Chiral cyclobutanamide is a privileged scaffold in drug discovery. Here, we describe, for the first time, the synthesis of axially chiral cyclobutanamides via phosphoric acid-catalyzed enantioselective condensation between N-arylcarbamyl cyclobutanones and hydroxylamines. Rational substrate design, incorporating an amide moiety (CONHR) into the cyclobutanone backbone and the formation of a multi-hydrogen bonding network involving the N–H of this amide portion, is responsible for the excellent enantioselectivity achieved in the stereodetermining dehydration process, which is supported by a detailed mechanistic study.
{"title":"Phosphoric Acid-Catalyzed Enantioselective Synthesis of Axially Chiral Cyclobutanamides","authors":"Guang Cheng, Jinfeng Zheng, Yilin Zhu, Yuming Yang, Guanyinsheng Qiu, Wei-Yi Ding, Shaoyu Li","doi":"10.1021/acs.orglett.5c00590","DOIUrl":"https://doi.org/10.1021/acs.orglett.5c00590","url":null,"abstract":"Chiral cyclobutanamide is a privileged scaffold in drug discovery. Here, we describe, for the first time, the synthesis of axially chiral cyclobutanamides via phosphoric acid-catalyzed enantioselective condensation between <i>N</i>-arylcarbamyl cyclobutanones and hydroxylamines. Rational substrate design, incorporating an amide moiety (CONHR) into the cyclobutanone backbone and the formation of a multi-hydrogen bonding network involving the N–H of this amide portion, is responsible for the excellent enantioselectivity achieved in the stereodetermining dehydration process, which is supported by a detailed mechanistic study.","PeriodicalId":54,"journal":{"name":"Organic Letters","volume":"14 1","pages":""},"PeriodicalIF":5.2,"publicationDate":"2025-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143546663","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 : 2025-03-05DOI: 10.1021/acs.orglett.5c00221
Dan Liu, Fang Xiao, Ben Ebel, Iris M. Oppel, Frederic W. Patureau
Direct gem-difluoroallylation at the α-carbonyl position is a challenging process by conventional methods. Herein we report the photocatalytic radical α-C(sp3)─H gem-difluoroallylation of amides with trifluoromethyl alkenes to access the target compounds with good yields and functional group tolerance. The mild and effective conditions allow gem-difluoroalkene motifs as carbonyl bioisosteres incorporated concisely to some complex molecules, including gemfibrozil and estrone derivatives, presenting great potential for late-stage functionalization of drugs, natural products, and bioactive intermediates. Mechanistic investigations suggest a radical pathway combining XAT and 1,5-HAT.
{"title":"Visible-Light-Mediated Radical α-C(sp3)─H gem-Difluoroallylation of Amides with Trifluoromethyl Alkenes via Halogen Atom Transfer and 1,5-Hydrogen Atom Transfer","authors":"Dan Liu, Fang Xiao, Ben Ebel, Iris M. Oppel, Frederic W. Patureau","doi":"10.1021/acs.orglett.5c00221","DOIUrl":"https://doi.org/10.1021/acs.orglett.5c00221","url":null,"abstract":"Direct <i>gem</i>-difluoroallylation at the α-carbonyl position is a challenging process by conventional methods. Herein we report the photocatalytic radical α-C(sp<sup>3</sup>)─H <i>gem</i>-difluoroallylation of amides with trifluoromethyl alkenes to access the target compounds with good yields and functional group tolerance. The mild and effective conditions allow <i>gem</i>-difluoroalkene motifs as carbonyl bioisosteres incorporated concisely to some complex molecules, including gemfibrozil and estrone derivatives, presenting great potential for late-stage functionalization of drugs, natural products, and bioactive intermediates. Mechanistic investigations suggest a radical pathway combining XAT and 1,5-HAT.","PeriodicalId":54,"journal":{"name":"Organic Letters","volume":"36 1","pages":""},"PeriodicalIF":5.2,"publicationDate":"2025-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143547073","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 : 2025-03-05DOI: 10.1021/acs.orglett.4c04837
Muskan, Akhilesh K. Verma
A stereoselective, metal-free synthesis of densely functionalized benzofulvenes via base-promoted regioselective iodocyclization followed by decarboxylative protodeiodination of o-alkynylaryl 2-cyanoacrylates is described. Michael addition of alcohol to the carbon–carbon double bond triggers the sequential formation of the C–O, C–C, and C–I bonds in a single operation. Subsequent decarboxylation and the elimination of HI furnish the final benzofulvene framework, featuring an exocyclic double bond and functional groups such as −CN and −OMe that can be easily transformed to afford biologically active pharmacophores.
{"title":"Molecular Iodine-Mediated One-Pot Sequential Iodocyclization–Decarboxylative Protodeiodination: Access to Densely Functionalized Benzofulvenes","authors":"Muskan, Akhilesh K. Verma","doi":"10.1021/acs.orglett.4c04837","DOIUrl":"https://doi.org/10.1021/acs.orglett.4c04837","url":null,"abstract":"A stereoselective, metal-free synthesis of densely functionalized benzofulvenes <i>via</i> base-promoted regioselective iodocyclization followed by decarboxylative protodeiodination of <i>o</i>-alkynylaryl 2-cyanoacrylates is described. Michael addition of alcohol to the carbon–carbon double bond triggers the sequential formation of the C–O, C–C, and C–I bonds in a single operation. Subsequent decarboxylation and the elimination of HI furnish the final benzofulvene framework, featuring an exocyclic double bond and functional groups such as −CN and −OMe that can be easily transformed to afford biologically active pharmacophores.","PeriodicalId":54,"journal":{"name":"Organic Letters","volume":"13 1","pages":""},"PeriodicalIF":5.2,"publicationDate":"2025-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143546661","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 : 2025-03-04DOI: 10.1021/acs.orglett.5c00444
Dongchang Han, Ao Wen, Ziheng Tian, Xiaowen Zhan, Chao Hu, Zhibin Luo, Peng Liu, Bin Liu
Following the successful construction of nitrilium/pyridinium and sulfonium salts, the Chan–Lam coupling has been significantly advanced with the first demonstration of quaternary phosphonium salt synthesis. We present a method employing copper(II) acetate in trifluoroethanol to efficiently produce a range of aryl and vinyl phosphonium salts from boronic acids, including those derived from complex natural products, thus overcoming phosphine oxidation issues and expanding the scope to functionalized phosphorus.
{"title":"Copper-Mediated Phosphoniumation of Aryl/Vinyl Boronic Acids","authors":"Dongchang Han, Ao Wen, Ziheng Tian, Xiaowen Zhan, Chao Hu, Zhibin Luo, Peng Liu, Bin Liu","doi":"10.1021/acs.orglett.5c00444","DOIUrl":"https://doi.org/10.1021/acs.orglett.5c00444","url":null,"abstract":"Following the successful construction of nitrilium/pyridinium and sulfonium salts, the Chan–Lam coupling has been significantly advanced with the first demonstration of quaternary phosphonium salt synthesis. We present a method employing copper(II) acetate in trifluoroethanol to efficiently produce a range of aryl and vinyl phosphonium salts from boronic acids, including those derived from complex natural products, thus overcoming phosphine oxidation issues and expanding the scope to functionalized phosphorus.","PeriodicalId":54,"journal":{"name":"Organic Letters","volume":"1 1","pages":""},"PeriodicalIF":5.2,"publicationDate":"2025-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143539266","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}
Here, we report a protocol for the synthesis of skipped dienes through the cross-coupling of bicyclo[1.1.0]butanes with trifluoromethyl triftosylhydrazones. The reaction is run using TpBr3Cu(NCMe) as a catalyst to give access to a library of trifluoromethylated skipped dienes (32 examples, ≤98% yield) with excellent E/Z selectivity under mild and operationally safe conditions. The presented methods proved to be compatible with various functionalized bicyclo[1.1.0]butanes and triftosylhydrazones.
{"title":"Copper-Catalyzed Cross-Coupling of Bicyclobutanes with Triftosylhydrazone Leading to Skipped Dienes","authors":"Xiaolong Zhang, Tian Tian, Peiqiu Liao, Zhaohong Liu, Karunanidhi Murali, Xihe Bi","doi":"10.1021/acs.orglett.4c04519","DOIUrl":"https://doi.org/10.1021/acs.orglett.4c04519","url":null,"abstract":"Here, we report a protocol for the synthesis of skipped dienes through the cross-coupling of bicyclo[1.1.0]butanes with trifluoromethyl triftosylhydrazones. The reaction is run using Tp<sup>Br3</sup>Cu(NCMe) as a catalyst to give access to a library of trifluoromethylated skipped dienes (32 examples, ≤98% yield) with excellent <i>E</i>/<i>Z</i> selectivity under mild and operationally safe conditions. The presented methods proved to be compatible with various functionalized bicyclo[1.1.0]butanes and triftosylhydrazones.","PeriodicalId":54,"journal":{"name":"Organic Letters","volume":"30 1","pages":""},"PeriodicalIF":5.2,"publicationDate":"2025-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143546813","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 : 2025-03-04DOI: 10.1021/acs.orglett.5c00419
Kathleen M. Morrison, Giulio Volpin, Sherif J. Kaldas, Philipp M. Holstein, Maximilian Lübbesmeyer, Mark James Ford, Nicolas Guimond, Mark Stradiotto
The palladium-catalyzed Sonogashira cross-coupling of (hetero)aryl fluorosulfates and terminal alkynes, featuring a synthetically useful scope and yields, is reported herein. Such transformations involving a diversity of (hetero)aryl fluorosulfate coupling partners, including chemoselective examples where contending chloro functionalities are present, are achieved using a DPPF/[Pd(cinnamyl)Cl]2 catalyst system without the requirement of a copper additive.
{"title":"Palladium-Catalyzed Sonogashira Cross-Couplings of (Hetero)Aryl Fluorosulfates","authors":"Kathleen M. Morrison, Giulio Volpin, Sherif J. Kaldas, Philipp M. Holstein, Maximilian Lübbesmeyer, Mark James Ford, Nicolas Guimond, Mark Stradiotto","doi":"10.1021/acs.orglett.5c00419","DOIUrl":"https://doi.org/10.1021/acs.orglett.5c00419","url":null,"abstract":"The palladium-catalyzed Sonogashira cross-coupling of (hetero)aryl fluorosulfates and terminal alkynes, featuring a synthetically useful scope and yields, is reported herein. Such transformations involving a diversity of (hetero)aryl fluorosulfate coupling partners, including chemoselective examples where contending chloro functionalities are present, are achieved using a DPPF/[Pd(cinnamyl)Cl]<sub>2</sub> catalyst system without the requirement of a copper additive.","PeriodicalId":54,"journal":{"name":"Organic Letters","volume":"11 1","pages":""},"PeriodicalIF":5.2,"publicationDate":"2025-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143546633","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 : 2025-03-04DOI: 10.1021/acs.orglett.4c04750
Maximilian Guhlke, Johannes Herbst, Tra Giang Nguyen, Andreas Schneider, Jeroen S. Dickschat, Dirk Menche
The central hexaene core of the labile polyene antibiotic bacillaene bearing three Z-configured olefins was prepared with excellent geometrical purity by an iterative cross-coupling strategy, involving improved syntheses of bimetallic reagents and efficient protocols for stereoselective polyene generation, revealing insights into the origin of bacillaene’s instability. Furthermore, a useful method for monitoring polyene iteration by UV–vis shift analyses and the absolute stereochemistry of this core by biosynthetic gene cluster analysis are reported.
{"title":"Total Synthesis and Stereochemical Proposal of the Hexaene Framework of Bacillaene","authors":"Maximilian Guhlke, Johannes Herbst, Tra Giang Nguyen, Andreas Schneider, Jeroen S. Dickschat, Dirk Menche","doi":"10.1021/acs.orglett.4c04750","DOIUrl":"https://doi.org/10.1021/acs.orglett.4c04750","url":null,"abstract":"The central hexaene core of the labile polyene antibiotic bacillaene bearing three <i>Z</i>-configured olefins was prepared with excellent geometrical purity by an iterative cross-coupling strategy, involving improved syntheses of bimetallic reagents and efficient protocols for stereoselective polyene generation, revealing insights into the origin of bacillaene’s instability. Furthermore, a useful method for monitoring polyene iteration by UV–vis shift analyses and the absolute stereochemistry of this core by biosynthetic gene cluster analysis are reported.","PeriodicalId":54,"journal":{"name":"Organic Letters","volume":"52 1","pages":""},"PeriodicalIF":5.2,"publicationDate":"2025-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143539265","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}
New derivatives of [4]dendralene with redox-active 1,3-dithiol-2-ylidene units were synthesized. X-ray crystal structure analysis of the dibenzo-tetramethyl derivative revealed that the molecule takes a conformation in which two vinyl-extended TTF moieties are significantly inclined to each other. The octamethyl derivative underwent cyclization with skeletal rearrangement in the dicationic state to give the corresponding dicationic trimethylenecylopentene, which exhibited a simultaneous two-electron reduction wave at a significantly negative potential of −0.42 V (V vs Fc/Fc+).
{"title":"Synthesis of [4]Dendralene Derivatives Possessing Quadruple 1,3-Dithiol-2-ylidenes and Transformation to a Trimethylenecylopentene in an Oxidation State","authors":"Yuji Kawasaki, Daisuke Kasai, Masafumi Ueda, Miyu Takezaki, Aya Yoshimura, Takashi Shirahata, Yohji Misaki","doi":"10.1021/acs.orglett.4c04770","DOIUrl":"https://doi.org/10.1021/acs.orglett.4c04770","url":null,"abstract":"New derivatives of [4]dendralene with redox-active 1,3-dithiol-2-ylidene units were synthesized. X-ray crystal structure analysis of the dibenzo-tetramethyl derivative revealed that the molecule takes a conformation in which two vinyl-extended TTF moieties are significantly inclined to each other. The octamethyl derivative underwent cyclization with skeletal rearrangement in the dicationic state to give the corresponding dicationic trimethylenecylopentene, which exhibited a simultaneous two-electron reduction wave at a significantly negative potential of −0.42 V (V vs Fc/Fc<sup>+</sup>).","PeriodicalId":54,"journal":{"name":"Organic Letters","volume":"44 1","pages":""},"PeriodicalIF":5.2,"publicationDate":"2025-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143539267","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.5c00082
María J. Cabrera-Afonso, Aida Jaafar, Christian Cristóbal, Javier Adrio, Maria Ribagorda
We report a metal-free synthesis of highly functionalized 1,6-amino alcohols through a visible-light 1,2-carboimination of alkenes and bifunctional starting materials prepared from commercially available alcohols. This protocol orchestrates the generation of up to four different types of radicals, which are efficiently recombined to yield 1,6-iminyl alcohols. The methodology demonstrated a broad functional group tolerance and was validated by the late-stage installation of the 1,6-amino alcohol motif in biomolecules and pharmaceuticals and the scale-up of the process. The versatility of the products was highlighted by their conversion into a variety of useful intermediates for target-directed synthesis.
{"title":"Visible-Light-Promoted Synthesis of 1,6-Imino Alcohols by Metal-Free 1,2-Carboimination of Alkenes","authors":"María J. Cabrera-Afonso, Aida Jaafar, Christian Cristóbal, Javier Adrio, Maria Ribagorda","doi":"10.1021/acs.orglett.5c00082","DOIUrl":"https://doi.org/10.1021/acs.orglett.5c00082","url":null,"abstract":"We report a metal-free synthesis of highly functionalized 1,6-amino alcohols through a visible-light 1,2-carboimination of alkenes and bifunctional starting materials prepared from commercially available alcohols. This protocol orchestrates the generation of up to four different types of radicals, which are efficiently recombined to yield 1,6-iminyl alcohols. The methodology demonstrated a broad functional group tolerance and was validated by the late-stage installation of the 1,6-amino alcohol motif in biomolecules and pharmaceuticals and the scale-up of the process. The versatility of the products was highlighted by their conversion into a variety of useful intermediates for target-directed synthesis.","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":"143539268","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.5c00302
Partha Pratim Mondal, Mahadev Ray, Soumitra Maity
Alkyl radicals represent some of the most intriguing prospects in organic synthesis, showing diverse patterns of reactivity for versatile transformations. In light of this, the methyl radical, in addition to being a methylating agent, is also a good proposition for hydrogen atom transfer (HAT). Similarly, acetonitrile also has dual facets to its reactivity, acting as an amination reagent in the Ritter reaction while also being the progenitor to cyanomethyl radicals through HAT. We hereby take advantage of the merging of the dual reactivities of these radicals, allowing facile access to amines of various types from olefins when conjugated with a photoredox Ritter amination.
{"title":"Photochemical Alkylamination of Olefins through Reactivity-Based Sorting of Alkyl Radicals","authors":"Partha Pratim Mondal, Mahadev Ray, Soumitra Maity","doi":"10.1021/acs.orglett.5c00302","DOIUrl":"https://doi.org/10.1021/acs.orglett.5c00302","url":null,"abstract":"Alkyl radicals represent some of the most intriguing prospects in organic synthesis, showing diverse patterns of reactivity for versatile transformations. In light of this, the methyl radical, in addition to being a methylating agent, is also a good proposition for hydrogen atom transfer (HAT). Similarly, acetonitrile also has dual facets to its reactivity, acting as an amination reagent in the Ritter reaction while also being the progenitor to cyanomethyl radicals through HAT. We hereby take advantage of the merging of the dual reactivities of these radicals, allowing facile access to amines of various types from olefins when conjugated with a photoredox Ritter amination.","PeriodicalId":54,"journal":{"name":"Organic Letters","volume":"16 1","pages":""},"PeriodicalIF":5.2,"publicationDate":"2025-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143539270","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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