One-Pot Assembly of Amino Acid Bridged Hybrid Macromulticyclic Cages through Multiple Multicomponent Macrocyclizations.

An important development in the field of macrocyclization strategies towards molecular cages is described. The approach comprises the utilization of a double Ugi four-component macrocyclization for the assembly of macromulticycles with up to four different tethers, that is, hybrid cages. The innovation of this method rests on setting up the macromulticycle connectivities not through the tethers but through the bridgeheads, which in this case involve N-substituted amino acids. Both dilution and metal-template-driven macrocyclization conditions were implemented with success, enabling the one-pot formation of cryptands and cages including steroidal, polyether, heterocyclic, peptidic, and aryl tethers. This method demonstrates substantial complexity-generating character and is suitable for applications in molecular recognition and catalysis.