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{"title":"The Role of AttractivenNon-Covalent Interactions innPeptide Macrocyclization","authors":"DiegoB. Diaz (1343376), Rozhin Rowshanpour (6528830), George J. Saunders (17783983), Travis Dudding (1334103), Andrei K. Yudin (1470634)","doi":"10.1021/acs.joc.3c02084.s001","DOIUrl":"https://doi.org/10.1021/acs.joc.3c02084.s001","url":null,"abstract":"Thenefficiency of macrocyclization reactions relies on the appropriatenconformational preorganization of a linear precursor, ensuring thatnreactive ends are in spatial proximity prior to ring closure. Traditionalnpeptide cyclization approaches that reduce the extent of terminalnion pairing often disfavor cyclization-conducive conformations andncan lead to undesired cyclodimerization or oligomerization side reactions,nparticularly when they are performed without high dilution. To addressnthis challenge, synthetic strategies that leverage attractive noncovalentninteractions, such as zwitterionic attraction between chain termininduring macrocyclization, offer a potential solution by reducing thenentropic penalty associated with linear peptides adopting precyclizationnconformations. In this study, we investigate the role of (<i>N</i>-isocyanoimino)triphenylphosphorane (Pinc) in facilitatingnthe cyclization of linear peptides into conformationally rigid macrocycles.nThe observed moderate diastereoselectivity is consistent with thenpreferential <i>Si</i>-facial addition of Pinc, where thenisocyanide adds to the <i>E</i>-iminium ion on the samenface as the l-proline amide group. The resulting peptidenchain reveals that the activated phosphonium ylide of Pinc bringsnthe reactive ends close together, promoting cyclization by enclosingnthe carboxylate within the interior of the pentapeptide and preventingnthe formation of byproducts. For shorter peptides with modified peptidenbackbones, the cyclization mechanism and outcome are redirected, asnnucleophilic motifs such as thiazole and imidazole can covalentlyntrap nitrilium intermediates. The isolation of the intermediate innthe unproductive macrocyclization pathway, along with nuclear magneticnresonance and density functional theory studies, provides insightsninto heterocycle-dependent selectivity. The Pinc-driven macrocyclizationnprocess has generated diverse collections of cyclic molecules, andnour models offer a comprehensive understanding of observed trends,nfacilitating the development of other heterocycle-forming macrocyclizationnreactions.","PeriodicalId":522556,"journal":{"name":"Figshare","volume":"1 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-01-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147899264","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}