Fragment Coupling Approach To C₁₉- AND C₂₀-Diterpenoid Alkaloids: Total Synthesis of (–)-Talatisamine, (–)-Liljestrandisine, and (–)-Liljestrandinine

Author: Fastuca, Nicholas James

Year: 2022

Degree: Dissertation (Ph.D.)

Advisor: Reisman, Sarah E.

Committee Members: Stoltz, Brian M.; Fu, Gregory C.; Peters, Jonas C.; Reisman, Sarah E.

Option: Chemistry

DOI: 10.7907/vf11-jy04

Abstract

A unified, convergent fragment coupling approach to the C₁₉- and C₂₀-diterpenoid alkaloid natural products is presented. The highly-caged aconitine, denudatine, and napelline cores are disconnected through the central B-ring cyclohexane to an A/E/F-ring fragment common to the structures all three subfamilies. 1,2-addition of an appropriate organometallic C/D-bicycle to an A/F-ring hydrindane epoxy ketone fragment followed by a Lewis acid-catalyzed semipinacol reaction couples the two fragments together and sets a key all-carbon quaternary center at C11. This strategy is realized in the synthesis of the C₁₉-aconitine core by using a [3.2.1]-bicyclooctene C/D-fragment as the nucleophile in the 1,2-addition. This C/D-fragment is prepared using a meta-photocycloaddition; this represents an alternative approach to the commonly employed biomimetic Wagner-Meerwein rearrangement of a [2.2.2]-bicyclooctane.

To complete the aconitine core, a radical cyclization cascade to form the E-ring piperidine and B-ring cyclohexane in a single step is investigated. N-centered radicals were evaluated to initiate the cascade via a 6-exo-trig cyclization. A neutral aminyl radical gave rise to an unexpected Hoffman-Löffler-Freytag type product resulting from 1,5-hydrogen atom transfer. Employing Lewis-acidic single electron reducing metal catalyst led to formation of the E-ring cyclized product, however the second cyclization to close the B-ring did not occur.

As an alternative approach, the E-ring was closed via an intramolecular aziridination. Treatment of this aziridine with acetyl bromide results in an aziridine-opened alkyl bromide product. This alkyl bromide is used as a functional group handle to form the final ring of the aconitine core. From there, the total synteheses of the C₁₉-diterpenoid alkaloids (–)-talatisamine, (–)-liljestrandisine, and (–)-liljestrandinine were completed in short order. These synthetic efforts led to revision of the proposed structure of (–)-liljestrandisine.

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