Tetracyclic Indole Derivatives Research Articles

NHC-Catalyzed Umpolung Driven Intramolecular Cyclizations for the Generation of 3,4-Cycloheptanone Annulated Tetracyclic Indole Derivatives.

In this Letter, we disclose the development and exploitation of umpolung reactivity of N-heterocyclic carbene (NHC) organocatalysts in generating tetracyclic indole derivatives with the introduction of a cycloheptane ring forming event. The NHC-catalyzed intramolecular vinylogous Stetter, Stetter, benzoin, and formal cross-dehydrogenative coupling transformations have been executed, enabling the construction of 3,4-cycloheptannulated indole derivatives in good to excellent yields. The developed protocols utilize an inexpensive catalyst and feature operational simplicity, atom economy, gram-scale syntheses, and postsynthetic availability.

Synthesis of N-Fused Polycyclic Indole Derivatives via Ru(II)-Catalyzed C-H Bond Activation and Intramolecular Hydroarylation.

A new synthesis of N-fused tetracyclic indole derivatives and their related polycyclic analogues has been developed based on ruthenium(II)-catalyzed C-H activation and intramolecular hydroarylation. A series of polycyclic indoles with a 3-formyl group have been prepared in good to high yields. Various aliphatic and aromatic amines have been studied to form a transient directing group with the aldehyde for the catalytic process. A significant impact of the structures of the aromatic amines was identified, and 1-naphthylamine was shown to enable the catalytic process. DFT computations were performed to gain further insight into the role of the transient directing groups.

Catalytic asymmetric dearomative azo-Diels–Alder reaction of 2-vinlyindoles

Due to the high electrophilic nature of azo-dienophiles, azo-Diels–Alder proceeds rapidly even without the need of a catalyst and is therefore regarded as the “click reaction”. This spontaneity causes strong background reaction and poses a daunting challenge to chemists for developing the catalytic asymmetric version. Reported herein is the first catalytic asymmetric dearomative azo-Diels–Alder reaction between 2-vinylindoles and triazoledione. This protocol makes use of the high energy barrier of dearomatization to avert the strong background reaction of azo-Diels–Alder reaction, allowing the implementation of the projected reaction at ambient temperature. Density functional theory calculations have been performed to gain insights into the reaction mechanism and the origins of the enantioselectivity. By using this method, a variety of tetracyclic indole derivatives have been readily prepared in good to excellent yields and with excellent diastereo- and enantio‑selectivities (33 examples, up to 97% yield and >99% ee, >20:1 dr).

Tandem Nenitzescu Reaction/Nucleophilic Aromatic Substitution to Form Novel Pyrido Fused Indole Frameworks

Abstract5‐Hydroxyindoles are privileged structures that form part of various bioactive compounds. The Nenitzescu reaction of quinones and enamines is one of the most powerful methods to obtain 5‐hydroxyindoles. In this work, we have applied the Nenitzescu reaction to 2‐(2‐chloropyrid‐3‐yl)benzoquinones. Mixtures of regioisomers were obtained that could be separated in the 4‐ and 6‐substituted analogues, and then cyclized separately in a metal‐free base‐catalyzed reaction, affording novel tetracyclic indole derivatives. These are indeed the first examples reported in the literature of the linear pyrido[3′,2′ : 4,5]furo[3,2‐b]indole and angular 1H‐pyrido[2′,3′ : 4,5]furo[2,3‐c]indole systems. The regioselectivity and the yield of the Nenitzescu reaction were found to be dependent on the N‐substituent at the enamine. Furthermore, we analyzed the UV‐Vis and PL spectra of the new systems, and this was supported by DFT calculations, allowing us to compare the properties of angular compared to linearly shaped compounds.

Tricyclic dihydrobenzoxazepine and tetracyclic indole derivatives can specifically target bacterial DNA ligases and can distinguish them from human DNA ligase I.

DNA ligases are critical components for DNA metabolism in all organisms. NAD(+)-dependent DNA ligases (LigA) found exclusively in bacteria and certain entomopoxviruses are drawing increasing attention as therapeutic targets as they differ in their cofactor requirement from ATP-dependent eukaryotic homologs. Due to the similarities in the cofactor binding sites of the two classes of DNA ligases, it is necessary to find determinants that can distinguish between them for the exploitation of LigA as an anti-bacterial target. In the present endeavour, we have synthesized and evaluated a series of tricyclic dihydrobenzoxazepine and tetracyclic indole derivatives for their ability to distinguish between bacterial and human DNA ligases. The in vivo inhibition assays that employed LigA deficient E. coli GR501 and S. typhimurium LT2 bacterial strains, rescued by ATP-dependent T4 DNA ligase or Mycobacterium tuberculosis NAD(+)-dependent DNA ligase (Mtb LigA), respectively, showed that the compounds can specifically inhibit bacterial LigA. The in vitro enzyme inhibition assays using purified MtbLigA, human DNA ligase I & T4 DNA ligase showed specific inhibition of MtbLigA at low micromolar range. Our results demonstrate that tricyclic dihydrobenzoxazepine and tetracyclic indole derivatives can distinguish between bacterial and human DNA ligases by ∼5-folds. In silico docking and enzyme inhibition assays identified that the compounds bind to the cofactor binding site and compete with the cofactor. Ethidium bromide displacement and gel-shift assays showed that the inhibitors do not exhibit any unwanted general interactions with the substrate DNA. These results set the stage for the detailed exploration of this compound class for development as antibacterials.

Synthesis of 3-Acyl-2-arylindole via Palladium-catalyzed Isocyanide Insertion and Oxypalladation of Alkyne

The synthesis of 3-acyl-2-arylindole derivatives was performed through palladium-catalyzed isocyanide insertion and oxypalladation of an alkyne. As a result of the introduction of internal nucleophiles, domino cyclization was also achieved for the synthesis of several tetracyclic indole derivatives. Imidoylpalladium generated by isocyanide insertion is a key intermediate in these reactions.

ChemInform Abstract: Gold‐Catalyzed Michael Addition/Intramolecular Annulation Cascade: An Effective Pathway for the Chemoselective‐ and Regioselective Synthesis of Tetracyclic Indole Derivatives in Water.

AbstractOptimum reaction conditions are examined for the synthesis of 28 title compounds of type (III) which are of potential biological interest.

Cascade Syntheses Routes to the Centrocountins

Cascade and domino reactions that proceed through multiple steps in one pot and include multiple bond formations are promising methods for the rapid and efficient generation of complex molecular architectures, including the scaffolds of classes of complex natural product. We describe the development of various one-pot cascade reaction sequences to yield centrocountins, which are tetracyclic indole derivatives with the basic scaffold of numerous polycyclic alkaloids. The mechanistic investigation of a sequence employing readily available alkynes and 3-formylchromones as starting materials provided evidence that this one-pot synthesis proceeds through at least twelve consecutive transformations and includes at least nine different chemical reactions, making it the longest cascade reaction sequence known to date. We describe the scope and limitations of the cascade synthesis approaches and the development of an enantioselectively catalyzed centrocountin synthesis.

Gold-catalyzed Michael addition/intramolecular annulation cascade: an effective pathway for the chemoselective- and regioselective synthesis of tetracyclic indole derivatives in water

The report describes a gold(I) complex and trifluoroacetic acid (TFA) cocatalyzed one-pot, Michael addition/intramolecular cyclization cascade reaction for the synthesis of unusual tetracyclic indoles containing a seven-membered ring in water with microwave irradiation (MW). This protocol presents an operationally simple, rapid and environmentally friendly strategy for preparing potential biologically interesting fused-indole molecular architectures from some simple starting materials.

ChemInform Abstract: Merging Organocatalysis and Gold Catalysis: Enantioselective Synthesis of Tetracyclic Indole Derivatives Through a Sequential Double Friedel—Crafts Type Reaction.

AbstractThe products are of a significant interest due to their potential pharmaceutical activity.

N-Alkenyl Indoles as Useful Intermediates for Alkaloid Synthesis

A mild cross-coupling reaction to access several N-alkenyl-substituted indoles has been developed. The coupling procedure involves treating a NH-indole with various alkenyl bromides using a combination of 10 mol % of copper(I) iodide and 20 mol % of ethylenediamine as the catalyst in dioxane at 110 °C in the presence of K(3)PO(4) as the base. When treated with acid, these unique enamines produce a dimeric product derived from a preferred protonation reaction at the enamine π-bond. A cationic cyclization reaction of the readily available 2-(2-(1H-indol-1-yl)allyl)cyclopentanol was utilized to construct tetracyclic indole derivatives with a quaternary stereocenter attached to the C(2)-position of the indole ring. An alternative strategy for selective functionalization at the C(2)-position of a N-alkenyl-substituted indole derivative that was also studied involves a radical cyclization of a xanthate derivative. The work described provides an attractive route to the tetracyclic core of some vinca alkaloids, including the tetrahydroisoquinocarbazole RS-2135.

Merging Organocatalysis and Gold Catalysis: Enantioselective Synthesis of Tetracyclic Indole Derivatives through a Sequential Double Friedel–Crafts Type Reaction

Merging Organocatalysis and Gold Catalysis: Enantioselective Synthesis of Tetracyclic Indole Derivatives through a Sequential Double Friedel–Crafts Type Reaction

Highly diastereoselective samarium diiodide induced cyclizations of new 3-substituted indole derivatives

Herein, we describe the synthesis of new functionalized tricyclic and tetracyclic indole derivatives via samarium diiodide induced ketyl cyclizations. The intermediate samarium organyls were either protonated using different proton sources or alkylated with various electrophiles in a highly diastereoselective manner. The obtained products were subjected to further transformations leading to synthetically interesting building blocks.

A Modified Bischler Synthesis of Some Tetracyclic Indole Derivatives

A Modified Bischler Synthesis of Some Tetracyclic Indole Derivatives