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Date Permissions Signed

6-1-2020

Date of Award

Spring 2020

Document Type

Masters Thesis

Department or Program Affiliation

Chemistry

Degree Name

Master of Science (MS)

Department

Chemistry

First Advisor

Vyvyan, James R.

Second Advisor

O'Neil, Gregory (Gregory W.)

Third Advisor

Larsen, Michael B.

Abstract

The rupestines, a family of guaipyridine alkaloids, are isolated from the plant Artemisia rupestris. Historically, this plant was used intraditional Chinese medicine due to its reported antitumor, antibacterial, and antiviral activities as well as reported protection of the liver. The rupestines can only be isolated from their parent plant in small quantities, making the total synthesis of these guaipyridine alkaloids of particular interest. Cananodine, anotherguaipyridine alkaloid, is a biologically active compound that can be isolated in small quantities from the fruits of Cananga odorata and displays activity against two types of hepatocellular carcinoma cell lines. It is hypothesized that the rupestines may also have anticancer activity. Synthesis of the rupestines would allow biological testing to determine if they, like cananodine, contain any activity against liver cancer or other types of cancer. In this project, the total synthesis of rupestines B and C was accomplished.The cyclic guaipyridine core in the synthesis of rupestines B and C was formed via intramolecular Mizoroki-Heck cyclization. In the first generation synthesis of rupestines B and C, a ketoester intermediate under went an undesired decarbonylation while producing only trace amounts of the desired product. To avoid the decarbonylation of the ketone, the starting material was changed such that a decarboxylation of anallylester would be favored. Alkylation of allyl 3-oxopentanoate with a substituted picolyl bromide provided the carbon-backboneof the target. Treatment ofadiallyl protected intermediate with palladium(0) in basic methanol resulted in the cleavage of both allyl groups and in situ decarboxylation of the intermediate keto acid. Triflation of the resulting phenolic hydroxyl gave the cyclization precursor. Exposureof the triflatetopalladium (0) in hot basic dioxane resulted in an intramolecular Mizoroki-Heck reaction that formed the seven-membered carbocycle of the guaipyridines. Finally, hydrogenation of the exocyclic alkene gave rupestines B and C in quantitative yield as a 1:2 mixture of diastereomers. While these diastereomers were not separable using flash column or radial chromatography, they were separableusing reverse phase MPLC. The 1H and 13C spectra for each diastereomer were assigned and matched the data reported in the isolation of the natural products.

Type

Text

Keywords

Guaipyridine, Alkaloid, Palladium, Mizoroki-Heck reaction

Publisher

Western Washington University

OCLC Number

1156495686

Subject – LCSH

Liver--Cancer--Treatment; Cancer--Alternative treatment--Research; Herbs--Therapeutic use; Alkaloids--Synthesis; Sagebrush--Therapeutic use

Format

application/pdf

Genre/Form

masters theses

Language

English

Rights

Copying of this document in whole or in part is allowable only for scholarly purposes. It is understood, however, that any copying or publication of this document for commercial purposes, or for financial gain, shall not be allowed without the author’s written permission.

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