We have developed a strain-release glycosylation method for thio/selenoglycosides utilizing donor–acceptor oxiranes (DAOs) and triflic acid (2 mol %) via C–C bond cleavage under ambient conditions. This protocol is effective for acid-sensitive and sterically hindered substrates, demonstrating broad applicability. Experimental results and DFT calculations reveal that DAO/TfOH-derived zwitterionic oxocarbenium species activate donors via glycosyl zwitterion intermediates, facilitating glycosidic bond formation and proton transfer. This approach pioneers epoxide-mediated thio/selenoglycosides activation, offering a mild, efficient platform for diverse glycoside synthesis and advancing methodologies in carbohydrate chemistry.
{"title":"Strain-Release Glycosylation of Thio- and Selenoglycosides Enabled by Activation of Donor–Acceptor Oxiranes with Catalytic TfOH","authors":"Xin-Yu Fang, Xing-Le Liu, Jia-Ying Shen, Long-Xuan Zhao, Xiong Xiao","doi":"10.1021/acs.orglett.5c01191","DOIUrl":"https://doi.org/10.1021/acs.orglett.5c01191","url":null,"abstract":"We have developed a strain-release glycosylation method for thio/selenoglycosides utilizing donor–acceptor oxiranes (DAOs) and triflic acid (2 mol %) via C–C bond cleavage under ambient conditions. This protocol is effective for acid-sensitive and sterically hindered substrates, demonstrating broad applicability. Experimental results and DFT calculations reveal that DAO/TfOH-derived zwitterionic oxocarbenium species activate donors via glycosyl zwitterion intermediates, facilitating glycosidic bond formation and proton transfer. This approach pioneers epoxide-mediated thio/selenoglycosides activation, offering a mild, efficient platform for diverse glycoside synthesis and advancing methodologies in carbohydrate chemistry.","PeriodicalId":54,"journal":{"name":"Organic Letters","volume":"260 1","pages":""},"PeriodicalIF":5.2,"publicationDate":"2025-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143858122","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 rhodium(III)-catalyzed dual-ring formation via cascade C–H activation/[4 + 2] annulation of 3,5-diaryoxadiazoles with alkynes was developed. This strategy has been demonstrated with a variety of 3,5-diaryloxadiazoles and alkynes, and it has been successfully scaled up to gram-scale synthesis, highlighting its potential significance in the direct construction of C–N atropisomers. Furthermore, the cleavage of the N–O bond is essential for the formation of the bicyclic structure in the absence of an external oxidant. Mechanistic studies revealed that cleavage of the C–H bond at the 3-phenyl group of oxadiazole was likely a rate-determining step in this reaction.
{"title":"Rhodium(III)-Catalyzed Redox-Neutral [4 + 2] Annulation of 3,5-Diaryloxadiazoles with Alkynes: A Dual C–H Activation Strategy for Constructing C–N Atropisomers","authors":"Siyuan Li, Yinsong Han, Zhen Yang, Chen Wang, Ruokun Feng, Minfeng Zeng, Zhanxiang Liu, Yuhong Zhang","doi":"10.1021/acs.orglett.5c00676","DOIUrl":"https://doi.org/10.1021/acs.orglett.5c00676","url":null,"abstract":"A rhodium(III)-catalyzed dual-ring formation via cascade C–H activation/[4 + 2] annulation of 3,5-diaryoxadiazoles with alkynes was developed. This strategy has been demonstrated with a variety of 3,5-diaryloxadiazoles and alkynes, and it has been successfully scaled up to gram-scale synthesis, highlighting its potential significance in the direct construction of C–N atropisomers. Furthermore, the cleavage of the N–O bond is essential for the formation of the bicyclic structure in the absence of an external oxidant. Mechanistic studies revealed that cleavage of the C–H bond at the 3-phenyl group of oxadiazole was likely a rate-determining step in this reaction.","PeriodicalId":54,"journal":{"name":"Organic Letters","volume":"43 1","pages":""},"PeriodicalIF":5.2,"publicationDate":"2025-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143858121","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}
Molecules containing fluorine atoms and trifluoromethyl groups are highly significant in medicinal chemistry. However, synthesizing compounds with adjacent F- and CF3-substituted tetrasubstituted centers remains a formidable challenge. Herein, we report an organocatalytic asymmetric approach for synthesizing pyran heterocycles bearing adjacent F- and CF3-substituted quaternary carbon stereocenters with excellent diastereo- and enantioselectivity (>20:1 dr, >99% ee). The process involves dehydration to generate fluorinated enolates, followed by trifluoroacetylation and cyclization with enones. This method is also applicable to the functionalization of bioactive molecules and drug derivatives, offering a versatile platform for constructing fluorinated architectures.
{"title":"Organocatalytic Asymmetric Synthesis of Pyran Derivatives with Adjacent F- and CF3-Tetrasubstituted Centers","authors":"Mingji Ke, Ji-Xiang Yang, Shuyi Mai, Yicheng Wang, Liangxi Wen, Ruoting Zhan, Shao-Fei Ni, Huicai Huang","doi":"10.1021/acs.orglett.5c01031","DOIUrl":"https://doi.org/10.1021/acs.orglett.5c01031","url":null,"abstract":"Molecules containing fluorine atoms and trifluoromethyl groups are highly significant in medicinal chemistry. However, synthesizing compounds with adjacent F- and CF<sub>3</sub>-substituted tetrasubstituted centers remains a formidable challenge. Herein, we report an organocatalytic asymmetric approach for synthesizing pyran heterocycles bearing adjacent F- and CF<sub>3</sub>-substituted quaternary carbon stereocenters with excellent diastereo- and enantioselectivity (>20:1 dr, >99% ee). The process involves dehydration to generate fluorinated enolates, followed by trifluoroacetylation and cyclization with enones. This method is also applicable to the functionalization of bioactive molecules and drug derivatives, offering a versatile platform for constructing fluorinated architectures.","PeriodicalId":54,"journal":{"name":"Organic Letters","volume":"108 1","pages":""},"PeriodicalIF":5.2,"publicationDate":"2025-04-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143858124","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 : 2025-04-21DOI: 10.1021/acs.orglett.5c01134
Jun Zhang, Qian Yun, Yuhan Dai, Mengmeng Zheng, Zhi Lin, Zixin Deng, Xudong Qu, Chun Lei
We report the first biosynthesis of trifluoromethyl (TFM)-containing extender unit and its incorporation into the polyketide biosynthetic pathway. Using engineered enzymes UkaQFAV and Arm13-ACCase, we synthesized a TFM-containing extender unit, which was successfully integrated into the antimycin structure. This modification resulted in stereochemical changes, leading to the formation of an unusual 7S-epimer. The TFM-modified antimycin derivatives exhibited significantly enhanced antifungal activity, providing a new strategy for polyketide diversification and drug development.
{"title":"Trifluoromethylation of Antimycin via Extender Unit Incorporation Improves Antifungal Potency","authors":"Jun Zhang, Qian Yun, Yuhan Dai, Mengmeng Zheng, Zhi Lin, Zixin Deng, Xudong Qu, Chun Lei","doi":"10.1021/acs.orglett.5c01134","DOIUrl":"https://doi.org/10.1021/acs.orglett.5c01134","url":null,"abstract":"We report the first biosynthesis of trifluoromethyl (TFM)-containing extender unit and its incorporation into the polyketide biosynthetic pathway. Using engineered enzymes UkaQ<sup>FAV</sup> and Arm13-ACCase, we synthesized a TFM-containing extender unit, which was successfully integrated into the antimycin structure. This modification resulted in stereochemical changes, leading to the formation of an unusual 7<i>S</i>-epimer. The TFM-modified antimycin derivatives exhibited significantly enhanced antifungal activity, providing a new strategy for polyketide diversification and drug development.","PeriodicalId":54,"journal":{"name":"Organic Letters","volume":"17 1","pages":""},"PeriodicalIF":5.2,"publicationDate":"2025-04-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143858232","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 : 2025-04-21DOI: 10.1021/acs.orglett.5c00942
Leyi Tao, Zhiyu Lei, Lianyun Zhao, Tao Ji, Yeon-Hee Lim, James Patrick Roane, Bin Hu, Xin Wen
Trifluoroethyl groups are important in medicinal chemistry since they can impart desirable properties, such as enhanced lipophilicity, metabolic stability, or binding affinity. A practical and scalable protocol has been developed for O-trifluoroethylation of alcohols with 2,2,2-trifluorodiazoethane using Cu(OTf)(Tol)1/2 catalyst under mild conditions. This novel approach demonstrated high reactivity and broad substrate scope toward a diverse range of alcohols, ranging from fused and bridged ring systems, linear alcohols, to even sugar motifs, which makes the protocol valuable for medicinal chemistry, material science, and other areas where the introduction of trifluoroethyl groups would be beneficial.
{"title":"CuOTf(Tol)1/2-Catalyzed O-Trifluoroethylation of Alcohols with 2,2,2-Trifluorodiazoethane","authors":"Leyi Tao, Zhiyu Lei, Lianyun Zhao, Tao Ji, Yeon-Hee Lim, James Patrick Roane, Bin Hu, Xin Wen","doi":"10.1021/acs.orglett.5c00942","DOIUrl":"https://doi.org/10.1021/acs.orglett.5c00942","url":null,"abstract":"Trifluoroethyl groups are important in medicinal chemistry since they can impart desirable properties, such as enhanced lipophilicity, metabolic stability, or binding affinity. A practical and scalable protocol has been developed for O-trifluoroethylation of alcohols with 2,2,2-trifluorodiazoethane using Cu(OTf)(Tol)<sub>1/2</sub> catalyst under mild conditions. This novel approach demonstrated high reactivity and broad substrate scope toward a diverse range of alcohols, ranging from fused and bridged ring systems, linear alcohols, to even sugar motifs, which makes the protocol valuable for medicinal chemistry, material science, and other areas where the introduction of trifluoroethyl groups would be beneficial.","PeriodicalId":54,"journal":{"name":"Organic Letters","volume":"11 1","pages":""},"PeriodicalIF":5.2,"publicationDate":"2025-04-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143853597","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}
We have developed a mild and practical synthesis of primary, secondary and tertiary alkyl iodides by iododecarboxylation (decarboxylative iodination) of the corresponding carboxylic acids using (diacetoxyiodo)benzene and iodoform under ambient conditions. The method does not require heating or intense light irradiation and can be used to install iodine at the bridgehead position of strained cycloalkanes, as well as in a variety of alkanes with complex frameworks/functionalities.
{"title":"Iodo-decarboxylation of Aliphatic Carboxylic Acids with PhI(OAc)2 and CHI3 under Ambient Conditions","authors":"Kyoka Sakamoto, Kazunori Miyamoto, Masataka Kubota, Tadafumi Matsunaga, Shinichiro Kamino, Masanobu Uchiyama","doi":"10.1021/acs.orglett.5c00924","DOIUrl":"https://doi.org/10.1021/acs.orglett.5c00924","url":null,"abstract":"We have developed a mild and practical synthesis of primary, secondary and tertiary alkyl iodides by iododecarboxylation (decarboxylative iodination) of the corresponding carboxylic acids using (diacetoxyiodo)benzene and iodoform under ambient conditions. The method does not require heating or intense light irradiation and can be used to install iodine at the bridgehead position of strained cycloalkanes, as well as in a variety of alkanes with complex frameworks/functionalities.","PeriodicalId":54,"journal":{"name":"Organic Letters","volume":"62 1","pages":""},"PeriodicalIF":5.2,"publicationDate":"2025-04-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143858123","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 : 2025-04-21DOI: 10.1021/acs.orglett.5c00914
Sheng-Hu Yuan, Meng-Ran Li, Zheng-Chun Yin, Jun Xuan, Hongping Zhou, Fei Li
Site-selective multiple addition reactions of fullerenes hold great promise for generating new nanocarbons with diverse material and biological applications. However, there are a lack of strategies for achieving site selectivity in a stepwise manner within this field. In this study, we discovered that tetrafluoropyridine-modified unsymmetrical 1,4-C60 adducts can undergo highly site-selective cycloadditions with diazoacetates. This finding suggests that leveraging the 1,4-unsymmetric bifunctional group effect can be an effective strategy for controlling the regioselectivity for further reactions of 1,4-(organo)[60]fullerene.
{"title":"Tetrafluoropyridine Regulated Site-Selective Cycloaddition of Diazoacetates with 1,4-Unsymmetrical [60]Fullerene Adducts","authors":"Sheng-Hu Yuan, Meng-Ran Li, Zheng-Chun Yin, Jun Xuan, Hongping Zhou, Fei Li","doi":"10.1021/acs.orglett.5c00914","DOIUrl":"https://doi.org/10.1021/acs.orglett.5c00914","url":null,"abstract":"Site-selective multiple addition reactions of fullerenes hold great promise for generating new nanocarbons with diverse material and biological applications. However, there are a lack of strategies for achieving site selectivity in a stepwise manner within this field. In this study, we discovered that tetrafluoropyridine-modified unsymmetrical 1,4-C<sub>60</sub> adducts can undergo highly site-selective cycloadditions with diazoacetates. This finding suggests that leveraging the 1,4-unsymmetric bifunctional group effect can be an effective strategy for controlling the regioselectivity for further reactions of 1,4-(organo)[60]fullerene.","PeriodicalId":54,"journal":{"name":"Organic Letters","volume":"63 1","pages":""},"PeriodicalIF":5.2,"publicationDate":"2025-04-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143853596","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 : 2025-04-20DOI: 10.1021/acs.orglett.5c00881
Daling Li, Jun Wei, Lixu Ren, Lingmin Zhou, Liya Huang, Ying Yu, Siping Wei, Na Hao, Jun Wang, Lin Yang, Xianchao Pan, Qiang Fu, Ji Lu
Herein, we report an unprecedented dual photoexcited palladium and photoredox-catalyzed remote C(sp3)–H acylation of amides free of external acylating reagents through sequential N–O/C–H/C–O bond cleavage and chemoselective C–C bond formation. This dual catalytic system shows high efficiency, good atom economy by deletion of oxygen, and diverse functional group tolerance. Experimental investigation of the reaction mechanism revealed that O-acyl hydroxamides enabled by photoexcited palladium generated the alkyl radicals via a 1,5-HAT process mediated by amidyl radicals and a palladium carboxylate complex, which, undergoing photoredox-catalyzed phosphoranyl radical-mediated C–O bond cleavage, leads to coupling with alkyl radicals to deliver the final products.
{"title":"Dual Photoexcited Palladium and Photoredox-Catalyzed Remote C(sp3)–H Acylation of Hydroxyamides","authors":"Daling Li, Jun Wei, Lixu Ren, Lingmin Zhou, Liya Huang, Ying Yu, Siping Wei, Na Hao, Jun Wang, Lin Yang, Xianchao Pan, Qiang Fu, Ji Lu","doi":"10.1021/acs.orglett.5c00881","DOIUrl":"https://doi.org/10.1021/acs.orglett.5c00881","url":null,"abstract":"Herein, we report an unprecedented dual photoexcited palladium and photoredox-catalyzed remote C(sp<sup>3</sup>)–H acylation of amides free of external acylating reagents through sequential N–O/C–H/C–O bond cleavage and chemoselective C–C bond formation. This dual catalytic system shows high efficiency, good atom economy by deletion of oxygen, and diverse functional group tolerance. Experimental investigation of the reaction mechanism revealed that <i>O</i>-acyl hydroxamides enabled by photoexcited palladium generated the alkyl radicals via a 1,5-HAT process mediated by amidyl radicals and a palladium carboxylate complex, which, undergoing photoredox-catalyzed phosphoranyl radical-mediated C–O bond cleavage, leads to coupling with alkyl radicals to deliver the final products.","PeriodicalId":54,"journal":{"name":"Organic Letters","volume":"22 1","pages":""},"PeriodicalIF":5.2,"publicationDate":"2025-04-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143853598","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}
The proposed structure of urupocidin A was synthesized. The bicyclic guanidino core was constructed by Pd(II) catalyzed cyclization-carbonylation-cyclization cascade reactions of the acyclic propargyl guanidine. The N-hydroxy guanidino functionality was protected as a THP ether.
{"title":"Synthesis of the Proposed Structure of Urupocidin A","authors":"Takuya Tsukamoto, Keisuke Takahashi, Kyoka Someya, Taichi Kusakabe, Keisuke Kato","doi":"10.1021/acs.orglett.5c01046","DOIUrl":"https://doi.org/10.1021/acs.orglett.5c01046","url":null,"abstract":"The proposed structure of urupocidin A was synthesized. The bicyclic guanidino core was constructed by Pd(II) catalyzed cyclization-carbonylation-cyclization cascade reactions of the acyclic propargyl guanidine. The <i>N</i>-hydroxy guanidino functionality was protected as a THP ether.","PeriodicalId":54,"journal":{"name":"Organic Letters","volume":"33 1","pages":""},"PeriodicalIF":5.2,"publicationDate":"2025-04-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143853599","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 : 2025-04-18DOI: 10.1021/acs.orglett.5c00940
Jun Zhao, Xiuqi Shi, Shuo Tan, Yue Li, Ran Li, Birou Zhang, Hao Song, Fei Xue, Yong Qin
A novel series of chiral phosphoric acid (CPA) catalysts based on a bioinspired aporphinol scaffold has been developed. The efficacy of these CPAs is demonstrated through enantioselective transfer hydrogenation of C2-substituted quinolines, achieving excellent enantioselectivities (93–99% enantiomeric excess). They also exhibit catalytic efficiency comparable to that of classic chiral phosphoric acids in the asymmetric Friedel–Crafts reaction and reduction of ketone. This work highlights the potential of aporphinol-based catalysts for diverse asymmetric transformations.
{"title":"Aporphinol-Derived Chiral Phosphoric Acids: Synthesis and Catalytic Performance","authors":"Jun Zhao, Xiuqi Shi, Shuo Tan, Yue Li, Ran Li, Birou Zhang, Hao Song, Fei Xue, Yong Qin","doi":"10.1021/acs.orglett.5c00940","DOIUrl":"https://doi.org/10.1021/acs.orglett.5c00940","url":null,"abstract":"A novel series of chiral phosphoric acid (CPA) catalysts based on a bioinspired aporphinol scaffold has been developed. The efficacy of these CPAs is demonstrated through enantioselective transfer hydrogenation of C2-substituted quinolines, achieving excellent enantioselectivities (93–99% enantiomeric excess). They also exhibit catalytic efficiency comparable to that of classic chiral phosphoric acids in the asymmetric Friedel–Crafts reaction and reduction of ketone. This work highlights the potential of aporphinol-based catalysts for diverse asymmetric transformations.","PeriodicalId":54,"journal":{"name":"Organic Letters","volume":"9 1","pages":""},"PeriodicalIF":5.2,"publicationDate":"2025-04-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143846677","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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