Development and Study of Light-Driven Methods for Catalytic Asymmetric Hydrogen Atom Transfer Using Peptide Thiols

Abstract

Hydrogen atom transfer (HAT) is a ubiquitous step in radical-based transformations of organic molecules. Alongside advances in radical chemistry as a whole, the synthetic community has recently developed asymmetric variants of a significant suite of radical elementary steps. However, development of methods which incorporate asymmetric HAT are scarce, and there are almost no methods which accomplish asymmetric HAT in a way which is both catalytic and highly enantioselective. Methods which have been reported are restricted to a very narrow scope of substrates and have not been generalized.Small molecule b-turn biased tetrapeptides have been demonstrated to be effective catalysts for a variety of asymmetric transformations and are advantageous in their ease of synthesis and generalizability. This dissertation describes advances in asymmetric HAT catalyzed by such peptides containing a cysteine-based thiol as the key reactive H-atom donor. In Chapter 2, the development and study of a method for light-driven asymmetric intermolecular hydroamination of olefins using sulfonamides is presented. Residue-by- residue modification of the peptide structure led to development of a highly selective peptide catalyst, and experimental and computational mechanistic studies highlight the key non-covalent interactions which govern enantioinduction. In Chapter 3, insights found during the development of the asymmetric transformation are applied to expand the scope of a racemic sulfonamide hydroamination procedure. In Chapter 4, ongoing efforts towards utilizing peptide thiols for a mechanistically distinct asymmetric hydroamination of olefins with heteroaryl amines are presented.