PART I: TOTAL SYNTHESIS OF PLEUROTINOID NATURAL PRODUCTS VIA A NONTRADITIONAL C-H EPIMERIZATION PART II: SYNTHESIS OF BENZOCYCLOBUTENES VIA PALLADIUM-CATALYZED β-METHYLENE-SELECTIVE C-H ACTIVATION

Abstract

Pleurotin, isolated in 1947, is an architecturally-complex hexacyclic benzoquinone natural product which displays significant anticancer and antibiotic properties. Since as early as 2010, our group pursued a synthesis of pleurotin based on a proximity-induced intramolecular Diels-Alder cycloaddition of a transient ortho-quinodimethide generated from a benzocyclobutene. Revisiting a prior model system in a more structurally-relevant context, we found this approach untenable and instead we developed an alternative construction featuring Gao’s titanium(IV)-mediated photoenolization Diels-Alder coupling of an ortho-tolualdehyde with a functionalized hydrindenone. While this pairing displayed excellent stereofacial selectivity, it produced an undesired cis-locked hydrindane. The stereochemistry was corrected to the required trans-hydrindane through alkoxy-radical induced epimerization of the unactivated hydrogen-bearing methine stereocenter at C-5. These efforts culminated in an 8-step synthesis of a known pentacyclic intermediate towards pleurotin, as well as the first total syntheses of the related pleurotinoid natural products pleurogrisein and 4-hydroxypleurogrisein. Benzocyclobutenes are useful synthetic building blocks and are also present in natural product scaffolds, but there are relatively few methods for their synthesis. By adapting our previous methodology for the synthesis of indanes via methylene-selective C-H functionalization, we developed a methodology for the synthesis of structurally unique benzocyclobutenes. The reaction utilizes glycine as a transient directing group and a 2-pyridone ligand, which may govern methylene selectivity by making intimate molecular associations with the substrate during concerted metallation deprotonation. This reaction is shown to be highly selective for intramolecular methylene C(sp3)‒H arylation, thus enabling sequential C(sp3)‒H functionalization.