Visible-light-mediated catalyst-free synthesis of unnatural alpha-amino acids and peptide macrocycles

To address the shortcomings in the application of bioactive peptides as drugs, incorporation of unnatural amino acids (UAAs) has been used. Here, the authors report an ionic compound-promoted C-N cleavage of alkyl pyridinium to generate alkyl radicals upon excitation by visible light, and apply it for deaminative hydroalkylation of alkenes to synthesise diverse beta-alkyl substituted UAAs. The visible light induced, photocatalysts or photoabsorbing EDA complexes mediated cleavage of pyridinium C-N bond were reported in the past years. Here, we report an ionic compound promote homolytic cleavage of pyridinium C-N bond by exploiting the photonic energy from visible light. This finding is successfully applied in deaminative hydroalkylation of a series of alkenes including naturally occurring dehydroalanine, which provides an efficient way to prepare beta-alkyl substituted unnatural amino acids under mild and photocatalyst-free conditions. Importantly, by using this protocol, the deaminative cyclization of peptide backbone N-terminals is realized. Furthermore, the use of Et3N or PPh3 as reductants and H2O as hydrogen atom source is a practical advantage. We anticipate that our protocol will be useful in peptide synthesis and modern peptide drug discovery.