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Date Permissions Signed

5-21-2021

Date of Award

Spring 2021

Document Type

Masters Thesis

Department or Program Affiliation

Chemistry

Degree Name

Master of Science (MS)

Department

Chemistry

First Advisor

Vyvyan, James R.

Second Advisor

Scheuermann, Margaret Louise

Third Advisor

Larsen, Michael B.

Abstract

Hepatocellular carcinoma (HCC) is a type of primary liver cancer that is responsible for roughly 700,000 deaths around the world each year. While invasive treatment methods for HCC have proven to be limited, there are drug treatments available that show promising features. The structural elements of these drugs have given rise to an interest in guaipyridine alkaloids, specifically a family of naturally occurring guaipyridine alkaloids known as the rupestines. The rupestines have previously been isolated from the flowers of the plant Artemisia rupestris. This plant has been known for its reported antitumor, antiviral and antibacterial properties when used in traditional Chinese medicine. An additional guaipyridine alkaloid worth noting is cananodine, which has been isolated from the fruits of Canaga odorata. Cananodine has shown activity toward two lines of HCC cancer cells, with potency greater than the HCC drug treatment Sorafenib. This increase in bioactivity has made the core guaipyridine structure of cananodine an attractive synthetic target. Considering the rupestines contain this same bicyclic core, it is possible that they will reveal similar activity to that of cananodine. In this report, rupestines B-D and J-M are targeted for total synthesis. The synthesis of rupestine D has been reported in 6 steps from a picolyl bromide substrate in good to excellent step-wise yields. The formation of the 7-membered carbocycle to establish the key guaipyridine core is accomplished via an intramolecular Mizoroki-Heck cyclization. This forms in a mixture of rupestine D and epi-rupestine D in a 1:2 ratio. Isolation of rupestine D has proven to be difficult when using the initial synthetic route. Upon reversal of the final two synthetic steps, the separation of diastereomers was accomplished with ease, allowing for the synthesis of rupestine D as a single diastereomer. These methods were employed for the synthesis and isolation of rupestine C in 6 steps with poor to excellent step-wise yields. The methyl ketone-containing rupestine D and epi-rupestine D can then serve as the starting material for the syntheses of rupestines J and K, as well as L and M. Rupestine K has been synthesized and isolated via a Rubottom oxidation of a silyl enol ether substrate. Progress is currently being made toward the synthesis of rupestine J, L and M.

Type

Text

Keywords

rupestines, guaipyridine alkaloids, hepatocellular carcinoma, synthesis, diastereomers, cananodine

Publisher

Western Washington University

OCLC Number

1255407094

Subject – LCSH

Alkaloids--Synthesis; Alkaloids--Therapeutic use; Liver--Cancer--Treatment; Diastereoisomers

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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