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9-Membered Carbocycle Formation: Development of Distinct Friedel–Crafts Cyclizations and Application to a Scalable Total Synthesis of (±)-Caraphenol A


  • We thank Dr. John Decatur and Dr. Yasuhiro Itagaki for NMR spectroscopic and mass spectrometric assistance, Alison Xiang Gao for the synthesis of some intermediates, and Marian Deuker for early studies. We also thank NSF (CHE-0619638) for an X-ray diffractometer and Prof. Gerard Parkin, Dr. Aaron Sattler, and Dr. Wesley Sattler for performing crystallographic analyses that aided our design. Financial support was provided by the National Institutes of Health (R01-GM84994), Bristol-Myers Squibb, Eli Lilly, Amgen, the NSF (Predoctoral Fellowship to N.E.W.), and the Research Corporation for Science Advancement (Cottrell Scholar Award to S.A.S.).


Explorations into a series of different approaches for 9-membered carbocycle formation have afforded the first reported example of a 9-exo-dig ring closure via a AuIII-promoted reaction between an alkyne and an aryl ring as well as several additional, unique Friedel–Crafts-type cyclizations. Analyses of the factors leading to the success of these transformations are provided, with the application of one of the developed 9-membered ring closures affording an efficient and scalable synthesis of the bioactive resveratrol trimer caraphenol A. That synthesis proceeded with an average yield of 89 % per step (7.8 % overall yield) and has provided access to more than 600 mg of the target molecule.