Revisitation of (+)-usnic acid reactivity, an interesting natural β-triketone

One of the most investigated lichen substance is the secondary metabolite usnic acid, a yellow cortical pigment easily isolated from Cladonia, Usnea or Romalina species where it occurs up to 26%.1 Usnic acid is a benzofurandione, phloroglucinol like2,3 which exists in two enantiomers, depending on the stereochemistry of the methyl group at the stereogenic center. The absolute configuration of (+)-usnic acid has been determined by X-ray analysis to be R, less toxic and more active than the S isomer. In spite of its recognized and proved in vitro activities,1,2 usnic acid potential has been so far underestimated due to its rapid metabolism, poor water solubility and in vivo toxicity.4 On this basis, we have synthesized a small library of (+)-usnic acid derivatives to improve its biological profile, and, with this purpose, we have investigated (+)-usnic acid reactivity, prevalently at the β-triketone moiety. Nucleophilic additions to the acylic methyl ketone at C-2 position easily led to hydrazones 1 or stable enamines 2;5 intramolecular cyclizations gave stable heterocyclic systems, like 1,5-benzodiazepines (3), or isoxazoles (4 and 5) and oxazocines (6).