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58993-79-6Relevant academic research and scientific papers
Iterative Alanine Scanning Mutagenesis Confers Aromatic Ketone Specificity and Activity of L-Amine Dehydrogenases
Mu, Xiaoqing,Wu, Tao,Mao, Yong,Zhao, Yilei,Xu, Yan,Nie, Yao
, p. 5243 - 5253 (2021/11/16)
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.
Development of an engineered thermostable amine dehydrogenase for the synthesis of structurally diverse chiral amines
Chen, Fei-Fei,Chen, Qi,Liu, Lei,Wang, Dong-Hao,Wang, Zhi-Long,Xu, Jian-He,Zhang, Zhi-Jun,Zheng, Gao-Wei
, p. 2353 - 2358 (2020/05/13)
Amine dehydrogenases (AmDHs) are emerging as a class of attractive biocatalysts for synthesizing chiral amines via asymmetric reductive amination of ketones with inexpensive ammonia as an amino donor. However, the AmDHs developed to date exhibit limited substrate scope. Here, using directed evolution, we engineered a GkAmDH based on a thermostable phenylalanine dehydrogenase from Geobacillus kaustophilus. The newly developed AmDH is able to catalyze reductive amination of a diverse set of ketones and functionalized hydroxy ketones with ammonia or primary amines with up to >99% conversion, thus accessing structurally diverse chiral primary and secondary amines and chiral vicinal amino alcohols, with excellent enantioselectivity (up to >99% ee) and releasing water as the sole by-product.
Addition of Highly Polarized Organometallic Compounds to N-tert-Butanesulfinyl Imines in Deep Eutectic Solvents under Air: Preparation of Chiral Amines of Pharmaceutical Interest
Capriati, Vito,Cicco, Luciana,García-álvarez, Joaquín,González-Sabín, Javier,Perna, Filippo M.,Ríos-Lombardía, Nicolás,Salomone, Antonio,Vitale, Paola
, (2020/07/04)
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).
An Ammonium-Formate-Driven Trienzymatic Cascade for ω-Transaminase-Catalyzed (R)-Selective Amination
Chen, Fei-Fei,Liu, Lei,Wu, Jian-Ping,Xu, Jian-He,Zhang, Yu-Hui,Zhang, Zhi-Jun,Zheng, Gao-Wei
, p. 14987 - 14993 (2019/12/02)
(R)-Amination mediated by (R)-specific ω-transaminases generally requires costly d-alanine in excess to obtain the desired chiral amines in high yield. Herein, a one-pot, trienzymatic cascade comprising an (R)-specific ω-transaminase, an amine dehydrogenase, and a formate dehydrogenase was developed for the economical and eco-friendly synthesis of (R)-chiral amines. Using inexpensive ammonium formate as the sole sacrificial agent, the established cascade system enabled efficient ω-transaminase-mediated (R)-amination of various ketones, with high conversions and excellent ee (>99%); water and CO2 were the only waste products.
Stereoselective Synthesis of 1-Arylpropan-2-amines from Allylbenzenes through a Wacker-Tsuji Oxidation-Biotransamination Sequential Process
González-Martínez, Daniel,Gotor, Vicente,Gotor-Fernández, Vicente
, p. 2582 - 2593 (2019/05/15)
Herein, a sequential and selective chemoenzymatic approach is described involving the metal-catalysed Wacker-Tsuji oxidation of allylbenzenes followed by the amine transaminase-catalysed biotransamination of the resulting 1-arylpropan-2-ones. Thus, a series of nine optically active 1-arylpropan-2-amines were obtained with good to very high conversions (74–92%) and excellent selectivities (>99% enantiomeric excess) in aqueous medium. The Wacker-Tsuji reaction has been exhaustively optimised searching for compatible conditions with the biotransamination experiments, using palladium(II) complexes as catalysts and iron(III) salts as terminal oxidants in aqueous media. The compatibility of palladium/iron systems for the chemical oxidation with commercially available and made in house amine transaminases was analysed, finding ideal conditions for the development of a general and stereoselective cascade sequence. Depending on the selectivity displayed by selected amine transaminase, it was possible to produce both 1-arylpropan-2-amines enantiomers under mild reaction conditions, compounds that present therapeutic properties or can be employed as synthetic intermediates of chiral drugs from the amphetamine family. (Figure presented.).
Upgraded Bioelectrocatalytic N2 Fixation: From N2 to Chiral Amine Intermediates
Chen, Hui,Cai, Rong,Patel, Janki,Dong, Fangyuan,Chen, Hsiaonung,Minteer, Shelley D.
, p. 4963 - 4971 (2019/03/26)
Enantiomerically pure chiral amines are of increasing value in the preparation of bioactive compounds, pharmaceuticals, and agrochemicals. ω-Transaminase (ω-TA) is an ideal catalyst for asymmetric amination because of its excellent enantioselectivity and wide substrate scope. To shift the equilibrium of reactions catalyzed by ω-TA to the side of the amine product, an upgraded N2 fixation system based on bioelectrocatalysis was developed to realize the conversion from N2 to chiral amine intermediates. The produced NH3 was in situ reacted with l-alanine dehydrogenase to generate alanine with NADH as a coenzyme. ω-TA transferred the amino group from alanine to ketone substrates and finally produced the desired chiral amine intermediates. The cathode of the upgraded N2 fixation system supplied enough reducing power to synchronously realize the regeneration of reduced methyl viologen (MV?+) and NADH for the nitrogenase and l-alanine dehydrogenase. The coproduct, pyruvate, was consumed by l-alanine dehydrogenase to regenerate alanine and push the equilibrium to the side of amine. After 10 h of reaction, the concentration of 1-methyl-3-phenylpropylamine achieved 0.54 mM with the 27.6% highest faradaic efficiency and >99% enantiomeric excess (eep). Because of the wide substrate scope and excellent enantioselectivity of ω-TA, the upgraded N2 fixation system has great potential to produce a variety of chiral amine intermediates for pharmaceuticals and other applications.
Improved synthetic method of (R)-1-aryl-2-propylamine
-
, (2018/07/30)
The invention provides an improved synthetic method of (R)-1-aryl-2-propylamine. The improved synthetic method comprises the following steps of: adopting 1-arylacetone as a raw material, adding (R)-1-phenylethylamine, carrying out reductive amination reaction with hydrogen under a common action of a Lewis acid additive and a transitional metal hydrogenation catalyst; carrying out Pd/C catalytic hydrogenation on an obtained intermediate to remove phenethyl on nitrogen and thus obtaining (R)-1-aryl-2-propylamine. The improved synthetic method provided by the invention has the beneficial effectsthat the operation is simple, the adopted Lewis acid additive is low in cost and easy in obtaining, the yield and the enantioselectivity of a product are high, and the application value for industrialsynthesis of (R)-1-aryl-2-propylamine is very high.
Direct Reductive Amination of Carbonyl Compounds with H2 Using Heterogeneous Catalysts in Continuous Flow as an Alternative to N-Alkylation with Alkyl Halides
Laroche, Benjamin,Ishitani, Haruro,Kobayashi, Shū
supporting information, p. 4699 - 4704 (2018/12/04)
A general continuous-flow procedure for direct reductive amination of secondary and primary amines with aromatic and aliphatic aldehydes as well as ketones is reported. The use of hydrogen gas and commercially available Pt/C as a heterogeneous catalyst is a key. In addition to exhibiting an excellent functional group tolerance, this method allows the fast formation of C?N bonds without production of any hazardous chemical waste. Applications to the synthesis of key intermediates toward active pharmaceutical ingredients (Donepezil and Arformoterol/Tamsulosin) are also described. (Figure presented.).
Amine dehydrogenases: Efficient biocatalysts for the reductive amination of carbonyl compounds
Knaus, Tanja,B?hmer, Wesley,Mutti, Francesco G.
supporting information, p. 453 - 463 (2017/08/14)
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.
Vicinal Diamines as Smart Cosubstrates in the Transaminase-Catalyzed Asymmetric Amination of Ketones
Payer, Stefan E.,Schrittwieser, Joerg H.,Kroutil, Wolfgang
supporting information, p. 2553 - 2559 (2017/05/12)
Transaminases (TAs) have recently been established as catalysts for the asymmetric, reductive amination of prochiral ketones. Depending on the ketone substrate and the amine donor (the cosubstrate), equilibrium constants may limit high conversions; thus, methods to overcome this limitation are required. Removal of the co-product from the reaction equilibrium through spontaneous, intramolecular reactions has provided a successful solution to this problem; therefore, these amine donors have been named “smart cosubstrates”. Here, we present a comparison of various bifunctional amine donors including vicinal diamines as potential structural cosubstrate motifs. Upon TA-catalyzed deamination of 1,2-diamines, spontaneous dimerization of the resulting α-aminoketones and oxidation gave heteroaromatic pyrazines.