RECENT ADVANCES IN IMINIUM SALT CATALYSED ASYMMETRIC EPOXIDATION By David P. Day Doctoral Thesis Submitted in partial fulfilment of the requirements for the award of Doctor of Philosophy The University of East Anglia Department of Chemistry September 2013 © This copy of the thesis has been supplied on condition that anyone who consults it is understood to recognise that its copyright rests with the author and that no quotation from the thesis, nor any information derived there from, may be published without the author’s prior, without consent. i ABSTRACT RECENT ADVANCES IN IMINIUM SALT CATALYSED ASYMMETRIC EPOXIDATION DAVID DAY Key Terms: Epoxidation, Olefin, Iminium-salt, Kinetic resolution, Chromene, Dihydroquinoline, Tetrahydroquinoline The research in this thesis depicts some of the most current developments in the area of asymmetric epoxidation of alkenes using chiral iminium salt catalysts. The first chapter reviews past and present developments in; catalytic asymmetric epoxidation, and covers the application of this reaction towards the kinetic resolution of racemic olefins. Chapter two is separated into two key areas; (i) asymmetric epoxidation as a tool in the kinetic resolution of racemic chromene substrates, and (ii) investigations into the asymmetric epoxidation of new N-protected dihydroquinoline substrates. In the first part of chapter two, the first examples of kinetic resolution in epoxidation reactions using iminium salt catalysts are reported, providing up to 98% ee in the epoxidation of racemic cis-chromenes. The second part of chapter two details the first known examples of asymmetric epoxidation upon nitrogen-protected dihydroquinoline substrates, affording enantioselectivities as high as 73% ee. In both parts of chapter two, non-aqueous epoxidation conditions were employed using Page’s dihydroisoquinolinium iminium salt catalyst. The later part of chapter two introduces a biphenylazepinium iminium salt catalyst used under aqueous epoxidation conditions. Chapter three includes experimental data for all the compounds mentioned in chapter two, with chapter four containing HPLC traces to show determination of enantiomeric excess of epoxides, and enantioenriched alkene traces. ii ACKNOWLEDGEMENTS I would like to give thanks to my supervisor Professor Philip C. B. Page for giving me the opportunity to study within his lab at the University of East Anglia. His guidance and support provided to me throughout my time here at the university have been invaluable. For technical assistance, I wish to thank Dr. Colin MacDonald at the University of East Anglia for NMR services, and the EPSRC in Swansea for running HRMS samples. I would like to thank all past and present page group members I’ve had the privilege of working alongside. Without them, days in the lab wouldn’t be the same. Past members include: Franklin Frimpong, Wei-Wei Wang, Miklos de Kiss, Chris Pearce, Christopher J. Bartlett, Matthias Menzel, Claude-Eric Roy, Ardalan Nabi, Priscilla Mendonça Matos. Current members I would like to thank include: Alexander Sheldon, Brian Mahoney, Mohammed Alahmdi, Ian Strutt, Ketan Panchal, Amy Abu Hasssan, Alix Horton. I’d like to thank our postdoctoral researcher Dr. Yohan Chan, for years of listening to my crazy ideas, giving invaluable lab advice and for generally being a top mate. Finally, I’d like to dedicate this thesis to my family; Rosemary, Edward, Martin & Emily for all their patience, love and support they have given me during this time of study. iii ABBREVIATIONS Å Ångström Ac acetyl [α]D specific optical rotation at the sodium D line aq. aqueous Ar aryl arom. aromatic B: base Bu butyl BOC tert-butyoxycarbonyl b.p. boiling point n-Bu normal butyl t-Bu tertiary butyl Bz benzoyl °C degrees Celcius cm-1 wavenumber conv. conversion CSA 10-camphorsulfonic acid δ chemical shift DDQ 2,3-dichloro-5,6-dicyano-1,4-benzoquinone DET diethyl tartrate DHPN dihydrophenylnaphthalene DHQ dihydroquinoline DIPT diisopropyl tartrate d.r. diastereomeric ratio DMAP 4-dimethylaminopyridine iv DMDO dimethyldioxirane DMF N,N-dimethylformamide DMP dimethyoxypropane E+ electrophile ee enantiomeric excess eq. equivalent(s) Et ethyl g gram(s) h hour(s) HPLC high performance liquid chromatography HRMS high resolution mass spectrometry Hz Hertz IPA iso-propyl alcohol IR infra red J coupling constant M molar mCPBA meta-chloroperbenzoic acid Me methyl MHz megaHertz min minutes(s) mmol millimole(s) mL millilitre(s) m.p. melting point MS molecular sieves NBS N-bromosuccinimide NMR nuclear magnetic resonance Nuc nucleophile v Oxone® potassium monoperoxysulfate (2KHSO5. KHSO4. K2SO4) Pd/C Palladium on carbon (10% Pd) Ph phenyl ppm parts per million pTSA para-toluenesulfonic acid i-Pr iso-propyl i-PrOH iso-propanol n-Pr normal propyl R alkyl r.t. room temperature salen salicylideneaminato ligand SM starting material TBHP tetrabutylhydrogen peroxide TEA triethylamine TFAA trifluoroacetic anhydride THF tetrahydrofuran THQ tetrahydroquinoline TLC thin layer chromatography TPPP tetraphenylphosphonium monoperoxysulfate Ts para-toluenesulfonyl vi CONTENTS TABLE CHAPTER ONE 1.0 Introduction: Epoxides.............................................................................................. 1 1.1 Natural Product Epoxides................................................................................ 4 1.2 Epoxidation Reactions..................................................................................... 5 1.2.1 Prileschajew Reaction........................................................................ 5 1.2.2 Sharpless Asymmetric Epoxidation................................................... 6 1.2.3 Jacobsen-Katsuki Epoxidation........................................................... 9 1.3 Organocatalysis................................................................................................ 14 1.4 Non-Metal Catalysed Epoxidations................................................................. 16 1.4.1 Ketone Catalysed Epoxidations......................................................... 16 1.4.2 Curci’s Ketones: The First Examples of Ketone Based Asymmetric Epoxidation....................................................................................................... 18 1.4.3 Yang’s Ketone-Based Epoxidations................................................... 19 1.4.4 Shi’s Fructose Ketone Epoxidations................................................... 24 1.4.5 Armstrong’s Tropinone-Catalysed Epoxidations................................ 31 1.4.6 Denmark’s Ketone-Catalysed Epoxidations....................................... 33 1.4.7 Oxaziridine Mediated Epoxidations................................................... 34 1.4.8 Aggarwal’s Amine-Catalysed Epoxidations....................................... 36 1.4.9 Yang’s Amine-Catalysed Epoxidations.............................................. 36 1.4.10 Page & Lacour’s Amine-Catalysed Epoxidations.............................. 37 1.4.11 Oxaziridinium Salt-Catalysed Epoxidations...................................... 37 1.4.12 Aggarwal’s Chiral Binaphthalene Azepinium Salt Catalyst............... 41 vii 1.4.13 Armstrong’s Exocyclic Iminium Salts............................................... 42 1.4.14 Yang’s Chiral Iminium Salts.............................................................. 42 1.4.15 Lacour’s TRISPHAT Counter Ions.................................................... 43 1.4.16 Page’s Iminium Salt-catalyzed Epoxidations..................................... 45 1.4.17 Analysis of the Reaction Parameters................................................. 47 1.4.17.1 Effect of Counter-Ion................................................................ 48 1.4.17.2 Effect of Solvent System........................................................... 48 1.4.17.3 Effect of Temperature................................................................ 49 1.4.17.4 Effect of Catalyst Loading......................................................... 50 1.4.18 Page’s Alcohol, Ether and Acetal Derived Dihydroisoquinolinium Salts.............................................................................................................. 50 1.4.18.1 Page’s Iminium Salts Derived From Chiral 1,2-Amino Alcohol Precursors Containing A Primary Hydroxyl Group...................................... 51 1.4.18.2 Page’s Iminium Salts From Chiral 1,2-Amino Alcohol Precursors Containing A Secondary Hydroxyl Group................................................... 52 1.4.18.3 Page’s Iminium Salts from Amino Ether Precursors..................................................................................................... 52 1.4.18.4 Page’s Iminium Salts from Amino Acetal Precursors..................................................................................................... 53 1.4.19 Variation of the Oxidant.................................................................... 55 1.4.19.1 Tetraphenylphosphonium Monoperoxysulfate......................... 55 1.4.19.2 Electrochemical Generation of Persulfate................................ 56 1.4.19.3 Utilization of Hydrogen Peroxide as an Oxidant..................... 57 viii 1.4.19.4 Utilization of Sodium Hypochlorite as an Oxidant.................. 57 1.5 Kinetic Resolution............................................................................................ 58 1.5.1 Alternative Resolution Methods......................................................... 60 1.5.2 Kinetic Resolution of Racemic Alkenes Using Catalytic Asymmetric Epoxidation.....................................................................................................