- Low-Temperature Nickel-Catalyzed C?N Cross-Coupling via Kinetic Resolution Enabled by a Bulky and Flexible Chiral N-Heterocyclic Carbene Ligand
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The transition-metal-catalyzed C?N cross-coupling has revolutionized the construction of amines. Despite the innovations of multiple generations of ligands to modulate the reactivity of the metal center, ligands for the low-temperature enantioselective amination of aryl halides remain a coveted target of catalyst engineering. Designs that promote one elementary reaction often create bottlenecks at other steps. We here report an unprecedented low-temperature (as low as ?50 °C), enantioselective Ni-catalyzed C?N cross-coupling of aryl chlorides with sterically hindered secondary amines via a kinetic resolution process (s factor up to >300). A bulky yet flexible chiral N-heterocyclic carbene (NHC) ligand is leveraged to drive both oxidative addition and reductive elimination with low barriers and control the enantioselectivity. Computational studies indicate that the rotations of multiple σ-bonds on the C2-symmetric chiral ligand adapt to the changing needs of catalytic processes. We expect this design would be widely applicable to diverse transition states to achieve other challenging metal-catalyzed asymmetric cross-coupling reactions.
- Hong, Xin,Shi, Shi-Liang,Wang, Zi-Chao,Xie, Pei-Pei,Xu, Youjun
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supporting information
p. 16077 - 16084
(2021/06/17)
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- Asymmetric Transfer Hydrogenation of Unhindered and Non-Electron-Rich 1-Aryl Dihydroisoquinolines with High Enantioselectivity
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The use of arene/Ru/TsDPEN catalysts bearing a heterocyclic group on the TsDPEN in the asymmetric transfer hydrogenation (ATH) of dihydroisoquinolines (DHIQs) containing meta- or para-substituted aromatic groups at the 1-position results in the formation of products of high enantiomeric excess. Previously, only 1-(ortho-substituted)aryl DHIQs, or with an electron-rich fused ring gave products with high enantioselectivity; therefore, this approach solves a long-standing challenge for imine ATH.
- Barrios-Rivera, Jonathan,Xu, Yingjian,Wills, Martin
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p. 6283 - 6287
(2020/09/02)
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- Josiphos-Type Binaphane Ligands for Iridium-Catalyzed Enantioselective Hydrogenation of 1-Aryl-Substituted Dihydroisoquinolines
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Convenient synthesis and useful application of a series of Josiphos-type binaphane ligands were described. The iridium complexes of these chiral diphosphines displayed excellent enantioselectivity and good reactivity in the asymmetric hydrogenation of challenging 1-aryl-substituted dihydroisoquinoline substrates (full conversions, up to >99% ee, 4000 TON). The use of 40% HBr (aqueous solution) as an additive dramatically improved the asymmetric induction of these catalysts. This transformation provided a highly efficient and enantioselective access to chiral 1-aryl-substituted tetrahydroisoquinolines, which were of great importance and common in natural products and biologically active molecules.
- Nie, Huifang,Zhu, Yupu,Hu, Xiaomu,Wei, Zhao,Yao, Lin,Zhou, Gang,Wang, Pingan,Jiang, Ru,Zhang, Shengyong
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p. 8641 - 8645
(2019/10/17)
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- Asymmetric Transfer Hydrogenation in Thermomorphic Microemulsions Based on Ionic Liquids
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A thermomorphic ionic-liquid-based microemulsion system was successfully applied for the Ru-catalyzed asymmetric transfer hydrogenation of ketones. On the basis of the temperature-dependent multiphase behavior of the targeted microemulsion, simple product separation as well as catalyst recycling could be realized. The use of water-soluble ligands improved the immobilization of the catalyst in the microemulsion phase and significantly decreased the catalyst leaching into the organic layer upon extraction of the product. Eventually, the optimized microemulsion system could be applied to a wide range of aromatic ketones that were reduced with good isolated yields (up to 98%) and enantioselectivities (up to 97%), while aliphatic ketones were less successful.
- Hejazifar, Mahtab,Pálv?lgyi, ádám Márk,Bitai, Jacqueline,Lanaridi, Olga,Bica-Schr?der, Katharina
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p. 1841 - 1851
(2019/10/11)
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- Breaking Symmetry: Engineering Single-Chain Dimeric Streptavidin as Host for Artificial Metalloenzymes
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The biotin-streptavidin technology has been extensively exploited to engineer artificial metalloenzymes (ArMs) that catalyze a dozen different reactions. Despite its versatility, the homotetrameric nature of streptavidin (Sav) and the noncooperative binding of biotinylated cofactors impose two limitations on the genetic optimization of ArMs: (i) point mutations are reflected in all four subunits of Sav, and (ii) the noncooperative binding of biotinylated cofactors to Sav may lead to an erosion in the catalytic performance, depending on the cofactor:biotin-binding site ratio. To address these challenges, we report on our efforts to engineer a (monovalent) single-chain dimeric streptavidin (scdSav) as scaffold for Sav-based ArMs. The versatility of scdSav as host protein is highlighted for the asymmetric transfer hydrogenation of prochiral imines using [Cp*Ir(biot-p-L)Cl] as cofactor. By capitalizing on a more precise genetic fine-tuning of the biotin-binding vestibule, unrivaled levels of activity and selectivity were achieved for the reduction of challenging prochiral imines. Comparison of the saturation kinetic data and X-ray structures of [Cp*Ir(biot-p-L)Cl]·scdSav with a structurally related [Cp*Ir(biot-p-L)Cl]·monovalent scdSav highlights the advantages of the presence of a single biotinylated cofactor precisely localized within the biotin-binding vestibule of the monovalent scdSav. The practicality of scdSav-based ArMs was illustrated for the reduction of the salsolidine precursor (500 mM) to afford (R)-salsolidine in 90% ee and >17 ?000 TONs. Monovalent scdSav thus provides a versatile scaffold to evolve more efficient ArMs for in vivo catalysis and large-scale applications.
- Wu, Shuke,Zhou, Yi,Rebelein, Johannes G.,Kuhn, Miriam,Mallin, Hendrik,Zhao, Jingming,Igareta, Nico V.,Ward, Thomas R.
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supporting information
p. 15869 - 15878
(2019/10/11)
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- A through halogen bond activation isoquinoline asymmetric hydrogenation method
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A through halogen bond activation isoquinoline asymmetric hydrogenation method, the catalyzing system is [...] complex, the activator is a halide. The reaction can be carried out under the following conditions, temperature: 25 - 100 °C; solvent: tetrahydr
- -
-
Paragraph 0031-0040; 0062
(2019/03/26)
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- Dual Stereocontrol for Enantioselective Hydrogenation of Dihydroisoquinolines Induced by Tuning the Amount of N-Bromosuccinimide
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An efficient dual stereocontrol in iridium-catalyzed hydrogenation of 1-substituted 3,4-dihydroisoquinolines was realized by tuning the amount of N-bromosuccinimide using chiral ligand of single configuration, providing both enantiomers of 1-substituted 1,2,3,4-tetrahydroisoquinolines with up to 89% ee (S) and 98% ee (R), respectively. Dual activation role of N-bromosuccinimide is proposed to be responsible for the reversal of enantioselectivity under two hydrogenation conditions.
- Ji, Yue,Wang, Jie,Chen, Muwang,Shi, Lei,Zhou, Yonggui
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supporting information
p. 139 - 142
(2018/01/05)
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- Directed Evolution of an Artificial Imine Reductase
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Artificial metalloenzymes, resulting from incorporation of a metal cofactor within a host protein, have received increasing attention in the last decade. The directed evolution is presented of an artificial transfer hydrogenase (ATHase) based on the biotin-streptavidin technology using a straightforward procedure allowing screening in cell-free extracts. Two streptavidin isoforms were yielded with improved catalytic activity and selectivity for the reduction of cyclic imines. The evolved ATHases were stable under biphasic catalytic conditions. The X-ray structure analysis reveals that introducing bulky residues within the active site results in flexibility changes of the cofactor, thus increasing exposure of the metal to the protein surface and leading to a reversal of enantioselectivity. This hypothesis was confirmed by a multiscale approach based mostly on molecular dynamics and protein–ligand dockings.
- Hestericová, Martina,Heinisch, Tillman,Alonso-Cotchico, Lur,Maréchal, Jean-Didier,Vidossich, Pietro,Ward, Thomas R.
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supporting information
p. 1863 - 1868
(2018/01/27)
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- A method catalyzed by iridium and used for bidirectional enantioselective synthesis of chiral tetrahydroisoquinoline
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A method catalyzed by iridium and used for bidirectional enantioselective synthesis of chiral tetrahydroisoquinoline is provided. A catalysis system adopted by the method is a chiral diphosphine complex of iridium. By utilizing a single chiral source and
- -
-
Paragraph 0035-0041
(2018/03/01)
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- Directed evolution of artificial metalloenzymes: Genetic optimization of the catalytic activity
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Artificial metalloenzymes (ArMs) based on the incorporation of a biotinylated metal cofactor within a streptavidin (Sav) combine attractive features of both enzymatic and homogeneous catalysis. To speed up their optimization, we present a directed evolution of an artificial transfer hydrogenase (ATHase) based on a streamlined and optimized protocol for the design, overexpression and screening of Sav isoforms. Ten positions have been subjected to mutagenesis to yield two variants with improved catalytic activity and selectivity for the reduction of cyclic imines, along with greater stability in a biphasic medium.
- Hestericová, Martina
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p. 189 - 192
(2018/05/22)
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- Ferritin encapsulation of artificial metalloenzymes: Engineering a tertiary coordination sphere for an artificial transfer hydrogenase
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Ferritin, a naturally occuring iron-storage protein, plays an important role in nanoengineering and biomedical applications. Upon iron removal, apoferritin was shown to allow the encapsulation of an artificial transfer hydrogenase (ATHase) based on the streptavidin-biotin technology. The third coordination sphere, provided by ferritin, significantly influences the catalytic activity of an ATHase for the reduction of cyclic imines.
- Hestericová, Martina,Heinisch, Tillmann,Lenz, Markus,Ward, Thomas R.
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supporting information
p. 10837 - 10841
(2018/08/23)
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- Genetic Engineering of an Artificial Metalloenzyme for Transfer Hydrogenation of a Self-Immolative Substrate in Escherichia coli's Periplasm
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Artificial metalloenzymes (ArMs), which combine an abiotic metal cofactor with a protein scaffold, catalyze various synthetically useful transformations. To complement the natural enzymes' repertoire, effective optimization protocols to improve ArM's performance are required. Here we report on our efforts to optimize the activity of an artificial transfer hydrogenase (ATHase) using Escherichia coli whole cells. For this purpose, we rely on a self-immolative quinolinium substrate which, upon reduction, releases fluorescent umbelliferone, thus allowing efficient screening. Introduction of a loop in the immediate proximity of the Ir-cofactor afforded an ArM with up to 5-fold increase in transfer hydrogenation activity compared to the wild-type ATHase using purified mutants.
- Zhao, Jingming,Rebelein, Johannes G.,Mallin, Hendrik,Trindler, Christian,Pellizzoni, Michela M.,Ward, Thomas R.
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supporting information
p. 13171 - 13175
(2018/10/23)
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- Chiral Carboxylic Acid Enabled Achiral Rhodium(III)-Catalyzed Enantioselective C?H Functionalization
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Reported is an achiral CpxRhIII/chiral carboxylic acid catalyzed asymmetric C?H alkylation of diarylmethanamines with a diazomalonate, followed by cyclization and decarboxylation to afford 1,4-dihydroisoquinolin-3(2H)-one. Secondary
- Lin, Luqing,Fukagawa, Seiya,Sekine, Daichi,Tomita, Eiki,Yoshino, Tatsuhiko,Matsunaga, Shigeki
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supporting information
p. 12048 - 12052
(2018/09/11)
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- Solifenacin succinate raw medicine synthesis process
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The invention discloses a solifenacin succinate raw medicine synthesis process. 2-phenylethylamine and 3-quinuclidinone hydrochloride are respectively used as starting raw materials for synthesizing afragment A and a fragment B; then, condensation reaction occurs to generate solifenacin; through salt formation, the solifenacin succinate is obtained. The process is characterized in that straight-chain paraffin and water are used as reaction solvents; alkali metal hydroxides or carbonate and bicarbonates of the alkali metal hydroxides are used as acid-binding agents; phenylethylamine and benzoyl chloride take acylation reaction to generate midbodies 1 of solid precipitation fragments A insoluble in reaction solvents; in the post treatment process, filtering is directly performed; isomers ofthe fragment A are subjected to catalytic racemization through alkali metal hydroxides by using dimethylsulfoxide as a solvent, so that the byproduct isomers can be recovered and utilized; in the second-step reaction post treatment of the fragment B, a conventional pressure reduced distillation method is used for obtaining high-purity and high-yield 3-acetoxyquinine acetate. The invention provides a novel synthesis process with the advantages of high yield and economic and environment-friendly effects, and is suitable for industrial mass production.
- -
-
Paragraph 0038; 0111; 0113
(2018/08/28)
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- A one-pot process for the enantioselective synthesis of tetrahydroquinolines and tetrahydroisoquinolines: Via asymmetric reductive amination (ARA)
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Asymmetric reductive amination for the synthesis of both chiral tetrahydroquinolines (THQs) and tetrahydroisoquinolines (THIQs) has been realized with an Ir/ZhaoPhos catalytic system via a one-pot N-Boc deprotection/intramolecular asymmetric reductive amination (ARA) sequence. Control experiments reveal that HCl plays a vital role to the success of this transformation. The HCl acid assists the removal of the N-Boc protecting group and also provides chloride ions to interact with the thiourea moiety in ZhaoPhos, thus leading to excellent reaction enantiocontrol.
- Yang, Tao,Yin, Qin,Gu, Guoxian,Zhang, Xumu
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supporting information
p. 7247 - 7250
(2018/07/05)
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- Identification of an Imine Reductase for Asymmetric Reduction of Bulky Dihydroisoquinolines
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A new imine reductase from Stackebrandtia nassauensis (SnIR) was identified, which displayed over 25- to 1400-fold greater catalytic efficiency for 1-methyl-3,4-dihydroisoquinoline (1-Me DHIQ) compared to other imine reductases reported. Subsequently, an efficient SnIR-catalyzed process was developed by simply optimizing the amount of cosolvent, and up to 15 g L-1 1-Me DHIQ was converted completely without a feeding strategy. Furthermore, the reaction proceeded well for a panel of dihydroisoquinolines, affording the corresponding tetrahydroisoquinolines (mostly in S-configuration) in good yields (up to 81%) and with moderate to excellent enantioselectivities (up to 99% ee).
- Li, Hao,Tian, Ping,Xu, Jian-He,Zheng, Gao-Wei
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p. 3151 - 3154
(2017/06/23)
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- Simultaneous engineering of an enzyme's entrance tunnel and active site: The case of monoamine oxidase MAO-N
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A new directed evolution approach is presented to enhance the activity of an enzyme and to manipulate stereoselectivity by focusing iterative saturation mutagenesis (ISM) simultaneously on residues lining the entrance tunnel and the binding pocket. This combined mutagenesis strategy was applied successfully to the monoamine oxidase from Aspergillus Niger (MAO-N) in the reaction of sterically demanding substrates which are of interest in the synthesis of chiral pharmaceuticals based on the benzo-piperidine scaffold. Reversal of enantioselectivity of Turner-type deracemization was achieved in the synthesis of (S)-1,2,3,4-tetrahydro-1-methyl-isoquinoline, (S)-1,2,3,4-tetrahydro-1-ethylisoquinoline and (S)-1,2,3,4-tetrahydro-1-isopropylisoquinoline. Extensive molecular dynamics simulations indicate that the altered catalytic profile is due to increased hydrophobicity of the entrance tunnel acting in concert with the altered shape of the binding pocket.
- Li, Guangyue,Yao, Peiyuan,Gong, Rui,Li, Jinlong,Liu, Pi,Lonsdale, Richard,Wu, Qiaqing,Lin, Jianping,Zhu, Dunming,Reetz, Manfred T.
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p. 4093 - 4099
(2017/07/10)
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- One-Pot N-Deprotection and Catalytic Intramolecular Asymmetric Reductive Amination for the Synthesis of Tetrahydroisoquinolines
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A one-pot N-Boc deprotection and catalytic intramolecular reductive amination protocol for the preparation of enantiomerically pure tetrahydroisoquinoline alkaloids is described. The iodine-bridged dimeric iridium complexes displayed superb stereoselectivity to give tetrahydroisoquinolines, including several key pharmaceutical drug intermediates, in excellent yields under mild reaction conditions. Three additives played important roles in this reaction: Titanium(IV) isopropoxide and molecular iodine accelerated the transformation of the intermediate imine to the tetrahydroisoquinoline product; p-toluenesulfonic acid contributed to the stereocontrol.
- Zhou, Huan,Liu, Yuan,Yang, Suhua,Zhou, Le,Chang, Mingxin
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supporting information
p. 2725 - 2729
(2017/02/26)
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- Asymmetric Transfer Hydrogenation of 1-Aryl-3,4-Dihydroisoquinolines Using a Cp*Ir(TsDPEN) Complex
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We report herein a simple alternative method for the asymmetric transfer hydrogenation (ATH) of 1-aryl-3,4-dihydroisoquinolines (1-Ar-DHIQs) that are known to be challenging substrates owing to their poor reactivity. The hydrogenation protocol employs the
- Václavíková Vilhanová, Bea,Budinská, Alena,Václavík, Ji?í,Matou?ek, Václav,Kuzma, Marek,?erveny, Libor
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supporting information
p. 5131 - 5134
(2017/09/22)
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- Enantioselective synthesis of 1-Aryl-substituted tetrahydroisoquinolines employing imine reductase
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Tetrahydroisoquinolines (THIQs) with a C1-aryl-substituted groups are common in many natural and synthetic compounds of biological importance. Currently, their enantioselective synthesis are primarily reliant on chemical catalysis. Enzymatic synthesis using imine reductase is very attractive, because of the cost-effectiveness, high catalytic efficiency, and enantioselectivity. However, the steric hindrance of the 1-aryl substituents make this conversion very challenging, and current successful examples are mostly restricted to the simple alkyl-THIQs. In this report, through extensive evaluation of a large collection of IREDs (including 88 enzymes), we successfully identified a panel of steric-hindrance tolerated IREDs. These enzymes are able to convert meta- and para-substituted chloro-, methyl-, and methoxyl-benzyl dihydroisoquinolines (DHIQs) into corresponding R- or S- THIQs with very high enantioselectivity and conversion. Among them, the two most hindrance-tolerated enzymes (with different stereospecificity) are also able to convert ortho-substituted chloro-, methyl-, and methoxyl-benzyl DHIQs and dimethoxyl 1-chlorobenzyl-DHIQs with good enantiometric excess. Furthermore, using in silico modeling, a highly conserved tryptophan residue (W191) was identified to be critical for substrate accommodation in the binding cavity of the S-selective IRED (IR45). Replacing W191 with alanine can dramatically increase the catalytic performance by decreasing the Km value by 2 orders of magnitude. Our results provide an effective route to synthesize these important classes of THIQs. Moreover, the disclosed sequences and substrate binding model set a solid basis to generate more-efficient and broad-selective enzymes via protein engineering.
- Zhu, Jinmei,Tan, Hongqun,Yang, Lu,Dai, Zheng,Zhu, Lu,Ma, Hongmin,Deng, Zixin,Tian, Zhenhua,Qu, Xudong
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p. 7003 - 7007
(2017/11/09)
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- Asymmetric Hydrogenation of Isoquinolines and Pyridines Using Hydrogen Halide Generated in Situ as Activator
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By employing halogenide trichloroisocyanuric acid as a traceless activation reagent, a general iridium-catalyzed asymmetric hydrogenation of isoquinolines and pyridines is developed with up to 99% ee. This method avoids tedious steps of installation and removal of the activating groups. The mechanism studies indicated that hydrogen halide generated in situ acted as an activator of isoquinolines and pyridines.
- Chen, Mu-Wang,Ji, Yue,Wang, Jie,Chen, Qing-An,Shi, Lei,Zhou, Yong-Gui
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supporting information
p. 4988 - 4991
(2017/09/23)
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- Enantioselective hydrogenation of cyclic imines catalysed by Noyori-Ikariya half-sandwich complexes and their analogues
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A method for enantioselective hydrogenation of cyclic imines with gaseous hydrogen has been developed. Easily accessible Noyori-Ikariya Ru(ii) and Rh(iii) complexes can be used directly without an inert atmosphere. Substrate activation has been achieved by trifluoroacetic acid. A new hydroxyl-functionalized complex is reported, showing high activity in transfer hydrogenation.
- Vilhanová,Václavík,?ot,Pechá?ek,Zápal,Pa?out,Maixner,Kuzma,Ka?er
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supporting information
p. 362 - 365
(2016/01/09)
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- Method for preparing chiral amine compound and its application
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The invention discloses a preparation method of a chiral amine compound. In presence of a semi-sandwich type complex and an acid additive, an asymmetrization reaction is carried out on a prochiral amine compound in a hydrogen atmosphere, and postprocessin
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-
Paragraph 0046; 0049; 0050; 0051; 0052
(2017/04/11)
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- Enantioselective Synthesis of 1-Aryl-Substituted Tetrahydroisoquinolines Through Ru-Catalyzed Asymmetric Transfer Hydrogenation
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A convenient and general asymmetric transfer hydrogenation of a wide array of 1-aryl-3,4-dihydroisoquinoline derivatives using a [RuIICl(η6-benzene)TsDPEN] complex in combination with a 5:2 HCOOH-Et3N azeotropic mixture as a hydrogen source was developed. Under mild reaction conditions, the described catalytic transformation secured a practical synthetic access to the corresponding valuable chiral 1-aryltetrahydroisoquinoline units with high atom economy, a broad substrate scope, high isolated yields (up to 97%) and good to excellent enantioselectivities (up to 99% ee). It was found that the stereochemical outcome of the reaction was strongly influenced by both the structure of the catalyst and the substituents present on the substrate. The synthetic utility of the present protocol has been demonstrated through the asymmetric synthesis of several biologically important alkaloids including the antiepileptic drug agent 1c, as well as (-)-nor-cryptostyline alkaloids I and II.
- Perez, Marc,Wu, Zi,Scalone, Michelangelo,Ayad, Tahar,Ratovelomanana-Vidal, Virginie
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p. 6503 - 6514
(2015/10/19)
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- Concise Redox Deracemization of Secondary and Tertiary Amines with a Tetrahydroisoquinoline Core via a Nonenzymatic Process
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A concise deracemization of racemic secondary and tertiary amines with a tetrahydroisoquinoline core has been successfully realized by orchestrating a redox process consisted of N-bromosuccinimide oxidation and iridum-catalyzed asymmetric hydrogenation. This compatible redox combination enables one-pot, single-operation deracemization to generate chiral 1-substituted 1,2,3,4-tetrahydroisoquinolines with up to 98% ee in 93% yield, offering a simple and scalable synthetic technique for chiral amines directly from racemic starting materials.
- Ji, Yue,Shi, Lei,Chen, Mu-Wang,Feng, Guang-Shou,Zhou, Yong-Gui
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supporting information
p. 10496 - 10499
(2015/09/28)
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- Development of an R-selective amine oxidase with broad substrate specificity and high enantioselectivity
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Amine oxidases are useful bio-catalysts for the synthesis of enantiomerically pure 1°, 2° and 3° chiral amines. Enzymes in this class (e.g., MAO-N from Aspergillus niger) reported previously have been shown to be highly S selective. Herein we report the development of an enantiocomplementary R-selective amine oxidase based on 6-hydroxy-D-nicotine oxidase (6-HDNO) with broadened substrate scope and high enantioselectivity. The engineered 6-HDNO enzyme has been applied to the preparative deracemisation of a range of racemic amines to yield S-configured products, for example, (S)-nicotine, in high ee. Nicotine rush: An R-selective amine oxidase based on 6-hydroxy-D-nicotine oxidase (6-HDNO) with broadened substrate scope and high enantioselectivity has been developed. The engineered 6-HDNO enzyme is applied to the preparative deracemization of a range of racemic amines to yield S-configured products, for example, (S)-nicotine, in high ee.
- Heath, Rachel S.,Pontini, Marta,Bechi, Beatrice,Turner, Nicholas J.
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p. 996 - 1002
(2014/05/06)
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- Expanding the chemical diversity in artificial imine reductases based on the biotin-streptavidin technology
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We report on the optimization of an artificial imine reductase based on the biotin-streptavidin technology. With the aim of rapidly generating chemical diversity, a novel strategy for the formation and evaluation of biotinylated complexes is disclosed. Tethering the biotin-anchor to the Cp* moiety leaves three free coordination sites on a d6 metal for the introduction of chemical diversity by coordination of a variety of ligands. To test the concept, 34 bidentate ligands were screened and a selection of the 6 best was tested in the presence of 21 streptavidin (Sav) isoforms for the asymmetric imine reduction by the resulting three legged piano stool complexes. Enantiopure α-amino amides were identified as promising bidentate ligands: up to 63 % ee and 190 turnovers were obtained in the formation of 1-phenyl-1,2,3,4-tetrahydroisoquinoline with [IrCp*biotin(L-ThrNH2)Cl]?SavWT as a catalyst. Biotinspired! A new strategy for the generation of chemical diversity in artificial transfer hydrogenases (ATHases) based on the biotin-streptavidin technology is disclosed. By combining a biotinylated MCp* fragment with 34 commercially available ligands in the presence of wild-type streptavidin, promising candidates for the asymmetric reduction of imines are identified. Selected ligands are screened against 21 streptavidin isoforms and the performance of the resulting constructs is evaluated.
- Quinto, Tommaso,Schwizer, Fabian,Zimbron, Jeremy M.,Morina, Albert,Koehler, Valentin,Ward, Thomas R.
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p. 1010 - 1014
(2014/05/06)
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- The role of the aromatic ligand in the asymmetric transfer hydrogenation of the CN bond on Noyori's chiral Ru catalysts
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Only four types of dimeric precursors [RuCl2(η6-arene)]2 for the synthesis of Noyori's half sandwich diamine catalysts [RuCl(TsDPEN)(η6-arene)] are commercially available, yet so far no study has tried to system
- ot, Petr,Vilhanov, Beta,Pechek, Jan,Vclavk, Ji,Zpal, Jakub,Kuzma, Marek,Kaer, Petr
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p. 1346 - 1351
(2015/02/02)
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- One-pot racemization process of 1-Phenyl-1,2,3,4-tetrahydroisoquinoline: A key intermediate for the antimuscarinic agent solifenacin
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(S)-(+)-1-Phenyl-1,2,3,4-tetrahydroisoquinoline, which is the key intermediate in preparing the urinary antispasmodic drug solifenacin, was racemized in quantitative yield by a simple one-pot procedure through N-chlorination with trichloroisocyanuric acid, conversion of the N-chloroamine into the imine hydrochloride, and reduction of the imine double bond. The racemized amine was successfully resolved by d-(-)-tartaric acid obtaining (S)-1-phenyl-1,2,3,4-tetrahydroisoquinoline in 81% yield and with 96.7% ee and, from the crystallization mother liquors, the R enriched form. This was racemized by the same one-pot process and resolved by d-(-)-tartaric acid with the same efficiency. Such an approach to the racemization of 1-phenyl-1,2,3,4- tetrahydroisoquinoline can be industrially useful to recycle the waste R enantiomer resulting from the classical resolution used to obtain the S enantiomer on a large scale.
- Bolchi, Cristiano,Pallavicini, Marco,Fumagalli, Laura,Straniero, Valentina,Valoti, Ermanno
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p. 432 - 437
(2013/05/09)
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- Asymmetric transfer hydrogenation of 1-phenyl dihydroisoquinolines using Ru(II) diamine catalysts
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A new [Ru(II)(η6-p-cymene)(1R,2R)-N-((1S,2S)-borneol-10- sulfonyl)-1,2-diphenylethylenediamine] catalyst for the asymmetric transfer hydrogenation of both 1-alkyl and 1-aryl dihydroisoquinolines has been isolated. For the first time in this type of reaction, the catalyst employs an N-alkylsulfonyl group instead of N-arylsulfonyl.
- P?ech, Jan,Václavík, Ji?í,?ot, Petr,Pechá?ek, Jan,Vilhanová, Beáta,Janu??ák, Jakub,Syslová, Kamila,Pa?out, Richard,Maixner, Jaroslav,Zápal, Jakub,Kuzma, Marek,Ka?er, Petr
-
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- Enantioselective iridium-catalyzed hydrogenation of 1- and 3-substituted isoquinolinium salts
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Asymmetric hydrogenation: The title reaction provides an efficient and rapid access to chiral 1- and 3-substituted 1,2,3,4-tetrahydroisoquinolines with excellent enantioselectivity (see scheme; L=ligand). A preliminary mechanistic study indicates that the 1,2-hydride addition might be the initial step in the reaction. The method has been used in the synthesis of urinary antispasmodic drug (+)-solifenacin. Copyright
- Ye, Zhi-Shi,Guo, Ran-Ning,Cai, Xian-Feng,Chen, Mu-Wang,Shi, Lei,Zhou, Yong-Gui
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p. 3685 - 3689
(2013/04/24)
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- The development of an asymmetric hydrogenation process for the preparation of solifenacin
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The successful development of a catalytic imine asymmetric hydrogenation process for the reduction of the hydrochloride salt of 1-phenyl-3,4- dihydroisoquinoline to 1-(S)-phenyl-1,2,3,4-tetrahydroisoquinoline is described. This represents a novel approach to the key intermediate in preparing the urinary antispasmodic drug solifenacin, (1S)-(3R)-1-azabicyclo[2.2.2]oct-3-yl-3, 4-dihydro-1-phenyl-2(1H)-isoquinoline carboxylate. Suitable reaction conditions were identified through an extensive screen of catalysts and combination of solvents and additives. The best reaction conditions: [Ir(COD)Cl] 2-(S)-P-Phos, molar substrate to catalyst ratio (S/C) of >1000/1, THF, 1-2 equiv of H3PO4, 60 °C, 20 bar H2, were reproduced on a 200 g scale (95% isolated yield, 98% ee and >99% HPLC product purity).
- Ruzic, Milos,Pecavar, Anica,Prudic, Darja,Kralj, David,Scriban, Corina,Zanotti-Gerosa, Antonio
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p. 1293 - 1300
(2012/09/21)
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- Enantioselective synthesis of 1-aryl-tetrahydroisoquinolines through iridium catalyzed asymmetric hydrogenation
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Asymmetric hydrogenation of 1-aryl-3,4-dihydroisoquinolines using the [IrCODCl]2/(R)-3,5-diMe-Synphos catalyst is reported. Under mild reaction conditions, this atom-economical process provides easy access to a variety of enantioenriched 1-aryl-1,2,3,4-tetrahydroisoquinoline derivatives, which are important pharmacophores found in several pharmaceutical drug candidates, in high yields and enantiomeric excesses up to 99% after a single crystallization.
- Berhal, Farouk,Wu, Zi,Zhang, Zhaoguo,Ayad, Tahar,Ratovelomanana-Vidal, Virginie
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supporting information; experimental part
p. 3308 - 3311
(2012/08/28)
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- Catalytic kinetic resolution of cyclic secondary amines
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The catalytic resolution of racemic cyclic amines has been achieved by an enantioselective amidation reaction featuring an achiral N-heterocyclic carbene catalyst and a new chiral hydroxamic acid cocatalyst working in concert. The reactions proceed at room temperature, do not generate nonvolatile byproducts, and provide enantioenriched amines by aqueous extraction.
- Binanzer, Michael,Hsieh, Sheng-Ying,Bode, Jeffrey W.
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supporting information; experimental part
p. 19698 - 19701
(2012/01/13)
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- A highly efficient and enantioselective access to tetrahydroisoquinoline alkaloids: Asymmetric hydrogenation with an iridium catalyst
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Efficient and enantioselective: Using the iodine-bridged dimeric iridium complex [{Ir(H)[(S,S)-(f)-binaphane]}2(μ-I)3] +I- (1) a wide range of tetrahydroisoquinoline alkaloids, including the substructure of the pharmaceutical drug solifenacin, were obtained with excellent enantioselectivities and high turnover numbers (see scheme). Copyright
- Chang, Mingxin,Li, Wei,Zhang, Xumu
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p. 10679 - 10681
(2011/12/05)
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- PROCESSES FOR THE PREPARATION OF SOLIFENACIN OR A SALT THEREOF
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The present invention describes recovery and racemization of (1R)-Phenyl- 1,2,3,4-tetrahydroisoquinoline of compound of formula (III) to obtain racemic 1- phenyl-1, 2,3,4-tetrahydroisoquinoline of compound of formula (I) and its further resolution to get ( IS)-1-phenyl-1, 2, 3, 4-tetrahydroisoquinoline (intermediate B) in high chemical and chiral purity, which is the key intermediate for the preparation of (3R)-azabicyclo[2.2.2]oct-3-yl (1S)-1-phenyl-3,4-dihydroisoquinoline-2-(1H)- carboxylate.
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- Efficient and single pot process for the preparation of enantiomerically pure solifenacin succinate, an antimuscarinic agent
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The development of an efficient and economic one-pot process, in which the configuration of the chiral centers of the starting materials is retained, for the preparation of highly pure solifenacin succinate, an antimuscarinic agent, is presented in this communication. The earlier reported processes suffer from the drawbacks of racemization and low yields due to the use of strong base, higher temperatures, and longer reaction times. The present work circumvents these issues by activating (3R)-quinuclidin-3-ol into a mixed active carbonate derivative by treating it with bis(4-nitrophenyl)carbonate. The subsequent reaction of the active carbonate with an enantiomerically pure amine without using any base at ambient temperature provided enantiomerically pure solifenacin with an overall yield of 90%. Graphical Abstract: [Figure not available: see fulltext.]
- Niphade, Navnath C.,Jagtap, Kunal M.,Mali, Anil C.,Solanki, Pavankumar V.,Jachak, Madhukar N.,Mathad, Vijayavitthal T.
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body text
p. 1181 - 1186
(2012/01/06)
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- A PROCESS FOR THE PREPARATION OF SOLIFENACIN SALTS AND THEIR INCLUSION INTO PHARMACEUTICAL DOSAGE FORMS
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The invention relates to the synthesis of solifenacin, the preparation of its salts and their inclusion into pharmaceutically acceptable dosage forms.
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Page/Page column 29
(2010/04/03)
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- SOLIFENACIN COMPOSITIONS
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Compositions and/or formulations comprising solifenacin or a salt thereof and processes for preparing the same. Certain compositions and formulations contain a stable amorphous form of solifenacin succinate.
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- Synthesis and antimuscarinic properties of quinuclidin-3-yl 1,2,3,4-tetrahydroisoquinoline-2-carboxylate derivatives as novel muscarinic receptor antagonists
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In the course of continuing efforts to develop potent and bladder-selective muscarinic M3 receptor antagonists, quinuclidin-3-yl 1-aryl-1,2,3,4-tetrahydroisoquinoline-2-carboxylate derivatives and related compounds were designed as conformationally restricted analogues of quinuclidin-3-yl benzhydrylcarbamate (8). Binding assays with rat muscarinic receptor subtypes revealed that the quinuclidin-3-yl 1-aryl-1,2,3,4- tetrahydroisoquinoline-2-carboxylate derivatives showed high affinities for the M3 receptor, and selectivity for the M3 receptor over the M2 receptor. Of these derivatives, (+)-(1S,3'R)-quinuclidin-3'-yl 1-phenyl-l,2,3,4-tetrahydroisoquinoline-2-carboxylate monohydrochloride (9b) exhibited almost the same inhibitory activity against bladder contraction to that of oxybutynin (1), and more than 10-fold selectivity for bladder contraction versus salivary secretion, demonstrating that 9b may be useful for the treatment of symptoms associated with overactive bladder without having side effects such as dry mouth.
- Naito, Ryo,Yonetoku, Yasuhiro,Okamoto, Yoshinori,Toyoshima, Akira,Ikeda, Ken,Takeuchi, Makoto
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p. 6597 - 6606
(2007/10/03)
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- Asymmetric synthesis of 1-substituted 1,2,3,4-tetra-hydroisoquinolines by asymmetric electrophilic α-amidoalkylation reactions
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An efficient method for the asymmetric synthesis of 1-substituted 1,2,3,4-tetrahydroisoquinolines via chiral N-acyliminium ions is presented. The N-acyl-1,2-dihydroisoquinolines (8) and (9) underwent smooth oxidation reactions with Ph3C+BF4- to give the chiral N-acylisoquinolinium ions (10) and (13), respectively. Stereoselective addition of organomagnesium and organozinc compounds to intermediates (10) and (13) provided the corresponding 1-substituted N-acyl-1,2-dihydroisoquinolines (11/12) and (14/15) in good yields. The diastereoselectivity of these reactions appeared to be dependent on the structure of the N-acyliminium ion intermediates (10) and (13) and on the nature of the trapping reagent with the zinc reagents in general leading to markedly improved stereoselectivities. Pure diastereomers were obtained by preparative HPLC and readily transformed into enantiopure 1-substituted 1,2,3,4-tetrahydroisoquinolines by catalytic hydrogenation and reductive removal of the chiral auxiliary.
- Ludwig, Matthias,Polborn,Wanner, Klaus T.
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p. 299 - 326
(2007/10/03)
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- A novel straightforward synthesis of enantiopure tetrahydroisoquinoline alkaloids
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A novel, direct, and high-yielding stereoselective method for enantiopure 1-substituted tetrahydroisoquinolines (THIQ) is described. The successful approach, which creates the stereocenter during the formation of the THIQ nucleus is based on (i) formation of chiral 2,3-substituted perhydro-1,3-benzoxazines derived from (-)-8-aminomenthol, (ii) diastereoselective intramolecular ring opening of the N,O-acetal moiety by an arylmetal generated from the substituent at the nitrogen atom in the perhydrobenzoxazine ring, and (iii) removal of the chiral auxiliary appendage. The starting perhydrobenzoxazines are easily prepared from (-)-8-aminomenthol and two different aldehydes, and the intramolecular opening is stereospecific, leading to a single stereoisomer. The method allows the preparation of a wide variety of enantiopure 1-substituted THIQ, with different substituents at C-1, by changing the nature of the starting aldehydes.
- Pedrosa,Andres,Iglesias
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p. 243 - 250
(2007/10/03)
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- Diastereoselective addition of chiral (2-lithiophenyl)acetaldehyde acetals to various imines as key step in the asymmetric synthesis of 1- aryltetrahydroisoquinolines, part 4
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A novel asymmetric synthesis of 1-aryl-1,2,3,4-tetrahydroisoquinolines has been developed. The key step in this synthesis is the diastereoselective addition of homochiral (2-lithiophenyl)acetaldehyde acetals to the sulfonylimine 25 and to the arylimines 28 and 31. The best diastereoselectivity is obtained by addition of the bis(2-methoxypropan-2- yl)-substituted 1,3-dioxolane 6e to benzylidene-p-anisidine (31) with an HPLC-determined diastereomeric ratio 32c/33c = 92.1:7.9. The N-tosyl and the N-(4-methoxyphenyl) groups of the addition products 26d, 27d, 32c, and 33c are cleaved with sodium in liquid ammonia and ammonium cerium(IV) nitrate, respectively, to yield the primary amines 35 and 36. The acid-catalysed cyclization of the sulfonamides 26d and 27d and the carbamates 37 and 38, prepared from 35 and 36, leads to the enantiomerically pure dihydroisoquinolines 40 and 41, respectively. During the cyclization of the sulfonamides 26d, 27d and the carbamates 37, 38 the chiral auxiliary - the diol 39 - is cleaved unchanged and can be recovered in good yields.
- Wuensch, Bernhard,Nerdinger, Sven
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p. 503 - 517
(2007/10/03)
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- Asymmetric synthesis and enantioselectivity of binding of 1-aryl-1,2,3,4-tetrahydroisoquinolines at the PCP site of the NMDA receptor complex
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A new method for the asymmetric synthesis of 1-substituted tetrahydroisoquinolines is presented. It is based on stereoselective addition reactions of organometallic compounds to the intermediate N-acylimimum ion 6, which is provided with an N-acyl group as a chiral auxiliary. In addition reactions with organomagnesium and organozinc reagents diastereoselectivities from 70:30 to 95:5 (for 7/8) were observed with the zinc reagents in general leading to markedly improved stereoselectivities. By catalytic hydrogenation of 7 and 8 and after removal of the chiral auxiliary the target compounds 11 and 12 were obtained. The enantiomerically pure 11c-g and 12c-g (ee > 99%), 1-aryltetrahydroisoquinolines, were evaluated for their affinity to the PCP [1-(1-phenylcyclohexyl)piperidine] binding site of the NMDA (N-methyl D-aspartate) receptor. In each case the enantiomers 11 exhibited a higher affinity than those of 12, with the potencies of the enantiomers differing by a factor of 4 (11/12g) to 27 (11/12c). The absolute configuration of the more potent enantiomers 11 is in accordance with the stereochemical requirement found for FR 115427 (3) which is a close analogue.
- Wanner, Klaus Th.,Beer, Herbert,H?fner, Georg,Ludwig, Matthias
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p. 2019 - 2029
(2007/10/03)
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- The absolute configuration of (1S)-(+)- and (1R)-(-)1-phenyl-1,2,3,4-tetrahydroisoquinoline. A revision of the literature assignment
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The title compounds (S)-(+)-8 and (R)-(-)-8 have been prepared by an asymmetric synthesis that is based on stereoselective additions to the chiral N-acylisoquinoliniumion 3. The absolute configuration of these compounds has been determined by an X-ray analysis performed on the intermediate 5. According to the results of this study the stereochemical assignment for (S)-(+)-8 and (R)-(-)-8 described in the literature has to be revised.
- Ludwig, Matthias,Beer, Herbert,Lotter, Hermann,Wanner, Klaus Th.
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p. 2693 - 2695
(2007/10/03)
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