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 synthesised for the first time in enantiopure form. The biocatalytic route applied herein represents one of the few successful examples of enzymatic resolution of β2‐amino acids. Model tetrapeptides, namely, Fmoc‐l‐Ala‐β‐TIC‐β‐Ala‐l‐Val‐OBn (Fmoc=fluorenylmethyloxycarbonyl, Bn=benzyl), containing both isomers of β‐TIC, were prepared. Both computational and NMR spectroscopy studies were performed. A reverse‐turn conformation was observed in the case of (R)‐β‐TIC enantiomer that was obtained in 99 % enantiomeric excess by enzymatic resolution. The 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 to increase the potential of this scaffold for the preparation of protein–protein interaction modulators. Flexibility and adaptability: Tetrahydroisoquinoline‐4‐carboxylic acid, a constrained β2‐amino acid named β‐TIC, was prepared in enantiopure form, for the first time, and used for the synthesis of model tetrapeptides. The (R)‐β‐TIC/β‐Ala construct represents the first example of a flexible turn mimetic, containing cyclic and acyclic β‐amino acids, which could promote hairpin formation (see scheme).