Photoredox C(2)-Arylation of Indole- and Tryptophan-Containing Biomolecules

Abstract

We introduce a novel and straightforward methodology for photoredox arylation of an indole scaffold using aryldiazonium salts under mild and metal-free conditions. Our approach enables the regioselective and chemoselective introduction of several aryl groups to the C(2) position of indoles and tryptophan, even in competition with other amino acids. This approach extends to the late-stage functionalization of peptides and lysozyme, heralding the unprecedented arylation of tryptophan residues in wild-type proteins and offering broad utility in chemical biology.

Scheme 1. Modification of Trp Residues in Biomolecules

Scheme 2. Photoredox C(2)-Arylation of the Indole Motif

Irradiation performed with 1 W blue LED power instead of 10 W. Overnight reaction. Recovered starting material in brackets. Determined by ¹H qNMR using 1,3-benzodioxole as the internal standard. Isolated yields.

Scheme 3. Photoredox C(2)-Arylation of Peptides and Lysozyme

Isolated yield. Recovered starting material in brackets. Three hours of reaction. (A) Trp residue positions in the protein structure. Arylation was detected in all these residues. (B) Deconvoluted intact mass spectra of the reaction mixture.

Scheme 4. Plausible Reaction Mechanism