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Synthesis of Thiacrown and Azacrown Ethers Based on the Spiroacetal Framework

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Synthesis of Thiacrown and Azacrown Ethers Based on the Spiroacetal Framework Synthesis of Thiacrown and Azacrown Ethers Based on the Spiroacetal Framework By Marica Nikac A Thesis submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy. University of Western Sydney February 2005. To my family and friends Acknowledgements I would like to express my enormous gratitude to my supervisors Dr. Robyn Crumbie, Prof. Margaret Brimble and Dr. Trevor Bailey for all their advice, support and encouragement throughout this project. I would also like to thank Assoc. Prof. Paul Woodgate and Dr. Vittorio “Cappy” Caprio for their suggestions. I would also like to thank the members of the Brimble group particularly Rosliana Halim, Michelle Lai, Christina Funnell, Jae Hyun Park and Kit Sophie Tsang for their encouragement and especially their friendship. I would not have made it without them. I would also like to thank Daniel Furkert and Adrian Blaser for their assistance and friendship. I would like to express my gratitude to Dr. Narsimha Reddy and Mike Walker for their help with everything to do with NMR. I also wish to thank the technical staff at the Universities of Auckland and Western Sydney particularly, Noel Renner, Chris Myclecharane and Gloria Tree. I would like to thank my family (especially my sister Milka) and friends for their support, encouragement and love throughout all these years. Finally I wish to thank all the students and staff at the Universities of Auckland and Western Sydney. Statement of Authentication The work presented in this thesis is, to the best of my knowledge and belief, original except as acknowledged in the text. I hereby declare that I have not submitted this material, either in whole or in part, for a degree at this or any other institution. …………………………………………. Table of Contents Page Table of Contents i List of Tables v List of Figures vi Abbreviations vii Abstract ix Chapter 1: Crown Ethers 1.0 Discovery of Crown Ethers 1 1.1 Crown Ethers Containing Carbohydrate Scaffolds 4 1.1.1 Crown Ethers Containing Pyranose Units 6 1.1.2 Lactose Trehalose and Other Di- and Trisaccharides 10 1.1.3 Furanoside Derivatives 12 1.2 Crown Ethers Containing the Spiroacetal Framework 13 1.2.1 Starands 13 1.2.2 Incorporation of the 1,4,7,10-Tetraoxaspiro[5.5]undecane Ring System 14 1.2.3 Polyspiroacetal Ligands 15 1.2.4 Incorporation of 1,7-Dioxaspiro[5.5]undecane Ring System 15 Chapter 2: Synthetic Strategies for the Preparation of Crown Ethers 2.0 General Synthetic Principles for the Preparation of Crown Ethers 20 2.0.1 The Effect of the Chain Length 20 2.0.2 Nature of the Atoms 21 2.0.3 Type Of Cyclisation 21 2.0.4 Ring Closure Methods 22 2.1 Selectivity of Crown Ethers for Metal Ions 23 2.2 Nitrogen Macrocycles (Azacrown Ethers) 26 i 2.2.1 Templated Syntheses 27 2.2.2 The Sulfonamide Method 29 2.2.3 Azacrown Ethers via Amide Formation 31 2.2.4 Peptide Chemistry 34 2.2.5 Crab-like Cyclisation 34 2.3 Sulfur Macrocycles (Thiacrown Ethers) 2.3.1 Synthesis of Thiacrown Compounds Using Cs2CO3 38 2.3.2 The Cesium Effect 38 2.3.3 Templated Syntheses 39 Chapter 3: Synthesis of Spiroacetal Thiacrown and Azacrown Ethers 3.0 Synthetic Targets 42 3.1 Synthesis of Spiroacetal Diol (50) 43 3.1.1 Synthesis of (±)-1,7-Dioxaspiro[5.5]undec-4-ene 43 3.1.2 Epoxidation of Olefin (114) 45 3.1.3 Base-Induced Ring opening of Epoxide (115) and Epoxidation of Allylic Alcohol (117) 46 3.1.4 Reduction of syn-Epoxy Alcohol (119) 48 3.2 Synthesis of the Spiroacetal Thiacrown Ethers via Path A 49 3.2.1 Synthesis of the β-Chloroethyl Sulfides (104), (127) and (128) 49 3.2.2 Reaction Between Spiroacetal Diol (50) and β-Chloroethyl Sulfide (104) 51 3.2.3 Attempted Synthesis of Thiacrown Ether (134) via Olefin 52 Metathesis of Diene (132) with Spiroacetal Diene (133) 52 3.2.3.1 Synthesis of Spiroacetal Bisallyl Ether (133) 53 3.2.3.2 Olefin Metathesis 54 3.4 Synthesis of the Spiroacetal thiacrown Ethers via Path B 61 3.4.1 Synthesis of Spiroacetal Diol (145) 62 3.4.2 Ditosylation of Spiroacetal Diol (145) 64 3.4.3 Synthesis of Spiroacetal Thiacrown Ethers (55), (56) and (57) 65 3.5 Synthesis of Spiroacetal Azacrown Ethers 68 3.5.1 Attempted Synthesis of Spiroacetal Azacrown Ethers (58), (59) And (60) via Imine Formation from Aldehyde (150) 69 ii 3.5.2 The Sulfonamide Method 70 3.6 Summary 74 Chapter 4: Spiroacetal Thiacrown Ethers As Primary and Secondary Ligands 4.0 Spiroacetal Thiacrown Ethers As Primary and Secondary Ligands 75 4.0.1 Crown Ethers As Primary Ligands 75 4.0.2 Second-Sphere Coordination 76 4.1 Binding Studies 78 4.1.1 Determination of Association Constants Using Picrate Salts 78 4.1.2 Interaction of Thiacrown Ethers (55), (56) and (57) with Neutral and Ionic Complexes (Second-Sphere Coordination) 82 4.1.2.1 Interaction With [Co(NH3)NO2](BPh4)2 (165) and [Co(en)3](BPh4)3 (166) 83 4.1.2.2 Interaction With [Al(acac)3] (164) 84 4.2 Summary 86 Chapter 5: Kinetic Resolution of the Spiroacetal Moiety 5.0 Kinetic Resolutions 87 5.1 Base-Induced Rearrangement Of Epoxides 88 5.1.1 Ring Opening of α-Epoxide (115) Using Chiral Non-Racemic Lithium Amide Bases 89 5.2 Hydrolytic Kinetic Resolution 91 5.2.1 Jacobsen Hydrolytic Resolution Reaction 91 5.2.2 Hydrolytic Kinetic Resolution of α-Epoxide (115) 92 5.3 Sharpless Epoxidation 94 5.3.1 Sharpless Epoxidation of Allylic Alcohol (117) 96 5.4 Summary 98 iii Chapter 6: Conclusion Conclusion 100 Chapter 7: Experimental 7.0 General Details 105 7.1 Preparation of [3R∗, 5S∗, 6S∗]-1,7-Dioxaspiro[5.5]undecan-3,5-diol (50) 106 7.2 Synthesis of [3R∗, 5S∗, 6S∗]-1,7-Dioxaspiro[5.5]undecan-3,5-diyl bis(ethyl p-toluenesulfonate) (146) 115 7.3 Preparation of β-Chloroethyl Sulfides (104) and (127) and Dithiols (122) and (123) 120 7.4 Synthesis of Spiroacetal Thiacrown Ethers (55), (56) and (57) 125 7.5 Synthesis of Spiroacetal Azacrown Ether (58) 128 7.6 Olefin Metathesis of Spiroacetal Bisallyl Ether (142) 132 7.7 Kinetic Resolution Reactions 134 7.8 Second-Sphere Complexation 142 Chapter 8: References References 143 iv List of Tables Page Table 1: Selected 1H Chemical Shifts and Coupling For Dimers (142a), (142b) and (142c) 60 Table 2: Reaction Conditions Used in the Synthesis of Diester (149) 62 Table 3: Reaction Conditions Used in the Synthesis of Protected Azacrown (159) 72 Table 4: Association Constants For Spiroacetal Thiacrown Ethers (55), (56) and (57) 79 Table 5: Base-Induced Rearrangement of α-Epoxide (115) Using Chiral Lithium Amide Bases 90 v List of Figures Page Figure 1: Association Constants of the Axial Crown Ethers 16 Figure 2: Association Constants of the Equatorial Crown Ethers 17 Figure 3: Resolution of Spiroacetal Diol (50) 19 Figure 4: Common Approaches to Synthesising Macrocycles 20 Figure 5: Sandwich Effect 24 Figure 6: Common Structure of Complexed Azacrown Ethers 25 Figure 7: Effect of the Longer Carbon-Sulfur Bond on the Cavity of Thiacrown Compounds 26 Figure 8: Cesium Effect 39 Figure 9: Hydrogen Bonding in the Epoxidation of Allylic Alcohol (117) using meta -chloroperoxybenzoic acid 48 Figure 10: Proton Driven Transport of Metal Ions Through Membranes 76 Figure 11: Second-Sphere Coordination 77 Figure 12: Second-Sphere Coordination of Carboplatin 77 Figure 13: Association Constants of the Thiacrown Ethers (55), (56) and (57) 80 Figure 14: Expanded Region 80 Figure 15: Holodirected and Hemidirected Geometry of Pb(II) 82 Figure 16: Electrostatic Potential Map of [Al(acac)3] 85 Figure 17: Electrostatic Potential Map of Thiacrown (55) 85 Figure 18: Differentiation Between Two syn β-Protons in Cyclohexene Oxide 88 Figure 19: Mechanism of the Sharpless Epoxidation 95 Figure 20: Kinetic Resolution of Stereochemically Rigid Compounds Using Sharpless Epoxidation 96 Figure 21: Determination of the Appropriate Tartrate in the Epoxidation of Allylic Alocohol (117) 97 vi Abbreviations 2D. two dimensional 18-Crown-6 1,4,7,10,13,16-hexaoxacyclooctadecane 18-S-6 1,4.7,10,13,16-hexathiacyclooctadecane 9-S-3 1,4,7-trithiacyclononane Ar. Aryl aq. aqueous ax. axial n-Bu, Bun. n-butyl t-Bu, But. tert-butyl CI. chemical ionisation (mass spectroscopy) cm3. cubic centimetres conc. concentration COSY. correlation spectroscopy D. deuterium deg. degrees DEPT. distortionless enhancement by polarisation transfer dil. dilute DMDO. dimethyldioxirane DMAP. 4-dimethylaminopyridine DMF. N,N-dimethylformamide DMSO. dimethylsulfoxide ee. enantiomeric excess EI. electron impact ionisation (mass spectroscopy) eq. equatorial equiv. equivalent Et. ethyl h. hour HMQC. Heteronuclear Multiple Quantum Correlation HMBC. Heteronuclear Multiple Bond Correlation HSQC. Heteronuclear Single Quantum Correlation vii IR. infrared spectroscopy J. NMR coupling constant Ka. association constant L. ligand m-CPBA. meta-chloroperoxybenzoicacid Me. methyl min. minute mmol. millimoles mol. moles mp. melting point NMR. nuclear magnetic resonance Ns. nosyl, o-nitrobenzenesulfonyl Oxone® potassium peroxymonosulfate IPr. isopropyl PPTS. pyridinium p-toluenesulfonate THF. tetrahydrofuran TMS. trimethylsilyl Ts. tosyl, p-toluenesulfonyl viii Abstract This thesis describes the synthesis of novel thiacrown and azacrown ethers based on the 1,7-dioxaspiro[5.5]undecane ring system. Chapter one presents an overview of the discovery and development of crown ethers. The incorporation of naturally occurring compounds into the crown ether framework such as carbohydrates and more recently the spiroacetal functionality is also described. Chapter two describes the synthetic strategies available for the synthesis of crown ethers, azacrown ethers and thiacrown ethers.
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