Development of a Divergent Synthesis of Pleurotinoid Natural Products

Herein, we describe the evolution of our syntheses of the pleurotinoid natural products pleurotin (<b>1</b>), pleurogrisein (<b>3</b>), and 4-hydroxypleurogrisein (<b>4</b>). An approach based on a proximity-induced intramolecular Diels–Alder cycloaddition of a transient <i>ortho</i>-quinone dimethide (e.g., <b>6</b>, Scheme 1) was inferior to an alternative construction featuring Gao’s titanium(IV)-mediated photoenolization Diels–Alder coupling of <i>ortho</i>-tolualdehyde <b>20</b> with functionalized hydrindenone <b>22</b>. While this pairing exhibited the desired stereoface selectivity and produced <i>cis</i>-fused hydrindanone <b>23</b>, the successful realization of our syntheses of <b>1</b>, <b>3</b>, and <b>4</b> required a post-Diels–Alder epimerization of the unactivated stereocenter at C-5 in compound <b>23</b>. Ultimately, it was possible to generate a reactive oxygen-centered radical via a reductive homolytic cleavage of the N–O bond in <b>23</b> 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 <i>cis</i>-hydrindane in <b>23</b> to the challenging <i>trans</i> configuration in <b>24</b> provided a firm foundation for a formal synthesis of pleurotin (<b>1</b>), as well as syntheses of pleurogrisein (<b>3</b>) and 4-hydroxypleurogrisein (<b>4</b>).