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.
McArthur et al. (Thu,) studied this question.