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University of California, San Diego UNIVERSITY OF CALIFORNIA, SAN DIEGO Development and implementation of isomorphic and isofunctional fluorescent nucleosides A dissertation submitted in partial satisfaction of the requirements for the degree Doctor of Philosophy in Chemistry by Alexander Raymond Rovira Committee in Charge: Professor Yitzhak Tor, Chair Professor Guy Bertrand Professor Stephen Dowdy Professor Joseph O’Connor Professor Francesco Paesani 2017 Copyright Alexander Raymond Rovira, 2017 All rights reserved. The dissertation of Alexander Raymond Rovira is approved, and it is acceptable in quality and form for publication on microfilm and electronically: Chair University of California, San Diego 2017 iii DEDICATION I dedicate this thesis to my parents. iv EPIGRAPH “Whatever our field - science, technology, humanities, art - we are excited by the challenge of research at an endless frontier, and also humbled by the vastness of our ignorance.” Elias James Corey, Nobel Prize Speech, December 10, 1990 v TABLE OF CONTENTS SIGNATURE PAGE ................................................................................................................................... iii DEDICATION ............................................................................................................................................. iv EPIGRAPH ................................................................................................................................................... v TABLE OF CONTENTS ............................................................................................................................. vi LIST OF ABBREVIATIONS ...................................................................................................................... ix LIST OF FIGURES ..................................................................................................................................... xi LIST OF SCHEMES ................................................................................................................................ xviii LIST OF TABLES ..................................................................................................................................... xxi LIST OF EQUATIONS ............................................................................................................................ xxii ACKNOWLEDGEMENTS ..................................................................................................................... xxiii VITA ........................................................................................................................................................ xxvi ABSTRACT OF THE DISSERTATION ............................................................................................. xxxvii Chapter 1: Introduction ................................................................................................................................. 1 1.1 Introduction to nucleic acid building blocks ................................................................................ 1 1.2 Fluorescent Nucleoside Analogues .............................................................................................. 4 1.2.1 Desirable Photophysical Properties ................................................................................................. 4 1.2.2 Desirable chemical and electronic properties .................................................................................. 8 1.2.3 Design of Emissive Nucleoside Analogues: Classification ........................................................... 10 1.2.4 Historically Important Developments of fluorescent nucleobases and nucleosides ...................... 13 1.3 Applications of fluorescent nucleosides as small molecule substrates ...................................... 15 1.4 Overview of Tor Lab Fluorescent Nucleoside Development..................................................... 17 1.4.1 Pyrimidine Analogues .................................................................................................................... 17 1.4.2 The thieno[3,4-d]pyrimidine purine analogues .............................................................................. 20 1.4.3 Adenosine deaminase: Exploring the caveat of thA isofunctionality ............................................. 22 1.4.4 Introduction to the isothiazolo[4,3-d]pyrimidine family ............................................................... 23 1.4.5 Investigating the isothiazolo RNA analogues ................................................................................ 24 1.5 References .................................................................................................................................. 25 Chapter 2: Synthesis of a novel family of purine-inspired C-nucleosides .................................................. 32 2.1 Introduction to C-nucleosides .................................................................................................... 32 2.1.1 Intro to C-Nucleosides ................................................................................................................... 32 vi 2.1.2 Glycosylation methods for C-nucleosides ..................................................................................... 33 2.2 Direct glycosylation of the isothiazolo heterocycle ................................................................... 35 2.2.1 Building the nucleobase ................................................................................................................. 35 2.2.2 Friedel-Crafts Construction ........................................................................................................... 36 2.2.3 Palladium-mediated Coupling Reactions ....................................................................................... 37 2.2.4 Lithiation Reactions ....................................................................................................................... 40 2.3 Building isothiazolo-based nucleosides from a functionalized sugar ........................................ 42 2.3.1 Building the isothiazolo ring from a ribose precursor ................................................................... 42 2.3.2 Synthesizing the thiol-substituted sugar ........................................................................................ 42 2.3.3 Reduction of the anomeric site ...................................................................................................... 44 2.4 Divergent syntheses of the isothiazolo nucleosides ................................................................... 45 2.4.1 Synthesis of the ester-derived tzG, tzX, and tz2-AA ........................................................................ 45 2.4.2 Synthesis of the amide-derived tzI, tzA and tzisoG .......................................................................... 48 2.5 Deprotection: Removal of the benzyl ethers .............................................................................. 49 2.5.1 Palladium Hydrogenolysis ............................................................................................................. 49 2.5.2 Ethanethiol deprotection ................................................................................................................ 49 2.6 Characterization via crystal structure analysis ........................................................................... 50 2.7 Synthesis of unique spirocyclic orthoester-type derivatives of isothiazolo[4,3- d]pyrimidine nucleosides ........................................................................................................... 53 2.7.1 Introducing spirocyclic orthoesters ................................................................................................ 53 2.7.2 Structural elucidation of the orthoesters ........................................................................................ 55 2.7.3 Expansion of substrate scope ......................................................................................................... 55 2.8 Concluding remarks ................................................................................................................... 56 2.9 Acknowledgements .................................................................................................................... 57 2.10 Methods...................................................................................................................................... 58 2.10.1 General methods ............................................................................................................................ 58 2.10.2 Synthetic Procedures for thiol sugar preparation ........................................................................... 58 2.10.3 Synthesis of isothiazolo[4,3-d] based guanosine analog ............................................................... 61 2.10.4 Synthesis of isothiazolo[4,3-d] based adenosine analog ................................................................ 64 2.10.5 Synthesis of isothiazolo[4,3-d] based inosine analog .................................................................... 67 2.10.6 Synthesis of isothiazolo[4,3-d] based cytidine and uridine analogs .............................................. 68 2.10.7 Synthesis of tzX .............................................................................................................................. 71 2.10.8 Synthesis of tzisoG ........................................................................................................................
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