The Development of Reactions for the Stereoselective Synthesis of Heterocycles and Benzylic Amines, and Exploration of Bisisoxazolidines as Small Molecule Transcriptional Activation Domains by Matthew L. Leathen A dissertation submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy (Chemistry) in The University of Michigan 2011 Doctoral Committee: Associate Professor John P. Wolfe, Chair Professor Anna K. Mapp Assistant Professor Garry D. Dotson Assistant Professor Pavel Nagorny Matthew L. Leathen 2011 Dedication To My Family ii Table of Contents Dedication .......................................................................................................................... ii List of Figures ................................................................................................................... vi List of Tables .................................................................................................................. viii List of Schemes ................................................................................................................. ix List of Abbreviations ........................................................................................................ x Abstract……… ............................................................................................................... xiv Chapter 1 Introduction..................................................................................................... 1 1.1 Importance of Alkaloids and Nitrogen-Containing Compounds ...................... 1 1.2 Standard Methods for Forming New Carbon-Nitrogen Bonds ......................... 2 1.3 Metal-Catalyzed Methods for Forming New Carbon-Nitrogen Bonds ............ 3 1.4 Conclusions ....................................................................................................... 5 1.5 References ......................................................................................................... 6 Chapter 2 Mild Conditions for the Synthesis of Functionalized Pyrrolidines via Palladium Catalyzed Carboamination Reactions ........................................ 8 2.1 Introduction ....................................................................................................... 8 2.2 Development of Reaction Conditions Utilizing Weak Base........................... 10 2.3 Exploration of Scope....................................................................................... 12 2.4 Conclusions ..................................................................................................... 15 2.5 Experimental Section ...................................................................................... 15 2.6 References ....................................................................................................... 35 iii Chapter 3 Synthesis of Substituted Morpholines via Palladium Catalyzed Carboamination Reactions ........................................................................... 38 3.1 Background ..................................................................................................... 38 3.2 Introduction ..................................................................................................... 40 3.3 Exploration of Reaction Conditions................................................................ 41 3.4 Synthesis of cis -3,5-Disubstituted Morpholines ............................................. 43 3.5 Expansion to Bicyclic Morpholines and Other Substitution Patterns. ............ 46 3.6 Conclusions ..................................................................................................... 52 3.7 Experimental Section ...................................................................................... 53 3.8 References ....................................................................................................... 91 Chapter 4 Development of a Mild Curtius Rearrangement for the Synthesis of Benzylic and Heteroarylmethyl Amines ..................................................... 95 4.1 Introduction ..................................................................................................... 95 4.2 Modern Developments and Current Challenges ............................................. 96 4.3 Initial Optimization ......................................................................................... 98 4.4 Synthesis of Methyl Carbamates .................................................................. 101 4.5 Synthesis of Various Carbamates ................................................................. 102 4.6 Conclusions ................................................................................................... 104 4.7 Experimental Section .................................................................................... 105 4.8 References ..................................................................................................... 115 Chapter 5 Exploration of Bisisoxazolidines as Small Molecule Transcriptional Activation Domains ..................................................................................... 118 5.1 Introduction ................................................................................................... 118 5.2 Synthesis of Bisisoxazolidines for Synergystic TAD Activity ..................... 122 5.3 Functional Evaluation of TADs ...................................................................... 129 5.4 Conclusion ..................................................................................................... 130 iv 5.5 Experimental Section .................................................................................... 131 5.6 References ..................................................................................................... 164 Chapter 6 Exploratory Studies on the Reactivity of Electrophiles with Enediol Diboronates .................................................................................................. 167 6.1 Introduction ................................................................................................... 167 6.2 Importance of Aldol Addition with Anti Selectivity .................................... 168 6.3 Selection for Anti-Selective Aldol Reactions via Oxonium Electrophiles ... 169 6.4 Selection for Anti-Selective Aldol Reactions via Metal Enolates ................ 171 6.5 Selection for Anti-Selective Aldol Reactions via Aldehyde Activation ....... 173 6.6 Investigating New Electrophiles for Tandem Wittig Rearrangment Reactions 174 6.7 Conclusions ................................................................................................... 176 6.8 Experimental Section .................................................................................... 177 6.9 References ..................................................................................................... 188 v List of Figures Figure 1-1: Important Nitrogen-Containing Compounds ................................................... 1 Figure 1-2: Some Standard Methods That Can Form Carbon-Nitrogen Bonds ................. 2 Figure 1-3: Metal-Catalyzed Alkene Amination Reactions................................................ 4 Figure 2-1: Biologically Active Pyrrolidines ...................................................................... 9 Figure 2-2: Pyrrolidine Synthesis via Palladium-Catalyzed Carboamination .................... 9 Figure 3-1: Biologically Important Morpholines .............................................................. 39 Figure 3-2: Known Methods for Synthesizing cis -3,5-Disubstituted Morpholines .......... 40 Figure 4-1: Example Chiral Benzylic Amines Found in Bilogically Active Molecules .. 98 Figure 4-2: Room temperature Curtius rearrangement in MeOH ..................................... 99 Figure 5-1: Activator TFs bind to DNA (black line) and recruit chromatin remodeling enzymes that help unwrap the DNA and allow initiation of transcription by RNA polymerase II .......................................................................................................... 118 Figure 5-2: Natural activation domains contain repeats of polar and hydrophobic residues ................................................................................................................................. 120 Figure 5-3: Isoxazolidines functionalized with mostly polar or hydrophobic functional groups are poor TADs. Amphipathic isoxazolidines robustly activate transcription ................................................................................................................................. 121 Figure 5-4: Compounds targeted for evaluation as TADs. Compounds containing varying functionality, regiochemistry, and stereochemistry are targeted ................................ 122 vi Figure 5-5: Synthetic Strategy for Bisisoxazolidine Synthesis...................................... 123 Figure 5-6: Synthesis of the first isoxazolidine ring ...................................................... 124 Figure 5-7: Synthesis of bisisoxazolidines ..................................................................... 125 Figure 5-8: Preparation of Targeted TADs for Activation Assay ................................... 126 Figure 5-9: Synthesis of TADs with Variable Alcohol Functionalization ..................... 127 Figure 5-10: Synthesis of a TAD to Probe the Influence of Nitrogen Substitution ........ 128 Figure 5-11: Synthesis of Isoxazolidine TADs with Variable Stereochemistry