View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by University of East Anglia digital repository Asymmetric Epoxidation of Enol Ethers and Esters Using Iminium Salt Catalysts Synthesis of α-Hydroxy- Carbonyls By Saud Muslih Almutairi A thesis submitted is partial fulfilment of the requirements for the degree of Doctor of Philosophy School of Chemistry University of East Anglia United Kingdom 2017 I DECLARATION This thesis is submitted to the University of East Anglia for the Degree of Doctor of Philosophy and has not been previously submitted at this or any university for assessment. This work is original and has been carried out by the author alone. Saud Muslih Almutairi II Abstract Asymmetric Epoxidation of Enol Ethers and Esters Using Iminium Salt Catalysts Synthesis of α-Hydroxy-Carbonyls Iminium salt organocatalysts can provide high selectivity and high efficiency in catalytic asymmetric epoxidation. Enantiomerically-enriched epoxides are useful intermediates that have found many applications in asymmetric synthesis, and development of efficient catalysts for asymmetric epoxidation has received considerable attention. In this manuscript, we describe the preparation, and use of highly selective iminium salt organocatalysts for asymmetric epoxidation. The new catalysts have been tested in the catalytic asymmetric oxidation of enols, and provide up to 98% ee. Also we tried to synthesize tatarinoid B 74 which used for the treatment of central nervous system diseases in traditional Chinese medicine. O O OH OH R R R R Catalyst O 4 or 7 or 9 O OR OR R R R R (HSO5) O R O R O O R P R R R O R O R R R R R N * N * R R O O N * N * R R OOSO OOSO N 3 3 * N * R - - O 2 SO 2 OR SO4 4 III Acknowledgements During my studies, there are a few people I would like to acknowledge. Firstly, I would like to thank Professor P.C. Bulman Page, for allowing me to work in his laboratory. Secondly, I wish to thank Dr. Yohan Chan for guiding me in my work and giving me advice during my project. I would like to thank all past and present page group members. I like to thank the Head of Environment department at King Abdulaziz City for Science and Technology Dr. Badr Alharbi. I would like to give thanks to my best friends Dr. Mouslim Messali and Dr. Ateyat allah for their support during my life. Finally, I would like to thank my family for supporting me during my studies at UEA, these include my father, my mother Rhma, my love Mashael, my son Albaraa, my daughter Aya, my brother Naif, my sisters Nouf and Nora. IV ABBREVIATIONS Ac acetyl Ac2O acetic anhydride [α]D specific optical rotation at the sodium D line aq. aqueous Ar aryl Arom. Aromatic AIBN azobis(isobutyronitrile) B: base n-BuLi n-Butyl lithium (in hexanes, 2.5 M) b.p. boiling point n-Bu normal butyl t-Bu tertiary butyl t-BuOH tert-butanol Bz benzoyl °C degrees Celcius CDCl3 deuterated chloroform conv. conversion CSA 10-camphorsulfonic acid δ chemical shift DET diethyl tartrate DHQ dihydroquinoline DMAP 4-dimethylaminopyridine DMF N,N-dimethylformamide DMP dimethyoxypropane V E+ electrophile ee enantiomeric excess eq. equivalent(s) Et ethyl Et3N triethylamine EtOAc ethyl acetate EtOH ethanol g gram(s) h hour(s) H2 hydrogen gas HPLC high performance liquid chromatography Hz hertz IR infra red J coupling constant M molar m-CpBA meta-chloroperbenzoic acid Me methyl MeOH methanol MHz megaHertz min minutes(s) mmol millimole(s) mL millilitre(s) m.p. melting point NBS N-bromosuccinamide NMR nuclear magnetic resonance Nuc nucleophile VI sat. saturated Oxone potassium monoperoxysulfate Ph phenyl ppm parts per million pTSA para-toluenesulfonic acid i-Pr iso-propyl i-PrOH isopropanol n-Pr normal propyl R alkyl r.t. room temperature SM starting material TEA triethylamine TFAA trifluoroacetic anhydride THF tetrahydrofuran TLC thin layer chromatography TPPP tetraphenylphosphonium monoperoxysulfate Ts para-toluenesulfonyl VII CONTENTS CHAPTER ONE 1.0 Introduction: Chirality............................................................................................ 1 1.1 Chirality in our life.................................................................................................. 3 1.2 Asymmetric synthesis.............................................................................................. 3 1.3 Chiral auxiliaries...................................................................................................... 4 1.4 Asymmetric catalysis............................................................................................... 6 1.5 Epoxides................................................................................................................... 6 1.5.1 Epoxides in natural products.................................................................................... 7 1.6 Epoxidation Reactions............................................................................................. 8 1.6.1 Prilezhaev Reaction................................................................................................. 8 16.2 Sharpless Asymmetric Epoxidation........................................................................ 9 16.3 Jacobsen-Katsuki Epoxidation.................................................................................10 1.7 Asymmetric Epoxidation of Silyl Enol Ethers and Enol Esters............................. 14 1.7.1 Rubottom Reaction .................................................................................................14 1.7.2 Shi Asymmetric Epoxidation.................................................................................. 15 1.8 Organocatalysis........................................................................................................16 1.8.1 Davis Oxaziridine - Mediated Epoxidations........................................................... 17 1.8.2 Lusinchi and Bohé’s Initial Studies........................................................................ 18 1.8.3 Aggarwal’s Chiral Binaphthalene Azepinium Salt Catalyst................................... 21 1.8.4 Armstrong’s Catalysts............................................................................................. 22 1.8.5 Yang’s Chiral Iminium Salt.................................................................................... 23 1.8.6 Page’s Studies........................................................................................................ 23 1.8.6.1 Page’s catalysts conditions.................................................................................... 27 1.8.6.2 Effect of the solvent.............................................................................................. 27 1.8.6.3 Effect of temperature............................................................................................ 28 1.8.6.4 Effect of Counter-Ion............................................................................................ 28 1.8.6.5 Effect of catalyst loading...................................................................................... 29 1.8.6.6 Page’s Catalysts from Chiral 1,2-Amino Alcohol Precursors Containing a Primary Hydroxyl Group................................................................................................................. 30 VIII 1.8.6.7 Page’s Catalysts From Chiral 1,2-Amino Alcohol Precursors Containing A Secondary Hydroxyl Group................................................................................................ 31 1.8.6.8 Page’s Catalysts from Amino Ether Precursors.................................................... 31 1.8.6.9 Page’s Catalysts from Amino Acetal Precursors.................................................. 32 1.8.6.10 Tetraphenylphosphonium Monoperoxysulfate.................................................... 33 1.9 Conclusions............................................................................................................... 33 1.10 Introduction references...............................................................................................35 CHAPTER TWO 2.0 RESULTS AND DISCUSSION........................................................................................ 39 2.1 Synthesis of catalysts................................................................................................. 45 2.1.1 Synthesis of Dihydroisoquinolinium Salt Catalyst 4.............................................. 46 2.1.2 Synthesis of biphenyl iminium salt catalyst 7........................................................ 49 2.1.3 Synthesis of binaphthalene iminium salt catalyst 9............................................... 51 2.2 Synthesis of Tetraphenylphosphonium Monoperoxysulphate 11 (TPPP)……..….. 54 2.3 Synthesis and epoxidation of the enol ethers and esters........................................... 54 2.3.1 Synthesis and epoxidation of enol ethers………………………………………... 55 2.3.1.1 Synthesis of (3,4-(dihydronaphthalen-1-yl)oxy)triisopropylsilane 22...…….... 55 2.3.1.2 Synthesis of 2,2-dimethyl-2H-chromen-4-yl)oxy)triisopropylsilane 16............ 57 2.3.1.3 Synthesis of tert-butyl (3,4-dihydronaphthalen-1-yl)oxy) diphenylsilane 18…. 59 2.3.2 Synthesis and epoxidation of enol esters............................................................... 60 2.3.2.1 Synthesis of 3,4-dihydronaphthalen-1-yl acetate 19………………………...... 60 2.3.2.2 Synthesis of 3,4-dihydronaphthalen-1-yl diethyl phosphate 14......................... 63 2.3.2.3 Synthesis of 3,4-dihydronaphthalen-1-yl 2,2,2-trifluoroacetate 12 ................ 65 2.3.2.4 Synthesis