Schmidt reaction of usnic acid

Abstract

Many natural compounds are interesting platforms for creating drugs. Therefore, synthetic transformations of isolated secondary metabolites continue to play an important role in medicinal chemistry. A promising starting material is the yellow lichen pigment (+)-usnic acid (1). It is known to possess a broad spectrum of biological activity including antiviral, antibiotic, antituberculosis, analgesic, and insecticidal activity [1]. Considering the biological activity of usninic acid and the relatively simple methods for isolating it from plant raw material [2], it seemed advisable to develop synthetic transformations that introduce new functional groups into its structure. Attempts were made previously to introduce an amide into ring A of usninic acid using a Schmidt reaction [3]. However, only starting (+)-usnic acid (1) was isolated in 93% yield from the reaction mixture containing an equimolar amount of sodium azide. We chose more forcing conditions for carrying out the Schmidt reaction that included 1 (1 mmol), CHCl3 (10 mL), and conc. H2SO4 (3 mL) with heating at 50-60°C for 2 h with a four-fold excess of sodium azide. The expected amide derivative 2 did not form. Further rearrangement occurred with involvement of the phenol hydroxyl in the o-position to the reacting acyl group to form oxazole 3. The reaction mixture was neutralized with aqueous KOH (5%) and extracted twice with CHCl3 (30 mL each). The combined CHCl3 extract was dried over calcined MgSO4. Compound 3 was purified by chromatography over silica gel (100-160 μ, Merck) with elution by CHCl3. The yield after chromatography was 70%. Cyclic oxazole-type products were observed previously from the Schmidt reaction of β-diketones [4].