Addition Cyclization Research Articles

A novel 4-hydroxypyrene-based “off–on” fluorescent probe with large Stokes shift for detecting cysteine and its application in living cells

This paper reports a novel fluorescent probe 4-acrylatepyrene (PYAC) based on 4-hydroxypyrene, which can effectively detect cysteine (Cys). The probe PYAC uses acrylate moiety as a recognition site and has relatively high selectivity and sensitivity for Cys with the detection limit of 0.062 μM. After treatment with Cys, PYAC exhibits “off–on” switching property and large Stokes shift (171 nm). Due to nucleophilic addition and specific intramolecular cyclization, it exhibits higher selectivity for Cys than other amino acids and common ions, including homocysteine (Hcy) and glutathione (GSH) with similar structures to Cys. The recognition mechanism has been characterized by high-performance liquid chromatography (HPLC) and nuclear magnetic resonance spectroscopy (1H NMR). Anti-interference test and pH influence test display it is suitable for detecting Cys in living cells. Finally, the probe PYAC has been successfully applied to cell imaging with negligible cytotoxicity.

Iron(III) Chloride/Phenylsilane‐Mediated Cascade Reaction of Allyl Alcohols with Maleimides: Synthesis of Poly‐Substituted γ‐Butyrolactones

AbstractA iron‐catalyzed free radical cascade reaction of allyl alcohols with N‐substituted maleimides for accessing poly‐substituted γ‐butyrolactones has been developed. In this protocol, various allyl alcohols can open N‐substituted maleimide rings to form allyl ester intermediates, and the allyl ester intermediates can be converted into an allyl ester alkyl radicals and undergo intramolecular free radical addition cyclization to form a polysubstituted γ‐butyrolactones. In this protocol, spiro γ‐butyrolactone compounds can be also synthesized. Meanwhile, the strategy could be applied to further construct a fully substituted tetrahydrofuran. The reaction is not sensitive to oxygen or moisture and has been performed on gram‐scale.magnified image

Recent progress of synthesis of new arylazoazoles based on bis(carbothioamides)

In this study, new bisthiazoles were efficiently synthesized from the reaction of hydrazine-1,2-bis(carbothioamide) with N-aryl-2-oxopropanehydrazonoyl chlorides or N-aryl C-ethoxycarbonyl methanehydrazonoyl chlorides. The formation of the final compounds starts by nucleophilic attack of thiolates to give S-alkylated intermediate, which in situ undergoes nucleophilic addition and intramolecular cyclization to give the final products as described in the synthetic schemes. The inexpensive and simple reaction conditions, commercial availability of the reagent, good yields and excellent purities of the products make this method valuable from a preparative point of view. Furthermore, the antibacterial activities values of the new compounds were evaluated against Gram-positive and Gram-negative microorganisms. The final products were identified and characterized by elemental analysis, Fourier transforms infrared spectroscopy (FT-IR), mass spectrometry (MS), and nuclear magnetic resonance (NMR).

A facile approach for synthesis of thiazines-, thiazoles- and triazoles-annulated 6-styryl-2-thiouracil derivative

Utility of 4-oxo-6-styryl-2-thioxo-1,2,3,4-tetrahydropyrimidine-5-carbonitrile 1 in synthesis of a new series of fused pyrimidines was described. Pyrimido[2,1-b][1,3]thiazines 6–9 were obtained via Michael addition of compound 1 to the polarized systems 2–5 in the presence of nanosized ZnO. S-alkylation of pyrimidine 1 followed by cyclization with phenacyl bromide, monochloroacetic acid, chloroacetonitrile and oxalyl chloride afforded the desired thiazolo[3,2-a]pyrimidines 10–13. Hydrazinolysis of compound 1 followed by addition cyclization with acetic anhydride, formic acid, carbon disulfide and benzoyl chloride afforded triazolo[4,3-a]pyrimidines 15–18. The antimicrobial screening showed high activity for thiazolo[3,2-a]pyrimidines 11 and 12 against both Gram (+ ve) and Gram (− ve) bacteria.

Synthesis and antitumor activity of sacroflavonoside

Sacroflavonoside, a new derivative of diphenylethene, was isolated from Artemisia sacrorum, which have been found to possess the inhibitory effect on the proliferation of gastric carcinoma cells (MKN-45) in vitro in our previous studies. With anisaldehyde (SM-A) as starting material, the sacroflavonoside was synthesized by nucleophilic addition, electrophilic substitution and dehydration cyclization. The structure of sacroflavonoside was established by 1 D (1H NMR and 13C NMR) and 2 D-NMR (HSQC and HMBC) spectral analysis. The antitumor activity and potential mechanism against MKN-45 cells of sacroflavonoside were evaluated in vitro. The results showed that sacroflavonoside could significantly induce MKN-45 cells apoptosis and autophagy by increasing the expression of Bax, Caspase-3, Beclin1 and LC3-II proteins and decreasing the expression of Bcl-2 protein at low micromole level. This investigation provided a valuable lead structure for the development of antitumor drugs.

Asymmetric Organocatalytic Michael Addition–Cyclisation Cascade of Cyclopentane-1,2-dione with Alkylidene Malononitriles

An asymmetric organocatalytic cascade reaction between cyclopentane-1,2-diones and alkylidene malononitriles affords highly substituted 4H-pyrans in moderate to high enantiomeric excess. The selective reduction of a bridged double bond leads to the formation of cis-substituted cyclopentanone with three contiguous stereogenic centres.

A water-soluble near-infrared fluorescent probe for sensitive and selective detection of cysteine

A near-infrared (NIR) fluorescent probe (Cys-AN) for selective and sensitive detection of cysteine (Cys) was designed and synthesized. The fluorescent probe was water-soluble and had a large Stokes shift of 150 nm, whose detection limit could reach to 0.96 μM in PBS buffer. After we analyzed the HRMS, TLC and optical data, a proposed sensing mechanism for the detection of Cys could result from the Michael addition and intramolecular cyclization reactions between the probe and Cys, followed by intramolecular charge transfer (ICT) process to afford the NIR fluorescent signal at 674 nm. Meanwhile, Cys-AN exhibited low cytotoxicity, and was successfully applied for bioimaging of Cys in living cells.

Sequential Intermolecular Radical Addition and Reductive Radical Cyclization of Tyrosine and Phenylalanine Derivatives with Alkenes via Photoinduced Decarboxylation: Access to Ring-Constrained γ-Amino Acids.

Sequential radical addition to alkenes and reductive radical cyclization of phenylalanine and tyrosine derivatives via photoinduced decarboxylation furnished ring-constrained γ-amino acids under mild conditions. A variety of alkenes such as acrylamides and acrylic esters could be employed in the photoinduced radical cascade cyclization. The yields of the ring-constrained γ-amino acids are dependent on the electron-accepting ability and steric hindrance of the alkene used. The proposed sequential reaction can also be applied for direct tethering of dipeptides to yield unique ring-constrained tetrapeptides.

Phase-Transfer-Catalyzed, Enantioselective Vinylogous Conjugate Addition-Cyclization of Olefinic Azlactones To Access Multifunctionalized Chiral Cyclohexenones.

An asymmetric, phase-transfer-catalyzed vinylogous conjugate addition-vinylogous cyclization cascade of olefinic azlactones with 4-nitro-5-styrylisoxazoles is reported. In the presence of an l- tert-leucine-derived urea-quaternary ammonium salt as a bifunctional phase-transfer catalyst and KF, two series of valuable optically pure cyclohexenones featuring two and three stereocenters were obtained in high yields with good to excellent enantio- and diastereoselectivities.

Addition–cyclization reactions of furan-2-carbonyl isothiocyanate with nitrogen nucleophiles as a synthetic route to novel azines and azoles of potential biological activity

Heterocyclization of furan-2-carbonyl isothiocyanate 1 with a variety of aliphatic and aromatic nitrogen nucleophiles resulted in the formation of a new series of heterocycles including triazines, pyrimidines, oxadiazines, imidazolidines, thiadiazoles and their condensed candidates. The antibacterial screening for a group of the newly synthesized compounds showed that they possess moderate antibacterial activities against examples of Gram-positive and Gram-negative bacteria.

Total Synthesis of (−)‐Daphenylline

AbstractA concise and highly stereoselective total synthesis of the Daphniphyllum alkaloids (−)‐daphenylline has been accomplished. The synthesis was started from (S)‐carvone and proceeded via a stereoselective Mg(ClO4)2‐catalyzed intramolecular amide addition cyclization, an intramolecular Diels–Alder reaction to construct the ABCD tetracyclic core architecture, and a Robinson annulation coupled with an oxidative aromatization sequence. Finally, the DF ring system was installed through an intramolecular Friedel–Crafts cyclization. The total synthesis of (−)‐daphenylline is achieved in 19 steps in the longest reaction sequence and in 7.6 % overall yield.

Total Synthesis of (−)‐Daphenylline

A concise and highly stereoselective total synthesis of the Daphniphyllum alkaloids (-)-daphenylline has been accomplished. The synthesis was started from (S)-carvone and proceeded via a stereoselective Mg(ClO4 )2 -catalyzed intramolecular amide addition cyclization, an intramolecular Diels-Alder reaction to construct the ABCD tetracyclic core architecture, and a Robinson annulation coupled with an oxidative aromatization sequence. Finally, the DF ring system was installed through an intramolecular Friedel-Crafts cyclization. The total synthesis of (-)-daphenylline is achieved in 19 steps in the longest reaction sequence and in 7.6 % overall yield.

A new fluorescent probe for specific detection of cysteine with facile preparation and living cell imaging

The detection of cysteine (Cys) is of great significance ascribed to its important role in physiological and psychological process. This paper reported a new fluorescent probe CBFA with red emission signal, which can be prepared through a simple method and exhibited potential application value. Solution experiments demonstrated that the probe revealed high selectivity towards Cys in spite of the interference of its two analogues, homocysteine (Hcy) and glutathione (GSH). And the sensitivity indicated that the probe was suitable for Cys detection in living cells. Furthermore, the recognition mechanism was confirmed to be a concerted reaction including Michael addition and intramolecular cyclization by high resolution mass spectrometer (HRMS) and high-performance liquid chromatography (HPLC). Besides, CBFA showed favorable pH adaptability in biological conditions and low cytotoxicity. Finally, CBFA was successfully applied to selectively imaging Cys in living MCF-7 cells with good cell permeability. We hope this probe will bring some help to the diagnosis of Cys-related diseases.

Synthesis of substituted dihydro-1H-pyrazoles and 1H-pyrazoles via formal [4+1] annulation of α-arylhydrazonoketones and dimethyl sulfonium methylides

A formal [4+1] annulation of readily available α-arylhydrazonoketones and dimethyl sulfonium methylides is described, which involving tandem ylide-mediated addition and nucleophilic cyclization reactions. This transformation features mild reaction conditions, simple execution, good to high yields, and provides straightforward synthesis of substituted dihydro-1H-pyrazoles and 1H-pyrazoles via C-C and C-N bond formation.

Trans-Diastereoselective Syntheses of γ-Lactones by Visible Light-Iodine-Mediated Carboesterification of Alkenes.

This study aims to develop an intermolecular lactonization reaction of alkenes with carbonyls mediated by visible light and molecular iodine. The one-step reaction involved the carboesterification of alkenes to produce the corresponding lactones in moderate to good yield. It was also revealed that it is possible to control the diastereoselectivity of the reaction by altering the base used and the reaction conditions. When water was added as a solvent, the reaction resulted in the formation of lactones with trans-selectivity. A mechanistic investigation was undertaken and it was found that the reaction requires the generation of an iodine radical from molecular iodine, driven by visible light irradiation, and proceeds via the formation of an iodine radical alkene adduct. The proposed reaction is an example of a rare-metal free intermolecular addition cyclization reaction, which is an environment-friendly chemical process that only uses molecular iodine. In addition, since diastereoselectivity was observed without the use of any specific reagents, the developed methodology is an example of a novel stereoselective transformation using only cost-effective reagents.

MOF‐promoted Three‐component Synthesis of Functionalized Pyrano[3,2‐c]chromen under Mild Conditions

A convenient and efficient route for synthesis of various derivatives of 3‐benzoyl‐4‐phenyl‐2‐(trifluoromethyl)pyrano[3,2‐c]chromen‐5(4H)‐one has been used via tandem Knoevenagel condensation–Michael addition and intramolecular cyclization sequence. These products have been synthesized in the presence of catalytic amount of metal–organic framework (MOF) and potassium carbonate as one‐pot, three‐component reaction. MOF catalyst has been separated easily with external magnet, and high purity of products has been obtained after washing with ethanol. This protocol has advantages of simplicity, mild condition, and high yield. More importantly, MOF has been easily recycled for three times.

Direct pathway cloning of the sodorifen biosynthetic gene cluster and recombinant generation of its product in E. coli

BackgroundSerratia plymuthica WS3236 was selected for whole genome sequencing based on preliminary genetic and chemical screening indicating the presence of multiple natural product pathways. This led to the identification of a putative sodorifen biosynthetic gene cluster (BGC). The natural product sodorifen is a volatile organic compound (VOC) with an unusual polymethylated hydrocarbon bicyclic structure (C16H26) produced by selected strains of S. plymuthica. The BGC encoding sodorifen consists of four genes, two of which (sodA, sodB) are homologs of genes encoding enzymes of the non-mevalonate pathway and are thought to enhance the amounts of available farnesyl pyrophosphate (FPP), the precursor of sodorifen. Proceeding from FPP, only two enzymes are necessary to produce sodorifen: an S-adenosyl methionine dependent methyltransferase (SodC) with additional cyclisation activity and a terpene-cyclase (SodD). Previous analysis of S. plymuthica found sodorifen production titers are generally low and vary significantly among different producer strains. This precludes studies on the still elusive biological function of this structurally and biosynthetically fascinating bacterial terpene.ResultsSequencing and mining of the S. plymuthica WS3236 genome revealed the presence of 38 BGCs according to antiSMASH analysis, including a putative sodorifen BGC. Further genome mining for sodorifen and sodorifen-like BGCs throughout bacteria was performed using SodC and SodD as queries and identified a total of 28 sod-like gene clusters. Using direct pathway cloning (DiPaC) we intercepted the 4.6 kb candidate sodorifen BGC from S. plymuthica WS3236 (sodA–D) and transformed it into Escherichia coli BL21. Heterologous expression under the control of the tetracycline inducible PtetO promoter firmly linked this BGC to sodorifen production. By utilizing this newly established expression system, we increased the production yields by approximately 26-fold when compared to the native producer. In addition, sodorifen was easily isolated in high purity by simple head-space sampling.ConclusionsGenome mining of all available genomes within the NCBI and JGI IMG databases led to the identification of a wealth of sod-like pathways which may be responsible for producing a range of structurally unknown sodorifen analogs. Introduction of the S. plymuthica WS3236 sodorifen BGC into the fast-growing heterologous expression host E. coli with a very low VOC background led to a significant increase in both sodorifen product yield and purity compared to the native producer. By providing a reliable, high-level production system, this study sets the stage for future investigations of the biological role and function of sodorifen and for functionally unlocking the bioinformatically identified putative sod-like pathways.

A coumarin chalcone ratiometric fluorescent probe for hydrazine based on deprotection, addition and subsequent cyclization mechanism.

A ratiometric fluorescent probe for hydrazine based on a coumarin chalcone framework and a levulinic acid terminal group with a low detection limit (0.1 ppb, 0.003 μM), a large ratiometric fluorescence change (I465/I575, 1265-fold enhancement) and a wide pH work range (3.0-12.0) was developed. The mechanism analysis of the isolated hydrazine product characterized by NMR, HRMS and the crystal structure indicates that the levulinic acid group is firstly removed by deprotection and then the dihydropyrazole ring is formed due to the addition and subsequent cyclization reaction in the presence of hydrazine.

1,2-Addition versus homoconjugate addition reactions of indoles and electron-rich arenes to α-cyclopropyl N-acyliminium ions: synthetic and computational studies.

An investigation of the reactivity of α-cyclopropyl N-acyliminium ions towards indoles has resulted in the unprecedented synthesis of 5-cyclopropyl-5-(3-indoyl)pyrrolidin-2-ones via 1,2-addition reactions and, in the case of highly electron deficient indoles and electron rich arenes, spiroheterocycles via sequential homoconjugate and 1,2-addition reactions with often high diastereoselective control at the C-5 quaternary stereocentres. Computational studies provided support for the proposed mechanisms and stereochemical outcome of these reactions, clearly showing that the 1,2-addition pathway is kinetically controlled. In reactions where the 1,2-adduct is destabilised, for example when the arene ring is less nucleophilic, the 1,2-addition is reversible and the thermodynamically preferred homoconjugate addition and subsequent rearrangement and cyclisation reactions become the major pathway.

Visible-light-induced tandem radical addition–cyclization of 2-aryl phenyl isocyanides catalysed by recyclable covalent organic frameworks

A heterogeneous visible-light-induced tandem radical addition–cyclization of isocyanides by photoactive covalent organic frameworks was developed, delivering diverse phenanthridines with high reaction efficiency and easy catalyst recyclability.