Heterocycles Old and New: Carbonylazoles as Chemoselective Acylation Reagents and the Synthesis and Applications of Benzindolizinones by Stephen Todd Heller A dissertation submitted in partial satisfaction of the requirements for the degree of Doctor of Philosophy in Chemistry in the Graduate Division of the University of California, Berkeley Committee in charge: Professor Richmond Sarpong, Chair Professor Robert G. Bergman Professor Daniel Nomura Fall 2012 1 Abstract Heterocycles Old and New: Carbonylazoles as Chemoselective Acylation Reagents and the Synthesis and Applications of Benzindolizinones By Stephen Todd Heller Doctor of Philosophy in Chemistry University of California, Berkeley Professor Richmond Sarpong, Chair Carbonylazole derivatives have been shown to be chemoselective and efficient acylating reagents under a variety of conditions. Catalysis with pyridinium salts, as well as with DBU or DABCO are discussed, as is the thermal reaction of imidazole carbamates with carboxylic acids to provide esters. The application of a protic solvent-mediated cycloisomerization approach to two isomers of benzindolizinone – a relatively unstudied heterocyclic system – and the syntheses of two Erythrina alkaloids are also discussed. Chapter 1 provides an overview of the fundamental importance of the carbonyl group in the chemistry of life, as well as in the service of man. Key processes through which these versatile groups react are illustrated with an emphasis on the chemistry of esters. The chapter concludes with a survey of the application of carbonylimidazoles as acyl donors from their first development by Staab to the present. Through another line of inquiry, it was discovered that imidazole carbamates and ureas are chemoselective esterification and amidation reagents. The optimization, substrate scope, and mechanism of esterification and amidation of carboxylic acids mediated by imidazole-based reagents are discussed in Chapter 2. The innate reactivity of carbonyl imidazole reagents with a range of nucleophiles is also explored. Following this initial discovery, it was found that pyridinium salts greatly enhance the reactivity of carbonylimidazole derivatives as acylation reargents for esterification and amidation. Chapter 3 details the development of this mode of catalysis and outlines a mechanistic proposal in which pyridinium salts act as both Brønsted acid and nucleophilic catalysts. Finally, the scope of this technology in the synthesis of difficult to access oxazolidinones, as well as esters and amides, is discussed. This work was executed in partnership with Tingting Fu. Drawing on the possibility that carbonylazole acyl donors could be potentiated through nucleophilic catalysis, a DBU-catalyzed N-acylation of indoles and oxazolidinones was devised. Chapter 4 covers the development of this reaction, as well as the subsequent finding that this 2 acylation was chemoselective even in the presence of more reactive amine and alcohol functional groups. This work was performed in collaboration with Erica Schultz. The solvent-promoted cycloisomerization of quinoline and isoquinoline propargylic carbinols to benz[e]- and benz[g]indolizinones, respectively, is described in Chapter 5. The study of the fundamental reactivity of these new heterocyclic motifs is discussed. The formal synthesis of 3- demethoxyerythratidinone using this cycloisomerization strategy, as well as its application in studies toward the synthesis of cocculidine are also detailed. i To my loving family, for all the warmth, light, and kisses ii Table of Contents Chapter One: Importance of the Carbonyl Group: Acylation and Its Applications 1.1 Carbonyls as Biological Lynchpins 1 1.2 Carbonyls in the Service of Man: A Primer on Carbonyl Reactivity 3 1.3 Acetic Acid and the Process of Acylation 5 1.4 Phosgene and the Process of Carbonylation 7 1.5 Carbonylimidazole Derivatives as Chloroformate and Acyl Chloride 11 Substitutes 1.6 Notes and References 16 Chapter Two: Carbonylimidazoles as Reagents for Esterification and Amidation 2.1 Introduction 19 2.2 The Origin of Our Interest in Carbonylimidazoles 20 2.3 Probing Novel Reactivity of Imidazole Carbamates 22 2.4 Mechanistic Investigations 26 2.5 Addressing Issues of Chemoselectivity 28 2.6 Alternative Reaction Pathways of Imidazole Carbamates 29 2.7 Extension to Amide Synthesis 32 2.8 Large Scale Synthesis of Esterification and Amidation Reagents 36 2.9 Experimental Section 37 2.10 Notes and References 55 Chapter Three: Dual Brønsted Acid/Nucleophilic Activation of Carbonylimidazoles 3.1 Introduction 58 3.2 Model System Studies 60 iii 3.3 Scope and Mechanism of Oxazolidinone Synthesis Under 64 Pyridinium Catalysis 3.4 Ester Synthesis Under Pyridinium Catalysis 67 3.5 Experimental Section 71 3.6 Notes and References 84 Chapter Four: Chemoselective N-Acylation of Indoles with Carbonylazoles 4.1 Introduction 87 4.2 Reaction Optimization and Initial Scope 90 4.3 Thermodynamic Control: Implications for Selectivity and 92 Reagent Design 4.4 Kinetic Control: Putting the Chemoselectivity Puzzle Together 96 4.5 Application to the Acylation of Oxazolidinones 98 4.6 Preliminary Mechanistic Investigations 99 4.7 Experimental Section 101 4.8 Notes and References 116 Chapter Five: Study and Synthesis of Benzindolizinones: Applications to Alkaloid Synthesis 5.1 Introduction 118 5.2 Synthesis of Indolizines and Indolizinones: A Point of Embarkation 121 5.3 Substrate Synthesis 124 5.4 Synthesis of Benz[e]indolizinones 126 5.5 Synthesis of Benz[g]indolizinones 128 5.6 Mechanistic Considerations 131 5.7 Application of the Benz[g]indolizinone Core to the Synthesis 135 of Erythrina Alkaloids iv 5.8 Formal Synthesis of (+)-3-Demethoxyerythratidinone 136 5.9 Toward the Total Synthesis of Cocculidine 141 5.10 Experimental Section 149 5.11 Notes and References 176 Appendix 1: Selected Spectra for Compounds Disclosed in Chapter 2 179 Appendix 2: Selected Spectra for Compounds Disclosed in Chapter 3 213 Appendix 3: Selected Spectra for Compounds Disclosed in Chapter 4 238 Appendix 4: Selected Spectra for Compounds Disclosed in Chapter 5 298 v Acknowledgements The Road Not Taken Two roads diverged in a yellow wood, And sorry I could not travel both And be the one traveler, long I stood And looked down one as far as I could To where it bent in the undergrowth; Then took the other, as just as fair, And having perhaps the better claim, Because it was grassy and wanted wear; Though as for that the passing there Had worn them really about the same, And both that morning equally lay In leaves no step had trodden black. Oh, I kept the first for another day! Yet knowing how way leads on to way, I doubted if I should ever come back. I shall be telling this with a sigh Somewhere ages and ages hence: Two roads diverged in a wood, and I— I took the one less traveled by, And that has made all the difference. -Robert Frost, Mountain Interval, 1920. It is impossible to name with certainty all of the people who have contributed to the road that I have walked to this point, but these mentors in particular have cumulatively shaped my scientific and professional outlook. Professor Richmond Sarpong provided me with a lab in a dark hour, afforded subtle and effective guidance, and provided me room to take wing. Professor Bergman has acted as an invaluable resource in planning mechanistic studies; however, he has also served as a pedagogical mentor, and my teaching will forever reflect his influence. Professors Toste and Trauner took the first cuts at an unhewn chemist, and their styles and traits are indelible. Professor Rousslang inspired a young man with too many interests and instilled a flame for chemistry. Dr. Ravi Natarajan removed the yoke of corporate science and provided a safe environment for a budding chemist to whet their curiosity through original research. Over the years, I have had the good fortune to work in the company of a diverse and stimulating group of people. My Toste group classmates, Chris Boyd, Dan Gray, and Jane Wang made time in lab more fun than it should have been. Our different areas of expertise also provided a ready- made discussion group. I am grateful for their friendship, advice, and support. vi My first fall in the Sarpong group was momentous for many reasons, but the introduction of a new cast of characters was one of the most enjoyable parts of this transition. I am deeply indebted to my labmates in the corner office of Latimer: Jesse Cortez, Amy Hamlin, David Lapointe, and Raul Leal. The entire Sarpong community gave me a warm welcome and I have continued to feel blessed to work with everyone in the group. Though they didn’t have the dubious distinction of sharing a lab with me, a number of other members of the Berkeley community were key players in my experience in graduate school. Aaron Lackner and Jeff Wu have been great friends and didn’t hold it against me when I left the Toste group. They even let me come back and use the HPLC. Even though we overlapped only relatively briefly, I relished my conversations with Ethan Fisher, whether they were about old school rap, chemistry, or topics not to be mentioned in a dissertation. I want to thank Terry Lebold for all of his encouragement, kind words, and stimulating discussion. In particular, his emphasis on working collaboratively has been invaluable to the group. My horizons have been greatly expanded by working with Erica Schultz, my partner in indole crime, and a fantastic resource for the group. I look forward to the day when we are both tenured faculty members and running into each other at conferences with students in tow. It has been great working directly with Jim Newton to win softball games, drink a bunch of bad beer, and develop the coolest ketone synthesis since Grignard. I was unbelievably lucky to work with a highly skilled undergraduate student, Tingting Fu for over a year, and her hard work and dedication are manifest in the pyridinium catalysis work.