Synthesis of naturally occurring rubilactone, mollugin, and dihydromollugin of Rubia cordifolia

Article abstract of DOI:10.1002/jccs.200100014

Rubilactone (1), dihydromollugin (2), and mollugin (3) are naturally occurring products found in Rubia cordifolia, which is a famous Chinese herb with antitumor, viral inhibition and other activities. Synthetic studies were carried out in these naphthoic acid esters starting from 1,4-dihydroxy-2-naphthoic acid. In this study, we finished the synthesis of rubilactone which has not been reported before and also synthesized dihydromollugin and mollugin with better yields with different approaches compared to those previously reported in the literature.

Full text of DOI:10.1002/jccs.200100014

JournaloftheChineseChemicalSociety, 2001, 48, 77-79
77
Synthesis of NaturallyOccurringRubilactone, Mollugin, and
Dihydromollugin of Rubia cordifolia
Li-Kang Hoa (
Chen-Ta Hob (
), Hsi-Jung Yub (
),
何禮剛
何程達
游錫榕
) and Ming-Jaw Donc* (
)
董明兆
aDepartmentofPharmacology,NationalYang-MingUniversity,Taipei112,Taiwan,R.O.C.
bDepartmentofChemistry,ChineseCultureUniversity,Taipei111,Taiwan,R.O.C.
cNationalResearchInstituteofChineseMedicine,Taipei112,Taiwan,R.O.C.
Rubilactone (1), dihydromollugin (2), and mollugin (3) are nat u rally oc cur ring prod ucts found inRubia
cordifolia, which is a fa mous Chi nese herb with antitumor, vi ral in hi bi tion and other ac tiv i ties. Synthetic
stud ies were car ried out in these naphthoic acid es ters start ing from 1,4-dihydroxy-2-naphthoic acid. In this
study, we fin ished the syn the sis of rubilactone which has not been re ported be fore and also synthesized
dihydromollugin and mollugin with better yields with dif fer ent ap proaches com pared to those pre viouslyre-
portedintheliterature.
Scheme Ia
INTRODUCTION
Rubilactone (1), dihydromollugin (2), and mollugin (3)
are three naphthoic acid es ters com po nents iso lated from the
roots of Rubia cordifolia L. (Rubiaceae),1-4 a Chi nese herbal
medicinewithantitumor,antiviralandotheractivities.3,5 In
our pre vi ous stud ies, both 2 and 3 showed strong and 1
showedweaksuppressiveactivityonHBsAgsecretioninhu-
man hepatoma Hep3B cells.3 Com pound 3 also pos sessed
stronginhibitionofarachidonicacid(AA)-inducedandcolla-
gen-inducedplateletaggregation.6 In an ear lier at tempt3 was
syn the sized from 1,4-dihydroxy-2-naphthoic acid and 3-
chloro-3-methyl-1-butyne in 23% over all yield.7 Com pound
2 wasobtainedbycatalytichydrogenationof3 over Pd/C8 or
synthesizedfrommethyl1,4-dihydroxy-2-naphthoatebutno
yield given.9 Synthesisof 1 has not been re ported yet so far.
Hereinwewouldliketoreportaconvenientsyntheticmethod
to pre pare com pounds 1, 2, and 3 from 1,4-dihydroxy-2-
naphthoicacid.
OH
O
O
OH
OH
O
OH
O
OCH
i
OCH
3
ii
OH
3
OH
O
rubilactone, 1
iii
iii
OH
O
OH
O
O
OH
O
OH
OCH
3
OCH
3
i
iv
O
O
mollugin, 3
dihydromollugin, 2
4
a(i) CH2N2, ether; (ii) ethyl propiolate, ZnCl2, reflux; (iii)
2-methyl-3-buten-2-ol, BF3-etherate, dioxane, re flux; (iv) DDQ,
dioxane, reflux.
tenylintermediate,whileatelevatedtemperatureitgavethe
intramolecularly cyclized prod uct 4. Withoutfurtherpurifi-
ca tion, esterification of crude prod uct 4 with ex cess CH2N2
produceddihydromollugin( 2) as a yel low solid in 40% over-
all yield (based on 1,4-dihydroxy-2-naphthoic acid). Al ter na-
tively, a mixture of methyl 1,4-dihydroxy-2-naphthoate,
2-methyl-3-buten-2-ol, and BF3-etherate in dioxane was
refluxed for 4 h to give 2in 54% yield.9 Mollugin (3) was then
eas ily ob tained from2 in 72% yield by heat ing with DDQ in
dioxane. Methods de scribed here to pre pare mollugin (3) are
more con ve nient and give better yield than ones in pre vi ous
reports.
RESULTSANDDISCUSSION
Compounds 1, 2, and 3 were prepared as shown in
Scheme I. Upon treat ment of methyl 1,4-dihydroxy-2- naph-
thoate, which was pre pared from 1,4-dihydroxy-2-naphthoic
acid and CH2N2 first, with ethyl propiolate and zinc chlo ride
un der re flux, rubilactone (1) was ob tained in 38% yield as a
yellowsolid.
1,4-Dihydroxy-2-naphthoic acid was con densed with
2-methyl-3-buten-2-ol in BF3-etherate to yield the isopen-

78 J. Chin. Chem. Soc., Vol. 48, No. 1, 2001
Ho et al.
In con clu sion we re ported here the first syn the sis of
rubilactone (1) in only two steps starting from 1,4-dihy-
droxy- 2-naphthoic acid with ethyl propiolate in mod er ate
yield and pro vided a con ve nient syn thetic method for prep a-
ra tion of dihydromollugin (2) and mollugin (3).
mmol). Thereactionmixturewasstirredatroomtemperature
for 30 min utes and then refluxed for 3 h. Af ter cool ing, Et2O
(60 mL) was added and the etheral so lu tion was washed with
H2O, dried over Na2SO4, and evap o rated to give crude solid
which was washed with a small amount of ethyl ac e tate to
yield crude prod uct4 (1.6 g) as a yel low solid and used in the
next step with out fur ther pu ri fi ca tion.1H NMR (CDCl3)
1.39 (s, 6H), 1.86 (t, J= 6.8 Hz, 2H), 3.18 (t, J = 6.8 Hz, 2H),
7.49-7.68 (m, 2H), 8.13-8.17 (m, 1H), 8.28-8,33 (m, 1H). To
a so lu tion of the crude prod uct4 in ether (40 mL) was added
ex cess CH2N2 at 0 C for 30 min utes. Sol vent was re moved
from a rotavapor, and the res i due was chromatographed on
sil ica gel eluting with hex ane/ethyl ac e tate (98:2) to yield
dihydromollugin (1.15 g, 40%) as a yel low solid: mp 96-97
EXPERIMENTALSECTION
Melting points were de ter mined with a Yanaco micro-
meltingpointapparatusandareuncorrected.Infraredspectra
wereobtainedonaNicoletAvatar320FTIRspectrophotom-
eter.Nuclearmagneticresonancespectrawererecordedona
Varian Gemini-200spectrometer. Chem i cal shifts are re-
ported in parts per mil lion ( unitsrelativetointernaltetra-
methylsilane. The mass spectra were measured from a
Finnigan GCQ GC/MS spec trom e ter at 30 eV. Dioxane was
dis tilled from Na/ben zo phe none and all other sol vents were
usedwithoutfurtherpurification.Columnchromatography
was per formed with E. Merck 230-400 mesh sil ica gel.
1
C; IR (KBr) 1645 cm-1; H NMR (CDCl3) 1.39 (s, 6H),
1.82 (t, J = 6.6 Hz, 2H), 3.04 (t, J= 6.6 Hz, 2H), 3.97 (s, 3H),
7.47 (t, J = 7.8 Hz, 1H), 7.58 (t, J = 7.8 Hz, 1H), 8.16 (d, J =
8.1 Hz, 1H), 8.35 (d, J = 8.1 Hz, 1H), 12.1 (s, 1H); EIMS m/z
(rel. int.) 286 (M+, 66), 254 (100), 239 (20), 211 (35).
B. To a so lu tion of methyl 1,4-dihydroxy-2-naphthoate
(0.5 g, 2.3 mmol) in dry dioxane (10 mL) was added BF3-
etherate (0.3 mL) and 2-methyl-3-buten-2-ol (0.36 mL, 3.4
mmol). The re ac tion mix ture was refluxed for 4 h. Af ter cool-
ing, Et2O (50 mL) was added and the etheral so lu tion was
washed with H 2O, dried over Na2SO4, and evap o rated to give
a crude yel low prod uct which was chromatographed on sil ica
gel eluting with hex ane/ethyl ac e tate (98:2) to yield dihydro-
mollugin (356 mg, 54%) as a yel low solid.
Methyl 1,4-dihydroxy-2-naphthoate
To a so lu tion of 1,4-dihydroxy-2-naphthoic acid (3.0 g,
14.7 mmol) in ether (40 mL) was added ex cess CH2N2 at 0 °C
for 30 min. Sol vent was re moved from a rotavapor, and the
res i due was chromatographed on sil ica gel eluting with hex-
ane/ethyl acetate (3:1) to yield methyl 1,4-dihydroxy-2-
naphthoate (2.7 g, 84%) as a yel low solid: mp 198-199 C
(lit.10 172-173 C); IR (KBr) 1649 cm-1; 1H NMR (CDCl3)
3.96 (s, 3H), 7.08 (s, 1H), 7.51-7.68 (m, 2H), 8.09-8.13 (m,
1H), 8.36-8.41 (m, 1H), 11.5 (s, 1H); EIMS m/z (rel. int.) 218
(M+, 97), 204 (85), 186 (100), 158 (21), 130 (32), 102 (71).
Mollugin (3)
To a solution of dihydroxymollugin (286 mg, 1.0
mmol) in dry dioxane (15 mL) was added DDQ (272 mg, 1.2
mmol), and the re ac tion mix ture was refluxed over night. Af-
ter cool ing, the pre cip i tates were fil tered off and the fil trate
was evap o rated. The res i due was chromatographed on sil ica
gelelutingwithhexane/ethylacetate(98:2)toyieldmollugin
(205 mg, 72%) as a yel low solid: mp 128-130 C (lit.1 132-
134 C); IR (KBr) 1649 cm-1; 1H NMR (CDCl3) 1.47 (s,
6H), 4.00 (s, 3H), 5.65 (d, J = 10.2 Hz, 1H), 7.09 (d, J = 10.2
Hz, 1H), 7.46-7.51 (m, 1H), 7.56-7.62 (m, 1H), 8.14-8.17 (m,
1H), 8.33-8.36 (m, 1H), 12.1 (s, 1H); EIMSm/z (rel. int.) 284
(M+, 45), 269 (35), 252 (33), 237 (100).
Rubilactone (1)
A mix ture of methyl 1,4-dihydroxy-2-naphthoate (0.4
g, 1.83 mmol), ethyl propiolate (4 mL), and ZnCl2 (0.35 g)
wasrefluxedfor4h. Aftercooling, theprecipitateswerecol-
lected by fil tra tion and recrystallized from chlo ro form/hex-
ane to yield rubilactone (190 mg, 38%) as a yel low solid: mp
207-208 C (lit.4 216-218 C); IR (KBr) 1737, 1645 cm-1; 1H
NMR (CDCl3) 4.10 (s, 3H), 6.51 (d, J = 10.2 Hz, 1H),
7.66-7.84 (m, 2H), 8.44-8.52 (m, 2H), 8.78 (d, J = 10.2 Hz,
1H), 11.7 (s, 1H); EIMS m/z (rel. int.) 270 (M+, 45), 256 (30),
238 (100), 210 (45), 182 (25), 126 (19).
ACKNOWLEDGMENT
Dihydromollugin (2)
A. To a so lu tion of 1,4-dihydroxy-2-naphthoic acid
(2.04 g, 10.0 mmol) in dry dioxane (20 mL) was added BF3-
etherate (0.6 mL) and 2-methyl-3-buten-2-ol (1.6 mL, 15.0
This re search was sup ported by grants from the Na-
tional Sci ence Coun cil of Re pub lic of China (NSC 82- 0208-
M-077-008).

Syn the sis of Rubilactone, Mollugin, and Dihydromollugin
Received August 8, 2000.
J. Chin. Chem. Soc., Vol. 48, No. 1, 2001 79
4. Hua, H. M.; Wang, S. X.; Wu, L. J.; Li, X.; Zhu, T. R.
Acta Pharm. Sinica 1992, 27, 279.
Key Words
5. Itokawa, H.; Takeya, K.; Mori, N.; Sonobe, T.; Mihashi,
S.; Hamanaka, T. Chem. Pharm. Bull. 1986, 34, 3762.
6. Chung, M.-I.; Jou, S.-J.; Cheng, T.-H.; Lin, C.-N. J. Nat.
Prod. 1994, 57, 313.
Rubilactone; Mollugin; Dihydromollugin; Rubia
cordifolia.
7. Schildknecht, H.; Straub, F. Liebigs Ann. Chem. 1976,
1307.
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