Synthesis of virgatol and virgatenol, two naturally occurring coumarins from Pterocaulon virgatum (L.) DC, and 7-(2,3-epoxy-3-methylbutoxy)-6- methoxycoumarin, isolated from Conyza obscura DC

Article abstract of DOI:10.1055/s-2004-829139

The synthesis of a number of naturally occurring coumarins from Pterocaulon virgatum (L.) and Conyza obscura DC is described for the first time. It concerns the synthesis of 7-(2-hydroxy-3-methoxy-3-methylbutoxy)-6- methoxycoumarin (virgatol, 1), 7-(2-hydroxy-3-methyl-3-butenyloxy)-6- methoxycoumarin (virgatenol, 2) and 7-(2,3-epoxy-3-methylbutoxy)-6- methoxycoumarin (3). In addition, a straightforward synthesis of scopoletin (4) (7-hydroxy-6-methoxycoumarin) is reported and the synthesis of a new coumarin derivative, 6-methoxy-7-(2-oxo-3-methylbutoxy)coumarin (7), is described.

Full text of DOI:10.1055/s-2004-829139

1844
PAPER
Synthesis of Virgatol and Virgatenol, Two Naturally Occurring Coumarins
from Pterocaulon virgatum (L.) DC, and 7-(2,3-Epoxy-3-methylbutoxy)-6-
methoxycoumarin, Isolated from Conyza obscura DC
Synthesis
a
of
V
irgatol
nand Virgatenol:
T
w
D
o Naturally
O
ccu
e
rring Coum
m
arins yttenaere,a Stijn Vervisch,a Silvia Debenedetti,b Jorge Coussio,c Dominick Maes,a Norbert De Kimpe*a
a
Department of Organic Chemistry, Faculty of Agricultural and Applied Biological Sciences, Ghent University, Coupure links 653,
9000 Ghent, Belgium
Fax +32(9)2646243; E-mail: norbert.dekimpe@ugent.be
b
c
Department of Biological Sciences, University of La Plata, Calle 115 and 47, 1900 La Plata, Argentina
IQUIMEFA, Faculty of Pharmacy, University of Buenos Aires, Junin 956, 1113 Buenos Aires, Argentina
Received 4 December 2003; revised 19 April 2004
CH3O
O
CH3O
O
CH3O
Abstract: The synthesis of a number of naturally occurring cou-
marins from Pterocaulon virgatum (L.) and Conyza obscura DC is
described for the first time. It concerns the synthesis of 7-(2-hy-
droxy-3-methoxy-3-methylbutoxy)-6-methoxycoumarin (virgatol,
O
O
O
O
O
OH
OH
1 (Virgatol)
2 (Virgatenol)
1),
7-(2-hydroxy-3-methyl-3-butenyloxy)-6-methoxycoumarin
(virgatenol, 2) and 7-(2,3-epoxy-3-methylbutoxy)-6-methoxycou-
marin (3). In addition, a straightforward synthesis of scopoletin (4)
(7-hydroxy-6-methoxycoumarin) is reported and the synthesis of a
new coumarin derivative, 6-methoxy-7-(2-oxo-3-methylbu-
toxy)coumarin (7), is described.
CH3O
O
MeO
HO
O
O
O
O
4
3
Keywords: virgatol, virgatenol, coumarins, natural products, Wit-
tig reactions, epoxides
Figure 1
The former two coumarins, virgatol (1) and virgatenol (2)
have been described as new isolated compounds from
Pterocaulon virgatum (L.) DC and P. polystachium
DC,17,18 while the latter coumarin 3 has been isolated from
Conyza obscura DC.19 Although 6,7-dioxygenated cou-
marins are quite common in plants, the synthesis of com-
pounds 1–3 has not been reported to date.
A very large number of coumarins has been isolated from
plants. Several comprehensive reviews deal with the oc-
currence, chemistry and biochemical properties of simple
and complex natural coumarins.1–4 However, to date, most
of the pharmacological and biochemical studies have been
carried out on coumarin itself and on mono- and dihy-
droxycoumarins or methoxycoumarins.5,6 Since the
1990’s, a large number of in vivo and in vitro studies has
revealed a diverse array of pharmacological and biochem-
ical properties, some of which are of potential pharmaceu-
tical interest, e.g. antibacterial,7 antimutagenic and
antitumor activity,8–13 inhibitory properties on human
platelet aggregation,14 anti-HIV-PR activity,15 effect on
cell growth and differentiation.16
In previous publications we described the isolation and
structural elucidation of a number of di- and trioxygenated
coumarins from Argentine medicinal plants.18,20,21 Our re-
cent findings on interesting physiological activities, such
as the determination of antiproliferation and differentia-
tion activity22 of these coumarins, encouraged us to ini-
tiate a program for synthesis of a whole range of
coumarins isolated from the Asteraceae family.
An important classification of the numerous coumarins is
based on an arbitrary but biogenetically related system of
the number of nuclear oxygen atoms. Thus coumarins are
commonly subdivided in classes depending on their oxy-
genation pattern. 7-(2-Hydroxy-3-methoxy-3-methylbu-
toxy)-6-methoxycoumarin (virgatol, 1), 7-(2-hydroxy-3-
methyl-3-butenyloxy)-6-methoxycoumarin (virgatenol,
2) and 7-(2,3-epoxy-3-methylbutoxy)-6-methoxycou-
marin (3) are examples of dioxygenated coumarins de-
rived from scopoletin (4) (Figure 1). The absolute optical
configuration of substances 1–3 is not known.
The present report deals with the synthesis of these three
coumarins virgatol (1), virgatenol (2) and 7-(2,3-epoxy-3-
methylbutoxy)-6-methoxycoumarin (3) via a synthesis of
the coumarin scopoletin (4) which holds a fundamental
position in coumarin chemistry.
This research has been carried out in the framework of the
synthesis of derivatives of natural coumarins in view of
planned structure–activity studies. For the synthesis of the
above-mentioned 6,7-dioxygenated coumarins it was de-
cided to develop routes via scopoletin (4). Several synthe-
ses of scopoletin have been reported in the literature.23–25
The Pechmann synthesis of 2,4-dihydroxyanisol with eth-
yl 3,3-diethoxypropionate26 afforded scopoletin in 73%.
However, 2,4-dihydroxyanisol is less accessible as it
needs to be synthesized in low yield from 4-nitroguaiacol
acetate23 or by the Baeyer–Villiger oxidation of isovanil-
SYNTHESIS 2004, No. 11, pp 1844–1848
x
x.
x
x
.
2
0
0
4
Advanced online publication: 13.07.2004
DOI: 10.1055/s-2004-829139; Art ID: T13103SS
© Georg Thieme Verlag Stuttgart · New York

PAPER
Synthesis of Virgatol and Virgatenol: Two Naturally Occurring Coumarins
1845
lin with peracetic acid.26 The Gattermann reaction of this from Bupleurum fruticosum roots as well.36 Bupleurum
pivotal 2,4-dihydroxyanisol leads to 2,4-dihydroxy-5- species have a major interest in Chinese traditional medi-
methoxybenzaldehyde23,27 which can undergo the classi- cine as Bupleuri Radix, i.e. the dried roots are one of the
cal coumarin synthesis. This important 2,4-dihydroxy-5- most frequently occurring crude drugs in the prescriptions
methoxybenzaldehyde (5b) is now readily accessible in a of Chinese traditional medicine.
one-step reaction from the commercially available 2,4,5-
trimethoxybenzaldehyde (5a) by reaction with alumini-
6-Methoxy-7-(3-methyl-2-butenyloxy)coumarin (6) was
epoxidized with meta-chloroperoxybenzoic acid in
dichloromethane at room temperature to afford 7-(2,3-ep-
oxy-3-methylbutoxy)-6-methoxycoumarin (3) in 70%
um(III) chloride in dichloromethane, followed by acid hy-
drolysis (Scheme 1).28
yield. This is the first synthesis of the natural coumarin 3
O
O
which has been isolated from Conyza obscura DC.18
CH3O
CH3O
CH3O
HO
a
H
H
Reaction of epoxide 3 with anhydrous hydrogen chloride
in methanol at room temperature for 16 h afforded 7-(2-
hydroxy-3-methoxy-3-methylbutoxy)-6-methoxycouma-
rin (virgatol, 1) in 28% yield (Scheme 2). The yield of
coumarin 1 could be drastically improved to 74% by reac-
tion of coumarin 3 with boron(III) fluoride etherate in
methanol at room temperature for 30 minutes.
OCH3
OH
5a
5b
b
CH3O
O
CH3O
HO
c
O
O
O
O
HCl, MeOH
r.t., 16 h
6
4
(28%)
CH3O
CH3O
d
O
O
O
O
O
O
HO
MeO
O
3
1 (Virgatol)
O
MeO
BF3⋅OEt2
MeOH
O
O
O
r.t., 30 min
(74%)
3
Scheme 1 Conditions and reagents: (a) AlCl3 (8 equiv), CH2Cl2, r.t.,
20 h, 71%; (b) (C6H5)3P=CHCOOCH3 (1.2 equiv), Et2NC6H5, N2, D,
4 h, 62%; (c) (CH3)2C=CHCH2Br (1.4 equiv), K2CO3, acetone, D, 15
h, 96%; (d) MCPBA, CH2Cl2, r.t., 30 min, 70%.
Scheme 2
Virgatol (1), virgatenol (2) together with compound 6 and
scopoletin (4) have been isolated from the aerial parts of
Pterocaulon virgatum and P. polystachium.16 Both Ptero-
caulon species are widely distributed in north eastern Ar-
gentina, southern Brazil and Paraguay. Aerial parts of this
plant are used in Argentine traditional medicine as a di-
gestive, emenagogue, insecticide and as agent against
snake bites.37–40
Condensation of 2,4-dihydroxy-5-methoxybenzaldehyde
with (methoxycarbonyl)methylene triphenylphosphorane
in N,N-diethylaniline under reflux in a nitrogen atmo-
sphere afforded scopoletin (4).28,29
The direct purification of the reaction mixture by column
chromatography (silica gel; CH2Cl2–MeOH, 95:5) left
large amounts of product adsorbed on the column (no im-
provement). A better yield of scopoletin (4) (62%) was
obtained by crystallization of the reaction mixture from
methanol, making it now the preferred synthetic route
from 2,4,5-trimethoxybenzaldehyde (5a) in two steps.
Scopoletin (4) is a suitable substrate for the synthesis of a
number of 6,7-dioxygenated coumarins which occur nat-
urally in plants. Scopoletin (4) has been converted into 6-
methoxy-7-(3-methyl-2-butenyloxy)coumarin (6) by
prenylation30,31 which has been synthesized from aescule-
tin (6,7-dihydroxycoumarin) by selective prenylation at
the 7-position, followed by methylation of the hydroxy
group at position 6.25,30–32 Coumarin 6 is a naturally occur-
ring coumarin which was isolated from Ptaeroxylon
obliquum (sneeze wood),30,31,33 Artemisia dracunculoides
Pursh. (from Arizona),34 Conyza obscura DC,18 Haplo-
pappus deserticola35 and Carduus tenuiflorus.32 Cou-
marin 6 together with virgatenol (2) has been isolated
Scheme 3 Conditions and reagents: (e) TsOH (1.5 equiv), CH2Cl2,
r.t., 1.5 h; (f) HCl (15 equiv), Et2O, –10 °C, 45 min; (g) t-BuOK, THF.
Synthesis 2004, No. 11, 1844–1848 © Thieme Stuttgart · New York

1846
J. Demyttenaere et al.
PAPER
plied. (Methoxycarbonyl)methylenetriphenylphosphorane was syn-
thesized according to the literature.41
Attempts were then made to perform a synthesis of 7-(2-
hydroxy-3-methyl-3-butenyloxy)-6-methoxycoumarin
(2) (Scheme 3), a natural product from the Argentine plant
Pterocaulon virgatum DC.22 The reaction of 7-(2,3-ep-
oxy-3-methylbutoxy)-6-methoxycoumarin (3) with a cat-
alytic amount of para-toluenesulfonic acid in a two phase
system of dichloromethane–water at reflux did not lead to
a conversion, while the reaction with aq HCl (2 M) in the
same biphasic system resulted in the formation of a mix-
ture of unidentified products. However, when 7-(2,3-ep-
oxy-3-methylbutyloxy)-6-methoxycoumarin (3) was
treated with para-toluenesulfonic acid (1.5 equiv) in
dichloromethane at room temperature for 1.5 h, a mixture
of 7-(2-hydroxy-3-methyl-3-butenyloxy)-6-methoxycou-
marin (2) (55%) and 6-methoxy-7-(2-oxo-3-methylbu-
toxy)coumarin (7) (45%) was obtained. Purification by
column chromatography led to the isolation of both com-
pounds 2 and 7 in 40 and 33% yield, respectively. It is the
first time that a synthesis of the naturally occurring cou-
marin 2 has been described. In addition, the synthesis of a
new coumarin 7, giving a full spectroscopic characteriza-
tion, is described here for the first time.
Scopoletin (4)
Scopoletin (4) was synthesized from 2,4,5-trimethoxybenzaldehyde
(5) as described recently by our group.28 As an alternative for the re-
crystallization from MeOH or MeOH–hexane, the filtrate was treat-
ed in high vacuo (0.01 mmHg) at 60–70 °C to remove N,N-
diethylaniline. The residual brown oil was dissolved in MeOH from
which scopoletin crystallized. The total yield of scopoletin 4 mount-
ed to 62%, as compared to 27% when the previous work-up proce-
dure was applied.28
Mp 205–206 °C (Lit.24 mp 204 °C, Lit.26 198–200 °C).
6-Methoxy-7-(3-methyl-2-butenyloxy)coumarin (6)
To a solution of scopoletin (4) (1.0 g, 5.20 mmol) in acetone (50
mL) was added K2CO3 (0.89 g, 6.44 mmol) and prenyl bromide
(1.11 g, 7.45 mmol). The mixture was heated at 50 °C for 15 h. Af-
ter filtration and evaporation of the solvent in vacuo, the residue was
dissolved in EtOAc (50 mL) and this solution was washed with sat.
aq NaHCO3 (2 × 50 mL) and water (2 × 50 mL). The organic layer
was dried (MgSO4), filtered and evaporated in vacuo to afford 6-
methoxy-7-(3-methyl-2-butenyloxy)coumarin (6).
Yield: 1.30 g (96%); mp (CHCl3–hexane) 82 °C (Lit.24 mp 80–
82 °C).
An alternative approach to the synthesis of coumarin 2
was tried via the chlorohydrin 8. Reaction of 7-(2,3-ep-
oxy-3-methylbutoxy)-6-methoxycoumarin (3) with a
large excess of saturated hydrogen chloride in diethyl
ether at 0 °C for 15 min afforded a complex mixture of
products. The reaction of this epoxide with hydrogen
chloride (5 equiv) in diethyl ether for 15 minutes gave
coumarin 8 and starting material, while the reaction of hy-
drogen chloride (15 equiv) in diethyl ether at –10 °C for
45 min resulted in the isolation of 7-(3-chloro-2-hydroxy-
3-methylbutoxy)-6-methoxycoumarin (8) in 62% yield.
All attempts to perform a dehydrochlorination of cou-
marin 8 with potassium tert-butoxide in THF at different
temperatures did not give rise to 7-(2-hydroxy-3-methyl-
3-butenyloxy)-6-methoxycoumarin (2).
IR (KBr): 1705 (C=O), 1605, 1555 cm–1.
1H NMR (270 MHz, CDCl3): d = 1.78 and 1.79 [each 3 H, each s,
(CH3)2C=], 3.90 (3 H, s, OCH3), 4.65 (2 H, d, J = 6.6 Hz, CH2O),
5.49 (1 H, tt, J1 = 6.6, J2 = 1.3 Hz, =CHCH2), 6.25 (1 H, d, J = 9.2
Hz, CH=CHCO), 6.80 (1 H, s, 8-CH), 6.88 (1 H, s, 5-CH), 7.64 (1
H, d, J = 9.2 Hz, CH=CHCO).
13C NMR (68 MHz, CDCl3): d = 18.4 and 25.8 [each (CH3)2C=],
56.3 (OCH3), 66.2 (CH2O), 101.0 (8-CH), 108.0 (5-CH), 111.3 (C-
4a), 113.2 (CH=CHCO), 118.7 (=CHCH2O), 139.0 [(CH3)2C=],
143.5 (CH=CHCO), 146.6 (C-6), 149.9 (C-8a), 152.1 (C-7), 161.5
(C=O).
MS (70 eV): m/z (%) = 260 (M+, 4), 245 (0.3), 217 (0.4), 204 (1),
193 (11), 192 (100), 191 (6), 177 (28), 164 (15), 149 (12), 135 (2),
121 (5), 92 (3), 79 (7), 69 [(CH3)2C=CH–CH2 , 50], 67 (11), 53
(11), 43 (13).
+
Several research works dealing with the structural deter-
mination of new isolated coumarins from natural sources
are incomplete and, as a consequence, several wrong
structures have been proposed. Thus, the synthesis of nat-
ural coumarins is not only a necessary tool to obtain large
quantities of these compounds for biological purposes but
it is a must for the unambiguous confirmation of the iden-
tity of the new isolated coumarins.
7-(2,3-Epoxy-3-methylbutoxy)-6-methoxycoumarin (3)
To a solution of coumarin 6 (1.90 g, 7.30 mmol) in CH2Cl2 (25 mL)
was added MCPBA (1.50 g, 8.75 mmol; purity 70–75%). The mix-
ture was stirred at r.t. for 30 min, after which the mixture was
poured into sat. aq NaHCO3 (25 mL). Extraction with CH2Cl2
(3 × 25 mL), drying (MgSO4), filtration and evaporation afforded 7-
(2,3-epoxy-3-methylbutoxy)-6-methoxycoumarin (3) (1.41 g,
70%). Column chromatography (benzene–CHCl3, 1:1) could be
used as well.
Rf = 0.06; mp (CHCl3) 123–124 °C (Lit.18 mp 125 °C).
IR (NaCl): 1720 (br, C=O), 1620, 1563, 1513 cm–1.
1H NMR (270 MHz, CDCl3): d = 1.36 and 1.37 [each 3 H, each s,
(CH3)2C], 3.17 (1 H, dd, J1 = 6.3, J2 = 4.0 Hz, OCHCH2O), 3.87 (3
H, s, OCH3), 4.08 and 4.30 (each 1 H, AMX, JAM = 11.4, JAX = 6.3,
JMX = 4.0 Hz, OCHCH2O), 6.24 (1 H, d, J = 9.2 Hz, CH=CHCO),
6.83 (1 H, s, 8-CH), 6.88 (1 H, s, 5-CH), 7.55 (1 H, d, J = 9.2 Hz,
CH=CHCO).
1H and 13C NMR spectra were recorded on a JEOL JNM-EX270
NMR spectrometer, operating at 270 MHz and 67.5 MHz, respec-
tively. GC analytical and preparative separations were done with a
DELSI Intersmat IGC 120 ML gas chromatograph. FT-IR spectra
were recorded on a Perkin–Elmer model 1310 spectrophotometer.
The Electron Impact (EI) mode mass spectra were obtained with a
Varian MAT 112 mass spectrometer, operating at 70 eV. THF was
distilled over sodium benzophenone ketyl prior to use. CH2Cl2 was
distilled over calcium hydride prior to use. Et2O was dried and dis-
tilled over sodium wire. Chromatographic separations were done
using Merck Kieselgel 60 (230–400 mesh ASTM). Reactions were
monitored with Merck Kieselgel 60 F254 precoated TLC plates (0.25
mm thickness). All other solvents and chemicals were used as sup-
13C NMR (68 MHz, CDCl3): d = 19.1 and 24.6 [each (CH3)2C], 56.4
(OCH3), 58.3 [(CH3)2C], 60.9 (OCHCH2), 68.5 (OCHCH2O), 101.5
(8-CH), 108.6 (5-CH), 112.0 (C-4a), 113.6 (CH=CHCO), 143.4
(CH=CHCO), 146.6 (C-6), 149.7 (C-8a), 151.8 (C-7), 161.4 (C=O).
Synthesis 2004, No. 11, 1844–1848 © Thieme Stuttgart · New York

PAPER
Synthesis of Virgatol and Virgatenol: Two Naturally Occurring Coumarins
1847
MS (70 eV): m/z (%) = no M+, 158 (6), 156 (20), 141 (6), 139 (19),
111 (10), 91 (2), 88 (7), 86 (42), 85 (25), 84 (68), 83 (36), 75 (6), 59
(7), 51 (31), 50 (9), 49 (100), 48 (10), 47 (20), 43 (23).
(each 1 H, each s, C=CH2), 6.30 (1 H, d, J = 9.6 Hz, CH=CHCO],
6.87 (2 H, s, 8-CH and 5-CH), 7.62 (1 H, d, J = 9.6 Hz,
CH=CHCO).
MS (70 eV): m/z (%) = 276(M+, 36), 245 (1), 206 (7), 201 (12), 199
(15), 193 (14), 192 (100), 191 (10), 190 (8), 185 (7), 183 (12), 177
(35), 164 (17), 152 (8), 149 (29), 113 (7), 86 (21), 79 (7), 71 (18),
71 (24), 69 (21), 58 (8), 57 (31), 56 (7), 55 (13), 51 (16), 47 (6), 44
(40), 43 (40).
7-(2-Hydroxy-3-methoxy-3-methylbutoxy)-6-methoxycouma-
rin (Virgatol, 1)
To a solution of 7-(2,3-epoxy-3-methylbutoxy)-6-methoxycou-
marin (3) (0.16 g, 0.58 mmol) in anhyd MeOH (5 mL) was added
an excess of a solution of anhyd hydrogen chloride in anhyd MeOH.
The mixture was stirred at r.t. for 16 h. After evaporation of the sol-
vent in vacuo, the residue was column chromatographed with tolu-
ene–i-PrOH (96:4) to give 7-(2-hydroxy-3-methoxy-3-
methylbutoxy)-6-methoxycoumarin (1).
6-Methoxy-7-(2-oxo-3-methylbutoxy)coumarin (7)
1H NMR (270 MHz, CDCl3): d = 1.20 [6 H, d, J = 6.9 Hz,
(CH3)2CH], 2.89 [1 H, septet, J = 6.9 Hz, (CH3)2CH], 3.93 (3 H, s,
OCH3), 4.83 (2 H, s, COCH2O), 6.30 (1 H, d, J = 9.6 Hz,
CH=CHCO), 6.64 and 6.90 (each 1 H, each s, 8-CH and 5-CH),
7.62 (1 H, d, J = 9.6 Hz, CH=CHCO).
Yield: 0.05 g (28%).
An alternative procedure for the synthesis of 7-(2-hydroxy-3-meth-
oxy-3-methylbutoxy)-6-methoxycoumarin (1) consists of the treat-
MS (70 eV): m/z (%) = 276 (M+, 2), 261 (M+ – CH3, 1), 248 (M+ –
CO, 1), 234 (4), 227 (7), 221 (4), 220 (10), 219 (12), 206 (8), 205
(4), 192 (7), 191 (8), 183 (4), 169 (4), 167 (7), 165 (4), 164 (4), 163
(5), 161 (4), 155 (6), 150 (5), 149 (29), 141 (7), 139 (8), 135 (11),
129 (20), 127 (8), 125 (7), 123 (6), 113 (14), 112 (8), 111 (18), 110
(5), 109 (8), 107 (6), 105 (7), 101 (5), 99 (16), 98 (10), 97 (20), 96
(9), 95 (11), 87 (6), 86 (6), 85 (32), 84 (13), 83 (26), 82 (10), 81 (13),
79 (7), 71 (55), 70 (19), 69 (37), 67 (11), 58 (8), 57 (100), 56 (21),
55 (51), 43 (75), 42 (11).
ment of
a
solution of 7-(2,3-epoxy-3-methylbutoxy)-6-
methoxycoumarin (3) (0.14 g, 0.51 mmol) in anhyd MeOH (7 mL)
with BF3·OEt2 (0.10 mL). The reaction mixture was stirred at r.t. for
30 min. The mixture was evaporated to half of its volume, and then
diluted with aq NaOH (0.1 M) (5 mL). After extraction with Et2O
(2 × 10 mL), drying (MgSO4), filtration and evaporation, 7-(2-hy-
droxy-3-methoxy-3-methylbutoxy)-6-methoxycoumarin (1) was
obtained. No further purification was needed.
Yield: 0.12 g (77%); mp (CHCl3) 60–61 °C (Lit.16 mp 60–62 °C).
7-(3-Chloro-2-hydroxy-3-methylbutoxy)-6-methoxycoumarin
(8)
IR (NaCl): 3670–3160 (br, OH), 2980, 1720 (C=O), 1615, 1560,
1515 cm–1.
To a stirred and cooled (–10 °C) solution of 7-(2,3-epoxy-3-meth-
ylbutoxy)-6-methoxycoumarin (3) (0.10 g, 0.36 mmol) in THF (10
mL) was added a sat. solution of HCl (5.40 mmol) in Et2O. The mix-
ture was stirred at this temperature for 45 min after which the sol-
vents were evaporated in vacuo. Column chromatography (hexane–
EtOAc, 3:7) of the residue gave pure 7-(3-chloro-2-hydroxy-3-me-
thylbutoxy)-6-methoxycoumarin (8).
1H NMR (270 MHz, CDCl3): d = 1.26 [6 H, s, (CH3)2C], 3.0 [1 H,
br s, CH(OH)CH2O], 3.27 [3 H, s, C(OCH3)], 3.88 (3 H, s,
ArOCH3), 4.01 [2 H, m, CH(OH)CH2O and CH(OH)HCHO], 4.26
[1 H, dd, J = 9.2, J = 2.0 Hz, CH(OH)HCHO], 6.27 (1 H, d, J = 9.4
Hz, CH=CHCO), 6.85 (1 H, s, 8-CH), 6.87 (1H, s, 5-CH), 7.61 (1
H, d, J = 9.4 Hz, CH=CHCO).
13C NMR (68 MHz, CDCl3): d = 20.4 and 21.2 [each (CH3)2C], 49.3
[C(OCH3)], 56.4 (ArOCH3), 70.7 [CH(OH)CH2O], 74.9
[CH(OH)CH2O], 76.1 [(CH3)2C], 101.5 (8-CH), 108.4 (5-CH),
111.7 (C-4a), 113.6 (CH=CHCO), 143.3 (CH=CHCO), 146.7 (C-6),
149.8 (C-8a), 152.2 (C-7), 161.4 (C=O).
MS (70 eV): m/z (%) = 308 (M+, 13), 277 (3), 193 (12), 192 (59),
191 (6), 177 (10), 164 (6), 149 (9), 94 (5), 85 (7), 74 (9), 73 (100),
71 (8), 69 (11), 59 (8), 57 (12), 45 (14), 43 (18).
Yield: 0.070 g (62%).
IR (NaCl): 3620–3140 (br, OH), 1720 (br, C=O) cm–1.
1H NMR (270 MHz, CDCl3): d = 1.68 and 1.69 [each 3 H, each s,
(CH3)2C], 2.8 (1 H, br s, OH), 3.89 (3 H, s, OCH3), 4.07–4.16 [2 H,
m, CH(OH)CH2O and CH(OH)HCHO], 4.41 (1 H, dd, J1 = 8.6,
J2 = 1.7 Hz, CH(OH)HCHO], 6.29 (1 H, d, J = 9.2 Hz,
CH=CHCO), 6.86 and 6.87 (each 1 H, each s, 8-CH and 5-CH),
7.61 (1 H, d, J = 9.2 Hz, CH=CHCO).
13C NMR (68 MHz, CDCl3): d = 28.3 and 29.4 [(CH3)2C=], 56.4
(OCH3), 70.7 (OCH2), 71.0 [(CH3)2C], 76.3 [CH(OH)], 101.9 (8-
CH), 108.4 (5-CH), 112.1 (C-4a), 113.9 (CH=CHCO), 143.2
(CH=CHCO), 146.7 (Cq), 149.7 (Cq), 151.7 (Cq), 161.2 (C=O).
MS (70 eV) : m/z (%) = 312/4 (M+, 19), 235 (5), 193 (15), 192 (100),
191 (11), 190 (5), 177 (29), 164 (15), 149 (12), 79 (6), 71 (9), 69
(15), 57 (9), 55 (7), 51 (5), 44 (5), 43 (26).
7-(2-Hydroxy-3-methyl-3-butenyloxy)-6-methoxycoumarin (2)
(Virgatenol) and 6-Methoxy-7-(2-oxo-3-methylbutoxy)cou-
marin (7)
To a solution of 7-(2,3-epoxy-3-methylbutoxy)-6-methoxycou-
marin (3) (0.10 g, 0.36 mmol) in CH2Cl2 (10 mL) was added TsOH
(0.10 g, 0.54 mmol). The mixture was stirred at r.t. for 1.5 h after
which the mixture was poured in aq NaOH (2 M; 5 mL). After ex-
traction with CH2Cl2 (3 × 15 mL), drying (MgSO4), filtration and
evaporation of the solvent in vacuo, the reaction mixture was found
to consist of a mixture of 7-(2-hydroxy-3-methyl-3-butenyloxy)-6-
methoxycoumarin (2) and 6-methoxy-7-(2-oxo-3-methylbu-
toxy)coumarin (7) in a ratio of 55:45. This mixture was separated
by column chromatography (CH2Cl2–MeOH, 98.5:1.5) to afford 6-
methoxy-7-(2-oxo-3-methylbutoxy)coumarin (7) [33 mg (33%);
Rf = 0.23] and 7-(2-hydroxy-3-methyl-3-butenyloxy)-6-methoxy-
coumarin (2) [40 mg (40%); Rf = 0.09].
Acknowledgment
The authors are indebted to the FWO-Flanders (Belgium) and Co-
nicet (Argentina) for financial support.
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