- 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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- 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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- Enzymatic Primary Amination of Benzylic and Allylic C(sp3)-H Bonds
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Aliphatic primary amines are prevalent in natural products, pharmaceuticals, and functional materials. While a plethora of processes are reported for their synthesis, methods that directly install a free amine group into C(sp3)-H bonds remain unprecedented. Here, we report a set of new-to-nature enzymes that catalyze the direct primary amination of C(sp3)-H bonds with excellent chemo-, regio-, and enantioselectivity, using a readily available hydroxylamine derivative as the nitrogen source. Directed evolution of genetically encoded cytochrome P411 enzymes (P450s whose Cys axial ligand to the heme iron has been replaced with Ser) generated variants that selectively functionalize benzylic and allylic C-H bonds, affording a broad scope of enantioenriched primary amines. This biocatalytic process is efficient and selective (up to 3930 TTN and 96percent ee), and can be performed on preparative scale.
- Jia, Zhi-Jun,Gao, Shilong,Arnold, Frances H.
-
supporting information
p. 10279 - 10283
(2020/07/27)
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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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- In Vitro and in Vivo One-Pot Deracemization of Chiral Amines by Reaction Pathway Control of Enantiocomplementary ω-Transaminases
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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
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p. 6945 - 6954
(2019/08/26)
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- Transition-Metal-Free Hydrogen Autotransfer: Diastereoselective N-Alkylation of Amines with Racemic Alcohols
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A practical method for the synthesis of α-chiral amines by alkylation of amines with alcohols in the absence of any transition-metal catalysts has been developed. Under the co-catalysis of a ketone and NaOH, racemic secondary alcohols reacted with Ellman's chiral tert-butanesulfinamide by a hydrogen autotransfer process to afford chiral amines with high diastereoselectivities (up to >99:1). Broad substrate scope and up to a 10 gram scale production of chiral amines were demonstrated. The method was applied to the synthesis of chiral deuterium-labelled amines with high deuterium incorporation and optical purity, including examples of chiral deuterated drugs. The configuration of amine products is found to be determined solely by the configuration of the chiral tert-butanesulfinamide regardless of that of alcohols, and this is corroborated by DFT calculations. Further mechanistic studies showed that the reaction is initiated by the ketone catalyst and involves a transition state similar to that proposed for the Meerwein–Ponndorf–Verley (MPV) reduction, and importantly, it is the interaction of the sodium cation of the base with both the nitrogen and oxygen atoms of the sulfinamide moiety that makes feasible, and determines the diastereoselectivity of, the reaction.
- Xiao, Miao,Yue, Xin,Xu, Ruirui,Tang, Weijun,Xue, Dong,Li, Chaoqun,Lei, Ming,Xiao, Jianliang,Wang, Chao
-
supporting information
p. 10528 - 10536
(2019/07/17)
-
- Method for synthesizing chiral amine compound
-
The present invention provides a method for synthesizing a chiral amine compound. The method comprises the following steps: (1) reacting a compound of formula I with t-butylsulfonamide in the presenceof a catalyst to obtain a compound having a structure represented by formula II; 2) reacting the compound of the formula II in a hydrogen atmosphere in the presence of an iridium catalyst and a ligand to obtain a compound of formula III; and (3) carrying out a t-butylsulfonyl group removal reaction on the compound of the formula III to obtain the chiral amine compound. The method constructs the structure of sulfonamide by a keto carbonylgroup, and synthesizes the chiral amine compound with the aralkylamine structure by an asymmetric catalytic hydrogenation reaction of the sulfonamide structure, the ee value is generally 80% or above, the highest ee value is 99% or above, the yield of each step reaction can reach 90% or above, and the total yield is high.
- -
-
Paragraph 0064; 0071-0073; 0117-0119
(2019/10/01)
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- 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)
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- Method for synthesis of (R)-1-(4-methyl phenyl) ethylamine
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The invention discloses a method for synthesis of (R)-1-(4-methyl phenyl) ethylamine. The method includes: subjecting a compound 3 to deacylation to obtain (R)-1-(4-methyl phenyl) ethylamine in a C4-C10 monoalcohol solvent and in the presence of alkali metal hydroxide, wherein R refers to ethanoyl, propionyl or butyryl. The method is low in synthesis cost, simple in step, safe in operation, low inby-products, simple in aftertreatment, easy to purify intermediate products and final products, high in whole yield, high in final product purity and easy in industrialization.
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- Mapping the substrate scope of monoamine oxidase (MAO-N) as a synthetic tool for the enantioselective synthesis of chiral amines
-
A library of 132 racemic chiral amines (α-substituted methylbenzylamines, benzhydrylamines, 1,2,3,4-tetrahydronaphthylamines (THNs), indanylamines, allylic and homoallylic amines, propargyl amines) was screened against the most versatile monoamine oxidase (MAO-N) variants D5, D9 and D11. MAO-N D9 exhibited the highest activity for most substrates and was applied to the deracemisation of a comprehensive set of selected primary amines. In all cases, excellent enantioselectivity was achieved (e.e. >99%) with moderate to good yields (55–80%). Conditions for the deracemisation of primary amines using a MAO-N/borane system were further optimised using THN as a template addressing substrate load, nature of the enzyme preparation, buffer systems, borane sources, and organic co-solvents.
- Herter, Susanne,Medina, Florian,Wagschal, Simon,Benha?m, Cyril,Leipold, Friedemann,Turner, Nicholas J.
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p. 1338 - 1346
(2017/10/06)
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- 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)
-
- 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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- 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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p. 453 - 463
(2017/08/14)
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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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- Whole-Cell Biocatalysts for Stereoselective C-H Amination Reactions
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Enantiomerically pure chiral amines are ubiquitous chemical building blocks in bioactive pharmaceutical products and their synthesis from simple starting materials is of great interest. One of the most attractive strategies is the stereoselective installation of a chiral amine through C-H amination, which is a challenging chemical transformation. Herein we report the application of a multienzyme cascade, generated in a single bacterial whole-cell system, which is able to catalyze stereoselective benzylic aminations with ee values of 97.5 %. The cascade uses four heterologously expressed recombinant enzymes with cofactors provided by the host cell and isopropyl amine added as the amine donor. The cascade presents the first example of the successful de novo design of a single whole-cell biocatalyst for formal stereoselective C-H amination.
- Both, Peter,Busch, Hanna,Kelly, Paul P.,Mutti, Francesco G.,Turner, Nicholas J.,Flitsch, Sabine L.
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p. 1511 - 1513
(2016/02/14)
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- A Single Lipase-Catalysed One-Pot Protocol Combining Aminolysis Resolution and Aza-Michael Addition: An Easy and Efficient Way to Synthesise β-Amino Acid Esters
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A novel one-pot protocol combining aza-Michael addition and aminolysis resolution was developed to obtain chiral β-amino acid esters with lipase B from Candida antarctica (CAL-B) as the only catalyst. This method is conducted under mild reaction conditions and is very easy to handle. After a series of detailed optimization studies, ten racemic aromatic or aliphatic amines were subjected to this one-pot procedure, and twelve chiral β-amino acid esters and ten chiral amides were successfully synthesised with excellent ee values in theoretical yields. Scaled-up procedures also worked without apparent reduction in reaction rate or enantioselectivity, which makes this method suitable for large-scale production of chiral β-amino acid esters. A one-pot protocol for simultaneous synthesis of chiral β-amino acid esters and amides was developed by combining single lipase B from Candida antarctica (CAL-B) catalysed aza-Michael addition and aminolysis resolution. This method requires mild reaction conditions and is very easy to handle. Chiral β-amino acid esters and chiral amides were obtained with excellent ee values and in theoretical yields.
- Xu, Fan,Wu, Qiongsi,Chen, Xiaoyang,Lin, Xianfu,Wu, Qi
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p. 5393 - 5401
(2015/08/24)
-
- 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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p. 1732 - 1740
(2015/06/02)
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- Enhancing thermostability and organic solvent tolerance of ω-transaminase through global incorporation of fluorotyrosine
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Here, we have utilized the incorporation of non-canonical amino acids as a tool kit to improve enzyme properties for organic synthesis applications. The global incorporation of 3-fluorotyrosine (FY) into ω-transaminase (ω-TA) to give ω-TA[FY] enhanced the thermostability and organic solvent tolerance without altering substrate specificity and enantioselectivity. Moreover, ω-TA[FY] was able to completely convert 25 mM of acetophenone into (S)-1-phenylethylamine (ee>99%) in the presence of 20% DMSO (v/v) which is 2-fold higher when compared to wild-type ω-TA.
- Deepankumar, Kanagavel,Shon, Minsu,Nadarajan, Saravanan Prabhu,Shin, Giyoung,Mathew, Sam,Ayyadurai, Niraikulam,Kim, Byung-Gee,Choi, Sei-Hyun,Lee, Sang-Hyeup,Yun, Hyungdon
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p. 993 - 998
(2014/04/03)
-
- A highly fluorescent metallosalalen-based chiral cage for enantioselective recognition and sensing
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A highly fluorescent coordination cage [Zn8L4I 8] has been constructed by treating enantiopure pyridyl- functionalized metallosalalen units (L) with zinc(II) iodide and characterized by a variety of techniques including microanalysis, thermogravimetric analysis (TGA), circular dichroism (CD) spectroscopy, and single-crystal and powder X-ray diffraction. Strong intermolecular π-π, CH-π, and CH-I interactions direct packing of the cage molecules to generate a 3D polycage network interconnected by pentahedral cages formed by adjacent pentamers. The cage has an amphiphilic helical cavity decorated with chiral NH functionalities capable of interactions with guest species such as saccharides. The fluorescence of the cage was greatly enhanced by five enantiomeric saccharides in solution, with enantioselectivity factors of 2.480-4.943, and by five enantiomeric amines in the solid state, with enantioselective fluorescence enhancement ratios of 1.30-3.60. This remarkable chiral sensing of both saccharides and amines with impressive enantioselectivity may result from the steric confinement of the cavity as well as its conformational rigidity. It holds great promise for the development of novel chiral cage materials for sensing applications. Cage-based chiral sensor: A highly fluorescent coordination cage [Zn8L 4I8] can be prepared from enantiopure pyridyl- functionalized metallosalalen units (L). The cage has an amphiphilic helical cavity decorated with chiral NH functionalities and supramolecular interactions generate a 3D polycage network interconnected by pentahedral cages formed by adjacent pentamers (see graphic). The fluorescence of the cage is greatly enhanced either in solution or in the solid state in the presence of enantiomeric saccharides or amines, respectively, with significant enantioselectivity factors.
- Dong, Jinqiao,Zhou, Yanfang,Zhang, Fangwei,Cui, Yong
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supporting information
p. 6455 - 6461
(2014/06/09)
-
- Enantioselective synthesis of (R)-2-arylpropanenitriles catalysed by ene-reductases in aqueous media and in biphasic ionic liquid-water systems
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The enantioselective reduction of α-methylene nitrile derivatives catalysed by ene-reductases affords the corresponding (R)-2-arylpropanenitriles with high conversion values. The reaction is investigated either in aqueous medium (with an organic cosolvent or by loading the substrate onto hydrophobic resins) or in a biphasic ionic liquid-water system. The use of ionic liquids, herein with isolated ene-reductases, is found to improve the work-up and the substrate recovery method. The synthetic manipulation of the final chiral nitrile derivatives indicates how this biocatalysed method can be exploited for the preparation of a wide range of chiral compounds.
- Brenna, Elisabetta,Crotti, Michele,Gatti, Francesco G.,Manfredi, Alessia,Monti, Daniela,Parmeggiani, Fabio,Santangelo, Sara,Zampieri, Davila
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p. 2425 - 2431
(2014/08/18)
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- Modification of supported Pd catalysts by alkalic salts in the selective racemization and dynamic kinetic resolution of primary amines
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Supported Pd nanoparticles (PdNPs) were modified with various alkalic salts by incipient wetness impregnation method. The effect of the salts on the catalytic activity and selectivity behavior of Pd catalysts for the racemization of (S)-1-phenylethylamine was investigated. The presence of alkalic salts can greatly enhance the selectivity of Pd catalysts, without significantly decreasing the catalytic activity. This modification method is suitable for PdNPs supported on various supports, such as micro/mesoporous silica and activated carbon. Combined with the immobilized lipases (Novozyme 435), this catalyst system can efficiently catalyze the dynamic kinetic resolution (DKR) of 1-phenylethylamine with yield and enantioselectivity up to 97% and 99%, respectively. The Royal Society of Chemistry.
- Jin, Qianru,Jia, Guoqing,Zhang, Yanmei,Li, Can
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p. 464 - 471
(2014/02/14)
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- One-pot one-step deracemization of amines using ω-transaminases
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In this study, we developed a one-pot one-step deracemization method for the production of various enantiomerically pure amines using two opposite enantioselective ω-TAs. Using this method, various aromatic amines were successfully converted to their (R)-forms (>99%) with good conversion.
- Shin, Giyoung,Mathew, Sam,Shon, Minsu,Kim, Byung-Gee,Yun, Hyungdon
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p. 8629 - 8631
(2013/09/23)
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- Asymmetric synthesis of nonracemic primary amines via spiroborate-catalyzed reduction of pure (E)- and (Z)-O-benzyloximes: Applications toward the synthesis of calcimimetic agents
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Highly enantiopure (1-aryl)- and (1-naphthyl)-1-ethylamines were synthesized by the borane-mediated reduction of single-isomeric (E)- and (Z)-O-benzyloxime ethers using the stable spiroborate ester derived from (S)-diphenyl valinol and ethylene glycol as the chiral catalyst. Primary (R)-arylethylamines were prepared by the reduction of pure (Z)-ethanone oxime ethers in up to 99% ee using 15% of catalyst. Two convenient and facile approaches to the synthesis of new and known calcimimetic analogues employing enantiopure (1-naphthalen-1-yl)ethylamine as chiral precursor are described.
- Ou, Wenhua,Espinosa, Sandraliz,Meléndez, Héctor J.,Farré, Silvia M.,Alvarez, Jaime L.,Torres, Valerie,Martínez, Ileanne,Santiago, Kiara M.,Ortiz-Marciales, Margarita
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p. 5314 - 5327
(2013/07/25)
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- Nickel nanoparticles as racemization catalysts for primary amines
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By combining bases that are known to racemize benzylic amines with a nickel(II) salt, active nickel nanoparticles were obtained that can be used as catalysts in the racemization of both aliphatic and benzylic primary amines. The nanoparticles are stable in the ionic liquid tetrabutylammonium bromide and can complete most racemizations within a few hours with excellent selectivity. The problem of the incompatibility of the strongly reducing racemization catalyst and the enzymatic amine resolution catalyst was overcome by using a two-pot system with a biphasic racemization step. Consecutive contact of a nonane layer that contained the amine with the acylating enzyme and with the racemizing Ni nanoparticles in the ionic liquid allowed the 50 % amide yield limit of a kinetic resolution to be successfully surpassed. Copyright
- Geukens, Inge,Plessers, Eva,Seo, Jin Won,De Vos, Dirk E.
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p. 2623 - 2628
(2013/07/11)
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- An efficient single-enzymatic cascade for asymmetric synthesis of chiral amines catalyzed by ω-transaminase
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An efficient single-enzymatic cascade approach for the asymmetric synthesis of chiral amines has been developed, which applies the amino donor 3-aminocyclohexa-1,5-dienecarboxylic acid spontaneously tautomerizing to reach reaction completion with excellen
- Wang, Bo,Land, Henrik,Berglund, Per
-
supporting information
p. 161 - 163
(2013/02/23)
-
- Organocatalytic asymmetric biomimetic transamination of aromatic ketone to optically active amine
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An asymmetric biomimetic transamination of aromatic ketones to optically active amines with o-HOPhCH2NH2 as amine source catalyzed by hydroquinine-derived chiral base is described. Up to 85% ee was obtained.
- Xie, Ying,Pan, Hongjie,Xiao, Xiao,Li, Songlei,Shi, Yian
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supporting information
p. 8960 - 8962,3
(2012/12/12)
-
- Organocatalytic asymmetric biomimetic transamination of aromatic ketone to optically active amine
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An asymmetric biomimetic transamination of aromatic ketones to optically active amines with o-HOPhCH2NH2 as amine source catalyzed by hydroquinine-derived chiral base is described. Up to 85% ee was obtained.
- Xie, Ying,Pan, Hongjie,Xiao, Xiao,Li, Songlei,Shi, Yian
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supporting information
p. 8960 - 8962
(2013/01/15)
-
- Cyclohexylamine oxidase as a useful biocatalyst for the kinetic resolution and dereacemization of amines
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The biocatalytic performance of a cloned cyclohexylamine oxidase derived from Brevibacterium oxydans IH-35A towards structurally different amines was investigated. Cycloalkyl primary amines, alkyl aryl amines, and α-carbon-substituted aliphatic amines were identified as suitable substrates for the biocatalyst based on an activity assay. Kinetic resolutions of several amines by either recombinant whole cells or crude enzyme extracts prepared therefrom gave enantiomerically pure (R)-amines besides the corresponding ketones. When cyclohexylamine oxidase in combination with a borane-ammonia complex as reducing agent was applied to the deracemization of several substrates, excellent enantiomeric ratios (>99:1) and good isolated yields (62%-75%) of the corresponding (R)-amines were obtained.
- Leisch, Hannes,Grosse, Stephan,Iwaki, Hiroaki,Hasegawa, Yoshie,Lau, Peter C.K.
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experimental part
p. 39 - 45
(2012/03/07)
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- Solvent-free kinetic resolution of primary amines catalyzed by Candida antarctica lipase B: Effect of immobilization and recycling stability
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Highly enantioselective (E >200) N-acylation of nine racemic primary amines with isopropyl methoxyacetate in the presence of Candida antarctica lipase B (Novozym 435) has been reported to yield the unreacted (S)-amines (ee ≥98%) and produced the (R)-amides (ee ≥95%) at 50% conversion under solvent-free conditions. One of the amines and the acyl donor have been used in an equimolar ratio at room temperature (23 °C). Under the reaction conditions, the reuse stability of Novozym 435 with 1-phenylethylamine (as a model compound) has been shown to be poor while somewhat improved stability has been observed with an in-house prepared sol-gel CAL-B catalyst.
- Paeivioe, Mari,Perkioe, Paeivi,Kanerva, Liisa T.
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experimental part
p. 230 - 236
(2012/06/15)
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- COMPOSITIONS AND METHODS FOR CYCLOFRUCTANS AS SEPARATION AGENTS
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The present invention relates to derivatized cyclofructan compounds, compositions comprising derivatized cyclofructan compounds, and methods of using compositions comprising derivatized cyclofructan compounds for chromatographic separations of chemical species, including enantiomers. Said compositions may comprise a solid support and/or polymers comprising derivatized cyclofructan compounds.
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Page/Page column 45-49; 62
(2010/12/31)
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- Transaminations with isopropyl amine: Equilibrium displacement with yeast alcohol dehydrogenase coupled to in situ cofactor regeneration
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Enantiopure chiral amines synthesis using ω-transaminases is hindered by an unfavourable equilibrium, but when using isopropylamine as the amine donor the equilibrium can be completely displaced by using a specific dehydrogenase in situ for removal of formed acetone. The Royal Society of Chemistry 2010.
- Cassimjee, Karim Engelmark,Branneby, Cecilia,Abedi, Vahak,Wells, Andrew,Berglund, Per
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supporting information; experimental part
p. 5569 - 5571
(2010/09/10)
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- Heterogeneous raney nickel and cobalt catalysts for racemization and dynamic kinetic resolution of amines
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Raney metals were studied as heterogeneous catalysts for racemization and dynamic kinetic resolution (DKR) of chiral amines, as an alternative to metals like palladium or ruthenium. Both Raney nickel and cobalt were able to selectively racemize various chiral amines with high selectivity. In the racemization of benzylic primary amines, the minor formation of side products, e.g., secondary amines, can be suppressed by varying the hydrogen pressure. In the racemization of aliphatic amines over Raney catalysts, the selectivity is very high, with the enantiomeric amine as the sole product. DKR of racemic aliphatic amines can be performed with immobilized Candida antarctica lipase B and Raney nickel in one pot; for 2-hexylamine, a yield of 95% of the acetylated amide was achieved, with 97% ee. Attention is devoted to the compatibility of the enzyme and the metal catalyst during the DKR. For benzylic primary amines, a two-pot process is proposed in which the liquid is alternatingly shuttled between two vessels containing the solid racemization catalyst and the biocatalyst. After 4 such cycles, the amide of (R)-1-phenylethylamine was obtained with 94% yield and more than 90% ee.
- Parvulescu, Andrei N.,Jacobs, Pierre A.,De Vos, Dirk E.
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scheme or table
p. 113 - 121
(2009/04/16)
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- Optically active amines by enzyme-catalyzed kinetic resolution
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Chiral amines are resolved by an enzyme-catalyzed kinetic resolution. Key steps are the selective acylation of one enantiomer with isopropyl methoxyacetate, separation of the resulting amide from the unreacted antipode, and finally amide hydrolysis. The p
- Ditrich, Klaus
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experimental part
p. 2283 - 2287
(2009/04/06)
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- Palladium catalysts on alkaline-earth supports for racemization and dynamic kinetic resolution of benzylic amines
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Palladium catalysts on alka-line-earth supports were studied as new heterogeneous catalysts for racemization of chiral benzylic amines such as 1-phenylethylamine. Particularly 5% Pd/BaSO4 and 5% Pd/CaCO 3 were able to selectively racemize amines, with minimal formation of secondary amines or hydrogenolysis to ethylbenzene. In contrast, these side reactions were pronounced on Pd/C. A reaction mechanism is proposed that is consistent with the reaction kinetics. The catalyst activity was found to depend on the number of available surface Pd atoms, determined by titration with CO. The selectivity crucially depends on the rate of condensation of the amine and the primary imine. which is highest on Pd/C. The racemization catalysts were combined in one pot with an immobilized lipase to perform dynamic kinetic resolution of chiral amines. High yields (up to 88%) of essentially enantiopure amides were obtained in a single step. The chemo-enzymatic catalyst system proved to be stable and could be reused without losing the initial activity.
- Parvulescu, Andrei N.,Jacobs, Pierre A.,De Vos, Dirk E.
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p. 2034 - 2043
(2008/02/03)
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- Asymmetric synthesis of primary amines via the spiroborate-catalyzed borane reduction of oxime ethers
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The enantioselective borane reduction of O-benzyloxime ethers to primary amines was studied under catalytic conditions using the spiroborate esters 5-10 derived from nonracemic 1,2-amino alcohols and ethylene glycol. Effective catalytic conditions were achieved using only 10% of catalyst 5 derived from diphenylvalinol in dioxane at 0°C resulting in complete conversion to the corresponding primary amine in up to 99% ee.
- Huang, Xiaogen,Ortiz-Marciales, Margarita,Huang, Kun,Stepanenko, Viatcheslav,Merced, Francisco G.,Ayala, Angel M.,Correa, Wildeliz,De Jesus, Melvin
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p. 1793 - 1795
(2008/02/02)
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- Resolution of 1-arylalkylamines with 3-O-hydrogen phthalate glucofuranose derivatives: Role of steric bulk in a family of resolving agents
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The development of three new acidic resolving agents which are hydrogen phthalates of 1,2:5,6-di-O-isopropylidene-α-d-glucofuranose 1, 1,2:5,6-di-O-cyclohexylidene-α-d-glucofuranose 2 and 1,2-O- cyclohexylidene-5,6-O-diphenylmethylidene-α-d-glucofuranose 3 is shown for the resolution of 1-arylalkylamines 7a-k. The salts between 1, 2 and (RS)-1-arylalkylamines 7a-k selectively crystallize 1?(S) 7a-j and 2?(S) 7a-h salts, allowing us to recover the corresponding bases (S) 7a-j and (S) 7a-h, respectively, in good yield and enantiomeric excess (73-95% ee). Whereas, the salts between 3 and (RS)-1-arylalkylamines 7a-c,g-i,k selectively crystallize 3?(S)-7a-c,g-i salts to recover the corresponding bases (S)-7a-c,g-i in poor enantiomeric excess (4-35% ee). The difference between the resolving ability of 1 and 2 for 1-arylalkylamines 7a-h is very slight, but there is considerable difference compared to ortho-substituted 1-arylalkylamines 7i and 7j. The role of substituents on a family of resolving agents 1, 2 and 3 is also discussed to interpret their resolving ability.
- Mereyala, Hari Babu,Koduru, Sreenivasulu Reddy,Cheemalapati, Venkata Narasimhaji
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p. 259 - 267
(2007/10/03)
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- Synthesis of enantiopure 6-methoxy-2-naphthylglycolic acid and its application as a resolving agent
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6-Methoxy-2-naphthylglycolic acid (6-MNGA) was designed as a novel acidic resolving agent, on the model of 2-naphthylglycolic acid (2-NGA). Enantiopure 6-MNGA was easily obtained from commercially available 2-bromo-6- methoxynaphthalene through four steps and was found to show a better chiral recognition ability for racemic 1-arylethylamines than the prototype 2-NGA did. The X-ray crystallographic analyses of less-soluble diastereomeric salts revealed that the introduction of a methoxy group at the 6-position of the 2-NGA skeleton made CH/π interaction(s) effective between 6-MNGA molecules and also between the 6-MNGA molecule and the target amine molecule. The methoxy group was also found to contribute to the realization of effective van der Waals interaction. These interactions played important roles for the stabilization of the less-soluble diastereomeric salts to improve the chiral recognition ability of 6-MNGA, compared to that of 2-NGA.
- Shimada, Takayoshi,Kobayashi, Yuka,Saigo, Kazuhiko
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p. 3807 - 3813
(2007/10/03)
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- Optical resolution reagent and manufacturing method of optically active amines that uses it
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PROBLEM TO BE SOLVEDTo provide an effective reagent for optical resolution which produce an optically active amines by resolving the (+/-)-amines and the method for producing the optically active amines characterized by using the same reagent. SOLUTION The O-alkylthiophosphoric acid represented as the following formula (1) is effective for the optical resolution of various amines.
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Page/Page column 19-20
(2008/06/13)
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- Resolution of 1-arylalkylamines with 6-(1,2:3,4-di-O-isopropylidene- α-D-galactopyranosyl)hydrogen phthalate
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The resolving ability of a new acidic resolving agent, the hydrogen phthalate of 1,2:3,4-di-O-isopropylidene-α-D-galactopyranose 1, against various 1-arylalkylamines 2a-k is described. Treatment of 1 with amines 2a-f to obtain diastereomeric salts 1·(S)2a-f in 2-propanol allowing the corresponding (S)-amines 2a-f to be recovered in good yield and 61-89% ee. Recrystallization in dichloromethane/hexane, and regeneration gave the amines in enhanced enantiomeric purity (>98% ee). 1 resolved 1-phenylpropylamine 2f in high enantiomeric purity (99% ee) than 1-phenylethylamine 2g (11% ee) and o- and m-methoxy 2h-i, o-chloro-2j and p-fluoro-2k substituted 1-arylamines (11-19% ee). A possible chiral recognition mechanism based on the ability of 1 to exist in two conformations is described.
- Mereyala, Hari Babu,Fatima, Liyakat,Pola, Pallavi
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p. 585 - 587
(2007/10/03)
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- Resolution of methyl-1-phenylethylamines by acidic derivatives of 1-phenylethylamine
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Methyl-1-phenylethylamines were resolved by phenylethylamine derivatives formed with a homologous series of dicarboxylic acids. The structure of the 4-methyl-1-phenylethylamine N-(1-phenylethylamine) succinic acid monoamide diastereoisomeric salt was investigated by single crystal X-ray diffraction.
- Balint, Jozsef,Schindler, Jozsef,Egri, Gabriella,Hanusz, Miklos,Marthi, Katalin,Juvancz, Zoltan,Fogassy, Elemer
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p. 3401 - 3405
(2007/10/03)
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- A new hydrogen-bonding motif for chiral recognition in the diastereomeric salts of racemic 1-phenylethylamine derivatives with enantiopure O-ethyl phenylphosphonothioic acid
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(Chemical Equation Presented) An enantiopure phosphonothioic acid showed a unique and superior chiral recognition ability, arising from its P-stereogenicity, for racemic 1-phenylethylamine derivatives through diastereomeric crystallization. Spherical molecular clusters, associated by hydrogen bonds and CH/π interactions, aggregated with high symmetry in the less-soluble diastereomeric salts.
- Kobayashi, Yuka,Morisawa, Fumi,Saigo, Kazuhiko
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p. 4227 - 4230
(2007/10/03)
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- Enantioselective synthesis of primary 1-(aryl)alkylamines by nucleophilic 1,2-addition of organolithium reagents to hydroxyoxime ethers and application to asymmetric synthesis of G-protein-coupled receptor ligands
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(E)-Arylaldehyde oxime ethers bearing a (1S)-2-hydroxy-1-phenylethyl or (2R)-1-hydroxy-2-phenylethyl group as a chiral auxiliary, both derived from a single precursor, methyl (R)-mandelate, underwent nucleophilic addition with organolithium reagents via six-membered chelates to give the diastereomerically enriched (R)- and (S)-adducts, respectively, which, after chiral auxiliary removal by reductive N-O bond cleavage, led to the corresponding (R)- and (S)-1-(aryl)ethylamines. This organolithium addition protocol using methyllithium was applied in an enantiodivergent fashion to the preparation of both enantiomers of 1-(2-hydroxyphenyl)ethylamine, which has been previously used as an efficient chiral auxiliary for the synthesis of natural products in this laboratory. The synthetic utility of this methodology involving diastereoselective methyl addition was demonstrated by further application to the asymmetric synthesis of a new type of calcium receptor agonist (calcimimetics), (R)-(+)-NPS R-568 and its thio analogue. Furthermore, diastereoselective vinylation was accomplished by application of the hydroxy oxime ether-based protocol using vinyllithium, which allowed the development of the enantioselective synthesis of the NK-1 receptor antagonists, (+)-CP-99,994 and (+)-CP-122,721.
- Atobe, Masakazu,Yamazaki, Naoki,Kibayashi, Chihiro
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p. 5595 - 5607
(2007/10/03)
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- Resolution of 1-arylethylamines with 5-(1,2-O-isopropylidene-3,6-anhydro- α-D-glucofuranosyl) hydrogen phthalate
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The potential of the hydrogen phthalate of 1,2-O-isopropylidene-3,6- anhydro-α-D-glucofuranose 1 obtainable by the reaction of phthalic anhydride with 1,2-O-isopropylidene-3,6-anhydro-α-D-glucofuranose 8 as a new resolving agent is shown. The salts between 1 and (RS)-1-arylethylamines 2-6 and (RS)-1-arylpropylamine 7 selectively crystallize 1·(R)-salts allowing the recovery of the corresponding (R)-amines 2-7. The more soluble 1·(S)-salts were analogously processed to obtain (S)-amines, respectively. In all of the cases (R)- and (S)-amines 2-7 were obtained in high chemical yield and enantiomeric excess >98%. Resolving agent 1 has been recovered in a quantitative yield and high purity.
- Mereyala, Hari Babu,Pola, Pallavi
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p. 2683 - 2685
(2007/10/03)
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- 3-oxopropane-1-sulphonic acids and sulphonates
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The invention relates to 1,3-disubstituted-3-oxopropane-1-sulfonic acids and sulfonates and enantiomerically inriched forms thereof. The invention further relates to the use of these enantiomerically inriched compounds to resolve mixtures of enantiomers, in particular mixtures of enantiomers of amino-functionalized compounds.
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Page/Page column 12
(2008/06/13)
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- Highly Enantioselective Hydrogen-Transfer Reductive Amination: Catalytic Asymmetric Synthesis of Primary Amines
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Ammonium formate is the hydrogen source in the catalytic asymmetric reductive amination of ketones presented here (Leuckart-Wallach-type reaction). The reaction proceeds smoothly in methanol in the presence of Ir, Rh, and Ru catalysts. Primary amines were obtained as products in good yields with high enantioselectivities after hydrolytic workup when [((R)-tol-binap) RuCl 2] was used as the catalyst (see scheme). R1, R 2=alkyl, aryl.
- Kadyrov, Renat,Riermeier, Thomas H.
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p. 5472 - 5474
(2007/10/03)
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- Synthesis of enantiomerically pure amino-substituted fused bicyclic rings
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This invention describes various processes for synthesis and resolution of racemic amino-substituted fused bicyclic ring systems. One process utilizes selective hydrogenation of an amino-substituted fused bicyclic aromatic ring system. An alternative process prepares the racemic amino-substituted fused bicyclic ring system via nitrosation. In addition, the present invention describes the enzymatic resolution of a racemic mixture to produce the (R)- and (S)-forms of amino-substituted fused bicyclic rings as well as a racemization process to recycle the unpreferred enantioner. Further provided by this invention is an asymmetric synthesis of the (R)- or (S)-enantiomer of primary amino-substituted fused bicyclic ring systems.
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- Nucleophilic addition of methyllithium to chiral oxime ethers: Asymmetric preparation of 1-(aryl)ethylamines and application to a synthesis of calcimimetics (+)-NPS R-568 and its thio analogue
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Chiral (E)-arylaldehyde oxime ethers, prepared using (R)-1-phenyl-1,2-ethanediol as a chiral auxiliary, undergo nucleophilic addition with methyllithium to give diastereomerically enriched O-alkyl hydroxylamines which, after reductive N-O bond cleavage, lead to the corresponding (R)-1-(aryl)ethylamines. This methodology has been applied to the enantioselective synthesis of a new type of arylalkylamine calcimimetics (R)-(+)-NPS R-568 and its thio analogue.
- Yamazaki, Naoki,Atobe, Masakazu,Kibayashi, Chihiro
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p. 5029 - 5032
(2007/10/03)
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- Ruthenium-catalysed asymmetric hydrosilylation of ketoximes using chiral oxazolinylferrocenylphosphines
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Chiral ruthenium(II) complexes, RuCl2(PPh3)(oxazolinylferrocenylphosphine), have been found to be effective catalysts for asymmetric hydrosilylation of ketoximes to give the corresponding primary amines in good yields with high enant
- Takei,Nishibayashi,Ishii,Mizobe,Uemura,Hidai
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p. 2360 - 2361
(2007/10/03)
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- A high-performance, tailor-made resolving agent: Remarkable enhancement of resolution ability by introducing a naphthyl group into the fundamental skeleton1
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A novel resolving agent, 2-naphthylglycolic acid (2-NGA), was designed for p-substituted 1-arylethylamines on the basis of the consideration that a rigid and large naphthyl group would be favorable for the close packing of supramolecular hydrogen-bond sheets formed between the carboxy groups of 2-NGA and the amino groups of p-substituted 1-arylethylamines. Racemic 2-NGA was readily available from commercially available raw materials, and both enantiopure forms could be obtained by simple diastereomeric resolution with enantiopure 1-phenyl-ethylamine. Thus-prepared enantiopure 2-NGA was found to have an excellent resolution ability not only for p-substituted 1-arylethylamines, but also for a wide variety of chiral primary amines. X-Ray crystallographic analyses of the less- and more-soluble diastereomeric salts revealed that this excellent resolution ability of 2-NGA arose from the formation of a supramolecular hydrogen-bond sheet with the primary amine, as we had expected, and also from the possible achievement of an infinite chain of CH... π interaction between its naphthyl group and the aromatic group of the amine, which was formed in the hydrophobic region of the supramolecular hydrogen-bond sheet.
- Kinbara, Kazushi,Harada, Yoshiko,Saigo, Kazuhiko
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p. 1339 - 1347
(2007/10/03)
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- Method for producing optically active 1-phenylethylamines
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PCT No. PCT/EP97/02988 Sec. 371 Date Dec. 17, 1998 Sec. 102(e) Date Dec. 17, 1998 PCT Filed Jun. 9, 1997 PCT Pub. No. WO97/49665 PCT Pub. Date Dec. 31, 1997The invention concerns a new method for producing optically active 1-phenylethylamines, wherein (a) racemic 1-phenylethylamines are reacted with (S)-(-)-N-phenylcarbamate lactic acid in the presence of an aliphatic or aromatic hydrocarbon and in the presence of a lower aliphatic alcohol, wherein the reaction components are measured so that for every mole of racemic amine, between 0.25 and 0.5 mole of (S)-(-)-N-phenylcarbamate lactic acid are present, the reaction mixture is then concentrated at a liquid-phase temperature of up to 40 DEG C., the resulting solid product is separated, treated with diluted, aqueous alkaline lye in the presence of a hydrocarbon, and the respective (R)-amine is isolated by distillation from the organic phase, and if necessary, (b) the mother liquor remaining after the separation of the solid product is reacted in the presence of a lower aliphatic alcohol with (S)-(-)-N-phenylcarbamate lactic acid, wherein the reaction components are measured so that the molar quantity of (S)-(-)-N-phenylcarbamate lactic acid is twice as great as the quantity of (R)-amine still remaining in the mother liquor, the reaction mixture is then concentrated at a liquid-phase temperature of up to 40 DEG C., the resulting solid product is separated and the (S)-amine is isolated by distillation from the mother liquor.
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