Side-Selective Solid-Phase Metallaphotoredox N_(in)-Arylation of Peptides

Area of Science:

• Chemical Biology
• Organic Chemistry
• Medicinal Chemistry

Background:

• Postsynthetic peptide modification advances drug discovery and chemical biology.
• Current methods primarily target reactive polar/ionizable side chains, leaving aromatic systems like tryptophan's N(in) challenging to modify.

Purpose of the Study:

• To develop a method for orthogonal N-arylation of tryptophan residues within peptide sequences.
• To expand the scope of postsynthetic peptide diversification.

Main Methods:

• Integration of metallaphotocatalysis with solid-phase peptide synthesis (SPPS).
• On-resin N-arylation of tryptophan-containing peptides.
• Chemoselective introduction of C(sp2)-N bonds.

Main Results:

• Successful orthogonal N-arylation at the N(in) of tryptophan in protected peptide sequences.
• Demonstrated chemoselectivity in the presence of native redox-sensitive side chains.
• Established a novel protocol for decorating aromatic amino acid side chains.

Conclusions:

• Metallaphotocatalysis fused with SPPS offers new avenues for postsynthetic diversification of native amino acid side chains.
• This method addresses a long-standing challenge in modifying tryptophan residues.
• Opens new perspectives in peptide drug discovery and chemical biology.