Building and breaking bonds: cyanoamidation and defluorination reactions in the synthesis of natural products and small molecules

Abstract

Chapter 1: An introduction to the development of cyanoamidation as a method to activate a C–CN bond and intramolecularly add it across a unit of unsaturation. The prior work related to the development of the cyanoamidation reaction is discussed, with an emphasis on asymmetric cyanoamidation.Chapter 2: We report the total synthesis of (+)–eburnamonine using enantioselective alkene cyanoamidation to form the all-carbon quaternary stereocenter. Palladium, phosphoramidite ligand, and a Lewis acid combine to form a co-catalyst that promotes C– CN bond activation of a cyanoformamide, followed by intramolecular alkene cyanoamidation. Overall, the synthesis of (+)–eburnamonine is accomplished in 8 steps from 4-methylene hexanoic acid and tryptamine, providing an example of asymmetric aliphatic-tethered alkene cyanoamidation and its use in total synthesis. Chapter 3: A discussion of the current research progress towards addressing limitations to cyanoamidation methods, involving a labile protecting group. Reaction optimization and HTE results are explored. Chapter 4: Work towards the development of a defluorination method of trifluoromethyl arenes to generate esters. Structure validation, reaction optimization, mechanistic analysis, and substrate scope are discussed.