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Synthesis of Nucleoside Analogues: Glycosylation, Rigid Nucleosides and Janus Wedge Derivatives

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Synthesis of Nucleoside Analogues: Glycosylation, Rigid Nucleosides and Janus Wedge Derivatives Synthesis Of Nucleoside Analogues: Glycosylation, Rigid Nucleosides And Janus Wedge Derivatives Author: Ayan Pal Persistent link: http://hdl.handle.net/2345/2750 This work is posted on eScholarship@BC, Boston College University Libraries. Boston College Electronic Thesis or Dissertation, 2012 Copyright is held by the author, with all rights reserved, unless otherwise noted. Boston College The Graduate School of Arts and Sciences Department of Chemistry SYNTHESIS OF NUCLEOSIDE ANALOGUES: GLYCOSYLATION, RIGID NUCLEOSIDES AND JANUS WEDGE DERIVATIVES a dissertation by AYAN PAL submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy June 2012 © copyright by AYAN PAL 2012 Abstract Nucleic Acids are unique biopolymers capable of encoding and transferring genetic information from one generation to the next for every form of life. This fascinating property has made them the topic of intense research from a variety of aspects. Some researchers try to understand how life might have started. Some try to elucidate how the whole process works. Some try to use the properties of nucleic acids as a tool for various purposes. The continuous effort over more than a century explored a lot about the structures and functions of nucleic acids. There is a lot to be discovered yet. This work began with the design and development of a new class of nucleoside analogue with the goal to study their ability to bind nucleic acids. The ongoing research will establish their application as therapeutics and as biomolecular tools. Along the way significant effort went into preparing these analogues. New methodology was developed to address some of the unanswered synthetic problems of nucleoside chemistry. Table of Contents Dedication and Acknowledgement………..………………………….……..……………………iv Abbreviations and Acronyms………………………………………………………………...…viii Chapter 1: Introduction 1.1 Nucleic Acids- Discovery and Brief History……………………….…………………………2 1.2 Structure of DNA and RNA…………………………………………………………………...5 1.3 Different forms of DNA…………………………………………………………………….....8 1.4 Nucleoside Analogues…………………………….…..…………………………………......16 1.5 Peptide Nucleic Acid…………………………………………………….…………………..22 1.6 Factors Determining the Modified Nucleic Acids Binding Properties………………………30 1.7. Potential Applications of Modified Oligonucleotides as Therapeutics……………………..32 1.8. Application of Modified Oligonucleotides as Diagnostic Tool……………………………..34 1.9. Applications of PNA………………………………………………………………………...35 1.10. Specific Examples of Modified Nucleosides Which Have Medicinal Applications………39 1.11. Scope of the Research……………………………………………………………………...41 Chapter 2: Bicyclo-1,1’-dicarboxylic Acid Cyclicanhydride as a Directing/Protecting Group Purine Glycosylations 2.0. Background……………………………….............................................................................54 i 2.1. Common Routes to prepare 2′-deoxyribonucleosides………………..……………………..56 2.2. Problems with Traditional Routes for Modified Nucleoside Synthesis……………………..60 2.3. Development of Bulky Substituent at C6-position of Purines………………………………61 2.4. Screening New Bulky Substituent at C6-position of Purines…………………….…………64 2.5. Bicyclo-1,1’-dicarboxylic Acid Cyclicanhydride as a Directing/Protecting Group………...70 2.6. Experimental………………………………………………………………………………...77 Chapter 3: Cyclic Oligonucleotides 3.1. Rigidified Nucleic Acids……………………………………………………………...........108 3.2 Synthesis of 8,5-(S)-cyclo-2’-deoxyguanosine......................................................................113 3.3 Synthesis of 6,8’-cyclo-2’-deoxyadenosine...........................................................................118 3.4 Experimental and Methods………………………................................................................122 Chapter 4: Purine-like Janus Wedge Residues 4.1 Triplex Forming Oligonucleotides.........................................................................................152 4.2 Janus Wedge (Jw) Triplexes..................................................................................................153 4.3 Limitation with Pyrimidine-like Jw Triplexes……………………………….......................159 4.4 Preparation of Monomer to target T-A base pair Y1……….................................................161 ii 4.5 PNA Synthesis incorporating Y1…………………………………………………………...165 4.6 Preparation of Modified Base to target A-T base pair...........................................................168 4.7. Preparation of Modified Base to target C-G base pair…………………...………………...174 4.8. Attempt to Synthesize Modified Base to target G-C base pair…………………………….176 4.9. Experimental and Methods………………………………………………………………...179 iii Dedicated to My Family and Teachers iv Acknowledgement The journey of the graduate life has been incredible. It had the moments of highs and lows. And it is always great to find someone around the corner. I wonder how everyone you meet or work influences your life and makes you the person who you are today. I am glad to be at this stage of my life and grateful to every one of them. It is impossible to be writing today without paying my regards to Prof. McLaughlin. I would like to thank him for giving me the opportunity to work in his laboratory. He is truly a guide; a person who showed me the path to become a scientist and a person I can always come to whenever I need advice. Needless to say his guidance has been invaluable to the work I will be presenting in my thesis. I would like to thank Profs. McLaughlin, Roberts, Gao and Christianson for being in my Graduate Committee. Prof. Gao read my progress report every year and gave me his thoughts. Prof. Weerapana was very helpful. She analyzed a few sample for one of my projects during a weekend. Profs. Gao and Weerapana always were very supportive whenever I dropped in their office for their advice. Prof. Roberts is always encouraging. I have had the opportunity to work with a number of talented post-docs, grad students and under- grads. It is incredible that I can reach any of our past groups members any time I needed advice or anything. I would to thank Dr. Meena, Dr. Han Chen, Dr. Greco, Dr. Horhota and Dr. Arico for their support. I cannot thank enough to Dr. Christianson who has helped me a lot during last stage of my graduate school. He has been doing an incredible job managing our lab and going through the manuscripts and thesis. All these wonderful people make your life so easy. v I am also lucky to have Han, Eric, Chris, Kerry and Hongchuan as labmates for a long stretch of time. They are not only talented chemists but also fun and encouraging. Later Nick, Alena and Yiran joined our lab and doing exceedingly well. I also need to mention about Rabih and Kenny, the two undergrads whom I worked with. They made teaching chemistry a lot of fun. Research would have been impossible without the support from our instrumentation departments. I would like to thank Dr. Boylan, our Director of NMR Center, Mr. Domin, Director of Mass Spectrometry and Dr. Li, Director, Center for X-Ray Crystallography for their continuous support and advice. As an international student it is always difficult to first come to a new country and find your way in. I heard a lot of these stories before I came to here. But I have to say I never felt that way. There were cultural differences. But the Department of Chemistry at Boston College made sure I have to feel that way. Everyone, from Professors to Administrative personals to International Student Center, made my life as easier as anyone can imagine. The warmth of my classmates made my initial days so much enjoyable. My quest for Science in general started when I was in my high school. I remember Ms. G. Uma, our chemistry teacher, influenced me the most. She used to spread hours after the school to make sure that every one learns their lesson. I also like to thank my Professors at my undergraduate school, Jadavpur University, and my masters’ school, IIT Kanpur. They are the people who encouraged me to become a chemist. I would like to express my gratitude to Prof. Bharadwaj, Prof. Murthy, Prof. Gupta-Bhaya and Prof. Khan for their teachings, support and guidance. Staying in Boston can be challenging sometimes. And it is great to know that whenever you are overwhelmed for any reason there are a few people you can always count on. Joby is always vi there guiding me whenever I feel low or I had any issues regarding immigration. My three years long roommate Ritaban and two years long roommate Aritra became my best friends here in Boston. They made staying in an apartment a lot of fun. During the last year or so Ranjan and Erika became very close friends of me. Hanging out with them is always stress-relieving. There are always a few people who you really can never thank because they define your existence. They are your family. It is impossible to acknowledge their importance in a sentence or two. Without their unconditional love and support I could not have accomplished anything. My parents have always been beside me and made me the person I am today. Life would not have been enjoyable and cheerful without my wife, Samragnee. Even though she had to stay in India for most of the time, she made sure that I never felt alone. Her presence inspires me to go for the unknown. Boston Ayan Pal 16th May, 2012. vii Abbreviations and Acronyms A adenosine Ac acetyl ACN acetonitrile Ad adenine AIBN azobis(isobutyronitrile) Bn benzyl Boc tert-butyloxycarbonyl But tert-butyl Bz benzoyl calcd calculated Cbz carbobenzyloxy CD circular dichromism CDCl3 chloroform-d6
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