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.
Keywords: amino acids; chiral resolution; enzymes; molecular modeling; peptidomimetics.
© 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.