SYNTHESIS AND EVALUATION OF ΑLPHA-FLUORO ANALOGUES OF CAPSAICIN AND 2-(AMINOMETHYL)PIPERIDINE DERIVATIVES Thomas Moraux A Thesis Submitted for the Degree of PhD at the University of St. Andrews 2011 Full metadata for this item is available in Research@StAndrews:FullText at: http://research-repository.st-andrews.ac.uk/ Please use this identifier to cite or link to this item: http://hdl.handle.net/10023/2094 This item is protected by original copyright This item is licensed under a Creative Commons License Synthesis and evaluation of α-fluoro analogues of capsaicin and 2-(aminomethyl)piperidine derivatives A thesis presented for the degree of Doctor of Philosophy to the School of Chemistry - University of St-Andrews Thomas Moraux April 2011 SUBMISSION OF PHD AND MPHIL THESES REQUIRED DECLARATIONS 1. Candidate’s declarations: I, Thomas Moraux, hereby certify that this thesis, which is approximately 35.000 words in length, has been written by me, that it is the record of work carried out by me and that it has not been submitted in any previous application for a higher degree. I was admitted as a research student in October 2005 and as a candidate for the degree of Doctor of Philosophy in August 2006; the higher study for which this is a record was carried out in the University of St Andrews between 2005 and 2010. Date …………………………….. signature of candidate ………………………………………………... 2. Supervisor’s declaration: I hereby certify that the candidate has fulfilled the conditions of the Resolution and Regulations appropriate for the degree of Doctor of Philosophy in the University of St Andrews and that the candidate is qualified to submit this thesis in application for that degree. Date ……………………………. signature of supervisor ………………………………………………... 3. Permission for electronic publication: In submitting this thesis to the University of St Andrews I understand that I am giving permission for it to be made available for use in accordance with the regulations of the University Library for the time being in force, subject to any copyright vested in the work not being affected thereby. I also understand that the title and the abstract will be published, and that a copy of the work may be made and supplied to any bona fide library or research worker, that my thesis will be electronically accessible for personal or research use unless exempt by award of an embargo as requested below, and that the library has the right to migrate my thesis into new electronic forms as required to ensure continued access to the thesis. I have obtained any third-party copyright permissions that may be required in order to allow such access and migration, or have requested the appropriate embargo below. The following is an agreed request by candidate and supervisor regarding the electronic publication of this thesis: Access to printed copy and electronic publication of thesis through the University of St Andrews. Date ………… signature of candidate ……………………… signature of supervisor ………..………… Acknowledgements I would like to express my gratitude to my supervisor Professor David O’Hagan, for having given me the opportunity to work in his group and for the numerous valuable discussions during my PhD. I would like to join to this acknowledgement all the technical staff at the School of Chemistry and the BMS for providing such outstanding working conditions. I thank Professor Alexandra M.Z. Slawin, Dr Tomas Lebl, Melanja Smith, Caroline Horsburgh and Peter Pogorzelec for their respective help in crystal structure, NMR analyses and mass spectroscopic analyses. This PhD also gave me the opportunity to meet numerous people, and I would like to thanks in particular the members of the DOH group, past and present. The three musketeers who read this work were Dr Nawaf Al-Maharzik, Dr Neil Keddie, Dr Michael Corr, and Dr Yi Wang. My thoughts are also going to the old-timers: Matthieu, Guillaume, Vincent, Nelly, Paul, Pitak, Romain, Dr Daniel Farran, Dr Margit Winkler… et al.! Finally, Stefan Lazy German, Maciek Cookie Monster, and particularly Danny Cheeky Chicken have made this lab the most enjoyable place to work in! Abbreviations ACN acetonitrile Bn benzyl br broad BuLi buthyl lithium CM cross-metathesis d doublet DAST diethylaminosulfur trifluoride DCM dichloromethane de diastereomeric excess DIEA diisopropylethyl amine DMAP 4-(N,N-dimethylamino)pyridine DMF N,N-dimethylformamide dr diastereomeric ratio ee enantiomeric excess eq equivalent Hz Hertz HRMS high resolution mass spectroscopy IR infrared spectroscopy J coupling constant LDA Litium diisopropyl amide m multiplet μmol micromol (10-6 mol) Mp melting point NFSI N-fluorobenzene sulfonimide NFOBS N-fluoro-O-benzenedisulfonimide NMR nuclear magnetic resonance ppm parts per million PTFE polytetrafluoroethylene RNA ribonucleic acid RTX resiniferatoxin rt room temperature s singlet t triplet TBAF N-tetrabutylammonium fluoride TfO trifluoromethanesulfonate (triflate) THF tetrahydrofurane TLC thin layer chromatography TMS trimethylsilyl TRPV1 transient receptor potential vanilloid subtype 1 TsO p-methyl benzene sulfonate (tosyl) 19F NMR fluorine nuclear magnetic resonance 19F{1H} NMR proton decoupled fluorine nuclear magnetic resonance Table of contents Chapter 1- Fluorine in bioactive molecules 1.1- Discovery and development of fluorine chemistry 1 1.2- Controversial effects of fluorine on health 6 1.3- Significance of fluorine in natural products 8 1.3.1- Metabolites from plants 9 1.3.2- Metabolites from micro-organisms 10 1.4- Properties of fluorine 11 1.4.1- The fluorine atom 11 1.4.2- Physical properties of the C–F bond 12 1.4.3- Stereoelectronic properties of the C–F bond 13 1.4.3.1- Polarity 13 1.4.3.2- Bond strength 14 1.5- Fluorine in medicinal chemistry 15 1.5.1- Effects of fluorine on the properties of organic molecules 15 1.5.1.1- Perturbation of pKa 15 1.5.1.2- Modulation of lipophilicity 17 1.5.1.3- Steric and conformational changes 18 1.5.2- Metabolic stability 19 1.5.2.1- Oxidative mechanism 19 1.5.2.2- Hydrolytic metabolism 21 1.5.2.3- In vivo racemisation 22 1.5.3- Protein–Ligand interactions 23 1.5.3.1- Electrostatic interactions 23 1.5.3.2- Hydrogen bonding 24 1.5.4- Fluorine in nuclear medicine 26 1.6- Methods of fluorination 28 1.6.1- Nucleophilic reagents for fluorination 29 1.6.2- Electrophilic reagents for fluorination 34 1.6.3- Enantioselective monofluorination 35 1.6.3.1- Substrate control 35 1.6.3.2- Reagent control 36 1.6.3.3- Catalyst control 37 1.7-Conclusion 42 Chapter 2: α-Fluorinated capsaicins to alter the biological response of TRPV1 pain receptor 2.1- Introduction 47 2.2- TRPV1 receptor 53 2.2.1- Structure of TRPV1 54 2.2.2- Activation of the TRPV1 receptor 55 2.2.2.1- The critical residues for binding to TRPV1 56 2.2.2.2- The activation stimuli 58 2.2.3- Recent structural insights 59 2.3- Capsaicinoids 61 2.3.1- Structural elucidation of the capsaicinoids 61 2.3.2- Biosynthesis of capsaicin 62 2.4- Previous syntheses of capsaicin 64 2.4.1- Synthesis of vanillylamine 65 2.4.2- Syntheses of 8-methylnon-6-enoic acid 66 2.4.3- The Wittig approach 67 2.4.4- The Ortho-ester Claisen rearrangement 69 2.5- Aims and objectives 71 2.6- Results and discussion 75 2.6.1- Synthesis of (S)-fluorocapsaicin with Evans’oxazolidinone chiral auxiliary 75 2.6.1.1- Cross-metathesis (CM) strategy 75 2.6.1.2- Wittig strategy 84 2.6.1.3- Inverse Wittig route 85 2.6.1.4- Removal of the Evans auxiliary 89 2.6.1.5- Amide coupling to generate α-fluorocapsaicins 93 2.6.1.6- Route to dehydrocapsaicin 95 2.6.2- The use of imidazolidinones as organocatalyst for asymmetric α-fluorination 98 2.6.3- Analogues of capsaicin 101 2.6.3.1- Synthesis of shorter chain capsaicinoids analogues 101 2.6.3.2- Synthesis of the non-fluorinated short chain analogue 101 2.6.3.3- Deaminative fluorination 102 2.6.3.4- Asymmetric fluorination by organocatalysis 106 2.7- α,α-Difluorinated analogues 110 2.7.1- Theory study of α,α-difluoroamides 110 2.7.2- Synthesis of 2,2-difluoro-4-methylpentanoic acid 242 113 2.7.2.1- α,α-Difluorination by organocatalysis 113 2.7.2.2- α,α-Difluorination of α-ketoesters 114 2.7.3- Amide coupling of α,α-difluoro acid 115 2.7.4- α,α-Difluorination of α-ketoamides 117 2.8- Biological evaluation 118 2.8.1- Biological assay 119 2.8.1.1- Fluorinated enantiomers of capsaicin 119 2.8.1.2- Short fluorinated analogues of capsaicin 121 2.9- Conclusion 125 Chapter 3: Synthesis and organocatalysis from 2-(aminomethyl)piperidine 3.1- Diamines in medicinal chemistry and catalysis 131 3.1.1- The occurrence of vicinal diamines in natural products 132 3.1.2- Applications in medicinal chemistry 133 3.1.3- Vicinal diamines in synthesis 134 3.1.4- Preparation of vicinal diamines 137 3.2- Synthesis of enantiopure 2-(aminomethyl)piperidine 139 3.2.1- Previous syntheses of 2-(aminomethyl)piperidine 139 3.2.2- Précis 143 3.2.3- Enantioselective synthesis of 2-(aminomethyl)piperidine 144 3.2.3.1- Development of the cyclisation process 144 3.2.3.2- Hydrogenolysis of 318 and preparation of dihydrochloride 251 150 3.2.3.3- Preparation of 2-(aminomethyl)piperidine tetrafluoroborate salt 153 3.2.3.4- Enantiopurity and pKa analysis of dihydrochloride 251 154 3.3- Development of [4,4,0]-1,4-diazobicyclodecane 332 and its derivatives 157 3.4- 2-(Aminomethyl)piperidine as asymmetric organocatalyst 164 3.4.1- N-(Piperidin-2-ylmethyl)benzamide 362 165 3.4.2- 2,2,2-Trifluoro-N-(piperidin-2-ylmethyl)acetamide 363 167 3.4.3- 4-Methyl-N-(piperidin-2-ylmethyl)benzenesulfonamide 364 169 3.5- New catalyst for asymmetric Mannich reactions 175 3.5.1- Reactions catalysed by proline 175 3.5.2- Reaction with trifluoroacetamide organocatalyst 363 178 3.5.3- Reactions with organocatalyst 364 182 3.5.4- Mechanistic insights 184 3.6- Conclusion 186 Chapter 4: Experimental 4.1- General Methods 191 4.1.1- Reagents, solvents and reaction conditions 191 4.1.2- Chromatography and mass spectrometry 192 4.1.3- Nuclear magnetic resonance spectroscopy (NMR) 192 4.1.4- Other analysis 193 4.2- Protocols 194 4.3- Appendix 259 Abstract Chapter 1 gives an overview of the fluorine chemistry field, from its early developments to recent applications in medicinal chemistry.