Strategies for the Regioselective N-Functionalization of Tetraazacycloalkanes. From Cyclam and Cyclen Towards More Sophisticated Molecules

Different approaches for the selective N-substitution of tetraazacycloalkanes and more specifically cyclam and cyclen are reported. The N-functionalization can be performed either before or after cyclization, and various protecting groups might be used to discriminate one, two or three nitrogen atoms. For example, tert-butyloxycarbonyl (Boc) appears to be a very convenient protecting group since it can be removed under mild conditions. trans-Disubstituted macrocycles are easily prepared by using trans-dioxotetraazacycloalkanes 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.

tetraazamacrocycles - regioselectivity - protecting groups - N-substitution - cryptands