Highly Constrained Linear Oligopeptides Containing Heterocyclic alpha-Amino Carboxylic Acids

Abstract

Two spiroheterocyclic 2H-azirin-3-amines, 1f and 1g, were shown to be useful synthons for the dipeptides N-(4-aminotetrahydro-2H-pyran-4-yl)prolinate (Thp-Pro) and the corresponding thiopyran derivative, Tht-Pro, respectively. By coupling of 4-bromobenzoic acid with 1f or 1g and saponification, followed by repeating the coupling and saponification steps, oligopeptides of type 4-BrBz-(Thp-Pro)n-OMe and 4-BrBz-(Tht-Pro)n-OMe were prepared, and their conformations were evaluated in solution by NMR techniques and in the crystalline state by X-ray crystallography. All of these sterically highly congested oligopeptides adopt fairly rigid helical conformations. It is interesting to note that the hexapeptide with Thp forms a 310-helix, whereas the Tht analog has a beta-bend ribbon spiral conformation