LADA strategy for the synthesis of unnatural amino acids and direct modifications of peptides

Unnatural amino acids (UAAs) are important building blocks in organic synthesis and drug discovery. They are also frequently integrated into peptides or proteins for biological studies. However, the direct and simplified synthesis of UAAs remains a great challenge. At the same time, vast known peptide modifications are based on carbon-heteroatom bonds. There are no general methods for peptide modifications via the construction of C-C bonds. To address this challenge, herein we propose the LADA strategy, which is composed of two steps: the selective labeling and activation of cysteine residues, the desulfurization to generate carbon-centered radical and the radical addition to alkenes to build C-C bond. This one-pot protocol has obvious advantages such as good functional group tolerance, biocompatible reaction conditions, and retained stereochemistry. This strategy was successfully utilized for the synthesis of unnatural amino acids and direct modifications of peptides.