ORGANIC
LETTERS
2008
Vol. 10, No. 10
1921-1922
First Total Synthesis of Cassiarin A, a
Naturally Occurring Potent
Antiplasmodial Alkaloid
Marcellino Rudyanto,† Yuichiro Tomizawa, Hiroshi Morita, and Toshio Honda*
Faculty of Pharmaceutical Sciences, Hoshi UniVersity, Ebara 2-4-41, Shinagawa-ku,
Tokyo 142-8501, Japan
Received February 22, 2008
ABSTRACT
The first total synthesis of cassiarin A, an antiplasmodial alkaloid isolated from Cassia siamea, was achieved via sequential alkynylation of
arenes with Sonogashira coupling and 6-endo-dig-cyclization of phenolic oxygens to the resulting alkynes.
The genus Cassia is widely distributed in tropical and
subtropical regions and is used in traditional folk medicine,
particularly for the treatment of periodic fever and malaria.1
Our basic strategy for the synthesis of cassiarin A is
outlined in Figure 1.
We envisaged that exploitation of sequential Sonogashira
coupling3 for introducing alkyne groups to aromatic rings
of B and G and subsequent 6-endo-dig cyclization3b,4 of
oxygen atoms to the resulting alkynes A and E would be
the most straightforward way to achieve the goal for
constructing heteroaromatic skeletons. Moreover, this strat-
egy is expected to have broad utility in searching for new
potential antiplasmodial compounds.
Thus, our synthesis commenced with the preparation of
the benzoate derivative G, which would readily be accessible
by application of known procedures to methyl 2,4-dihy-
droxybenzoate.5
The synthesis was started by MOM protection of the
known dihydroxy-ester 3 that was prepared by Hegedus’
procedures6 (Scheme 1). While our attempts to convert
iodobenzoate 4 directly to the isoquinolone derivative by a
Recently, we have isolated two novel heteroaromatic
alkaloids, cassiarins A (1) and B (2), from the leaves of
Cassia siamea (Leguminosae).2 These alkaloids possess an
unprecedented tricyclic skeleton and exhibit potent antiplas-
modial activity.1
Due to the unique structural feature and also to the strong
antiplasmodial activity of cassiarin A, we have been inter-
ested in the synthesis of this alkaloid.
(3) (a) Abraham, E.; Suffert, J. Synlett 2002, 328. (b) Subramanian, V.;
Batchu, V. R.; Barange, D.; Pal, M. J. Org. Chem. 2005, 70, 4778–4783.
(c) Sonogashira, K.; Toha, Y.; Hagira, N. Tetrahedron Lett. 1975, 4467,
4470.
† Visiting scientist for the Open Research Center Project from Faculty
of Pharmacy, Airlangga University, Jalan Dharmawangsa Dalam, Surabaya
60286, Indonesia.
(4) (a) Cherry, K.; Parrain, J.-L.; Thibonnet, J.; Duchene, A.; Abarbri,
M. J. Org. Chem. 2005, 70, 6669–6675. (b) Weingarten, M. D.; Padwa, A.
Tetrahedron Lett. 1995, 36, 4717–4720. (c) Ramana, C. V.; Mallik, R.;
Gonnade, R. G.; Gurjar, M. K. Tetrahedron Lett. 2006, 47, 3649–3652.
(5) Kalivretenos, A.; Stille, J. K.; Hegedus, L. S. J. Org. Chem. 1991,
56, 2883–2894.
(1) (a) Mbatchi, S. F.; Mbatchi, B.; Banzouzi, J. T.; Bansimba, T.;
Nsonde Ntandou, G. F.; Ouamba, J. M.; Berry, A.; Benoit-Vical, F. J.
Ethnopharmacol. 2006, 104, 168–174. (b) Sanon, S.; Ollivier, E.; Azas,
N.; Mahiou, V.; Gasquet, M.; Ouattara, C. T.; Nebie, I.; Traore, A. S.;
Esposito, F.; Balansard, G.; Timon-David, P.; Fumoux, F. J. Ethnophar-
macol. 2003, 86, 143–147.
(6) (a) Stevenson, L.; Pimlott, S. L.; Sutherland, A. Tetrahedron Lett.
2007, 48, 7137–7139. (b) Chattopadhyay, S. K.; Maity, S.; Pal, B. K.; Panja,
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(2) Morita, H.; Oshimi, S.; Hirasawa, Y.; Koyama, K.; Honda, T.;
Ekasari, W.; Indrayanto, G.; Zaini, N. C. Org. Lett. 2007, 9, 3691–3693.
10.1021/ol8004112 CCC: $40.75
Published on Web 04/16/2008
2008 American Chemical Society