The halenaquinol family of naphthoquinol natural products includes a few closely related polycyclic compounds that feature an activated, electrophilic furan ring. This motif is likely responsible for the rich biological activity attributed to these secondary metabolites. Their interesting structures-related via their electrophilic furan to the biologically important furanosteroids-and their activities prompted significant efforts by organic chemists that resulted in many strategically compelling laboratory syntheses of these targets. These different strategies are compared and contrasted in this Microreview, and the authors' recent work on the structurally different but biogenetically related natural product exiguaquinol is put into the context of the previous studies on halenaquinol-type targets.

A concise and stereoselective synthesis of exiguaquinol dessulfate is described. Sequential application of a Diels-Alder cycloaddition, a desymmetrizing aldol addition, and a reductive Heck cyclization established most of the architecture of exiguaquinol, and a carefully choreographed introduction of the polar substituents afforded the title compound; unfortunately, naphthoquinol sulfation could not be achieved to deliver exiguaquinol. Our hypothesis regarding the configurational preference of the N-acyl hemiaminal, which was based upon an analysis of internal hydrogen-bonding interactions with polar functional groups, was proven correct. A late-stage intermediate did not demonstrate bactericidal activity against H. pylori cultures.

A Diels-Alder reaction, a desymmetrizing aldol reaction, and a reductive Heck cyclization are employed in a short synthesis of a tetracycle relevant to exiguaquinol, a potential antibiotic. Ground-state energies of this advanced model system and the natural product rationalize the incorrect hemiaminal configuration experimentally obtained and point to the importance of the sulfonate in dictating the relative configuration of the natural product.