Pub Date : 2025-03-03DOI: 10.1021/acs.orglett.5c00420
Abhijit Gogoi, Raju Chouhan, Sajal Kumar Das
Described herein is a mild catalytic dehydrative Friedel–Crafts alkylation of 1,1-diarylalkanols─a challenging reaction with exceedingly rare previous success, presumably because of the unfavorable steric hindrance around the reactive centers and the competitive E1 reaction. Executing in an intramolecular fashion and benefiting from the high nucleophilicity of indole, we have successfully utilized this reaction in synthesizing 3,4-fused indoles. Interestingly, the Friedel–Crafts alkylation strategy could also be applied to access 4,5-fused indoles via modification of the tether connecting the alcohol and indole moieties.
{"title":"C3 versus C5 Regioselectivity in the Intramolecular Dehydrative Friedel–Crafts Alkylation of Indole C4-Tethered Carbinols","authors":"Abhijit Gogoi, Raju Chouhan, Sajal Kumar Das","doi":"10.1021/acs.orglett.5c00420","DOIUrl":"https://doi.org/10.1021/acs.orglett.5c00420","url":null,"abstract":"Described herein is a mild catalytic dehydrative Friedel–Crafts alkylation of 1,1-diarylalkanols─a challenging reaction with exceedingly rare previous success, presumably because of the unfavorable steric hindrance around the reactive centers and the competitive E1 reaction. Executing in an intramolecular fashion and benefiting from the high nucleophilicity of indole, we have successfully utilized this reaction in synthesizing 3,4-fused indoles. Interestingly, the Friedel–Crafts alkylation strategy could also be applied to access 4,5-fused indoles via modification of the tether connecting the alcohol and indole moieties.","PeriodicalId":54,"journal":{"name":"Organic Letters","volume":"52 1","pages":""},"PeriodicalIF":5.2,"publicationDate":"2025-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143539271","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-03-03DOI: 10.1021/acs.orglett.5c00684
Linjie Yang, Yuanfang Zhong, Wanzhi Chen
An efficient Pd-catalyzed N-arylation of sulfoximines with (hetero)aryl chlorides was developed under mild aqueous conditions. This reaction proceeded smoothly with a low loading of the Pd catalyst (down to 0.5 mol %) and was completed rapidly within 30 min. A wide range of (hetero)aryl chlorides and sulfoximines were well tolerated, delivering the corresponding (hetero)aryl sulfoximines in good to excellent yields. The gram-scale reaction and pharmaceutical derivatization demonstrated good practicality.
{"title":"Palladium-Catalyzed N-Arylation of NH-Sulfoximines with (Hetero)aryl Chlorides in an Aqueous Micellar Environment","authors":"Linjie Yang, Yuanfang Zhong, Wanzhi Chen","doi":"10.1021/acs.orglett.5c00684","DOIUrl":"https://doi.org/10.1021/acs.orglett.5c00684","url":null,"abstract":"An efficient Pd-catalyzed N-arylation of sulfoximines with (hetero)aryl chlorides was developed under mild aqueous conditions. This reaction proceeded smoothly with a low loading of the Pd catalyst (down to 0.5 mol %) and was completed rapidly within 30 min. A wide range of (hetero)aryl chlorides and sulfoximines were well tolerated, delivering the corresponding (hetero)aryl sulfoximines in good to excellent yields. The gram-scale reaction and pharmaceutical derivatization demonstrated good practicality.","PeriodicalId":54,"journal":{"name":"Organic Letters","volume":"52 1","pages":""},"PeriodicalIF":5.2,"publicationDate":"2025-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143539186","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-03-03DOI: 10.1021/acs.orglett.5c00199
Meiqing Zhai, Jian Zhang, Zhonglin Tao
A dinickel-catalyzed direct asymmetric allylic alkylation of benzocyclic ketones has been developed. This method enables the efficient transformation of various α-alkyl benzocyclohexanones and benzocyclopentanones with allylic sulfonamides, affording chiral ketones bearing α-quaternary carbon stereocenters in high yields and with excellent enantioselectivities.
{"title":"Dinickel-Catalyzed Asymmetric Allylic Alkylation of Cyclic Ketones with Allylic Amine Derivatives","authors":"Meiqing Zhai, Jian Zhang, Zhonglin Tao","doi":"10.1021/acs.orglett.5c00199","DOIUrl":"https://doi.org/10.1021/acs.orglett.5c00199","url":null,"abstract":"A dinickel-catalyzed direct asymmetric allylic alkylation of benzocyclic ketones has been developed. This method enables the efficient transformation of various α-alkyl benzocyclohexanones and benzocyclopentanones with allylic sulfonamides, affording chiral ketones bearing α-quaternary carbon stereocenters in high yields and with excellent enantioselectivities.","PeriodicalId":54,"journal":{"name":"Organic Letters","volume":"35 1","pages":""},"PeriodicalIF":5.2,"publicationDate":"2025-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143539264","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-03-03DOI: 10.1021/acs.orglett.5c00328
Zhang-Hai Li, Yu Dai, Jing Zhou, Li Yang, Shu-Ming Li
Gene duplication significantly contributes to the diversification of biosynthetic potential and increases the structural diversity of secondary metabolites. Here, we report the second alkyl salicylaldehyde derivative biosynthetic gene cluster in Penicillium roqueforti, being responsible for the formation of ethanolamine-containing derivatives. Heterologous expression and feeding experiments provided evidence for their formation via collaboration and modification with one cytochrome P450 and two flavin-containing monooxygenases in a highly ordered manner before and after ethanolamine incorporation.
{"title":"Formation of N-Hydroxyethylisoindolinone Derivatives in Fungi Requires Highly Coordinated Consecutive Oxidation Steps","authors":"Zhang-Hai Li, Yu Dai, Jing Zhou, Li Yang, Shu-Ming Li","doi":"10.1021/acs.orglett.5c00328","DOIUrl":"https://doi.org/10.1021/acs.orglett.5c00328","url":null,"abstract":"Gene duplication significantly contributes to the diversification of biosynthetic potential and increases the structural diversity of secondary metabolites. Here, we report the second alkyl salicylaldehyde derivative biosynthetic gene cluster in <i>Penicillium roqueforti</i>, being responsible for the formation of ethanolamine-containing derivatives. Heterologous expression and feeding experiments provided evidence for their formation via collaboration and modification with one cytochrome P450 and two flavin-containing monooxygenases in a highly ordered manner before and after ethanolamine incorporation.","PeriodicalId":54,"journal":{"name":"Organic Letters","volume":"86 1","pages":""},"PeriodicalIF":5.2,"publicationDate":"2025-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143532614","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-03-03DOI: 10.1021/acs.orglett.5c00570
Prachi Shah, Wojciech Chaładaj
Trifluoromethylthiolative difunctionalization of alkynes typically proceeds in an anti-fashion delivering the SCF3 group in the β-position (anti-Markovnikov). Herein, we disclose a vicinal syn-arylation-trifluoromethylthiolation of alkynes enabling α-selective introduction of the SCF3 group (Markovnikov). The unique selectivity was achieved via a merge of Ni-catalyzed carbomagnesiation with a subsequent Cu-mediated trifluoromethylthiolation of the resulting vinyl-magnesium species. The former component of the sequential process determines both the regio- and stereoselectivity of the overall transformation.
{"title":"α-Selective syn-Carbotrifluoromethylthiolation of Alkynes","authors":"Prachi Shah, Wojciech Chaładaj","doi":"10.1021/acs.orglett.5c00570","DOIUrl":"https://doi.org/10.1021/acs.orglett.5c00570","url":null,"abstract":"Trifluoromethylthiolative difunctionalization of alkynes typically proceeds in an <i>anti</i>-fashion delivering the SCF<sub>3</sub> group in the β-position (<i>anti</i>-Markovnikov). Herein, we disclose a vicinal <i>syn</i>-arylation-trifluoromethylthiolation of alkynes enabling α-selective introduction of the SCF<sub>3</sub> group (Markovnikov). The unique selectivity was achieved via a merge of Ni-catalyzed carbomagnesiation with a subsequent Cu-mediated trifluoromethylthiolation of the resulting vinyl-magnesium species. The former component of the sequential process determines both the regio- and stereoselectivity of the overall transformation.","PeriodicalId":54,"journal":{"name":"Organic Letters","volume":"23 1","pages":""},"PeriodicalIF":5.2,"publicationDate":"2025-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143539185","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-03-03DOI: 10.1021/acs.orglett.5c00359
Yong Zhou, Qinman Zhang, Shuaipeng Jia, Hebo Ye, Lei You
The impact of varied chalcogen bonds (sulfur, selenium, tellurium, and telluronium) on dynamic imine chemistry in aqueous solution is presented by introducing a carboxylate group or cationic telluronium into arylaldehydes. The role of chalcogen bonding in regulating the kinetics and thermodynamics of imine formation/exchange was elucidated through experimental and computational evidence, affording the largest effect for tellurium/telluronium compounds. By leveraging multivalent chalcogen bonding, telluronium-containing aldehyde enabled labeling of the N-terminus of amino acids in neutral buffer.
{"title":"Neighboring Chalcogen Bonding for Controlling Dynamic Imine Chemistry in Aqueous Media","authors":"Yong Zhou, Qinman Zhang, Shuaipeng Jia, Hebo Ye, Lei You","doi":"10.1021/acs.orglett.5c00359","DOIUrl":"https://doi.org/10.1021/acs.orglett.5c00359","url":null,"abstract":"The impact of varied chalcogen bonds (sulfur, selenium, tellurium, and telluronium) on dynamic imine chemistry in aqueous solution is presented by introducing a carboxylate group or cationic telluronium into arylaldehydes. The role of chalcogen bonding in regulating the kinetics and thermodynamics of imine formation/exchange was elucidated through experimental and computational evidence, affording the largest effect for tellurium/telluronium compounds. By leveraging multivalent chalcogen bonding, telluronium-containing aldehyde enabled labeling of the <i>N</i>-terminus of amino acids in neutral buffer.","PeriodicalId":54,"journal":{"name":"Organic Letters","volume":"12 1","pages":""},"PeriodicalIF":5.2,"publicationDate":"2025-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143539269","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-03-03DOI: 10.1021/acs.orglett.5c00129
Yan-Ling Ji, Hong Wang, Xiang-Hong He, Junchao Zhu, Cheng Peng, Qian Zhao, Gu Zhan, Bo Han
A visible-light-driven Se/Fe synergistic catalytic reaction between isocyanides and amines has been developed, employing air as the terminal oxidant. This efficient strategy offers facile access to 2-aminoquinoline scaffolds. The use of cost-effective and readily available Fe(OTf)3 modulates the selenium catalyst’s oxidation state, enhancing the method’s environmental friendliness and practicality. The protocol is further distinguished by its good yields, broad substrate scope, and mild reaction conditions.
{"title":"Visible-Light-Driven Synergistic Se/Fe Catalysis for the Synthesis of 2-Aminoquinoline Derivatives","authors":"Yan-Ling Ji, Hong Wang, Xiang-Hong He, Junchao Zhu, Cheng Peng, Qian Zhao, Gu Zhan, Bo Han","doi":"10.1021/acs.orglett.5c00129","DOIUrl":"https://doi.org/10.1021/acs.orglett.5c00129","url":null,"abstract":"A visible-light-driven Se/Fe synergistic catalytic reaction between isocyanides and amines has been developed, employing air as the terminal oxidant. This efficient strategy offers facile access to 2-aminoquinoline scaffolds. The use of cost-effective and readily available Fe(OTf)<sub>3</sub> modulates the selenium catalyst’s oxidation state, enhancing the method’s environmental friendliness and practicality. The protocol is further distinguished by its good yields, broad substrate scope, and mild reaction conditions.","PeriodicalId":54,"journal":{"name":"Organic Letters","volume":"32 1","pages":""},"PeriodicalIF":5.2,"publicationDate":"2025-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143532611","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-03-03DOI: 10.1021/acs.orglett.5c00388
Ahmed Atito, Jasper S. Dumalaog, Kuei-Yao Tseng, Yen-Ju Ting, Medel Manuel L. Zulueta, Shang-Cheng Hung
β-Mannosides play a crucial role in cellular processes and immune responses, and their synthesis remains one of the most challenging tasks in carbohydrate chemistry. Glycosyl donors, such as thiomannosides, are stable and compatible with a range of protection and deprotection conditions. In this study, we demonstrate that molecular iodine efficiently induces the activation and coupling of thiomannosides with various 1,6-anhydrosugars as acceptors. This method provides mild activation conditions and high β-stereoselectivity for the synthesis of multiple β-mannosides.
{"title":"Molecular Iodine-Mediated β-Glycosylation of Thiomannosides with 1,6-Anhydrosugars","authors":"Ahmed Atito, Jasper S. Dumalaog, Kuei-Yao Tseng, Yen-Ju Ting, Medel Manuel L. Zulueta, Shang-Cheng Hung","doi":"10.1021/acs.orglett.5c00388","DOIUrl":"https://doi.org/10.1021/acs.orglett.5c00388","url":null,"abstract":"β-Mannosides play a crucial role in cellular processes and immune responses, and their synthesis remains one of the most challenging tasks in carbohydrate chemistry. Glycosyl donors, such as thiomannosides, are stable and compatible with a range of protection and deprotection conditions. In this study, we demonstrate that molecular iodine efficiently induces the activation and coupling of thiomannosides with various 1,6-anhydrosugars as acceptors. This method provides mild activation conditions and high β-stereoselectivity for the synthesis of multiple β-mannosides.","PeriodicalId":54,"journal":{"name":"Organic Letters","volume":"46 1","pages":""},"PeriodicalIF":5.2,"publicationDate":"2025-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143532616","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Glycopeptide antibiotics (GPAs) are the frontline medicines to treat multidrug-resistant Gram-positive infections. Resistance to GPAs warrants the development of new antibiotics. Phylogeny reclassification of GPA biosynthetic gene clusters with a focus on the type V subgroup bearing a heptapeptide scaffold identified new GPAs, varsomycins, possessing unprecedented 3,5-dihydroxyphenylalanine at position 5 and an F-G biphenyl cross-link. Varsomycins are broadly active against clinical isolates of methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococcus and are promising lead compounds for resistance-oriented drug innovation.
{"title":"Phylogeny-Informed Discovery of New Glycopeptide Antibiotics Produced by a Minimal Biosynthetic Gene Cluster","authors":"Xingkun Li, Mengru Wang, Lixin Yin, Jiawei Cao, Rui Wang, Wei Guo, Jing Lu, Zhilong Zhao, Zixin Deng, Anwei Hou, Min Xu","doi":"10.1021/acs.orglett.5c00378","DOIUrl":"https://doi.org/10.1021/acs.orglett.5c00378","url":null,"abstract":"Glycopeptide antibiotics (GPAs) are the frontline medicines to treat multidrug-resistant Gram-positive infections. Resistance to GPAs warrants the development of new antibiotics. Phylogeny reclassification of GPA biosynthetic gene clusters with a focus on the type V subgroup bearing a heptapeptide scaffold identified new GPAs, varsomycins, possessing unprecedented 3,5-dihydroxyphenylalanine at position 5 and an F-G biphenyl cross-link. Varsomycins are broadly active against clinical isolates of methicillin-resistant <i>Staphylococcus aureus</i> and vancomycin-resistant <i>Enterococcus</i> and are promising lead compounds for resistance-oriented drug innovation.","PeriodicalId":54,"journal":{"name":"Organic Letters","volume":"39 1","pages":""},"PeriodicalIF":5.2,"publicationDate":"2025-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143532615","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
A novel and efficient method for the synthesis of multisubstituted arylnitriles via Tf2O-mediated [3 + 2 + 1] benzannulation of enaminones and acylacetonitriles has been developed. This reaction proceeds under mild conditions with excellent functional group compatibility. Mechanistic studies have revealed that the cyclization involves two consecutive nucleophilic additions, followed by a cascade Knoevenagel condensation and aromatization. Additionally, trifluoromethanesulfonate 6 has been identified as a crucial intermediate in this process.
{"title":"Synthesis of Multisubstituted Arylnitriles via Tf2O-Mediated Benzannulation of Enaminones with Acylacetonitriles","authors":"Xiaohan Zhang, Fei Li, Yue Zhou, Junxian Zhang, Benwei Zhou, Lulu Chen, Jianping Lin, Changyuan Zhang","doi":"10.1021/acs.orglett.5c00261","DOIUrl":"https://doi.org/10.1021/acs.orglett.5c00261","url":null,"abstract":"A novel and efficient method for the synthesis of multisubstituted arylnitriles <i>via</i> Tf<sub>2</sub>O-mediated [3 + 2 + 1] benzannulation of enaminones and acylacetonitriles has been developed. This reaction proceeds under mild conditions with excellent functional group compatibility. Mechanistic studies have revealed that the cyclization involves two consecutive nucleophilic additions, followed by a cascade Knoevenagel condensation and aromatization. Additionally, trifluoromethanesulfonate <b>6</b> has been identified as a crucial intermediate in this process.","PeriodicalId":54,"journal":{"name":"Organic Letters","volume":"40 1","pages":""},"PeriodicalIF":5.2,"publicationDate":"2025-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143532618","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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