- Zinc-Catalyzed Asymmetric Hydrosilylation of Cyclic Imines: Synthesis of Chiral 2-Aryl-Substituted Pyrrolidines as Pharmaceutical Building Blocks
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The first successful enantioselective hydrosilylation of cyclic imines promoted by a chiral zinc complex is reported. In situ generated zinc-ProPhenol complex with silane afforded pharmaceutically relevant enantioenriched 2-aryl-substituted pyrrolidines in high yields and with excellent enantioselectivities (up to 99% ee). The synthetic utility of presented methodology is demonstrated in an efficient synthesis of the corresponding chiral cyclic amines, being pharmaceutical drug precursors to the Aticaprant and Larotrectinib. (Figure presented.).
- W?glarz, Izabela,Michalak, Karol,Mlynarski, Jacek
-
supporting information
p. 1317 - 1321
(2020/12/09)
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- Enantioselective Intermolecular C-H Amination Directed by a Chiral Cation
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The enantioselective amination of C(sp3)-H bonds is a powerful synthetic transformation yet highly challenging to achieve in an intermolecular sense. We have developed a family of anionic variants of the best-in-class catalyst for Rh-catalyzed C-H amination, Rh2(esp)2, with which we have associated chiral cations derived from quaternized cinchona alkaloids. These ion-paired catalysts enable high levels of enantioselectivity to be achieved in the benzylic C-H amination of substrates bearing pendant hydroxyl groups. Additionally, the quinoline of the chiral cation appears to engage in axial ligation to the rhodium complex, providing improved yields of product versus Rh2(esp)2 and highlighting the dual role that the cation is playing. These results underline the potential of using chiral cations to control enantioselectivity in challenging transition-metal-catalyzed transformations.
- Fanourakis, Alexander,Paterson, Kieran J.,Phipps, Robert J.,Williams, Benjamin D.
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p. 10070 - 10076
(2021/07/21)
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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.
-
supporting information
p. 15869 - 15878
(2019/10/11)
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- Enantioselective Synthesis of 2-Substituted Pyrrolidines via Intramolecular Reductive Amination
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Catalyzed by the complex generated in situ from iridium and the chiral ferrocene ligand, tert -butyl (4-oxo-4-arylbutyl)carbamate substrates were deprotected and then reductively cyclised to form 2-substituted arylpyrrolidines in a one-pot manner, in which the intramolecular reductive amination was the key step. A range of chiral 2-substituted arylpyrrolidines were synthesised in up to 98percent yield and 92percent ee.
- Chang, Mingxin,Guo, Haodong,Huang, Haizhou,Zhang, Tao,Zhao, Wenlei,Zhou, Huan
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p. 2713 - 2719
(2019/06/19)
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- Sequence-Based In-silico Discovery, Characterisation, and Biocatalytic Application of a Set of Imine Reductases
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Imine reductases (IREDs) have recently become a primary focus of research in biocatalysis, complementing other classes of amine-forming enzymes such as transaminases and amine dehydrogenases. Following in the footsteps of other research groups, we have established a set of IRED biocatalysts by sequence-based in silico enzyme discovery. In this study, we present basic characterisation data for these novel IREDs and explore their activity and stereoselectivity using a panel of structurally diverse cyclic imines as substrates. Specific activities of >1 U/mg and excellent stereoselectivities (ee>99 %) were observed in many cases, and the enzymes proved surprisingly tolerant towards elevated substrate loadings. Co-expression of the IREDs with an alcohol dehydrogenase for cofactor regeneration led to whole-cell biocatalysts capable of efficiently reducing imines at 100 mM initial concentration with no need for the addition of extracellular nicotinamide cofactor. Preparative biotransformations on gram scale using these ‘designer cells’ afforded chiral amines in good yield and excellent optical purity.
- Velikogne, Stefan,Resch, Verena,Dertnig, Carina,Schrittwieser, Joerg H.,Kroutil, Wolfgang
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p. 3236 - 3246
(2018/08/03)
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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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- 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.
-
supporting information
p. 13171 - 13175
(2018/10/23)
-
- Synthesis of chiral cyclic amines via Ir-catalyzed enantioselective hydrogenation of cyclic imines
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A highly enantioselective hydrogenation of cyclic imines for synthesis of chiral cyclic amines has been realized. With the complex of iridium and (R,R)-f-spiroPhos as the catalyst, a range of cyclic 2-aryl imines were smoothly hydrogenated under mild conditions without any additive to provide the corresponding chiral cyclic amines with excellent enantioselectivities of up to 98% ee. Moreover, this method could be successfully applied to the synthesis of (+)-(6S,10bR)-McN-4612-Z.
- Zhang, Ying,Kong, Duanyang,Wang, Rui,Hou, Guohua
-
p. 3006 - 3012
(2017/04/11)
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- Enantioselective Direct Synthesis of Free Cyclic Amines via Intramolecular Reductive Amination
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Chiral cyclic amines can be prepared via intramolecular reductive amination of N-Boc-protected amino ketones in a one-pot process. With the complex of iridium and f-spiroPhos as the catalyst, a range of N-Boc-protected amino ketones are smoothly transformed into chiral cyclic free amines in high yields and excellent enantioselectivities (up to 97% ee). Moreover, this method can also be successfully applied to the synthesis of a κ-opioid receptor selective antagonist, (S)-1.
- Zhang, Ying,Yan, Qiaozhi,Zi, Guofu,Hou, Guohua
-
supporting information
p. 4215 - 4218
(2017/08/23)
-
- 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)
-
- Determination of the Absolute Configuration of Cyclic Amines with Bode's Chiral Hydroxamic Esters Using the Competing Enantioselective Conversion Method
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The competing enantioselective conversion (CEC) strategy has been extended to cyclic amines. The basis for the CEC approach is the use of two complementary, enantioselective reactions to determine the configuration of the enantiopure substrate. Bode's chiral acylated hydroxamic acids are very effective enantioselective acylating agents for a variety of amines. Pseudoenantiomers of these acyl-transfer reagents were prepared and demonstrated to react with enantiopure cyclic amines with modest to high selectivity. The products were analyzed by ESI-MS to determine selectivity, and the results were used to assign the configuration of the amine substrate. The method was applicable to a variety of cyclic amines as well as primary amines and acyclic secondary amines. The method is limited to amines that are unhindered enough to react with the reagents, and not all amine substitution patters lead to high selectivity.
- Burtea, Alexander,Rychnovsky, Scott D.
-
supporting information
p. 4195 - 4198
(2017/08/23)
-
- Stereoselectivity and Structural Characterization of an Imine Reductase (IRED) from Amycolatopsis orientalis
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The imine reductase AoIRED from Amycolatopsis orientalis (Uniprot R4SNK4) catalyzes the NADPH-dependent reduction of a wide range of prochiral imines and iminium ions, predominantly with (S)-selectivity and with ee's of up to >99%. AoIRED displays up to 100-fold greater catalytic efficiency for 2-methyl-1-pyrroline (2MPN) compared to other IREDs, such as the enzyme from Streptomyces sp. GF3546, which also exhibits (S)-selectivity, and thus, AoIRED is an interesting candidate for preparative synthesis. AoIRED exhibits unusual catalytic properties, with inversion of stereoselectivity observed between structurally similar substrates, and also, in the case of 1-methyl-3,4-dihydroisoquinoline, for the same substrate, dependent on the age of the enzyme after purification. The structure of AoIRED has been determined in an "open" apo-form, revealing a canonical dimeric IRED fold in which the active site is formed between the N- and C-terminal domains of participating monomers. Co-crystallization with NADPH gave a "closed" form in complex with the cofactor, in which a relative closure of domains, and associated loop movements, has resulted in a much smaller active site. A ternary complex was also obtained by cocrystallization with NADPH and 1-methyl-1,2,3,4-tetrahydroisoquinoline [(MTQ], and it reveals a binding site for the (R)-amine product, which places the chiral carbon within 4 ? of the putative location of the C4 atom of NADPH that delivers hydride to the C? -N bond of the substrate. The ternary complex has permitted structure-informed mutation of the active site, resulting in mutants including Y179A, Y179F, and N241A, of altered activity and stereoselectivity.
- Aleku, Godwin A.,Man, Henry,France, Scott P.,Leipold, Friedemann,Hussain, Shahed,Toca-Gonzalez, Laura,Marchington, Rebecca,Hart, Sam,Turkenburg, Johan P.,Grogan, Gideon,Turner, Nicholas J.
-
p. 3880 - 3889
(2016/07/06)
-
- One-Pot Cascade Synthesis of Mono- and Disubstituted Piperidines and Pyrrolidines using Carboxylic Acid Reductase (CAR), ω-Transaminase (ω-TA), and Imine Reductase (IRED) Biocatalysts
-
Access to enantiomerically pure chiral mono- and disubstituted piperidines and pyrrolidines has been achieved using a biocatalytic cascade involving carboxylic acid reductase (CAR), ω-transaminase (ω-TA), and imine reductase (IRED) enzymes. Starting from keto acids or keto aldehydes, substituted piperidine or pyrrolidine frameworks can be generated in high conversion, ee, and de in one pot, with each biocatalyst exhibiting chemo-, regio-, and/or stereoselectivity during catalysis. The study also includes a systematic investigation of the effect of the position of a methyl group ring substituent on the IRED-catalyzed reduction of a chiral imine. Analysis of the selectivity observed in these reactions revealed an interesting balance between substrate versus enzyme control; the configurations of the products obtained were rationalized on the basis of minimizing 1,3- or 1,2-steric interactions with incoming NADPH.
- France, Scott P.,Hussain, Shahed,Hill, Andrew M.,Hepworth, Lorna J.,Howard, Roger M.,Mulholland, Keith R.,Flitsch, Sabine L.,Turner, Nicholas J.
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p. 3753 - 3759
(2016/07/06)
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- Combined Imine Reductase and Amine Oxidase Catalyzed Deracemization of Nitrogen Heterocycles
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A novel amine oxidase (AO)/imine reductase (IRED) system was developed for the deracemization of racemic amines. By combining (R)-6-hydroxy-d-nicotine oxidase (6-HDNO) with an (R)-IRED, a panel of racemic 2-substituted piperidines and pyrrolidines were deracemized to yield the (S)-amines in high yields and enantiomeric excess values. Other N-heterocycles were deracemized with monoamine oxidase (MAO-N) or 6-HDNO in combination with ammonia borane, which allowed comparison of the two enzyme deracemization approaches with that involving a chemical reducing agent.
- Heath, Rachel S.,Pontini, Marta,Hussain, Shahed,Turner, Nicholas J.
-
p. 117 - 120
(2016/01/26)
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- A chiral 2-phenyl pyrrolidine synthetic method
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The invention discloses a synthetic method of chiral 2-phenylpyrrolidine. The synthetic method comprises the following steps: (1) butoxycarbonyl protective reaction: carrying out reaction on chiral 2-amino-phenylacetic acid and di-tert-butyl dicarbonate to obtain chiral 2-( butoxycarbonyl amino)-2-phenylacetic acid; (2) condensation and reduction reaction: carrying out condensation on the chiral 2-(butoxycarbonyl amino)-2-phenylacetic acid and 2, 2-dimethyl-1, 3-dioxane-4, 6-dione, and carrying out reduction by virtue of sodium borohydride to obtain chiral 2-(2, 2-dimethyl-4, 6-dicarbonyl-1, 3-dioxane-5-yl)-1-phenyl ethyl tert-butyl carbamate; (3) de-protection and heating ring closure reaction: carrying out de-protection and heating ring closure reaction on the chiral 2-(2, 2-dimethyl-4, 6-dicarbonyl-1, 3-dioxane-5-yl)-1-phenyl ethyl tert-butyl carbamate to obtain chiral 5-phenylpyrrolidine-2-ketone; and (4) reduction reaction: reducing the chiral 5-phenylpyrrolidine-2-ketone by virtue of lithium aluminium hydride to obtain the chiral 2-phenylpyrrolidine. The synthetic method is simple in operation, high in yield and cheap and easily acquired in raw materials and is suitable for industrial production.
- -
-
Paragraph 0047; 0048
(2017/02/02)
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- An (R)-imine reductase biocatalyst for the asymmetric reduction of cyclic imines
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Although the range of biocatalysts available for the synthesis of enantiomerically pure chiral amines continues to expand, few existing methods provide access to secondary amines. To address this shortcoming, we have over-expressed the gene for an (R)-imine reductase [(R)-IRED] from Streptomyces sp. GF3587 in Escherichia coli to create a recombinant whole-cell biocatalyst for the asymmetric reduction of prochiral imines. The (R)-IRED was screened against a panel of cyclic imines and two iminium ions and was shown to possess high catalytic activity and enantioselectivity. Preparative-scale synthesis of the alkaloid (R)-coniine (90 % yield; 99 % ee) from the imine precursor was performed on a gram-scale. A homology model of the enzyme active site, based on the structure of a closely related (R)-IRED from Streptomyces kanamyceticus, was constructed and used to identify potential amino acids as targets for
- Hussain, Shahed,Leipold, Friedemann,Man, Henry,Wells, Elizabeth,France, Scott P.,Mulholland, Keith R.,Grogan, Gideon,Turner, Nicholas J.
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p. 579 - 583
(2015/03/05)
-
- Mass Spectrometric Screening of Racemic Amine Catalysts for Enantioselective Michael Additions
-
In extension of a concept of Lloyd-Jones, based on the combination of a racemic catalyst with a scalemic substrate, we have recently developed a method for determining the enantioselectivity of a chiral catalyst from its racemic form by mass spectrometric screening of a non-equal mixture of two mass-labeled quasi-enantiomeric substrates. After an initial proof of principle using palladium-catalyzed allylic substitution as test reaction, we report now the successful application of this approach to the screening of chiral amines as catalysts for the enantioselective Michael addition to α,β-unsaturated aldehydes. The results confirm that our method allows fast and reliable evaluation of chiral racemic catalysts. This opens up new possibilities for investigating catalyst structures that are not easily available in enantiomerically pure form.
- B?chle, Florian,Fleischer, Ivana,Pfaltz, Andreas
-
supporting information
p. 2247 - 2254
(2015/07/27)
-
- 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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- 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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- Asymmetric reduction of cyclic imines catalyzed by a whole-cell biocatalyst containing an (S)-imine reductase
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Biocatalytic imine reduction: A whole-cell recombinant E. coli system, producing an (S)-selective imine reductase (IRED) from Streptomyces sp. GF3546, is developed. This biocatalyst is used for the enantioselective reduction of a broad range of substrates such as dihydroisoquinolines and dihydro-β- carbolines as well as iminium ions. Copyright
- Leipold, Friedemann,Hussain, Shahed,Ghislieri, Diego,Turner, Nicholas J.
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p. 3505 - 3508
(2014/01/06)
-
- Highly enantioselective synthesis of chiral allenes by sequential creation of stereogenic center and chirality transfer in a single pot operation
-
Chiral allenes are readily accessed in a single pot operation in the reaction of terminal alkynes, aldehydes, chiral secondary amines, and zinc halides in good yields (up to 77% yield) and excellent enantioselectivities (up to 99% ee) in toluene at 120 °C. The reaction proceeds through initial formation of chiral propargylamine intermediates with creation of a new stereogenic center and subsequent chirality transfer via an intramolecular hydride shift to produce chiral allenes with high enantiomeric purities.
- Periasamy, Mariappan,Sanjeevakumar, Nalluri,Dalai, Manasi,Gurubrahamam, Ramani,Reddy, Polimera Obula
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p. 2932 - 2935
(2012/08/28)
-
- Highly stereoselective double (R)-phenylglycinol-induced cyclocondensation reactions of symmetric aryl bis(oxoacids)
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The double cyclocondensation of symmetric pyridyl bis(oxoacids) 2b and 3b with (R)-phenylglycinol stereoselectively gave access to bis-phenylglycinol- derived oxazolopyrrolidine 9 and oxazolopiperidone 10, respectively. Application of the stereocontrolled
- Amat, Mercedes,Arroniz, Carlos,Molins, Elies,Escolano, Carmen,Bosch, Joan
-
p. 2175 - 2184
(2011/05/08)
-
- Development of an asymmetric trimethylenemethane cycloaddition reaction: Application in the enantioselective synthesis of highly substituted carbocycles
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A protocol for the enantioselective [3+2] cycloaddition of trimethylenemethane (TMM) with electron-deficient olefins has been developed. The synthesis of novel phosphoramidite ligands was critical in this effort, and the preparation and reactivity of these ligands is detailed. The evolution of the ligand design, commencing with acyclic amine-derived phosphoramidites and leading to cyclic pyrrolidine and azetidine structures, is discussed. The conditions developed to effect an asymmetric TMM reaction using 2-trimethylsilylmethyl allyl acetate were shown to be tolerant of a wide variety of alkene acceptors, providing the desired methylenecyclopentanes with high levels of enantioselectivity. The donor scope was also explored, and substituted systems were tolerated, including one bearing a nitrile moiety. These donors were reactive with unsaturated acylpyrroles, giving the product cyclopentane rings bearing three stereocenters in high enantioselectivity and complete diastereoselectivity.
- Trost, Barry M.,Silverman, Steven M.,Stambuli, James P.
-
supporting information; experimental part
p. 19483 - 19497
(2012/01/06)
-
- Nicotinic pharmacophore: The pyridine N of nicotine and carbonyl of acetylcholine hydrogen bond across a subunit interface to a backbone NH
-
Pharmacophore models for nicotinic agonists have been proposed for four decades. Central to these models is the presence of a cationic nitrogen and a hydrogen bond acceptor. It is now well-established that the cationic center makes an important cation-π interaction to a conserved tryptophan, but the donor to the proposed hydrogen bond acceptor has been more challenging to identify. A structure of nicotine bound to the acetylcholine binding protein predicted that the binding partner of the pharmacophore's second component was a water molecule, which also hydrogen bonds to the backbone of the complementary subunit of the receptors. Here we use unnatural amino acid mutagenesis coupled with agonist analogs to examine whether such a hydrogen bond is functionally significant in the α4β2 neuronal nAChR, the receptor most associated with nicotine addiction. We find evidence for the hydrogen bond with the agonists nicotine, acetylcholine, carbamylcholine, and epibatidine. These data represent a completed nicotinic pharmacophore and offer insight into the design of new therapeutic agents that selectively target these receptors.
- Blum, Angela P.,Lester, Henry A.,Dougherty, Dennis A.
-
experimental part
p. 13206 - 13211
(2011/01/03)
-
- Asymmetric synthesis of 2-arylpyrrolidines starting from γ-chloro N-(tert-butanesulfinyl)ketimines
-
The enantioselective reductive cyclization of γ-chloro N-(tert-butanesulfinyl)ketimines towards the short and efficient synthesis of (S)- and (R)-2-arylpyrrolidines (ee >99%) is described for the first time by treatment with LiBEt3H and subsequ
- Leemans, Erika,Mangelinckx, Sven,De Kimpe, Norbert
-
scheme or table
p. 3122 - 3124
(2010/09/04)
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- Asymmetric synthesis of 2-substituted pyrrolidines by addition of Grignard reagents to γ-chlorinated N-tert-butanesulfinyl imine
-
A highly diastereoselective addition of various Grignard reagents to chiral γ-chlorinated N-tert-butanesulfinyl imine resulting in the formation of 2-substituted pyrrolidines is reported. This method is general and also efficient for the preparation of both enantiomers of 2-aryl, 2-alkyl and 2-vinyl substituted pyrrolidines in high yields.
- Reddy, Leleti Rajender,Prashad, Mahavir
-
supporting information; experimental part
p. 222 - 224
(2010/05/01)
-
- Enantioselective syntheses of 2-substituted pyrrolidines from allylamines by domino hydroformylation-condensation: Short syntheses of (S)-nicotine and the alkaloid 225C
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Short routes to chiral 2-substituted pyrrolidines based on rhodium-catalyzed hydroformylations of allylamines and their N-alkyl and N-acyl derivatives, which were prepared by asymmetric allylic substitutions, are described. The outcome of the hydroformyla
- Dübon, Pierre,Farwick, Andreas,Helmchen, Günter
-
scheme or table
p. 1413 - 1416
(2009/10/23)
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- A chemo-enzymatic route to enantiomerically pure cyclic tertiary amines
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Deracemization of racemic chiral tertiary amines has been achieved by combination of an enantioselective amine oxidase, obtained through directed evolution, and ammonia borane in a one-pot process. Copyright
- Dunsmore, Colin J.,Carr, Reuben,Fleming, Toni,Turner, Nicholas J.
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p. 2224 - 2225
(2007/10/03)
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- An efficient and practical chemoenzymatic preparation of optically active secondary amines
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(Chemical Equation Presented) An efficient and practical chemoenzymatic method was developed for the preparation of a variety of chiral secondary amines. Here, oxalamic esters were identified as unique derivatives amenable to the enzyme-catalyzed kinetic resolution of racemic secondary amines. Both enantiomers of the amines were produced in high optical purity and yields after the cleavage of the oxalamic groups.
- Hu, Shanghui,Tat, David,Martinez, Carlos A.,Yazbeck, Daniel R.,Tao, Junhua
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p. 4329 - 4331
(2007/10/03)
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- A rapid and general method for the asymmetric synthesis of 2-substituted pyrrolidines using tert-butanesulfinamide
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A new method for the asymmetric synthesis of 2-substituted pyrrolidines in three steps from commercially available starting materials is described. Addition of the Grignard reagent prepared from 2-(2-bromoethyl)-1,3-dioxane to N-tert-butanesulfinyl aldimines proceeds in high yields and with good diastereoselectivities. The sulfinamide products are then cleanly converted into pyrrolidines in one step. The Royal Society of Chemistry 2005.
- Brinner, Kristin M.,Ellman, Jonathan A.
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p. 2109 - 2113
(2007/10/03)
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- Asymmetric alkyldifluoroboranes and their use in secondary amine synthesis
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(matrix presented) Asymmetric diol boronic esters with potassium bifluoride form the corresponding alkyltrifluoroborate and free diol under mild conditions. Defluoridation with tetrachlorosilane produces an alkyldifluoroborane intermediate. This conversio
- Matteson, Donald S.,Kim, Gyung Youn
-
p. 2153 - 2155
(2007/10/03)
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- Synthesis of enantiopure pyrrolidine and piperidine derivatives via ring closing metathesis
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The additions of lithiated allylsulfone carbanion to chiral N-sulfinylimines were found to proceed with good to excellent selectivity. The resulting intermediates 4a-d after transformation to dienylamides 7a-d and 16a-d, were converted to functionalized enantiopure piperidines and pyrrolines, respectively, via ring closing metathesis (RCM). (C) 2000 Elsevier Science Ltd.
- Kumareswaran,Balasubramanian,Hassner
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p. 8157 - 8162
(2007/10/03)
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- Asymmetric thermal transformation, a new way to enantiopure biphenyl- bridged titanocene and zirconocene complexes: Efficient catalysts for asymmetric imine hydrogenation
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Enantiopure biphenyl-bridged titanocene and zirconocene complexes were obtained, by an asymmetric thermal transformation of the binaphthol complexes formed from the metallocene racemates and subsequent transformation to the corresponding dichlorides, in practically quantitative yields. Increased rates of this transformation in the presence of O2 gas or TEMPO indicate a radical reaction mechanism. The biphenyl-bridged titanocene enantiomers give rise to an efficient asymmetric catalysis for the hydrogenation of cyclic and noncyclic imines.
- Ringwald, Markus,Stürmer, Rainer,Brintzinger, Hans H.
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p. 1524 - 1527
(2007/10/03)
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- Asymmetric deprotonation by BuLi/(-)-sparteine: Convenient and highly enantioselective syntheses of (S)-2-aryl-Boc-pyrrolidines
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Highly enantioselective syntheses of (S)-2-aryl-Boc-pyrrolidines (Boc = tert-butoxycarbonyl) can be achieved by treatment of the corresponding (arylmethyl)(3-chloropropyl)-Boc-amines with s-BuLi/(-)-sparteine. The reactions are solvent dependent with the phenyl, p-chlorophenyl, p-fluorophenyl, p-methylphenyl, m-methoxyphenyl, 1-naphthyl, and 2-naphthyl derivatives 1-7- providing 11-17 in yields of 46-75% with enantiomeric excesses of 84-96% in toluene. The 2-thienyl and 3-furyl analogs 8 and 9 afford the (S)-2-heteroaryl-Boc-pyrrolidines 18 and 19 in 51 and 21% yields with 93-96% enantiomeric excesses. The p-methoxyphenyl derivative 10 gives 20 as a racemic product in 42% yield under the same conditions. Reactions of n-BuLi/(-)-sparteine with 1 and 8 give results comparable to those with s-BuLi/(-)-sparteine. Illustrative syntheses of (S)-2-phenyl-(S)-5-methyl-Boc-pyrrolidine (22) and 1,2-(bis-(S)-2-phenylpyrrolindyl)ethane (23) are reported. The mechanism of the reaction is shown to be an asymmetric deprotonation of 1 to give an enantioenriched organolithium intermediate (S)-24 which undergoes cyclization faster than racemization.
- Wu,Lee,Beak
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p. 715 - 721
(2007/10/03)
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- Baker's yeast reduction of prochiral γ-nitroketones: Enantioselective synthesis of (S)-4-nitroalcohols
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The baker's yeast reduction of seven different prochiral nitroketones 1a-g occurred on the re face of the carbonyl group, thus affording the (S)-nitroalcohols 2a-g, with different level of enantioselectivity (e.e. 15-99%). The best results (e.e. = 99%) we
- Guarna, Antonio,Occhiato, Ernesto G.,Spinetti, Laura M.,Vallecchi, Maria E.,Scarpi, Dina
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p. 1775 - 1788
(2007/10/02)
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- Diastereoselective addition of chiral imines and 1,3-oxazolidines with Grignard reagents; asymmetric synthesis of (R)-2-aryl- and (R,R)-2,5-bis(aryl)pyrrolidines
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Asymmetric syntheses of (R)-2-aryl- and (R,R)-2,5-bis(aryl)pyrrolidines were described starting from chiral aromatic imines derived from (R)-phenylglycinol, in which the diastereoselective additions of Grignard reagents to the chiral imines and 1,3-oxazol
- Higashiyama, Kimio,Inoue, Hiroaki,Takahashi, Hiroshi
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p. 1083 - 1092
(2007/10/02)
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- Catalytic asymmetric hydrogenation of imines with a chiral titanocene catalyst: Scope and limitations
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The asymmetric hydrogenation of imines with a chiral titanocene catalyst derived from Brintzinger's ansatitanocene complex 1 proceeds to afford amines with good to excellent enantioselectivity. The catalyst is particularly effective for the reduction of cyclic imines. For these substrates enantiomeric excesses from 95 to 99% were achieved. For acyclic imines lower enantiomeric excesses were observed. The reason for this is likely due to the fact that the acyclic imines are mixtures of anti and syn isomers which interconvert during the reaction. The catalyst was found to be tolerant of many functional groups found in organic synthesis. Thus the reaction represents an effective method for the synthesis of chiral cyclic amines.
- Willoughby, Christopher A.,Buchwald, Stephen L.
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p. 8952 - 8965
(2007/10/02)
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- Catalytic asymmetric hydrogenation of imines with a chiral titanocene catalyst: Kinetic and mechanistic investigations
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A kinetic study of the asymmetric titanocene-catalyzed imine hydrogenation has revealed the rate law to be rate = kobs[Ti][H2], for cyclic imine 2 and acyclic imine 4. This rate law is consistent with a mechanism in which the imine r
- Willoughby, Christopher A.,Buchwald, Stephen L.
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p. 11703 - 11714
(2007/10/02)
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- Reductiv Amination of 1,4- and 1,5-Dicarbonyl Compounds with (S)-Valine Methyl Ester. Synthesis of (S)-2-Phenylpyrrolidine and (S)-2-Phenylpiperidine
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The reductive amination of 4-phenyl-4-oxobutanal and 5-phenyl-5-oxopentanal with (S)-valine methyl ester and sodium cyanoborohydride afforded the N-substituted (S)-2-phenylpyrrolidine (88percent d. e.) and (S)-2-phenylpiperidine (96percent d.e.), from whi
- Manescalchi, Francesco,Nardi, Anna R.,Savoia, Diego
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p. 2775 - 2778
(2007/10/02)
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- Synthesis of Highly Enantiomerically Enriched Cyclic Amines by the Catalytic Asymmetric Hydrogenation of Cyclic Imines
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The asymmetric hydrogenation of cyclic ketimines with a chiral titanocene catalyst affords amines with excellent enantioselectivity under a variety of conditions.The reaction is general for cyclic imines of ring size 5-7 and exhibits a high degree of functional group compatibility.
- Willoughby, Christopher A.,Buchwald, Stephen L.
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p. 7627 - 7629
(2007/10/02)
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- A Simple Asymmetric Synthesis of 2-Substituted Pyrrolidines and 5-Substituted Pyrrolidinones
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An efficient procedure for the preparation of the title compounds in high enantiomeric purity has been realized starting from 3-acylpropionic acids.Stereoselective reduction of chiral bicyclic lactams 2a-h, prepared from the corresponding γ-keto acid and
- Burgess, Laurence E.,Meyers, A. I.
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p. 1656 - 1662
(2007/10/02)
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- A Simple Asymmetric Synthesis of 2-Substituted Pyrrolidines from 3-Acylpropionic Acids
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The title compounds have been prepared from 3-acylpropionic acids 2 and (-)-R-phenylglycinol in a three-step sequence in >98percent enantiomeric excess.The R group in 2 ultimately becomes the 2-substituent in the chiral pyrrolidine.
- Meyers, A. I.,Burgess, Laurence E.
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p. 2294 - 2296
(2007/10/02)
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