Solid-phase synthesis of bis-heterocyclic compounds from resin-bound orthogonally protected lysine

An efficient method for the solid-phase synthesis of bis-heterocydic compou nds from resin-bound orthogonally protected lysine is presented. The initia l reaction step involves the exhaustive reduction of resin-bound tetra-amid es using borane-THF, followed by cyclization of the resulting tetra-amine w ith either carbonyldiimidazole, thiocarbonyldiimidaziole, or oxalyldiimidaz ole to generate resin-bound his-cyclic ureas, bis-cyclic thioureas, and bis -cyclic diketopiperazines, respectively. Cleavage from the solid support us ing hydrogen fluoride, followed by extraction and lyophilization, yields th e desired bis-heterocyclic compounds in excellent yield and high purity.