Indole derivatives

Reduction of 2,2,4-trimethyl-, 2,2,4,4,6-pentamethyl-, and 2,2, 4,4,9-pentamethyl-1,2,3,4-tetrahydro-γ-carboline gives 1,2,3,4, 4a,9a-hexahydro-γ-carbolines, along with products of destructive hydrogenation. The sole reduction product of 2,2,3,4,4-pentamethyl-1,2,3,4-tetrahydro-γ-carboline is 2-(β-methylaminoisobutyl)indoline.     

New tetracyclic compounds containing the β-carboline moiety

Oxidation of 1-methyl-3-methoxycarbonyl-β-carboline with selenium dioxide gave 1-formyl-3-methoxycarbonyl-β-carboline II . Compound II reacted with acetic or propionic anhydride to give easily the 2-methoxycarbonyl-6H-indolo[3,2,1-d,e][1,5]naphthyridin-6-ones III ; reaction of II with some primary amines led to the formation of the Schiff bases IV , which were reduced to the 1-aminomethyl-3-methoxycarbonyl-β-carbolines V with sodium borohydride. Cyclization of V with aqueous formaldehyde led to the pyrimido[3,4,5-lm]pyrido[3,4-b]indoles VI . Analogously, cyclization with formaldehyde, acetone or 1,1′-carbonyldiimidazole of the 3-aminomethyl- 1,2,3,4-tetrahydro-β-carbolines VIII , obtained by reaction of 3-methoxycarbonyl-1,2,3,4-tetrahydro-β-carboline VII with amines followed by lithium aluminium hydride reduction of the resulting amides, gave the imidazo[1′,5′-1,6]pyrido[3,4-b]indoles IX and X . Dieckmann cyclization of 3-methoxycarbonyl-2-[(3-ethoxycarbonyl)-1-propyl]-1,2,3,4-tetrahydro-β-carboline XI led to a 1:1 mixture of the β-ketoesters XII and XIII , which underwent deethoxycarbonylation to 5,6,8,9,10,11,11a,12-octahydroindolo[3,2-b]quinolizin-11-one XIV . Finally, the polyphosphoric acid (or esters) catalyzed cyclization of the N-acyl derivatives XVI of 3-hydrazinocarbonyl-β-carboline XV led smoothly to the 3-(1,3,4-oxadiazol-2-yl)-β-carbolines XVII .     

Synthetic researches in the field of curare alkaloids XVIII. Synthesis of the methiodide of 1,3,4-(1′hydroxy-3′-methyl-4′-ethylidenepentane-1′, 3′, b, 5′-triyl)-3, 4, 5, 6-tetrahydro-β-carboline

The methiodide of 1,3, 4-(1′-hydroxy-3′-methyl-4′-ethylidenepentan1′, 3′, b, 5′-triyl]-3,4, 5, 6-tetrahydro-β-carboline is synthesized.     

Alkaloids of <Emphasis Type="Italic">Arundo donax</Emphasis> L.

The structure of a new dimeric indole alkaloid, arundarine, isolated from the roots of the plant Arundo donax L. (Poaceae) was determined. On the basis of spectroscopic data, arundarine was identified as 5-[3-(2-dimethylaminoethyl)indol-1-yl]-6-hydroxy-N ²-methyl-1,2,3,4-tetrahydro--carboline.Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 8, pp. 1697–1699, August, 2004.For Part 14, see Ref. 1.     

Indole derivatives

The cyclization of 1-R-2-(-aminoisobutyl)indoles with various cyclic ketones forms imines or spiro compounds of the 1,2,3,4-tetrahydro--carboline series, depending on the conditions and the structure of the ketone.For communication XL, see [1].Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 7, pp 942–944, July, 1973.     

Mild and Efficient Syntheses of 1-Aryl-3,4-dihydroisoquinolines and 1-Aryl-3,4-dihydro-β-carbolines via Regiospecific β-Eliminations of the Corresponding N-Tosyl-1,2,3,4-tetrahydroisoquinolines and N-Tosyl-1,2,3,4-tetrahydro-β-carbolines

Treatment of N-tosyl-1-aryl-1,2,3,4-tetrahydro-isoquinolines or N-tosyl-1-aryl-1,2,3,4-tetrahydro-β-carbolines with a strong base such as NaOH or KOH at 70 °C in dimethylsulfoxide (DMSO) produced 1-aryl-3,4-dihydroisoquinolines or 1-aryl-3,4-dihydro-β-carbolines in good yields via mild and regiospecific β-eliminations. A dramatic solvent effect was observed, DMSO was crucial for the reactions. The temperature is also crucial for the reactions and should be kept between 60 and 80 °C.     

EPC-Synthesis of Tetrahydroisoquinolines by Diastereoselective Alkylation at the 1-Position of Phenylalanine-Derived Precursors. Synthesis of the Alkaloid (+)-Corlumine

The 1,2,3,4-tetrahydro-N-pivaloyl-isoquinoline-3-carboxylic acids 1d , 2d , and 3d , derived from (R)- or (S)-phenylalanine, (S)-dopa, and (S)-α-methyldopa, respectively, are doubly deprotonated with (tert-butyl)lithium in THF and alkylated at the 1-position (products 5 – 10 ). The major diastereoisomers formed are the result of electrophilic attack from the face opposite to the carboxylate group (rel. topicity ul-1,3). Even the addition to benzaldehyd (→ 7,8 ) is highly stereoselective (one of four diastereoisomers is formed exclusively (300-MHz ¹H-NMR analysis)), if MgBr₂ etherate is added prior to the electrophile. Some of the obtained amino-acid derivatives are decarboxylated by anodic oxidation in MeOH (→ 11 , 12 , 17 ) and NaBH₃CN reduction, and converted to the known 1-methyl- and 1-benzyltetrahydroisoquinolines ( 15 , 16 ) of > 95% ee as well as to the phthalide isoquinoline alkaloid (+)-corlumine of ≥80% ee. The synthetic approach described here is compared with other methods of synthesizing enantiomerically pure 1-substituted tetrahydroisoquinolines (and thus an important group of alkaloids, Scheme 1).     

A new approach to indolo[2,3-a]quinolizidines through radical cyclization of 2-acyl-1-phenylthiotetrahydro-β-carbolines bearing pendent α,β-unsaturated esters

A new method is reported for the preparation of indolo[2,3-a]quinolizidines based on radical cyclization of a 2-acyl-1-phenylthiotetrahydro-β-carboline bearing a pendent α,β-unsaturated ester. The required radical cyclization precursor is efficiently assembled from E-5-ethoxycarbonyl-4-pentenoic acid and 3,4-dihydro-β-carboline through a DCC/HOBt-activation/N-acylation and BF₃·Et₂O/PhSH iminium-ion trapping sequence. Tin-mediated radical cyclization of the radical cyclization precursor affords stereoselectively a cis-lactam (dr = 7:1) in good yield (81%), bearing the correct D/E ring fusion stereochemistry for the Tacaman alkaloids. The methodology has been applied to formal syntheses of the indoloquinolizidine alkaloids, (±)-eburnaminol and (±)-larutensine.     

Facile Synthesis of 7-Amino-1,2,3,4-tetrahydro-β-carboline

Abstract

7-Amino-1,2,3,4-tetrahydro-β-carboline has been prepared by a short efficient synthetic sequence based on a regioselective nitration of a fully protected 1,2,3,4-tetrahydro-β-carboline.     

Proton magnetic resonance studies of compounds with bridgehead nitrogen atoms: XXXII—The 1H n.m.r. spectra and stereochemistry of 4-aryl-1,6,7,11b-tetrahydro-2H,4H-[1,3]oxazino[4,3-a]isoquinoline, 4-aryl-1,2,6,7,12,12b-hexahydro-4H-[1,3]oxazino[3′,4′:1,2]pyrido[3,4-b]indole and of related systems

cis(4-H,11b-H)-4-Aryl-1,6,7,11b-tetrahydro-2H,4H-[1,3]oxazino [4,3-a]isoquinoline and the related thiazino compound preferentially adopt in solution the O (or S) inside cis-conformation in contrast to cis(1-H,4a-H)-1-arylperhydropyrido[1,2-c][1,3]oxazine which adopts the trans fused conformation. 1-(β-Hydroxy-ethyl)-1,2,3,4-tetrahydro-β-carboline condenses with benzaldehyde to give the 1,3-oxazine derivative rather than the dimeric structure reported in the literature.     

A new synthesis of 4-oxygenated β-carboline derivatives by Fischer indolization

A new and short synthetic route to the 4-methoxy-β-carboline skeleton is described. The route involves Fischer indolization of enehydrazine of 1-tosylpiperidine-3,5-dione and successive acetalization-elimination for aromatization of 1,2,3,4-tetrahydro-2-tosyl-9H-β-carbolin-4-one. This method is efficiently applicable to synthesis of the benzene-part substituted 4-oxygenated β-carboline derivatives.     

Diborane as a reducing agent IX: Reduction of aTris(trifluoroacetyl)enaminospiroindoline

Summary Reduction of the title compound (2) with diborane furnishes 1-trifluoroethyl-3-(2-(trifluoroethylamino)ethyl)-3-vinylindoline (4), 1-hydroxy-trifluoroethyl-3-(2-(trifluoroethylamino)ethyl)indole (5), and 1-methyl-2-trifluoroethyl-1,2,3,4-tetrahydro--carboline (6). However, treatment of2 with lithium aluminum hydride, H₂/Pd on charcoal, and sodium borohydride affords hydroxyspiroindolenine8, hydroxy-bis(trifluoroacetyl)enaminospiroindoline9, andN-ethyltryptamine7, respectively. The results are discussed and the mechanisms of the reactions leading to4–8 are presented.

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Diboran als Reduktionsmittel, 9. Mitt.: Reduktion einesTris(trifluoroacetyl)enaminospiroindolins

Zusammenfassung Reduktion der Titelverbindung (2) mit Diboran ergibt 1-Trifluoroethyl-3-(2-(trifluoroethylamino)ethyl)-3-vinylindolin (4), 1-Hydroxy-trifluoroethyl-3-(2-(trifluoroethylamino)ethyl)indol (5) und 1-Methyl-2-trifluoroethyl-1,2,3,4-tetrahydro--carbolin (6). Behandlung von2 mit Lithiumaluminiumhydrid, H₂/Pd auf Aktivkohle und Natriumborhydrid führt jedoch zu Hydroxyspiroindolenin8, Hydroxy-bis(trifluoroacetyl)enaminospiroindolin9 und N-Ethyltryptamin (7). Die Ergebnisse werden diskutiert und die Mechanismen der zu den Produkten4–8 führenden Reaktionen werden vorgestellt.

     

Tetracyclische Imidazole

2-(Phenacyl)-tetrahydro--carboline (2) was transformed to theE/Z-oximes3 and4 and the isolated species cyclodehydrogenated to the nitrone5 and oxadiazine6. These compounds were dehydrated in acidic medium to the imidazole9.

     

Alkaloids ofNitraria komarovii. VII. Structure and synthesis of komarovinine

The new alkaloid komarovinine has been isolated from the total ether-extracted alkaloids of the epigeal part ofNitraria komarovii. It has also been found among the products of the dehydrogenation of nitrarine by selenium and sulfur. On the basis of the available facts, the structure of one of the isomers of 1-quinolinyl-β-carboline was proposed for komarovinine. A direct comparison with synthetic samples shows the identity of the alkaloid to 1-(quinolin-6′-yl)-β-carboline. 1-(Quinolin-7′-yl)-β-carboline, not previously described in the literature, has been characterized.     

Anti-inflammatory alkaloids from the stems of Picrasma quassioides BENNET

During further chemical and biological investigations of Picrasma quassioides BENNET, four new bis-β-carboline alkaloids, quassidines E-H (1-4), and three new β-carboline alkaloids, canthin-16-one-14-butyric acid (5), 3-(1,1-dimethoxylmethyl)-β-carboline (6), and 6,12-dimethoxy-3-formyl-β-carboline (7), were isolated from its anti-inflammatory CHCl(3)-soluble fraction. Structures of new compounds were elucidated and characterized by MS and NMR analysis. A plausible biogenetic pathway for quassidine E (1), the first bis-β-carboline alkaloid in which a canthin-6-one moiety and a β-carboline moiety were connected together by a single carbon-carbon bond from the nature, was proposed. Quassidines E-G (1-3) showed potent inhibitory activity on the production of nitric oxide (NO), tumor necrosis factor α (TNF-α), or interleukin 6 (IL-6) in mouse monocyte-macrophage RAW264.7 cells stimulated by lipopolysaccharide (LPS). Analysis of anti-inflammatory activity of all β-carboline and bis-β-carboline alkaloids from P. quassioides showed that the carbonyl groups or double carbon-carbon bonds at C-14 for β-carbolines and C-14' for bis-β-carbolines were bioactive groups for their in vitro anti-inflammatory activity. Structure-activity relationship of these compounds on inhibitory activity of the three inflammatory cytokines was discussed.     

Electrochemical oxidation of 6-hydroxy-1,2,3,4-tetrahydro-β-carboline in aqueous solution

The electrochemical oxidation of 6-hydroxy-1,2,3,4-tetrahydro-β-carboline (1), an alkaloid which occurs naturally in the mammalian brain, has been studied in aqueous solution particularly at physiological pH. The first voltammetric oxidation peak of 1 observed at the pyrolytic graphite electrode generates a radical intermediate which dimerizes to give 5,5′-bi-(6-hydroxy-1,2,3,4-tetrahydro-β-carboline) (3). However, the putative radical intermediate can also be further oxidized (1e) to give a C(5)-centered carbocation which can either dimerize in an ion-substrate reaction to give 3 or be attacked by water to give 5,6-dihydroxy-1,2,3,4-tetrahydro-β-carboline (8) which is rapidly oxidized further to 1,2,3,4-tetrahydro-β-carboline-5,6-dione (9). In the presence of glutathione dione 9 forms the 8-S-glutathionyl conjugate of 8 which is easily oxidized to the 8-S-glutathionyl conjugate of 9. It is suggested that 1 might be an alkaloid which is elevated in the brain as a result of chronic alcoholism, and the roles of the oxidative transformations of this compound in some of the addictive and neurophathological consequences of ethanol consumption are discussed.     

Unexpected ipso-Substitutions at the β-Carboline Nucleus

Abstract

Minisci-type radical carbamoylation of 1-bromo-β-carboline (1) gives the 3-substituted product in low yield, whereas 1-acetyl-β-carboline (3a) reacts under ipso-substitution of the acetyl group. Cyanations of the N-oxides of 1 and 3a occur under clean ipso-substitution of the groups in 1-position. 1-Methyl derivatives show no tendency to react under ipso-substitution.     

Polar steroidal compounds from the Far-Eastern starfish Lethasterias nanimensis chelifera

In addition to the salts described previously (with a sulfated steroid as the anion and the alkaloid salsolinol as the cation), nine other steroidal compounds including three new compounds were isolated from the Far-Eastern starfish Lethasterias nanimensis chelifera collected near the coast of the Onekotan island (Kuril isles). A nonsteroidal compound found in this starfish is (1S,3S)-1-methyl-1,2,3,4-tetrahydro--carboline-3-carboxylic acid. The structures of the isolated compounds were determined by NMR spectroscopy and mass spectrometry.     

Determination by High Performance Liquid Chromatography of Stability of Tetrahydro-β-carbolines at Different Ambient Temperatures

Abstract

To determine the stability of tetrahydro-β-carboline compounds over time and at different temperatures, a reversed-phase high pressure liquid chromatography system with electrochemical detection was utilized. Noreleagnine (1,2,3,4-tetrahydro-β-carboline) and tetrahydroharman (1-methyl-1,2,3,4-tetrahydro-β-carboline) were dissolved in water or ascorbate (0.1 mg/ml) vehicle and stored at ?20°C, 22°C, or 37°C for one, seven or 12 days. After each solution was injected in the column in a concentration of 400–600 ng/10 μl, peak height values were obtained for the compound under each condition. Analysis of percent recovery showed that the two β-carbolines were relatively stable with a maximal degradation of 14% occurring only at the 12-day assay interval. These results suggest that this class of compound can be used in pharmacological studies in which they can be dispensed from a mini-pump implanted in tissue. Further, an HPLC system with electrochemical detector provides a valid and reliable procedure for quantification of indoleamine-aldehyde condensation products.     

Two new β-carboline alkaloids from the roots of Gypsophila oldhamiana

Phytochemical investigation of the roots of Gypsophila oldhamiana afforded two new β-carboline alkaloids, oldhamiaines A and B (1 and 2), along with a known analogue (3). Their structures were elucidated by using spectroscopic and chemical methods. This is the first report of β-carboline alkaloids in the genus Gypsophila.