Selective Native N_(in)-H Bond Activation in Peptides with Metallaphotocatalysis

Author(s)

Delgado, Jose A. C. ; Amaral, JessicaC. ; Penteado, Paula S. ; Ferreira, Antonio G. ; da Silva, Maria FatimaG. F. ; Koenig, Burkhard ; Paixao, Marcio W.

• Document type: Journal article
• Source: JACS AU; v. N/A, p. 7-pg., 2025-03-28.

Abstract

The development of chemical methods enabling site-selective incorporation of noncanonical amino acids into peptide backbones with precise functional tailoring remains a critical challenge. Particularly compelling is the use of underexplored endogenous amino acid hotspots, such as the N- (in) of tryptophan, as versatile anchors for diversification. Herein, we report a chemoselective N(sp(2))-H bond activation strategy targeting native tryptophan residues within peptide frameworks, exemplified by GLP-1 (7-37), using nickel metallaphotocatalysis under postsynthetic solid-phase conditions. This selective N- (in)-arylation reaction proceeds efficiently within 3 h of light irradiation in highly functionalized heterogeneous environments, employing minimal excesses of electrophile and base, alongside catalytic quantities of nickel, ligand, and photocatalyst. The method affords homogeneous peptide products with high chemoselectivity and operational simplicity. We envision that this strategy could contribute to advancing the design of the next-generation long-acting class II G protein-coupled receptor agonist therapeutics. (AU)

• FAPESP's process: 24/09943-0 - Sustainable Development of Drugs with Chalcogens: From Synthesis to Application
• Grantee: Márcio Weber Paixão
• Support Opportunities: Regular Research Grants
• FAPESP's process: 21/06099-5 - Development of new photochemical methodologies for the synthesis of small molecule and biomolecule modifications
• Grantee: Márcio Weber Paixão
• Support Opportunities: Regular Research Grants