Total Synthesis of (−)-Neocucurbol C Enabled by Pattern Recognition and MHAT Cyclization

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Abstract
We report an asymmetric total synthesis of (-)-neocucurbol C, a diterpene natural product possessing a unique and complex 6/6/5/5/6 polycyclic skeleton and nine stereocenters. Pattern-recognition analysis led us to the chiral pool molecule (+)-nootkatone as the starting material, already containing the AB ring system and two key stereocenters encoded by the target molecule. The extra isopropenyl group of (+)-nootkatone was removed by Kwon's hydrodealkenylative bond fragmentation. Other key steps include a Suzuki-Miyaura cross coupling to introduce an aromatic ring as the E ring precursor, an oxidative dearomatization cyclization to form the key oxa-bridge, and a metal-catalyzed hydrogen atom transfer (MHAT)-initiated reductive radical cyclization to complete the entire framework for subsequent peripheral decorations, which eventually delivered (-)-neocucurbol C in 24 steps for the first time. In addition, the cytotoxicity evaluation of (-)-neocucurbol C and its synthetic intermediates against multiple cancer cell lines identified new lead compounds with promising anticancer activity for further development.
Funding Information
  • National Institutes of Health (GM128570, R61CA297953)

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