Synthesis of Echinotinctone, A Fungal Fluorone Pigment

Abstract

Echinotinctone (3) is formed by acid-catalyzed condensation of 1,2,4-trihydroxytoluene (1) with orcylaldehyde (2), a reaction mimicking the probable biosynthesis. A more efficient stepwise synthesis proceeds via the benzophenone intermediate 11, which can be converted to 2,6-dihydroxy-1,8-dimethyl-3H-xanthen-3-one (3) by LiAlH 4 reduction and subsequent acid-catalyzed ring closure.Echinotinctone (3) is a rust-red pigment from fruit bodies of the wood-rotting Indian Paint Fungus, Echinodontium tinctorium, and Pyrofomes albomarginatus. 1 It represents the first natural product with a simple fluorone chromophore. 2 Structurally closely related are the more complex natural quinone methides trametin 3 and santalin A 4 and the artificial xanthene dyes fluorescein and eosin. We reasoned that echinotinctone (3) might be derived biosynthetically from 1,2,4-trihydroxytoluene (1) and orcylaldehyde (2) by C-C-bond formation followed by the elimination of two molecules of water (Scheme 1). Scheme 1In this publication we report that this reaction can be mimicked in vitro, albeit in low yield, and that echinotinctone (3) can be prepared more efficiently by a stepwise version of this procedure.The biomimetic approach commences with aldehyde 6, which was obtained in 77% yield by O-benzylation 5 of orcinol (4) and Vilsmeier formylation of the resulting dibenzyl ether 5 (Scheme 2). Treatment of aldehyde 6 with 30% H 2 O 2 under acidic conditions 6 afforded phenol 7 in 92% yield which was deprotected by catalytic hydrogenation to give the air sensitive 1,2,4-trihydroxy-6-methylbenzene (1) in 67% overall yield. This sequence is superior to a literature procedure 7 in which orcylaldehyde (2) is directly oxidized with H 2 O 2 . Scheme 2The condensation of 2 with aldehyde 1 8,9 in acetic anhydride/sulfuric acid 10 (cf. Scheme 1) afforded a complex reaction mixture from which echinotinctone (3) was isolated in 11% yield. The physical and spectroscopic properties of synthetic 3 were identical with those of the natural product. 1The low yield in the last step of the biomimetic approach caused us to develop a more efficient synthesis of echinotinctone (3) by a stepwise procedure (Scheme 3). Benzylation of 7 under standard conditions yielded the tribenzyl ether 8 that was converted to benzophenone 10 in 66% yield by trifluoroacetic anhydride-mediated acylation with O,O-dibenzylorsellinic acid (9). 11 Benzophenone 10 was deprotected by catalytic hydrogenation to give the polyphenolic intermediate 11, which after reduction with an excess of LiAlH 4 and acidic workup afforded echinotinctone (3) in 80% yield.The ease of this cyclization can be explained by the formation of carbinol 12, which on treatment with acid undergoes water elimination, ring closure and formation of 3 by a second dehydration step as illustrated in Scheme 4.Since several attempts to close the xanthone ring from the o,o'-dihydroxybenzophenone 11 by literature procedures Downloaded by: University of Arizona Library. Copyrighted material.

Pigments of fungi (Macromycetes)

“…Hydrogenolysis of the benzophenone 181, reduction of the carbonyl group in the intermediate 182, and acid-catalysed double-dehydration afforded echinotinctone 176 in high yield. 76 The final step is regarded as being far superior to earlier methods reported for the assembly of the fluorone ring system.…”

“…76 The yield of echinotinctone 176 obtained in this way was low but could be considerably improved by following the stepwise process shown in Scheme 14. 76 Accordingly, the dibenzyl ether 177, from the previous approach, was benzylated under standard conditions and then acylated with di-O-benzylorsellinic acid 180 in the presence of trifluoroacetic acid (TFA). Hydrogenolysis of the benzophenone 181, reduction of the carbonyl group in the intermediate 182, and acid-catalysed double-dehydration afforded echinotinctone 176 in high yield.…”

“…A 'biomimetic' synthesis of the unique rust-red fluorone pigment echinotinctone 176, isolated from the 'Indian Paint Fungus' Echinodontium tinctorium and from Pyromyces albomargimatus, has been developed 3 and improved. 76 Based on the suggestion that the fluorone 176 arises, in vivo, by condensation between 1,2,4-trihydroxytoluene and orcylaldehyde, the first synthesis (Scheme 13) involved acid-catalysed condensation of the sensitive trihydroxytoluene 178 with the aldehyde 179 under acidic conditions. 76 The yield of echinotinctone 176 obtained in this way was low but could be considerably improved by following the stepwise process shown in Scheme 14.…”

“…76 Based on the suggestion that the fluorone 176 arises, in vivo, by condensation between 1,2,4-trihydroxytoluene and orcylaldehyde, the first synthesis (Scheme 13) involved acid-catalysed condensation of the sensitive trihydroxytoluene 178 with the aldehyde 179 under acidic conditions. 76 The yield of echinotinctone 176 obtained in this way was low but could be considerably improved by following the stepwise process shown in Scheme 14. 76 Accordingly, the dibenzyl ether 177, from the previous approach, was benzylated under standard conditions and then acylated with di-O-benzylorsellinic acid 180 in the presence of trifluoroacetic acid (TFA).…”