Photocatalytic Decarboxylation of Carboxylic Acids to Construct Unnatural Amino Acids and Peptides-Containing Piperidine Rings.

Unnatural amino acids are fundamental building blocks in drug discovery, as their structural diversity critically influences both biological activity and pharmacokinetic properties. Although the piperidine ring is widely prevalent as a privileged scaffold in approved drugs, efficient methodologies for constructing piperidine-containing unnatural amino acids remain underdeveloped. In this study, we report a visible-light-driven decarboxylative conjugate addition reaction that utilizes piperidine carboxylic acids as radical precursors and dehydroalanine derivatives as radical acceptors, enabling the efficient synthesis of piperidine-incorporated unnatural amino acids. This protocol features mild conditions, broad substrate scope, and avoids preactivation steps, demonstrating excellent atom economy and functional group tolerance. The method provides a concise and efficient synthetic platform for the construction of piperidine-based unnatural amino acid libraries and the late-stage modification of peptides, holding significant promise for applications in innovative drug discovery.