One Step Back and Two Steps Forward – Cleaving Bonds to Trigger Alkene Addition Reactions

My seminar presents catalysts for the addition of C–H, C–C, & C–N bonds across alkenes. Our general approach is to cleave these bonds with transition metal catalysts to trigger the addition reactions. Our mechanistic work in this area elucidated the role of Lewis base and Lewis acid additives in these reaction through a combination of initial rate kinetics, natural abundance 13C isotope effects, control experiments, and crossover studies. In alkene aminocyanation, Lewis acid reactivity can dominate the reaction – in some cases acting as the sole catalytic agent. For cyanoamidation, we established a linear solvation energy relationship between enantioselectivity and solvent polarity through construction of a Kamlet-Taft multiparameter solvatochromic equation. Our mechanism-focused approach paved the way for the application of cyanoamidation in the total synthesis of the alkaloid (+)-eburnamonine. I will present our lab’s work on applying these lessons to the madangamine alkaloids via a palladium-catalyzed C–C bond functionalization cascade reaction. Finally, I will present our re-entry into the popular area of alkene hydroacylation. We have developed chiral 2-aminopyridine co-catalysts capable of useful levels of enantioinduction in Rh-catalyzed hydroacylation. Catalyst development and applications in synthesis will be presented.