Applications and Synthesis of [2]Rotaxanes for Artificial Molecular Machines A thesis submitted to The University of Manchester for the degree of Doctor of Philosophy in the Faculty of Science and Engineering 2019 Adrian Martin Haertsch School of Chemistry Blank page 2 dedicated to my parents 3 Blank page 4 Table of Contents 1. List of Abbreviations ................................................................................................. 8 1. Abstract ..................................................................................................................... 11 1. Declaration and Copyright Statement ................................................................... 12 1. Acknowledgements .................................................................................................. 13 1. An Introduction to [2]Rotaxanes and Molecular Walkers ................................... 17 1.1 An Introduction to [2]Rotaxanes ................................................................................ 20 1.1.1 Definition of a [2]Rotaxane ............................................................................... 20 1.1.2 Synthetic Strategies to Make [2]Rotaxanes ....................................................... 21 1.2 An Introduction to Synthetic Molecular Walkers ...................................................... 25 1.2.1 Features of Molecular Walkers .......................................................................... 25 1.2.2 Walking Mechanisms ......................................................................................... 26 1.2.3 Ratcheting Mechanisms and Thermodynamic Sinks ......................................... 26 1.2.4 Motor Proteins in Biology .................................................................................. 29 1.2.5 Kinesin I ............................................................................................................. 30 1.2.6 Molecular Walkers Based on Dynamic Covalent Chemistry............................. 32 1.2.7 Molecular Walkers Based on Covalent Bonds ................................................... 35 1.2.8 Molecular Walkers on Biological Tracks .......................................................... 37 1.2.9 Molecular Walkers Based on Metal Coordination Chemistry ........................... 40 1.2.10 Molecular Walkers that Walk on a Surface ....................................................... 42 1.2.11 DNA-Based Molecular Walkers ........................................................................ 46 1.2.12 Conclusion and Outlook ..................................................................................... 50 1.3 References .................................................................................................................. 51 2. A Molecular Walker Based on Secondary Interactions ....................................... 55 2.1 Synopsis ..................................................................................................................... 58 2.2 Introduction ................................................................................................................ 59 2.2.1 Bipedal Molecular Walkers ............................................................................... 59 2.2.2 Walkers Based on Hydrazone and Disulfide Exchange Reactions .................... 60 2.2.3 Chemical Fuels for pH Oscillations ................................................................... 64 2.3 Aim and Scope ........................................................................................................... 67 2.4 Design Considerations and Retrosynthesis of Walker 1-2.7 ...................................... 71 2.5 Results and Discussion .............................................................................................. 75 2.5.1 Choice of Linker ................................................................................................ 75 2.5.2 Synthesis of Walker Building Blocks ................................................................ 76 2.5.3 Rotaxane Synthesis ............................................................................................ 80 2.5.4 Transformation of [3]Rotaxane 2.47 into Walker 1-2.7..................................... 84 5 2.5.5 Operation of Walker 1-2.7 with an Aliphatic Walking Unit .............................. 89 2.5.6 Redesigning the Walking Unit ......................................................................... 103 2.6 Summary and Conclusion ........................................................................................ 108 2.7 Synthetic Procedures ................................................................................................ 111 2.7.1 General Methods and Equipment ..................................................................... 111 2.7.2 Synthesis of Formylated Dibenzo-24-Crown-8 Macrocycle 2.17 .................... 112 2.7.3 Synthesis of First Disulfide Foothold 2.19 ....................................................... 114 2.7.4 Synthesis of Second Disulfide Foothold 2.16 .................................................. 117 2.7.5 Synthesis of Linker 2.43 ................................................................................... 121 2.7.6 Synthesis of Aliphatic Walking Unit 2.13 ........................................................ 123 2.7.7 Synthesis of Dibenzylic Walking Unit 2.63 ..................................................... 124 2.7.8 Synthesis of Dibenzylamine Unit 2.18 ............................................................. 126 2.7.9 Synthesis of [3]Rotaxane 2.47 .......................................................................... 127 2.7.10 Methylated [3]Rotaxane 2.48 ........................................................................... 128 2.7.11 [2]Rotaxane Walker 1-2.7 (Introduction of Walking Unit) .............................. 130 2.7.12 Operation of [2]Rotaxane Walker 1-2.7 ........................................................... 131 2.7.13 [2]Rotaxane 1-2.68 (Introduction of Walking Unit) ........................................ 135 2.7.14 Operation of [2]Rotaxane Walker 1-2.68 ......................................................... 137 2.8 References ................................................................................................................ 139 3. A Peptide Synthesiser Based on Direct Aminolysis of Thioester Barriers ........ 141 3.1 Synopsis ................................................................................................................... 144 3.2 Introduction .............................................................................................................. 145 3.2.1 Rotaxane Based Molecular Machines for Peptide Synthesis ........................... 145 3.2.2 Peptide Ligation Reactions ............................................................................... 150 3.2.3 Cooperation Between Biological Molecular Machines .................................... 153 3.3 Aim and Scope ......................................................................................................... 155 3.4 Design and Retrosynthesis of a Thioester-based Peptide Synthesisers .................... 157 3.5 Results and Discussion ............................................................................................. 160 3.5.1 Ligation Studies ................................................................................................ 160 3.5.2 A New Mode of Operation: Direct Aminolysis of Thioester Barriers ............. 163 3.5.3 Synthesis of a Thioester Barrier ....................................................................... 164 3.5.4 Synthesis of a Truncated Thioester Barrier ...................................................... 168 3.5.5 Synthesis of 2-Barrier Tailpiece ....................................................................... 169 3.5.6 Protecting Group Choice for Alanine Residue ................................................. 169 3.5.7 1-Barrier Rotaxane Synthesis via an AMT Reaction ....................................... 170 3.5.8 Synthesis and Operation of a 2-Barrier Thioester Machine ............................. 173 3.5.9 Synthesis and Operation of a 3-Barrier Thioester Machine ............................. 175 6 3.6 Summary and Conclusion ........................................................................................ 178 3.7 Synthetic Procedures ................................................................................................ 180 3.7.1 General Methods and Equipment ..................................................................... 180 3.7.2 Synthesis of Ligated Product 3.34 ................................................................... 181 3.7.3 Synthesis of Truncated Thioester Barrier 3.27 ................................................ 182 3.7.4 Synthesis of Thioester Barriers 3.55 and 3.69 ................................................. 187 3.7.5 1-Barrier Rotaxane Synthesis ........................................................................... 197 3.7.6 2-Barrier Tailpiece Synthesis ........................................................................... 199 3.7.7 2-Barrier Thioester Machine ............................................................................ 201 3.7.8 3-Barrier Thioester Machine ............................................................................ 202 3.7.9 Operation of 2-Barrier Machine 3.75 ............................................................... 204