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KEYWORDS include ball-milling, cyclization, green chemistry, and solvent-free peptide macrocyclization.",{"@graph":14,"@context":73},[15,34,56],{"@type":16,"itemListElement":17},"BreadcrumbList",[18,23,27,31],{"item":19,"name":20,"@type":21,"position":22},"https://docshare.wps.com","Home","ListItem",1,{"item":24,"name":25,"@type":21,"position":26},"https://docshare.wps.com/document/","Document",2,{"item":28,"name":29,"@type":21,"position":30},"https://docshare.wps.com/document/research-report/","Research & Report",3,{"item":32,"name":10,"@type":21,"position":33},"https://docshare.wps.com/document/rapid-and-green-anion-assisted-mechanochemical-peptide-cyclization/332917/",4,{"url":32,"name":10,"@type":35,"image":36,"author":41,"headline":10,"publisher":44,"fileFormat":47,"inLanguage":8,"description":12,"dateModified":48,"datePublished":49,"encodingFormat":47,"isAccessibleForFree":50,"interactionStatistic":51},"DigitalDocument",{"url":37,"@type":38,"width":39,"height":40},"https://docshare.wps.com/thumbnails/rapid-and-green-anion-assisted-mechanochemical-peptide-cyclization/332917.png","ImageObject",300,407,{"name":42,"@type":43},"Ethan Miller","Person",{"url":19,"name":45,"@type":46},"DocShare","Organization","application/pdf","2026-10-31","2026-09-21",true,{"@type":52,"interactionType":53,"userInteractionCount":55},"InteractionCounter",{"@type":54},"ViewAction",7,{"@type":57,"mainEntity":58},"FAQPage",[59,65,69],{"name":60,"@type":61,"acceptedAnswer":62},"What cyclization targets does the mechanochemical method address?","Question",{"text":63,"@type":64},"The approach is described for chloride-templated head-to-tail macrocyclization of both a pentapeptide and a hexapeptide.","Answer",{"name":66,"@type":61,"acceptedAnswer":67},"How does this method improve on conventional solution-based cyclization?",{"text":68,"@type":64},"It is solvent-free, gives yields comparable to solution approaches, eliminates the need for high dilution, and reduces reaction times and organic waste.",{"name":70,"@type":61,"acceptedAnswer":71},"What role does chloride anion play in the macrocyclization?",{"text":72,"@type":64},"A chloride anion acts as a directing/assisting agent that promotes the cyclization of linear peptide precursors via anion-assisted macrocyclization.","https://schema.org",{"og:url":32,"og:type":75,"og:title":10,"og:site_name":45,"og:description":12},"article",{"robots":77,"canonical":32},"index,follow",{"doc_id":79,"site_id":7},332917,1790820817,{"code":4,"msg":82,"data":83},"success",[84,88,92,96,101,106,110,114,119,122,126],{"id":22,"doc_module":4,"doc_module_name":25,"category_name":85,"show_sort_weight":86,"slug":87},"Story & Novel",90,"story-novel",{"id":26,"doc_module":4,"doc_module_name":25,"category_name":89,"show_sort_weight":90,"slug":91},"Literature",80,"literature",{"id":33,"doc_module":4,"doc_module_name":25,"category_name":93,"show_sort_weight":94,"slug":95},"Exam",70,"exam",{"id":97,"doc_module":4,"doc_module_name":25,"category_name":98,"show_sort_weight":99,"slug":100},5,"Comic",60,"comic",{"id":102,"doc_module":4,"doc_module_name":25,"category_name":103,"show_sort_weight":104,"slug":105},6,"Technology",50,"technology",{"id":55,"doc_module":4,"doc_module_name":25,"category_name":107,"show_sort_weight":108,"slug":109},"Healthcare",40,"healthcare",{"id":111,"doc_module":4,"doc_module_name":25,"category_name":29,"show_sort_weight":112,"slug":113},8,30,"research-report",{"id":115,"doc_module":4,"doc_module_name":25,"category_name":116,"show_sort_weight":117,"slug":118},9,"Religion & Spirituality",20,"religion-spirituality",{"id":117,"doc_module":4,"doc_module_name":25,"category_name":120,"show_sort_weight":117,"slug":121},"World Cup","world-cup",{"id":123,"doc_module":4,"doc_module_name":25,"category_name":124,"show_sort_weight":123,"slug":125},10,"Lifestyle","lifestyle",{"id":127,"doc_module":4,"doc_module_name":25,"category_name":128,"show_sort_weight":97,"slug":129},19,"General","general",{"code":4,"msg":82,"data":131},{"doc_id":79,"user_id":132,"nickname":42,"user_avatar":133,"doc_module":4,"category_id":111,"category_name":29,"doc_title":10,"doc_description":12,"doc_content":134,"file_id":135,"file_url":136,"file_type":137,"file_size":138,"view_count":55,"is_deleted":4,"is_public":22,"is_downloadable":22,"audit_status":22,"page_count":102,"language":139,"language_code":8,"site_id":7,"html_lang":8,"table_of_contents":140,"faqs":141,"seo_title":142,"seo_description":12,"update_tm":143,"read_time":144,"preview_page_count":4},687207017582,"https://ap-avatar.wpscdn.com/davatar_994ba38a5ba835b3df7d355c54d3ed8d","[pubs.acs.org/journal/ascecg](pubs.acs.org/journal/ascecg)  Research Article   \nRapid and Green Anion-Assisted Mechanochemical Peptide Cyclization  \nMirko Duvnjak, Nikolina Vidovíc, Krunoslav Ǔzarevíc, Gordan Horvat, Vladislav Tomǐsíc, Giovanna Speranza, and Nikola Cindro *  \n Cite This: ACS Sustainable Chem. Eng. 2025, 13, 30−35  \nRead Online  \nDownloaded via RUDJER BOSKOVIC INST on May 2, 2025 at 09:09:49 (UTC) . See [https://pubs.acs.org/sharingguidelines](https://pubs.acs.org/sharingguidelines) for options on how to legitimately share published articles.  \nACCESS  \n Metrics & More  \n Article Recommendations  \n*sı   \nSupporting Information  \nABSTRACT: A novel mechanochemical approach is described for chloridetemplated head-to-tail macrocyclization of a pentapeptide and a hexapeptide. This straightforward method allows the solvent-free preparation of cyclopeptides with yields comparable to solution-based approaches without the need for high dilution of the reaction mixture and with significantly reduced reaction times and organic waste amount.  \nKEYWORDS: ball-milling, cyclization, green chemistry, peptides and proteins, solvent-free  \n■ INTRODUCTION  \nSince the discovery of Gramicidin S, there have been a lot of research efforts aimed at finding high-yielding experimental conditions for the preparation of cyclic peptides. In the last 2 decades, almost 20 new cyclic peptides were approved for clinical use.1 Synthesis of cyclopeptides represents a significant synthetic challenge, especially in the head-to-tail cyclization of small peptides containing up to seven all-L-amino acids. Besides ring size,2 the selection of coupling reagents plays an important role.3 Additionally, the macrocyclization step requires high dilution to minimize unwanted intermolecular processes such as oligo- and polymerization.4 The success of cyclization depends on the ability of the linear precursor to conformationally preorganize its reactive ends, forming in this way entropically unfavorable structures.5 In such structures, reactive ends are in spatial proximity, which favors macrocyclization over intermolecular processes. Over the years, many strategies relying on conformational preorganization have been developed. They can be classified under two categories: (1) internal, which requires covalent modification of the peptide chain, and (2) external, based on molecular scaffolds that are neither covalently bound to the peptides nor consumed during the cyclization reaction.6 Internal conformational elements include the introduction of turn-inducing elements by the incorporation of Pro in the middle of the peptide chain, Damino acids, β-amino acids, or N-methyl amino acids in the sequence.7 Other methods of ring formation require the use of different chemical reactions, such as the creation of lactam bridges or disulfide bridges, which are most commonly used for sequences with two cysteine amino acids,8,9 insertion of heterocycle rings such as triazole, 10 imidazole, 11 oxazole,11 or thiazole rings,12 and metathesis.13 Also, new methods have  \n© 2025 The Authors. Published by American Chemical Society  \nbeen used in the past decade to cyclize linear peptides using enzymes9, 14 and microwaves.15 Most of these methods are sequence-dependent and cannot be applied generally. In addition, the reaction yields are mostly very low. External conformational elements include the design of cavities large enough for only one linear peptide to enter and cyclize at a time 16, 17 or ion-assisted macrocyclization.18, 19 The inspiration for the last strategy was found in nature; specifically, it relies on the well-known ability of cyclopeptides to form stable complexes with metal ions in vivo.20,21 In one of our previous studies, we demonstrated that not only cations but also anions can act as directing agents for promoting the cyclization of linear peptides.22 In particular, we found that for cyclization of tetra-, penta-, and hexapeptides, the best results were ","cbCaiaG8j0npkaBH","https://ap.wps.com/l/cbCaiaG8j0npkaBH","pdf",2301202,"English","# Introduction\n## Background on cyclic peptide synthesis challenges\n## Conformational preorganization strategies (internal vs external)\n## Anion-assisted macrocyclization concept\n## Mechanochemistry as a green alternative","[{\"question\":\"What cyclization targets does the mechanochemical method address?\",\"answer\":\"The approach is described for chloride-templated head-to-tail macrocyclization of both a pentapeptide and a hexapeptide.\"},{\"question\":\"How does this method improve on conventional solution-based cyclization?\",\"answer\":\"It is solvent-free, gives yields comparable to solution approaches, eliminates the need for high dilution, and reduces reaction times and organic waste.\"},{\"question\":\"What role does chloride anion play in the macrocyclization?\",\"answer\":\"A chloride anion acts as a directing/assisting agent that promotes the cyclization of linear peptide precursors via anion-assisted macrocyclization.\"}]","Rapid and Green Anion-Assisted Mechanochemical Peptide Cyclization | PDF",1789999995,15]