- Synthesis of 15-methylene-eburnamonine from (+)-vincamine, evaluation of anticancer activity, and investigation of mechanism of action by quantitative NMR
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The biological role of installing a critical exocyclic enone into the structure of the alkaloid, (-)-eburnamonine, and characterization of the new chemical reactivity by quantitative NMR without using deuterated solvents are described. This selective modification to a natural product imparts potent anticancer activity as well as bestows chemical reactivity toward nucleophilic thiols, which was measured by quantitative NMR. The synthetic strategy provides an overall conversion of 40%. In the key synthetic step, a modified Peterson olefination was accomplished through the facile release of trifluoroacetate to create the requisite enone in the presence of substantial steric hindrance.
- Woods, James R.,Riofski, Mark V.,Zheng, Mary M.,O'Banion, Melissa A.,Mo, Huaping,Kirshner, Julia,Colby, David A.
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- NITROINDOLENINES EN SERIE VINCADIFFORMINE : INTERMEDIAIRES D'ACCES A LA VINCAMONE ET A UN SQUELETTE AZAHOMOASPIDOSPERMANE
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Vincadifformine and its 10-substituted analogs give in good yields 16-nitro indolenines of which the reactivity has been studied. By a two step process (demethoxycarbonylation and chloration on C16) nitro-indolenine 2b leads to gem-chloro-nitro 6.By an other two step sequence (NaBH3CN, NaH) nitro-indolenine 2c yields compound 10 via a 16 -> 1 COOCH3 migration.By heating compounds 6 and 10 in CF3COOH, rearranged products are obtained : vincamone 5 from 6 and azahomoaspidospermane 13 from 18.Mechanisms of formation of 5, 10 and 13 are discussed.
- Lewin, G.,Poisson, J.,Toffoli, P.
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- The Enantioselective Synthesis of Eburnamonine, Eucophylline, and 16′-epi-Leucophyllidine
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A synthetic approach to the heterodimeric bisindole alkaloid leucophyllidine is disclosed herein. An enantioenriched lactam building block, synthesized through palladium-catalyzed asymmetric allylic alkylation, served as the precursor to both hemispheres. The eburnamonine-derived fragment was synthesized through a Bischler–Napieralski/hydrogenation approach, while the eucophylline-derived fragment was synthesized by Friedl?nder quinoline synthesis and two sequential C?H functionalization steps. A convergent Stille coupling and phenol-directed hydrogenation united the two monomeric fragments to afford 16′-epi-leucophyllidine in 21 steps from commercial material.
- Hayashida, Kohei,Korch, Katerina M.,Ngamnithiporn, Aurapat,Reimann, Christopher E.,Saito, Daisuke,Stoltz, Brian M.
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supporting information
p. 17957 - 17962
(2021/07/12)
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- Catalytic Asymmetric Alkynylation of 3,4-Dihydro-β-carbolinium Ions Enables Collective Total Syntheses of Indole Alkaloids
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Chiral tetrahydro-β-carboline (THβC) is not only a prevailing structural feature of many natural alkaloids but also a versatile synthetic precursor for a vast array of monoterpenoid indole alkaloids. Asymmetric synthesis of C1-alkynyl THβCs remains rarely explored and challenging. Herein, we describe the development of two complementary approaches for the catalytic asymmetric alkynylation of 3,4-dihydro-β-carbolinium ions with up to 96 % yield and 99 % ee. The utility of chiral C1-alkynyl THβCs was demonstrated by the collective total syntheses of seven indole alkaloids: harmicine, eburnamonine, desethyleburnamonine, larutensine, geissoschizol, geissochizine, and akuammicine.
- Liang, Lixin,Zhou, Shiqiang,Zhang, Wei,Tong, Rongbiao
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p. 25135 - 25142
(2021/10/23)
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- Intermediate and preparation method and application thereof in synthesis of vinorchine
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The invention relates to the technical field of chemical drug synthesis, and discloses an application of an intermediate or a preparation method thereof in synthesis of vinorchin, adopts a modular synthetic strategy, adopts the compound D with 1 ring structures and C20 quaternary carbon centers, 5 (i.e. the compound 5) as a synthesis building block. The operation is simple and reaction conditions are easy for large-scale amplification effect.
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- Intermediate, preparation method and application of intermediate in synthesis of vincamine
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The invention relates to the technical field of chemical drug synthesis, and discloses an intermediate, a preparation method and application of the intermediate in synthesis of vincamine. A modular synthesis strategy is adopted, and a compound 1 with a D ring structure and a C20 quaternary carbon center and a tryptophol derivative 7 (namely the compound 7) with an indole ring are adopted as synthesis blocks for synthesis. The synthesis method is efficient; each step of the synthesis route is simple in reaction; the used reagent and solvent are cheap and easy to obtain; the operation is simple and convenient; the yield is high; and large-scale production is easy.
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- Preventing Morphine-Seeking Behavior through the Re-Engineering of Vincamine's Biological Activity
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Innovative discovery strategies are essential to address the ongoing opioid epidemic in the United States. Misuse of prescription and illegal opioids (e.g., morphine, heroin) has led to major problems with addiction and overdose. We used vincamine, an indole alkaloid, as a synthetic starting point for dramatic structural alterations of its complex, fused ring system to synthesize 80 diverse compounds with intricate molecular architectures. A select series of vincamine-derived compounds were screened for both agonistic and antagonistic activities against a panel of 168 G protein-coupled receptor (GPCR) drug targets. Although vincamine was without an effect, the novel compound 4 (V2a) demonstrated antagonistic activities against hypocretin (orexin) receptor 2. When advanced to animal studies, 4 (V2a) significantly prevented acute morphine-conditioned place preference (CPP) and stress-induced reinstatement of extinguished morphine-CPP in mouse models of opioid reward and relapse. These results demonstrate that the ring distortion of vincamine offers a promising way to explore new chemical space of relevance to opioid addiction.
- Norwood, Verrill M.,Brice-Tutt, Ariana C.,Eans, Shainnel O.,Stacy, Heather M.,Shi, Guqin,Ratnayake, Ranjala,Rocca, James R.,Abboud, Khalil A.,Li, Chenglong,Luesch, Hendrik,McLaughlin, Jay P.,Huigens, Robert W.
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p. 5119 - 5138
(2020/06/10)
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- ANALOGS OF VINCAMINE AND USES THEREOF
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The present disclosure provides compounds of any one of Formulae (I'), (I), (IA), (II'), (II), (IIA), (IIIA), (III"), (III'), (III), (IIIA), (IV), (V'), (V), (VI), (VII), (VIII'), (VIII), (ΙΧ'), (IX), and (X). The compounds described herein may be useful in treating and/or preventing a broad range of diseases (e.g., proliferative disease (e.g., cancers (e.g., non-small cell lung cancer, or glioma), inflammatory diseases, autoimmune diseases), CNS disorder (e.g., drug addiction), metabolic disorder (e.g., diabetes), or infectious disease (e.g., bacterial infection or parasitic infection (e.g., malaria))). Also provided in the present disclosure are pharmaceutical compositions, methods of synthesis of a compound described herein, kits, methods, and uses including or using a compound described herein.
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Paragraph 00336; 00397
(2018/09/12)
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- Asymmetric Total Synthesis of Eburnamine and Eucophylline: A Biomimetic Attempt for the Total Synthesis of Leucophyllidine
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The first enantiospecific total synthesis of (+)-6 has been achieved employing a Friedl?nder quinoline synthesis as a key step. Asymmetric synthesis of the architecturally complex eburnamine 5 has also been accomplished utilizing an intramolecular acid-mediated cyclization of a carbinol amine lactone moiety. Highlights of the effective modular synthetic strategy include development of the common precursor 4 for the construction of the privileged scaffolds 5 and 6 with an all-carbon quaternary stereocenter utilizing a Johnson-Claisen rearrangement strategy. Attempts have been made to synthesize 1 by the biomimetic coupling of 5 and (+)-6; however, regioisomeric 26 was formed.
- Pandey, Ganesh,Mishra, Akash,Khamrai, Jagadish
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p. 3267 - 3270
(2017/06/23)
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- A Radical Cascade Enabling Collective Syntheses of Natural Products
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Natural products have long been important inspirations for the development of chemical methodologies, theories, and technologies, and ultimately, discoveries of new drugs and materials. Chemical syntheses have traditionally yielded individual or small groups of natural products; however, methodology development allowing the synthesis of a large collection of natural products remains scarce. Here, we report an efficient photocatalytic radical cascade method that enables access to libraries of chiral and multiple-ring-fused tetrahydrocarbolinones. The radical cascade can controllably introduce complexity and functionality into products with excellent chemo-, regio-, and diastereoselectivity. The power of this distinct method has been demonstrated by the efficient syntheses of 33 monoterpenoid indole alkaloids belonging to four families.
- Wang, Xiaobei,Xia, Dongliang,Qin, Wenfang,Zhou, Ruijie,Zhou, Xiaohan,Zhou, Qilong,Liu, Wentao,Dai, Xiang,Wang, Huijing,Wang, Shuqing,Tan, Ling,Zhang, Dan,Song, Hao,Liu, Xiao-Yu,Qin, Yong
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supporting information
p. 803 - 816
(2017/06/13)
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- Enantiospecific total synthesis of indole alkaloids (+)-eburnamonine, (-)-aspidospermidine and (-)-quebrachamine
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An enantiospecific total synthesis of indole alkaloids eburnamonine, aspidospermidine and quebrachamine is described from lactic acid. Synthesis of all three alkaloids is accomplished from a single chiral building block. Johnson-Claisen rearrangement of a chiral allyl alcohol is the main feature for the installation of the required quaternary centre.
- Nidhiry, John Eugene,Prasad, Kavirayani R.
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p. 5525 - 5536
(2013/07/05)
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- Total synthesis of (+)-eburnamonine
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The enantiospecific total synthesis of vinca alkaloid (+)-eburnamonine is accomplished from l-ethyl lactate. Key feature of the synthesis is the construction of the chiral quaternary center involving a Johnson-Claisen rearrangement and assembly of the pentacyclic core by the Pictet-Spengler reaction and ring-closing metathesis. Georg Thieme Verlag Stuttgart · New York.
- Prasad, Kavirayani R.,Nidhiry, John E.
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p. 1477 - 1480
(2012/07/31)
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- Synthesis of 18-hydroxyvincamines and epoxy-1,14-secovincamines; A new proof for the aspidospermane-eburnane rearrangement
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Chemical transformations started from tabersonine were studied. A one-pot oxidative ring-transformation with permaleic acid in methanol yielded 17,18-dehydrovincamine. Hydroboration-oxidation of the latter compound led to alkaloid 17,18-dehydrovincamone. Hydroboration-oxidation of tabersonine resulted 14β-hydroxyvincadifformine and 15β-hydroxyvincadifformine. Allowing 14β- and 15β- hydroxyvincadifformines to react with permaleic acid/methanol provided 1,14-secovincamines, serving as new evidence for the mechanism of the aspidospermane-eburnane transformation. On the other hand 18β-hydroxyvincamine was obtained from 14β-hydroxyvincadifformine by reaction with 3-chloroperbenzoic acid and successive treatment with triphenylphosphine/aqueous acetic acid.
- Nemes, Andras,Szantay Jr., Csaba,Czibula, Laszlo,Greiner, Istvan
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p. 2347 - 2362
(2008/09/18)
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- Asymmetric synthesis of (-)-eburnamonine and (+)-epi-eburnamonine from (4s)-4-ethyl-4-[2-(hydroxycarbonyl)ethyl]-2-butyrolactone
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The key chiral nonracemic 4,4-disubstituted 2-butyrolactone carboxylic acid, (S)-4, is readily accessible via an efficient and stereospecific dirhodium(II) tetraacetate catalyzed tertiary C-H insertion reaction of the diazomalonate (S)-5. The coupling of the acid (S)-4 with tryptamine produces the amide (S)-3, which is then transformed into the aldehyde 23 and hydroxy-lactam 24. Acid-mediated Pictet-Spengler cyclization of 23 and 24 produces the tetracyclic indole lactams (1S,-12bS)-25a and (1S,12bR)-25b. Compounds 25a and 25b are converted, via the lactam alcohols 30a and 30b, to (-)-eburnamonine (1a) and (+)-epi-eburnamonine (1b).
- Wee,Yu
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p. 8935 - 8943
(2007/10/03)
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- Total synthesis of (-)-eburnamonine and (+)-epi-eburnamonine from a chiral non-racemic 4,4-disubstituted γ-lactone
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The total synthesis of (-)-eburnamonine and (+)-epi-eburnamonine was successfully achieved using a key chiral non-racemic 4,4-disubstituted γ- lactone 4 that was prepared via the Rh(II) carbenoid mediated tertiary C-H insertion reaction of a chiral non-racemic diazomalonate 5. (C) 2000 Elsevier Science Ltd.
- Wee, Andrew G.H.,Yu, Qing
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p. 587 - 590
(2007/10/03)
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- Desymmetrization of benzoic acid in the context of the asymmetric Birch reduction-alkylation protocol. Asymmetric total syntheses of (-)-eburnamonine and (-)-aspidospermidine
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The highly diastereoselective potassium in ammonia reduction-ethylation (EtI) of the chiral 2-(trimethylsilyl)benzamide 1b to give 1,4-cyclohexadiene 3 is the key step in asymmetric syntheses of (-)-eburnamonine (4) and (-)- aspidospermidine (5). Cyclohexadiene 3 was converted to cyclohexanone 7, which provided the trimethylsilyl-substituted butyrolactone 9 utilized for the synthesis of 4 and butyrolactone 13 required for the synthesis of 5. The preparation of 9 depended upon the completely regioselective silicon-directed Baeyer-Villiger oxidation 7 → 8; Baeyer-Villiger oxidation of the cyclohexenone 10 also was regioselective to give the desired enol lactone 11 in 92% yield. Remarkable diastereoselectivity was observed for the kinetically controlled cyclization of the acyl imminium ion derived from the vinyl-substituted carboxaldehyde 16b; treatment of 16b with 5 equiv of CF3CO2H in CH2Cl2 at -55 °C gave an 18:1 mixture of 17 and its C(3) β- epimer in 93% yield. The oxidation of alcohol 18 containing sensitive indole and piperidine rings was best carried out with tetrapropylammonium perruthenate/N-methylmorpholine N-oxide to give (-)-eburnamonine (4) in 97% yield. The asymmetric synthesis of (-)-aspidospermidine 5 involved the conversion of butyrolactone 13 to the hydroxylactam 22, the Harley-Mason cyclization of 22 to 23, and reduction of 23 with LiAlH4.
- Schultz, Arthur G.,Pettus, Liping
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p. 6855 - 6861
(2007/10/03)
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- Syntheses and Cardiovascular Activity of Stereoisomers and Derivatives of Eburnane Alkaloids
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The synthesis of all the possible isomers of the eburnamenine-vincamine type alkaloids 1b, 2a*, 3a and derivatives 4, 8, 9, 10 is described.Structures were determined by 1H- and 13C-NMR spectroscopy including special techniques such as DR, DEPT, DNOE, and 2D-HSC.In contrast to the known cerebrovascular effects of cis-(3S,16S) compounds, trans-(3S,16R) derivatives show a significant peripheral vasodilator effect. Key Word: Eburnanes / Alkaloids / Cardiovascular effects / Indoloquinolizines
- Czibula, Laszlo,Nemes, Andras,Visky, Gyoergy,Farkas, Maria,Szombathelyi, Zsolt,et al.
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p. 221 - 230
(2007/10/02)
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- Racemic and optically active octahydro-indolo(2,3-a) tetrahydropyranyl (2,3-c) quinolizine diester derivatives and process for preparing the same
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New intermediate compounds are disclosed of the formula I, STR1 wherein R1 and R2 are independently alkyl having 1 to 4 carbon atoms, or acid-addition salts thereof of formula Ib, STR2 wherein X represents an acid residue, and a process for the preparation of the intermediate compounds.
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- ALTERNATIVE ROUTES TO VINCAMINE
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The preparation of vincamine (1a) via indoloquinolizine propionic esters (7) is discussed.A new synthesis of the starting material methyl 2-acetoxyacrylate and an oxidative transformation of 7b to 1a are described and an alternative, more efficient route is reported.
- Nemes, Andras,Czibula, Laszlo,Visky, Gyorgy,Farkas, Maria,Kreidl, Janos
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p. 2329 - 2338
(2007/10/02)
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- Chiral Total Synthesis of Indole Alkaloids of the Aspidosperma and Hunteria Types
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Expeditious enantioselective syntheses of (+)-quebrachamine (6), (-)-aspidospermidine (7), (+)-demethoxyaspidospermine (8), and (-)-eburnamonine (9) were accomplished starting from (S)-lactone 1.The syntheses also complete formal, total syntheses of 12 other indole alkaloids of the Aspidosperma and Hunteria types.The key step in the synthesis of (+)-quebrachamine (6) was the Pictet-Spengler condensation of chiral C9 unit 10, derived from 1, with tryptamine.Another C9 unit (15) was also prepared from 1 and utilized for the syntheses of three other alkaloids, 7, 8, and 9.
- Node, Manabu,Nagasawa, Hideko,Fuji, Kaoru
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p. 517 - 521
(2007/10/02)
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- Kinetics and mechanisms of vinpocetine degradation in aqueous solutions
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Under stressed conditions, vinpocetine (1; ethyl apovincamin-22-oate) equilibrates with vincaminic acid ethyl ester (2) and 14-epivincaminic acid ethyl ester (3), and hydrolyzes to apovincaminic acid (4). Sequentially, 2 is equilibrated with 14-epivincaminic acid ethyl ester (3) and hydrolyzes to vincaminic acid (5), which equilibrates with 4 and 14-epivincaminic acid (6). At acidic pH, the major route of degradation is 1?2→5. However, at neutral pH, the major route of degradation is 1→4?5. The kinetics for the degradation of 1 in the pH 1-3 region is represented by a consecutive reaction with a reversible step (second-order), but the degradation of 1 in the pH 3.5-6.0 region follows pseudo first-order kinetics. Significant buffer catalysis is observed with acetate and phosphate buffers. Reactions are dependent on the ionic strength, pH, and temperature. No oxygen effect on the degradation of vinpocetine is found.
- Muhammad,Adams,Lee
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p. 126 - 131
(2007/10/02)
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- Reactions with indole derivatives-LV. An enantiodivergent route to both vincamine enantiomers
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The enantioselective synthesis of the tetracyclic lactam 4 is reported which by enantiodivergent techniques is converted into (+)- as well as (-)-vincamine via the corresponding eburnamonine enantiomers.
- Hakam, Khalida,Thielmann, Marion,Thielmann, Thomas,Winterfeldt, Ekkehard
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p. 2035 - 2044
(2007/10/02)
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- Total Synthesis of (-)-Kopsinilam, (-)-Kopsinine, and the Bis-indole Alkaloids (-)-Norpleiomutine and (-)-Pleiomutine
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The racemic tetracyclic amine (5) was resolved and converted into (-)-kopsinine (16); subsequent coupling to (-)-eburnamine (2) gave (-)-norpleiomutine (4).
- Magnus, Philip,Brown, Peter
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p. 184 - 186
(2007/10/02)
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- Chiral Synthesis of (+)-Eburnamine, (-)-Eburnamenine, and (-)-Eburnamonine
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The (S)-trityl-lactone (6), easily prepared from L-glutamic acid or D-mannitol, has been stereoselectively converted into (+)-eburnamine (3), (-)-eburnamenine (4), and (-)-eburnamonine (2), via the dithiane-lactone (15).
- Takano, Seiichi,Yonaga, Masahiro,Morimoto, Masamichi,Ogasawara, Kunio
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p. 305 - 310
(2007/10/02)
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- Process for the preparation of eburnamonine derivatives
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The invention relates to a new process for the preparation of eburnamonine derivatives of the general Formula I STR1 (wherein R1 is an alkyl group having 1-6 carbon atoms) and optical and geometrical isomers thereof which comprises reacting a hydroxyimino-octahydro-indolo[2,3-a]quinolizine derivative of the general Formula II STR2 (wherein R1 is as stated above and R2 stands for an alkyl group having 1-6 carbon atoms being identical with or different from R1, or a hydrogen atom) or an acid addition salt thereof in an organic protic solvent or solvent mixture with an inorganic base, optionally under the addition of water or an aqueous mineral acid, at a temperature between 60° C. and 200° C. The compounds of the present invention are known drugs having blood pressure decreasing and cerebral vasodilatatory effect. The advantage of the process of the present invention is that it is readily feasible on industrial scale too, provides isomer-free pure products with high yield and requires the use of readily available simple starting materials.
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- THERMAL REARRANGEMETS OF SOME INDOLE ALKALOID DERIVATIVES
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Under both static and flow thermolysis conditions, several compounds with an "aspidosperma" framework rearranged to "vinca" derivatives.Thus (-)1,2-dehydroaspidospermidine (4) rearranged to (-)aspidospermidine and compound 17 on pyrolysis (200 deg C) while flow termolysis (580 deg C) gave vincane (14).Compound 6 rearranged to vincamine (13a) and 16-epivincamine (13b) under either condition; increasing the temperature resulted in formation of apovincamine (19) (pyrolysis) or vincamone (16) (flow thermolysis).
- Hugel, Georgette,Levy, Jean
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p. 1067 - 1074
(2007/10/02)
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- Nouvelles hemisyntheses de la (+)vincamine et de la (-)vincamone
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A new course in the hemisynthesis of (+)vincamine 2a and (-)vincamone 3 indole alkaloids of medicinal interest from (-)apovincamine 1a is described.Apovincamine itself was obtained from vincadifformine 4 by an original process recently related (N-chlorosuccinimide in pure CF3COOH or HCOOH).The conversion of apovincamine into vincamine involves three steps, with or without isolation of the intermediate compounds: a) addition of bromine in methanol to the double bond (C-16)-(C-17) b) catalytic hydrogenolysis of the (C-17)-Br bond in vincamine O-methyl ether 9 c) hydrolysis of 9 resulting in a mixture of vincamine 2a and 16-epivincamine 2b.The conversion of apovincamine into vincamone is carried out after saponification to apovincaminic acid 1b.Addition of bromine in aqueous medium, and further acidification and heating yields vincamone by a single step process.
- Lewin, Guy,Poisson, Jacques
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p. 435 - 437
(2007/10/02)
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- Synthesis of vinca alkaloids and related compounds. XVI. New route to the stereoselective synthesis of (+)-vincamine, (-)-vincamone and (+)-apovincaminic acid esters
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A stereoselective methods has been elaborated for the synthesis of oxime esters, from which, as common intermediates, (+)-apovincaminic acid esters, (+)-vincamine and (-)-vincamone can be prepared.
- Szabo,Sapi,Kalaus,et al.
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p. 3737 - 3747
(2007/10/02)
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- Metabolism of vincamine in the rat in vivo and in vitro
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Metabolism of vincamine has been studied in rats in vivo and in vitro using tritium labelled vincamine. Radioactivity was excreted with urine and faeces in an amount of about 62% during 72 h after i.v., i.p. and p.o. administration of the drug. From bile about 40% radioactivity could be recovered during 6 h following i.p. administration. Vincamine is excreted in unchanged form in an amount of 4-6%. In an in vitro system containing rat liver homogenate 6α- and 6β-hydroxy-vincamine are formed, as their structures could be deduced from the mass spectrometric data. Rat plasma probably hydrolizes vincamine to vincaminic acid, but the presence of vincaminic acid could not be demonstrated, neither in urine nor in bile. Mass spectrometric investigations of the urinary and biliary metabolites have shown that beyond 6α- and 6β-hydroxy-vincamine, their further oxidized form, 6-keto-vincamine also appears. 6α-, 6β-hydroxy-vincamine, 6-keto-vincamine and vincamine are eliminated with urine and bile in part as conjugates. Among the metabolites (+)-eburnamonine (vincamone) was also found, which is supposed to be the degradation product of vincaminic acid. The identified compounds are responsible for about 70% of urinary and 30% of biliary radioactivities.
- Vereczkey,Tamas,Czira,Szporny
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p. 1861 - 1865
(2007/10/02)
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