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Total Synthesis of (±) and (+)-Lyconadin A and Mechanistic Studies of Oxidative C-N Bond Formation

  • Author(s): West, Scott P.
  • Advisor(s): Sarpong, Richmond
  • et al.
Abstract

An overview of the Lycopodium alkaloids is presented covering their isolation, structural classification and biosynthesis. The isolation, biological activity and biosynthesis of the miscellaneous group of the Lycopodium alkaloids are discussed in detail. Synthetic studies on the miscellaneous Lycopodium alkaloids are summarized and an overview of a previous total synthesis of (+)-lyconadin A and an approach to lyconadin A is presented.

The development of a unified strategy to access several miscellaneous Lycopodium alkaloids has been achieved. Utilizing this approach, the racemic and enantioselective syntheses of lyconadin A were achieved in 17 steps. Key strategic bond formations in the synthesis include olefin cross-metathesis, intramolecular Heck reaction, Curtius rearrangement, and intramolecular reductive amination. The lyconadin pentacycle was assembled by an unprecedented oxidative C-N bond-forming reaction from a dianion intermediate. The enantioselective route utilizes a Corey-Bakshi-Shibata reduction and a diastereoselective hydrogenation to set three key stereocenters.

An overview of oxidative bond-forming reactions from dianion intermediates is presented. The mechanism of the oxidative C-N bond formation was examined. NMR studies and DFT calculations were conducted to investigate the structure of the dianion intermediate. Several oxidants were found to promote C-N bond formation by oxidation of the dianion intermediate. The reactivity studies revealed that the C-N bond formation may proceed by polar or SET mechanisms and that the mechanistic pathway is dependent on the type of oxidant utilized.

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