PART Ⅰ: DEVELOPMENT OF DIRECT ASYMMETRIC ALDOL REACTIONS MEDIATED BY PRIMARY AMINO ACID-DERIVED ORGANOCATALYSTS PART Ⅱ: EXPLORING DNA-CLEAVING ACTIVITIES OF VARACIN B AND VARACIN C JIANG ZHAOQIN NATIONAL UNIVERSITY OF SINGAPORE 2009 PART Ⅰ: DEVELOPMENT OF DIRECT ASYMMETRIC ALDOL REACTIONS MEDIATED BY PRIMARY AMINO ACID-DERIVED ORGANOCATALYSTS PART Ⅱ: EXPLORING DNA-CLEAVING ACTIVITIES OF VARACIN B AND VARACIN C JIANG ZHAOQIN (M.Sc., Soochow Univ.) A THESIS SUBMITTED FOR THE DEGREE OF DOCTOR OF PHILOSOPHY OF SCIENCE DEPARTMENT OF CHEMISTRY NATIONAL UNIVERSITY OF SINGAPORE 2009 PhD Thesis Jiang Zhaoqin Acknowledgements I would like to express my wholehearted gratitude to my supervisor, Dr Lu Yixin for his profound knowledge, invaluable guidance, constant support, inspiration and encouragement throughout my graduate studies He is not only an extraordinary supervisor, a complete mentor, but a truly friend The knowledge, both scientific and otherwise, that I accumulated under his supervision, will aid me greatly throughout my life I am deeply grateful to our collaborators, Prof Li Tianhu and his group members from our Department of Chemistry, NTU, for their assistance in the biological tests of our synthetic compounds I also wish to thank Prof Wong Ming Wah and his group members from Department of Chemistry, NUS, for their computational calculations of our experimental findings I also give my sincere thanks to my colleagues: Choo En, Liang Zhian, Dr Wu Xiaoyu, Dr Cheng Lili, Dr Xu Liwen, Dr Wang Youqing, Dr Yuan Qing, Han Xiao, Zhu Qiang, Luo Jie and other labmates for their cordiality and friendship I wish to express my deepest appreciation to my family and my husband for their love and support Without their help, I can not complete this work I want to express my appreciation to the members of instruments test in NMR, Mass Lab They gave me too much help for my research work Last but not least, my acknowledgement goes to National University of Singapore for the research scholarship and the financial support -i- PhD Thesis Jiang Zhaoqin Table of Contents Acknowledgements i Table of Contents ii Summary ix List of Tables xi List of Schemes xiii List of Figures xv List of Abbreviations xvi List of Publications xix PART Ⅰ: DEVELOPMENT OF DIRECT ASYMMETRIC ALDOL R E A C T I O N S M E D I AT E D B Y P R I M A R Y A M I N O ACID-DERIVED ORGANOCATALYSTS Chapter Introduction and Literature Survey 1.1 Asymmetric Synthesis 1.2 Asymmetric Organocatalysis 1.2.1 Introduction 1.2.2 Enamine Catalysis and Iminium Catalysis 1.3 Direct Asymmetric Aldol Reactions Catalyzed by L-Proline and its Derivatives 1.3.1 Direct Asymmetric Aldol Reactions Catalyzed by L-Proline 1.3.1.1 Introduction 1.3.1.2 Intramolecular Aldol Reactions - ii - PhD Thesis Jiang Zhaoqin 1.3.1.3 Intermolecular Aldol Reactions 1.3.2 Direct Asymmetric Aldol Reactions Catalyzed by L-Proline Derivatives 10 12 1.4 Direct Asymmetric Aldol Reactions Catalyzed by Primary Amino Acids and their Derivatives as Organocatalysts 15 1.4.1 Primary versus Secondary Amino Acids in Intermolecular Aldol Reactions: Mechanistic Considerations 15 1.4.2 Intramolecular Aldol Reactions 17 1.4.3 Intermolecular Aldol Reactions 18 1.5 Organocatalytic Reactions in Aqueous Media 21 1.6 Objectives of Research 24 Chapter Direct Asymmetric Aldol Reactions Catalyzed by L-Tryptophan and its Derivatives in the Presence of Water 28 2.1 Introduction 28 2.2 Organocatalysts Based on Primary Amino Acids 30 2.2.1 Selection of Organocatalysts 30 2.2.2 Catalyst Preparation 31 2.3 Results and Discussion 32 2.3.1 Aldol Reaction Catalyzed by Primary Amino Acids and Tryptophan Analogues 2.3.1.1 Investigation of the Reaction Parameters 2.3.1.1.1 Effects of Different Catalysts 32 32 32 - iii - PhD Thesis Jiang Zhaoqin 2.3.1.1.2 Effects of Different Solvents 34 2.3.1.1.3 Effects of Water 36 2.3.1.1.4 Substrate Ratio and Catalyst Loading 37 2.3.1.2 Scope of Substrates 39 2.3.1.2.1 Various Ketones as Donor 39 2.3.1.2.2 Aldehyde Acceptors 42 2.3.1.3 Theoretical Calculations and Proposed Mechanism 45 2.3.2 Exploration of Reaction Pathway for Tryptophan-Catalysed Aldol Reactions in Aqueous Media 52 2.3.2.1 Aldol Reactions Catalyzed by Tryptophan with Various ee Values 54 2.3.2.2 The Mass and ee Distribution of Tryptophan in Different Phases 56 2.3.2.3 Formation of Enamine Intermediate in Water 57 2.3.2.4 The Influences of the Tryptophan-Catalysed Aldol Reactions in the Mixture of Surfactant Sodium Dodecyl Sulfate and Water 59 2.4 Conclusion 60 2.5 Experimental Section 61 2.5.1 Experimental Materials and General Methods 61 2.5.2 Representative Experiment for Aldol Reaction 63 2.5.3 Synthesis and Characterization of Substrate 64 2.5.4 Synthesis and Characterization of Tryptophan Derivatives 65 2.5.5 Characterization of Aldol Products 69 - iv - PhD Thesis Jiang Zhaoqin Chapter High Efficient Threonine-Derived Organocatalysts for Direct Asymmetric Aldol Reactions in the Presence of Water 83 3.1 Introduction 83 3.2 Synthesis of Catalysts 84 3.2.1 Catalyst Design 84 3.2.2 Catalyst Preparation 85 3.3 Results and Discussion 3.3.1 The Aldol Reactions of Cyclohexanone 87 87 3.3.1.1 Catalyst Screening 87 3.3.1.2 Aldehyde Acceptors 90 3.3.1.3 The Practical Synthetic Value of 3-1a-Catalysed Aldol Reaction 91 3.3.2 The Aldol Reaction of Functional Hydroxyacetones 92 3.3.2.1 Catalyst Screening 92 3.3.2.2 Effects of Catalyst Loading 94 3.3.2.3 Effects of Water 95 3.3.2.4 Derivatization of Hydroxyacetone 96 3.3.2.5 Aldehyde Acceptors 98 3.3.3 Synthesis of Chiral 1,2-Diols 101 3.3.4 Effects of Catalysts with Different ee Values 102 3.3.5 Proposed Mechanism and Transition State 105 3.4 Conclusion 106 3.5 Experimental Section 106 -v- PhD Thesis Jiang Zhaoqin 3.5.1 Experimental Materials and General Methods 106 3.5.2 Catalysts Synthesis and Characterization 107 3.5.3 Synthesis and Characterization of Functional Hydroxyacetones 122 3.5.4 Experimental Procedure for the Aldol Reactions 124 3.5.5 Characterization of Aldol Products 126 Chapter Direct Asymmetric Aldol Reactions of Acetone with α-Keto Esters Catalyzed by Primary-Tertiary Diamine Organocatalyst 139 4.1 Introduction 139 4.2 Primary-Tertiary Amine Catalysts Derived from Natural Amino Acids 140 4.2.1 Catalyst Design 140 4.2.2 Synthesis of Catalysts 141 4.3 Results and Discussion 143 4.3.1 Catalyst Screening 143 4.3.2 Additives 144 4.3.3 Effects of Solvents 145 4.3.4 Scope of Substrates 146 4.3.5 Preparation of Chiral Lactones with Adjacent Quaternary Centers 149 4.4 Conclusion 150 4.5 Experimental Section 151 4.5.1 Experimental Materials and General Methods 151 4.5.2 Catalyst Synthesis and Characterization 151 - vi - PhD Thesis Jiang Zhaoqin 4.5.3 Synthesis and Characterization of Reaction Substrates 171 4.5.4 Experimental Procedure for the Aldol Reaction 180 4.5.5 Characterization of Aldol Products 180 4.5.6 Synthesis and Characterization of Chiral Lactones 190 PART II: EXPLORING DNA-CLEAVING ACTIVITIES OF VARACIN B AND VARACIN C 192 Chapter Synthesis, Characterization and DNA-Cleaving Activities of Varacin B and Varacin C 192 5.1 Introduction 192 5.1.1 Varacin Family 192 5.1.2 Varacin B and Varacin C 193 5.1.3 Project Objectives 194 5.2 Results and Discussion 195 5.2.1 Preparation of Varacin B and Varacin C 195 5.2.1.1 Synthetic Route of Varacin B and Varacin C 195 5.2.1.2 UV-Induced Isomerization 197 5.2.1.3 Optimization of UV Irradiated Isomerization 198 5.2.1.3.1 Effects of UV Wavelengths 199 5.2.1.3.2 Effects of Various Solvents 200 5.2.2 DNA-Cleaving Activities of Varacin B and Varacin C 5.2.2.1 Acid-Promoted DNA-Cleaving Activities of Varacin B 201 202 - vii - PhD Thesis Jiang Zhaoqin 5.2.2.2 Photo-Induced DNA-Cleaving Activities of Varacin B and Varacin C 205 5.3 Conclusion 206 5.4 Experimental Section 207 5.4.1 Experimental Materials and General Methods 207 5.4.2 Synthesis and Characterization of Intermediates, Varacin B and Varacin C 209 Chapter References Appendix: 1H NMR, 13 216 C NMR, HPLC Data of Some Selected Examples I - viii - PhD Thesis Jiang Zhaoqin Compound 3-19a O OH OTBS NO2 -V- PhD Thesis Jiang Zhaoqin - VI - PhD Thesis Jiang Zhaoqin Compound 3-19c O OH NO2 OTBS - VII - PhD Thesis Jiang Zhaoqin - VIII - PhD Thesis Jiang Zhaoqin Compound 3-19n O OH OTBS - IX - PhD Thesis Jiang Zhaoqin -X- PhD Thesis Jiang Zhaoqin Compound 4-1c N OH Ph Ph NH2 - XI - PhD Thesis Jiang Zhaoqin Compound 4-18a O COOCH3 OH - XII - PhD Thesis Jiang Zhaoqin - XIII - PhD Thesis Jiang Zhaoqin Compound 4-23 O COOCH3 O2N - XIV - PhD Thesis Jiang Zhaoqin 10 Compound 4-23a O COOCH3 OH NO2 - XV - PhD Thesis Jiang Zhaoqin - XVI - PhD Thesis Jiang Zhaoqin 11 Compound 4-29 O H O OH NO2 H 3C - XVII - PhD Thesis Jiang Zhaoqin 12 Compound 5-11b O S H3CO H3CO S S NH3+TFA- - XVIII - PhD Thesis Jiang Zhaoqin 13 Compound 5-11c S H3CO H3CO S S O NH3+TFA- - XIX - ...PART Ⅰ: DEVELOPMENT OF DIRECT ASYMMETRIC ALDOL REACTIONS MEDIATED BY PRIMARY AMINO ACID- DERIVED ORGANOCATALYSTS PART Ⅱ: EXPLORING DNA- CLEAVING ACTIVITIES OF VARACIN B AND VARACIN C JIANG ZHAOQIN... 2-hydroxy-γ-butyrolactones 150 Scheme 5-1 Structures of varacin, varacin A, varacin B and varacin C 193 Scheme 5-2 Proposed mechanism of DNA cleavage by varacin C 194 Scheme 5-3 Synthesis of varacin B and. .. molybdate CAN ceric ammonium nitrate Cbz benzyloxycarbonyl C- C bond carbon-carbon bond CMC critical micelle concentration D-A reaction Diels-Alder reaction DCC Dicyclohexyl carbodiimide DCM dichloromethane