Carboxyl polyethers from Actinomycetes have diverse bioactivities, being biosynthesized by type-I polyketide synthetases. Of them, ionomycin, the commercial calcium ionophore, bears a unique enolized 1,3-diketone moiety. Herein, mutagenetic analysis of ionomycin biosynthesis revealed a rare dehydrogenase gene inoJ putatively involved in enol moiety formation. Interruption of the enolized 1,3-diketone formation by inactivating a ketoreductase domain yielded the first natural polyether with an α-pyrone ring, which was demonstrated with significant anti-inflammatory activity in a mouse colitis model.
{"title":"Anti-Inflammatory α-Pyrone Polyethers Generated by Interrupting the Enolized 1,3-Diketone Formation in the Polyketide Synthases of Calcium-Ionophore Ionomycin.","authors":"Mengjia Li, Jing Xu, Haixia Zang, Wen-Rui Peng, Li-Li Hong, Chang Xu, Wanlu Li, Wei-Hua Jiao, Hou-Wen Lin, Yongjun Zhou","doi":"10.1021/acs.orglett.4c04711","DOIUrl":"10.1021/acs.orglett.4c04711","url":null,"abstract":"<p><p>Carboxyl polyethers from <i>Actinomycetes</i> have diverse bioactivities, being biosynthesized by type-I polyketide synthetases. Of them, ionomycin, the commercial calcium ionophore, bears a unique enolized 1,3-diketone moiety. Herein, mutagenetic analysis of ionomycin biosynthesis revealed a rare dehydrogenase gene <i>ino</i>J putatively involved in enol moiety formation. Interruption of the enolized 1,3-diketone formation by inactivating a ketoreductase domain yielded the first natural polyether with an α-pyrone ring, which was demonstrated with significant anti-inflammatory activity in a mouse colitis model.</p>","PeriodicalId":54,"journal":{"name":"Organic Letters","volume":" ","pages":"1806-1811"},"PeriodicalIF":4.9,"publicationDate":"2025-02-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143447437","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 : 2025-02-28Epub Date: 2025-02-18DOI: 10.1021/acs.orglett.5c00037
Na Lin, Ruize Xie, Haoqing Jia, Yin Chen
Efficient one-pot synthesis of tridentate bicyclocalixarenes was developed by condensing phloroglucinol with dechlorinated pyrimidine or triazine with a yield up to 58%. These cage-like molecules adopt a symmetric three-blade propeller structure with different terminal function groups and arm spans ranging from 7.5 to 15.8 Å. Due to the 1,3-alternate configuration of intermediate heterocalixarenes, the cage molecules can be prepared only with benzene rings as the upper and lower caps. They will be an ideal scaffold for the preparation of ultrathin two-dimensional materials.
{"title":"One-Pot Synthesis of Tridentate Bicyclocalixarene Cage Molecules.","authors":"Na Lin, Ruize Xie, Haoqing Jia, Yin Chen","doi":"10.1021/acs.orglett.5c00037","DOIUrl":"10.1021/acs.orglett.5c00037","url":null,"abstract":"<p><p>Efficient one-pot synthesis of tridentate bicyclocalixarenes was developed by condensing phloroglucinol with dechlorinated pyrimidine or triazine with a yield up to 58%. These cage-like molecules adopt a symmetric three-blade propeller structure with different terminal function groups and arm spans ranging from 7.5 to 15.8 Å. Due to the 1,3-alternate configuration of intermediate heterocalixarenes, the cage molecules can be prepared only with benzene rings as the upper and lower caps. They will be an ideal scaffold for the preparation of ultrathin two-dimensional materials.</p>","PeriodicalId":54,"journal":{"name":"Organic Letters","volume":" ","pages":"1853-1857"},"PeriodicalIF":4.9,"publicationDate":"2025-02-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143447443","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 : 2025-02-28DOI: 10.1021/acs.orglett.5c00242
Xiaoyi Yu, Hao An, Wenbin Wu, Fei Xue, Yina Jiang, Siew Yin Chan, Zhifeng Tu, Shenci Lu
The in situ-generated pyrrolin-3-ones serve as novel and versatile synthons, being employed as intermediates for the efficient production of pyrrole-fused lactones with high yield and excellent enantioselectivity. Herein, we introduce emerging rhodium and oxidative N-heterocyclic carbene relay catalysis that enables a highly enantioselective cascade annulation between easily available 1,2,3-triazoles and enals. In this proof-of-concept study, the in situ-generated pyrrolin-3-ones engage α,β-unsaturated acylazolium intermediates generated from enals via oxidative N-heterocyclic carbene catalysis.
{"title":"Enantioselective Cascade Annulation of 1,2,3-Triazoles and Enals Enabled by Sequential Rhodium and Oxidative NHC Catalysis Involving Cleavage, Migration, and Cyclization","authors":"Xiaoyi Yu, Hao An, Wenbin Wu, Fei Xue, Yina Jiang, Siew Yin Chan, Zhifeng Tu, Shenci Lu","doi":"10.1021/acs.orglett.5c00242","DOIUrl":"https://doi.org/10.1021/acs.orglett.5c00242","url":null,"abstract":"The in situ-generated pyrrolin-3-ones serve as novel and versatile synthons, being employed as intermediates for the efficient production of pyrrole-fused lactones with high yield and excellent enantioselectivity. Herein, we introduce emerging rhodium and oxidative N-heterocyclic carbene relay catalysis that enables a highly enantioselective cascade annulation between easily available 1,2,3-triazoles and enals. In this proof-of-concept study, the in situ-generated pyrrolin-3-ones engage α,β-unsaturated acylazolium intermediates generated from enals via oxidative N-heterocyclic carbene catalysis.","PeriodicalId":54,"journal":{"name":"Organic Letters","volume":"49 1","pages":""},"PeriodicalIF":5.2,"publicationDate":"2025-02-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143526113","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 : 2025-02-28Epub Date: 2025-02-19DOI: 10.1021/acs.orglett.5c00188
Jyotish Barman, Spoorthi Ananda, Subhas Chandra Pan
A diastereo- and enantioselective (3 + 3)-cycloannulation of in situ generated carbonyl ylides and (Z)-3-benzylidene-3H-indoles enabled by cooperative Rh/chiral phosphoric acid catalysis is reported. This study is the first to describe an enantioselective synthesis of cyclohepta[b]indole with an oxa-bridged motif. The scope of the reaction is broad, and the oxa-bridged cyclohepta[b]indole products were obtained in moderate to good yields and with excellent diastereoselectivities and good to high enantioselectivities.
{"title":"Stereoselective (3 + 3)-Cycloannulation of Carbonyl Ylides and (<i>Z</i>)-3-Benzylidene-3<i>H</i>-indoles Enabled by Cooperative Rh/Chiral Phosphoric Acid Catalysis.","authors":"Jyotish Barman, Spoorthi Ananda, Subhas Chandra Pan","doi":"10.1021/acs.orglett.5c00188","DOIUrl":"10.1021/acs.orglett.5c00188","url":null,"abstract":"<p><p>A diastereo- and enantioselective (3 + 3)-cycloannulation of in situ generated carbonyl ylides and (<i>Z</i>)-3-benzylidene-3<i>H</i>-indoles enabled by cooperative Rh/chiral phosphoric acid catalysis is reported. This study is the first to describe an enantioselective synthesis of cyclohepta[<i>b</i>]indole with an oxa-bridged motif. The scope of the reaction is broad, and the oxa-bridged cyclohepta[<i>b</i>]indole products were obtained in moderate to good yields and with excellent diastereoselectivities and good to high enantioselectivities.</p>","PeriodicalId":54,"journal":{"name":"Organic Letters","volume":" ","pages":"1929-1934"},"PeriodicalIF":4.9,"publicationDate":"2025-02-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143447446","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 : 2025-02-28Epub Date: 2025-02-19DOI: 10.1021/acs.orglett.5c00230
Xiuli Li, Jianchao Liu, Jie-Ping Wan
A rhodium-catalyzed annulation of 2H-azirines with enaminones is presented. This protocol affords a convenient approach to the diversity-oriented synthesis of 4-acyl- and 4-formyl pyrroles with good functional group tolerance. The utility of this reaction has been demonstrated by scale-up preparation, late-stage modification of natural molecules, and synthesis of diverse derivatives.
{"title":"Tunable Synthesis of 4-Acyl- and 4-Formyl Pyrroles by Rhodium-Catalyzed Ring-Expansion of Azirines with Enaminones.","authors":"Xiuli Li, Jianchao Liu, Jie-Ping Wan","doi":"10.1021/acs.orglett.5c00230","DOIUrl":"10.1021/acs.orglett.5c00230","url":null,"abstract":"<p><p>A rhodium-catalyzed annulation of 2<i>H</i>-azirines with enaminones is presented. This protocol affords a convenient approach to the diversity-oriented synthesis of 4-acyl- and 4-formyl pyrroles with good functional group tolerance. The utility of this reaction has been demonstrated by scale-up preparation, late-stage modification of natural molecules, and synthesis of diverse derivatives.</p>","PeriodicalId":54,"journal":{"name":"Organic Letters","volume":" ","pages":"1949-1954"},"PeriodicalIF":4.9,"publicationDate":"2025-02-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143447449","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 : 2025-02-28Epub Date: 2025-02-20DOI: 10.1021/acs.orglett.5c00330
Haruka Matsui, Yuki Kojima, Kosuke Yasui, Yuji Nishii, Koji Hirano
A copper hydride (CuH)-catalyzed regio- and enantioselective hydroboration of 1-trifluoromethylseleno (SeCF3)-alkenes with H-Bpin has been developed. The regio- and enantioselective hydrocupration of an in situ generated CuH species is followed by a boration reaction to successfully construct a SeCF3- and Bpin-substituted chiral carbon center. The key to success is the appropriate choice of tBu-modified biphosphine ligands, which enables an overwhelming high reaction efficiency.
{"title":"Asymmetric Construction of a SeCF<sub>3</sub>-Substituted Stereocenter by CuH-Catalyzed Hydroboration of 1-SeCF<sub>3</sub>-Alkenes.","authors":"Haruka Matsui, Yuki Kojima, Kosuke Yasui, Yuji Nishii, Koji Hirano","doi":"10.1021/acs.orglett.5c00330","DOIUrl":"10.1021/acs.orglett.5c00330","url":null,"abstract":"<p><p>A copper hydride (CuH)-catalyzed regio- and enantioselective hydroboration of 1-trifluoromethylseleno (SeCF<sub>3</sub>)-alkenes with H-Bpin has been developed. The regio- and enantioselective hydrocupration of an <i>in situ</i> generated CuH species is followed by a boration reaction to successfully construct a SeCF<sub>3</sub>- and Bpin-substituted chiral carbon center. The key to success is the appropriate choice of <i>t</i>Bu-modified biphosphine ligands, which enables an overwhelming high reaction efficiency.</p>","PeriodicalId":54,"journal":{"name":"Organic Letters","volume":" ","pages":"2005-2010"},"PeriodicalIF":4.9,"publicationDate":"2025-02-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143456282","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 : 2025-02-28DOI: 10.1021/acs.orglett.5c00244
Takahiro Sawano, Natsuki Suzuki, Kana Takahashi, Yuta Goto, Kazunori Miyashita, Ryo Takeuchi
We report an asymmetric allylation of silyl enol ethers derived from α-ketoesters with allylic alcohols by an iridium/chiral (P,olefin)-ligand catalyst. Allylation with a broad range of silyl enol ethers and allylic alcohols formed the allylated products with excellent enantioselectivities. Silyl enol ethers derived from α-diketones as well as α-ketoesters were also compatible with the asymmetric allylation to achieve nearly perfect enantioselectivities. The utility of allylated products bearing an α-ketoester group and an α-diketone group is demonstrated by transformation to valuable functional groups, exemplified by α-aminoester, aldehyde, 2(1H)-quinoxalinone, and quinoxaline.
{"title":"Iridium-Catalyzed Asymmetric Allylation of Silyl Enol Ethers Derived from α-Ketoesters and α-Diketones with Allylic Alcohols","authors":"Takahiro Sawano, Natsuki Suzuki, Kana Takahashi, Yuta Goto, Kazunori Miyashita, Ryo Takeuchi","doi":"10.1021/acs.orglett.5c00244","DOIUrl":"https://doi.org/10.1021/acs.orglett.5c00244","url":null,"abstract":"We report an asymmetric allylation of silyl enol ethers derived from α-ketoesters with allylic alcohols by an iridium/chiral (P,olefin)-ligand catalyst. Allylation with a broad range of silyl enol ethers and allylic alcohols formed the allylated products with excellent enantioselectivities. Silyl enol ethers derived from α-diketones as well as α-ketoesters were also compatible with the asymmetric allylation to achieve nearly perfect enantioselectivities. The utility of allylated products bearing an α-ketoester group and an α-diketone group is demonstrated by transformation to valuable functional groups, exemplified by α-aminoester, aldehyde, 2(1<i>H</i>)-quinoxalinone, and quinoxaline.","PeriodicalId":54,"journal":{"name":"Organic Letters","volume":"4 1","pages":""},"PeriodicalIF":5.2,"publicationDate":"2025-02-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143526114","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 : 2025-02-28DOI: 10.1021/acs.orglett.5c00033
Ling Huang, Peng Wang, Fan Xia, Lu Chen, Wengui Wang, Gang Xu, Jun Deng
We report a bioinspired synthesis of microstegiol and biosynthetically related skeleton-rearranged abietane diterpenoids from commercially available carnosic acid. The strategy features a Wagner–Meerwein type methyl migration followed by several cascade transformations, enabling the divergent synthesis of five abietane diterpenoids, including viridoquinone, prattinin A, saprorthoquinone, microstegiol, and 1-deoxyviroxocin.
{"title":"Bioinspired Synthesis of Microstegiol and Biosynthetically Related Skeleton-Rearranged Abietanes","authors":"Ling Huang, Peng Wang, Fan Xia, Lu Chen, Wengui Wang, Gang Xu, Jun Deng","doi":"10.1021/acs.orglett.5c00033","DOIUrl":"https://doi.org/10.1021/acs.orglett.5c00033","url":null,"abstract":"We report a bioinspired synthesis of microstegiol and biosynthetically related skeleton-rearranged abietane diterpenoids from commercially available carnosic acid. The strategy features a Wagner–Meerwein type methyl migration followed by several cascade transformations, enabling the divergent synthesis of five abietane diterpenoids, including viridoquinone, prattinin A, saprorthoquinone, microstegiol, and 1-deoxyviroxocin.","PeriodicalId":54,"journal":{"name":"Organic Letters","volume":"24 1","pages":""},"PeriodicalIF":5.2,"publicationDate":"2025-02-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143518612","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 : 2025-02-28Epub Date: 2025-02-20DOI: 10.1021/acs.orglett.5c00389
Joshua M Paolillo, Mahmoud R Saleh, Ethan W Junk, Marvin Parasram
Herein we describe the oxidation of alkenes to carbonyls and acetonides via the interplay of photoexcited nitroarenes and Lewis acid catalysis. A wide range of alkenes were oxidized to aldehyde and ketone products with anti-Markovnikov selectivity and to acetonides when acetone was employed as a co-solvent. Mechanistic studies support that Lewis acid coordination to the 1,3,2-dioxazolidine intermediate results in a 1,2-shift to generate carbonyl derivatives and a nucleophilic substitution pathway for the formation of acetonides.
{"title":"Merging Photoexcited Nitroarenes with Lewis Acid Catalysis for the Anti-Markovnikov Oxidation of Alkenes.","authors":"Joshua M Paolillo, Mahmoud R Saleh, Ethan W Junk, Marvin Parasram","doi":"10.1021/acs.orglett.5c00389","DOIUrl":"10.1021/acs.orglett.5c00389","url":null,"abstract":"<p><p>Herein we describe the oxidation of alkenes to carbonyls and acetonides via the interplay of photoexcited nitroarenes and Lewis acid catalysis. A wide range of alkenes were oxidized to aldehyde and ketone products with anti-Markovnikov selectivity and to acetonides when acetone was employed as a co-solvent. Mechanistic studies support that Lewis acid coordination to the 1,3,2-dioxazolidine intermediate results in a 1,2-shift to generate carbonyl derivatives and a nucleophilic substitution pathway for the formation of acetonides.</p>","PeriodicalId":54,"journal":{"name":"Organic Letters","volume":" ","pages":"2011-2015"},"PeriodicalIF":4.9,"publicationDate":"2025-02-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11877499/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143456285","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Herein, we describe the successful development of an azido-fluorosulfonylation reaction of alkenes under photoredox catalysis, which could allow the installation of the two “clickable” groups, −N3 and −SO2F, on a C–C double bond, with TMSN3 as the azide source. The utilization of the difunctionalization products is also demonstrated in the construction of a library of 1,2,3-triazolesulfonyl fluoride compounds as well as drug molecule ligation by merging copper-catalyzed azide–alkyne cycloaddition (CuAAC) and sulfur(VI) fluoride exchange (SuFEx), the two generations of click reactions. Mechanistic studies suggest a radical fluorosulfonylation/azidation mechanism and unveil FSO2N3 as a new and potential fluorosulfonyl radical precursor.
{"title":"Photocatalytic Radical Azido/Fluorosulfonylation of Unactivated Alkenes: Accessing Hubs Bridging CuAAC and SuFEx Click Chemistry","authors":"Guanhua Pei, Peng Wang, Lu Lin, Honghai Zhang, Rongbiao Wei, Saihu Liao","doi":"10.1021/acs.orglett.5c00426","DOIUrl":"https://doi.org/10.1021/acs.orglett.5c00426","url":null,"abstract":"Herein, we describe the successful development of an azido-fluorosulfonylation reaction of alkenes under photoredox catalysis, which could allow the installation of the two “clickable” groups, −N<sub>3</sub> and −SO<sub>2</sub>F, on a C–C double bond, with TMSN<sub>3</sub> as the azide source. The utilization of the difunctionalization products is also demonstrated in the construction of a library of 1,2,3-triazolesulfonyl fluoride compounds as well as drug molecule ligation by merging copper-catalyzed azide–alkyne cycloaddition (CuAAC) and sulfur(VI) fluoride exchange (SuFEx), the two generations of click reactions. Mechanistic studies suggest a radical fluorosulfonylation/azidation mechanism and unveil FSO<sub>2</sub>N<sub>3</sub> as a new and potential fluorosulfonyl radical precursor.","PeriodicalId":54,"journal":{"name":"Organic Letters","volume":"28 1","pages":""},"PeriodicalIF":5.2,"publicationDate":"2025-02-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143518302","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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