- 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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- Robust cyclometallated Ir(iii) catalysts for the homogeneous hydrogenation of N-heterocycles under mild conditions
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Cyclometallated Cp*Ir(N∧C)Cl complexes derived from N-aryl ketimines are highly active catalysts for the reduction of N-heterocycles under ambient conditions and 1 atm H2 pressure. The reaction tolerates a broad range of other potentially reducible functionalities and does not require the use of specialised equipment, additives or purified solvent.
- Wu, Jianjun,Barnard, Jonathan H.,Zhang, Yi,Talwar, Dinesh,Robertson, Craig M.,Xiao, Jianliang
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supporting information
p. 7052 - 7054
(2013/09/02)
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- 4,5-Dihydrothiazoline - A new protecting and activating group for generation of α-aminocarbanions of secondary amines
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4,5-Dihydrothiazoline has been successfully used as a protecting and activating group for synthesis of various 1-substituted 1,2,3,4- tetrahydroisoquinolines via a lithiation-electrophillic substitution reaction sequence. Copyright Taylor & Francis Group, LLC.
- Singh, Kamal Nain,Singh, Paramjit,Kaur, Amarjit
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p. 3339 - 3343
(2007/10/03)
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- Prototype Pictet-Spengler reactions catalyzed by superacids. Involvement of dicationic superelectrophiles
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The Pictet-Spengler reaction, an acid-catalyzed intramolecular cyclization of intermediate imines of 2-arylethylamine to give 1,2,3,4- tetrahydroisoquinolines, has long been limited to active substrates which bear strongly electron-donating groups such as a methoxy or a hydroxy group on the cyclizing benzene ring. In this paper, we present superacid-catalyzed Pictet-Spengler reactions of imines of 2-phenethylamine, including the prototype Pictet-Spengler reaction of N-methylene-2-phenethylamine, to give the parent and 1-substituted 1,2,3,4-tetrahydroisoquinolines in moderate to high yields. The yields are dependent on the acidity of the media. A linear relationship was found between the rate of the cyclization and the acidity of the reaction media in kinetic studies of N-methylene-2-phenethylamine and related imines, strongly supporting the intervention of an additional protonative activation of the N-protonated imines, that is, the involvement of dicationic superelectrophiles, N,N-diprotonated imines (ammonium- carbenium dications). We further found that the prototype cyclization of the parent N-methylene-2-phenethylamine is also catalyzed by TFA to give 1,2,3,4- tetrahydroisoquinoline in good yield, although the cyclization is significantly slower than that catalyzed by superacids. The prototype Pictet- Spengler cyclization of N-methylene-2-phenethylamine can thus take place both through the monocation (the N-monoprotonated imine) and the dication (the N,N-diprotonated imine), the latter reaction being predominant in superacids.
- Yokoyama, Akihiro,Ohwada, Tomohiko,Shudo, Koichi
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p. 611 - 617
(2007/10/03)
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- Free-Radical Chemistry of Imines
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Aryl radicals bearing an aldimino functional group as part of an ortho substituent cyclized by addition to C and/or N of the imino group.When the choice was between 5-exo closure to C and 6-endo closure to N, the former predominated.However, 6-endo closure to C predominated over 5-exo cyclization to N in isomeric imines.Absolute values of cyclization rate constants were determined and an explanation for the unusual 6-endo preference is offered.Chiral induction in 6-endo cyclization to C of an aldimine from D-glyceraldehyde acetonide was observed, and its sense was determined.
- Tomaszewski, Miroslaw J.,Warkentin, John,Werstiuk, Nick H.
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p. 291 - 322
(2007/10/02)
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- O,O'-Bistributyltin Benzopinacolate (1,1,2,2-Tetraphenylethane-1,2-bisolate) as Thermal Source of Tributylstannyl Radicals
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The previously unknown bistributyltin benzopinacolate was prepared by photolysis of benzophenone in the presence of bistributyltin and used for thermal formation of aryl radicals that undergo subsequent intramolecular addition to an imine bond in an ortho-substituent.
- Tomaszewski, Miroslaw J.,Warkentin, John
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p. 1407 - 1408
(2007/10/02)
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- New strategies for enantioselective syntheses of 1-alkyl- and 1,4-dialkyl-1,2,3,4-tetrahydroisoquinolines: Diastereoselective additions of nucleophiles and electrophiles to isoquinoline mediated by an easily resolved and recycled chiral transition metal auxiliary
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The chiral rhenium isoquinoline complex [(η5-C5H5)Re(NO)(PPh 3)(iso-NC9H7)]+ TfO- (1) and (CH3)3-SiCH2Li give the addition product (η5-C5H5)Re(NO)(PPh3)(N?CH = CHC(CH)4CCHCH2Si(CH3)3) (2) in 71% yield as a 94:6 SS,RR/SR,RS diastereomer mixture. Similar reactions with RMgX (R = (CH3)2CH, CH3CH2, C6H5CH2, CH3(CH2)2, CH3, CH3(CH2)3) give analogous adducts (3-8) as 89-82:11-18 diastereomer mixtures. Reactions of 2 and ROTf (R = H/D, (CH3)3SiCH2, CH3) give alkyl-1,4-dihydroisoquinoline complexes [(η5-C5H5)Re(NO)-(PPh3)(N = CHCHRC(CH)4CCHCH2Si(CH3)3)] + TfO- in 84-72% yields as 94:6 diastereomer mixtures. Related complexes are prepared from 3-5 and HOTf. These react with NaBH4/CH3OH to give alkyl-1,2,3,4-tetrahydroisoquinoline complexes, which are in turn treated with (CH3CH2)4N+ CN- to give (η5-C5H5)Re(NO)(PPh3)(CN) (17) and the title compounds. A reaction sequence starting with (+)-(S)-1 and (CH3)3SiCH2Li yields (+)-(SS)-NHCH2-CH(CH2Si(CH3) 3)C(CH)4CCHCH2Si(CH3)3 (84% overall, 88% ee) and (+)-(S)-17 (82%, >98% ee). Other optically active alkyl tetrahydroisoquinolines are similarly prepared. Complexes 17 and (+)-(S)-17 are converted to (η5-C5H5)Re(NO)(PPh3)(CH 3) (CH3OTf/NaBH4; 88-53%) and thence to 1 or (+)-(S)-1 (92-74%, >98% ee). A crystal structure and other data confirm the configurations assigned to the preceding compounds.
- Richter-Addo, George B.,Knight, D. Andrew,Dewey, Michael A.,Arif, Atta M.,Gladysz
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p. 11863 - 11873
(2007/10/02)
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- Rate constants for aryl radical cyclization of aldimines: Synthesis of tetrahydroisoquinolines by fast 6-endo closures to carbon
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Aryl radicals cyclize to an imino functional group in a competition involving 6-endo closure to C and 5-exo closure to N. there is a large 6-endo preference forming tetrahydroisoquinolinyl radicals with k(6-endo) (80°C) > 108 s-1.
- Tomaszewski,Warkentin
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p. 2123 - 2126
(2007/10/02)
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- Phencyclidine-like Effects of Tetrahydroisoquinolines and Related Compounds
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A series of 1,2,3,4-tetrahydroisoquinolines, tetrahydrothienopyridines, and related compounds were evaluated for their ability to inhibit binding of -1--N-allylnormetazocine to phencyclidine (PCP) and ? receptors, respectively.A representative series of compounds was evaluated in behavioral assays to determine the ability of the compounds to induce PCP-like stereotyped behavior and ataxia.All of the compounds caused stereotyped behavior and ataxia, indicating their agonist actions at the PCP site.
- Gray, Nancy M.,Cheng, Brian K.,Mick, Stephen J.,Lair, Cecelia M.,Contreras, Patricia C.
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p. 1242 - 1248
(2007/10/02)
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- CARBON DOIXIDE: A REAGENT FOR THE PROTECTION OF NUCLEOPHILIC CENTERS AND THE SIMULTANEOUS ACTIVATION OF ELECTROPHILIC ATTACK. PART II. A NEW SYNTHETIC METHOD FOR THE 1-SUBSTITUTION OF 1,2,3,4-TETRAHYDROISOQUINOLINES.
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Tetrahydroisoquinoline was converted into several 1-substituted derivatives by using carbon dioxide both for N-protection and to give an intermediate carbanion stabilizing group. t-Butyllithium was used as a lithating agent at the alpha-carbon atom of the secondary amino group.The resulting 1-substituted 1,2,3,4-tetrahydroisoquinoline-2-carboxylic acids underwent smooth acid-catalysed decarboxylation under mild conditions.
- Katritzky, Alan R.,Akutagawa, Kunihiko
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p. 2571 - 2574
(2007/10/02)
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- ALKYLATION OF THE ISOQUINOLINE SKELETON IN THE 1-POSITION: LITHIATED 2-PIVALOYL- AND 2-BIS(DIMETHYLAMINO)-PHOSPHINOYL-1,2,3,4-TETRAHYDROISOQUINOLINES
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Nucleophilic reactivity in the 1-position of 1,2,3,4-tetrahydroisoquinoline is generated by lithiation of the N-pivaloyl- (16a) and N-phosphinoyl-derivatives (17a).The organolithium compounds (16b, 17b) thus obtained are highly nucleophilic and can be alkylated even with poor alkylating reagents such as secondary halides, neopentyl bromide and cyclopentanone.Hydrolysis of the phosphorylamide products with hydrochloric acid leads to 1-substituted tetrahydroisoquinolines in excellent yields (Table 2).
- Seebach, Dieter,Lohmann, Jean-Jacques,Syfrig, Max A.,Yoshifuji, Masaaki
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p. 1963 - 1974
(2007/10/02)
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- REDUCTION OF 1-ISOQUINOLYL-DIMETHYLMETHANOL AND 1-(1-ISOQUINOLYL)CYCLOHEXANOL
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Reduction of alcohols Ia and IIa with zinc and formic acid afforded 1-isopropylisoquinoline (Ib) and 1-cyclohexylisoquinoline (IIb), respectively, reduction with sodium in 1-butanol led to the 1,2,3,4-tetrahydroisoquinoline derivatives III, IV and Va and electrolytical reduction gave 1-isopropyl-1.2.3.4-tetrahydroisoquinoline (Vd) and the 1-cyclohexyl derivative Ve, respectively.
- Ferles, Miloslav,Sputova, Michaela,Tegza, Marian
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p. 262 - 265
(2007/10/02)
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- 2-Bis(dimethylamino)phosphinoyl-1-lithio-1,2,3,4-tetrahydro-isoquinoline. A Highly Nucleophilic d1-Reagent for the Preparation of 1-Substituted Tetrahydroisoquinolines
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The title compound 4 is generated from the phosphoric amide 5 in tetrahydrofuran with butyllithium.The lithium reagent 4 is stable at room temperature; its reactions with electrophiles furnish the products 6-22, 26,27, see Table 1 and the Scheme.A second alkylation is also possible, see 23-25.The cleavage to tetrahydroisoquinolines is accomplished in refluxing aqueous-methanolic hydrochloric acid, see Table 2.Phosphinoylation, lithiation, reaction with electrophiles and cleavage constitute an efficient sequence for 1-alkylation of the isoquinoline nucleus.
- Seebach, Dieter,Yoshifuji, Masaaki
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p. 643 - 647
(2007/10/02)
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