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Hydroxylamines and Hydrazines As Surrogates of Sp3 Carbons in Medicinal Chemistry

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Hydroxylamines and Hydrazines As Surrogates of Sp3 Carbons in Medicinal Chemistry Wayne State University Wayne State University Dissertations January 2018 Hydroxylamines And Hydrazines As Surrogates Of Sp3 Carbons In Medicinal Chemistry Sandeep Dhanju Wayne State University, [email protected] Follow this and additional works at: https://digitalcommons.wayne.edu/oa_dissertations Part of the Chemistry Commons Recommended Citation Dhanju, Sandeep, "Hydroxylamines And Hydrazines As Surrogates Of Sp3 Carbons In Medicinal Chemistry" (2018). Wayne State University Dissertations. 2156. https://digitalcommons.wayne.edu/oa_dissertations/2156 This Open Access Dissertation is brought to you for free and open access by DigitalCommons@WayneState. It has been accepted for inclusion in Wayne State University Dissertations by an authorized administrator of DigitalCommons@WayneState. HYDROXYLAMINES AND HYDRAZINES AS SURROGATES OF SP3 CARBONS IN MEDICINAL CHEMISTRY by SANDEEP DHANJU DISSERTATION Submitted to the Graduate School of Wayne State University, Detroit, Michigan in partial fulfillment of the requirements for the degree of DOCTOR OF PHILOSOPHY 2019 MAJOR: CHEMISTRY (Organic) Approved By: Advisor Date DEDICATION I dedicate my PhD work to my parents Sanubhai Shrestha and Punamaya Dhanju, for their endless love and support. ii ACKNOWLEDGEMENTS First and foremost, I would like to express my sincere gratitude to my Ph.D. advisor Prof. David Crich for his incessant support and guidance for my Ph.D. research work during the past five years in his laboratory. I am grateful and fortunate to be one of his graduate students. His encouragement and motivation drove me to the end of this thesis, and I was able to develop an in-depth knowledge and enthusiasm in the areas of organic chemistry and medicinal chemistry. I would like to extend my gratitude to Prof. Jin K Cha, Prof. Ashok Bhagwat, and Prof. Jian Wang (Wayne State University, school of medicine), for serving as my committee members and providing valuable suggestions and intuitive comments. Their guidance was crucial for the completion of this thesis. I would like to extend my appreciation to our collaborator, Dr. Fred Valeriote from Henry Ford Hospital, for enormous contribution in biological assessment for my research. I am grateful to Professors Jennifer L Stockdill, Jeremy Kodanko, Mary K Pflum, Charles Winter, and Christine Chow for teaching me several courses during my first year at Wayne State University. These courses served as basics to understand my research work. I would like to appreciate all the present and past Crich group members. Dr. Takayuki Kato, Dr. Suresh Dharuman, Dr. Takahiko Matsushita, Dr. Appi Mandhapati, Dr. Peng Wen, Dr. Girish Sati, Dr. Philip Adero, Dr. Amr Sonousi, and Harsha Amarasekhara helped me to acquire the basic laboratory techniques and familiarize myself with the laboratory during my first year. I have enjoyed working with Dr. Szymon Buda, Dr. Oskar Popik, Dr. Vikram Sarpe, Dr. Parasuraman Rajasekaran, Dr. Govind Pratap Singh, Dr. Anura Wickramasinghe, Dr. Xiaoxiao Liao, Dr. Guanyu Yang, Bibek Dhakal, Michael G. iii Pirrone, Mohammed Hawsawi, Philemon Ngoje, Nuwan Kondasinghe, Timothy McMillan, Jonathan Quirke, Sameera Jayanath, Courtney Kondor, Rukshana Mohamad Ramshan, Emmanuel Onobun, Amirreza Samarbakhsh, Dean Jarois, Brendan Blazejewski, and Shuay Farhad. Their help and support made the work and life much easier and enjoyable. I am also grateful to the helpful staff in the chemistry department. Not least of all, I owe so much to my whole family for their endless support and belief that I can achieve this horizon. Thanks to my parents Sanubhai Shrestha and Punamaya Dhanju, my siblings Sanumaya Dhukuchhu and Sanjaya Dhanju, my sister in law Krishna Dhanju, my wife Suntali Giri Dhanju, and my son Aarav Dhanju for their endless love and support throughout my life. iv TABLE OF CONTENTS DEDICATION ...................................................................................................................ii ACKNOWLEDGEMENTS ............................................................................................... iii LIST OF TABLES .......................................................................................................... viii LIST OF FIGURES ..........................................................................................................ix LIST OF SCHEMES ....................................................................................................... xii LIST OF ABBREVIATIONS ............................................................................................xv CHAPTER 1. INTRODUCTION ....................................................................................... 1 1.1. Motives of the research ....................................................................................... 1 1.1.1. Medicinal chemistry lacks diversity in compound collections ....................... 1 1.1.2. Hydroxylamines and hydrazines as surrogates of sp3 carbons ..................... 3 1.1.3. Aims of the research ..................................................................................... 5 1.2. Hydroxylamines ................................................................................................... 6 1.2.1. Introduction ................................................................................................... 6 1.2.2. Conformational properties of hydroxylamines ............................................... 7 1.2.3. Hydroxylamines in medicinal chemistry ........................................................ 9 1.2.4. Synthesis of tri-substituted hydroxylamines ................................................ 12 1.3. Hydrazine .......................................................................................................... 15 1.3.1. Introduction ................................................................................................. 15 1.3.2. Conformational properties of hydrazines ..................................................... 16 1.3.3. Hydrazines in medicinal chemistry .............................................................. 20 1.3.4. Synthesis of tetra-substituted hydrazines .................................................... 26 1.4. Designing hydroxylamine and hydrazine analogs of kalkitoxin .......................... 31 v 1.4.1. Discovery of kalkitoxin and its biological activitites ...................................... 31 1.4.2. Total syntheses of kalkitoxin ....................................................................... 32 1.4.3. SAR studies of kalkitoxin ............................................................................. 38 1.4.4. Design of hydroxylamine and hydrazine analogs ........................................ 41 CHAPTER 2. SYNTHESIS OF N,N,O-TRISUBSTITUTED HYDROXYLAMINES ......... 43 2.1. Design and development of the method ............................................................ 43 2.1.1. Synthesis of N,N-disubstituted hydroxylamines ......................................... 45 2.1.2. Synthesis of N-acyloxyamines ................................................................... 47 2.1.3. Synthesis of N,N,O-trisubstituted hydroxylamines ..................................... 48 2.1.4. Synthesis of tri-substituted hydroxylamines with C-C bond formation .......... 51 2.1.5. Study of stereoselectivity of the addition of nucleophiles ............................. 53 2.1.6. Considering an analogy between tetra-substituted hydrazines and tri- substituted hydroxylamines .................................................................................... 54 2.2. Conclusion ......................................................................................................... 57 2.3. Future directions ................................................................................................ 58 CHAPTER 3. CONFORMATIONAL DYNAMICS OF N-ALKOXYPIPERIDINES AND PYRROLIDINES ........................................................................................................... 59 3.1. Conclusion .......................................................................................................... 70 CHAPTER 4. SYNTHESES OF HYDROXYLAMINE AND HYDRAZINE ANALOGS OF KALKITOXIN ................................................................................................................. 71 4.1. Synthesis of kalkitoxin (107) .............................................................................. 73 4.2. Synthesis of 6-oxa-7-azakalkitoxin (108) ........................................................... 78 4.3. Synthesis of 9-oxa-10-azakalkitoxin (109) ......................................................... 79 4.4. Synthesis of 7,8-diazakalkitoxin (110) ............................................................... 91 4.5. Biological assessments ..................................................................................... 99 vi 4.6. Conclusion ....................................................................................................... 103 CHAPTER 5. CONCLUSION ...................................................................................... 105 CHAPTER 6. EXPERIMENTAL SECTION .................................................................. 107 REFERENCES ............................................................................................................ 206 ABSTRACT ................................................................................................................. 218 AUTOBIOGRAPHICAL STATEMENT ........................................................................
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