Stereo flexible synthesis of the C8-C23 fragment of antarlides, androgen receptor antagonists.

A practical and efficient synthesis of the C8-C23 fragment of antarlides A-H, incorporating six stereocenters and a conjugated diene, is reported. A strategic combination of synthetic methods, including CBS reduction, Evans' aldol reaction, Keck-Maruoka allylation, and enzymatic resolution, enabled the selective introduction of these stereocenters. Furthermore, the pivotal coupling of key fragments is successfully executed through a Julia-Kocienski olefination reaction, connecting the C8-C14 and C15-C23 subunits.

An unconventional iron oxide catalyst for 5-hydroxymethylfurfural oxidation to 2,5-diformylfuran.

Commonly used magnetic iron oxide (γ-Fe2O3) was examined for the first time as an unconventional catalyst for 5-hydroxymethylfurfural (5-HMF) oxidation to 2,5-diformylfuran (DFF). Fascinatingly, the magnetic support showed remarkable catalytic activity for this conversion, especially in nanoscale size (≤50 nm). The developed mild reagent system consisting of γ-Fe2O3 and molecular O2 in xylene solvent delivered DFF with 94% selectivity and 82% conversion at 135 °C for 12 h. A deep inspection of the mechanistic study through IR and XPS analysis revealed a phase transition (γ-Fe2O3 to Fe3O4) during the reaction, and then its reversal to the parent form after catalyst activation. The loss in crystallinity and increase in the particle size of the catalyst after the reaction were explicitly analysed by XRD and TEM studies, respectively. The excellent activity of the catalyst was even noticed by a recyclability test for six cycles. The method avoided the requirement of high-pressure equipment, costly noble and transition metals, and harsh basic environments.

Identification of acridinedione scaffolds as potential inhibitor of DENV-2 C protein: An in silico strategy to combat dengue.

Dengue is a prominent viral disease transmitted by mosquitoes to humans that affects mainly tropical and subtropical countries worldwide. The global spread of dengue virus (DENV) is mainly occurred by Aedes aegypti and Aedes albopictus mosquitoes. The dengue virus serotypes-2 (DENV-2) is a widely prevalent serotype of DENV, that causes the hemorrhagic fever and bleeding in the mucosa, which can be fatal. In the life cycle of DENV-2, a structural capsid (DENV-2 C) protein forms the nucleocapsid assembly and bind to the viral progeny RNA. For DENV-2 maturation, the nucleocapsid is a vital component. We used virtual ligand screening to filter out the best in-house synthesized acridinedione analogs (DSPD molecules) that could efficiently bind to DENV-2 C protein. The molecular docking and dynamics simulations studies were performed to analyze the effect of DSPD molecules on DENV-2 C protein after binding. Our findings showed that DSPD molecules strongly interacted with DENV-2 C protein, as evident from molecular interactions and several time-dependent molecular dynamics-driven analyses. Moreover, this study was also supported by the thermodynamic binding free energy and steered molecular dynamics simulations. Therefore, we intend to suggest that the DSPD3 molecule could be used as a potential therapeutic molecule against dengue complications as compared to the cocrystallized inhibitor ST-148. However, further studies are required to demonstrate the ability of DSPD3 to induce DENV-2 C tetramer formation.

Supported Palladium Catalyzed Carbonylative Coupling Reactions using Carbon Monoxide as C1 Source.

The carbonylative reactions of aryl halides, boronic acids, amines, activated alkene and alkynes under CO and supported palladium catalyzed conditions are very popular reactions for the synthesis of bioactive molecules, pharmaceuticals, polymers, peptides, intermediates and fine chemicals synthesis. Due to cost effectiveness and easy handling of recyclable supported palladium catalyst, it became more popular among researchers either working in academic institute or industry. In recent years, irrespective of poisoning effect of CO with palladium as major limitation, several advancements have been done through surface selection, designing and condition improvement to achieve high yield in the area of carbonylative coupling reactions. We hope this review will be helpful as a ready reference of last 20 years in the field of CO insertion reactions using diverse range of supported palladium catalysts under carbon monoxide or its sources as C1 source.

Free Amine, Hydroxyl and Sulfhydryl Directed C-H Functionalization and Annulation: Application to Heterocycle Synthesis.

Transition metal-catalyzed direct C-H bond functionalization is recognized as an efficient strategy to assemble heterocyclic frameworks. For this purpose, directing groups (DGs) installation on an organic molecule has remained a widely exploited strategy for the years. The installation of directing groups, especially for the amine, alcohol and thiol containing reactants and their removal after the reaction need additional steps. In this regard, the use of free amine, hydroxyl and sulfhydryl as directing groups in native form is advantageous and in recent times, these transformations have stirred undisputable advancements for applications to heterocycle synthesis. In this review, the aromatic sp2 -C attached free amine, hydroxyl and sulfhydryl as native functionalities are shown to be useful for the construction of five to seven-membered N-, O- and S-heterocycles.

Discovery and in silico evaluation of aminoarylbenzosuberene molecules as novel checkpoint kinase 1 inhibitor determinants.

Checkpoint kinase 1 (CHK1) is an essential kinase with a critical function in cell cycle arrest. Several potent inhibitors targeting CHK1 have been published, but most of them have failed in clinical trials. Acknowledging the emerging consequence of CHK1 inhibitors in medication of cancer, there is a demand for widening the chemical range of CHK1 inhibitors. In this research, we considered a set of in-house plant based semi-synthetic aminoarylbenzosuberene molecules as potential CHK1 inhibitors. Based on a combined computational research that consolidates molecular docking and binding free energy computations we recognized the crucial determinants for their receptor binding. The drug likeness of these molecules were also scrutinized based on their toxicity and bioavailibilty profile. The computational strategy indicates that the Bch10 could be regarded as a potential CHK1 inhibitor in comparison with top five co-crystallize molecules. Bch10 signifies a promising outlet for the development of potent inhibitors for CHK1.

Mechanochemical Approach towards Multi-Functionalized 1,2,3-Triazoles and Anti-Seizure Drug Rufinamide Analogs Using Copper Beads.

Highly regiospecific, copper-salt-free and neat conditions have been demonstrated for the 1,3-dipolar azide-alkyne cycloaddition (AAC) reactions under mechanochemical conditions. A group of structurally challenging alkynes and heterocyclic derivatives was efficiently implemented to achieve highly functionalized 1,4-disubstituted-1,2,3-triazoles in good to excellent yield by using the Cu beads without generation of unwanted byproducts. Furthermore, the high-speed ball milling (HSBM) strategy has also been extended to the synthesis of the commercially available pharmaceutical agent, Rufinamide, an antiepileptic drug (AED) and its analogues. The same strategy was also applied for the synthesis of the Cl-derivative of Rufinamide. Analysis of the single crystal XRD data of the triazole was also performed for the final structural confirmation. The Cu beads are easily recoverable from the reaction mixture and used for the further reactions without any special treatment.

Pd-Catalysed Decarbonylation Free Approach to Carbonylative Esterification of 5-HMF to Its Aryl Esters Synthesis Using Aryl Halides and Oxalic Acid as C1 Source.

A decarbonylation free, polystyrene-supported, Pd (Pd@PS)-catalysed carbonylative esterification of the hydroxy group of 5-hydroxymethyl furfural (5-HMF) to its corresponding aryl esters has been developed. The use of Pd@PS, oxalic acid as CO source, and aryl halides was first explored for the aryl ester of 5-HMF synthesis. Here, we investigated the vital role of a polystyrene support to avoid the commonly known decarbonylation of 5-HMF. The reaction exhibits vast substrate scope with comparably good yield and catalyst recyclability.

Application of cyclohexane-1,3-diones for six-membered oxygen-containing heterocycles synthesis.

Cyclohexan-1,3-dione derivatives are versatile scaffolds for the synthesis of a variety of value-added organic molecules including heterocycles and natural products. Six-membered oxygen heterocycles prepared from cyclohexan-1,3-diones are of much importance as they are intermediate for the synthesis of a number of natural products and several other valuable bioactive molecules which shows anti-viral, anti-bacterial, analgesic, antimalarial, anti-inflammatory, anti-allergic, anti-tumor and anti-cancer activities. These advantages have inspired us to write a detailed survey on the newly developed methods which are very essential in the construction of six-membered oxygen heterocycles. Further, the versatility in the chemistry of cyclohexan-1,3-dione and its derivatives is due to the presence of highly active methylene moiety and its active di-carbonyl groups. Recently, reactions of cyclohexane-1,3-dione and its derivatives with other substrates for instance aldehydes, malononitriles, NMSM, chalcones, isatin etc. have been established for the construction of a variety of six-membered oxygen heterocycles. The studies reported in this review article involved the synthesis of six-membered oxygen-containing heterocycles which includes 4H-chromen-5(6H)-one, 2H-xanthen-1(9H)-one, 2H-xanthen-1,8(5H,9H)-dione, 6H-chromen-2,5-dione derivatives and natural products having six-membered oxygen heterocycles from cyclohexane-1,3-dione and its derivatives as one of the substrate.

Benzosuberene-sulfone analogues synthesis from Cedrus deodara oil and their therapeutic evaluation by computational analysis to treat type 2 diabetes.

Benzosuberene-sulfone (BSS) analogues have been semi-synthesized following green approaches from himachalenes, which has been extracted from essential oil of Cedrus deodara. In this process, benzosuberene in presence of different aryl or alkyl sodium sulfinates, I2 and potassium persulfate (K2S2O8) in acetonitrile-water solvent conditions gave BSS-analogues at room temperature. Under this reaction, a facile endocyclic ß-H elimination has been noticed for BSS-analogues synthesis instead of vinyl sulfones and the reason may be due to its specific structure and electronic environment. The BSS-compounds were obtained with moderate to excellent yields under mild conditions. All the compounds were computationally subjected to drug likeliness and toxicity prediction studies. Further, the synthesized molecules were evaluated under in-silico studies for their binding affinity towards the native Peroxisome Proliferator-Activated Receptor Gamma (PPARG), and two PPARG mutants (R357A and V290M). Both the mutant forms of PPARG are deficient in eliciting a response to treatment with full and partial agonists. Our computational studies suggested that the molecule 3q performed better than the standard drug (Rosiglitazone) in all three protein structures. This implies that our suggested molecule could act as a more potent antagonist to native PPARG and could also be developed to treat type-2 diabetes patients with R357A and V290M mutations, which didn't elicit any response to currently available drugs in the market.

Plant-based analogues identified as potential inhibitor against tobacco mosaic virus: A biosimulation approach.

Benzosuberene compounds with a pyrrolone group adhered to it are compounds extracted from the oils of Cedrus deodara plant, that bear inhibitory capabilities. Tobacco mosaic virus is known to affect crop production every year. The currently known inhibitors against TMV have a weak inhibition effect and also tend to be toxic towards non-target living organisms as well as the environment. Thus, the requirement of non-toxic potent inhibitors is the need of the hour, which led us to test our benzosuberene molecules on the binding site of TMV and check their affinity as well as stability. The non-toxic nature of these molecules has already been experimentally established. Through in-silico analysis involving docking and simulation experiments, we compared the interaction pattern of these ligand molecules with the already present inhibitors. Our investigation proved that the reported ligands (ligands 3, 7, 9, and 17 obtained -177.103, -228.632, -184.134, and - 188.075 kJ/mol binding energies, respectively) interacted with the binding site of TMV much efficiently than the known inhibitors (Ribavirin and Zhao et al. 2020 obtained 121.561 and - 221.393 kJ/mol binding energies, respectively). Moreover, they acquired a stable conformation inside the binding pocket, where a higher number of binding site residues contributed towards interaction. Thus, their structural framework can be optimized for the exploration of their antiviral properties to develop potent botanical viricides against plant virus infection.

Supported palladium catalyzed aminocarbonylation of aryl iodides employing bench-stable CO and NH3 surrogates.

A simple, efficient and phosphine free protocol for carbonylative synthesis of primary aromatic amides under polystyrene supported palladium (Pd@PS) nanoparticle (NP) catalyzed conditions has been demonstrated. Herein, instead of using two toxic and difficult to handle gases simultaneously, we have employed the solid, economical, bench stable oxalic acid as the CO source and ammonium carbamate as the NH3 source in a single pot reaction. For the first time, we have applied two non-gaseous surrogates simultaneously under heterogeneous catalyst (Pd@PS) conditions for the synthesis of primary amides using an easy to handle double-vial (DV) system. The developed strategy showed a good functional group tolerance towards a wide range of aryl iodides and afforded primary aromatic amides in good yields. The Pd@PS catalyst was easy to separate and can be recycled up to four consecutive runs with small loss in catalytic activity. We have successfully extended the scope of the methodology to the synthesis of isoindole-1,3-diones from 1,2-dihalobenzene, 2-halobenzoates and 2-halobenzoic acid following double and single carbonylative cyclization approaches.

Iodine(iii) promoted ring-rearrangement reaction of 1-arylamino-2-oxocyclopentane-1-carbonitriles to synthesize N-aryl-δ-valerolactams.

The first example of N-aryl-δ-valerolactam synthesis via an intramolecular ring rearrangement reaction of 1-arylamino-2-oxocyclopentane-1-carbonitrile promoted by phenyliodine bis(trifluoroacetate) (PIFA) was reported. We show that this unprecedented regio-selective ring-rearrangement reaction driven by hypervalent iodine (PIFA) involves C5-H elimination, C1-C2 bond opening, and C1-N bond rearrangement steps and restraining the leaving tendency of the CN group. The structure of the lactam was further confirmed by single crystal X-ray diffraction (XRD) analysis. The present protocol showed a diverse array of functional group tolerance under the reaction conditions and offered good to excellent yields of lactams.

Polystyrene-Supported Palladium (Pd@PS)-Catalyzed Carbonylative Annulation of Aryl Iodides Using Oxalic Acid as a Sustainable CO Source for the Synthesis of 2-Aryl Quinazolinones.

An efficient and convenient strategy for the synthesis of diversely substituted quinazolinones from o-carbamoyl/cyano aniline and aryl iodides using oxalic acid as a CO source under polystyrene supported palladium (Pd@PS) nanoparticles (NPs) catalyzed conditions has been developed. In this study, oxalic acid has been employed as safe, economic, environmentally benign, sustainable and bench-stable, solid CO surrogate under Double-Layer-Vial (DLV) system for the synthesis of 2-aryl quinazolinones. This methodology does not require any special high-pressure equipment like autoclaves, microwaves, etc. Moreover, a simple procedure for catalyst preparation, catalyst recyclability, easy handling of reaction, additive and base-free generation of CO, excellent to good yields and vast substrate scope are the additional features of developed protocol.

Supported Palladium Nanoparticles that Catalyze Aminocarbonylation of Aryl Halides with Amines using Oxalic Acid as a Sustainable CO Source.

Polystyrene-supported palladium (Pd@PS) nanoparticles (NPs) have been used to catalyze the aminocarbonylation of aryl halides with amines using oxalic acid as a CO source for the first-time for the synthesis of amides. Furthermore, o-iodoacetophenones participated in amidation and cyclization reactions to give isoindolinones in a single step following a concerted approach. Oxalic acid has been used as a safe, environmentally benign and operationally simple ex situ sustainable CO source under double-layer-vial (DLV) system for different aminocarbonylation reactions. Catalyst stability under a CO environment is a challenging task, however, Pd@PS was found to be recyclable and applicable for a vast substrate scope avoiding regeneration steps. Easy handling of oxalic acid, additive and base-free CO generation, catalyst stability and effortless catalyst separation from the reaction mixture by filtration and introduce of DLV are the added advantages to make the overall process a sustainable approach.

Hypervalent Iodine(III)-Mediated Counteranion Controlled Intramolecular Annulation of Exocyclic ß-Enaminone to Carbazolone and Imidazo[1,2-a]pyridine Synthesis.

A highly efficient and flexible protocol for intramolecular annulation of exocyclic ß-enaminones has been disclosed for the synthesis of carbazolones and imidazo[1,2-a]pyridines through a counter-anion-controlled free-radical mechanism promoted by hypervalent iodine(III). The cooperative behavior of HTIB and AgSbF6 plays a crucial role in the intramolecular annulation process through C-C and C-N bond formation to give the desired products. The mechanistic insights suggest that the two competitive reactions involved in the system are guided by the nature of the counteranion, which determines the formation of the final products. A wide variety of carbazolones and imidazo[1,2-a]pyridine molecules have been prepared and isolated in good to excellent yields.

Synthesis of α,ß-alkynyl ketones via the nickel catalysed carbonylative Sonogashira reaction using oxalic acid as a sustainable C1 source.

An efficient and economic nickel-dppb catalyzed, carbonylative Sonogashira cross-coupling reaction was demonstrated to provide rapid access to various α,ß-alkynyl ketones from aryl iodides and terminal alkynes using oxalic acid as the ex situ C1 source in a double vial (DV) system. Notably, the role of the ligand in combination with the Ni catalyst for the selective formation of carbonylative Sonogashira products was investigated and supported with control experiments. Yet, no reports are available for carbonylative Sonogashira coupling by using a CO-surrogate under Ni-catalyzed conditions. In this process, for the first time, oxalic acid is used as an ex situ solid, bench stable, easy to handle and efficient CO surrogate in a DV-system for the carbonylative Sonogashira coupling reaction with vast substrate scope.

Oxalic/malonic acids as carbon building blocks for benzazole, quinazoline and quinazolinone synthesis.

An oxidant, base and metal free methodology has been developed for the synthesis of various 2-substituted and non-substituted benzazoles, quinazolines and quinazolinones using oxalic/malonic acids as an in situ carbon source. This methodology is applicable for a wide range of substituted o-phenylenediamine, o-aminothiophenol, o-aminophenol and o-aminobenzamide containing various functional groups and provides good to excellent yields of the corresponding product. Furthermore an easy workup procedure, high yield and easy isolation of products are key features of this methodology. The developed protocol is also applicable for the gram scale synthesis of benzimidazoles.

Ethyl 3-(2,4-dioxocyclohexyl)propanoate as a novel precursor for N-substituted 4,4a,5,6-tetrahydroquinoline-2,7(1H,3H)-diones and their corresponding 3,4-dihydro-7-hydroxyquinolin-2(1H)-ones and 7-hydroxyquinolin-2(1H)-ones synthesis.

Ethyl 3-(2,4-dioxocyclohexyl)propanoate has been explored as a precursor for the synthesis of N-substituted 4,4a,5,6-tetrahydroquinoline-2,7(1H,3H)-diones following conventional protecvtion, selective amidation, and deprotective-cyclization approaches. Moreover, a facile process for the selective dehydrogenative aromatization of these diones was developed to afford the corresponding N-substituted 3,4-dihydro-7-hydroxyquinolin-2(1H)-ones and N-substituted 7-hydroxyquinolin-2(1H)-ones under mild conditions.

Oxalic acid as a dual C1 surrogate for heterogeneous palladium-catalyzed tandem four-component quinazolinone synthesis.

Herein, a heterogeneous Pd/C-catalyzed direct one-step four-component double carbonylative approach for cascade synthesis of 2-aryl quinazolinones has been reported for the first time starting from 2-iodoaniline derivatives and aryl iodides. The given reaction involves the simultaneous implementation of two different gaseous surrogates i.e., ammonium carbamate as an NH3 precursor and oxalic acid as a bi-functional reagent acting as a CO as well as a C-atom surrogate under ligand-free conditions.