Rational Design and Asymmetric Synthesis of Potent and Neurotrophic Ligands for FK506‐Binding Proteins (FKBPs)

To create highly efficient inhibitors for FK506-binding proteins, a new asymmetric synthesis for pro-(S)-C5-branched [4.3.1] aza-amide bicycles was developed. The key step of the synthesis is an HF-driven N-acyliminium cyclization. Functionalization of the C5 moiety resulted in novel protein contacts with the psychiatric risk factor FKBP51, which led to a more than 280-fold enhancement in affinity. The most potent ligands facilitated the differentiation of N2a neuroblastoma cells with low nanomolar potency.