Asymmetric Total Synthesis of (–)-Verrucarol

We disclose a concise, asymmetric synthesis of (–)-verrucarol, the natural product precursor of bioactive trichothecene macrocycles including verrucarins A and J. Historically, enantioselective construction of the 6/6/5 (A/B/C) ring system of the 12,13-epoxytrichothec-9-ene (EPT) core has represented a significant challenge, which has hindered trichothecene SAR development. This architecture was constructed beginning with a chiral Lewis acid-catalyzed, enantioselective [4+2] cycloaddition to afford a cis-fused A/B ring fragment. The cycloadduct could be further enriched on gram-scale to high enantiomeric purity through preferential enrichment. En route to completing the 6/6/5 ring system, we demonstrate diastereoselective modifications of the [4+2] cycloadduct including silylative generation and addition to a vinyl oxocarbenium. Final C-ring closure was achieved by a diastereoselective 5-endo-trig cyclization, thereby completing a formal [3+2] annulation over two steps. Alkene transposition and hydroxyl-directed epoxidation completed the shortest asymmetric synthesis of (–)-verrucarol to date.