Efficient synthesis of cis- and trans-3,4-dihydroxy-3,4-dihydromollugin

Article abstract of DOI:10.1021/jo800312j

(Chemical Equation Presented) An efficient synthesis of naturally occurring compounds isolated from Pentas longiflora, cis-3,4-dihydroxy-3,4- dihydromollugin 2, and trans-3,4-dihydroxy-3,4-dihydromollugin 3 is described. The O-protected mollugins were dih

Full text of DOI:10.1021/jo800312j

Efficient Synthesis of cis- and
trans-3,4-Dihydroxy-3,4-dihydromollugin
Naga Venkata Sastry Mudiganti, 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 February 6, 2008
An efficient synthesis of naturally occurring compounds isolated from Pentas longiflora, cis-3,4-dihydroxy-
3,4-dihydromollugin 2, and trans-3,4-dihydroxy-3,4-dihydromollugin 3 is described. The O-protected
mollugins were dihydroxylated using OsO4 to achieve the corresponding cis-dihydroxy derivatives in
excellent yield. The synthesis of trans-3,4-dihydroxy-3,4-dihydromollugin was achieved using Oxone in
good yield. A mechanism for the formation of cis-3,4-dihydroxymollugin acetonide from the reaction of
mollugin with Oxone is proposed.
1. Introduction
is mollugin 1, which is a benzisochromene antibiotic.5 Com-
pound 1 not only showed potent suppressive activity on hepatitis
B surface antigen (HBsAg) secretion in human hepatoma Hep3B
cells but also possessed strong inhibition of arachidonic acid
(AA)-induced and collagen-induced platelet aggregation.6 Be-
cause of its importance, mollugin 1 has been synthesized by
several groups (Figure 1).7
Next to mollugin 1, several derivatives of mollugin 1 were
isolated by us5h and others5a–g from Pentas longiflora, e.g., cis-
3,4-dihydroxy-3,4-dihydromollugin 2 and trans-3,4-dihydroxy-
3,4-dihydromollugin 3. Recently, the synthesis of trans-3,4-
dihydroxy-3,4-dihydromollugin 3 in 62% yield has been reported
It has been estimated that 80% of the world population
depends on alternative systems of medicine.1 This traditional
medicine is merely based on the knowledge of how to use
medicinal plants. For instance, the African medicinal plant
Pentas longiflora (Rubiaceae) is used to treat skin diseases such
as pityriasis versicolar, itchy rashes, or mycoses.2 The same
plant is also used as medicine for treating diseases such as
malaria, diarrhea, tapeworm, gonorrhea, and syphilis and is used
as a purgative in Kenya and Rwanda.3 The plant Galium
mollugo is phytochemically related to Pentas longiflora and is
used as an herbal medicine with antitumor, antiviral, and other
activities.4 An important constituent isolated from both plants
(5) (a) Inoue, K.; Shiobara, Y.; Nayenshiro, H.; Inouye, H.; Wilson, G.; Zenk,
M. H. Phytochemistry 1984, 73, 307. (b) Gonzalez, A. G.; Barroso, J. T.; Cardona,
R. J.; Medina, J. M.; Rodriguez Luis, F. An. Quim. 1977, 73, 538. (c) Itokawa,
H.; Qiao, Y.; Takeya, K. Phytochemistry 1989, 28, 3465. (d) Koyama, J.; Ogura,
T.; Tagahara, K.; Konoshima, T.; Kozuka, M. Phytochemistry 1992, 31, 2907.
(e) Itokawa, H.; Ibraheim, Z. Z.; Qiao, Y.; Takeya, K. Chem. Pharm. Bull. 1993,
41, 1869. (f) Itokawa, H.; Qiao, Y.; Takeya, K. Phytochemistry 1991, 30, 637.
(g) Kuo, S.-C.; Chen, P.-R.; Lee, S.-W.; Chen, Z.-T. J. Chin. Chem. Soc. 1995,
42, 869. (h) El-Hady, S.; Bukuru, J.; Kesteleyn, B.; Van Puyvelde, L.; Nguyen
Van, T.; De Kimpe, N. J. Nat. Prod. 2002, 65, 1377.
(1) Daniel, M. Medicinal Plants: Chemistry and Properties; Science Publish-
ers: New York, 2006.
(2) De Kimpe, N.; Van Puyvelde, L.; Schripsema, J.; Erkelius, C.; Verpoorte,
R. Magn. Reson. Chem. 1993, 31, 329.
(3) (a) Wanyoike, G. N.; Chhabra, S. C.; Lang’at-Thoruwa, C. C.; Omar,
S. A. J. Ethnopharmacol. 2004, 90, 129. (b) Cos, P.; Hermans, N.; De Bruyne,
T.; Apers, S.; Sindambiwe, J. P.; Vanden Berghe, D.; Pieters, L.; Vlietinck, A. J.
J. Ethnopharmacol. 2002, 79, 155. (c) Van Puyvelde, L.; El Hady, S.; De Kimpe,
N.; Feneau-Dupont, J.; Declercq, J. P. J. Nat. Prod. 1998, 61, 1020. (d) Hari,
L.; De Buyck, L.; De Pooter, H. L. Phytochemistry 1991, 30, 172. (e) Chabra,
S. C.; Mahunnah, R. L. A.; Mshiu, E. N. J. Ethnopharmacol. 1991, 33, 143.
(4) (a) Itokawa, H.; Mihara, K.; Takeya, K. Chem. Pharm. Bull. 1983, 31,
2353. (b) Kawasaki, Y.; Goda, Y.; Yoshihira, K. Chem. Pharm. Bull. 1992, 40,
1504. (c) Marec, F.; Kollarova, I.; Jegorov, A. Planta Med. 2001, 67, 127. (d)
Ho, L.-K.; Don, M.-J.; Chen, H.-C; Yeh, S.-F.; Chen, J.-M. J. Nat. Prod. 1996,
59, 330. (e) Takeya, K.; Mori, N.; Sonobe, T.; Mihashi, S.; Hamanaka, T. Chem.
Pharm. Bull. 1986, 34, 3762.
(6) Chung, M. I.; Jou, S. J.; Cheng, H. C.; Lin, C. N.; Ko, F. N.; Teng,
C. M. J. Nat. Prod. 1994, 57, 313.
(7) (a) Schildknecht, H.; Straub, F. Liebigs Ann. Chem. 1976, 1307. (b) Ho,
L.-K.; Yu, H.-J.; Ho, C.-T.; Don, M.-J. J. Chin. Chem. Soc. 2001, 48, 77. (c)
Lumb, J-P.; Trauner, D. Org. Lett. 2005, 26, 5865. (d) Claessens, S.; Kesteleyn,
B.; Nguyen Van, T.; De Kimpe, N. Tetrahedron 2006, 62, 8419. (e) Habonimana,
P.; Claessens, S.; De Kimpe, N. Synlett 2006, 15, 2472. (f) Jung, H. W.; Oh,
J. S.; Lee, S. H.; Liang, J. L.; Kim, D. H.; Rahman, A. F. M. M.; Jahng, Y.
Bull. Korean Chem. Soc. 2007, 28, 1863–1866.
10.1021/jo800312j CCC: $40.75
Published on Web 04/16/2008
2008 American Chemical Society
J. Org. Chem. 2008, 73, 3867–3874 3867

Mudiganti et al.
TABLE 1. Effect of Various Parameters on the Dihydroxylation
of Mollugin 1 Using OsO4
NMMO
(equiv)
yield of 2b
entry
reaction conditionsa
(%)
OsO4 (4 wt % solution in H2O)
10 mol %
20 mol %
5 mol %
10 mol %
1
2
3
4
5
1.0
1.0
1.0
1.5
0.5
40
30
18
33
28
FIGURE 1. Benzisochromenes isolated from Pentas longiflora.
10 mol %
SCHEME 1
OsO4 (4 wt % solution in t-BuOH)
10 mol %
6
7
1.0
1.0
15
0
OsO4 (solid)c
10 mol %
a All reactions were performed at 0.5 mmol scale in a solvent mixture
of t-BuOH/THF/H2O (10:3:1). b Isolated yields. c Reaction performed in
acetone/H2O (1:1) at 0 °C for 30 min.
SCHEME 2
by Wang et al. by reacting dimethyldioxirane (DMD) with
mollugin 1.8 However, in our hands, by employing the same
reaction conditions the trans-3,4-dihydroxy-3,4-dihydromollugin
3 was only formed in 30% yield along with the formation of
several side products. Therefore, a more detailed investigation
was necessary which will be presented in this paper. This fact,
taken together with the important biological activities and
medicinal properties associated with these compounds, urged
us to present our results in the synthesis of cis-3,4-dihydroxy-
3,4-dihydromollugin 2 and trans-3,4-dihydroxy-3,4-dihydro-
mollugin 3, respectively.
TABLE 2. Reaction Conditions for the Synthesis of O-Protected
Mollugin Derivatives 4–6
entry
1
reaction conditions
result
2. Results and Discussion
1.5 equiv of MeI, 1.25 equiv of
K2CO3, acetone, rt, 24 h
R ) Me, 4, 95%
2.1. Synthesis of cis-3,4-Dihydroxy-3,4-dihydromollugin
2. Our initial aim was to synthesize cis-3,4-dihydroxy-3,4-
dihydromollugin 2 by a direct dihydroxylation reaction onto
mollugin 1 using various oxidizing agents. Mollugin 1 was
prepared following the efficient three-step strategy recently
reported by our group, by alkylation of methyl 1,4-dihydrox-
ynaphthalene 1-carboxylate with 3-methyl-3-buten-1-ol and
subsequent dehydrogenation using DDQ.7e Starting from mol-
lugin, several reactions were performed using oxidizing agents
such as KMnO4 (under neutral conditions as well as with 5 mol
% of ruthenium (III) chloride), sodium periodate/lithium bro-
mide, or phenyliodonium diacetate/lithium bromide for the
dihydroxylation of mollugin. In most cases, complex reaction
mixtures were obtained pointing to the complex nature of this
reaction due to the presence of the free phenolic hydroxyl group.
In the latter two cases, using lithium bromide under oxidizing
conditions, 3-bromomollugin was formed in 18% and 17%
yields, respectively.9 After considerable experimentation, it was
observed that OsO4 (4 wt % solution in H2O) is the oxidant of
choice. The reaction of mollugin 1 with 10 mol % of OsO4 in
the presence of 1 equiv of 4-methylmorpholine N-oxide mono-
hydrate (NMMO) as co-oxidant resulted in cis-3,4-dihydroxy-
3,4-dihydromollugin 2 for the first time in 40% yield (Scheme
1). In an effort to improve the yield of compound 2, several
parameters were explored such as variation in the catalytic
loading of OsO4, the number of equivalents of NMMO, and
2
3
4
1.2 equiv of BnBr, 1.25 equiv of
K2CO3, DMF, 60 °C, 4 h
1.5 equiv of NaH, 1.5 equiv of
MOM-Cl, DMF, 60 °C, 12 h
1.5 equiv of iPrNEt2, 1.5 equiv of
MOM-Cl, CH2Cl2, 0 °C-rt, 18 h
R ) Bn, 5, 90%
R ) CH2OMe, 6, 0%
R ) CH2OMe, 6, 92%
the reaction times. However, no appreciable improvement was
observed in these cases (Table 1).
By increasing or decreasing the number of equivalents of
NMMO, a decrease in the product yield was observed along
with unidentified side products. Conducting the reaction at lower
temperature or for prolonged periods of time did not alter the
product yield to an appreciable amount. During the course of
these investigations, mostly complex reaction mixtures with
difficulty in isolating the required diol 2 were obtained. In view
of the encountered failures to improve the yield in the cis-
dihydroxylation of mollugin 1, a survey of the literature revealed
that the dihydroxylation of a double bond using OsO4 with
substrates containing a free phenolic-OH made use of their
O-protected ethers in most cases. Therefore, it was decided to
protect the aromatic hydroxyl group of mollugin to avoid the
assumed complex formation of the osmium species with the
acidic phenolic hydroxyl moiety of mollugin 1. Based on this
assumption, several protecting groups were chosen to protect
the phenolate of mollugin after which the dihydroxylation
reaction on O-protected mollugin was performed. The reaction
of mollugin 1 with methyl iodide and potassium carbonate in
acetone yielded the corresponding O-methylmollugin 4 in 95%
yield (Scheme 2).
(8) (a) Wang, X.; Lee, Y. R. Tetrahedron Lett. 2007, 48, 6275. (b) 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.
(9) 3-Bromomollugin was formed by direct bromination of mollugin 1 with
bromine, generated in situ by the oxidation of LiBr, either with sodium periodate
or phenyliodonium acetate.
Using a standard protocol for dihydroxylation by means of
OsO4 (10 mol %, 4% in H2O), the required cis-O-methyl 3,4-
3868 J. Org. Chem. Vol. 73, No. 10, 2008

Synthesis of cis- and trans-3,4-Dihydroxy-3,4-dihydromollugin
SCHEME 3
SCHEME 4
droxylated compounds (7–9), but also reduced the amount of
the corresponding R-hydroxy ketones (10–12). However, the
characteristic reasons of this photochemical influence are not
yet known and a degradation study of mollugin 1 in the presence
of light in different alcoholic solvents is under progress to
identify the related degradation products. Observing the benefits
of performing the dihydroxylation reaction in darkness, prompted
us to check the initial reaction of mollugin 1 with 10 mol%
OsO4, according to the conditions described in Scheme 1, in
darkness. However, no significant improvements with respect
to the yield were found. It is interesting to note that a decreasing
trend in the formation of R-hydroxy ketone was observed with
the increasing electron donating power of the protecting group.
The increased electron donating property of MOM-protected
mollugin 6 is responsible for obtaining the highest yield of
dihydroxy compound 9 with OsO4. With these vicinal dihydroxy
compounds (7-9) in hand, efforts were made to obtain the
required cis-diol 2 by deprotection (Scheme 4).
However, attempts to deprotect the methyl ether in compound
7 either by boron(III) bromide in dichloromethane or cerium(IV)
ammonium nitrate (CAN) in acetonitrile failed, affording com-
plex reaction mixtures only. The O-debenzylation reaction with
compound 8 was carried out either in EtOH or in a solvent
mixture of EtOH and EtOAc using 10 mol% of Pd(0) under H2
atmosphere (4 bar) resulting in the recovery of starting material.
The same reaction using 20 mol% of Pd(0) in MeOH, resulted
in the formation of unidentified products. On the other hand,
using 2.5 equiv of CAN under biphasic conditions in a solvent
mixture of CH2Cl2/H2O (1:1) at 10 °C for 2 h afforded the
O-benzyl-protected R-hydroxy ketone 11 in 65% yield (Scheme
4). Although the deprotection of methyl and benzyl ethers failed,
next it was focused on the deprotection of O-(methoxymethyl)
group (MOM) of dihydroxy compound 9. It is interesting to
note that the concentration of the acid in fact influenced the
deprotection of O-(methoxymethyl) group. Initially, the depro-
tection of compound 9 performed under mild reaction conditions
using 2 N HCl (1:1) in THF either at 0 °C or at ambient
temperature for several hours did not provided the required diol
2. To our surprise, stirring compound 9 in an excess of 6 N
HCl (1:1) in THF at 0 °C to room temperature for 3 h afforded
both cis-3,4-dihydroxy-3,4-dihydromollugin 2 and trans-3,4-
dihydroxy-3,4-dihydromollugin 3 in 68% and 20% yield, respec-
tively. This unusual formation of a trans-diol 3 from cis-diol 9
can be explained as follows (Scheme 5). Deprotection of the
MOM-ether 9 obviously results in cis-diol 2. However, under
excess acidic conditions the hydroxyl moiety at position 4 can
be protonated and easily eliminated by an electron push
mechanism starting from the electron lone pair of the pyranyl
oxygen. In this way, a reactive charged o-quinomethide is
formed to which water attacks and results in the formation of
the thermodynamically more stable trans isomer 3. The spectral
data of compounds 2 and 3 were in accordance with those
reported in literature.5 The O-(methoxymethyl) deprotection
reaction of the compound 9 was successfully achieved using 4
dihydroxy-3,4-dihydromollugin 7 was obtained in 55% yield
accompanied by the corresponding R-hydroxy ketone 10 in 17%
yield (Scheme 3). Although the improvement in the product
yield was not successful, we were able to eliminate the undesired
side reactions, except the formation of the overoxidized product
10, and thus facilitated the product purification thoroughly. The
formation of such R-hydroxy ketones is frequent in oxidation
reactions of benzochromene derivatives, such as acronycine.10
To overcome these shortcomings, the hydroxy moiety of
mollugin 1 was protected as the corresponding benzyl ether 5.
Using 1.2 equiv of benzyl bromide and potassium carbonate in
N,N-dimethylformamide for 4 h at 60 °C, mollugin 1 afforded
the benzyl ether of mollugin 5 in 90% yield. A similar protection
of mollugin as methoxymethyl ether was also performed by use
of 1.5 equiv of MOM chloride and N-ethyldiisopropylamine in
dichloromethane for 18 h resulting in the corresponding MOM
ether of mollugin 6 in 92% yield (Table 2). The O-protected
mollugins (5 and 6) were successfully dihydroxylated using 10
mol % of OsO4 in the presence of 1 equiv of NMMO to afford
the corresponding O-protected dihydroxylated mollugins (8 and
9) in 70% and 72% yields, respectively (Scheme 3). However,
the corresponding O-protected R-hydroxy ketones were also
formed as minor products (11, 15%, and 12, 5%).
The formation of these R-hydroxy ketones was thought to
depend on the interaction of light. Photochromism of 2-H-
chromenes (2H-1-benzopyrans) is well-known in which a
reversible pyran ring opening would occur by the interaction
of light.11 A related photolability was found before at our
department in the case of pentalongin (also isolated from Pentas
longiflora), a 3,4-dehydropyranonaphthoquinone, which is known
to degrade in alcoholic solvents in the presence of daylight.12
A black coloration in the reaction flask was always observed
after the addition of OsO4 to a predissolved solution of NMMO
and mollugin or O-protected mollugin in a solvent mixture of
t-BuOH/THF/H2O (10:3:1).
To avoid such undesired side reactions associated with light,
a reaction of O-methylmollugin 4 with OsO4 was carried out
in darkness under identical experimental conditions. Interest-
ingly, this dark coloration was not observed in the absence of
light. In this way it was found that, conducting the reaction in
darkness not only improved the yield of the required dihy-
(10) (a) Bernardin, A.; Francois, E.; Philippe, E.; Elisabeth, S.; Francois, T.;
Olivier, L. J. Heterocycl. Chem. 2005, 42, 1267. (b) Magiatis, P.; Mitaku, S.;
Skaltsounis, A.-L.; Tillequin, F.; Koch, M.; Pierre, A.; Atassi, G. J. Nat. Prod.
1998, 61, 198. (c) Nguyen, T. M.; Sittisombut, C.; Boutejnouchet, S.; Lallemand,
M.-L.; Michel, S.; Koch, M.; Tillequin, F.; Mazinghien, R.; Lansiaux, A.; David,
C.; Marie, H.; Pfeiffer, B.; Kraus, B. L.; Leonce, S.; Pierre, A. J. Med. Chem.
2006, 49, 3383.
(11) (a) Queiroz, R. P. M.-J.; Plasencia, M. S. P.; Dubest, R.; Aubard, J.;
Gugliemetti, R. Tetrahedron 2003, 59, 2567. (b) Federova, A. O.; Maurel, F.;
Ushakov, N. E.; Nazarov, B. V.; Gromov, P. S.; Chebunkova, V. A.; Feofanov,
V. A.; Alaverdian, S. I.; Alfimov, V. M.; Barigelletti, F. New J. Chem. 2003,
27, 1720.
(12) Claessens, S.; Verniest, G.; El-Hady, S.; Nguyen, V. T.; Kesteleyn, B.;
Van Puyvelde, L.; De Kimpe, N. Tetrahedron 2006, 62, 5152.
J. Org. Chem. Vol. 73, No. 10, 2008 3869

Mudiganti et al.
SCHEME 5
SCHEME 6
N HCl. Thus, a reaction between O-(methoxymethyl)dihydroxy-
mollugin 9 and 4 N HCl at 0 °C for 18 h resulted in the exclusive
formation of cis-diol 2 in 85% yield (Scheme 5). The hypotheti-
cal assumption of the transformation of cis-diol 2 to a thermo-
dynamically more stable trans isomer 3 was also proved by
conducting the reaction independently using cis-diol 2. Thus,
the reaction of cis-diol 2 using 6 N HCl in THF afforded a 7:3
mixture of cis- and trans-diols.
TABLE 3. Effect of Various Parameters in the Reaction of
Mollugin 1 with Oxone
2.2. Synthesis of trans-3,4-Dihydroxy-3,4-dihydromollu-
gin 3. After the successful synthesis of cis-diol 2, attention was
focused toward the synthesis of the related trans-diol 3, which
was previously synthesized by Wang et al.8 As already stated,
in our hands, applying these conditions gave rise to the formation
of several side products. Therefore, a more detailed investigation
of the synthesis of trans-3,4-dihydroxy,3,4-dihydromollugin 3
was necessary. The strategy for the synthesis of this trans-diol
3 is based on initial synthesis of the corresponding epoxide 14,
followed by anti ring opening of 3,4-epoxymollugin 14. In an
attempt to synthesize the target epoxide 14, several epoxidation
reactions were explored either by using hydrogen peroxide/base
in nucleophilic conditions or by means of m-chloroperbenzoic
acid (m-CPBA), sodium hypochlorite or Oxone under electro-
philic conditions. Epoxidation of electron-poor alkenes such as
R ꢀ-unsaturated carbonyl compounds are well-known with
hydrogen peroxide.13 It was assumed that mollugin 1 with a γ
δ-unsaturated ester in conjugation with an aromatic ring is more
susceptible for epoxidation using H2O2. However, the use of 6
equivalents of 30% H2O2 and 1.5 equiv of sodium carbonate in
Oxone
time yield of yield of
3 (%) 13 (%)
entry (equiv) T (°C) (h)
solvent
1
2
3
4
5
6
7
8
9
1.2
1.2
1.5
2.0
3.0
3.0
3.0
6.0
3.0
rt
rt
rt
rt
80
80
80
80
80
96
96
96
120
5
THF/H2O (1:1)
MeOH/H2O (1:1)
15
15
10
8
10
18
32
48
30
25
22
CH3COCH3/H2O (1:1)
CH3COCH3/H2O (1:1)
CH3COCH3/H2O (2:1)
CH3COCH3/H2O (2:1)
CH3COCH3/H2O (2:1)
CH3COCH3/H2O (2:1)
CH3COCH3/H2O (1:2)
12
24
24
12
5
5
31
a solvent mixture of acetone/H2O (5:2) did not afford the re-
quired epoxide 14. Repeated endeavors by varying the amount
of H2O2 using different bases in diverse solvents, e.g., acetone/
H2O (5:2) (2 equiv of Na2CO3), EtOH/H2O (5:2) (1.5 equiv of
Na2CO3), or THF/H2O (3:1) (2 equiv of LiOH), failed. Sub-
(13) Jones, C. W. Application of Hydrogen Peroxide DeriVatiVes: RSC:
London, 1999.
3870 J. Org. Chem. Vol. 73, No. 10, 2008

Synthesis of cis- and trans-3,4-Dihydroxy-3,4-dihydromollugin
SCHEME 7
SCHEME 8. Mechanistic Proposal for the Dioxirane-Mediated Formation of 3,4-Dihydromollugin Acetonide 13
sequently, electrophilic epoxidizing agents such as m-CPBA,
sodium hypochlorite, and Oxone (2KHSO5, KHSO4, K2SO4)
were investigated. The reaction of mollugin 1 either with
m-CPBA in the presence of base or using sodium hypochlorite/
pyridine, did not lead to one distinct product. Interestingly,
stirring of mollugin 1 with 2 equiv of Oxone in a solvent mixture
of acetone/H2O (1:1) for 120 h at ambient temperature resulted
in the formation of a mixture of two compounds (Scheme 6).
One of the compounds was identified as trans-3,4-dihydroxy-
3,4-dihydromollugin 3 (15%), while the other was surprisingly
identified as 3,4-dihydroxymollugin acetonide 13 on the basis
of following evidence. The 1H NMR spectrum of the tetracyclic
compound 13 showed two singlets corresponding to two
additional methyl groups and also an extra quaternary acetal
carbon at δ 104.67 in its 13C NMR spectrum (CDCl3).
were subjected to a reaction with Oxone in aqueous acetone
(Scheme 7). The reaction of O-methylmollugin 4 or O-ben-
zylmollugin 5 with 3 equiv of Oxone in acetone/H2O at 80 °C
for 6 h resulted in the corresponding trans-diols 15 and 16 in
58% and 70%, respectively. Surprisingly, during these re-
actions the corresponding acetonides 17 (R ) Me) and 18 (R
) Bn) were not observed as expected, but their corresponding
cis-diols (10, 18%; 11, 22%) were obtained. These cis-diols (10-
11) can be formed from their corresponding acetonides (17 and
18) due to the slight acidic conditions associated with Oxone.
Interestingly, the MOM-ether of mollugin 6 reacted with Oxone
under these conditions to afford the required trans-diol 3 in 52%
yield along with 8% of 3,4-dihydroxymollugin acetonide 13.
This deprotection of MOM group may be due to the acidic
character of oxone.
In order to improve the yield of the required trans-diol 3,
various parameters have been examined (Table 3). The reaction
did not work with solvent mixtures such as THF/H2O and
MeOH/H2O. It is interesting to note that the increase in the
amount of Oxone at elevated temperature led to an increment
in the formation of 3,4-dihydroxymollugin acetonide 13 along
with a simultaneous decrease in the amount of trans-diol 3. It
was observed that the temperature of the reaction also affected
the rate of the reaction. The ratio of solvents (acetone/H2O)
also played an important role in determining the product
formation. For instance, a solvent mixture of acetone/H2O (2:
1) favors the formation of acetonide 13 in 48% yield (entry 6),
whereas the same reaction in acetone/H2O (1:2) resulted in the
formation of trans-diol 3 as the major product (31%, entry 9).
The unsatisfactory results for the synthesis of compound 3
starting from mollugin turned the attention to look again for
O-protected mollugin derivatives. It was thought that the same
reasons which are preventing to obtain good yields in the cis-
dihydroxylation of mollugin 1 using OsO4 are also playing a
role here. With this intention, the O-protected mollugins (4–6)
By considering the mechanistic features of this reaction, the
formation of cis-3,4-dihydroxymollugin acetonide 13 is an
important issue for discussion. In general, the mechanism of
Oxone-mediated epoxidations of alkenes involves the initial in
situ formation of an active species, i.e., 3,3-dimethyldioxirane,
by the reaction of Oxone with acetone. The generated 3,3-
dimethyldioxirane can react in two ways such that it follows
either an ionic pathway or a radical path.14 Electrophilic attack
of 3,3-dimethyldioxirane across mollugin 1 in a concerted way
leads to 3,4-epoxymollugin 14 (Scheme 8).
Due to the instability of 3,4-epoxymollugin 14, the epoxide
readily opens to form the reactive o-quinomethide intermediate
19. Antiattack of water as nucleophile across intermediate 19
leads to the corresponding trans-diol 3. Addition of acetone to
o-quinomethide 19 results in the formation of intermediate 20,
finally leading to cis-acetonide 13. Alternatively, it is also
suggested to be possible to generate bis(oxyl)diradicals, which
(14) (a) Murray, R. W. Chem. ReV. 1989, 89, 1187. (b) Curci, R.; Dinoi, A.;
Rubino, M. F. Pure Appl. Chem. 1995, 67, 811.
J. Org. Chem. Vol. 73, No. 10, 2008 3871

Mudiganti et al.
4.1.2. Methyl 6-Benzyloxy-2,2-dimethyl-2H-benzo[h]chromene-
5-carboxylate 5 (Mollugin 6-Benzyl Ether). K2CO3 (0.86 g, 6.25
mol) followed by benzyl bromide (0.72 mL, 6.0 mol) were added
to a stirred solution of mollugin 1 (1.42 g, 5 mol) in N,N-di-
methylformamide (30 mL), and the reaction mixture was heated at
65 °C for 4 h. After completion of the reaction (monitoring with
TLC), water (50 mL) was added and the aqueous phase was
extracted with ethyl acetate (3 × 30 mL). The combined organic
layers were dried over MgSO4 and evaporated in vacuo, and the
crude product was purified by flash column chromatography
(petroleum ether/ethyl acetate 95/5 Rf 0.18) to give 5: white solid
(1.68 g, 90%); mp 72–73 °C; 1H NMR (CDCl3) δ 1.53 (6H, s, 2 ×
CH3), 3.90 (3H, s, COOCH3), 3.99 (3H, s, OCH3), 5.10 (2H, s,
OCH2), 5.70 (1H, d, J ) 9.9 Hz, CH-3), 6.44 (1H, d, J ) 9.9 Hz,
CH-4), 7.33–7.55 (2H, m, CHar), 8.03–8.10 (1H, m, CHar),
8.19–8.25 (1H, m, CHar); 13C NMR (CDCl3) δ 27.8 (2 × CH3),
52.5 (COOCH3), 77.5 (Cquat), 77.9 (OCH2), 112.6 (Cquat), 119.9
(CHar), 121.1 (Cquat), 122.6 (CHar), 122.8 (CHar), 126.8 (Cquat), 126.9
(CHar), 127.0 (Cquat), 127.9 (2 × CHar), 128.1 (Cquat), 128.2 (CHar),
128.6 (2 × CHar), 130.3 (CHar), 137.4 (CHar), 145.2 (Cquat), 146.4
(Cquat), 167.9 (CdO); IR (KBr) νmax 1726 (CdO); MS (ES+) m/z
375 (M + H+, 100). Anal. Calcd for C24H22O4: C, 76.99; H, 5.92.
Found: C, 76.79; H, 6.14.
follow path B leading to 3,4-dihydroxymollugin acetonide 13.
Spectroscopic analysis by NOE study of compound 13 indicated
a cis-configuration of the acetonide. In the NOE spectrum of
3,4-dihydroxymollugin acetonide 13, a nuclear Overhauser effect
between the two vicinal hydrogens indicated the cis-configu-
ration. The formation of the cis-diols (10 and 11) from their
corresponding O-protected mollugins (4 and 5) in the reaction
with Oxone also stands as an indirect evidence for the cis
configuration of acetonide 13. Furthermore, literature studies
revealed that the formation of such acetonide via a dioxyl radical
with less reactive double bonds is feasible as is previously
described in the case of patulin.15 It is also possible to explain
why protected acetonides 17 (R ) Me) and 18 (R ) Bn) were
not formed from their corresponding mollugin derivatives on
the basis of the mechanism. The electron density associated with
O-protected mollugins makes their double bond more electron
rich and thereby facilitate DMD to react in an electrophilic
manner to produce more of the trans-diol 3 rather than the
acetonide 13.
3. Conclusions
4.1.3. Methyl 6-Methoxymethoxy-2,2-dimethyl-2H-benzo[h]-
chromene-5-carboxylate 6 (Mollugin 6-Methoxymethyl Ether).
N,N-Diisopropylethylamine (1.07 mL, 6.5 mol) was added at 0 °C
under N2 atmosphere to a stirred solution of mollugin 1 (1.42 g, 5
mol) in dry dichloromethane (10 mL). After the reaction mixture
was stirred for 15 min at this temperature, MOM-Cl (0.569 mL,
7.5 mol) was added, and stirring was continued at room temperature.
After 24 h, 2 N HCl (20 mL) was added, and the aqueous phase
was extracted with dichloromethane (3 × 20 mL). The combined
organic layers were evaporated in vacuo, and the crude product
was purified by flash column chromatography (petroleum ether/
ethyl acetate 95/5 Rf 0.18) to give 6 as a thick viscous yellow liquid
In conclusion, the natural products cis-3,4-dihydroxy-3,4-
dihydromollugin 2 and trans-3,4-dihydroxy-3,4-dihydromollugin
3 were successfully synthesized in good to very good yield for
the first time. The electronic properties and thus the reactivity
of the double bond of mollugin is remarkably influenced by its
protecting group. It is unequivocally important to conduct the
cis-dihydroxylation reactions onto O-protected mollugin in
darkness. In the reaction of mollugin 1 with Oxone afforded
trans-3,4-dihydroxy-3,4-dihydromollugin 3 albeit together with
the formation of the remarkable cis-3,4-dihydroxymollugin
acetonide 13. The formation of cis-3,4-dihydroxymollugin
acetonide 13 in the reaction between mollugin 1 and Oxone
clearly explains the less reactive nature of the double bond
present in it. A plausible mechanism for the formation of trans-
diol 3 and the cis-acetonide 13 from mollugin 1 using Oxone
was proposed.
1
(1.50 g, 92%): H NMR (CDCl3) δ 1.51 (6H, s, 2 × CH3), 3.61
(3H, s, COOCH3), 3.98 (3H, s, OCH3), 5.12 (2H, s, OCH2), 5.69
(1H, d, J ) 9.9 Hz, CH-3), 6.42 (1H, d, J ) 9.9 Hz, CH-4),
7.45–7.55 (2H, m, CHar), 8.04–8.12 (1H, m, CHar), 8.16–8.23 (1H,
m, CHar); 13C NMR (CDCl3) δ 27.8 (2 × CH3), 52.5 (COOCH3),
57.8 (OCH3), 76.6 (OCH2), 77.5 (Cquat), 101.3 (Cquat), 112.5 (Cquat),
120.0 (CHar), 121.3 (Cquat), 122.4 (CHar), 123.0 (CHar), 126.8 (Cquat),
127.0 (CHar), 128.3 (Cquat), 130.3 (Cquat), 144.8 (Cquat), 145.5 (Cquat),
167.7 (CdO); IR (KBr) νmax 1713 (CdO); MS (ES+) m/z 329 (M
+ H+, 100). Anal. Calcd for C19H20O5: C, 69.50; H, 6.14. Found:
C, 69.34; H, 6.18.
4. Experimental Section
4.1. Synthesis of O-Protected Mollugins 4–6. 4.1.1. Methyl
6-Methoxy-2,2-dimethyl-2H-benzo[h]chromene-5-carboxylate 4
(Mollugin 6-Methyl Ether). Potassium carbonate (0.86 g, 6.25 mol)
followed by methyl iodide (0.46 mL, 7.5 mol) were added to a
stirred solution of mollugin 1 (1.42 g, 5 mol) in acetone (40 mL).
The reaction mixture was stirred at room temperature for 18 h,
after which K2CO3 was filtered and washed with acetone (10 mL).
The combined organic layers were evaporated in vacuo, and the
crude product was purified by flash column chromatography
(petroleum ether/ethyl acetate 95/5 Rf 0.17) to give 4 as a thick
viscous yellow liquid, which solidifies on standing for several days:
4.2. General Procedure for the Dihydroxylation of O-Protected
Mollugin Derivatives 4–6 Using OsO4 in Darkness. The dihydroxy-
lation of compound 4 is taken as a representative example.
Compound 4 (149 mg, 0.5 mmol) was added to a stirred solution
of osmium tetraoxide (4% in H2O, 0.317 mL, 0.05 mmol) and
4-methylmorpholine N-oxide monohydrate (NMMO) (58.5 mg, 0.5
mmol) in t-BuOH/THF/H2O (10:3:1, 10 mL) at 0 °C in darkness.
The reaction mixture was allowed to warm to room temperature,
and stirring was continued for 14 h. After the addition of a saturated
solution of aqueous sodium bisulfite (10 mL), the mixture was
stirred for 1 h and then extracted with dichloromethane (3 × 20
mL). The combined organic layers were washed with brine (30
mL), dried over magnesium sulfate, and evaporated under reduced
pressure. The crude product was purified by flash column chro-
matography on silica gel (petroleum ether/ethyl acetate 60/40 Rf
0.80) affording O-methyl-3,4-dihydroxy-3,4-dihydromollugin 7
(petroleum ether/ethyl acetate 80/20 Rf 0.60) and methyl 3-hydroxy-
6-methoxy-2,2-dimethyl-4-oxo-3,4-dihydro-2H-benzo[h]chromene-
5-carboxylate 10.
1
yellow solid (1.41 g, 95%); mp 68–69 °C; H NMR (CDCl3) δ
1.51 (6H, s, 2 × CH3), 3.96 (3H, s, COOCH3), 3.99 (3H, s, OCH3),
5.69 (1H, d, J ) 9.9 Hz, CH-3), 6.42 (1H, d, J ) 9.9 Hz, CH-4),
7.47–7.55 (2H, m, CHar), 8.00–8.08 (1H, m, CHar), 8.17–8.24 (1H,
m, CHar); 13C NMR (CDCl3): δ 27.7 (2 × CH3), 52.5 (COOCH3),
63.6 (OCH3), 76.5 (Cquat), 77.5 (Cquat),112.5 (Cquat), 119.9 (CHar),
120.6 (Cquat), 122.6 (CHar), 122.7 (CHar), 126.8 (CHar), 126.9 (CHar),
127.9 (Cquat), 130.3 (CHar), 145.0 (Cquat), 147.6 (Cquat), 167.9 (CdO);
IR (KBr) νmax 1713 (CdO); MS (ES+) m/z 299 (M + H+, 100).
Anal. Calcd for C18H18O4: C, 72.47; H, 6.08. Found: C, 72.83; H,
6.49.
4.2.1. (()-Methyl cis-3,4-dihydroxy-6-methoxy-2,2-dimethyl-
3,4-dihydro-2H-benzo[h]chromene-5-carboxylate 7: white solid
(136 mg, 78%); mp 115–117 °C; 1H NMR (CDCl3) δ 1.42 (3H, s,
CH3), 1.54 (3H, s, CH3), 2.64 (1H, br s, OH-3), 3.54 (1H, br s,
(15) Ghisalberti, L. E.; Hargreaves, R. J.; Skelton, W. B.; White, H. A. Aust.
J. Chem. 2000, 53, 995–997.
3872 J. Org. Chem. Vol. 73, No. 10, 2008

Synthesis of cis- and trans-3,4-Dihydroxy-3,4-dihydromollugin
OH-4), 3.79 (1H, d, J ) 4.4 Hz, CH-3), 3.97 (3H, s, COOCH3),
4.00 (3H, s, OCH3), 4.97 (1H, d, J ) 4.4 Hz, CH-4), 7.50–7.62
(2H, m, CHar), 8.04–8.10 (1H, m, CHar), 8.19–8.28 (1H, m, CHar);
13C NMR (CDCl3) δ 23.3 (CH3), 24.2 (CH3), 52.9 (COOCH3), 63.7
(OCH3), 64.3 (CH-4), 71.5 (CH-3), 77.5 (Cquat), 78.4 (Cquat), 113.5
(Cquat), 122.7 (CHar), 123.1 (CHar), 127.1 (Cquat), 127.3 (CHar), 127.4
(CHar), 128.3 (Cquat), 144.2 (Cquat), 148.7 (Cquat), 169.3 (CdO); IR
(KBr) νmax 1729 (CdO); MS (ES+) m/z 333 (M + H+, 10), 315
(M - OH-, 100). Anal. Calcd for C18H20O6: C, 65.05; H, 6.07.
Found: C, 65.29; H, 6.31.
4.2.2. Methyl 3-hydroxy-6-methoxy-2,2-dimethyl-4-oxo-3,4-
dihydro-2Hbenzo[h]chromene-5-carboxylate 10:. yellow solid
(20.7 mg, 12%); mp 122–123 °C; 1H NMR (CDCl3) δ 1.31 (3H, s,
CH3), 1.79 (3H, s, CH3), 3.76 (1H, d, J ) 2.3 Hz, OH), 3.98 (3H,
s, COOCH3), 4.02 (3H, s, OCH3), 4.55 (1H, d, J ) 2.3 Hz, CH-4),
7.59–7.66 (1H, m, CHar), 7.70–7.77 (1H, m, CHar), 8.08 (1H, d, J
) 8.4 Hz, CHar), 8.34 (1H, d, J ) 8.4 Hz, CHar); 13C NMR (CDCl3)
δ 17.3 (CH3), 27.0 (CH3), 53.0 (COOCH3), 63.7 (OCH3), 76.5 (CH-
4), 85.2 (Cquat), 109.4 (Cquat), 119.7 (Cquat), 123.0 (CHar), 124.5
(CHar), 126.6 (Cquat), 127.7 (CHar), 130.7 (CHar), 132.1 (Cquat), 147.3
(Cquat), 155.4 (Cquat), 167.8 (CdO), 192.5 (CdO); IR (KBr) νmax
1691 (CdO), 1706 (COOMe); MS (ES+) m/z 331 (M + H+, 80),
299 (M - OMe, 100). Anal. Calcd for C18H18O6: C, 65.45; H, 5.49.
Found: C, 65.62; H, 5.78.
(KBr) vmax 1706 (CdO); MS (ES+) m/z 345 (M - OH-, 100).
Anal. Calcd for C19H22O7: C, 62.97; H, 6.12. Found: C, 62.87; H,
6.20.
4.2.6. Methyl 3-hydroxy-6-methoxymethoxy-2,2-dimethyl-4-
oxo-3,4-dihydro-2H-benzo[h]chromene-5-carboxylate 12: yellow
1
solid (1.8 mg, 1%); mp 119–120 °C; H NMR (CDCl3): δ 1.30
(3H, s, CH3), 1.79 (3H, s, CH3), 3.65 (3H, s, COOCH3), 3.80 (1H,
d, J ) 2.0 Hz, OH), 4.00 (3H, s, OCH2OCH3), 4.56 (1H, d, J )
2.0 Hz, CH-4), 5.12–5.22 (2H, m, OCH2), 7.58–7.67 (1H, m, CHar),
7.70–7.78 (1H, m, CHar), 8.16 (1H, d, J ) 8.4 Hz, CHar), 8.29–8.35
(1H, d, J ) 8.4 Hz, CHar); 13C NMR (CDCl3) δ 17.3 (CH3), 27.0
(CH3), 53.0 (OCH3), 57.9 (OCH3), 76.5 (Cquat), 85.3 (CH-4), 101.5
(Cquat), 109.5 (Cquat), 120.3 (Cquat), 123.5 (CHar), 124.2 (CHar), 126.5
(Cquat), 127.8 (CHar), 130.8 (CHar), 132.7 (Cquat), 144.9 (Cquat), 155.6
(Cquat), 167.7 (COOMe), 192.5 (CdO); IR (KBr) νmax 1684 (CdO),
1732 (COOMe); MS (ES+) m/z 361 (M + H+, 100). Anal. Calcd
for C19H20O7: C, 63.33; H, 5.59. Found: C, 62.98; H, 5.73.
4.3. Procedure for the O-Deprotection of the MOM Ether
of (()-Methyl cis-3,4-Dihydroxy-6-methoxymethoxy-2,2-dimeth-
yl-3,4-dihydro-2H-benzo[h]chromene-5-carboxylate 9. To a stirred
solution of compound 9 (362 mg, 1 mmol) in THF (2 mL) at 0 °C
was added 4 N HCl (2 mL) dropwise. The reaction mixture was
allowed to stir at 0–10 °C for 18 h, the solution was diluted with
water (6 mL), and the aqueous phase was extracted with ethyl
acetate (3 × 10 mL). The combined organic layers were dried over
magnesium sulfate and evaporated under reduced pressure. The
crude product was purified by flash column chromatography on
silica gel (petroleum ether/ethyl acetate 65/35 Rf 0.85) affording
cis-3,4-dihydroxy-3,4-dihydromollugin 2 as a white solid.
4.2.3. (()-Methyl cis-3,4-dihydroxy-6-benzyloxy-2,2-dimeth-
yl-3,4-dihydro-2H-benzo[h]chromene-5-carboxylate 8. white solid
1
(184 mg, 90%) mp 91–93 °C; H NMR (CDCl3) δ 1.47 (3H, s,
CH3), 1.57 (3H, s, CH3), 2.56 (1H, d, J ) 9.1 Hz, OH-3), 3.55
(1H, d, J ) 7.3 Hz, OH-4), 3.85 (1H, dd, J ) 9.1 Hz, 4.7 Hz,
CH-3), 3.91 (3H, s, OCH3), 4.99 (1H, dd, J ) 7.3 Hz, 4.7 Hz,
CH-4), 5.06 (1H, d, J ) 11.0 Hz, OCH2), 5.16 (1H, d, J ) 11.0
Hz, OCH2), 7.34–7.47 (3H, m, CHar), 7.48–7.60 (4H, m, CHar),
8.07–8.15 (1H, m, CHar), 8.23–8.30 (1H, m, CHar); 13C NMR
(CDCl3) δ 23.1 (CH3), 24.5 (CH3), 52.9 (COOCH3), 64.4 (OCH2),
71.7 (CH-4), 78.0 (CH-3), 78.4 (Cquat), 113.7 (Cquat), 122.8 (CHar),
123.1 (CHar), 123.2 (Cquat), 127.2 (Cquat), 127.4 (CHar), 127.5 (CHar),
127.9 (2 × CHar), 128.2 (CHar), 128.6 (Cquat), 128.7 (2 × CHar),
137.3 (Cquat), 144.4 (Cquat), 147.6 (Cquat), 169.3 (CdO); IR (KBr)
4.3.1. (()-Methyl cis-3,4,6-trihydroxy-2,2-dimethyl-3,4-dihy-
dro-2H-benzo[h]chromene-5-carboxylate 2 (cis-3,4-dihydroxy-
3,4-dihydromollugin): white solid (269 mg, 85%); mp 134–135
°C (hexane/CH2Cl2, 5/1) [lit.5b mp 107.6–108 °C (CHCl3)]; H
1
NMR (CDCl3) δ 1.50 (3H, s, CH3), 1.51 (3H, s, CH3), 2.79 (1H,
d, J ) 9.5 Hz, OH-3), 3.53 (1H, d, J ) 6.6 Hz, OH-4), 3.85 (1H,
dd, J ) 9.5 Hz, 5.2 Hz, CH-3), 4.06 (3H, s, COOCH3), 5.22 (1H,
dd, J ) 6.6 Hz, 5.2 Hz, CH-4), 7.53–7.68 (2H, m, CHar), 8.20
(1H, d, J ) 8.3 Hz, CHar), 8.37 (1H, d, J ) 8.3 Hz, CHar), 11.23
(1H, s, OH); 13C NMR (CDCl3) δ 22.1 (CH3), 24.9 (CH3), 52.9
(OCH3), 64.4 (CH-4), 72.3 (CH-3), 77.5 (Cquat), 104.7 (Cquat), 112.9
(Cquat), 122.6 (CHar), 124.0 (CHar), 125.7 (Cquat), 127.1 (CHar), 128.9
(Cquat), 129.6 (CHar), 140.9 (Cquat), 155.9 (Cquat), 171.3 (CdO); IR
(KBr) vmax 1654 (CdO), 3453 (OH); MS (ES-) m/z 317 (M - H+,
100). Anal. Calcd for C17H18O6: C, 64.14; H, 5.70. Found: C, 64.63;
H, 5.14.
4.3.2. (()-Methyl trans-3,4,6-trihydroxy-2,2-dimethyl-3,4-di-
hydro-2H-benzo[h]chromene-5-carboxylate 3 (trans-3,4-dihy-
droxy-3,4-dihydromollugin): white solid (64 mg, 20%); mp 162–
163 °C; 1H NMR (CDCl3) δ 1.40 (3H, s, CH3), 1.58 (3H, s, CH3),
2.41 (1H, br. s, OH-3), 3.18 (1H, br. s, OH-4), 3.80 (1H, d, J )
6.2 Hz, CH-3), 4.06 (3H, s, COOCH3), 5.06 (1H, d, J ) 6.2 Hz,
CH-4), 7.53–7.68 (2H, m, CHar), 8.19 (1H, d, J ) 8.3 Hz, CHar),
8.37 (1H, d, J ) 8.3 Hz, CHar), 11.51 (1H, s, OH); 13C NMR
(CDCl3) δ 19.7 (CH3), 25.6 (CH3), 52.9 (OCH3), 69.8 (CH-4), 76.1
(CH-3), 77.5 (Cquat), 103.8 (Cquat), 112.9 (Cquat), 122.6 (CHar), 124.1
(CHar), 125.7 (Cquat), 127.1 (CHar), 129.1 (Cquat), 129.7 (CHar), 141.0
(Cquat), 156.6 (Cquat), 171.4 (CdO); IR (KBr) vmax 1630 (CdO),
3325 (OH). MS (ES-) m/z 317 (M - H+, 100). Anal. Calcd for
C17H18O6: C, 64.14; H, 5.70. Found: C, 64.90; H, 6.32.
ν
max 1718 (CdO); MS (ES+) m/z 391 (M - OH-, 100). Anal. Calcd
for C24H24O6: C, 70.57; H, 5.92. Found: C, 70.66; H, 6.09.
4.2.4. Methyl 3-hydroxy-6-benzyloxy-2,2-dimethyl-4-oxo-3,4-
dihydro-2H-benzo[h]chromene-5-carboxylate 11: yellow crystals
1
(10 mg, 5%); mp 133–134 °C; H NMR (CDCl3) δ 1.33 (3H, s,
CH3), 1.80 (3H, s, CH3), 3.79 (1H, br s, OH), 3.96 (3H, s,
COOCH3), 4.58 (1H, s, CH-3), 5.07 (1H, d, J ) 10.7 Hz), 5.15
(1H, d, J ) 10.7 Hz), 7.34–7.48 (3H, m, CHar), 7.49–7.57 (2H, m,
CHar), 7.58–7.76 (2H, m, CHar), 8.10 (1H, d, J ) 8.4 Hz, CHar),
8.35 (1H, d, J ) 8.4 Hz, CHar); 13C NMR (CDCl3) δ 17.3 (CH3),
27.1 (CH3), 53.0 (COOCH3), 76.5 (CH-4), 78.2 (CH-3), 85.3 (Cquat),
109.5 (Cquat), 120.4 (Cquat), 123.1 (CHar), 124.4 (CHar), 126.6 (Cquat),
127.8 (CHar), 128.1 (2 × CHar), 128.4 (CHar), 128.7 (2 × CHar),
130.8 (CHar), 132.4 (Cquat), 136.9 (Cquat), 146.2 (Cquat), 155.5 (Cquat),
167.9 (CdO), 192.5 (CdO); IR (KBr) νmax 1675 (CdO), 1733
(COOMe); MS (ES+) m/z 407 (M + H+, 100). Anal. Calcd for
C24H22O6: C, 70.92; H, 5.46. Found: C, 69.26; H, 5.31.
4.2.5. (()-Methyl cis-3,4-dihydroxy-6-methoxymethoxy-2,2-
dimethyl-3,4-dihydro-2H-benzo[h]chromene-5-carboxylate 9:
1
white solid (172 mg, 95%); mp 128–129 °C; H NMR (CDCl3) δ
4.4. General Procedure for the Dihydroxylation of O-Pro-
tected Mollugin Derivatives 4–6 Using Oxone. The dihydroxy-
lation of compound 4 is taken as a representative example.
To a stirred solution of compound 4 (298 mg, 1.0 mmol) in
acetone (10 mL) was added a solution of Oxone (2KHSO5, KHSO4,
K2SO4,) (1.84 g, 3 mmol) dissolved in water (20 mL). The reaction
mixture was heated at 80 °C for 6 h and was then allowed to cool
to room temperature. Aqueous saturated sodium bicarbonate was
added (40 mL), and the aqueous phase was extracted into ethyl
acetate (3 × 30 mL). The combined organic layers were washed
1.45 (3H, s, CH3), 1.56 (3H, s, CH3), 2.46 (1H, d, J ) 9.2 Hz,
OH-3), 3.47 (1H, d, J ) 7.5 Hz, OH-4), 3.63 (3H, s, COOCH3),
3.82 (1H, dd, J ) 9.2 Hz, 4.7 Hz, CH-3), 4.00 (3H, s, OCH3), 4.99
(1H, dd, J ) 7.5 Hz, 4.7 Hz, CH-4), 5.11 (1H, d, J ) 6.0 Hz,
OCH2), 5.15 (1H, d, J ) 6.0 Hz, OCH2), 7.52–7.61 (2H, m, CHar),
8.07–8.15 (1H, m, CHar), 8.20–8.28 (1H, m, CHar); 13C NMR
(CDCl3) δ 23.4 (CH3), 24.2 (CH3), 52.9 (OCH3), 57.9 (OCH2), 64.4
(CH-4), 71.6 (CH-3), 78.4 (Cquat), 101.3 (Cquat), 113.5 (Cquat), 122.9
(CHar), 123.0 (CHar), 123.6 (Cquat), 127.0 (Cquat), 127.4 (CHar), 127.6
(CHar), 128.7 (Cquat), 144.5 (Cquat), 146.0 (Cquat), 169.1 (CdO); IR
J. Org. Chem. Vol. 73, No. 10, 2008 3873

Mudiganti et al.
with water (2 × 20 mL), dried over magnesium sulfate, and
evaporated under reduced pressure. The crude product was purified
by flash column chromatography on silica gel (petroleum ether/
ethyl acetate 60/40 Rf 0.94) to afford the trans-O-methyl 3,4-
dihydroxy-3,4-dihydromollugin 15 along with (petroleum ether/
ethylacetate 65/35 Rf 0.82) cis-O-methyl 3,4-dihydroxy-3,4-
dihydromollugin 7 (59 mg, 18%).
4.4.1. (()-Methyl trans-3,4-dihydroxy-6-methoxy-2,2-dimeth-
yl-3,4-dihydro-2H-benzo[h]chromene-5-carboxylate 15: white
solid (193 mg, 58%); mp 82–83 °C; 1H NMR (CDCl3) δ 1.22 (3H,
s, CH3), 1.37 (3H, s, CH3), 3.55 (1H, d, J ) 7.8 Hz, CH-3), 3.88
(3H, s, OCH3), 3.93 (3H, s, OCH3), 4.15 (1H, brs, OH-3), 4.40
(1H, brs, OH-4), 4.81 (1H, d, J ) 7.8 Hz, CH-4), 7.47–7.57 (2H,
m, CHar), 7.97–8.03 (1H, m, CHar), 8.08–8.15 (1H, m, CHar); 13C
NMR (CDCl3) δ 19.7 (CH3), 25.9 (CH3), 52.9 (OCH3), 63.7 (Ar-
OCH3), 69.1 (CH-4), 76.1 (CH-3), 78.9 (Cquat), 113.5 (CHar), 122.0
(Cquat), 122.6 (Cquat), 123.1 (CHar), 127.0 (CHar), 127.2 (Cquat), 127.4
(CHar), 128.2 (CHar), 144.5 (Cquat), 148.5 (Cquat), 169.5 (CdO); IR
(KBr) vmax: 1712 (CdO); MS (ES+) m/z 333 (M + H+, 10), 315
(M - OH-, 100). Anal. Calcd for C18H20O6: C, 65.05; H, 6.07.
Found: C, 64.78; H, 6.14.
1.0 mmol) in acetone (20 mL) was added a solution of Oxone
(2KHSO5, KHSO4, K2SO4,) (1.84 g, 3 mmol) dissolved in water
(10 mL). The reaction mixture was heated at 80 °C for 12 h and
then allowed to return to room temperature. Aqueous saturated
sodium bicarbonate was added (40 mL) and the aqueous phase was
extracted with ethyl acetate (3 × 30 mL). The combined organic
extracts were washed with water (2 × 20 mL), dried over
magnesium sulfate and evaporated under reduced pressure. The
crude product was purified by flash column chromatography on
silica gel (petroleum ether/ethylacetate 85/15 Rf 0.65) to afford cis-
3,4-dihydroxymollugin acetonide 13 together with trans-3,4-dihy-
droxy-3,4-dihydromollugin 3 (26 mg, 8%; petroleum ether/ethyl
acetate 60/40 Rf 0.94).
4.5.1. (()-cis-3,4-Dihydroxymollugin acetonide 13: yellow
crystals (172 mg, 48%); mp 142–143 °C; 1H NMR (CDCl3) δ 1.01
(3H, s, CH3), 1.38 (3H, s, CH3), 1.39 (3H, s, CH3), 1.55 (3H, s,
CH3), 4.02 (3H, s, COOCH3), 4.18 (1H, d, J ) 6.1 Hz CH-3), 5.80
(1H, d, J ) 6.1 Hz CH-4), 7.50–7.66 (2H, m, CHar), 8.22 (1H, d,
J ) 8.3 Hz, CHar), 8.36 (1H, d, J ) 8.3 Hz, CHar), 11.65 (1H, s,
OH); 13C NMR (CDCl3) δ 23.2 (CH3), 24.7 (CH3), 26.9 (CH3),
27.5 (CH3), 52.4 (OCH3), 70.9 (CH-3), 74.8 (Cquat), 78.1 (CH-4),
104.6 (Cquat), 109.5 (Cquat), 111.6 (Cquat), 122.7 (CHar), 123.8 (CHar),
125.6 (Cquat), 126.9 (CHar), 127.1 (CHar), 128.8 (Cquat), 129.2 (CHar),
140.9 (Cquat), 155.9 (Cquat), 172.4 (CdO); IR (KBr) νmax 1645
(CdO), 3285 (OH); MS (ES+) m/z 359 (M + H+, 100). Anal. Calcd
for C20H22O6: C, 67.03; H, 6.19. Found: C, 67.48; H, 6.33.
4.4.2. (()-Methyl trans-3,4-dihydroxy-6-benzyloxy-2,2-di-
methyl-3,4-dihydro-2H-benzo[h]chromene-5-carboxylate 16:
1
white solid (286 mg, 70%); mp 88–90 °C; H NMR (CDCl3) δ
1.40 (3H, s, CH3), 1.60 (3H, s, CH3), 2.36 (1H, br. s, OH-3), 3.08
(1H, br. s, OH-4), 3.82 (1H, d, J ) 7.2 Hz, CH-3), 3.89 (3H, s,
OCH3), 4.82 (1H, d, J ) 7.2 Hz, CH-4), 5.05 (1H, d, J ) 11.1 Hz,
OCH2), 5.17 (1H, d, J ) 11.1 Hz, OCH2), 7.35–7.59 (7H, m, CHar),
8.07–8.13 (1H, m, CHar), 8.23–8.28 (1H, m, CHar); 13C NMR
(CDCl3) δ 19.9 (CH3), 25.9 (CH3), 52.9 (OCH3), 69.2 (Ar-OCH3),
76.0 (CH-4), 77.9 (Cquat), 78.6 (Cquat), 113.7 (Cquat), 122.5 (Cquat),
122.7 (CHar), 123.1 (CHar), 127.1 (Cquat), 127.3 (CHar), 127.5 (CHar),
127.9 (2 × CHar), 128.2 (CHar), 128.5 (Cquat), 128.6 (2 × CHar),
137.3 (Cquat), 144.6 (Cquat), 147.4 (Cquat), 169.4 (CdO); IR (KBr)
Acknowledgment. This work was financially supported by
the Flemish Institute for the Promotion of Scientific-Techno-
logical research in Industry (IWT) and the Fund for Scientific
Research-Flanders (FWO-Vlaanderen).
Supporting Information Available: Experimental proce-
dures and characterization. This material is available free of
charge via the Internet at http://pubs.acs.org.
ν
max 1709 (CdO); MS (ES+) m/z 391 (M - OH-, 100). Anal. Calcd
for C24H24O6: C, 70.57; H, 5.92. Found: C, 69.93; H, 6.41.
4.5. Synthesis of (()-cis-3,4-Dihydroxymollugin Acetonide
13 from Mollugin 1. To a stirred solution of mollugin 1 (284 mg,
JO800312J
3874 J. Org. Chem. Vol. 73, No. 10, 2008