88547-38-0Relevant academic research and scientific papers
Predicting CYP2C19 catalytic parameters for enantioselective oxidations using artificial neural networks and a chirality code
Hartman, Jessica H.,Cothren, Steven D.,Park, Sun-Ha,Yun, Chul-Ho,Darsey, Jerry A.,Miller, Grover P.
, p. 3749 - 3759 (2013)
Cytochromes P450 (CYP for isoforms) play a central role in biological processes especially metabolism of chiral molecules; thus, development of computational methods to predict parameters for chiral reactions is important for advancing this field. In this study, we identified the most optimal artificial neural networks using conformation-independent chirality codes to predict CYP2C19 catalytic parameters for enantioselective reactions. Optimization of the neural networks required identifying the most suitable representation of structure among a diverse array of training substrates, normalizing distribution of the corresponding catalytic parameters (k cat, Km, and kcat/Km), and determining the best topology for networks to make predictions. Among different structural descriptors, the use of partial atomic charges according to the CHelpG scheme and inclusion of hydrogens yielded the most optimal artificial neural networks. Their training also required resolution of poorly distributed output catalytic parameters using a Box-Cox transformation. End point leave-one-out cross correlations of the best neural networks revealed that predictions for individual catalytic parameters (kcat and K m) were more consistent with experimental values than those for catalytic efficiency (kcat/Km). Lastly, neural networks predicted correctly enantioselectivity and comparable catalytic parameters measured in this study for previously uncharacterized CYP2C19 substrates, R- and S-propranolol. Taken together, these seminal computational studies for CYP2C19 are the first to predict all catalytic parameters for enantioselective reactions using artificial neural networks and thus provide a foundation for expanding the prediction of cytochrome P450 reactions to chiral drugs, pollutants, and other biologically active compounds.
Minor enantiomer recycling: Application to enantioselective syntheses of beta blockers
Wen, Ye-Qian,Hertzberg, Robin,Gonzalez, Inanllely,Moberg, Christina
, p. 3806 - 3812 (2014/04/03)
Continuous recycling of the minor product enantiomer obtained from the acetylcyanation of prochiral aldehydes provided access to highly enantiomerically enriched products. Cyanohydrin derivatives, which under normal conditions are obtained with modest or poor enantiomeric ratios, were formed with high enantiomeric purity by using a reinforcing combination of a chiral Lewis acid catalyst and a biocatalyst. The primarily obtained products were transformed into β-adrenergic antagonists (S)-propanolol, (R)-dichloroisoproterenol, and (R)-pronethalol by means of a two-step procedure.
A new catalyst for the asymmetric Henry reaction: Synthesis of β-nitroethanols in high enantiomeric excess
White, James D.,Shaw, Subrata
, p. 6270 - 6273 (2013/02/23)
A new chiral tetrahydrosalen ligand has been designed and synthesized from cis-2,5-diaminobicyclo[2.2.2]octane. The complex generated in situ by the interaction of the ligand with (CuOTf)2·C6H 5CH3 was an efficient catalyst for the asymmetric Henry reaction, producing nitroaldol products in high yield and good stereoselectivity. Henry reactions catalyzed by this tetrahydrosalen-Cu(I) complex led to syntheses of β-adrenergic blocking agents (S)-toliprolol, (S)-moprolol, and (S)-propanolol.
New chemoenzymatic pathway for β-adrenergic blocking agents
Kamal, Ahmed,Khanna, G.B. Ramesh,Krishnaji,Tekumalla, Venkatesh,Ramu
, p. 1485 - 1494 (2007/10/03)
The lipase mediated kinetic resolution of pharmaceutically important β-hydroxy nitriles is described in high enantiomeric excesses and good yields. Some of the chiral β-hydroxy nitriles have been employed in the synthesis of β-adrenergic blocking agents such as propranolol, alprenolol and moprolol. This protocol has also been extended for the enantiopure preparation of 5-(4-tosyloxymethyl)-1,3-oxazolidine-2-one and 3-hydroxy-4-tosyloxybutanenitrile, chiral intermediates of high synthetic value.
Aminoalcohols II: Preparation of Enantiomerically Pure Pharmacologically Active β-Aminoalcohols
Noe, C. R.,Knollmueller, M.,Gaertner, P.,Fleischhacker, W.,Katikarides, E.
, p. 481 - 494 (2007/10/02)
A synthesis of β-aminoalcohols is described starting from racemic or enantiomerically pure α-hydroxynitriles which were O-protected using enantiomerically pure acetal type protective groups.Reduction with lithium aluminium hydride yielded O-protected β-aminoalcohols.Whenever diastereomeric O-protected cyanohydrins could not be separated, the mixture was reduced and the resulting O-protected aminoalcohols were separated.Removal of the protective group using hydrogen chloride and methanol yielded enantiomerically pure β-aminoalcohols or their corresponding hydrochlorides. - Keywords: 1,2-Amino-alcohols, enantiomerically pure; Lithium aluminium hydride reduction
Methods of making novel R and S diastereomers of N6 -[(2-hydroxypropyl)aryl]adenosines
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, (2008/06/13)
A method of making novel R and S diastereomers of an N6 -[(2-hydroxypropyl)aryl] adenosine, which diastereomers exhibit fewer CNS side effects than the racemate, but with no decrease in cardiovascular activity.
AN EFFICIENT SYNTHESIS OF (R)-(+)- AND (S)-(-)-PROPRANOLOL FROM RESOLVED 5-IODOMETHYLOXAZOLIDIN-2-ONES
Cardillo, Giuliana,Orena, Mario,Sandri, Sergio,Tomasini, Claudia
, p. 2505 - 2512 (2007/10/02)
(1'S*,5S,R)-3-(1'-phenyleth-1'-yl)-5-iodomethyloxazolidin-2-ones, 4a,b, have been synthesized and easily resolved by silica gel chromatography.Each pure diastereomer has been then converted to (S)-(-)-propranolol 1a and (R)-(+)-propranolol 1b, respectively.An empirical correlation of configuration and 1H NMR chemical shift for alternate diastereomers has been devised and has proved to be applicable in assigning the configuration of 5-substituted 3-(1'-phenyleth-1'-yl)oxazolidin-2-ones.
