Late‐stage Tyrosine ortho ‐C(sp 2 )‐H Alkenylation for Macrocyclic Peptide SuFEx Proximity Labeling and Targeted Degradation

Abstract Cyclic peptides hold great promise in drug discovery due to their conformational stability, proteolytic resistance, and ability to disrupt protein–protein interactions (PPIs). However, their therapeutic potential is often constrained by reversible binding, while covalent labeling strategies such as Sulfur(VI) Fluoride Exchange (SuFEx) have largely been limited to linear scaffolds. Here, we report a late‐stage Pd(II)‐catalyzed ortho‐C(sp 2 )‐H alkenylation of tyrosine that achieves directing‐group‐free late‐stage peptide macrocyclization. This strategy preserves the phenolic side chain, which can subsequently be converted into an arylfluorosulfate for SuFEx‐driven covalent labeling. The dual functionality of tyrosine thus enables the construction of macrocyclic scaffolds with enhanced conformational rigidity, intrinsic fluorescence, and covalent reactivity. As proof of concept, we synthesized a cyclic GnRH analogue (c‐leuprolide) that exhibits superior antiproliferative activity compared with its linear counterpart. We further developed a covalent cyclic peptide‐lysosome targeting chimera (CCP‐TAC) that selectively degrades PD‐L1, remodels the tumor immune microenvironment, and exhibits favorable biosafety in vivo. Together, these findings establish tyrosine‐directed C─H functionalization as a versatile platform for multifunctional cyclic peptides, bridging synthetic methodology with therapeutic application and advancing peptide stapling, covalent labeling, and degrader technologies.