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However, the chemical space of imidazole\u2010containing side chains remains remarkably underexplored, largely due to the synthetic challenges associated with the selective installation and diversification of imidazole motifs on complex biomolecules. Classical reactions for forming or modifying imidazoles typically require harsh conditions, limiting their applicability in sensitive biomolecular settings. Here, we report a mild and modular late\u2010stage multi\u2010component annulative imidazolation strategy for the direct installation of histidine\u2010analogous side chains in peptides and proteins. In contrast to classical Debus\u2013Radziszewski protocols, the reaction proceeds efficiently at ambient temperature under near\u2010neutral to basic aqueous conditions, with water as the optimal cosolvent. The method enables rapid access to structurally diverse imidazole motifs with high chemoselectivity and biomolecular compatibility. Beyond providing facile access to noncanonical histidine analogues, this platform offers a programmable approach for tuning peptide electrostatics and function through late\u2010stage side\u2010chain modification.<\/jats:p>","DOI":"10.1002\/anie.2539581","type":"journal-article","created":{"date-parts":[[2026,9,12]],"date-time":"2026-09-12T03:43:27Z","timestamp":1789184607000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Late\u2010Stage Annulative Imidazolation for Expanding Histidine\u2010Analogous Side Chains in Peptides and Proteins"],"prefix":"10.1002","author":[{"given":"Huixing","family":"Zhang","sequence":"first","affiliation":[{"name":"State Key Laboratory of Elemento\u2010Organic Chemistry College of Chemistry Nankai University  Tianjin China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Limeng","family":"Wang","sequence":"additional","affiliation":[{"name":"School of Chemistry and 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As a result the aldehyde component in these systems was largely restricted to HCHO. In contrast because 1 2\u2010diketones do not undergo decarbonylative annulation under the standard conditions they can be paired with a broader range of aldehydes."},{"key":"e_1_2_8_65_1","unstructured":"In intermediate INT7 the dissociation pathway is understood to proceed via a synchronized deprotonation and OH\u2010elimination sequence. This concerted process is found to be endothermic by approximately 20\u00a0kcal\/mol a thermodynamic requirement substantially lower than those calculated for the non\u2010aromatizing analogues8and9(>70\u00a0kcal\/mol). This notable lowering of the barrier can be reasonably attributed to the significant driving force of imidazole ring aromatization."},{"key":"e_1_2_8_66_1","doi-asserted-by":"publisher","DOI":"10.1039\/c3cc41099d"},{"key":"e_1_2_8_67_1","doi-asserted-by":"publisher","DOI":"10.1002\/psc.2867"},{"key":"e_1_2_8_68_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.joc.9b02504"},{"key":"e_1_2_8_69_1","doi-asserted-by":"publisher","DOI":"10.1021\/jf001082d"},{"key":"e_1_2_8_70_1","doi-asserted-by":"publisher","DOI":"10.1021\/ja208009r"},{"key":"e_1_2_8_71_1","doi-asserted-by":"publisher","DOI":"10.1038\/nchembio.1792"},{"key":"e_1_2_8_72_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467\u2010021\u201022654\u20107"},{"key":"e_1_2_8_73_1","doi-asserted-by":"publisher","DOI":"10.1039\/d0sc02933e"},{"key":"e_1_2_8_74_1","doi-asserted-by":"publisher","DOI":"10.1021\/bi960835f"},{"key":"e_1_2_8_75_1","doi-asserted-by":"publisher","DOI":"10.1039\/C7SC00215G"},{"key":"e_1_2_8_76_1","doi-asserted-by":"publisher","DOI":"10.1002\/anie.202402880"},{"key":"e_1_2_8_77_1","doi-asserted-by":"publisher","DOI":"10.1007\/s12551\u2010025\u201001309\u20107"},{"key":"e_1_2_8_78_1","doi-asserted-by":"publisher","DOI":"10.1002\/advs.202507946"},{"key":"e_1_2_8_79_1","doi-asserted-by":"publisher","DOI":"10.1002\/pro.19"},{"key":"e_1_2_8_80_1","doi-asserted-by":"publisher","DOI":"10.1002\/cbic.201800628"},{"key":"e_1_2_8_81_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jcim.4c01957"},{"key":"e_1_2_8_82_1","unstructured":"Unlike the canonical His side chain the N\u2010linked imidazole ring in iso\u2010His lacks an exchangeable proton preventing it from serving as a proton shuttle via tautomerization."},{"key":"e_1_2_8_83_1","doi-asserted-by":"publisher","DOI":"10.1002\/anie.202008528"},{"key":"e_1_2_8_84_1","unstructured":"Predicted pKavalues of Lys His and Arg differ slightly from reported experimental values (see Ref. [78]). 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