Cyclization Process Research Articles

Au- and Pd-catalyzed cyclization processes: synthesis of polyfunctionalized cyclopropanes

Reported herein is an efficient 2-step process involving an Au-catalyzed Prins-type cyclization and a Pd-catalyzed cyclopropane C–H activation for the synthesis of polysubstituted cyclopropanes.

Diversity of Self-Assembled RNA Complexes: From Nanoarchitecture to Nanomachines.

New tool development for various nucleic acid applications is an essential task in RNA nanotechnology. Here, we determined the ability of self-limited complex formation by a pair of oligoribonucleotides carrying two pairwise complementary blocks connected by a linker of different lengths in each chain. The complexes were analyzed using UV melting, gel shift assay analysis, and molecular dynamics (MD) simulations. We have demonstrated the spontaneous formation of various self-limited and concatemer complexes. The linear concatemer complex is formed by a pair of oligomers without a linker in at least one of them. Longer linkers resulted in the formation of circular complexes. The self-limited complexes formation was confirmed using the toehold strand displacement. The MD simulations indicate the reliability of the complexes' structure and demonstrate their dynamics, which increase with the rise of complex size. The linearization of 2D circular complexes into 1D structures and a reverse cyclization process were demonstrated using a toehold-mediated approach. The approach proposed here for the construction and directed modification of the molecularity and shape of complexes will be a valuable tool in RNA nanotechnology, especially for the rational design of therapeutic nucleic acids with high target specificity and the programmable response of the immune system of organisms.

Redox-Neutral Cyclization of 2-Isocyanobiaryls through Photoredox/PPh3 Dual Catalysis.

The photoredox/PPh3-mediated cyclization of 2-isocyanobiaryls has been developed. A substantial range of functional-group-rich phenanthridine derivatives were synthesized at room temperature in a highly selective and atom-economic manner. Mechanistic studies suggested that the cyclization process is probably mediated both by Ph3P radical cation with key 1,2-hydride transfer and hydrogen atom generated through O-H bond homolytic cleavage of Ph3P-OH radical intermediate.

Pyrrolizine-3-ones: Synthesis and evaluation of photophysical properties

We describe a synthetic approach for pyrrolizine-3-one derivatives and their photophysical properties. These compounds are prepared by a series of reactions employing the substituted pyrroles in one-pot, two-step oxidation, and intramolecular cyclization processes. The photophysical properties of the synthesized compounds were studied by using UV–Vis and fluorescence spectroscopy in different solvents. Maximum absorbance peaks were observed around 306–416 nm and maximum fluorescence emission around 603–614 nm and 465–498 nm for pyrrolyl and N-methyl pyrrolyl substituents, respectively. The introduction of a pyrrolyl substituent had a significant impact on the Stokes shifts (192–206 nm) and quantum yield values ranged from 0.002 to 0.046.

“Stepwise or concerted or a hybrid mechanism for berberine bridge enzyme?”: A computational mechanistic study by QM-MM and QM methods

Berberine bridge enzyme (BBE) is a plant-based amine oxidase that catalyzes conversion of (S)-reticuline into (S)-scoulerine using flavin as cofactor in a stereospecific way in an alkaloid biosynthesis pathway. Based on the active site enzyme variants, a concerted mechanism was proposed involving hydride transfer, proton transfer, and substrate cyclization processes in a single step. In this mechanism, Glu417 residue acts as the catalytic base which deprotonates the phenolic proton of the substrate while a hydride ion transfers from the substrate to flavin and the substrate cyclizes. However, based on solvent and substrate deuterium kinetic isotope effect studies, it was proposed that the oxidation process occurs in a stepwise fashion in which a hydride ion transfer from substrate to flavin first, then cyclization of the substrate occurs together with the proton transfer process. In this study, we formulated computational models to elucidate the oxidation mechanism of (S)-reticuline into (S)-scoulerine using the crystal structure of enzyme complexed with (S)-reticuline. Both QM and QM-MM calculations revealed that a hybrid of concerted and stepwise mechanisms might be operative during the catalysis. It was found that a concerted hydride-proton transfer processes occurs forming a reactive intermediate which subsequently cyclize without an energy barrier as a decoupled step.

Surface Modification of Ga-Doped-LLZO (Li7La3Zr2O12) by the Addition of Polyacrylonitrile for the Electrochemical Stability of Composite Solid Electrolytes

Composite solid electrolytes (CSEs), often incorporating succinonitrile (SCN), offer promi I confirm sing solutions for improving the performance of all-solid-state batteries. These electrolytes are typically made of ceramics such as Li7La3Zr2O12 (LLZO) and polymers such as poly(vinylidene fluoride-co-hexafluoropropylene) (PVDF-HFP). Garnet-applied polymer–ceramic electrolyte (g-PCE) is composed of PVDF-HFP, SCN, and LLZO. However, the interface between SCN and LLZO is reportedly unstable owing to the polymerization of SCN. This polymerization could cause two serious problems: (1) gelation during the mixing of LLZO and SCN and (2) degradation of ionic performance during charge and discharge. To prevent this catalytic reaction, polyacrylonitrile (PAN) can be added to the g-PCE (g-PPCE). PAN blocks the polymerization of SCN through a cyclization process involving La ions which occurs more rapidly than SCN polymerization. In this study, the enhanced chemical stability of the garnet-applied PAN-added polymer ceramic electrolyte (g-PPCE) was achieved by using an impregnation process which added SCN with 5 wt.% of PAN. The resulting CSE has an ionic conductivity of ~10-⁴ S/cm at room temperature. Coin-type cells assembled with LFP (LiFePO4) and LNCM (LiNi0.6Co0.2Mn0.2O2) cathodes with Li-metal anodes show specific discharge capacities of 150 and 167 mAh/g at 0.1 C, respectively, and stable cycle performance. Additionally, a pouch-type cell with a discharge capacity of 5 mAh also exhibits potential electrochemical performance.

Theoretical Investigations on the Rh(III)-Catalyzed Oxidative C-H Activation/Annulation of Salicylaldehydes with Masked Enynes: Mechanism Insights and Regioselectivity Origins.

The mechanism underlying the rhodium(III)-catalyzed reaction of the C-H alkenylation/annulation reaction of salicylaldehydes with enynes has been thoroughly investigated using DFT calculations. Based on mechanistic studies, our focus primarily lies on the regioselectivity of asymmetric alkynes inserting into the Rh-C bond and the involvement of the auxiliary group OAc- in these reactions. Our theoretical study uncovers that, with acetate assistance, a stepwise SN2' cyclization, 1,3-Rh migration, β-H elimination, and reductive elimination process occur. Furthermore, we also explore the role of substitution at Cα (CH3 vs H) in the reaction. As demonstrated in this work, these findings are applicable to other related reactions.

Total synthesis of natural pyrano[3,2-a]carbazole alkaloids

An efficient approach for the total synthesis of pyrano[3,2-a]carbazole alkaloids was reported, resulting in the synthesis of six natural pyrano[3,2-a]carbazole alkaloids, namely girinimbine (1), mukoenine C (2), koenimbine (3), koenigine (4), koenine (5), and koenidine (6). In the present study, the readily available 2-methyl-5-nitrophenol was employed as a starting material for the synthesis of aminochromenes. The intermediate diphenylamine was produced through the Buchwald-Hartwig coupling reaction, which ultimately facilitated the synthesis of pyrano[3,2-a]carbazole via the intramolecular palladium(II)-catalyzed oxidative cyclization of diphenylamine. In the palladium-catalyzed oxidative cyclization process, this approach successfully circumvents the Wacker oxidation by restricting the involvement of water, ultimately enabling the selective dehydrogenative oxidative cyclization of the C–C bond of the aryl ring. Consequently, this strategy simplifies the complexity of the reaction and reduces the synthesis steps.

Discovery of a novel tetrahydroimidazo[1,2-a]pyridine-5-carboxylic acid derivative as a potent and selective heparanase-1 inhibitor utilizing an improved synthetic approach

Heparanase-1 (HPSE1) is an endo-β-d-glucuronidase that catalyzes degradation of heparan sulfate proteoglycans. Inhibition of HPSE1 appears to be a useful therapeutic target against cancer and proteinuric kidney diseases. We previously reported tetrahydroimidazo[1,2-a]pyridine 2 as a potent HPSE1 inhibitor after optimization of the synthetic reaction. However, synthesis of 2 involves a total of 19 steps, including a cyclization process that accompanies a strong odor due to the use of Lawesson’s reagent and an epimerization reaction; furthermore, 2 exhibited insufficient selectivity for HPSE1 over exo-β-d-glucuronidase (GUSβ) and glucocerebrosidase (GBA), which also needed to be addressed. First, the cyclization reaction was optimized to synthesize tetrahydroimidazo[1,2-a]pyridine without using Lawesson’s reagent or epimerization, with reference to previous reports. Next, 16 and 17 containing a bulkier substituent at position 6 than the 6-methoxyl group in 2 were designed and synthesized using the improved cyclization conditions, so that the synthetic route of 16 and 17 was shortened by five steps as compared with that of 2. The inhibitory activities of 16 and 17 against GUSβ and GBA were reduced as compared with those of 2, that is, the compounds showed improved selectivity for HPSE1 over GUSβ and GBA. In addition, 16 showed enhanced inhibitory activity against HPSE1 as compared with that of 2. Compound 16 appears promising as an HPSE1 inhibitor with therapeutic potential due to its highly potent inhibitory activity against HPSE1 with high selectivity for HPSE1.

Synthesis and Anti-Plant Pathogenic Fungal Activity of Flavokawain-Derived Flavones and Related Flavones Against Rhizoctonia solani

Flavones are organic compounds in the flavonoid family that have a diverse range of biological functions. In this research, many flavones with various substituents were designed and synthesized from flavokawains A, B, and C, and their chalcone derivatives via an iodine-catalyzed oxidative cyclization process. All synthetic flavones were investigated for antifungal activities against Rhizoctonia solani, a plant pathogenic fungus. At 400 µg, most of the substances did not inhibit the tested species and R. solani growth was inhibited by only o-bromoflavone (40) by 74.88±0.91%. This indicated that the detrimental effect of flavones depends on the type and position of substituent, with the ortho bromo group showing the most promise. The molecular docking study on the succinate dehydrogenase (SDH) enzyme revealed that the bromophenyl moiety (ring B) is a key molecular substructure of the flavone fungicide. The findings of this study will be used to develop novel plant pathogenic fungicides.

Metal‐Free Photocatalytic [4+2] Annulation of Acrylamides with 2‐Benzyl‐2‐bromocarbonyls to Assemble Tetralin‐1‐carboxamides

Comprehensive SummaryTetralin‐1‐carboxamides are frequently incorporated in myriad medicinally important molecules. However, their existing synthetic routes not only suffer from some drawbacks such as tedious procedures, harsh reaction conditions, narrow substrate scope, low yields, and environmental problems, but are also based upon the elaboration of uneasily available non‐linear tetralin derivatives. Herein, we describe a metal‐ and additive‐free visible light‐induced [4+2] annulation of two simple linear starting materials, namely acrylamides and 2‐benzyl‐2‐bromocarbonyls, through a cascade C(sp3)−Br/C(sp2)−H bond cleavage, double C−C bond formation, and aromatization sequence. The developed protocol provides a convenient, efficient, and green approach to a variety of tetralin‐1‐carboxamide derivatives with good functional group compatibility. Importantly, the resulting products could also undergo the LiCl‐mediated mono‐decarboxylative cyclization process to further furnish the architecturally novel bridged polycyclic imides with excellent cis‐diastereoselectivities.

TBAF-Mediated [3+1] Cycloaddition of Difluorocarbene to Access gem-Difluorinated 1,2-Diazetidine Analogues as Potent Anticancer Agents.

The facile synthesis of gem-difluorinated 1,2-diazetidines was achieved by metal-free [3+1] annulation between C,N-cyclic azomethine imines with difluorocarbene. A library of 30 compounds benefiting from the TBAF-mediated cyclization process could be directly assembled in moderate to good yield under mild conditions. A plausible mechanism involving the difluorocarbene pathway was proposed based on carbene trapping and control experiments. Many compounds exhibited dramatic antiproliferative activity in 4T1, A549, and HeLa tumor cell lines.

Enantioselective Total Syntheses of the Cephalotaxus Alkaloids (-)-Fortuneicyclidins A and B and (-)-Cephalotine B.

Fortuneicyclidins A and B are a pair of recently isolated Cephalotaxus alkaloids with an unprecedented rearranged polycyclic skeleton possessing multiple complex stereocenters and functionalization. In this work, highly stereocontrolled asymmetric total syntheses for title alkaloids were outlined. Key features include an underexplored Ir-catalyzed α-allylation of aldehyde to strategically install a vicinal N-substituted quaternary center and a tertiary stereocenter, Heck and RCM reactions to construct the critical polycyclic framework rapidly, two different tandem oxidation-transannular aldol cyclization processes, one through ozonolysis and another via Swern oxidation, to forge the last ring for fortuneicyclidins A and B, respectively. In this approach, the challenging C-2 hydroxyl group can be installed stereospecifically.

Cascade Cyclization of 1,5-Diynols and (RO)2P(O)SH to Construct Benzo[b]fluorenyl S-Alkyl Phosphorothioates under Catalyst-Free Conditions.

An efficient and practical cascade cyclization of 1,5-diynols with (RO)2P(O)SH as the acid promoter and nucleophile under mild conditions was developed. A variety of highly substituted benzo[b]fluorenyl-containing S-alkyl phosphorothioates were successfully constructed in moderate to excellent yields. Furthermore, this protocol exhibited good functional group tolerance, a broad substrate scope, and potential practical applications, with water as the only byproduct. The reaction proceeded with allenyl thiophosphate as a key intermediate, followed by a Schmittel-type cyclization process to produce the target product.

6-Endo-dig cyclization: Flexible enforce to develop synthetic route in organic syntheses

The organic ring closure reaction of diverse acyclic compounds is governed mostly by the Baldwin rule. The ring closure compounds shows emergent application. In recent years, ring closure reactions that are favoured by the Baldwin rules have received a lot of attention. In particular, the Baldwin rule favours the usage of sp- geometrical (diagonal) molecules in the cyclization reaction. The endo-dig cyclization help for synthesis of bulky compound in simple manner via radical coupling. The radical coupling method help for synthesis of various cyclized compounds, also heterocyclic compounds like, three – eight memebered ring compounds. Also, the endo dig cyclization used for synthesis of C-C, C-N, C-O, C-S bond forming compounds. From the all ring closing reaction, 6-endo dig cyclization has great important for synthesis of highly active 6, 7, 8 membered ring compounds. The formed 6-endo dig cyclized product has selective activity against various field cosmetics, medicinal, dye, agrochemical. There are come list of organic compounds are synthesis via 6-endo-dig cyclization like, carbazole, fused benzimidazole, fused pyrimidine, oxazole, chromenos, pyridine, quinoline etc., analogues. The 6-endo-dig cyclization reaction proceed presence of transition metal catalyst and with out catalyst. The 6-endo-dig cyclization processes can be used to synthesise a wide range of 6 membered heterocycles and carbocycles. This review compiles the significant uses of 6-endo-dig cyclization in organic synthesis from a variety of perspectives.

Electrochemical Oxidative C−C Bond Functionalization of Methylenecyclopropanes with Diselenides/Ditellurides Leading to 2‐Substituted‐3,4‐Dihydronaphthalenes

AbstractThis study presents an approach for the electrochemical oxidation ring‐opening/cyclization reaction of methylcyclopropane with diselenides/ditellurides, leading to the synthesis of diverse 2‐substituted‐3,4‐dihydronaphthalene derivatives with exceptional selectivity and efficiency. This methodology involves C(sp3)−H functionalization, ring opening and cyclization processes. One characteristic of this method is its ability to accommodate a wide range of substrates with various functional groups.

Photochemical Synthesis of S,N,O-Containing Polyheterocycles via an α-C(sp3)-H Functionalization/Radical Cyclization Cascade.

A highly effective approach based on an organophotocatalytic α-C(sp3)-H functionalization/radical cyclization cascade has been developed. This method enables the synthesis of various tricyclic heterocycles containing S, O, and N atoms with excellent site selectivity and diastereoselectivity. Mechanistic investigations have confirmed that the reaction involves photoredox-triggered C(sp3)-H cleavage followed by a radical cyclization and aromatization process. These findings are expected to pave the way for developing cost-effective tandem radical reactions and synthesizing heterocyclic drugs.

Multicomponent Reactions between Heteroatom Compounds and Unsaturated Compounds in Radical Reactions.

In this mini-review, we present our concepts for designing multicomponent reactions with reference to a series of sequential radical reactions that we have developed. Radical reactions are well suited for the design of multicomponent reactions due to their high functional group tolerance and low solvent sensitivity. We have focused on the photolysis of interelement compounds with a heteroatom-heteroatom single bond, which readily generates heteroatom-centered radicals, and have studied the photoinduced radical addition of interelement compounds to unsaturated compounds. First, the background of multicomponent radical reactions is described, and basic concepts and methodology for the construction of multicomponent reactions are explained. Next, examples of multicomponent reactions involving two interelement compounds and one unsaturated compound are presented, as well as examples of multicomponent reactions involving one interelement compound and two unsaturated compounds. Furthermore, multicomponent reactions involving intramolecular cyclization processes are described.

Highly Efficient One-Pot Synthesis of Hexakis(m-phenyleneimine) Macrocyle Cm6 and the Thermostimulated Self-Healing Property through Dynamic Covalent Chemistry.

Highly efficient one-pot synthesis of hexakis(m-phenyleneimine) macrocycle Cm6 from acetalprotected AB-type monomer, m-aminobenzaldehyde diethylacetal, was successfully achieved based on imine dynamic covalent chemistry and precipitation-driven cyclization. The structure of Cm6 in the solid state was determined using CP/MAS NMR, X-ray single crystallographic analysis, and WAXD. Macrocycle Cm6 is composed of six phenylene and imine bonds facing the same direction, with nitrogen atoms arranged on the outside of the ring, and has a chair conformation, as predicted from DFT calculation. The macrocycle forms π-stacked columnar aggregates and hexagonally closest-packed structure. The cyclization process was investigated using MALDI-TOF MS and NMR. A mechanism of precipitation-driven cyclization based on imine dynamic covalent chemistry and π-stacked columnar aggregation is proposed. Both the nature of imine linkage and the shape anisotropy of the macrocycle played an important role in the single one-pot synthesis. The water-mediated mutual conversion between macrocycle Cm6 and linear oligomers driven by thermal stimulation was analyzed using MALDI-TOF MS and GPC methods. Macrocycle Cm6 with a dynamic covalent imine bond exhibited self-healing properties when stimulated using heat.

Synthesis of benzothienofuranones and dihydrobenzothienopyranones by palladium iodide-catalyzed carbonylative double cyclization

3-(2-(Methylthio)phenyl)prop-2-yn-1-ols have been successfully converted in one synthetic step into benzo[4,5]thieno[2,3-c]furan-1-ones by a PdI2/KI-catalyzed oxidative carbonylative double cyclization process, performed in MeCN under relative mild conditions (1–10 mol % PdI2, 7 equiv of KI, 80 °C, 60 atm of a 4:1 mixture CO–air). The process takes place through an ordered sequence of steps, involving 5-endo-dig S-cyclization, iodide-promoted demethylation of the ensuing sulfonium salt, CO insertion, a second cyclization (possibly, through the formation of a palladacycle intermediate followed by reductive elimination), and Pd(0) reoxidation by oxygen (from air) used as external benign oxidant. Under similar conditions, 4-(2-(methylthio)phenyl)but-3-yn-1-ols, bearing a butynol moiety ortho to the methylthio group, led to a mixture of double cyclization and dicarbonylation products, however, by slightly tuning the reaction conditions, dihydrobenzo[4,5]thieno[3,2-c]pyran-1-ones could be selectively obtained with no formation of the dicarbonylated byproduct. The structures of four representative products, including two tetracyclic derivatives, have been confirmed by XRD analysis.