Tandem Tetrahydroisoquinoline-4-carboxylic Acid/β-Alanine as a New Construct Able to Induce a Flexible Turn

Tetrahydroisoquinoline-4-carboxylic acid, a constrained β2-amino acid named β-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 β2-amino acids. Model tetrapeptides, i.e. Fmoc-L-Ala-β-TIC-β-Ala-L-Val-OBn, containing both isomers of β-TIC, were prepared. Both computational and NMR studies were performed. A reverse-turn conformation was observed in the case of R-β-TIC enantiomer, the enantiomer obtained in 99% e.e. by enzymatic resolution. β-TIC/β-Ala construct represents the first example of a flexible turn mimetic containing a cyclic and an acyclic β-amino acid. Furthermore, the presence of an aromatic ring of β-TIC could facilitate non-covalent interactions increasing the potential of this scaffold for the preparation of protein-protein interaction modulators.