Enantiopure constrained pseudodipeptides based on pipecolic acid scaffold are obtained by a two-step synthesis involving an aza-Prins cyclization to deliver piperidine-lactones, followed by LiNTf₂-promoted aminolysis with various amino acids.

Abstract

Peptidomimetics, that can take advantage of bioavailability and metabolic stability, are considered as an important class of molecules and constitute thus a large research field in medicinal chemistry. With the aim of obtaining constrained examples for drug discovery, we designed a two-step synthesis of cis-4-hydroxy pipecolic acid derivatives as pseudodipeptides mimics. This straightforward procedure concerns the coupling of amino acid-derived homoallylic amines with glyoxylic acid via an aza-Prins cyclization to deliver piperidine-lactones, followed by LiNTf₂-promoted aminolysis of the lactone with various amino acids. The 4-hydroxy pipecolic acid peptidomimetics are obtained as single enantiomers and with a high diastereomeric control and they represent original and modular scaffolds for drug discovery.