{"title":"线性肽和环状肽中丙氨酸的配体驱动、半胱氨酸导向的 β-C(sp3)-H 芳基化作用:克服肽键的抑制作用","authors":"Zhen-Lin Hou, Yinian Tang, Yu Lu* and Bo Yao*, ","doi":"10.1021/acscatal.4c02357","DOIUrl":null,"url":null,"abstract":"<p >Peptide modification by coordination-assisted C(sp<sup>3</sup>)–H functionalization on the aliphatic side chains of residues at the internal positions remains underdeveloped because of the inhibitory effect of peptide bonds. Using <i>S</i>-alkyl cysteine as the directing group and 2-pyridones as the ligands of Pd catalysts, we developed a Pd-catalyzed β-C(sp<sup>3</sup>)–H arylation approach for highly position-selective modification of both linear and cyclic peptides at the internal positions. Control experiments supported that the <i>S</i>-alkyl cysteine acted as a <i>N,S</i>-bidentate directing group, and the choice of protecting groups on the sulfur atom was vital to retaining the coordinating ability and preventing the side reaction of cysteine. The result inspired us to discover a protecting group, 4-methoxy-3-nitrobenzyl (PMNB), which was stable under the reaction conditions to facilitate efficient C–H arylation and easily removed by a sequential four-step reaction. In addition, the facile transformation of <i>S</i>-methyl cysteine to dehydroalanine (Dha) and the desulfurization of <i>S</i>-(<i>p</i>-nitrobenzyl)cysteine to alanine under mild conditions further expanded the synthetic utilities of the established C–H arylation protocol.</p>","PeriodicalId":9,"journal":{"name":"ACS Catalysis ","volume":null,"pages":null},"PeriodicalIF":11.3000,"publicationDate":"2024-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Ligand-Enabled, Cysteine-Directed β-C(sp3)–H Arylation of Alanine in Linear and Cyclic Peptides: Overcoming the Inhibitory Effect of Peptide Bonds\",\"authors\":\"Zhen-Lin Hou, Yinian Tang, Yu Lu* and Bo Yao*, \",\"doi\":\"10.1021/acscatal.4c02357\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p >Peptide modification by coordination-assisted C(sp<sup>3</sup>)–H functionalization on the aliphatic side chains of residues at the internal positions remains underdeveloped because of the inhibitory effect of peptide bonds. Using <i>S</i>-alkyl cysteine as the directing group and 2-pyridones as the ligands of Pd catalysts, we developed a Pd-catalyzed β-C(sp<sup>3</sup>)–H arylation approach for highly position-selective modification of both linear and cyclic peptides at the internal positions. Control experiments supported that the <i>S</i>-alkyl cysteine acted as a <i>N,S</i>-bidentate directing group, and the choice of protecting groups on the sulfur atom was vital to retaining the coordinating ability and preventing the side reaction of cysteine. The result inspired us to discover a protecting group, 4-methoxy-3-nitrobenzyl (PMNB), which was stable under the reaction conditions to facilitate efficient C–H arylation and easily removed by a sequential four-step reaction. In addition, the facile transformation of <i>S</i>-methyl cysteine to dehydroalanine (Dha) and the desulfurization of <i>S</i>-(<i>p</i>-nitrobenzyl)cysteine to alanine under mild conditions further expanded the synthetic utilities of the established C–H arylation protocol.</p>\",\"PeriodicalId\":9,\"journal\":{\"name\":\"ACS Catalysis \",\"volume\":null,\"pages\":null},\"PeriodicalIF\":11.3000,\"publicationDate\":\"2024-07-09\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"ACS Catalysis \",\"FirstCategoryId\":\"92\",\"ListUrlMain\":\"https://pubs.acs.org/doi/10.1021/acscatal.4c02357\",\"RegionNum\":1,\"RegionCategory\":\"化学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"CHEMISTRY, PHYSICAL\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"ACS Catalysis ","FirstCategoryId":"92","ListUrlMain":"https://pubs.acs.org/doi/10.1021/acscatal.4c02357","RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"CHEMISTRY, PHYSICAL","Score":null,"Total":0}
Ligand-Enabled, Cysteine-Directed β-C(sp3)–H Arylation of Alanine in Linear and Cyclic Peptides: Overcoming the Inhibitory Effect of Peptide Bonds
Peptide modification by coordination-assisted C(sp3)–H functionalization on the aliphatic side chains of residues at the internal positions remains underdeveloped because of the inhibitory effect of peptide bonds. Using S-alkyl cysteine as the directing group and 2-pyridones as the ligands of Pd catalysts, we developed a Pd-catalyzed β-C(sp3)–H arylation approach for highly position-selective modification of both linear and cyclic peptides at the internal positions. Control experiments supported that the S-alkyl cysteine acted as a N,S-bidentate directing group, and the choice of protecting groups on the sulfur atom was vital to retaining the coordinating ability and preventing the side reaction of cysteine. The result inspired us to discover a protecting group, 4-methoxy-3-nitrobenzyl (PMNB), which was stable under the reaction conditions to facilitate efficient C–H arylation and easily removed by a sequential four-step reaction. In addition, the facile transformation of S-methyl cysteine to dehydroalanine (Dha) and the desulfurization of S-(p-nitrobenzyl)cysteine to alanine under mild conditions further expanded the synthetic utilities of the established C–H arylation protocol.
期刊介绍:
ACS Catalysis is an esteemed journal that publishes original research in the fields of heterogeneous catalysis, molecular catalysis, and biocatalysis. It offers broad coverage across diverse areas such as life sciences, organometallics and synthesis, photochemistry and electrochemistry, drug discovery and synthesis, materials science, environmental protection, polymer discovery and synthesis, and energy and fuels.
The scope of the journal is to showcase innovative work in various aspects of catalysis. This includes new reactions and novel synthetic approaches utilizing known catalysts, the discovery or modification of new catalysts, elucidation of catalytic mechanisms through cutting-edge investigations, practical enhancements of existing processes, as well as conceptual advances in the field. Contributions to ACS Catalysis can encompass both experimental and theoretical research focused on catalytic molecules, macromolecules, and materials that exhibit catalytic turnover.