Synthesis of vulpinic and pulvinic acids from tetronic acid Yann Bourdreux, Ewen Bodio, Catherine Willis, Ce ´ lia Billaud, Thierry Le Gall * , Charles Mioskowski 1 CEA, iBiTecS, Service de Chimie Bioorganique et de Marquage, Ba ˆt. 547, 91191, Gif-sur-Yvette, France article info Article history: Received 22 April 2008 Received in revised form 11 June 2008 Accepted 16 June 2008 Available online 20 June 2008 Keywords: Natural products Pulvinic acid Vulpinic acid Tetronic acid Suzuki–Miyaura cross-coupling abstract A common precursor, tetronic acid, was used in the synthesis of several vulpinic acids and pulvinic acids, which are pigments found in several lichens and mushrooms. The key features of this method are a two- step alkylidenation of benzyl tetronate and a Suzuki–Miyaura cross-coupling. The synthesis of several natural products, vulpinic acid, pinastric acid, xerocomic acid is described. Ó 2008 Elsevier Ltd. All rights reserved. 1. Introduction Pulvinic acids (1) and vulpinic acids (2, methyl esters of pulvinic acids) are yellow and orange pigments found in lichens and in mushrooms, which display various biological activities. 1 Vulpinic acid has been reported to display antimicrobial activity against Gram-positive organisms. 2 It displayed anti-inflammatory activity in rats, 3 but also caused hyperventilation in rats, 3 cats, and guinea pigs. 4 Lichens containing vulpinic acid were employed in northern Europe to poison wolves. The antiviral, antimicrobial, and antitu- mor activities of pinastric acid were recently reported. 5 Xerocomic acid was reported as an inhibitor of HIV-1 integrase. 6 Studies in our laboratory have shown that several pulvinic de- rivatives have interesting antioxidant properties, 7,8 and we thus became interested in the synthesis of these compounds or their analogs in a convergent, efficient fashion. Structurally, a pulvinic acid is constituted by a b-hydroxylated a,b-unsaturated butyr- olactone, which is substituted by an a-aryl group, and by a g- methylidene bonded to a hydroxycarbonyl group and to an aryl group. Efficient processes have been reported for the access to sym- metrical pulvinic acids (in which the two aryl groups are identical). A classical example involves the reaction of 2 equiv of arylaceto- nitrile anion with dialkyl oxalate, 9,3 which is followed by a cyclization to a bis(lactone), and by the selective opening of one lactone ring that affords the pulvinic acid. The bis(lactone) can also be prepared by oxidation of a terphenylquinone. 10 We recently reported another process that makes use of the reaction of at least 2 equiv of silyl ketene acetal with oxalyl chloride, 11 followed by a base-mediated cyclization to the corresponding pulvinic acid methyl ester. The access to non-symmetrical pulvinic acids cannot be performed under such straightforward ways. The hydrolytic cleavage of a non-symmetrical bis(lactone) leads to a mixture of regioisomers. 12 Various regioselective approaches have then been reported. 13 The key reactions in these approaches are Dieckmann cyclizations of enol esters, 13a alkylidenations of methyl 4-arylte- tronates, 13b Reformatsky-type reactions with arylmethoxymaleic anhydrides, 13c,d reactions of lithium enolates of arylacetic esters with 4-alkylidene-1,3-dioxolan-4-ones, 13e Wadsworth–Emmons olefinations involving 2-aryl-4-methoxy-2(5H)-furanone phos- phonates, and a-oxoarylacetates. 13f A palladium-mediated cross-coupling is particularly useful to create a linkage between an aryl group and a double bond, it was thus quite appropriate for the introduction of the aryl group bonded on the lactone ring. This strategy, which made use of a tri- flate such as 3, has been employed by us 14 as well as by Langer et al. 15 for the preparation of several pulvinic acids (Scheme 1). It was recently applied to the synthesis of norbadione A, a mushroom pigment related to the pulvinic acids. 16 The access to this triflate relied on the Langer cyclocondensation of a bis(trimethylsilyloxy)- diene on oxalyl chloride. 17 We have then devised another approach, which makes also use of a Suzuki–Miyaura cross-coupling 18 as key reaction, but which involves an iodide such as 4, which would * Corresponding author. Tel.: þ39 1 6908 7105; fax: þ39 1 6908 7991. E-mail address: thierry.legall@cea.fr (T. Le Gall). 1 Deceased on June 2007. 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.2008.06.058 Tetrahedron 64 (2008) 8930–8937