Total synthesis of a dienynone from Echinacea pallida Stefania Morandi a , Federica Pellati a , Stefania Benvenuti a, * , Fabio Prati b, * a Department of Pharmaceutical Sciences, University of Modena and Reggio Emilia, via Campi 183, 41100 Modena, Italy b Department of Chemistry, University of Modena and Reggio Emilia, via Campi 183, 41100 Modena, Italy article info Article history: Received 4 February 2008 Received in revised form 10 April 2008 Accepted 24 April 2008 Available online 29 April 2008 Keywords: Echinacea pallida Total synthesis Acetylenes Polyenes Cytotoxicity abstract The first total synthesis of (8Z,13Z)-pentadeca-8,13-dien-11-yn-2-one is described. This dienynone was recently isolated from the n-hexane extract of Echinacea pallida roots and displayed a selective cytotoxic activity toward cancer cells, thus featuring as a potential anticancer lead. The product was obtained in 11 steps in 25% overall yield. Ó 2008 Elsevier Ltd. All rights reserved. 1. Introduction The in vitro cytotoxic and pro-apoptotic activities of the n-hexane root extracts from the three medicinally important Ech- inacea species (Echinacea purpurea, Echinacea angustifolia var. angustifolia, and Echinacea pallida; Asteraceae family) have been recently demonstrated. 1 A more pronounced cytotoxic effect for E. pallida root extracts in comparison with the other two species was observed. 1 This is in agreement with the different chemical com- position of this species with respect to the others belonging to the genus Echinacea: in fact, the typical hydrophobic constituents of E. pallida extracts were found to be polyacetylenes and polyenes, whereas the lipophilic extracts of E. purpurea and E. angustifolia mainly consist of alkamides. 2–7 More recently, the bioassay-guided isolation and characterization of most of the lipophilic constituents of E. pallida roots have been performed. 6,7 Among them, (8Z,13Z)- pentadeca-8,13-dien-11-yn-2-one (1) was found to be one of the major constituents (0.98 mg/g in the plant material and 0.19– 1.90 mg/g in the herbal products) 6 as well as the most active compound. 7,8 Compound 1 displayed a very low IC 50 value toward the colonic COLO320 cancer cell line (IC 50 ¼2.34 mM) and a note- worthy activity toward pancreatic Mia PaCa-2 cancer cell line (IC 50 ¼32.17 mM), the latter being a type with generally low sensi- tivity to therapeutic agents. 9 Apoptotic cell death was found to be involved in the cytotoxic activity of this molecule. 8 Dienynone 1 displayed a selective effect on cancer cells versus non-cancer cells, with an IC 50 value higher than 100 mM against human embryonic kidney HEK-293 cell. 8 Furthermore, this compound was found to be able to cross the Caco-2 monolayer, 8 which is an accepted model of intestinal absorption, 10 indicating a potential good absorption in humans after oral administration. Due to the difficulty in purifying this compound from E. pallida roots, whose extracts contain many other constituents of similar polarity, and owing to the need of higher amounts of 1 for biological assays, the total synthesis of this secondary metabolite was undertaken. 2. Discussion 2.1. Retrosynthesis By analogy to the total synthesis of related structures, 11,12 our synthetic strategy hinged on a Sonogashira coupling reaction for the insertion of the terminal alkene moiety. Enyne precursor A can be disconnected by chain extension and selective reduction to alkyne B, which can be traced back to commercially available 1-hexyne and propylenoxide (Scheme 1). 2.2. Synthesis Alkynol 3 13 (Scheme 2) was synthesized in 72% overall yield by coupling of propyleneoxide and 1-hexyne (2) with n-butyllithium and boron trifluoride 14 followed by migration of the triple bond to * Corresponding authors. Tel.: þ39 059 205 5056; fax: þ39 059 373543 (F.P.); tel.: þ39 059 205 5144; fax: þ39 059 205 5131 (S.B.). E-mail addresses: stefania.benvenuti@unimore.it (S. Benvenuti), fabio.prati@ unimore.it (F. Prati). Contents lists available at ScienceDirect Tetrahedron journal homepage: www.elsevier.com/locate/tet 0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved. doi:10.1016/j.tet.2008.04.094 Tetrahedron 64 (2008) 6324–6328