Total synthesis of seco-lateriflorone Eric J. Tisdale, Binh G. Vong, Hongmei Li, Sun Hee Kim, Chinmay Chowdhury and Emmanuel A. Theodorakis * Department of Chemistry and Biochemistry, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0358, USA Received 28 March 2003; revised 29 May 2003; accepted 29 May 2003 Abstract—A convergent strategy toward the synthesis of lateriflorone (5) is described. Our approach is based on biosynthetic considerations and draws on a sequence of prenylation, oxygenation and Claisen reactions for the construction of chromenequinone 6, and a tandem Claisen/Diels – Alder reaction cascade for the synthesis of caged tricycle 7. Union of fragments 6 and 7 led to the synthesis of seco- lateriflorone (49). q 2003 Elsevier Ltd. All rights reserved. 1. Introduction and retrosynthetic analysis The Garcinia species of plants provide a rich source of secondary metabolites that are characterized by interesting chemical architectures and diverse biological activities. 1 Among them is included a family of xanthone-based natural products exemplified by morellin (1), 2 desoxymorellin (2), 3 scortechinone A (3), 4 forbesione (4) 5 and lateriflorone (5) 6 (Fig. 1). The chemical structure of these compounds is highlighted by the fusion of a unique 4-oxa-tricy- clo[4.3.1.0 3,7 ]decan-2-one scaffold onto a common xanthone motif. This unusual caged structure plays an essential role in the biological activity of the above metabolites and constitutes an intriguing synthetic target. An added level of architectural complexity is encountered in the structure of lateriflorone (5), in which the caged scaffold is connected to a chromenequinone fragment via an unprecedented spiroxalactone functionality. From a biosynthetic point of view, all these natural products are postulated to derive from benzophenone or benzophe- none-like intermediates that, upon an intramolecular oxidative coupling, produce a common xanthone scaffold. 7 A series of plant-specific oxygenations and prenylations could then set the stage for a tandem Claisen/Diels–Alder reaction thereby constructing the caged scaffold. This biosynthetic scenario was initially proposed by Quillinan and Scheinmann in 1971 8 and subsequently put to test by Nicolaou and Li during their pursuit of the total synthesis of forbesione (4). 9 Moreover, two related biosynthetic hypoth- eses were proposed for the unique spiroxalactone core of lateriflorone (5). 6 The first is based on an oxidative rearrangement of a xanthone precursor, while the second rests upon condensation of two fully functionalized fragments such as 6 and 7 (Fig. 2). In the synthetic direction, these two fragments are envisioned to combine at the C3 0 center of 6 (lateriflorone numbering) through a biomimetic type of condensation, i.e. spirolactonization, to produce 5. The chromenequinone functionality of 6 was projected to be formed via a double Claisen rearrangement 10 revealing phenolic ether 8 as the putative synthetic precursor. This type of disconnection suggested the use of pyrogallol (9), having three of the four needed hydroxyl groups at positions 3 0 ,4 0 and 5 0 (lateriflorone numbering), as the starting material of choice. On the other hand, the tricyclic motif of 7 was projected to be formed from benzodioxanone 10 via a biomimetic Claisen/Diels – Alder reaction. 11 The latter compound could be synthetically accessible from commercially available 4-hydroxysalicylic acid (11). Herein, we disclose the results of our studies based on such retrosynthetic considerations. 12 2. Synthesis of the chromenequinone fragment 6 Our initial studies towards fragment 6 commenced with exhaustive benzylation of pyrogallol (9) 13 to produce the corresponding tris-benzyloxybenzene, which after oxidation with nitric acid, 14 led to 3 0 ,5 0 -bis-benzyloxy- [1 0 ,4 0 ]benzoquinone (12) in 44% overall yield (Scheme 1). The other major product of this reaction, isolated in 39% yield, was found to be the 3 0 ,4 0 ,5 0 -tris-benzyloxy-1 0 - nitrobenzene. Clemmensen reduction of benzoquinone 12 using Zn dust in hot 25% H 2 SO 4 /EtOH afforded the intermediate hydroquinone which, without extensive puri- fication, was alkylated with KOH and MeI in refluxing acetone to afford 3 0 ,5 0 -bis-benzyloxy-1 0 ,4 0 -dimethoxyben- zene in 81% overall yield. 15 Exposure of the latter 0040–4020/$ - see front matter q 2003 Elsevier Ltd. All rights reserved. doi:10.1016/S0040-4020(03)00862-7 Tetrahedron 59 (2003) 6873–6887 * Corresponding author. Tel.: þ1-858-822-0456; fax: þ1-858-822-0386; e-mail: etheodor@chem.ucsd.edu Keywords: Claisen/Diels–Alder reaction; chromenequinone; spiroxalactone.