STEREOSELECTIVE 1,2‒ AND 1,4‒ADDITIONS ENABLED BY ASYMMETRIC ORGANOCATALYSIS Jennifer Lynn Fulton A dissertation submitted to the faculty of the University of North Carolina at Chapel Hill in partial fulfillment of the requirements for the degree of Doctor of Philosophy in the Department of Chemistry in the College of Arts and Sciences. Chapel Hill 2020 Approved by: Jeffrey Johnson Marcey Waters Frank Leibfarth Jeffrey Aubé Simon Meek © 2020 Jennifer Lynn Fulton ALL RIGHTS RESERVED ii ABSTRACT Jennifer Lynn Fulton: Stereoselective 1,2‒ and 1,4‒Additions Enabled by Asymmetric Organocatalysis (Under the direction of Jeffrey S. Johnson) I. Enantio- and Diastereoselective Organocatalytic Conjugate Additions of Nitroalkanes to Enone Diesters Enantio- and diastereoselective conjugate addition reactions between nitroethane or nitropropane and enone diesters are described. A bifunctional triaryliminophosphorane catalyzed the addition reaction with consistently excellent stereoselectivities and yields across a wide range of substrates. Using the geminal diester functional handle present in the adducts, local desymmetrization via diastereotopic group discrimination was demonstrated and a polyfunctionalized lactam with three contiguous stereocenters was synthesized. II. Asymmetric Organocatalytic Sulfa-Michael Addition to Enone Diesters iii An asymmetric sulfa-Michael addition of alkyl thiols to enone diesters is reported. The reaction is catalyzed by a bifunctional triaryliminophosphorane-thiourea organocatalyst and provides a range of α-sulfaketones in high yields and enantioselectivities. Leveraging the gem- diester functional handle via a subsequent diastereotopic group discrimination generates functionalized lactones with three contiguous stereocenters. III. Efforts Towards the Reduction of α-Imino Esters via Dynamic Kinetic Resolution Efforts toward the enantioconvergent trichlorosilane-mediated reduction of β- substituted α-imino esters are described. Chiral Lewis base catalysis enables the synthesis of N-aryl unnatural amino esters with β-alkyl or β-halo substitution in moderate yields and stereoselectivities. Reactions of β-alkyl α-imino esters provided suffered from poor diastereoselectivity, whereas decomposition and product instability plagued the β-halo analogs. Additional complicating factors associated with dynamic kinetic resolution and imine chemistry are broadly discussed and noted in this work. IV. Organocatalytic Iso-Pictet-Spengler Reaction for the Enantioconvergent Synthesis of Tetrahydro-γ-Carbolines iv Progress towards an enantioconvergent iso-Pictet-Spengler reaction using thiourea/Brønsted acid co-catalysis is reported. Preliminary control studies demonstrated a significant difference in reactivity between α-substituted β-formyl amides and esters, with the latter proving amenable for asymmetric reaction development. Optimized conditions provide unprotected tetrahydro-γ-carbolines with two contiguous stereocenters, including an exocyclic stereogenic center and orthogonal ester functional handle. Finally, promising efforts to expand the substrate scope to include α- and β-keto esters are disclosed. v To Karen, David, and Robert Fulton, for the sacrifices you made to get me to this point. and To Joan Bierwirth & Nancie Blaine, for endless love and support here on earth, and in heaven. vi ACKNOWLEDGEMENTS First and foremost, I would like to thank my advisor Jeff Johnson for his mentorship. Under your tutelage I have grown as a chemist, problem solver, and communicator, and I thank you for your patience and unending support when I have struggled. Through these actions, and countless others, you have demonstrated how I can be a better leader, advocate, and compassionate human being. I am so grateful to have had the opportunity to be a member of your lab, and for your guidance throughout my doctoral research. Moreover, as a graduate student and advocate for underrepresented groups, I would be remiss not to mention my gratitude for your leadership as chair of the department during these past five years. You have supported AM_WISE’s mission from day 1, and you helped us make our ambitions a reality. I have witnessed the growth of this department under your direction, and I am even more proud to be a member of the UNC chemistry department than the day I arrived. Thank you for all you have done, and will do, to advocate for and support both your lab group, and the UNC chemistry community. I would also like to thank my final defense committee: Professors Marcey Waters, Frank Leibfarth, Simon Meek, and Jeff Aubé. Thank you for taking the time to serve on my committee, and for the conversations we have had over the years. You all have contributed to my growth as a chemist and leader, and I am grateful for your efforts. I would also like to thank Professors Dave Nicewicz, Bo Li, and Alex Miller for serving on my preliminary oral exam committee. vii To all of the past and present Johnson lab members: thank you, thank you, thank you. I would not be the chemist or person I am today without all of you. You all have provided invaluable guidance for so many of my projects, presentations, and practical skills, and I am so thankful to have learned from each and every one of you. More importantly, thank you for making graduate school not just livable, but enjoyable. I will deeply miss all of our impromptu chemistry chats, random trips to Benny’s or Starbucks, daily zoom chats during quarantine, and countless other fun times we have had living life in lab. Thank you to Matt Horwitz and Ericka Bruske for collaborating on the iminophosphorane-catalyzed projects, and to Matt especially for teaching me a great deal about asymmetric organocatalysis. Thank you to Blane Zavesky for obtaining X-ray crystal structure data for the thiol addition product, and to Evan Crawford for obtaining X-ray crystal structure data for the iso-Pictet-Spengler reaction product. Thank you to Laura Wonilowicz for being a fantastic mentee and partner for the trichlorosilane reduction chemistry. A huge thank you to Will Cassels for collaborating on the iso-Pictet-Spengler project, and for also being such a wonderful friend and labmate. Thank you to Jacob Robins and Pedro de Jesus Cruz for countless hours of wonderful conversation about anything and everything. You both are phenomenal chemists who work far too hard, and I have learned a great deal from the two of you. Thank you to Kim Alley for your wonderful sense of humor and passion for chemistry. Thank you to Desiree Matias for your support from day 1 of graduate school, and for a friendship that I would not trade for the world. Thank you to Jessica Griswold for spending four years with me in Caudill 223, for your support and guidance, for loving cats as much as I do, for playing softball with me, and for a thousand other things. I am so grateful for the network of support among the women of the Johnson lab. viii Thank you to every member of Allies for Minorities and Women in Science and Engineering (AM_WISE), and to the faculty and staff who have helped us along the way. Thank you to Leah Bowers for being an incredible co-president and even better friend. Thank you for being so passionate and determined to achieve even our most ambitious dreams, and for the blood, sweat, and tears it took to tackle our goals. Thank you to Morgan Clark and Tayliz Rodriguez for taking up the mantle and leading AM_WISE to bigger and better things. Thank you to Marcey Waters and Frank Leibfarth for their service as faculty advisors. You both give AM_WISE the freedom and independence to be truly graduate-run, but also dropped everything to support and defend us any time we asked for help. Thank you to my mentors at Grinnell College and UC-Irvine, who helped me reach this point. Thank you to Professor Stephen Sieck for igniting my passion for organic chemistry, and for teaching me the value of independence and decision-making in research. Thank you to Minna Mahlab for teaching me how to mentor students, but also for showing me how to advocate for underrepresented groups in science. Thank you to my extended lab family from the Rychnovsky lab at UC-Irvine (Alex Wagner, Jacob DeForest, Emily Gish, Ryan King). You all showed me what a supportive and fun lab community looks like, and made me part of the team. A special thank you to Alex Wagner for teaching me countless practical skills at the hood, for helping me with graduate school applications, and for your continued mentorship. Thank you to my Greenleaf Vineyard Church community. I am so grateful I found this church home to restore and grow my faith during my graduate studies, and I could never fully express my gratitude for all of the hugs, prayers, and words of encouragement you have given me. ix I am especially grateful for the support of my amazing friends: Sara Musetti, Emily Howe, and Samantha Pilicer. Sara, thank you for being the very best roommate-turned-best friend. It’s a true miracle we connected as strangers, and I am so blessed to have gone on this PhD journey with you. Emily, thank you for encouraging and supporting me from Grinnell to Chapel Hill, and everywhere in between. Sam, thank you for being one of my biggest cheerleaders, and for always picking up the phone when I call. Though we have been in different states, in different labs, I always know I can always look to you for encouragement, a good rant, laughter, or just to cry. I look forward to many, many more years of adventures with all three of you. Thank you to my amazing Dungeons and Dragons crew in Raleigh (John, Jason, Evan, Alex, Keith, and Kyle). Considering we met on Reddit, I did not anticipate finding a group of friends that I would laugh with nearly every week for the last 2.5 years. Thank you for all of our crazy adventures together, but also for the wonderful friendship we have built.