- Indole alkaloids and other constituents of Rauwolfia serpentina
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From the dried roots of Rauwolfia serpentina were isolated five new indole alkaloids, Nb-methylajmaline (1), Nb-methylisoajmaline (2), 3-hydroxysarpagine (3), yohimbinic acid (4), isorauhimbinic acid (5), a new iridoid glucoside, 7-epiloganin (6), and a new sucrose derivative, 6′-O-(3,4,5-trimethoxybenzoyl)glomeratose A (7), together with 20 known compounds. The structures of the new compounds were determined by spectroscopic and chemical means. The inhibitory activities of the selected alkaloids on topoisomerase I and II and their cytotoxicity against the human promyelocytic leukemia (HL-60) cell lines were assessed.
- Itoh, Atsuko,Kumashiro, Tomoko,Yamaguchi, Machiko,Nagakura, Naotaka,Mizushina, Yoshiyuki,Nishi, Toyoyuki,Tanahashi, Takao
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- Microwave-enhanced, stereospecific ring-closure of medium-ring cyanamide ethers to yohimbine
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A highly efficient acid-promoted, stereospecific, transannular ring-closure of medium-ring ether compounds to the indole alkaloid yohimbine is described. Microwave-enhanced acetic acid degradation of cyanamide compounds involves loss of (R)- or (S)-ethers, followed by a stereospecific, nucleophilic ring-closure from the cyanamide to afford yohimbine in up to 74% yield in as little as one minute. This nucleophilic reactivity of the amino moiety of the cyanamide highlights an alternative reactivity profile from its traditional electrophilic properties. Additionally, this reaction pathway highlights a rare case of an SN1 pathway that proceeds with complete stereospecificity.
- Paciaroni, Nicholas G.,Norwood, Verrill M.,Garcia, Daniel E.,Huigens, Robert W.
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- Total synthesis of (+)-yohimbine via an enantioselective organocatalytic Pictet-Spengler reaction
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The binolphosphoric acid-catalyzed Pictet-Spengler reaction of an N-(5-oxy-2,4-pentadienyl)tryptamine derivative with methyl 5-oxo-2- (phenylseleno)pentanoate leads to the tetrahydro-β-carboline in a 92:8 enantiomeric ratio. This product is easily converted into the substrate for a stereoselective intramolecular Diels-Alder reaction of the type earlier reported by Jacobsen. These two key steps constitute the basis for a nine-step total synthesis of (+)-yohimbine from tryptamine. A similar asymmetric Pictet-Spengler reaction was applied to the synthesis of an intermediate in the recent total synthesis of corynantheidine by Sato.
- Herle, Bart,Wanner, Martin J.,Van Maarseveen, Jan H.,Hiemstra, Henk
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p. 8907 - 8912
(2011/12/21)
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- Compounds and compositions for treating infection
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Compounds from 14 Kenyan plants, including from the root of Dovyalis abyssinica and Clutia robusta have been characterized and isolated, and their uses are disclosed.
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- THERAPY FOR COMPLICATIONS OF DIABETES
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A method for enhancing glycemic control and/or insulin sensitivity in a human subject having diabetic nephropathy and/or metabolic syndrome comprises administering to the subject a selective endothelin A (ETA) receptor antagonist in a glycemic control and/or insulin sensitivity enhancing effective amount. A method for treating a complex of comorbidities in an elderly diabetic human subject comprises administering to the subject a selective ETA receptor antagonist in combination or as adjunctive therapy with at least one additional agent that is (i) other than a selective ETA receptor antagonist and (ii) effective in treatment of diabetes and/or at least one of said comorbidities other than hypertension. A therapeutic combination useful in such a method comprises a selective ETA receptor antagonist and at least one antidiabetic, anti-obesity or antidyslipidemic agent other than a selective ETA receptor antagonist.
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- ANTIHYPERTENSIVE THERAPY
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A new use of darusentan is provided in preparation of a pharmaceutical composition for lowering blood pressure in a patient exhibiting resistance to a baseline antihypertensive therapy with one or more drugs. The composition comprises darusentan in an amount providing a therapeutically effective daily dose; wherein (a) the composition is orally deliverable and/or (b) the daily dose of darusentan is effective to provide a reduction of at least about 3 mmHg in one or more blood pressure parameters selected from trough sitting systolic, trough sitting diastolic, 24-hour ambulatory systolic, 24-hour ambulatory diastolic, maximum diurnal systolic and maximum diurnal diastolic blood pressures. Further provided is a new use of darusentan in preparation of a pharmaceutical composition for lowering blood pressure in a patient exhibiting resistance to a baseline antihypertensive therapy, wherein the composition is administered adjunctively with at least one diuretic and at least one antihypertensive drug selected from ACE inhibitors, angiotensin II receptor blockers, beta-adrenergic receptor blockers and calcium channel blockers.
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- Catalytic asymmetric total synthesis of (+)-yohimbine
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The total synthesis of (+)yohimbine was achieved in 11 steps and 14% overall yield. The absolute configuration was established through a highly enantioselective thiourea-catalyzed acyl-Pictet-Spengler reaction, and the remaining 4 stereocenters were set simultaneously in a substrate-controlled intramolecular Diels Alder reaction.
- Mergott, Dustin J.,Zuend, Stephan J.,Jacobsen, Eric N.
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supporting information; experimental part
p. 745 - 748
(2009/04/06)
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- Method for treating resistant hypertension
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A method is provided for lowering blood pressure in a patient having clinically diagnosed resistant hypertension. The method comprises administering darusentan to the patient adjunctively with a baseline antihypertensive regimen that comprises administration of at least one diuretic and at least two antihypertensive drugs selected from at least two of (a) ACE inhibitors and angiotensin II receptor blockers, (b) beta-adrenergic receptor blockers and (c) calcium channel blockers. The darusentan is orally administered at a dose and frequency effective, in combination with the baseline regimen, to provide a reduction of at least about 3 mmHg in one or more blood pressure parameters selected from trough sitting systolic, trough sitting diastolic, 24-hour ambulatory systolic, 24-hour ambulatory diastolic, maximum diurnal systolic and maximum diurnal diastolic blood pressures.
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- Enantiospecific synthesis of (-)-3-iso-19,20-dehydro-β-yohimbine from secologanin: A route to normal and pseudo stereoisomers of yohimbine
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Hydrolysis of secologanin ethylene acetal at pH 7 resulted in stereoselective aldol cyclisation to a cyclohexene aldehyde, which, on reductive amination and cyclisation with tryptamine afforded (-)-3-iso-19,20- dehydro-β-yohimbine, converted into various normal and pseudo isomers of yohimbine. (C) 2000 Elsevier Science Ltd.
- Brown, Richard T.,Pratt, Simon B.,Richards, Paul
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p. 5627 - 5630
(2007/10/03)
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- Biomimetic synthesis of monoterpenoid indole alkaloids from aglucones of secologanin derivatives: pH controlled product selectivity
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Variation of the pH for hydrolysis of secologanin derivatives with β-glucosidase controls rearrangement of the aglucone to afford different products, and hence stercoselective syntheses of heteroyohimbine, yohimbine and Aspidosperma-type alkaloids; with baker's yeast chemoselective reduction can also be achieved to give a precursor for antirhine and related alkaloids.
- Brown
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p. 609 - 616
(2007/10/03)
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- A reinvestigation of the oxidative rearrangement of yohimbane-type alkaloids. Part B. Formation of oxindol (= 1,3-dihydro-2H-indol-2-one) derivatives
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The methanolysis of the epimeric 7-chloro-7H-yohimbine derivatives 2 and 3 was reinvestigated. In case of the 7α-epimer 2, the reaction was uneventful and conformed with earlier observations, i.e., under sufficiently mild conditions, only the imino ether 4 (= imino ether A) was produced. Under the same conditions, the less reactive β-isomer 3 furnished a mixture of both imino ethers 4 and 5, accompanied by the elimination product 11, and by equal amounts of yohimbine (1) and 3,4,5,6-tetradehydroyohimbine (12), which are believed to arise through a disproportionation process of the putative intermediate 5,6-didehydroyohimbine (23). The nature of this divergent reactivity and of the ready equilibration of 4 and 5 was investigated by means of extensive force-field and semi-empirical calculations (AM1 and PM3) of various conformers of the compounds 2-5 and of some possible reaction intermediates.
- Stahl,Borschberg,Acklin
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p. 1361 - 1378
(2007/10/03)
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- Symmetry-driven synthesis of indole alkaloids: Asymmetric total synthesis of (+)-yohimbine, (-)-yohimbone, (-)-yohimbane, and (+)-alloyohimbane
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Total asymmetric syntheses of the target alkaloids are reported. The syntheses involve the preparation of enantiomerically pure (S,S)-1,3,3a,4,7,7a-hexahydro-2(H)-inden-2-one 7 and its meso isomer 5. Each ketone is then converted into a ring-expanded lactam using an oxaziridine synthesis/rearrangement protocol. The applications of Bischler-Napieralski ring constructions along with appropriate functional group transformations afford enantiomerically enriched alloyohimbane or yohimbane from the meso-or C2-symmetric ketones, respectively. A cis-5,6-diacetoxy compound (18) derived from the (S,S)-ketone served as the starting material for the total syntheses of the more highly functionalized alkaloids. Accordingly, a site-specific insertion of the indole-containing side chain was accomplished via stereoselective formation of an oxaziridine followed by its stereospecific rearrangement. The selectivity of this sequence allowed for the differentiation of alcohols at C-17 and C-18 (yohimbine numbering) and the synthesis of Δ18,19-yohimbone. This α,β-unsaturated ketone was converted into either (-)-yohimbone or (+)-yohimbine using standard chemistry.
- Aube,Ghosh,Tanol
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p. 9009 - 9018
(2007/10/02)
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- Total Syntheses of Yohimbe Alkaloids, with Stereoselection for the Normal, Allo, and 3-Epiallo Series, Based on Annelations of 4-Methoxy-1,2-dihydropyridones
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N--2,3-dihydro-4-pyridone (31) was generated in two steps (77percent yield) from tryptamine and N-methyl-4-piperidone methiodide.Its cyclization (90percent yield) and oxidation (91percent yield) provided the tetracyclic analogue 32.O-Methylation and Robinson-type annelation of these vinylogous lactams (the latter in form of its Na-carbamate) furnished the dienones 38 (64percent) and 43 (90percent).Further elaboration by cyclization and/or reduction reactions selectively provided the 15,16-didehydroyohimbinones 7 and 44.Their reductions then led to yohimbinone (52, 20percent overall yield from tryptamine), alloyohimbinone (11, 19percent overall yield), and 3-epi-alloyohimbinone (10, 23percent overall yield), which led to yohimbine (3), β-yohimbine (9), 3-epi-alloyohimbine (53), and 3-epi-17-epi-alloyohimbine (54).
- Kuehne, Martin E.,Muth, Randy S.
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p. 2701 - 2712
(2007/10/02)
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