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Asymmetric Catalysis and Sensing with Rigid C2- Symmetric Ligands and Development of Heme-Targeted Antimalarials

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Asymmetric Catalysis and Sensing with Rigid C2- Symmetric Ligands and Development of Heme-Targeted Antimalarials ASYMMETRIC CATALYSIS AND SENSING WITH RIGID C2- SYMMETRIC LIGANDS AND DEVELOPMENT OF HEME-TARGETED ANTIMALARIALS A Dissertation submitted to the Faculty of the Graduate School of Arts and Sciences of Georgetown University in partial fulfillment of the requirements for the degree of Doctor of Philosophy in Chemistry By Kimberly Yearick Spangler Washington, DC August, 2009 ASYMMETRIC CATALYSIS AND SENSING WITH RIGID C2- SYMMETRIC LIGANDS AND DEVELOPMENT OF HEME-TARGETED ANTIMALARIALS Kimberly Yearick Spangler Thesis Advisor: Christian Wolf, Ph. D. ABSTRACT The first general procedure for the ligand-catalyzed nucleophilic addition of diethylzinc to trifluoromethyl ketones was developed. A range of 2-aryl-1,1,1- trifluorobutan-2-ols have been prepared in up to 99% yield using 10 mol % of TMEDA to favor alkylation over β-hydride elimination. These findings provide a new route for the asymmetric synthesis of trifluoromethyl-derived tertiary alcohols which are important components in many pharmaceuticals. Accordingly, the first asymmetric variant of this reaction was introduced. Screening of 16 chiral ligands revealed that excellent yields and ee’s up to 61% can be obtained with TBOX as catalyst. The first general procedure utilizing a bisoxazolidine – copper(I) complex in the asymmetric Henry reaction was developed. A range of aromatic nitroaldol compounds have been prepared in up to 95% yield and up to 89% ee using 10 mol % of the bisoxazolidine catalyst. The reaction of aliphatic substrates proved even more successful, and the corresponding nitroaldol products were obtained in up to 97% yield and 97% ee. ii An interesting switch in enantioselectivity when employing the same chiral ligand with either copper(I) acetate or dimethylzinc was also discovered. In both cases, nitroaldol products are obtained in high yields and ee’s but with opposite chiral induction. 1,8-bis(3’-(3,5-dimethylphenyl)-9’-acridyl)naphthalene N,N’-dioxide was introduced to new asymmetric catalysis and enantioselective sensing applications. The synthesis of the ligand was successfully scaled-up, and 1 gram of material was prepared. A chiral HPLC method was developed that allowed convenient preparative isolation of the enantiomers of this ligand. Initial progress made towards the asymmetric desymmetrization of meso-epoxides is promising from both a synthetic protocol development and enantioselective sensing standpoint. N-Oxide units of the ligand can also be protonated by a strong acid, which is accompanied by a significant UV-response. This finding opens entries towards the development of a Brønsted acid sensor. Twelve heme-targeted antimalarials have been prepared by systematically varying side chain lengths, N-terminal branching and substitutions, and heteroatom substitution at the 4-position of quinoline. This study reveals that methodical variation of the side chain of chloroquine provides affordable heme-targeted antimalarials that may overcome the ever-increasing problem with worldwide drug resistance. iii Acknowledgements I would like to thank my advisor Dr. Christian Wolf for his unwavering support and guidance throughout the course of my Ph. D. studies. Christian truly led by example and taught me to work diligently, effectively, and with purpose. In my future endeavors, I will always aspire to be as successful as a manager as Christian. Thank you so much for all of your help. I would also like to sincerely thank my committee members: Dr. Travis Holman, Dr. Paul Roepe, and Dr. Timothy Warren. All of my committee members challenged me to think critically about scientific problems and helped me to truly become a well- rounded researcher. I also appreciate the hard work of my undergraduate collaborators, Michelle Corder and Rhia Martin. I especially thank Michelle for helping with the daunting task of synthesizing our ligand. I would also like to current and former group members of the “Wolf pack:” Dr. Gilbert Tumambac, Dr. Xuefeng Mei, Dr. Rachel Lerebours, Dr. Shuanglong Liu, Dr. Kekeli Ekoue-Kovi, Daniel Iwaniuk, Marwan Ghosn, Hanhui Xu, Brian Reinhardt, Mikki Boswell, Max Moscowitz, and Peng Zheng. I would especially like to thank Daniel Iwaniuk for his constant support and scientific discussion. iv I would also like to thank Dr. Robert Fairchild, Dr. Marie Melzer, and Matthew Varonka for their scientific insights. I would especially like to thank Matthew Varonka for helping me with geometry optimizations. I would like to thank the members of the Georgetown Malaria Collaboration, the de Dios group, the Roepe group, and the Wolf group. Specifically, I would like to thank John Alumasa for his antimalarial activity measurements and Dr. Kekeli-Ekoue Kovi, Daniel Iwaniuk, John Alumasa, and Dr. Jayakumar Natarajan for synthesizing the complementary compounds in the antimalarial drug series. Thank you also to Mrs. Kay Bayne and Mrs. Inez Traylor for all of the administrative support during my time at Georgetown University. I would also like to thank my parents, Patrick and Susan Yearick for their support from when I was a child until now. Without them, I would not understand the value of hard work and education. Words cannot express how much I sincerely appreciate the love and support I receive from my husband, Ryan Spangler. I cannot imagine experiencing the challenges of graduate school without him by my side, and I am truly indebted for all of the sacrifices he made for me. Thank you so much! Lastly, I would like to thank the Department of Chemistry, the Graduate School of Arts and Sciences, and Georgetown University for the opportunity to complete my graduate studies. I have many great memories from Georgetown, and my experiences here have shaped who I am today. v Table of Contents Abstract……………………………………………………………………………... ii Acknowledgements…………………………………………………………………. iv Table of Contents…………………………………………………………………… vi List of Figures………………………………………………………………………. x List of Schemes……………………………………………………………………... xiii List of Tables……………………………………………………………………….. xvi List of Abbreviations…………………………………………………...................... xvii I. Introduction……………………………………………………………………….. 1 1.1 The importance of chirality……………………………………………….... 1 1.2 Enantioselective reactions………………………………………………….. 4 1.3 Stereoselective analysis…………………………………………………….. 11 1.4 Development of heme-targeted antimalarials combating chloroquine resistant malaria……………………………………………………………….......... 17 1.5 References………………………………………………………………...... 23 II. Objectives………………………………………………………………………... 29 III. Asymmetric catalysis with a bisoxazoline ligand………………………………. 34 3.1 Introduction to bisoxazoline catalysts…………………………………… 34 vi 3.2 The application of bisoxazoline catalysts in the asymmetric addition of diethylzinc to trifluoromethyl ketones……………………………………………… 37 3.2.1 Racemic addition of diethylzinc to trifluoromethyl ketones………… 39 3.2.2 Enantioselective addition of diethylzinc to trifluoromethyl ketones... 44 3.3 Conclusions………………………………………………………………... 50 3.4 Experimental details……………………………………………………….. 51 3.4.1 Synthesis of chiral ligands…………………………………………... 51 3.4.2 TMEDA catalyzed synthesis of racemic trifluoromethyl alcohols….. 53 3.4.3 Enantioselective synthesis of trifluoromethyl alcohols……………... 53 3.4.4 Purification and characterization of trifluoromethyl alcohols………. 54 3.5 References……………………………………………………………….... 61 IV. Asymmetric catalysis with a bisoxazolidine ligand…………………………….. 65 4.1 Introduction to the bisoxazolidine catalyst………………………………... 65 4.2 The application of the bisoxazolidine catalyst in the asymmetric Henry reaction……………………………………………………………………………… 67 4.2.1 Henry reaction optimization and substrate scope determination……... 69 4.2.2 Metal-controlled reversal of enantioselectivity………………………. 75 4.2.4. Application of the Henry reaction in the synthesis of alkaloid precursors…………………………………………………………………………… 82 4.3 Conclusions………………………………………………………………... 82 vii 4.4 Experimental details……………………………………………………….. 84 4.4.1 Synthetic procedures…………………………………………………. 84 4.4.2 Characterization of nitroaldol products……………………………… 85 4.4.3 Synthesis and characterization of methyl 4-hydroxy-4- nitropentanoate……………………………………………………………………… 91 4.4.4 Synthesis and characterization of 5-hydroxypiperidin-2-one………. 92 4.5 References………………………………………………………………….. 93 V. Asymmetric catalysis and enantioselective sensing with a sterically congested N,N '-dioxide………………………………………………………………………… 98 5.1 Introduction……………………………………………………………….. 98 5.2 Synthesis of 1,8-bis(3’-(3,5-dimethylphenyl)-9’-acridyl)naphthalene N,N’ -dioxide……………………………………………………………………….. 102 5.3 Applications of 1,8-bis(3’-(3,5-dimethylphenyl)-9’-acridyl)naphthalene N,N’ -dioxide in asymmetric catalysis………………………………………………. 107 5.3.1 Introduction…………………………………………………………... 107 5.3.2 Applications of 1,8-bis(3’-(3,5-dimethylphenyl)-9’-acridyl) naphthalene N,N’ -dioxide as a chiral catalyst for reactions utilizing silicon compounds………………………………………………………………………….. 109 5.4 Applications of 1,8-bis(3’-(3,5-dimethylphenyl)-9’-acridyl)naphthalene N,N’ -dioxide as a Brønsted acid sensor…………………………………………….. 111 viii 5.4.1 Introduction…………………………………………………………... 112 5.4.2 Synthesis and applications of a strong Brønsted acid sensor………… 114 5.5 Conclusions………………………………………………………………… 120 5.6 Experimental details………………………………………………………... 120 5.7 References………………………………………………………………….. 127 VI. The development of heme-targeted antimalarials………………………………. 130 6.1 Introduction………………………………………………………………… 130 6.2 Synthesis of antimalarial drug candidates………………………………….. 137 6.2.1 Synthesis of 4-aminoquinolines
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