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Angewandte Chemie (International Ed. in... Nov 2022Amino acid biosynthesis initiates with the reductive amination of α-ketoglutarate with ammonia to produce glutamate. However, the other α-keto acids derived from the...
Amino acid biosynthesis initiates with the reductive amination of α-ketoglutarate with ammonia to produce glutamate. However, the other α-keto acids derived from the glyoxylate and Krebs cycles are converted into amino acids by transamination, rather than by reductive amination. Why is only one amino acid synthesized by reductive amination and not the others? To explore this question, we quantified the inherent reactivities of keto acids in nonenzymatic reduction and reductive amination by using BH CN as a model nucleophile. Biological α-keto acids were found to show pronounced nonenzymatic reactivity differences for the formation of amino acids (α-ketoglutarate
Topics: Amination; Ammonia; Ketoglutaric Acids; Amino Acids; Keto Acids; Glutamic Acid; Amines
PubMed: 36121198
DOI: 10.1002/anie.202212237 -
Journal of the American Chemical Society Jul 2021The reaction mechanism and the origin of the selectivity for the photocatalytic intermolecular anti-Markovnikov hydroamination of unactivated alkenes with primary amines...
The reaction mechanism and the origin of the selectivity for the photocatalytic intermolecular anti-Markovnikov hydroamination of unactivated alkenes with primary amines to furnish secondary amines have been revealed by time-resolved laser kinetics measurements of the key reaction intermediates. We show that back-electron transfer (BET) between the photogenerated aminium radical cation (ARC) and reduced photocatalyst complex (Ir(II)) is nearly absent due to rapid deprotonation of the ARC on the sub-100 ns time scale. The selectivity for primary amine alkylation is derived from the faster addition of the primary ARCs (as compared to secondary ARCs) to alkenes. The turnover of the photocatalyst occurs via the reaction between Ir(II) and a thiyl radical; the formation of an off-cycle disulfide from thiyl radicals suppresses this turnover, diminishing the efficiency of the reaction. With these detailed mechanistic insights, the turnover of the photocatalyst has been optimized, resulting in a >10-fold improvement in the quantum yield. These improvements enabled the development of a scalable flow protocol, demonstrating a potential strategy for practical applications with improved energy efficiency and cost-effectiveness.
Topics: Amination; Amines; Catalysis; Molecular Structure; Oxidation-Reduction; Photochemical Processes
PubMed: 34191486
DOI: 10.1021/jacs.1c03644 -
Journal of the American Chemical Society Jan 2019A Rh-catalyzed enantioselective hydroamination of allylamines using a chiral BIPHEP-type ligand is reported. Enantioenriched 1,2-diamines are formed in good yields and...
A Rh-catalyzed enantioselective hydroamination of allylamines using a chiral BIPHEP-type ligand is reported. Enantioenriched 1,2-diamines are formed in good yields and with excellent enantioselectivities. A diverse array of nucleophiles and amine directing groups are demonstrated, including deprotectable motifs. Finally, the methodology was demonstrated toward the rapid synthesis of 2-methyl-moclobemide.
Topics: Allyl Compounds; Amination; Amines; Catalysis; Coordination Complexes; Ligands; Moclobemide; Rhodium; Stereoisomerism
PubMed: 30614700
DOI: 10.1021/jacs.8b09811 -
The Journal of Organic Chemistry Apr 2017A method for the catalytic, enantioselective, intramolecular sulfenoamination of alkenes with aniline nucleophiles has been developed. The method employs a chiral, Lewis...
A method for the catalytic, enantioselective, intramolecular sulfenoamination of alkenes with aniline nucleophiles has been developed. The method employs a chiral, Lewis basic selenophosphoramide catalyst and a Brønsted acid co-catalyst to promote stereocontrolled C-N and C-S bond formation by activation of an achiral sulfenylating agent. Benzoannulated nitrogen-containing heterocycles such as indolines, tetrahydroquinolines, and tetrahydrobenzazepines were prepared with high to excellent enantioselectivities. The impact of tether length and electron density of both the nucleophile and olefin on the reactivity, site selectivity, and enantioselectivity were investigated and interpreted in terms of substrate-dependent stereodetermining thiiranium ion formation or capture.
Topics: Alkenes; Amination; Aniline Compounds; Catalysis; Lewis Bases; Stereoisomerism
PubMed: 28294614
DOI: 10.1021/acs.joc.7b00391 -
Molecules (Basel, Switzerland) Feb 2023The design, synthesis, and initial study of amino-functionalized porphyrins as a new class of bifunctional catalysts for asymmetric organophotocatalysis is described....
The design, synthesis, and initial study of amino-functionalized porphyrins as a new class of bifunctional catalysts for asymmetric organophotocatalysis is described. Two new types of amine-porphyrin hybrids derived from 5,10,15,20-tetraphenylporphyrin (TPPH), in which a cyclic secondary amine moiety is covalently linked either to a β-pyrrolic position (Type A) or to the -position of one of the phenyl groups (Type B), were prepared by condensation, reductive amination, or amidation reactions from the suitable porphyrins (either formyl or methanamine derivatives) with readily available chiral amines. A preliminary study of the possible use of Type A amine-porphyrin hybrids as asymmetric, bifunctional organophotocatalysts was performed using the chiral, imidazolidinone-catalyzed Diels-Alder cycloaddition between cyclopentadiene 28 and -cinnamaldehyde 29 as a benchmark reaction. The yield and the stereochemical outcome of this process, obtained under purely organocatalytic conditions, under dual organophocatalysis, and under bifunctional organophotocatalysis, were compared.
Topics: Amines; Amination; Porphyrins; Catalysis; Cycloaddition Reaction; Stereoisomerism
PubMed: 36838985
DOI: 10.3390/molecules28041997 -
Chemistry (Weinheim An Der Bergstrasse,... Feb 2021The l-lysine-ϵ-dehydrogenase (LysEDH) from Geobacillus stearothermophilus naturally catalyzes the oxidative deamination of the ϵ-amino group of l-lysine. We previously...
The l-lysine-ϵ-dehydrogenase (LysEDH) from Geobacillus stearothermophilus naturally catalyzes the oxidative deamination of the ϵ-amino group of l-lysine. We previously engineered this enzyme to create amine dehydrogenase (AmDH) variants that possess a new hydrophobic cavity in their active site such that aromatic ketones can bind and be converted into α-chiral amines with excellent enantioselectivity. We also recently observed that LysEDH was capable of reducing aromatic aldehydes into primary alcohols. Herein, we harnessed the promiscuous alcohol dehydrogenase (ADH) activity of LysEDH to create new variants that exhibited enhanced catalytic activity for the reduction of substituted benzaldehydes and arylaliphatic aldehydes to primary alcohols. Notably, these novel engineered dehydrogenases also catalyzed the reductive amination of a variety of aldehydes and ketones with excellent enantioselectivity, thus exhibiting a dual AmDH/ADH activity. We envisioned that the catalytic bi-functionality of these enzymes could be applied for the direct conversion of alcohols into amines. As a proof-of-principle, we performed an unprecedented one-pot "hydrogen-borrowing" cascade to convert benzyl alcohol to benzylamine using a single enzyme. Conducting the same biocatalytic cascade in the presence of cofactor recycling enzymes (i.e., NADH-oxidase and formate dehydrogenase) increased the reaction yields. In summary, this work provides the first examples of enzymes showing "alcohol aminase" activity.
Topics: Amination; Amines; Biocatalysis; Oxidoreductases
PubMed: 33073866
DOI: 10.1002/chem.202003140 -
Molecules (Basel, Switzerland) Dec 2023A synthetic pathway to a novel 4-aryl-3,4-dihydro-2-1,4-benzoxazine scaffold was developed and a series of compounds based on the scaffold were synthesised as potential...
A synthetic pathway to a novel 4-aryl-3,4-dihydro-2-1,4-benzoxazine scaffold was developed and a series of compounds based on the scaffold were synthesised as potential anticancer agents. The 4-aryl-substituted compounds were prepared via Buchwald-Hartwig cross-coupling between substituted bromobenzenes and various 1,4-benzoxazines, which in turn were generated from a cascade hydrogenation and reductive amination one-pot reaction. These analogues exhibited moderate to good potency against various cancer cell lines. Structure-activity relationship analysis indicated that the inclusion of hydroxyl groups on ring A and ring B was beneficial to biological activity, while having a -amino group on ring C significantly enhanced potency. Molecule displayed the most potent anticancer activity (IC = 7.84-16.2 µM against PC-3, NHDF, MDA-MB-231, MIA PaCa-2, and U-87 MG cancer cell lines), indicating its potential as a lead compound for further structural optimisation. All the synthesised compounds were fully characterised with NMR, HMRS, and IR. The novel benzoxazine scaffold described in this study holds promise and deserves further in-depth studies.
Topics: Benzoxazines; Hydrogenation; Amination; Bromobenzenes; Cell Line
PubMed: 38202749
DOI: 10.3390/molecules29010166 -
Organic Letters Jul 2022The first example of an aromatic haloform reaction is reported, defining a conceptually new haloform-type approach to the metal-free functionalization of arenes. We...
The first example of an aromatic haloform reaction is reported, defining a conceptually new haloform-type approach to the metal-free functionalization of arenes. We demonstrated that heteroarenes bearing a vinylogous nitromethane system, via the stage of a trichloromethane derivative, could undergo aromatic amination to produce N-functionalized arenes in quantitative yields and without the need for transition-metal catalysis. The haloform-type amination was implemented in the development of effective orthogonal N-protection strategies, establishing a new promising N-protecting reagent.
Topics: Amination; Catalysis
PubMed: 35763040
DOI: 10.1021/acs.orglett.2c01494 -
Molecules (Basel, Switzerland) Nov 2021The 3-hydroxy-1,5-dihydro-2-pyrrol-2-one motif is a valuable scaffold in drug discovery. The replacement of the 3-oxy fragment in...
The 3-hydroxy-1,5-dihydro-2-pyrrol-2-one motif is a valuable scaffold in drug discovery. The replacement of the 3-oxy fragment in 3-hydroxy-1,5-dihydro-2-pyrrol-2-ones-based compounds with a 3-amino one (3-amino analogs of 3-hydroxy-1,5-dihydro-2-pyrrol-2-ones, 3-amino-1,5-dihydro-2-pyrrol-2-ones) can play a crucial role in their biological effect. Thus, approaches to 3-amino-1,5-dihydro-2-pyrrol-2-ones are of significant interest. We developed an approach to 5-spiro-substituted 3-amino-1,5-dihydro-2-pyrrol-2-ones that could not be obtained using previously reported approaches (reactions of 3-hydroxy-1,5-dihydro-2-pyrrol-2-ones with amines). The developed approach is based on the thermal decomposition of 1,3-disubstituted urea derivatives of 5-spiro-substituted 3-hydroxy-1,5-dihydro-2-pyrrol-2-ones, which were prepared their reaction with carbodiimides.
Topics: Amination; Amines; Carbodiimides; Drug Discovery; Molecular Structure; Pyrroles
PubMed: 34885757
DOI: 10.3390/molecules26237179 -
Nature Communications Jun 2022Direct asymmetric reductive amination is one of the most efficient methods for the construction of chiral amines, in which the scope of the applicable amine coupling...
Direct asymmetric reductive amination is one of the most efficient methods for the construction of chiral amines, in which the scope of the applicable amine coupling partners remains a significant challenge. In this study we describe primary alkyl amines effectively serve as the N-sources in direct asymmetric reductive amination catalyzed by the iridium precursor and sterically tunable chiral phosphoramidite ligands. The density functional theory studies of the reaction mechanism imply the alkyl amine substrates serve as a ligand of iridium strengthened by a (N)H-O(P) hydrogen-bonding attraction, and the hydride addition occurs via an outer-sphere transition state, in which the Cl-H H-bonding plays an important role. Through this concise procedure, cinacalcet, tecalcet, fendiline and many other related chiral amines have been synthesized in one single step with high yields and excellent enantioselectivity.
Topics: Amination; Amines; Catalysis; Iridium; Ligands
PubMed: 35688909
DOI: 10.1038/s41467-022-31045-5