Polycyclic Indole Research Articles

Synthesis and evaluation of polyacrylamides derived from polycyclic pendant naphthalene, indole, and phenothiazine based chalcone moiety as potent antimicrobial agents

Polycyclic chalcone-containing polyacrylamides, namely, poly ((N-(4-((E)-3-(naphthalen-6-yl)-3-oxoprop-1-enyl) phenyl) acrylamide), poly((N-(4-((E)-3-(1H-indol-3-yl)-3-oxoprop-1-enyl) phenyl) acrylamide), and poly((N-(4-((E)-3-oxo-3-(10H-phenothiazin-8-yl) prop-1-enyl) phenyl) acrylamide), were synthesized by Claisen–Schmidt condensation reaction, followed by ultrasonic irradiation reduction. The synthesized polymers were characterized by Fourier transform infrared spectroscopy, 1H nuclear magnetic resonance, and 13C nuclear magnetic resonance spectroscopic technique. The newly synthesized polymers have been screened for antibacterial and antifungal activities by using resazurin reduction assay method, and the resulting polyacrylamides showed promising activity against various tested bacteria and fungi. Among the polymers, poly((N-(4-((E)-3-oxo-3-(10H-phenothiazin-8-yl) prop-1-enyl) phenyl) acrylamide) and poly((N-(4-((E)-3-(1H-indol-3-yl)-3-oxoprop-1-enyl) phenyl) acrylamide) exhibited better antifungal and antibacterial activities than poly ((N-(4-((E)-3-(naphthalen-6-yl)-3-oxoprop-1-enyl) phenyl) acrylamide), whereas all the polymers do not show any sign of antibacterial and antifungal activity against Streptococcus faecalis and Candida glabrata. Copyright © 2016 John Wiley & Sons, Ltd.

ChemInform Abstract: Rhodium‐Catalyzed Pyridannulation of Indoles with Diazoenals: A Direct Approach to Pyrido[1,2‐a]indoles.

A novel rhodium catalyzed pyridannulation of 3-substituted indoles with diazoenals furnished privileged pyrido[1,2-a]indoles. The reaction is proposed to involve a [4 + 2]-annulation of the diacceptor rhodium enalcarbenoid via C-2 functionalization of the indole. The utility of the methodology was demonstrated with a short synthesis of the tetrahydropyrido[1,2-a]indole core, present in a large number of biologically important polycyclic indole alkaloids.

A Palladium-Catalyzed Dearomatization for the Synthesis of Polycyclic Indoles

Key words indoles - dearomatization - palladium - formal cycloaddition

Pd-Catalyzed Intramolecular Cyclization via Direct C-H Addition to Nitriles: Skeletal Diverse Synthesis of Fused Polycyclic Indoles.

The first example of Pd-catalyzed intramolecular C-H addition of indoles bearing cyanohydrin components at the C(3), C(2), and N(1) positions to nitriles is described. A wide range of functionalized partially saturated carbazoles, tetrahydropyrido[1,2-a]indole, and carbazoles can be prepared in good to excellent yields under the optimal conditions. In addition, fused polycyclic indoles with seven- or eight-membered rings can also be formed smoothly.

Rh-Catalyzed [3 + 2] Cycloaddition of 1-Sulfonyl-1,2,3-triazoles: Access to the Framework of Aspidosperma and Kopsia Indole Alkaloids.

A Rh(II)-catalyzed dearomative intramolecular [3 + 2] dipolar cycloaddition involving the indolic C2-C3 carbon-carbon double bond has been developed. The reaction was launched from the triazole moiety within the substrate and proceeded efficiently under mild conditions. A wide range of functional groups could be tolerated. These features render the current reaction a highly useful tool for the synthesis of polycyclic indole alkaloids, as showcased by a rapid assembly of the core structure of Aspidosperma and the related alkaloids.

Highly Efficient Formal [2+2+2] Strategy for the Rapid Construction of Polycyclic Spiroindolines: A Concise Synthesis of 11-Demethoxy-16-epi-myrtoidine.

A novel formal [2+2+2] strategy for the stereoselective elaboration of polycyclic indole alkaloids is described. Upon treatment with the catalyst InCl3 (5 mol %), tryptamine-derived enamides reacted readily with methylene malonate, thus enabling rapid and gram-scale access to versatile tetracyclic spiroindolines with excellent diastereoselectivity (21 examples, up to 95 % yield, up to d.r.>95:5). This strategy provides a concise approach to alkaloids isolated from Strychnos myrtoides, as demonstrated by a short synthesis of 11-demethoxy-16-epi-myrtoidine.

Highly Efficient Formal [2+2+2] Strategy for the Rapid Construction of Polycyclic Spiroindolines: A Concise Synthesis of 11‐Demethoxy‐16‐epi‐myrtoidine

AbstractA novel formal [2+2+2] strategy for the stereoselective elaboration of polycyclic indole alkaloids is described. Upon treatment with the catalyst InCl3 (5 mol %), tryptamine‐derived enamides reacted readily with methylene malonate, thus enabling rapid and gram‐scale access to versatile tetracyclic spiroindolines with excellent diastereoselectivity (21 examples, up to 95 % yield, up to d.r.>95:5). This strategy provides a concise approach to alkaloids isolated from Strychnos myrtoides, as demonstrated by a short synthesis of 11‐demethoxy‐16‐epi‐myrtoidine.

Bioinspired Discovery of Chemical Reactions and Biological Probes

Indole alkaloids are a large and diverse family of natural products that display a variety of medicinal properties. These natural products have consistently proven difficult to synthesize, due in large part to their complex skeletons and sterically hindered quaternary carbon centers. We have reported the efficient syntheses of polycyclic indole derivatives using gold catalysts, which selectively activate alkynylindoles for tandem cyclizations with high stereospecificity. The facile nature of these methods has allowed previously implausible diversity syntheses to be carried out yielding a large and highly diverse library of polycyclic indolines. Biological screenings revealed compounds that selectively re-sensitize methicillin-resistant Staphylococcus aureus (MRSA) to β-lactam antibiotics, which may herald a new way of staving off the incursion of drug-resistant strains of common human pathogens. 1 Introduction 2 Gold-Catalyzed Cyclizations 3 Chemical Probe Discovery 4 Outlook

Building polycyclic indole scaffolds via gold(I)-catalyzed intra- and inter-molecular cyclization reactions of 1,6-enynes

A gold(I) catalyzed cycloisomerization of indolyl-1,6-enynes via 5-exo-dig cyclization is reported. The reaction passes through an intermediate whose fate can be steered to yield different indole polycyclic scaffolds through various intra- and inter-molecular cyclization reactions. One of the key transformations of indolyl-1,6-enynes was a formal [2+2+2] cycloaddition reaction with various aldehydes to afford natural product-like tetracyclic indoles.

ChemInform Abstract: An Enantioselective Total Synthesis of (—)‐Isoschizogamine.

A concise enantioselective total synthesis of (-)-isoschizogamine, a complex bridged polycyclic monoterpene indole alkaloid, was accomplished. N-Alkylation of an enantio-enriched imine with an alkyl iodide afforded an iminium salt, which, upon heating by microwave irradiation in the presence of pivalic acid, was converted into the hexacyclic structure of natural product by a complex but ordered domino sequence. The one-pot process leading to the formation of one C-C bond and three C-N bonds created three rings and three contiguous stereogenic centers with complete control of both the relative and absolute stereochemistry.

ChemInform Abstract: Synthesis of Fused Polycyclic Indoles by Broensted Acid‐Catalyzed Intramolecular Alkylation of Indoles with Alcohols.

ChemInform Abstract: Synthesis of Fused Polycyclic Indoles by Broensted Acid‐Catalyzed Intramolecular Alkylation of Indoles with Alcohols.

ChemInform Abstract: Selective Synthesis of Acenaphtho[1,2‐b]indole Derivatives via Tandem Regioselective Aza‐Ene Addition/N‐Cyclization/SN1 Type Reaction.

A concise and efficient synthesis of acenaphtho[1,2-b]indoles with different substitution patterns from a [3+2] condensation of enaminones with acenaphthoquinone has been developed. During the first pathway, products 3 were synthesized in the presence of Et3N, while a second reaction in the presence of p-toluenesulfonic acid leads to compounds 5 via intramolecular cyclization and highly regioselective SN1-type reaction with alcohols under solvent-free conditions. Both procedures give excellent yields and are highly eco-benign, are convenient one-pot operations, are highly regioselectivity, and use environmentally friendly solvent systems or operate under solvent-free conditions. This method offers an alternative to regioselective construction of biologically meaningful polycyclic indoles.

Rhodium-catalyzed pyridannulation of indoles with diazoenals: a direct approach to pyrido[1,2-a]indoles.

A novel rhodium catalyzed pyridannulation of 3-substituted indoles with diazoenals furnished privileged pyrido[1,2-a]indoles. The reaction is proposed to involve a [4 + 2]-annulation of the diacceptor rhodium enalcarbenoid via C-2 functionalization of the indole. The utility of the methodology was demonstrated with a short synthesis of the tetrahydropyrido[1,2-a]indole core, present in a large number of biologically important polycyclic indole alkaloids.

An Enantioselective Total Synthesis of (-)-Isoschizogamine.

A concise enantioselective total synthesis of (-)-isoschizogamine, a complex bridged polycyclic monoterpene indole alkaloid, was accomplished. N-Alkylation of an enantio-enriched imine with an alkyl iodide afforded an iminium salt, which, upon heating by microwave irradiation in the presence of pivalic acid, was converted into the hexacyclic structure of natural product by a complex but ordered domino sequence. The one-pot process leading to the formation of one C-C bond and three C-N bonds created three rings and three contiguous stereogenic centers with complete control of both the relative and absolute stereochemistry.

An Enantioselective Total Synthesis of (−)‐Isoschizogamine

AbstractA concise enantioselective total synthesis of (−)‐isoschizogamine, a complex bridged polycyclic monoterpene indole alkaloid, was accomplished. N‐Alkylation of an enantio‐enriched imine with an alkyl iodide afforded an iminium salt, which, upon heating by microwave irradiation in the presence of pivalic acid, was converted into the hexacyclic structure of natural product by a complex but ordered domino sequence. The one‐pot process leading to the formation of one CC bond and three CN bonds created three rings and three contiguous stereogenic centers with complete control of both the relative and absolute stereochemistry.

Enantioselective Synthesis of Polycyclic Indole Derivatives Based on aza-Morita–Baylis–Hillman Reaction

A chiral phosphine-catalyzed asymmetric aza-Morita–Baylis–Hillman reaction between indole-derived sulfonyl imines and bis(3-chlorophenyl)methyl acrylate has been developed, giving the desired adducts in good yields and enantiomeric excess values along with the further transformations to polycyclic indoles such as dihydropyrido[1,2-a]indole and dihydropyrazino[1,2-a]indole skeleton.

Synthesis of Fused Polycyclic Indoles by Brønsted Acid-Catalyzed Intramolecular Alkylation of Indoles with Alcohols.

An efficient methodology for the synthesis of a series of new fused polyclyclic indoles has been developed by Brønsted acid-catalyzed intramolecular Friedel-Crafts reactions of properly designed indolyl alcohols.

Selective Synthesis of Acenaphtho[1,2‐b]indole Derivatives via Tandem Regioselective Aza‐Ene Addition/N‐Cyclization/SN1 Type Reaction

AbstractA concise and efficient synthesis of acenaphtho[1,2‐b]indoles with different substitution patterns from a [3+2] condensation of enaminones with acenaphthoquinone has been developed. During the first pathway, products 3 were synthesized in the presence of Et3N, while a second reaction in the presence of p‐toluenesulfonic acid leads to compounds 5 via intramolecular cyclization and highly regioselective SN1‐type reaction with alcohols under solvent‐free conditions. Both procedures give excellent yields and are highly eco‐benign, are convenient one‐pot operations, are highly regioselectivity, and use environmentally friendly solvent systems or operate under solvent‐free conditions. This method offers an alternative to regioselective construction of biologically meaningful polycyclic indoles.

Divergent Functionalization of Indoles with Acryloyl Silanes via Rhodium-Catalyzed C-H Activation.

A protocol enabled by rhodium-catalyzed C-H functionalization of indoles with acryloyl silanes was developed, providing a convenient and highly effective method for the synthesis of functionalized acylsilane derivatives. By tuning the reaction condition, this C-H-activation-initiated reaction proceeds divergently with acryloyl silianes to selectively afford alkylation or alkenylation products via hydroarylation or oxidative cross-coupling, respectively. The mild reaction conditions employed in both cases enable the tolerance of a wide scope of functionalities as well as high reaction efficiency. Furthermore, polycyclic indole derivatives were easily accessed from 2-alkenylation products through a visible-light-induced reaction cascade.

Rhodium-catalyzed regioselective direct C–H arylation of indoles with aryl boronic acids

A highly efficient Rh(III)-catalyzed direct C–H arylation of indoles with aryl boronic acids under mild conditions has been developed. The methodology features wide substrate scope and excellent functional group compatibility (34 examples, up to 99% yield). The arylated products can also be conveniently transformed into biologically active polycyclic indole derivatives.