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1.
Nat Commun ; 15(1): 2592, 2024 Mar 22.
Artículo en Inglés | MEDLINE | ID: mdl-38519475

RESUMEN

Carbon isotope labelling of bioactive molecules is essential for accessing the pharmacokinetic and pharmacodynamic properties of new drug entities. Aryl carboxylic acids represent an important class of structural motifs ubiquitous in pharmaceutically active molecules and are ideal targets for the installation of a radioactive tag employing isotopically labelled CO2. However, direct isotope incorporation via the reported catalytic reductive carboxylation (CRC) of aryl electrophiles relies on excess CO2, which is incompatible with carbon-14 isotope incorporation. Furthermore, the application of some CRC reactions for late-stage carboxylation is limited because of the low tolerance of molecular complexity by the catalysts. Herein, we report the development of a practical and affordable Pd-catalysed electrocarboxylation setup. This approach enables the use of near-stoichiometric 14CO2 generated from the primary carbon-14 source Ba14CO3, facilitating late-stage and single-step carbon-14 labelling of pharmaceuticals and representative precursors. The proposed isotope-labelling protocol holds significant promise for immediate impact on drug development programmes.


Asunto(s)
Carbono , Paladio , Carbono/química , Isótopos de Carbono , Radioisótopos de Carbono , Paladio/química , Marcaje Isotópico/métodos , Dióxido de Carbono/química , Catálisis
2.
J Am Chem Soc ; 146(3): 1753-1759, 2024 Jan 24.
Artículo en Inglés | MEDLINE | ID: mdl-38193812

RESUMEN

Herein, we report the direct carboxylation of unactivated secondary alkyl bromides enabled by the merger of photoredox and nickel catalysis, a previously inaccessible endeavor in the carboxylation arena. Site-selectivity is dictated by a kinetically controlled insertion of CO2 at the initial C(sp3)-Br site by the rapid formation of Ni(I)-alkyl species, thus avoiding undesired ß-hydride elimination and chain-walking processes. Preliminary mechanistic experiments reveal the subtleties of stereoelectronic effects for guiding the reactivity and site-selectivity.

3.
Chem Soc Rev ; 52(19): 6601-6616, 2023 Oct 02.
Artículo en Inglés | MEDLINE | ID: mdl-37655600

RESUMEN

Disproportionation and comproportionation reactions have become increasingly important electron transfer events in organometallic chemistry and catalysis. The renewed interest in these reactions is in part attributed to the improved understanding of first-row metals and their ability to occupy odd and even oxidation states. Disproportionation and comproportionation reactions enable metal complexes to shuttle between various oxidation states, a matter of utmost relevance for controlling the speciation and catalytic turnover. In addition, these reactions have a direct impact in the thermodynamic and kinetic stability of the corresponding metal complexes. This review covers the relevance and impact of these processes in electron transfer reactions and provides valuable information about their non-negligible influence in Ni- and Cu-catalysed transformations.

4.
Angew Chem Int Ed Engl ; 62(35): e202308238, 2023 Aug 28.
Artículo en Inglés | MEDLINE | ID: mdl-37439487

RESUMEN

Herein, we report a methodology to access isotopically labeled esters and amides from carbonates and carbamates employing an oxygen deletion strategy. This methodology utilizes a decarboxylative carbonylation approach for isotope labeling with near stoichiometric, ex situ generated 12 C, or 13 C carbon monoxide. This reaction is characterized by its broad scope, functional group tolerance, and high yields, which is showcased with the synthesis of structurally complex molecules. A complementary method that operates by the catalytic in situ generation of CO via the reduction of CO2 liberated during decarboxylation has also been developed as a proof-of-concept approach that CO2 -derived compounds can be converted to CO-containing frameworks. Mechanistic studies provide insight into the catalytic steps which highlight the impact of ligand choice to overcome challenges associated with low-pressure carbonylation methodologies, along with rational for the development of future methodologies.

5.
JACS Au ; 3(3): 756-761, 2023 Mar 27.
Artículo en Inglés | MEDLINE | ID: mdl-37006775

RESUMEN

Herein, we report a strategy for the formation of isotopically labeled carboxylic esters from boronic esters/acids using a readily accessible palladium carboxylate complex as an organometallic source of isotopically labeled functional groups. The reaction allows access to either unlabeled or full 13C- or 14C-isotopically labeled carboxylic esters, and the method is characterized by its operational simplicity, mild conditions, and general substrate scope. Our protocol is further extended to a carbon isotope replacement strategy, involving an initial decarbonylative borylation procedure. Such an approach allows access to isotopically labeled compounds directly from the unlabeled pharmaceutical, which can have implications for drug discovery programs.

6.
J Am Chem Soc ; 2023 Feb 13.
Artículo en Inglés | MEDLINE | ID: mdl-36780535

RESUMEN

Remote hydrofunctionalizations of alkenes incorporate functional groups distal to existing carbon-carbon double bonds. While remote carbonylations are well-known, remote hydrofunctionalizations are most common for addition of relatively nonpolar B-H, Si-H, and C-H bonds with alkenes. We report a system for the remote hydroamination of disubstituted alkenes to functionalize an alkyl chain selectively at the subterminal, unactivated, methylene position. Critical to the high regioselectivity and reaction rates are the electronic properties of the substituent on the amine and the development of the ligand DIP-Ad-SEGPHOS by evaluating the steric and electronic effects of ligand modules on reactivity and selectivity. The remote hydroamination is compatible with a broad scope of alkenes and aminopyridines and enables the regioconvergent synthesis of amines from an isomeric mixture of alkenes. The products can be derivatized by nucleophilic aromatic substitution on the amino substituent with a variety of nucleophiles.

8.
Angew Chem Int Ed Engl ; 62(15): e202214633, 2023 Apr 03.
Artículo en Inglés | MEDLINE | ID: mdl-36416716

RESUMEN

Herein, we report a Cu-mediated trifluoromethylation of carbonyl-type compounds and unactivated olefins enabled by visible-light irradiation via σ C(sp3 )-C bond-functionalization. The reaction is distinguished by its modularity, mild conditions and wide scope-even in the context of late-stage functionalization-thus offering a complementary approach en route to valuable C(sp3 )-CF3 architectures from easily accessible precursors.

9.
Angew Chem Int Ed Engl ; 61(50): e202212983, 2022 Dec 12.
Artículo en Inglés | MEDLINE | ID: mdl-36254803

RESUMEN

A nickel-catalyzed site-selective intermolecular amidation of saturated C(sp3 )-H bonds is reported. This mild protocol exhibits a predictable reactivity pattern to incorporate amide functions at C(sp3 )-H sites adjacent to nitrogen and oxygen atoms in either cyclic or acyclic frameworks, thus offering a complementary reactivity profile to existing oxidative-type processes or metal-catalyzed C(sp3 )-N bond-forming reactions operating via two-electron manifolds.

10.
Organometallics ; 41(19): 2662-2667, 2022 Oct 10.
Artículo en Inglés | MEDLINE | ID: mdl-36249447

RESUMEN

Herein we disclose the synthesis of sterically encumbered dialkylnickel(II) complexes bearing 2,9-dimethyl-1,10-phenanthroline ligands. A comparison with their unsubstituted analogues by both X-ray crystallography and theoretical calculations revealed significant distortions in their molecular structures. Eyring plots along with stoichiometric and photoexcitation studies revealed that sterically encumbered dialkylnickel(II) complexes enable facile C(sp 3)-C(sp 3) reductive elimination, thus offering an improved understanding of Ni catalysis.

11.
J Am Chem Soc ; 144(29): 13109-13117, 2022 Jul 27.
Artículo en Inglés | MEDLINE | ID: mdl-35830190

RESUMEN

Herein, we report the synthesis of highly reduced bipyridyl magnesium complexes and the first example of a stable organic magnesium electride supported by quantum mechanical computations and X-ray diffraction. These complexes serve as unconventional homogeneous reductants due to their high solubility, modular redox potentials, and formation of insoluble, non-coordinating byproducts. The applicability of these reductants is showcased by accessing low-valent (bipy)2Ni(0) species that are challenging to access otherwise.

12.
Org Lett ; 24(28): 5109-5114, 2022 07 22.
Artículo en Inglés | MEDLINE | ID: mdl-35815401

RESUMEN

Herein, we report a modular catalytic technique that streamlines the preparation of gem-difluoroalkanes from unactivated sp3 precursors. The method is characterized by its simplicity, generality, and site selectivity, including the functionalization of advanced intermediates and olefin feedstocks. Our approach is enabled by a cooperative interplay of halogen- and hydrogen-atom transfer, thus offering a new entry point to difluorinated alkyl bioisosteres of interest in drug discovery.


Asunto(s)
Alquenos , Hidrógeno , Catálisis
13.
J Am Chem Soc ; 143(39): 16184-16196, 2021 10 06.
Artículo en Inglés | MEDLINE | ID: mdl-34559970

RESUMEN

An in-depth study of the mechanism of the azidation of C(sp3)-H bonds with Zhdankin's λ3-azidoiodane reagent catalyzed by iron(II)(pybox) complexes is reported. Previously, it was shown that tertiary and benzylic C(sp3)-H bonds of a range of complex molecules underwent highly site-selective azidation by reaction with a λ3-azidoiodane reagent and an iron(II)(pybox) catalyst under mild conditions. However, the mechanism of this reaction was unclear. Here, a series of mechanistic experiments are presented that reveal critical features responsible for the high selectivity and broad scope of this reaction. These experiments demonstrate the ability of the λ3-azidoiodane reagent to undergo I-N bond homolysis under mild conditions to form λ2-iodanyl and azidyl radicals that undergo highly site-selective and rate-limiting abstraction of a hydrogen atom from the substrate. The resultant alkyl radical then combines rapidly with a resting state iron(III)-azide complex, which is generated by the reaction of the λ3-azidoiodane with the iron(II)(pybox) complex, to form the C(sp3)-N3 bond. This mechanism is supported by the independent synthesis of well-defined iron complexes characterized by cyclic voltammetry, X-ray diffraction, and EPR spectroscopy, and by the reaction of the iron complexes with alkanes and the λ3-azidoiodane. Reaction monitoring and kinetic studies further reveal an unusual effect of the catalyst on the rate of formation of product and consumption of reactants and suggest a blueprint for the development of new processes leading to late-stage functionalization of C(sp3)-H bonds.


Asunto(s)
Hierro/química , Compuestos Organometálicos/síntesis química , Catálisis , Enlace de Hidrógeno , Modelos Moleculares , Estructura Molecular , Compuestos Organometálicos/química
14.
J Am Chem Soc ; 143(17): 6395-6400, 2021 05 05.
Artículo en Inglés | MEDLINE | ID: mdl-33904726

RESUMEN

A site-selective defluorinative sp3 C-H alkylation of secondary amides that rapidly and reliably incorporates gem-difluoroalkene motifs into previously unfunctionalized sp3 sites is disclosed. This protocol is distinguished by its mild conditions, wide scope, and exquisite site-selectivity, thus unlocking a new platform to introduce carbonyl isosteres at saturated hydrocarbon sites.

15.
J Am Chem Soc ; 143(13): 4949-4954, 2021 04 07.
Artículo en Inglés | MEDLINE | ID: mdl-33724815

RESUMEN

A Ni-catalyzed reductive carboxylation of N-substituted aziridines with CO2 at atmospheric pressure is disclosed. The protocol is characterized by its mild conditions, experimental ease, and exquisite chemo- and regioselectivity pattern, thus unlocking a new catalytic blueprint to access ß-amino acids, important building blocks with considerable potential as peptidomimetics.

16.
Sci Transl Med ; 13(579)2021 02 03.
Artículo en Inglés | MEDLINE | ID: mdl-33536278

RESUMEN

Dengue virus (DENV) is a mosquito-borne flavivirus that poses a threat to public health, yet no antiviral drug is available. We performed a high-throughput phenotypic screen using the Novartis compound library and identified candidate chemical inhibitors of DENV. This chemical series was optimized to improve properties such as anti-DENV potency and solubility. The lead compound, NITD-688, showed strong potency against all four serotypes of DENV and demonstrated excellent oral efficacy in infected AG129 mice. There was a 1.44-log reduction in viremia when mice were treated orally at 30 milligrams per kilogram twice daily for 3 days starting at the time of infection. NITD-688 treatment also resulted in a 1.16-log reduction in viremia when mice were treated 48 hours after infection. Selection of resistance mutations and binding studies with recombinant proteins indicated that the nonstructural protein 4B is the target of NITD-688. Pharmacokinetic studies in rats and dogs showed a long elimination half-life and good oral bioavailability. Extensive in vitro safety profiling along with exploratory rat and dog toxicology studies showed that NITD-688 was well tolerated after 7-day repeat dosing, demonstrating that NITD-688 may be a promising preclinical candidate for the treatment of dengue.


Asunto(s)
Virus del Dengue , Dengue , Animales , Antivirales/uso terapéutico , Dengue/tratamiento farmacológico , Perros , Ratones , Modelos Animales , Ratas , Serogrupo
17.
Angew Chem Int Ed Engl ; 60(21): 11740-11744, 2021 May 17.
Artículo en Inglés | MEDLINE | ID: mdl-33630396

RESUMEN

A catalytic 1,1-difunctionalization of unactivated olefins en route to sp3 bis-organometallic B,B(Si)-reagents is described. The protocol is characterized by exceptional reaction rates, mild conditions, wide scope, and exquisite selectivity pattern, constituting a new platform to access sp3 bis-organometallics.

18.
J Am Chem Soc ; 142(49): 20594-20599, 2020 12 09.
Artículo en Inglés | MEDLINE | ID: mdl-33252234

RESUMEN

A dual platform for forging sp2-sp3 and sp3-sp3 carbon bonds via catalytic ß-scission of aliphatic alcohol derivatives with both aryl and alkyl halides is disclosed. This protocol is distinguished by its wide substrate scope and broad applicability, even in the context of late-stage functionalization.

19.
Chem Commun (Camb) ; 56(59): 8273-8276, 2020 Jul 28.
Artículo en Inglés | MEDLINE | ID: mdl-32568331

RESUMEN

Herein, aminoquinolate diarylboron complexes are utilized as photocatalysts in dual Ni/photoredox catalyzed carbon-oxygen construction reactions. Via this unified metallaphotoredox platform, diverse (hetero)aryl halides can be conveniently coupled with acids, alcohols and water. This method features operational simplicity, broad substrate scope and good compatibility with functional groups.

20.
Antiviral Res ; 162: 61-70, 2019 02.
Artículo en Inglés | MEDLINE | ID: mdl-30521834

RESUMEN

Enterovirus D68 (EV-D68) is a non-polio enterovirus that affects the respiratory system and can cause serious complications, especially in children and older people with weakened immune systems. As an emerging virus, there are no current antiviral therapies or vaccines available. Our goal was to develop a mouse model of human EV-D68 infection that mimicked the disease observed in humans and could be used for evaluation of experimental therapeutics. This is the first report of a respiratory disease model for EV-D68 infection in mice. We adapted the virus by 30 serial passages in AG129 mice, which are deficient in IFN- α/ß and -γ receptors. Despite a lack of weight loss or mortality in mice, lung function measured by plethysmography, showed an increase in enhanced pause (Penh) on days 6 and 7 post-infection. In addition, as virus adapted to mice, virus titer in the lungs increased 50-fold, and the pro-inflammatory cytokines MCP-1 and RANTES increased 15-fold and 2-fold in the lung, respectively. In addition, a time course of mouse-adapted EV-D68 infection was determined in lung, blood, liver, kidney, spleen, leg muscle, spinal cord and brain. Virus in the lung replicated rapidly after intranasal inoculation of adapted virus, 106 CCID50/mL by 4 h and 108.3 CCID50/mL by 24 h. Virus then spread to the blood and other tissues, including spinal cord and brain. This mouse model for EV-D68 infection includes enhanced pause (Penh) as an indicator of morbidity, and viremia, virus titers and proinflammatory cytokines in the lung, and lung histopathology as indicators of disease. Our mouse-adapted virus has a similar antiviral profile to the original isolate as well as another respiratory picornavirus, rhinovirus-14. This model will be valuable in evaluating experimental therapies in the future.


Asunto(s)
Modelos Animales de Enfermedad , Infecciones por Enterovirus/inmunología , Infecciones por Enterovirus/virología , Pulmón/virología , Infecciones del Sistema Respiratorio/virología , Animales , Antivirales/uso terapéutico , Quimiocinas/inmunología , Citocinas/inmunología , Enterovirus Humano D , Infecciones por Enterovirus/tratamiento farmacológico , Femenino , Masculino , Ratones , Infecciones del Sistema Respiratorio/tratamiento farmacológico , Infecciones del Sistema Respiratorio/inmunología , Carga Viral , Viremia
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