Vitaliy A. Bilenko, Viktor Huliak, Serhii Kinakh, Ryan A. Inwood, Thomas Stowe, Elvis J. M. Maduli, Brian Broadbelt, Rosemary H. Crampton, Ed J. Griffen, Tetiana Matviiuk, Igor V. Komarov, Oleksandr O. Grygorenko
As a part of the ongoing COVID Moonshot project, an expedient approach to 1‐oxo‐1,2,3,4‐tetrahydroisoquinoline‐4‐carboxylates is described. The method is based on a one‐pot tandem Michael amination–lactamization sequence starting from 2‐(3‐alkoxymethoxy‐3‐oxoprop‐1‐en‐2‐yl)benzoic acids and primary amines. The scope of the N ‐nucleophiles included various aliphatic, aromatic, and heteroaromatic primary amines. The reaction tolerated and was compatible with ether, ester, amide, alcohol, carbamate, free alcohol, azole, or azine moieties. The developed protocol allowed for the preparation of target tetrahydroisoquinoline derivatives in 40%–75% yield on up to 109 g scale (later extended up to 0.86 kg). A mechanistic scheme involving a ring‐chain tautomerism for the electrophilic component of the reaction is proposed. The method was used in the synthesis of DNDI‐6510, a SARS‐CoV‐2 main protease inhibitor that showed promising results obtained in preclinical studies.
{"title":"Expedient Synthesis of 1‐Oxo‐1,2,3,4‐Tetrahydroisoquinoline‐4‐Carboxylates","authors":"Vitaliy A. Bilenko, Viktor Huliak, Serhii Kinakh, Ryan A. Inwood, Thomas Stowe, Elvis J. M. Maduli, Brian Broadbelt, Rosemary H. Crampton, Ed J. Griffen, Tetiana Matviiuk, Igor V. Komarov, Oleksandr O. Grygorenko","doi":"10.1002/ejoc.202500842","DOIUrl":"https://doi.org/10.1002/ejoc.202500842","url":null,"abstract":"As a part of the ongoing COVID Moonshot project, an expedient approach to 1‐oxo‐1,2,3,4‐tetrahydroisoquinoline‐4‐carboxylates is described. The method is based on a one‐pot tandem Michael amination–lactamization sequence starting from 2‐(3‐alkoxymethoxy‐3‐oxoprop‐1‐en‐2‐yl)benzoic acids and primary amines. The scope of the <jats:italic>N</jats:italic> ‐nucleophiles included various aliphatic, aromatic, and heteroaromatic primary amines. The reaction tolerated and was compatible with ether, ester, amide, alcohol, carbamate, free alcohol, azole, or azine moieties. The developed protocol allowed for the preparation of target tetrahydroisoquinoline derivatives in 40%–75% yield on up to 109 g scale (later extended up to 0.86 kg). A mechanistic scheme involving a ring‐chain tautomerism for the electrophilic component of the reaction is proposed. The method was used in the synthesis of DNDI‐6510, a SARS‐CoV‐2 main protease inhibitor that showed promising results obtained in preclinical studies.","PeriodicalId":167,"journal":{"name":"European Journal of Organic Chemistry","volume":"55 1","pages":""},"PeriodicalIF":2.8,"publicationDate":"2025-12-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145673948","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Hugo Madec, Yanis Tigherghar, Sylvain Roland, Matthieu Sollogoub
Homogeneous copper‐based systems for air‐mediated oxidation of arylboronic acids in water remain scarce. Herein, it is shown that water‐soluble cyclodextrin(CD)‐encapsulated N ‐heterocyclic carbene (NHC)–copper(I) complexes based on modified permethylated α or β CDs, catalyze the ipso ‐hydroxylation‐deborylation reaction of arylboronic acids in pure water at low copper loading. Optimum conditions for the formation of phenols included the presence of stoichiometric triethylamine, which renders the catalytic system totally homogeneous. Although the reaction is relatively slow, it is compatible with a wide range of substrates, including substrates which are usually inert to oxidation by H 2 O 2 . The efficiency of the α and β‐CD‐based catalysts is compared, revealing a significant cavity effect on the reaction rate. The effect of the nature and position of the arylboronic acid substituents on the conversion is studied, showing a significant “ ortho ” effect in many cases. An experimental study of the mechanism shows that water acts as a formal oxidant and that the reaction does not requires dioxygen. These results, combined with previous knowledge of the constraints imposed by the CD cavity on metal coordination, led us to propose a copper(I)‐based mechanism involving CuOH‐type active species.
{"title":"Cyclodextrin‐Encapsulated N ‐Heterocyclic Carbene–Copper(I) Complexes for Homogeneous Catalysis in Pure Water: Anaerobic Oxidation of Arylboronic Acids with Water as the Formal Oxidant","authors":"Hugo Madec, Yanis Tigherghar, Sylvain Roland, Matthieu Sollogoub","doi":"10.1002/ejoc.202500635","DOIUrl":"https://doi.org/10.1002/ejoc.202500635","url":null,"abstract":"Homogeneous copper‐based systems for air‐mediated oxidation of arylboronic acids in water remain scarce. Herein, it is shown that water‐soluble cyclodextrin(CD)‐encapsulated <jats:italic>N</jats:italic> ‐heterocyclic carbene (NHC)–copper(I) complexes based on modified permethylated α or β CDs, catalyze the <jats:italic>ipso</jats:italic> ‐hydroxylation‐deborylation reaction of arylboronic acids in pure water at low copper loading. Optimum conditions for the formation of phenols included the presence of stoichiometric triethylamine, which renders the catalytic system totally homogeneous. Although the reaction is relatively slow, it is compatible with a wide range of substrates, including substrates which are usually inert to oxidation by H <jats:sub>2</jats:sub> O <jats:sub>2</jats:sub> . The efficiency of the α and β‐CD‐based catalysts is compared, revealing a significant cavity effect on the reaction rate. The effect of the nature and position of the arylboronic acid substituents on the conversion is studied, showing a significant “ <jats:italic>ortho</jats:italic> ” effect in many cases. An experimental study of the mechanism shows that water acts as a formal oxidant and that the reaction does not requires dioxygen. These results, combined with previous knowledge of the constraints imposed by the CD cavity on metal coordination, led us to propose a copper(I)‐based mechanism involving CuOH‐type active species.","PeriodicalId":167,"journal":{"name":"European Journal of Organic Chemistry","volume":"28 1","pages":""},"PeriodicalIF":2.8,"publicationDate":"2025-12-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145673947","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
A highly efficient, metal‐free, atom‐economical green protocol for the synthesis of N , S ‐polyheterocycles via dearomative [3 + 2] cycloaddition of N ‐phenacylbenzothiazolium salts with alkylidene acenaphthylenones and barbiturate‐derived alkenes. This reaction tolerates diverse substituents on the acenaphthylenone and barbiturate partners, underscoring its broad scope and providing an efficient method to construct desired cycloadducts in good to excellent yields with high diastereoselectivity. This strategy provides the formation of two CC bonds with multiple contiguous stereocenters, including one spiro‐center, in a one‐pot reaction. Significantly, no hydro‐quenching, solvent separations, or chromatographic/recrystallization purifications are required. Overall, this efficient, selective, and eco‐friendly strategy offers rapid access to N , S ‐frameworks relevant to medicinal chemistry and materials science.
一种高效、无金属、原子经济的绿色方案，通过N -苯并噻唑盐与烷基烯苊酮和巴比妥酸衍生烯烃的脱芳香[3 + 2]环加成合成N， S -多杂环。该反应可耐受苊酮和巴比妥酸盐上的多种取代基，强调了其广泛的适用范围，并提供了一种高效的方法来构建所需的环加合物，收率高，非对映选择性高。这种策略提供了在一锅反应中形成两个具有多个连续立体中心的C - _ - C键，包括一个螺旋中心。值得注意的是，不需要水淬，溶剂分离或色谱/再结晶纯化。总的来说，这种高效、选择性和生态友好的策略提供了与药物化学和材料科学相关的N， S -框架的快速访问。
{"title":"Highly Diastereoselective Synthesis of N , S ‐Polyheterocyclic Scaffolds via [3 + 2] Cycloaddition of N ‐Phenacylbenzothiazolium Bromides","authors":"Jyoti Sikarwar, Jyoti Chauhan, Rama Krishna Peddinti","doi":"10.1002/ejoc.202500986","DOIUrl":"https://doi.org/10.1002/ejoc.202500986","url":null,"abstract":"A highly efficient, metal‐free, atom‐economical green protocol for the synthesis of <jats:italic>N</jats:italic> , <jats:italic>S</jats:italic> ‐polyheterocycles via dearomative [3 + 2] cycloaddition of <jats:italic>N</jats:italic> ‐phenacylbenzothiazolium salts with alkylidene acenaphthylenones and barbiturate‐derived alkenes. This reaction tolerates diverse substituents on the acenaphthylenone and barbiturate partners, underscoring its broad scope and providing an efficient method to construct desired cycloadducts in good to excellent yields with high diastereoselectivity. This strategy provides the formation of two CC bonds with multiple contiguous stereocenters, including one spiro‐center, in a one‐pot reaction. Significantly, no hydro‐quenching, solvent separations, or chromatographic/recrystallization purifications are required. Overall, this efficient, selective, and eco‐friendly strategy offers rapid access to <jats:italic>N</jats:italic> , <jats:italic>S</jats:italic> ‐frameworks relevant to medicinal chemistry and materials science.","PeriodicalId":167,"journal":{"name":"European Journal of Organic Chemistry","volume":"14 1","pages":""},"PeriodicalIF":2.8,"publicationDate":"2025-12-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145673623","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
An unprecedented deprotonative functionalization of difluoromethoxylated compounds is described herein using a lithiated base under in situ trapping conditions. Aryl α , α ‐difluoroalkyl ethers could be obtained in a two‐step process via difluoro(trimethylsilyl)methylated compounds without any intermediate purification. These new silylated scaffolds act as intermediates to mask the highly unstable difluorinated carbanion and to limit the formation of fluorocarbenes. Desilylative trapping with various electrophiles using a fluoride source gave rise to a library of new α , α ‐difluorinated ethers, which could be of particular interest in various fields such as life sciences or materials chemistry.
{"title":"Synthesis of Aryl Difluoroalkyl Ethers by Deprotonative Functionalization of the Difluoromethoxy (OCHF 2 ) Moiety","authors":"Guillaume Siegel, Anaïs Loison, Gilles Hanquet, Frédéric R. Leroux, Armen Panossian","doi":"10.1002/ejoc.202500852","DOIUrl":"https://doi.org/10.1002/ejoc.202500852","url":null,"abstract":"An unprecedented deprotonative functionalization of difluoromethoxylated compounds is described herein using a lithiated base under in situ trapping conditions. Aryl <jats:italic>α</jats:italic> , <jats:italic>α</jats:italic> ‐difluoroalkyl ethers could be obtained in a two‐step process via difluoro(trimethylsilyl)methylated compounds without any intermediate purification. These new silylated scaffolds act as intermediates to mask the highly unstable difluorinated carbanion and to limit the formation of fluorocarbenes. Desilylative trapping with various electrophiles using a fluoride source gave rise to a library of new <jats:italic>α</jats:italic> , <jats:italic>α</jats:italic> ‐difluorinated ethers, which could be of particular interest in various fields such as life sciences or materials chemistry.","PeriodicalId":167,"journal":{"name":"European Journal of Organic Chemistry","volume":"5 1","pages":""},"PeriodicalIF":2.8,"publicationDate":"2025-12-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145673945","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
This article provides a brief compendium on the production of chiral monocyclic γ‐lactone derivatives through asymmetric hydrogenation of keto acids and keto esters using different type of catalytic approaches: homogeneous, heterogeneous as well as chemoenzymatic. Homogeneous catalysis has always been ahead with this issue, addressing the problem from different perspectives, ranging from the use of transition metal complexes (i.e., Ru, Ir, Pd, and Ni) to ligand design (mainly phosphanes) to seeking a change in the nature of the process: a) direct hydrogenation using H 2 gas or b) transfer hydrogenation. This contrasts greatly with the scarce number of references found with heterogeneous catalysts, a fact that should be taken as an incentive for researchers, leaving a large field open to future research toward increasing both catalytic performance and recyclability. The integration of biocatalysis with synthetic chemistry is also an upward trend and opens up opportunities for the development of greener and more sustainable processes, due to the biogenicity/biodegradability of enzymes and to the mild reaction conditions. It is expected that continued advancements in genetic engineering and bioprocess optimization will drive further innovation and developments at a large scale, especially for stereoselective processes.
{"title":"Asymmetric Catalytic Hydrogenation toward a Value‐Added Chiral Building Block: Optically Active γ‐Butyrolactone Scaffold from Renewable and Synthetic Derived Feedstocks","authors":"Marta Feliz, Maria J. Sabater","doi":"10.1002/ejoc.202500584","DOIUrl":"https://doi.org/10.1002/ejoc.202500584","url":null,"abstract":"This article provides a brief compendium on the production of chiral monocyclic γ‐lactone derivatives through asymmetric hydrogenation of keto acids and keto esters using different type of catalytic approaches: homogeneous, heterogeneous as well as chemoenzymatic. Homogeneous catalysis has always been ahead with this issue, addressing the problem from different perspectives, ranging from the use of transition metal complexes (i.e., Ru, Ir, Pd, and Ni) to ligand design (mainly phosphanes) to seeking a change in the nature of the process: a) direct hydrogenation using H <jats:sub>2</jats:sub> gas or b) transfer hydrogenation. This contrasts greatly with the scarce number of references found with heterogeneous catalysts, a fact that should be taken as an incentive for researchers, leaving a large field open to future research toward increasing both catalytic performance and recyclability. The integration of biocatalysis with synthetic chemistry is also an upward trend and opens up opportunities for the development of greener and more sustainable processes, due to the biogenicity/biodegradability of enzymes and to the mild reaction conditions. It is expected that continued advancements in genetic engineering and bioprocess optimization will drive further innovation and developments at a large scale, especially for stereoselective processes.","PeriodicalId":167,"journal":{"name":"European Journal of Organic Chemistry","volume":"10 1","pages":""},"PeriodicalIF":2.8,"publicationDate":"2025-12-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145673944","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Meso‐β fused porphyrins with tunable optoelectronic properties are attractive candidates for applications in light‐harvesting, sensing, and catalysis, yet their synthesis often requires harsh conditions or tedious synthetic routes. Herein, a mild, operationally simple, and Cu(OTf) 2 ‐catalyzed protocol is reported to access meso‐N ‐aryliminonaphtho‐fused and N‐ arylcarboxamide porphyrins from readily available β ‐cyanoporphyrins and diaryliodonium salts. Reaction selectivity is controlled by the water content present in the reaction mixture, affording either fused imines or carboxamides in high yields. The protocol tolerates different symmetrical diaryliodonium salts and enables the preparation of free‐base, Zn (II), and Cu (II) porphyrin derivatives, all fully characterized by NMR, UV–visible spectroscopy, high resolution mass spectrometry, electrochemistry, and single crystal X‐ray diffraction. The π‐extended systems exhibit distinct bathochromic shifts (≈42 nm in Soret and ≈80–90 nm in Q‐bands) and narrowed highest molecular orbital‐lowest unoccupied molecular orbital (HOMO‐LUMO) gaps up to 1.54 eV. Electrochemical studies reveal that fused porphyrins exhibited anodically shifted reduction potentials, while Density functional theory calculations attribute the gap reduction to LUMO stabilization and HOMO destabilization induced by fusion. Overall, this strategy provides rapid access to structurally diverse π‐extended porphyrins with tailored photophysical and redox properties.
{"title":"Iodine(III)‐Induced Cascade Annulation of β ‐Cyanoporphyrins for the Efficient Synthesis of N ‐Aryliminonaphtho‐Fused and N‐ Aryl‐Carboxamide Porphyrins","authors":"Narshimha Verma, Santosh B. Khandagale, Eldhose Iype, Nitika Grover, Dalip Kumar","doi":"10.1002/ejoc.202501000","DOIUrl":"https://doi.org/10.1002/ejoc.202501000","url":null,"abstract":"<jats:italic>Meso‐β</jats:italic> fused porphyrins with tunable optoelectronic properties are attractive candidates for applications in light‐harvesting, sensing, and catalysis, yet their synthesis often requires harsh conditions or tedious synthetic routes. Herein, a mild, operationally simple, and Cu(OTf) <jats:sub>2</jats:sub> ‐catalyzed protocol is reported to access <jats:italic>meso‐N</jats:italic> ‐aryliminonaphtho‐fused and <jats:italic>N‐</jats:italic> arylcarboxamide porphyrins from readily available <jats:italic>β</jats:italic> ‐cyanoporphyrins and diaryliodonium salts. Reaction selectivity is controlled by the water content present in the reaction mixture, affording either fused imines or carboxamides in high yields. The protocol tolerates different symmetrical diaryliodonium salts and enables the preparation of free‐base, Zn (II), and Cu (II) porphyrin derivatives, all fully characterized by NMR, UV–visible spectroscopy, high resolution mass spectrometry, electrochemistry, and single crystal X‐ray diffraction. The π‐extended systems exhibit distinct bathochromic shifts (≈42 nm in Soret and ≈80–90 nm in Q‐bands) and narrowed highest molecular orbital‐lowest unoccupied molecular orbital (HOMO‐LUMO) gaps up to 1.54 eV. Electrochemical studies reveal that fused porphyrins exhibited anodically shifted reduction potentials, while Density functional theory calculations attribute the gap reduction to LUMO stabilization and HOMO destabilization induced by fusion. Overall, this strategy provides rapid access to structurally diverse π‐extended porphyrins with tailored photophysical and redox properties.","PeriodicalId":167,"journal":{"name":"European Journal of Organic Chemistry","volume":"118 1","pages":""},"PeriodicalIF":2.8,"publicationDate":"2025-12-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145665169","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Ahlem N. Khelf‐Maghraoui, Ghenia Bentabed‐Ababsa, Nicolas Mast, William Erb, Jean‐Pierre Hurvois, Thierry J. Roisnel, Nicolas Richy, Guillaume Calvez, Olivier Mongin, Charline Piroud, Thomas Robert, Stéphane Bach, Florence Mongin
The physical properties of anthraquinones can be modulated by the introduction of arylamino groups next to the carbonyl function. Indeed, formation of an intramolecular hydrogen bond can enhance atom polarization and thus reduce their highest occupied molecular orbital‐lowest unoccupied molecular orbital energy gap, resulting in light absorption at longer wavelength. In this study, it successfully prepares different arylamino derivatives of anthraquinone, xanthone, and thioxanthone, compounds that are readily converted to their respective boracycles by reaction with BF 3 ·Et 2 O. The effect of the BF 2 moiety on the electronic properties is evaluated by electrochemical and photophysical studies. These studies respectively reveal for the complexes easier reduction and red‐shifted absorption wavelengths. In addition, promising 8% fluorescence quantum yield and 52% singlet oxygen quantum yield are recorded for one of the diboron‐anthraquinone complexes. Representative compounds are finally tested on a panel of disease‐related protein kinases.
{"title":"BF 2 Complexes of N ‐arylated 1‐amino‐anthraquinone, ‐xanthone, ‐thioxanthone, and Related Compounds: Synthesis and Properties","authors":"Ahlem N. Khelf‐Maghraoui, Ghenia Bentabed‐Ababsa, Nicolas Mast, William Erb, Jean‐Pierre Hurvois, Thierry J. Roisnel, Nicolas Richy, Guillaume Calvez, Olivier Mongin, Charline Piroud, Thomas Robert, Stéphane Bach, Florence Mongin","doi":"10.1002/ejoc.202500470","DOIUrl":"https://doi.org/10.1002/ejoc.202500470","url":null,"abstract":"The physical properties of anthraquinones can be modulated by the introduction of arylamino groups next to the carbonyl function. Indeed, formation of an intramolecular hydrogen bond can enhance atom polarization and thus reduce their highest occupied molecular orbital‐lowest unoccupied molecular orbital energy gap, resulting in light absorption at longer wavelength. In this study, it successfully prepares different arylamino derivatives of anthraquinone, xanthone, and thioxanthone, compounds that are readily converted to their respective boracycles by reaction with BF <jats:sub>3</jats:sub> ·Et <jats:sub>2</jats:sub> O. The effect of the BF <jats:sub>2</jats:sub> moiety on the electronic properties is evaluated by electrochemical and photophysical studies. These studies respectively reveal for the complexes easier reduction and red‐shifted absorption wavelengths. In addition, promising 8% fluorescence quantum yield and 52% singlet oxygen quantum yield are recorded for one of the diboron‐anthraquinone complexes. Representative compounds are finally tested on a panel of disease‐related protein kinases.","PeriodicalId":167,"journal":{"name":"European Journal of Organic Chemistry","volume":"7 1","pages":""},"PeriodicalIF":2.8,"publicationDate":"2025-12-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145658021","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Eunsol Jo, Hyojung Ahn, Guldana Issabayeva, On-Yu Kang, Jungtaek Kim, Young-Chul Song, Ik Jae Lee, Hei-Cheul Jeung, Ji Young Hyun, Seong Jun Park, Hwan Jung Lim
The development of noncanonical amino acids (ncAAs) provides a powerful strategy to expand the chemical space of proteins beyond the natural repertoire, thereby overcoming intrinsic pharmacodynamic limitations of peptides and proteins. Among these, boron-containing ncAAs are of particular interest due to the versatile reactivity of boron and its proven therapeutic relevance in clinically approved drugs. However, poor aqueous solubility, instability under physiological conditions, and oxidative degradation have hindered their broader biological application. Here, we report the design and synthesis of a new class of boron-containing ncAAs with enhanced solubility and stability. Structural modifications around the boron center and optimized substituents were employed to improve compatibility with biological systems while retaining functional reactivity. Moreover, fluorescence analysis revealed distinct photophysical properties, indicating potential applications in protein engineering and biosensing. These results highlight the utility of cyclic boron architectures as a versatile platform for the development of boron-based amino acid analogs with broad implications in chemical biology, drug discovery, and biomolecular design.
{"title":"Design and Synthesis of Boron-Containing Noncanonical Amino Acids With Enhanced Stability and Solubility","authors":"Eunsol Jo, Hyojung Ahn, Guldana Issabayeva, On-Yu Kang, Jungtaek Kim, Young-Chul Song, Ik Jae Lee, Hei-Cheul Jeung, Ji Young Hyun, Seong Jun Park, Hwan Jung Lim","doi":"10.1002/ejoc.202501158","DOIUrl":"https://doi.org/10.1002/ejoc.202501158","url":null,"abstract":"The development of noncanonical amino acids (ncAAs) provides a powerful strategy to expand the chemical space of proteins beyond the natural repertoire, thereby overcoming intrinsic pharmacodynamic limitations of peptides and proteins. Among these, boron-containing ncAAs are of particular interest due to the versatile reactivity of boron and its proven therapeutic relevance in clinically approved drugs. However, poor aqueous solubility, instability under physiological conditions, and oxidative degradation have hindered their broader biological application. Here, we report the design and synthesis of a new class of boron-containing ncAAs with enhanced solubility and stability. Structural modifications around the boron center and optimized substituents were employed to improve compatibility with biological systems while retaining functional reactivity. Moreover, fluorescence analysis revealed distinct photophysical properties, indicating potential applications in protein engineering and biosensing. These results highlight the utility of cyclic boron architectures as a versatile platform for the development of boron-based amino acid analogs with broad implications in chemical biology, drug discovery, and biomolecular design.","PeriodicalId":167,"journal":{"name":"European Journal of Organic Chemistry","volume":"10 1","pages":""},"PeriodicalIF":2.8,"publicationDate":"2025-12-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145665165","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Mykhailo O. Redka, Nazar Dovhaniuk, Oleksandr Blahun, Oleksandr S. Liashuk, Anastasiia M. Hurieva, Dmytro Lesyk, Daniil Skrypnik, Yuliia Holota, Dmytro Durylin, Petro Borysko, Ivan S. Kondratov, Oleksandr O. Grygorenko
Fluorinated saturated heterocycles are valuable yet underexplored motifs in drug design. Here, we present a scalable strategy for the synthesis of fluorinated tetrahydrofuran (THF) and tetrahydrothiophene (THT) building blocks from simple and readily available starting materials. The optimized conditions enabled access to CF3-substituted ketones and the corresponding stereodefined alcohol, amine, and amino acid derivatives on a decagram scale. Physicochemical profiling established clear structure–property relationships. pKa and isoelectric point (pI) values were affected by strong inductive effects of heteroatoms and SO2 groups, with CF3 substitution consistently enhancing the compound's acidity and lowering isoelectric points. Lipophilicity (LogP) measurements highlighted scaffold- and substituent-dependent lipophilicity, with sulfur-containing motifs being most lipophilic and sulfone derivatives beingleast lipophilic. Overall, this work delivers a robust platform for accessing versatile fluorinated building blocks (including noncanonical amino acids) for drug discovery.
{"title":"Synthesis and Physicochemical Characterization of 5-Trifluoromethyl-Substituted Tetrahydrofurans and Tetrahydrothiophenes","authors":"Mykhailo O. Redka, Nazar Dovhaniuk, Oleksandr Blahun, Oleksandr S. Liashuk, Anastasiia M. Hurieva, Dmytro Lesyk, Daniil Skrypnik, Yuliia Holota, Dmytro Durylin, Petro Borysko, Ivan S. Kondratov, Oleksandr O. Grygorenko","doi":"10.1002/ejoc.202501086","DOIUrl":"https://doi.org/10.1002/ejoc.202501086","url":null,"abstract":"Fluorinated saturated heterocycles are valuable yet underexplored motifs in drug design. Here, we present a scalable strategy for the synthesis of fluorinated tetrahydrofuran (THF) and tetrahydrothiophene (THT) building blocks from simple and readily available starting materials. The optimized conditions enabled access to CF<sub>3</sub>-substituted ketones and the corresponding stereodefined alcohol, amine, and amino acid derivatives on a decagram scale. Physicochemical profiling established clear structure–property relationships. p<i>K</i><sub>a</sub> and isoelectric point (pI) values were affected by strong inductive effects of heteroatoms and SO<sub>2</sub> groups, with CF<sub>3</sub> substitution consistently enhancing the compound's acidity and lowering isoelectric points. Lipophilicity (Log<i>P</i>) measurements highlighted scaffold- and substituent-dependent lipophilicity, with sulfur-containing motifs being most lipophilic and sulfone derivatives beingleast lipophilic. Overall, this work delivers a robust platform for accessing versatile fluorinated building blocks (including noncanonical amino acids) for drug discovery.","PeriodicalId":167,"journal":{"name":"European Journal of Organic Chemistry","volume":"51 1","pages":""},"PeriodicalIF":2.8,"publicationDate":"2025-12-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145665166","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Halogen‐atom transfer (XAT) is an important method for the generation of carbon radicals. Hence, the development of new XAT agents has emerged as an important research avenue in organic synthesis. Aryl radicals are particularly promising XAT agents but have witnessed limited application. Herein, we introduce a protocol that repurposes widely available aryl boronic acids as XAT agents for alkyl iodide activation. We exemplify this concept on a Giese reaction, constructing valuable, sp 3 ‐rich scaffolds. The reaction is highly efficient and tolerant of a variety of sensitive functional groups. Furthermore, we showcase the compatibility of our boronic acid XAT agents in processes based on the use of transition metals, like cobalt for desaturative purposes.
{"title":"Repurposing Aryl Boronic Acids as Halogen‐Atom Transfer Agents","authors":"Daigo Hayashi, Thomas Sephton, Daniele Leonori","doi":"10.1002/ejoc.202501051","DOIUrl":"https://doi.org/10.1002/ejoc.202501051","url":null,"abstract":"Halogen‐atom transfer (XAT) is an important method for the generation of carbon radicals. Hence, the development of new XAT agents has emerged as an important research avenue in organic synthesis. Aryl radicals are particularly promising XAT agents but have witnessed limited application. Herein, we introduce a protocol that repurposes widely available aryl boronic acids as XAT agents for alkyl iodide activation. We exemplify this concept on a Giese reaction, constructing valuable, sp <jats:sup>3</jats:sup> ‐rich scaffolds. The reaction is highly efficient and tolerant of a variety of sensitive functional groups. Furthermore, we showcase the compatibility of our boronic acid XAT agents in processes based on the use of transition metals, like cobalt for desaturative purposes.","PeriodicalId":167,"journal":{"name":"European Journal of Organic Chemistry","volume":"25 1","pages":""},"PeriodicalIF":2.8,"publicationDate":"2025-12-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145658020","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"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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