Total Syntheses of the C19 Diterpenoid Alkaloids (–)-Liljestrandisine and (–)-Liljestrandinine

Citation

Wong, Alice Rose (2019) Total Syntheses of the C19 Diterpenoid Alkaloids (–)-Liljestrandisine and (–)-Liljestrandinine. Dissertation (Ph.D.), California Institute of Technology. doi:10.7907/0KR7-PP68. https://resolver.caltech.edu/CaltechTHESIS:06082019-154532666

Abstract

A unified synthetic strategy to access diterpenoid alkaloid natural products is presented. The highly bridged hexacyclic natural products are characterized as having a hydrindane bridged piperidyl motif that is common to the C₁₉ aconitine type diterpenoid alkaloids and the C₂₀ napelline and denudatine type diterpenoid alkaloids. A unified strategy to the C₁₉ and C₂₀ diterpenoid alkaloids is developed. An asymmetric synthesis of an epoxy-hydrindane fragment enables the development of the key unified strategy, involving a 1,2-addition followed by a semipinacol rearrangement in a key fragment coupling process. The fragment coupling is demonstrated generally with a variety of substrates, including an aromatic substrate that is advanced to a key bicyclo[2.2.1]heptane intermediate towards the C20 diterpenoid alkaloids.

The developed 1,2-addition/semipinacol-rearrangement strategy is ultimately leveraged in the total synthesis of two different C₁₉ aconitine type diterpenoid alkaloids. An asymmetric synthesis of a bridged bicyclo[3.2.1]octane fragment is presented. The bridged bicyclo[3.2.1]octane fragment is advanced through the developed 1,2-addition/semipinacol rearrangement fragment coupling strategy affording a key tetracyclic intermediate. This work ultimately culminates in the total syntheses of two natural products (–)-liljestrandisine and (–)-liljestrandinine. Key steps for the completion of the total syntheses include advancement of the key tetracyclic intermediate from the fragment coupling through a series of C–N and C–C bond forming reactions, including an intramolecular aziridination reaction and a radical cyclization.

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