We delineate a viable, tandem annulation strategy for accessing indoloindolizines. This one-pot, transition-metal-free approach involves the stitching of preformed 2-methyl-3-nitro/3-carbonyl-1H-indoles with assorted ynones through sequential aza-Michael addition and a vinylogous aldol condensation reaction cascade. The protocol displays high regioselectivity and broad substrate scope, providing concise access to a diverse library with 24 examples. This has further enabled access to two analogues of marine-derived alkaloid homofascaplysin C (a red pigment) exhibiting selective anti-cancer activity.

Herein, we report a divergent approach for the total synthesis of polycyclic lignans yatein (1), sumatranin A (2), isodeoxypodophyllotoxin (3) and isostegane (4) from dibenzyltetrahydrofuran acetals, which could be constructed by the nickel-catalyzed tandem reductive cyclization-coupling as a key step. These advanced intermediates were readily converted to yatein and sumatranin A via an oxidation reaction or acid-mediated cyclization, respectively. Subsequently, the six- or eight-membered carbon ring in isodeoxypodophyllotoxin or isostegane could be constructed through a reagent-controlled regioselective oxidative coupling reaction of yatein.

Two mirror-symmetric approaches for the chemical synthesis of sphingosines 1via olefin metathesis can be distinguished. The widely used approach D is based on the head group with an allylic alcohol moiety and leads to the formation of sphingosines in moderate yields. An alternative pathway E, involving a head group with a vinyl ketone moiety, has been described but is currently not used, although the metathesis of such olefins occurs with high yields of cross-coupling products. Based on a systematic comparison, we show that the new pathway E provides up to 3.4-fold higher yield and is a practically superior strategy compared to the currently used pathway D at the metathesis step. In pathway D, we observed allylic isomerization of the starting hydroxyl-containing head group 3a to the saturated ketone 17 on a Grubbs 2nd generation catalyst. On the one hand, this isomerization reduces the efficiency of metathesis. On the other hand, the Grubbs catalyst was found to be effective for the isomerization of allylic alcohols to ketones in the absence of a base. The second isomerization along route D was detected at the stage of metathesis product formation, where migration of the double bond along the aliphatic chain to the distant π-system occurred. Pathway E is free of the isomerization side reaction. In the final step of sphingosine 1 synthesis, we observed the formation of N-trifluoroacetylsphingosines 24 upon removal of Boc protection with trifluoroacetic acid. The use of HCl eliminates this transacylation reaction.

A modular, metal-free multicomponent cascade reaction protocol has been developed for the synthesis of pyrazole-/isoxazole-/chromene-fused pyrimidines from 1,3-bisnucleophiles, aldehydes, and NH4OAc under neat reaction conditions. This protocol involves the in situ generation of diene and dienophile and subsequent reaction via hetero-Diels-Alder-type [4 + 2] cycloaddition followed by aerial oxidation, which leads to the title products with the formation of one C-C and three C-N bonds. The advantages of this green synthetic method are its simple reaction conditions, readily available substrates, and excellent yields even at gram-scale synthesis.

The high-value N,S-heterocyclic scaffolds of 2-thiobenzothiazoles (Bth-SR) were efficiently assembled through an atom-economical synthetic strategy employing cascade Cs2CO3-promoted RSH-NCS addition and CuI-catalyzed S-C(sp2) coupling. A library of diverse Bth-SR compounds, including bioactive molecules, was readily afforded in generally high yields from 2-iodoaryl isothiocyanates and thiols under green and benign conditions. Also investigated were the reaction mechanism and the late-stage modifications of Bth-SR.

m,m-CBPP and p,p-CBPP, neutral analogues of m,m-CBPQT4+ and the Bluebox, were synthesized via platinum-mediated homocoupling. The concave m,m-isomer and convex p,p-isomer display distinct ring strain and weak orbital interactions, with the latter showing a narrowed HOMO-LUMO gap and a red-shifted UV absorption, highlighting how connectivity governs cyclophane properties.

Diverse 2-fluoroalkyl-3-aminoindoles were synthesized through an efficient radical fluoroalkylation/cyclization between fluoroalkyl bromides and aryl isocyanides induced by visible light via an EDA complex. This reaction avoids the use of noble transition metal catalysts and photocatalysts and exhibits environmental benignity. The reaction mechanism is also provided based on detailed experimental evidence.

A novel series of pyrazole-pyridine-1,3,4-oxadiazole hybrid derivatives (10a-m) was designed, synthesized, and characterized by IR, [1]H NMR, [13]C NMR, mass spectrometry, and elemental analysis. The multi-step route proceeded via nucleophilic aromatic substitution, cyclocondensation, oxidative aromatization, and S-alkylation, affording target compounds in good to excellent yields (88-93%). Derivatives were screened for anticancer activity against A549 (lung) and MCF-7 (breast) cell lines using Foretinib as reference. Compound 10d (2,4-di-OCH3) was most potent, with IC50 values of 0.29 ± 0.15 μM (A549) and 3.1 ± 0.5 μM (MCF-7), comparable to, or numerically better than, Foretinib (IC50 = 0.49 ± 0.026 μM, A549); no formal statistical comparison was performed. SAR analysis showed electron-donating substituents, especially methoxy groups, enhanced potency. Compounds 10c, 10d, and 10h were markedly less cytotoxic toward non-cancerous NIH/3T3 fibroblasts (IC50 = 138.41, 66.36, and 95.03 μM) than toward the cancer lines, indicating a favorable selectivity margin. Docking against c-Met (PDB: 3LQ8) showed 10d had the highest binding affinity (-5.54 kcal mol[-1]), forming hydrogen-bond and π-cation interactions with ASP 1222 and ARG 1203, consistent with c-Met as a plausible target, though direct biochemical confirmation is needed. DFT calculations (B3LYP/6-311++G(d,p)) for 10c, 10d, and 10h confirmed that 10d has the smallest HOMO-LUMO gap (3.74 eV) and highest chemical softness, consistent with its superior activity. Collectively, these findings identify 10d as a promising scaffold for further optimization and biological evaluation.

Pyrimidine is a biologically significant nitrogen-containing heterocycle and a key structural motif in nucleic acids, vitamins, and functional materials. Incorporation of pyrimidine units into porphyrinoid frameworks offers opportunities to modulate their electronic structure, hydrogen-bonding behaviour, and photophysical properties. Herein, we unveil the first examples of pyrimidine-embedded porphyrinoids synthesized via condensation of 2,5-di(1H-pyrrol-2-yl)pyrimidine with 2,2'-bithiophene-5,5'-diyl bis(aryl methanol) under BF3·OEt2 catalyzed conditions in 8-15% yields. HR-MS and 1D/2D NMR analyses confirmed the formation of macrocycles comprising four pyrrole, two thiophene, and two pyrimidine units linked via two meso-carbons. In [1]H NMR, the four inner pyrrole NH protons appeared as two broad resonances: one resonance in the upfield region at 6.35 ppm and the other resonance in the downfield region at 9.58 ppm. The downfield shifting of the two NH protons at 9.58 ppm was due to their involvement in intramolecular hydrogen bonding with inner pyrimidine "N" atoms. Absorption spectral studies showed that the macrocycles exhibited nonaromatic panchromatic absorption features covering the entire UV-visible region and their diprotonated macrocycles showed strong absorption in the visible-NIR region. DFT studies indicated that the macrocycles were almost planar except for the thiophene rings which were deviated from the mean plane by an angle of 9.2°.

Herein, we report a simple and efficient method for the room-temperature synthesis of novel 4-aryl diazenyl-5-hydroxy pyrazoles using a three-component reaction involving aromatic amines, tert-butyl nitrite (TBN), and pyrazolones. In this process, TBN serves as the nitrogen source for the in situ generation of the corresponding diazonium salts from aromatic amines. The subsequent coupling proceeds smoothly in the absence of any catalyst or additives. A wide range of anilines and pyrazolone derivatives were found to be compatible with this protocol, demonstrating its broad substrate scope. Considering the presence of azo, hydroxy, and pyrazole moieties, the synthesized compounds are anticipated to exhibit important medicinal properties.

Over the past several decades, biocatalysis has become a valuable complement to synthetic chemistry due to its high efficiency, exceptional selectivity, and environmental compatibility. Thiamine diphosphate (ThDP), the biologically active form of vitamin B1, serves as an essential coenzyme for core metabolic processes in all organisms. This review systematically elucidates the structural characteristics, classification, and diverse reactions catalyzed by ThDP-dependent enzymes, with a primary focus on their potential for stereoselective C-C bond formation and cleavage. These enzymes are widely distributed across all domains of life and catalyze the formation and cleavage of C-C, C-N, C-S, and C-O bonds. The catalytic mechanism centers on the formation of the Breslow intermediate, which undergoes nucleophilic addition to various electrophiles. Despite considerable sequence diversity, all ThDP-dependent enzymes share two conserved domains-the pyrimidine (PYR) binding domain and the pyrophosphate (PP) binding domain-and are classified into five structural types and nine superfamilies. In terms of substrate scope, the decarboxylase family is predominantly R-selective, whereas the transketolase family is S-selective. These enzymes hold significant promise for biotechnological applications, particularly through protein engineering to tailor catalytic activity and stereoselectivity. Moreover, ThDP-dependent enzymes have been implicated in the pathogenesis of Alzheimer's disease, diabetes, and tumor proliferation. This review also summarizes relevant clinical applications and the use of competitive inhibitors. By integrating modular architectures, cofactor synergy mechanisms, regulatory networks, and emerging frontiers in photoelectrochemical biocatalysis, this review highlights the broad potential of ThDP-dependent enzymes in both fundamental research and translational applications.

Quinoline- and tetrahydroquinoline-containing heterocyclic compounds display potent and varied biological activity against several clinically relevant targets. Many strategies to construct the quinoline core have been described over several decades, but the Povarov and Doebner reactions stand out for operational simplicity and use of readily available starting materials. Hence, these two multicomponent reactions have been utilized as powerful tools in industrial and academic labs to quickly and efficiently synthesize chemically diverse drug-like molecules. In drug discovery, these reactions have been applied to rapidly synthesize extensive libraries of pharmaceutically relevant compounds. This review highlights the synthetic method advancements of the Povarov and Doebner reactions and their applications in drug development. Synthetic methods, both traditional and cutting-edge, are discussed with a focus on recent advances in photochemistry, asymmetric synthesis, intramolecular, electrochemistry, and metal-catalyzed atom-economical multicomponent chemistry. Further, we describe many compounds that are synthesized via these chemistries, which have shown potent anticancer, anti-inflammatory, antioxidant, antiviral, and antiparasitic bioactivity, in addition to being efficacious against neurodegenerative disease.

Fragment condensation of suitable bisphenols afforded 2-monothiacalix[4]arene on a multigram scale. Using reaction conditions known from classical calixarene chemistry, the macrocycle was alkylated to study the conformational preferences and dynamic behavior of the corresponding tetraalkylated derivatives. While the introduction of propyl residues leads to the immobilization of the respective conformers, shorter substituents (Me and Et) represent dynamic systems depending on temperature. A combination of X-ray crystallography, DFT calculations and NMR techniques demonstrated that the presence of a sulfur atom in the backbone leads to significant changes in the selectivity of the respective conformers. Although six different conformations/atropisomers are theoretically possible, it turns out that only five of them are accessible by direct propylation. Selective preparations of some conformers suggest that this mixed-bridged calixarene could find application in supramolecular chemistry as a potential molecular scaffold.

The asymmetric Henry reaction represents a powerful method for constructing chiral β-nitro alcohols; however, most existing catalytic systems suffer from poor recyclability, which limits their sustainable application. To address this challenge, based on the concept of green organocatalysis, this study is dedicated to developing a novel recyclable chiral catalytic system. A dual-core design strategy was adopted: (i) methoxy polyethylene glycol, which exhibits good biocompatibility, was selected as an environmentally friendly carrier; (ii) readily available L-tert-leucine was used as the precursor of the chiral catalytic center. A novel methoxy polyethylene glycol-supported chiral Schiff base ligand, L12, was successfully prepared. This ligand, in cooperation with copper acetate, facilitated the construction of a rationally designed catalytic system that exhibits remarkable activity for asymmetric Henry reactions. The system enables the efficient synthesis of various chiral β-nitro alcohols with considerable stereoselectivity. Notably, the catalytic system demonstrates satisfactory recyclability, further enhancing its practical value. Based on these performance advantages, the system shows significant application potential in the synthesis of chiral drug molecules and active intermediates. Overall, this work not only provides an efficient and recyclable protocol for the green synthesis of chiral β-nitro alcohols, but also offers a promising route for the sustainable preparation of key intermediates in chiral drug synthesis, highlighting its potential for industrial application.

A unique strategy involving SmI2-mediated tandem cyclization reaction of suitably substituted dialdehyde embedded with an α,β-unsaturated ester for the synthesis of the structural core of the complex alkaloid daphenylline is presented. This strategy involves the formation of two C-C bonds and a C-O bond in the form of a lactone in a single simultaneous operation.