Effective synthesis of bis-bispidinone and facile difunctionalization of highly rigid macrocyclic tetramines

An effective synthesis which provides facile access to highly rigid tetraazamacrocycles possessing labile functional groups is reported. Essential to the approach is bis-bispidinone, a versatile substrate which can be prepared from an unusually stable bispidine diethyl ketal building block and requires a non-aqueous isolation process. Further functionalization of the substrate allows direct and concurrent incorporation of functionalities onto the bis-bispidine tetraazamacrocyclic framework, in particular those that are labile during the macrocycle formation.