Development of Synthetic Strategies for the Total Synthesis of Ent-Kauranoid and Diterpenoid Alkaloid Natural Products

Citation

Mak, Victor Wei-Dek (2018) Development of Synthetic Strategies for the Total Synthesis of Ent-Kauranoid and Diterpenoid Alkaloid Natural Products. Dissertation (Ph.D.), California Institute of Technology. doi:10.7907/Z9ST7N04. https://resolver.caltech.edu/CaltechTHESIS:08042017-162439257

Abstract

As part of an ongoing synthetic effort directed towards biologically active ent-kauranoid natural products, the preparation of two structurally unique natural products, (–)-trichorabdal A and (–)-longikaurin E, is presented. The syntheses intercept an early intermediate from the synthetic route towards the rearranged natural product (–)-maoecrystal Z, and thus, represents a unified synthetic strategy to access structurally unique ent-kauranoids. Specifically, the syntheses are enabled by a palladium-mediated oxidative cyclization of a silyl ketene acetal to install a key quaternary center within the bicyclo[3.2.1]octane unit, as well as a reductive cyclization of an aldehyde-lactone to construct the oxabicyclo[2.2.2]octane motif of (–)-longikaurin E.

A synthetic strategy to access C19-diterpenoid alkaloids, specifically of the aconitine type, is presented. These highly bridged polycyclic natural products are generally characterized by a substituted piperidyl ring bridging a hydrindane framework that is further attached to a bicyclo[3.2.1]octane. The synthetic strategy relies on the enantioselective synthesis of two bicyclic fragments, which are coupled in a convergent fashion through a 1,2-addition/semipinacol rearrangement sequence to forge a sterically hindered quaternary center. Efficient access to late stage intermediates has enabled the synthesis of the aconitine carbocyclic core, with appropriate functionality for advancement to a selective voltage-gated K⁺ channel blocker, talatisamine. Additionally, the synthetic strategy described herein is well applicable to the synthesis of related denudatine and napelline type C₂₀-diterpenoid alkaloids.

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