Regioselective Cyclization Research Articles

Gold(I)-Catalyzed Regioselective Cyclization to Access Cyclopropane-Fused Tetrahydrobenzochromenes.

Gold(I)-catalyzed efficient synthetic transformation was achieved to access the tetrahydrobenzo[h]cyclopropa[c]chromenes from allyl-substituted 1,6-diynes. Cyclopropane-fused tetrahydrobenzochromenes were obtained regioselectively in ≤92% yields. In this atom-economic organic transformation, three new C-C bonds were formed sequentially in one pot.

Cp*RhIII-Catalyzed Cascade Annulation of Arylimidates with Pyridotriazoles toward Isoquinolin-3-ol Derivatives.

A Cp*RhIII-catalyzed efficient synthesis of isoquinolin-3-ol derivatives bearing a pyridinyl ring using imidate as a directing group under C-H activation strategy with pyridotriazoles as carbene reagents is reported. In this reaction, cascade C-H activation, regioselective cyclization, and elimination occur in one pot. The present methodology featured a good range of functional group tolerance and furnished the target products in moderate-to-excellent yields.

Synthesis of Pyrrolidin-5-one-2-carboxamides through Cyclization of N-Substituted-2-alleneamides

The synthesis of pyrrolidin-5-one-2-carboxamides 6a-p has been developed via a one-pot Ugi reaction of allenic acids, primary amines, isocyanides, and aldehydes followed by regioselective cyclization of the resultant N-substituted-2-allenamides with KOt-Bu at room temperature. The cyclization reaction was carried out through a 5-exo-dig approach, which resulted in good yields and high atom-economy under transition-metal-free and mild reaction conditions.

Synthesis of Tetrahydrofuro[2,3-d]oxazoles and Oxazoles by Hypervalent Iodine (III)-Promoted [2 + 2 + 1] Annulation.

Reaction of a hypervalent iodine reagent with bistriflimide efficiently promotes three-component regioselective cyclization of tetrahydrofuro[2,3-d]oxazoles and oxazoles from homopropargyl alcohols bearing a phenyl group, with different substituents on the aryl alkyne compounds affecting the selectivity of the resulting product. Utilizing the hydroxyethyl oxazole derivatives obtained in this research could aid in the development of various peroxisome proliferator-activated receptor agonist derivatives.

Fe(III)-catalyzed regioselective and faster synthesis of isocoumarins with 3-oxoalkyl moiety at C-4: Identification of new inhibitors of PDE4

In search of potent and new anti-inflammatory agents, we explored a new class of isocoumarin derivatives possessing the 3-oxoalkyl moiety at C-4 position. These compounds were synthesized via the FeCl3 catalyzed construction of isocoumarin ring. The methodology involved coupling of 2-alkynyl benzamides with alkyl vinyl ketone and proceeded via a regioselective cyclization to give the desired compound as a result of formation of CO and CC bonds. A large number of isocoumarins were synthesized and assessed against PDE4B in vitro. While isocoumarins containing an aminosulfonyl moiety attached to the C-3 aryl ring showed encouraging inhibition of PDE4B, some of the derivatives devoid of aminosulfonyl moiety also showed considerable inhibition. According to the SAR analysis the C6H4NHSO2R2-m moiety at C-3 position of the isocoumarin ring was favorable when the R2 was chosen as an aryl or 2-thienyl group whereas the presence of F or OMe substituent at C-7 of the isocoumarin ring was found to be beneficial. The compound 5f with IC50 values 0.125 ± 0.032 and 0.43 ± 0.013 µM against PDE4B and 4D, respectively was identified as an initial hit. It showed in silico interaction with the PHE678 residue in the CR3 region of PDE4B and relatively less number of interactions with PDE4D. Besides showing the PDE4 selectivity over other PDEs and TNF-α inhibition in vitro the compound 5f at an intraperitoneal dose of 30 mg/kg demonstrated the protective effects against the development of arthritis and potent immunomodulatory activity in adjuvant induced arthritic (AIA) rats. Furthermore, no significant adverse effects were observed for this compound when evaluated in a systematic toxicity (e.g. teratogenicity, hepatotoxicity and cardiotoxicity) studies in zebrafish at various concentrations. Collectively, being a new, potent, moderately selective and safe inhibitor of PDE4B the isocoumarin 5f can be progressed into further pharmacological studies.

Deciphering and reprogramming the cyclization regioselectivity in bifurcation of indole alkaloid biosynthesis.

The metabolism of monoterpene indole alkaloids (MIAs) is an outstanding example of how plants shape chemical diversity from a single precursor. Here we report the discovery of novel enzymes from the Alstonia scholaris tree, a cytochrome P450, an NADPH dependent oxidoreductase and a BAHD acyltransferase that together synthesize the indole alkaloid akuammiline with a unique methanoquinolizidine cage structure. The two paralogous cytochrome P450 enzymes rhazimal synthase (AsRHS) and geissoschizine oxidase (AsGO) catalyse the cyclization of the common precursor geissoschizine and they direct the MIA metabolism towards to the two structurally distinct and medicinally important MIA classes of akuammilan and strychnos alkaloids, respectively. To understand the pathway divergence, we investigated the catalytic mechanism of the two P450 enzymes by homology modelling and reciprocal mutations. Upon conducting mutant enzyme assays, we identified a single amino acid residue that mediates the space in active sites, switches the enzymatic reaction outcome and impacts the cyclization regioselectivity. Our results represent a significant advance in MIA metabolism, paving the way for discovery of downstream genes in akuammilan alkaloid biosynthesis and facilitating future synthetic biology applications. We anticipate that our work presents, for the first time, insights at the molecular level for plant P450 catalytic activity with a significant key role in the diversification of alkaloid metabolism, and provides the basis for designing new drugs.

Synthesis and biological evaluation of polyfluoroalkyl-containing 4-arylhydrazinylidene-isoxazoles as antifungal agents with antioxidant activity

The regioselective cyclization of 2-arylhydrazinylidene-3-polyfluoroalkyl-3-oxo esters with hydroxylamine resulted in 4-arylhydrazinylidene-3-polyfluoroalkylisoxazol-5-ones, while the analogous reaction of 2-arylhydrazinylidene-3-polyfluoroalkyl-1,3-diketones led to 4-arylhydrazinylidene-5-polyfluoroalkyldihydroisoxazol-5-oles, which were dehydrated to 4-arylhydrazinylidene-5-polyfluoroalkylisoxazoles. To explain a regioselectivity of reactions, the quantum-chemical calculations were performed. The structure of the synthesized compounds was confirmed by IR, NMR spectroscopy, mass spectrometry, elemental analysis and X-Ray diffraction analysis. Almost all isoxazolones and dihydroisoxazoles demonstrated an inhibitory action against the majority of investigated strains of dermatophytes Trichophyton family, E. floccosum, and M. canis, while isoxazoles were found to be inactive. The lead compounds were 4-tolylhydrazinylidene-3-trifluoromethylisoxazol-5-one, 3-methyl-5-pentafluoroethyl- and 3-phenyl-5-trifluoromethyl-4-tolylhydrazinylidenedihydroisoxazol-5-oles having the antifungal activity against all dermatophyte strains (MIC 0.78…25 μg/kg) and C. ablicans yeasts (MIC 25 μg/kg). Seven derivatives showed a moderate antibacterial activity against N. gonorrhoeae (MIC 31.2…62.5 μg/kg). In addition, dihydroisoxazololes demonstrated a high antioxidant activity in the ABTS (TEAC is up to 2.0) and FRAP (TE is up to 1.91) tests, which could be helpful for hepatotoxicity reducing. The results obtained show the absence of anticholinesterase activity in all the compounds and demonstrate a weak inhibition of CES by most of the compounds, that should be taken into consideration in the therapeutic use of the compounds in high doses.

Palladium Catalyzed Regioselective Cyclization of Arylcarboxylic Acids via Radical Intermediates with Diaryliodonium Salts

Palladium-catalyzed C2-arylation/intramolecular acylation with arylcarboxylic acids was developed by using diaryliodonium salts. The protocol has the advantage of good step-economy by two chemical bonds formation in one pot.

New Synthesis of Thioflavones by the Regioselective Cyclization of 1-(2-Benzylthio)phenyl-3-phenylprop-2-yn-1-ones Using Hydrobromic Acid

New Synthesis of Thioflavones by the Regioselective Cyclization of 1-(2-Benzylthio)phenyl-3-phenylprop-2-yn-1-ones Using Hydrobromic Acid

Enantioselective Total Syntheses of the Proposed and Revised Structures of Methoxystemofoline: A Stereochemical Revision.

This article describes the full details of our synthetic efforts toward the enantioselective total synthesis of the complex alkaloid methoxystemofoline. The enantioselective construction of the tetracyclic core features: (1) the Keck allylation at the N-α bridgehead carbon to forge the tetrasubstituted stereocenter; (2) an olefin cross-metathesis reaction for the side-chain elongation that is amenable for the synthesis of congeners and analogues; and (3) a regioselective aldol addition reaction with methyl pyruvate that ensured the subsequent regioselective cyclization reaction to construct the fourth ring. Overman's method was employed to install the 5-(alkoxyalky1idene)-3-methyl-tetronate moiety. In the last step, a nonstereoselective reaction resulted in the formation of both the proposed structure of methoxystemofoline and its E-stereoisomer, the natural product (revised structure), in a 1:1 ratio. We suggest to rename the natural product as isomethoxystemofoline, and report for the first time the complete 1H NMR data for this natural product.

Sulfonyl radical-induced regioselective cyclization of 3-aza-1,5-enynes with sulfonyl chlorides to produce 1,2-dihydropyridines by copper catalysis

A Cu-catalyzed regioselective cyclization of 3-aza-1,5-enynes with sulfonyl chlorides for the synthesis of 1,2-dihydropyridines is described.

Synthesis of Spirocyclic Piperidines by Radical Hydroarylation.

Reported here are conditions for the construction of spirocyclic piperidines from linear aryl halide precursors. These conditions employ a strongly reducing organic photoredox catalyst in combination with a trialkylamine reductant to achieve formation of aryl radical species. Regioselective cyclization followed by hydrogen-atom transfer affords a range of complex spiropiperidines. This system operates efficiently under mild conditions without the need for toxic reagents or precious metals.

Regioselective Intermolecular Cyclization of Methyl (E)-3-[(4S,5S)-5-Acetyl-2,2-dimethyl-1,3-dioxolan-4-yl)]prop-2-enoate

Regioselective Intermolecular Cyclization of Methyl (E)-3-[(4S,5S)-5-Acetyl-2,2-dimethyl-1,3-dioxolan-4-yl)]prop-2-enoate

Gold(I)-Catalyzed Domino Reaction for Furopyrans Synthesis.

We report herein an efficient synthesis of furopyran derivatives through a gold(I)-catalyzed domino reaction. The cascade reaction starts with two regioselective cyclizations, a 5-endo-dig and a 8-endo-dig, followed with a Grob-type fragmentation and a hetero Diels–Alder. The obtained furopyran derivatives contain fused and spiro-heterocycles. During this one-pot process, four bonds and four controlled stereogenic centers including a quaternary center are formed.

Synthesis of glycosides of 1H-Pyrazolo[3,4-b]pyridin-3(2H)-ones

Abstract A number of new fluorinated and non-fluorinated glycosides of 1H-pyrazolo[3,4-b]pyridin-3(2H)-ones were synthesized by direct attachment of the carbohydrate moiety to the heterocycle using the silyl Hilbert-Jones glycosylation method. The products were obtained in good to excellent yields and with very good anomeric stereoselectivity. The starting 1H-pyrazolo[3,4-b]pyridin-3(2H)-ones were prepared by regioselective cyclization of 1,3-dicarbonyl compounds with electron-rich heterocycles containing an enamine functionality.

Front Cover: A Gold‐Catalyzed Acid‐Assisted Regioselective Cyclization for the Synthesis of Polysubstituted Oxazoles (Eur. J. Org. Chem. 16/2020)

Front Cover: A Gold‐Catalyzed Acid‐Assisted Regioselective Cyclization for the Synthesis of Polysubstituted Oxazoles (Eur. J. Org. Chem. 16/2020)

Biosynthesis of a New Benzazepine Alkaloid Nanangelenin A from Aspergillus nanangensis Involves an Unusual l-Kynurenine-Incorporating NRPS Catalyzing Regioselective Lactamization.

1-Benzazepine is a pharmaceutically important scaffold but is rare among natural products. Nanangelenin A (1), containing an unprecedented 3,4-dihydro-1-benzazepine-2,5-dione-N-prenyl-N-acetoxy-anthranilamide scaffold, was isolated from a novel species of Australian fungus, Aspergillus nanangensis. Genomic and retrobiosynthetic analyses identified a putative nonribosomal peptide synthetase (NRPS) gene cluster (nan). The detailed biosynthetic pathway to 1 was established by heterologous pathway reconstitution in A. nidulans, which led to biosynthesis of intermediates nanagelenin B-F (2-5 and 7). We demonstrated that the NRPS NanA incorporates anthranilic acid (Ant) and l-kynurenine (l-Kyn), which is supplied by a dedicated indoleamine-2,3-dioxygenase NanC encoded in the gene cluster. Using heterologous in vivo assays and mutagenesis, we demonstrated that the C-terminal condensation (CT) and thiolation (T3) domains of NanA are responsible for the regioselective cyclization of the tethered Ant-l-Kyn dipeptide to form the unusual benzazepine scaffold in 1. We also showed that NanA-CT catalyzes the regioselective cyclization of a surrogate synthetic substrate, Ant-l-Kyn-N-acetylcysteamine, to give the benzazepine scaffold, while spontaneous cyclization of the dipeptide yielded the alternative kinetically favored benzodiazepine scaffold. The discovery of 1 and the characterization of NanA have expanded the chemical and functional diversities of fungal NRPSs.

A Gold‐Catalyzed Acid‐Assisted Regioselective Cyclization for the Synthesis of Polysubstituted Oxazoles

Polysubstituted oxazole derivatives are obtained through a regioselective gold‐catalyzed reaction of α‐alkynylamides and alkynoates in the presence of nitriles. The intermediary obtained gold carbenes are generated by alkyne oxidation with a pyridine N‐oxide. Acidic conditions ensure that only one of the two carbonyl oxygen atoms in these intermediates selectively cyclizes to the products in excellent yields.

New Synthesis of Thioflavanones by the Regioselective Cyclization of 1‐(2‐Benzylthio)phenyl‐3‐phenyl‐2‐propen‐1‐ones with Hydrobromic Acid

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Ortho-substituent-controlled regioselective cyclisation of 1,4-phenylenediacrylic acid to a linear benzo[1,2-b:4,5-b′]dithiophene derivative as a building block for semiconducting materials

The regioselective synthesis of a linear benzo[b]dithiophene (BDT) regioisomer 10 is described. Regioselectivity is accomplished by di-substitution with bromine atoms in the starting material 9. The properties and structures of all prepared compounds 9–11 were studied in detail by NMR spectroscopy and X-ray crystallography analysis. This method should provide an efficient and simple way to obtain linear BDT derivatives 10 and 11, which are crucial building blocks for modern semiconducting materials. In particular BDT 10 obtained by the described method features three different types of halogen atom in the structure; therefore, it could be an excellent precursor for further selective molecular design.