Tandem tetrahydroisoquinoline-4-carboxylic acid/β-alanine as a new construct able to induce a flexible turn

Tetrahydroisoquinoline-4-carboxylic acid, a constrained \u3b22-amino acid named \u3b2-TIC, was for the first time synthesized in enantiopure form. The biocatalytic route here applied represents one of the few successful examples of enzymatic resolution of \u3b22-amino acids. Model tetrapeptides, i.e. Fmoc-L-Ala-\u3b2-TIC-\u3b2-Ala-L-Val-OBn, containing both isomers of \u3b2-TIC, were prepared. Both computational and NMR studies were performed. A reverse-turn conformation was observed in the case of R-\u3b2-TIC enantiomer, the enantiomer obtained in 99% e.e. by enzymatic resolution. \u3b2-TIC/\u3b2-Ala construct represents the first example of a flexible turn mimetic containing a cyclic and an acyclic \u3b2-amino acid. Furthermore, the presence of an aromatic ring of \u3b2-TIC could facilitate non-covalent interactions increasing the potential of this scaffold for the preparation of protein-protein interaction modulators