Synthesis of piloquinone, a metabolite of Streptomyces pilosus ettlinger

Synthesis of piloquinone [1,8-dihydroxy-2-methyl-3-(4-methylpentanoyl)-9,10-phenanthraquinone](1) is described. Of the methods investigated the most successful started from 2,6-dinitrotoluene (48) which was converted into 2-bromo-6-hydroxytoluene (52). This on bromination at –70 to 20° in the presence of isopropylamine gave 3,6-dibromo-2-hydroxytoluene (53) and thence 3,6-dibromo-2-methoxytoluene (54). This was converted by an organometallic method into 4-bromo-2-methoxy-3-methylbenzaldehyde (57) which on Wittig reaction with 2-methoxybenzyltriphenylphosphonium chloride gave 4-bromo-2,2′-dimethoxy-3-methylstilbene (37). The latter was converted, via 4-cyano-2,2′-dimethoxy-3-methylstibene (36), into methyl 2,2′-dimethoxy-3-methylstilbene-4-carboxylate (39), which on u.v. irradiation gave chiefly methyl 1,8-dimethoxy-2-methyl-phenanthrene-3-carboxylate (42). The latter on reduction and oxidation gave 1,8-dimethoxy-2-methylphenanthrene-3-carbaldehyde (44) which on reaction with isopentylmagnesium bromide followed by oxidation with Jones reagent gave 1,8-dimethoxy-2-methyl-3-(4-methylpentanoyl)phenanthrene (63). This on demethylation and acetylation gave 1,8-diacetoxy-2-methyl-3-(4-methylpentanoyl)phenanthrene (64) which on oxidation followed by treatment with base gave piloquinone (1).