A simple and highly efficient route to the FKBP-binding domain (FKBD) from the natural product rapamycin has been developed, which entails a sequence of ozonolysis/Baeyer-Villiger/Wittig reactions. The newly synthesized FKBD may serve as a core to assemble hybrid macrocyclic libraries for the discovery of novel probes of protein function and to synthesize new ligands for the FKBP family of proteins.