Polycyclic Indole Research Articles

Total synthesis of kopsine, fruticosine, and structurally related polycyclic caged Kopsia indole alkaloids

Kopsine, fruticosine and related caged and polycyclic Kopsia indole alkaloids have been attractive synthetic targets since 1983.

The C-H functionalization of N-alkoxycarbamoyl indoles by transition metal catalysis.

Indole and its congeners are ubiquitous nitrogen-containing organic scaffolds present in a plethora of natural products, marketed drugs, and other organic functional molecules. Recent years have witnessed tremendous advances in the diversification of this motif and its biological applications via transition-metal-catalyzed auxiliary assisted site-selective inert C-H functionalization. In this burgeoning field, N-methoxy/ethoxy/pivaloxy amide functionality has emerged as a most potent auxiliary/DG (directing group) for a wide range of C-C and C-heteroatom bond formations, providing a new advance for forging structurally fabricated polycyclic indole frameworks. This review aims to highlight evolved transformations, like arylation, alkylation, alkenylation, allylation, amidation, difluorovinylation, deuteration, hydroarylation, etc., and the applications of N-alkoxycarbamoyl indole derivatives made within the period of 2014-August 2021. Additionally, explicit mechanistic underpinnings have also been provided in the appropriate places.

Catalytic asymmetric dipolar cycloadditions of indolyl delocalized metal-allyl species for the enantioselective synthesis of cyclopenta [b]indoles and pyrrolo[1,2-a]indoles

The development of novel synthons and efficient methods to synthesize chiral polycyclic indoles has been a hot topic in organic synthesis and medicinal chemistry owing to their broad applications in medicines, pesticides, and other functional molecules. Here, we disclosed novel indolyl substituted metal-allyl zwitterionic intermediates through the decarboxylation of conveniently available vinyl indoloxazolidones, which could be regarded as two types of dipolar species through the anionic delocalization. The palladium-π-allyl species tended to serve as an all-carbon 1,3-dipole in the asymmetric [3+2] cycloaddition with electron-deficient alkenes, which furnished polysubstituted cyclopenta[ b ]indoles with high regio- and stereoselectivities. Meanwhile, the iridium-π-allyl species was recognized as an aza-1,3-dipole in asymmetric [3+2] cycloaddition with in situ generated C1 ammonium enolates, affording pyrrolo[1,2- a ]indoles with high diastereo- and enantioselectivities. In addition, the dipolar cycloadditions could be easily scaled-up and several synthetic transformations of the cycloadducts were demonstrated for the rapid synthesis of diverse chiral polycyclic indoles.

Chemistry of the chippiine/dippinine/tronocarpine class of indole alkaloids.

The chippiines/dippinines/tronocarpine are a family of biologically and structurally interesting polycyclic tryptamine-derived indole alkaloids isolated from the leaf and bark extracts of plants belonging to the Tabernaemontana genus. To date, 14 members of this family have been isolated and characterized. This review discusses the isolation, structure determination, biological activity, and proposed biosynthesis of these metabolites. In addition, synthetic studies on the alkaloids are described including approaches to tronocarpine and dippinine B core intermediates and total syntheses of (+)-dippinine B and (+)-tronocarpine.

Metal and Oxidant Free Construction of Substituted‐ and/or Polycyclic Indoles: A Useful Alternative to Bischler and Related Syntheses

A wide range of substituted indoles or polycyclic derivatives containing the indole core are easily accessible by acidic treatment of aromatic amines and 1,2‐diaza‐1,3‐dienes. Unlike the related indole‐Bischler synthesis, the regioselectivity of the method here reported is unique and predictable, the yields are generally good and also electron withdrawing substituted indoles are smoothly recovered.

Palladium-Catalyzed, Enantioselective (3 + 2)-Cycloannulation of β-Keto Esters with Alkylidene 2H-Indoles toward Complex Indole-Based Heterocycles.

A cooperative approach toward biologically important N-fused polycyclic indoles with synthetically challenging tetracyclic [6-5-5-6] and [6-5-5-5] core structures has been developed. The concept is based on a highly stereoselective (3 + 2)-cycloannulation of chiral metal enolates with a reactive vinylogous iminium ion, both generated in situ via dual activation with a single chiral Pd catalyst (5 mol %). Densely functionalized pyrrolo[1,2-a]indoles with three contiguous chiral centers were constructed with high stereoselectivities (>95:5 d.r. and up to >99% ee) and excellent yields (up to 99%). ESI-MS studies and additional control experiments provided a clear mechanistic picture of the cycloannulation event. The products were readily transformed into an array of valuable, indole-based, highly complex heterocycles.

Copper-Catalyzed Three-Component Formal [3 + 1 + 2] Benzannulation for Carbazole and Indole Synthesis.

Three-component formal [3 + 1 + 2] benzannulation reactions of indole-3-carbaldehydes or 1-methyl-pyrrole-2-carbaldehydes with two different molecules of saturated ketones have been successfully developed under Cu-catalyzed and 2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO)-mediated conditions. Various unsymmetrically substituted carbazoles and indoles were obtained up to 95% yield. Furthermore, the resulting products exhibit unusual aggregation-induced emission (AIE) properties in the solid state. This method features high atom-economy, cheap catalysts and oxidants, wide substrate scope, and saturated ketones as one-carbon and two-carbon sources, thus providing an efficient approach to polycyclic carbazole and indole compounds.

Highly selective Diels-Alder and Heck arylation reactions in a divergent synthesis of isoindolo- and pyrrolo-fused polycyclic indoles from 2-formylpyrrole.

A highly regio-, chemo- and stereoselective divergent synthesis of isoindolo- and pyrrolo-fused polycyclic indoles is herein described, starting from 2-formylpyrrole and employing Diels–Alder and Heck arylation reactions. 3-(N-Benzyl-2-pyrrolyl)acrylates and 4-(pyrrol-2-yl)butenones underwent a highly endo-Diels–Alder cycloaddition with maleimides to furnish octahydropyrrolo[3,4-e]indoles, which served as precursors in the regioselective synthesis of aza-polycyclic skeletons via an intramolecular Heck arylation reaction. Through the latter reaction, the 3-(N-benzyl-2-pyrrolyl)acrylates give rise to 3-(pyrrolo[2,1-a]isoindol-3-yl)acrylates. A further oxidative aromatization of the polycyclic intermediates provides the corresponding polycyclic pyrrolo-isoindoles and isoindolo-pyrrolo-indoles. A theoretical study on the stereoselective Diels–Alder reactions, carried out by calculating the endo/exo transition states, revealed the assistance of non-covalent interactions in governing the endo stereocontrol.

Thioether-Directed C4-Selective C-H Acylmethylation of Indoles Using α-Carbonyl Sulfoxonium Ylides.

Site-selective direct functionalization of an indole benzenoid core has been a great challenge due to its inherently poor reactivity. We herein demonstrate an iridium-catalyzed C4-selective acylmethylation of indoles using α-carbonyl sulfoxonium ylides as carbene precursors. This method exhibits high efficiency and broad functional group compatibility. The directing group was easily removed or converted to other functionalities after the catalysis. The potential synthetic utility of the coupling products was highlighted by constructing medium-sized polycyclic indoles.

Cu(OAc)2-Promoted Oxidative Cross-Dehydrogenative Coupling Reaction of α-Acylmethyl Malonates with Indole Derivatives to Access 3-Functionalized Indoles and Polycyclic Indoles.

A Cu(OAc)2-promoted oxidative cross-dehydrogenative coupling reaction of α-acylmethyl malonates with indole derivatives was developed. In the case of indoles, the regioselective coupling products were formed through a sequential dehydrogenation-addition-dehydrogenation process. When a second nucleophilic center was located in the 2-position of indoles, further successive nucleophilic cyclization occurred to give polycyclic indole derivatives. The Cu(OAc)2 was proved to act as not only an oxidant but also a catalyst.

Blue LED Mediated Intramolecular C-H Functionalization and Cyclopropanation of Tryptamines: Synthesis of Azepino[4, 5-b]indoles and Natural Product Inspired Polycyclic Indoles.

We report a novel blue LED mediated intramolecular C-H functionalization of tryptamine derivatives to generate azepino[4, 5-b]indoles (4) in moderate to good yields. By altering the substitution at the tryptamine nitrogen, intramolecular cyclopropanation is achieved in high yields under the same reactions condition to provide natural product inspired polycyclic indoles (6), which are further transformed to spiropiperidino (5 and 8) indoles in decent yields. The mechanism of formation of the compounds was investigated through DFT studies.

Exploring the Chemistry of Spiroindolenines by Mechanistically-Driven Reaction Development: Asymmetric Pictet-Spengler-type Reactions and Beyond.

The Pictet-Spengler reaction is a fundamental named reaction in organic chemistry, and it is the most straightforward method for the synthesis of tetrahydro-β-carbolines, a core structure embedded in numerous alkaloids. Spiroindolenines are often proposed as possible intermediates in Pictet-Spengler reactions. However, whether the spiroindolenine species is an intermediate in the mechanism of the asymmetric Pictet-Spengler reaction remains unclear. Questions about the role of the spiroindolenine species regarding the mechanism include the following: Can the spiroindolenine species be formed effectively under Pictet-Spengler conditions? If so, what is its fate? Is the delivery of the enantioenriched tetrahydro-β-carboline product related to the spiroindolenine intermediate? Previous studies regarding these questions have not reached a consensus. Therefore, elucidating these questions will advance the field of synthetic organic chemistry.The first highly enantioselective synthesis of spiroindolenines that have the same molecular scaffold as the proposed key intermediate of the Pictet-Spengler reaction was accomplished by an Ir-catalyzed intramolecular asymmetric allylic substitution reaction of an indol-3-yl allylic carbonate. In this reaction, a piperidine, pyrrolidine, or cyclopentane ring can be introduced in conjunction with the indolenine structure.Spiroindolenines were found to undergo ring-expansive migration reactions when treated with a catalytic amount of an acid, leading to tetrahydro-β-carbolines or related tetrahydrocarbazoles. Comprehensive DFT calculations and Born-Oppenheimer molecular dynamics simulations have provided insight into the mechanism of the migration process. It has been found that the stereochemistry is strongly correlated with the electronic properties of the migratory group along with the acidity of the catalyst. Close interactions between the positively charged migratory group and the electron-rich indole ring favor the stereospecificity of the migration. Furthermore, a continuous mechanistic spectrum of the Pictet-Spengler reactions can be obtained on the basis of two readily accessible energetic parameters that are derived from computed energies for competing transition states relative to a key intermediate species. This theoretical model provides a unified mechanistic understanding of the asymmetric Pictet-Spengler reaction, which has been further supported by rationally designed prototype reactions. Chemically and stereochemically controllable migration can be achieved when multiple potential migratory groups are available.The reactivity of spiroindolenines has also been explored beyond Pictet-Spengler reactions. A one-pot Ir-catalyzed asymmetric allylic dearomatization/stereoconvergent migration allows the facile synthesis of enantioenriched tetrahydro-β-carbolines from racemic starting materials. An unprecedented six- to seven-membered ring-expansive migration can be achieved when a vinyliminium moiety is involved as a highly reactive migratory group. This reaction facilitates the stereoselective synthesis of thermodynamically challenging indole-annulated seven-membered rings. It has also been found that the migration process can be interrupted. The electrophilic migratory group released from the retro-Mannich reaction of a spiroindolenine can be captured by an inter- or intramolecular nucleophile, thus providing new entries into structurally diverse polycyclic indole derivatives.Therefore, the mechanism of the Pictet-Spengler reaction can be probed by manipulating the reactivity of the spiroindolenine species. In turn, the mechanistic insights gained herein will aid in chemical transformations toward various target molecules. This study serves as a vivid example of the positive interplay between experimental and theoretical investigations in synthetic organic chemistry.

Novel Polycondensed Partly Saturated β-Carbolines Including Ferrocene Derivatives: Synthesis, DFT-Supported Structural Analysis, Mechanism of Some Diastereoselective Transformations and a Preliminary Study of Their in vitro Antiproliferative Effects.

Use of a Pictet-Spengler reaction of tryptamine and l-tryptophan methyl ester and subsequent reduction of the nitro group followed by further cyclocondensation with aryl aldehydes and formyl–substituted carboxylic acids, including ferrocene-based components, furnished a series of diastereomeric 6-aryl-substituted 5,6,8,9,14,14b-hexahydroindolo[2′,3′:3,4]pyrido[1-c]-quinazolines and 5,5b,17,18-tetrahydroindolo[2′,3′:3,4]pyrido[1,2-c]isoindolo[2,1-a]quinazolin-11-(15bH)-ones with the elements of central-, planar and conformational chirality. The relative configuration and the conformations of the novel polycyclic indole derivatives were determined by 1H- and 13C-NMR methods supplemented by comparative DFT analysis of the possible diastereomers. The structure of one of the pentacyclic methyl esters with defined absolute configuration “S” was also confirmed by single crystal X-ray diffraction measurement. Accounting for the characteristic substituent-dependent diastereoselective formation of the products multistep mechanisms were proposed on the basis of the results of DFT modeling. Preliminary in vitro cytotoxic assays of the products revealed moderate-to-significant antiproliferative effects against PANC-1-, COLO-205-, A-2058 and EBC-1 cell lines that proved to be highly dependent on the stereostructure and on the substitution pattern of the pending aryl substituent.

FeCl3-Promoted Annulation of 2-Haloindoles: Switchable Synthesis of Spirooxindole-chromeno[2,3-b]indoles and Spirooxindole-chromeno[3,2-b]indoles.

Electrophilic indoles bearing a leaving group at C2 undergo C3-regioselective dearomative hydroaryloxylation and subsequent 1,2-tertiary alkyl migration/aromatization. This is the first ring-opening migration of the spiroindolenine intermediate formed by the C3 nucleophilic addition reaction. Various spiro-oxindole-chromeno[3,2-b]/[2,3-b]indoles were successfully synthesized in excellent yields (up to 98%). This reaction features selective ring-opening migration (C-C/C-O) of the tertiary alkyl group from the indole C3 position to the C2 position stereoselectively, providing a unique synthetic method for constructing novel polycyclic indole skeletons.

Diastereoselective Syntheses of Spiro[indoline-3,4'-pyridin]-2-yl Carbamates via AgOTf/Ph3P-Catalyzed Tandem Cyclizations of Tryptamine-Ynesulfonamides.

Spiro[indoline-3,4'-piperidine] is a significant structural scaffold in numerous polycyclic indole alkaloids with a variety of bioactivities. In this study, a synthetic strategy was developed to access spiro[indoline-3,4'-pyridin]-2-yl carbamate via an AgOTf/PPh3-catalyzed tandem cyclization of tryptamine-ynesulfonamides. The unique feature of this strategy is the efficient intermolecular capturing of the in situ generated spiroindoleninium intermediates with carbamates, leading to the diastereoselective syntheses of spiro[indoline-3,4'-pyridin]-2-yl carbamate derivatives. A broad scope of this cyclization was demonstrated by a variety of tryptamine-ynesulfonamide substrates and several carbamates. A plausible mechanism of this reaction was proposed.

Visible-light-induced intramolecular radical cascade of α-bromo-N-benzyl-alkylamides: a new strategy to synthesize tetracyclic N-fused indolo[2,1-a]isoquinolin-6(5H)-ones.

Polycyclic indole scaffolds are ubiquitous in pharmaceuticals and natural products and in materials science. Here, we present a visible-light-initiated intramolecular aryl migration/desulfonylation/cyclization cascade reaction for the synthesis of tetracyclic indolo[2,1-a]isoquinolin-6(5H)-ones. This protocol not only exhibited a wide substrate scope but also provided a mild route to access a variety of tetracyclic N-fused indoles.

Synthesis of polycyclic indoles via organocatalytic bicyclization of α-alkynylnaphthalen-2-ols with nitrones.

A new organocatalytic bicyclization of α-alkynylnaphthalen-2-ols with nitrones was first reported, leading to the convergent synthesis of polycyclic indoles with substantial substitution diversity in generally good yields through scission of the N-O bond of nitrones via [3,3]-sigmatropic rearrangement. This transformation showcases the use of a quinine catalyst in a complicated cascade system that has been shown to effectively construct polycyclic heterocycles via alkyne difunctionalization.

Chiral Bis(oxazoline)-Copper Complex Catalyzed Asymmetric Alkenylation of Isatin Imines and 3-Vinylindoles for Construction of Optically Active 3-Alkenyl-3-aminooxindoles.

The first catalytic asymmetric alkenylation of isatin imines is described. The reaction, which is promoted by a chiral bis(oxazoline)-copper complex, gives structurally diverse 3-alkenyl-3-aminooxindole derivatives in excellent yields, and with excellent diastereoselectivities and high-to-excellent enantioselectivities. The products can be readily converted to polycyclic indole derivatives without loss of enantioselectivity. A plausible chirality-induced mechanism is proposed to explain the observed stereoselective control.

Reactivity and stereoselectivity of oxazolopyridines with a ring‐junction nitrogen atom

AbstractThe present study demonstrates a synopsis of the scientific researches reported on the different reactions of oxazolo[3,2‐a]pyridines, besides the preparation of significant fused heterocycles up till now. The different main sections that described the reactivity of the inspected analogues include stereoselective alkylation, reactions involved oxazolidine ring, synthesis of polycyclic systems, indole alkaloids, and alkyl amines. The stereochemical selectivity of oxazolopiperidone lactams is studied, in which the configuration of the stereocenter C8a and substituents at the C8 and C8a effect on the stereoselectivity. On the other hand, the synthetic consequence of the alkylation products provides diverse routes for the synthesis of substituted enantiopure piperidines that are used for the synthesis of natural products, for example, (−)‐rhazinilam, (+)‐eburnamonine, (+)‐aspidospermidine, indole alkaloids such as dihydrocleavamine, nor‐20‐epiuleine, (+)‐dasycarpidone, (+)‐uleine, indoloquinolizidine, (+)‐dihydrocorynantheine, (−)‐dihydrocorynantheol, and indolizines, eg, octahydroindolizines, monomorine I, (−)‐S‐coniceine, and (−)‐R‐coniceine.

Secondary metabolites of the genus Penicillium from undisturbed and anthropogenically altered Antarctic habitats.

From undisturbed Antarctic habitats (permafrost sediments 30-150 thousand years of age, water of Radok Lake) and superficial deposits contaminated with petroleum products, we isolated 14 and 9 strains of Penicillium fungi, respectively. Comparison of the fungal complexes showed them to differ by species composition; only two species-P. palitans and P. solitum-were in the species lists of both groups. The identified secondary metabolites in the investigated strains belonged to diketopiperazine (group of roquefortines, rugulosuvin B), benzodiazepine (anacin, cyclopenins), quinoline alkaloids (viridicatins), clavine ergot alkaloids (α-cyclopiazonic acid, festuclavine, fumigaclavines), polycyclic indole alkaloids (communesin B, chaetoglobosin A), amino acid derivatives (N-acetyltryptamine, chrysogins, penicillin G), polyketides (citreoviridin A, mycophenolic acid), and terpenes (andrastins, phomenone). Strains isolated from anthropogenically altered habitats produced a more complete and characteristic profile of exometabolites, as compared with strains isolated from undisturbed habitats. It is only from contaminated soils there were isolated fungi that produced more structurally diverse secondary metabolites pertaining to polycyclic indole alkaloids and terpenoids. The fungi isolated from contaminated samples can be used in biodegradation of oil spills and bioremediation of the environment, and also as producers of promising biologically active compounds.