Synthesis of purpurasol, a highly oxygenated coumarin from Pterocaulon purpurascens

Article abstract of DOI:10.1016/j.tet.2006.02.055

Purpurasol 1, a 6,7,8-trioxygenated coumarin, isolated from Pterocaulon purpurascens (Asteraceae) and Haplophyllum obtusifolium (Rutaceae), was synthesized for the first time by a three-step synthesis starting from the natural coumarin fraxetin. This synthesis confirmed unambiguously the structure of purpurasol 1 and obtusifol.

Full text of DOI:10.1016/j.tet.2006.02.055

Tetrahedron 62 (2006) 4426–4429
Synthesis of purpurasol, a highly oxygenated coumarin
from Pterocaulon purpurascens
Dominick Maes,a Kris Van Syngel,a Silvia Debenedettib and Norbert De Kimpea,
*
aDepartment of Organic Chemistry, Faculty of Bioscience Engineering, Ghent University, Coupure Links 653, B-9000 Ghent, Belgium
bDepartment of Biological Sciences, Faculty of Sciences, National University of La Plata, Calle 115 and 47, 1900 La Plata, Argentina
Received 23 January 2006; revised 13 February 2006; accepted 20 February 2006
Abstract—Purpurasol 1, a 6,7,8-trioxygenated coumarin, isolated from Pterocaulon purpurascens (Asteraceae) and Haplophyllum
obtusifolium (Rutaceae), was synthesized for the first time by a three-step synthesis starting from the natural coumarin fraxetin.
This synthesis confirmed unambiguously the structure of purpurasol 1 and obtusifol.
q 2006 Elsevier Ltd. All rights reserved.
1. Introduction
The genus Pterocaulon is widely distributed in north eastern
Argentina, southern Brazil and Paraguay. Plants of this
genus are traditionally used in folk medicine for various
purposes. The aerial parts of Pterocaulon purpurascens are
used against snakebites and as an insecticide.1,2 A number
of strongly related tri- and tetraoxygenated coumarins were
isolated from P. purpurascens, more precisely purpurenol
2,1 purpurasol 12 and purpurasolol 3.3 Isopurpurasol 4, a
regioisomer of purpurasol, was isolated from another
Pterocaulon species, namely Pterocaulon virgatum.4 All
these coumarins show a characteristic benzodioxine moiety,
which is very rare in natural coumarins.5 The present report
deals with the synthesis of purpurasol 1 in order to secure
unambiguously its structure and those of analogous
coumarins 2 and 3. The structure of purpurasol 1 was
revealed based on spectroscopic data and by comparison
with the earlier described purpurenol, of which the structure
was unequivocally established based on X-ray spectro-
scopic analysis.1 Later it was discovered that the spectro-
scopic, as well as the physical data obtained for purpurasol
1, matched completely with those from an earlier described
coumarin from Haplophyllum obtusifolium.6,7 The structure
of this coumarin, which was given the trivial name
obtusifol, was first proposed as 5,6 but was later revised to
6.7,8 Based on spectroscopic evidence it was shown that the
coumarin from H. obtusifolium was identical to purpurasol
1.9 In order to confirm this hypothesis, a synthesis of
2. Results and discussion
purpurasol was developed.
Purpurasol 1 was synthesized starting from 7,8-dihydroxy-
6-methoxy-2H-1-benzopyran-2-one, known as fraxetin 7.
Fraxetin 7 is a natural coumarin that occurs in many plant
Keywords: Coumarin; Purpurasol; Pterocaulon purpurascens.
*
Corresponding author. Tel.: C32 9 264 59 51; fax: C32 9 264 62 43;
e-mail: norbert.dekimpe@ugent.be
0040–4020/$ - see front matter q 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2006.02.055

D. Maes et al. / Tetrahedron 62 (2006) 4426–4429
4427
species, including Aesculus turbinate (Hippocastanacea)10
and several Fraxinus spp. (Oleaceae).11,12 Fraxetin 7 was
also isolated from P. purpurascens,3 which indicates that
fraxetin 7 might be a natural precursor in the biosynthesis of
purpurasol. The first synthetic step involved regioselective
prenylation of fraxetin. Because of delocalization towards
the electron withdrawing carbonyl group, the 7-OH group is
of 7-(2,3-epoxy-3-methylbutoxy)-8-hydroxy-6-methoxy-
coumarin 10 was obtained. Cyclisation of epoxide 10 to
purpurasol 1 was accomplished by treating it with potassium
carbonate in ethyl acetate, affording purpurasol 1 in 79%
yield. Purpurasol 1 could also be obtained in one step from
capensin 8 by reaction with 3-chloroperbenzoic acid in ethyl
acetate for 48 h, affording purpurasol 1 in 68% yield.
3. Experimental
3.1. General
more acidic than the OH group at the 8-position. Although
selective prenylation of fraxetin 7 was described before in
70% yield using sodium bicarbonate and 4-bromo-2-
methyl-2-butene,13 in our hands only, and after numerous
experiments under these and other reaction conditions, very
low 0yields of the desired capensin 8 [8-hydroxy-6-methoxy-
7-(3 -methyl-20-butenyloxy)coumarin] were obtained. This
problem of reproducibility is probably due to hydrolysis
during aqueous workup. However, when the workup only
consisted of the filtration of the reaction mixture, followed
by rinsing the filter with dry acetone, the obtained
yields were also very low. These low yields demanded
for further evaluation of the reaction conditions. Much
better results were obtained when the reaction was
performed with triethylamine as a base. When fraxetin 7
was reacted with 2 equiv of prenylbromide and 2 equiv of
triethylamine at room temperature for 24 h, the desired
product, capensin 8 [8-hydroxy-6-methoxy-7-(30-methyl-20-
butenyloxy)coumarin] was isolated in 62%0 yield. The
regioisomeric 7-hydroxy-6-methoxy-8-(3 -methyl-20-
butenyloxy)coumarin 9 was isolated in 12% yield. In this
reaction, purification was achieved by evaporating acetone
from the reaction mixture and purifying the residual crude
mixture by column chromatography. Capensin 8 is a
naturally occurring coumarin and was isolated from several
plant species, including Phyllosma capensis14 and
Bupleurum fruticosum.15 To our knowledge 7-hydroxy-6-
methoxy-8-(30-methyl-20-butenyloxy)coumarin 9 has never
been reported from natural sources. The next step in the
synthesis involved the epoxidation of the double bond of the
prenyl group of capensin 8. When capensin 8 was treated
with 3-chloroperbenzoic acid in ethyl acetate, after 8 h 63%
1H NMR spectra (300 MHz) and 13C NMR spectra
(75 MHz) were recorded with a Joel Eclipse FT 300 NMR
spectrometer. IR spectra were recorded on a Perkin Elmer
Spectrum One spectrophotometer. Mass spectra were
recorded on an Agilent 1100 Series VL mass spectrometer
(ES 70 eV) or on a Varian MAT 112 mass spectrometer (EI
70 eV). Melting points were measured with a Bu¨chi B-450
apparatus. Elemental analyses were measured with a Perkin-
Elmer 2400 Elemental Analyzer. Flash chromatography
was performed with ACROS silica gel (particle size 0.035–
0.070 mm, pore diameter ca. 6 nm) using a glass column.
7,8-Dihydroxy-6-methoxycoumarin was obtained from
Aldrich Chemical Company. All other reagents were
obtained from Acros Organics and were used as such,
except for 3-chloroperbenzoic acid. 3-Chloroperbenzoic
acid (%77%, remainder 3-chlorobenzoic acid and water)
was obtained from Acros Organics and was kept under
reduced pressure (5 mmHg) at room temperature for 3 h in
order to remove most of the water.
3.2. Synthetic procedures
3.2.1. 8-Hydroxy-6-methoxy-7-(30-methyl-20-butenyloxy)-
coumarin (capensin) 8 and 7-hydroxy-6-methoxy-8-
(30-methyl-20-butenyloxy)coumarin 9. 7,8-Dihydroxy-6-
methoxycoumarin 7 (208 mg, 1 mmol) was dissolved in
10 ml acetone, and 202 mg (2 mmol) of triethylamine and
298 mg (2 mmol) of 4-bromo-2-methyl-2-butene were added.

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D. Maes et al. / Tetrahedron 62 (2006) 4426–4429
After stirring at room temperature for 24 h, the acetone was
evaporated in vacuo and the residue was chromatographed
over silica gel using 40% hexane, 50% diethyl ether and 10%
tetrahydrofuran as mobile phase. This procedure yielded 62%
(172 mg) of 8-hydroxy-6-methoxy-7-(30-methyl-20-butenyl-
oxy)coumarin (capensin) 8 (RfZ0.23) and 12% (21 mg)
7-hydroxy-6-methoxy-8-(30-methyl-20-butenyloxy)coumarin
9 (RfZ0.14), both appearing as a yellow powder.
7.62 (1H, d, 4-CH). 13C NMR (75 MHz, CDCl3): d 18.7 en
24.6 (2!CH3); 56.1 (OCH3); 59.3 (30-Cq); 61.5 (20-CH);
72.1 (10-CH2); 99.7 (5-CH); 114.6 (Cq); 115.2 (3-CH);
138.0 (2!Cq); 138.3 (Cq); 143.8 (4-CH); 149.8 (6-Cq);
160.6 (C]O). MS (70 eV, EI, m/z (%)): 292 (MC, 16); 208
(100); 193 (15); 139 (20); 85 (75); 83 (17); 71 (52); 69 (64);
55 (32); 49 (16); 43 (73).
3.2.3. Purpurasol 1.
8-Hydroxy-6-methoxy-7-(30-methyl-20-butenyloxy)-
coumarin (capensin) 8
Procedure 1
Mp (8C): 135 (lit. 135–1361). IR (KBr, cmK1): 3392 (broad,
OH); 1692 (C]O). H NMR (300 MHz, CDCl3): d 1.68
7-(2,3-Epoxy-3-methylbutoxy)-8-hydroxy-6-methoxycou-
marin 10 (29 mg, 0.1 mmol) was dissolved in 1 ml of
EtOAc. 0.05 mmol (7 mg) of potassium carbonate was
added and the reaction was stirred at room temperature for
24 h. Water (10 ml) and ethyl acetate (5 ml) were added,
and the aqueous phase was further extracted with 2!10 ml
of ethyl acetate. The combined organic layers were dried
(MgSO4) and, after filtration and evaporation of the solvent,
23 mg (79%) of purpurasol was obtained as a white
crystalline solid, which was recrystallized from ethanol.
1
(3H, s, 40-CH3); 1.75 (3H, s, 50-CH3); 3.90 (3H, s, OCH3);
4.69 (1H, d, JZ7.4 Hz, 10-CH2); 5.52 (1H, t, JZ7.4 Hz, 20-
CH); 6.16 (1H, br s, OH); 6.34 (1H, d, JZ9.6 Hz, 3-CH);
6.50 (1H, s, 5-CH); 7.62 (1H, d, JZ9.6 Hz, 4-CH). 13C
NMR (68 MHz, CDCl3): d 18.0 en 25.9 (2!CH3); 56.2
(OCH3); 70.0 (10-CH2); 100.0 (5-CH); 114.4 (Cq); 115.2 (3-
CH); 119.5 (20-CH); 137.8 (Cq); 138.0 (2!Cq); 140.5 (30-
Cq); 143.7 (4-CH); 149.8 (6-Cq); 160.4 (C]O). MS (70 eV,
ES, m/z (%)): 275 (MK1). Anal. Calcd for C15H16O5: C,
65.21%; H, 5.84%. Found: C, 65.01%; H, 5.68%.
Procedure 2
7-Hydroxy-6-methoxy-8-(30-methyl-20-butenyloxy)-
coumarin 9
8-Hydroxy-6-methoxy-7-(30-methyl-20-butenyloxy)-
coumarin (capensin) 8 (28 mg, 0.1 mmol) was dissolved in
1 ml of ethyl acetate. The reaction mixture was cooled to
0 8C and 20 mg (0.12 mmol) of 3-chloroperoxybenzoic acid
was added. The reaction was stirred at room temperature for
48 h. The solvent was evaporated and the resulting mixture
was dissolved in dichloromethane (10 ml) and washed with
10 ml of saturated aqueous sodium bicarbonate and 10 ml of
water, respectively. The organic phase was dried (MgSO4)
and, after filtration and evaporation of the solvent, 20 mg
(69%) of purpurasol was obtained as a white solid.
Mp (8C): 126.5. IR (KBr, cmK1): 3401 (broad, OH); 17002
1
(C]O). H NMR (300 MHz, CDCl3): d 1.70 (3H, s, 4 -
CH3); 1.75 (3H, s, 50-CH3); 3.93 (3H, s, OCH3); 4.80 (1H, d,
JZ7.4 Hz, 10-CH2); 5.55 (1H, t, JZ7.4 Hz, 20-CH); 6.27
(1H, d, JZ9.6 Hz, 3-CH); 6.66 (1H, s, 5-CH); 7.61 (1H, d,
JZ9.6 Hz, 4-CH). 13C NMR (75 MHz, CDCl3): d 18.1 en
25.9 (2!CH3); 56.4 (OCH3); 70.3 (10-CH2); 103.5 (5-CH);
111.1 (Cq); 113.3 (3-CH); 119.4 (20-CH); 133.1 (Cq); 140.6
(Cq); 143.0 (Cq); 143.2 (Cq); 143.9 (4-CH); 144.6 (6-Cq);
160.7 (C]O). MS (70 eV, ES, m/z (%)): 275 (MK1). Anal.
Calcd for C15H16O5: C, 65.21%; H, 5.84%. Found: C,
65.39%; H, 5.98%.
Mp (8C): 148 (lit. 148–1492). IR (KBr, cmK1): 3400 (broad,
OH); 1702 (C]O). H NMR (300 MHz, CDCl3): d 1.37 en
1
1.46(2!3H, s, CH3);2.75(1H, br s, OH); 3.92(3H, s, OCH3);
3.99 (1H, dd, JaxZ9.1 Hz, JbxZ1.9 Hz, 20-CH); 4.13 (1H, dd,
JabZ11.3 Hz, JaxZ9.1 Hz, 10-CHaHb); 4.65 (1H, dd, JabZ
11.3 Hz, JbxZ1.9 Hz, 10-CHaHb); 6.31 (1H, d, JZ9.6 Hz,
3-CH); 6.51 (1H, s, 5-CH); 7.61(1H, d, JZ9.6 Hz, 4-CH). 13C
NMR (75 MHz, CDCl3): d 25.1 en 26.0 (2!CH3); 56.4
(OCH3); 65.5 (10-CH2); 70.6 (30-Cq); 79.0 (20-Cq); 100.1
(5-CH); 111.6 (4a-Cq), 114.1 (3-CH); 132.4 (8-Cq); 136.7 (8a-
Cq); 139.0 (7-Cq); 143.8 (4-CH); 145.7 (6-Cq); 160.9 (C]O).
MS (70 eV, EI, m/z (%)): 293 (MC1, 35); 292 (MC, 99); 235
(26); 234 (100); 219 (57); 208 (46); 207 (23); 206 (23); 205
(78); 191 (23); 176 (25); 79 (35); 71 (21); 59 (92); 57 (52); 51
(26); 47 (23); 43 (75). Anal. Calcd for C15H16O6: C, 61.64%;
H, 5.52%. Found: C, 61.49%; H, 5.40%.
3.2.2. 7-(2,3-Epoxy-3-methylbutoxy)-8-hydroxy-6-meth-
oxycoumarin 10. 8-Hydroxy-6-methoxy-7-(30-methyl-20-
butenyloxy)coumarin (capensin) 8 (69 mg, 0.25 mmol) was
dissolved in 2.5 ml of ethyl acetate. The reaction mixture
was cooled to 0 8C and 52 mg (0.3 mmol) of 3-chloroper-
oxybenzoic acid was added, after which the reaction was
stirred at room temperature for 8 h. The solvent was
evaporated in vacuo and the resulting mixture was dissolved
in dichloromethane (25 ml) and washed with 25 ml of
saturated aqueous sodium bicarbonate and 20 ml of water,
respectively. The organic phase was dried (MgSO4) and
after filtration and evaporation of the solvent, 46 mg (63%)
of crude 7-(2,3-epoxy-3-methylbutoxy)-8-hydroxy-6-meth-
oxycoumarin 10 (purity: 95%) was obtained as a sticky
residue, which was used without further purification.
References and notes
IR (KBr, cmK1): 3419 (broad, OH); 1715 (C]O). 1H NMR
(300 MHz, CDCl3): d 1.32 en 1.38 (each 3H, each s,
(CH3)2C]), 3.23 (1H, dd, JZ6.60, 4.68 Hz, OCHCH2O),
3.90 (3H, s, OCH3), 4.16 (1H, dd, JZ6.60, 11.56 Hz,
OCHCHaHbO), 4.44 (1H, dd, JZ4.68, 11.56 Hz, OCHCHa-
HbO), 6.35 (1H, d, JZ9.63 Hz, 3-CH), 6.50 (1H, s, 5-CH),
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