A practical asymmetric synthesis of carnitine
TL;DR: The first efficient chemical synthesis of (R)-carnitine has been accomplished on the basis of homogeneous enantioselective hydrogenation of ethyl 4-chloro-3-oxobutanoate as discussed by the authors.
About: This article is published in Tetrahedron Letters.The article was published on 1988-01-01. It has received 127 citations till now. The article focuses on the topics: Enantioselective synthesis & Chemical synthesis.
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TL;DR: The increasing demand to produce enantiomerically pure pharmaceuticals, agrochemicals, flavors, and other fine chemicals has advanced the field of asymmetric catalytic technologies, and asymmetric hydrogenation utilizing molecular hydrogen to reduce prochiral olefins, ketones, and imines has become one of the most efficient methods for constructing chiral compounds.
Abstract: The increasing demand to produce enantiomerically pure pharmaceuticals, agrochemicals, flavors, and other fine chemicals has advanced the field of asymmetric catalytic technologies.1,2 Among all asymmetric catalytic methods, asymmetric hydrogenation utilizing molecular hydrogen to reduce prochiral olefins, ketones, and imines, have become one of the most efficient methods for constructing chiral compounds.3 The development of homogeneous asymmetric hydrogenation was initiated by Knowles4a and Horner4b in the late 1960s, after the discovery of Wilkinson’s homogeneous hydrogenation catalyst [RhCl(PPh3)3]. By replacing triphenylphosphine of the Wilkinson’s catalystwithresolvedchiralmonophosphines,6Knowles and Horner reported the earliest examples of enantioselective hydrogenation, albeit with poor enantioselectivity. Further exploration by Knowles with an improved monophosphine CAMP provided 88% ee in hydrogenation of dehydroamino acids.7 Later, two breakthroughs were made in asymmetric hydrogenation by Kagan and Knowles, respectively. Kagan reported the first bisphosphine ligand, DIOP, for Rhcatalyzed asymmetric hydrogenation.8 The successful application of DIOP resulted in several significant directions for ligand design in asymmetric hydrogenation. Chelating bisphosphorus ligands could lead to superior enantioselectivity compared to monodentate phosphines. Additionally, P-chiral phosphorus ligands were not necessary for achieving high enantioselectivity, and ligands with backbone chirality could also provide excellent ee’s in asymmetric hydrogenation. Furthermore, C2 symmetry was an important structural feature for developing new efficient chiral ligands. Kagan’s seminal work immediately led to the rapid development of chiral bisphosphorus ligands. Knowles made his significant discovery of a C2-symmetric chelating bisphosphine ligand, DIPAMP.9 Due to its high catalytic efficiency in Rh-catalyzed asymmetric hydrogenation of dehydroamino acids, DIPAMP was quickly employed in the industrial production of L-DOPA.10 The success of practical synthesis of L-DOPA via asymmetric hydrogenation constituted a milestone work and for this work Knowles was awarded the Nobel Prize in 2001.3k This work has enlightened chemists to realize * Corresponding author. 3029 Chem. Rev. 2003, 103, 3029−3069
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TL;DR: Asymmetric catalysts, either chemical or biological, effect the reactions of enantiomeric substrates at unequal rates, allowing for the kinetic resolution of racemates as discussed by the authors, which is a powerful tool for the stereoselective synthesis of chiral compounds, as exemplified by the biochemical hydrolysis of hydantoins or oxazolinones and microbial reductions or BINAP-Ru(II) catalyzed hydrogenation of certain α-substituted β-keto esters.
Abstract: Asymmetric catalysts, either chemical or biological, effect the reactions of enantiomeric substrates at unequal rates, allowing for the kinetic resolution of racemates. The asymmetric reaction of chirally labile compounds capable of undergoing in situ racemization can, in principle, afford a single stereoisomer in 100% ee and in 100% yield. The second-order reaction provides a powerful tool for the stereoselective synthesis of chiral compounds, as exemplified by, among others, the biochemical hydrolysis of hydantoins or oxazolinones and microbial reductions or BINAP–Ru(II) catalyzed hydrogenation of certain α-substituted β-keto esters. Such transformations are characterized by the presence of parallel reactions interrelated by the stereoinversion of the enantiomeric substrates. The efficiency is decisively affected by the kinetic parameters, particularly the relative rates of the stereoinversion and reaction as well as the intrinsic stereochemical parameters of the catalyst and substrate. Such stereoselec...
428 citations
TL;DR: Stereoselectivite dans l'hydrogenation de cetoesters and d'un aminoester conjugue, catalysee par des complexes du ruthenium.
Abstract: Stereoselectivite dans l'hydrogenation de cetoesters et d'un aminoester conjugue, catalysee par des complexes du ruthenium
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TL;DR: The hypotensive, antiepileptic compound (R)-(-)-y-amino-@-hydroxybutyric acid (GABOB) (8) has been synthesized from ascorbic acid via nine steps in 10% overall yield.
Abstract: Ascorbic acid (Vitamin C) (9) is shown to be a useful, inexpensive chiral starting material for natural products synthesis. It is converted in high yield via two synthetic operations into (R)-glycerol acetonide (7), the more inaccessible enantiomer of glycerol acetonide. Since D-(R)-glyceraldehyde acetonide (4) and the corresponding alcohol 1 have been used in many total syntheses of a wide variety of compounds, the ready availability of the opposite enantiomers L-(S)-glyceraldehyde acetonide (6) and glycerol 7 should be of great value. As one indication of this potential synthetic utility, the hypotensive, antiepileptic compound (R)-(-)-y-amino-@-hydroxybutyric acid (GABOB) (8) has been synthesized from ascorbic acid (9) via nine steps in 10% overall yield. As further evidence of the importance of these compounds in synthesis, several useful intermediates for the preparation of the highly active hypotensive agents, the aryloxypropanolamines (5), were prepared from Vitamin C.
230 citations
TL;DR: Prolonged treatment with oral carnitine over a six-month period resulted in increased muscle strength, a dramatic reduction in cardiac size, relief of cardiomyopathy, partial repletion of carnitin levels in plasma and muscle, and complete repletions in the liver.
Abstract: A 3 1/2-year-old boy presented at three months of age with an acute episode of lethargy, somnolence, hypoglycemia, hepatomegaly, and cardiomegaly, which responded poorly to restoration of the blood sugar level to normal. The absence of ketonuria during subsequent episodes of severe hypoglycemia prompted a search for a defect in fatty acid oxidation. Plasma carnitine (2.0 to 5.0 mumol per liter), muscle carnitine (0.01 to 0.02 mumol per gram, wet weight) and liver carnitine (0.021 to 0.065 mumol per gram, wet weight) were all less than 5 per cent of the normal mean. During a 36-hour fast, ketones were barely detectable. Prolonged treatment with oral carnitine over a six-month period resulted in increased muscle strength, a dramatic reduction in cardiac size, relief of cardiomyopathy, partial repletion of carnitine levels in plasma and muscle, and complete repletion in the liver. Systemic carnitine deficiency is an easily treatable cause of recurrent Reye's-like syndrome. Its diagnosis requires measurement of carnitine levels.
224 citations