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Iii Explorations in Synthetic Ion Channel Research iii Explorations in synthetic ion channel research: metal-ligand self-assembly and dissipative assembly by Andrew Krisjanis Dambenieks Master of Science, The University of Western Ontario, 2006 Bachelor of Science, The University of Western Ontario, 2004 A Doctoral Dissertation Submitted in Partial Fulfillment of the Requirements for the Degree of DOCTOR OF PHILOSOPHY in the Department of Chemistry Andrew Krisjanis Dambenieks, 2013 University of Victoria All rights reserved. This dissertation may not be reproduced in whole or in part, by photocopy or other means, without the permission of the author. ii Supervisory Committee Explorations in synthetic ion channel research: metal-ligand self-assembly and dissipative assembly by Andrew Krisjanis Dambenieks Master of Science, The University of Western Ontario, 2006 Bachelor of Science, The University of Toronto, 2004 Supervisory Committee Dr. Thomas Fyles, Department of Chemistry Supervisor Dr. Natia L. Frank, Department of Chemistry Departmental Member Dr. Fraser Hof, Department of Chemistry Departmental Member Dr. Francis E. Nano, Department of Biochemistry Outside Member iii Abstract Supervisory Committee Dr. Thomas Fyles, Department of Chemistry Supervisor Dr. Natia L. Frank, Department of Chemistry Departmental Member Dr. Fraser Hof, Department of Chemistry Departmental Member Dr. Francis E. Nano, Department of Biochemistry Outside Member This thesis explores fundamental design strategies in the field of synthetic ion channel research from two different perspectives. In the first part the synthesis of complex, shape persistent and thermodynamically stable structures based on metal- ligand self-assembly is explored. The second part examines transport systems with dynamic transport behavior in response to chemical inputs which more closely mimic the dissipative assembly of Natural ion channels. In part one, two model systems, the ethylenediamine palladium(II) - 4,4’- bipyridine squares of Fujita and the trimeric bis(terpyridine) - iron(II) hexagonal macrocycles of Newkome, were targeted for structural modification towards becoming transport competent systems via improving the membrane partitioning characteristics of the final coordination compounds by increasing their lipophilicity. Modifications of the Fujita system involved the generation of two lipophilic 4,4’- bipyridines with addition of lipophilic groups of 13 and 17 carbon long alkyl chains respectively at the 3 and 3’ positions. After pursuing multiple unsuccessful synthetic routes the successful syntheses afforded the final lipophilic 4,4’-bipyridines in overall yields of 19 to 21% over two synthetic steps. Mixtures of the newly generated lipophilic 4,4’-bipyridines with a known lipophilic ethylenediamine palladium(II) “corner” iv exhibited evidence of self-assembly from NMR spectroscopy experiments however attempts at further characterization by ESI-MS and X-ray crystallography were unproductive. The putative self-assembled structures were inactive in HPTS vesicle assays but showed erratic conductance activity in bilayer clamp experiments. However, the magnitude of the conductance observed was not indicative of the passage of ions through the internal pore of the square complex. Modifications to the Newkome hexagons were aimed at generating overall neutral assemblies with external lipophilic groups. These modifications involved imparting a net -2 charge to the ligand via modifications to the terminal tridentate ligands so that upon coordination to octahedral metal centers in the +2 oxidation state the overall hexagonal complex would be neutrally charged. Two bis-polydentate ligands were generated; a dissymmetric molecule comprising one terpyridine and one dipicolinate tridentate ligand (TERPY-DPA) and a symmetrical molecule comprising two 2,2’-bipyridine-6-carboxylate tridentate ligands (BIPYA-BIPYA). The successful syntheses provided the desired trimethylsilylethyl ester protected compounds in yields of 9.2 and 7.5 % over 6 and 8 total synthetic steps for TERPY-DPA and BIPYA-BIPYA respectively. A new approach to metal-ligand complex formation by concomitant fluoride deprotection and assembly was demonstrated with a monomeric complex. Polymetallic complexes formed with a variety of transition metals based on colorimetric changes but the products were very intractable and resisted full structural or transport characterization. Part two develops a system potentially capable of exhibiting dissipative assembly of active transporters. A library of six thioester containing compounds structurally related to known active oligoester compounds was synthesized. The successful syntheses provided the desired compounds in overall yields of 1.0 to 17.7% over 11 to 13 total synthetic steps. The intramolecular cyclization - truncation and thioester exchange reactions central to the dissipative assembly strategy were explored using a model compound. The full length compounds showed transport activity via the HPTS vesicle assay that was significantly below that of the lead compound. Bilayer clamp experiments however, revealed significant transport activity for both the full length as v well as the truncated thiol molecules. In the case of the latter the transport events had exceedingly high conductivity for such a small molecule. This unexpected activity for both the full length and truncated compounds, although different, prevented a full implementation of dissipative assembly of transport. vi Table of Contents Supervisory Committee .......................................................................................................ii Abstract ............................................................................................................................... iii Table of Contents ................................................................................................................ vi List of Tables ..................................................................................................................... viii List of Figures ...................................................................................................................... ix List of Schemes.................................................................................................................. xxi List of Abbreviations ...................................................................................................... xxvii List of Numbered Compounds ......................................................................................... xxx Acknowledgements ........................................................................................................... xlii 1 Introduction ................................................................................................................ 1 1.1 Summary ............................................................................................................. 1 1.2 Origins - The Lipid Bilayer Membrane ................................................................ 1 1.3 The Challenge - Ion Transport ............................................................................. 6 1.3.1 Natural Ion Channels .................................................................................... 11 1.3.2 Synthetic Ion Channels.................................................................................. 12 1.4 Studying Ion Channel Activity ........................................................................... 15 1.4.1 Vesicle Based Transport Activity Experiments.............................................. 16 1.4.2 Planar Lipid Bilayer Based Transport Activity Experiments .......................... 19 1.5 New Challenges of Synthetic Ion Channel Research ........................................ 24 1.5.1 Supramolecular Chemistry and Non-Covalent Interactions ......................... 26 1.5.2 The Hydrophobic Effect ................................................................................ 29 1.5.3 Metal - Ligand Interactions ........................................................................... 31 1.5.4 Reversible Covalent Bonds ........................................................................... 33 1.6 Molecular Recognition Strategies ..................................................................... 34 1.6.1 Complementarity .......................................................................................... 34 1.6.2 Preorganization ............................................................................................. 39 1.7 Designing Synthetic Self-Assembled Supramolecular Systems in Water ......... 44 1.7.1 Existing Synthetic Ion Channels Incorporating Metal-Ligand Self-Assembly 45 1.8 Outline of the Thesis ......................................................................................... 49 2 Thermodynamic Metal - Ligand Self-Assembly of Semi-Rigid Macrocycles ............. 51 2.1 Conceptual Ion Channel Motifs ........................................................................ 51 2.2 Macrocycles and Supramolecular Self-Assembly ............................................. 53 2.3 The Fujita Square .............................................................................................. 54 2.4 Previous Work - First Generation Modified Fujita Squares .............................. 54 2.5 Design Considerations for Second Generation Modified Fujita Squares ......... 56 2.6 Target Molecules and Retrosynthetic Analysis ................................................. 58 2.7 Synthesis ..........................................................................................................
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