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.