129446-45-3Relevant academic research and scientific papers
1,3-Dipolar cycloadditions to unsymmetrical ketone-derived chiral stabilized azomethine ylides: Strategies for the synthesis of highly substituted amino acids
Aldous, David J.,Drew, Michael G. B.,Draffin, William N.,Hamelin, Estelle M.-N.,Harwood, Laurence M.,Thurairatnam, Sukanthini
, p. 3271 - 3278 (2005)
We report herein, the first generation of unsymmetrical ketone-derived chiral stabilized azomethine ylides. Intramolecular and intermolecular cycloaddition strategies have been utilized to synthesize both an enantiomerically pure bicyclic proline derivati
Improving and Inverting Cβ-Stereoselectivity of Threonine Aldolase via Substrate-Binding-Guided Mutagenesis and a Stepwise Visual Screening
Chen, Qijia,Chen, Xi,Feng, Jinhui,Wu, Qiaqing,Zhu, Dunming,Ma, Yanhe
, p. 4462 - 4469 (2019)
Threonine aldolase (TA)-catalyzed aldol condensation is a powerful tool for C-C bond formation under mild conditions, but the low Cβ-stereoselectivity has hampered its wide application. A stepwise visual screening method was developed to measure the activity and stereoselectivity of threonine aldolase-catalyzed aldol condensation by employing a stereoselective phenylserine dehydratase, enabling direct selection of mutants with higher Cβ-stereoselectivity. Mutants of l-PsTA from Pseudomonas sp. with improved or inverted stereoselectivity toward aromatic aldehydes were obtained by simultaneously mutating amino acid residues which interact with the amino and hydroxyl groups of the substrate and screening the resulting mutant libraries with this method. The mutation and enzyme-substrate docking studies provided some insights into the regulation of the Cβ-stereoselectivity by the enzyme-substrate interactions. This study offers a tool and useful guidance for further engineering of TAs to address the Cβ-stereoselectivity problem.
Scalable and Selective β-Hydroxy-α-Amino Acid Synthesis Catalyzed by Promiscuous l-Threonine Transaldolase ObiH
Doyon, Tyler J.,Kumar, Prasanth,Thein, Sierra,Kim, Maeve,Stitgen, Abigail,Grieger, Abbigail M.,Madigan, Cormac,Willoughby, Patrick H.,Buller, Andrew R.
, (2021/11/23)
Enzymes from secondary metabolic pathways possess broad potential for the selective synthesis of complex bioactive molecules. However, the practical application of these enzymes for organic synthesis is dependent on the development of efficient, economical, operationally simple, and well-characterized systems for preparative scale reactions. We sought to bridge this knowledge gap for the selective biocatalytic synthesis of β-hydroxy-α-amino acids, which are important synthetic building blocks. To achieve this goal, we demonstrated the ability of ObiH, an l-threonine transaldolase, to achieve selective milligram-scale synthesis of a diverse array of non-standard amino acids (nsAAs) using a scalable whole cell platform. We show how the initial selectivity of the catalyst is high and how the diastereomeric ratio of products decreases at high conversion due to product re-entry into the catalytic cycle. ObiH-catalyzed reactions with a variety of aromatic, aliphatic and heterocyclic aldehydes selectively generated a panel of β-hydroxy-α-amino acids possessing broad functional-group diversity. Furthermore, we demonstrated that ObiH-generated β-hydroxy-α-amino acids could be modified through additional transformations to access important motifs, such as β-chloro-α-amino acids and substituted α-keto acids.
Characteristics of l-threonine transaldolase for asymmetric synthesis of β-hydroxy-α-amino acids
Xu, Lian,Wang, Li-Chao,Xu, Xin-Qi,Lin, Juan
, p. 5943 - 5952 (2019/11/14)
l-Threonine transaldolase (LTTA) is a putative serine hydroxymethyltransferase (SHMT) that can catalyze the trans-aldehyde reaction of l-threonine and aldehyde to produce l-threo-β-hydroxy-α-amino acids with excellent stereoselectivity. In the present study, an l-threonine transaldolase from Pseudomonas sp. (PsLTTA) was mined and expressed in Escherichia coli BL21 (DE3). A substrate spectrum assay indicated that PsLTTA only consumed l-threonine as the donor substrate and could accept a wide range of aromatic aldehydes as acceptor substrates. Among these substrates, PsLTTA could catalyze p-methylsulfonyl benzaldehyde and l-threonine to produce l-threo-p-methylsulfonylphenylserine with a high conversion rate (74.4%) and a high de value (79.9%). The conversion and stereoselectivity of PsLTTA were found to be dramatically influenced by the concentration of the whole cell, the co-solvent and the reaction temperature. Through conditional optimization, l-threo-p-methylsulfonylphenylserine was obtained with 67.1% conversion and a near-perfect de value (94.5%), the highest stereoselectivity for an l-threo-β-hydroxy-α-amino acid so far reported by enzymatic synthesis. Finally, synthesis of l-threo-p-methylsulfonylphenylserine at a 100 mL scale by whole-cell biocatalysis was conducted. This is the first systematic report of l-threonine transaldolase as a robust biocatalyst for preparation of β-hydroxy-α-amino acids, which can provide new insights for β-hydroxy-α-amino acids synthesis.
Exploring the scope of an α/β-aminomutase for the amination of cinnamate epoxides to arylserines and arylisoserines
Shee, Prakash K.,Ratnayake, Nishanka Dilini,Walter, Tyler,Goethe, Olivia,Onyeozili, Edith Ndubuaku,Walker, Kevin D.
, p. 7418 - 7430 (2019/08/20)
Biocatalytic process-development continues to advance toward discovering alternative transformation reactions to synthesize fine chemicals. Here, a 5-methylidene-3,5-dihydro-4H-imidazol-4-one (MIO)-dependent phenylalanine aminomutase from Taxus canadensis (TcPAM) was repurposed to irreversibly biocatalyze an intermolecular amine transfer reaction that converted ring-substituted trans-cinnamate epoxide racemates to their corresponding arylserines. From among 12 substrates, the aminomutase ring-opened 3′-Cl-cinnamate epoxide to 3′-Cl-phenylserine 140 times faster than it opened the 4′-Cl-isomer, which was turned over slowest among all epoxides tested. GC/MS analysis of chiral auxiliary derivatives of the biocatalyzed phenylserine analogues showed that the TcPAM-transamination reaction opened the epoxides enantio- A nd diastereoselectively. Each product mixture contained (2S)+(2R)-anti (erythro) and (2S)+(2R)-syn (threo) pairs with the anti-isomers predominating (-90:10 dr). Integrating the vicinal proton signals in the 1H NMR spectrum of the enzyme-catalyzed phenylserines and calculating the chemical shift difference (?"?) between the anti and syn proton signals confirmed the diastereomeric ratios and relative stereochemistries. Application of a (2S)-threonine aldolase from E. coli further established the absolute stereochemistry of the chiral derivatives of the diastereomeric enzymatically derived products. The 2R:2S ratio for the biocatalyzed anti-isomers was highest (88:12) for 3′-NO2-phenylserine and lowest (66:34) for 4′-F-phenylserine. This showed that the stereospecificity of TcPAM is in part directed by the substituent-type on the cinnamate epoxide analogue. The catalyst also converted each cinnamate epoxide analogue to its corresponding isoserine, highlighting a biocatalytic route to arylisoserines, which play a key role in building the pharmacophore seen in anticancer and protease inhibitor drugs.
ENGINEERED POLYPEPTIDES AND THEIR APPLICATIONS IN SYNTHESIS OF BETA-HYDROXY-ALPHA-AMINO ACIDS
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Page/Page column 26-32; 67, (2019/01/04)
Provided are engineered polypeptides that are useful for the asymmetric synthesis of β-hydroxy-α-amino acids under industrial-relevant conditions. The engineered polypeptides disclosed are developed through directed evolution based on the ability of catalytic synthesis of (2S, 3R) -2-amino-3-hydroxy-3- (4-nitrophenyl) propanoic acid. Also provided are polynucleotides encoding the engineered polypeptides, host cells capable of expressing engineered polypeptides, and methods of producing β-hydroxy-α-amino acids using engineered polypeptides. Compared to other processes of preparation, the use of the engineered polypeptides for the preparation of β-hydroxy-α-amino acids results in high purity of the desired stereoisomers, mild reaction conditions, low pollution and low energy consumption. It has good industrial application prospects.
ENGINEERED ALDOLASE POLYPEPTIDES AND USES THEREOF
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Page/Page column 65-66, (2019/01/05)
Provided herein are engineered polypeptides that are useful for the asymmetric synthesis of β-hydroxy-α-amino acids under industrial-relevant conditions. Also provided are polynucleotides encoding engineered polypeptides, host cells capable of expressing engineered polypeptides, and methods of producing β-hydroxy-α-amino acids using engineered polypeptides. Compared to other processes of preparation, the use of the engineered polypeptides for the preparation of β-hydroxy-α-amino acids results in high purity of the desired stereoisomers, mild reaction conditions, low pollution and low energy consumption.
Engineered L-serine hydroxymethyltransferase from streptococcus thermophilus for the synthesis of α,α-dialkyl-α-amino acids
Bujons, Jordi,Claps, Pere,Hernandez, Karel,Joglar, Jesffls,Zelen, Igor,Usn, Isabel,Petrillo, Giovanna,Wandtke, Claudia M.,Parella, Teodor
supporting information, p. 3013 - 3017 (2015/10/05)
α,α-Disubstituted a-amino acids are central to biotechnological and biomedical chemical processes for their own sake and as substructures of biologically active molecules for diverse biomedical applications. Structurally, these compounds contain a quaternary stereocenter, which is particularly challenging for stereoselective synthesis. The pyridoxal-5′-phosphate (PLP)-dependent l -serine hydroxymethyltransferase from Streptococcus thermophilus (SHMTSth; EC 2.1.2.1) was engineered to achieve the stereoselective synthesis of a broad structural variety of α,α-dialkyl-α-amino acids. This was accomplished by the formation of quaternary stereocenters through aldol addition of the amino acids D-Ala and D-Ser to a wide acceptor scope catalyzed by the minimalist SHMTSth Y55T variant overcoming the limitation of the native enzyme for Gly. The SHMTSth Y55T variant tolerates aromatic and aliphatic aldehydes as well as hydroxy- and nitrogen-containing aldehydes as acceptors.
Stereoselective synthesis of (-)-chloramphenicol, (+)-thiamphenicol and (+)-sphinganine via chiral tricyclic iminolactone
Li, Qiong,Zhang, Hongbo,Li, Chenguang,Xu, Pengfei
, p. 149 - 153 (2013/08/24)
The stereoselective syntheses of (-)-chloramphenicol, (+)-thiamphenicol and (+)-sphinganine are described. The two continuous chiral centers within three target molecules were constructed through aldol reaction of chiral tricyclic iminolactone and aldehyde. Concise and efficient syntheses of (-)-chloramphenicol, (+)-thiamphenicol and (+)-sphinganine have been accomplished in practical four or three steps. The synthetic route featured in an aldol reaction between iminolactone 1a and 1b with aldehyde, which introduced the two continuous chiral centers within three target molecules. Copyright
Threonine aldolases-an emerging tool for organic synthesis
Steinreiber, Johannes,Fesko, Kateryna,Reisinger, Christoph,Schürmann, Martin,van Assema, Friso,Wolberg, Michael,Mink, Daniel,Griengl, Herfried
, p. 918 - 926 (2007/10/03)
In a systematic study, 21 ring-substituted benzaldehydes were reacted with glycine under catalysis with a l-threonine aldolase (lTA) from Pseudomonas putida and a d-threonine aldolase (dTA) from Alcaligenes xylosoxidans to form the corresponding β-hydroxy-α-amino acids 1-18. dTA proved to be highly selective with ee's >99% (d) and de's up to 99% (syn). Two thiamphenicol precursors were synthesized utilizing dTA on a preparative scale. lTA-catalyzed reactions led to ee's >99% (l) but low to moderate de's (20-50%, syn).
