Oral Presentation 8th Modern Solid Phase Peptide Synthesis & Its Applications Symposium 2022

Among 21 proteinogenic amino acids, cysteine (Cys) and selenocysteine (Sec) plays unique and critical roles for biological functions of peptides and proteins. In addition, these ꞵ-thiolated/selenolated amino acids are essential for producing proteins with potential medicinal applications by peptide ligation protocols. Despite that, a general and concise method to enantio-pure ꞵ-thiolated/selenolated amino acids remains an unsolved problem. Here, we present a general strategy for stereoselective addition of alkyl radicals, which can be produced from ubiquitous carboxylic acids or their derivatives, to thiazoline and selenozoline bearing a chiral pivalaldehyde acetal for both steric control of radical addition and a “smart” protecting group, which are orthogonal to peptide synthesis conditions. The simple access to a broad family of enantio-pure ꞵ-thio/selenolated amino acids will broaden the utility of ligation-dechalcogenenation strategy, allow incorporation of unnatural amino acids at will and ready rebuilding of disulfide-engineered peptides and proteins, which were highlighted by the preparation of a series of peptide analogs bearing unnatural amino acids, Cytochrome c oxidase subunit protein 7C and peptide drug oxytocin.