In Situ Generation of Fluorescent Amino Acids and Peptides via Double C–H Activation/Annulation
Liangliang Song, Zhefan Zhang, Zhenwei Lv, Jinyuan Xu, Mengru Zhan, Shuo Tang, Huanhuan Li, Nanxi Wang, Lingchao Cai
Abstract
Unnatural fluorescent amino acids have been synthesized to obtain better emission wavelengths, fluorescence lifetime, and quantum yields. Despite major advances, most of them face inherent restrictions as fluorophores and are limited to the methods from coupling between amino acids and fluorophores. Herein, we develop a Rh(III)-catalyzed double C–H activation/annulation reaction of diverse benzamides with alkynes for the synthesis of tricyclic-fused aromatic hydrocarbon carbocations. The robustness of this strategy is demonstrated by the diversification of Lys-based amino acids and peptides, in situ generating tricyclic fluorophores. This method features broad substrate scope and high atom and step economy as well as high chemo- and site selectivity. Unsymmetrical double C–H activation/annulation employing two different alkynes is well tolerated to produce the unnatural fluorescent amino acids in high yields. These tricyclic fluorophores display tunable fluorescence emission, low cytotoxicity, and the potential for specifically targeting lysosomes.