- Metal-Free Synthesis of Oxazolidine-2,4-diones and 3,3-Disubstituted Oxindoles via ICl-Induced Cyclization
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A metal-free method for the construction of oxazolidine-2,4-diones and oxindoles was discussed. Using iodine monochloride (ICl) as both the reaction promoter and iodide source, the iodolactonization of N-Boc acrylamides proceeded readily and provided the corresponding iodo oxazolidine-2,4-diones and oxazolidin-2-ones in good isolated yields. The obtained oxazolidine-2,4-diones can be used as key intermediates in the synthesis of toloxatone. When N-alkyl-N-arylacrylamide derivatives were subjected to the same reaction, iodocarbocyclization products 3,3-disubstituted oxindoles were obtained. The obtained oxindoles can be used as key intermediates in the synthesis of the alkaloids (±)-esermethole and (±)-physostigmine.
- Yi, Wei,Fang, Xing-Xiao,Liu, Qing-Yun,Liu, Gong-Qing
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p. 6671 - 6681
(2019/01/04)
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- A novel and efficient total synthesis of (±)-physostigmine
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Application of the Wittig olefination-Claisen rearrangement protocol for the total synthesis of (±)-physostigmine.
- Kulkarni, Mukund G.,Dhondge, Attrimuni P.,Borhade, Ajit S.,Gaikwad, Dnyaneshwar D.,Chavhan, Sanjay W.,Shaikh, Yunnus B.,Ningdale, Vijay B.,Desai, Mayur P.,Birhade, Deekshaputra R.,Shinde, Mahadev P.
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supporting information; experimental part
p. 2411 - 2413
(2009/07/26)
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- Palladium-catalyzed enantioselective domino heck-cyanation sequence: Development and application to the total synthesis of esermethole and physostigmine
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An efficient synthesis of functionalized 3-alkyl-3-cyanomethyl-2-oxindole 1 by a palladium-catalyzed domino Heck-cyanation reaction has been developed. Reaction of ortho-iodoanilide 5 with potassium ferro(II)cyanide, K 4[Fe(CN)6], dissolved in DMF in the presence of palladium acetate and sodium carbonate afforded oxindole 1 in good to excellent yields. An enantioselective domino Heck-cyanation process has been developed for the first time using (S)-DIFLUORPHOS as a chiral supporting ligand, and an enantioselectivity of up to 79% ee in the enantiomerically enriched oxindole was obtained under optimized conditions. A concise total synthesis of esermethole and physostigmine, powerful inhibitors of acetyl- and butyryl-cholinesterase, is documented.
- Pinto, Artur,Jia, Yanxing,Neuville, Luc,Zhu, Jieping
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p. 961 - 967
(2007/10/03)
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- Inhibition of human acetyl- and butyrylcholinesterase by novel carbamates of (-)- and (+)-tetrahydrofurobenzofuran and methanobenzodioxepine
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A new enantiomeric synthesis utilizing classical resolution provided two novel series of optically active inhibitors of cholinesterase: (-)- and (+)-O-carbamoyl phenols of tetrahydrofurobenzofuran and methanobenzodioxepine. An additional two series of (-)- and (+)-O-carbamoyl phenols of pyrroloindole and furoindole were obtained by known procedures, and their anticholinesterase actions were similarly quantified against freshly prepared human acetyl- (AChE) and butyrylcholinesterase (BChE). Both enantiomeric forms of each series demonstrated potent cholinesterase inhibitory activity (with IC50 values as low as 10 nM for AChE and 3 nM for BChE), with the exception of the (+)-O-carbamoyl phenols of pyrroloindole, which lacked activity (IC50 values > 1 μM). Based on the biological data of these four series, a structure-activity relationship (SAR) analysis was provided by molecular volume calculations. In addition, a probable transition-state model was established according to the known X-ray structure of a transition-state complex of Torpedo californica AChE-m-(N,N,N-trimethylammonio)-2,2,2-trifluoroacetophenone (TcAChE-TMTFA). This model proved valuable in explaining the enantioselectivity and enzyme subtype selectivity of each series. These carbamates are more potent than, or similarly potent to, anticholinesterases in current clinical use, providing not only inhibitors of potential clinical relevance but also pharmacological tools to define drug-enzyme binding interactions within an enzyme crucial in the maintenance of cognition and numerous systemic physiological functions in health, aging, and disease.
- Luo, Weiming,Yu, Qian-Sheng,Kulkarni, Santosh S.,Parrish, Damon A.,Holloway, Harold W.,Tweedie, David,Shafferman, Avigdor,Lahiri, Debomoy K.,Brossi, Arnold,Greig, Nigel H.
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p. 2174 - 2185
(2007/10/03)
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- TRICYCLIC COMPOUNDS, PREPARATION THEREOF AND USE THEREOF AS CHOLINESTERASE ACTIVITY INHIBITORS
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Described herein are tricyclic compounds of formula (I) and (II) and methods of making them and using them as cholinesterase activity inhibitors.
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Page/Page column 12
(2010/11/08)
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- Catalytic asymmetric synthesis of either enantiomer of the calabar alkaloids physostigmine and physovenine
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A potentially versatile asymmetric route to hexahydropyrrolo[2,3-b]indoles having carbon substituents at C-3a (Scheme 1) is demonstrated through enantioselective total syntheses of the Calabar alkaloids (-)physostigmine (2), (-)-physovenine (10), and their enantiomers. The synthesis of enantiopure (-)physostigmine proceeds from commercially available 2-butyn-1-ol (11) and N-methyl-p-anisidine (15) in 15-20% overall yield by way of eight isolated and purified intermediates. The central step is catalytic asymmetric Heck cyclization of (Z)-2-methyl-2-butenanilide 17 to-form oxindole aldehyde (S)-19 in 84% yield and 95% ee.
- Matsuura, Takaharu,Overman, Larry E.,Poon, Daniel J.
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p. 6500 - 6503
(2007/10/03)
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- Process for the enantioselective synthesis of intermediates used in the preparation of physostigmine
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This invention relates to a process of obtaining optically pure enantiomers of an alkylated oxindole selected from STR1 where R is methyl, ethyl or benzyl.
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- TOTAL SYNTHESIS OF RACEMIC PHYSOSTIGMINE, PHYSOVENINE AND ITS SULFUR ANALOGUE BY THE OXINDOLE-5-O-TETRAHYDROPYRANYL ETHER ROUTE
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1,3-Dimethyl-5-tetrahydropyranyloxyoxindole (4) was synthesized from 4-methylaminophenol sulfate (metol) (1).Phase transfer catalyzed C3-alkylation of compound (4) produced alcohol (5), nitrile (8), and thioalkohol (13) after treatment of bromide (12) with thiourea.Compound (5) and (13) were converted into racemic physovenine (7) and thiaphysovenine (15) by reaction with LAH, in situ deprotection, and reaction of phenols with methyl isocyanate.Conversion of nitrile (8) into racemic physostigmine (11) which included a reductive N-methylation of 9 was similarly accomplished.
- Yu, Qian-sheng,Lu, Bao-yuan,Pei, Xue-Feng
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p. 519 - 526
(2007/10/02)
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- Catalytic asymmetric synthesis of either enantiomer of physostigmine. Formation of quaternary carbon centers with high enantioselection by intramolecular Heck reactions of (Z)-2-butenanilides
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A practical method for preparing either enantiomer of physostigmine and congeners is reported. The Z stereochemistry of the butenanilide cyclization substrate is required to obtain high enantioselection (95% ee) in the key asymmetric Heck insertion.
- Ashimori,Matsuura,Overman,Poon
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p. 6949 - 6951
(2007/10/02)
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- Process for the enantioselective synthesis of intermediates used in the preparation of physostigmine
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A process for the stereoselective synthesis of [R]- and [S]-2,3-dihydro-1,3-dimethyl-2-oxo-1H-indole-3-acetonitriles comprises reacting racemic and 5-alkoxy-substituted (±)-1,3-dimethyloxindoles with a halogenated acetonitrile in the presence of a substituted N-benzyl cinchoninium, quinidinium, cinchonidinium, or quininium catalyst. The resulting alkylated oxindoles can be converted to primary amines by catalytic reduction in the presence of hydrogen gas. One of the primary amines, such as enantiomers of 3-(2-aminoethyl)-1,3-dihydro-1,3-dimethyl-5-methoxy-2H-indol-2-one, can be enriched by contact with a chiral tartaric acid in an amount sufficient to preferentially precipitate a salt of the chiral acid and one of the enantiomers. The product can be used in the synthesis of stereospecific forms of physostigmine and related compounds having pharmaceutical activity.
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- 2-Azonianorbornene-2-spiro-1'-aziridinium triflate - A novel ethylene immonium ion equivalent: Application to a synthesis of physostigmine
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A unique protocol for either the aminoethylation or the N-methyl aminoethylation of carbonyl compounds featuring the preparation and use of a novel spiroaziridinium salt, 2-azonianorbornene-2-spiro-1'-aziridinium triflate 2, is described.
- Grieco,Carroll
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p. 4401 - 4404
(2007/10/02)
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- The enantioselective synthesis of (-)-physostigmine via chiral sulfoxides
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The total synthesis of naturally occurring (-)-physostigmine is described. The key element for the asymmetric induction is the chirality transfer from optically active 2-(alkylsulfmyl)indoles to indoline butyrolactones bearing two chiral centers. Novel features of this synthesis involve the use of a new class of sulfoxylating agents, N-(alkylsulfinyljoxazolidinones, to prepare the starting indolyl sulfoxides and the correlation of the size of the alkyl group on the sulfoxide with the degree of asymmetric induction. The overall synthesis requires a dozen steps from commercially available 5-(benzyloxy)indole.
- Marino,Bogdan,Kimura
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p. 5566 - 5572
(2007/10/02)
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- Rapid Syntheses of Some Indole Alkaloids of the Calabar Bean
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A rapid, efficient route to 3,3-disubstituted oxindoles from o-iodo anilines has been developed.It involves the cyclisation of the corresponding fumarate amides 4 and 15 with butyllithium at -100 deg C in the presence of an excess of trimethylchlorosilane.An X-ray crystal structure of 4 suggests that the speed and efficiency of this intramolecular Michael addition is dependent on the conformation adopted by 4 which is particularly suitable for the reaction.This method has been applied to the synthesis of the alkaloids physovenine, physostigmine and esermethole in very high overall yields.
- Horne, Stephen,Taylor, Nicholas,Collins, Scott,Rodrigo, Russell
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p. 3047 - 3052
(2007/10/02)
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- Enantiocontrolled Total Syntheses of (-)-Physovenine and (-)-Physostigmine
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Enantiocontrolled total syntheses of the Calabar bean alkaloid (-)-physovenine (1) and (-)-physostigmine (2) have been achieved in a concise manner starting from the optically active tricyclic enone 3 employing a Fischer indolization reaction under nonacidic conditions as the key step.
- Takano, Seiichi,Moriya, Minoru,Ogasawara, Kunio
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p. 5982 - 5984
(2007/10/02)
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- Synthesis and Anticholinesterase Activity of (-)-N1-Norphysostigmine, (-)-Eseramine, and Other N(1)-Substituted Analogues of (-)-Physostigmine
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(-)-N1-Benzylnorphysostigmine (4), prepared from synthetic (-)-O-methyl-N1-noreseroline (1) by N-benzylation, ether cleavage, and reaction of (-)-N1-benzylnoreseroline (3) with methyl isocyanate, was the intermediate used to prepare the title compounds.Catalytic debenzylation of (4) afforded (-)-N1-norphysostigmine (5), and (-)-eseramine (6) was obtained by reaction of 5 with methyl isocyanate.Reductive N-methylation of 5 gave (-)-physostigmine (9) while reaction of 5 with allyl bromide and phenethyl bromide afforded carbamates 7 and 8, respectively.Data on the in vitro potencies (IC50) and activities of certain of these compounds (4-8) as inhibitors of electric eel acetyl cholinesterase are reported. (-)-N1-Norphysostigmine (5) was found to be similarly potent against AChE as (-)-physostigmine (9).
- Yu, Qian-Sheng,Atack, John R.,Rapoport, Stanley I.,Brossi, Arnold
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p. 2297 - 2300
(2007/10/02)
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