APPLICATION OF THE DIELS-ALDER REACTION TO THE SYNTHESIS OF NATURAL PRODUCT- LIKE LIBRARIES John Reed School of Chemistry Faculty of Science UNSW Australia A thesis submitted in fulfilment of the requirements for the degree of Master of Science in Chemistry January 2017 PLEASE TYPE THE UNIVERSITY OF NEW SOUTH WALES Thesis/Dissertation Sheet Surname or Family name: Reed First name: John Other name/s: Abbreviation for degree as given in the University calendar: MSc School: Chemistry Faculty: Science Title: Application of the Diels-Alder Reaction to the Synthesis of Natural Product-like Libraries Abstract 350 words maximum: (PLEASE TYPE) This thesis is focussed on the use of the diene-regenerative Diels-Alder reaction to assemble bicyclic molecular frameworks that are commonly found in bioactive natural products. Chapter 1 examines the history of natural products in pharmaceuticals, and introduces the concept of natural product derivatisation to improve biological activity. The development of focussed libraries of compounds to discover potent natural product derivatives is contrasted with combinatorial chemistry, using two illustrative case studies. The diene-regenerative Diels-Alder reaction is introduced, and key literature examples of this transformation are discussed. Chapter 2 describes the application of the diene-regenerative Diels-Alder reaction to the synthesis of functionalised 1,2,3,4-tetrahydroisoquinolines bearing aromatic substituents at the C(5)-position. This strategy provides access to a number of compounds that would be difficult to generate using existing methods for 1,2,3,4-tetrahydroisoquinoline synthesis. The diene-regenerative Diels-Alder reaction was tolerant to a broad range of substrates in terms of both sterics and electronic character. Furthermore, the reaction was used to prepare a 1,2,3,4-tetrahydroisoquinoline containing three contiguous synthetic handles in the form of an aryl silane, aryl bromide and aryl ether. In Chapter 3, the use of the diene-regenerative Diels-Alder reaction in the preparation of carbocylic compounds is discussed. Ten 1,5,6,7,8,8a- hexahydronaphthalenes were prepared in this manner. One of these compounds was selected as a model substrate and subjected to a variety of conditions to illustrate the broad spectrum of reactivity these 1,5,6,7,8,8a-hexahydronaphthalenes exhibit. This enabled the synthesis of a variety of highly functionalised molecules containing a decalin scaffold. A summary of the work described in this thesis, and the future directions for the project, is provided in Chapter 4. Full experimental procedures are listed in Chapter 5. Declaration relating to disposition of project thesis/dissertation I hereby grant to the University of New South Wales or its agents the right to archive and to make available my thesis or dissertation in whole or in part in the University libraries in all forms of media, now or here after known, subject to the provisions of the Copyright Act 1968. I retain all property rights, such as patent rights. I also retain the right to use in future works (such as articles or books) all or part of this thesis or dissertation. I also authorise University Microfilms to use the 350 word abstract of my thesis in Dissertation Abstracts International (this is applicable to doctoral theses only). …………………………………………………………… ……………………………………..……………… ……….……………………...…….…23/01/2017 Signature Witness Signature Date The University recognises that there may be exceptional circumstances requiring restrictions on copying or conditions on use. Requests for restriction for a period of up to 2 years must be made in writing. Requests for a longer period of restriction may be considered in exceptional circumstances and require the approval of the Dean of Graduate Research. FOR OFFICE USE ONLY Date of completion of requirements for Award: A[GrabPPLICATION your reader’s attention OF with aTHE great quote DIELS from the-A documentLDER or use R thisEACTION space to emphasize a key point. To place this text box anywhere on the page, just drag it.] TO THE SYNTHESIS OF NATURAL PRODUCT- LIKE LIBRARIES John Reed School of Chemistry Faculty of Science UNSW Australia A thesis submitted in fulfilment of the requirements for the degree of Master of Science in Chemistry January 2017 This thesis is dedicated to May, who has been sorely missed since December. i Ye! Who behold perchance this simple urn, Pass on – it honours none you wish to mourn. To mark a friend’s remains these stones arise; I never knew but one – and here he lies. -Lord Byron, “Epitaph to a Dog” ii ORIGINALITY STATEMENT I hereby declare that this submission is my own work and to the best of my knowledge it contains no materials previously published or written by another person, or substantial proportions of material which have been accepted for the award of any other degree or diploma at UNSW or any other educational institution, except where due acknowledgement is made in the thesis. Any contribution made to the research by others, with whom I have worked at UNSW or elsewhere, is explicitly acknowledged in the thesis. I also declare that the intellectual content of this thesis is the product of my own work, except to the extent that assistance from others in the project’s design and conception or in style, presentation and linguistic expression is acknowledged. Signed:............................................................................................................................................... Date:..................................................................................................................................................23/01/2017 iii COPYRIGHT STATEMENT I hereby grant the University of New South Wales or its agents the right to archive and to make available my thesis of dissertation in whole or part in the University libraries in all forms of media, now or here after known, subject to the revisions of the Copyright Act 1968. I retain all propriety rights, such as patent rights. I also retain the right to use in future works (such as articles or books) all or part of this thesis or dissertation. I also authorise University microfilms to use the 350 word abstract of my thesis in Dissertation Abstract International. I have either used no substantial portions of copyright material in my thesis or I have obtained permission to use copyright material; where permission has not been granted I have applied/will apply for a partial restriction of the digital copy of my thesis or dissertation. Signed:............................................................................................................................................... Date:..................................................................................................................................................23/01/2017 AUTHENTICITY STATEMENT I certify that the Library deposit digital copy is a direct equivalent of the final officially approved version of my thesis. No emendation of content has occurred and if there are any minor variations in formatting, they are the result of the conversion to digital format. Signed:……………………………………………………………………………………………………….. Date:…………………………………………………………………………………………………………..23/01/2017 iv Thesis Title Goes Here - Your Name – Month Year ACKNOWLEDGEMENTS I would like to thank Associate Professor Jonathan Morris for supervising me for the duration of this degree. The guidance you have provided for my research has been perfectly complemented by the thought-provoking questions you have asked, and the helpful answers you have provided. Thanks also to the members of the Morris group, particularly Steve for convincing me to join the group, and to Jono and Joana for collecting mass spectrometry data for me. There are many aspects of life in the Morris group that I will miss, none more so than the maturity displayed by each and every member. Thanks to the members of the NMR facility in the Mark Wainwright Analytical Centre. In particular, thanks to Don for helping me with some of the more sophisticated NMR experiments and providing easy-to-understand explanations of the underlying theory behind them. A massive shout out to the Normo’ boys. We finally got it! Thanks for making every summer Saturday unbelievably fun. I could write a whole other thesis on the hilarious moments that occurred over the last three seasons, both on and off the field… Thanks to all family and friends, especially those who were stuck living with me over the last two years. I would have driven myself crazy a long time ago without you. Finally, a special thanks to Veronica. I can’t wait to begin life in Europe together. v ABSTRACT This thesis is focussed on the use of the diene-regenerative Diels-Alder reaction to assemble bicyclic molecular frameworks that are commonly found in bioactive natural products. Chapter 1 examines the history of natural products in pharmaceuticals, and introduces the concept of natural product derivatisation to improve biological activity. The development of focussed libraries of compounds to discover potent natural product derivatives is contrasted with combinatorial chemistry, using two illustrative case studies. The diene-regenerative Diels-Alder reaction is introduced, and key literature examples of this transformation are discussed. Chapter 2 describes the application of the diene-regenerative Diels-Alder reaction to the synthesis of functionalised 1,2,3,4-tetrahydroisoquinolines bearing aromatic substituents at the C(5)-position. This strategy provides access to a number of