Synthesis of the natural products 3-hydroxymollugin and 3-methoxymollugin

Article abstract of DOI:10.1021/jo100024b

(Figure Presented) 3-Hydroxymollugin 2 and 3-methoxymollugin 3 are cytotoxic compounds isolated as minor compounds from Pentas longiflora and Rubia cordifolia. Syntheses of 3-hydroxymollugin 2 and 3-methoxymollugin 3 were developed starting from easily available 3-bromomollugin 6. Surprisingly, it was found that the reaction of 3-bromomollugin 6 with sodium methoxide in methanol resulted in the formation of 3-methoxymollugin 3 and the ring-contracted methyl isopropenylfuromollugin 7. A mechanism for this ring contraction is proposed on the basis of a pericyclic retro oxa-6π ring-opening reaction. A second synthesis of 3-hydroxymollugin 2 was based on epoxidation of methyl 3-(3-methylbut-2-enyl)-l,4-naphthoquinone-2-carboxylate 17 and subsequent reduction of the quinone moiety, ring transformation, and DDQ oxidation. The latter oxidation process results in 3-hydroxymollugin 2 along with the rearranged furomollugin 4, which is a ring-contracted analogue of the natural product mollugin 1.

Full text of DOI:10.1021/jo100024b

pubs.acs.org/joc
Synthesis of the Natural Products 3-Hydroxymollugin
and 3-Methoxymollugin
Mudiganti Naga Venkata Sastry, Sven Claessens, Pascal Habonimana,
and Norbert De Kimpe*
Department of Organic Chemistry, Faculty of Bioscience Engineering. Ghent University,
Coupure Links 653, B-9000 Ghent, Belgium
norbert.dekimpe@ugent.be
Received January 15, 2010
3-Hydroxymollugin 2 and 3-methoxymollugin 3 are cytotoxic compounds isolated as minor
compounds from Pentas longiflora and Rubia cordifolia. Syntheses of 3-hydroxymollugin 2 and
3-methoxymollugin 3 were developed starting from easily available 3-bromomollugin 6. Surpris-
ingly, it was found that the reaction of 3-bromomollugin 6 with sodium methoxide in methanol
resulted in the formation of 3-methoxymollugin 3 and the ring-contracted methyl isopropenyl-
furomollugin 7. A mechanism for this ring contraction is proposed on the basis of a pericyclic retro
oxa-6π ring-opening reaction. A second synthesis of 3-hydroxymollugin 2 was based on epoxidation
of methyl 3-(3-methylbut-2-enyl)-1,4-naphthoquinone-2-carboxylate 17 and subsequent reduction
of the quinone moiety, ring transformation, and DDQ oxidation. The latter oxidation process results
in 3-hydroxymollugin 2 along with the rearranged furomollugin 4, which is a ring-contracted
analogue of the natural product mollugin 1.
Introduction
Mollugin 1 is a naturally occurring benzochromene re-
puted for its anticarcinogenic1,2 and antiviral activities.3-5
This natural product 1 is well investigated, and several
synthetic procedures were described in the last years.2-8
Interesting analogues of mollugin 1 were also identified from
plant sources, but in contrast to mollugin 1 itself, they were
not synthesized hitherto (Figure 1). 3-Hydroxymollugin 2,
3-methoxymollugin 3, and furomollugin 4 are cytotoxic
FIGURE 1. Compounds isolated from R. cordifolia and P. longi-
flora.
compounds which have been isolated from Rubia cordifolia9
and Pentas longiflora.10 In this paper, the first synthesis of
3-hydroxymollugin 2 and 3-methoxymollugin 3 along with a
novel synthetic route toward furomollugin 7 are reported.
(1) Itokawa, H.; Mihara, K.; Takeya, K. Chem. Pharm. Bull. 1983, 31,
2353–2358.
(2) Ho, L.-K.; Yu, H.-J.; Ho, C.-T.; Don, M.-J. J. Chin. Chem. Soc. 2001,
67, 127–131.
Results and Discussion
(3) Ho, L.-K.; Don, M.-J.; Chen, H.-C.; Yeh, S.-F.; Chen, J.-M. J. Nat.
Prod. 1996, 59, 330–333.
(4) Wang, X.; Lee, Y. R. Tetrahedron Lett. 2007, 48, 6275.
(5) Lee, Y. R.; Wang, X.; Kim, Y. M.; Shin, J. J.; Kim, B. N.; Han, B. H.
Bull. Korean Chem. Soc. 2007, 28, 1735–1738.
In a previous report, it was found that 3-bromomollugin 6
can easily be formed starting from 3,4-dihydromollugin 5 by
(6) Habonimana, P.; Claessens, S.; De Kimpe, N. Synlett 2006, 2472–
2475. and references cited therein.
(7) Claessens, S.; Kesteleyn, B.; Nguyen, V. T.; De Kimpe, N. Tetra-
hedron 2006, 62, 8419–8424.
(8) Lumb, J.-P.; Trauner, D. Org. Lett. 2005, 7, 5865–5868.
(9) Itokawa, H.; Ibraheim, Z. Z.; Qiao, Y. F.; Takeya, K. Chem. Pharm.
Bull. 1993, 41, 1869–72.
(10) El-Hady, S.; Bukuru, J.; Kesteleyn, B.; Van Puyvelde, L.; Nguyen,
V. T.; De Kimpe, N. J. Nat. Prod. 2002, 65, 1377–1379.
2274 J. Org. Chem. 2010, 75, 2274–2280
Published on Web 03/04/2010
DOI: 10.1021/jo100024b
r
2010 American Chemical Society

Sastry et al.
JOCArticle
SCHEME 1
TABLE 1. Reaction Conditions for the Reactions with 3-Bromomollugin 6 Leading to Compounds 2, 3, and 7a
entry
reaction conditions
6b (%)
7 (%)
3 (%)
2 (%)
1
2
3
4
5
6
7
8
3 equiv of 2 M NaOMe, MeOH/DMF (1/1), 0.05 equiv of CuI, 56 h, Δ
4 equiv of 2 M NaOMe, MeOH/ DMF (1/1), 0.05 equiv of CuI, 56 h, Δ
3 equiv of 2 M NaOMe, MeOH/ DMF (1/1), 56 h, Δ
4 equiv of 4 M NaOMe, MeOH/DMF (1/1), 2 h, Δ
5 equiv of K2CO3, DMF, 24 h, rt
0
0
50
40
10
35
0
10
57
49
0
2
5
20
5
0
0
0
0
10
42
25
2
0
0
0
30
50
18
25
2
0
35
42
38
47
5
0
0
0
5 equiv of K2CO3, DMF, 4 h, 80 °C
5 equiv of K2CO3, DMF, 0.5% H2O, 4 h, 80 °C
5 equiv of K2CO3, DMF, 5% H2O, 4 h, 80 °C
5 equiv of K2CO3, MeOH/DMF (1/1), 24 h, rt
8 equiv of 4 M NaOMe, MeOH, 24 h, Δ
2
9
80
52
35
0
10
11
12
6
6
10
16 equiv of 4 M NaOMe, MeOH, 24 h, Δ
microwave, MeOH/DMF (1/1), 0.5 h
aA complete overview of all attempted reactions can be found in the Supporting Information. bYields determined by 1H NMR of the crude reaction
mixtures.
SCHEME 2
reaction with 2 equiv of N-bromosuccinimide in CCl4 in the
presence of benzoyl peroxide (Scheme 1).7 In the present paper,
the synthesis of 3-bromomollugin 6 is improved from 58%
to 72% by direct bromination of mollugin 1, using N-bromo-
succinimide in the presence of benzoyl peroxide (Scheme 1).
It was thought that the reaction of 3-bromomollugin 6
with sodium methoxide would lead to the target 3-methoxy-
mollugin 3 via an addition-elimination reaction. Therefore,
3-bromomollugin 6 was reacted with 3 equiv of 2 M sodium
methoxide and 0.05 equiv of copper(I) iodide in methanol11
(Scheme 2, Table 1, entry 1). However, after 56 h of reflux
only 2% of 3-methoxymollugin 3 was obtained together with
50% of a new compound, which was identified as methyl
5-hydroxy-2-isopropenylnaphtho[1,2-b]furan-4-carboxylate
or 2-isopropenylfuromollugin 7.
This rearranged compound 7 is an interesting compound
as it can be viewed as a structural unit of the natural products
rubicordifolin 8, rubioncolin A 9, and rubioncolin B 10
(Figure 2).12 This statement, together with the finding that
these compounds are often isolated together with mollugin 1
from Rubiaceae, led to the conclusion that these compounds
8, 9, and 10 might be biochemically related to mollugin 1.
Several reaction conditions were verified in order to im-
prove the yields of the reaction of 3-bromomollugin 6 with
sodium methoxide (Table 1). Increasing the number of
FIGURE 2. Natural products isolated from Rubiaceae.
equivalents of NaOMe resulted in a slight increase in the
yield of 3-methoxymollugin 3 (entry 2). Surprisingly, in the
absence of the catalyst copper(I) iodide, bromomollugin 6
and 3 equiv of 2 M sodium methoxide in methanol for 56 h
under reflux resulted in an improvement in the yield of
3-methoxymollugin (20%) and with a decrease in the amount
of isopropenylfuromollugin 7 (entry 3). Shifting the solvent to
DMF and reacting 3-bromomollugin 6 with 4 M NaOMe in
methanol (ratio MeOH/DMF 1/1) at 80 °C for 2 h afforded
35% isopropenylfuromollugin 7 along with 5% 3-methoxy-
mollugin 3 (entry 4). Performing the reaction under similar
basic conditions at room temperature gave no reaction, and
only starting material was recovered. In order to investigate the
mechanism of the formation of isopropenylfuromollugin 7,
which was thought to proceed via a thermochemical pericyclic
ring-opening reaction, 3-bromomollugin 6 was heated in
DMF. After heating at 100 °C for 16 h only starting material
was recovered. However, this result completely changed upon
addition of base. After reaction of 3-bromomollugin 6 with
5 equiv of potassium carbonate in DMF for 24 h at room
temperature, the natural product 3-hydroxymollugin 2 was
isolated in 35% yield (entry 5). The same reaction, when heated
at 80 °C for 4 h, resulted in the formation of 3-hydroxymollugin
2 in 42% yield along with 5% isopropenylfuromollugin 7
(11) Norrby, P. O.; Kolb, H. C.; Sharpless, K. B. Organometallics 1994,
13, 344–347.
(12) Lumb, J.-P.; Trauner, D. J. Am. Chem. Soc. 2005, 127, 2870–2871.
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SCHEME 3
SCHEME 4
(entry 6). This result is explained by the inherent water content
in DMF and K2CO3. In order to evaluate the role of water, two
experiments were carried out with additional 0.5% and 5% of
water. Surprisingly, both reactions proceeded smoothly, and
the reaction carried out with 5% of water facilitated the
formation of the required 3-hydroxymollugin 2 (47%) when
compared to the reaction carried out with 0.5% water (38%)
(entries 7 and 8). The experiments carried out with 5 equiv of
K2CO3 as a base and 3-bromomollugin 6 either with 5% H2O
in DMF at 50 °C for 14 h (or 24 h) at ambient temperature or
prolonged heating at 80 °C in DMF without H2O (24 h) led to
the formation of complex reaction mixtures. Using the same
amount of base, the reaction of 3-bromomollugin 6in methanol
for 24 h at room temperature resulted in the recovery of starting
material, whereas the same reaction under reflux conditions
provided a complex reaction mixture. However, the reaction of
3-bromomollugin 6 in the presence of 5 equiv of K2CO3 in a
solvent mixture of MeOH/DMF (1:1) for 24 h at room
temperature resulted in the formation of 3-methoxymollugin
3 and 3-hydroxymollugin 2 in 10% and 5% yield, respectively
(entry 9). Finally, by switching the base from potassium
carbonate to NaOMe, 3-methoxymollugin 3 was obtained in
an acceptable yield. Thus, when 8 equiv of a 4 M NaOMe in
methanol under reflux for 24 h was used, 3-methoxymollugin 3
was obtained in 42% yield along with 6% of isopropenylfuro-
mollugin 7 (entry 10). Under similar conditions, i.e., 8 equiv of
4 M NaOMe in MeOH and DMF (1:1), 3-bromomollugin 6
resulted in a complex reaction mixture. With an increase in the
amount of base (8 equiv to 16 equiv of 4 M NaOMe), the
reaction of compound 6 in methanol under reflux for 24 h
decreased the formation of both 3-methoxymollugin 3 (only
25%) and 7 (6%) (entry 11) (Scheme 3). A microwave reaction
was attempted, but the reaction of 3-bromomollugin 6 with
5 equiv of K2CO3 resulted only in a low yield of 3-methoxy-
mollugin 3 (∼2%) along with 10% of isopropenylfuromollugin
7 (entry 12). Further research under microwave conditions was
abandoned.
These results allow the synthesis of the natural products
3-hydroxymollugin 2, 3-methoxymollugin 3, and isopropenyl-
furomollugin 7 in acceptable yields as represented in Scheme 4.
Based on these results, the following reaction mecha-
nism for the formation of the ring contracted isopropenyl-
furomollugin 7 was proposed (Scheme 5). Apparently, ther-
mal activation is necessary for the formation of isoprope-
nylfuromollugin 7 as there is no formation of this compound
7 at room temperature versus its formation in 10% yield at
80 °C (entry 6).
Therefore, it is proposed that the reaction is initiated by a
pericyclic retro oxa-6π ring-opening. Next, the allylic hydro-
gen in intermediate 12 is deprotonated by the base after
which the phenolate 13 intramolecularly attacks the double
bond which is activated by the electron-withdrawing ester
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SCHEME 5
SCHEME 6
moiety. Addition-dehydrobromination results in the ob-
tained isopropenylfuromollugin 7 (route b). Elimination of
bromide in compound 11 occurs when sodium methoxide or
hydroxide acts as a nucleophile across the conjugated vinyl
bromide, leading to 3-methoxymollugin 3 or 3-hydroxy-
mollugin 2, respectively (route a).
Subsequently, an alternative route for the synthesis of
3-hydroxymollugin 2, not starting from 3-bromomollugin 6,
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SCHEME 7
SCHEME 8. Plausible Mechanism for the Formation of Furomollugin 21
SCHEME 9
was evaluated (Scheme 6). This alternative synthesis of
3-hydroxymollugin 2 started from methyl 3-prenyl-1,4-
naphthoquinone-2-carboxylate 17,6 which is considered to
be the biochemical precursor of mollugin 1 and its analogues.
Compound 17 was prepared by our previously disclosed
method of prenylation of methyl naphthoquinone-2-carboxy-
late 15 with tributylprenyltin in the presence of boron(III)
fluoride etherate and subsequent oxidation of the intermedi-
ate naphthol 16 with silver(I) oxide.6 In this report, a more
detailed investigation of the obtained reaction products is
revealed. It has been found that the desired compound 17 is
formed in 45% yield together with unoxidized naphthalene
16 (5%), reduced starting material 18 (3%), and mollugin 1
(12%). Epoxidation of the olefinic double bond in the prenyl
side chain of methyl 3-prenyl-1,4-naphthoquinone 17 with
m-CPBA in dichloromethane at 0 °C for 2 h resulted in
epoxide 19 in excellent yield (82%). Reduction of the qui-
none 19 with sodium dithionite in ethyl acetate/H2O (3/2)7
afforded the corresponding naphthalene-1,4-diol as inter-
mediate, which subsequently suffered ring opening of the
epoxide by the proximate phenolic hydroxyl group during
silica gel chromatography to give rise to chromanol 20.
In this way, the desired chromanol 20 was obtained in a
moderate combined yield (57%). Surprisingly, oxidation of
compound 20 using DDQ in different solvents afforded differ-
ent products along with the required 3-hydroxymollugin 2.
An oxidation protocol using DDQ in dioxane/water (20/1)
was found to oxidize chromanol 20 at room temperature
resulting in the target 3-hydroxymollugin 2 in excellent
yield (82%). Other conditions, which used DDQ in toluene,
afforded mixtures of oxidation compounds 2, 7, and 21
(Scheme 7; see the Supporting Information for more details).
Mechanistically, the formation of furomollugin 4 is
thought to proceed via the formation of mollugin 1, which
is successfully oxidized by DDQ to compound 21 (Scheme 8).
Based on the observations by Trauner et al.,13 it is believed
that ring contraction and elimination of the elements of
acetone lead to the formation of furomollugin 4.
Having in hand a high-yielding synthesis of 3-hydroxy-
mollugin 2, methylation reactions were attempted in order to
obtain 3-methoxymollugin 3 in high yield. Unfortunately, all
attempted reaction conditions were unsuccessful (Scheme 9,
see the Supporting Information). When 1.5 equiv of Me2SO4
or 2 equiv of iodomethane was used as methylating agent in
the presence of 2 equiv of K2CO3 in acetone, only the
(13) Lumb, J.-P.; Choong, K. C.; Trauner, D. J. Am. Chem. Soc. 2008,
130, 9230–9231.
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formation of O-methyl-3-hydroxymollugin 24 was observed.
Attempts to further methylate O-methyl-3-hydroxymollugin
24 at the vinylic hydroxyl group were not successful using
Me2SO4 or MeI. It was also observed that prolonged reac-
tion times of more than 24 h led to a slow decomposition of
the starting material.
over magnesium sulfate, and the solvent was evaporated to afford a
thick brown viscous liquid which was purified by flash chromato-
graphy using silica gel (petroleum ether/ethyl acetate 9/1) to afford
0.163 g of methyl 3,6-dihydroxy-2,2-dimethyl-3,4-dihydro-2H-
benzo[h]chromene-5-carboxylate 20 (45% yield) as a yellow crystals.
Mp: 116-117 °C. 1H NMR (CDCl3, 300 MHz): δ 1.25 (3H, s), 1.39
(3H, s), 2.14 (1H, sbroad) 3.42 (2H, d, J = 9.4 Hz), 3.92 (3H, s),
4.68 (1H, t, J = 9.4 Hz), 7.46 (1H, t, J = 7.4 Hz), 7.56 (1H, t, J =
7.4 Hz), 7.85 (1H, d, J = 8.3 Hz), 8.32 (1H, d, J = 8.3 Hz), 11.77
(1H, s). 13C NMR (CDCl3, 75 MHz): δ 24.1, 26.1, 34.2, 52.3, 72.1,
89.2, 103.3, 116.8, 121.2, 124.0, 124.5, 125.6, 129.2, 147.2, 156.1,
171.8. IR (NaCl) νmax: 1645, 3456. MS (ES-) m/z: 301 (M - Hþ,
100). Anal. Calcd for C17H18O5: C, 67.54; H, 6.00. Found: C, 67.79;
H 6.14.
Conclusion
In conclusion, the first synthesis of the natural products
3-hydroxymollugin 2 and 3-methoxymollugin 3 was success-
fully accomplished in acceptable yields. It was found that
addition-dehydrobromination of 3-bromomollugin 6 is
a feasible strategy to obtain compounds 2 and 3. When
3-bromomollugin 6 is thermally activated, a retro-oxa-6π peri-
cyclic reaction occurs with the formation of the interesting iso-
propenylfuromollugin 7. In the case of 3-hydroxymollugin 2, an
alternative synthesis was presented based on epoxidation
and subsequent ring closure of 3-prenyl-1,4-naphthoqui-
none-2-carboxylate 17. DDQ-oxidation results in 3-hydro-
xymollugin 2 along with the rearranged furomollugin 4,
which is a ring-contracted analogue of mollugin 1.
3-Hydroxymollugin (Methyl 3,6-Dihydroxy-2,2-dimethyl-2H-
benzo[h]chromene-5-carboxylate) 2. To a solution of methyl 3,6-
dihydroxy-2,2-dimethyl-3,4-dihydro-2H-benzo[h]chromene-5-
carboxylate 20 (0.25 g, 0.827 mmol) in a solvent mixture of dioxane/
H2O (20:1) (5 mL) was added 2,3-dichloro-5,6-dicyano-1,4-benzo-
quinone (0.23 g, 0.278 mmol). After being stirred for 14 h at room
temperature, the reaction mixture was poured into 30 mL of
saturated sodium bicarbonate solution and extraction was per-
formed with EtOAc (3 ꢀ 20 mL). The combined organic layers
were dried and evaporated in vacuo to obtain crude 3-hydroxymol-
lugin 2 as a brown solid which was flashed through a pad of silica gel
to obtain 0.203 g of pure methyl 3,6-dihydroxy-2,2-dimethyl-2H-
benzo[h]chromene-5-carboxylate 2 (82% yield) as a white solid.
Experimental Section
3-Bromomollugin 6. To a stirred solution of mollugin 1
(2 mmol, 0.568 g) in CCl4 (10 mL) were added benzoyl peroxide
(0.2 equiv, 0.4 mmol, 96 mg) and N-bromosuccinimide (1.5 equiv,
3 mmol, 0.534 g). The reaction mixture was heated under reflux for
5 h and subsequently cooled in an ice bath. The reaction mixture
was filtered and evaporated in vacuo to yield 3-bromomollugin 6.
The residue was purified by column chromatography (petroleum
ether/ethyl acetate 97/3) to afford yellow crystals (0.78 g, 72%
yield). Mp: 117.9-118 °C. 1H NMR (CDCl3, 300 MHz): δ 1.59
(6H, s), 4.03 (3H, s), 7.52 (1H, ddd, J = 8.3 Hz, J = 6.9 Hz, J =
1.4 Hz), 7.56 (1H, s), 7.62 (1H, ddd, J = 8.3 Hz, J = 6.9 Hz, J =
1.4 Hz), 8.11 (1H, ddd, J = 8.3 Hz, J = 1.4 Hz, J = 0.8 Hz), 8.36
1
Mp: 142.3-143.5 °C (lit.6 mp 143-145 °C). H NMR (CDCl3,
300 MHz): δ1.57 (6H, s), 4.09 (3H, s), 7.21 (1H, d, J= 1.9 Hz), 7.53
(1H, dddJ=8.3Hz,J=6.9Hz, 1.4Hz),7.72(1H,dddJ=8.3Hz,
J= 6.9Hz,J=1.4Hz), 7.74(1H, d, J=1.9Hz), 8.20(1H, dq, J=
8.3 Hz, J = 0.7 Hz), 8.47 (1H, dq, J = 8.3 Hz, J = 0.7 Hz), 12.28
(1H, s). 13C NMR (CDCl3, 75 MHz): δ 29.7, 52.3, 74.7, 99.2, 109.4,
119.9, 120.0, 123.0, 125.0, 125.1, 125.2, 130.2, 144.4, 159.4, 162.6,
172.1. IR (KBr) νmax: 1659, 3500. MS (ESþ) m/z: 301 (M þ Hþ,
100). Anal. Calcd for C17H16O5: C, 67.99; H, 5.37. Found: C, 67.81;
H 5.78.
Procedure for the Synthesis of 3-Methoxymollugin 3 Using
NaOMe. To a solution of freshly prepared 4 M sodium metho-
xideinmethanol(2.2mL, 4.4 mmol)was added3-bromomollugin
6 (0.20 g, 0.55 mmol). The reaction mixture was heated under
reflux for 24 h. Then methanol was removed in vacuo and the
residue partitioned between ethyl acetate and water. The organic
phase was separated, washed with water, and dried over MgSO4,
and the solvent was removed in vacuo. Purification by silica gel
column chromatography using petroleum ether/ethyl acetate
(90:10) as eluent afforded 72 mg of 3-methoxymollugin 3 (42%
yield, white crystals) along with 9 mg of methyl 5-hydroxy-2-
isopropenylnaphtho[1,2-b]furan-4-carboxylate 7 (6% yield).
3-Methoxymollugin (Methyl 6-Hydroxy-3-methoxy-2,2-di-
methyl-2H-benzo[h]chromene-5-carboxylate) 3. Mp: 119.5-121 °C
(1H, ddd, J = 8.3 Hz, J = 1.4 Hz, J = 0.8 Hz), 12.27 (1H, s). 13
C
NMR (CDCl3, 75 MHz): δ 25.8, 52.6, 78.7, 101.2, 113.1, 121.85,
123.8, 124.3, 125.2, 125.3, 126.7, 128.8, 129.8, 140.3, 157.3, 172.2.
IR (KBr) νmax: 1650 (CdO). MS (ESþ) m/z: 362/364 (Mþ, 100).
Methyl 3-(3,3-Dimethyloxiranylmethyl)-1,4-naphthoquinone-
2-carboxylate 19. To a stirred solution of methyl 3-(3-methyl-
but-2-enyl)-1,4-naphthoquinone-2-carboxylate 17 (0.42 g, 1.47
mmol) in dichloromethane (20 mL) at 0 °C was added 1.2 equiv
of 70% m-chloroperbenzoic acid (0.305 g, 1.77 mmol). Stirring
was continued for 2 h after which time the reaction mixture was
poured into water and the organic phase was separated, washed
with a saturated aqueous solution of sodium bicarbonate (TLC
monitoring), and dried over magnesium sulfate. Removal of the
solvent in vacuo afforded 0.36 g of methyl 3-(3,3-dimethyl-
1
(lit.6 mp 121-123 °C). H NMR (CDCl3, 300 MHz) δ: 1.70
oxiranylmethyl)-1,4-naphthoquinone-2-carboxylate 19 as
a
(6H, s), 3.17 (3H, s), 4.09 (3H, s), 7.04 (1H, s), 7.50 (1H, ddd, J =
8.3 Hz, J = 6.9 Hz, J = 1.4 Hz), 7.69 (1H, ddd, J = 8.3 Hz, J =
6.9 Hz, J = 1.4 Hz), 8.23 (1H, d, J = 8.3 Hz), 8.45 (1H, d, J =
8.3 Hz), 12.25 (1H, s). 13C NMR (CDCl3, 75 MHz): δ 25.6, 51.2,
52.4, 73.7, 99.2, 106.6, 120.0, 120.3, 122.9, 124.9, 125.0, 125.1,
130.1, 144.1, 159.3, 159.6, 172.1. IR (KBr) νmax: 1656. MS (ES-)
m/z: 313 (M - Hþ, 100). Anal. Calcd for C18H18O5: C, 68.78; H,
5.77. Found: C, 68.52; H, 5.98.
brown oil (82% yield), which was used directly in the next step,
without purification. 1H NMR (CDCl3, 300 MHz): δ 1.30 (3 H, s),
1.37 (3 H, s), 2.70 (1 H, dd, J = 12.9 Hz, J = 6.6 Hz), 2.96
(1 H, dd, J = 6.6 Hz, J = 4.7 Hz), 3.02 (1 H, dd, J = 12.9 Hz,
J = 4.7 Hz), 3.95 (3 H, s), 7.77 (2 H, m), 8.10 (2 H, m). 13C NMR
(CDCl3, 75 MHz): δ 18.9, 24.6, 27.7, 53.0, 59.4, 62.2, 126.6,
126.9, 131.4, 134.4, 134.4, 140.7, 144.0, 164.9, 181.7, 184.5. IR
(NaCl) νmax: 1668, 1698, 1738. MS (ESþ) m/z: 301 (M þ Hþ, 100).
Methyl 3,6-Dihydroxy-2,2-dimethyl-3,4-dihydro-2H-benzo-
[h]chromene-5-carboxylate 20. A solution of methyl 3-(3,3-dimethyl-
oxiranylmethyl)-1,4-naphthoquinone-2-carboxylate 19 (0.36 g, 1.19
mmol) in ethyl acetate (30 mL) was vigorously stirred at room temp-
erature, and a solution of sodium dithionite (2.08 g, 11.98 mmol) in
water (20 mL) was added. After 1.5 h of stirring at room tempera-
ture, the organic phase was separated, washed with water, and dried
Procedure for the Synthesis of 3-Hydroxymollugin 2 Using
K2CO3. To a solution of 3-bromomollugin 6 (0.20 g, 0.55 mmol)
in DMF (6 mL) were added potassium carbonate (0.380 g, 2.75
mmol) and water (0.15 mL). The reaction mixture was heated
at 80 °C for 4 h and then poured into 30 mL of water. The aque-
ous phase was extracted with dichloromethane (3 ꢀ 20 mL).
The combined organic extracts were washed with water (2 ꢀ
50 mL), dried over MgSO4, and evaporated. Purification of
J. Org. Chem. Vol. 75, No. 7, 2010 2279

Sastry et al.
JOCArticle
the crude residue by column chromatography using petro-
leum ether/ethyl acetate (90:10) as eluent afforded 76 mg of
3-isopropenylfuromollugin 7 as white crystals (49% yield), and
petroleum ether/ethyl acetate (70:30) as eluent afforded 77 mg of
3-hydroxymollugin 2 (yield 47%).
2-Isopropenylfuromollugin (Methyl 5-Hydroxy-2-isopropenyl-
naphtho[1,2-b]furan-4-carboxylate) 7. Mp: 96.3-98 °C (lit.12 mp
95-100 °C). 1H NMR (CDCl3, 300 MHz): δ 2.19 (3H, s), 4.09
(3H, s), 5.18 (1H, s), 5.86 (1H, s), 7.01 (1H, s), 7.51 (1H, ddd, J =
8.3 Hz, J = 7.2 Hz, J = 1.1 Hz), 7.68 (1H, ddd, J = 8.3 Hz,
7.2 Hz, 1.1 Hz), 8.26 (1H, dt, J = 8.3 Hz, J = 0.6 Hz), 8.45 (1H,
dt, J = 8.3 Hz, 0.6 Hz), 12.27 (1H, s). 13C NMR (CDCl3,
75 MHz): δ 19.5, 52.4, 99.1, 105.6, 112.5, 112.0, 121.3, 123.1, 124.7,
with (3 ꢀ 20 mL) of EtOAc. The combined organic extracts were
dried and evaporated to give a dark viscous liquid which was
purified by flash chromatography to afford methyl 3-hydroxy-
6-methoxy-2,2-dimethyl-2H-benzo[h]chromene-5-carboxylate 25
(0.167 g, 80% yield, brown crystals). Mp: 122-123 °C. 1H NMR
(CDCl3, 300 MHz) δ: 1.75 (6H, s), 4.05 (3H, s), 4.03 (3H, s), 7.04
(1H, s), 7.50-7.57 (1H, m), 7.61-7.69 (1H, m), 8.22-8.30 (2H,
m). 13C NMR (CDCl3, 75 MHz): δ 29.0, 52.3, 64.0, 69.5, 103.1,
113.8, 120.3, 122.6, 123.8, 124.6, 125.7, 126.1, 128.8, 146.6, 154.8,
163.1, 166.4. IR (KBr) νmax: 1656. MS (ES-) m/z: 313 (M - Hþ,
100). Anal. Calcd for C18H18O5: C, 68.78; H, 5.77. Found: C,
68.93; H, 6.02.
125.1, 125.1, 130.1, 133.0, 144.0, 156.6, 159.3, 172.1. IR (KBr) νmax
:
Acknowledgment. We are indebted to the Research Foun-
dation - Flanders (FWO-Vlaanderen) for financial support.
The Burundian Government is thanked for providing a
bursary to P.H.
1654, 3434. MS (ESþ) m/z: 283 (M þ Hþ, 100). Anal. Calcd for
C17H14O4: C, 72.33; H, 5.00. Found: C, 71.98; H, 5.11.
O-Methyl 3-Hydroxymollugin 24. To a 10 mL acetone solu-
tion of 3-hydroxymollugin 2 (0.20 g, 0.67 mmol) were added
potassium carbonate (0.184 g, 1.33 mmol) and MeI (0.189 g,
1.33 mmol). The reaction mixture was stirred at ambient temp-
erature for 14 h, and the acetone was evaporated. The crude
residue was partitioned between EtOAc and water and extracted
Supporting Information Available: 1H and 13C NMR spec-
tra of newly synthesized and target compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
2280 J. Org. Chem. Vol. 75, No. 7, 2010