Efficient syntheses of mollugin

Article abstract of DOI:10.1055/s-2006-950441

Two different strategies are presented to synthesize mollugin, based upon a close investigation of possible natural precursors. The best total synthesis of mollugin, a natural product isolated from rubiaceous herbs, is achieved in an overall yield of 61% starting from 1,4-dihydroxynaphthalene-2-carboxylic acid. The key reaction is the prenylation and spontaneous pyran ring formation. Subsequent oxidation of the intermediate 3,4-dihydromollugin with DDQ afforded mollugin. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2006-950441

2472
LETTER
Efficient Syntheses of Mollugin
B
iomimetic Sy
a
nthese
s
of
sMollugincal Habonimana, Sven Claessens, Norbert De Kimpe*
Department of Organic Chemistry, Faculty of Bioscience Engineering, Ghent University, Coupure links 653, 9000 Ghent, Belgium
Fax +32(9)2646243; E-mail: norbert.dekimpe@UGent.be
Received 29 June 2006
mycoses. This medicinal plant is also used in Kenya and
Abstract: Two different strategies are presented to synthesize mol-
Rwanda against malaria, diarrhea, tapeworm, gonorrhea,
lugin, based upon a close investigation of possible natural precur-
sors. The best total synthesis of mollugin, a natural product isolated
from rubiaceous herbs, is achieved in an overall yield of 61% start-
syphilis, and as a purgative.6 An earlier report mentioned
the synthesis of mollugin (1) in 23% yield in two steps by
ing from 1,4-dihydroxynaphthalene-2-carboxylic acid. The key re- the condensation of 3-chloro-3-methyl-1-butyne and 1,4-
action is the prenylation and spontaneous pyran ring formation.
dihydroxynaphthalene-2-carboxylic acid in the presence
Subsequent oxidation of the intermediate 3,4-dihydromollugin with
of aluminum(III) chloride and subsequent esterification of
DDQ afforded mollugin.
the intermediate molluginic acid with diazomethane.7
Heide and Leistner reported, without mentioning the
Key words: quinones, natural products, oxidations
yield, the synthesis of 3,4-dihydromollugin (2) by
condensing 2-methyl-3-buten-2-ol and methyl 1,4-dihy-
Many naturally occurring naphthoquinones possess inter- droxynaphthalene-2-carboxylate (5) in dioxane, in the
esting physiological properties. Among them, mollugin presence of BF3 as a Lewis acid catalyst.8 In a recent
(1), 3,4-dihydromollugin (2), and their analogues have publication,9 the synthesis of mollugin (1) was achieved
shown anti-tumor activity,1 antiviral activity against the in two steps from methyl 1,4-dihydroxynaphthalene-2-
hepatitis B virus,2 antibacterial, and mutagenic3 activities. carboxylate (5) in 39% yield. According to this report,
Chung et al. reported that mollugin strongly inhibited 3,4-dihydromollugin (2) was obtained after electrophilic
collagen-induced and arachidonic acid induced platelet aromatic addition of 2-methyl-3-buten-2-ol onto methyl
aggregation.4
1,4-dihydroxynaphthalene-2-carboxylate (5). Subsequent
pyran ring closure in the presence of BF3·OEt2 resulted in
3,4-dihydromollugin (2) in 54% yield. Refluxing 3,4-di-
hydroxymollugin 2 in dioxane in the presence of DDQ
yielded mollugin (1) in 72% yield. Recently, a lengthy but
promising synthesis of mollugin was published in which
the methoxycarbonyl moiety was adhered at the end of the
route.10
OH
O
OH
O
OMe
OMe
O
O
In this report, two new and alternative pathways towards
mollugin (1) are presented. In order to facilitate the search
for promising reaction pathways, the design of the strate-
gy was based on the search and observation of possible
precursors in the biosynthesis of mollugin in the plant ma-
terial. By looking in the literature at isolated compounds
in Gallium mollugo and Pentas longiflora, two possible
precursors were selected.
3,4-dihydromollugin (2)
mollugin (1)
O
O
O
OMe
methyl 3-(3-methyl-2-butenyl)-
1,4-naphthoquinone-2-carboxylate (3)
The first route (Scheme 1) was based upon the idea that
the biosynthesis of mollugin proceeds via the formation of
methyl 3-(3-methyl-2-butenyl)-1,4-naphthoquinone-2-
carboxylate (3), since this compound 3 is often isolated
from plant materials together with mollugin.8,11 An impor-
tant feature of prenylated naphthoquinones is their ability
to tautomerize to orthoquinone methides.12 It is expected
that this compound 3 would give rise to an electrocycliza-
tion reaction and subsequent pyran-ring formation result-
ing in mollugin. This mechanism is also responsible for
the photoracemization of cyclopropyl chromenes.13 Dur-
ing the course of our research, this strategy was applied
independently by Trauner’s research group.14 In their
research, triethylamine was used as a base in dichlo-
romethane resulting in an elegant synthesis of mollugin in
Figure 1
Mollugin (1) was isolated first from the rhizome of
Gallium mollugo (Rubiaceae) and has been found in many
rubiaceous herbs growing in Europe, Africa, and
Asia.1,2,4,5 At our department, mollugin (1) was isolated
from Pentas longiflora (Rubiaceae), a very important
plant species used by traditional African healers to treat
skin diseases like pityriasis versicolor, itchy rashes, or
SYNLETT 2006, No. 15, pp 2472–2475
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8
.0
9
.2
0
0
6
Advanced online publication: 08.09.2006
DOI: 10.1055/s-2006-950441; Art ID: G19806ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
Biomimetic Syntheses of Mollugin
2473
81% yield. Their synthesis of methyl 3-(3-methyl-2-bute- prenylation (48% and part converted to mollugin) give an
nyl)-1,4-naphthoquinone-2-carboxylate (3) as a precursor indication of the non-radical character of the prenylation
was performed by an allylation reaction and subsequent in nature.
Grubbs cross-metathesis with 2-methyl-2-butene to yield
the precursor 3 in a total yield of 33%.
O
O
O
O
O
OMe
COOH
OMe
(1.8 equiv)
AgNO3 (0.5 equiv)
(NH4)2S2O8 (1.8 equiv)
MeCN–H2O, 80 °C, 16 h
O
OH
O
oxa 6π
OH
O
O
pericyclic
reaction
4
3 (20%)
OMe
OMe
pyridine,
r.t., 10 min
O
OH
O
mollugin (1)
OMe
O
O
O
O
+
1 (79%)
3 (48%)
OMe
base
1)
SnBu3
(1.2 equiv)
1 (13%)
BF3·OEt2, CH2Cl2, (3 equiv)
–78 °C, 1.5 h
2) Ag2O, Et2O, r.t., 5 h (3.5 equiv)
one pot
Scheme 1
Scheme 2
The C-3 allylation of 2-acetyl-1,4-naphthoquinone had
been achieved using either 3-butenoic acid in the presence
of silver(I) nitrate and potassium persulfate (43% yield)15
or using allyltrimethylstannane in the presence of
BF3·OEt2.16
The above-mentioned strategy worked out as outlined but
the synthesis of the precursor 3 was merely low-yielding
(48%). Taking a closer look at the isolated compounds in
Rubiaceae species suggests another possible synthetic
route (Scheme 3). The next scheme is based upon the syn-
thesis of the key intermediate 3,4-dihydromollugin (2),
which was isolated together with mollugin from Gallium
mollugo.5b,18 If 3,4-dihydromollugin (2) can be synthe-
sized in a reasonable yield, it would constitute a suitable
route to synthesize mollugin by an oxidation process.
We chose to introduce the prenyl chain directly without
making the detour via the allyl side chain and Grubbs
cross-metathesis. Radical C-3 prenylation of methyl 1,4-
naphthoquinone-2-carboxylate (4) with 4-methyl-3-pen-
tenoic acid in the presence of 0.5 equivalent of silver(I) ni-
trate and 1.8 equivalents of ammonium peroxydisulfate17
yielded methyl 3-(3-methyl-2-butenyl)-1,4-naphtho-
quinone-2-carboxylate (3) in 20% yield together with un-
reacted and unidentified material. The nucleophilic
addition of tributylprenyltin to methyl 1,4-naphthoquino-
ne-2-carboxylate (4) in the presence of BF3·OEt2 in
dichloromethane at –78 °C, followed by silver(I) oxida-
tion gave the prenylated naphthoquinone 3 in 48% yield.
The initial yield of this prenylated naphthoquinone 3 was
higher but, surprisingly, under the given conditions, al-
ready a part of the prenylated naphthoquinone 3 is con-
verted into the desired mollugin (1) (13% yield). This
unexpected result is a positive indication for the useful-
ness of the proposed strategy (Scheme 2). Unfortunately,
the efforts to improve the yield (13%) of mollugin in this
reaction by varying the reaction conditions were not suc-
cessful. It seemed better to synthesize mollugin in a two-
step protocol. In this way, the precursor 3 was treated in
basic conditions by using a 10% solution in pyridine af-
fording the desired mollugin in 79% yield, together with
some unidentified materials. The low-yielding radical
prenylation (20%) next to the higher-yielding tributyltin
OH
O
OH
O
OMe
OMe
O
O
1
2
OH
OH
O
OMe
5
Scheme 3
Therefore, methyl 1,4-dihydroxynaphthalene-2-carboxy-
late (5) was prepared by esterification of the carboxylic
acid 6 with diazomethane. In the following step, the me-
thyl ester 5 was heated under reflux with 3-methyl-3-
buten-1-ol in tetrahydrofuran in the presence of 1.2 equiv-
alents of BF3·OEt2 to give rise to 3,4-dihydromollugin (2)
Synlett 2006, No. 15, 2472–2475 © Thieme Stuttgart · New York

2474
P. Habonimana et al.
LETTER
OH
O
O
mollugin (1) (61% total yield) in a short reaction sequence
was developed. The reaction sequence was based upon
electrophilic addition of 3-methyl-3-buten-1-ol onto the
ortho position of an aromatic alcohol in the presence of
BF3, immediately followed by pyran ring formation and
subsequent DDQ oxidation. This pathway reveals the
highest-yielding synthesis of mollugin at this moment.
OH
OH
O
1) CH2N2, Et2O
2)
OMe
OH
OH
(1.5 equiv)
BF3·OEt2 (1.2 equiv)
THF, ∆, 64 h
6
2 (75%)
OH
O
NBS (2.5 equiv)
BPO (0.1 equiv)
CCl4, ∆, 18 h
OMe
Br
Acknowledgment
O
The authors are indebted to the Research Foundation – Flanders
(FWO-Vlaanderen), the Burundian Government, and the IWT
(Flemish Institute for the promotion of Scientific Technological
Research in Industry) for financial support.
7 (58%)
DDQ (1.2 equiv)
OH
O
dioxane, ∆, 16 h
22%
2
OMe
References and Notes
DDQ (1.2 equiv)
toluene, ∆, 18 h
O
(1) Itokawa, H.; Mihara, K.; Takeya, K. Chem. Pharm. Bull.
1983, 31, 2353.
2
1
81%
(2) (a) Ho, L.-K.; Don, M.-J.; Chen, H.-C.; Yeh, S.-F.; Chen, J.-
M. J. Nat. Prod. 1996, 59, 330. (b) Itokawa, H.; Takeya, K.;
Mori, N.; Sonobe, T.; Mihashi, S.; Hamanaka, T. Chem.
Pharm. Bull. 1986, 34, 3762.
(3) Kawasaki, Y.; Goda, Y.; Yoshishira, K. Chem. Pharm. Bull.
1992, 40, 1504.
Scheme 4
in 75% yield. The reaction proceeded faster when per-
formed in dioxane for 16 hours but the observed yield was
a little lower (61%). BF3 activates the alcohol moiety by
borate formation. Subsequent ortho-alkylation of the aro-
matic alcohol by the homoallylborate and cyclization by
attack of the phenol oxygen onto the proton-activated car-
bon–carbon double bond of the isoprenyl group afforded
3,4-dihydromollugin (2).
(4) Chung, M.-L.; Jou, S.-J.; Cheng, T.-H.; Lin, C.-N. J. Nat.
Prod. 1994, 57, 313.
(5) (a) Gonzalez, A. G.; Barroso, J. T.; Cardona, R. J.; Medina,
J. M.; Rodriguez, L. An. Quim. 1977, 73, 538. (b) Itokawa,
H.; Qiao, Y. F.; Takeya, K. Phytochemistry 1989, 28, 3465.
(c) Itokawa, H.; Qiao, Y. F.; Takeya, K. Phytochemistry
1991, 30, 637. (d) Hua, H. M.; Wang, S. X.; Wu, L. J.; Li,
X.; Zhu, T. R. Acta Pharm. Sinica 1992, 27, 279. (e) Kuo,
S.-C.; Chen, P.-R.; Lee, S.-W.; Chen, Z.-T. J. Chin. Chem.
Soc. (Taipei) 1995, 42, 869. (f) Inoue, K.; Shiobara, Y.;
Naynshiro, H.; Inouye, H.; Wilson, G.; Zenk, M. H.
Phytochemistry 1984, 23, 307.
(6) (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.
In a next step, 3,4-dihydromollugin was oxidized to the
desired mollugin. The literature9 revealed an existing
method using DDQ in dioxane resulting in mollugin in
72% yield, but in our hands the yields were much lower
(22%), even after repeated attempts. In an attempt to
search for alternatives, oxidation using Pd/C in toluene
was tried, but only starting material was recovered. The
reaction of 3,4-dihydromollugin (2) with one equivalent
of NBS and 0.1 equivalent of benzoyl peroxide (BPO) in
tetrachloromethane did not result in the expected mollu-
gin (1) but instead gave rise to the interesting and new
compound 3-bromomollugin ( 7) in 40% yield.19 Appar-
ently, the radical bromination–dehydrobromination se-
quence afforded mollugin, but in the given conditions
mollugin reacts further with NBS to give rise to 3-bromo-
mollugin. The yield of this reaction could be improved to
58% by using 2.5 equivalents of NBS in tetrachlo-
romethane. Finally, it was found that mollugin could be
obtained in 81% yield by using a DDQ oxidation of dihy-
dromollugin (2) in toluene, which is an improved oxida-
tion procedure compared to the literature.9
(7) Schildknecht, H.; Straub, F. Liebigs Ann. Chem. 1976, 1307.
(8) Heide, L.; Leistner, E. J. Chem. Soc., Chem. Commun. 1981,
334.
(9) Ho, L.-K.; Yu, H.-J.; Ho, C.-T.; Don, M.-J. J. Chin. Chem.
Soc. 2001, 48, 77.
(10) Claessens, S.; Kesteleyn, B.; Nguyen, V. T.; De Kimpe, N.
Tetrahedron 2006, 62, 8419.
(11) Giles, R. G. F.; Green, I. R.; Hugo, V. I.; Mitchell, P. R. K.;
Yorke, S. C. J. Chem. Soc., Perkin Trans. 1 1983, 2309.
(12) (a) Khanna, R. N.; Sharma, P. K.; Thomson, R. H. J. Chem.
Soc., Perkin Trans. 1 1987, 1821. (b) Nicolaou, K. C.;
Sasmal, P. K.; Xu, H. J. Am. Chem. Soc. 2004, 126, 5493.
(13) Wipf, P.; Weiner, W. S. J. Org. Chem. 1999, 64, 5321.
(14) Lumb, J. P.; Trauner, D. Org. Lett. 2005, 7, 5865.
(15) Naruta, Y.; Uno, H.; Maruyama, K. J. Chem. Soc., Chem.
Commun. 1981, 1277.
In summary, in this report, the present synthetic strategies
for mollugin are based upon the observation of possible
biosynthetic precursors. Two alternative precursors were
presented and this resulted in two different approaches.
Both worked out well but the second strategy, based upon
3,4-dihydromollugin as a precursor is the most promising.
In this way, a synthesis which produced the naturally
occurring 3,4-dihydromollugin (2) (75% total yield) and
(16) Naruta, Y. J. Org. Chem. 1980, 45, 4097.
(17) Jacobsen, N.; Torsell, K. Acta Chem. Scand. 1973, 27, 3211.
Synlett 2006, No. 15, 2472–2475 © Thieme Stuttgart · New York

LETTER
Biomimetic Syntheses of Mollugin
2475
(18) Schildknecht, H.; Straub, F. Liebigs Ann. Chem. 1976, 1295.
(19) 3-Bromomollugin 7: IR (KBr): 1650 cm–1 (C=O). 1H NMR
(CDCl3, 300 MHz): d = 1.59 (6 H, s, 2 ꢀ CH3), 4.04 (3 H, s,
OCH3), 7.54 (1 H, ddd, J = 8.2, 6.9, 1.4 Hz, CH-8 or CH-9),
7.56 (1 H, s, CH), 7.63 (1 H, ddd, J = 8.2, 6.9, 1.4 Hz, CH-8
or CH-9), 8.13 (1 H, ddd, J = 8.2, 1.4, 0.8 Hz, CH-7), 8.37 (1
NMR (CDCl3, 75 MHz): d = 25.82 (2 ꢀ CH3), 52.62 (OMe),
78.73 (=CBr), 101.24 (Cquat), 113.15 (Cquat), 121.85 (CH-7),
123.80 (Cquat), 124.29 (CH-10), 125.25 (Cquat), 125.31
(=CH), 126.73 (CH-8 or CH-9), 128.81 (Cquat), 129.77 (CH-
8 or CH-9), 140.32 (Cquat), 157.27 (Cquat), 172.20 (C=O). MS
(ES+): m/z (%) = 362/364 [M]+(100).
H, ddd, J = 8.2, 1.4, 0.8 Hz, CH-10), 12.27 (1 H, s, OH). 13
C
Synlett 2006, No. 15, 2472–2475 © Thieme Stuttgart · New York