Synthesis of mollugin

Article abstract of DOI:10.1016/j.tet.2006.06.014

The total synthesis of mollugin, a major constituent of rubiaceous herbs, using a straightforward synthetic approach starting from 1,4-naphthoquinone via a sequence of reactions, including selective prenylation, epoxidation, reduction of the quinone moiety, acid-catalysed ring expansion, bromination, dehydration and methoxycarbonylation is presented.

Full text of DOI:10.1016/j.tet.2006.06.014

Tetrahedron 62 (2006) 8419–8424
Synthesis of mollugin
y
*
Sven Claessens, Bart Kesteleyn, Tuyen Nguyen Van and Norbert De Kimpe
Department of Organic Chemistry, Faculty of Bioscience Engineering, Ghent University,
Coupure Links 653, B-9000 Ghent, Belgium
Received 19 April 2006; revised 31 May 2006; accepted 2 June 2006
Available online 7 July 2006
Abstract—The total synthesis of mollugin, a major constituent of rubiaceous herbs, using a straightforward synthetic approach starting from
1,4-naphthoquinone via a sequence of reactions, including selective prenylation, epoxidation, reduction of the quinone moiety, acid-catalysed
ring expansion, bromination, dehydration and methoxycarbonylation is presented.
Ó 2006 Elsevier Ltd. All rights reserved.
1. Introduction
rubiaceous herbs are of great importance in the Chinese
folk medicine for their blood circulation promoting, expec-
torant, cough-healing and antitumor properties.5c,6,8 Particu-
larly, in view of the antitumor activities of mollugin 1, there
is a renewed interest in the synthesis of 2H-naphtho[1,2-
b]pyran-5-carboxylate derivatives related to mollugin 1.
Mollugin was synthesised previously according to the
synthetic plan in Scheme 1. Condensation of diethyl
3,6-dihydroxyphthalate 5 and diethyl succinate 6 followed
by acid-catalysed decarboxylation afforded 1,4-dihydroxy-
naphthalene-2-carboxylic acid 8, which was further
elaborated to mollugin 1 by reaction with 3-chloro-3-methyl-
1-butyne in the presence of aluminium(III) chloride and
subsequent esterification of the intermediate molluginic
acid 9 with diazomethane.12 This synthesis, although basi-
cally only four steps long, suffers from the disadvantage of
a low overall yield, originating mainly from the variable
yields of the double Claisen condensation (often as low as
5% and mounting to 48%, pointing to a tricky reaction).
The natural product mollugin 1 was isolated first from the
rhizome of Galium mollugo (Rubiaceae) and identified as
methyl 2,2-dimethyl-6-hydroxy-2H-naphtho[1,2-b]pyran-
5-carboxylate.1 Later, mollugin 1 together with several
structurally related compounds such as 3-hydroxymollugin
2, cis-3,4-dihydro-3,4-dihydroxymollugin 3a and trans-
3,4-dihydro-3,4-dihydroxymollugin 3b2 and also methyl
2,3-epoxy-3-prenyl-1,4-dioxonaphthalene-2-carboxylate 4,
a precursor in the biosynthesis of mollugin via the shikimate
biosynthetic pathway,3 have been reported as major cons-
tituents in many rubiaceous herbs including Putoria
calabrica,4 Rubia cordifolia,5 Rubia oncotricha,6 Pentas
longiflora,2b Rubia lanceolata7 and Rubia tinctorum.8
Mollugin 1 has been shown to possess antitumor activity,5a
antimutagenic activity8,9 and antiviral activity10 against the
hepatitis B virus (Fig. 1). Strong inhibition of arachidonic
acid (AA)-induced and collagen-induced platelet aggre-
gation has been shown for mollugin 1.11 As a result, many
Mollugin has also been synthesised starting from 1,4-
dihydroxynaphthalene-2-carboxylic acid 8. 3,4-Dihydro-
mollugin 11 as a key step intermediate was obtained after
electrophilic aromatic substitution of 2-methyl-3-buten-
2-ol onto methyl 1,4-dihydroxynaphthalene-2-carboxylate
10. Subsequent pyran ring closure in the presence of
BF3$OEt2 resulted in 3,4-dihydromollugin 11 in 54% yield.
Reflux of 3,4-dihydromollugin 11 in dioxane in the presence
of DDQ yielded mollugin 1 in 72%.13 Very recently,
mollugin has been synthesised by treating methyl 3-(3-
methyl-but-2-enyl)-1,4-dioxo-1,4-dihydro-naphthalene-2-
carboxylate with triethylamine, which gave rise to an
oxa-6p pericyclic reaction and subsequent formation of
mollugin 1.14
OH
O
O
O
O
O
OH
O
OMe
OH
OMe
OMe
R
O
O
OH
4
1 R = H (Mollugin)
2 R = OH
3acis
3btrans
Figure 1.
Keywords: Quinones; Natural products; Mollugin.
* Corresponding author. E-mail: norbert.dekimpe@ugent.be
Present address: Institute of Chemistry, Vietnamese Academy of Sciences
and Technology, Vietnam.
y
In this paper, the total synthesis of mollugin 1 is presented
using a straightforward synthetic approach starting from
0040–4020/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2006.06.014

8420
S. Claessens et al. / Tetrahedron 62 (2006) 8419–8424
O
EtO
OH
O
O
O
O
OH
OH
O
OEt
6
O
OMe
OEt
OEt
OEt
OEt
5M NaOEt in EtOH
100-110°C, 2h
O
5
1 (72%)
7 (5-48%)
1) 6M NaOH
2) 12M HCl
1 equiv. DDQ,
dioxane, ∆, 8h
Ref. 12
OH
O
O
OH
O
OH
O
OH
2 equiv.
Cl
1 equiv.
OR
OR
OMe
2.4 equiv. AlCl3,
CH2Cl2, 0°C, 3h
1 equiv. BF3.Et2O,
Et2O, -78°, 1h,
rt, 3h
OH
O
9 R = H (23%)
8 R = H (87%)
10R = Me (100%)
CH2N2,
ether, 0°C
CH2N2,
0°C
11R = Me (54%)
1 R = Me (100%)
Scheme 1. Previous synthetic approach.
1,4-naphthoquinone 12 via reductive acid-catalysed intra-
molecular cycylisation of 2-prenyl-1,4-naphthoquinone 13
as a key step for the construction of the 2H-naphtho[1,2-b]-
pyran skeleton.
and potassium carbonate in refluxing acetone. Bromination
of 17 in ortho-position of the methoxy substituent with N-
bromosuccinimide in dichloromethane gave the brominated
derivative 18 in 95% yield. However, the dehydration of
alcohol 18, with the objective of introducing a double
bond between C(3) and C(4) in the pyran ring was quite
troublesome. The alcoholic function of 18, which is of a neo-
pentylic nature could not be forced to dehydrate under acid-
catalysed conditions using either p-toluenesulfonic acid or
dry oxalic acid in refluxing anhydrous benzene or upon treat-
ment with concentrated hydrochloric acid or sulfuric acid
in acetic acid. The dehydration could, however, be accom-
plished via tosylation of alcohol 18 and subsequent treat-
ment of the tosylate 19 with potassium tert-butoxide in dry
THF to afford the dehydrated derivative 20 in 73% yield.
For the introduction of the methoxycarbonyl group, com-
pound 20 was treated with n-butyllithium in dry THF at
ꢀ78 ꢁC to afford, via bromine–lithium exchange and
trapping of the intermediate lithium salt with methyl chloro-
formate, a mixture of the desired ester 21 in 52% yield,
together with 8% of the debrominated naphthopyrane 22.18
Treatment of the ester 21 with excess aluminium(III) chlo-
ride finally gave mollugin 1 in 77% yield. Recrystallisation
from methanol afforded mollugin 1 as yellow-green flakes
with physical and spectral data identical to those of the nat-
ural product.1 In this way, mollugin 1 was prepared in 10
steps in a total yield of 11% from 1,4-naphthoquinone 12.
2. Results and discussion
The synthesis of mollugin 1 is presented in Scheme 2.
2-Prenyl-1,4-naphthoquinone 13, the starting material for
the synthesis of mollugin 1, was reported previously to be
available in a yield of 58% by radical prenylation of 1,4-
naphthoquinone 12 with 4-methyl-3-pentenoic acid15 in
the presence of silver nitrate and ammonium persulfate.16
In our hands, using these published reaction conditions,
mixtures of starting material 12 together with the mono-
prenylated and diprenylated 1,4-naphthoquinones 13 and
14 were obtained in variable ratios depending on the applied
reaction conditions. Optimisation of the reaction using an
excess of allylating carboxylic acid, which was added in por-
tions during the reaction, and purification of the resulting
reaction mixtures via chromatography and subsequent
recrystallisation afforded 2-prenyl-1,4-naphthoquinone 13
in a maximum yield of 35%. On the other hand, according
to a recently published procedure for the monoallylation of
quinones, reaction of 1,4-naphthoquinone 12 with prenyltri-
fluorosilane in the presence of FeCl3$6H2O as a Lewis acid,
afforded the monoprenylated 1,4-naphthoquinone 13 in
98%.17 Chemoselective epoxidation of the prenylic double
bond with m-chloroperbenzoic acid in dichloromethane
and subsequent reduction of the intermediate epoxide 15
using sodium dithionite in a biphase system with ether and
water, followed by acid-catalysed intramolecular cyclisation
of the intermediate hydroquinone epoxide with a solution of
10% sulfuric acid in acetic acid afforded 2H-naphtho[1,2-
b]pyran-3,6-diol 16 in an overall yield of 52% (two steps).
This diol 16, which already reveals the basic skeleton of
mollugin, was further elaborated via protection of the pheno-
lic hydroxyl group as the methyl ether with dimethyl sulfate
3. Experimental
3.1. General
1H NMR (270 MHz) and 13C NMR (68 MHz) peak assign-
ments were performed with the aid of the DEPT technique,
2D COSY spectra and HETCOR spectra. Dry tetrahydro-
furan (THF) was obtained by distillation from sodium.
Diethylether was dried and distilled from sodium. Other
solvents were used as received from the supplier.

S. Claessens et al. / Tetrahedron 62 (2006) 8419–8424
8421
O
O
O
O
HOOC
2 equiv.
+
0.1 equiv. AgNO3,
2 equiv. (NH4)2S2O8,
CH3CN, H2O, 65-70°C, 6h
O
O
12
13 (35%)
14 (8%)
F
F
Si
F
3 equiv.
5 equiv. FeCl3.6H2O
DMF, CH3CN, rt, 63h
1) Na2S2O4 (excess)
O
OH
O
O
O
ether, H2O, rt,
30 min, N2
1.2 equiv. m-CPBA
CH2Cl2, rt, 16h
O
2) 10% H2SO4,
AcOH, rt, 6h
O
15
OH
13 (96%)
16 (52%;
1.2 equiv. Me2SO4,
5 equiv. K2CO3,
acetone, ∆, 3h
two steps)
OMe
OMe
OMe
Br
1.1 equiv. NBS,
CH2Cl2, rt, 10min
Br
1.1 equiv. TsCl
pyridine, rt, 16h
O
O
O
OTs
OH
OH
19 (86%)
18 (95%)
17 (90%)
5 equiv. KOtBu
THF, rt, 6h
OMe
O
OMe
O
1) 1.1 equiv. BuLi,
MeO
O
O
THF, -78°C, 30 min
Br
OMe
+
2) 1.2 equiv. ClCOOMe
THF, -78°C, 2h, rt, 16h
20 (73%)
21 (52%)
22 (8%)
20 equiv. AlCl3,
CH2Cl2, rt, 4h
OH
O
OMe
O
1 (77%)
Scheme 2.
3.1.1. 2-(3-Methyl-2-butenyl)-1,4-naphthoquinone (13).
Method A:15 a solution of 1,4-naphthoquinone (12)
(0.09 mol, 15.94 g), 4-methyl-3-pentenoic acid15 (0.09 mol,
12.83 g of technical grade, i.e., 80% pure) and silver nitrate
(9 mmol, 2 g) in acetonitrile (100 ml) and demineralised
water (200 ml) were heated at 65–70 ꢁC, and to the stirred
solution was added dropwise, over a period of 2 h, a solution
of ammonium persulfate (0.09 mol, 20.52 g) in demineral-
ised water (50 ml). Stirring was continued at the same tem-
perature for 1 h. A second portion of 4-methyl-3-pentenoic
acid (0.045 mol, 6.40 g of 80% technical grade) was added
and to the resulting mixture, a second portion of ammonium
persulfate (0.09 mol, 20.52 g) in demineralised water
(50 ml) was added dropwise over a period of 2 h and the
stirred mixture was kept at the same temperature for 1 h.
Afterwards the reaction mixture was cooled to room temper-
ature, poured in water (500 ml) and extracted with ethyl
acetate. The combined organic extracts were washed with
a saturated solution of sodium hydrogen carbonate, dried
(MgSO4) and evaporated in vacuo. Flash chromatography
over a short column of silica gel using ethyl acetate/petro-
leum ether (1:9) as eluent gave first a residual amount
of 1,4-naphthoquinone (10) followed by a mixture of
2-(3-methyl-2-butenyl)-1,4-naphthoquinone (13) and 2,3-
bis(3-methyl-2-butenyl)-1,4-naphthoquinone (14), which
eluted together as a second fraction from the column
(Rf¼0.35). The latter fraction was further purified by recrys-
tallisation from petroleum ether to afford 2-(3-Methyl-2-
butenyl)-1,4-naphthoquinone 13 (7.12 g, 35%) as yellow
needles, mp 58–58.5 ꢁC (lit.16 mp 60–61 ꢁC). 1H NMR
(CDCl3): d 1.67 (3H, s, CH3), 1.79 (3H, s, CH3), 3.28 (2H,
m, CH2), 5.19–5.26 (1H, m, CH]CMe2), 6.77 (1H, t,
J¼1.6 Hz, H-3), 7.69–7.76 (2H, m, H-6 and H-7), 8.04–
8.12 (2H, m, H-5 and H-8). 13C NMR (CDCl3): d 17.81
(CH3), 25.79 (CH3), 28.01 (CH2), 118.29 (CH]Me2),
126.02 and 126.50 (C-5 and C-8), 132.15 (]Cquat), 132.33

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S. Claessens et al. / Tetrahedron 62 (2006) 8419–8424
(]Cquat), 133.55 and 133.60 (C-6 and C-7), 134.61 (C-3),
136.33 (]Cquat), 150.76 (]Cquat), 185.23 (2ꢂC]O). IR
(NaCl): nmax 1659 (C]O), 1619 (C]O), 1595 (C]C)
cmꢀ1. MS m/z (%): 226 (M+, 24), 211 (46), 183 (9), 146
(62), 41 (100). Anal. Calcd for C15H14O2: C 79.62%, H
6.24%. Found: C 79.48%, H 6.33%
evaporated in vacuo. The residue was dissolved in acetic acid
(100 ml) and the stirred solution was mixed with a 10%
solution of sulfuric acid in water (50 ml), while stirring
was continued for 6 h under a nitrogen atmosphere. The re-
action mixture was poured in water and extracted with
dichloromethane. The combined organic extracts were
washed with a saturated solution of sodium hydrogen car-
bonate and then with brine, dried (MgSO4) and concentrated
in vacuo to a residual volume of 30 ml. The solution was
kept overnight at ꢀ20 ꢁC causing product 16 to precipitate
as small white transparent cubes (1.26 g, 52%), mp 173.5–
3.1.2. 2,3-Bis(3-Methyl-but-2-enyl)-1,4-naphthoquinone
(14). 1H NMR (CDCl3): d 1.68 (6H, d, J¼1.3 Hz,
2ꢂCH3), 1.79 (6H, s, 2ꢂCH3), 3.36 (4H, d, J¼6.9 Hz,
2ꢂCH2), 5.01 (2H, tꢂq, J¼6.9, 1.3 Hz, 2ꢂ]CH), 7.68
(2H, m, 2ꢂCHar), 8.07 (2H, m, 2ꢂCHar). 13C NMR
1
174.8 ꢁC. H NMR (acetone-d6): d 1.34 (3H, s, CH3), 1.49
(CDCl3):
d
18.18 (2ꢂCH3), 25.87 (2ꢂCH3), 2.14
(3H, CH3), 2.79 (1H, dd, JAB¼16.7 Hz, Jd¼7.6 Hz, CHaHb),
3.06 (1H, dd, JAB¼16.7 Hz, Jd¼5.6 Hz, CHaHb), 3.88–3.95
(1H, m, CH–OH), 4.26 (1H, d, J¼5.6 Hz, CH–OH), 6.64
(1H, s, H-5), 7.43–7.51 (2H, m, H-8 and H-9), 8.12–8.19
(2H, m, H-7 and H-10), 8.43 (1H, s, phenolic-OH). 13C
NMR (acetone-d6): d 20.02 (CH3), 26.19 (CH3), 32.51
(CH2), 70.22 (CHOH), 77.63 (CMe2), 10.61 (C-5), 114.77
(]Cquat), 122.08 and 122.75 (C-7 and C-10), 125.08 and
125.95 (C-8 and C-9), 125.62 (]Cquat), 126.92 (]Cquat),
141.23 (]C–O), 146.97 (]C–O). IR (KBr): nmax 3511
(OH), 3236 (OH), 1639, 1600, 1107, 1335, 1272, 1140,
1052, 766 cmꢀ1. MS m/z (%): 244 (M+, 63), 211 (49), 173
(81), 43 (100). Anal. Calcd for C15H16O3: C 73.75%, H
6.60%. Found: C 73.42%, H 6.66%.
(2ꢂCH2), 119.94 (2ꢂCH), 126.30 (2ꢂCHar), 132.29
(2ꢂCquat), 133.39 (2ꢂCHar), 133.89 (2ꢂCquat), 146.04
(2ꢂCquat), 185.26 (2ꢂC]O). IR (KBr): nmax 1659
(C]O), 1614 (C]C), 1592 (C]C). MS (ES+) m/z (%):
295 (M+H+, 100). Anal. Calcd for C20H22O2: C 81.60%,
H 7.53%. Found: C 81.48%, H 7.61%
Method B:17 to a mixture of 1,4-naphthoquinone (12)
(0.63 mmol, 100 mg) and FeCl3$H2O (3 mmol, 810 mg) in
DMF (9 ml) and acetonitrile (3 ml), was added prenyltri-
fluorosilane (1.8 mmol, 300 mg) and the mixture was stirred
overnight at room temperature. The reaction mixture was
poured in water and extracted with ethyl acetate. The extract
was washed with water and dried (MgSO4). Evaporation of
the solvent in vacuo and purification of the residue by means
of flash chromatography on silica gel using ethyl acetate/
petroleum ether (1/9) as eluent gave 13 (140 mg, 96%) as
a pale yellow solid.
3.1.5. Synthesis of 6-methoxy-2,2-dimethyl-3,4-dihydro-
2H-naphtho[1,2-b]pyran-3-ol (17). A mixture of 2,2-di-
methyl-3,4-dihydro-2H-naphtho[1,2-b]pyran-3,6-diol (16)
(4.5 mmol, 1.1 g), dimethyl sulfate (5.4 mmol, 0.68 g) and
potassium carbonate (22.5 mmol, 3.1 g) in acetone (50 ml)
was heated under reflux for 3 h, cooled to room temperature,
filtered and evaporated in vacuo. Flash chromatography on
silica gel using ethyl acetate/petroleum ether (1:4) gave
pure 17 (1.05 g, 90%). Recrystallisation from ethyl acetate/
petroleum ether (1:9) afforded 17 as white cubes, mp
3.1.3. 2-(2,3-Epoxy-3-methylbutyl)-1,4-naphthoquinone
(15). To a cooled (0 ꢁC) solution of 2-prenyl-1,4-naphtho-
quinone (13) (1 mmol, 0.23 g) in dichloromethane (10 ml)
was added m-chloroperbenzoic acid (1.2 mmol, 0.28 g)
and the mixture was stirred for 16 h at room temperature.
The solvent was evaporated in vacuo and the residual
white-yellow solid was dissolved in ether, washed with
2 M sodium hydroxide and then with water, dried
(MgSO4) and evaporated in vacuo to afford the crude epox-
ide 15 (170 mg, 70%, purity>95%) as a yellow oil, which
was used as such in the next step. 1H NMR (CDCl3):
d 1.37 (6H, s, 2ꢂCH3), 2.63–2.73 (1H, m, CHaHb), 2.91–
3.04 (2H, m, CHaHb and CH–O), 6.93 (1H, s, H-3), 7.70–
7.77 (2H, m, H-6 and H-7), 8.02–8.11 (2H, m, H-5 and
H-8). 13C NMR (CDCl3): d 18.83, 24.65, 29.33, 58.65,
61.45, 126.11, 126.56, 132.00, 133.69, 133.82, 135.85,
147.90, 184.62, 184.83. IR (NaCl): nmax 1660 (C]O),
1623 (C]O). MS m/z (%): 242 (M+, 2), 184 (100), 156 (50).
1
122.3–122.8 ꢁC. H NMR (CDCl3): d 1.36 (3H, s, CH3),
1.46 (3H, s, CH3), 1.92 (1H, br s, OH), 2.85 (1H, dd, JAB
¼
17.2 Hz, J¼4.6 Hz, CHaHb), 3.16 (1H, dd, JAB¼17.2 Hz,
J¼4.8 Hz, CHaHb), 3.85–3.89 (1H, m, CH–OH), 3.94 (3H,
s, MeO), 6.45 (1H, s, H-5), 7.44–7.49 (2H, m, H-8 and H-
9), 8.14–8.19 (2H, m, H-7 and H-10). 13C NMR (CDCl3):
d 22.32 (CH3), 24.47 (CH3), 32.15 (CH2), 55.67 (MeO),
69.83 (CH–OH), 76.71 (CMe2), 105.21 (C-5), 111.52
(]Cquat), 121.52 and 121.69 (C-7 and C-10), 125.21 and
125.87 (C-8 and C-9), 125.42 (]Cquat), 126.18 (]Cquat),
141.26 (]C–O), 149.27 (]C–O). IR (KBr): nmax 3313
(OH), 1631, 1598, 1458, 1387, 1273, 769 cmꢀ1. MS m/z
(%): 258 (M+, 6), 200 (19), 105 (100). Anal. Calcd for
C16H18O3: C 74.39%, H 7.02%. Found: C 74.28%, H 7.13%.
3.1.4. 2,2-Dimethyl-3,4-dihydro-2H-naphtho[1,2-b]-
pyran-3,6-diol (16). To a cooled (0 ꢁC) solution of
2-prenyl-1,4-naphthoquinone (13) (10 mmol, 2.3 g) in
dichloromethane (100 ml) was added m-chloroperbenzoic
acid (12 mmol, 2,8 g) and the mixture was stirred for 16 h
at room temperature. The solvent was evaporated in vacuo
and the residual solid was dissolved in ether (100 ml),
washed with 2 M sodium hydroxide and the ether solution,
under a nitrogen atmosphere, was vigourously stirred for
30 min with a 20% solution of sodium dithionite in water
(100 ml), while the yellow colour of the solution slowly be-
came pale. The ether phase was separated by decantation and
3.1.6. 5-Bromo-6-methoxy-2,2-dimethyl-2,3-dihydro-2H-
naphtho[1,2-b]-pyran-3-ol (18). 6-Methoxy-2,2-dimethyl-
3,4-dihydro-2H-naphtho[1,2-b]pyran-3-ol (17) (2 mmol,
0.51 g) was dissolved in dichloromethane (50 ml, dichloro-
methane was washed twice with concentrated sulfuric acid
and filtered over sodium carbonate before use, to eliminate
all traces of ethanol) and to this stirred solution, N-bromo-
succinimide (2.2 mmol, 0.39 g) was added portionwise
over a period of 10 min. The organic solution was washed
successively with water, 5% solution of sodium hydrogen
sulfite, saturated solution of sodium hydrogen carbonate

S. Claessens et al. / Tetrahedron 62 (2006) 8419–8424
8423
and finally with brine, dried (MgSO4) and evaporated in va-
cuo. Flash chromatography on silica gel using ethyl acetate/
petroleum ether (1:4) afforded 18 (0.64 g, 95%) as a brown
oil, which slowly solidified, mp 87–88 ꢁC. 1H NMR
(CDCl3): d 1.36 (3H, s, CH3), 1.43 (3H, s, CH3), 2.09 (1H,
br s, OH), 2.89 (1H, dd, JAB¼17.5 Hz, J¼5.0 Hz, CHaHb),
3.10 (1H, dd, JAB¼17.5 Hz, J¼5.3 Hz, CHaHb), 3.88 (1H,
m, CH–OH), 3.93 (3H, s, MeO), 7.44–7.52 (2H, m, H-8
and H-9), 8.00–8.03 and 8.18–8.21 (each 1H, each m, H-7
and H-10). 13C NMR (CDCl3): d 21.92 (CH3), 24.40
(CH3), 33.35 (CH2), 61.28 (MeO), 77.10 (CMe2), 112.88
(]Cquat), 116.12 (]Cquat), 121.74 and 122.30 (C-7 and
C-10), 125.32 (]Cquat), 125.82 and 126.72 (C-8 and C-9),
127.62 (]Cquat), 145.08 (]C–O), 146.83 (]C–O). IR
(KBr): nmax 3313 (OH), 1574, 1450, 1366, 1350, 1142,
1082, 991, 767 cmꢀ1. MS m/z (%): 336/8 (M+, 40), 303/5
(17), 265/7 (28), 264/6 (33), 49 (100). Anal. Calcd for
C16H17BrO3: C 56.99%, H 5.08%. Found: C 57.28%, H
5.01%.
The combined organic extracts were washed with a saturated
solution of sodium hydrogen carbonate, dried (MgSO4) and
evaporated in vacuo. Flash chromatography on silica gel us-
ing ethyl acetate/petroleum ether (5:95) afforded 20 (0.32 g,
73%) as a white solid. Recrystallisation from methanol gave
20 as light yellow needles, mp 59.5–60 ꢁC. 1H NMR
(CDCl3): d 1.51 (6H, s, 2ꢂCH3), 3.95 (3H, s, MeO), 5.72
(1H, d, J¼9.9 Hz, H-3), 6.81 (1H, d, J¼9.9 Hz, H-4),
7.44–7.52 (2H, m, H-8 and H-9), 7.99–8.03 and 8.16–8.19
(each 1H, each m, H-7 and H-10). 13C NMR (CDCl3):
d 27.48 (2ꢂCH3), 61.28 (MeO), 76.48, (CMe2), 112.65
(]Cquat), 115.18 (]Cquat), 121.81 and 122.51 (C-7 and
C-10), 121.90 (C-4), 125.08 (]Cquat), 125.84 and 127.02
(C-8 and C-9), 128.30 (]Cquat), 130.31 (C-3), 145.60
(]C–O), 146.72 (]C–O). IR (KBr): nmax 1632, 1556,
1355, 1270, 1163, 1129, 1081, 766 cmꢀ1. MS m/z (%):
318/20 (M+, 27), 303/5 (100), 288/90 (19), 225 (28). Anal.
Calcd for C16H15BrO2: C 60.21%, H 4.74%. Found: C
60.09%, H 4.91%.
3.1.7. 5-Bromo-6-methoxy-2,2-dimethyl-3-tosyloxy-
3,4-dihydro-2H-naphtho[1,2-b]pyran (19). A solution of
5-bromo-6-methoxy-2,2-dimethyl-2,3-dihydro-2H-naphtho-
[1,2-b]-pyran-3-ol (18) (1.9 mmol, 0.64 g), and p-toluene-
sulfonyl chloride (2.1 mmol, 0.40 g) in pyridine (5 ml) was
stirred for 16 h in a flask fitted with a calcium chloride
tube. The solution was diluted with ether (100 ml), washed
twice with 2 M HCl and then with a saturated solution of
sodium hydrogen carbonate and then with brine, dried
(MgSO4) and evaporated in vacuo to afford 17 (0.80 g,
86%, purity>95%) as a brown oil, which was used without
purification in the next step. An analytical sample of com-
pound 19 was obtained using chromatography on silica gel
with ethyl acetate/petroleum ether (1:4) as eluent to afford
19 as a light brown oil, which slowly solidified, mp
3.1.9. Synthesis of 6-methoxy-2,2-dimethyl-2H-naphtho-
[1,2-b]pyran (22) and methyl 6-methoxy-2,2-dimethyl-
2H-naphtho[1,2-b]pyran-5-carboxylate (21). A solution
of 5-bromo-6-methoxy-2,2-dimethyl-2H-naphtho[1,2-b]-
pyran (20) (0.53 mmol, 170 mg) in dry tetrahydrofuran
(5 ml) was cooled to ꢀ78 ꢁC and to the stirred solution, in
a nitrogen atmosphere, was added dropwise a solution of
n-butyllithium (2.5 M) in hexane (0.58 mmol, 0.23 ml).
After 30 min at this temperature, a solution of methyl
chloroformate (0.64 mmol, 60 mg) in dry THF (1 ml) was
added and the reaction mixture was kept for an additional
2 h at ꢀ78 ꢁC. Afterwards, the reaction mixture was allowed
to warm to room temperature overnight. The reaction mix-
ture was poured in 1 M HCl and extracted with ether. The
combined organic phases were washed with brine, dried
(MgSO4) and evaporated in vacuo. Flash chromatography
on silica gel using ethyl acetate/petroleum ether (5:95) as
eluent afforded first 6-methoxy-2,2-dimethyl-2H-naphtho-
[1,2-b]pyran (22)18 (Rf ¼0.29, 10 mg, 8%) as a pale yellow
oil. 1H NMR (CDCl3): d 1.49 (6H, s, 2ꢂCH3), 3.94 (3H, s,
MeO), 5.64 (1H, d, J¼9.5 Hz, H-3), 6.39 (1H, d,
J¼9.5 Hz, H-4), 6.50 (1H, s, H-5), 7.42–7.49 (2H, m, H-8
and H-9), 8.13–8.16 (2H, m, H-7 and H-10). MS m/z (%):
240 (M+, 25), 225 (100), 210 (10). Using the same solvent
combination, methyl 6-methoxy-2,2-dimethyl-2H-naphtho-
[1,2-b]pyran-5-carboxylate (21) (Rf ¼0.13, 90 mg, 57%)
was collected as a second fraction and appeared as a pale yel-
low oil. 1H NMR (CDCl3): d 1.51 (6H, s, 2ꢂCH3), 3.96 (3H,
s, MeO), 3.99 (3H, s, MeO), 5.68 (1H, d, J¼9.9 Hz, H-3),
6.42 (1H, d, J¼9.9 Hz, H-4), 7.47–7.53 (2H, m, H-8 and
H-9), 8.01–8.06 and 8.18–8.22 (each 1H, each m, H-7 and
H-10). 13C NMR (CDCl3): d 27.65 (2ꢂCH3), 52.40
(MeO), 63.49 (MeO), 76.44 (CMe2), 112.36 (]Cquat),
119.80 (]CH), 120.52 (]Cquat), 122.46 (]CH), 122.59
(]CH), 126.75 (]CH), 126.83 (]CH), 127.78 (]Cquat),
130.24 (]CH), 144.89 (]C–O), 147.53 (]C–O), 167.78
(C]O). IR (NaCl): nmax 1731 (C]O) cmꢀ1. MS m/z (%):
298 (M+, 7), 283 (13), 143 (88), 84 (92), 49 (100). Anal.
Calcd for C18H18O4: C 72.47%, H 6.08%. Found: C
72.22%, H 5.84%.
1
124 ꢁC. H NMR (CDCl3): d 1.32 (3H, s, CH3), 1.36 (3H,
s, CH3), 2.45 (3H, s, CH3-Ar), 2.87 (1H, dd, JAB¼17.8 Hz,
Jd¼6,1 Hz, CHaHb), 3.15 (1H, dd, JAB¼17.8 Hz, Jd¼5.3 Hz,
CHaHb), 3.92 (3H, s, MeO), 4.75 (1H, t, Jz6 Hz, CH-OTs),
7.34 (2H, d, J¼7.9 Hz, 2ꢂ]CH), 7.44–7.54 (2H, m, H-8
and H-9), 7.80 (2H, d, J¼8.3 Hz, 2ꢂ]CH), 7.99–8.15
(2H, m, H-7 and H-10). 13C NMR (CDCl3): d 21.67
(CH3), 21.79 (CH3), 24.67 (CH3), 30.73 (CH2), 61.28
(MeO), 75.27 (CH-OTs), 78.87 (CMe2), 111.62 (]Cquat),
115.15 (Cquat), 121.76 and 122.23 (C-7 and C-10),
125.12 (]Cquat), 125.96 and 126.92 (C-8 and C-9), 127.71
(]Cquat), 127.85 (2ꢂ]CH), 129.94 (2ꢂCH), 133.78
(]Cquat), 144.74 (]Cquat), 145.10 (]C–O), 147.01
(]C–O). IR (KBr): nmax 1571, 1450, 1350, 1189, 906,
863, 765 cmꢀ1. MS m/z (%): 490/2 (M+, 40), 336/8 (12),
318/20 (23), 303/5 (62), 264/6 (30), 224 (30), 91 (53), 43
(100). Anal. Calcd for C23H23BrO5S: C 56.22%, H 4.72%.
Found: C 56.11%, H 4.91%.
3.1.8. 5-Bromo-6-methoxy-2,2-dimethyl-2H-naphtho-
[1,2-b]pyran (20). To a cooled (0 ꢁC) solution of 5-bromo-
6-methoxy-2,2-dimethyl-3-tosyloxy-3,4-dihydro-2H-naphtho-
[1,2-b]pyran (19) (1.3 mmol, 0.66 g) in dry tetrahydrofuran
(20 ml) was added potassium tert-butoxide (6.5 mmol,
0.73 g), and the reaction mixture was kept at room tempera-
ture for 6 h in a flask fitted with a calcium chloride tube. The
reaction mixture was quenched by the addition of 1 M HCl
(100 ml) and the aqueous solution was extracted with ether.
3.1.10. Mollugin (1). To a cooled (0 ꢁC) solution of methyl 6-
methoxy-2,2-dimethyl-2H-naphtho[1,2-b]pyran-5-carboxylate

8424
S. Claessens et al. / Tetrahedron 62 (2006) 8419–8424
2. (a) Hari, L.; De Buyck, L. F.; De Pooter, H. L. Phytochemistry
1991, 30, 1726–1727; (b) De Kimpe, N.; Van Puyvelde, L.;
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(21) (0.69 mmol, 220 mg) in dry dichloromethane (20 ml)
was added aluminium(III) chloride (13.8 mmol, 1.84 g)
and the reaction mixture was stirred for 4 h in a flask fitted
with a calcium chloride tube. The reaction mixture was
quenched by the addition of water (50 ml) (cooling!) and
the aqueous solution was further diluted with 1 M HCl
(50 ml), extracted with dichloromethane, dried (MgSO4)
and evaporated in vacuo. Flash chromatography on silica
gel using ethyl acetate/petroleum ether (5:95) afforded mol-
lugin (1) (150 mg, 77%) as a yellow powder. Recrystallisa-
tion from methanol gave mollugin (1) as yellow-green
flakes, mp 129.5–131 ꢁC (lit.1 mp 128.8 ꢁC). The spectral
data of mollugin (1) were in complete accordance with those
reported for the natural mollugin. 1H NMR (CDCl3): d 1.48
(6H, s, 2ꢂCH3), 4.00 (3H, s, MeO), 5.66 (1H, d, J¼9.9 Hz,
H-3), 7.09 (1H, d, J¼9.9 Hz, H-4), 7.46–7.53 and 7.57–7.63
(each 1H, each m, H-8 and H-9), 8.15–8.18 and 8.34–8.38
(each 1H, each m, H-7 and H-10), 12.17 (1H, s, OH), 13C
NMR (CDCl3): d 26.83 (2ꢂCH3), 52.29 (MeO), 74.61
(CMe2), 102.19 (]Cquat), 112.54 (]Cquat), 121.90
(]CH), 122.30 (]CH), 124.06 (]CH), 125.05 (]Cquat),
126.27 (]CH), 128.98 (]Cquat), 129.32 (]CH), 141.54
(]C–O), 156.48 (]C–O), 172.49 (C]O), IR (KBr): nmax
1651 (C]O), 1449, 1360, 1342, 1238, 769 cmꢀ1. MS m/z
(%): 284 (M+, 23), 252 (32), 237 (85), 84 (69), 49 (100).
Anal. Calcd for C17H16O4: C 71.82%, H 5.67%. Found: C
71.63%, H 5.77%.
11. Chung, M. I.; Jou, S. J.; Cheng, H. C.; Lin, C. N.; Ko, F. N.;
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1312.
Acknowledgements
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The authors are indebted to the Fund for Scientific
Research—Flanders (FWO—Vlaanderen) and the Flemish
Institute for the Promotion of Scientific-Technological
Research in Industry (IWT) for financial supports.
17. (a) Hagiwara, E.; Hatanaka, Y.; Gohda, K.-L.; Hiyama, T.
Tetrahedron Lett. 1995, 36, 2773–2776.
References and notes
18. (a) See Ref. 4; (b) Costa, S. M. O.; Lemis, T. L. G.; Pessoa,
O. D. L.; Pessoa, C.; Montenegro, R. C.; Braz-Filho, R.
J. Nat. Prod. 2001, 64, 792–795.
1. Schildknecht, H.; Straub, F.; Scheidel, V. Liebigs Ann. Chem.
1976, 1295–1306.