University of New Orleans ScholarWorks@UNO University of New Orleans Theses and Dissertations Dissertations and Theses Fall 12-20-2013 Synthesis of Novel Azetidines Amber Thaxton UNO, [email protected] Follow this and additional works at: https://scholarworks.uno.edu/td Part of the Medicinal and Pharmaceutical Chemistry Commons, and the Organic Chemistry Commons Recommended Citation Thaxton, Amber, "Synthesis of Novel Azetidines" (2013). University of New Orleans Theses and Dissertations. 1764. https://scholarworks.uno.edu/td/1764 This Dissertation is protected by copyright and/or related rights. It has been brought to you by ScholarWorks@UNO with permission from the rights-holder(s). You are free to use this Dissertation in any way that is permitted by the copyright and related rights legislation that applies to your use. For other uses you need to obtain permission from the rights-holder(s) directly, unless additional rights are indicated by a Creative Commons license in the record and/ or on the work itself. This Dissertation has been accepted for inclusion in University of New Orleans Theses and Dissertations by an authorized administrator of ScholarWorks@UNO. For more information, please contact [email protected]. Synthesis of Novel Azetidines A Dissertation Submitted to the Graduate Faculty of the University of New Orleans in partial fulfillment of the requirements for the degree of Doctor of Philosophy in Chemistry by Amber Nichole Thaxton B.S. Clemson University, 2004 M.S. University of New Orleans, 2013 December 2013 For my family: To my mom, Bee Thaxton, for everything she has done for me. I am extremely thankful for her constant support and reassurance. To Teddy for his ability to make me smile especially when I am stressed. To Robby who has my heart. ii Acknowledgement I would like to express my extreme gratitude to my adviser Dr. Mark Trudell for taking a chance on me, and for providing his support and guidance throughout my classes and research. I would like to also thank my advisory board members Dr. Branko Jursic, Dr. Edwin Stevens, and Dr. Dhruva Chakravorty. I would like to acknowledge Dr. Edwin Stevens for the X-ray crystal structure, as well as Dr. David Mobley and Vivan Jaber for the structure overlay. I would also like to thank Dr. Sari Izenwasser and Mr. Dean Wade of the University of Miami Miller School of Medicine for their collaborative efforts in producing biological analysis for this dissertation. I wish to express my appreciation to my group members past and present for their encouragement and support: Dr. April Noble-Brooks, Dr. Andréa “Tascha” Forsyth, Alex Sherwood, Kiran Thoa, Tushar Apsunde, Maria Lindsay, Patrick Apipanyakul, and Majeed Bajaber. The National Institute of Drug Abuse and the University of New Orleans Graduate School and College of Sciences are gratefully acknowledged for financial support of this work. iii Table of Contents List of Figures ....................................................................................................................................... vii List of Schemes .................................................................................................................................... viii List of Tables ............................................................................................................................................ x Abstract ..................................................................................................................................................... x Part I: Synthesis and Biological Evaluation of 3-aryl-3-arylmethoxy azetidines ........... 1 Abstract ....................................................................................................................................... 1 Introduction ............................................................................................................................... 3 1.1History of Methamphetamine ............................................................................. 3 1.2 Effects of Meth ......................................................................................................... 9 1.4 Effects of METH on Neurotransporters ...................................................... 12 1.5 Methamphetamine vs Cocaine ........................................................................ 15 1.6 Attempted Methamphetamine Medications.............................................. 16 1.7 Dual Target Hypothesis ..................................................................................... 18 1.8 Triple Re-uptake Inhibitors in Clinical Trials ........................................... 20 1.9 Ibudilast ................................................................................................................... 21 1.10 Approach and Investigation of 3-Aryl-3-arylmethoxytropanes ..... 22 1.11 Design Strategy for Novel 3-Aryl-3-arylmethoxyazetidines ............ 30 iv Results and Discussion ......................................................................................................... 34 2.1 Synthesis of 3-Aryl-3-arylmethoxyazetidine and N-Methyl-3-aryl- 3-arylmethoxyazetidine ....................................................................................... 34 2.1.1 Synthesis of N-Boc-3-aryl-3-azetidinol ................................................ 34 2.1.2 Synthesis of N-Boc-3-aryl-3-arylmethoxyazetidine ...................... 37 2.1.3 Optimization for Formation of N-Methyl Azetidine ........................ 42 2.1.4 Optimization of Formation of 3-Aryl-3-arylmethoxyazetidine .. 45 2.1.5 Forward Synthesis and Crystallographic Representation............ 51 2.2 Binding Affinity ................................................................................................. 53 2.3 Binding Affinities of 3-Aryl-3-arylmethoxyazetidine and N-Methyl- 3-aryl-3-arylmethoxy analogs ............................................................................ 54 Conclusion ................................................................................................................................ 59 Experimental Section ............................................................................................................ 61 Part II: Synthesis of 3,3-diaryl Azetidines .................................................................................. 95 Abstract ..................................................................................................................................... 95 Introduction ............................................................................................................................. 96 4.1 Pharmaceutical Examples of Diaryl Heterocycles ............................................. 97 4.2.1 Synthesis of 3,3-Diarylpyrrolidine from Benzophenone ............................ 98 4.2.2 Synthesis of 3,3-Diarylpyrrolidine from Diphenylbutylamine ................. 99 4.2.3 Synthesis of 3,3-Diarylpyrrolidine from Diphenylacetonitrile ............... 100 4.2.4 Synthesis of 4,4-Diarylpiperidines from 4-Piperidinone .......................... 101 v 4.3 New Methodology ........................................................................................................ 103 Results and Discussion ...................................................................................................... 106 5.1 Proposed Mechanism of Formation of 3,3-Diarylheterocycles .................. 106 5.2 Synthesis of Symmetrical and Asymmetrical 3,3-Diarylazetidines .......... 107 5.3 Synthesis of 4,4-Diarylpiperidine, 3,3-Diarylpyrrolidine, and 4,4- Diaryltropane ........................................................................................................................ 109 Conclusions ........................................................................................................................... 115 Experimental ........................................................................................................................ 116 References .......................................................................................................................................... 131 Appendix I ........................................................................................................................................... 144 Appendix II ......................................................................................................................................... 145 Vita ........................................................................................................................................................ 155 vi List of Figures FIGURE 1: TRANSPORTATION OF DOPAMINE AT A DOPAMINE TRANSPORTER SYNAPTIC CLEFT .................... 11 FIGURE 2: EFFECTS OF METH ON DOPAMINE TRANSPORTER .......................................................................... 12 FIGURE 3: PET SCAN EVALUATING DOPAMINE LEVELS OF A HEALTHY BRAIN AND A BRAIN OF A METH ABUSER ............................................................................................................................................................ 13 FIGURE 4: EFFECT OF COCAINE ON THE DOPAMINE TRANSPORTER SYSTEM .................................................... 15 FIGURE 5: APPROACH TO PHARMACOPHORE SCAFFOLD .................................................................................... 27 FIGURE 6: MODIFICATION AREAS FOR INCREASED BINDING AFFINITIES .......................................................... 30 FIGURE 7: SUPERIMPOSED PREDICTED