
described in Scheme 1 and have been confirmed by melting point, IR, H
NMR, MS, or elemental analysis.
Figure 1. Structures of xanthotoxin and xanthotoxol.

Total Synthesis of Xanthotoxol
363
Scheme 1. Route for synthesis of Xanthoxol. Reagents and conditions: (i) Ac
pyridine, rt, 24 h; (ii) AlCl , 1608C, 2 h; (iii) allyl bromide, K CO , adcetone, refluing
overnight; (iv) N,N-diethylaniline, refluing 3.5 h; (v) (1) KIO , cat. OsO , MeOH-H O,
2
O,
3
2
3
4
4
2
3 4 2 2
rt, 16 h; (2) 85%H PO , 0.5 h; and (vi) H O , NaOH.
In conclusion, a facile, efficient method for the total synthesis of xantho-
toxol has been demonstrated. This process has afforded concise synthesis of
xanthotoxol through six steps in 29% overall yield. In addition to providing
the desired xanthotoxol for biological activity testing, this approach also
allows the generation of new furocoumarin derivatives for drug research.
Syntheses of these natural-product-like compounds are under investigation
in our research group.
EXPERIMENTAL
Melting points are uncorrected. Infrared spectra were recorded with KBr disks
on Nicolet Magna 750 spectrometer and only characteristic absorptions were
reported. NMR spectra were recorded on Bruker AM-400 spectrometer, using
tetramethylsilane as the internal standard. Mass spectra were performed on a
Varian MAT-711 spectrometer. Element analyses were obtained using a Foss-
Heraeus Vario EL instrument. All the solvents and chemicals were obtained
from commercial sources and were used without further purification unless
otherwise stated.
7
-Acetoxycoumarin, 2
Acetic anhydride (2.8 mL, 30 mmol) was added to a chilled, stirred solution of
-hydroxycoumarin (2.43 g, 15 mmol) in pyridine (40 mL) at such a rate as to
7
keep the temperature below 208C. After stirring at room temperature for 24 h,
the reaction mixture was poured into ice water and then extracted with EtOAc
(
3 ꢀ 50 mL). The combined organic layer was washed with 5% HCl and
brine. After drying over anhydrous sodium sulfate and evaporating in
vacuo, the residue was flash chromatographed using petroleum ether and
acetone (4:1, v/v) as eluent to afford 7-acetoxycoumarin (3.02 g, yield 98%).

3
64
W. He et al.
[
9]
1
Mp 142 2 1438C [lit. yield 97%; mp 143 2 1458C]. H NMR (400 M,
CDCl ) d 7.74 (d, J ¼ 9.4 Hz, 1H), 7.52 (d, J ¼ 8.2 Hz, 1H), 7.12 (s, 1H),
3
1
3
7
.10 (d, J ¼ 8.2 Hz, 1H), 6.43 (d, J ¼ 9.4 Hz, 1H), 2.33 (s, 3H); C NMR
(
100 M, CDCl ) d 169.2, 160.9, 155.2, 153.6, 143.4, 129.0, 119.6, 117.1,
3
þ
1
16.5, 110.9, 21.6; EI-MS m/z (%) 204 (M , 100), 162 (70), 105 (25); IR
21
KBr): 1751, 1742, 1615, 1204, 746 cm .
(
Fries Rearrangement for the Synthesis of 8-Acetyl-
-hydroxycoumarin, 3
7
The mixture of compound 2 (2.65 g, 13 mmol) and anhydrous aluminium
chloride (6.40 g, 48 mmol) was heated to 1608C and stirred for 2 h at the
same temperature. When the reaction mixture was cooled to room temperature,
5% HCl (30 mL) was added. The resulted mixture was stirred for 1 h at room
temperature and then heated under a steam bath for another 0.5 h. The
solution was cooled and extracted with EtOAc. The combined organic layer
was washed with brine and dried over anhydrous sodium sulfate. After evapo-
rating in vacuo, the residue was purified by flash chromatograph using petroleum
ether and acetone (5:1, v/v) as eluent to give 1.92 g of product (yield 72%). Mp
[
9]
1
1
1
66–1678C [lit. yield 79%; mp 165 2 1678C]. H NMR (400 M, CDCl ) d
3
3.65 (s, 1H), 7.65 (d, J ¼ 9.4 Hz, 1H), 7.52 (d, J ¼ 8.8 Hz, 1H), 6.90
1
3
(
CDCl ) d 200.1, 162.2, 161.1, 151.4, 143.6, 133.2, 118.2, 115.3, 111.4, 111.3,
d, J ¼ 8.8 Hz, 1H), 6.28 (d, J ¼ 9.4 Hz, 1H), 2.97 (s, 3H); C NMR (100 M,
3
þ
3
C H O : C, 64.71; H, 3.95; found: C, 64.74; H, 3.90. IR (KBr): 3161, 1720,
1.4; EI-MS m/z (%) 204 (M , 100), 161 (55), 105 (30); anal. calcd. for
1
1 8 4
21
21
632, 1205, 764 cm ; IR (KBr): 1738, 1721, 1380, 752 cm .
1
8-Acetyl-7-allyloxycoumarin, 4
A mixture of 3 (1.60 g, 8 mmol), allyl bromide (4.0 mL), and anhydrous
potassium carbonate (3.30 g, 24 mmol) in acetone (80 mL) was stirred and
refluxed overnight under N . After cooling to room temperature, the reaction
2
mixture was filtered, washed with acetone, and concentrated to dryness in
vacuo. The crude product was purified by flash chromatography on silica gel
(
eluent: petroleum ether–acetone ¼ 3:1, v/v) to afford 4 (1.87 g, yield 96%).
1
Mp 89 2 908C; H NMR (400 M, CDCl ) d 7.62 (d, J ¼ 9.6 Hz, 1H), 7.43
3
(
(
(
d, J ¼ 9.0 Hz, 1H), 6.86 (d, J ¼ 9.0 Hz, 1H), 6.27 (d, J ¼ 9.6 Hz, 1H), 6.01
1
3
m, 1H), 5.42–5.30 (m, 2H), 4.65 (d, J ¼ 5.1 Hz, 2H), 2.61 (s, 3H); C NMR
100 M, CDCl ) d 199.9, 161.0, 158.2, 151.4, 143.4, 133.4, 132.9, 118.1,
3
þ
1
15.1, 113.5, 111.3, 110.4, 69.6, 31.2; EI-MS m/z (%) 244 (M , 100), 215
(
C, 68.86; H, 4.91. IR (KBr): 3161, 1720, 1632, 1205, 764 cm ; IR (KBr):
45), 201 (35), 189 (85); anal. calcd. for C H O : C, 68.85; H, 4.95; found:
14 12 4
21
21
742, 1708, 1645, 758 cm .
1

Total Synthesis of Xanthotoxol
365
Claisen Rearrangement for the Synthesis of 8-Acetyl-6-allyl-
7
-hydroxycoumarin, 5
A solution of 4 (1.22 g, 5 mmol) in N,N-diethylaniline (5 mL) was heated
under refluxing for 3.5 h. After cooling to room temperature, EtOAc
(100 mL) was added, and the mixture was washed several times with 0.5 M
HCl and then brine. After drying over anhydrous sodium sulfate, the
organic phase was evaporated in vacuo. The crude product was purified by
flash chromatography on silica gel to furnish 5 (0.89 g, yield 73%). Mp
1
1
30 2 1328C; H NMR (400 M, CDCl ) d 13.00 (s, 1H), 7.80 (s, 1H), 7.64
3
(
(
d, J ¼ 9.6 Hz, 1H), 6.32 (d, J ¼ 9.6 Hz, 1H), 5.99 (m, 1H), 5.15 ꢀ 5.01
1
3
m, 2H), 3.62 (d, J ¼ 5.6 Hz, 2H), 2.69 (s, 3H); C NMR (100 M, CDCl )
3
d 200.1, 161.7, 161.1, 146.2, 144.5, 137.2, 132.7, 125.2, 118.2, 116.9,
1
þ
14.6, 111.7, 39.2, 30.2; EI-MS m/z (%) 244 (M , 100), 201 (25), 189
25); anal. calcd for C H O : C, 68.85; H, 4.95; found: C, 68.80; H, 4.92.
(
IR (KBr): 3161, 1720, 1632, 1205, 764 cm ; IR (KBr): 3340, 1720, 1612,
14 12 4
2
1
2
1
1
204 cm
.
9
-Acetyl-7H-furo[3,2-g]chromen-7-one, 6
A solution of osmium tetroxide (7 mg) in water (3 mL) was added to a vigo-
rously stirred mixture of potassium periodate (1.24 g, 5.8 mmol) and 5 (0.7 g,
2
.9 mmol) in methanol (20 mL). After stirring for 16 h, the mixture was
diluted with dichloromethane and washed with saturated brine. The dichloro-
methane layer was dried over sodium sulfate and evaporated in vacuo.
Without further purification of the residue, 85% phosphoric acid (10 mL)
was added, and the mixture was heated on a steam bath with stirring for
0
.5 h. When cooling to room temperature, the mixture was poured into
water and extracted three times with EtOAc. After drying over anhydrous
sodium sulfate and evaporating in vacuo, the residue was purified by flash
chromatography on silica gel to afford the product 0.46 g (yield 71%). Mp
[
10]
1
2
06 2 2088C [lit.
mp 207 2 2088C].; H NMR (400 M, CDCl ) d 7.79
3
(
d, J ¼ 9.0 Hz, 1H), 7.73 (s, 1H), 7.70 (d, J ¼ 2.2 Hz, 1H), 6.81 (d,
1
3
J ¼ 2.2 Hz, 1H), 6.30 (d, J ¼ 9.0 Hz, 1H), 2.79 (s, 3H); C NMR
(100 M, CDCl ) d 201.0, 161.8, 161.1, 147.1, 146.9, 144.3, 125.3, 122.4,
3
þ
1
14.6, 114.1, 113.2, 107.0, 29.3; EI-MS m/z (%) 228 (M , 100), 144
10), 115 (25); anal. calcd. for C H O : C, 68.42; H, 3.53; found: C, 68.36;
(
H, 3.60. IR (KBr): 3161, 1720, 1632, 1205, 764 cm
13 8 4
21
.
Baeyer–Villiger Oxidation for the Synthesis of Xanthotoxol, 1
A suspension of 6 (0.45 g, 2 mmol) in 2 M NaOH (10 mL) and dioxane
(15 mL) was heated for 10 min and then cooled to 08C in an ice bath.

3
66
W. He et al.
Aqueous H O (30%, 15 mL) was added dropwise within 30 min. The
2
2
resulting solution was stirred until the reaction was complete (about 2 h,
thin-laser chromatography: petroleum ether–acetone 2:1). The reaction was
quenched at 08C by the addition of 2 M HCl, and the aqueous mixture was
extracted three times with EtOAc. The combined extracts were dried over
sodium sulfate and evaporated in vacuo. The residue was purified by flash
chromatography on silica gel (eluent: petroleum ether–acetone 3:1) to afford
the title compound (0.33 g) in 82% yield. mp 242 2 2438C (crystallization in
[
6b]
1
acetone) [lit.
244 2 2468C]; H NMR (400 M, CDCl ) d 7.81 (d,
3
J ¼ 9.8 Hz, 1H), 7.72 (d, J ¼ 2.2 Hz, 1H), 7.28 (s, 1H), 6.83 (d, J ¼ 2.2 Hz,
1
3
1
1
H), 6.38 (d, J ¼ 9.8 Hz, 1H), 6.20 (s, br, 1H); C NMR (100 M, CDCl ) d
3
60.1, 147.4, 145.4, 145.3, 139.9, 130.3, 125.4, 116.4, 113.9, 110.2, 107.1; EI-
þ
MS m/z (%) 202 (M , 100), 174 (70), 157 (30), 146 (10); anal. calcd. for
C H O : C, 65.35; H, 2.99; found: C, 65.36; H, 3.03. IR (KBr): 3341, 1712,
1
1 6 4
21
629, 1235, 765 cm .
1
ACKNOWLEDGMENT
Financial support of the National Natural Science Foundation of China (No.
20372083) and the Natural Science Foundation of Shaanxi Province
(
2002B20) are gratefully acknowledged.
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