SELECTIVE TRANSFORMATIONS OF EPOXIDES USING BIMETALLIC CATALYSTS: CATALYST DEVELOPMENT, METHODOLOGY, AND MECHANISTIC STUDIES A Dissertation Presented to the Faculty of the Graduate School of Cornell University In Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy by Jessica Rachel Lamb August 2017 © 2017 Jessica Rachel Lamb SELECTIVE TRANSFORMATIONS OF EPOXIDES USING BIMETALLIC CATALYSTS: CATALYST DEVELOPMENT, METHODOLOGY, AND MECHANISTIC STUDIES Jessica Rachel Lamb, Ph.D. Cornell University 2017 Epoxides are versatile building blocks in organic chemistry due to their inherent reactivity and synthetic availability. One particularly interesting reaction is the carbonylation of epoxides to β-lactones. β-Lactones are themselves high-value intermediates for natural-product and aliphatic-polyester synthesis. Bimetallic [Lewis + − acid] [Co(CO)4] catalysts allow for the mild and economical synthesis of β-lactones from epoxides and the inexpensive feedstock carbon monoxide. The modular salen ligand is a common framework for the Lewis acid portion of these catalysts and recent extensive tuning of the ligand sterics has improved the regio- and enantioselectivity for the carbonylation of 2,3-disubstituted epoxides. Herein, we report further development and application of these bimetallic catalysts to a variety of reactions. First, electronic variations are studied for the enantioselective carbonylation of meso- and racemic cis-epoxides. Enantioselectivity was improved for every substrate, resulting in some of the highest levels of enantioenrichment for epoxide carbonylation. We then applied the knowledge gained from previous catalyst development to design a new ligand for the contrasteric carbonylation of isobutylene oxide to the important polyester monomer pivalolactone. This catalyst is the first to give pivalolactone as the major product of an epoxide carbonylation reaction, representing a major advance in the field. Next, we applied previously developed bimetallic catalysts to the isomerization of epoxides to ketones. A wide array of monosubstituted epoxides were rearranged to methyl ketones under mild conditions and low catalyst loadings. We further expanded this methodology to the regioselective isomerization of trans-epoxides. This method displayed high and complementary selectivities to the Wacker oxidation of internal olefins. The mechanism of this reaction was thoroughly studied and additional catalyst tuning allowed for the first kinetic resolution of benzyl-substituted trans-epoxides with synthetically useful selectivity factors. Finally, related [Lewis acid][Mn(CO)5] catalysts were developed and applied to the deoxygenation of epoxides to alkenes using carbon monoxide as the terminal reductant. This is a rare example of a catalytic system that proceeds with clean inversion of stereochemistry for cis- and trans-epoxides, highlighting the potential for stereospecific alkene inversion through a two-step epoxidation-deoxygenation. Collectively, these studies demonstrate the utility of these catalysts for a range of selective epoxide transformations. BIOGRAPHICAL SKETCH Jessica Lamb was born in Madison, WI and grew up in Fargo, ND. She attributes her love of science to teachers in middle and high school who inspired her and helped her test out of sophomore general chemistry, starting her love affair with the central science. Upon graduating from South High School in 2008, she attended the University of North Dakota as a chemistry major with minors in mathematics and Spanish. After one semester of inorganic chemistry research, she found her home in organic and organometallic chemistry in the lab of Prof. Irina Smoliakova, where she worked on the synthesis of cyclopalladated complexes on silica gel for her senior honors thesis. She also did two summers of research in the coatings and polymeric materials lab of Prof. Victoria Johnston-Gelling. This background in organic and polymer chemistry drew her to the research of Prof. Geoffrey Coates. After graduating summa cum laude with a B.S. in chemistry as a scholar in the Honors Program in 2012, she moved to Cornell University and joined the Coates group for her graduate career. As an NSF graduate research fellow, she worked on selective reactions of epoxides using [Lewis acid][nucleophilic anion] catalysts. Outside of lab, she joined the ballroom dance team, engaged in science outreach, and tried to keep up with her unreasonable number of hobbies, including crafting, music, reading, and photography. Upon completing her Ph.D. in 2017, she will begin her professional career as a postdoctoral researcher in the lab of Jeremiah Johnson at M.I.T. iii ACKNOWLEDGMENTS First and foremost, I have to thank my advisor, Prof. Geoff Coates, for supporting me during the last five years. He is an endless fountain of new ideas and he has inspired me to become a better scientist and mentor. I learned so much about how to ask the right questions, how to troubleshoot difficult reactions (run it neat and heat it up!), and how to optimize white space in a figure. I wouldn’t be the chemist I am today if it wasn’t for all of your guidance and advice. The Coates group is a special place to do research and it wouldn’t be possible without you. Next, I have to thank Prof. William Dichtel and Prof. Chad Lewis for serving on my A exam committee and Prof. Brett Fors and Prof. Song Lin for stepping up and serving on my B exam committee. I have been fortunate to have not two, but four amazing chemists available for discussions and answering my unending questions. I am grateful for the opportunity to know and have learned from you all. Thank you to all of the previous members of the Coates group who have contributed to the great group culture of excellent science and comradery, especially to the carbonylation subgroup; I feel like I know you all even if we haven’t met. Furthermore, thank you to all of the members of 572 during my tenure. Special shout out to Michael Mulzer for laying the ground work for all of my projects; teaching me how to make catalysts, run columns, and set up carbonylations; bequeathing me countless ligands, catalysts, and epoxides; helping me write my first Coates group paper; answering all of my questions; and generally being an awesome inspiration. If I have had any success in graduate school, it is from standing on your giant shoulders. Chad Ellis taught me how to cannula transfer and crystallize things. Brandon Tiegs taught me about the glovebox and so much more during our two years as the sole (permanent) inhabitants of 572. I have also had the pleasure to work with Zachary Nelson, Veronika iv Kottisch, Xiaopeng Yu, Michelle Lee, and Aran Hubbell. You have all made coming to work more enjoyable and you have made me a better mentor, colleague, and friend. I am fortunate to have gone through this amazing adventure with the other fifth years in the Coates group: Kyle O’Connor, Qi Zheng, and Dave Vaccarello. You have all provided emotional support, especially during this last crazy year! We are almost done! Thank you to all of the other members of the Coates group with whom I have overlapped during my five years! Everyone has always been open for great discussions or a trip to the Dairy bar. I will forever look back at my time in this group with fond memories because of all the wonderful people I met here. Special thanks to Anne LaPointe and Kelly Case for keeping the Coates group running! We wouldn’t be able to do anything without the two of you. Other people in the chemistry department I have to thank are Sam MacMillan for helping me get my first crystal structure, Anthony Condo for helping me with GCMS and DART, and especially Ivan Keresztes for all of the NMR help and discussions on the “beast” that is the mechanism paper, which is unfortunately (or fortunately?) not included herein. Of course, I must also thank the National Science Foundation for a graduate research fellowship and the Department of Energy for supporting my research. Outside of lab, I need to thank the members of the Cornell DanceSport Team and Expanding Your Horizons, particularly Maria Carrizales and Lilli Morris; it was a great honor to serve as your Finance Chair. The ballroom team and EYH will always have a special place in my heart as the non-lab things that kept me sane. Finally, I need to thank all of my friends and family who have stood by me and supported me throughout graduate school and my whole life. There are too many to list, but I would be nothing without you. You have all dealt with my crazy, Dan more than most, and I will be forever grateful for the shoulders to lean on, encouraging words, and funny distractions that have helped me through this journey. v TABLE OF CONTENTS BIOGRAPHICAL SKETCH iii ACKNOWLEDGMENTS iv LIST OF FIGURES x LIST OF SCHEMES xiii LIST OF TABLES xv CHAPTER 1: Overview of Properties and Reactions of Epoxides 1 1.1 Introduction and Synthetic Routes to Epoxides 2 1.2 Carbonylation of Epoxides to β-Lactones 4 1.2.1 Background 4 1.2.2 Carbonylation of Epoxides Using [Lewis acid]+[Co(CO) ]− 4 5 Catalysts 1.2.3 Recent Catalyst Advances for Regio- and Enantioselective 8 Carbonylation of Epoxides 1.3 Isomerization of Epoxides to Carbonyl Compounds 12 1.4 Deoxygenation of Epoxides to Alkenes 16 REFERENCES 19 CHAPTER 2: Catalyst Development for the Enantio- and Regioselective 29 Carbonylation of Disubstituted Epoxides 2.1 Introduction 30 2.2 Catalyst Electronic Variation for the Enantioselective Carbonylation 33 of Cis-Epoxides to Trans-β-Lactones 2.2.1 Background