RESUMEN
Bridged amides and anilines display interesting properties owing to perturbation of conjugation of the nitrogen lone-pair with the adjacent π-system. A convergent approach to diazabicyclic scaffolds which contain either twisted amides or anilines is described, based on the photocatalysed hydroamination of cyclic enecarbamates and subsequent cyclisation. The modular nature of the synthesis allows for variation of the degree of 'twist' and hence the properties of the amides and anilines.
RESUMEN
A 'top down' scaffold remodelling approach to library synthesis was applied to spirotricyclic ureas prepared by a complexity-generating oxidative dearomatisation. Eighteen structurally-distinct, sp3 -rich scaffolds were accessed from the parent tricycle through ring addition, cleavage and expansion strategies. Biological screening of a small compound library based on these scaffolds using the cell-painting assay demonstrated distinctive phenotypic responses engendered by different library members, illustrating the functional as well as structural diversity of the compounds.
Asunto(s)
Bibliotecas de Moléculas Pequeñas , Bibliotecas de Moléculas Pequeñas/química , Biblioteca de GenesRESUMEN
The stereocontrolled synthesis of complex spirotricyclic systems containing an embedded syn-1,2-diaminocyclohexane unit is reported, based upon a dearomatising oxidation of phenols bearing pendant ureas capable of acting as double nucleophiles. This complexity-generating transformation yields products with rich functionality suitable for application in the synthesis of potentially bioactive compounds.
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Diaminas , Fenoles , Oxidación-ReducciónRESUMEN
A three-component synthesis of polysubstituted pyridines has been developed, based upon the synthesis of 2-azadienes by a redox-neutral catalytic intermolecular aza-Wittig reaction and their subsequent Diels-Alder reactions. The two-pot process has been demonstrated using a range of aryl and heteroaromatic aldehydes, substituted α,ß-unsaturated acids and push-pull enamines, to give rapid access to diverse tri- and tetrasubstituted pyridines.
RESUMEN
A convenient and simple three-component synthesis of substituted pyridylacetic acid derivatives is reported. The approach centers on the dual reactivity of Meldrum's acid derivatives, initially as nucleophiles to perform substitution on activated pyridine-N-oxides, then as electrophiles with a range of nucleophiles to trigger ring-opening and decarboxylation.
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DioxanosRESUMEN
A "top-down" synthetic approach enabled the step-efficient synthesis of 21 diverse novel molecular scaffolds. The scaffolds were derived from four complex intermediates that had been prepared using cycloaddition chemistry. Scaffold-hopping of these intermediates was achieved through attachment of an additional ring, ring cleavage, ring expansion and/or ring fusion. It was shown that the resulting scaffolds could be decorated to yield diverse lead-like screening compounds.
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Estructura Molecular , Reacción de CicloadiciónRESUMEN
The regioselective γ-C-H amination of the side-chain of saturated 2-alkyl nitrogen heterocycles is reported, proceeding through a sulfamide-directed 1,6-radical translocation. The practicality of this rapid access to 1,3-diamines is highlighted in a short synthesis of the alkaloid tetraponerine T8 and non-natural analogues.
RESUMEN
Regioselective and stereospecific directed C-H arylation of simple amine substrates, and cyclisation, delivered 30 diverse, three-dimensional scaffolds. The unified approach significantly expanded the range of bridged ring systems that contain both a nitrogen atom and an aromatic ring.
RESUMEN
3-Amino-substituted saturated nitrogen heterocycles are an important subclass of ß-diamines, appearing in a number of clinical agents. Herein, we report a unified approach to these products based upon the regioselective photoredox-mediated hydroamination of enecarbamates. The amine coupling partner can encompass diverse amine types under a single set of reaction conditions, including primary alkyl amines, ammonia, aryl and heteroaryl amines, and N-H heterocycles. The method enables the synthesis of a wide range of pharmaceutically relevant building blocks.
RESUMEN
A strategy for the ß-sp3 functionalisation of cyclic amines is described. Regioselective conversion of protected amines to enecarbamates is achieved through electrochemical oxidation; these intermediates can be derivatised by functionalised alkyl halides under photoredox catalysis. The potential of the methods is highlighted by direct growth of a DCP2B-binding fragment.
RESUMEN
A unified synthetic approach was developed that enabled the synthesis of diverse tropane-related scaffolds. The key intermediates that were exploited were cycloadducts formed by reaction between 3-hydroxy-pyridinium salts and vinyl sulfones or sulfonamides. The diverse tropane-related scaffolds were formed by addition of substituents to, cyclisation reactions of, and fusion of additional ring(s) to the key bicyclic intermediates. A set of 53 screening compounds was designed, synthesised and evaluated in order to determine the biological relevance of the scaffolds accessible using the synthetic approach. Two inhibitors of Hedgehog signalling, and four compounds with weak activity against the parasite P. falciparum, were discovered. Three of the active compounds may be considered to be indotropane or pyrrotropane pseudo natural products in which a tropane is fused with a fragment from another natural product class. It was concluded that the unified synthetic approach had yielded diverse scaffolds suitable for the design of performance-diverse screening libraries.
Asunto(s)
Antimaláricos/farmacología , Proteínas Hedgehog/antagonistas & inhibidores , Plasmodium falciparum/efectos de los fármacos , Bibliotecas de Moléculas Pequeñas/farmacología , Tropanos/farmacología , Antimaláricos/síntesis química , Antimaláricos/química , Proteínas Hedgehog/metabolismo , Estructura Molecular , Pruebas de Sensibilidad Parasitaria , Bibliotecas de Moléculas Pequeñas/síntesis química , Bibliotecas de Moléculas Pequeñas/química , Relación Estructura-Actividad , Tropanos/síntesis química , Tropanos/químicaRESUMEN
Aryl dialkyl amines, valuable subunits of a wide range of effect chemicals, are accessed by intramolecular amination of aromatic C-H bonds employing UV photolysis of N-chloroamines. The reactions show good functional group tolerance and allow access to a range of fused and bridged polycyclic structures. The homogeneous reaction conditions allow for the one-pot conversion of secondary amines to their arylated derivatives. Experimental and theoretical evidence supports the involvement of electrophilic aminium radicals which react via direct ortho-attack on the arene.
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The availability of high-quality screening compounds is of paramount importance for the discovery of innovative new medicines. Natural product (NP) frameworks can inspire the design of productive compound libraries. Here, we describe the design and synthesis of four compound libraries based on scaffolds that have broad NP-like features, but that are only distantly related to specific NPs. The optimisation of syntheses of the scaffolds using [5 + 2] cycloaddition chemistry is detailed, together with methods to yield exemplar decorated screening compounds. In each case, a library was nominated for production, leading to a total of >2900 screening compounds that augmented the Joint European Compound Library of the European Lead Factory.
RESUMEN
Current fragment sets tend to be dominated by flatter molecules, and their shape diversity does not reflect that of the fragments that are theoretically possible. The design and synthesis of a set of bridged fragments containing a bridgehead nitrogen is described. Many of these fragments contain twisted lactams whose modulated electronic properties may present unusual opportunities for interaction with target proteins. The demonstrated novelty, three-dimensionality and molecular properties of the set of 22 fragments may provide valuable, and highly distinctive, starting points for fragment-based drug discovery.
Asunto(s)
Compuestos Bicíclicos Heterocíclicos con Puentes/química , Diseño de Fármacos , Lactamas/farmacología , Compuestos Bicíclicos Heterocíclicos con Puentes/farmacología , Cristalografía por Rayos X , Lactamas/síntesis química , Estructura Molecular , Fragmentos de Péptidos/químicaRESUMEN
The organocatalytic asymmetric transfer hydrogenation of N-alkyl aryl imino esters for the direct synthesis of N-alkylated arylglycinate esters is reported. High yields and enantiomeric ratios were obtained, and tolerance to a diverse set of functional groups facilitated the preparation of more complex molecules as well as intermediates for active pharmaceuticals. A simple recycling protocol was developed for the Brønsted acid catalyst which could be reused through five cycles with no loss of activity or selectivity.
RESUMEN
The productive exploration of chemical space is an enduring challenge in chemical biology and medicinal chemistry. Natural products are biologically relevant, and their frameworks have facilitated chemical tool and drug discovery. A "top-down" synthetic approach is described that enabled a range of complex bridged intermediates to be converted with high step efficiency into 26 diverse sp3 -rich scaffolds. The scaffolds have local natural product-like features, but are only distantly related to specific natural product frameworks. To assess biological relevance, a set of 52 fragments was prepared, and screened by high-throughput crystallography against three targets from two protein families (ATAD2, BRD1 and JMJD2D). In each case, 3D fragment hits were identified that would serve as distinctive starting points for ligand discovery. This demonstrates that frameworks that are distantly related to natural products can facilitate discovery of new biologically relevant regions within chemical space.
Asunto(s)
Productos Biológicos/química , ATPasas Asociadas con Actividades Celulares Diversas/química , ATPasas Asociadas con Actividades Celulares Diversas/metabolismo , Sitios de Unión , Productos Biológicos/síntesis química , Productos Biológicos/metabolismo , Dominio Catalítico , Proteínas de Unión al ADN/química , Proteínas de Unión al ADN/metabolismo , Ensayos Analíticos de Alto Rendimiento , Histona Acetiltransferasas , Chaperonas de Histonas , Humanos , Histona Demetilasas con Dominio de Jumonji/química , Histona Demetilasas con Dominio de Jumonji/metabolismo , Ligandos , Simulación del Acoplamiento Molecular , Proteínas Nucleares/química , Proteínas Nucleares/metabolismo , Dominios Proteicos , Teoría Cuántica , Bibliotecas de Moléculas Pequeñas/síntesis química , Bibliotecas de Moléculas Pequeñas/química , Bibliotecas de Moléculas Pequeñas/metabolismoRESUMEN
A one-pot, three-component synthesis of α-pyridyl, α-substituted amino acid derivatives is described. The key transformation is a direct, precious-metal-free heteroarylation of readily available, amino acid derived azlactones with electrophilically activated pyridine N-oxides. The resulting intermediates can be used directly as efficient acylating agents for a range of nucleophiles, leading to the heteroarylated amino acid derivatives in a single vessel.
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Aminoácidos/síntesis química , Piridinas/síntesis química , Catálisis , Etilaminas/química , Lactonas/química , Metanol/química , Óxidos/química , Solventes/químicaRESUMEN
As our understanding of the impact of specific molecular properties on applications in discovery-based disciplines improves, the extent to which published synthetic methods meet (or do not meet) desirable criteria is ever clearer. Herein, we show how the application of simple (and in many cases freely available) computational tools can be used to develop a semiquantitative understanding of the potential of new methods to support molecular discovery. This analysis can, among other things, inform the design of improved substrate scoping studies; direct the prioritization of specific exemplar structures for synthesis; and substantiate claims of potential future applications for new methods.
RESUMEN
A synthetic approach to diverse scaffolds was developed that was inspired by diterpene biosynthesis. Initial scaffolds, generated using Diels-Alder reactions of furyl-functionalised amines, were transformed into alternative scaffolds using cleavage, ring expansion, annulation and rearrangement reactions. In total, 25 diverse scaffolds were prepared that were shown to have high natural product-likeness.
Asunto(s)
Aminas/síntesis química , Productos Biológicos/síntesis química , Biomimética/métodos , Reacción de Cicloadición/métodos , Furanos/síntesis química , Aminas/química , Productos Biológicos/química , Furanos/química , Modelos Moleculares , EstereoisomerismoRESUMEN
Complementary cyclisation reactions of hex-2-ene-1,6-diamine derivatives were exploited in the synthesis of alternative molecular scaffolds. The value of the synthetic approach was analysed using LLAMA, an open-access computational tool for assessing the lead-likeness and novelty of molecular scaffolds.