An Efficient Solid‐Phase Synthetic Approach to Prepare TACN‐Functionalized Peptides

1,4,7‐triazacyclononane (TACN) derivatives play important roles in various metal‐based biomedical applications. However, the unmanageable functionalization of TACN remains a long‐standing challenge to yield useful partially substituted building blocks. Herein, by utilizing nitrobenzoxadiazole (NBD) as a thiol‐liable protecting group for secondary amines, a bis‐NBD‐substituted TACN was obtained as the first example in the preparation of partially substituted TACN without strict stoichiometric control and column chromatography. Upon facile deprotection of NBD using solid‐phase synthesis, a series of TACN‐peptide conjugates with different bioactive peptides and chelating units were derivatized from the TACN building block, demonstrating the potential widespread application of this work. By recruiting fluorescent dye NBD as a protecting group, Bis‐NBD‐NO1A is developed as a universal building block to functionalize peptides with TACN derivatives via SPPS. The protection of TACN with NBD becomes the first example to functionalize TACN in a controllable manner. The colour‐guided deprotection of NBD enables further elaborations of TACN as metal ion chelators for different biomedical applications (PET, MRI, etc.).