A Convergent Total Synthesis of (+)-Ineleganolide

Creators: Gross, Benjamin M.; Han, Seojung; Virgil, Scott C.; Stoltz, Brian M.¹

1. California Institute of Technology

Abstract

We report the total synthesis of the furanobutenolide-derived diterpenoid (+)-ineleganolide. The synthetic approach relies on a convergent strategy, based on the coupling of two enantioenriched fragments which are derived from (-)-linalool and (+)-norcarvone respectively. A high-yielding, one-step Michael addition and aldol cascade furnishes a pentacyclic framework as a single diastereomer, overcoming previous challenges in controlling stereochemistry. The endgame features an O₂ facilitated C-H oxidation and a samarium diiodide induced semi-pinacol rearrangement to furnish the highly rigid central seven membered ring.

Additional Information

The content is available under CC BY 4.0 License. The authors thank NIH (R35GM145239) and the Heritage Medical Research Institute Investigator Program. The authors thank David VanderVelde for NMR assistance and maintenance of the Caltech NMR facility and Dr. Michael Takase and the Caltech XRD facility for XRD assistance. The authors thank Dr. Nick Hafeman, Elliot Hicks and Hao Yu for thoughtful discussion. The authors thank Prof. John L. Wood and Joseph P. Tuccinardi for graciously providing synthetic NMR data for 1. Special thanks to all of the students and postdocs who have worked on the ineleganolide project in the Stoltz lab over more than 20 years, especially Dr.'s Jennifer L. Roizen and Robert A. Craig II, whose Ph.D. theses paved the way for the completion of this synthesis. The authors declare no competing financial interest.

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