Tethered libraries: Solid-phase synthesis of substituted urea-linked bicyclic guanidines

The general concept of tethered combinatorial libraries of compounds in whi ch two pharmacophores are found is described. In particular, an improved me thod for the solid-phase synthesis of bicyclic guanidines from reduced N-ac ylated dipeptides, and its use in the synthesis of urea-linked bicyclic gua nidines, is described. The exhaustive reduction of glutamine-containing res in-bound N-acylated dipeptides, using borane-THF, generated compounds conta ining three secondary amines and one primary amine. Following selective tri tyl protection of the primary amine, treatment of the three secondary amine s with thiocarbonyldiimidazole (CSIm(2)) and mercuric acetate (Hg(OAc)(2)) generated the resin-bound bicyclic guanidines. Following trityl deprotectio n, an Fmoc-amino acid was coupled. Upon removal of the Fmoc protecting grou p, the resulting primary amine was treated with hexyl isocyanate to generat e the urea-linked bicyclic guanidines. The desired products were cleaved fr om the resin using hydrogen fluoride. The selection of building blocks and characterization of controls for the synthesis of a combinatorial library i s discussed.