Diversifiable Total Synthesis of Pleurotin Natural Products through Alternative Endgame Strategies Enabling Unprecedented C7/C8-Axial Functionalization

Pleurotin (<b>1</b>) and dihydropleurotinic acid (<b>2</b>) are antibiotic antitumor benzoquinone meroterpenoids, particularly as potent inhibitors of thioredoxin reductase (TrxR). However, producing new derivatives by semisynthesis is underexplored due to a limited number of functional group handles. Herein we report alternative endgame strategies for construction of the lactone F-ring in the asymmetric total synthesis of pleurotin natural products, harvesting C7-/axial C8-functionalized pleurotin analogs previously unavailable. Essentially, we deployed selective allylic oxidation for C7 functionalization and Tebbe olefination followed by hydroboration-oxidation delivering unprecedented C8-axial analogs from the advanced pentacyclic scaffold <b>7</b> accessible in preparative scale. These novel analogs exhibited notable cytotoxicity against TrxR-overexpressed human cancer cells, with C8-axially substituted analogue <b>23</b> showcasing 9- and 16.7-fold enhancement in the potency inhibiting TrxR enzyme relative to <b>1</b> and the positive control auranofin, respectively. This detoured endgame strategy enables access to diverse analogs that were previously inaccessible, expanding the chemical and biological space of pleurotin natural products for translational medicine applications.