A Bifunctional Aminoxyl–Bipyridine Peptide Catalyst for the Atroposelective Copper-Catalyzed Aerobic Oxidation of Biaryl Diols

High Resolution Image Download MS PowerPoint Slide Chiral aminoxyl catalysts have shown promise for applications in asymmetric oxidations but have been historically synthetically challenging to develop. The paucity of chiral catalysts is particularly severe in aerobic oxidations when cocatalysis involves the combined action of an aminoxyl species and a Cu-based metal complex. In these oxidations, the venerable bipyridine ligand (bpy) is most commonly employed to bind to the Cu metal center. The utility of bpy ligands, in this context and many others, has created great interest in the development of modular chiral variants. However, the design of efficient chiral versions within this ligand class remains a significant challenge. Herein, we report a bifunctional chiral peptide ligand featuring both an aminoxyl and a bipyridyl motif and demonstrate its utility in the copper(I)-catalyzed aerobic oxidation of biaryl diols to furnish axially chiral aldehydes. This catalyst was found to efficiently catalyze atroposelective oxidations using ambient air as the terminal oxidant. Additionally, catalyst bifunctionality was found to be essential for enantioselectivity in this desymmetrization, affording axially chiral products in up to >99.5:0.5 er, facilitated by combined initial enantiotopic group selection followed by varying levels of secondary kinetic resolution. Central to catalyst design is the synthesis and incorporation of bipyridylalanine into an aminoxyl-containing peptide. Mechanistic studies reveal a first-order kinetic profile on the catalyst, which, in combination with computational experiments, suggest that the aminoxyl and bipyridyl moieties of a single bifunctional peptide function in unison throughout the catalytic cycle.