Enantioselective Synthesis of Diketopiperazines and Triketopiperazines Alejandro Cabanillas Navarro Thesis submitted to the University of Birmingham for the degree of Doctor of Philosophy August 2015 School of Chemistry The University of Birmingham University of Birmingham Research Archive e-theses repository This unpublished thesis/dissertation is copyright of the author and/or third parties. The intellectual property rights of the author or third parties in respect of this work are as defined by The Copyright Designs and Patents Act 1988 or as modified by any successor legislation. Any use made of information contained in this thesis/dissertation must be in accordance with that legislation and must be properly acknowledged. Further distribution or reproduction in any format is prohibited without the permission of the copyright holder. Abstract The diketopiperazine scaffold can be found in a large number of natural products and commercialised drugs. Conversely, the triketopiperazine one is far less common in Nature and scarce research has been conducted to determine its utility. The project goal was to develop enantioselective organocatalysis on these two frameworks. Chapter 1 gives an introduction on their presence in Nature and the pharmaceutical industry, the most relevant synthetic advances as well as an overview of the organocatalysis tools previously reported. Although diketopiperazines have been the subject of intense research, no asymmetric methods have been previously reported despite the myriad of available methodologies. Chapter 2 discusses the particular organocatalytic precedents that motivated this project and the initial efforts devoted to develop such methodology. Unfortunately, diketopiperazines showed complete lack of reactivity under a wide range of conditions. Our interest in developing this enantioselective method in heterocycles related to diketopiperazines made us turn our attention to the triketopiperazine scaffold. The successful application of a cinchona alkaloid derived catalysed Michael addition on this scaffold is described in Chapter 3. Progresses made in the manipulation of the chiral products are also included. An extension of the previously developed methodology, where selected Michael acceptors afford bicycle[2.2.2]diazaoctane derived products via a tandem Michael–ring-closure process, is discussed in Chapter 4. i Acknowledgments First and foremost, I would like to thank Professor Nigel S. Simpkins for giving me the opportunity to work on this PhD project as well as for his encouragement, advice and inspiration over this period. I would also like to thank Dr Christopher Davies for organising my placement in AstraZeneca, his interest and dedication and for his willingness to assist on my future career. I am very grateful to the University of Birmingham and AstraZeneca for the financial support of this work. The analytical facilities at both sites have also played a key part in bringing this project to fruition, particularly Dr Chi Tsang and Neil Sumner. I would like to acknowledge Dr Louise Male for acquiring and interpreting the X-ray data sets as well as for helping with the Appendix 2. I thank every member of the Simpkins group and other labmates I have had the chance of working with –Yang, François, Matt, Mike, Jen, Pete Dale, Jack, Gary, Pete Crick, Ryan and Edgar– for their invaluable help, friendship and all the good times we have had. Special thanks to Dr Sam Butterworth for his sincere commitment, for taking his time to help me expand my chemistry views and for giving me the opportunity to keep growing professionally. It has been great working along side his group too. Thanks to my friends, Miguel, Fer, Patri, Javi and Gonzalo, for always being there, no matter how far we are. I also want to thank my family for all their support and encouragement. Last but not least, thanks to Sara, nothing of this would have been possible without you, I love you. ii Table of Contents Abstract ........................................................................................................................................ i Acknowledgments ...................................................................................................................... ii Table of Contents ...................................................................................................................... iii Glossary of Abbreviations ......................................................................................................... vi Chapter One: Introduction .......................................................................................................... 1 1.1 Diketopiperazines ............................................................................................................ 1 1.2 2,5-Diketopiperazines in Nature and drugs ..................................................................... 5 1.2.1 Medicinal Chemistry .................................................................................................. 5 1.2.2 Peptidomimetics ....................................................................................................... 10 1.2.3 Bioactive Natural 2,5-Diketopiperazines ................................................................. 10 1.2.4 Bioactive Bridged 2,5-Diketopiperazines ................................................................ 13 1.2.5 Synthesis and Transformations ................................................................................ 17 1.3. Triketopiperazines ......................................................................................................... 24 1.3.1 Triketopiperazines in Nature .................................................................................... 26 1.4 Organocatalysis ............................................................................................................. 28 1.4.1 Enantioselective Organocatalysis ............................................................................. 29 1.4.2 Hydrogen-Bonding Catalysis ................................................................................... 35 iii 1.4.3 The Cinchona Alkaloid Family ................................................................................ 44 Chapter Two: Organocatalysis Chemistry of 2,5-Diketopiperazines ....................................... 55 2.1. Aims and Objectives ...................................................................................................... 55 2.2. Synthesis of 1,3-Dicarbonyl N,N’-Alkyl protected DKPs ............................................. 63 2.3. Synthesis of 1,3-Dicarbonyl N,N’-Carbonyl protected DKPs ....................................... 67 2.4. Summary and Future Work ........................................................................................... 71 Chapter Three: Enantioselective Synthesis of Polyfunctional 2,3,5-Triketopiperazines ......... 73 3.1. Aims and Objectives ...................................................................................................... 73 3.2. Synthesis of 2,3,5-Triketopiperazines ........................................................................... 75 3.2.1. Synthesis of 6-Acyl Triketopiperazines .............................................................. 79 3.3. Enantioselective Michael Reactions on 2,3,5-Triketopiperazines derivatives .............. 82 3.4. Synthesis of 6-Alkyl Triketopiperazines ..................................................................... 105 3.5. Further Transformations .............................................................................................. 113 3.5.1. Reduction of the C-3 position ............................................................................ 113 3.5.1.1 Cyclisations via N-Acyl Iminium .......................................................... 128 3.5.1.2 Synthesis of Polyfunctional 2,5-Diketopiperazine ................................ 130 3.5.2. TKP Deprotection .............................................................................................. 131 3.5.3. Unveiling the Amino Acid ................................................................................ 133 3.6. Summary and Future Work ......................................................................................... 137 iv Chapter 4: Synthesis of Bridged [2.2.2] Diketopiperazines ................................................... 139 4.1. Aims and Objectives .................................................................................................... 139 4.2. Organocatalysed Tandem Michael-Aldol Reaction on Triketopiperazines ................ 141 4.3. Further Transformations .............................................................................................. 151 4.4. Summary and Future Work ......................................................................................... 152 Chapter Five: Experimental part............................................................................................. 154 5.1. General Methods ......................................................................................................... 154 5.2. Experimental for Chapter 2 ......................................................................................... 155 5.3. Experimental for Chapter 3 ......................................................................................... 166 5.4. Experimental for Chapter 4 ......................................................................................... 240 Appendix 1 - NMR Spectra