Photoinduced Decarboxylative Radical Addition Reactions for Late Stage Functionalization of Peptide Substrates

Abstract

Photoredox chemistry has greatly stimulated the application of radical based transformations in medicinal chemistry and early drug discovery in recent years. Carboxylate groups have been identified as traceless leaving groups that can be converted into radical intermediates capable of undergoing 1,4‐conjugate addition reactions to Michael acceptors. Herein, we show the successful C‐terminal derivatization of small peptide substrates by using this methodology in a parallel synthesis setting. Finally, we outline a general strategy for the γ‐homologation of several drugs derived from α‐amino acids in a late stage functionalization (LSF) approach.

Photocatalysis in the Life Science Industry

“…A similar protocol was developed by Sanofi Aventis as a general strategy to derivatize small peptidic substrates. Using a parallel photoreactor and automated purification libraries of peptide analogues could be prepared (Scheme b) . Derivatization of nateglinide and benazepril precursors was also reported.…”

“…Using a parallel photoreactor and automated purification libraries of peptide analogues could be prepared (Scheme 60b). 181 Derivatization of nateglinide and benazepril precursors was also reported.…”

Direct decarboxylative Giese reactions

“…Very recently, Ruf and co-workers expanded upon the work of MacMillan and co-workers to show successful C-terminal derivatisation of small peptide substrates. 39 They used a more extensive array of Michael acceptors including a,b-unsaturated ketones, as well as less electrophilic olefins such as cinnamic acid ester and vinyl-substituted (hetero)aromatic motifs.…”

Selective synthesis of functionalized linear aliphatic primary amines via decarboxylative radical-polar crossover

“…1B). In addition, decarboxylation, 71,80–85 desilylation 70,86,87 and other pathways for α-aminomethyl radical generations 88–92 have also been reported. Although the developed HAM reactions typically exhibit high product yields, certain limitations persist.…”