Photocatalytic Methodology for Fluoroalkylation and Peptide Cyclization

Abstract

Photoredox catalysis represents the use of photo-excitable molecules to activate substrates via single-electron transfer. The strong redox properties of photocatalysts enable oxidation and reduction of generally unreactive functional groups, converting organic substrates to radical intermediates that can be engaged in useful and otherwise challenging reactivity manifolds. As such, photoredox has been established as a powerful platform for accessing and diversifying complex molecular architectures under mild conditions. Metallaphotoredox, the merger of photoredox with transition metal catalysis, has further expanded chemists’ synthetic toolbox and enabled difficult bond disconnections via metal-catalyzed radical cross-coupling and light-facilitated elementary organometallic steps. Additionally, due to its mildness and biocompatibility, photoredox has found novel applications in biorelevant contexts, such as protein functionalization and peptide macrocyclization. New technologies for the selective installation of fluorinated moieties into organic molecules are highly sought after in drug discovery due to the pharmacological benefits of fluorine incorporation, yet are typically challenging to develop. Chapters 2 and 3 demonstrate the potential of metallaphotoredox to enable novel polyfluoroalkylation platforms. In particular, Chapter 2 describes a nickel/photoredox-catalyzed protocol for (hetero)aryl bromide difluoromethylation. Silyl radical-mediated halogen atom abstraction renders bromodifluoromethane a convenient difluoromethylating agent, with broad arene and heteroarene scope. A notable correlation between optimal reagent stoichiometry and substrate electronic character is discussed. Chapter 3 details the first merger of decatungstate photocatalysis with copper catalysis, enabling a general aliphatic C(sp3)–H trifluoromethylation platform. Abundant feedstocks, natural products, and pharmaceuticals are site-selectively trifluoromethylated, with high tolerance for traditionally challenging polar functional groups. Mechanistic studies provide insight into the role of the copper catalyst, a finding with significant implications for the growing field of iodonium-based copper-mediated trifluoromethylation. Macrocyclic peptides are an established class of therapeutics with unique properties, but the scale-up and validation of these promising structure remains a bottleneck in the drug discovery process. Chapter 4 describes ongoing development of a photocatalytic technology for the streamlined synthesis of thioether-linked peptides via tandem solid-support release/cyclization. The platform relies on the use of light-enabled spin-center shift for mild cleavage from solid supports, made possible by implementing a phenyl ketone linker compatible with automated solid-phase synthesis.