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.