Privileged Motif Research Articles

Sulfonamide Derivatives as Potent Antituberculosis Agents: A Literature Survey of the Past Decade

AbstractTuberculosis (TB) is a serious, life‐threatening infectious disease that mostly affects the lungs and is caused by Mycobacterium tuberculosis (MTB). Still, in 2024, because of its widespreadness, contagious nature, and an increasing number of patients with other diseases, it is hard to cure, and leftovers as the deadliest disease to mankind across the world. In recent years, abundant efforts have been made to cure and eradicate TB, but drug‐resistant TB (DR‐TB) or multidrug‐resistant TB (MDR‐TB) surges the rate of mortality. Recently, World Health Organization (WHO) released the Global Tuberculosis (TB) Report 2022, in which the millions of infections and deaths stretched a line of serious concern to the scientists. In pursuit of searching for novel anti‐TB agents, several derivatives of sulfonamides have been synthesized and tested for their anti‐TB activity. It is noteworthy that lead compounds contain sulfonamide functionalities, which are the privileged motifs that act as crucial pharmacophores in many bioactive compounds and have diverse biological activities, including analgesics, antitubercular, antifungal, antidepressant, anti‐inflammatory, antihypertensive, antidiabetic, anticancer, antimalarial, antioxidant, antimicrobial, etc. The review encapsulates the latest methods for preparing sulfonamide derivatives and their groundbreaking medicinal applications from 2007 to 2020.

Biocatalytic Dearomatisation Reactions

AbstractBiocatalytic dearomatisation offers the advantages of high chemo-, regio- and stereoselectivity over chemical strategies. Mono- and dioxygenases with dearomatising properties are already well-established tools for the synthesis of natural products and beyond. Herein, we review investigations of protein sequence–activity relationships, as well as protein-engineering approaches that have been employed to expand the substrate scope of biocatalysts and achieve product regio- and stereodiversity. Thus, oxidative dearomatising biocatalysts offer an increasingly diverse toolbox for the synthesis of asymmetric, oxidised cyclic scaffolds, as illustrated through selected examples of biocatalytic applications in synthetic routes towards natural products and derivatives thereof. Reductases with dearomatising properties have been less well investigated, so we review recent mechanistic findings which, henceforth, allow for expanding applications of this class of biocatalysts. Additionally, chemoenzymatic strategies have been developed to overcome the limitations of purely biocatalytic or chemical dearomatisation approaches. We highlight examples of those combination strategies for the synthesis of asymmetric privileged motifs.1 Introduction2 Oxidative Biocatalytic Dearomatisation3 Reductive Biocatalytic Dearomatisation4 Chemoenzymatic Dearomatisation5 Conclusion

6‐Hydroxy Picolinohydrazides Promoted Cu(I)‐Catalyzed Hydroxylation Reaction in Water: Machine‐Learning Accelerated Ligands Design and Reaction Optimization

Hydroxylated (hetero)arenes are privileged motifs in natural products, materials, small‐molecule pharmaceuticals and serve as versatile intermediates in synthetic organic chemistry. Herein, we report an efficient Cu(I)/6‐hydroxy picolinohydrazide‐catalyzed hydroxylation reaction of (hetero)aryl halides (Br, Cl) in water. By establishing machine learning (ML) models, the design of ligands and optimization of reaction conditions were effectively accelerated. L32 (6‐HPA‐DMCA) demonstrated high efficiency for (hetero)aryl bromides, promoting hydroxylation reactions with a minimal catalyst loading of 0.01 mol% (100 ppm) at 80 °C to reach 10000 TON or under near‐room temperature conditions for substrates containing sensitive functional groups (3.0 mol%); L42 (6‐HPA‐DTBCA) displayed superior reaction activity for chloride substrates, enabling hydroxylation reactions at 100 °C with 2‐3 mol% catalyst loading. These represent the state of art for both lowest catalyst loading and temperature in the copper‐catalyzed hydroxylation reactions. Furthermore, this method features a sustainable and environmentally friendly solvent system, accommodates a wide range of substrates, and shows potential for developing robust and scalable synthesis processes for key pharmaceutical intermediates.

6-Hydroxy Picolinohydrazides Promoted Cu(I)-Catalyzed Hydroxylation Reaction in Water: Machine-Learning Accelerated Ligands Design and Reaction Optimization.

Hydroxylated (hetero)arenes are privileged motifs in natural products, materials, small-molecule pharmaceuticals and serve as versatile intermediates in synthetic organic chemistry. Herein, we report an efficient Cu(I)/6-hydroxy picolinohydrazide-catalyzed hydroxylation reaction of (hetero)aryl halides (Br, Cl) in water. By establishing machine learning (ML) models, the design of ligands and optimization of reaction conditions were effectively accelerated. L32 (6-HPA-DMCA) demonstrated high efficiency for (hetero)aryl bromides, promoting hydroxylation reactions with a minimal catalyst loading of 0.01 mol% (100 ppm) at 80 °C to reach 10000 TON or under near-room temperature conditions for substrates containing sensitive functional groups (3.0 mol%); L42 (6-HPA-DTBCA) displayed superior reaction activity for chloride substrates, enabling hydroxylation reactions at 100 °C with 2-3 mol% catalyst loading. These represent the state of art for both lowest catalyst loading and temperature in the copper-catalyzed hydroxylation reactions. Furthermore, this method features a sustainable and environmentally friendly solvent system, accommodates a wide range of substrates, and shows potential for developing robust and scalable synthesis processes for key pharmaceutical intermediates.

De Novo Synthesis of α-Ketoamides via Pd/TBD Synergistic Catalysis.

Precisely controlling the product selectivity of a reaction is an important objective in organic synthesis. α-Ketoamides are vital intermediates in chemical transformations and privileged motifs in numerous drugs, natural products, and biologically active molecules. The selective synthesis of α-ketoamides from feedstock chemicals in a safe and operationally simple manner under mild conditions is a long-standing catalysis challenge. Herein, an unprecedented TBD-switched Pd-catalyzed double isocyanide insertion reaction for assembling ketoamides in aqueous DMSO from (hetero)aryl halides and pseudohalides under mild conditions is reported. The effectiveness and utility of this protocol are demonstrated by its diverse substrate scope (93 examples), the ability to late-stage modify pharmaceuticals, scalability to large-scale synthesis, and the synthesis of pharmaceutically active molecules. Mechanistic studies indicate that TBD is a key ligand that modulates the Pd-catalyzed double isocyanide insertion process, thereby selectively providing the desired α-ketoamides in a unique manner. In addition, the imidoylpalladium(II) complex and α-ketoimine amide are successfully isolated and determined by X-ray analysis, confirming that they are probable intermediates in the catalytic pathway.

Visible-Light-Mediated Three-Component Strategy for the Synthesis of Isoxazolines and Isoxazoles.

Isoxazolines and isoxazoles commonly serve as core structures of many therapeutic agents and natural products. However, the metal-free and catalysis-free strategy for the synthesis of these privileged motifs at room temperature remains a challenging task. Herein, we report a three-component strategy to afford diverse isoxazolines and isoxazoles via [3 + 2] cycloadditions of in situ-formed nitronates and olefins/alkynes under visible-light irradiation.

A continuous flow approach for the desulfurative bromination of sulfides

The preparation of alkyl bromides is a pivotal transformation in organic chemistry. The wide range of applications that bromides have as building blocks render this class of compounds a privileged motif widely used in the manufacture of active pharmaceutical ingredients. Traditionally prepared from the deoxygenation of alcohols, alkyl bromides have been recently obtained from sulfides in high yields, a transformation we have named desulfurative bromination. In order to improve the efficiency of this transformation, we report herein the investigation and optimisation of a continuous flow strategy. The influence of the flow rate; role of the brominating agent; and substrate scope have been studied delivering an in-flow protocol to access multigram quantities of these valuable intermediates.

A Disconnection for Rapid Access to Heterocyclic Benzylic Amines with Fully Substituted α-Carbons.

2- or 4-Pyridyl benzylic amines represent a privileged motif in drug discovery. However, the formation of heterocyclic benzylic amines with fully substituted α-carbons can require the execution of lengthy synthetic routes, which limit their application. Addition of various nucleophilic agents to Ellman's imines has been well established; however, there is no precedented literature reported for pyridyl-type nucleophiles, which are very important for medicinal chemistry. In this letter, we disclose the development of a one-step synthesis of heterocyclic benzylic amines with fully substituted α-carbons from heteroaryl halides and sulfinyl imines. Starting from 2,4-dibromopyridine, regioselective synthesis of 2- or 4-pyridyl benzylic amines could be achieved by choosing toluene or MTBE as a solvent.

Development of a selective and scalable N1-indazole alkylation.

N1-Alkyl indazoles are a ubiquitous and privileged motif within medicinal chemistry, yet methods to selectively furnish N1-alkyl indazoles with simple alkyl side chains remain sparse. Herein, negative data from high-throughput experimentation (HTE) enabled a confident pivot of resource from continued optimisation to the development of an alternative reaction. This workflow culminated in a methodology for the synthesis of N1-alkyl indazoles. The procedure is highly selective for N1-alkylation, practical, and broad in scope, with no N2-alkyl products detected at completion. Mechanistic understandings were consistent with attributing the high selectivity to thermodynamic control. Additional data-driven process development led to this reaction being safely demonstrated on a 100 g scale, with potential for further scale up. This study highlights pragmatic principles followed to develop a necessitated methodology, suitable for large scale manufacture.

Stereoselective Synthesis of Allylic Alcohols via Substrate Control on Asymmetric Lithiation.

Allylic alcohols are a privileged motif in natural product synthesis and new methods that access them in a stereoselective fashion are highly sought after. Toward this goal, we found that chiral acetonide-protected polyketide fragments performing the Hoppe-Matteson-Aggarwal rearrangement in the absence of sparteine with high yields and diastereoselectivities rendering this protocol a highly valuable alternative to the Nozaki-Hiyama-Takai-Kishi reaction. Various stereodyads and -triads were investigated to determine their substrate induction. The mostly strong inherent stereoinduction was attributed to a combination of steric and electronic effects.

Diastereoselective Construction of α‐Fluoroalkyl Cycloalkanols via Radical Alkylation of α‐Fluoroalkyl Ketones†

Comprehensive Summaryα‐Fluoroalkyl (Rf) alcohols are privileged motifs in drugs and pharmaceutically active compounds. As such, it is highly desirable to develop efficient methods for assembling these scaffolds. Herein, a visible‐light‐induced cascade radical cyclization of alkenyl fluoroalkyl ketones is developed, producing a variety of decorate α‐Rf cycloalkanols in promising yields with up to >20 : 1 dr selectivity. A radical chain mechanism involving an intramolecular radical addition to the α‐Rf carbonyl group and a subsequent intermolecular hydrogen atom transfer (HAT) has been proposed. Density functional theory (DFT) calculations indicate that a fluorine effect contributes to the radical addition to carbonyls by lowering the π* (C=O) orbital energy of CORf and energy barrier of the HAT between alkoxy radicals and THF, which may be valuable for controllable transformations of fluorinated molecules.

Intermolecular Enantioselective Benzylic C(sp3)−H Amination by Cationic Copper Catalysis**

AbstractChiral benzylic amines are privileged motifs in pharmacologically active molecules. Intramolecular enantioselective radical C(sp3)−H functionalization by hydrogen‐atom transfer has emerged as a straightforward, powerful tool for the synthesis of chiral amines, but methods for intermolecular enantioselective C(sp3)−H amination remain elusive. Herein, we report a cationic copper catalytic system for intermolecular enantioselective benzylic C(sp3)−H amination with peroxide as an oxidant. This mild, straightforward method can be used to transform an array of feedstock alkylarenes and amides into chiral amines with high enantioselectivities, and it has good functional group tolerance and broad substrate scope. More importantly, it can be used to synthesize bioactive molecules, including chiral drugs. Preliminary mechanistic studies indicate that the amination reaction involves benzylic radicals generated by hydrogen‐atom transfer.

Intermolecular Enantioselective Benzylic C(sp3)-H Amination by CationicCopper Catalysis.

Chiral benzylic amines are privileged motifs in pharmacologically active molecules. Intramolecular enantioselective radical C(sp3)-H functionalization by hydrogen-atom transfer has emerged as a straightforward, powerful tool for the synthesis of chiral amines, but methods for intermolecular enantioselective C(sp3)-H amination remain elusive. Herein, we report a cationic copper catalytic system for intermolecular enantioselective benzylic C(sp3)-H amination with peroxide as an oxidant. This mild, straightforward method can be used to transform an array of feedstock alkylarenes and amides into chiral amines with high enantioselectivities, and it has good functional group tolerance and broad substrate scope. More importantly, it can be used to synthesize bioactive molecules, including chiral drugs. Preliminary mechanistic studies indicate that the amination reaction involves benzylic radicals generated by hydrogen-atom transfer.

Ene Reductase Enabled Intramolecular β-C-H Functionalization of Substituted Cyclohexanones for Efficient Synthesis of Bridged Bicyclic Nitrogen Scaffolds.

Herein we report that ene reductases (EREDs) can facilitate an unprecedented intramolecular β-C-H functionalization reaction for the synthesis of bridged bicyclic nitrogen heterocycles containing the 6-azabicyclo[3.2.1]octane scaffold. To streamline the synthesis of these privileged motifs, we developed a gram-scale one-pot chemoenzymatic cascade by combining iridium photocatalysis with EREDs, using readily available N-phenylglycines and cyclohexenones that can be obtained from biomass. Further derivatization using enzymatic or chemical methods can convert 6-azabicyclo[3.2.1]octan-3-one into 6-azabicyclo[3.2.1]octan-3α-ols, which can be potentially utilized for the synthesis of azaprophen and its analogues for drug discovery. Mechanistic studies revealed the reaction requires oxygen, presumably to produce oxidized flavin, which can selectively dehydrogenate the 3-substituted cyclohexanone derivatives to form the α,β-unsaturated ketone, which subsequently undergoes spontaneous intramolecular aza-Michael addition under basic conditions.

Ene Reductase Enabled Intramolecular β‐C−H Functionalization of Substituted Cyclohexanones for Efficient Synthesis of Bridged Bicyclic Nitrogen Scaffolds

AbstractHerein we report that ene reductases (EREDs) can facilitate an unprecedented intramolecular β‐C−H functionalization reaction for the synthesis of bridged bicyclic nitrogen heterocycles containing the 6‐azabicyclo[3.2.1]octane scaffold. To streamline the synthesis of these privileged motifs, we developed a gram‐scale one‐pot chemoenzymatic cascade by combining iridium photocatalysis with EREDs, using readily available N‐phenylglycines and cyclohexenones that can be obtained from biomass. Further derivatization using enzymatic or chemical methods can convert 6‐azabicyclo[3.2.1]octan‐3‐one into 6‐azabicyclo[3.2.1]octan‐3α‐ols, which can be potentially utilized for the synthesis of azaprophen and its analogues for drug discovery. Mechanistic studies revealed the reaction requires oxygen, presumably to produce oxidized flavin, which can selectively dehydrogenate the 3‐substituted cyclohexanone derivatives to form the α,β‐unsaturated ketone, which subsequently undergoes spontaneous intramolecular aza‐Michael addition under basic conditions.

Precise Regulation of Emission Maxima and Construction of Highly Efficient Electroluminescent Materials with High Color Purity

AbstractAdvanced multiple resonance induced thermally activated delayed fluorescence (MR‐TADF) emitters have emerged as a privileged motif for applications in organic light‐emitting diodes (OLEDs), because they furnish highly tunable TADF characteristics and high color purity emission. Herein, based on the unique nitrogen‐atom embedding molecular engineering (NEME) strategy, a series of compounds BN‐TP‐Nx (x=1, 2, 3, 4) have been customized. The nitrogen‐atom anchored at different position of triphenylene hexagonal lattice entails varying degrees of perturbation to the electronic structure. The newly‐constructed emitters have demonstrated the precise regulation of emission maxima of MR‐TADF emitters to meet the actual industrial demand, and further enormously enriched the MR‐TADF molecular reservoir. The BN‐TP‐N3‐based OLED exhibits ultrapure green emission, with peak of 524 nm, full‐width at half‐maximum (FWHM) of 33 nm, Commission Internationale de L'Eclairage (CIE) coordinates of (0.23, 0.71), and maximum external quantum efficiency (EQE) of 37.3 %.

Precisely Slight Regulation of Emission Maxima and Construction of Highly Efficient Electroluminescent Materials with High Color Purity.

Advanced multiple resonance induced thermally activated delayed fluorescence (MR-TADF) emitters have emerged as a privileged motif for applications in organic light-emitting diodes (OLEDs), because they furnish highly tunable bandgap with emission ranges spanning the visible light region, and have the intrinsic properties of outstanding TADF characteristics and high color purity emission. One of the typical construction paradigms of MR-TADF molecule is based on polycyclization of MR parent core and a representative target model molecule BN-TP has been prepared. Herein, based on the unique nitrogen-atom embedding molecular engineering (NEME) strategy, a series of congeners of BN-TP, namely BN-TP-Nx (x = 1, 2, 3, 4), have been customized. The nitrogen-atom anchored at different position of triphenylene hexagonal lattice entails varying degrees of perturbation to the electronic structure. The newly-constructed emitters have demonstrated the precisely slight regulation of emission maxima of MR-TADF emitters to meet the actual industrial demand, and further enormously enriched the MR-TADF molecular reservoir. The BN-TP-N3-based OLED exhibits ultrapure green emission, with peak of 524 nm, full-width at half-maximum (FWHM) of 33 nm, Commission Internationale de L'Eclairage (CIE) coordinates of (0.23, 0.71), and maximum external quantum efficiency (EQE) of 37.3%.

The Multi‐Pharmacological Targeted Role of Indole and its Derivatives: A review

AbstractHeterocycles are a privileged motif that appears as a momentous objective in medicinal chemistry. An important class of compounds for drug discovery and design is indole and its derivatives, which have been examined for a variety of biological activities. Therefore, it is noteworthy in the modern progress of synthetic, medicinal chemistry; the last decade has been onlooker with a multitude of reports on several indole derivatives corroborating these chemical entities to be a renowned target for the discovery of new drugs. The current study includes brief natural sources of indole, and a new range of commercially available indole‐based drugs. Additionally, this review discusses the numerous facets of the structure‐activity relationship study (SARs) and provides information about the varied pharmacological effects of indole derivatives. The literature data presented for the anti‐pharmacological agents herein covers largely from the year 2015 to mid of 2022.

A comparison of non-covalent interactions in the crystal structures of two σ-alkane complexes of Rh exhibiting contrasting stabilities in the solid state.

Non-covalent interactions surrounding the cationic Rh σ-alkane complexes within the crystal structures of [(Cy2PCH2CH2PCy2)Rh(NBA)][BArF4], [1-NBA][BArF4] (NBA = norbornane, C7H12; ArF = 3,5-(CF3)2C6H3), and [1-propane][BArF4] are analysed using Quantum Theory of Atoms in Molecules (QTAIM) and Independent Gradient Model approaches, the latter under a Hirshfeld partitioning scheme (IGMH). In both structures the cations reside in an octahedral array of [BArF4]- anions within which the [1-NBA]+ cation system exhibits a greater number of C-H⋯F contacts to the anions. QTAIM and IGMH analyses indicate these include the strongest individual atom-atom non-covalent interactions between the cation and the anion in these systems. The IGMH approach highlights the directionality of these C-H⋯F contacts that contrasts with the more diffuse C-H⋯π interactions. The accumulative effects of the latter lead to a more significant stabilizing contribution. IGMH %δGatom plots provide a particularly useful visual tool to identify key interactions and highlight the importance of a -{C3H6}- propylene moiety that is present within both the propane and NBA ligands (the latter as a truncated -{C3H4}- unit) and the cyclohexyl rings of the phosphine substituents. The potential for this to act as a privileged motif that confers stability on the crystal structures of σ-alkane complexes in the solid-state is discussed. The greater number of C-H⋯F inter-ion interactions in the [1-NBA][BArF4] system, coupled with more significant C-H⋯π interactions are all consistent with greater non-covalent stabilisation around the [1-NBA]+ cation. This is also supported by larger computed δGatom indices as a measure of cation-anion non-covalent interaction energy.

A highly diastereoselective strain-release Doyle-Kirmse reaction: access to functionalized difluoro(methylene)cyclopropanes.

Difluoro(methylene)cyclopropanes (F2MCPs) show better anti-cancer properties and chemical reactivities compared to their nonfluorinated analogues. However, catalytic stereoselective methods to access these privileged motifs still remain a challenging goal. The Doyle-Kirmse reaction is a powerful strategy for the concomitant formation of carbon-carbon and carbon-sulfur bonds. Although the enantioselective variants of this reaction have been achieved with high levels of selectivity, the methods that control the diastereoselectivity have been only moderately successful. Herein, we report a catalytic, highly diastereoselective strain-release Doyle-Kirmse reaction for synthesizing functionalized F2MCPs using an inexpensive copper catalyst. The transformation proceeds under mild conditions and displays excellent functional group compatibility on both diazo compounds and difluorocyclopropenyl methyl sulfane/selane derivatives. Furthermore, the obtained products were efficiently transformed into valuable building blocks, such as functionalized spiroheterocycles, difluorocyclopropanes, and skipped dienes.