ORGANIC
LETTERS
2005
Vol. 7, No. 26
5865-5868
Pericyclic Reactions of Prenylated
Naphthoquinones: Biomimetic
Syntheses of Mollugin and
Microphyllaquinone
Jean-Philip Lumb and Dirk Trauner*
Department of Chemistry, UniVersity of California, Berkeley, California 94720
Received October 12, 2005
ABSTRACT
A total synthesis of the bioactive naphthohydroquinone mollugin and the related naphthoquinone dimer microphyllaquinone is described.
Both syntheses exploit the propensity of prenylated quinones to undergo tautomerization/oxa 6 -electrocyclizations.
π
Natural products derived from prenylated naphthoquinones
show significant biological activities (Figure 1).1 In fact,
plants that produce compounds of this class have long been
recognized for their therapeutic benefits. For example, the
Chinese medicinal plant Rubia cordifolia has yielded the
achiral chromene mollugin (3) and the racemic dimer rubi-
cordifolin (4), both of which show potential as antitumor
compounds.2 Rubioncolin A (5) and B (6) were isolated as
racemates from the related Rubia oncotricha.3 Firmianone
A (7) was recently isolated as a single enantiomer from the
tree Firmia plantanifolia, the root bark of which is used to
treat rheumatism and asthma in Chinese herbal medicine.4
Extracts from the roots of Lippia microphylla, commonly
known as “alecrim-de-tabuleiro”, are widely used as expec-
torants, astringents, and diuretics in Brazilian traditional
medicine.5 Phytochemical investigations have yielded the
cytotoxic naphthoquinone dimers microphyllaquinone (8) and
tecomaquinone I (9) as active ingredients.6 Tecomaquinone
I (9) has also been isolated from Tectona grandis (teak) and
several other tree species.7 Although 8 and 9 were found to
be optically active, their absolute configurations remain
unknown.
One of the distinct chemical features of prenylated naph-
thoquinones, and of allylic para-quinones in general, is their
ability to tautomerize to vinyl ortho-quinone methides. These
can undergo subsequent pericyclic reactions, such as elec-
trocyclizations or cycloadditions. As shown in Scheme 1,
tautomerization of 10 affords ortho-quinone methides 11 or
12. The latter can undergo oxa 6π-electrocyclization to afford
chromene 13. This facile conversion has been utilized by
Thomson in an elegant total synthesis of tecomaquinone I
(9)7 and was further investigated by Nicolaou et al. in the
(1) Singh, R.; Geetanjali; Chauhan, S. M. S. Chem. BiodiVersity 2004,
1, 1241-1264.
(2) (a) Itokawa, H.; Ibraheim, Z. Z.; Qiao, Y. F.; Takeya, K. Chem.
Pharm. Bull. 1993, 41, 1869-1872. (b) Lumb, J. P.; Trauner, D. J. Am.
Chem. Soc. 2005, 127, 2870-2871.
(5) Pascual, M. E.; Slowing, K.; Carretero, E.; Mata, D. S.; Villar, A. J.
Ethnopharmacol. 2001, 76, 201-214.
(6) Santos, H. S.; Costa, S. M. O.; Pessoa, O. D. L.; Moraes, M. O.;
Pessoa, C.; Fortier, S.; Silveira, E. R.; Lemos, T. L. G. Z. Naturforsch., C:
Biosci. 2003, 58, 517-520.
(3) Qiao, Y. F.; Takeya, K.; Itokawa, H.; Iitaka, Y. Chem. Pharm. Bull.
1990, 38, 2896-2898.
(4) Bai, H. Y.; Li, S.; Yin, F.; Hu, L. H. J. Nat. Prod. 2005, 68, 1159-
1163.
(7) Khanna, R. N.; Sharma, P. K.; Thomson, R. H. J. Chem. Soc., Perkin
Trans. 1 1987, 1821-1824.
10.1021/ol052472u CCC: $30.25
© 2005 American Chemical Society
Published on Web 11/23/2005