Synthesis of 12-membered macrocyclic templates and library analogs for PPI

We report novel syntheses of 12-membered macrocyclic templates and a library of 4000 macrocyclic analogs. The key macrocyclization step was performed at up to 100g scale without resorting to syringe pumps, flow reactors or large volumes of solvent. An interesting observation of considerably different permeability properties was made on diastereomeric analogs due to differences in intramolecular hydrogen bond interactions.