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Discovery of a Novel Ring Fragmentation Reaction; Efficient University of Vermont ScholarWorks @ UVM Graduate College Dissertations and Theses Dissertations and Theses 2009 Discovery of a Novel Ring Fragmentation Reaction; Efficient Preparation of Tethered Aldehyde Ynoates and N-Containing Heterocycles;Radical Addition Approach to Asymmetric Amine Synthesis Cristian Draghici University of Vermont Follow this and additional works at: https://scholarworks.uvm.edu/graddis Recommended Citation Draghici, Cristian, "Discovery of a Novel Ring Fragmentation Reaction; Efficient Preparation of Tethered Aldehyde Ynoates and N- Containing Heterocycles;Radical Addition Approach to Asymmetric Amine Synthesis" (2009). Graduate College Dissertations and Theses. 70. https://scholarworks.uvm.edu/graddis/70 This Dissertation is brought to you for free and open access by the Dissertations and Theses at ScholarWorks @ UVM. It has been accepted for inclusion in Graduate College Dissertations and Theses by an authorized administrator of ScholarWorks @ UVM. For more information, please contact [email protected]. DISCOVERY OF A NOVEL RING FRAGMENTATION REACTION; EFFICIENT PREPARATION OF TETHERED ALDEHYDE YNOATES AND N-CONTAINING HETEROCYCLES; RADICAL ADDITION APPROACH TO ASYMMETRIC AMINE SYNTHESIS A Dissertation Presented by Cristian Draghici to The Faculty of the Graduate College of The University of Vermont In Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy Specializing in Chemistry May, 2009 Accepted by the Faculty of the Graduate College, The University of Vermont, in partial fulfillment of the requirements for the degree of Doctor of Philosophy specializing in Organic Chemistry. .Thesis Examination Committee: Advisor Chairperson Victor May, Ph.D. bk~~iaAb~&.Interim Dean, Graduate College Patricia A. Stokowski, Ph.D. Date: February 27, 2009 ABSTRACT This dissertation describes the development of a novel ring fragmentation reaction in which cyclic γ-silyloxy-β-hydroxy-α-diazoesters undergo efficient rupture of the Cβ−Cγ bond when treated with tin tetrachloride to provide tethered aldehyde ynoate products with varying tether length, in high yield. Tethered aldehyde ynoates are versatile intermediates and this functional group combination is unique to this fragmentation. The synthetic utility of tethered aldehyde ynoates is highlighted by their predisposition to undergo facile intramolecular [1,3]- dipolar cycloaddition reactions in presence of bistrimethylsylil-α-amino acids to provide 2,5-dihydropyroles. The ability to quickly assemble such structural motifs encouraged studies on the synthesis of steroidal alkaloid solanidine. A new method for the N-amination of oxazolidiones with NH2Cl was investigated and provides efficient access to acyl hydrazines. However, the full scope of the reaction has not been yet fully explored. The study of isopropyl radical additions to N-acylhydrazones and comparison of several stereocontrol elements on the oxazolidinone moiety revealed that all are effective. CITATION Material from this dissertation has been published in the following form: Draghici, C., Brewer, M.. (2008). Lewis acid promoted carbon-carbon bond cleavage of γ-silyloxy-β-hydroxy-α-diazoesters. Journal of the American Chemical Society, 130, 3766-3767. ii Pentru Ion, Veronica si Oana cu dragoste iii ACKNOWLEDGMENTS I would like to express my gratitude to Professor Matthias Brewer for allowing me the independence to formulate my own ideas and the support to push them to new understanding. I thank Professor Gregory K. Firestad for his guidance and support, and Dr. Jean-Charles Marié for the time he took to carefully answer every single question I had in my first year as a graduate student. I am indebted to Dr. Paul A. Krapcho and Dr. Martin Kuehne for offering me almost limitless access to two of the most remarkable minds in chemistry. I thank Jodi Wyman, Ali Bayir, Nezar Al Bataineh, Dr. Qiufeng Huang, and in particular, Irfan Mohmmad Javed and Derek Laws, for their company, support and scientific insights over the years. With my deepest feelings I thank Katrin Sara Sadigh for the love and encouragement with which she has provided me from the onset. I would like to thank Jeff Powers and Michelle LaMalfa for their unlimited support and friendship. I would also like to thank the Kishes for their love and support and for welcoming me as part of the family. Finally, I am sincerely grateful to my parents, Ion and Veronica Draghici, and my sister, Oana Draghici, for having the courage and the heart to allow me to pursue my dreams on another continent. Without their presence, this work would not have been possible. iv TABLE OF CONTENTS Page CITATION.......................................................................................................................... ii ACKNOWLEDGMENTS ................................................................................................. iv LIST OF FIGURES ........................................................................................................... ix LIST OF TABLES.............................................................................................................. x 1. Chapter 1: Background ............................................................................................... 1 1.1. The Chemistry of α-Diazo Carbonyl Compounds.................................................. 1 1.1.1. Structure of α-diazo carbonyl compounds.......................................................1 1.1.2. Reactivity profile of α-diazo carbonyl compounds .........................................3 1.1.3. Reactivity profile of vinyl cation species generated from β-hydroxy-α-diazo carbonyl compounds ......................................................................................................10 1.1.4. Thermal stability of diazo compounds...........................................................13 1.1.5. Conclusions....................................................................................................14 1.2. Heterolytic Carbon-Carbon (C-C) bond cleavage reactions................................. 14 1.2.1. Classification of heterolytic fragmentation reactions ....................................16 1.2.2. Alkyne-forming fragmentation reactions of acyclic systems ........................20 1.2.3. Alkyne-forming fragmentation reactions of cyclic systems ..........................22 1.2.4. Miscellaneous transition metal induced fragmentations................................24 1.2.5. Conclusions....................................................................................................26 2. Chapter 2: Discovery of a new mode of reactivity for diazo-esters ......................... 27 2.1. Novel approach to keto-furans with an unexpected result.................................... 27 v 2.2. Hypothesis............................................................................................................. 33 2.3. Testing the hypothesis........................................................................................... 33 2.4. Optimization of reaction conditions...................................................................... 35 2.4.1. Lewis Acid Screening....................................................................................35 2.4.2. Temperature Effect........................................................................................36 2.4.3. Solvent Effect.................................................................................................37 2.4.4. Concentration Effect......................................................................................37 2.5. Synthesis of ring fragmentation precursors .......................................................... 37 2.5.1. Synthesis of α-silyloxy ketones.....................................................................38 2.5.2. Synthesis of the requisite γ-silyloxy-β-hydroxy-α-diazo esters ....................42 2.5.3. Determination of stereochemical outcome of ethyl lithio-diazoacetate addition to cyclic α-silyloxy ketones.............................................................................44 2.6. Fragmentation results............................................................................................ 48 2.7. Discussion of proposed reaction mechanisms ...................................................... 51 2.8. Exploring the versatility of the fragmentation protocol........................................ 60 2.9. Pursuit of alternate fragmentation strategies......................................................... 65 2.10. Future perspective............................................................................................. 69 2.10.1. Expanding the utility of the novel fragmentation reaction ............................69 2.11. Conclusions....................................................................................................... 73 3. Chapter 3: Tethered aldehyde ynoates – useful synthetic intermediates .................. 74 3.1. Background........................................................................................................... 74 3.1.1. Previously reported preparative routes to tethered aldehyde ynoates............74 3.1.2. Recent applications of tethered aldehyde ynoates .........................................76 vi 3.1.3. Intramolecular [1,3]-dipolar cycloaddition reactions of tethered alkynyl aldehydes………………………………………………………………………………79 3.2. Intramolecular [1,3]-dipolarcycloadditions of tethered aldehyde ynoates with stabilized and unstabilized azomethine
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