Development of a Divergent Synthesis of Pleurotinoid Natural Products.

Herein, we describe the evolution of our syntheses of the pleurotinoid natural products pleurotin ( 1 ), pleurogrisein ( 3 ), and 4-hydroxypleurogrisein ( 4 ). An approach based on a proximity-induced intramolecular Diels-Alder cycloaddition of a transient ortho -quinone dimethide (e.g., 6 , Scheme 1) was inferior to an alternative construction featuring Gao's titanium(IV)-mediated photoenolization Diels-Alder coupling of ortho -tolualdehyde 20 with functionalized hydrindenone 22 . While this pairing exhibited the desired stereoface selectivity and produced cis -fused hydrindanone 23 , the successful realization of our syntheses of 1 , 3 , and 4 required a post-Diels-Alder epimerization of the unactivated stereocenter at C-5 in compound 23 . Ultimately, it was possible to generate a reactive oxygen-centered radical via a reductive homolytic cleavage of the N-O bond in 23 and capitalize on its ability to break the C5-H bond in an intramolecular 1,5-hydrogen atom transfer (HAT). The carbon radical arising from this pivotal 1,5-HAT was subsequently trapped in situ by an exogenous thiol in a kinetically controlled HAT reaction to establish the natural configuration at C-5. The successful flipping of the cis -hydrindane in 23 to the challenging trans configuration in 24 provided a firm foundation for a formal synthesis of pleurotin ( 1 ), as well as syntheses of pleurogrisein ( 3 ) and 4-hydroxypleurogrisein ( 4 ).