TETRAHEDRON LETTERS Tetrahedron Letters 44 (2003) 3281–3284 Pergamon Total synthesis of atroviridin Eric J. Tisdale, David A. Kochman and Emmanuel A. Theodorakis* Department of Chemistry and Biochemistry, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093 -0358, USA Received 17 January 2003; accepted 5 March 2003 Abstract—A total synthesis of atroviridin (1) based on biosynthetic principles is presented. The tetracyclic xanthone structure of the natural product was constructed by coupling aryl bromide 8 with aldehyde 7 and subsequent intramolecular conjugate addition on a quinone precursor. Bromide 8 was produced from aldehyde 9 via a sequence of steps involving Baeyer–Villiger oxidation and Claisen cyclization. © 2003 Elsevier Science Ltd. All rights reserved. Atroviridin (1) 1 (Fig. 1) is a tetracyclic polyhydroxyl- ated xanthone recently isolated from the stem bark of Garcinia atroviridis, a lofty tree indigenous to Thailand. Although the precise biological mode of action of this natural product has not yet been reported, it is noted that a decoction of the leaves of the parent tree has been traditionally used for the treatment of earache. From a structural standpoint, atroviridin (1) belongs to a growing family of xanthone and xanthonoid natural products isolated from Garcinia -related tropical plants. 2 Representative members of this family include osajax- anthone (2), 3 morellin (3), 4 morellic acid (4) 5 and late- riflorone (5) 6 (Fig. 1). All these compounds are presumed to derive from benzophenone or benzophe- none-like intermediates generated by means of a mixed shikimate–acetate biosynthetic pathway that, upon an intramolecular oxidative coupling or conjugate addi- tion, produce a common xanthone scaffold. 7 A series of plant specific oxygenations, prenylations and pericyclic reactions are postulated to bring about the final struc- ture and are accountable for the observed biological activities of these natural products. In continuation with our synthetic studies in this area, 8 we present herein the first total synthesis of atroviridin (1). In step with the presumed biosynthetic pathway, atro- viridin was thought to be accessible from benzophe- none-like intermediate 6 through an intramolecular conjugate addition (Fig. 2). Moreover, disconnection across the C9C9a bond (xanthone numbering) sug- gests a synthetic route toward 6 based on coupling of aldehyde 7 with aryl bromide 8. The latter compound was envisioned to arise from protected hydroquinone 9 9 by a sequence of steps including a Baeyer–Villiger oxidation (introduction of O1 atom) and a Claisen rearrangement (construction of C2C4 bond). 10 Reduc- tion of this plan to the synthesis of 1 is shown in Schemes 1 and 2. The synthesis of aryl bromide 8 is shown in Scheme 1 and began with commercially available benzaldehyde 10. Regioselective bromination of 10 at the 9a position (atroviridin numbering) with a slight excess of bromine in acetic acid produced adduct 9 in 45% yield. 9 Baeyer– Figure 1. Selected xanthones from the Garcinia family of plants. * Corresponding author. Tel.: +1-(858)-822-0456; fax: +1-(858)-822- 0386; e-mail: etheodor@ucsd.edu 0040-4039/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved. doi:10.1016/S0040-4039(03)00629-4