Synthesis of polyaza macropolycyclic ligands

General routes to macropolycycles containing small rings and pyridine me described. The routes utilize macrocyclic lactams as precursors with diphenylphosphoryl azide (DPPA) as an activating agent for the dicarboxylic acids. In bridged lactams, traditional methods of total deprotection (HBr-HOAc in the presence of phenol or concentrated H2SO4) are not successful, because the deprotection in the smaller rings is incomplete. Small rings can be totally deprotected using sodium metal. In the case of pyridine-containing macrocycles with small rings, the use of sodium is undesirable; hence, initial benzyl protection of the small cyclononane ring, allows for deprotection by the traditional HBr-HOAc method. The synthesis of four different macropolycyclic lactams, their reduction and deprotection are described.