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The Synthesis of Cyclic Hexapeptide Host Molecules

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The Synthesis of Cyclic Hexapeptide Host Molecules THE SYNTHESIS OF CYCLIC HEXAPEPTIDE HOST MOLECULES by Stephen Anthony John Leah A Thesis Submitted for the Degree of Doctor of Philosophy University of York Department of Chemistry April 1997 ABSTRACT In recent years, the field of host-guest chemistry has become a large and rapidly advancingarea of researchwith a vast number of new host molecules being reported. Many of thesedevelopments are outlined in Chapter 1. The aim of this project was to achieve the synthesisand isolation of seven host molecules based upon a cyclic hexapeptide structure. Within this cyclic peptide, two glycine residues were incorporated to encourage the stabilization of the structure via the formation of ß-toms. Four lysine residues made up the complement of six amino acid residues in each target molecule. In three of the synthetic targets, these lysineswere to be crosslinked with different units to form polycyclic peptides with a cavity. In the other four synthetic targets, the lysines were to be used to allow the capping of a porphyrin unit onto the cyclic hexapeptide. With the aim of synthesisingthe three polycyclic peptides, it was necessaryto prepare and isolate a tripeptide crosslinked with an appropriate crosslinker. As described in Chapter 2, successfulcrosslinking was achieved when an NE-tosyl protected tripeptide was reacted with 1,2-bis(2-tosylethoxy)ethane, 1,6-dibromohexane and 1,4-a, a'-dibromo p- xylene. In Chapter 3, the final stages in the attempted synthesis of two of these polycyclic peptides are described via the successful cyclodimerisation of a crosslinked tripeptide and its resultant detosylation. Evidence from FAB mass spectrometry indicated that following a crosslinlcing reaction with 1,4-a, a'-dibromo p-xylene, a polycyclic peptide was 1H successfully formed. However, whereas the NMR spectra were consistent with the desired molecule, they could not be used to conclusively prove its synthesis. The attempts made to synthesise a porphyrin capped cyclic peptide are described in Chapter 4. However, none of these attempts were successful, either due to problems encountered in the purification of advanced intermediates or unsuccessful capping of the cyclic peptide by the appropriate porphyrin. 2 Page ACKNOWLEDGEMENTS 8 ABBREVIATIONS 11 CHAPTER 1: INTRODUCTION 15 1.1 HOST-GUEST CHEMISTRY 16 1.1.1 Basic concepts in host-guest chemistry 16 1.1.2 Lock and key principle 18 1.1.3 Induced-fit theory 19 1.1.4 Principle of preorganisation 21 1.1.5 Recent developments in host-guest chemistry 23 1.2 MOLECULAR RECOGNITION 23 1.2.1 Natural host molecules 23 1.2.1.1 Vancomycin 23 1.2.1.2 Carboxypeptidase A 24 1.2.2 Synthetic host molecules 26 1.2.2.1 Early host molecules 26 1.2.2.2 The binding of barbiturates 27 1.2.2.3 The binding of nucleic acid bases 29 1.2.2.4 The binding of amino acids and peptides 32 1.3 TRANSPORT 39 1.3.1 Natural transport systems 39 1.3.1.1 Valinomycin 39 1.3.2 Synthetic transport systems 41 1.3.2.1 Transport of amino acid anions 41 1.3.2.2 Transport of nucleotides and nucleosides 43 1.4 CATALYSIS 45 1.4.1 Natural catalytic systems 45 1.4.1.1 Chymotrypsin 46 3 Page 1.4.2 Synthetic catalytic systems 48 1.4.2.1 Acyl transfer catalysts 48 1.4.2.2 Catalysis of ATP and ADP hydrolysis 51 1.4.2.3 Catalysis of the benzoin condensation 52 1.4.2.4 Oxidation of aromatic aldehydes 54 1.4.2.5 Catalysis of the Diels-Alder reaction 55 1.5 SYNTHESIS OF HOST MOLECULES 56 1.6 POLYCYCLIC PEPTIDE HOST MOLECULES 63 1.6.1 Early results 63 1.6.2 Project aims 66 CHAPTER 2: SYNTHESIS OF CROSSLINKED TRIPEPTIDES 68 2.1 GENERAL SOLUTION-PHASE PEPTIDE SYNTHESIS 69 2.1.1 Protecting groups 69 2.1.2 Amino acid coupling reactions 72 2.1.3 Racemisation 79 2.2 SOLID-PHASE PEPTIDE SYNTHESIS 81 2.3 SYNTHESIS OF CROSSLINKED TRIPEPTIDE PRECURSORS 84 2.3.1 Synthetic strategy for the synthesis of polycyclic peptides 84 2.3.2 Synthesis of Boc-Lys(Ts)-OH 86 2.3.3 Synthesis of protected tripeptide 88 2.3.4 Synthesis of crosslinked tripeptide 89 2.3.4.1 Crosslinking with 4,4'-bis-bromomethylbiphenyl 89 2.3.4.2 Synthesis of a 1,2-bis(2-ethoxy)ethane crosslinked 95 tripeptide 2.4 SUMMARY 107 4 Page CHAPTER 3: TOWARDS THE SYNTHESIS OF POLYCYCLIC 110 PEPTIDE HOST MOLECULES 3.1 HEMERYTHRIN AND HEMOCYANIN 111 3.1.1 Hemerythrin 111 3.1.2 Hemocyanin 113 3.2 SYNTHETIC BIOMIMETIC COMPLEXES 115 3.3 THE STRUCTURE OF POLYCYCLIC PEPTIDE METAL 119 CHELATOR (80) 3.3.1 The macrocyclic ring of polycyclic peptide (80) 119 3.3.2 The cyclic peptide moiety of polycyclic peptide (80) 121 3.4 TOWARDS THE SYNTHESIS OF POLYCYCLIC PEPTIDE METAL 122 CHELATORS 3.3.1 Cyclodimerisation studies 122 3.3.2 Detosylation of the cyclic peptide 129 3.3.3 Final crosslinking reactions 135 3.4 SUMMARY 141 CHAPTER 4: TOWARDS THE SYNTHESIS OF A PORPHYRIN CAPPED 142 CYCLIC PEPTIDE 4.1 OXIDATIONS CATALYSED BY METALLOPORPHYRINS 143 4.2 TETRAARYLPORPHYRIN SYNTHESIS 147 4.3 SYNTHESIS OF CAPPED PORPHYRINS 150 4.4 SYNTHESIS AND DERIVATISATION OF PORPHYRINS 154 4.4.1 Attempted capping of 157 5,10,15,20-tetrakis(3-bromomethylphenyl)porphyrin 4.4.2 Attempted capping of 165 3-chlorosulphonyl-4-methoxyphenylporphyrin 4.4.3 Attempted porphyrin synthesis from a cyclic peptide 168 tetraaldehyde 5 Page 4.5S UMMARY 178 CHAPTER 5: EXPERIMENTAL 179 5.1 GENERAL 180 5.1.1 Instrumentation/physical methods 180 5.1.2 Chromatography 180 5.1.3 Solvents and reagents 181 5.2 EXPERIMENTAL RELATING TO CHAPTER 2 182 5.2.1 Addition of t-butoxycarbonyl protecting group to lysine 182 5.2.2 General methods in peptide synthesis 183 5.2.2.1 General method for peptide couplings using EDC/HOBt 183 peptide coupling reagents 5.2.2.2 N-t-butoxycarbonyl deprotection 184 5.2.3 Peptide couplings 184 5.2.4 Synthesis of crosslinkers 190 5.2.5 General procedure for crosslinking reactions 194 5.2.5.1 Using syringe pump 194 5.2.5.1 Without syringe pump 194 5.2.6 Preparation of crosslinked tripeptides 195 5.3 EXPERIMENTAL RELATING TO CHAPTER 3 210 5.3.1 General method for the cyclodimerisation of tripeptides 210 5.3.2 Cyclodimerisation of tripeptides 211 5.3.3 Detosylation of the cyclic peptide 216 5.3.4 Final crosslinking reactions 219 6 Page 5.4 EXPERIMENTAL RELATING TO CHAPTER 4 222 5.4.1 Porphyrin synthesis 222 5.4.2 Preparation of cyclic peptides 229 5.4.3 Attempted capping of a cyclic peptide onto a porphyrin 234 5.4.4 Attempted porphyrin synthesis from a cyclic peptide 238 tetraaldehyde 6. REFERENCES 245 7 Firstly, I would like to thank my supervisors Dr. John Lindsay Smith in York and ProfessorPat Bailey in Heriot-Watt for their guidance,advice and assistance throughout this project. I am also very grateful to Professor Bruce Gilbert in York for his support and concern following the difficult personal circumstances experienced during the third year of my study. My grateful thanks go to the William Briggs Scholarship Committee at the Royal Society of Chemistry for their generous funding of this project and in particular for extending their support following the difficulties encountered in the third year. I would like to thank Dr. Graham Barlow, Mrs. Barbara Chamberlain, Dr. Trevor Dransfield, Mr. Ben Glennie, Dr. Derek Londesbrough and Mr. Gary Gray for the provision of departmental analytical services at York. My thanks go to Dr. Alan Boyd, Dr. Rod Ferguson and Mr. Ian Scullion for conducting analytical services at Heriot-Watt. I am grateful to Mr. Bill Stirling at Heriot-Watt, for designingand constructing one of the syringe pumps used during this project. My thanks go to all my colleagues in the chemistry departments at York and Heriot- Watt for their help and friendship during the past few years. Amongst many others, I am particularly grateful to Steve C., Jo T., Derek, Gary, Pete, Brian, Norbert and George in York as well as Jo C., Anja, Frances,Helena, Keith, Simon, Ian, John, Steve S., Johnny and Rab in Heriot-Watt. I am very grateful to all my friends for their support and encouragement when most needed. In particular, amongst many others, I wish to thank all my friends at Cheadle Hulme, Melbourne Terrace and Nicholson Square Methodist Churches as well as Ed and Karen, Will and Helen, Ziad, Mohannad, Saba, Angelica and Maria. Special thanks go to all my family and in particular to Gran, Sheila, Mark, Tim, Nicole, Mick, Marianne, Daniel, David, Gordon, Gill, Caroline, Richard and Muriel, for their constant love, support and encouragement. My greatest thanks, however, are reserved for my Mum, without whose love, encouragement,wisdom and inspiration this project would never have been completed. It is a source of great sadnessthat her untimely death prevents me from placing a copy of this thesisinto her hands. Nevertheless,it is to her memory and to the memory of my Dad, that this thesis is dedicated. 8 In loving memory of Mum and Dad Of making many books there is no end, and much study wearies the body. Ecclesiastes 12: 12b 10 ABBREVIATIONS Ac acetyl Adorn adamantyloxymethyl ADP adenosine diphosphate AIDS acquired immune deficiency syndrome Ala alanine aq aqueous Ar aromatic Asp aspartic acid ATP adenosine triphosphate AZT 3'-azido-2',3'-dideoxythymidine Boc `butyloxycarbonyl Bom benzyloxymethyl BOP benzotriazolyloxy-tris(dimethylamino)-phosphonium hexafluorophosphate Bn benzyl bp boiling point Bt benzotriazole Bu butyl 'Bu CH2CH2CH2CH3 `Bu tert-butyl (1,1-dimethylethyl) Bz benzyl cm centimetre(s) COSY correlation spectroscopy DCC dicyclohexylcarbodiimide DCU dicyclohexylurea DDQ 2,3-dichloro-5,6-dicyanobenzo-1,4-quinone DIBAL-H diisobutylaluminium hydride DIPEA N, N-diisopropylethylamine dm decimetre(s) DMA N, N-dimethylacetamide DMAP 4-N, N-dimethylaminopyridine 11 DMF N, N-dimethylformamide DMSO dimethylsulphoxide EDC 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride e.e.
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