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A catalytic asymmetric synthesis of palmerolide A Open Access

Descriptions

Other title
Subject/Keyword
melanoma
organo-boron
total sythesis
palmerolide A
enantioselective
catalytic
asymmetric
natural product
biological activity
Type of item
Thesis
Degree grantor
University of Alberta
Author or creator
Penner, Marlin
Supervisor and department
Hall, Dennis (Chemistry)
Examining committee member and department
Veinot, Jonathan (Chemistry)
Underhill, D. Alan (Oncology & Medical Genetics)
Barriault, Louis (Chemistry)
Clive, Derrick (Chemistry)
West, Frederick (Chemistry)
Department
Department of Chemistry
Specialization

Date accepted
2012-05-31T15:10:31Z
Graduation date
2011-11
Degree
Doctor of Philosophy
Degree level
Doctoral
Abstract
In the Introduction of this thesis, consideration is given to historical and ongoing value of investing research efforts in the total synthesis of natural products. Following this discussion is an explanation of the factors that guided the selection of palmerolide A as a synthetic target. The current status of palmerolide A in the academic literature is overviewed in the remainder of the introductory chapter, followed by a summary of research objectives at the conclusion. Chapter Two begins with a consideration of overall synthetic strategy and then narrows the focus to synthetic investigations that were directed towards what is defined as the “Eastern Hemisphere” of palmerolide A. These investigations involved extension of an inverse electron demand hetero-Diels-Alder-cycloaddition/allylboration methodology catalyzed by Jacobsen’s chromium(III) catalyst that was developed in the research group of Professor Dennis Hall for application to this synthesis. This highly enantioselective methodology was employed to set the desired relative and absolute stereochemistry of the entire Eastern Hemisphere through the introduction of a borono-Ireland-Claisen rearrangement; a unique variation of the Ireland-Claisen rearrangement developed during the synthesis. Also detailed are challenges and strategies employed to overcome issues in selectivity, protecting groups, and purification culminating in an optimized synthetic route to the Eastern Hemisphere. This project was collaborative in nature and a portion of the unique contributions by collaborators Dr. Vivek Rauniyar and Dr. Ludwig Kaspar are briefly described in Chapter 3. Chapter 4 recounts the key synthetic steps employed to join the hemispheres (Suzuki-Miyaura coupling), close the ring (Yamaguchi macrolactonization), form the dienamide side arm (Curtius rearrangement) and complete the synthesis. Of note was the challenge of overcoming a problematic late stage deprotection of a p-methoxybenzyl group. Chapter 5 presents preliminary research directed towards the synthesis of palmerolide A analogues focussed on modification of the macrocyclic backbone with an aromatic ring and modifications in protecting group strategy to address the problem encountered in the total synthesis followed by a conclusion in Chapter 6.
Language
English
DOI
doi:10.7939/R3VQ2SN33
Rights
Permission is hereby granted to the University of Alberta Libraries to reproduce single copies of this thesis and to lend or sell such copies for private, scholarly or scientific research purposes only. Where the thesis is converted to, or otherwise made available in digital form, the University of Alberta will advise potential users of the thesis of these terms. The author reserves all other publication and other rights in association with the copyright in the thesis and, except as herein before provided, neither the thesis nor any substantial portion thereof may be printed or otherwise reproduced in any material form whatsoever without the author's prior written permission.
Citation for previous publication
Marlin Penner, Journal of the American Chemical Society (2009)

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File size: 9222068
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File title: ForSubmission
File author: Marlin Penner
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