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Chembiochem : a European Journal of... Jan 2023The development of methods to engineer and immobilize amine transaminases (ATAs) to improve their functionality and operational stability is gaining momentum. The quest...
The development of methods to engineer and immobilize amine transaminases (ATAs) to improve their functionality and operational stability is gaining momentum. The quest for robust, fast, and easy-to-use methods to screen the activity of large collections of transaminases, is essential. This work presents a novel and multiplex fluorescence-based kinetic assay to assess ATA activity using 4-dimethylamino-1-naphthaldehyde as an amine acceptor. The developed assay allowed us to screen a battery of amine donors using free and immobilized ATAs from different microbial sources as biocatalysts. As a result, using chromatographic methods, 4-hydroxybenzylamine was identified as the best amine donor for the amination of 5-(hydroxymethyl)furfural. Finally, we adapted this method to determine the apparent Michaelis-Menten parameters of a model immobilized ATA at the microscopic (single-particle) level. Our studies promote the use of this multiplex, multidimensional assay to screen ATAs for further improvement.
Topics: Amines; Biocatalysis; Amination; Enzymes, Immobilized; Transaminases
PubMed: 36385460
DOI: 10.1002/cbic.202200614 -
Organic & Biomolecular Chemistry Jun 2022The direct coupling of benzoxazoles and amines was realized by visible light irradiation and CuCl catalysis. Various aminated benzoxazoles were successfully synthesized...
The direct coupling of benzoxazoles and amines was realized by visible light irradiation and CuCl catalysis. Various aminated benzoxazoles were successfully synthesized under mild conditions with air as an oxidant.
Topics: Amination; Amines; Benzoxazoles; Catalysis; Oxidants
PubMed: 35704388
DOI: 10.1039/d2ob00687a -
Journal of the American Chemical Society Sep 2023Hydroxylamine-derived reagents have enabled versatile nitrene transfer reactions for introducing nitrogen-containing functionalities in small-molecule catalysis, as well...
Hydroxylamine-derived reagents have enabled versatile nitrene transfer reactions for introducing nitrogen-containing functionalities in small-molecule catalysis, as well as biocatalysis. These reagents, however, result in a poor atom economy and stoichiometric organic waste. Activating hydroxylamine (NHOH) for nitrene transfer offers a low-cost and sustainable route to amine synthesis, since water is the sole byproduct. Despite its presence in nature, hydroxylamine is not known to be used for enzymatic nitrogen incorporation in biosynthesis. Here, we report an engineered heme enzyme that can utilize hydroxylammonium chloride, an inexpensive commodity chemical, for nitrene transfer. Directed evolution of protoglobin generated efficient enzymes for benzylic C-H primary amination and styrene aminohydroxylation. Mechanistic studies supported a stepwise radical pathway involving rate-limiting hydrogen atom transfer. This unprecedented activity is a useful addition to the "nitrene transferase" repertoire and hints at possible future discovery of natural enzymes that use hydroxylamine for amination chemistry.
Topics: Hydroxylamine; Hydroxylamines; Amination; Nitrogen
PubMed: 37671894
DOI: 10.1021/jacs.3c08053 -
Topics in Current Chemistry (Cham) Jan 2024Amination reactions play a pivotal role in synthetic organic chemistry, facilitating the generation of nitrogen-containing scaffolds with broad applications in drug... (Review)
Review
Amination reactions play a pivotal role in synthetic organic chemistry, facilitating the generation of nitrogen-containing scaffolds with broad applications in drug synthesis, material production, polymer formation, and the generation of amino acids and peptides. Amination offers the potential to fine tune the properties of natural products and produce functional materials for various applications. Palladium N-heterocyclic carbene (Pd-NHC) emerges as an innovative and highly effective catalyst in this context. Under favorable reaction conditions, this robust and simple catalyst efficiently facilitates the synthesis of a diverse range of compounds with varying complexity and utility. Pd-NHC complexes exhibit significant σ-electron donating potential, enhancing the ease of the oxidative addition process in their mechanistic pathway. Their steric topography further contributes to a rapid reductive elimination. These complexes demonstrate remarkable stability, a result of the strong Pd-ligand bond. The wide variety of Pd-NHC complexes has proven highly efficient in catalyzing reactions across a spectrum of complexities, from simple to intricate. The domain of aminations catalyzed by Pd-NHC has undergone significant diversification, presenting new opportunities, particularly in the realms of material chemistry and natural product synthesis. This review outlines the advancements in Pd-NHC-catalyzed amination reactions, covering literature up to date.
Topics: Amination; Palladium; Methane; Amino Acids; Biological Products
PubMed: 38265533
DOI: 10.1007/s41061-024-00449-w -
Chemical Reviews Dec 2019Reductive amination plays a paramount role in pharmaceutical and medicinal chemistry owing to its synthetic merits and the ubiquitous presence of amines among... (Review)
Review
Reductive amination plays a paramount role in pharmaceutical and medicinal chemistry owing to its synthetic merits and the ubiquitous presence of amines among biologically active compounds. It is one of the key approaches to C-N bond construction due to its operational easiness and a wide toolbox of protocols. Recent studies show that at least a quarter of C-N bond-forming reactions in the pharmaceutical industry are performed via reductive amination. This Review concisely compiles information on 71 medical substances that are synthesized by reductive amination. Compounds are grouped according to the principle of action, which includes drugs affecting the central nervous system, drugs affecting the cardiovascular system, anticancer drugs, antibiotics, antiviral and antifungal medicines, drugs affecting the urinary system, drugs affecting the respiratory system, antidiabetic medications, drugs affecting the gastrointestinal tract, and drugs regulating metabolic processes. A general synthetic scheme is provided for each compound, and the description is focused on reductive amination steps. The green chemistry metric of reaction mass efficiency was calculated for all reactions.
Topics: Amination; Amines; Chemistry, Pharmaceutical; Lewis Acids; Oxidation-Reduction; Pharmaceutical Preparations
PubMed: 31633341
DOI: 10.1021/acs.chemrev.9b00383 -
Journal of the American Chemical Society Jul 2022Sulfur functional groups are common motifs in bioactive molecules. Sulfonamides are most prevalent but related aza-derivatives, in which oxygen atoms are replaced by...
Sulfur functional groups are common motifs in bioactive molecules. Sulfonamides are most prevalent but related aza-derivatives, in which oxygen atoms are replaced by imidic nitrogens, such as sulfoximines and sulfonimidamides, are gaining attraction. Despite this activity, the double aza-variants of sulfonamides, termed sulfondiimidamides, are almost completely absent from the literature. The reason for this is poor synthetic accessibility. Although a recent synthesis has established sulfondiimidamides as viable motifs, the length of the route and the capricious nature of the key sulfondiimidoyl fluoride intermediates mean that direct application to discovery chemistry is challenging. Herein, we describe a two-step synthesis of sulfondiimidamides, exploiting a hypervalent iodine-mediated amination as the key step. The starting materials are organometallic reagents, an unsymmetrical sulfurdiimide, and amines. The method allowed >40 examples to be prepared, including derivatives of three sulfonamide-based drugs. The operational simplicity, broad scope, and concise nature make this route attractive for discovery chemistry applications.
Topics: Amination; Amines; Imides; Indicators and Reagents; Sulfonamides
PubMed: 35729783
DOI: 10.1021/jacs.2c04404 -
Journal of the American Chemical Society Sep 2021Allylic amination enables late-stage functionalization of natural products where allylic C-H bonds are abundant and introduction of nitrogen may alter biological...
Allylic amination enables late-stage functionalization of natural products where allylic C-H bonds are abundant and introduction of nitrogen may alter biological profiles. Despite advances, intermolecular allylic amination remains a challenging problem due to reactivity and selectivity issues that often mandate excess substrate, furnish product mixtures, and render important classes of olefins (for example, functionalized cyclic) not viable substrates. Here we report that a sustainable manganese perchlorophthalocyanine catalyst, [Mn(ClPc)], achieves selective, preparative intermolecular allylic C-H amination of 32 cyclic and linear compounds, including ones housing basic amines and competing sites for allylic, ethereal, and benzylic amination. Mechanistic studies support that the high selectivity of [Mn(ClPc)] may be attributed to its electrophilic, bulky nature and stepwise amination mechanism. Late-stage amination is demonstrated on five distinct classes of natural products, generally with >20:1 site-, regio-, and diastereoselectivity.
Topics: Amination; Amines; Catalysis; Molecular Structure; Coordination Complexes
PubMed: 34514799
DOI: 10.1021/jacs.1c06335 -
Angewandte Chemie (International Ed. in... Aug 2022Reported here is the first catalytic atroposelective electrophilic amination of indoles, which delivers functionalized atropochiral N-sulfonyl-3-arylaminoindoles with...
Reported here is the first catalytic atroposelective electrophilic amination of indoles, which delivers functionalized atropochiral N-sulfonyl-3-arylaminoindoles with excellent optical purity. This reaction was furnished by 1,6-nucleophilic addition to p-quinone diimines. Control experiments suggest an ionic mechanism that differs from the radical addition pathway commonly proposed for 1,6-addition to quinones. The origin of 1,6-addition selectivity was investigated through computational studies. Preliminary studies show that the obtained 3-aminoindoles atropisomers exhibit anticancer activities. This method is valuable with respect to enlarging the toolbox for atropochiral amine derivatives.
Topics: Amination; Amines; Catalysis; Indoles
PubMed: 35612900
DOI: 10.1002/anie.202205159 -
The Journal of Organic Chemistry Jan 2023Arylamines represent a class of compounds widely found in natural products and pharmaceuticals. Among methodologies devoted to their synthesis, nickel-catalyzed...
Arylamines represent a class of compounds widely found in natural products and pharmaceuticals. Among methodologies devoted to their synthesis, nickel-catalyzed amination of aryl halides constitutes one of the most employed conventional strategies. However, C-N cross-couplings often involve elaborated nickel complexes, which are expensive and/or air and moisture sensitive. To circumvent this issue, we herein report an electrochemical method based on a sacrificial anode process to generate a catalytic amount of nickel salts allowing amination of aryl halides. The approach, simple to set up, proceeds under mild reaction conditions and enables access to a large panel of arylamines.
Topics: Nickel; Amines; Amination; Catalysis
PubMed: 36516437
DOI: 10.1021/acs.joc.2c01964 -
Journal of the American Chemical Society Jun 2018C-N cross-coupling is an important class of reactions with far-reaching impacts across chemistry, materials science, biology, and medicine. Transition metal complexes...
C-N cross-coupling is an important class of reactions with far-reaching impacts across chemistry, materials science, biology, and medicine. Transition metal complexes can elegantly orchestrate diverse aminations but typically require demanding reaction conditions, precious metal catalysts, or oxygen-sensitive procedures. Here, we introduce a mild nickel-catalyzed C-N cross-coupling methodology that operates at room temperature using an inexpensive nickel source (NiBr·3HO), is oxygen tolerant, and proceeds through direct irradiation of the nickel-amine complex. This operationally robust process was employed for the synthesis of diverse C-N-coupled products (40 examples) by irradiating a solution containing an amine, an aryl halide, and a catalytic amount of NiBr·3HO with a commercially available 365 nm LED at room temperature without added photoredox catalyst and the amine substrate serving additional roles as the ligands and base. Density functional theory calculations and kinetic isotope effect experiments were performed to elucidate the observed C-N cross-coupling reactivity.
Topics: Amination; Amines; Catalysis; Coordination Complexes; Nickel; Ultraviolet Rays
PubMed: 29787252
DOI: 10.1021/jacs.8b03744