Concise Asymmetric Total Syntheses of (+)-Dihydropleurotinic Acid and (−)-Pleurotin, Enabling Rapid Late-Stage Diversification

(-)-Pleurotin (<b>1</b>) and (+)-dihydropleurotinic acid (<b>2</b>) are benzoquinone meroterpenoids isolated from fungal sources with powerful antitumor and antibiotic activities. Concise asymmetric total syntheses of the stereochemically pure (+)-dihydropleurotinic acid (<b>2</b>) and (-)-pleurotin (<b>1</b>) from the chiral pool (<i>R</i>)-Roche ester-derived vinyl bromide <b>7</b> have been achieved in 12 and 13 longest linear steps, respectively. The key transformations feature a Michael addition/alkylation cascade reaction to forge three contiguous stereocenters matched with the natural products, a PtO₂-catalyzed stereoselective reduction of olefin to generate the correct stereocenter at C3, a palladium-catalyzed Negishi cross-coupling between triflate and zinc reagent to introduce the redox-sensitive para-quinone moiety, and a hydroboration/copper-catalyzed carboxylation sequence to incorporate the vital carboxyl group. Thus, the highly efficient and scalable preparation of pleurotin's pentacyclic skeleton enables the late-stage diversification, affording otherwise unavailable pleurotin analogs with significantly improved antiproliferative activities against the thioredoxin reductase (TrxR) overexpressed human breast cancer cell lines relative to the natural product pleurotin (<b>1</b>).