Divergent Synthesis of ΔAA-Peptides Using a Bioorthogonal pro-Amino Acid and Aqueous Flavin Photocatalyst: Green...

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.