Photocatalytic Methodology for C–N and C–C Bond Formation

Abstract

Visible light photocatalysis has recently been identified as a fruitful area within which to discover new reaction methodology. Photocatalytic strategies involve the use of visible light to drive electron and energy transfer events from organic and transition metal catalysts. This in turn enables radical generation from common functional groups under mild reaction conditions. The combination of photocatalysis with alternate catalytic modes has been particularly successful in providing access to novel bond disconnections. More specifically, photocatalysts are able to modulate the reactivity of transition metals by generating reactive intermediates, performing single electron transfers, and engaging in triplet-triplet energy transfer.

Macrocyclic peptides are a class of structures with clear therapeutic potential but are often challenging to synthesize in an efficient manner. Chapter 2 describes the development of a head to tail cyclization of linear peptides utilizing photoredox catalysis. Importantly, this constitutes a rare example of a carbon-carbon bond forming reaction for peptide macrocyclization. This strategy was broadly effective for peptides containing varied amino acid residues and for a wide range of ring sizes.

Merging photocatalysis with nickel catalysis is an area of intense research interest within the MacMillan laboratory. A strategy combining these areas of catalysis for the cross-coupling of alkyl carboxylic acids with vinyl halide electrophiles is outlined in Chapter 3. Notably, judicious reaction design allowed the use of unstabilized primary and secondary carboxylic acid nucleophiles, an important advance.

It has long been recognized that excited state metal complexes undergo reactivity that is unavailable to their ground state counterparts. However, access to excited electronic states has typically relied on bespoke transition metal complexes or high energy light. In Chapter 4, a photosensitization strategy for carbon-heteroatom bond forming reductive elimination from nickel is described. Within this context, a nickel-catalyzed cross- coupling between sulfonamides and aryl halides exhibiting broad substrate scope is enabled by the light-harvesting capacity of a photocatalyst.