{"doi":"10.1002/anie.202511832","title":"Divergent Synthesis of ΔAA‐Peptides Using a Bioorthogonal <i>pro</i> ‐Amino Acid and Aqueous Flavin Photocatalyst: Green Light Enhances Catalyst Performance and Product Selectivity","abstract":"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.","journal":"Angewandte Chemie International Edition","year":2025,"id":532822,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":3,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9449,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":658840,"name":"Steven Bloom","orcid":"0000-0002-4205-4459","position":1,"is_corresponding":false},{"id":1017373,"name":"Pei‐Hsuan Chen","orcid":null,"position":0,"is_corresponding":true}],"reference_count":85,"raw_metadata":null,"created_at":"2026-07-19T02:51:27.893975Z","pmid":"40842206","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}