RESUMEN
The direct utilization of simple and abundant feedstocks in carbon-carbon bond-forming reactions to embellish sp3 -enriched chemical space is highly desirable. Herein, we report a novel photochemical deoxygenative hydroalkylation of unactivated alkenes with readily available carboxylic acid derivatives. The reaction displays broad functional group tolerance, accommodating carboxylic acid-, alcohol-, ester-, ketone-, amide-, silane-, and boronic ester groups, as well as nitrile-containing substrates. The reaction is operationally simple, mild, and water-tolerant, and can be carried out on multigram-scale, which highlights the utility of the method to prepare value-added compounds in a practical and scalable manner. The synthetic application of the developed method is further exemplified through the synthesis of suberanilic acid, a precursor of vorinostat, a drug used for the treatment of cutaneous T-cell lymphoma. A novel mechanistic approach was identified using thiol as a nucleophilic catalyst, which forms a key intermediate for this transformation. Furthermore, electrochemical studies, quantum yield, and mechanistic experiments were conducted to support a proposed catalytic cycle for the transformation.
RESUMEN
The Rh(III)-catalyzed C-H functionalization and subsequent oxidative annulation between 5-aryl pyrazinones and internal alkynes are reported. This protocol provides facile access to a wide range of pyrazinone-linked naphthalenes via the C(sp2)-H alkenylation and subsequent annulation. This transformation is characterized by mild conditions, simplicity, and excellent functional group compatibility. Notably, it is a first report of the utilization of pyrazinones as directing groups in C-H functionalization.
Asunto(s)
Alquinos , Rodio , Catálisis , Oxidación-Reducción , Estrés OxidativoRESUMEN
The direct methylation of N-heterocycles is an important transformation for the advancement of pharmaceuticals, agrochemicals, functional materials, and other chemical entities. Herein, the unprecedented C(sp2 )-H methylation of iminoamido heterocycles as nucleoside base analogues is described. Notably, trimethylsulfoxonium salt was employed as a methylating agent under aqueous conditions. A wide substrate scope and excellent level of functional-group tolerance were attained. Moreover, this method can be readily applied to the site-selective methylation of azauracil nucleosides. The feasibility of gram-scale reactions and various transformations of the products highlight the synthetic potential of the developed method. Combined deuterium-labeling experiments aided the elucidation of a plausible reaction mechanism.
RESUMEN
A transition-metal-free deoxygenative C-H amination reaction of azine-N-oxides with acyl azides is described. The initial formation of an isocyanate from the starting acyl azide via a Curtius rearrangement can trigger a [3 + 2] dipolar cycloaddition of polar N-oxide fragments to generate the aminated azine derivative. The applicability of this method is highlighted by the late-stage and sequential amination reactions of complex bioactive compounds, including quinidine and fasudil. Moreover, the direct transformation of aminated azines into various bioactive N-heterocycles illustrates the significance of this newly developed protocol.
RESUMEN
Ruthenium(II)-catalyzed C(sp2)-H functionalization of N-aryl phthalazinones with a range of aldehydes and activated ketone is described. Initial formation of hydroxyalkylated phthalazinones and subsequent Mitsunobu cyclization provided facile access to biologically relevant indazolophthalazinones. The utility of this method is highlighted by synthetic transformations into a series of potentially bioactive scaffolds.
RESUMEN
The preparation of phthalazinone derivatives is pivotal for their utilization as pharmaceutical agents and other entities. Herein, we report the phthalazinone-assisted carbon-nitrogen bond forming reaction using dioxazolones as robust amidation sources under Rh(III) catalysis. The broad functional group tolerance and complete site-selectivity are observed. Notably, a series of transformations of synthesized compounds into biologically relevant N-heterocycles demonstrates the applicability of the developed methodology.
RESUMEN
The rhodium(III)-catalyzed C-H functionalization followed by intramolecular annulation reactions between azobenzenes and sulfoxonium ylides is described. This protocol leads to the efficient formation of 3-acyl (2 H)-indazoles with a range of substrate scope. A high level of chemoselectivity and functional group tolerance of this transformation were also observed.
RESUMEN
The ability to alkylate pyridines and quinolines is important for their further development as pharmaceuticals and agrochemicals, and for other purposes. Herein we describe the unprecedented reductive alkylation of pyridine and quinoline N-oxides using Wittig reagents. A wide range of pyridine and quinoline N-oxides were converted into C2-alkylated pyridines and quinolines with excellent site selectivity and functional-group compatibility. Sequential C-H functionalization reactions of pyridine and quinoline N-oxides highlight the utility of the developed method. Detailed labeling experiments were performed to elucidate the mechanism of this process.
RESUMEN
The aldimine-directed C-H amidation of various arenes with N-acyl azides as amidation surrogates under cationic iridium(III) catalysis is described. This transformation efficiently provides a range of 2-aminobenzaldehyde derivatives with excellent site selectivity and functional group compatibility. The resulting 2-aminobenzaldehyde framework provides facile access to a range of biologically interesting heterocycles. In addition, all synthetic compounds were screened for anti-inflammatory activity against interleukin-1ß (IL-1ß) and tumor necrosis factor alpha (TNF-α) with lipopolysaccharide (LPS)-induced RAW264.7 cells. Generally, a range of ortho-amidated benzaldehydes displayed promising inhibitory activity against IL-1ß and TNF-α compared to dexamethasone as a positive control. Notably, compounds (3ae and 4ac) were found to exhibit potent anti-inflammatory activity stronger than that of dexamethasone.
Asunto(s)
Antiinflamatorios no Esteroideos/farmacología , Azidas/química , Benzaldehídos/farmacología , Iminas/química , Interleucina-1beta/antagonistas & inhibidores , Factor de Necrosis Tumoral alfa/antagonistas & inhibidores , Amidas/síntesis química , Amidas/química , Amidas/farmacología , Animales , Antiinflamatorios no Esteroideos/síntesis química , Antiinflamatorios no Esteroideos/química , Benzaldehídos/síntesis química , Benzaldehídos/química , Catálisis , Supervivencia Celular/efectos de los fármacos , Células Cultivadas , Iridio/química , Lipopolisacáridos/antagonistas & inhibidores , Lipopolisacáridos/farmacología , Ratones , Estructura Molecular , Compuestos Organometálicos/química , Células RAW 264.7RESUMEN
The weakly coordinating ketone group directed C-H functionalizations of chromones, 1,4-naphthoquinones, and xanthones with various maleimides under rhodium(III) catalysis are described. These protocols efficiently provide a range of succinimide-containing chromones, naphthoquinones, and xanthones with excellent site selectivity and functional group compatibility. All synthetic compounds were screened for in vitro anticancer activity against human breast adenocarcinoma cell lines (MCF-7). In particular, compounds 7aa and 7ca with a naphthoquinone scaffold were found to be highly cytotoxic, with an activity competitive with anticancer agent doxorubicin.
Asunto(s)
Antineoplásicos/farmacología , Cromonas/síntesis química , Naftoquinonas/síntesis química , Rodio/química , Succinimidas/análisis , Xantonas/síntesis química , Antineoplásicos/síntesis química , Antineoplásicos/química , Espectroscopía de Resonancia Magnética con Carbono-13 , Catálisis , Proliferación Celular/efectos de los fármacos , Cromonas/química , Cromonas/farmacología , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Células MCF-7 , Naftoquinonas/química , Naftoquinonas/farmacología , Espectroscopía de Protones por Resonancia Magnética , Especies Reactivas de Oxígeno/metabolismo , Espectrometría de Masa por Ionización de Electrospray , Xantonas/química , Xantonas/farmacologíaRESUMEN
Azaspiro[3.3]heptanes are valuable synthetic targets for drug discovery programs. The challenges associated with the preparation and diversification of this moiety as compared to other small, saturated rings have led to limited applications of compounds containing this spirocycle. In this regard, important advances in the field of synthetic photochemistry have exploited the biradical nature of the triplet excited state of 2-isoxazoline-3-carboxylates, engaging these species in intermolecular coupling reactions under visible light irradiation. As a continuation of our program preparing F(sp3)-rich, structurally complex molecules for DNA-encoded library technology (DELT) applications via photocatalysis, we disclose herein the incorporation of unique and densely functionalized 2-oxa-1-azabicyclo[3.2.0]heptanes via [2+2] cycloaddition energy transfer sensitization, providing access to an unexplored library of azaspiro compounds, many of which include additional synthetic handles important for further functionalization of the DNA-conjugated products and for library production.
Asunto(s)
Heptanos , Luz , Transferencia de Energía , Catálisis , ADNRESUMEN
The emergence of DNA-encoded library (DEL) technology has provided a considerable advantage to the pharmaceutical industry in the pursuit of discovering novel therapeutic candidates for their drug development initiatives. This combinatorial technique not only offers a more economical, spatially efficient, and time-saving alternative to the existing ligand discovery methods, but also enables the exploration of additional chemical space by utilizing novel DNA-compatible synthetic transformations to leverage multifunctional building blocks from readily available substructures. In this report, a decarboxylative-based hydroalkylation of DNA-conjugated N-vinyl heterocycles enabled by single-electron transfer (SET) and subsequent hydrogen atom transfer through electron-donor/electron-acceptor (EDA) complex activation is detailed. The simplicity and robustness of this method permits inclusion of a broad array of alkyl radical precursors and DNA-tethered nitrogenous heterocyles to generate medicinally relevant substituted heterocycles with pendant functional groups. Moreover, a successful telescoped route provides the opportunity to access a broad range of intricate structural scaffolds by employing basic carboxylic acid feedstocks.
RESUMEN
In this study, we examine the site-selctive iridium(III)-catalyzed C-H amidation between 2-aryl azlactones and acyl azides. This transformation produces a range of ortho-amidated azlactones, which act as precursors for the synthesis of chiral amino acids via organocatalyzed ring-opening reactions. To test its effectiveness, the method developed is applied to the late-stage C-H amidation of complex drug molecules. The isolation of an iridacycle species supports a proposed reaction pathway.
Asunto(s)
Aminoácidos , Iridio , Iridio/química , Estructura Molecular , Catálisis , Azidas/químicaRESUMEN
The success of cancer chemotherapy is limited by multidrug resistance (MDR), which is mainly caused by P-glycoprotein (P-gp) overexpression. In the present study, we describe a novel microtubule inhibitor, 5-(N-methylmaleimid-3-yl)-chromone (SPC-160002), that can be used to overcome MDR. A synthetic chromone derivative, SPC-160002, showed a broad spectrum of anti-proliferative effects on various human cancer cells without affecting P-gp expression and its drug efflux function. Treatment with SPC-160002 arrested the cell cycle at the M phase, as evidenced using fluorescence-activated cell sorting analysis, and increased the levels of mitotic marker proteins, including cyclin B, pS10-H3, and chromosomal passenger complex. This mitotic arrest by SPC-160002 was mediated by promoting and stabilizing microtubule polymerization, similar to the mechanism observed in case of taxane-based drugs. Furthermore, SPC-160002 suppressed the growth and sphere-forming activity of cancer stem cells. Our data herein strongly suggest that SPC-160002, a novel microtubule inhibitor, can be used to overcome MDR and can serve as an attractive candidate for anticancer drugs.
Asunto(s)
Cromonas/farmacología , Resistencia a Múltiples Medicamentos/efectos de los fármacos , Resistencia a Antineoplásicos/efectos de los fármacos , Maleimidas/química , Células Madre Neoplásicas/metabolismo , Moduladores de Tubulina/farmacología , Células A549 , Subfamilia B de Transportador de Casetes de Unión a ATP/metabolismo , Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Cromonas/síntesis química , Cromonas/química , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Células HCT116 , Células Hep G2 , Humanos , Células MCF-7 , Células Madre Neoplásicas/efectos de los fármacos , Moduladores de Tubulina/síntesis química , Moduladores de Tubulina/químicaRESUMEN
The synthesis of alkylated diazine derivatives is important for their practical utilization as pharmaceuticals and for other purposes. Herein, we describe the metal-free site-selective C-H alkylation of diazine N-oxides using phosphonium ylides that affords a variety of alkylated diazine derivatives with broad functional group tolerance. The utility of this method is showcased by the late-stage functionalization of a commercially available drug such as varenicline. Notably, the sequential C-H alkylation of pyrazine N-oxides for the total synthesis of a pyrazine-containing natural product, paenibacillin A, highlights the importance of this method.
RESUMEN
The transient directing group promoted C(sp2)-H functionalization of benzaldehydes with anthranils by a cationic rhodium(III) catalyst is described. Notably, anthranils have been used as both transient directing groups and amination sources to afford 2-acyl acridines through direct C-H amination followed by acid-mediated cyclization. A range of substrate scopes and functional group tolerance were observed.
RESUMEN
The rhodium(iii)-catalyzed cross-coupling reaction of 8-methylquinolines with a range of allylic alcohols in water is described. This approach leads to the synthesis of various γ-quinolinyl carbonyl compounds, which are synthetically useful precursors for the construction of bioactive tetrahydroquinoline and azasteroid derivatives.
RESUMEN
The rhodium(III)-catalyzed cross-coupling reaction of 8-methylquinolines and maleimides is described. In contrast to the C(sp(2))-H functionalization, a first catalytic functionalization of sp(3) C-H bonds with maleimides is reported. This protocol provides a facile access to various succinimide scaffolds on 8-methylquinolines via a direct C-H cleavage approach.