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72522-20-4Relevant academic research and scientific papers
Two-Enzyme Hydrogen-Borrowing Amination of Alcohols Enabled by a Cofactor-Switched Alcohol Dehydrogenase
Thompson, Matthew P.,Turner, Nicholas J.
, p. 3833 - 3836 (2017)
The NADPH-dependent secondary alcohol dehydrogenase from Thermoanaerobacter ethanolicus (TeSADH), displaying broad substrate specificity and low enantioselectivity, was engineered to accept NADH as a cofactor. The engineered TeSADH showed a >10 000-fold switch from NADPH towards NADH compared to the wildtype enzyme. This TeSADH variant was applied to a biocatalytic hydrogen-borrowing system that employed catalytic amounts of NAD+, ammonia, and an amine dehydrogenase, which thereby enabled the conversion a range of alcohols into chiral amines.
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.
Asymmetric synthesis of primary amines catalyzed by thermotolerant fungal reductive aminases
Cosgrove, Sebastian C.,Grogan, Gideon,Mangas-Sanchez, Juan,Marshall, James R.,Palmer, Ryan B.,Ramsden, Jeremy I.,Sharma, Mahima,Thorpe, Thomas W.,Turner, Nicholas J.
, p. 5052 - 5057 (2020/06/09)
Chiral primary amines are important intermediates in the synthesis of pharmaceutical compounds. Fungal reductive aminases (RedAms) are NADPH-dependent dehydrogenases that catalyse reductive amination of a range of ketones with short-chain primary amines supplied in an equimolar ratio to give corresponding secondary amines. Herein we describe structural and biochemical characterisation as well as synthetic applications of two RedAms fromNeosartoryaspp. (NfRedAm andNfisRedAm) that display a distinctive activity amongst fungal RedAms, namely a superior ability to use ammonia as the amine partner. Using these enzymes, we demonstrate the synthesis of a broad range of primary amines, with conversions up to >97% and excellent enantiomeric excess. Temperature dependent studies showed that these homologues also possess greater thermal stability compared to other enzymes within this family. Their synthetic applicability is further demonstrated by the production of several primary and secondary amines with turnover numbers (TN) up to 14 000 as well as continous flow reactions, obtaining chiral amines such as (R)-2-aminohexane in space time yields up to 8.1 g L?1h?1. The remarkable features ofNfRedAmand NfisRedAm highlight their potential for wider synthetic application as well as expanding the biocatalytic toolbox available for chiral amine synthesis.
Successful use of a novel lux i-Amylose-1 chiral column for enantioseparation of “legal highs” by HPLC
Kadkhodaei, Kian,Kadisch, Marlene,Schmid, Martin G.
, p. 42 - 52 (2019/11/14)
Bath salts, fumigations, cleaners and air fresheners, behind these terms substances are hidden, which count as “Legal Highs”. These fancy names are used to pretend Legal Highs as harmless compounds, to circumvent legal regulations for marketing as well as to increase the sales. Besides classic illicit drugs of synthetic origin such as amphetamines, cocaine and MDMA, the trade of these compounds, also known as new psychoactive substances (NPS), is not uncommon today. In many countries, NPS are still not subject to drug control. Among them, there are stimulants such as new amphetamine derivatives or cathinones, which possess a chiral centre. Little is known about the fact that the two possible enantiomers may differ in their pharmacological effect. The aim of this study was to test a novel HPLC column for the enantioseparation of a set of 112 NPS coming from different chemical groups and collected by internet purchases during the years 2010–2018. The CSP, namely Lux 5?μm i-Amylose-1, LC Column 250 x 4.6?mm, was run in normal phase mode under isocratic conditions, UV detection was performed at 245?nm and 230?nm, injection volume was 10?μl and flow rate was 1?ml/min. With a mobile phase consisting of n-hexane/isopropanol/diethylamine (90:10:0.1), herein, 79 NPS were resolved into their enantiomers successfully, for 37 of them baseline resolution was achieved. After increase of lipophily of the mobile phase to 99:1:0.1, another 27 compounds were baseline separated. It was found that all separated NPS are traded as racemic compounds.
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.
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.
Deracemization of Racemic Amines to Enantiopure (R)- and (S)-amines by Biocatalytic Cascade Employing ω-Transaminase and Amine Dehydrogenase
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)
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.
Mechanistic Insight into the Catalytic Promiscuity of Amine Dehydrogenases: Asymmetric Synthesis of Secondary and Primary Amines
Tseliou, Vasilis,Masman, Marcelo F.,B?hmer, Wesley,Knaus, Tanja,Mutti, Francesco G.
, p. 800 - 812 (2019/02/20)
Biocatalytic asymmetric amination of ketones, by using amine dehydrogenases (AmDHs) or transaminases, is an efficient method for the synthesis of α-chiral primary amines. A major challenge is to extend amination to the synthesis of secondary and tertiary amines. Herein, for the first time, it is shown that AmDHs are capable of accepting other amine donors, thus giving access to enantioenriched secondary amines with conversions up to 43 %. Surprisingly, in several cases, the promiscuous formation of enantiopure primary amines, along with the expected secondary amines, was observed. By conducting practical laboratory experiments and computational experiments, it is proposed that the promiscuous formation of primary amines along with secondary amines is due to an unprecedented nicotinamide (NAD)-dependent formal transamination catalysed by AmDHs. In nature, this type of mechanism is commonly performed by pyridoxal 5′-phosphate aminotransferase and not by dehydrogenases. Finally, a catalytic pathway that rationalises the promiscuous NAD-dependent formal transamination activity and explains the formation of the observed mixture of products is proposed. This work increases the understanding of the catalytic mechanism of NAD-dependent aminating enzymes, such as AmDHs, and will aid further research into the rational engineering of oxidoreductases for the synthesis of α-chiral secondary and tertiary amines.
Enantiomeric separation of Novel Psychoactive Substances by capillary electrophoresis using (+)-18-crown-6-tetracarboxylic acid as chiral selector
H?gele, Johannes S.,Schmid, Martin G.
, p. 1019 - 1026 (2018/07/29)
In the recent years, hundreds of Novel Psychoactive Substances (NPS) have entered both the European and the global drug market. These drugs, which are mainly used for recreational matters, have caused serious social problems. Every year, the spectrum of these misused drugs is enlarged by new derivatives, which are produced by modifications of basic structures of already well-known substances. Additionally, a lot of them possess a stereogenic center which leads to 2 enantiomeric forms. The fact that the pharmacological effects and potencies of the enantiomers of these chiral NPS may differ can be assumed from a broad spectrum of active pharmaceutical ingredients. For this reason, analytical method development regarding enantiomeric separation for these classes of substances is of great pharmaceutical and medical interest. The aim of this work was to create an easy-to-prepare chiral capillary electrophoresis method for the enantioseparation of NPS which contains a primary amino group by means of (+)-18-crown-6-tetracarboxylic acid as chiral selector. Novel Psychoactive Substances were purchased at various Internet stores or represent samples seized by Austrian police. The effects of selector concentration, the electrolyte composition, and the addition of organic modifiers to the background electrolyte on enantioseparation were investigated. Under optimized conditions, the use of 20-mM (+)-18-crown-6-tetracarboxylic acid, 10-mM Tris, and 30-mM citric acid buffer at pH 2.10 turned out to be effective. Fifteen of 24 tested NPS were resolved in their enantiomers within 15?minutes. It was found that all NPS were traded as racemic mixtures.
In vitro biocatalytic pathway design: Orthogonal network for the quantitative and stereospecific amination of alcohols
Knaus, Tanja,Cariati, Luca,Masman, Marcelo F,Mutti, Francesco G.
, p. 8313 - 8325 (2017/10/19)
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.