Sequential nucleophilic substitution on halogenated triazines, pyrimidines, and purines: A novel approach to cyclic peptidomimetics

A novel concept for the synthesis of macrocyclic peptidomimetics which inco rporate heteroaromatic units is reported. The method involves sequential. S NAr reactions of orthogonally protected amino groups of peptides and other linear oligomers on halogenated heterocycles such as 2,4,6-trichloro[1,3,5] triazine, 2,4,6-trichloropyrimidine, 4,6-dichloro-5-nitropyrimidine, and 2, 6,8-trichloro-7-methylpurine. The scope of this novel solid-phase approach was systematically evaluated by means of the SPOT-synthesis methodology on planar cellulose membranes. Besides the question of the accessibility of di fferent ring sizes and the compatibility with protecting groups of commonly used amino acids, the applicability of the technique toward different halo genated heteroaromatics and peptidomimetics was studied. It was found that the procedure is well suited to assemble a wide variety of cyclic peptidomi metics differing in both size (11- to 37-membered rings) and chemical natur e of the assembled backbones.