Sugar Silanes: Versatile Reagents for Stereocontrolled Glycosylation via Intramolecular Delivery by Jordan Thomas Walk A dissertation submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy (Chemistry) in the University of Michigan 2015 Doctoral Committee: Professor John Montgomery, Chair Assistant Professor Amanda L. Garner Assistant Professor Pavel Nagorny Professor John P. Wolfe Dedication To my mother and my grandparents. Without their strength, character, and support, I could never have accomplished the things that I have. ii Acknowledgments First and foremost, I am most grateful for my family. I have been surrounded by incredible people my entire life. It was only with your love that I have achieved what I have. My success is your success. John Montgomery has provided wonderful guidance and mentorship as my career has developed. I’d also like to thank John Wolfe, Pavel Nagorny, Amanda Garner, and Jason Gestwicki for their insights into the sugar silane project. I’ve had the great pleasure of working next to wonderful people in the Montgomery Lab. More than coworkers, these friends have enriched my life and helped to create memories that I will always cherish. Last but not least, I love Kelli Sullivan with all of my heart. iii Table of Contents Dedication .......................................................................................................................... ii Acknowledgements ......................................................................................................... iii List of Figures .....................................................................................................................v List of Schemes ................................................................................................................. vi List of Tables .................................................................................................................... ix List of Abbreviations ....................................................................................................... xi Abstract ........................................................................................................................... xiii Chapter 1: Carbohydrate Chemistry ...............................................................................1 1.1) General Overview of Carbohydrates .......................................................1 1.2) Development of Glycosylation Strategies.................................................6 1.3) The Synthesis of 1,2-Cis Glycosides ........................................................10 1.4) Direct Intramolecular Delivery ..............................................................15 1.5) Synthesis of 2-Deoxy-β-Glycosides .........................................................21 Chapter 2: Review of Sugar Silanes ...............................................................................25 2.1) Introduction ..............................................................................................25 2.2) Hydrosilylation of Ketones ......................................................................31 2.3) Aldehyde and Alkyne Coupling ..............................................................35 2.4) Dehydrogenative Silylation of Alcohols .................................................38 Chapter 3: Sugar Silanes and C6 Delivery ....................................................................41 3.1) Glucose and Mannose C2 Sugar Silanes ................................................41 3.2) Background and Strategy Towards 1,2-Trans Glycosides via IAD .....43 3.3) 2-Acetoxy and 2-Benzoyloxy Sugar Silanes ...........................................47 3.4) 2-Benzyloxy and 2-Azido C6 Sugar Silanes ...........................................71 3.5) 2-Deoxy Sugar Silanes .............................................................................85 Chapter 4: Experimental Procedures and Spectral Data ..........................................108 References .......................................................................................................................179 iv List of Figures Figure 1.1 – D-Glucose and D-Mannose ..........................................................................2 Figure 1.2 – The Anomeric Effect ....................................................................................4 Figure 1.3 – Disaccharides and Oligosaccharides ...........................................................5 Figure 2.1 – The Versatility of Sugar Silanes ................................................................28 Figure 3.1 – Potential Intramolecular Anomerization Mechanism ............................98 v List of Schemes Scheme 1.1 – Mutarotation of Glucose ............................................................................3 Scheme 1.2 – First Chemical Glycosylations by Michael and Fischer ..........................7 Scheme 1.3 – Koenigs-Knorr Glycosylation and Proposed Mechanism .......................7 Scheme 1.4 – Different Reactivity Between 1,2-Cis and 1,2-Trans Donors ..................8 Scheme 1.5 – Mechanistic Differences between 1,2-Cis and 1,2-Trans Donors ............9 Scheme 1.6 – Neighboring Group Participation to Give 1,2-Trans Glycosides ..........10 Scheme 1.7 – Lemieux’s in situ Anomerization Strategy .............................................13 Scheme 1.8 – Non-Direct Intramolecular Methods to Obtain 1,2-Cis Glycosides .....15 Scheme 1.9 – Intramolecular Aglycone Delivery to Give 1,2-Cis Glycosides .............16 Scheme 1.10 – Hindsgaul’s Mixed Acetal Strategy .......................................................17 Scheme 1.11 – Use of NIS as Electrophile ......................................................................17 Scheme 1.12 – Enol Ethers as Tethers ...........................................................................18 Scheme 1.13 – PMB Ethers as Tethers...........................................................................18 Scheme 1.14 – Silicon Tethers to Obtain β-Mannosides ...............................................19 Scheme 1.15 – Silicon Tethers to Obtain α-Glucosides ................................................20 Scheme 1.16 – 2-Deoxy-Glucose and 2-Deoxy-Ribose ..................................................21 Scheme 1.17 – Glycosyl Phosphites as Glycosyl Donors ...............................................22 Scheme 1.18 – Anchimeric Assistance from C3 Hydroxyl ...........................................22 Scheme 1.19 – Use of Temporary Directing Groups ....................................................23 Scheme 1.20 – 1,2-Migration of Thioglycosides ............................................................24 Scheme 1.21 – Cycloaddition to Form 2-Deoxy-β-Glycosides......................................24 Scheme 2.1 – Dimethylsilylketals Tethers for Intramolecular Aglycone Delivery ....26 vi Scheme 2.2 – Chlorosilanes for Efficient Heterocoupling ............................................27 Scheme 2.3 – Transition Metal Catalyzed Formation of Oxygen-Silicon Bonds .......29 Scheme 2.4 – Sugar Silane Approach Versus Traditional Approach .........................30 Scheme 2.5 – Synthesis of C2 Sugar Silanes ..................................................................31 Scheme 2.6 – Hydrosilylation of Ketones Using Sugar Silanes ....................................32 Scheme 2.7 – Glycosylation of C2 Sugar Silanes ...........................................................33 Scheme 2.8 – Site Selectivity with Sugar Silanes ...........................................................34 Scheme 2.9 – Chemoselectivity Using Sugar Silanes ....................................................35 Scheme 2.10 – Sugar Silane Approach Versus Traditional Approach .......................36 Scheme 2.11 – Efficient Route to Glycosylated Macrocycle ........................................37 Scheme 2.12 – Aldehyde-Alkyne Coupling to Access Glycosylated Alcohols.............37 Scheme 3.1 – C6 Delivery with Pyrimidine Bases .........................................................44 Scheme 3.2 – Silyl Tethers at Distal Hydroxyl Groups ................................................45 Scheme 3.3 – Intramolecular Glycosylation from the C6 Hydroxyl ...........................46 Scheme 3.4 – Strategy to Overcome 1,6-Anhydro Byproduct Formation ..................46 Scheme 3.5 – Initial Attempt Towards 1,2-Trans Diol Protected Donor ....................47 Scheme 3.6 – Synthesis of 3,4-Trans Diol Protected Thioglucoside .............................48 Scheme 3.7 – Synthesis of 2-Acetoxy Sugar Silanes ......................................................49 Scheme 3.8 – Synthesis of 2-Benzoyloxy Sugar Silanes ................................................50 Scheme 3.9 – Comparison of C2 and C6 Sugar Silanes in Alcohol Silylation ............51 Scheme 3.10 – Formation of Homodimer ......................................................................53 Scheme 3.11 – Formation of Active Catalyst .................................................................55 Scheme 3.12 – Synthesis of Diisopropyl C6 Sugar Silanes ...........................................58 Scheme 3.13 – Comparison of C2 and C6 Sugar Silanes Using B(C6F5)3 ...................60 Scheme 3.14 – Synthesis of Discrete Catalyst ................................................................62 Scheme 3.15 – Control Experiment with Exogenous Alcohol ......................................67 Scheme 3.16 – 2-Acetoxy and 2-Benzoyloxy Crossover