Direct asymmetric vinylogous reactions of furanones and phthalide derivatives with bifunctional and trifunctional organocatalysts

Direct Asymmetric Vinylogous Reactions of Furanones and Phthalide Derivatives with Bifunctional and Trifunctional Organocatalysts Luo Jie NATIONAL UNIVERSITY OF SINGAPORE 2011 Direct Asymmetric Vinylogous Reactions of Furanones and Phthalide Derivatives with Bifunctional and Trifunctional Organocatalysts Luo Jie (BSc, Zhejiang Univ.) A THESIS SUBMITTED FOR THE DEGREE OF DOCTOR OF PHILOSOPHY DEPARTMENT OF CHEMISTRY NATIONAL UNIVERSITY OF SINGAPORE 2011 Acknowledgements I would like to express my deep and sincere gratitude to people who have helped and inspired me during my Ph.D studies in the Department of Chemistry, National University of Singapore (NUS). This thesis would not have been possible without their firm support. Foremost, I would like to thank my supervisor A/P Lu Yixin for offering me the opportunity to study in NUS and giving me continuous support during my Ph.D study and research. His patience, motivation, enthusiasm, and immense knowledge have been of great value for me. He is not only an extraordinary supervisor, a complete mentor, but a truly friend. I could not have imagined having a better advisor and mentor for my Ph.D study. Besides my advisor, I am deeply grateful to our collaborators, Prof. Huang KuoWei from KAUST Catalysis Center (KCC) & Division of Chemical and Life Sciences and Engineering, Kingdom of Saudi Arabia, and Prof. Xu Li-Wen from Hangzhou Normal University for their kind assistance in the computational calculations and experimental support. I would also like to thank my colleagues: Dr. Animesh Ghosh, Dr. Wu Xiaoyu, Dr Wang Youqing, Dr Yuan Qing, Dr Xie Xiaoan, Dr Wang Haifei, Dr Cheng Lili, Dr Jiang Zhaoqin, Dr Wang Suxi, Han Xiao, Liu Xiaoqian, Chen Guoying, Zhu Qiang, Han Xiaoyu, Liu Chen, Zhong Fangrui, Dou Xiaowei, Jacek Kwiatkowski, Liu Guannan, Jiang Chunhui and other labmates. They had helped me a lot not only in chemistry but also in life. I also want to express my appreciation to the members of instruments tests in NMR, Mass lab. They gave me too much help during my research work. Last but not least, I would like to give my deepest appreciation to my family for their love and support throughout my studies. Without their help, I cannot complete this work. Table of Contents Summary List of Tables List of Schemes List of Figures List of Abbreviations List of Publications Chapter Introduction 1.1 1.2 Asymmetric organocatalysis 1.1.1 Introduction 1.1.2 Historical background of organocatalysis Chiral hydrogen-bonding based organocatalysis 1.2.1 Chiral monofunctional organocatalysis 1.2.1.1 Hydroxy-containing organocatalysts 1.2.1.2 Monofunctional urea and thiourea-based catalysts 1.2.2 1.2.3 1.3 13 Chiral bifunctional organocatalysis 18 1.2.2.1 Bifunctional urea and thiourea-based catalysts 18 1.2.2.2 Guandines 27 1.2.2.3 Chiral phosphoric acids 29 1.2.2.4 Other examples 34 Chiral multifunctional organocatalysis 36 Project objectives 38 Chapter Direct Asymmetric Vinylogous Aldol Reaction of Furanones with αKetoesters: Access to Chiral γ-Butenolides and Glycerol Derivatives 2.1 Introduction 41 2.2 Results and discussion 43 2.2.1 Reaction optimization 43 2.2.2 Substrate scope 47 2.2.3 Plausible reaction mechanisms 49 2.2.4 50 Synthetic manipulations of the vinylogous aldol adduct 2.3 Conclusions 52 2.4 Experimental section 53 2.4.1 General information 53 2.4.2 Representative procedure 54 2.4.3 X-ray cryatllographic analysis of 2-14f 55 2.4.4 Derivatizations of the vinylogous aldol adducts 57 2.4.4.1 Preparation of lactone 57 2.4.4.2 Preparation of glycerol derivatives 60 2.4.4.3 Preparation of antifungal agent 62 2.4.5 Analytical data of products 66 Chapter Direct Asymmetric Vinylogous Mannich-Type Reaction of Phthalide Derivatives: Facile Access to Chiral Substituted Isoquinolines and Isoquinolinones 3.1 Introduction 82 3.2 Results and discussion 85 3.2.1 Reaction optimization 85 3.2.2 Substrate scope 88 3.2.3 90 Plausible trasition-state model 3.2.4 Large scale synthesis of the vinylogous mannich adduct 91 3.2.5 Chiral isoquinoline and isoquinolinone synthesis 92 3.3 Conclusions 93 3.4 Experimental section 94 3.4.1 General information 94 3.4.2 Preparaton of phthalide derivatives 95 3.4.3 Representative procedure of the vinylogous mannich reaction 98 3.4.4 Synthetic manipulations 99 3.4.5 Experimental procedure of large scale synthesis 102 3.4.6 Analytical data of vinylogous mannich adducts 103 Chapter Highly Diastereoselective and Enantioselective Direct Vinylogous Michael Addition of Phthalide Derivatives 4.1 Introduction 118 4.2 Vinylogous Michael addition to nitrolefins 120 4.2.1 Reaction optimization 120 4.2.2 Substrate scope 122 4.2.3 Synthetic manipulations 124 4.2.4 Conclusions 124 4.3 Vinylogous Michael addition to chalcones 125 4.3.1 Reaction optimization 4.4 125 4.3.1.1 Iminium activation 125 4.3.1.2 Base catalyzed method 126 4.3.2 Substrate scope 129 4.3.3 130 Conclusions Experimental section 131 4.4.1 Vinylogous addition to nitroolefins 131 4.4.2 4.4.1.1 General information 131 4.4.1.2 Representative procedure 132 4.4.1.3 X-ray cryatllographic analysis of 4-3f 133 4.4.1.4 Synthetic manipulations 135 4.4.1.5 Analytical data of products 138 Vinylogous Michael addition to chalcones 153 4.4.2.1 General information 153 4.4.2.2 Representative procedure 154 4.4.2.3 X-ray cryatllographic analysis of 4-7b 155 4.4.2.4 Analytical data of products 157 Annex: Asymmetric Michael Addition Mediated by Novel Cinchona AlkaloidDerived Bifunctional Catalysts Containing Sulfonamides 5.1 Introduction 170 5.2 Results and discussion 172 5.2.1 172 Catalyst design 5.2.2 Reaction optimization 5.2.2.1 Catalyst screening 173 5.2.2.2 175 Solvent screening 5.2.2.3 Other donors tested 5.3 Reference Appendix 173 176 5.2.3 Substrate scope 177 5.2.4 Proposed transition model 179 5.2.5 179 Conclusions Experimental section 181 5.3.1. General information 181 5.3.2. Preparation of cinchona alkaloid-derived catalysts 182 5.3.3. Representative procedure 184 5.3.4. Analytical data of Michael adducts 185 201 Summary This thesis describes the development of direct enantioselective vinylogous reaction of furanones and phthalide derivatives with bifunctional and trifunctional organocatalysis. Chapter presents a brief historical background and development of asymmetric organocatalysis. Paticularly, chiral hydrogen-bonding based organocatalysis are introduced in detail. A selection of examples showing recent advancements in this field of catalysis is described, including monofunctional, bifunctional and multifunctional organocatalysis. In Chapter 2, the direct asymmetric vinylogous aldol reaction of furanones with -ketoesters will be demonstrated using L-tryptophan derived bifunctional thiourea catalyst. 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Ed. 2005, 44, 105. [182] T. Okino, Y. Hoashi, T. Furukawa, X. Xu, Y. Takemoto, J. Am. Chem. Soc. 2005, 127, 119. 224 Appendix Thesis Declaration The work in this thesis is the original work of Luo Jie, performed independently under the supervision of A/P Lu Yixin, Chemistry Department, National University of Singapore, between August 2007 and July 2011. The content of the thesis has been partly published in: 1) Luo, J.; Wang, H.; Han, X.; Xu, L-W.; Kwiatkowski, J.; H, K-W.; Lu, Y. “The Direct Asymmetric Vinylogous Aldol Reaction of Furanones with -Ketoesters: Access to Chiral -Butenolides and Glycerol Derivatives”, Angew. Chem. Int. Ed. 2011, 50, 1861. 2) Luo, J.; Xu, L.; Hay, A. S.; Lu, Y. "Asymmetric Michael addition mediated by novel cinchona alkaloid-derived bifunctional catalysts containing sulfonamides", Org. Lett. 2009, 11, 437. Luo Jie Name 04/08/2011 Signature Date [...]...List of Tables Table 1.1 Average numbers of chiral centers in synthetics, drugs and natural products Table 2.1 Screening of bifunctional catalysts for the vinylogous aldol reaction Table 2.2 Substrate scope of Trp-2 catalyzed direct vinylogous aldol reaction Table 3.1 Screening of bifunctional and trifunctional catalysts for the vinylogous mannich reaction Table 3.2 Scope of the direct vinylogous. .. Diastereoselective and Enantioselective Direct Vinylogous Michael Addition of Phthalide Derivatives to Nitroolefins”, Org Lett Manuscript in preparation 5 Luo, J.; Zhong, F.; Xu, L-W.; Lu, Y Direct Asymmetric Vinylogous Michael Addition of Phthalide Derivatives to Chalcones” Adv Synth Catal Manuscript in preparation 6 Luo, J.; Wu, W.; Xu, L-W.; Lu, Y Direct Phase Transfer Catalyzed Asymmetric Fluorination and Chlorination... by trifunctional catalyst Q-2 Table 4.1 Screening of bifunctional and trifunctional catalysts for the vinylogous Michael reaction Table 4.2 Scope of the direct vinylogous Michael reaction catalyzed by trifunctional catalyst Table 4.3 Initial screening results employing primary amine as the catalyst Table 4.4 Catalyst screening results of the vinylogous Michael addition to chalcone Table 4.5 Solvent and. .. nitroolefins List of Schemes Scheme 1.1 Structures of some representative ligands Scheme 1.2 Early examples of asymmetric reactions using organic catalysts Scheme 1.3 L-Proline catalyzed Robinson annulation Scheme 1.4 Selected examples of chiral organocatalysts Scheme 1.5 Different types of hydrogen-bonding organocatalysts Scheme 1.6 Kelly and Jørgensen’s activation models Scheme 1.7 Structures of orgnaocatalysts... hydrocyanation reactions2 7 and phase-transfer catalyzed asymmetric alkylation reactions. 28 However, the ‘golden age of organocatalysis’ did not begin until the late 1990s.29 Inspired by the elegant studies of Jacobsen,29 List and Barbas,30 MacMillan31 and Maruoka,32 the field of organocalysis has become a hot research area and a vast large number of organic catalysts have appeared in the past few years, and some... condensation and Stetter reactions 5) Phosphine based organocatalysts The nucleophilicity of phosphine makes them to be powerful catalysts in a number of reaction like Morita-Baylis-Hillman reaction and cycloaddition 7 Chapter 1 Introduction Scheme 1.4 Selected examples of chiral organocatalysts 1.2 Chiral hydrogen-bonding-based organocatalysis Enantioselective synthesis of organocatalysts with chiral... toluenesulfonyl Tr trityl   List of Publications 1 Luo, J.; Wang, H.; Han, X.; Xu, L-W.; Kwiatkowski, J.; H, K-W.; Lu, Y “The Direct Asymmetric Vinylogous Aldol Reaction of Furanones with -Ketoesters: Access to Chiral -Butenolides and Glycerol Derivatives , Angew Chem Int Ed 2011, 50, 1861 (Highlighted in SYNFACTS 2011, 4, 445.) 2 Luo, J.; Xu, L.; Hay, A S.; Lu, Y "Asymmetric Michael addition mediated... screening of the vinylogous Michael addition Table 4.6 Substrate scope of the vinylogous Michael addition to chalcone Table 5.1 Catalyst screening of Michael addition of ketoester to nitrostyrene Table 5.2 Influence of solvent on the Michael addition to nitrostyrene Table 5.3 Screening of other donors for the Michael addition to nitrostyrene Table 5.4 QD-4-catalyzed direct Michael addition of bicyclic... ruthenium(II)/binap (1-1) complex by Noyori and co-workers has opened the asymmetric hydrogenation towards practical synthetic applications (Scheme 1.1).12 Other famous examples include the asymmetric epoxidation of alkenes with chiral salen (1-2)-Mn complexes,13 and asymmetric cyclopropanation of alkenes with chiral bisoxazoline (1-3)-copper (II) complexes.14 Meanwhile the use of chiral Lewis acids15 became more... 4-additions and aza-Henry reactions catalyzed by Takemoto bifunctional catalyst Scheme 1.23 Reactions catalyzed by Jacobsen’s bifunctional thiourea catalysts Scheme 1.24 Iodolactonization reactions catalyzed by tertiary aminourea catalyst Scheme 1.25 Wang’s binaphthyl containing bifunctional thiourea catalyst Scheme 1.26 Friedel-Crafts alkylation of indoles and nitroalkenes Scheme 1.27 Chiral bifunctional . NATIONAL UNIVERSITY OF SINGAPORE 2011 Direct Asymmetric Vinylogous Reactions of Furanones and Phthalide Derivatives with Bifunctional and Trifunctional Organocatalysts . Direct Asymmetric Vinylogous Reactions of Furanones and Phthalide Derivatives with Bifunctional and Trifunctional Organocatalysts Luo Jie. Summary This thesis describes the development of direct enantioselective vinylogous reaction of furanones and phthalide derivatives with bifunctional and trifunctional organocatalysis. Chapter