Palladium-Catalyzed C2 Functionalization of an Iodinated Tryptophan Scaffold for Fluorescent Probe Discovery

Fluorescent unnatural amino acids are important tools for peptide and biomolecular imaging, yet the development of new probes that combine strong emission with minimal structural perturbation remains a challenge. Herein, we report a versatile strategy for the diversification of tryptophan based on a stable and isolable C2-iodinated building block that is readily compatible with palladium-catalyzed cross-coupling reactions. This approach allows for the installation of alkynyl and aryl substituents at the C2 position, providing rapid access to a range of unnatural tryptophan derivatives and peptides in good to high yields. Photophysical studies revealed that aryl-substituted tryptophan analogues exhibit strong fluorescence, high quantum yields, and environment-sensitive emission. Strong fluorescence was retained upon incorporation into a tryptophan-containing dipeptide, highlighting the potential of these relatively small C2-substituted analogues as imaging probes for biomolecular imaging applications.