European Journal of Organic Chemistry最新文献

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.

Copper-catalyzed reactions of 2-benzothiazolimines, terminal ynones, and sulfonyl azides afforded benzothiazolopyrimidine diastereomers. The transformation involved a tandem CuAAC/ring-cleavage/[4 + 2] cycloaddition procedure with one-pot synthesis under mild conditions. The benzothiazolopyrimidine diastereomers could be isolated, and their structure is confirmed by X-ray single-crystal diffraction.

Multifunctional platforms are essential tools in biomedical research, particularly to develop dual imaging probes that combine, for example, fluorescence imaging (FLI) and positron emission tomography (PET). We report the design of a modular trisubstituted 1,3,5-triazine scaffold synthesized from 2,4,6-trichloro-1,3,5-triazine via sequential nucleophilic aromatic substitutions with amino-functionalized spacers. Orthogonal protecting groups enabled selective conjugation with a cyanine dye (Cy) and a DOTA chelator for FLI and PET, respectively. The third arm was functionalized with DUPA, a prostate-specific membrane antigen (PSMA)-targeting pseudopeptide, via CuAAC chemistry. Despite unsuccessful attempts with Cy7 derivative (IR780), dual labeling with Cy5 and DOTA was achieved efficiently. Compound 19 exhibited optical properties comparable to commercial Cy5. These results highlight the versatility of this synthetic strategy and the potential of 19 as a dual-modality imaging agent.

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 H₂O₂. 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.

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 H₂ 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.

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.

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.

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. pK_a 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.

With the aim to understand the role of the 2-isopropoxybenzylidene ligand, we synthesized Hoveyda-Grubbs 1^st and 2^nd generation precatalysts (HG-I and HG-II) analogs modified in the phenyl ring with 5-octyloxy, 5-(3,3,4,4,5,5,6,6,7,7,8,8,8-tridecafluorooctyloxy), 5-(2,2,3,3,4,4,5,5,6,6,7,7,7-tridecafluoroheptyloxy) or 5-(2,2,4,4,5,5,7,7,7-nonafluoro-3,6-dioxaheptyloxy) ponytails and/or instead of isopropoxy group with longer decan-2-yloxy or 5,5,6,6,7,7,8,8,9,9,10,10,10-tridecafluorodecan-2-yloxy groups. To improve the fluorophilicity of the precatalysts, we further modified selected precatalysts by two or four 3,3,4,4,5,5,6,6,7,7,8,8,8-tridecafluorooctyl ponytails in the NHC ligand. All modified HG-I analogs were more active than precatalyst HG-I in the ring-closing metathesis (RCM) of diethyl allyl(methallyl)malonate (DEAMM, RCM3). On the other hand, only HG-II complexes modified with fluorinated chain in the isopropoxy group surpassed commercial HG-II precatalyst in the RCM3. In the most demanding RCM reaction of diethyl dimethallylmalonate (DEDMM, RCM4), both precatalysts modified with sec-decyloxy group initiated more quickly than HG-II, but seem to be less stable over long reaction times. Medium fluorous HG-II analogs bearing two or three polyfluorinated chains in the alkoxybenzylidene ligand were successfully tested in repeated RCM3 using medium fluorous recycle. Release-return mechanism, essential for medium fluorous recycle, was confirmed by partial exchange of the alkoxybenzylidene moieties in the recycled precatalysts using combinations of precatalysts and styrenes bearing different alkoxy groups.

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 BF₃·Et₂O. The effect of the BF₂ 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.