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A Silylation-Based Kinetic Resolution of Hydroxy Lactones and Lactams with Subsequent Mechanistic Investigations Robert W

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A Silylation-Based Kinetic Resolution of Hydroxy Lactones and Lactams with Subsequent Mechanistic Investigations Robert W University of South Carolina Scholar Commons Theses and Dissertations 2015 A Silylation-Based Kinetic Resolution of Hydroxy Lactones and Lactams with Subsequent Mechanistic Investigations Robert W. Clark University of South Carolina Follow this and additional works at: https://scholarcommons.sc.edu/etd Part of the Chemistry Commons Recommended Citation Clark, R. W.(2015). A Silylation-Based Kinetic Resolution of Hydroxy Lactones and Lactams with Subsequent Mechanistic Investigations. (Doctoral dissertation). Retrieved from https://scholarcommons.sc.edu/etd/3662 This Open Access Dissertation is brought to you by Scholar Commons. It has been accepted for inclusion in Theses and Dissertations by an authorized administrator of Scholar Commons. For more information, please contact [email protected]. A SILYLATION-BASED KINETIC RESOLUTION OF HYDROXY LACTONES AND LACTAMS WITH SUBSEQUENT MECHANISTIC INVESTIGATIONS by Robert W. Clark Bachelor of Science The Citadel, The Military College of South Carolina, 2009 Submitted in Partial Fulfillment of the Requirements For the Degree of Doctor of Philosophy in Chemistry College of Arts and Sciences University of South Carolina 2015 Accepted by: Sheryl L. Wiskur, Major Professor John J. Lavigne, Committee Member Andrew B. Greytak, Committee Member Mike D. Wyatt, Committee Member Lacy Ford, Senior Vice Provost and Dean of Graduate Studies © Copyright by Robert W. Clark, 2015 All Rights Reserved. ii Acknowledgements It is impossible to mention all of the people that have had an impact on my life up until this point. First and foremost I must thank my advisor Dr. Sheryl Wiskur for the countless hours of personal attention and mentorship. Thanks to all those that provided new and interesting research goals during my graduate tenure. Dr. Cody Sheppard was instrumental in the seminal works that eventually led to the studies herein. To Max Deaton, in the end, you taught me more than I taught you. It was a pleasure to mentor you and to be a spectator of your excitement for science. Dr. Ravish Akhani, our fruitful and meaningful discussions both in and outside of the lab will be remembered. To those in the Wiskur group, keep your heads up you will have accomplished so much before you even realize it. My passion for scientific study began long before my arrival at the University of South Carolina. I know I would not be here without the passion for synthetic organic chemistry instilled upon me while working in the lab with Dr. Randy Blanton and the scientific interest inspired from another exceptional teacher, Mrs. Sherry Arledge. I am fortunate to have an extremely supportive family. My parents both set the example of hard work and dedication that have unquestionably led to my success thus far. Words cannot express my gratitude for all your love and support. Finally to my wife Taylor, you are the foundation upon which I have built all of my success. You have been with me and for me through the good times and the bad. I am so thankful and feel blessed to have you in my life. You have supported me with a smile on your face, and I love you for that. Can you believe it? We finally made it. iii Abstract The work contained herein focuses on the methodology and design of new reactions for the production of stereoenriched compounds. The primary focus of research discussed is kinetic resolution, a classic and powerful methodology for the separation of a single enantiomer from a racemic mixture. In 2011, a silylation-based resolution catalyzed by a chiral isothiourea produced synthetically useful selectivity factors for mono-functional secondary alcohols. In chapter 2, this methodology was subsequently expanded to include α-hydroxy lactones with selectivity factors up to 100. This study resulted in the most selective reaction reported to date for the aforementioned silylation- based resolution. In addition to lactones, α-hydroxy lactams, amides and esters were resolved with synthetically useful enantioselectivity. This is notably the first successful non-enzymatic resolution of hydroxy lactams ever reported. In an effort to remove chromatography completely from the kinetic resolution process, an alternate polymer-supported version of the reaction was studied. The successful use of polymer-bound triphenylsilyl chloride to eliminate chromatographic purification steps is contained in Chapter 3. The polymer-supported reagent was utilized to produce useful selectivities for the resolution of benzylic alcohols and α-hydroxy lactones. The polymer-bound silyl source was also successfully recycled without loss in enantioselectivity. In Chapter 4, our attempts to elucidate the mechanism of the kinetic resolution via reaction progress kinetic analysis will be demonstrated. Preliminary results of this iv investigation suggest the reaction is very sensitive to silyl chloride concentration. This finding suggests a more complex reaction than our previous hypothesis. Additionally, a stereoenriched silyl chloride was tested in the silylation reaction. The overall inversion of stereochemistry observed in these experiments does not support our previously proposed double inversion mechanism. Results of the kinetic studies and chiral probe reactions will be utilized to propose a plausible mechanistic cycle for the silylation reaction. Finally, research to expand silylation-based resolutions to include an asymmetric borane Lewis acid catalyzed silicon-oxygen coupling will be highlighted. A variety of stereogenic at silicon silanes were prepared and tested in the reaction. The low diastereoselectivity of these reactions does not support the ability to affect resolution of racemic alcohols via this method. The reaction was further complicated by reactivity that appeared substrate-dependent. The results of the silicon-oxygen coupling kinetic resolution of substrates to include secondary alcohols and propargylic alcohols will be discussed in Chapter 5. v Table of Contents Acknowledgements ............................................................................................................ iii Abstract .............................................................................................................................. iv List of Tables .......................................................................................................................x List of Schemes .................................................................................................................. xi List of Figures ....................................................................................................................xv Chapter 1 Foundations and Current Outlook of Enantioselective Methodologies ............. 1 1.1. Introduction and Scope .................................................................................... 1 1.2. Chirality and its Implications to Biology ......................................................... 1 1.3. Methods of Obtaining Enantiopure Molecules ................................................ 4 1.4. Organocatalyzed Resolutions ......................................................................... 15 1.5. Silylation-Based Resolution Methods for the Preparation of Non-Racemic Alcohols ......................................................................................... 21 1.6. Conclusions and Outlook ............................................................................... 27 1.7. References ...................................................................................................... 29 Chapter 2 Silylation-Based Kinetic Resolution of α-Hydroxy Lactones and Lactams .... 36 2.1. Introduction and Scope................................................................................... 36 vi 2.2. Initial Investigations and Optimization .......................................................... 40 2.3. Synthesis of Hydroxy Lactones ..................................................................... 44 2.4. Examining the Lactones in the Silylation-Based Kinetic Resolution ................................................................................................ 48 2.5. Synthesis of Hydroxy Lactams ...................................................................... 50 2.6. Testing the Lactams in the Silylation-Based Kinetic Resolution .................. 51 2.7. Synthesis of Amides and Esters ..................................................................... 54 2.8. Testing Amides and Esters in the Silylation-Based Resolution ..................... 55 2.9. Conclusions and Outlook ............................................................................... 56 2.10. Experimental ................................................................................................ 58 2.11. References .................................................................................................. 135 Chapter 3 Polymer-Bound Triphenylsilyl Chloride for the Kinetic Resolution of Secondary Alcohols ...................................................................................................... 142 3.1 Introduction and Scope.................................................................................. 142 3.2 Polymerization-Based Kinetic Resolutions .................................................. 146 3.3 Enzymatic Kinetic Resolutions on Polymer Supports .................................. 149 3.4 Silylation-Based Kinetic Resolutions on Polymer Supports ......................... 151 3.5 Synthesis of Polystyrene Supported Triphenylsilyl Chloride ......................
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