- Catalytic Behaviour of Optically Active Amino Alcohol-Borane Complex in the Enantioselective Reduction of Acetophenone Oxime O-Alkyl Ethers
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In the presence of the optically active amino alcohol-borane complex, an oxime ether was reduced with various hydride reducing agents to give a chiral primary amine of high optical purity.Catalytic use of the chiral complex was also investigated.
- Itsuno, Shinichi,Sakurai, Yoshiki,Ito, Koichi,Hirao, Akira,Nakahama, Seiichi
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- A new procedure for the synthesis of optically active t-butylphenylphosphinothioic acid
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A new procedure for the synthesis of optically active t-butylophenylphosphinothioic acid as an enantiomerically pure dextrorotatory enantiomer having the absolute configuration (R), by a reaction of the racemate of secondary t-butylphenylphosphine oxide with elemental sulfur in the presence of a molar equivalent of the levorotatory enantiomer of enantiomerically pure (S)-α-phenylethylamine, is reported. It is obvious that with the use of the dextrorotatory enantiomer of α-phenylethylamine, the levorotatory enantiomer of this thioacid will be isolated.
- Drabowicz, Jzef,Pokora-Sobczak, Patrycja,Zajc, Adrian,Wach-Panfilow, Paulina
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- Influence of Z,E-isomerism on the chiral-optical properties of amides
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The study of the chiral-optical properties of N-acyl-(-)-1-methyl-1,2,3,4-tetrahydroisoquinolines and their acyclic analogs, the n-acyl-(-)-1-phenylethylamines, with the known ratio of Z- and E-isomers showed that the Z-isomers are characterized by the negative Cotton effect in the region of the absorption band of the amide chromophore. The observed Cotton effects of amides of phenylethy lamine, which are higher by comparison with those of amides of tetrahydroisoquinoline, are explained by the interaction of the amide and aromatic chromophores, which are in proximity in certain conformations, possible for acyclic conformationally free phenylethylamides. 1997 Plenum Publishing Corporation.
- Dem'yanovich,Shishkina
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- Engineering transaminase for stability enhancement and site-specific immobilization through multiple noncanonical amino acids incorporation
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In general, conventional enzyme engineering utilizes 20 canonical amino acids to alter and improve the functional properties of proteins such as stability, and activity. In this study, we utilized the noncanonical amino acid incorporation technique to enh
- Deepankumar, Kanagavel,Nadarajan, Saravanan Prabhu,Mathew, Sam,Lee, Sun-Gu,Yoo, Tae Hyeon,Hong, Eun Young,Kim, Byung-Gee,Yun, Hyungdon
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- Tuneable 3D printed bioreactors for transaminations under continuous-flow
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A method to efficiently immobilize enzymes on 3D printed continuous-flow devices is presented. Application of these chemically modified devices enables rapid screening of immobilization mechanisms and reaction conditions, simple transfer of optimised conditions into tailored printed microfluidic reactors and development of continuous-flow biocatalytic processes. The bioreactors showed good activity (8-20.5 μmol h-1 mgenz-1) in the kinetic resolution of 1-methylbenzylamine, and very good stability (ca. 100 h under flow).
- Peris, Edgar,Okafor, Obinna,Kulcinskaja, Evelina,Goodridge, Ruth,Luis, Santiago V.,Garcia-Verdugo, Eduardo,O'Reilly, Elaine,Sans, Victor
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- Chromobacterium violaceum ω-transaminase variant Trp60Cys shows increased specificity for (S)-1-phenylethylamine and 4′-substituted acetophenones, and follows Swain-Lupton parameterisation
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For biocatalytic production of pharmaceutically important chiral amines the ω-transaminase enzymes have proven useful. Engineering of these enzymes has to some extent been accomplished by rational design, but mostly by directed evolution. By use of a homology model a key point mutation in Chromobacterium violaceum ω-transaminase was found upon comparison with engineered variants from homologous enzymes. The variant Trp60Cys gave increased specificity for (S)-1-phenylethylamine (29-fold) and 4′-substituted acetophenones (~5-fold). To further study the effect of the mutation the reaction rates were Swain-Lupton parameterised. On comparison with the wild type, reactions of the variant showed increased resonance dependence; this observation together with changed pH optimum and cofactor dependence suggests an altered reaction mechanism.
- Cassimjee, Karim Engelmark,Humble, Maria Svedendahl,Land, Henrik,Abedi, Vahak,Berglund, Per
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- Engineering the active site of the amine transaminase from vibrio fluvialis for the asymmetric synthesis of aryl-alkyl amines and amino alcohols
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Although the amine transaminase from Vibrio fluvialis has often been applied as a catalyst for the biocatalytic preparation of various chiral primary amines, it is not suitable for the transamination of α-hydroxy ketones and aryl-alkyl ketones bearing an alkyl substituent larger than a methyl group. We addressed this problem through a systematic mutagenesis study of active site residues to expand its substrate scope towards two bulky ketones. We identified two mutants (F85L/V153A and Y150F/V153A) showing 30-fold increased activity in the conversion of (S)-phenylbutylamine and (R)-phenylglycinol, respectively. Notably, they facilitated asymmetric synthesis of these amines with excellent enantiomeric purities of 98 ee. Excavating the active site: The constrained active site of the amine-transaminase from Vibrio fluvialis was engineered in order to achieve the conversion of bulky ketones. This led to the discovery of mutants with a 30-fold increase in activity which enabled the asymmetric synthesis of (S)-phenylbutylamine and (R)-phenylglycinol
- Nobili, Alberto,Steffen-Munsberg, Fabian,Kohls, Hannes,Trentin, Ivan,Schulzke, Carola,H?hne, Matthias,Bornscheuer, Uwe T.
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- Towards a continuous dynamic kinetic resolution of 1-phenylethylamine using a membrane assisted, two vessel process
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A continuous process with two separated reaction vessels provides a solution to the problems surrounding the combination of two catalysts in dynamic kinetic resolution reactions by retaining the biocatalyst in a lower temperature vessel with a microfiltration membrane and allowing the racemisation to occur efficiently in a higher temperature vessel. The Royal Society of Chemistry.
- Roengpithya, Chayaporn,Patterson, Darrell A.,Livingston, Andrew G.,Taylor, Paul C.,Irwin, Jacob L.,Parrett, Mark R.
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- 'Easy-on, easy-off' resolution of chiral 1-phenylethylamine catalyzed by Candida antarctica lipase B
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An 'easy-on, easy-off' process for the effective resolution of (±)-1-phenylethylamine was designed using the lipase B of Candida antarctica. This two step lipase-catalyzed process for the resolution of a chiral arylalkylamine involves a high-conversion enantioselective condensation of (R)-(+)-1-phenylethylamine with capric acid (conversion 99%, 24 h), followed by the hydrolysis of the corresponding synthesized (R)-(+)-amide (conversion 98%, 48 h). As a result, this efficient enzymatic process yields both (R)- and (S)-enantiomers of 1-phenylethylamine in high enantiomeric purity.
- Torres-Gavilan,Escalante,Regla,Lopez-Munguia,Castillo
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- CRYSTAL STRUCTURES OF THE DIASTEREOMERIC SALT PAIR OF THE PROSTAGLANDIN INTERMEDIATE 1R,2S(+)-cis-2-HYDROXYCYCLOPENT-4-ENYLACETIC ACID WITH S- and R-1-PHENYLETHYLAMINE
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Crystal structures of an enantiomeric salt pair formed between 1R,2S-cis-2-hydroxycyclopent-4-enylacetic acid (S-HCA) and R(+)-1-phenylethylamine (R-PEA) and the corresponding S-PEA salt have been determined by X-ray crystallography.The S-HCA:R-PEA 1:1 salt (R-HCAPEA hereafter) is orthorhombic, P212121, with the unit-cell parameters a=5.806(1), b=9.261(1), c=27.624(2) Angstroem and R=0.056 for 1162 reflections at ambient temperature.The S-HCA:S-PEA 1:1 salt (S-HCAPEA) is also orthorhombic, P212121, with the unit-cell data a=6.034(2), b=11.840(7), c=20.198(11) Angstroem at 170 K, R=0.082 for 1196 data measured at low temperatures (170 K).The R-HCAPEA salt has its two components assembled into an elongated rod-like shape via two-dimensional hydrogen bonding between cations and anions thus forming a well-ordered crystal.In contrast, the cation and anion in the S-HCAPEA salt forms a more globular aggregate and displays orientation disorder in the five-membered ring part of the anion and maintains an essentially one-dimensional hydrogen-bond network, while the total number of hydrogen bonds between cationic and anionic species remains three in both crystals.
- Czugler. Matyas,Csoeregh, Ingeborg,Kalman, Alajos,Faigl, Ferenc,Acs, Maria
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- Rapid screening and scale-up of transaminase catalysed reactions
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A rapid, high-throughput screening methodology has been developed for the determination of transaminase activity. This pH based, colorimetric assay can also be used to scale reactions directly from 100 μL screening scale to 25 mL development scale. Additionally, three techniques have been developed to drive transamination reactions toward complete conversion. The first method uses lactate dehydrogenase to remove the inhibitory pyruvate keto acid by-product from the reaction and drive reaction equilibrium toward the desired amine. The second method is a single enzyme system, and uses a large excess of isopropylamine to drive the transamination. Method three requires only a catalytic amount of amine donor, as an amino acid dehydrogenase is employed to regenerate the amine donor in situ using ammonia. All three systems have been demonstrated for the production of optically pure methylbenzylamine from acetophenone. An enantiomeric excess of >99% was achieved for both the R- and S-methylbenzylamine products.
- Truppo, Matthew D.,Rozzell, J. David,Moore, Jeffrey C.,Turner, Nicholas J.
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- Optical rotation study on solvent dependence of diastereomeric salt discrimination properties
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The optical rotation properties have been studied for two diastereomeric salts of four kinds of amine-carboxylic acid salt systems, and the results have been compared among them and their chiral salts. The diastereomeric salts of 2-(4-methylphenyl)-1-phenylethylamine/mandelic acid (1-phenyl-2-(4-methylphenyl) ethylamine; PTE/MA) and α-amino-ε-caprolactam/N-tosylphenylalanine (ACL/TPA) exhibited relatively large differences in optical rotation values and solvent dependency. In contrast, the diastereomeric salts of α-methylbenzylamine/MA and piperazine-2-carboxylic acid t-butylamide/TPA possessed similar optical rotation behavior; the values and solvent dependency were almost identical. These results were discussed in relation to the dielectrically controlled resolution phenomenon for the formers, PTE/MA and ACL/TPA, and were also compared with the crystal structures.
- Taniguchi, Kayoko,Sakurai, Rumiko,Sakai, Kenichi,Yasutake, Mikio,Hirose, Takuji
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- Reciprocal resolutions between 1-phenylethylamine and carboxyesters of isopropylidene glycerol: Improvement of the method by replacing mono-phthalate with 3-carboxy-2-naphthoate
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A novel resolving agent, isopropylidene glycerol 3-carboxy-2-naphthoate 2, was designed on the basis of the consideration that replacement of phenyl group with a naphthyl group would improve the resolving ability of isopropylidene glycerol hydrogen phthalate 1 while also conferring more suitable physicochemical properties for such a specific use. Indeed, 1-phenylethylamine 4 was resolved by 2 more efficiently than by 1 (respective resolution efficiencies, (S) 0.88 and 0.81), while 1 and 2 were resolved by 4 with S ranging between 0.54 and 0.59. Furthermore, 2 is a solid, whereas 1 is a viscous oil, and its recovery at the end of the resolution procedure is easier than that of 1. In order to understand the chiral discrimination mechanism of the two reciprocal resolutions, the binary melting point phase diagrams of the four diastereomeric systems (S)-2·(S)-4/(S)-2·(R)-4, (S)-2·(S)-4/(R)-2·(S)-4, (S)-1·(S)-4/(S)-1·(R)-4 and (S)-1·(S)-4/(R)-1·(S)-4 were determined. The first two systems form ideal conglomerates, characterised by identical diagrams, in which the eutectic corresponds to a 0.10 molar ratio of (S)-2·(S)-4. The same behaviour was shown by the other two systems, whose eutectics, however, correspond to a 0.18 molar ratio of (S)-1·(S)-4. On the basis of the present results, which indicate an excellent resolution ability of 2 for 4, the application of this new acid to the resolution of other 1-arylalkylamines seems to have very good prospects, worthy of investigation.
- Pallavicini, Marco,Valoti, Ermanno,Villa, Luigi,Piccolo, Oreste
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- Asymmetric synthesis of (S)-α-methylbenzylamine by recombinant Escherichia coli co-expressing omega-transaminase and acetolactate synthase
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To produce (S)-α-methylbenzylamine (MBA) from acetophenone, recombinant Escherichia coli co-expressing ω-transaminase and acetolactate synthase was used as a whole-cell biocatalyst. The solvent-bridge reaction system increased the yield of the whole-cell reaction by 2.5-fold, and the inhibitory (S)-α-MBA produced in the ω-transaminase reaction solution (pH 8.0) moved into the extraction solution (pH 3.0) via an organic solvent.
- Yun, Hyungdon,Kim, Byung-Gee
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- Structure Study of Host-Guest Molecular Association in Solution and in the Solid State
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A correlation between the mechanism of 1H NMR shift of a chiral guest by association with an optically active host compound in solution and in the solid state is revealed by an X-ray analysis of the host-guest inclusion crystal.
- Toda, Fumio,Tanaka, Koichi,Ootani, Minoru,Hayashi, Atsuhiro,Miyahara, Ikuko,Hirotsu, Ken
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- Artificial plant cell walls as multi-catalyst systems for enzymatic cooperative asymmetric catalysis in non-aqueous media
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The assembly of cellulose-based artificial plant cell wall (APCW) structures that contain different types of catalysts is a powerful strategy for the development of cascade reactions. Here we disclose an APCW catalytic system containing a lipase enzyme and nanopalladium particles that transform a racemic amine into the corresponding enantiomerically pure amide in high yieldviaa dynamic kinetic resolution.
- B?ckvall, Jan-E.,Córdova, Armando,Deiana, Luca,Naidu, Veluru Ramesh,Rafi, Abdolrahim A.,Tai, Cheuk-Wai
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supporting information
p. 8814 - 8817
(2021/09/07)
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- Highly Stable Zr(IV)-Based Metal-Organic Frameworks for Chiral Separation in Reversed-Phase Liquid Chromatography
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Separation of racemic mixtures is of great importance and interest in chemistry and pharmacology. Porous materials including metal-organic frameworks (MOFs) have been widely explored as chiral stationary phases (CSPs) in chiral resolution. However, it remains a challenge to develop new CSPs for reversed-phase high-performance liquid chromatography (RP-HPLC), which is the most popular chromatographic mode and accounts for over 90% of all separations. Here we demonstrated for the first time that highly stable Zr-based MOFs can be efficient CSPs for RP-HPLC. By elaborately designing and synthesizing three tetracarboxylate ligands of enantiopure 1,1′-biphenyl-20-crown-6, we prepared three chiral porous Zr(IV)-MOFs with the framework formula [Zr6O4(OH)8(H2O)4(L)2]. They share the same flu topological structure but channels of different sizes and display excellent tolerance to water, acid, and base. Chiral crown ether moieties are periodically aligned within the framework channels, allowing for stereoselective recognition of guest molecules via supramolecular interactions. Under acidic aqueous eluent conditions, the Zr-MOF-packed HPLC columns provide high resolution, selectivity, and durability for the separation of a variety of model racemates, including unprotected and protected amino acids and N-containing drugs, which are comparable to or even superior to several commercial chiral columns for HPLC separation. DFT calculations suggest that the Zr-MOF provides a confined microenvironment for chiral crown ethers that dictates the separation selectivity.
- Jiang, Hong,Yang, Kuiwei,Zhao, Xiangxiang,Zhang, Wenqiang,Liu, Yan,Jiang, Jianwen,Cui, Yong
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supporting information
p. 390 - 398
(2021/01/13)
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- Rational Design of Chiral Nanohelices from Self-Assembly of Meso-tetrakis (4-Carboxyphenyl) Porphyrin-Amino Acid Conjugates
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In this article, meso-tetrakis (4-carboxyphenyl) porphyrins modified with different amino acids were designed, synthesized, and researched. The chiral self-assembly behavior of these porphyrin-amino acid molecules can be precisely controlled by adjusting the pH, constituent amino acids, and temperature, thereby giving rise to chiral nanostructures with precisely tailored helical pitch and handedness. This research provides a certain reference for the design and preparation of chiral nanomaterials and has potential application prospects in chiral resolution and chiral catalysis.
- Yang, Xuejiao,Shen, Yuhe,Liu, Jiayu,Wang, Yuefei,Qi, Wei,Su, Rongxin,He, Zhimin
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p. 13067 - 13074
(2021/11/16)
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- Engineering the large pocket of an (S)-selective transaminase for asymmetric synthesis of (S)-1-amino-1-phenylpropane
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Amine transaminases offer an environmentally benign chiral amine asymmetric synthesis route. However, their catalytic efficiency towards bulky chiral amine asymmetric synthesis is limited by the natural geometric structure of the small pocket, representing a great challenge for industrial applications. Here, we rationally engineered the large binding pocket of an (S)-selective ?-transaminase BPTA fromParaburkholderia phymatumto relieve the inherent restriction caused by the small pocket and efficiently transform the prochiral aryl alkyl ketone 1-propiophenone with a small substituent larger than the methyl group. Based on combined molecular docking and dynamic simulation analyses, we identified a non-classical substrate conformation, located in the active site with steric hindrance and undesired interactions, to be responsible for the low catalytic efficiency. By relieving the steric barrier with W82A, we improved the specific activity by 14-times compared to WT. A p-p stacking interaction was then introduced by M78F and I284F to strengthen the binding affinity with a large binding pocket to balance the undesired interactions generated by F44. T440Q further enhanced the substrate affinity by providing a more hydrophobic and flexible environment close to the active site entry. Finally, we constructed a quadruple variant M78F/W82A/I284F/T440Q to generate the most productive substrate conformation. The 1-propiophenone catalytic efficiency of the mutant was enhanced by more than 470-times in terms ofkcat/KM, and the conversion increased from 1.3 to 94.4% compared with that of WT, without any stereoselectivity loss (ee > 99.9%). Meanwhile, the obtained mutant also showed significant activity improvements towards various aryl alkyl ketones with a small substituent larger than the methyl group ranging between 104- and 230-fold, demonstrating great potential for the efficient synthesis of enantiopure aryl alkyl amines with steric hindrance in the small binding pocket.
- Liu, He,Wang, Hualei,Wei, Dongzhi,Xie, Youyu,Xu, Feng,Xu, Xiangyang,Yang, Lin
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p. 2461 - 2470
(2021/04/22)
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- Polydopamine-Encapsulated Dendritic Organosilica Nanoparticles as Amphiphilic Platforms for Highly Efficient Heterogeneous Catalysis in Water
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Aqueous heterogeneous catalysis is a green, sustainable catalytic process that attracts increasing attention, but it often suffers from poor mass transfer, substrate adsorption and catalyst dispersion. Herein, we synthesized a type of amphiphilic core-shell catalysts with a hydrophilic polydopamine (PDA) shell and a hydrophobic dendritic organosilica nanoparticle (DON) core for heterogeneous catalysis in water. The hydrophilic shell allowed the catalyst dispersing well in water, and the hydrophobic core facilitated the absorption of organic reactants. The hierarchical core-shell structure facilitated rational arrangement of the location of catalytic species to match the reaction sequence. The obtained metal, enzyme and metal-enzyme amphiphilic catalysts demonstrated improved stability, selectivity and activity in aqueous reactions, including Pd-catalyzed cross-couplings (Suzuki, Liebeskind-Srogl, Heck and Sonogashira), enzymatic enantioselective reduction, chemoenzymatic cascade synthesis of chiral compounds and chemoenzymatic cascade degradation of organophosphates. The amphiphilic catalysts could be easily in situ recovered, and their high catalytic performance was sustained for five cycles.
- Gao, Jing,Guo, Na,Jiang, Yanjun,Liu, Guanhua,Liu, Pengbo,Liu, Yunting,Wang, Zihan,Zhang, Lei
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supporting information
p. 1975 - 1982
(2021/06/09)
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- Preparation method of optically pure 4-(1-amino) ethyl benzoate and salt thereof
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The invention relates to a preparation method of of optically pure 4-(1-amino) ethyl benzoate and salt thereof. The method has the characteristics of low cost, environmental friendliness, high opticalpurity, simplicity and convenience in operation and easiness in industrial production.
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Paragraph 0112-0114
(2021/03/30)
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- An Iridium Catalytic System Compatible with Inorganic and Organic Nitrogen Sources for Dual Asymmetric Reductive Amination Reactions
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Asymmetric reductive amination (ARA) is one of the most promising methods for the synthesis of chiral amines. Herein we report our efforts on merging two ARA reactions into a single-step transformation. Catalyzed by a complex formed from iridium and a steric hindered phosphoramidite, readily available and inexpensive aromatic ketones initially undergo the first ARA with ammonium acetate to afford primary amines, which serve as the amine sources for the second ARA, and finally provide the enantiopure C2-symmetric secondary amine products. The developed process competently enables the successive coupling of inorganic and organic nitrogen sources with ketones in the same reaction system. The Br?nsted acid additive plays multiple roles in this procedure: it accelerates the formation of imine intermediates, minimizes the inhibitory effect of N-containing species on the iridium catalyst, and reduces the primary amine side products.
- Chang, Mingxin,Gao, Zhaofeng,Geng, Huiling,Huang, Haizhou,Liu, Jingwen
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supporting information
p. 27307 - 27311
(2021/11/17)
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- Kinetic Resolution of Racemic Primary Amines Using Geobacillus stearothermophilus Amine Dehydrogenase Variant
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A NADH-dependent engineered amine dehydrogenase from Geobacillus stearothermophilus (LE-AmDH-v1) was applied together with a NADH-oxidase from Streptococcus mutans (NOx) for the kinetic resolution of pharmaceutically relevant racemic α-chiral primary amines. The reaction conditions (e. g., pH, temperature, type of buffer) were optimised to yield S-configured amines with up to >99 % ee.
- Tseliou, Vasilis,Knaus, Tanja,Vilím, Jan,Masman, Marcelo F.,Mutti, Francesco G.
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p. 2184 - 2188
(2020/03/11)
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- Synthesis and characterization of a magnetic hybrid catalyst containing lipase and palladium and its application on the dynamic kinetic resolution of amines
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Recent papers estimates that about 40 % of drugs present chiral amines in their structure and their synthesis in a sustainable and cost-competitive way is still a challenge for the industry. Kinetic resolution is one of the most applied method to produce these desired compounds where the association with lipase as a catalyst is a good alternative. However, the use of separate racemization catalyst and enzymes in the reaction medium still limits recovery, recycling and can occasionally be responsible for decreasing in selectivity for the desired product. In this work we proposed the synthesis and characterization of a hybrid magnetic catalyst composed containing lipase CaL B and Pd immobilized on the same recovered nanometric magnetic support for the application on Dynamic Kinetic Resolution of (rac)-1-phenylethylamine both in batch and continuous flow conditions. As results it was possible to achieve 99 % of conversion, with 95 % of selectivity and 93 % of enantiomeric excess after 12 h in batch. For a continuous flow system, it was possible to achieve 95 % of conversion with 71 % of selectivity and ee > 99 % after 60 min of reaction. The hybrid catalyst had around 50?100 nm with nanoparticulated Pd (5?10 nm) on its surface, presented a superparamagnetic behavior without remaining magnetization and 22 emu/g of saturation magnetization.
- Almeida, Rhudson F. O.,Caraballo, Richard,Dalm?nico, Gisele,Ferraz, Clara A.,Finotelli, Priscilla V.,Itabaiana, Ivaldo,Junior, Aldo A. T.,Le?o, Raquel A. C.,Sergio, Gabriella G.,Wojcieszak, Robert,de Souza, Rodrigo O. M. A.,do Nascimento, Marcelo A.
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- Addition of Highly Polarized Organometallic Compounds to N-tert-Butanesulfinyl Imines in Deep Eutectic Solvents under Air: Preparation of Chiral Amines of Pharmaceutical Interest
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Highly polarized organometallic compounds of s-block elements are added smoothly to chiral N-tert-butanesulfinyl imines in the biodegradable d-sorbitol/choline chloride eutectic mixture, thereby granting access to enantioenriched primary amines after quantitatively removing the sulfinyl group. The practicality of the method is further highlighted by proceeding at ambient temperature and under air, with very short reaction times (2 min), enabling the preparation of diastereoisomeric sulfinamides in very good yields (74–98 %) and with a broad substrate scope, and the possibility of scaling up the process. The method is demonstrated in the asymmetric syntheses of both the chiral amine side-chain of (R,R)-Formoterol (96 % ee) and the pharmaceutically relevant (R)-Cinacalcet (98 % ee).
- Capriati, Vito,Cicco, Luciana,García-álvarez, Joaquín,González-Sabín, Javier,Perna, Filippo M.,Ríos-Lombardía, Nicolás,Salomone, Antonio,Vitale, Paola
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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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- A Simple Biosystem for the High-Yielding Cascade Conversion of Racemic Alcohols to Enantiopure Amines
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The amination of racemic alcohols to produce enantiopure amines is an important green chemistry reaction for pharmaceutical manufacturing, requiring simple and efficient solutions. Herein, we report the development of a cascade biotransformation to aminate racemic alcohols. This cascade utilizes an ambidextrous alcohol dehydrogenase (ADH) to oxidize a racemic alcohol, an enantioselective transaminase (TA) to convert the ketone intermediate to chiral amine, and isopropylamine to recycle PMP and NAD+ cofactors via the reversed cascade reactions. The concept was proven by using an ambidextrous CpSADH-W286A engineered from (S)-enantioselective CpSADH as the first example of evolving ambidextrous ADHs, an enantioselective BmTA, and isopropylamine. A biosystem containing isopropylamine and E. coli (CpSADH-W286A/BmTA) expressing the two enzymes was developed for the amination of racemic alcohols to produce eight useful and high-value (S)-amines in 72–99 % yield and 98–99 % ee, providing with a simple and practical solution to this type of reaction.
- Li, Zhi,Tian, Kaiyuan
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supporting information
p. 21745 - 21751
(2020/09/21)
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- Enantioselective Bioamination of Aromatic Alkanes Using Ammonia: A Multienzymatic Cascade Approach
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Chiral amines are common drug building blocks and important active pharmaceutical ingredients. Preparing these functionalized compounds from simple materials, such as alkanes, is of great interest. We recently developed an artificial bioamination cascade for the C?H amination of cyclic alkanes by combining P450 monooxygenase, alcohol dehydrogenase, and amine dehydrogenase. Herein, this system has been extended to the synthesis of chiral aromatic amines. In the first hydroxylation step, process optimization increased the conversion to 77 %. Two stereoselectively complementary alcohol dehydrogenases and an amine dehydrogenase were selected for the bioconversion of aromatic hydrocarbons to amines. The amination reaction was optimized with respect to cofactor addition and enzyme dosage. Isopropanol was added to decrease ketone intermediate accumulation in the amination step, which further enhanced the overall conversion. This cascade system converted a panel of hydrocarbon substrates into the corresponding amines with excellent optical purity (>99 % ee) and moderate conversion ratios (13–53 %).
- Chen, Fei-Fei,Wang, Hui,Xu, Jian-He,Yu, Hui-Lei,Zheng, Yu-Cong
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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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- 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
-
p. 1898 - 1902
(2019/02/27)
-
- In Vitro and in Vivo One-Pot Deracemization of Chiral Amines by Reaction Pathway Control of Enantiocomplementary ω-Transaminases
-
Biocatalytic cascade conversion of racemic amines into optically pure ones using enantiocomplementary ω-transaminases (ω-TAs) has been developed by thermodynamic and kinetic control of reaction pathways where 12 competing reactions occur with pyruvate and isopropylamine used as cosubstrates. Thermodynamic control was achieved under reduced pressure for selective removal of a coproduct (i.e., acetone), leading to elimination of six undesirable reactions. Engineered orthogonality in substrate specificities of ω-TAs was exploited for kinetic control, enabling suppression of four additional reactions. Taken together, the net reaction pathway could be directed to two desired reactions (i.e., oxidative deamination of R-amine and reductive amination of the resulting ketone into antipode S-amine). This strategy afforded one-pot deracemization of various chiral amines with >99% eeS and 85-99% reaction yields of the resulting S-amine products. The in vitro cascade reaction could be successfully implemented in a live microbe using glucose or l-threonine as a cheap amino acceptor precursor, demonstrating a synthetic metabolic pathway enabling deracemization of chiral amines which has never been observed in living organisms.
- Han, Sang-Woo,Jang, Youngho,Shin, Jong-Shik
-
p. 6945 - 6954
(2019/08/26)
-
- Preparation of chiral primary amine through asymmetric reductive amination of simple ketone under catalytic action of ruthenium-diphosphine catalyst
-
The invention relates to a method for preparing chiral primary amine. The method comprises the steps: performing a hydrogenation reductive amination reaction on simple ketone and an ammonium salt RCOONH4 under the action of a ruthenium-chiral diphosphine catalyst, then adding an acid, performing heating for hydrolysis, and adopting a one-pot method to prepare the chiral primary amine. The method has the advantages of good universality of the substrate, high reaction efficiency and the like.
- -
-
Paragraph 0060-0067
(2019/07/04)
-
- Decorated single-enantiomer phosphoramide-based silica/magnetic nanocomposites for direct enantioseparation
-
The nano-composites Fe3O4SiO2(-O3Si[(CH2)3NH])P(O)(NH-R(+)CH(CH3)(C6H5))2 (Fe3O4SiO2PTA(+)) and Fe3O4SiO2(-O3Si[(CH2)3NH])P(O)(NH-S(-)CH(CH3)(C6H5))2 (Fe3O4SiO2PTA(-)) were prepared and used for the chiral separation of five racemic mixtures (PTA = phosphoric triamide). The separation results show chiral recognition ability of these materials with respect to racemates belonging to different families of compounds (amine, acid, and amino-acid), which show their feasibility to be potential adsorbents in chiral separation. The nano-composites were characterized by FTIR, TEM, SEM, EDX, XRD, and VSM. The VSM curves of nano-composites indicate their superparamagnetic property, which is stable after their use in the separation process. Fe3O4, Fe3O4SiO2, Fe3O4SiO2PTA(+) and Fe3O4SiO2PTA(-) are regularly spherical with uniform shape and the average sizes of 17-20, 18-23, 36-47 and 43-52 nm, respectively.
- Karimi Ahmadabad, Fatemeh,Pourayoubi, Mehrdad,Bakhshi, Hadi
-
p. 27147 - 27156
(2019/09/12)
-
- Combinatorial Mutation Analysis of ω-Transaminase to Create an Engineered Variant Capable of Asymmetric Amination of Isobutyrophenone
-
ω-Transaminase (ω-TA) is an important enzyme for asymmetric synthesis of chiral amines. Rapid creation of a desirable ω-TA variant, readily available for scalable process operation, is demanded and has attracted intense research efforts. In this study, we aimed to develop a quantitative mutational analysis (i. e., R-analysis) that enables prediction of combinatorial mutation outcomes and thereby provides reliable guidance of enzyme engineering through combination of already characterized mutations. To this end, we determined three mutatable active-site residues of ω-TA from Ochrobactrum anthropi (i. e., leucine 57, tryptophan 58 and valine 154) by examining activities of nine alanine-scanning mutants for seven substrate pairs. The R-analysis of the mutatable residues is based on assessment of changes in relative activities for a series of structurally analogous substrates. Using three sets of substrates (five α-keto acids, six arylalkylamines and three arylalkyl ketones), we found that combination of two point mutations display additive effects of each mutational outcome such as steric relaxation for bulky substrates or catalytic enhancement for amination of ketones. Consistent with the R-analysis-based prediction, the ω-TA variant harboring triple alanine mutations, i. e. L57A, W58A and V154A, showed high activity improvements for bulky substrates, e. g. a 3.2×104-fold activity increase for 1-phenylbutylamine. The triple mutant even enabled asymmetric amination of isobutyrophenone, carrying a branched-chain alkyl substituent to be accepted in a small binding pocket that normally shows a steric limit up to an ethyl group, with >99% ee of a resulting (S)-amine. (Figure presented.).
- Kim, Hong-Gon,Han, Sang-Woo,Shin, Jong-Shik
-
p. 2594 - 2606
(2019/05/15)
-
- Glutamate as an Efficient Amine Donor for the Synthesis of Chiral β- and γ-Amino Acids Using Transaminase
-
A recyclable glutamate amine donor system employing transaminase (TA), glutamate dehydrogenase (GluDH) and mutant formate dehydrogenase (FDHm) was developed, wherein amine donor Glu was regenerated using GluDH and thereby circumvented the inhibition of TA by α-ketoglutarate. Various enantiopure β-, γ-amino acids, and amines were successfully synthesized with high conversions and excellent enantiomeric excess using this system.
- Kim, Geon-Hee,Jeon, Hyunwoo,Khobragade, Taresh P.,Patil, Mahesh D.,Sung, Sihyong,Yoon, Sanghan,Won, Yumi,Sarak, Sharad,Yun, Hyungdon
-
p. 1437 - 1440
(2019/02/06)
-
- Combining Photo-Organo Redox- and Enzyme Catalysis Facilitates Asymmetric C-H Bond Functionalization
-
In this study, we combined photo-organo redox catalysis and biocatalysis to achieve asymmetric C–H bond functionalization of simple alkane starting materials. The photo-organo catalyst anthraquinone sulfate (SAS) was employed to oxyfunctionalise alkanes to aldehydes and ketones. We coupled this light-driven reaction with asymmetric enzymatic functionalisations to yield chiral hydroxynitriles, amines, acyloins and α-chiral ketones with up to 99 % ee. In addition, we demonstrate functional group interconversion to alcohols, esters and carboxylic acids. The transformations can be performed as concurrent tandem reactions. We identified the degradation of substrates and inhibition of the biocatalysts as limiting factors affecting compatibility, due to reactive oxygen species generated in the photocatalytic step. These incompatibilities were addressed by reaction engineering, such as applying a two-phase system or temporal and spatial separation of the catalysts. Using a selection of eleven starting alkanes, one photo-organo catalyst and 8 diverse biocatalysts, we synthesized 26 products and report for the model compounds benzoin and mandelonitrile > 97 % ee at gram scale.
- Zhang, Wuyuan,Fueyo, Elena Fernandez,Hollmann, Frank,Martin, Laura Leemans,Pesic, Milja,Wardenga, Rainer,H?hne, Matthias,Schmidt, Sandy
-
supporting information
p. 80 - 84
(2019/01/04)
-
- Rapid and Quantitative Profiling of Substrate Specificity of ω-Transaminases for Ketones
-
ω-Transaminases (ω-TAs) have gained growing attention owing to their capability for asymmetric synthesis of chiral amines from ketones. Reliable high-throughput activity assay of ω-TAs is essential in carrying out extensive substrate profiling and establishing a robust screening platform. Here we report spectrophotometric and colorimetric methods enabling rapid quantitation of ω-TA activities toward ketones in a 96-well microplate format. The assay methods employ benzylamine, a reactive amino donor for ω-TAs, as a cosubstrate and exploit aldehyde dehydrogenase (ALDH) as a reporter enzyme, leading to formation of benzaldehyde detectable by ALDH owing to concomitant NADH generation. Spectrophotometric substrate profiling of two wild-type ω-TAs of opposite stereoselectivity was carried out at 340 nm with 22 ketones, revealing subtle differences in substrate specificities that were consistent with docking simulation results obtained with cognate amines. Colorimetric readout for naked eye detection of the ω-TA activity was also demonstrated by supplementing the assay mixture with color-developing reagents whose color reaction could be quantified at 580 nm. The colorimetric assay was applied to substrate profiling of an engineered ω-TA for 24 ketones, leading to rapid identification of reactive ketones. The ALDH-based assay is expected to be promising for high-throughput screening of enzyme collections and mutant libraries to fish out the best ω-TA candidate as well as to tailor enzyme properties for efficient amination of a target ketone.
- Han, Sang-Woo,Shin, Jong-Shik
-
p. 3287 - 3295
(2019/06/21)
-
- One-Pot Absolute Stereochemical Identification of Alcohols via Guanidinium Sulfate Crystallization
-
A novel technique for the absolute stereochemical determination of alcohols has been developed that uses crystallization of guanidinium salts of organosulfates. The simple one-pot, two-step process leverages facile formation of guandinium organosulfate single crystals for the straightforward determination of the absolute stereochemistry of enantiopure alcohols by means of X-ray crystallography. The strong hydrogen bonding network drives the stability of the crystal lattice and allows for a diverse range of organic alcohol substrates to be analyzed.
- Brummel, Beau R.,Lee, Kinsey G.,McMillen, Colin D.,Kolis, Joseph W.,Whitehead, Daniel C.
-
supporting information
p. 9622 - 9627
(2019/12/02)
-
- Synthesis method of chiral compound R-(+)-2-methyl-3-phenyl-1-propyl alcohol
-
The invention discloses a synthesis method of a chiral compound R-(+)-2-methyl-3-phenyl-1-propyl alcohol. The synthesis method comprises the following steps: taking alpha-methyl cinnamaldehyde as a raw material and performing a catalytic hydrogenation reaction on the alpha-methyl cinnamaldehyde to obtain (plus or minus)-2-methyl-3-phenyl-1-propyl alcohol; performing an esterification reaction on the (plus or minus)-2-methyl-3-phenyl-1-propyl alcohol and phthalic anhydride to form monoester; performing an acid-base reaction on the monoester and S-(-)-alpha-phenylethylamine to form salt; separating and purifying a single chiral isomer in the salt through crystallization and recrystallization; performing a hydrolysis reaction to obtain R-(+)-2-methyl-3-phenyl-1-propyl alcohol and a hydrolysisby-product; and finally, removing the hydrolysis by-product through separation and purification to obtain the R-(+)-2-methyl-3-phenyl-1-propyl alcohol.
- -
-
Paragraph 0019; 0027-0029; 0030; 0038-0040; 0041; 0049-0051
(2019/04/04)
-
- Asymmetric Synthesis of Chiral Primary Amines by Ruthenium-Catalyzed Direct Reductive Amination of Alkyl Aryl Ketones with Ammonium Salts and Molecular H2
-
A ruthenium/C3-TunePhos catalytic system has been identified for highly efficient direct reductive amination of simple ketones. The strategy makes use of ammonium acetate as the amine source and H2 as the reductant and is a user-friendly and operatively simple access to industrially relevant primary amines. Excellent enantiocontrol (>90% ee for most cases) was achieved with a wide range of alkyl aryl ketones. The practicability of this methodology has been highlighted by scalable synthesis of key intermediates of three drug molecules. Moreover, an improved synthetic route to the optimal diphosphine ligand C3-TunePhos is also presented.
- Tan, Xuefeng,Gao, Shuang,Zeng, Weijun,Xin, Shan,Yin, Qin,Zhang, Xumu
-
supporting information
p. 2024 - 2027
(2018/02/19)
-
- METHOD FOR THE HOMOGENEOUS CATALYTIC REDUCTIVE AMINATION OF CARBONYL COMPOUNDS
-
The present invention relates to a method for the reductive amination of a carbonyl compound, comprising one or more carbonyl groups amenable to reductive amination, forming the corresponding primary amine, characterized in that the reaction is carried out in the presence of a homogeneously dissolved catalyst complex K, comprising at least one metal atom from Group 8, 9 or 10 of the periodic table, bearing a bidentate phosphane ligand, a carbonyl ligand, a neutral ligand and a hydride ligand, and also an acid as co-catalyst.
- -
-
Paragraph 0212; 0222-0223; 0224; 0225-0226
(2018/07/29)
-
- Chiral Organic Cages with a Triple-Stranded Helical Structure Derived from Helicene
-
We report the use of helicene with an intrinsic helical molecular structure to prepare covalent organic cages via imine condensation. The organic cages revealed a [3+2]-type architecture containing a triple-stranded helical structure with three helicene units arranged in a propeller-like fashion with the framework integrally twisted. Such structural chirality was retained upon dissolution in organic solvents, as indicated by a strong diastereotopy effect in proton NMR and unique Cotton effects in circular dichroism spectra. Further study on chiral adsorption showed that the chiral organic cages possess considerable enantioselectivity toward a series of aromatic racemates.
- Malik, Abaid Ullah,Gan, Fuwei,Shen, Chengshuo,Yu, Na,Wang, Ruibin,Crassous, Jeanne,Shu, Mouhai,Qiu, Huibin
-
supporting information
p. 2769 - 2772
(2018/03/08)
-
- Evaluation of the Edman degradation product of vancomycin bonded to core-shell particles as a new HPLC chiral stationary phase
-
A modified macrocyclic glycopeptide-based chiral stationary phase (CSP), prepared via Edman degradation of vancomycin, was evaluated as a chiral selector for the first time. Its applicability was compared with other macrocyclic glycopeptide-based CSPs: TeicoShell and VancoShell. In addition, another modified macrocyclic glycopeptide-based CSP, NicoShell, was further examined. Initial evaluation was focused on the complementary behavior with these glycopeptides. A screening procedure was used based on previous work for the enantiomeric separation of 50 chiral compounds including amino acids, pesticides, stimulants, and a variety of pharmaceuticals. Fast and efficient chiral separations resulted by using superficially porous (core-shell) particle supports. Overall, the vancomycin Edman degradation product (EDP) resembled TeicoShell with high enantioselectivity for acidic compounds in the polar ionic mode. The simultaneous enantiomeric separation of 5 racemic profens using liquid chromatography-mass spectrometry with EDP was performed in approximately 3?minutes. Other highlights include simultaneous liquid chromatography separations of rac-amphetamine and rac-methamphetamine with VancoShell, rac-pseudoephedrine and rac-ephedrine with NicoShell, and rac-dichlorprop and rac-haloxyfop with TeicoShell.
- Hellinghausen, Garrett,Lopez, Diego A.,Lee, Jauh T.,Wang, Yadi,Weatherly, Choyce A.,Portillo, Abiud E.,Berthod, Alain,Armstrong, Daniel W.
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p. 1067 - 1078
(2018/08/01)
-
- Reductive amination of ketones with ammonium catalyzed by a newly identified Brevibacterium epidermidis strain for the synthesis of (S)-chiral amines
-
The asymmetric reductive amination of achiral ketones with ammonia is a particularly attractive reaction for the synthesis of chiral amines. Although several engineered amine dehydrogenases have been developed by protein engineering for the asymmetric reductive amination of ketones, they all display (R)-stereoselectivity. To date, there is no report of an (S)-stereoselective biocatalyst for this reaction. Herein, a microorganism named Brevibacterium epidermidis ECU1015 that catalyzes the (S)-selective reductive amination of ketones with ammonium has been successfully isolated from soil. Using B. epidermidis ECU1015 as the catalyst, the asymmetric reductive amination of a set of phenylacetone derivatives was successfully carried out, yielding the corresponding (S)-chiral amines with moderate conversion and >99% enantiomeric excess.
- Li, Qing-Hua,Dong, Yuan,Chen, Fei-Fei,Liu, Lei,Li, Chun-Xiu,Xu, Jian-He,Zheng, Gao-Wei
-
p. 1625 - 1632
(2018/08/21)
-
- Optimization of 2-alkoxyacetates as acylating agent for enzymatic kinetic resolution of chiral amines
-
In this study, the activity of acetic acid esters modified with electron withdrawing 2-alkoxy-groups was investigated as acylating agent in kinetic resolution (KR) of racemic amines. A homologous series of the isopropyl esters of four 2-alkoxyacetic acids (2-methoxy-, 2-ethoxy-, 2-propoxy- and 2-butoxyacetic acids) were prepared and investigated for enantiomer selective N-acylation, catalyzed by lipase B from Candida antarctica, under batch and continuous-flow conditions. In the first set of experiments, isopropyl 2-propoxyacetate showed the highest effectivity with all of the four racemic amines [(±)-1-phenylethylamine, (±)-4-phenylbutan-2-amine, (±)-heptan-2-amine and (±)-1-methoxypropane-2-amine] in the set enabling excellent conversions (≥46%) and enantiomeric excess values (ee ≥ 99%) with each amines in continuous-flow mode KRs under the optimized reaction conditions. In a second set of experiments, KRs of five additional amines – being substituted derivatives of (±)-1-phenylethylamine – further demonstrated the usefulness of isopropyl 2-propoxyacetate – being the best acylating agent in the first set of KRs – in KRs leading to (R)-N-propoxyacetamides with high ee values (≥99.8%).
- Oláh, Márk,Kovács, Dániel,Katona, Gabriel,Hornyánszky, Gábor,Poppe, László
-
p. 3663 - 3670
(2018/06/04)
-
- n-Butylamine as an alternative amine donor for the stereoselective biocatalytic transamination of ketones
-
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.
-
-
- Dynamic kinetic resolution of amines by using palladium nanoparticles confined inside the cages of amine-modified MIL-101 and lipase
-
Dynamic kinetic resolution (DKR) of amines is an important strategy for the synthesis of chiral drugs and their building blocks; however, improving the matchability of metal-catalyzed racemization and enzymatic resolution is still a task. In this paper, P
- Xu, Sen,Wang, Meng,Feng, Bo,Han, Xinchen,Lan, Zijie,Gu, Huajun,Li, Hexing,Li, Hui
-
-
- Amide Synthesis via Aminolysis of Ester or Acid with an Intracellular Lipase
-
A unique lipase (SpL) from Sphingomonas sp. HXN-200 was discovered as the first intracellular enzyme for the aminolysis of ester or acid to produce amide. Reactions of a series of esters and amines with SpL gave the corresponding amides 3a-g in high yield with high activity. SpL also showed high enantioselectivity and high activity for enantioselective ester aminolysis, producing amides (R)-3h-j in high ee from the corresponding racemic ester or amine. Moreover, SpL was found to be highly active for the aminolysis of carboxylic acid, which was generally considered infeasible with the known aminolysis enzymes. The aminolysis of several carboxylic acids afforded the corresponding amides 3a, 3d, 3k, 3l, and 3n in good yield. The intracellular SpL was expressed in Escherichia coli cells to give an efficient whole-cell biocatalyst for amide synthesis. Remarkably, high catalytic activity was observed in the presence of water at 2-4% (v/v) for free enzyme and 16% (v/v) for whole cells, respectively. Accordingly, E. coli (SpL) wet cells were used as easily available and practical catalysts for the aminolysis of ester or acid, producing a group of useful and valuable amides in high concentration (up to 103 mM) and high yield. The newly discovered intracellular SpL with unique properties is a promising catalyst for green and efficient synthesis of amides.
- Zeng, Shichao,Liu, Ji,Anankanbil, Sampson,Chen, Ming,Guo, Zheng,Adams, Joseph P.,Snajdrova, Radka,Li, Zhi
-
p. 8856 - 8865
(2018/09/06)
-
- New Biosilified Pd-lipase hybrid biocatalysts for dynamic resolution of amines
-
In this work lipase CaLB was immobilized on functionalized Pd-SiO2 nanoparticles in order to simplify the DKR of α-methylbenzylamine. Hybrid biocatalysts showed immobilization efficiencies of 82%, 80% and 76% when containing 1, 5 and 10% of Pd respectively. On DKR reaction values of ee > 99% and conversion of 82% were found with only 1% of Pd, generating a productivity of 2.21 mg of product h?1 mg of support?1 against 0.76 found by N435. Compared to commercial N435, the novel biocatalysts showed protein loads about 15-fold lower and higher activity, demonstrating competitive performances and high industrial applications.
- de Souza, Stefania P.,Le?o, Raquel A.C.,Bassut, Jonathan F.,Leal, Ivana C.R.,Wang, Shuai,Ding, Qiqi,Li, Yingying,Lam, Frank Leung-Yuk,de Souza, Rodrigo O.M.A.,Itabaiana Jr, Ivaldo
-
p. 4849 - 4854
(2017/11/29)
-
- Asymmetric catalysis of the carbonyl-amine condensation: Kinetic resolution of primary amines
-
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)
-
- Biocatalytic transamination with near-stoichiometric inexpensive amine donors mediated by bifunctional mono- and di-amine transaminases
-
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.
-
supporting information
p. 361 - 366
(2017/08/14)
-
- Diastereoselective Hydrosilylation of N-(tert-Butylsulfinyl)imines Catalyzed by Zinc Acetate
-
An efficient zinc-catalyzed diastereoselective hydrosilylation of N-(tert-butylsulfinyl)imines has been developed that does not require the use of ligands or noble metals. A variety of N-(tert-butylsulfinyl)imines were reduced by this protocol in the presence of a catalytic amount of zinc acetate (5 mol-%) to provide the corresponding secondary amines in high yields with excellent diastereoselectivities (up to 98 % de). This experimentally simple catalytic procedure is easily applicable to the synthesis of both aromatic and aliphatic amines by using triethoxysilane as an efficient hydrogen source.
- Adamkiewicz, Anna,Mlynarski, Jacek
-
p. 1060 - 1065
(2016/03/01)
-
- Integrated Heterogeneous Metal/Enzymatic Multiple Relay Catalysis for Eco-Friendly and Asymmetric Synthesis
-
Organic synthesis is in general performed using stepwise transformations where isolation and purification of key intermediates is often required prior to further reactions. Herein we disclose the concept of integrated heterogeneous metal/enzymatic multiple relay catalysis for eco-friendly and asymmetric synthesis of valuable molecules (e.g., amines and amides) in one-pot using a combination of heterogeneous metal and enzyme catalysts. Here reagents, catalysts, and different conditions can be introduced throughout the one-pot procedure involving multistep catalytic tandem operations. Several novel cocatalytic relay sequences (reductive amination/amidation, aerobic oxidation/reductive amination/amidation, reductive amination/kinetic resolution and reductive amination/dynamic kinetic resolution) were developed. They were next applied to the direct synthesis of various biologically and optically active amines or amides in one-pot from simple aldehydes, ketones, or alcohols, respectively.
- Palo-Nieto, Carlos,Afewerki, Samson,Anderson, Mattias,Tai, Cheuk-Wai,Berglund, Per,Córdova, Armando
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p. 3932 - 3940
(2016/07/06)
-
- A split preparation of the optically pure S-1-benzoethylamine method
-
The present invention relates to a method for resolution preparation of S-1-phenylethylamine in a dynamic kinetics manner. According to the method, 1-phenylethylamine is adopted as a raw material, Novozym435 is adopted as a resolution catalyst, S-1-phenethyl acetate is adopted as an acyl donor, raney nickel is adopted as a racemic catalyst, and hydrogen is introduced into an autoclave to carry out a reaction, wherein the 1-phenylethylamine is completely converted to obtain (S)-(1-phenylethyl)acetamide (ee value of 99%), the amide is purified and then acidolysis is performed to obtain a S-1-phenylethylamine salt, and the salt is subjected to alkalization, extraction, drying, concentration and other operations to obtain the S-1-phenylethylamine, wherein the product yield in each step can achieve more than 90%, and the ee values are more than 99%. The method of the present invention has characteristics of cheap and easily-available racemic catalyst, complete raw material use, good product yield, high optical purity and the like. In addition, great guidance and application values are provided in the S-1-phenylethylamine production preparation.
- -
-
-
- (R)- SELECTIVE AMINATION
-
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 0118
(2016/03/22)
-
- SYNTHESIS OF AMIDES AND AMINES FROM ALDEHYDES OR KETONES BY HETEROGENEOUS METAL CATALYSIS
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This invention concerns the first mild and efficient synthesis of primary amines and amides from aldehydes or ketones using a heterogeneous metal catalystand amine donor. The initial heterogeneous metal- catalyzed reaction between the carbonyl and the amine donor components is followed up with the addition of a suitable acylating agent component in one-pot. Hence, the present invention provides a novel catalytic one-pot three-component synthesis of amides. Moreover, the integration of enzyme catalysis allows for eco-friendly one-pot co-catalytic synthesis ofamides from aldehyde and ketone substrates, respectively. The process can be applied to the co-catalytic one-pot three-component synthesis of capsaicin and its analogues from vanillin or vanillyl alcohol. It can also be applied for asymmetric synthesis. In the present invention, a novel co-catalytic reductive amination/dynamic kinetic resolution (dkr) relay sequence for the asymmetric synthesis of optically active amides from ketones is disclosed. Moreover, implementation of a catalytic reductive amination/kinetic resolution (kr) relay sequence produces the corresponding optically active amide product and optical active primary amine product with the opposite stereochemistry from the starting ketones.
- -
-
Page/Page column 25
(2016/07/05)
-
- METHOD FOR PRODUCING NOVEL ORGANOMETALLIC COMPLEX AND AMINE COMPOUND
-
The purpose of the invention is to provide a novel organometallic compound that can be utilized as a catalyst having high generality, high activity, and excellent functional group selectivity. The invention pertains to a novel organometallic compound represented by general formula (1) that catalyzes a reductive amination reaction.
- -
-
Paragraph 0206
(2016/03/19)
-
- Identification of novel thermostable ω-transaminase and its application for enzymatic synthesis of chiral amines at high temperature
-
A novel thermostable ω-transaminase from Thermomicrobium roseum which showed broad substrate specificity and high enantioselectivity was identified, expressed and biochemically characterized. The advantage of this enzyme to remove volatile inhibitory by-products was demonstrated by performing asymmetric synthesis and kinetic resolution at high temperature.
- Mathew, Sam,Deepankumar, Kanagavel,Shin, Giyoung,Hong, Eun Young,Kim, Byung-Gee,Chung, Taeowan,Yun, Hyungdon
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p. 69257 - 69260
(2016/08/05)
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- Highly Productive and Enantioselective Enzyme Catalysis under Continuous Supported Liquid–Liquid Conditions Using a Hybrid Monolithic Bioreactor
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Enzyme-containing ionic liquids (ILs) were immobilized in cellulose-2.5-acetate microbeads particles embedded in a porous monolithic polyurethane matrix. This bioreactor was used under continuous liquid-liquid conditions by dissolving the substrates in a nonpolar organic phase immiscible with the ILs, thereby creating a biphasic system. Lipases (candida antarctica lipase B, CALB, candida rugosa lipase, CRL) were used to catalyze the enantioselective transesterification of racemic (R,S)-1-phenylethanol with vinyl butyrate and vinyl acetate, the esterification of (+/-)-2-isopropyl-5-methylcyclohexanol with propionic anhydride and the amidation of (R,S)-1-phenylethylamine with ethyl methoxyacetate. With this unique setup, very high productivities, that is, turnover numbers (TONs) up to 5.1×106 and space-time yields (STYs) up to 28 g product L?1 h?1, exceeding the corresponding values for batch-type reactions by a factor of 3100 and 40, respectively, were achieved while maintaining or even enhancing enantioselectivity compared to batch reactions via kinetic resolution. To our best knowledge, this is the first continuously operated bioreactor using supported liquid-liquid conditions that shows these features in the synthesis of chiral esters and amides.
- Sandig, Bernhard,Buchmeiser, Michael R.
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p. 2917 - 2921
(2016/11/02)
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- A New Generation of Smart Amine Donors for Transaminase-Mediated Biotransformations
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The application of ω-transaminase biocatalysts for the synthesis of optically pure chiral amines presents a number of challenges, including difficulties associated with displacing the challenging reaction equilibria. Herein, we report a highly effective approach using low equivalents of the new diamine donor, cadaverine, which enables high conversions of challenging substrates to the corresponding chiral amines in excellent ee. This approach paves the way for the design of self-sufficient fermentation processes combining transaminase biotransformations with existing strategies for cadaverine production by decarboxylation of endogenous lysine.
- Gomm, Andrew,Lewis, William,Green, Anthony P.,O'Reilly, Elaine
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supporting information
p. 12692 - 12695
(2016/08/30)
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- Cellulose as an efficient matrix for lipase and transaminase immobilization
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Immobilization of enzymes is important to improve their stability and to facilitate their recyclability, aiming to make biocatalytic processes more efficient. One of the important aspects is the utilization of cheap, abundant, and environmentally friendly carriers for enzyme immobilization. Here we report the use of functionalized cellulose for lipase and transaminase immobilization. High immobilization efficiencies (up to 90%) could be achieved for the transaminase from Vibrio fluvialis. For immobilized lipase CAL-B as well as the transaminase, good conversions and recyclability could be demonstrated in kinetic resolutions to afford chiral alcohols or amines. Moreover, such application of the immobilized transaminase enabled very high conversions in a continuous-flow process in the asymmetric synthesis of (S)-phenylethylamine (80% conversion, >99% ee).
- De Souza, Stefania P.,Junior, Ivaldo I.,Silva, Guilherme M. A.,Miranda, Leandro S. M.,Santiago, Marcelo F.,Leung-Yuk Lam, Frank,Dawood, Ayad,Bornscheuer, Uwe T.,De Souza, Rodrigo O. M. A.
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p. 6665 - 6671
(2016/02/03)
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- Stereoelectronic effects in the reaction of aromatic substrates catalysed by: Halomonas elongata transaminase and its mutants
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A transaminase from Halomonas elongata and four mutants generated by an in silico-based design were recombinantly produced in E. coli, purified and applied to the amination of mono-substituted aromatic carbonyl-derivatives. While benzaldehyde derivatives were excellent substrates, only NO2-acetophenones were transformed into the (S)-amine with a high enantioselectivity. The different behaviour of wild-type and mutated transaminases was assessed by in silico substrate binding mode studies.
- Contente, Martina Letizia,Planchestainer, Matteo,Molinari, Francesco,Paradisi, Francesca
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p. 9306 - 9311
(2016/10/13)
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- Isopropyl 2-ethoxyacetate—an efficient acylating agent for lipase-catalyzed kinetic resolution of amines in batch and continuous-flow modes
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Productivity [conversion (c) and specific reaction rate (rbatchor rflow)] and enantiomer selectivity [enantiomeric ratio (E) and enantiomeric excess (ee) of the products] of ethyl and isopropyl esters of acetic, 2-methoxyacetic and 2-ethoxyacetic acids as acylating agents were compared in the N-acylation of (±)-1-phenylethanamine rac-1 catalyzed by variously immobilized forms of Candida antarctica lipase B (CaLB) using shake flasks and continuous-flow reactors. The effect of the temperature in the 0–80 °C range on productivity and enantiomer selectivity in KRs of rac-1 was investigated with the isopropyl esters in continuous-flow mode using CaLB-filled minireactors. Isopropyl 2-ethoxyacetate surpassed the performance of ethyl 2-methoxyacetate in terms of both productivity (1.9–2.9 times higher rate in batch mode) and enantiomeric selectivity (ee(R)-amide>99.9% compared to 99.8%) providing at 40 °C high volumetric productivity (2.22 kg L?1h?1), specific reaction rate and enantiomeric excess (rflow=783 μmol min?1g?1, ee(R)-2c>99.9%).
- Oláh, Márk,Boros, Zoltán,Hornyánszky, Gábor,Poppe, László
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p. 7249 - 7255
(2016/10/26)
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- Chiroptical Asymmetric Reaction Screening via Multicomponent Self-Assembly
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Self-assembly of a stereodynamic phosphine ligand, Pd(II), and a chiral amine, amino alcohol, or amino acid generates characteristic UV and CD signals that can be used for quantitative stereochemical analysis of the bound substrate. A robust mix-and-measure chiroptical sensing protocol has been developed and used to determine the absolute configuration, ee, and yield of an amine produced by Ir-catalyzed asymmetric hydrogenation of an iminium salt. The analysis requires only 1 mg of the crude reaction mixture and minimizes cost, labor, time, and waste.
- De Los Santos, Zeus A.,Wolf, Christian
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supporting information
p. 13517 - 13520
(2016/10/31)
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