Expedient Synthesis of <i>N</i> -Protected/ <i>C</i> -Activated Unnatural Amino Acids for Direct Peptide Synthesis

Unnatural amino acids play a pivotal role in protein engineering and drug discovery. However, their efficient and enantioselective synthesis remains a central challenge in organic chemistry. Here, we describe a concise and practical two-step approach for the synthesis of diverse unnatural amino acid building blocks from readily available terminal alkynes. This method utilizes mild gold(I) catalysis in combination with inexpensive chiral <i>tert</i>-butylsulfinamide to deliver these valuable structures with excellent enantiomeric excesses─often upgraded to enantiopurity by simple recrystallization─and broad substrate scope. These unnatural amino acid derivatives are bench-stable and preequipped with a novel <i>t</i>-butylsulfenyl as the N-protecting group and a mildly activated carboxylic acid, making them immediately applicable to peptide synthesis under both solution- and solid-phase conditions. Furthermore, we demonstrate their successful incorporation into multiple peptide sequences using a coupling protocol that proceeds with negligible to no epimerization, even in challenging cases.