- Stereo-Divergent Enzyme Cascades to Convert Racemic 4-Phenyl-2-Butanol into either (S)- or (R)-Corresponding Chiral Amine
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The synthesis of enantiopure chiral amines from racemic alcohols is a key transformation in the chemical industry, e. g., in the production of active pharmaceutical ingredients (APIs). However, this reaction remains challenging. In this work, we propose a one-pot enzymatic cascade for the direct conversion of a racemic alcohol into either (S)- or (R)-enantiomers of the corresponding amine, with in-situ cofactor recycling. This enzymatic cascade consists of two enantio-complementary alcohol dehydrogenases, both NADH and NADPH oxidase for in-situ recycling of NAD(P)+ cofactors, and either (S)- or (R)-enantioselective transaminase. This cell-free biocatalytic system has been successfully applied to the conversion of racemic 4-phenyl-2-butanol into the high value (S)- or (R)-enantiomers of the amine reaching good (73 % (S)) and excellent (>99 % (R)) enantioselectivities.
- Paradisi, Francesca,Romero-Fernandez, Maria
-
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- Iterative Alanine Scanning Mutagenesis Confers Aromatic Ketone Specificity and Activity of L-Amine Dehydrogenases
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Direct reductive amination of prochiral ketones catalyzed by amine dehydrogenases is attractive in the synthesis of active pharmaceutical ingredients. Here, we report the protein engineering of L-Bacillus cereus amine dehydrogenase to allow reactivity on synthetically useful aromatic ketone substrates using an iterative, multiple-site alanine scanning mutagenesis approach. Mutagenesis libraries based on molecular docking, iterative alanine scanning, and double-proximity filter approach significantly expand the scope of active pharmaceutical ingredients relevant building blocks. The eventual quintuple mutant (A115G/T136A/L42A/V296A/V293A) showed reactivity toward aromatic ketones 12 a (5-phenyl-pentan-2-one) and 13 a (6-phenyl-hexan-2-one), which have not been reported to serve as targets of reductive amination by currently available amine dehydrogenases. Docking simulation and tunnel analysis provided valuable insights into the source of the acquired specificity and activity.
- Mu, Xiaoqing,Wu, Tao,Mao, Yong,Zhao, Yilei,Xu, Yan,Nie, Yao
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p. 5243 - 5253
(2021/11/16)
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- Simultaneous Preparation of (S)-2-Aminobutane and d -Alanine or d -Homoalanine via Biocatalytic Transamination at High Substrate Concentration
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(S)-2-Aminobutane, d-alanine, and d-homoalanine are important intermediates for the production of various active pharmaceutical ingredients and food additives. The preparation of these small chiral amine or amino acids with high water solubility still demands searching for efficient methods. In this work, we identified an ω-transaminase (ω-TA) from Sinirhodobacter hungdaonensis (ShdTA) that catalyzed the kinetic resolution of racemic 2-aminobutane at a concentration of 800 mM using pyruvate as the amino acceptor, leading to the simultaneous isolation of enantiopure (S)-2-aminobutane and d-alanine in 46% and 90% yield, respectively. In addition, (S)-2-aminobutane (98% ee) and d-homoalanine (99% ee) were isolated in 45% and 93% yield, respectively, in the kinetic resolution of racemic 2-aminobutane at a concentration of 400 mM coupled with deamination of l-threonine by threonine deaminase. We thus developed a biocatalytic process for the practical synthesis of these valuable small chiral amine and d-amino acids.
- Li, Jianjiong,Wang, Yingang,Wu, Qiaqing,Yao, Peiyuan,Yu, Shanshan,Zhu, Dunming
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supporting information
(2022/03/01)
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- Parallel interconnected kinetic asymmetric transformation (PIKAT) with an immobilized ω-transaminase in neat organic solvent
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Comprising approximately 40% of the commercially available optically active drugs, α-chiral amines are pivotal for pharmaceutical manufacture. In this context, the enzymatic asymmetric amination of ketones represents a more sustainable alternative than traditional chemical procedures for chiral amine synthesis. Notable advantages are higher atom-economy and selectivity, shorter synthesis routes, milder reaction conditions and the elimination of toxic catalysts. A parallel interconnected kinetic asymmetric transformation (PIKAT) is a cascade in which one or two enzymes use the same cofactor to convert two reagents into more useful products. Herein, we describe a PIKAT catalyzed by an immobilized ω-transaminase (ωTA) in neat toluene, which concurrently combines an asymmetric transamination of a ketone with an anti-parallel kinetic resolution of an amine racemate. The applicability of the PIKAT was tested on a set of prochiral ketones and racemic α-chiral amines in a 1:2 molar ratio, which yielded elevated conversions (up to >99%) and enantiomeric excess (ee, up to >99%) for the desired products. The progress of the conversion and ee was also monitored in a selected case. This is the first report of a PIKAT using an immobilized ωTA in a non-aqueous environment.
- B?hmer, Wesley,Koenekoop, Lucien,Mutti, Francesco G.,Simon, Timothée
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- Asymmetric synthesis of primary amines catalyzed by thermotolerant fungal reductive aminases
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Chiral primary amines are important intermediates in the synthesis of pharmaceutical compounds. Fungal reductive aminases (RedAms) are NADPH-dependent dehydrogenases that catalyse reductive amination of a range of ketones with short-chain primary amines supplied in an equimolar ratio to give corresponding secondary amines. Herein we describe structural and biochemical characterisation as well as synthetic applications of two RedAms fromNeosartoryaspp. (NfRedAm andNfisRedAm) that display a distinctive activity amongst fungal RedAms, namely a superior ability to use ammonia as the amine partner. Using these enzymes, we demonstrate the synthesis of a broad range of primary amines, with conversions up to >97% and excellent enantiomeric excess. Temperature dependent studies showed that these homologues also possess greater thermal stability compared to other enzymes within this family. Their synthetic applicability is further demonstrated by the production of several primary and secondary amines with turnover numbers (TN) up to 14 000 as well as continous flow reactions, obtaining chiral amines such as (R)-2-aminohexane in space time yields up to 8.1 g L?1h?1. The remarkable features ofNfRedAmand NfisRedAm highlight their potential for wider synthetic application as well as expanding the biocatalytic toolbox available for chiral amine synthesis.
- Cosgrove, Sebastian C.,Grogan, Gideon,Mangas-Sanchez, Juan,Marshall, James R.,Palmer, Ryan B.,Ramsden, Jeremy I.,Sharma, Mahima,Thorpe, Thomas W.,Turner, Nicholas J.
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p. 5052 - 5057
(2020/06/09)
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- Development of a: Corynebacterium glutamicum bio-factory for self-sufficient transaminase reactions
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The development of biocatalytic routes for the synthesis of chiral amines starting from achiral building blocks is highly desirable. Here, we report a self-sufficient whole-cell system for the conversion of a model ketone to the corresponding cyclic imine, in good isolated yield (42%) and excellent enantioselectivity (>99% ee). The Corynebacterium glutamicum host produces the transaminase biocatalyst, cofactor and 'smart' amine donor (cadaverine or putrescine) in vivo, and highlights the potential for producing high-value chemicals from readily available building blocks. The report represents the first example of the application of a metabolically engineered organism for the production of smart diamine donors and their application in a transaminase biotransformation.
- Grigoriou, Stylianos,Kugler, Pierre,Kulcinskaja, Evelina,Walter, Frederik,King, John,Hill, Phil,Wendisch, Volker F.,O'Reilly, Elaine,O'Reilly, Elaine
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supporting information
p. 4128 - 4132
(2020/07/30)
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- One-Pot Synthesis of Chiral N-Arylamines by Combining Biocatalytic Aminations with Buchwald–Hartwig N-Arylation
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The combination of biocatalysis and chemo-catalysis increasingly offers chemists access to more diverse chemical architectures. Here, we describe the combination of a toolbox of chiral-amine-producing biocatalysts with a Buchwald–Hartwig cross-coupling reaction, affording a variety of α-chiral aniline derivatives. The use of a surfactant allowed reactions to be performed sequentially in the same flask, preventing the palladium catalyst from being inhibited by the high concentrations of ammonia, salts, or buffers present in the aqueous media in most cases. The methodology was further extended by combining with a dual-enzyme biocatalytic hydrogen-borrowing cascade in one pot to allow for the conversion of a racemic alcohol to a chiral aniline.
- Ahmed, Syed T.,Cosgrove, Sebastian C.,Parmeggiani, Fabio,Thompson, Matthew P.,Turner, Nicholas J.
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supporting information
p. 18156 - 18160
(2020/08/13)
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- Development of an engineered thermostable amine dehydrogenase for the synthesis of structurally diverse chiral amines
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Amine dehydrogenases (AmDHs) are emerging as a class of attractive biocatalysts for synthesizing chiral amines via asymmetric reductive amination of ketones with inexpensive ammonia as an amino donor. However, the AmDHs developed to date exhibit limited substrate scope. Here, using directed evolution, we engineered a GkAmDH based on a thermostable phenylalanine dehydrogenase from Geobacillus kaustophilus. The newly developed AmDH is able to catalyze reductive amination of a diverse set of ketones and functionalized hydroxy ketones with ammonia or primary amines with up to >99% conversion, thus accessing structurally diverse chiral primary and secondary amines and chiral vicinal amino alcohols, with excellent enantioselectivity (up to >99% ee) and releasing water as the sole by-product.
- Chen, Fei-Fei,Chen, Qi,Liu, Lei,Wang, Dong-Hao,Wang, Zhi-Long,Xu, Jian-He,Zhang, Zhi-Jun,Zheng, Gao-Wei
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p. 2353 - 2358
(2020/05/13)
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- Multi-enzyme pyruvate removal system to enhance (: R)-selective reductive amination of ketones
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Biocatalytic transamination is widely used in industrial production of chiral chemicals. Here, we constructed a novel multi-enzyme system to promote the conversion of the amination reaction. Firstly, we constructed the ArR-ωTA/TdcE/FDH/LDH multi-enzyme system, by combination of (R)-selective ω-transaminase derived from Arthrobacter sp. (ArR-ωTA), formate dehydrogenase (FDH) derived from Candida boidinii, formate acetyltransferase (TdcE) and lactate dehydrogenase (LDH) derived from E. coli MG1655. This multi-enzyme system was used to efficiently remove the by-product pyruvate by TdcE and LDH to facilitate the transamination reaction. The TdcE/FDH pathway was found to dominate the by-product pyruvate removal in the transamination reaction. Secondly, we optimized the reaction conditions, including d-alanine, DMSO, and pyridoxal phosphate (PLP) with different concentration of 2-pentanone (as a model substrate). Thirdly, by using the ArR-ωTA/TdcE/FDH/LDH system, the conversions of 2-pentanone, 4-phenyl-2-butanone and cyclohexanone were 84.5%, 98.2% and 79.3%, respectively.
- Li, Chao,Song, Hao,Zhang, Jinhua,Zhao, Yanshu
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p. 28984 - 28991
(2020/08/25)
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- An Ammonium-Formate-Driven Trienzymatic Cascade for ω-Transaminase-Catalyzed (R)-Selective Amination
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(R)-Amination mediated by (R)-specific ω-transaminases generally requires costly d-alanine in excess to obtain the desired chiral amines in high yield. Herein, a one-pot, trienzymatic cascade comprising an (R)-specific ω-transaminase, an amine dehydrogenase, and a formate dehydrogenase was developed for the economical and eco-friendly synthesis of (R)-chiral amines. Using inexpensive ammonium formate as the sole sacrificial agent, the established cascade system enabled efficient ω-transaminase-mediated (R)-amination of various ketones, with high conversions and excellent ee (>99%); water and CO2 were the only waste products.
- Chen, Fei-Fei,Liu, Lei,Wu, Jian-Ping,Xu, Jian-He,Zhang, Yu-Hui,Zhang, Zhi-Jun,Zheng, Gao-Wei
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p. 14987 - 14993
(2019/12/02)
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- Deracemization of Racemic Amines to Enantiopure (R)- and (S)-amines by Biocatalytic Cascade Employing ω-Transaminase and Amine Dehydrogenase
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A one-pot deracemization strategy for α-chiral amines is reported involving an enantioselective deamination to the corresponding ketone followed by a stereoselective amination by enantiocomplementary biocatalysts. Notably, this cascade employing a ω-transaminase and amine dehydrogenase enabled the access to both (R)-and (S)-amine products, just by controlling the directions of the reactions catalyzed by them. A wide range of (R)-and (S)-amines was obtained with excellent conversions (>80 %) and enantiomeric excess (>99 % ee). Finally, preparative scale syntheses led to obtain enantiopure (R)- and (S)-13 with the isolated yields of 53 and 75 %, respectively.
- Yoon, Sanghan,Patil, Mahesh D.,Sarak, Sharad,Jeon, Hyunwoo,Kim, Geon-Hee,Khobragade, Taresh P.,Sung, Sihyong,Yun, Hyungdon
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p. 1898 - 1902
(2019/02/27)
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- Amine Transaminase from Exophiala Xenobiotica - Crystal Structure and Engineering of a Fold IV Transaminase that Naturally Converts Biaryl Ketones
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Amine transaminases are frequently used for the production of chiral amines starting from prochiral ketones. These amines can be applied as active pharmaceutical ingredients or drug precursors. However, there are still limitations to the use of amine transaminases when it comes to bulky ketone substrates, such as biaryl ketones. Using data mining, an (R)-selective amine transaminase from Exophiala xenobiotica was identified which naturally converts biaryl ketone substrates to the corresponding amines with up to 85% conversion and excellent enantioselectivity (>99% ee). Its protein crystal structure was obtained with a resolution of 1.52 ?, which enabled us to explain this interesting substrate acceptance. Structure-guided protein engineering resulted in a quintuple variant with increased stability. Moreover, the amino acid exchange T273S increased the activity and broadened the substrate scope, enabling conversions of various biaryl ketones with up to >99%. A preparative biotransformation of 1-(4-(pyridin-3-yl)phenyl)ethenone at 75 mM (15 g/L) resulted in 96% of isolated yield of the respective amine.
- Telzerow, Aline,Paris, Juraj,H?kansson, Maria,González-Sabín, Javier,Ríos-Lombardía, Nicolás,Schürmann, Martin,Gr?ger, Harald,Morís, Francisco,Kourist, Robert,Schwab, Helmut,Steiner, Kerstin
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p. 1140 - 1148
(2019/01/21)
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- One-Pot Transformation of Ketoximes into Optically Active Alcohols and Amines by Sequential Action of Laccases and Ketoreductases or ω-Transaminases
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An enzymatic one-pot process for asymmetric transformation of prochiral ketoximes into alcohols or amines was developed by sequential coupling of a laccase-catalyzed deoximation either with a ketone reduction (ketoreductase, KRED) or bioamination (ω-transaminase, ω-TA) in aqueous medium. An accurate selection of biocatalysts provided the corresponding products in excellent enantiomeric excesses and overall conversions ranging from 83 to >99 % for alcohols and 70 to >99 % for amines. Likewise, the employment of exclusively 1 % (w/w) of Cremophor, a polyethoxylated castor oil, as co-solvent enabled to reach concentrations up to 100 mM in the chiral alcohols cascade.
- Correia Cordeiro, Raquel S.,Ríos-Lombardía, Nicolás,Morís, Francisco,Kourist, Robert,González-Sabín, Javier
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p. 1272 - 1277
(2019/01/24)
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- Upgraded Bioelectrocatalytic N2 Fixation: From N2 to Chiral Amine Intermediates
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Enantiomerically pure chiral amines are of increasing value in the preparation of bioactive compounds, pharmaceuticals, and agrochemicals. ω-Transaminase (ω-TA) is an ideal catalyst for asymmetric amination because of its excellent enantioselectivity and wide substrate scope. To shift the equilibrium of reactions catalyzed by ω-TA to the side of the amine product, an upgraded N2 fixation system based on bioelectrocatalysis was developed to realize the conversion from N2 to chiral amine intermediates. The produced NH3 was in situ reacted with l-alanine dehydrogenase to generate alanine with NADH as a coenzyme. ω-TA transferred the amino group from alanine to ketone substrates and finally produced the desired chiral amine intermediates. The cathode of the upgraded N2 fixation system supplied enough reducing power to synchronously realize the regeneration of reduced methyl viologen (MV?+) and NADH for the nitrogenase and l-alanine dehydrogenase. The coproduct, pyruvate, was consumed by l-alanine dehydrogenase to regenerate alanine and push the equilibrium to the side of amine. After 10 h of reaction, the concentration of 1-methyl-3-phenylpropylamine achieved 0.54 mM with the 27.6% highest faradaic efficiency and >99% enantiomeric excess (eep). Because of the wide substrate scope and excellent enantioselectivity of ω-TA, the upgraded N2 fixation system has great potential to produce a variety of chiral amine intermediates for pharmaceuticals and other applications.
- Chen, Hui,Cai, Rong,Patel, Janki,Dong, Fangyuan,Chen, Hsiaonung,Minteer, Shelley D.
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p. 4963 - 4971
(2019/03/26)
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- Transaminase-Catalyzed Racemization with Potential for Dynamic Kinetic Resolutions
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Dynamic kinetic resolution (DKR) reactions in which a stereoselective enzyme and a racemization step are coupled in one pot would represent powerful tools for the production of enantiopure amines through enantioconvergence of racemates. The exploitation of DKR strategies is currently hampered by the lack of effective, enzyme-compatible and scalable racemization strategies for amines. In the present work, the proof of concept of a fully biocatalytic method for amine racemization is presented. Both enantiomers of the model compound 1-methyl-3-phenylpropylamine could be racemized in water and at room temperature using a couple of wild-type, non-proprietary, enantiocomplementary amine transaminases and a minimum amount of pyruvate/alanine as a co-substrate couple. The biocatalytic simultaneous parallel cascade reaction presented here poses itself as a customizable amine racemization system with potential for the chemical industry in competition with traditional transition-metal catalysis.
- Ruggieri, Federica,van Langen, Luuk M.,Logan, Derek T.,Walse, Bj?rn,Berglund, Per
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p. 5026 - 5032
(2018/10/20)
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- Co-immobilized Whole Cells with ω-Transaminase and Ketoreductase Activities for Continuous-Flow Cascade Reactions
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An improved sol–gel process involving the use of hollow silica microspheres as a supporting additive was applied for the co-immobilization of whole cells of Escherichia coli with Chromobacterium violaceum ω-transaminase activity and Lodderomyces elongisporus with ketoreductase activity. The co-immobilized cells with two different biocatalytic activities could perform a cascade of reactions to convert racemic 4-phenylbutan-2-amine or heptan-2-amine into a nearly equimolar mixture of the corresponding enantiomerically pure R amine and S alcohol even in continuous-flow mode. The novel co-immobilized whole-cell system proved to be an easy-to-store and durable biocatalyst.
- Nagy-Gy?r, László,Abaházi, Emese,Bódai, Viktória,Sátorhelyi, Péter,Erdélyi, Balázs,Balogh-Weiser, Diána,Paizs, Csaba,Hornyánszky, Gábor,Poppe, László
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p. 1845 - 1848
(2018/09/10)
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- n-Butylamine as an alternative amine donor for the stereoselective biocatalytic transamination of ketones
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Formal reductive amination has been a main focus of biocatalysis research in recent times. Among the enzymes able to perform this transformation, pyridoxal-5′-phosphate-dependent transaminases have shown the greatest promise in terms of extensive substrate scope and industrial application. Despite concerted research efforts in this area, there exist relatively few options regarding efficient amino donor co-substrates capable of allowing high conversion and atom efficiency with stable enzyme systems. Herein we describe the implementation of the recently described spuC gene, coding for a putrescine transaminase, exploiting its unusual amine donor tolerance to allow use of inexpensive and readily-available n-butylamine as an alternative to traditional methods. Via the integration of SpuC homologues with tandem co-product removal and cofactor regeneration enzymes, high conversion could be achieved with just 1.5 equivalents of the amine with products displaying excellent enantiopurity.
- Slabu, Iustina,Galman, James L.,Iglesias, Cesar,Weise, Nicholas J.,Lloyd, Richard C.,Turner, Nicholas J.
-
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- Two-Enzyme Hydrogen-Borrowing Amination of Alcohols Enabled by a Cofactor-Switched Alcohol Dehydrogenase
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The NADPH-dependent secondary alcohol dehydrogenase from Thermoanaerobacter ethanolicus (TeSADH), displaying broad substrate specificity and low enantioselectivity, was engineered to accept NADH as a cofactor. The engineered TeSADH showed a >10 000-fold switch from NADPH towards NADH compared to the wildtype enzyme. This TeSADH variant was applied to a biocatalytic hydrogen-borrowing system that employed catalytic amounts of NAD+, ammonia, and an amine dehydrogenase, which thereby enabled the conversion a range of alcohols into chiral amines.
- Thompson, Matthew P.,Turner, Nicholas J.
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p. 3833 - 3836
(2017/09/25)
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- Biocatalytic transamination with near-stoichiometric inexpensive amine donors mediated by bifunctional mono- and di-amine transaminases
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The discovery and characterisation of enzymes with both monoamine and diamine transaminase activity is reported, allowing conversion of a wide range of target ketone substrates with just a small excess of amine donor. The diamine co-substrates (putrescine, cadaverine or spermidine) are bio-derived and the enzyme system results in very little waste, making it a greener strategy for the production of valuable amine fine chemicals and pharmaceuticals.
- Galman, James L.,Slabu, Iustina,Weise, Nicholas J.,Iglesias, Cesar,Parmeggiani, Fabio,Lloyd, Richard C.,Turner, Nicholas J.
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supporting information
p. 361 - 366
(2017/08/14)
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- Vicinal Diamines as Smart Cosubstrates in the Transaminase-Catalyzed Asymmetric Amination of Ketones
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Transaminases (TAs) have recently been established as catalysts for the asymmetric, reductive amination of prochiral ketones. Depending on the ketone substrate and the amine donor (the cosubstrate), equilibrium constants may limit high conversions; thus, methods to overcome this limitation are required. Removal of the co-product from the reaction equilibrium through spontaneous, intramolecular reactions has provided a successful solution to this problem; therefore, these amine donors have been named “smart cosubstrates”. Here, we present a comparison of various bifunctional amine donors including vicinal diamines as potential structural cosubstrate motifs. Upon TA-catalyzed deamination of 1,2-diamines, spontaneous dimerization of the resulting α-aminoketones and oxidation gave heteroaromatic pyrazines.
- Payer, Stefan E.,Schrittwieser, Joerg H.,Kroutil, Wolfgang
-
supporting information
p. 2553 - 2559
(2017/05/12)
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- Coupled Immobilized Amine Dehydrogenase and Glucose Dehydrogenase for Asymmetric Synthesis of Amines by Reductive Amination with Cofactor Recycling
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The amine dehydrogenase (AmDH) engineered from the phenylalanine dehydrogenase of Rhodococcus sp. M4 was directly immobilized on magnetic nanoparticles (MNP) from the cell-free extract containing his-tagged AmDH through affinity attachment to give AmDH-MNPs with high yield, enzyme loading efficiency, and specific enzyme loading. AmDH-MNPs showed higher activity and productivity than the free enzyme for the asymmetric reductive amination of 4-phenyl-2-butanone 1 a and phenylacetone 1 b, producing the corresponding amines (R)-2 a,b in 99 % ee and 99 % yield, and with recycling of NADH for up to 3956 times. AmDH-MNPs were easily recycled, retaining 91 % of the original productivity in the third cycle of the reductive amination of 1 a. Coupling of immobilized AmDH and immobilized glucose dehydrogenase (GDH) for the asymmetric reductive amination of 1 a gave (R)-2 a in 99 % ee and 74 % yield, with a total turnover number (TTN) of 2940 for NADH recycling. Both immobilized enzymes showed good recyclability, retaining 81 % productivity in the third reaction cycle. The developed method with coupled immobilized AmDH and immobilized GDH for the asymmetric reductive amination of ketones is useful for the synthesis of enantiopure amines, superior to the use of coupled isolated enzymes with enhanced catalytic performance and reduced enzyme cost through catalyst recycling.
- Liu, Ji,Pang, Bryan Q. W.,Adams, Joseph P.,Snajdrova, Radka,Li, Zhi
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p. 425 - 431
(2017/02/15)
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- Amine dehydrogenases: Efficient biocatalysts for the reductive amination of carbonyl compounds
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Amines constitute the major targets for the production of a plethora of chemical compounds that have applications in the pharmaceutical, agrochemical and bulk chemical industries. However, the asymmetric synthesis of α-chiral amines with elevated catalytic efficiency and atom economy is still a very challenging synthetic problem. Here, we investigated the biocatalytic reductive amination of carbonyl compounds employing a rising class of enzymes for amine synthesis: amine dehydrogenases (AmDHs). The three AmDHs from this study-operating in tandem with a formate dehydrogenase from Candida boidinii (Cb-FDH) for the recycling of the nicotinamide coenzyme-performed the efficient amination of a range of diverse aromatic and aliphatic ketones and aldehydes with up to quantitative conversion and elevated turnover numbers (TONs). Moreover, the reductive amination of prochiral ketones proceeded with perfect stereoselectivity, always affording the (R)-configured amines with more than 99% enantiomeric excess. The most suitable amine dehydrogenase, the optimised catalyst loading and the required reaction time were determined for each substrate. The biocatalytic reductive amination with this dual-enzyme system (AmDH-Cb-FDH) possesses elevated atom efficiency as it utilizes the ammonium formate buffer as the source of both nitrogen and reducing equivalents. Inorganic carbonate is the sole by-product.
- Knaus, Tanja,B?hmer, Wesley,Mutti, Francesco G.
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supporting information
p. 453 - 463
(2017/08/14)
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- In vitro biocatalytic pathway design: Orthogonal network for the quantitative and stereospecific amination of alcohols
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The direct and efficient conversion of alcohols into amines is a pivotal transformation in chemistry. Here, we present an artificial, oxidation-reduction, biocatalytic network that employs five enzymes (alcohol dehydrogenase, NADP-oxidase, catalase, amine dehydrogenase and formate dehydrogenase) in two concurrent and orthogonal cycles. The NADP-dependent oxidative cycle converts a diverse range of aromatic and aliphatic alcohol substrates to the carbonyl compound intermediates, whereas the NAD-dependent reductive aminating cycle generates the related amine products with >99% enantiomeric excess (R) and up to >99% conversion. The elevated conversions stem from the favorable thermodynamic equilibrium (K′eq = 1.88 × 1042 and 1.48 × 1041 for the amination of primary and secondary alcohols, respectively). This biocatalytic network possesses elevated atom efficiency, since the reaction buffer (ammonium formate) is both the aminating agent and the source of reducing equivalents. Additionally, only dioxygen is needed, whereas water and carbonate are the by-products. For the oxidative step, we have employed three variants of the NADP-dependent alcohol dehydrogenase from Thermoanaerobacter ethanolicus and we have elucidated the origin of the stereoselective properties of these variants with the aid of in silico computational models.
- Knaus, Tanja,Cariati, Luca,Masman, Marcelo F,Mutti, Francesco G.
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p. 8313 - 8325
(2017/10/19)
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- Asymmetric catalysis of the carbonyl-amine condensation: Kinetic resolution of primary amines
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A Br?nsted acid catalyzed kinetic resolution of primary amines is described that is based on the condensation between an amine and a carbonyl compound. 1,3-Diketones react with racemic α-branched amines to furnish the corresponding enantioenriched enaminone and recovered starting material. Good to excellent enantioselectivity was observed with both aromatic and aliphatic primary amines. This process represents the first small-molecule catalyzed kinetic resolution of aliphatic amines.
- Das, Sayantani,Majumdar, Nilanjana,De, Chandra Kanta,Kundu, Dipti Sankar,Dohring, Arno,Garczynski, Anika,List, Benjamin
-
supporting information
p. 1357 - 1359
(2017/02/10)
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- Synthesis method of (R)-(-)-1-methyl-3-amphetamine
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The invention relates to a synthesis method of (R)-(-)-1-methyl-3-amphetamine (I), and mainly solves the technical problems of complexity and high cost in existing synthesis methods of (R)-(-)-1-methyl-3-amphetamine compounds. According to the technical scheme of the invention, synthesis of the (R)-(-)-1-methyl-3-amphetamine compound comprises: a first step of reaction, i.e. taking phenylpropyl aldehyde as the raw material, subjecting the raw material to lewis acid catalyzed condensation reaction in a solvent, and then carrying out reaction with triphenylmethylamine to obtain benzyl triphenyl methyl imine (II); and a second step of reaction, reacting the compound II with a Grignard reagent in a solvent to obtain (R)-(-)-1-methyl-3-amphetamine, which is shown as the specification.
- -
-
Paragraph 0024; 0025; 0026; 0027
(2016/11/17)
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- (R)- SELECTIVE AMINATION
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The present invention relates to a method for the enzymatic synthesis of enantiomerically enriched (R)-amines of general formula [1][c] from the corresponding ketones of the general formula [1][a] by using novel transaminases. These novel transaminases are selected from two different groups: either from a group of some 20 proteins with sequences as specified herein, or from a group of proteins having transaminase activity and isolated from a microorganism selected from the group of organisms consisting of Rahnella aquatilis, Ochrobactrum anthropi, Ochrobactrum tritici, Sinorhizobium morelense, Curtobacterium pusiffium, Paecilomyces lilacinus, Microbacterium ginsengisoli, Microbacterium trichothecenolyticum, Pseudomonas citronellolis, Yersinia kristensenii, Achromobacter spanius, Achromobacter insolitus, Mycobacterium fortuitum, Mycobacterium frederiksbergense, Mycobacterium sacrum, Mycobacterium fluoranthenivorans, Burkhoideria sp., Burkhoideria tropica, Cosmospora episphaeria, and Fusarium oxysporum.
- -
-
Paragraph 0120; 0121; 0122
(2016/03/22)
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- Conversion of alcohols to enantiopure amines through dual-enzyme hydrogen-borrowing cascades
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α-Chiral amines are key intermediates for the synthesis of a plethora of chemical compounds at industrial scale. We present a biocatalytic hydrogen-borrowing amination of primary and secondary alcohols that allows for the efficient and environmentally benign production of enantiopure amines. The method relies on a combination of two enzymes: an alcohol dehydrogenase (from Aromatoleum sp., Lactobacillus sp., or Bacillus sp.) operating in tandem with an amine dehydrogenase (engineered from Bacillus sp.) to aminate a structurally diverse range of aromatic and aliphatic alcohols, yielding up to 96% conversion and 99% enantiomeric excess. Primary alcohols were aminated with high conversion (up to 99%). This redox self-sufficient cascade possesses high atom efficiency, sourcing nitrogen from ammonium and generating water as the sole by-product.
- Mutti, Francesco G.,Knaus, Tanja,Scrutton, Nigel S.,Breuer, Michael,Turner, Nicholas J.
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p. 1525 - 1529
(2015/10/05)
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- Immobilisation of ω-transaminase for industrial application: Screening and characterisation of commercial ready to use enzyme carriers
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Despite of the advantages that enzyme immobilisation can bring to industrial biocatalysis, its utilisation is still limited to a small number of enzymes and processes. Transaminase catalysed processes are a good example where immobilisation can be of major importance and even decisive for economic feasibility. This work presents results obtained for screening of enzyme carriers for immobilisation of ω-transaminase for industrial application. A total of 6 commercial enzyme carriers (polymeric resins) were screened and two suitable enzyme carriers were selected for immobilisation of both (S)- and (R)-selective ω-transaminases. These carriers allowed the re-use of the immobilised enzyme for 8 cycles of 24 h each, under relevant process conditions, corresponding to approximately 250 h of operation, with more than 50% of the initial activity retained. Likewise the stability towards higher temperatures and possibility to store the biocatalyst for more than 70 days (at room temperature) were obtained as result of the immobilisation on the selected supports.
- Neto, Watson,Schürmann, Martin,Panella, Lavinia,Vogel, Andreas,Woodley, John M.
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- Mechanism-Guided Engineering of ω-Transaminase to Accelerate Reductive Amination of Ketones
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Asymmetric reductive amination of ketones using ω-transaminases (ω-TAs) offers a promising alternative to the chemocatalytic synthesis of chiral amines. One fundamental challenge to the biocatalytic strategy is the very low enzyme activities for most ketones compared with native substrates (i.e., cat/KM for acetophenone). The W58L mutant afforded an efficient synthesis of enantiopure amines (i.e., >99% ee) using isopropylamine as an amino donor.
- Han, Sang-Woo,Park, Eul-Soo,Dong, Joo-Young,Shin, Jong-Shik
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supporting information
p. 1732 - 1740
(2015/06/02)
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- Chiral amine synthesis using ω-transaminases: An amine donor that displaces equilibria and enables high-throughput screening
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The widespread application of ω-transaminases as biocatalysts for chiral amine synthesis has been hampered by fundamental challenges, including unfavorable equilibrium positions and product inhibition. Herein, an efficient process that allows reactions to proceed in high conversion in the absence of by-product removal using only one equivalent of a diamine donor (ortho-xylylenediamine) is reported. This operationally simple method is compatible with the most widely used (R)- and (S)-selective ω-TAs and is particularly suitable for the conversion of substrates with unfavorable equilibrium positions (e.g., 1-indanone). Significantly, spontaneous polymerization of the isoindole by-product generates colored derivatives, providing a high-throughput screening platform to identify desired ω-TA activity. ω-Transaminases (ω-TA) have been employed as biocatalysts in a simple and efficient process for the synthesis of chiral amines. A dual-function diamine donor (ortho-xylylenediamine) serves to displace challenging reaction equilibria towards product formation whilst generating intensely colored by-products, which have allowed the development of liquid-phase and colony-based assays.
- Green, Anthony P.,Turner, Nicholas J.,O'Reilly, Elaine
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supporting information
p. 10714 - 10717
(2015/05/13)
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- Engineering of amine dehydrogenase for asymmetric reductive amination of ketone by evolving Rhodococcus phenylalanine dehydrogenase
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Triple mutant K66Q/S149G/N262C (TM-pheDH) of Rhodococcus phenylalanine dehydrogenase (pheDH) was engineered by directed evolution as the first enzyme for the highly enantioselective reductive amination of phenylacetone 1 and 4-phenyl-2-butanone 3, giving (R)-amphetamine 2 and (R)-1-methyl-3-phenylpropylamine 4 in >98% ee, respectively. The new amine dehydrogenase TM-pheDH with special substrate specificity is a valuable addition to the amine dehydrogenase family with very limited number, for asymmetric reductive amination of ketone, an important reaction in sustainable pharmaceutical manufacturing. Molecular docking provided insight into the role of key mutations of pheDH, being useful for engineering new amine dehydrogenases with higher activity and unique substrate scope. (Chemical Equation Presented).
- Ye, Li Juan,Toh, Hui Hung,Yang, Yi,Adams, Joseph P.,Snajdrova, Radka,Li, Zhi
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p. 1119 - 1122
(2015/02/19)
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- Asymmetric Biocatalytic Amination of Ketones at the Expense of NH3 and Molecular Hydrogen
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A biocatalytic system is presented for the stereoselective amination of ketones at the expense of NH3 and molecular hydrogen. By using a NAD+-reducing hydrogenase, an alanine dehydrogenase, and a suitable ω-transaminase, the R- as well as the S-enantiomer of various amines could be prepared with up to >99% ee and 98% conversion. (Chemical Equation Presented).
- Holzer, Anja K.,Hiebler, Katharina,Mutti, Francesco G.,Simon, Robert C.,Lauterbach, Lars,Lenz, Oliver,Kroutil, Wolfgang
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supporting information
p. 2431 - 2433
(2015/06/02)
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- Substrate profile of an ω-transaminase from Burkholderia vietnamiensis and its potential for the production of optically pure amines and unnatural amino acids
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A new (S)-enantioselective ω-transaminase (ω-TA) gene from Burkholderia vietnamiensis G4 was functionally expressed in Escherichia coli BL21 (DE3), and the purified recombinant N-terminal His-tagged ω-TA (HBV-ω-TA) had a dimeric structure with optimum pH and temperature of 8.4 and 40 C, respectively. The enzyme showed higher activities toward aromatic amines than aliphatic amines and (S)-1-methylbenzylamine ((S)-α-MBA) was the most active amino donor. For amino acceptor, keto acids, keto esters and aldehydes were more reactive than ketones with pyruvate ethyl ester being most active. Several chiral amines and unnatural amino acids or esters were synthesized using HBV-ω-TA as the catalyst and isopropylamine or (S)-α-MBA as amino donor. Notably, HBV-ω-TA catalyzed the amino transfer to β-keto esters to give optically pure β-amino acid esters. In addition, glyoxylate was used as amino acceptor for the first time in the kinetic resolution of racemic amines and optically pure amines, such as (R)-1-methylbenzylamine, (R)-1-phenylpropylamine, (R)-2-amino-4-phenylbutane and (R)-1-aminotetraline, were obtained.
- Jiang, Jinju,Chen, Xi,Feng, Jinhui,Wu, Qiaqing,Zhu, Dunming
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- Artificial multi-enzyme networks for the asymmetric amination of sec-alcohols
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Various artificial network designs that involve biocatalysts were tested for the asymmetric amination of sec-alcohols to the corresponding α-chiral primary amines. The artificial systems tested involved three to five redox enzymes and were exemplary of a range of different sec-alcohol substrates. Alcohols were oxidised to the corresponding ketone by an alcohol dehydrogenase. The ketones were subsequently aminated by employing a ω-transaminase. Of special interest were redox-neutral designs in which the hydride abstracted in the oxidation step was reused in the amination step of the cascade. Under optimised conditions up to 91 % conversion of an alcohol to the amine was achieved. Trickle-down effect: The asymmetric amination of sec-alcohols to the corresponding α-chiral primary amines was performed with a biocatalytic cascade whereby the various steps were interconnected through the cofactors/cosubstrates. In a redox-neutral cascade and under optimised conditions, up to 91 % conversion of an alcohol to the amine was achieved. Copyright
- Tauber, Katharina,Fuchs, Michael,Sattler, Johann H.,Pitzer, Julia,Pressnitz, Desiree,Koszelewski, Dominik,Faber, Kurt,Pfeffer, Jan,Haas, Thomas,Kroutil, Wolfgang
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p. 4030 - 4035
(2013/04/10)
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- Step-efficient access to chiral primary amines
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Routes to enantioenriched amines are outlined that employ reductive amination and carbanion addition methods. The strategies require either one or two reaction steps from prochiral carbonyl compounds for the synthesis of the corresponding chiral primary amines. Georg Thieme Verlag Stuttgart New York.
- Nugent, Thomas C.,Marinova, Sofiya M.
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p. 153 - 166
(2013/02/25)
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- Investigation of one-enzyme systems in the ω-transaminase-catalyzed synthesis of chiral amines
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ω-Transaminase (TA) catalyzed asymmetric syntheses of amines were carried out in the one enzyme systems with wild-type enzymes (S)-TA from Pseudomonas aeruginosa, (S)-TA from Paracoccus denitrificans and (R)-TA from Aspergillus terreus. The scope of amine donors and aromatic carbonyl substrates was thoroughly explored. Among the range of potential amino donors, 2-propylamine, 2-butylamine and 1-phenylethylamine were found as promising candidates, which gave superior conversions in the amination reactions compared to other donors. Various prochiral aromatic ketones were accepted as substrates by the investigated enzymes. In most cases, good to excellent conversions (up to 98%) to the amine products with excellent e.e.-values (>99.9% for (S) or (R)) were obtained by the action of a single enzyme and an appropriate amino donor. (S)-TA from Paracoccus denitrificans was found to accept bulky ketones, e.g. 1-indanone, α- and β-tetralone or 2-acetonaphthone, in the asymmetric amination. In some cases the enantiomeric excesses in the amination reactions were dependent on the amino donor. More-over, the influence of the pH, temperature and cosolvents on the outcome of reactions was additionally investigated.
- Fesko, Kateryna,Steiner, Kerstin,Breinbauer, Rolf,Schwab, Helmut,Schuermann, Martin,Strohmeier, Gernot A.
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p. 103 - 110
(2013/10/22)
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- ω-Transaminase-catalyzed kinetic resolution of chiral amines using l-threonine as an amino acceptor precursor
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Kinetic resolution of chiral amines using l-threonine as a cosubstrate was demonstrated by a biocatalytic strategy in which (S)-selective ω-transaminase (ω-TA) was coupled with threonine deaminase (TD), eliminating the need to use an expensive keto acid as an amino acceptor. The coupled enzyme reaction enabled simultaneous production of enantiopure (R)-amine and l-homoalanine which are pharmaceutically important building blocks. To extend the versatility of this strategy to production of both enantiomers of chiral amines, (R)-selective ω-TA coupled with TD was employed to produce (S)-amine.
- Malik, M. Shaheer,Park, Eul-Soo,Shin, Jong-Shik
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supporting information; experimental part
p. 2137 - 2140
(2012/09/25)
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- N-octanoyldimethylglycine trifluoroethyl ester, an acyl donor leading to highly enantioselective protease-catalysed kinetic resolution of amines
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The use of N-octanoyldimethylglycine trifluoroethyl ester as acyl donor in the kinetic resolution of aliphatic amines catalysed by proteases led to enantiomeric ratios >200 in most cases. The resolutions mediated by Protex 6L were shown to be much faster
- Queyroy, Severine,Vanthuyne, Nicolas,Gastaldi, Stephane,Bertrand, Michele P.,Gil, Gerard
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supporting information; experimental part
p. 1759 - 1764
(2012/08/08)
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- Enantioselective organocatalytic reductive amination of aliphatic ketones by benzothiazoline as hydrogen donor
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The chiral phosphoric acid-catalyzed enantioselective reductive amination of aliphatic ketones with aromatic amines was successfully achieved by the use of benzothiazoline as the hydrogen donor. Corresponding chiral aliphatic amines were obtained with exc
- Saito, Kodai,Akiyama, Takahiko
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supporting information; experimental part
p. 4573 - 4575
(2012/06/15)
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- A versatile Ru catalyst for the asymmetric transfer hydrogenation of both aromatic and aliphatic sulfinylimines
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A highly efficient Ru catalyst based on an achiral, very simple, and inexpensive amino alcohol ligand (2-amino-2-methylpropan-1-ol) has been developed for the asymmetric transfer hydrogenation (ATH) of chiral N-(tert-butylsulfinyl)imines. This complex is able to catalyze the ATH of both aromatic and the most challenging aliphatic sulfinylimines by using isopropyl alcohol as the hydrogen source. The diastereoselective reduction of aromatic, heteroaromatic, and aliphatic sulfinylketimines, including sterically congested cases, over short reaction times (1-4 h), followed by desulfinylation of the nitrogen atom, affords the corresponding highly enantiomerically enriched (ee up to >99%) α-branched primary amines in excellent yields. The same ligand was equally effective for the synthesis of both (R)- and (S)-amines by using the appropriate absolute configuration in the iminic substrate. DFT mechanistic studies show that the hydrogen-transfer process is stepwise. Moreover, the origin of the diastereoselectivity has been rationalized.
- Pablo, Oscar,Guijarro, David,Kovacs, Gabor,Lledos, Agusti,Ujaque, Gregori,Yus, Miguel
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p. 1969 - 1983
(2012/03/26)
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- Amination of ketones by employing two new (S)-selective ω-transaminases and the his-tagged ω-TA from Vibrio fluvialis
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Two recently identified (S)-selective ω-transaminases (ω-TAs) that originate from Paracoccus denitrificans (Strep-PD-ωTA, cloned with an N-terminal Strep-tag II) and Pseudomonas fluorescens (PF-ωTA) were employed for the asymmetric amination of selected prochiral ketones. The substrates tested were transformed into optically pure amines (>99 % ee) with high conversion (up to >99 %). The ω-TAs led to higher conversion in the absence of dimethyl sulfoxide as a cosolvent than in its presence (15 %, v/v). Additionally, it was shown that a His-tagged recombinant transaminase from Vibrio fluvialis (His-VF-ωTA, cloned with an N-terminal His 6-tag) showed for a single substrate, ethyl acetoacetate, significantly higher stereoselectivity for the amination compared to the corresponding commercial enzyme preparation (>99 vs. 50 %). The (S)-selective ω-transaminases (ω-TAs) from Paracoccus denitrificans and Pseudomonas fluorescens transformed various ketones into optically pure amines (>99 % ee). These enzymes extend the substrate spectrum of highly (S)-stereoselective ω-TAs. Copyright
- Mutti, Francesco G.,Fuchs, Christine S.,Pressnitz, Desiree,Turrini, Nikolaus G.,Sattler, Johann H.,Lerchner, Alexandra,Skerra, Arne,Kroutil, Wolfgang
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experimental part
p. 1003 - 1007
(2012/04/04)
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- Asymmetric bio-amination of ketones in organic solvents
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ω-Transaminases, employed as a lyophilised crude cell-free extract, were successfully employed in organic solvent for the asymmetric amination of ketones without the need for immobilisation. Best activity was found for methyl tert-butyl ether (MTBE) at a water activity of 0.6. The ω-transaminases (9 different enzymes) accepted efficiently 2-propylamine as amine donor when used in the solvent, which is not the case when they are used in aqueous solution. The bio-amination in organic solvent showed several advantages such as higher reaction rates (up to 17-fold), general acceptance of 2-propylamine as amine donor, simple work-up procedure (i.e., no basification and extraction required), easy recycling of the catalyst and lack of substrate inhibition. The biocatalysts maintained their excellent stereoselectivity in MTBE allowing the preparation of optically pure amines (ee >99%) with up to >99% conversion.
- Mutti, Francesco G.,Kroutil, Wolfgang
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supporting information
p. 3409 - 3413
(2013/02/25)
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- Sequential reductive amination-hydrogenolysis: A one-pot synthesis of challenging chiral primary amines
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Difficult-to-access chiral primary amines were formed in good to high yield and ee using a rare example of a one-pot synthesis from prochiral ketones (sequential reductive amination-hydrogenloysis). As a highlight we also demonstrate a one-pot reductive amination-hydrogenolysis-reductive amination (five reactions) of ortho-methoxyacetophenone resulting in the chiral diamine 1-(2-methoxyphenyl)ethyl-(2-pyridylmethyl)-amine (4) (58% overall yield, >99% ee), a new organocatalyst for aqueous enantioselective aldol reactions. Copyright
- Nugent, Thomas C.,Negru, Daniela E.,El-Shazly, Mohamed,Hu, Dan,Sadiq, Abdul,Bibi, Ahtaram,Umar, M. Naveed
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p. 2085 - 2092
(2011/10/19)
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- Stereoselectivity of four (R)-selective transaminases for the asymmetric amination of ketones
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Four (R)-ω-transaminases originating from Hyphomonas neptunium (HN-ωTA), Aspergillus terreus (AT-ωTA) and Arthrobacter sp. (ArR-ωTA), as well as an evolved transaminase (ArRmut11-ωTA) were successfully employed for the amination of prochiral ketones leading to optically pure (R)-amines. The first three transaminases displayed perfect stereoselectivity for the amination of all substrates tested (ee >99%). Furthermore, the transaminase AT-ωTA led in most cases to better conversion than ArR-ωTA and HN-ωTA using D-alanine as amine donor. α-Tetralone, which was the only substrate not accepted by HN-ωTA, ArR-ωTA, and AT-ωTA, was successfully transformed with perfect enantioselectivity (ee >99%) into the corresponding optically pure amine employing the variant ArRmut11-ωTA. Copyright
- Mutti, Francesco G.,Fuchs, Christine S.,Pressnitz, Desiree,Sattler, Johann H.,Kroutil, Wolfgang
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experimental part
p. 3227 - 3233
(2012/01/03)
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- Enzymatic asymmetric synthesis of enantiomerically pure aliphatic, aromatic and arylaliphatic amines with (R)-selective amine transaminases
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Seven (R)-selective amine transaminases (R-ATAs) recently discovered by an in silico-based approach in sequence databases were produced recombinantly in Escherichia coli and subjected to partial purification by ammonium sulfate precipitation. A range of additives and various buffers were investigated to identify best conditions to ensure good storage stability and stable activity during biocatalysis. All enzymes show pH optima between pH 7.5-9. These R-ATAs were then applied in the asymmetric synthesis of twelve aliphatic, aromatic and arylaliphatic (R)-amines starting from the corresponding prochiral ketones using a lactate dehydrogenase/glucose dehydrogenase system to shift the equilibrium. For all ketones, at least one enzyme was found that allows complete conversion to the corresponding chiral amine having excellent optical purities >99% ee. Variations in substrate profiles are also discussed based on the phylogenetic relationships between the seven R-ATAs. Thus, we have identified a versatile toolbox of (R)-amine transaminases showing remarkable properties for application in biocatalysis. Copyright
- Schaetzle, Sebastian,Steffen-Munsberg, Fabian,Thontowi, Ahmad,Hoehne, Matthias,Robins, Karen,Bornscheuer, Uwe T.
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experimental part
p. 2439 - 2445
(2011/11/06)
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- METHODS FOR TREATING DISEASES ASSOCIATED WITH THE MODULATION OF SERCA
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Provided herein are compounds, compositions, and methods for treating or ameliorating diseases associated with the modulation of SERCA.
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Page/Page column 243-244
(2010/08/09)
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- Asymmetric intermolecular hydroamination of unactivated alkenes with simple amines
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A hard nut to crack: The asymmetric intermolecular Markovnikov addition of simple amines to unactivated alkenes can be achieved utilizing binaphtholate rare-earth-metal catalysts with up to 61% ee and 73% de in the case where R 2 contains a stereogenic center.
- Reznichenko, Alexander L.,Nguyen, Hiep N.,Hultzsch, Kai C.
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supporting information; experimental part
p. 8984 - 8987
(2011/02/21)
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- Switching from (R)- to (S)-selective chemoenzymatic DKR of amines involving sulfanyl radical-mediated racemization
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Chemoenzymatic dynamic kinetic resolution (DKR) of amines involving sulfanyl radical-induced racemization happened to be the very first switchable DKR process allowing the synthesis of either (R)- or (S)-amides, in good yield and high enantiomeric excess,
- El Blidi, Lahssen,Vanthuyne, Nicolas,Siri, Didier,Gastaldi, Stephane,Bertrand, Michele P.,Gil, Gerard
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supporting information; experimental part
p. 4165 - 4168
(2010/11/02)
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- Organocerium additions to proline-derived hydrazones: Synthesis of enantiomerically enriched amines
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The addition of organocerium reagents (from both organolithium and organomagnesium precursors) to chiral aldehyde hydrazones prepared from 1-aminoproline derivatives has been studied. The additions proceed in good yield and high diastereoselectivity and with good nucleophile (Me, n-Bu, i-Pr, t-Bu, Ph, etc.) and substrate scope (alkyl, alkenyl and aryl). The resulting hydrazines can be converted to amines by N-N bond cleavage through hydrogenolysis (Raney nickel) or by acylation and cleavage with Li/NH 3. The influence of the side chain on the diastereoselectivity was investigated through variation of the substituents to include more coordinating atoms (oxygen and nitrogen) as well as the removal of coordinating atoms. The SAMEMP auxiliary bearing a 2-methoxyethoxymethyl group gave the highest diastereoselectivities. Remarkably, auxiliaries bearing simple methyl and isobutyl substituents gave high selectivities as well. Hypotheses for the origin of the selectivity are presented.
- Denmark, Scott E.,Edwards, James P.,Weber, Theodor,Piotrowski, David W.
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experimental part
p. 1278 - 1302
(2010/11/02)
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