Constrained phenylalanine analogues: Preferred conformation of the 1,2,3,4‐tetrahydroisoquinoline‐3‐carboxylic acid (Tic) residue

Three Tic‐containing (Tic = 1,2,3,4‐tetrahydroisoquinoline‐3‐carboxylic acid) model peptides were synthesized to assess the tendency of this constrained Phe analogue to fold into a β‐bend and a helical structure, and to adopt a preferred side‐chain disposition. The results of the solution conformational analysis, performed by using Fourier transform infrared absorption and ¹H nuclear magnetic resonance, indicate that in chloroform the ‐Aib‐D‐Tic‐Aib‐, ‐(Aib)₂‐D‐Tic‐(Aib)₂‐, and ‐l‐Pro‐D‐Tic‐ sequences fold into intramolecularly H‐bonded forms to a great extent. An X‐ray diffraction analysis on p‐BrBz‐(Aib)₂‐dl‐Tic‐(Aib)₂‐OMe monohydrate and p‐BrBz‐l‐Pro‐D‐Tic‐NHMe allows us to conclude that, while the pentapeptide methylester forms an incipient (distorted) 3₁₀‐helix, the dipeptide methylamide adopts a type‐II β‐bend conformation. In both cases, the d‐Tic side‐chain conformation is d, gauche(‐). The implications for the use of the Tic residue in designing conformationally restricted analogues of bioactive peptides are briefly discussed.