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

5 years ago

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

Andrea Bonetti, Alessandro Contini, Raffaella Bucci, Davide Tessaro, Donatella Nava, Francesca Clerici, Sara Pellegrino, Maria Luisa Gelmi

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).

Publisher URL: http://onlinelibrary.wiley.com/resolve/doi

DOI: 10.1002/chem.201701045