- 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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- 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 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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- 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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Page/Page column 10
(2009/01/24)
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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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- 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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- 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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- 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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Page/Page column 8
(2010/02/11)
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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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- 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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- 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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- 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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