Strategies for the regioselective N-functionalization of tetraazacycloalkanes. From cyclam and cyclen towards more sophisticated molecules

Different approaches for the selective N-substitution of tetraazacycloalkan es and more specifically cyclam and cyclen are reported. The N-functionaliz ation can be performed either before or after cyclization, and various prot ecting groups might be used to discriminate one, two or three nitrogen atom s. For example, tert-butyloxycarbonyl (Boc) appears to be a very convenient protecting group since it can be removed under mild conditions. trans-Disu bstituted macrocycles are easily prepared by using trans-dioxotetraazacyclo alkanes or a cyclam containing a bisaminal moiety as the starting material. These precursors allow for the synthesis of preorganized molecules such as cryptands and macrotricycles in relatively large scale and in very decent yields.