Multiple Electrophilic Aromatic Substitution Reactions of Phloroglucinol and Studies Towards the Total Synthesis of Hopeanol by Matthew Kenneth Hiron Campbell Bachelor of Science, Simon Fraser University, 2006 THESIS SUBMITTED IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF MASTER OF SCIENCE in the Department of Chemistry © Matthew Kenneth Hiron Campbell 2011 SIMON FRASER UNIVERSITY Summer 2011 All rights reserved. However, in accordance with the Copyright Act of Canada, this work may be reproduced, without authorization, under the conditions for "Fair Dealing." Therefore, limited reproduction of this work for the purposes of private study, research, criticism, review and news reporting is likely to be in accordance with the law, particularly if cited appropriately. APPROVAL Name: Matthew Campbell Degree: Master of Science Title of Thesis: Multiple Electrophilic Aromatic Substitution Reactions of Phloroglucinol and Studies Towards The Total Synthesis of Hopeanol Examining Committee: Dr. Erika Plettner Chair Associate Professor, Department of Chemistry Dr. Peter D. Wilson Senior Supervisor Associate Professor, Department of Chemistry Dr. Charles J. Walsby Committee Member Associate Professor, Department of Chemistry Dr. Robert N. Young Committee Member Professor, Department of Chemistry Dr. Robert A. Britton Internal Examiner Assistant Professor, Department of Chemistry Date Defended/Approved: August 5,2011 11 Declaration of Partial Copyright Licence The author, whose copyright is declared on the title page of this work, has granted to Simon Fraser University the right to lend this thesis, project or extended essay to users of the Simon Fraser University Library, and to make partial or single copies only for such users or in response to a request from the library of any other university, or other educational institution, on its own behalf or for one of its users. The author has further granted permission to Simon Fraser University to keep or make a digital copy for use in its circulating collection (currently available to the public at the “Institutional Repository” link of the SFU Library website <www.lib.sfu.ca> at: <http://ir.lib.sfu.ca/handle/1892/112>) and, without changing the content, to translate the thesis/project or extended essays, if technically possible, to any medium or format for the purpose of preservation of the digital work. The author has further agreed that permission for multiple copying of this work for scholarly purposes may be granted by either the author or the Dean of Graduate Studies. It is understood that copying or publication of this work for financial gain shall not be allowed without the author’s written permission. Permission for public performance, or limited permission for private scholarly use, of any multimedia materials forming part of this work, may have been granted by the author. This information may be found on the separately catalogued multimedia material and in the signed Partial Copyright Licence. While licensing SFU to permit the above uses, the author retains copyright in the thesis, project or extended essays, including the right to change the work for subsequent purposes, including editing and publishing the work in whole or in part, and licensing other parties, as the author may desire. The original Partial Copyright Licence attesting to these terms, and signed by this author, may be found in the original bound copy of this work, retained in the Simon Fraser University Archive. Simon Fraser University Library Burnaby, BC, Canada Last revision: Spring 09 Abstract An investigation of the triple electrophilic aromatic substitution (EAS) reactions of phloroglucinol (1,3,5-trihydroxybenzene) has led to the preparation of both symmetrical triple Mannich bases and structurally-complex polycyclic adducts. This research was based on two synthetic approaches that were developed separately for the total synthesis of the polycyclic and C3-symmetric natural product xyloketal A. The first systematic study led to the synthesis of a series of functionalized C3-symmetric dendrimer cores. In the second study, polycyclic analogues of xyloketal A were prepared via the triple EAS reactions of phloroglucinol with various carbon-based electrophiles. In addition, a novel C2-symmetric polycyclic quinone was isolated from the reaction of phloroglucinol with (+)-p-mentha-2-ene-1,8-diol. In a separate study, the total synthesis of the natural product hopeanol was undertaken. This involved the preparation of a 1,2-diketone precursor which was tested with an array of acid promoters in an attempt to complete this synthesis in a single synthetic operation. iii Quotation “It makes you think of something solid, stable, well-linked. In fact it happens also in chemistry as in architecture that „beautiful‟ edifices, that is symmetrical and simple, are also the most sturdy: in short the same thing happens with molecules as with the cupolas of cathedrals or the arches of bridges. And it is also possible that the explanation is neither remote nor metaphysical... ever since man has built he has wanted to build at the smallest expense and in the most durable fashion, and the aesthetic enjoyment he experiences when contemplating his work comes afterward.” Primo Levi, on the structure of alloxan in The Periodic Table. Pg. 179 iv Acknowledgements First, I would like to thank my senior supervisor, Dr. Peter Wilson, for offering me the opportunity to pursue a graduate degree in his research group. I am very grateful for the advice, mentoring and training I received over the course of my studies. The other members of my supervisory committee, Dr. Charles Walsby and Dr. Robert Young are thanked for their suggestions and encouragement throughout my time as a graduate student. Also, I would like to thank Dr. Robert Britton for agreeing to be my internal examiner. I am extremely grateful to all of them for taking the time to read my thesis. Dr. Tim Storr, Dr. Charles Walsby and Ms. Caterina Ramogida are thanked for providing their time and equipment and for their help and guidance in carrying out the cyclic voltammetry and EPR experiments. Dr. Andrew Lewis (NMR), Mr. Colin Zhang (NMR), Mr. Hongwen Chen (MS), Mr. Simon Wong (MS), and Dr. Nag S. Kumar (HRMS) are gratefully acknowledged for their technical expertise and support. My past and present colleagues, Mr. Jason Lamontagne, Mr. Brendan Whelan and in particular Mr. Patrick Chen, are thanked for the friendship and helpful discussions over the years. As well the Britton group past and present, especially, Mr. Jeffrey Mowat, Mr. Bal Kang and Mr. Labros Meimetis, are likewise thanked. Dr. Nabyl Merbouh is also thanked for his support over the course of my studies. v Table of Contents Approval .......................................................................................................................................... ii Abstract ........................................................................................................................................... iii Quotation ........................................................................................................................................ iv Acknowledgements .......................................................................................................................... v Table of Contents ............................................................................................................................ vi List of Tables .................................................................................................................................. ix List of Figures .................................................................................................................................. x List of Schemes .............................................................................................................................. xii List of Abbreviations .................................................................................................................... xvi Chapter 1: Introduction to Multiple Electrophilic Aromatic Substitution Reactions of Phloroglucinol and Studies Towards the Total Synthesis of Hopeanol ......................................................................................................... 1 1.1 Thesis Introduction ................................................................................................................. 1 1.2 Overview of the Electrophilic Aromatic Substitution Reaction ............................................. 2 1.3. Introduction to the Chemistry of Phloroglucinol [1,3,5-Trihydroxybenzene (9)] .................. 4 1.4 Overview of the Chemical Reactions of Phloroglucinol (9) ................................................... 7 1.4.1 The Triple Electrophilic Aromatic Substitution Reaction of Phloroglucinol (9) with Bromine ........................................................................................................ 7 1.4.2 Overview of the Xyloketal Family of Natural Products ............................................ 7 1.4.3 Brief Review of the Total Synthesis of Xyloketal A (15) and D (18) ..................... 10 1.4.4 Brief Review of Phenylboronic Acid-Mediated Triple Condensation Reaction of Phloroglucinol (9) ................................................................................ 18 1.4.5 Brief Review of the Total Synthesis of Xyloketal A (15) via a Triple Electrophilic Aromatic Substitution Reaction of Phloroglucinol (9) ....................... 21 1.4.6