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Published May 1, 2019 | Supplemental Material
Journal Article Open

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.

Additional Information

© 2019 American Chemical Society. Received: January 30, 2019; Published: March 25, 2019. B.M.S. and C.W.L. thank the NSF (CHE-1800511), Amgen, and Caltech for support of this research. K.N.H. thanks the NSF (CHE-1361104 and 1764238) for financial support of this research. B.L.H.T. gratefully acknowledges the National Institutes of Health for a postdoctoral fellowship (F32GM106596). B.M.S. and K.N.H. thank the NSF under the CCI Center for Selective C−H Functionalization (CHE-1205646). Calculations were performed on the Hoffman2 Cluster at UCLA and the Extreme Science and Engineering Discovery Environment (XSEDE), which is supported by the NSF (OCI-1053575). The authors thank Mr. Austin Wright (Caltech) for thoughtful comments about the manuscript. The co-authors dedicate this publication to the memory of Keiji Morokuma. Author Contributions: C.W.L. and B.L.H.T contributed equally. The authors declare no competing financial interest.

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Supplemental Material - ja9b01146_si_003.cif


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