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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\u2010stage Pd(II)\u2010catalyzed ortho\u2010C(sp\n                    <jats:sup>2<\/jats:sup>\n                    )\u2010H alkenylation of tyrosine that achieves directing\u2010group\u2010free late\u2010stage peptide macrocyclization. This strategy preserves the phenolic side chain, which can subsequently be converted into an arylfluorosulfate for SuFEx\u2010driven 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\u2010leuprolide) that exhibits superior antiproliferative activity compared with its linear counterpart. We further developed a covalent cyclic peptide\u2010lysosome targeting chimera (CCP\u2010TAC) that selectively degrades PD\u2010L1, remodels the tumor immune microenvironment, and exhibits favorable biosafety in vivo. Together, these findings establish tyrosine\u2010directed C\u2500H functionalization as a versatile platform for multifunctional cyclic peptides, bridging synthetic methodology with therapeutic application and advancing peptide stapling, covalent labeling, and degrader technologies.\n                  <\/jats:p>","DOI":"10.1002\/anie.202524685","type":"journal-article","created":{"date-parts":[[2025,12,26]],"date-time":"2025-12-26T14:12:18Z","timestamp":1766758338000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Late\u2010stage Tyrosine\n                    <i>ortho<\/i>\n                    \u2010C(sp\n                    <sup>2<\/sup>\n                    )\u2010H Alkenylation for Macrocyclic Peptide SuFEx Proximity Labeling and Targeted Degradation"],"prefix":"10.1002","volume":"65","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7800-180X","authenticated-orcid":false,"given":"Peng","family":"Wang","sequence":"first","affiliation":[{"name":"Key Laboratory of Bioorganic Synthesis of Zhejiang Province College of Biotechnology and Bioengineering Zhejiang University of Technology  Hangzhou 310014 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kai","family":"Wang","sequence":"additional","affiliation":[{"name":"Key Laboratory of Bioorganic Synthesis of Zhejiang Province College of Biotechnology and Bioengineering Zhejiang University of Technology  Hangzhou 310014 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuailong","family":"Yin","sequence":"additional","affiliation":[{"name":"Key Laboratory of Bioorganic Synthesis of Zhejiang Province College of Biotechnology and Bioengineering Zhejiang University of Technology  Hangzhou 310014 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoyan","family":"Liu","sequence":"additional","affiliation":[{"name":"Key Laboratory of Bioorganic Synthesis of Zhejiang Province College of Biotechnology and Bioengineering Zhejiang University of Technology  Hangzhou 310014 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wuyan","family":"Xie","sequence":"additional","affiliation":[{"name":"Key Laboratory of Bioorganic Synthesis of Zhejiang Province College of Biotechnology and Bioengineering Zhejiang University of Technology  Hangzhou 310014 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haohui","family":"Li","sequence":"additional","affiliation":[{"name":"Key Laboratory of Bioorganic Synthesis of Zhejiang Province College of Biotechnology and Bioengineering Zhejiang University of Technology  Hangzhou 310014 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiuxiu","family":"Yang","sequence":"additional","affiliation":[{"name":"Key Laboratory of Bioorganic Synthesis of Zhejiang Province College of Biotechnology and Bioengineering Zhejiang University of Technology  Hangzhou 310014 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0761-9434","authenticated-orcid":false,"given":"Qing","family":"Zhu","sequence":"additional","affiliation":[{"name":"Key Laboratory of Bioorganic Synthesis of Zhejiang Province College of Biotechnology and Bioengineering Zhejiang University of Technology  Hangzhou 310014 China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,12,26]]},"reference":[{"key":"e_1_2_7_1_1","doi-asserted-by":"publisher","DOI":"10.1186\/gm441"},{"key":"e_1_2_7_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tips.2023.04.003"},{"key":"e_1_2_7_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bmc.2017.06.052"},{"key":"e_1_2_7_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejmech.2015.01.014"},{"key":"e_1_2_7_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bcp.2022.114985"},{"key":"e_1_2_7_6_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.chemrev.4c00066"},{"key":"e_1_2_7_7_1","doi-asserted-by":"publisher","DOI":"10.1021\/acsmedchemlett.6b00395"},{"key":"e_1_2_7_8_1","first-page":"973","volume":"20","author":"Stebbins J. 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