- Enantioselective 1,6-Conjugate Addition of Dialkyl α-Diazo Methylphosphonate to para-Quinone Methides
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An asymmetric 1,6-conjugate addition reaction of dialkyl diazomethylphosphonates to para-quinone methides promoted by phase-transfer catalysis has been developed. A series of chiral diarylmethylated diazomethylphosphonates were accessed with up to 85% yields and 99% ee enantioselectivities. The resulting products were further transformed into bioactive compounds, namely, a chiral dihydrocinnoline phosphonate and a chiral α-aminophosphonate, bearing diarylmethine stereogenic centers. (Figure presented.).
- Chen, Yuan,Yu, Rui,Wang, Min,Huang, Yanmin,Peng, Yungui
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- A Cation-Directed Enantioselective Sulfur-Mediated Michael/Mannich Three-Component Domino Reaction involving Chalcones as Michael Acceptors
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A new approach has been developed for an asymmetric sulfur-mediated three-component intermolecular Michael/Mannich domino reaction using chalcones as Michael acceptors. This reaction is catalyzed by chiral quaternary ammonium salts derived from modified quinine and provides facile access to complex sulfur-containing compounds with three contiguous stereogenic centers in yields of up to 93%, with 95:5 dr and 95% ee. These compounds were further elaborated to give the equivalent of a chiral aza-Morita-Baylis-Hillman reaction involving chalcones and azetidines bearing four chiral centers.
- Ding, Ran,Zheng, Bo,Wang, Yan,Peng, Yungui
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- Antimalarial efficacy of hydroxyethylapoquinine (SN-119) and its derivatives
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Quinine and other cinchona-derived alkaloids, although recently supplanted by the artemisinins (ARTs), continue to be important for treatment of severe malaria. Quinine and quinidine have narrow therapeutic indices, and a safer quinine analog is desirable, particularly with the continued threat of antimalarial drug resistance. Hydroxyethylapoquinine (HEAQ), used at 8 g a day for dosing in humans in the 1930s and halving mortality from bacterial pneumonias, was shown to cure bird malaria in the 1940s and was also reported as treatment for human malaria cases. Here we describe synthesis of HEAQ and its novel stereoisomer hydroxyethylapoquinidine (HEAQD) along with two intermediates, hydroxyethylquinine (HEQ) and hydroxyethylquinidine (HEQD), and demonstrate comparable but elevated antimalarial 50% inhibitory concentrations (IC50) of 100 to 200 nM against Plasmodium falciparum quinine-sensitive strain 3D7 (IC50, 56 nM). Only HEAQD demonstrated activity against quinine-tolerant P. falciparum strains Dd2 and INDO with IC50s of 300 to 700 nM. HEQD had activity only against Dd2 with an IC50 of 313 nM. In the lethal mouse malaria model Plasmodium berghei ANKA, only HEQD had activity at 20 mg/kg of body weight comparable to that of the parent quinine or quinidine drugs measured by parasite inhibition and 30-day survival. In addition, HEQ, HEQD, and HEAQ (IC50>90 μM) have little to no human ether-a-go-go-related gene (hERG) channel inhibition expressed in CHO cells compared to HEAQD, quinine, and quinidine (hERG IC50s of 27, 42, and 4 μM, respectively). HEQD more closely resembled quinine in vitro and in vivo for Plasmodium inhibition and demonstrated little hERG channel inhibition, suggesting that further optimization and preclinical studies are warranted for this molecule. Copyright
- Sanders, Natalie G.,Meyers, David J.,Sullivan, David J.
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- A Catalyst-Controlled Enantiodivergent Bromolactonization
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A catalyst-controlled enantiodivergent bromolactonization of olefinic acids has been developed. Quinine-derived amino-amides bearing the same chiral core but different achiral aryl substituents were used as the catalysts. Switching the methoxy substituent in the aryl amide system from meta- to ortho-position results in a complete switch in asymmetric induction to afford the desired lactone in good enantioselectivity and yield. Mechanistic studies, including chemical experiments and density functional theory calculations, reveal that the differences in steric and electronic effects of the catalyst substituent alter the reaction mechanism.
- Chan, Yuk-Cheung,Lam, Ying-Pong,Tse, Ying-Lung Steve,Wang, Xinyan,Wong, Jonathan,Yeung, Ying-Yeung
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supporting information
p. 12745 - 12754
(2021/08/30)
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- Early and Late Steps of Quinine Biosynthesis
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The enzymatic basis for quinine 1 biosynthesis was investigated. Transcriptomic data from the producing plant led to the discovery of three enzymes involved in the early and late steps of the pathway. A medium-chain alcohol dehydrogenase (CpDCS) and an esterase (CpDCE) yielded the biosynthetic intermediate dihydrocorynantheal 2 from strictosidine aglycone 3. Additionally, the discovery of an O-methyltransferase specific for 6′-hydroxycinchoninone 4 suggested the final step order to be cinchoninone 16/17 hydroxylation, methylation, and keto-reduction.
- Trenti, Francesco,Yamamoto, Kotaro,Hong, Benke,Paetz, Christian,Nakamura, Yoko,O'Connor, Sarah E.
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supporting information
p. 1793 - 1797
(2021/04/05)
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- Enantioselective γ-Alkylation of α,β-Unsaturated Aldehydes Using New Cinchona-Based Primary Amine Catalyst
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New cinchona-based primary amine catalysts were prepared and screened as organocatalysts for the γ-alkylation of α,β-unsaturated aldehydes with bis(4-dimethylaminophenyl)methanol. Catalyst C3 containing acetic acid group yielded γ-alkylated products in good yields (up to 94 %) with up to 90 % ee. This new primary aminocatalyst provide new opportunities to explore novel asymmetric transformations.
- Huang, Yong-Shuang,Song, Shuang-Gui,Ren, Lei,Li, You-Gui,Wu, Xiang
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supporting information
p. 6838 - 6841
(2019/11/11)
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- Organocatalytic Nitroaldol Reaction Associated with Deuterium-Labeling
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A deuterium-labeling reaction of nitroalkanes in deuterium oxide and the subsequent nitroaldol reaction have been accomplished under basic and organocatalytic conditions to provide the deuterium-labeled β-nitroalcohols in high yields and high deuterium contents. β-Deuterated β-nitroalcohols could be smoothly obtained from the reaction of nitroalkanes and various electrophiles using the easily-removal basic resin WA30. Furthermore, the asymmetric nitroaldol reaction using nitromethane and α-keto esters as electrophiles in the presence of a quinine-derived organocatalyst in deuterium oxide could provide the desired β-deuterated nitroalcohol derivatives with high enantioselectivities. (Figure presented.).
- Yamada, Tsuyoshi,Kuwata, Marina,Takakura, Ryoya,Monguchi, Yasunari,Sajiki, Hironao,Sawama, Yoshinari
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supporting information
p. 637 - 641
(2017/12/13)
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- DERIVATIVES OF QUINOLINE AS INHIBITORS OF DYRK1A AND/OR DYRK1B KINASES
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The present invention relates to the compound of formula (I) and salts, stereoisomers, tautomers or N-oxides thereof. The present invention is further concerned with the use of such a compound or salt, stereoisomer, tautomer or N-oxide thereof as medicament and a pharmaceutical composition comprising said compound.
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Paragraph 0503-0504
(2018/07/15)
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- ENANTIOENRICHED VIRIDICATUMTOXIN B ANALOGS
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In one aspect, the present disclosure provides derivatives of viridicatumtoxin of the formula wherein the variables are as defined herein. Also provided herein are compositions and methods of treating a bacterial infection, a viral infection, or in the treatment of cancer. The present disclosure also provides methods of synthesizing enantiopure viridicatumtoxin and other anthrone compounds.
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Page/Page column 67; 68; 71
(2017/11/10)
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- Enantioselective Spirocyclopropanation of para-Quinone Methides Using Ammonium Ylides
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The use of Cinchona alkaloid-based chiral ammonium ylides allows for the first highly enantioselective and broadly applicable spirocyclopropanation reactions of para-quinone methides. This strategy provides a straightforward protocol toward the chiral spiro[2.5]octa-4,7-dien-6-one skeleton, which is a frequently found structural motif in important biologically active molecules.
- Roiser, Lukas,Waser, Mario
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supporting information
p. 2338 - 2341
(2017/05/12)
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- Asymmetric Alkylation of Anthrones, Enantioselective Total Synthesis of (?)- and (+)-Viridicatumtoxins B and Analogues Thereof: Absolute Configuration and Potent Antibacterial Agents
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A phase transfer catalyzed asymmetric alkylation of anthrones with cyclic allylic bromides using quinidine- or quinine-derived catalysts is described. Utilizing mild basic conditions and as low as 0.5 mol % catalyst loading, and achieving up to >99:1 dr selectivity, this asymmetric reaction was successfully applied to produce enantioselectively (?)- and (+)-viridicatumtoxins B, and thus allowed assignment of the absolute configuration of this naturally occurring antibiotic. While the developed asymmetric synthesis of C10 substituted anthrones is anticipated to find wider applications in organic synthesis, its immediate application to the construction of a variety of designed enantiopure analogues of viridicatumtoxin B led to the discovery of highly potent, yet simpler analogues of the molecule. These studies are expected to facilitate drug discovery and development efforts toward new antibacterial agents.
- Nicolaou,Liu, Guodu,Beabout, Kathryn,McCurry, Megan D.,Shamoo, Yousif
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supporting information
p. 3736 - 3746
(2017/03/20)
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- Development of C-6′-modified quinine-derived phase-transfer catalysts and their application in the enantioselective α-hydroxylation of β-dicarbonyl compounds
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We have developed C-6′-modified quinine quaternary ammonium salts as phase transfer catalysts for α-hydroxylation of β-dicarbonyl compounds. The quinine quaternary ammonium salts, which was modified at C-6′ and the N atom, had good activity for α-hydroxylation of β-dicarbonyl compounds. By using 5?mol?% of 6-hydroxyl-N-(4′-fluoro-2′-trifluoromethyl)quinine quaternary ammonium salt as the organocatalyst, cumene hydroperoxide as the oxidant, toluene as the solvent, and 50% K2HPO4as the aqueous alkali at room temperature, the yield and enantioselectivity of the α-hydroxylation of β-keto esters were 95% and 88%, respectively. This catalytic system was also applicable for β-keto amides (92% yield and 76% ee).
- Qing, Hai,Wang, Yakun,Zheng, Zehao,Chen, Shuai,Meng, Qingwei
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p. 834 - 842
(2016/09/02)
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- Stereoselective reaction of 2-carboxythioesters-1,3-dithiane with nitroalkenes: An organocatalytic strategy for the asymmetric addition of a glyoxylate anion equivalent
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An efficient organocatalytic methodology has been developed to perform the stereoselective addition of 2-carboxythioesters-1,3-dithiane to nitroalkenes. Under mild reaction conditions γ-nitro-β-aryl-α-keto esters with up to 92% ee were obtained, realizing a formal catalytic stereoselective conjugate addition of the glyoxylate anion synthon. The reaction products are versatile starting materials for further synthetic transformations; for example, the simultaneous reduction of the nitro group and removal of the dithiane ring was accomplished, allowing the preparation of a GABAB receptor agonist baclofen.
- Massolo, Elisabetta,Benaglia, Maurizio,Genoni, Andrea,Annunziata, Rita,Celentano, Giuseppe,Gaggero, Nicoletta
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supporting information
p. 5591 - 5596
(2015/05/27)
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- Organocatalytic enantioselective 1,3-dipolar cycloadditions between seyferth-gilbert reagent and isatylidene malononitriles: Synthesis of chiral spiro-phosphonylpyrazoline-oxindoles
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A new method has been developed for the catalytic enantioselective 1,3-dipolar cycloaddition of the Seyferth-Gilbert reagent (SGR) to isatylidene malononitriles using a cinchona alkaloid derivative as a catalyst. This method allowed for the synthesis of a series of chiral spiro-phosphonylpyrazoline-oxindoles in good yields with excellent enantioselectivities. The synthetic utility of this method was further demonstrated by its use in a three-component domino reaction involving isatin, malononitrile, and SGR based on sequential Knoevenagel condensation and 1,3-dipolar cycloaddition reactions.
- Du, Taiping,Du, Fei,Ning, Yanqiang,Peng, Yungui
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supporting information
p. 1308 - 1311
(2015/03/14)
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- METHOD FOR THE PREPARATION OF BETA-SUBSTITUTED GAMMA-AMINO CARBOXYLIC ACIDS
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The present invention relates to the preparation of β-substituted γ-amino carboxylic acids, preferably in enantiomerically enriched or even enantiomerically pure form, by a one-pot conversion of a β-substituted γ-nitro dicarboxylic acid ester or of a β-substituted γ-nitro dicarboxylate of general formula to a β-substituted γ-nitro carboxylic acid and a subsequent reduction of the γ-nitro group to an amine group. In particular, the present invention relates to the preparation of ( S ) -pregabalin. In addition, the formation of enantiomerically enriched β-substituted γ-amino carboxylic acids and β-substituted γ-nitronate carboxylic acid salts are also described.
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Page/Page column 31; 32
(2016/01/01)
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- Enantioselective α-hydroxylation of β-keto esters catalyzed by cinchona alkaloid derivatives
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A highly efficient α-hydroxylation of β-keto esters catalyzed by cupreidine in the presence of cumyl hydroperoxide (CHP) was achieved. The reaction was applied to a wide variety of β-keto esters to give products in high yields (up to 95%) with excellent enantioselectivities (up to 97% ee). The reaction had been successfully scaled up to a gram quantity and (S)-5-chloro-2-hydroxy-1-oxo-2,3-dihydro-1H-indene-2-carboxylate - the important intermediate of Indoxacarb were obtained in 96% yield with 86% ee. The enantiomeric excess could be improved to 99% by crystallization, and this method has prospect of industrial application for its advantages of enantioselectivity, ease of catalyst preparation and reclamation of catalyst. Georg Thieme Verlag Stuttgart. New York.
- Wang, Yakun,Li, Zhi,Xiong, Ting,Zhao, Jingnan,Meng, Qingwei
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p. 2155 - 2160
(2014/11/08)
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- METHOD FOR PRODUCING PHENYL-SUBSTITUTED HETEROCYCLIC DERIVATIVE
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The present invention is a method for producing a phenyl-substituted heterocyclic derivative represented by general formula (1), which has a step wherein a heteroaromatic compound represented by general formula (2) is reacted with a phenol derivative represented by general formula (3) in the presence of a nickel compound, 1,2-bis(dicyclohexylphosphino)ethane, and a base.
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Paragraph 0143
(2014/09/29)
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- Catalytic enantioselective construction of quaternary stereocenters by direct vinylogous Michael addition of deconjugated butenolides to nitroolefins
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A direct vinylogous Michael reaction of γ-substituted deconjugated butenolides with nitroolefins has been developed with the help of a newly identified quinine-derived bifunctional catalyst, allowing the synthesis of densely functionalized products with contiguous quaternary and tertiary stereocenters in excellent yield with perfect diastereoselectivity (>20:1 dr) and high enantioselectivity (up to 99:1 er).
- Manna, Madhu Sudan,Kumar, Vikas,Mukherjee, Santanu
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supporting information; experimental part
p. 5193 - 5195
(2012/06/01)
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- Expeditious diastereoselective construction of a thiochroman skeleton via a cinchona alkaloid-derived catalyst
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An example of diastereoselective and enantioselective synthesis of thiochroman derivatives through a sulfa-Michael-Michael cascade sequence is disclosed. This is a significant complement of the quinine-thiourea catalyzed sulfa-Michael-Michael cascade reaction. The densely functionalized target thiochromans were obtained in high diastereoselectivities, and with high to excellent enantioselectivities.
- Du, Zhiyun,Zhou, Chenggang,Gao, Yaojun,Ren, Qiao,Zhang, Kun,Cheng, Hansong,Wang, Wei,Wang, Jian
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supporting information; scheme or table
p. 36 - 39
(2012/01/06)
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- Nickel-catalyzed C-H/C-O coupling of azoles with phenol derivatives
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The first nickel-catalyzed C-H bond arylation of azoles with phenol derivatives is described. The new Ni(cod)2/dcype catalytic system is active for the coupling of various phenol derivatives such as esters, carbamates, carbonates, sulfamates, triflates, tosylates, and mesylates. With this C-H/C-O biaryl coupling, we synthesized a series of privileged 2-arylazoles, including biologically active alkaloids. Moreover, we demonstrated the utility of the present reaction for functionalizing estrone and quinine.
- Muto, Kei,Yamaguchi, Junichiro,Itami, Kenichiro
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supporting information; experimental part
p. 169 - 172
(2012/03/07)
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- Organocatalytic asymmetric direct vinylogous Michael addition of α,β-unsaturated γ-butyrolactam to nitroolefins
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The first organocatalytic enantioselective direct vinylogous Michael reaction of α,β-unsaturated γ-butyrolactam to nitroolefins is developed using cinchona alkaloids as the catalysts. Both product enantiomers are accessible with moderate to good enantioselectivity.
- Choudhury, Abhijnan Ray,Mukherjee, Santanu
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supporting information; experimental part
p. 7313 - 7320
(2012/10/07)
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- Catalyst-free and catalytic Friedel-Crafts alkylations of indoles in Solkane 365mfc, an environmentally benign alternative solvent
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Solkane 365mfc is a proven environmentally benign alternative solvent for catalyst-free Friedel-Crafts (F-C) alkylations of indoles with trifluoropyruvate and glyoxylate. Their enantioselective variants are also achieved by virtue of the high-affinity of fluorous cinchona alkaloids catalysts to Solkane 365mfc to provide F-C adducts in excellent yields with good to excellent ees (up to 96% ee).
- Xu, Xiu-Hua,Kusuda, Akihiro,Tokunaga, Etsuko,Shibata, Norio
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supporting information; experimental part
p. 46 - 50
(2011/03/20)
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- Organocatalytic sequential Michael reactions: Stereoselective synthesis of multifunctionalized tetrahydroindan derivatives
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Multifunctionalized tetrahydroindan derivatives with four stereocenters were constructed via two sequential Michael reactions between cyclic γ,δ-unsaturated-β-ketoester and nitroalkenes initiated with 0.5-2 mol % of cinchona alkaloid based bifunctional organocatalysts and then with 1 equiv of tetramethylguanidine for cyclization. The desired products could be obtained in high yields (up to 99% yield) with excellent enantioselectivities (95-99% ee) as well as diastereoselectivities (up to >99:1 dr) even on a gram scale.(Figure Presented)
- He, Peng,Liu, Xiaohua,Shi, Jian,Lin, Lili,Feng, Xiaoming
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supporting information; experimental part
p. 936 - 939
(2011/04/23)
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- Enantioselective bromoaminocyclization using amino-thiocarbamate catalysts
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A facile and efficient enantioselective bromoaminocyclization of unsaturated sulfonamides has been developed using an amino-thiocarbamate catalyst. A range of enantioenriched pyrrolidines were prepared with up to 99% yield and 99% ee. The corresponding lactams could be obtained through oxidation of the pyrrolidines.
- Zhou, Ling,Chen, Jie,Tan, Chong Kiat,Yeung, Ying-Yeung
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supporting information; scheme or table
p. 9164 - 9167
(2011/08/04)
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- FLUORINATION OF ORGANIC COMPOUNDS
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Methods for fluorinating organic compounds are described herein.
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Page/Page column 43
(2010/07/10)
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- Enantioselective synthesis of SSR 241586 by using an organo-catalyzed Henry reaction
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An organo-catalyzed Henry reaction, applied to an α-keto ester, has allowed the enantioselective synthesis of SSR 241586, a 2,2-disubstituted morpholine active in the treatment of schizophrenia and irritable bowel syndrome (IBS).
- Cochi, Anne,Metro, Thomas-Xavier,Pardo, Domingo Gomez,Cossy, Janine
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supporting information; experimental part
p. 3693 - 3695
(2010/10/20)
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- Continuous separation of racemic 3,5-dinitrobenzoyl-amino acids in a centrifugal contact separator with the aid of cinchona-based chiral host compounds
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The resolution of racemates is mostly performed by crystallisation of diastereomeric salts. Direct physical separation could be much more efficient, but so far most concepts, with the exception of SMB, have proven to be non-scaleable. Here we report the f
- Hallett, Andrew J.,Kwant, Gerard J.,De Vries, Johannes G.
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experimental part
p. 2111 - 2120
(2009/09/30)
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- Direct electrophilic monofluoromethylation
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Monofluoromethyl derivatives of various nucleophiles have been synthesized using a new electrophilic monofluoromethylating reagent developed. The S-(monofluoromethyl)diarylsulfonium tetrafluoroborate has been shown to be effective for the introduction of an electrophilic monofluoromethyl group into C, S, O, N, and P nucleophiles. This methodology has been expanded for the synthesis of various biologically important compounds.
- Prakash, G. K. Surya,Ledneczki, Istvan,Chacko, Sujith,Olah, George A.
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p. 557 - 560
(2008/04/12)
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- An enantioselective Michael addition of malonate to nitroalkenes catalyzed by low loading demethylquinine salts in water
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An enantioselective Michael addition of malonate to nitroalkenes is efficiently catalyzed by low loading demethylquinine salts in water; the yield range from 49% to 93% and the ee up to 90%.
- Chen, Fu-Xin,Shao, Cheng,Wang, Quan,Gong, Pin,Zhang, Dong-Yan,Zhang, Bang-Zhi,Wang, Rui
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p. 8456 - 8459
(2008/03/13)
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- Enantioselective nitroaldol reaction of α-ketoesters catalyzed by cinchona alkaloids
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The development of highly enantioselective and general catalytic nitroaldol (Henry) reactions with ketones is a challenging yet desirable task in organic synthesis. In this communication, we report an asymmetric nitroaldol reaction with α-ketoesters catalyzed by a new C6′-OH cinchona alkaloid catalyst. This is the first highly efficient organocatalytic asymmetric Henry reaction with ketones. This reaction is operationally simple and affords high enantioselectivity as well as good to excellent yield for a broad range of α-ketoesters. . Copyright
- Li, Hongming,Wang, Baomin,Deng, Li
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p. 732 - 733
(2007/10/03)
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- ASYMMETRIC MICHAEL AND ALDOL ADDITION USING BIFUNCTIONAL CINCHONA-ALKALOID-BASED CATALYSTS
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One aspect of the present invention relates to quinine-based and quinidine-based catalysts. Another aspect of the invention relates to a method of preparing a derivatized quinine-based or quinidine-based catalyst comprising 1) reacting quinine or quinidine with 5 base and a compound that has a suitable leaving group, and 2) converting the ring methoxy group to a hydroxy group. Another aspect of the present invention relates to a method of preparing a chiral, non-racemic compound from a prochiral electron-deficient alkene or azo compound or prochiral aldehyde or prochiral ketone, comprising the step of: reacting a prochiral electron-deficient alkene or azo compound or prochiral aldehyde or prochiral 10 ketone with a nucleophile in the presence of a catalyst; thereby producing a chiral, non racemic compound; wherein said catalyst is a derivatized quinine or quinidine. Another aspect of the present invention relates to a method of kinetic resolution, comprising the step of reacting racemic chiral alkene with a nucleophile in the presence of a derivatized quinine or quinidine.
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Page/Page column 87
(2008/06/13)
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- Highly enantioselective conjugate addition of malonate and β-ketoester to nitroalkenes: Asymmetric C-C bond formation with new bifunctional organic catalysts based on cinchona alkaloids
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The development of readily accessible bifunctional chiral catalysts is a desirable yet challenging goal in catalytic asymmetric synthesis. In this communication, we describe the development of a new class of readily accessible chiral bifunctional organic catalysts that could be derived in one or two steps in high yield from either quinidine or quinine. These catalysts have been shown to catalyze a highly enantioselective conjugate addition of methyl and ethyl malonates and β-ketoesters to a broad range of β-substituted nitroalkenes, an synthetically important C-C bond-forming reaction utilizing readily available starting materials. This new catalytic asymmetric reaction proceeds in 91-98% ee and 71-99% yield. Copyright
- Li, Hongming,Wang, Yi,Tang, Liang,Deng, Li
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p. 9906 - 9907
(2007/10/03)
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- Quinidine immunoassay and reagents
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Novel quinidine derivatives are provided which can be used in an improved immunoasssay for the detection of quinidine and quinidine metabolites.
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