- Catalytic Asymmetric Total Syntheses of (-)-Galanthamine and (-)-Lycoramine
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The catalytic asymmetric total syntheses of the biologically important and therapeutically valuable Amaryllidaceae alkaloids (-)-galanthamine and (-)-lycoramine have been divergently achieved from commercially available 3-butyn-1-ol. A newly developed spirocyclic pyrrolidine (SPD)-catalyzed enantioselective Robinson annulation rapidly constructs the key cis-hydrodibenzofuran core, which bears an all-carbon quaternary stereocenter of the target molecules with an excellent stereoselective control. Additionally, the current asymmetric synthetic strategy provides an alternative approach toward the syntheses of (-)-galanthamine and its analogues.
- Zhang, Qing,Zhang, Fu-Min,Zhang, Chang-Sheng,Liu, Si-Zhan,Tian, Jin-Miao,Wang, Shao-Hua,Zhang, Xiao-Ming,Tu, Yong-Qiang
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- Synthesis of 3H-(-)-galanthamine
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3H-(-)-galanthamine (0.881TBq/mmol) was synthesized via stereoselective reduction of (-)-narwedine with tritiated L-Selectride. This reaction sequence was favored over an exchange of aromatic bromine with lithium aluminium tritide. Copyright
- Linnemann,Fels
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Read Online
- Catalytic Asymmetric Total Synthesis of (-)-Galanthamine and (-)-Lycoramine
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The catalytic asymmetric total syntheses of (-)-galanthamine (1) and (-)-lycoramine (2) have been achieved by using a conceptually new strategy featuring two metal-catalyzed reactions as the key steps. A new method for the construction of 3,4-fused benzofurans has been developed through a palladium-catalyzed intramolecular Larock annulation reaction, which was successfully applied to the construction of the ABD tricyclic skeleton of 1 and 2. To achieve the asymmetric synthesis of 1 and 2, a ScIII/N,N′-dioxide complex was used to catalyze the enantioselective conjugate addition of 3-alkyl-substituted benzofuranone to methyl vinyl ketone for the construction of a chiral quaternary carbon center.
- Li, Lei,Yang, Qiao,Wang, Yuan,Jia, Yanxing
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Read Online
- Transition-Metal-Mediated Chemo- and Stereoselective Total Synthesis of (?)-Galanthamine
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An asymmetric synthetic route to (?)-galanthamine (1), a pharmacologically active Amaryllidaceae alkaloid used for the symptomatic treatment of early onset Alzheimer’s disease, was successfully established with very high levels of stereocontrol. The key to achieving high chemo- and stereo-selectivity in this approach was the use of transition-metal-mediated reactions, namely, enyne ring-closing metathesis, Heck coupling, and titanium-based asymmetric allylation.
- Ajavakom, Vachiraporn,Bellingham, Richard K.,Brown, Richard C. D.,Camp, Nicholas P.,Kemp, Stephen C.,McLean, Neville J.,Miller, Iain R.,Moustafa, Gamal A. I.
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p. 1325 - 1334
(2022/01/27)
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- Total Syntheses of Galanthamine and Lycoramine via a Palladium-Catalyzed Cascade Cyclization and Late-Stage Reorganization of the Cyclized Skeleton
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Herein, we report the highly efficient total syntheses of galanthamine and lycoramine from a common tetracyclic intermediate. This concise synthetic route features a two-phase strategy, which includes the early-stage rapid construction of a tetracyclic skeleton followed by the late-stage selective reorganization of the tetracyclic skeleton. Key to the success of this strategy are a palladium-catalyzed carbonylative cascade annulation, a DDQ-mediated intramolecular regioselective oxidative lactamization, as well as a BF3·Et2O-promoted reorganization of the bridged tetracyclic skeleton.
- Chang, Ya-Ping,Ma, Xia,Shao, Hui,Zhao, Yu-Ming
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p. 9659 - 9663
(2021/12/17)
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- Total synthesis of (±)-galanthamine from GABA through regioselective aryne insertion
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The total synthesis of (±)-galanthamine is achieved in ～5% overall yield using a key regioselective aryne insertion reaction into a GABA (γ-amino butyric acid) derivative. The strategy presented involves only two sub-critical temperature reactions and less than five chromatographic purifications to achieve the synthesis of galanthamine.
- Venkatesh, Telugu,Mainkar, Prathama S.,Chandrasekhar, Srivari
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p. 2192 - 2198
(2019/02/27)
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- The application of a specific morphinan template to the synthesis of galanthamine
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(–)-Galanthamine (4) was synthesized from naltrexone (1) in 18 steps with 3% total yield by overcoming many specific side reactions derived from the 4,5-epoxymorphinan skeleton. The key features are cleavage of the D-ring by the Hofmann elimination and the following the one-pot C9–C10 and C9–14 bond cleavages concomitant with the C9 removal by the OsO4–NaIO4 combination reaction. Then, the treatment with zinc powder in acetic acid led to not only removal of the 2,2,2-trichloroethoxycarbonyl (Troc) group, but also reductive amination of the resulting imine to give the desired 7-membered ring.
- Yamamoto, Naoshi,Okada, Takahiro,Harada, Yukimasa,Kutsumura, Noriki,Imaide, Satomi,Saitoh, Tsuyoshi,Fujii, Hideaki,Nagase, Hiroshi
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p. 5751 - 5758
(2017/09/05)
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- An Eleven-Step Synthesis of Galanthamine from Commercially Available Materials
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Narwedine, an immediate precursor to the therapeutically valuable alkaloid (–)-galanthamine, has been synthesised by engaging an iodinated isovanillin derivative in an intermolecular Mitsunobu reaction with a 2-cyclohexen-1-ol derivative. The resulting aryl ether participated in an exceptionally efficient intramolecular Heck reaction to give a tetracyclic lactol after the hydrolysis of the primary cyclisation product. This last compound is an advanced intermediate associated with the Magnus synthesis of narwedine and could be elaborated to narwedine itself under reductive amination conditions. As a result, an eleven-step synthesis of galanthamine has been established.
- Nugent, Jeremy,Banwell, Martin G.
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p. 5862 - 5867
(2016/12/18)
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- Stereoselective syntheses of galanthamine and its stereoisomers by complementary Luche and L-selectride reductions
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A diastereodivergent approach for the stereoselective syntheses of all four stereoisomers of galanthamine, (-)-galanthamine 1, (+)-galanthamine 2, (-)-epigalanthamine 3, and (+)-epigalanthamine 4, from (±)-narwedine 5 is reported. Thus (±)-narwedine 5 was resolved by dynamic kinetic resolution to obtain enantiomerically pure (-)-narwedine 6 and (+)-narwedine 7. Each enantiomerically pure isomer of narwedine was subjected to Luche and L-selectride reactions to obtain all four isomers of galanthamine. In these reactions, the (-)-galanthamine 1 and (+)-galanthamine 2 isomers were obtained with an enantiomeric purity of >99.5%, whereas (-)-epigalanthamine 3 and (+)-epigalanthamine 4 are obtained with a chiral purity of >97%. The axial hydride attack by the Luche reduction and the equatorial hydride attack by the L-selectride reduction on the cyclic enone system are explored in the stereoselective synthesis of the galanthamine isomers and thus it was demonstrated that the stereoselective synthesis involving the Luche and L-selectride reductions are complementary in yielding enantiomeric stereogenic centers from a prochiral carbonyl group on the cyclic enone system.
- Trinadhachari, Ganala Naga,Kamat, Anand Gopalkrishna,Raghu Babu, Korupolu,Sanasi, Paul Douglas,Prabahar, Koilpillai Joseph
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p. 117 - 124
(2014/02/14)
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- Synthesis and evaluation of (-)- and (+)-[11C]galanthamine as PET tracers for cerebral acetylcholinesterase imaging
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Improved radiopharmaceuticals for imaging cerebral acetylcholinesterase (AChE) are needed for the diagnosis of Alzheimer's disease (AD). Thus, 11C-labeled (-)-galanthamine and its enantiomers were synthesized as novel agents for imaging the localization and activity of AChE by positron emission tomography (PET). C-11 was incorporated into (-)- and (+)-[ 11C]galanthamine by N-methylation of norgalanthamines with [ 11C]methyl triflate. Simple accumulation of 11C in the brain was measured in an in vivo biodistribution study using mice, whilst donepezil was used as a blocking agent in analogous in vivo blocking studies. In vitro autoradiography of rat brain tissue was performed to investigate the distribution of (-)-[11C]galanthamine, and confirmed the results of PET studies in mice. The radiochemical yields of N-methylation of (-)- and (+)-norgalanthamines were 13.7% and 14.4%, respectively. The highest level of accumulation of 11C in the brains of mice was observed at 10 min after administration (2.1% ID/g). Intravenous pretreatment with donepezil resulted in a 30% decrease in accumulation of (-)-[11C]galanthamine in the striatum; however, levels in the cerebellum were unchanged. In contrast, use of (+)-[11C]galanthamine led to accumulation of radioactivity in the striatum equal to that in the cerebellum, and these levels were unaffected by pretreatment with donepezil. In in vitro autoradiography of regional radioactive signals of brain sections showed that pretreatment with either (-)-galanthamine or donepezil blocked the binding of (-)-[11C] galanthamine to the striatum, while sagittal PET imaging revealed accumulation of (-)-[11C]galanthamine in the brain. These results indicate that (-)-[11C]galanthamine showed specific binding to AChE, whereas (+)-[11C]-galanthamine accumulated in brain tissue by non-specific binding. Thus, optically pure (-)-[11C]galanthamine could be a useful PET tracer for imaging cerebral AChE.
- Kimura, Hiroyuki,Kawai, Tomoki,Hamashima, Yoshio,Kawashima, Hidekazu,Miura, Kenji,Nakaya, Yuta,Hirasawa, Makoto,Arimitsu, Kenji,Kajimoto, Tetsuya,Ohmomo, Yoshiro,Ono, Masahiro,Node, Manabu,Saji, Hideo
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p. 285 - 291
(2014/01/17)
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- Commercial scale process of galanthamine hydrobromide involving Luche reduction: Galanthamine process involving regioselective 1,2-reduction of α,β-unsaturated ketone
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Effect of lanthanide chloride in the Luche regioselective 1,2-reduction of 1-bromo-11-formyl-nornarwedine (5) was studied. Thus, 1-bromo-11-formyl- nornarwedine (5) is reduced with sodium borohydride in the presence of lanthanide chloride to yield 1-bromo-11-formyl-galanthamine isomers (6), which is a key intermediate for the commercial production of highly pure galanthamine hydrobromide (1), a modern drug against Alzheimer's disease.
- Trinadhachari, Ganala Naga,Kamat, Anand Gopalkrishna,Prabahar, Koilpillai Joseph,Handa, Vijay Kumar,Srinu, Kukunuri Naga Venkata Satya,Babu, Korupolu Raghu,Sanasi, Paul Douglas
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p. 406 - 412
(2013/06/05)
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- Total synthesis of (-)-galanthamine and (-)-lycoramine via catalytic asymmetric hydrogenation and intramolecular reductive Heck cyclization
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A synthetic strategy featuring efficient ruthenium-catalyzed asymmetric hydrogenation of racemic α-aryloxy cyclic ketone via dynamic kinetic resolution and palladium-catalyzed intramolecular reductive Heck cyclization has been developed for the asymmetric total synthesis of (-)-galanthamine (20.1%, 12 steps) and (-)-lycoramine (40.2%, 10 steps)
- Chen, Ji-Qiang,Xie, Jian-Hua,Bao, Deng-Hui,Liu, Sheng,Zhou, Qi-Lin
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p. 2714 - 2717
(2012/08/08)
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- Asymmetric synthesis of bioactive hydrodibenzofuran alkaloids: (-)-lycoramine, (-)-galanthamine, and (+)-lunarine
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Divergent route: A direct C-C bond-forming approach to the key aryl-substituted all-carbon quaternary stereogenic center present in bioactive hydrodibenzofuran alkaloids has been discovered. This approach involves an unprecedented organocatalytic enantioselective Michael addition of α-cyanoketones with acrylates (see scheme) and was used in a novel and divergent synthetic strategy for the title compounds in asymmetric fashion.
- Chen, Peng,Bao, Xu,Zhang, Le-Fen,Ding, Ming,Han, Xiao-Jie,Li, Jing,Zhang, Guo-Biao,Tu, Yong-Qiang,Fan, Chun-An
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supporting information; experimental part
p. 8161 - 8166
(2011/10/18)
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- Total synthesis of (±)-Galanthamine via a C3-selective stille coupling and IMDA cycloaddition cascade of 3,5-dibromo-2-pyrone
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Figure presented A new efficient synthetic route to (±)-galanthamine was devised by using a tandem C3-selective Stille coupling-IMDA cascade of 3,5-dibromo-2-pyrone as a key strategy.
- Chang, Jay Hyok,Kang, Ho-Ung,Jung, In-Hak,Cho, Cheon-Gyu
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supporting information; experimental part
p. 2016 - 2018
(2010/06/21)
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- METHOD FOR THE PRODUCTION OF HIGH-PURITY 4A, 5, 9, 10, 11, 12,-HEXAHYDRO-6H-BENZOFURO [3A, 3, 2-EF] [2] BENZAZEPINE, AND THE DERIVATIVES THEREOF
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A process for the production of extremely pure galanthamine or extremely pure galanthamine derivatives, whereby a start is made from racemic bromine narwedine, which is debrominated under palladium catalysis. The working-up of the reaction mixture, which is carried out in the presence of oxygen or peroxides, is essential to the process, so that the palladium catalyst is converted into an insoluble form, a form that can be easily separated. The further reaction is carried out by reduction of enantiomerically pure narwedine to form enantiomerically pure galanthamine, whereby it is then alkylated or dealkylated, so that a corresponding substitution on the ring-nitrogen atom is achieved. By further purification, such as recrystallization, residual portions of palladium of below 5 ppm are achieved, so that the direct use as a pharmaceutical raw material is made possible.
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(2010/05/13)
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- Synthesis, spectral characterization and biological evaluation of phosphorylated derivatives of galanthamine
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A series of novel phosphorylated derivatives of galanthamine 6-11 and 12-17 were synthesized in two step process with high yields. In the first step galanthamine 1 was reacted with bis (2-chloroethyl) phosphoramidic dichloride 2/4-nitrophenyl phosphorodichloridate 3 in presence of triethylamine (TEA) in dry tetrahydrofuran (THF) yielded the intermediates 4/5. They were further reacted with various compounds like 2-aminoethanol, ethyleneglycol, ethylenediamine, 2-aminoethanethiol, 2-hydroxyethanethiol, monopotassium dihydrogenphosphate to obtain the title compounds 6-11 and 12-17. The title compounds showed promising antimicrobial, antioxidant activities and was greatly influenced by the presence of different bioactive groups.
- Koteswara Rao,Janardhan Rao,Subba Reddy,Naga Raju,Visweswara Rao,Ghosh
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experimental part
p. 203 - 209
(2010/04/06)
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- Total synthesis of (+)- and (-)-galanthamine
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The stereoselective total synthesis of (+)-galanthamine [(+)-1], an antipode of the natural product, and (-)-galanthamine [(-)-1] starting from D-glucose is described. The cyclohexene unit in (+)-1 was prepared in an optically active form from D-glucose using Ferrier's carbocyclization reaction, and the benzylic quaternary carbon was stereoselectively generated via chirality transfer by Johnson-or Eschenmoser-Claisen rearrangement. The dibenzofuran skeleton was effectively constructed by the bromonium ion-mediated intramolecular dealkylating etherification. After the introduction of a carbon-carbon double bond, the Pictet-Spengler type cyclization, followed by reduction of an amide function afforded (+)-1. Starting from D-glucose, (-)-galanthamine [(-)-1] was also totally synthesized. The Japan Institute of Heterocyclic Chemistry.
- Kato, Tomoaki,Tanimoto, Hiroki,Yamada, Hisako,Chida, Noritaka
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p. 563 - 597
(2013/09/12)
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- SYNTHESIS OF MORPHINE AND RELATED DERIVATIVES
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The present invention relates to methods for the synthesis of galanthamine, morphine, intermediates, salts and derivatives thereof, wherein the starting compound is biphenyl.
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Page/Page column 86; 87
(2010/12/17)
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- ANTI-AMNESIC COMPOUNDS AND PHARMACEUTICAL COMPOSITIONS COMPRISING THEM
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The present invention relates to the use of at least one compound of formula (I) as follows: or of at least one pharmaceutically acceptable salt thereof for the preparation of a drug for the prevention or treatment of memory disorders.
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- An improved process for the preparation of galantamine hydrobromide
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The present invention relates to an improved process for the preparation of [4aS,6R,8aS]-4a,5,9,10,11,12-hexahydro-3-methoxy-11-methyl-6H-benzofuro[3a,3,2-ef][2]benzazepin-6-ol of Formula I
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(2009/01/24)
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- Syntheses and Preparations of Narwedine and Related Novel Compounds
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The present invention relates to a process for preparing racemic narwedine (which can be can be kinetically resolved) to yield (?)-narwedine and which is the biogenic precursor of (?)-galanthamine) and the use thereof as a starting material for producing (?)-galanthamine. The invention further includes processes for preparing (?)-galanthamine and (?)-galanthamine hydrobromide, as well as related novel compounds.
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(2009/01/20)
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- Domino double Michael-Claisen cyclizations: A powerful general tool for introducing quaternary stereocenters at C(4) of cyclohexane-1,3-diones and total synthesis of diverse families of sterically congested alkaloids
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(Chemical Equation Presented) Reactions of substituted acetone derivatives with acrylic acid esters (>200 mol %) in the presence of t-BuOK (200 mol %) in t-BuOH-THF (1:1 by volume) turned out to proceed as a cascade process consisting of the first Michael addition, the second Michael addition, and the last Claisen reaction to afford 4,4-disubstituted cyclohexane-1,3-diones. Only more substituted enolates play the role of a Michael donor in this cascade process, and therefore the ketone took up two alkoxycarbonylethyl groups on the same carbon bearing more substituents. Such intermediates were followed by intramolecular Claisen reactions leading to cyclohexane-1,3-diones bearing quaternary stereogenic centers at C(4), which bears an alkoxycarbonylethyl group and the substituent of the starting acetone derivatives. Thus-obtained 4,4-disubstituted cyclohexane-1,3-diones were successfully employed for total syntheses of intricate alkaloids of biological interest such as (+)-aspidospermidine, (±)-galanthamine, (±)-lycoramine, and (±)-mesembrine, all featuring quaternary stereogenic centers. DFT calculations provided us with clear-cut explanations for the observed chemoselectivity of the cascade process involving ketone-based enolates under thermodynamically controlled conditions.
- Ishikawa, Teruhiko,Kudo, Kazuhiro,Kuroyabu, Ken,Uchida, Satoshi,Kudoh, Takayuki,Saito, Seiki
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p. 7498 - 7508
(2008/12/22)
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- Stereocontrolled synthesis of (-)-galanthamine
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An enantiosetective synthesis of (-)-galanthamine has been realized in 11 linear steps starting from isovanillin. A Mitsunobu aryl ether forming reaction was used to assemble the galanthamine backbone, which was stitched together using enyne ring-closing metathesis, Heck, and N-alkylatton reactions affording the tetracyclic ring system. Control of relative and absolute stereochemistry was derived from an easily accessible enantiomerically enriched propargylic alcohol 13.
- Satcharoen, Vachiraporn,McLean, Neville J.,Kemp, Stephen C.,Camp, Nicholas P.,Brown, Richard C. D.
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p. 1867 - 1869
(2008/02/05)
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- Biomimetic synthesis of (±)-galanthamine and asymmetric synthesis of (-)-galanthamine using remote asymmetric induction
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(±)-Galanthamine (1) was synthesized in excellent yield by applying PIFA-mediated oxidative phenol coupling of N-(4-hydroxy)phenethyl-N-(3′, 4′,5′-trialkoxy)benzyl formamide (15b) as a key step. Because of the symmetrical characteristics of the pyrogallol moiety in the substrate (15b), the phenol coupling resulted in a sole coupling product except for volatile components from the oxidizing agent. On the basis of the successful results of the above strategy, (-)-galanthamine (1) was synthesized by employing a novel remote asymmetric induction, where conformation of the seven-membered ring in the product of the phenol coupling was restricted by forming a fused-chiral imidazolidinone ring with D-phenylalanine on the benzylic C-N bond of the tri-O-alkylated gallyl amino moiety. The conformational restriction and successive debenzylation of the protected hydroxyl groups on the pyrogallol ring caused diastereoselective cyclization to yield a cyclic ether having the desired stereochemistry for the synthesis of (-)-1.
- Node, Manabu,Kodama, Sumiaki,Hamashima, Yoshio,Katoh, Takahiro,Nishide, Kiyoharu,Kajimoto, Tetsuya
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p. 1662 - 1679
(2007/10/03)
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- ISOLATION OF GALANTHAMINE FROM BIOLOGICAL MATERIAL
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The subject matter of present invention relates to the process for isolation and purification of galanthamine and its derivatives produced by numerous plants.
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(2008/06/13)
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- Total synthesis of (±)-galanthamine
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A practical and efficient total synthesis of (±)-galanthamine was achieved from commercially available materials through a novel approach, in which the construction of its core structure and the special allylic group were based on a successive semipinacol
- Hu, Xiang-Dong,Tu, Yong Qiang,Zhang, En,Gao, Shuanhu,Wang, Shaohua,Wang, Aixia,Fan, Chun-An,Wang, Min
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p. 1823 - 1825
(2007/10/03)
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- Divergent enantioselective synthesis of (-)-galanthamine and (-)-morphine
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An efficient divergent synthetic strategy for the synthesis of the opiate and amaryllidaceae alkaloids emerges by employing a Pd-catalyzed asymmetric allylic alkylation (AAA) to set the stereochemistry. Three generations of syntheses of galanthamine are discussed in detail with particular focus on the scope of the palladium-catalyzed AAA reactions and intramolecular Heck reactions. The pivotal tricyclic intermediate is available in six steps from 2-bromovanillin and the monoester of methyl 6-hydroxycyclohexene-1-carboxylate. This intermediate requires only two steps to convert to (-)-galanthamine. Using a Heck vinylation, we found that the fourth ring of codeine/morphine could be formed. The final ring formation involves a novel visible light-promoted hydroamination. Thus, six steps are required to convert the pivotal tricyclic intermediate into codeine, which has been demethylated in high yield to morphine.
- Trost, Barry M.,Tang, Weiping,Toste, F. Dean
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p. 14785 - 14803
(2007/10/03)
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- Total synthesis of galanthamine, analogues and derivatives thereof
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The invention relates to a method for the synthesis of galanthamine, the derivatives and analogues thereof of formula (1) where R1=a hydrogen atom. R2=a hydroxy group, R1 and R2 together form =0, R3,
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(2010/02/11)
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- Carboxylate salts of galantamine and their pharmaceutical use
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Disclosed are novel carboxylate salts of galantamine including galantamine gluconate, galantamine lactate, galantamine citrate and galantamine glucarate. These salts of galantamine have more than a 5 fold increase in solubility compared to galantamine hydrobromide. These galantamine salts can be administered to an individual to inhibit acetylcholinesterase in the treatment of such diseases as Alzheimer's disease, atony of the smooth muscle of the intestinal tract and urinary bladder, glaucoma, myasthenia gravis, and termination of the effects of competitive neuromuscular blocking drugs.
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- Total synthesis of (-)-galanthamine by remote asymmetric induction
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A pivotal intramolecular Michael addition to form a fused 5,7,5 ring system and the skeleton of (-)-galanthamine (1) was completely controlled by a remote chiral imidazolidinone auxiliary derived from D-phenylalanine (see scheme). This total synthesis of the allylic alcohol 1 avoids the corresponding enone narwedine, a highly allergenic intermediate in previous syntheses of 1.
- Kodama, Sumiaki,Hamashima, Yoshio,Nishide, Kiyoharu,Node, Manabu
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p. 2659 - 2661
(2007/10/03)
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- Novel derivatives and analogues of galanthamin
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New compounds of general formula I 1
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- Synthesis and stereoselective dealkylation of N-chiral quarternary N-alkyl galanthaminium halides
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The synthesis of N-chiral galanthaminium halides and their stereoselective dealkylation is described. The stereochemistry of two key compounds was determined by X-ray structure analysis.
- Hirnschall, Manfred,Treu, Matthias,Mereiter, Kurt,Hametner, Christian,Froehlich, Johannes,Jordis, Ulrich
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p. 675 - 681
(2007/10/03)
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- Optical resolution of narwedine-type compounds
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A process for the asymmetric transformation of a racemic compound of formula (I) wherein R1is H or a alkyl group having up to 20 carbon atoms, R2is H, or an alkyl, aryl, alkaryl or aralkyl group having up to 20 carbon atoms, and X is H, a halogen atom, tert-butyl, or any other removable substituent, comprises reaction of racemic compound (I) with an enantiomerically-enriched acid HY*, wherein Y* is a chiral group, to form a diastereomeric salt of compound (I) having Y* as a counterion. The salt obtained can then be reduced to give enantiomerically-enriched galanthamine, or a derivative thereof.
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(2008/06/13)
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- Processes for the preparation of derivatives of 4a, 5, 9, 10, 11, 12-hexahydro-6H-benzofuro-[3a, 3, 2-ef][2]benzazepine
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The invention relates to processes for the preparation of 4a,5,9,10,11,12-hexahydro-6H-benzofuro[3a,3,2-ef][2]benzazepine, or derivatives thereof. Furthermore, the invention also relates to the compounds formed during the preparation of 4a, 5,9,10,11,12-hexahydro-6H-benzofuro[3a,3,2-ef][2]benzazepine.
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- An efficient enantioselective synthesis of (-)-galanthamine
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An effective sequence: Palladium-catalyzed asymmetric allylic alkylation, Heck cyclization, and diastereoselective allylic oxidation were used in the total synthesis of (-)-galanthamine (3) in 14.8 % overall yield (from 1 and 2, Troc = 2,2,2-trichloroethoxycarbonyl) and with 96 % ee. This improved procedure provides the shortest and most efficient nonbiomimetic synthesis of the acetylcholinesterase inhibitor.
- Trost, Barry M.,Tang, Weiping
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p. 2795 - 2797
(2007/10/03)
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- An efficient total synthesis of (±)-galanthamine
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Intramolecular Heck reaction of 3 generates a spiro quaternary C atom-a key step in an efficient synthesis of galanthamine (1). Galanthamine can be readily obtained from the spiro tricyclic dienone 2, which was prepared by nonclassical dehydrogenation of
- Guillou, Catherine,Beunard, Jean-Luc,Gras, Emmanuel,Thal, Claude
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p. 4745 - 4746
(2007/10/03)
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- New achievements in the field of intramolecular phenolic coupling reactions, using hypervalent (III) iodine reagent: Synthesis of galanthamine
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Our investigations on the Oxidative possibilities of the hypervalent iodine(III) reagent established that phenyliodine(III)bis(trifluoroacctate (PIFA) can provide one-pot contiguous coupling-cyclization reaction giving a product with narwedine skeleton, when used in a phenolic coupling reaction of p'-bromonorbelladine derivatives. A suitably selected precursor gave up to 60% yield of the coupled product.
- Krikorian, Dikran,Tarpanov, Vclichko,Parushev, Stoyan,Mechkarova, Pepa
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p. 2833 - 2846
(2007/10/03)
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- Process for preparing galanthamine derivatives by asymmetric reduction
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The subject invention concerns a process for preparing a compound of formula (3) STR1 in enantio-enriched form, comprising reducing a compound of formula (4) STR2 using an asymmetric enantiospecific reductant, wherein A1 =A2 =H or A1, A2 =O; B1 =B2 =H or B1, B2 =O; Z=H, C1-20 alkyl or a precursor thereof, or a removable protecting group for nitrogen, e.g, acyl or alkyloxycarbonyl; Y=H or a substituent; R1 =C1-20 alkyl; and R is an optional, additional substituent.
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- Oxidative Intramolecular Phenolic Coupling Reaction Induced by a Hypervalent Iodine(III) Reagent: Leading to Galanthamine-Type Amaryllidaceae Alkaloids
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By extending our oxidative phenol-coupling reactions using a hypervalent iodine(III) reagent, a versatile synthetic procedure for the galanthamine-type Amaryllidaceae alkaloids was accomplished. The first total synthesis of (±)-sanguinine and the total syntheses of (±)-galanthamine, (±)- narwedine, (±)-lycoramine, and (±)-norgalanthamine were also successfully carried out.
- Kita, Yasuyuki,Arisawa, Mitsuhiro,Gyoten, Michiyo,Nakajima, Makiko,Hamada, Ryuji,Tohma, Hirofumi,Takada, Takeshi
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p. 6625 - 6633
(2007/10/03)
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- Dynamic diastereomeric salt resolution narwedine and its transformation to (-)-galanthamine
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Racemic narwedine may be resolved by means of a dynamic diastereomeric salt formation using di-p-toluoyl-D-tartaric acid. Both the 1:1 and 2:1 salts are formed in excellent yields and diastereomeric excesses. These salts are reduced in a highly diastereoselective and chemoselective manner to give (- )-galanthamine.
- Chaplin, David A.,Johnson, Nicholas B.,Paul, Jane M.,Potter, Gerard A.
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p. 6777 - 6780
(2007/10/03)
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- Method of manufacture of (-)-galanthamine in high yield and purity substantially free of epigalanthamine
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(-)-Galanthamine is obtained in substantially high yield and purity substantially without concomitant production of epigalanthamine by conversion of racemic narwedine to (-)-narwedine and subsequent reduction to (-)-galanthamine using bulky organo-aluminum or organo-boron reducing agents.
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- Facile synthesis of (±)-, (+)-, and (-)-galanthamine
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The Amarylidacea alkaloid galanthamine (1a) is an acetylcholinesterase inhibitor that has been evaluated as a potential agent for the treatment of Alzheimer's disease. We report a very efficent synthesis of (±)-galanthamine [(±)-1a] from readily available
- Szewczyk,Wilson,Lewin,Carroll
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p. 195 - 199
(2007/10/02)
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- Spectroscopic studies of galanthamine and galanthamine methiodide
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Structural studies of the alkaloid galanthamine 1 and its salt, galanthamine methiodide 2, were carried out both in solution and in the solid state, using spectroscopic methods (UV, IR, 1H NMR, 13C NMR and X-ray analysis).Several one- and two-dimensional techniques were used to assign the 1H NMR and 13C NMR spectra of 1.The types of hydrogen bonding exhibited by 1 and 2, in solution and in the solid state, were investigated.Keywords: galanthamine / galanthamine methiodide / spectral studies / hydrogen bonding
- Carroll, P.,Furst, G. T.,Han, S. Y.,Joullie, M.
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p. 769 - 780
(2007/10/02)
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- SYNTHESIS OF GALANTHAMINE AND RELATED ALKALOIDS - NEW APPROARCHES. I.
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Modifications of protecting groups and of the oxidative coupling conditions led to pure crystalline intermediates in the synthesis of galanthamine derivatives and gave dienone A in better yields than reported before.The E-configuration of amide 3' in crystalline state has been determined by X-ray diffraction.Streptomyces affinis 6737 reduces A to the optically active (-)-epigalanthamine derivative C, whose absolute configuration was determined by Bijvoet's method.Nematospora corylii CBS 2608 reduces to racemic B.With Ashbya gossypii IFO 1355 a mixture of racemic B and of optically active C is obtained.Some other microbial transformations are described.
- Vlahov, Radoslav,Krikorian, Dikran,Spassov, Grigor,Chinova, Maja,Vlahov, Ioncho,et al.
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p. 3329 - 3346
(2007/10/02)
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- An improved synthesis of galanthamine
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Modifications in the total synthesis of the Amarylidaceae alkaloid of galanthamine from commercially available isovanillin and tyramine have resulted in a shortened reaction sequence, which is amenable to upscaling and in improved product yield.
- Szewczyk,Lewin,Carroll
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p. 1809 - 1811
(2007/10/02)
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- Alkaloidal Constituents of Leucojum asetivum L. (Amaryllidaceae)
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Two novel alkaloids, leucotamine (1) and O-methylleucotamine (2), with a 3R-hydroxybutyryl group, and another new alkaloid, 3-O-acetylungiminorine (3), were isolated from leaves of Leucojum asetivum (Amaryllidaceae) together with five known alkaloids.O-Methylleucotamine (2) and 3-O-acetylungiminorine (3), as well as four known bases, were also isolated from bulbs of this plant.The stereochemistries of the new compounds 1, 2, and 3 were established on the basis of chemical and spectral data.Keywords - Leucojum asetivum; Amaryllidaceae; leucotamine; O-methylleucotamine; 3-O-acetylungiminorine; galanthamine; pretazettine; demethylhomolycorine; lycorine
- Kobayashi, Shigeru,Kihara, Masaru,Yuasa, Kazuyoshi,Imakura, Yasuhiro,Shingu, Tetsuro,et al.
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p. 5258 - 5263
(2007/10/02)
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- NEW ALKALOIDS, LEUCOTAMINE AND O-METHYLLEUCOTAMINE, FROM LEUCOJUM ASETIVUM L.
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The structures of leucotamine and O-methylleucotamine isolated from the leaves of Leucojum asetivum L., have been determinated as 3 and 4, respectively, on the basis of spectral and chemical evidence.
- Kobayashi, Shigeru,Yuasa, Kazuyoshi,Sato, Kimihito,Imakura, Yasuhiro,Shingu, Tetsuro
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p. 1219 - 1222
(2007/10/02)
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