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1.
Nature ; 584(7819): 75-81, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32760044

RESUMO

Chemical reactions that reliably join two molecular fragments together (cross-couplings) are essential to the discovery and manufacture of pharmaceuticals and agrochemicals1,2. The introduction of amines onto functionalized aromatics at specific and pre-determined positions (ortho versus meta versus para) is currently achievable only in transition-metal-catalysed processes and requires halogen- or boron-containing substrates3-6. The introduction of these groups around the aromatic unit is dictated by the intrinsic reactivity profile of the method (electrophilic halogenation or C-H borylation) so selective targeting of all positions is often not possible. Here we report a non-canonical cross-coupling approach for the construction of anilines, exploiting saturated cyclohexanones as aryl electrophile surrogates. Condensation between amines and carbonyls, a process that frequently occurs in nature and is often used by (bio-)organic chemists7, enables a predetermined and site-selective carbon-nitrogen (C-N) bond formation, while a photoredox- and cobalt-based catalytic system progressively desaturates the cyclohexene ring en route to the aniline. Given that functionalized cyclohexanones are readily accessible with complete regiocontrol using the well established carbonyl reactivity, this approach bypasses some of the frequent selectivity issues of aromatic chemistry. We demonstrate the utility of this C-N coupling protocol by preparing commercial medicines and by the late-stage amination-aromatization of natural products, steroids and terpene feedstocks.


Assuntos
Compostos de Anilina/síntese química , Hidrogênio/química , Processos Fotoquímicos , Aminação , Aminas/química , Compostos de Anilina/química , Produtos Biológicos/síntese química , Produtos Biológicos/química , Catálise/efeitos da radiação , Cicloexanonas/química , Oxirredução/efeitos da radiação , Processos Fotoquímicos/efeitos da radiação , Esteroides/síntese química , Esteroides/química , Terpenos/síntese química , Terpenos/química
2.
J Am Chem Soc ; 146(34): 24042-24052, 2024 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-39137918

RESUMO

Alkyl organoborons are powerful materials for the construction of C(sp3)-C(sp2) bonds, predominantly via Suzuki-Miyaura cross-coupling. These species are generally assembled using 2-electron processes that harness the ability of boron reagents to act as both electrophiles and nucleophiles. Herein, we demonstrate an alternative borylation strategy based on the reactivity of amine-ligated boryl radicals. This process features the use of a carboxylic acid containing amine-ligated borane that acts as boryl radical precursor for photoredox oxidation and decarboxylation. The resulting amine-ligated boryl radical undergoes facile addition to styrenes and imines through radical-polar crossover manifolds. This delivers a new class of sp3-organoborons that are stable solids and do not undergo protodeboronation. These novel materials include unprotected α-amino derivatives that are generally unstable. Crucially, these aliphatic organoboron species can be directly engaged in Suzuki-Miyaura cross-couplings with structurally complex aryl halides. Preliminary studies suggest that they enable slow-release of the corresponding and often difficult to handle alkyl boronic acids.

3.
Chem Rev ; 122(2): 2907-2980, 2022 01 26.
Artigo em Inglês | MEDLINE | ID: mdl-34558888

RESUMO

In the pursuit of new pharmaceuticals and agrochemicals, chemists in the life science industry require access to mild and robust synthetic methodologies to systematically modify chemical structures, explore novel chemical space, and enable efficient synthesis. In this context, photocatalysis has emerged as a powerful technology for the synthesis of complex and often highly functionalized molecules. This Review aims to summarize the published contributions to the field from the life science industry, including research from industrial-academic partnerships. An overview of the synthetic methodologies developed and strategic applications in chemical synthesis, including peptide functionalization, isotope labeling, and both DNA-encoded and traditional library synthesis, is provided, along with a summary of the state-of-the-art in photoreactor technology and the effective upscaling of photocatalytic reactions.


Assuntos
Disciplinas das Ciências Biológicas , DNA , DNA/química
4.
J Org Chem ; 87(4): 2075-2086, 2022 02 18.
Artigo em Inglês | MEDLINE | ID: mdl-34652911

RESUMO

Route design and proof of concept synthesis was conducted on a synthetically challenging atropisomeric KRASG12C inhibitor to support clinical API manufacture. Improvements to the synthesis of a chiral piperazine fragment gave reduced step count and streamlined protecting group strategy via the formation and methanol ring opening of an N-carboxy-anhydride (NCA). The complex atropisomeric nitroquinoline was accessed via an early stage salt-resolution followed by a formal two-part nitromethane-carbonylation, avoiding a high temperature Gould-Jacobs cyclization that previously led to atropisomer racemization. The substrate scope of the formal nitromethane-carbonylation strategy was further explored for a range of ortho-substituted bromo/iodo unprotected anilines.


Assuntos
Proteínas Proto-Oncogênicas p21(ras) , Metano/análogos & derivados , Nitroparafinas
5.
Angew Chem Int Ed Engl ; 61(18): e202201870, 2022 Apr 25.
Artigo em Inglês | MEDLINE | ID: mdl-35196413

RESUMO

Aromatic aldehydes are fundamental intermediates that are widely utilised for the synthesis of important materials across the broad spectrum of chemical industries. Accessing highly substituted derivatives can often be difficult as their functionalizations are generally performed via electrophilic aromatic substitution, SE Ar. Here we provide an alternative and mechanistically distinct approach whereby aromatic aldehydes are assembled from saturated precursors via a desaturative process. This novel strategy harnesses the high-fidelity of Diels-Alder cycloadditions to quickly construct multi-substituted cyclohexenecarbaldehyde cores which undergo desaturation via the synergistic interplay of enamine, photoredox and cobalt triple catalysis.

6.
Org Biomol Chem ; 17(7): 1839-1842, 2019 02 13.
Artigo em Inglês | MEDLINE | ID: mdl-30623963

RESUMO

The direct decarboxylative azidation of cyclic α-amino acids has been achieved via visible light-mediated organo-photoredox catalysis. This synthetic strategy allows the simple preparation of azide-contaning building blocks and has been used in the selective modification of N-terminal proline residues of two di-peptides.

7.
Chemistry ; 24(47): 12154-12163, 2018 Aug 22.
Artigo em Inglês | MEDLINE | ID: mdl-29787627

RESUMO

In recent years, hydroxylamines derivatives have been exploited as nitrogen-radical precursors in visible-light photochemistry. Their ability to serve as electrophores in redox chemistry has propelled the development of many novel transformations. Fundamental mechanistic aspects as well as the importance in the preparation of nitrogen-containing molecules will be highlighted.

8.
Angew Chem Int Ed Engl ; 57(3): 744-748, 2018 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-29114978

RESUMO

A photoinduced cascade strategy leading to a variety of differentially functionalised nitriles and ketones has been developed. These reactions rely on the oxidative generation of iminyl radicals from simple oximes. Radical transposition by C(sp3 )-(sp3 ) and C(sp3 )-H bond cleavage gives access to distal carbon radicals that undergo SH 2 functionalisations. These mild, visible-light-mediated procedures can be used for remote fluorination, chlorination, and azidation, and were applied to the modification of bioactive and structurally complex molecules.

9.
Angew Chem Int Ed Engl ; 57(39): 12945-12949, 2018 09 24.
Artigo em Inglês | MEDLINE | ID: mdl-30074300

RESUMO

The selective functionalization of C(sp3 )-H bonds at distal positions to functional groups is a challenging task in synthetic chemistry. Reported here is a photoinduced radical cascade strategy for the divergent functionalization of amides and protected amines. The process is based on the oxidative generation of electrophilic amidyl radicals and their subsequent transposition by 1,5-H-atom transfer, resulting in remote fluorination, chlorination and, for the first time, thioetherification, cyanation, and alkynylation. The process is tolerant of most common functional groups and delivers useful building blocks that can be further elaborated. The utility of this strategy is demonstrated through the late-stage functionalization of amino acids and a dipeptide.

10.
Crit Care Med ; 44(11): 2018-2027, 2016 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-27441903

RESUMO

OBJECTIVES: Angiopoietins modulate endothelial permeability via endothelial cell junctions. Angiopoietin-2 blocks the angiopoietin-1/Tie-2 interaction that stabilizes these junctions, and elevated plasma angiopoietin-2 levels are associated with vascular leakage. We hypothesized that plasma angiopoietin-1 and angiopoietin-2 levels are associated with indirect markers of increased vascular permeability, organ dysfunction, mortality, and plasma proinflammatory cytokine levels in human septic shock. DESIGN: Multicenter observational cohort study derived from a randomized controlled trial (Vasopressin and Septic Shock Trial of vasopressin versus norepinephrine in septic shock). SETTING: ICUs of hospitals in Canada, Australia, and the United States. PATIENTS: Three hundred forty-one patients in the randomized, controlled Vasopressin and Septic Shock Trial trial of vasopressin versus norepinephrine in septic shock. INTERVENTIONS: None. MEASUREMENT AND MAIN RESULTS: We measured plasma levels of angiopoietin-1 and angiopoietin-2 at study baseline and determined their association with percent fluid overload and acute organ dysfunction and generated a receiver operating characteristic curve for plasma angiopoietin-2 levels versus acute kidney injury. We also determined the association of angiopoietin-1 and angiopoietin-2 levels with hemodynamics, mortality, and plasma cytokine levels. Plasma angiopoietin-2 levels were directly associated with percent fluid overload at baseline (rs = 0.18; p = 0.0008) and at 6 hours (rs = 0.13; p = 0.023), but not at 24 hours (rs = 0.041; p = 0.46). Plasma angiopoietin-2 levels were associated with the development of hepatic (p < 0.0001) and coagulation (p < 0.0001) dysfunction and acute kidney injury (p < 0.0001). Receiver operating characteristic curve had an area under the curve of 0.73 for acute kidney injury. angiopoietin-2 levels were also inversely associated with days alive (r = -0.24; p = 0.010) and positively associated with increased 7-day (log-rank trend chi-square = 5.9; p = 0.015) and 28-day (log-rank chi square = 4.9; p = 0.027) mortality. A threshold of angiopoietin-2 levels above the first quartile (> 5,807 pg/mL) was observed to be associated with increased mortality risk, which aligns with prior studies. Plasma angiopoietin-2 levels were positively associated with plasma cytokine levels, including tumor necrosis factor-α and interleukin-6 at baseline (rs = 0.39; p < 0.0001 and rs = 0.51; p < 0.0001) and at 24 hours (rs = 0.29; p < 0.0001 and rs = 0.41; p < 0.0001). CONCLUSIONS: Increased plasma angiopoietin-2 levels are associated with increased fluid overload, hepatic and coagulation dysfunction, acute kidney injury, mortality, and plasma cytokines in human septic shock. angiopoietin-2 activation may increase vascular leakage leading to increased fluid requirements, organ dysfunction, and death from septic shock.


Assuntos
Injúria Renal Aguda/epidemiologia , Angiopoietina-2/sangue , Transtornos da Coagulação Sanguínea/epidemiologia , Hepatopatias/epidemiologia , Choque Séptico/mortalidade , Desequilíbrio Hidroeletrolítico/epidemiologia , Austrália/epidemiologia , Biomarcadores/sangue , Canadá/epidemiologia , Estudos de Coortes , Citocinas/sangue , Feminino , Glucocorticoides/uso terapêutico , Humanos , Ácido Láctico/sangue , Masculino , Pessoa de Meia-Idade , Estados Unidos/epidemiologia
11.
Chemistry ; 21(46): 16354-8, 2015 Nov 09.
Artigo em Inglês | MEDLINE | ID: mdl-26406613

RESUMO

Stereo- and chemodivergent enantioselective reaction pathways are observed upon treatment of alkylarylketenes and trichloroacetaldehyde (chloral) with N-heterocyclic carbenes, giving selectively either ß-lactones (up to 88:12 dr, up to 94 % ee) or α-chloroesters (up to 94 % ee). Either 2-arylsubstitution or an α-branched iPr alkyl substituent within the ketene favours the chlorination pathway, allowing chloral to be used as an electrophilic chlorinating reagent in asymmetric catalysis.

12.
Angew Chem Int Ed Engl ; 54(49): 14898-902, 2015 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-26474077

RESUMO

A visible-light-mediated radical Smiles rearrangement has been developed to address the challenging synthesis of the gem-difluoro group present in an opioid receptor-like 1 (ORL-1) antagonist that is currently in development for the treatment of depression and/or obesity. This method enables the direct and efficient introduction of the difluoroethanol motif into a range of aryl and heteroaryl systems, representing a new disconnection for the synthesis of this versatile moiety. When applied to the target compound, the photochemical step could be conducted on 15 g scale using industrially relevant [Ru(bpy)3Cl2] catalyst loadings of 0.01 mol %. This transformation is part of an overall five-step route to the antagonist that compares favorably to the current synthetic sequence and demonstrates, in this specific case, a clear strategic benefit of photocatalysis.


Assuntos
Radicais Livres/química , Compostos Heterocíclicos/síntese química , Compostos Heterocíclicos/farmacologia , Luz , Receptores Opioides/metabolismo , Compostos de Espiro/síntese química , Compostos de Espiro/farmacologia , Radicais Livres/efeitos da radiação , Compostos Heterocíclicos/química , Estrutura Molecular , Compostos de Espiro/química , Receptor de Nociceptina
13.
Curr Opin Crit Care ; 20(4): 378-84, 2014 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-24979550

RESUMO

PURPOSE OF REVIEW: We discuss the goals of resuscitation, in both the early and the later phases, measures of organ perfusion, fluid responsiveness and the consequences of tissue edema. RECENT FINDINGS: The cost of over-aggressive fluid resuscitation is increased organ failure and mortality. In anticipation of the upcoming trials on early goal-directed therapy, we explore strategies to maximize effectiveness of resuscitation. Furthermore, we review recent data on the choice of fluid therapy. SUMMARY: Rapid diagnosis and early fluid resuscitation are crucial to patients with septic shock, initially with the primary goal to relieve the overt tissue hypoxia. Early fluid therapy is important with the caveat that patients must show an increase in their cardiac output. Beyond 6-12 h further positive fluid balance may not usefully improve tissue oxygenation and may be counterproductive.


Assuntos
Hidratação , Choque Séptico/terapia , Hidratação/efeitos adversos , Hidratação/métodos , Humanos , Oxigênio/metabolismo , Ressuscitação , Choque Séptico/diagnóstico , Choque Séptico/fisiopatologia , Resultado do Tratamento
14.
J Org Chem ; 79(23): 11631-43, 2014 Dec 05.
Artigo em Inglês | MEDLINE | ID: mdl-25356724

RESUMO

We report a detailed investigation into the application of visible light-mediated photocatalysis to a challenging bond construction in a complex pharmaceutical target. The optimized reaction allowed the direct coupling of N-methylmorpholine with an unfunctionalized pyridazine in good yield and selectivity, and with high purity of the product isolated via crystallization. The reaction also facilitated the expedient synthesis of a range of analogues via the use of other commercially available N-methyl substituted tertiary amines, and therefore it represents an attractive tool for medicinal chemistry. Furthermore, a number of other interesting photoredox reactions were discovered during the course of this investigation, such as a formal methylation reaction via C-N bond cleavage, functionalization of C-H bonds alpha to amides, and a visible light-mediated iminium ion reduction.


Assuntos
Imidazóis/síntese química , Janus Quinase 2/antagonistas & inibidores , Janus Quinase 2/química , Pirazóis/síntese química , Piridazinas/síntese química , Catálise , Imidazóis/química , Luz , Estrutura Molecular , Oxirredução , Processos Fotoquímicos , Pirazóis/química , Piridazinas/química
15.
Science ; 385(6712): 991-996, 2024 Aug 30.
Artigo em Inglês | MEDLINE | ID: mdl-39208115

RESUMO

The trifluoromethyl group (CF3) is a key functionality in pharmaceutical and agrochemical development, greatly enhancing the efficacy and properties of resulting compounds. However, attaching the CF3 group to heteroatoms such as sulfur, oxygen, and nitrogen poses challenges because of the lack of general synthetic methods and reliance on bespoke reagents. Here, we present a modular flow platform that streamlines the synthesis of heteroatom-CF3 motifs. Our method uses readily available organic precursors in combination with cesium fluoride as the primary fluorine source, facilitating the rapid generation of N-trifluoromethyl(R) [NCF3(R)], SCF3 (trifluoromethylthio), and OCF3 (trifluoromethoxy) anions on demand without reliance on perfluoroalkyl precursor reagents. This strategy offers a more environmentally friendly synthesis of trifluoromethyl(heteroatom)-containing molecules, with the potential for scalability in manufacturing processes facilitated by flow technology.

16.
Nat Chem ; 16(7): 1141-1150, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38570728

RESUMO

Versatile, efficient and robust (pre)catalysts are pivotal in accelerating the discovery and optimization of chemical reactions, shaping diverse synthetic fields such as cross-coupling, C-H functionalization and polymer chemistry. Yet, their scarcity in certain domains has hindered the advancement and adoption of new applications. Here we present a highly reactive air- and moisture-stable ruthenium precatalyst [(tBuCN)5Ru(H2O)](BF4)2, featuring a key exchangeable water ligand. This versatile precatalyst drives an array of transformations, including late-stage C(sp2)-H arylation, primary/secondary alkylation, methylation, hydrogen/deuterium exchange, C(sp3)-H oxidation, alkene isomerization and oxidative cleavage, consistently outperforming conventionally used ruthenium (pre)catalysts. The generality and applicability of this precatalyst is exemplified through the potential for rapid screening and optimization of photocatalytic reactions with a suite of in situ generated ruthenium photocatalysts containing hitherto unknown complexes, and through the rapid discovery of reactivities previously unreported for ruthenium. The diverse applicability observed is suggestive of a generic platform for reaction simplification and accelerated synthetic discovery that will enable broader applicability and accessibility to state-of-the-art ruthenium catalysis.

17.
Crit Care ; 17(5): 186, 2013 Sep 20.
Artigo em Inglês | MEDLINE | ID: mdl-24053782

RESUMO

Different types of shock induce distinct metabolic changes. The myocardium at rest utilizes free fatty acids as its primary energy source, a mechanism that changes to aerobic glycolysis during sepsis and is in contrast to hemorrhagic shock. The immune system also uses this mechanism, changing its substrate utilization to activate innate and adaptive cells. Cardiomyocytes share a number of features similar to antigen-presenting cells and may use this mechanism to augment the immune response at the reversible expense of cardiac function.


Assuntos
Modelos Animais de Doenças , Endotoxemia/metabolismo , Glucose/metabolismo , Miocárdio/metabolismo , Choque Hemorrágico/metabolismo , Animais , Feminino
18.
Green Chem ; 25(6): 2394-2400, 2023 Mar 20.
Artigo em Inglês | MEDLINE | ID: mdl-36960441

RESUMO

Direct C-H functionalisation methodologies represent an opportunity to improve the overall 'green' credentials of organic coupling reactions, improving atom economy and reducing overall step count. Despite this, these reactions frequently run under reaction conditions that leave room for improved sustainability. Herein, we describe a recent advance in our ruthenium-catalysed C-H arylation methodology that aims to address some of the environmental impacts associated with this procedure, including solvent choice, reaction temperature, reaction time, and loading of the ruthenium catalyst. We believe that our findings demonstrate a reaction with improved environmental credentials and showcase it on a multi-gram scale within an industrial setting.

19.
Chem Sci ; 12(31): 10448-10454, 2021 Aug 11.
Artigo em Inglês | MEDLINE | ID: mdl-34447537

RESUMO

Radical hydroxymethylation using formaldehyde as a C1 synthon is challenging due to the reversible and endothermic nature of the addition process. Here we report a strategy that couples alkyl iodide building blocks with formaldehyde through the use of photocatalysis and a phosphine additive. Halogen-atom transfer (XAT) from α-aminoalkyl radicals is leveraged to convert the iodide into the corresponding open-shell species, while its following addition to formaldehyde is rendered irreversible by trapping the transient O-radical with PPh3. This event delivers a phosphoranyl radical that re-generates the alkyl radical and provides the hydroxymethylated product.

20.
Chem Sci ; 10(33): 7728-7733, 2019 Sep 07.
Artigo em Inglês | MEDLINE | ID: mdl-32180920

RESUMO

A divergent strategy for the remote arylation, vinylation and alkylation of nitriles is described. These processes proceed through the photoredox generation of a cyclic iminyl radical and its following ring-opening reaction. The distal nitrile radical is then engaged in nickel-based catalytic cycles to form C-C bonds with aryl bromides, alkynes and alkyl bromides.

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