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Date Permissions Signed

3-6-2014

Date of Award

2014

Document Type

Masters Thesis

Degree Name

Master of Science (MS)

Department

Chemistry

First Advisor

Vyvyan, James R.

Second Advisor

O'Neil, Gregory (Gregory W.)

Third Advisor

Vannelli, Tommaso A.

Abstract

The guaipyridines are a class of naturally occurring alkaloids isolated from plants native to the Pacific Islands and Southeast Asia. One member of this family, cananodine, has displayed potent in vitro cytotoxic effects against two different types of hepatocellular carcinoma cell lines. More recently discovered guaipyridine compounds, rupestines A-M, share structural similarities to cananodine and might possess similar anti-cancer properties. The potential medical benefits and the rare and interesting structure of the guaipyridines make them desirable and challenging synthetic targets. Two distinct synthetic routes were developed to access the guaipyridine core, and in doing so the total synthesis of cananodine and its diastereomers was accomplished. The initial route (epoxide-opening route) had previously been explored by the Vyvyan group (see Meyer, Ligon thesis; Yarbrough unpublished results) although room for improved efficiency and the final stereoselective hydrogenation reaction left significant work to be completed on this project. The critical Suzuki-Miyaura cross-coupling step involving a dienyl boronate ester and pyridyl triflate produced lower than desired yields, thus numerous combinations of coupling partners and reaction conditions were explored to improve the performance of this reaction. Once optimized conditions were developed, the sequence was continued and both enantiomers of the key 7-exo cyclization precursor was successfully isolated after base-promoted epoxide-opening. Exhaustive hydrogenation and reduction efforts of the remaining 1,1-disubstituted alkene provided a ~1:1 diastereomeric mixture of cananodine and its C5 epimer. The second route (intramolecular Heck cross-coupling route) to the guaipyridine skeleton is new to the Vyvyan lab and hinges on two key reaction steps. After preparation of picolyl bromide and tert-butyl hexenoate precursors, an alkylation reaction provided the carbon-backbone compound in satisfactory yields. Subsequent phenol deprotection and functionalization allowed for intramolecular Heck coupling between the 1,1-disubstituted side-chain alkene and a newly formed pyridyl triflate group provided the cyclized guaipyridine core compound in good yields.

Type

Text

DOI

https://doi.org/10.25710/hmtd-xb07

Publisher

Western Washington University

OCLC Number

872277661

Subject – LCSH

Alkaloids--Synthesis; Organic compounds--Synthesis; Cananga odorata--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 thesis for commercial purposes, or for financial gain, shall not be allowed without the author's written permission.

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