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

An efficient method for the solid-phase synthesis of bis-heterocyclic compounds from resin-bound orthogonally protected lysine is presented. The initial reaction step involves the exhaustive reduction of resin-bound tetra-amides using borane-THF, followed by cyclization of the resulting tetra-amine with either carbonyldiimidazole, thiocarbonyldiimidazole, or oxalyldiimidazole to generate resin-bound bis-cyclic ureas, bis-cyclic thioureas, and bis-cyclic diketopiperazines, respectively. Cleavage from the solid support using hydrogen fluoride, followed by extraction and lyophilization, yields the desired bis-heterocyclic compounds in excellent yield and high purity.

Solid-phase synthesis of bis-2-imidazolidinethiones from resin-bound tripeptides.

The exhaustive reduction of resin-bound tripeptides with borane afforded three secondary amines and one primary amine. The treatment of the solid-support polyamines with thiocarbonyldiimidazole afforded, following cleavage of the solid support, the corresponding bis-cyclic thiourea in good purity and yield.