Brønsted Acid-Promoted Cyclodimerization of α,ß-Unsaturated γ-Ketoesters: Construction of Fused Pyrano-ketal-lactones and γ-Ylidene-butenolides.

Unprecedented MsOH-promoted diastereoselective cascade dimerization and intramolecular lactonization of readily accessible α,ß-unsaturated γ-ketoesters are presented. The results obtained in this work, control experiments, and density functional theory (DFT) calculations suggested that the initial enolization and E to Z isomerization/equilibration of olefin (C=C) of substrate α,ß-unsaturated γ-ketoesters give a Z-isomer preferentially over an E-isomer. Subsequently, the Z-isomer undergoes intermolecular annulation with α,ß-unsaturated γ-ketoesters via domino Michael addition/ketalization/lactonization steps to furnish fused tetracyclic pyrano-ketal-lactone. However, the Z-isomer prefers intramolecular trans-esterification in a competing pathway and gives bicyclic γ-ylidene-butenolide. The key features of this work include simple Brønsted acid catalysis, the formation of three bonds, two rings, and three contiguous stereogenic centers in a single step, DFT calculations, and the assignment of relative stereochemistry through X-ray diffraction (XRD) and two-dimensional (2D) nuclear magnetic resonance (NMR) analyses.

Visible-Light-Induced Radical Sulfonylative-Cyclization Cascade of 1,6-Enynol Derivatives with Sulfinic Acids: A Sustainable Approach for the Synthesis of 2,3-Disubstituted Benzoheteroles.

Benzoheteroles are promising structural scaffolds in the realm of medicinal chemistry, but sustainable synthesis of 2,3-difunctionalized benzoheterole derivatives is still in high demand. Indeed, we have conceptually rationalized the intrinsic reactivity of propargylic-enyne systems for the flexible construction of 2,3-disubstituted benzoheteroles through radical sulfonylative-cyclization cascade under organophotoredox catalysis. We hereby report an efficient visible-light-induced sulfonyl radical-triggered cyclization of 1,6-enynols with sulfinic acids under the dual catalytic influence of 4CzIPN and NiBr2⋅DME, which led to the formation of 2,3-disubstituted benzoheteroles in good to high yields. Additionally, the Rose Bengal (RB)-catalyzed radical sulfonylative-cycloannulation of acetyl-derived 1,6-enynols with sulfinic acids under blue LED irradiation allowed to access 3-(E-styryl)-derived benzofurans and benzothiophenes in moderate to good yields. The scope and limitations of the present strategies were successfully established using different classes of 1,6-enynols and sulfinic acids bearing various sensitive functional groups, yielding the desired products in a highly stereoselective fashion. Plausible mechanistic pathways were also proposed based on the current experimental and control experiments.

Base controlled rongalite-mediated reductive aldol/cyclization and dimerization of isatylidene malononitriles/cyanoacetates.

In this study, we developed a novel methodology involving a base-controlled, rongalite-mediated reductive/aldol reaction, followed by cyclization of isatylidene malononitriles/cyanoacetates, resulting in the synthesis of spiro[2,3-dihydrofuran-3,3'-oxindole]. Additionally, we have disclosed a rongalite-mediated dimerization process for isatylidene malononitriles, yielding dispiro[cyclopent-3'-ene]bisoxindole. The utilization of rongalite in this reaction serves a dual purpose, acting both as a reducing agent and a C1 synthon. The developed approach has several advantages like a simple reaction setup, a wide substrate scope, requiring less time, using water as a green solvent, no metal or catalyst is required and products can be easily isolated via filtration with excellent yields under mild reaction conditions.

Metal-Free One-Pot Domino Synthesis of Oxazolidinethione Derivatives of Quaternary Amino Acids from α-Amino Esters and Aldehydes Using CS2.

We present a streamlined, metal-free, one-pot domino approach to efficiently synthesize oxazolidinethione derivatives containing substituted quaternary amino acids. This method employs α-amino esters, aldehydes, and CS2 under mild conditions, constructing three new bonds (C-N, C-C, and C-O) to produce oxazolidinethione compounds featuring a quaternary center and a beta-hydroxy derivative in high yields. This scalable protocol enables the creation of libraries of biologically significant, intricate amino acid derivatives using amino esters and aldehydes.

Regioselective Synthesis of Benzannulated [5,6]-Oxaspirolactones via Cu(II)-Catalyzed Cycloisomerization of 2-(5-Hydroxyalkynyl)benzoates.

Spiroketals and oxaspirolactones are widely found in biologically active natural products, serving as important structural motifs. In this study, we present a Cu(II)-catalyzed cascade cycloisomerization of 2-(5-hydroxyalkynyl)benzoates, enabling the regioselective synthesis of benzannulated [5,6]-oxaspirolactones containing an isochromen-1-one moiety. This strategy offers a rapid and efficient approach to access a diverse array of benzannulated [5,6]-oxaspirolactones. The methodology presented here showcases a broad substrate scope, delivering good yields and scalability up to gram scale. The structures of the oxaspirolactones were unequivocally confirmed through single-crystal X-ray analysis and by analogy using 1H and 13C{1H} NMR data.

Metabolites from Lactococcus lactis subsp. lactis: Isolation, Structure Elucidation, and Antimicrobial Activity.

Herein, we disclose the identification of novel metabolites from a potential probiotic strain, Lactococcus lactis subsp. lactis, obtained from traditional dairy milk samples collected in Maharashtra, India (in January 2021). Isolated metabolites include pyrazin-2-carboxamide [1, pyrazinamide, a potential antitubercular drug], 3,5-dihydroxy-6-methyl-2,3-dihydro-4H-pyran-4-one (2, DDMP), 2,4-di-tert-butylphenol (3), and hexadecanoic acid (4, palmitic acid). The chemical structures of these metabolites were elucidated through extensive 1D NMR (1H and 13C) and 2D NMR (HSQC, HMBC, and NOESY) analyses, high-resolution mass spectrometry, high-performance liquid chromatography, and single-crystal X-ray crystallography. Furthermore, these novel metabolites exhibited potent inhibitory activities against various bacteria, fungi, and yeast strains with minimum inhibitory concentrations ranging between 1.56 and 25 µg/mL, and compounds 1 and 3 were found to be most active against a wide range of microbial strains tested.

Radical Cascade Cyclization of Unactivated Alkene-Tethered Indoles with Aryldiazonium Salt and Sodium Metabisulfite to Access Azo- and Sulfonylated-2,3-Dihyro-1H-pyrrolo[1,2-a]indoles.

A method for the construction of heterocyclic scaffold 2,3-dihyro-1H-pyrrolo[1,2-a]indoles via arylsulfonyl radical-triggered cascade cyclization of unactivated alkene-tethered indoles in the absence of any external photocatalyst has been developed. This protocol features easily accessible starting materials such as sodium metabisulfite and aryldiazonium tetrafluoroborates at room temperature and offers good functional group compatibility, enabling the introduction of various functionalized sulfonyl and azo groups into pyrrolo[1,2-a]indoles.

Design and synthesis of novel quinazolinyl-bisspirooxindoles as potent anti-tubercular agents: an ultrasound-promoted methodology.

The essential need for the potent anti-tubercular (anti-TB) agents with high selectivity and safety profile prompted us to synthesize a new series of quinazolinyl-bisspirooxindoles. The title compounds were synthesized by one-pot multicomponent [3 + 2] cycloaddition reaction under ultrasonication. Further, in vitro anti-TB activity was evaluated against Mycobacterium tuberculosis H37Rv. Among the screened compounds, two compounds (4q and 4x) showed potent activity with MIC value 1.56 µg/mL and four compounds exhibited significant activity (MIC = 3.125 µg/mL), and also cytotoxicity studies against RAW 264.7 cell lines reveal that most active compounds were less toxic to humans. In addition, in order to demonstrate the inhibitory properties, molecular docking studies were carried out and the results showed that the target compounds have good binding energy and better binding affinity within the active pocket, thus these compounds may consider to be as potent inhibitors toward selective targets.

Ready Access to Benzannulated [5,5]-Oxaspirolactones Using Au(III)-Catalyzed Cascade Cyclizations.

This work showcases an unprecedented Au(III)-catalyzed cascade cyclization of 2-(4-hydroxyalkynyl)benzoates to access benzannulated [5,5]-oxaspirolactones related to biologically active natural products. This reaction proceeds through an initial 5-endo-dig mode of hydroalkoxylation of the alkynol segment to give the oxocarbenium species (via cyclic enol-ether) followed by the addition of carboxylate onto the oxocarbenium that delivers the oxaspirolactone scaffold. While testing this method's scope, we found that the steric and electronic environment of the hydroxyl group could alter the reaction pathway that delivers isochromenone through a competitive 6-endo-dig mode of attack of the carboxylate onto the tethered alkyne.

Stereoselective Total Synthesis of (±)-Pleurospiroketals A and B.

A full account of our efforts toward the stereoselective total synthesis of sesquiterpenoid-derived natural products (±)-pleurospiroketals A and B is described. Commercially available 3-methyl-2-cyclohexenone and 2,2-dimethyloxirane were used as key building blocks, and the substrate-controlled stereoselection was exploited to access the entire stereochemistry of these natural products. Initially, a planned synthetic route involving a [6,5]-bicyclic lactone intermediate was found to be insurmountable, and the later strategy comprising OsO4-NMO-mediated dihydroxylation of 3-methyl-2-cyclohexenone, followed by Luche reduction, Eschenmoser methylenation, and Brønsted acid-induced spiroketalization steps, was ultimately identified as the reliable strategy.

Tuning of α-Silyl Carbocation Reactivity into Enone Transposition: Application to the Synthesis of Peribysin D, E-Volkendousin, and E-Guggulsterone.

A reliable method for enone transposition has been developed with the help of silyl group masking. Enantio-switching, substituent shuffling, and Z-selectivity are the highlights of the method. The developed method was applied for the first total synthesis of peribysin D along with its structural revision. Formal synthesis of E-guggulsterone and E-volkendousin was also claimed using a short sequence.

Phenylboronic acid-catalyzed tandem construction of S-S and C-S bonds: a new method for the synthesis of benzyl disulfanylsulfone derivatives from S-benzyl thiosulfonates.

A unique phenylboronic acid-catalyzed dimerization-sulfonylation of S-benzyl thiosulfonates has been disclosed. A metal-free tandem construction of S-S and C-S bonds is an operationally simple method to access a wide range of benzyl disulfanylsulfone derivatives in high to excellent yields. Moreover, the robustness of this tandem transformation has been demonstrated by gram-scale reactions, and a plausible mechanism is also proposed.