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N-aryl-substituted pyrrolidines are important moieties widely found in bioactive substances and drugs. Herein, we present a practical reductive amination of diketones with anilines for the synthesis of N-aryl-substituted pyrrolidines in good to excellent yields. In this process, the N-aryl-substituted pyrrolidines were furnished via successive reductive amination of diketones via iridium-catalyzed transfer hydrogenation. The scale-up performance, water as a solvent, simple operation, as well as derivation of drug molecules showcased the potential application in organic synthesis.

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A simple and effective three-component one-pot green methodology was employed for the synthesis of a new thiazolidine-2,4-dione based bisspirooxindolo-pyrrolidine derivatives using [Bmim]BF4 ionic liquid via [3 + 2] cycloaddition reaction. It is an environmentally benign, column chromatography-free, shorter reaction time, good yield and easy product isolation method. The synthesized compounds 10a-x, were thoroughly characterized by using various spectroscopic methods like FT-IR, 1H NMR, 13C NMR, Mass spectrometry and finally by single crystal X-ray diffraction method. In vitro anti-tubercular (anti-TB) activity studies were carried out on these synthesized compounds, and they showed good to moderate anti-TB activity against Mycobacterium tuberculosis H37Rv strain. The compound 10a exhibited good anti-TB activity, with an MIC (Minimum Inhibitory Concentration) value of 12.5 µg/mL, and the compounds 10m, 10o and 10r showed moderate activity with an MIC value of 25.0 µg/mL. Remaining compounds exhibited poor activity against Mycobacterium tuberculosis. Ethambutol, rifampicin and isoniazid were used as standard drugs. Furthermore, in silico molecular docking experiments on the TB protein (PDB ID: 1DF7) were carried out to understand the binding interactions, and they showed least binding energy values ranging from -8.9 to -7.2 kcal/mol.

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A concise asymmetric synthesis of clickable enantiomeric pyrrolidines was achieved using Crabbé-Ma allenation. The synthesized iminosugars were grafted by copper-free strain-promoted alkyne-azide cycloaddition onto phosphorus dendrimers. The hexavalent and dodecavalent pyrrolidines were evaluated as ß-glucocerebrosidase inhibitors. The level of inhibition suggests that monofluorocyclooctatriazole group may contribute to the affinity for the protein leading to potent multivalent inhibitors. Docking studies were carried out to rationalize these results. Then, the iminosugars clusters were evaluated as pharmacological chaperones in Gaucher patients' fibroblasts. An increase in ß-glucocerebrosidase activity was observed with hexavalent and dodecavalent pyrrolidines at concentrations as low as 1 µM and 0.1 µM, respectively. These iminosugar clusters constitute the first example of multivalent pyrrolidines acting as pharmacological chaperones against Gaucher disease.

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The synthesis and biological assessment of novel multi-functionalized pyrrolidine-containing benzenesulfonamides were reported along with their antimicrobial, antifungal, CAs inhibition, and AChE inhibition as well as DNA-binding effects. The chemical structure of the compounds was elucidated by using FTIR, NMR, and HRMS. Compound 3b, which had Ki values of 17.61 ± 3.58 nM (hCA I) and 5.14 ± 0.61 nM (hCA II), was found the be the most potent CAs inhibitor. Compounds 6a and 6b showed remarkable AChE inhibition effects with Ki values 22.34 ± 4.53 nM and 27.21 ± 3.96 nM in comparison to tacrine. Compounds 6a-6c had moderate antituberculosis effect on M. tuberculosis with a MIC value of 15.62 µg/ml. Compounds had weaker antifungal and antibacterial activity in the range of MIC 500-62.5 µg/ml against standard bacterial and fungal strains. Besides these above, molecular docking studies were performed to examine and evaluate the interaction of the remarkable compounds (3b, 6a and 6b) against the current enzymes (CAs and AChE). Novel compounds gained interest in terms of enzyme inhibitory potencies. Therefore, the most potent enzyme inhibitors may be considered lead compounds to be modified for further research.Communicated by Ramaswamy H. Sarma.

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The review focuses on recent advances in the methodologies for the formation or introduction of the CH2F moiety in N-heterocyclic substrates over the past 5 years. The monofluoromethyl group is one of the most versatile fluorinated groups used to modify the properties of molecules in synthetic medical chemistry. The review summarizes two strategies for the monofluoromethylation of N-containing heterocycles: direct monofluoromethylation with simple XCH2F sources (for example, ICH2F) and the assembly of N-heterocyclic structures from CH2F-containing substrates. The review describes the monofluoromethylation of pharmaceutically important three-, five- and six-membered N-heterocycles: pyrrolidines, pyrroles, indoles, imidazoles, triazoles, benzothiazoles, carbazoles, indazoles, pyrazoles, oxazoles, piperidines, morpholines, pyridines, quinolines and pyridazines. Assembling of 6-fluoromethylphenanthridine, 5-fluoromethyl-2-oxazolines, C5-monofluorinated isoxazoline N-oxides, and α-fluoromethyl-α-trifluoromethylaziridines is also shown. Fluoriodo-, fluorchloro- and fluorbromomethane, FCH2SO2Cl, monofluoromethyl(aryl)sulfoniummethylides, monofluoromethyl sulfides, (fluoromethyl)triphenylphosphonium iodide and 2-fluoroacetic acid are the main fluoromethylating reagents in recent works. The replacement of atoms and entire functional groups with a fluorine atom(s) leads to a change and often improvement in activity, chemical or biostability, and pharmacokinetic properties. The monofluoromethyl group is a bioisoster of -CH3, -CH2OH, -CH2NH2, -CH2CH3, -CH2NO2 and -CH2SH moieties. Bioisosteric replacement with the CH2F group is both an interesting task for organic synthesis and a pathway to modify drugs, agrochemicals and useful intermediates.

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In 1971, chemists from Hoffmann-La Roche and Schering AG independently discovered a new asymmetric intramolecular aldol reaction catalyzed by the natural amino acid proline, a transformation now known as the Hajos-Parrish-Eder-Sauer-Wiechert reaction. These remarkable results remained forgotten until List and Barbas reported in 2000 that L-proline was also able to catalyze intermolecular aldol reactions with non-negligible enantioselectivities. In the same year, MacMillan reported on asymmetric Diels-Alder cycloadditions which were efficiently catalyzed by imidazolidinones deriving from natural amino acids. These two seminal reports marked the birth of modern asymmetric organocatalysis. A further important breakthrough in this field happened in 2005, when Jørgensen and Hayashi independently proposed the use of diarylprolinol silyl ethers for the asymmetric functionalization of aldehydes. During the last 20 years, asymmetric organocatalysis has emerged as a very powerful tool for the facile construction of complex molecular architectures. Along the way, a deeper knowledge of organocatalytic reaction mechanisms has been acquired, allowing for the fine-tuning of the structures of privileged catalysts or proposing completely new molecular entities that are able to efficiently catalyze these transformations. This review highlights the most recent advances in the asymmetric synthesis of organocatalysts deriving from or related to proline, starting from 2008.

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Asymmetric [3+2] cycloaddition reactions are fascinating and powerful methods for the synthesis of enantioenriched pyrrolidines up to four stereocentres. Pyrrolidines are important compounds for both biology and organocatalytic applications. This review summarizes the most recent advances in the enantioselective synthesis of pyrrolidines by [3+2] cycloadditions of azomethine ylides using metal catalysis. It has been organized by the type of metal catalysis used and further arranged by the complexity nature of dipolarophile. The presentation of each reaction type highlights their advantages and limitations.

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We have prepared a ligand library based on a ferrocenyl aziridinyl methanol core unit (simply called FAM) having a phenyl group, a cyclohexyl group, and a naphthyl group to be used in 1,3-dipolar cycloaddition (1,3-DC) reactions for the synthesis of chiral pyrrolidines. These chiral ligands were used with AgOAc in 1,3-DC reactions taking place between the aryl-substituted azomethine ylides and N-methylmaleimide as the dipolarophile. In each case, the expected aryl-substituted pyrrolidines were obtained in good to excellent yields with acceptable enantioselectivities favoring only the endo product. The chiral catalyst system CFAM4-AgOAc was also used in 1,3-DC reaction with different dipolarophiles such as dimethyl maleate, tert-butyl acrylate, methyl acrylate, trans-chalcone, and vinyl sulfone. In each case, the cycloadducts were obtained in acceptable yields albeit with low ee. Fortunately, it was possible to increase the ee up to >99% upon crystallization.

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The AgOAc-catalysed reaction of 3-nitro-2-phenyl-2H-chromenes with stabilized azomethine ylides generated from the imines based on methyl glycinate and arylaldehydes leads to a mixture of endo and endo' isomers of the corresponding chromeno[3,4-c]pyrrolidines in a ratio of 2.0-2.3:1 in 85-93% total yields as a result of a Michael addition/Mannich reaction sequence. In a similar reaction involving 2-trifluoromethyl-3-nitro-2H-chromenes, only endo chromeno[3,4-c]pyrrolidines are formed in 85-94% yields. 3-Nitro-2-(trichloromethyl)-2H-chromenes under the same conditions react with these azomethine ylides to give the corresponding Michael adducts as individual anti-isomers with the cis,trans-configuration of the chromane ring in 40-67% yields. Some 4-CF3-substituted chromano[3,4-c]pyrrolidines exhibited high cytotoxic activity against HeLa human cervical carcinoma cells.

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The title compound, bis-(oxotremorine) fumarate bis-(fumaric acid) {systematic name: 1-[4-(2-oxopyrrolidin-1-yl)but-2-yn-yl]pyrrolidinium (2E)-but-2-ene-di-o-ate bis-[(2E)-but-2-enedioic acid]}, 2C12H19N2O+·C4H2O4 2-·2C4H4O4, has a single oxotremorine monocation protonated at the pyrrolidine nitro-gen, one fumaric acid mol-ecule and half of a fumarate dianion in the asymmetric unit. The ions and fumaric acid mol-ecules are held together by N-H⋯O and O-H-⋯O hydrogen bonds in 40-membered rings with graph-set notation R 6 6(40). The fumarate ions join these rings into infinite chains along [001].

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A new series of syn-functionalised chiral hydroxy pyrrolidines and pyrrolidones containing α,ß-contiguous stereocenters were synthesized via a diphenylprolinol-catalysed asymmetric cross aldol reaction. The synthesized compounds were characterised and evaluated for their α-glucosidase inhibitory potential. The hydroxy pyrrolidine series (9a-9i) was found to be selectively more potent against the α-glucosidase enzyme as compared to the pyrrolidone series (10a-10i). Pyrrolidine 9b was the most efficacious analogue with an IC50 of 48.31 µM. Compounds 9c, 9d, & 9f were also found to be more potent than the standard drugs acarbose, miglitol and deoxynojirimycin. Furthermore, these compounds were investigated by computational studies using the GLIDE docking module of the Schrödinger suite 2021-4 in which 9b and 9c showed more promising results than the standard drugs acarbose, miglitol, and deoxynojirimycin.

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Applications of piperazine and homopiperazine in drug design are well-established, and these heterocycles have found use as both scaffolding and terminal elements and also as a means of introducing a water-solubilizing element into a molecule. In the accompanying review (10.1021/acs.jafc.2c00726), we summarized applications of piperazine and homopiperazine and their fused ring homologues in bioactive compound design along with illustrations of the use of 4-substituted piperidines and a sulfoximine-based mimetic. In this review, we discuss applications of pyrrolidine- and fused-pyrrolidine-based mimetics of piperazine and homopiperazine and illustrate derivatives of azetidine that include stretched and spirocyclic motifs, along with applications of a series of diaminocycloalkanes.

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A general and flexible approach toward the development of α-l-rhamnosidase (α-l-Rha-ase) inhibitors is described. Five enantiopure poly-substituted pyrrolidine-based scaffolds bearing the C1-aminomethyl moiety were designed and synthesized from five-membered cyclic nitrones. Each structurally diversified amide library of these scaffolds was rapidly generated via combinatorial parallel synthesis and applied for in-situ inhibition study against α-l-Rha-ase, allowing us to efficiently identify new inhibition hits. Surprisingly, all promising inhibitors are derived from the same scaffold 3. Among them, the most potent and selective inhibitor is pyrrolidine 19 with Ki =0.24 µM, approximately 24-fold more potent than the reference compound DAA (Ki =5.7 µM). It is the first study to comprehensively prepare pyrrolidine-based scaffolds and libraries for inhibition study against α-l-Rha-ase.

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A phosphine-catalyzed highly enantioselective and diastereoselective (up to 98 % ee and >20 : 1 dr) (3+2) annulation between vinylcyclopropanes and N-tosylaldimines has been developed, which allows facile access to a range of highly functionalized chiral pyrrolidines. Notably, this method makes use of vinylcyclopropanes as a synthon for phosphine-mediated asymmetric annulation reaction, which will offer new opportunities for potential applications of cyclopropanes substrates in phosphine-catalyzed organic transformations.

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Nature often uses cascade reactions in a highly stereocontrolled manner for assembly structurally diverse nitrogen-containing heterocyclic scaffolds, i.e. secondary metabolites, important for medicinal chemistry and pharmacy. Five-membered nitrogen-containing heterocycles as standalone rings, as well as spiro and polycyclic systems are pharmacophores of drugs approved in various therapies, i.a. antibacterial or antiviral, antifungal, anticancer, antidiabetic, as they target many key enzymes. Furthermore, a large number of pyrrolidine derivatives are currently considered as drug candidates. Cascade transformations, also known as domino or tandem reactions, offer straightforward methods to build N-heterocyclic libraries of the great structural variety desired for drawing SAR conclusions. The tandem transformations are often atom economic and time-saving because they are performed as the one-pot, so no need for purification after each 'virtual' step and the limited necessity of protective groups are characteristic for these processes. Thus, the same results as in classical multistep synthesis can be achieved at markedly lower costs and shorter time, which is in line with modern green chemistry rules. Great advantage of cascade reactions is often reflected in their high regio- and stereoselectivities, enabling the preparing of the heterocyclic compound better fitted to the expected target in cells. This review reveals the biological relevance of N-heterocyclic scaffolds based on saturated 5-membered rings since we showed a number of examples of approved drugs together with the recent biologically attractive leading structures of drug candidates. Next, novel cascade synthetic procedures, taking into account the structure of the reactants and reaction mechanisms, enabling to obtain biological-relevant heterocyclic frameworks with good yields and relatively high stereoselectivity, were reviewed and compared. The review covers the advances of designing biological active N-heterocycles mainly from 2018 to 2021, whereas the synthetic part is focused on the last 7 years.

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The synthesis of a variety of enantioenriched 2,2-disubstituted pyrrolidines is described. A stereogenic quaternary center is first formed utilizing an asymmetric allylic alkylation reaction of a benzyloxy imide, which can then be reduced to a chiral hydroxamic acid. This compound can then undergo a thermal "Spino" ring contraction to afford a carbamate protected 2,2-disubstituted pyrrolidine stereospecifically. These pyrrolidines can be further advanced to enantioenriched indolizidine compounds. This reaction sequence allows access to new molecules that could be useful in the development of pharmaceutical agents.

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Objective:To establish an optimized automatic synthesis method of 18F-fallypride, and evaluate its biodistribution and microPET/CT characteristics. Methods:18F-fallypride was automatically prepared by AIO synthesis module and disposable cassette & reagents kit. The crude product was purified by a dedicated coupled column (HLB+ Alumin-N) to obtain the final product. Radiochemical purity and radiolabeling yield were determined. Parkinson′s disease (PD) model mice and rats were established. The radioactive distribution of different organs of PD model mice ( n=24) were monitored. The distribution process of the agent in the SD rat brain (PD model, n=6; normal rat, n=6) were evaluated by microPET/CT imaging. Results:The radiochemical yield of 18F-fallypride synthesized by automatic synthesis module was stable at (10±1)% ( n=5, no decay corrected). The total synthesis time was about 40 min. The radiochemical purity of 18F-fallypride was more than 95%, and the radiochemical purities were also over 95% after being stored in saline and serum for 120 min at room temperature. 18F-fallypride was mainly excreted by the kidneys, and it was less radioactive intake in the liver and spleen in PD mice. MicroPET/CT imaging showed that higher accumulation of 18F-fallypride was noted in corpus striatum and the SUV ratio of PD group was lower than that of control group (5.00±0.93 vs 6.53±1.96). Conclusion:18F-fallypride can be successfully prepared automatically by improved multifunctional module, with the advantages of convenient preparation, stable radiochemical yield, satisfying purity and quality control, so it can be used in the follow-up standardized production of Good Manufacture Practice (GMP) system.

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The reactions of N-sulfonylhydrazones derived from cyclic ketones with γ-azidopropylboronic acid and 2-(azidomethyl)phenylboronic acid give rise to spirocyclic pyrrolidines and spiroisoindolines, respectively. The reactions proceed without the need of any transition-metal catalyst through a domino process that comprises the formation of a Csp3 -C and a Csp3 -N bond of the former hydrazonic carbon. The scope of the reaction has been explored by the preparation of over 50 examples of NH-unprotected spirocyclic derivatives. Importantly, this methodology could be applied for the preparation of alkaloid steroids from steroid N-tosylhydrazones.

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A new highly diastereoselective synthesis of the polyhydroxylated pyrrolidine alkaloid (±)-codonopsinol B and its N-nor-methyl analogue, starting from achiral materials, is presented. The strategy relies on the trans-stereoselective epoxidation of 2,3-dihydroisoxazole with in situ-generated DMDO, the syn-selective α-chelation-controlled addition of vinyl-MgBr/CeCl3 to the isoxazolidine-4,5-diol intermediate, and the substrate-directed epoxidation of the terminal double bond of the corresponding γ-amino-α,ß-diol with aqueous hydrogen peroxide catalyzed by phosphotungstic heteropoly acid. Each of the key reactions proceeded with an excellent diastereoselectivity (dr > 95:5). (±)-Codonopsinol B was prepared in 10 steps with overall 8.4% yield. The antiproliferative effect of (±)-codonopsinol B and its N-nor-methyl analogue was evaluated using several cell line models.

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1,3-Dipolar cycloaddition reactions of 2-substituted 5-R-3-nitropyridines and isomeric 3-R-5-nitropyridines with N-methyl azomethine ylide were studied. The effect of the substituent at positions 2 and 5 of the pyridine ring on the possibility of the [3+2]-cycloaddition process was revealed. A number of new derivatives of pyrroline and pyrrolidine condensed with a pyridine ring were synthesized.