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Nature Aug 2021The substitution of an alkyl electrophile by a nucleophile is a foundational reaction in organic chemistry that enables the efficient and convergent synthesis of organic...
The substitution of an alkyl electrophile by a nucleophile is a foundational reaction in organic chemistry that enables the efficient and convergent synthesis of organic molecules. Although there has been substantial recent progress in exploiting transition-metal catalysis to expand the scope of nucleophilic substitution reactions to include carbon nucleophiles, there has been limited progress in corresponding reactions with nitrogen nucleophiles. For many substitution reactions, the bond construction itself is not the only challenge, as there is a need to control stereochemistry at the same time. Here we describe a method for the enantioconvergent substitution of unactivated racemic alkyl electrophiles by a ubiquitous nitrogen-containing functional group, an amide. Our method uses a photoinduced catalyst system based on copper, an Earth-abundant metal. This process for asymmetric N-alkylation relies on three distinct ligands-a bisphosphine, a phenoxide and a chiral diamine. The ligands assemble in situ to form two distinct catalysts that act cooperatively: a copper/bisphosphine/phenoxide complex that serves as a photocatalyst, and a chiral copper/diamine complex that catalyses enantioselective C-N bond formation. Our study thus expands enantioselective N-substitution by alkyl electrophiles beyond activated electrophiles (those bearing at least one sp- or sp-hybridized substituent on the carbon undergoing substitution) to include unactivated electrophiles.
Topics: Amides; Bromides; Carbon; Catalysis; Copper; Cyclization; Diamines; Ligands; Nitrogen; Phosphines; Photochemistry
PubMed: 34182570
DOI: 10.1038/s41586-021-03730-w -
Bioorganic Chemistry Jun 2020A series of mono and bimetallic ruthenium(II) arene complexes bearing diamine (Ru) were prepared and fully characterized by H, C, F, and P NMR spectroscopy and elemental...
A series of mono and bimetallic ruthenium(II) arene complexes bearing diamine (Ru) were prepared and fully characterized by H, C, F, and P NMR spectroscopy and elemental analysis. The crystal structure of the bimetallic complex (Ru) was determined by X-ray crystallography. Monometallic analogues (Ru) were synthesized to investigate the contributions of ruthenium and the other organic groups (aren, ethylenediamine, butyl) to the activity. The electrochemical behaviors of mono and bimetallic complexes were obtained from the relationship between cyclic voltammetry (CV) and the biological activities of the compounds. The cytotoxic activities of the complexes (Ru) were tested against wide-scale cancer cell lines, namely HeLa, MDA-MB-231, DU-145, LNCaP, Hep-G2, Saos-2, PC-3, and MCF-7, and normal cell lines 3T3-L1 and Vero. Diamine Ru(II) arene complexes have unique biological characteristics and they are promising models for new anticancer drug development. MTT analysis reveals that each synthesized Ru complex showed cytotoxic activity towards the different cancer cells. In particular, three Ru complexes (Ru, Ru and Ru) showed less toxic effects on the cancer cells than the others. These novel Ru complexes affected both cancer and normal cell lines. As they had a toxic effect on the cells, the dosage applied should be tested before being used for in vivo applications. Cytotoxicity tests have shown that the bimetallic complex Ru was effective on all cancer cells. The effect of bimetallic enhancement on cancer cell lines, the systematic variation of the intermetallic distance and the ligand donor properties of the mono and bimetallic complexes were explored based on the cytotoxic activity. The interaction with FS-DNA and the stability/aquation of the complexes (Ru and Ru) were investigated with H NMR spectroscopy. The binding modes between the complexes (Ru and Ru) and DNA were investigated via UV-Vis spectroscopy.
Topics: 3T3-L1 Cells; Animals; Antineoplastic Agents; Cell Proliferation; Cells, Cultured; Chlorocebus aethiops; Diamines; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Humans; Mice; Molecular Structure; Organometallic Compounds; Ruthenium; Structure-Activity Relationship; Vero Cells
PubMed: 32278205
DOI: 10.1016/j.bioorg.2020.103793 -
British Dental Journal Jul 2020
Topics: Diamines; Fluorides, Topical; Quaternary Ammonium Compounds; Silver Compounds
PubMed: 32710030
DOI: 10.1038/s41415-020-1942-7 -
The Journal of Organic Chemistry Aug 2021Novel 1,2-diamines based on the mefloquine scaffold prepared in enantiomerically pure forms resemble 9-amino- alkaloids. Most effectively, 11-aminomefloquine with an...
Novel 1,2-diamines based on the mefloquine scaffold prepared in enantiomerically pure forms resemble 9-amino- alkaloids. Most effectively, 11-aminomefloquine with an configuration was obtained by conversion of 11-alcohol into azide and hydrogenation. Alkylation of a secondary amine unit was needed to arrive at diastereomeric -11-aminomefloquine and to introduce diversity. Most of the substitution reactions of the hydroxyl group to azido group proceeded with net retention of the configuration and involved actual aziridine or plausible aziridinium ion intermediates. Enantiomerically pure products were obtained by the resolution of either the initial mefloquine or one of the final products. The evaluation of the efficacy of the obtained vicinal diamines in enantioselective transformations proved that -11-aminomefloquine is an effective catalyst in the asymmetric Michael addition of nitromethane to cyclohexanone (up to 96.5:3.5 er) surpassing -aminoquinine in terms of selectivity.
Topics: Amines; Diamines; Mefloquine; Molecular Structure; Stereoisomerism
PubMed: 34314190
DOI: 10.1021/acs.joc.1c01316 -
Metabolic Engineering Mar 2020Microbial production of chemicals and materials from renewable carbon sources is becoming increasingly important to help establish sustainable chemical industry. In this... (Review)
Review
Microbial production of chemicals and materials from renewable carbon sources is becoming increasingly important to help establish sustainable chemical industry. In this paper, we review current status of metabolic engineering for the bio-based production of linear and saturated dicarboxylic acids and diamines, important platform chemicals used in various industrial applications, especially as monomers for polymer synthesis. Strategies for the bio-based production of various dicarboxylic acids having different carbon numbers including malonic acid (C3), succinic acid (C4), glutaric acid (C5), adipic acid (C6), pimelic acid (C7), suberic acid (C8), azelaic acid (C9), sebacic acid (C10), undecanedioic acid (C11), dodecanedioic acid (C12), brassylic acid (C13), tetradecanedioic acid (C14), and pentadecanedioic acid (C15) are reviewed. Also, strategies for the bio-based production of diamines of different carbon numbers including 1,3-diaminopropane (C3), putrescine (1,4-diaminobutane; C4), cadaverine (1,5-diaminopentane; C5), 1,6-diaminohexane (C6), 1,8-diaminoctane (C8), 1,10-diaminodecane (C10), 1,12-diaminododecane (C12), and 1,14-diaminotetradecane (C14) are revisited. Finally, future challenges are discussed towards more efficient production and commercialization of bio-based dicarboxylic acids and diamines.
Topics: Diamines; Dicarboxylic Acids; Metabolic Engineering; Microorganisms, Genetically-Modified
PubMed: 30905694
DOI: 10.1016/j.ymben.2019.03.005 -
Contrast Media & Molecular Imaging 2020The semistable chelate manganese (Mn) dipyridoxyl diphosphate (MnDPDP, mangafodipir), previously used as an intravenous (i.v.) contrast agent (Teslascan™, GE... (Review)
Review
The semistable chelate manganese (Mn) dipyridoxyl diphosphate (MnDPDP, mangafodipir), previously used as an intravenous (i.v.) contrast agent (Teslascan™, GE Healthcare) for Mn-ion-enhanced MRI (MEMRI), should be reappraised for clinical use but now as a diagnostic drug with cytoprotective properties. Approved for imaging of the liver and pancreas, MnDPDP enhances contrast also in other targets such as the heart, kidney, glandular tissue, and potentially retina and brain. Transmetallation releases paramagnetic Mn for cellular uptake in competition with calcium (Ca), and intracellular (IC) macromolecular Mn adducts lower myocardial to midway between native values and values obtained with gadolinium (Gd). What is essential is that mapping and, to a lesser degree, weighted imaging enable quantification of viability at a cellular or even molecular level. IC Mn retention for hours provides delayed imaging as another advantage. Examples in humans include quantitative imaging of cardiomyocyte remodeling and of Ca channel activity, capabilities beyond the scope of Gd based or native MRI. In addition, MnDPDP and the metabolite Mn dipyridoxyl diethyl-diamine (MnPLED) act as catalytic antioxidants enabling prevention and treatment of oxidative stress caused by tissue injury and inflammation. Tested applications in humans include protection of normal cells during chemotherapy of cancer and, potentially, of ischemic tissues during reperfusion. Theragnostic use combining therapy with delayed imaging remains to be explored. This review updates MnDPDP and its clinical potential with emphasis on the working mode of an exquisite chelate in the diagnosis of heart disease and in the treatment of oxidative stress.
Topics: Brain; Contrast Media; Edetic Acid; Heart; Humans; Magnetic Resonance Imaging; Manganese; Pyridoxal Phosphate; Retina
PubMed: 32994754
DOI: 10.1155/2020/3262835 -
Nature Protocols Dec 2021Fluorine is a key element present in ~35% of agrochemicals and 25% of marketed pharmaceutical drugs. The availability of reliable synthetic protocols to prepare... (Review)
Review
Fluorine is a key element present in ~35% of agrochemicals and 25% of marketed pharmaceutical drugs. The availability of reliable synthetic protocols to prepare catalysts that allow the efficient incorporation of fluorine in organic molecules is therefore essential for broad applicability. Herein, we report a protocol for the multigram synthesis of two representative enantiopure N-alkyl bis-urea organocatalysts derived from (S)-(-)-1,1'-binaphthyl-2,2'-diamine ((S)-BINAM). These tridentate hydrogen bond donors are highly effective phase-transfer catalysts for solubilizing safe and inexpensive metal alkali fluorides (KF and CsF) in organic solvents for enantioselective nucleophilic fluorinations. The first catalyst, characterized by N-isopropyl substitution, was obtained by using a two-step sequence consisting of reductive amination followed by urea coupling from commercially available starting materials (14 g, 48% yield and 5-d total synthesis time). The second catalyst, featuring N-ethyl alkylation and meta-terphenyl substituents, was accessed via a novel, scalable, convergent route that concluded with the coupling between N-ethylated (S)-BINAM and a preformed isocyanate (52 g and 52% overall yield). On this scale, the synthesis requires ~10 d. This can be reduced to 5 d by performing some steps in parallel. Compared to the previous synthetic route, this protocol avoids the final chromatographic purification and produces the desired catalysts in very high purity and improved yield.
Topics: Alkylation; Amination; Catalysis; Chemistry Techniques, Synthetic; Diamines; Fluorides; Fluorine; Halogenation; Humans; Hydrogen Bonding; Isocyanates; Naphthalenes; Oxidation-Reduction; Stereoisomerism; Terphenyl Compounds; Urea
PubMed: 34759385
DOI: 10.1038/s41596-021-00625-y -
Organic Letters Feb 2021A cobalt-catalyzed method for the C(sp)-C(sp) Suzuki-Miyaura cross coupling of aryl boronic esters and alkyl bromides is described. Cobalt-ligand combinations were...
A cobalt-catalyzed method for the C(sp)-C(sp) Suzuki-Miyaura cross coupling of aryl boronic esters and alkyl bromides is described. Cobalt-ligand combinations were assayed with high-throughput experimentation, and cobalt(II) sources with -,'-dimethylcyclohexane-1,2-diamine (DMCyDA, L) produced optimal yield and selectivity. The scope of this transformation encompassed steric and electronic diversity on the aryl boronate nucleophile as well as various levels of branching and synthetically valuable functionality on the electrophile. Radical trap experiments support the formation of electrophile-derived radicals during catalysis.
Topics: Bromides; Catalysis; Cobalt; Diamines; Esters; Ligands; Molecular Structure
PubMed: 32996312
DOI: 10.1021/acs.orglett.0c02934 -
Journal of Food Protection Sep 2021Essential foods as part of a daily meal may include numerous kinds of biogenic amines (BAs) at various concentrations. BAs have a variety of toxicological effects on... (Review)
Review
ABSTRACT
Essential foods as part of a daily meal may include numerous kinds of biogenic amines (BAs) at various concentrations. BAs have a variety of toxicological effects on human health and have been linked to multiple outbreaks of foodborne disease. BAs also are known to cause cancer based on their ability to react with nitrite salts, resulting in the production of carcinogenic organic compounds (nitrosamines). Ingestion of large quantities of BAs in food causes toxicological effects and health disorders, including psychoactive, vasoactive, and hypertensive effects and respiratory, gastrointestinal, cardiovascular, and neurological disorders. The toxicity of BAs is linked closely to the BAs histamine and tyramine. Other amines, such as phenylethylamine, putrescine, and cadaverine, are important because they can increase the negative effects of histamine. The key method for reducing BA concentrations and thus foodborne illness is management of the bacterial load in foods. Basic good handling and hygiene practices should be used to control the formation of histamine and other BAs and reduce the toxicity histamine and tyramine. A better understanding of BAs is essential to enhance food safety and quality. This review also includes a discussion of the public health implications of BAs in foods.
Topics: Biogenic Amines; Cadaverine; Food Contamination; Histamine; Humans; Putrescine; Tyramine
PubMed: 34375430
DOI: 10.4315/JFP-21-047 -
Veterinary Parasitology Aug 2021Gastrointestinal nematodes (GIN) infections are a serious problem in livestock production due to the great economic losses they cause. Their control is increasingly...
Gastrointestinal nematodes (GIN) infections are a serious problem in livestock production due to the great economic losses they cause. Their control is increasingly difficult because of the rapid development of drug resistance and the limited number of available drugs. Therefore, this study evaluated 18 aminoalcohol and 16 diamine derivatives against eggs, first and third stage larvae from a susceptible and a resistant isolate of Teladorsagia circumcincta collected from sheep. The effectiveness of the in vitro anthelmintic activity of the compounds was evaluated using three different procedures: Egg Hatch Test (EHT), Larval Mortality Test (LMT) and Larval Migration Inhibition Test (LMIT). Those compounds with activities higher than 90 % in the initial screening at 50 μM were selected to determine their half maximal effective concentration (EC). In parallel, cytotoxicity assays were conducted on Caco2 and HepG2 cell lines to calculate Selectivity Indexes (SI) for each compound. The diamine 30 presented the best results in preventing egg hatching, displaying the lowest EC value (1.01 ± 0.04 μM) of all compounds tested and the highest SI (21.21 vs. Caco-2 cells). For the LMIT, the diamine 34 showed the highest efficacy, with EC values of 2.67 ± 0.08 and 3.02 ± 0.09 μM on the susceptible and resistant isolate of the parasite, respectively.
Topics: Alcohols; Animals; Anthelmintics; Caco-2 Cells; Diamines; Drug Resistance; Feces; Humans; Nematoda; Ovum; Sheep; Sheep Diseases
PubMed: 34147018
DOI: 10.1016/j.vetpar.2021.109496