An unexpected Ireland–Claisen rearrangement cascade during the synthesis of the tricyclic core of Curcusone C: Mechanistic elucidation by trial-and-error and automatic artificial force-induced reaction (AFIR) computations

In the course of a total synthesis effort directed toward the natural product curcusone C, the Stoltz group discovered an unexpected thermal rearrangement of a divinylcyclopropane to the product of a formal Cope/1,3-sigmatropic shift sequence. Since the involvement of a thermally forbidden 1,3-shift seemed unlikely, theoretical studies involving two approaches, the "trial-and-error" testing of various conceivable mechanisms (Houk group) and an "automatic" approach using the Maeda–Morokuma AFIR method (Morokuma group) were applied to explore the mechanism. Eventually, both approaches converged on a cascade mechanism shown to have some partial literature precedent: Cope rearrangement/1,5-sigmatropic silyl shift/Claisen rearrangement/retro-Claisen rearrangement/1,5-sigmatropic silyl shift, comprising a quintet of five sequential thermally allowed pericyclic rearrangements.