Divergent Synthesis of ΔAA-Peptides Using a Bioorthogonal pro-Amino Acid and Aqueous Flavin Photocatalyst: Green Light Enhances Catalyst Performance and Product Selectivity

Dehydroamino acids (ΔAAs) are vital building blocks in the design and optimization of peptide drugs. The exact olefin geometry, side chain chemotype, and ancillary β-carbon substituents play a significant role. Unfortunately, general approaches to install these motifs into peptides are lacking, complicated by the instability of unsaturated residues during traditional amide-bond coupling and failure of divergent protocols, such as oxidative Heck and Horner–Wadsworth–Emmons, to accommodate a complete range of substrate classes. Herein, we conceive and interrogate an original bioorthogonal reagent, β-sulfonyldehydroamino acid (ΔSulf), that can be site-specifically encoded into standard peptides through solid- or liquid-phase synthesis. When combined with an aqueous flavin photocatalyst, myriad boronic acids and 525 nm light—a more biologically benign portion of the flavin visible absorption spectra that has not previously been exploited for flavin photoredox catalysis,—this latent residue becomes one of several (Z)-ΔAA variants (aromatic, heteroaromatic, aliphatic) via stereoretentive radical conjugate addition and β-scission. The importance of green light is established through mechanistic studies showing that it tempers radical formation and discourages flavin-catalyzed isomerization, controlling product selectivity. We apply our original reagent and catalytic platform in a brief medicinal chemistry campaign to discover tetrapeptides that modulate Aβ42 aggregation for the treatment of Alzheimer's disease.