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Hiroshige Ogawa, [Yuuya Nagata](https://orcid.org/0000-0001-5926-5845), Tsz Ki Chan, Yudai Matsuda, Hugh Nakamura

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[Rapid Construction of a Tyr C6–Trp C5′ Linkage: Application in the Total Synthesis of Micitide 982, a Noncanonical Cyclic Peptide](https://mdr.nims.go.jp/datasets/8c33affd-91e8-4e21-825b-4c5ea578b0b1)

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Research ArticleHow to cite: Angew. Chem. Int. Ed. 2025, 64, e202516053doi.org/10.1002/anie.202516053Total Synthesis Hot PaperRapid Construction of a Tyr C6–Trp C5′ Linkage: Application in theTotal Synthesis of Micitide 982, a Noncanonical Cyclic PeptideHiroshige Ogawa, Yuuya Nagata, Tsz Ki Chan, Yudai Matsuda, and Hugh Nakamura*Abstract: In this study, a facile synthesis method for ahighly strained Tyr C6-to-Trp C5′ linkage was developed.This method enables the convergent introduction ofarbitrary biaryls to peptide linkers through electrochem-ically assisted Ni-catalyzed cross-electrophile coupling,followed by regioselective Larock macrocyclization.Additionally, using this approach, the total synthesisof the ribosomally synthesized and post-translationallymodified peptide (RiPP) molecule micitide 982 wasaccomplished. Furthermore, this synthetic strategy allowsfor the incorporation of various biaryls.IntroductionA variety of RiPPs have been isolated in recent years dueto their ability to quickly and accurately predict chemicalstructures from genomic sequences, making them moreaccessible for prediction than natural compounds such asterpenoids and alkaloids.[1–6] These RiPPs, synthesized byribosomes and subsequently generated by diverse tailoringenzymes, exhibit intriguing structures and biological activities.Among the natural products of these RiPPs, highly strainedstructures and those containing peculiar biaryl linkages arefrequently observed.[5][*] H. Ogawa, Prof. Dr. H. NakamuraThe Hong Kong University of Science and Technology (HKUST),Clear Water Bay, HK SAR 999077, ChinaE-mail: hnakamura@ust.hkProf. Dr. Y. NagataWPI Institute for Chemical Reaction Design and Discovery(WPI-ICReDD), Hokkaido University, Sapporo 001-0021, Japan &Autonomous Polymer Design and Discovery Group Research Centerfor Macromolecules and Biomaterials, National Institute forMaterials Science (NIMS), 1-2-1 Sengen, Tsukuba, Ibaraki 305-0047,JapanT. K. Chan, Prof. Dr. Y. MatsudaCity University of Hong Kong, Kowloon, Tat Chee Avenue, HK SAR,ChinaAdditional supporting information can be found online in theSupporting Information section© 2025 The Author(s). Angewandte Chemie International Editionpublished by Wiley-VCH GmbH. This is an open access article underthe terms of the Creative Commons Attribution License, whichpermits use, distribution and reproduction in any medium, providedthe original work is properly cited.To date, numerous noncanonical cyclic peptides containingbiaryl moieties have been isolated (Figure 1a). Amongthese, some are known to possess atropoisomerism at thelinkage site connecting the two aromatic rings. Representativeframeworks exhibiting atropisomerism within biaryl regionsinclude cross-linkages formed by tryptophan–tryptophan,tryptophan–tyrosine, and tryptophan–histidine linkages; forseveral of these cross-linkages, established synthetic methodsare available. However, a synthesis strategy has yet to bedeveloped for certain linkages (Figure 1a). In this study, wereport the development of a simple method for constructingthe highly strained Tyr C6-to-Trp C5′ linkage present inmicitide 982 (1).Micitide 982 (1), isolated in 2023, is a novel cyclic peptidebelonging to the RiPPs class (Figure 1a).[7] Structurally, itconsists of three amino acid residues, namely l-tyrosine,l-proline, and l-tryptophan, forming a highly strained Tyr-Trp linkage with a cyclic peptide structure. Micitide 982 (1)was isolated from a 10 L of fermentation of a bacterialstrain expressing the precursor peptide and P450 for itsbiosynthesis, yielding 5 mg of the compound. However, dueto its limited quantity, the biological activity of micitide 982(1) remains unknown. Furthermore, the highly strained Tyr-Trp linkage, composed of the three amino acid residues inmicitide 982 (1), is also found in pseudosporamide (2), whichwas isolated in 2020.[8] In this study, a new and convenientsynthetic route for the highly strained Tyr C6-to-Trp C5′linkage was developed, utilizing Ni-catalyzed electrochemicalcross-electrophile coupling followed by regioselective Larockmacrocyclization. This modular approach enabled the conciseconstruction of the Tyr C6-to-Trp C5′ linkage, markingthe total synthesis of micitide 982 (1), and facilitated thestraightforward synthesis of its analogs.The biosynthetic pathway for biaryl-containing RiPPshas been proposed as follows (Figure 1b).[9–18] Ribosomallysynthesized linear peptides containing leader sequences arecyclized through oxidation by cytochrome P450 (CYP450)enzymes that harbor heme at their active sites, resultingin the formation of cross-linkages with biaryl moieties.Subsequently, the leader peptides, which serve as recogni-tion elements for the enzymes, are enzymatically cleaved,ultimately yielding noncanonical cyclic peptides that featurebiaryl cross-linkages.Recently, considerable progress has been made in the arti-ficial biosynthesis of biaryl cross-linkages (Figure 1c).[6,7,19–26]Typically, this involves harnessing enzymes identified throughgenomics that catalyze the formation of biaryl bonds.For example, P450 enzymes, implicated in cross-linkageAngew. Chem. Int. Ed. 2025, 64, e202516053 (1 of 10) © 2025 The Author(s). Angewandte Chemie International Edition published by Wiley-VCH GmbHhttps://orcid.org/0000-0001-5475-7883mailto:hnakamura@ust.hkhttp://creativecommons.org/licenses/by/4.0/http://crossmark.crossref.org/dialog/?doi=10.1002%2Fanie.202516053&domain=pdf&date_stamp=2025-09-17Research Articlea)b)c)d)Figure 1. a) Representative noncanonical cyclic peptides. b) Proposed biosynthetic pathway. Cc) Biosynthesis. d) This work.Angew. Chem. Int. Ed. 2025, 64, e202516053 (2 of 10) © 2025 The Author(s). Angewandte Chemie International Edition published by Wiley-VCH GmbH 15213773, 2025, 46, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/anie.202516053 by Yuuya Nagata - National Institute For , Wiley Online Library on [02/09/2026]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons LicenseResearch Articlebiosynthesis according to genomic data, are expressed inEscherichia coli. Then, chemical synthesis can producelinear peptides, which are subsequently incubated with thecultured P450 enzymes to enable atroposelective and artificialbiosynthesis of biaryl moieties.[19,20] However, due to theenzyme-specific nature of these reactions, their applicabilityis often limited to specific substrates, making the creation ofdiverse biaryl cross-linkages a persistent challenge.[7,21]This study reports the development of a modularand straightforward chemical synthesis method for biaryl-containing cross-linkages—specifically, the Tyr C6-to-Trp C5′linkage that does not rely on enzymatic catalysis (Figure 1d).By employing peptide linkers bearing terminal halogens andalkynes, this approach allows for the modular introduction ofvarious biaryl units. Notably, the combination of Ni-catalyzedelectrochemical cross-electrophile coupling and subsequentregioselective Larock macrocyclization proved to be highlyeffective. The electrochemical cross-electrophile couplingfacilitated by Ni catalysts occurs under mild conditionsat room temperature, enabling the facile incorporation ofbiaryl motifs into peptide linkers with only three aminoacid residues. Furthermore, the subsequent Larock macro-cyclization enabled the construction of the Tyr C6-to-TrpC5′ linkage from simple starting materials in just two steps.This modular strategy also enables the synthesis of analogsthat are difficult to produce via enzymatic methods, therebyexpanding the diversity of biaryl cross-linkages that can begenerated.Results and DiscussionOne of the most common methods for the synthesis of cyclicpeptides is macrocyclization through amide coupling.[27–41]Therefore, an attempt was made to construct the highlystrained Tyr C6-to-Trp C5′ linkage in 4 through macrocy-clization via amide coupling (Figure 2a). Compounds 2 and3 were synthesized as precursors for cyclization, and variousrepresentative amide coupling reagents were screened. As aresult, compound 4 derived from 2 was not observed underthe conditions employing EDCI, DCC, DMTMM, PyBOP,HATU, or COMU. Even when using compound 3, compound4 was not observed under the conditions employing EDCI,DCC, DMTMM, or PyBOP. Further screening revealed thatwhile trace amounts of 4 were detected using compound3 under the conditions employing HATU or COMU, theyield was significantly low (<5%). From these results, it wasrevealed that the synthesis of the Tyr C6-to-Trp C5′ linkage 4via macrocyclization using amide coupling is challenging dueto the significant strain caused by the rigidity and linearity ofthe biaryl moiety.Based on the above background, the design for thestraightforward construction of the Tyr C6-to-Trp C5′ linkageand the synthesis plan for micitide 982 (1) are depictedin Figure 2b. The most challenging aspect of synthesizingmicitide 982 (1) lies in forming the highly strained Tyr C6-to-Trp C5′ linkage. Conversely, our group recently reportedthe synthesis of several RiPPs containing biaryl motifs,such as cihunamide B,[42] strecintide 839,[43] lapparbin,[44]and neopetromin.[45] In these syntheses, Larock macrocy-clization was demonstrated to be effective for constructingstrained cyclic peptides. Specifically, for the total synthesesof cihunamide B[42] and strecintide 839,[28] atroposelectiveconstruction of the Trp N1-to-Trp C7′ linkage was achievedthrough Larock macrocyclization. Additionally, in the synthe-ses of lapparbin[44] and neopetromin,[45] a modular approachutilizing C─H arylation of alanine derivatives followed byLarock macrocyclization enabled the formation of the TyrC6-to-Trp N1′ linkage. However, in all these methods, thedirect incorporation of arbitrary biaryl moieties into peptidelinkers containing multiple amino acid residues remainedchallenging. For example, in the syntheses of lapparbin[44]and neopetromin,[45] C─H arylation was performed using analanine derivative bearing an aminoquinoline as a directinggroup. In 2024, the construction of the micitide core viacarboxylate-assisted C–H activation using N-phthaloylalaninewas reported by our group.[46] In both cases, the directincorporation of diverse biaryl units into polypeptides wasnot feasible. Consequently, assembling the macrocyclic corerequired multiple amide couplings after C─H arylation,rendering the approach less convergent and of limited scope.To address this, we devised a synthetic strategy enabling theefficient and convergent construction of the highly strainedTyr C6-to-Trp C5′ linkage and micitide 982 (1) with highermodularity. This involved installing the biaryl unit intopeptide linkers with multiple amino acid residues in just twosteps. This approach allows for the late-stage introductionof any desired biaryl motif, making the synthesis moreconvergent and suitable for analog development.The core structure of micitide 982 (1), the Tyr C6-to-TrpC5′ linkage, was planned to be constructed via a combinationof Ni-catalyzed electrochemical cross-electrophile couplingand subsequent Larock macrocyclization, applied to a three-residue peptide linker bearing terminal halogen and alkynefunctionalities (Figure 2b). The corresponding biaryl frag-ments were prepared through Suzuki coupling of the specified3-substituted aromatic precursor 9 or 10. Meanwhile, thepeptide linkers were synthesized via amide coupling of aminoacid fragments 11–16. This synthetic strategy is advantageousbecause it employs inexpensive, readily accessible buildingblocks to synthesize rigid biaryl linkages in a straightforwardmanner, exhibiting high convergence.The synthesis of the Tyr C6-to-Trp C5′ linkage andsynthesis of micitide 982 (1) commenced from peptide linkerconstruction (Scheme 1). N-Boc-L-proline (16) was coupledwith alkyne fragment 11 using HATU-mediated amideformation to afford compound 17. Subsequently, compound17 underwent Boc deprotection with TFA, followed bycondensation with N-Boc-L-serine (18) using DMTMM toyield the three-residue peptide linker. This intermediate wasthen selectively brominated at the primary alcohol usingtriphenylphosphine (PPh3) and N-bromosuccinimide (NBS),resulting in peptide linker 19. The synthesis of the biarylfragment 22 was initiated from 2-bromo-4-iodoaniline (9).Following protection of the amino group with an acetyl group,boronic acid 20 was obtained on a decagram scale via Miyauraborylation, followed by pinacol deprotection. Boronic acid20 was then subjected to Suzuki coupling with aryl iodideAngew. Chem. Int. Ed. 2025, 64, e202516053 (3 of 10) © 2025 The Author(s). Angewandte Chemie International Edition published by Wiley-VCH GmbH 15213773, 2025, 46, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/anie.202516053 by Yuuya Nagata - National Institute For , Wiley Online Library on [02/09/2026]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons LicenseResearch Articlea)b)Figure 2. a) High level summary of documented failures. b) A synthetic approach to micitide 982 (1).10 to afford biaryl compound 21. To prepare for subsequentNi-catalyzed electrochemical cross-electrophile coupling,biaryl 21 was scaled up to a decagram quantity and convertedto aryl iodide 22 through Boc deprotection and a Sandmeyerreaction.Subsequently, the Ni-catalyzed cross-electrophile couplingof peptide linker 19 with aryl iodide 22 was attempted. Aspreviously mentioned, the direct introduction of the biarylderivative 22 into the three-residue peptide linker 19 isa critical challenge for increasing the overall convergenceAngew. Chem. Int. Ed. 2025, 64, e202516053 (4 of 10) © 2025 The Author(s). Angewandte Chemie International Edition published by Wiley-VCH GmbH 15213773, 2025, 46, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/anie.202516053 by Yuuya Nagata - National Institute For , Wiley Online Library on [02/09/2026]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons LicenseResearch ArticleScheme 1. Concise construction of the Tyr C6-to-Trp C5′ linkage and the total synthesis of micitide 982 (1)a. aFor detailed reagents and conditions, seethe Supporting Information.Angew. Chem. Int. Ed. 2025, 64, e202516053 (5 of 10) © 2025 The Author(s). Angewandte Chemie International Edition published by Wiley-VCH GmbH 15213773, 2025, 46, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/anie.202516053 by Yuuya Nagata - National Institute For , Wiley Online Library on [02/09/2026]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons LicenseResearch ArticleScheme 2. Thermodynamic stability of conformers 26 and 27.of the synthetic route. In recent years, numerous usefulreactions for Ni-catalyzed cross-electrophile coupling havebeen reported.[47–50] Many of these reactions proceed undermild conditions at room temperature, making them effectivefor substrates with complex and sensitive functional groups,such as peptides.[51–67] Initially, the coupling was performedusing the most common reaction conditions reported forNi-catalyzed cross-electrophile coupling, with DMF (N,N-dimethylformamide) as the solvent, NiBr2 (20 mol%) as theNi source, 4,4′-Di-tert-butyl-2,2′-bipyridyl (dtbbpy (L12), 40mol%) as the ligand, and zinc dust (3.0 equivalents) as thereducing agent.[51–67] The mixture of linker 19 and aryl iodide22 was stirred under a nitrogen atmosphere at 25 °C for 12hours. However, the desired coupling product 23 was notobtained; only complex mixtures were observed. Substitutingzinc dust with manganese (Mn) or indium (In) dust was alsoattempted. While no product was formed using indium, theuse of Mn dust yielded the desired coupling product 23 in an11% isolated yield. Further efforts to improve the reactionconditions, including the optimization of the Ni source,ligands, and additives, were conducted; however, the yieldof product 23 remained consistently low, making efficientsynthesis challenging under these conditions. Additionally,cross-electrophile coupling using iodine instead of bromine inthe alkyl bromide 19 was tested, but the yields of the desiredproduct remained low and showed no significant improve-ment (for further details, see Supporting Information).Meanwhile, recent advances have reported electrochem-ical Ni-catalyzed cross-electrophile coupling for sp2–sp3carbon–carbon bond formation.[68–75] These reactions arehighly advantageous due to their ability to form C─C bondsunder mild conditions. Consequently, an attempt was madeto synthesize coupling product 23 by applying Ni-catalyzedelectrochemical cross-electrophile coupling between linker19 and aryl iodide 22. After screening a broad range ofreaction conditions, it was determined that using NiBr2(20 mol%) as the Ni source, with a constant current of4 mA in an undivided cell equipped with zinc and nickelfoam electrodes under a nitrogen atmosphere, produced thebest results. Further ligand screening was undertaken tooptimize the conditions: initial trials with pyridine derivatives(L1) and 1,10-phenanthroline (L2) resulted in low yields of8% and 6%, respectively. Substituted 1,10-phenanthrolinederivatives (L3–L6) were also tested; however, the highestyield achieved was only 18% (L3). Among bipyridine-typeligands (L7–L12), the use of more electron-rich ligands suchas 4,4′-dimethoxy-2,2′-bipyridine (L11) and 4,4′-di-tert-butyl-2,2′-bipyridyl (dtbbpy, L12) enhanced yields, reaching 34%and 47%, respectively (for further details, see SupportingInformation). Based on these results, direct installation ofbiaryl 22 onto the three-residue peptide linker 19 under mildroom temperature conditions was successfully achieved.Next, the construction of the highly strained Tyr C6-to-Trp C5′ linkage 24 from coupling product 23 was attempted.Angew. Chem. Int. Ed. 2025, 64, e202516053 (6 of 10) © 2025 The Author(s). Angewandte Chemie International Edition published by Wiley-VCH GmbH 15213773, 2025, 46, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/anie.202516053 by Yuuya Nagata - National Institute For , Wiley Online Library on [02/09/2026]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons LicenseResearch ArticleFigure 3. Substrate scope for the modular biarylationa. aFor detailed reagents and conditions, see the Supporting Information.Angew. Chem. Int. Ed. 2025, 64, e202516053 (7 of 10) © 2025 The Author(s). Angewandte Chemie International Edition published by Wiley-VCH GmbH 15213773, 2025, 46, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/anie.202516053 by Yuuya Nagata - National Institute For , Wiley Online Library on [02/09/2026]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons LicenseResearch ArticleThe most challenging aspect of the synthesis of micitide982 (1) is the formation of this highly strained linkage.As previously described, using intramolecular amide bondformation conditions with precursors 2 and 3 led to excessivestrain caused by the rigidity (linearity) of the biaryl moiety,preventing formation of the desired highly strained Tyr–Trplinkage 4 (Figure 2a). In contrast, Larock macrocyclization isa chemo-selective organic chemistry reaction that proceedsunder mild conditions with Pd catalysts in the presenceof alkynes.[76–88] It has been proven to be highly effectivein synthesizing macrocyclic peptides with substantial strain.Utilizing Larock macrocyclization conditions inspired bythe prior studies reported by Riesman,[88] Baran,[82] andSarlah[83] et al., precursor 23 was successfully converted to thetarget macrocyclic compound 24 in 45% yield. The conforma-tional state of the obtained cyclized product was confirmed byNOESY spectroscopy to be identical to that of micitide 982(1). The optimal conditions for this macrocyclization involvedPd(OAc)2 as the catalyst and tri-tert-butylphosphine (tBu3P)as the ligand.The remaining challenges for the synthesis of micitide982 (1) involve the introduction of side-chain amino acidsto macrocyclic compound 24 and the removal of protectinggroups. The macrocyclic intermediate 24 obtained via Larockcyclization was subjected to deprotection with HCl to removeBoc and TES groups, followed by coupling with Boc- l -alanine (12) using HATU, thereby introducing the aminoacid side chain. In a similar manner, additional amino acids(Boc-glycine (14), Boc-l-alanine (12), Boc- l-leucine (13),Boc-l-alanine (12)) were sequentially incorporated. Subse-quently, hydrolysis of the methyl ester and the introduction ofl-histidine methyl ester (15) afforded the protected micitide982 (25) on a 2.0 g scale. Finally, the Boc and methyl-etherprotecting groups of compound 25 were removed with BBr3,and the methyl ester was hydrolyzed with LiOH. These stepsculminated in the synthesis of micitide 982 (1).The mechanistic elucidation of the Larock cyclization isillustrated in Scheme 2. To determine whether conformationalstate 26 can rotate and isomerize into 27, the thermody-namic stability and rotational barrier between conformationalstates 26 and 27 were evaluated by DFT calculations.The computed activation free energy for interconversion(�G‡) was +32.6 kJ/mol, and the thermodynamic energydifference between the two conformers was determined tobe 11.4 kJ/mol. These results suggest that, although the con-formational conversion from 26 to 27 is kinetically accessibleat room temperature, the pronounced thermodynamic biasleads to an existence ratio of approximately 99:1 at 25 °C.Even at elevated temperatures (e.g., 120 °C), conformer 26remains the predominant species, with a calculated ratio of97:3. Accordingly, the isomerization is effectively negligibleunder ambient conditions, consistent with the experimentalobservation that conformer 26 was obtained as a single,isolable conformer. Furthermore, to address the conforma-tional selectivity of the Larock cyclization from a kineticstandpoint, transition state calculations were conducted.These calculations demonstrated that conformer 26 is formedthrough a more stable transition state, thereby confirmingits kinetic preference as the major product. (see Figure S4)Together, these findings confirm that conformer 26 is bothkinetically and thermodynamically favored.To demonstrate the utility of this synthetic strategy, anapplication was explored in which an arbitrary biaryl unitwas directly introduced into a three-residue peptide linker19. As shown in Figure 3, cyclic peptides are generallymore resistant to proteolytic degradation compared to linearpeptides due to their cyclic structure, conferring enhancedstability within biological systems.[89–92] Furthermore, theircyclic conformation increases lipophilicity and membrane per-meability, making cyclic peptides attractive as next-generationmedium molecule drugs for therapeutic applications.[93,94]Four biaryl derivatives (compounds 28–31) were prepared asmodel compounds. Subsequently, the incorporation of thesebiaryl derivatives into peptide linker 19 was attempted viaNi-catalyzed electrochemical cross-electrophile coupling. Thedesired C─C bond formation products were obtained in yieldsranging from 34% to 59%. Notably, the reaction proceededunder mild, room-temperature conditions. After this, eachmacrocyclization precursor was subjected to Larock macro-cyclization using Pd catalysis, which proceeded smoothly toafford the target macrocyclic compounds 32–35 in isolatedyields of 53%–70%. This synthetic approach offers a conciseand convergent methodology, enabling the introduction ofbiaryl units into peptides in just two steps starting frompeptide linker 19.ConclusionIn summary, this study demonstrated that the highly strainedTyr C6-to-Trp C5′ linkage could be introduced into pep-tide linkers in just two steps by combining Ni-catalyzedelectrochemical cross-electrophile coupling with subsequentregioselective Larock macrocyclization. Furthermore, thisscalable and modular strategy facilitated the total synthesisof micitide 982 (1). Notably, protected micitide 982 (25) wasprepared on a 2.0 g scale. In addition, this modular strategyfacilitated the incorporation of various biaryl derivatives intopeptide linkers. It is anticipated that this methodology willfind broad applications in the field of medicinal chemistry,particularly in the synthesis of macrocyclic peptides andrelated bioactive molecules. Moreover, the two-step biary-lation approach developed in this study has the potentialfor extensive application in the synthesis of a wide range ofbioactive RiPPs beyond micitide 982 (1).AcknowledgementsFinancial support for this work was provided by a grantfrom the RGC of the Hong Kong SAR, China (ECS,HKUST 26302024), and start-up funds from HKUST (ProjectNo. R9820) to H.N. This work was partly supported byJSPS KAKENHI Grant Number JP23H03810, JST-ERATO(JPMJER1903), and the Institute for Chemical ReactionDesign and Discovery (ICReDD), which was established bythe World Premier International Research Initiative (WPI),MEXT, Japan (Y.N.), as well as a grant from the CityAngew. Chem. Int. Ed. 2025, 64, e202516053 (8 of 10) © 2025 The Author(s). Angewandte Chemie International Edition published by Wiley-VCH GmbH 15213773, 2025, 46, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/anie.202516053 by Yuuya Nagata - National Institute For , Wiley Online Library on [02/09/2026]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons LicenseResearch ArticleUniversity of Hong Kong (7020157). The computation waspartly performed using Research Center for ComputationalScience, Okazaki, Japan (Project: 23-IMS-C119, Y.N.).Conflict of InterestsThe authors declare no conflict of interest.Data Availability StatementThe data that support the findings of this study are availablein the supplementary material of this article.Keywords: Biaryl Peptides • Electrochemistry • NoncanonicalCyclic Peptide • RiPPs • Total Synthesis[1] T. Q. N. Nguyen, Y. W. Tooh, R. Sugiyama, T. P. D. Nguyen, M.Purushothaman, L. 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Chem.Lett. 2023, 14, 1174–1178.Manuscript received: July 22, 2025Revised manuscript received: August 28, 2025Manuscript accepted: September 10, 2025Version of record online: September 17, 2025Angew. Chem. Int. Ed. 2025, 64, e202516053 (10 of 10) © 2025 The Author(s). Angewandte Chemie International Edition published by Wiley-VCH GmbH 15213773, 2025, 46, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/anie.202516053 by Yuuya Nagata - National Institute For , Wiley Online Library on [02/09/2026]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License Rapid Construction of a Tyr C6-Trp C5 Linkage: Application in the Total Synthesis of Micitide 982, a Noncanonical Cyclic Peptide  Introduction  Results and Discussion  Conclusion  Acknowledgements  Conflict of Interests  Data Availability Statement