146297-34-9

Upstream product

• 2922-83-0 L-kynurenine 
• 100-52-7 benzaldehyde 
• 943-73-7 D-homophenylalanine 
• 56-84-8 L-Aspartic acid 
• 699432-85-4 (2R,5S,2'S)-2-tert-butyl-5-(2'-phenyl-2'-hydroxy-ethyl)-3-methylimidazolidin-4-one 
• 100-42-5 styrene 

Relevant academic research and scientific papers

Modulating Chemoselectivity in a Fe(II)/α-Ketoglutarate-Dependent Dioxygenase for the Oxidative Modification of a Nonproteinogenic Amino Acid

Modification of aliphatic C-H bonds in a regio- and stereoselective manner can pose a formidable challenge in organic chemistry. In this context, the use of nonheme iron and α-ketoglutarate-dependent dioxygenases (αKGDs) represents an interesting tool for C-H activation as this enzyme family can catalyze a broad set of synthetically valuable reactions including hydroxylations, oxidations, and desaturations. The consensus reaction mechanism of αKGDs proceeds via the formation of a Fe(IV)-oxo complex capable of hydrogen atom transfer (HAT) from an sp3-hybridized substrate carbon center. The resulting substrate radical and Fe(III)-OH cofactor are considered to be the branch point toward the possible reaction outcomes which are determined by the enzyme's active site architecture. To date, the modulation of the reaction fate in Fe(II)/α-ketoglutarate-dependent dioxygenases via enzyme engineering has been mainly elusive. In this study, we therefore set out to engineer the l-proline cis-4-hydroxylase SmP4H from Sinorhizobium meliloti for selective oxidative modifications of the nonproteinogenic amino acid l-homophenylalanine (l-hPhe) to produce pharmacological relevant small molecule intermediates. Using structure-guided directed evolution, we improved the total turnover number, the kcat, as well as the kcat/Km of the hydroxylation reaction yielding the desired γ-hydroxylation product by approximately 10-fold, >100-fold, and >300-fold, respectively. Notably, the exchange of only one amino acid in the active site (W40Y) allowed us to reprogram the natural hydroxylase to predominantly act as a desaturase, presumably through tyrosine's capability to serve as a catalytic entity in the reaction mechanism. An investigation of the substrate scope revealed additional acceptance of the noncanonical amino acids l-homotyrosine and (S)-α-amino-3,4-dichlorobenzenebutanoic acid by SmP4H variants.

Stereo-selective synthesis of non-canonical γ-hydroxy-α-amino acids by enzymatic carbon-carbon bond formation

Carbon-carbon (C-C) bond formation is the fundamental reaction type in organic synthesis. Biocatalytic methods for C-C bond formation have been limited to a few types of enzymes. In this report, we demonstrated the capability of a PLP-dependent enzyme ApUstD performing both C-C bond activation and asymmetric C-C bond formation, which resulted in non-canonical γ-hydroxy-α-amino acids. The reaction showed high efficiency (conversion up to 98%), stereo-selectivity (ratio up to >97:3), a broad substrate scope (25 isolated examples) and significant simplicity. Our results have extended the biocatalytic function of PLP-dependent enzymes for asymmetric C-C formation.

2-tert-butyl-3-methyl-2,3-dihydroimidazol-4-one-N-oxide: A new nitrone-based chiral glycine equivalent

Cycloaddition reactions between a new homochiral imidazolone-derived nitrone afford cycloadducts in high yield and with high stereoselectivity. Subsequent cycloadduct elaboration affords the γ-lactones of γ-hydroxy-α-amino acids as well as the optically pure amino acids themselves.

Kynureninase in organic synthesis : Preparation of γ-hydroxy-α-L-amino acids

Kynureninase, which is known to catalyze the transaldol reaction between benzaldehyde and kynurenine, accepted many kinds of other aromatic aldehydes and propargyl aldehydes as the substrates to afford novel γ-hydroxy-α-L-amino acids. The L-configuration of the α-carbons was confirmed by an enzymatic method using both D- and L-amino acid oxidases. The stereochemistry of the newly formed chiral center (γ-position) in major isomers was determined to be R-configuration by the observed NOEs in the NMR spectroscopy of lactones derived from the γ-hydroxy-α-L-amino acids.

Stereochemistry and mechanism of aldol reactions catalyzed by Kynureninase

Kynureninase from Pseudomonas has been reported to catalyze aldol and retro-aldol reactions, in addition to the physiological hydrolytic cleavage of L-kynurenine to anthranilic acid and L-alanine. However, the stereochemistry of these novel aldol reactions has not been previously determined. We have determined that the reaction of L-kynurenine and benzaldehyde catalyzed by kynureninase results in (2S,4A)-2-amino-4-hydroxy-4-phenylbutanoic acid. Similarly, the 4R isomer of dihydro-L-kynurenine readily undergoes retro-aldol cleavage, while the 4S isomer is unreactive as a substrate. Both isomers of dihydro-L-kynurenine are competitive inhibitors of kynureninase from Pseudomonas. However, the 4S isomer of dihydro-L-kynurenine is the most potent inhibitor, with a Ki of 0.3 μM. These results provide additional support for a general base mechanism for kynureninase, and suggest that the hydration occurs on the re face of the carbonyl group of kynurenine to give an (S)-gem-diolate intermediate.