Department of Chemistry Imperial College London South Kensington Campus London SW7 2AY (UK)

Synthesis and modif ication of paracyclophanes A thesis presented by Cristina Lecci In partial fulfilment of the requirements for the degree of DoCtor of Philosophy of the University of London Department of Chemistry Imperial College London South Kensington Campus London SW7 2AY (UK) October 2005 rat. Alkstract&&j Two main research topics are discussed in this thesis: a) the synthesis and reactivity of small and medium size paracyclophanes; b) the synthesis and applications of new classes of chiral macrocycles derived from amino acids. The first chapter is a concise review on the synthesis and use of [2.21paracyclophane derivatives as ligands in asymmetric catalysis and molecular recognition processes, with particular emphasis on tricarbonylchromium(O) complexes of [2.21paracyclophane. In the second chapter the synthesis and reactivity of tricarbonyl chromium (0) complexes of small and medium size paracyclophanes towards asymmetric derivatisation is described. Various synthetic systems have been examined in asymmetric deprotonation/quench sequences directed towards obtaining enantioenriched derivatives by a procedure that would provide an alternative to more classical methods such as enzymatic and chemical resolution. The third chapter is a comprehensive critical review of the applications of chiral macrocycles derived from amino acids in areas as diverse as ion transport across membranes, catalysis, development of new antibiotics and new materials. The fourth chapter describes the synthesis of two new classes of chiral macrocycles via a versatile route, which potentially gives diverse and useful systems. The structure of the synthetic macrocycles, whose chirality is derived from the incorporation of amino acids as building blocks, has been examined by X-ray analysis. This led to the prediction that the presence of hydrogen bond donors and acceptors in the structure of these systems plays an important role in determining the interaction of such macrocycles with guest candidates. This chapter also details a study of the host properties of the synthetic macrocycles towards organic and metal guests. The fifth chapter contains the experimental details of the work described in chapters 2 and 4. The appendix (Chapter 6) contains supporting information for the X-ray analyses performed during the course of the work while Chapter 7 provides the reader with full bibliographic details. Acknowledgements I would like to thank my supervisor Professor Sue Gibson for her continuous support throughout my PhD experience and for always seeing the bright side of things. I would like to thank Jon Cobb at King's College London and Pete Haycock at Imperial College London for their great NMR service. I also wish to thank the Mass Spectrometry Service at King's College and at Imperial College, Dr. Andrew White at Imperial College for the X-ray analyses and Stephen Boyer at London Metropolitan University for the elemental analysis service. I also would like to thank the past and present members of the Gibson group and my friends at King's College and at Imperial College, who have made these three years enjoyable and stimulating either from the scientific and the human point of you. I am indebted to Aaron, Karina, Ayako and Paolo for carefully and helpfully proof-reading this thesis. I am particularly grateful to Paola, Matt, Nello,, Andrea,, Patsy and Jamie for being very good friends and terrific companions inside and outside the work environment. And finally I would like to thank my parents, my sisters and Paolo for being my constant moral support and for always believing in my capabilities. Table of contents Abbreviations v Chapter I Synthesis and applications of [2.21paracyclophane derivatives Introduction 2 1.2 Synthesis of enantioenriched paracyclophanes 2 1.3 [2.2]Paracyclophane derivatives in asymmetric catalysis 5 1.4 Bioactive [2.2]paracyclophanes 8 1.5 Synthesis of tricarbonylchromium(O) complexes of paracyclophanes 10 1.6 Reactivity of tricarbonylchromium(O) complexes of [2.21paracyclophane 13 Chapter 2 Synthesis and modification of small and medium-size paracyclophanes 18 2.1 The proposal 19 2.1.1 Desy=etrising paracyclophanes 19 2.2 Reactivity of [2.21paracyclophane 22 2.2.1 Studies of achiral deprotonation 22 2.2.2 Studies of enantioselective deprotonation 27 2.3 2,11-Dithia[3.3]paracyclophane and related systems 37 2.3.1 Synthesis of sulfur-containing paracyclophanes 37 2.3.2 Synthesis and reactivity of tricarbonylchromium(O) complexes of sulfur-containing paracyclophanes 41 2.3.3 Reactivity of complexes 84 and 85 44 2.4 Synthesis and reactivity of a medium-size paracyclophane 53 2.5 Summary 54 i 0 Chapter 3 Amino-acid derived macrocycles -an area driven by synthesis or application? 55 3.1 Introduction 56 3.2 Transport across membranes 59 3.2.1 Introduction 59 3.2.2 Transport of small molecules across a lipidic membrane 61 3.2.3 Transport of small molecules across a chloroform/water membrane 67 3.3 Catalysis mediated by amino acid-derived macrocycles 69 3.4 Gelators 75 3.5 Organic nanotubes 77 3.6 Recognition of biologically important molecules 79 3.6.1 Introduction 79 3.6.2 Recognition of amino acid and peptide derivatives 82 3.6.3 Recognition of carboxylic anions 85 3.6.4 Recognition of steroids and purine derivatives 87 Chapter 4 Synthesis of new classes of chiral macrocycles derived from amino acids 90 4.1 The proposal 91 4.2 Synthesis of a novel class of macrocycles with an increased number of nitrogen atoms 96 4.2.1 Synthesis of the appropriate aldehyde 96 4.2.2 Synthesis of chiral aminoalcohol 165 97 4.2.3 Synthesis of new alkene acceptors containing the (S)-proline unit 98 4.2.4 Testing the Heck macrocyclisation on substrate 160 107 4.2.5 The Heck macrocyclisation on substrate 162 4.2.6 Synthesis of amine 170 and introduction of (S)-valine into the picture 113 4.2.7 The Heck macrocyclisation on substrates 168 and 169 118 11 4.2.8 An experimental assessment for the selective formation of "dimers" during the macrocyclisation step 121 4.3 Synthesis of a novel class of pyrrole-containing macrocycles 123 4.3.1 Background to the introduction of pyrroles 123 4.3.2 Synthesis of the appropriate aldehyde 125 4.3.3 Synthesis of a proline-derived alkene precursor 127 4.3.4 Synthesis of a valine-derived alkene precursor 130 4.3.5 The Heck macrocyclisation on substrates 188 and 193 134 4.3.6 Attempts to remove the benzyl protecting group from macrocycles 194 and 195 137 4.4 Application of the synthetic macrocycles: host-guest chemistry 140 4.4.1 Introduction 140 4.4.2 Investigation of the host properties of the synthetic macrocycles 143 4.5 Application of the synthetic macrocycles: asymmetric catalysis 146 4.5.1 Introduction 146 4.5.2 Testing the synthetic macrocycles as chiral ligands in the RE (OTf) 3-catalysed Mukaiyama aldol reaction 148 4.5.3 Assessment of the nature of the interaction between the ligand and the metal 153 4.6 Summary and outlook 156 Chapter 5 Experimental 158 5.1 General Experimental 159 5.2 Experimental of Chapter 2 162 5.3 Experimental of Chapter 4 178 5.3.1 Experimental of Section 4.2 towards the synthesis of alkenes 160,162,168 and 169 178 111 5.3.2 Experimental of Section 4.3 towards the synthesis of alkenes 188 and 193 197 5.3.3 Typical procedure for the Heck coupling reactions 213 5.3.4 Experimental of Section 4.4 220 Chapter 6 Appendix 223 6.1 Crystal data for macrocycle 158 224 6.2 Crystal data for macrocycle 179 230 6.3 Crystal data for complex 204 233 Chapter 7 References 243 iv Abbreviations a selectivity factor Ac acetyl Ala alanine atm. atmosphere(s) Ar aryl Bn benzyl Boc tert-butoxycarbonyl Bu butyl nBu normal-butyl tBu tert-butyl C concentration OC degrees centigrade cal calories CI Chemical Ionisation cm centimetre(s) COSY Correlated Spectroscopy mCPBA meta-chloroperbenzoic acid CSP Chiral Stationary Phase dba trans, trans-dibenzylideneacetone DCM dichloromethane d. e. diastereomeric excess DEAD diethyl azodicarboxylate dec. p. decomposition point DEPT Distortionless Enhancement by Polarization Transfer DIPEA di-iso-propylethylamine DMAP 4-N, N-dimethylaminopyridine DME 1.2-dimethoxyethane DMF AT,AT-dimethylf ormamide DMSO dimethyl sulfoxide DNA deoxyribonucleic acid dppf 1,1'-bis(diphenylphosphino)ferrocene V d. r. diastereomeric ratio e. e. enantiomeric excess EEDQ 2-ethoxy-l-ethoxycarbonyl-1,2-dihydroquinoline EI Electron Impact eq. equivalent(s) ESI Electronspray Ionisation Et ethyl FAB Fast Atom Bombardment FT Fourier Transform G molar free energy (Gibb's energy) Gln glutamine Glu glutamic acid GPC Gel Permeation Chromatography h hour(s) h-v light a-HL a-hemol_ysin HETCOR Heteronuclear Correlation HPLC High-Pressure Liquid Chromatography HRMS High-Resolution Mass Spectroscopy Hz Hertz IR Infra Red i coupling constant in Hz K partition coefficient k' capacity factor Kass association constant KC1-Tris tris(hydroxymethyl)aminomethane potassium chloride LDA lithium diisopropylamide ln natural logarithm Ln lanthanide M molar M+ molecular ion MALDI Matrix Assisted Laser Desorption/Ionization Me methyl MHz MegaHertz vi min. minute(s) M. P. melting point MS Mass Spectrometry M/Z mass/charge NAD + nicotinamide adenine dinucleotide NADH hydrogenated nicotinamide adenine dinucleotide NADP + nicotinamide adenine dinucleotide phosphate NADPH hydrogenated nicotinamide adenine dinucleotide phosphate NHCs AT-heterocyclic carbene ligands nm nanometre(s) NMR Nuclear Magnetic Resonance NOESY Nuclear Overhauser Effect Spectroscopy ORTEP Oak Ridge Thermal Ellipsoid Plot PDC Pyridinium Dichromate Ph Phenyl PPM

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