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 of trichothecene natural products has been a significant challenge. This architecture was constructed beginning with a chiral Lewis acid-catalyzed, enantioselective 4+2 cycloaddition to afford a cis-fused A/B ring fragment. A mechanistic hypothesis for the pivotal 4+2 cycloaddition was developed through experimentation and density functional theory (DFT). En route to completing the 6/6/5 core, 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 formal 3+2 annulation over two steps. Late-stage alkene transposition and hydroxyl-directed epoxidation furnished the target compound, (-)-verrucarol.
Powers et al. (Wed,) studied this question.