Direct Organocatalytic Chemoselective Synthesis of Pharmaceutically Active 1,2,3-Triazoles and 4,5'-Bitriazoles.

Carbonyl-containing 1,4,5-trisubstituted- and 1,4-disubstituted-1,2,3-triazoles are well-known for their wide range of applications in pharmaceutical and medicinal chemistry, but their high-yielding metal-free synthesis has always remained challenging, as no comprehensive protocol has been outlined to date. Owing to their structural and medicinal importance, herein, we synthesized various carbonyl-containing 1,4,5-trisubstituted- and 1,4-disubstituted-1,2,3-triazoles and unsymmetrical 4,5'-bitriazoles with high yields and chemo-/regioselectivity from the library of 2,4-diketoesters and azides in a sequential one-pot manner through the combination of organocatalytic enolization, in situ [3 + 2]-cycloaddition, and hydrolysis reactions. The commercial availability of the starting materials/catalysts, diverse substrate scope, performance in a one-pot manner, chemo-/regioselectivity of organo-click reaction, quick synthesis of unsymmetrical 4,5'-bitriazoles, a large number of synthetic applications, and numerous medicinal applications of carbonyl-containing 1,2,3-triazoles are the key attractions of this metal-free organo-click work.

Two-step, high-yielding total synthesis of antibiotic pyrones.

A simple two-step dialkylation protocol was developed to synthesize biologically active antibiotics photopyrones, pseudopyronines, and violapyrones from bio-renewable triacetate lactone in excellent yields. These pyrones are functionally modified into another set of pyrone natural products by a single -methylation reaction. The high-yielding gram scale synthesis of four natural products [pseudopyronine A, photopyrone A, pseudopyronine B and photopyrone C] demonstrated the viability for industrial applications.

Organocatalytic Reductive Amination of the Chiral Formylcyclopropanes: Scope and Applications.

We developed a sustainable three-component reductive amination protocol for the chemoselective coupling of optically active functionally rich donor-acceptor carbonyl-cyclopropanes with various amines under 10 mol % of diphenyl phosphate in the presence of Hantzsch ester as a hydride source. The catalytic selective reductive C-N coupling has wide advantages like no epimerization, no ring opening, large substrate scope, generating only mono -alkylation products and simultaneously resulting in chiral cyclopropane-containing amines possessing many applications in the medicinal chemistry. In this article, we have shown the synthetic applications of reductive C-N coupling reaction to make chiral α-carbonyl-cyclopropane containing amines , double C-N coupled cyclopropane-amines , unusual C-N/C-C coupled cyclopropane-amines , chiral -butylsulfinamide containing cyclopropanes , and functionally rich chiral cyclopropane-fused -heterocycles .

Direct organocatalytic transfer hydrogenation and C-H oxidation: high-yielding synthesis of 3-hydroxy-3-alkyloxindoles.

Readily available 3-alkylideneoxindoles were effectively reduced to 3-alkyloxindoles through transfer hydrogenation using Hantzsch ester as a reducing agent at ambient temperature and the greenness/sustainability of this protocol was assessed by correlation with Pd/C-mediated hydrogenation with hydrogen gas. Furthermore, an organocatalytic method was developed to access drug-like 3-alkyl-3-hydroxyoxindoles by C-H oxidation of 3-alkyl-indolin-2-one, using a catalytic amount of 1,1,3,3-tetramethylguanidine (TMG) as an organic base and dissolved oxygen in THF as an oxidant at room temperature. Key reaction intermediates were observed by controlled on-line ESI-HRMS experiments and identified by their corresponding mass (/) analysis.

Direct Organocatalytic Chemoselective Reductive Alkylation of Chiral 2-Aroylcyclopropanecarbaldehydes: Scope and Applications.

We developed a simple and practically feasible protocol for the chemoselective coupling of optically active functionally rich 2-aroylcyclopropanecarbaldehydes with various CH acids or active methylene compounds under 10 mol % of ()-proline in the presence of Hantzsch ester as a hydrogen source through a three-component reductive alkylation reaction. The metal-free, organocatalytic selective reductive C-C coupling method has wide advantages/applications like no epimerization, no ring opening, high carbonyl control, and large substrate scope, generating only monoalkylated 2-aroylcyclopropanes, and the resulting chiral products can be synthons in medicinal to material chemistry. We have also shown the synthetic applications of chiral CH-acid-containing 2-aroylcyclopropanes by transforming them into the interesting molecules of pyrimidine analogues , dimethyl cyclopropane-malonates , functionally rich dihydropyran , cyclopropane-alcohols , and cyclopropane-olefins .

Direct Organocatalytic Reductive Alkylation of Syncarpic Acid: Scope and Applications.

Biologically important 4-alkylsyncarpic acids, which resemble the core structure of many natural products, were synthesized in one-pot through the organocatalytic three-component reductive alkylation with excellent yields and -selectivity. Synthetic applications of 4-alkylsyncarpic acids were demonstrated by converting into the functionally rich molecules through different reactions like Michael, -Michael, reduction, and oxidation reactions. In a continuation, formal total synthesis of (±)-triumphalone, (±)-isotriumphalone, and monomeric phloroglucinol derivatives was reported in a few steps starting from 4-alkylsyncarpic acids in overall very good yields.

The seven-step, one-pot regioselective synthesis of biologically important 3-aryllawsones: scope and applications.

3-Aryllawsones are well known for their wide range of applications in medicinal chemistry, but their synthesis has always remained challenging as no comprehensive protocol has been outlined to date. Owing to their structural importance, we synthesized various 3-aryllawsones with high regioselectivity from simple lawsone and aldehydes in a seven-step double-cascade one-pot reaction through the combination of organocatalytic Ramachary reductive coupling and Hooker oxidation reactions. The commercial availability of the starting materials, diverse substrate scope, possibility of a one- or two-pot approach, regioselectivity of alkyl transfer (with mechanistic proof provided X-ray crystal structure analysis), and numerous medicinal applications of 3-aryllawsones are the key attractions of this work.

Parts-per-Million-Level, Catalytic [3+2]-Annulations for the Asymmetric Synthesis of Methanobenzo[7]annulenes.

3-Alkyl-lawsones selectively reacted with α-alkyl-nitroethylenes under 500 parts-per-million (ppm) quinine-NH-thiourea-catalysis to furnish the chiral methanobenzo[7]annulenes in up to >99 % ee with >20 : 1 dr and TON up to 1820 through tandem Michael/Henry [3+2]-annulations. These asymmetric ppm-level, catalytic tandem [3+2]-annulations would be highly inspirational for the design of many more ppm-level organocatalytic reactions, and at the same time these final molecules are basic skeletons of antibiotics.

Organocatalytic Enantiospecific Total Synthesis of Butenolides.

Biologically important, chiral natural products of butenolides, (-)-blastmycinolactol, (+)-blastmycinone, (-)-NFX-2, (+)-antimycinone, lipid metabolites, (+)-ancepsenolide, (+)-homoancepsenolide, mosquito larvicidal butenolide and their analogues were synthesized in very good yields in a sequential one-pot manner by using an organocatalytic reductive coupling and palladium-mediated reductive deoxygenation or organocatalytic reductive coupling and silica-mediated reductive deamination as the key steps.

Catalytic Asymmetric Synthesis of Benzobicyclo[3.2.1]octanes.

Lawsone aldehydes were directly transformed into the biologically important, unique carbon skeleton of chiral methanobenzo[f]azulenes/methanodibenzo[a,d][7]annulenes in high dr and ee and in very good yields by using quinine-thiourea-catalyzed tandem Wittig/intramolecular Michael/intramolecular aldol reactions. This asymmetric catalytic tandem protocol will be highly useful because these final molecules are basic skeletons of important antibiotics.

Catalytic Ynone-Amidine Formal [4 + 2]-Cycloaddition for the Regioselective Synthesis of Tricyclic Azepines.

A Ca(OTf)- and self-promoted ynone-amidine atom-economic formal [4 + 2]-cycloaddition of various ynones with amidines is reported for the construction of highly functionalized tricyclic azepines. High reaction rate, ease of operation, and high product selectivity with wide substrate scope are the key advantages of the present annulation protocol.

Organocatalytic Selective [3 + 2] Cycloadditions: Synthesis of Functionalized 5-Arylthiomethyl-1,2,3-triazoles and 4-Arylthio-1,2,3-triazoles.

An organocatalytic azide-ketone [3 + 2] cycloaddition (OrgAKC) of a variety of 1-aryl-3-(arylthio)propan-2-ones and 1-alkyl-3-(arylthio)propan-2-ones with different aryl/vinyl/alkyl azides is reported under ambient conditions to furnish the medicinally important 1,4-disubstituted-5-arylthiomethyl-1,2,3-triazoles and 1,5-disubstituted-4-arylthio-1,2,3-triazoles, respectively, in a regioselective manner with high yields/rates. With controlled and online NMR experiments, we proved that the reaction path is following the organocatalytic enolization through selective deprotonation followed by a [1,3]-H shift. Surprisingly, the [3 + 2] cycloaddition of aryl/vinyl/alkyl azides with the -generated equilibrated thermodynamic ↔ kinetic enolates furnished the highly regioselective functionally rich 1,2,3-triazoles by discriminating their reactivities.

[3+2]-Cycloaddition for Fully Decorated Vinyl-1,2,3-Triazoles: Design, Synthesis and Applications.

The small heterocyclic ring of the 1,2,3-triazole module is one of the most widely investigated compounds in numerous applications of biological, medicinal, pharmaceutical and materially important molecules. In this regard, a large number of synthetic methodologies and approaches have already been reported to construct such a heterocyclic core structure in a selective manner. However, the vinyl-substituted 1,2,3-triazole moiety is another privileged segment in heterocyclic chemistry.

Organocatalytic enone-azide [3 + 2]-cycloaddition: synthesis of functionally rich C/N-double vinyl 1,2,3-triazoles.

An enolate-mediated organocatalytic [3 + 2]-cycloaddition of enones with less reactive vinyl/alkyl/aryl azides is reported at room temperature for short reaction times. The metal-free amine-mediated catalytic conditions of this [3 + 2]-cycloaddition allowed us to synthesize a collection of C/N-double vinyl-1,2,3-triazoles and C-vinyl-1,2,3-triazoles through functionalized enones as quality azidophiles with various azides. It is an efficient catalytic [3 + 2]-cycloaddition for the synthesis of biologically important fully decorated C/N-double vinyl-1,2,3-triazoles with excellent outcomes with reference to the reaction rate, selectivity, operation simplicity, substrate scope, yields, and synthetic applications as demonstrated in the paper.

One-Pot Knoevenagel and [4 + 2] Cycloaddition as a Platform for Calliviminones.

Bioactive compounds featuring an unusual core of spiro[5.5]undecenes and calliviminones were synthesized in very good yield with good regio- and diastereoselectivities through a one-pot Knoevenagel and [4 + 2] cycloaddition from the readily available aldehydes, cyclic-1,3-diones, dienes, and a catalytic amount of ()-proline.

Organocatalytic Reductive Propargylation: Scope and Applications.

An amino acid-catalyzed three-component reductive coupling protocol has been developed for the selective high-yielding synthesis of nearly fifty examples of propargylated cyclic/acyclic systems from the various propargyl aldehydes, cyclic/acyclic CH acids, and Hantzsch ester under ambient conditions. It is an economical, efficient, catalytic, metal-free protocol for the quick gram-scale synthesis of propargylated cyclic/acyclic compounds, and many of these coupling compounds were purified by a simple precipitation-filtration technique instead of column chromatography. Functionally rich propargylated cyclic-1,3-diketones were specifically transformed into dihydropyrans found in natural products and drugs through an annulative etherification reaction by using Lewis-acid (AgOTf) catalysis.

Organocatalytic Formal Intramolecular [3+2]-Cycloaddition to Acquire Biologically Important Methanodibenzo[a,f]azulenes and Methanobenzo[f]azulenes.

Lawsones were transformed into the functionally rich framework of methanodibenzo[a,f]azulenes and methanobenzo[f]azulenes in a single- or two-pot operation through five organocatalytic sequential reactions in very good yields with excellent selectivities. These resultant molecules are basic skeletons of important antibiotics, which highlights the value of this formal intramolecular [3+2]-cycloaddition as a key protocol.

Stereoselective Insertion of Benzynes into Lawsones: Synthesis of Biologically Important Benzannulated Bicyclo[3.3.0]octanes.

An ideal stereoselective insertion of in situ generated benzynes into lawsones through domino formal [2+2]-cycloaddition followed by rearrangement is disclosed. The reaction allowed for the preparation of biologically important benzannulated bicyclo[3.3.

Catalytic [3 + 3]-Cycloaddition for Regioselective Preparation of Tricyclic Oxadiazines.

Agrochemically useful and structurally important, functionally rich tricyclic-oxadiazines were synthesized in very good yields with excellent diastereoselectivities through a catalytic [3 + 3]-cycloaddition from the readily available p-quinols, azomethine imines, and a catalytic amount of Brønsted base (KO tBu).

Modular Access to Chiral 2,3-Dihydrofurans and 3,4-Dihydro-2 H-pyrans by Stereospecific Activation of Formylcyclopropanes through Combination of Organocatalytic Reductive Coupling and Lewis-Acid-Catalyzed Annulative Ring-Opening Reactions.

An organocatalytic reductive coupling and Lewis-acid-catalyzed annulative ring-opening strategy is developed as a two-step protocol for the stereoselective synthesis of dihydropyrans as the major products from the chiral formylcyclopropanes, CH acids, and Hantzsch ester. It is an efficient, catalytic, two-step protocol for the chiral synthesis of dihydropyrans and dihydrofurans. Structurally important and challenging functionally rich cyclopropanes containing cyclic-1,3-diones were synthesized in very good yields with excellent chemo-, enantio-, and diastereoselectivities from the readily available starting materials, chiral formylcyclopropanes, cyclic-1,3-diones, or CH acids and Hantzsch ester through an organocatalytic reductive coupling reaction at ambient conditions, especially without harming the cyclopropane ring.

Unraveling the Stability of Plasma Proteins upon Interaction of Synthesized Androstenedione and Its Derivatives-A Biophysical and Computational Approach.

4-Androstene-3-17-dione (4A), also known as androstenedione, is the key intermediate of steroid metabolism. 5β-Androstane-3-17-dione (5A) and (+)-6-methyl-5β-androstane-3-17-dione (6M) are the steroid derivatives of androstenedione. The interactions of androstenedione and its derivatives with plasma proteins are important in understanding the distribution and bioavailability of these molecules.

Spectroscopic evaluation of synthesized 5β-dihydrocortisol and 5β-dihydrocortisol acetate binding mechanism with human serum albumin and their role in anticancer activity.

Our study focus on the biological importance of synthesized 5β-dihydrocortisol (Dhc) and 5β-dihydrocortisol acetate (DhcA) molecules, the cytotoxic study was performed on breast cancer cell line (MCF-7) normal human embryonic kidney cell line (HEK293), the IC values for MCF-7 cells were 28 and 25 μM, respectively, whereas no toxicity in terms of cell viability was observed with HEK293 cell line. Further experiment proved that Dhc and DhcA induced 35.6 and 37.

Organocatalytic umpolung annulative dimerization of ynones for the synthesis of 5-alkylidene-2-cyclopentenones.

A novel phosphine-catalyzed umpolung [3 + 2]-annulative dimerization of ynones was developed to furnish functionally rich 5-alkylidene-2-cyclopentenones. In this protocol, ynone acts as both C2 and C3 synthons, which undergo [3 + 2]-annulative dimerization.

Organocatalytic Asymmetric Formal [3+2] Cycloaddition as a Versatile Platform to Access Methanobenzo[7]annulenes.

Pharmaceutically and structurally important methanobenzo[7]annulenes were synthesized in very good yields with excellent enantio- and diastereoselectivities through an unprecedented organocatalytic formal [3+2] cycloaddition from readily available 2-alkyl-3-hydroxynaphthalene-1,4-diones and alkyl vinyl ketones.

Unravelling the binding mechanism and protein stability of human serum albumin while interacting with nefopam analogues: a biophysical and insilico approach.

In this study, molecular binding affinity was investigated for Nefopam analogues (NFs), a functionalized benzoxazocine, with human serum albumin (HSA), a major transport protein in the blood. Its binding affinity and concomitant changes in its conformation, binding site and simulations were also studied. Fluorescence data revealed that the fluorescence quenching of HSA upon binding of NFs analogues is based on a static mechanism.