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New Green Technologies for Organocatalytic Asymmetric Epoxidation Applications in Synthesis

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New Green Technologies for Organocatalytic Asymmetric Epoxidation Applications in Synthesis NEW GREEN TECHNOLOGIES FOR ORGANOCATALYTIC ASYMMETRIC EPOXIDATION APPLICATIONS IN SYNTHESIS Noor Armylisas Binti Abu Hassan Submitted in partial fulfillment for the requirements for the award of Doctor of Philosophy University of East Anglia School of Chemistry University of East Anglia March 2014 ©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 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 or for any other degree. Except where stated, and reference and acknowledgement is given, this work is original and has been carried out by the author alone. NOOR ARMYLISAS BINTI ABU HASSAN ii ABSTRACT New Green Technologies for Organocatalytic Asymmetric Epoxidation Applications in Synthesis Noor Armylisas Binti Abu Hassan This thesis describes the application of asymmetric epoxidation reactions on chromene substrates mediated by Page’s iminium salt catalysts. Organocatalytic asymmetric epoxidation is an efficient tool to access enantiomerically rich epoxides. This study is divided into three main parts which are discussed in each chapter. The first part of this research is the preparation of iminium salt catalysts followed by synthesis of several chromene substrates. The final part is the application of the asymmetric epoxidation of the readily prepared iminium salts on chromene substrates. The first chapter reviews brief introduction and historical background of organocatalysis, chromene substrates and asymmetric epoxidation reactions. Towards the end of the chapter, several examples are described of past and current development of asymmetric epoxidation by organocatalysts. In the last part of Chapter 1, the discussion focuses on asymmetric epoxidation on chromene substrates. Chapter 2 discusses the preparation of Page’s iminium salts and improvement of previous methods followed by several approaches to synthesis of chromene substrates. The final part is discussing application of asymmetric epoxidation using synthesized iminium salts on the chromene substrates. Excellent enantioselectivities were observed in nonaqueous condition using TPPP as oxidant for 6-cyano-2,2’-dimethylchromene giving ee >99% while reactions under aqueous conditions afforded the corresponding diol giving ees as high as 71%. In Chapter 3, experimental procedures and data for all the compounds synthesized are included. Appendices contain HPLC trace data, NMR and IR data of several compounds. iii Acknowledgements Firstly thank you Allah, Alhamdulillah for this blessing and the chance YOU gave me. I am very grateful and will always be for everything I’ve received throughout my life. I would like to extend my sincere gratitude to my supervisor Professor Philip Bulman Page for giving me the wonderful opportunity to come to Norwich and conducting my PhD research under his instruction at University of East Anglia. The guidance, support, patience and repeated explanations were invaluable. Also, I would like to thank Dr. Yohan Chan for being there in the lab, giving advice and teaching me the chemistry, fixing the HPLC. Thanks Yo! To my second supervisor, Dr. Chris Richards and all the lecturers in Organic Chemistry Department, UEA, I am indebted for all the lessons and help I got for the past three and half years. I would like also to thank past members; Dr. Wei-Wei Wang and Miklos de Kiss – the lovely couple who helping me going through my first year in the lab, zillion thanks to Dr. David Day – patiently answering my epoxidation and mechanism questions, willingly scanning through my thesis and helped me with my poor English, Brian Mahoney – the one who is always having fun in the lab, Dr. Chris Bartlett, Dr. Chris Pearce, Priscilla Mendonca, Ian Strutt, Tara Dixon, unforgettable and cheerful guy Franklin Frimpong – RIP. All the present members of Page’s group, especially go to Cristina Macarov for always trying to cheer me up, Mohammed – who always sharing the papers he found, Francesca Kinsey, James Harvey, Saud for all the fun and banter along the way. To all Malaysian fellows in Norwich who had been with me throughout my PhD study years – Cik Umi, kak Yana and family, thanks for accepting me in your lovely home, all my sisters I met here in Norwich especially Dr. Sharifah, for showing me the fun living in England, kak Suriyani, kak Widad and abang Rizal, Dr. Anis Shobirin and family, and also all other families. I would like to also show my appreciation to Dr. Sam Chan, Leong Ka-Hui, Elmie Abu Bakar, Amirul, Diba Rinol, Sara Syahrain, and all the other Malaysians I’ve known all iv these years. Special thanks to kak Laili and family for taking care of me, cooked for me and gave me advice in so many things in life. To my wonderful family, I couldn’t have completed my PhD without you all. You are everything to me. Special thanks to my parents, Azizah binti Long and Abu Hassan bin Mahmad. Your encouragement and love has gotten me through all the difficult times and I am so grateful for the non-stop support and life-guidance from both of you. Thank you for always telling me I could achieve whatever I want to do in life. This whole thesis is dedicated to both of you. To all my beloved sisters – Azians, Noor Hassliza’s, Noor Azleen’s, Noorulakmar Fakhiah, my brothers – Noorkamarul Hairuls, Noor Azlizan’s, my little brother – Noor Hazerul Hisyam’s, sister-in-laws and brother-in-laws – thanks for all the support you showed from preparing all the needs for me to start studying overseas, sending me off to England, picking me up from the airport, the advice and love had all gave me strength to keep my study going. I love you all. I strongly believe I wouldn’t be able to finish my PhD successfully without everyone I mentioned above and everyone around me that I missed out here. The loss of two treasures in my life; my “Tok Wan” in 2012 and my 3-day-old little niece whom I couldn’t even meet on 21st February 2014; Fiqah Alaisya binti Ahmad Izwan. Words cannot even begin the sorrow but my prayers will always be with you. v Abbreviation Ac acetyl Ac2O acetic anhydride AcOH acetic acid AIBN azobis(isobutyronitrile) ANDA abbreviated new drug application aq aqueous Ar argon gas - BPh4 tetraphenylborate ion Bz benzoyl BzCl benzoyl chloride CSA camphorsulfonic acid DBU 1, 8-diazabicycloundec-7-ene DCM dichloromethane DDQ 2, 3-dichloro-5, 6-dicyanobenzoquinone DET diethyl tartrate DIPT diisopropyl tartrate DMAP (N,N)-dimethylaminopyridine DMDO dimethyldioxirane DNA deoxyribonucleic acid ee enantiomeric excess equiv equivalent vi er enantiomeric ratio Et2O diethyl ether EtOAc ethyl acetate EtOH ethanol g gram(s) GC gas chromatography h hour(s) HPLC high performance liquid chromatography Hz Hertz IUPAC International Union of Pure and Applied Chemistry IVIVC in-vitro and in vivo correlation J coupling constant KR kinetic resolution M molar m-CPBA meta-chloroperoxybenzoic acid MeCN acetonitrile MeOH methanol MHz mega hertz mL millilitre mmol milimol MsCl mesyl chloride NaBPh4 sodium tetraphenylborate NaOMe sodium methoxide vii NBS N-bromosuccinimide NDA new drug application NMR nuclear magnetic resonance o- ortho- p- para- p-TsOH para-toluenesulfonic acid PhB(OH)2 phenylboronic acid PMC 2,2,5,7,8-pentamethyl-6-hydroxychroman RBF round bottom flask rt room temperature SUPAC scale-up and post-approval changes TBARS thiobarbituric acid-reactive substance TBS tert-butyldimethylsilyl TBHP tert-butyl hydroperoxide TEA triethylamine TFA trifluoroacetic acid TFAA trifluoroacetic anhydride THF tetrahydrofuran Ti titanium Ti (O-i-Pr)4 titanium tetra-isopropoxide TLC thin layer chromatography TMHQ trimethylhydroquinone TMS tetramethylsilane viii TPPP tetraphenylphosphonium monoperoxysulfate TRF tocotrienol-rich-fraction ix Table of Contents CHAPTER 1 INTRODUCTION........................................................................................ 1 1.1 Green Technologies and Green Chemistry........................................... 1 1.2 Organocatalysis........................................................................................ 1 1.2.1 Asymmetric Organocatalysis....................................................... 4 1.2.1.1 Historical Background of Asymmetric Organocatalysis.............................................................. 4 1.2.2 Advantages of Organocatalytic Research.................................... 9 1.2.3 Iminium Salts as Organocatalysts in Asymmetric Epoxidation................................................................................ 11 1.2.3.1 Introduction to Iminium Catalysis.................................. 11 1.2.3.2 Historical Development of Iminium Catalysis................. 11 1.2.3.3 Chiral Iminium Salt-Catalysed Epoxidation..................... 14 1.3 Chromene Substrates............................................................................... 21 1.3.1 2H-Chromenes (2H-1-Benzopyrans)............................................ 21 1.3.2 Properties of 2H-Chromene Compounds and Their Derivatives................................................................................... 22 1.3.2.1 Biological Activities......................................................... 22 1.3.2.2 Photochromism.............................................................. 26 1.3.3 Syntheses
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