Total Synthesis of 7′-Desmethylkealiiquinone, 4′-Desmethoxykealiiquinone, and 2-Deoxykealiiquinone

Synthetic approaches to the imidazonaphthoquinone core of kealiiquinone and related Leucetta-derived alkaloids are described. The polysubstituted benzimidazole framework can be constructed through intramolecular Diels-Alder reactions of propiolate-derived enynes followed by oxidation. Adjustment of the oxidation state of the thus formed lactone allows introduction of the 2,3-dihydroxybenzoquinone moiety through a presumed benzoin-like condensation between a phthaldehyde derivative and a masked glyoxal equivalent catalyzed by a cyanide ion. Oxidation of the C2-position can be accomplished through application of an operationally simple treatment of an imidazolium salt with bleach, thus producing the corresponding 2-imidazolone. Debenzylation of a late stage intermediate en route to kealiiquinone was compromised by concomitant O-demethylation upon treatment with triflic acid resulting in the formation of non-natural 7'-desmethylkealiiquinone. Other endgame strategies were evaluated; however, these efforts did not lead to completion of a synthesis of kealiiquinone but did provide access to other closely related analogues.