• Supplements
• Publisher-DOI

Access to small, rigid, and sp³‐rich molecules is a major limitation in the drug discovery for challenging protein targets. FK506‐binding proteins hold high potential as drug targets or enablers of molecular glues but are fastidious in the chemotypes accepted as ligands. We here report an enantioselective synthesis of a highly rigidified pipecolate‐mimicking tricyclic scaffold that precisely positions functional groups for interacting with FKBPs. This was enabled by a 14‐step gram‐scale synthesis featuring anodic oxidation, stereospecific vinylation, and N‐acyl iminium cyclization. Structure‐based optimization resulted in the discovery of FKBP inhibitors with picomolar biochemical and subnanomolar cellular activity that represent the most potent FKBP ligands known to date.