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Justin J. B. Perry - One of the best experts on this subject based on the ideXlab platform.
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investigation of the acid base behaviour of the opium alkaloid Thebaine in lc esi ms mobile phase by nmr spectroscopy
Royal Society Open Science, 2017Co-Authors: Michelle Carlin, John R. Dean, Jonathan L. Bookham, Justin J. B. PerryAbstract:As part of a research programme to establish an analytical method for the simultaneous detection of the five major opium alkaloids in poppy seeds by liquid chromatography–electrospray ionization–mass spectrometry (LC-ESI-MS) it was discovered that the inclusion of Thebaine produced two peaks for the same compound. This was in contrast to the effective simultaneous detection, by LC-ESI-MS, of morphine, codeine, papaverine and noscapine. The presence of these two peaks for Thebaine was investigated using nuclear magnetic resonance spectroscopy with deuterated solvents to emulate the mobile phase conditions experienced. It was found that the presence of 80%, or higher ratios of, water caused two epimeric forms of Thebaine to be formed; this explained the presence of two peaks on the chromatogram. In contrast, when a lower water content was used with 1% acetic acid, one stable form of Thebaine could be analysed and resulted in a single peak visible in the subsequent chromatography.
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NMR Spectra of Thebaine from Investigation of the acid/base behaviour of the opium alkaloid Thebaine in LC-ESI-MS mobile phase by NMR spectroscopy
2017Co-Authors: Michelle G. Carlin, John R. Dean, Jonathan L. Bookham, Justin J. B. PerryAbstract:As part of a research programme to establish an analytical method for the simultaneous detection of the five major opium alkaloids in poppy seeds by liquid chromatography-electrospray ionization-mass spectrometry (LC-ESI-MS) it was discovered that the inclusion of Thebaine produced two peaks for the same compound. This was in contrast to the effective simultaneous detection, by LC-ESI-MS, of morphine, codeine, papaverine and noscapine. The presence of these two peaks for Thebaine was investigated using nuclear magnetic resonance (NMR) spectroscopy with deuterated solvents to emulate the mobile phase conditions experienced. It was found that the presence of 80%, or higher ratios of, water caused two epimeric forms of Thebaine to be formed; this explained the presence of two peaks on the chromatogram. In contrast, when a lower water content was used with 1% acetic acid, one stable form of Thebaine could be analysed and resulted in a single peak visible in the subsequent chromatography
Jillian M Hagel - One of the best experts on this subject based on the ideXlab platform.
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Neopinone isomerase is involved in codeine and morphine biosynthesis in opium poppy.
Nature chemical biology, 2019Co-Authors: Mehran Dastmalchi, Jillian M Hagel, Xue Chen, Rongji Chen, Sukanya Ramasamy, Sam Yeaman, Peter J. FacchiniAbstract:The isomerization of neopinone to codeinone is a critical step in the biosynthesis of opiate alkaloids in opium poppy. Previously assumed to be spontaneous, the process is in fact catalyzed enzymatically by neopinone isomerase (NISO). Without NISO the primary metabolic products in the plant, in engineered microbes and in vitro are neopine and neomorphine, which are structural isomers of codeine and morphine, respectively. Inclusion of NISO in yeast strains engineered to convert Thebaine to natural or semisynthetic opiates dramatically enhances formation of the desired products at the expense of neopine and neomorphine accumulation. Along with Thebaine synthase, NISO is the second member of the pathogenesis-related 10 (PR10) protein family recently implicated in the enzymatic catalysis of a presumed spontaneous conversion in morphine biosynthesis.
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A pathogenesis-related 10 protein catalyzes the final step in Thebaine biosynthesis
Nature Chemical Biology, 2018Co-Authors: Xue Chen, Limei Chang, Joseph E. Tucker, Stacey A. Shiigi, Yuora Yelpaala, Hsiang-yun Chen, Rodrigo Estrada, Jeffrey Colbeck, Jillian M Hagel, Maria Enquist-newmanAbstract:Although the conversion of (7S)-salutaridinol 7-O-acetate to Thebaine can occur spontaneously, the identification of a Thebaine synthase enzyme that catalyzes the reaction indicates how nature avoids the formation of labile hydroxylated byproducts. The ultimate step in the formation of Thebaine, a pentacyclic opiate alkaloid readily converted to the narcotic analgesics codeine and morphine in the opium poppy, has long been presumed to be a spontaneous reaction. We have detected and purified a novel enzyme from opium poppy latex that is capable of the efficient formation of Thebaine from (7 S )-salutaridinol 7- O -acetate at the expense of labile hydroxylated byproducts, which are preferentially produced by spontaneous allylic elimination. Remarkably, Thebaine synthase (THS), a member of the pathogenesis-related 10 protein (PR10) superfamily, is encoded within a novel gene cluster in the opium poppy genome that also includes genes encoding the four biosynthetic enzymes immediately upstream. THS is a missing component that is crucial to the development of fermentation-based opiate production and dramatically improves Thebaine yield in engineered yeast.
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Dioxygenases catalyze the O-demethylation steps of morphine biosynthesis in opium poppy
Nature chemical biology, 2010Co-Authors: Jillian M HagelAbstract:Two previously undetected enzymes involved in morphine biosynthesis and unique among plants to opium poppy have been identified as non-heme dioxygenases, in contrast to the functionally analogous cytochrome P450s found in mammals. We used functional genomics to isolate Thebaine 6-O-demethylase (T6ODM) and codeine O-demethylase (CODM), the only known 2-oxoglutarate/Fe(II)-dependent dioxygenases that catalyze O-demethylation. Virus-induced gene silencing of T6ODM and CODM in opium poppy efficiently blocked metabolism at Thebaine and codeine, respectively.
K Helliwell - One of the best experts on this subject based on the ideXlab platform.
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papaver bracteatum lindley Thebaine content in relation to plant development
Journal of Pharmacy and Pharmacology, 2011Co-Authors: J W Fairbairn, K HelliwellAbstract:Four Thebaine-rich varieties of P. bracteatum have been grown in the open over two seasons and the Thebaine distribution in aerial parts examined to determine the most suitable source material for commercial production. The leaves contained only 0·1 to 0·15%; the capsules 0·5 to 3·0% and the bled latex 28 to 53%. The maximum for the latter occurred about 3–4 weeks after petal opening and during the day, at about 15.00 h. A product ‘bractium’ prepared exactly as opium from P. somniferum contained up to 55% Thebaine and calculations from the 1974 results gave theoretical yields up to 58 kg of Thebaine per hectare. However this is a very labour intensive method; furthermore bled latex only represents about 46% of the total Thebaine of the capsule. In addition the pedicels contain significant amounts of Thebaine, so that fruiting tops may be recommended as source material. In the capsule the Thebaine content reaches a peak 3 to 4 weeks after petal opening and again two weeks later. At this fully ripe stage there is a theoretical yield of 50 kg per hectare. Two further advantages accrue from collection at this time: the ripe seeds can probably be used for similar purposes as poppy seed; and the pericarps at this stage contain no ‘bound Thebaine’ (i.e., Thebaine insoluble in MeOH:NH4OH but soluble in acetic acid—in unripe capsules bound Thebaine represents 18 to 36% of the total Thebaine). There is some evidence that, as this perennial plant increases in age, the capacity for Thebaine production seems to continue increasing. Storage of raw material, even in ideal conditions, led to a loss of Thebaine of 12 to 20% in one year.
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the determination of Thebaine in papaver bracteatum lindl by gas liquid chromatography
Journal of Pharmacy and Pharmacology, 2011Co-Authors: J W Fairbairn, K HelliwellAbstract:Several solvents have been examined in the process of developing a convenient method for extracting powdered material and removing interfering pigments to produce an extract of Papaver bracteatum suitable for g.l.c. assay. The most suitable extracting solvent was aqueous acetic acid (5%); the assay method gave satisfactory reproducibility with a wide range of plant materials (coefficient of variation 0.63 to 3.33%). The accuracy was checked by recovery experiments with pure Thebaine and by examination of exhausted marcs. The presence of other alkaloids did not interfer with the assay. There were substantial differences in the amounts of Thebaine extracted from capsule and root samples by ammoniacal methanol and by aqueous acetic acid, indicating the presence of Thebaine in a "bound" form. The minimum amount of Thebaine that could readily be determined by the g.l.c. method was 0.3 mg in the sample of powder used for the assay.
Michelle Carlin - One of the best experts on this subject based on the ideXlab platform.
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investigation of the acid base behaviour of the opium alkaloid Thebaine in lc esi ms mobile phase by nmr spectroscopy
Royal Society Open Science, 2017Co-Authors: Michelle Carlin, John R. Dean, Jonathan L. Bookham, Justin J. B. PerryAbstract:As part of a research programme to establish an analytical method for the simultaneous detection of the five major opium alkaloids in poppy seeds by liquid chromatography–electrospray ionization–mass spectrometry (LC-ESI-MS) it was discovered that the inclusion of Thebaine produced two peaks for the same compound. This was in contrast to the effective simultaneous detection, by LC-ESI-MS, of morphine, codeine, papaverine and noscapine. The presence of these two peaks for Thebaine was investigated using nuclear magnetic resonance spectroscopy with deuterated solvents to emulate the mobile phase conditions experienced. It was found that the presence of 80%, or higher ratios of, water caused two epimeric forms of Thebaine to be formed; this explained the presence of two peaks on the chromatogram. In contrast, when a lower water content was used with 1% acetic acid, one stable form of Thebaine could be analysed and resulted in a single peak visible in the subsequent chromatography.
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ESM
2017Co-Authors: John R. Dean, Michelle Carlin, Justin Perry, Jon BookhamAbstract:Thebaine NMR dat
Tomas Hudlicky - One of the best experts on this subject based on the ideXlab platform.
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model studies toward the total synthesis of Thebaine by an intramolecular cycloaddition strategy
ChemistrySelect, 2017Co-Authors: Josef Hajicek, Petr Koukal, Setu Gupta, Tomas HudlickyAbstract:The present studies describe recent progress toward the synthesis of the Thebaine. Model substrates were synthesized using pyridazine derivatives as a starting material, which allowed to assess the key Diels-Alder reaction as a route to construct the Thebaine core.
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direct synthesis of noroxymorph one from Thebaine unusual ceiv oxidation of a methoxydiene iron complex to an enone γ nitrate
European Journal of Organic Chemistry, 2016Co-Authors: Ales Machara, Mary Ann A Endomaarias, Phillip D Cox, Ivana Cisařova, Tomas HudlickyAbstract:Noroxymorphone was prepared from Thebaine in seven operations. The key steps involved the successive N- and O-demethylations of an iron tricarbonyl complex of Thebaine followed by the unusual ceric ammonium nitrate oxidation of the methoxydiene moiety to the corresponding enone-γ-nitrate during the decomplexation of the iron tricarbonyl functionality.
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improved synthesis of buprenorphine from Thebaine and or oripavine via palladium catalyzed n demethylation acylation and or concomitant o demethylation
Advanced Synthesis & Catalysis, 2012Co-Authors: Ales Machara, Lukas Werner, Mary Ann A Endomaarias, Phillip D Cox, Tomas HudlickyAbstract:An improved preparation of buprenorphine via palladium-catalyzed N-demethylation/acylation is reported. Three routes were investigated and compared in overall yield. The first involved N-demethylation/acylation of an advanced intermediate obtained from Thebaine followed by hydrolysis of the N-acetamide and alkylation with cyclopropylmethyl bromide and/or reduction of the N-acetyl group with the Schwartz reagent followed by N-alkylation. The second route employed cyclopropylcarboxylic acid anhydride in the N-demethylation/acylation protocol and subsequent reduction of the cyclopropylcarboxamide by either lithium aluminum hydride or under hydrosilylation conditions. Both of these routes originated in Thebaine and therefore required O-demethylation as a final step. The third route employed an N-demethylation/acylation sequence starting from oripavine rather than Thebaine, thus avoiding the O-demethylation. The routes are compared for overall efficiency and experimental and spectral data are provided for all new compounds.
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one pot conversion of Thebaine to hydrocodone and synthesis of neopinone ketal
Journal of Organic Chemistry, 2009Co-Authors: Robert J Carroll, Tomas Hudlicky, Hannes Leisch, Lena Rochon, Phillip D CoxAbstract:The ethylene glycol ketal of neopinone was prepared in a one-pot procedure by the reaction of Thebaine with ethylene glyocol in the presence of p-toluenesulfonic acid. The ketal is also an intermediate in the conversion of Thebaine to hydrocodone with ethylene glycol and Pd(OAc)(2), followed by hydrogenation. Additionally, a one-pot procedure for the conversion of Thebaine to hydrocodone was achieved by employing palladium catalysis in aqueous medium. Palladium serves a dual purpose in this transformation, first for the activation of the dienol ether of Thebaine and second as a hydrogenation catalyst. This procedure was found to be comparable to the two-step protocol which employs diimide reduction of Thebaine followed by acid-catalyzed hydrolysis of the resulting 8,14-dihydroThebaine to hydrocodone. Experimental and spectral data are provided for all compounds.
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studies on regioselective hydrogenation of Thebaine and its conversion to hydrocodone
Tetrahedron Letters, 2007Co-Authors: Hannes Leisch, Tomas Hudlicky, Robert J Carroll, Phillip D CoxAbstract:Thebaine was subjected to catalytic hydrogenation under a variety of conditions in order to determine the regioselectivity for C-6/C-7 versus C-8/C-14 olefin saturation.
