617-41-4Relevant academic research and scientific papers
Asymmetric Synthesis of Atorvastatin Calcium through Intramolecular Oxidative Oxygen-Nucleophilic Bromocyclization
Wu, Yan,Liu, Min-Jie,Huang, Hai-Qing,Huang, Guan-Xin,Xiong, Fang-Jun,Chen, Fen-Er
, p. 3681 - 3688 (2017/07/22)
The stereocontrolled synthesis of atorvastatin calcium starting from commercially available d-aspartic acid using an intramolecular oxidative oxygen-nucleophilic bromocyclization of a homoallylic tert-butyl carbonate is described. This strategy allows the formation of the chiral syn-1,3-diol moiety with the desired stereochemistry, and provides a functionalized bromomethyl group for the construction of the atorvastatin side-chain with high regio- and diastereoselectivity. This route is attractive as it represents an efficient and environmentally sensitive approach to the large-scale synthesis of statins and their analogues.
Identification and pharmacological characterization of succinate receptor agonists
Geubelle, Pierre,Gilissen, Julie,Dilly, Sébastien,Poma, Laurence,Dupuis, Nadine,Laschet, Céline,Abboud, Dayana,Inoue, Asuka,Jouret, Fran?ois,Pirotte, Bernard,Hanson, Julien
supporting information, p. 796 - 808 (2017/04/14)
Background and Purpose: The succinate receptor (formerly GPR91 or SUCNR1) is described as a metabolic sensor that may be involved in homeostasis. Notwithstanding its implication in important (patho)physiological processes, the function of succinate receptors has remained ill-defined because no pharmacological tools were available. We report on the discovery of the first family of potent synthetic agonists. Experimental Approach: We screened a library of succinate analogues and analysed their activity on succinate receptors. Also, we modelled a pharmacophore and a binding site for this receptor. New agonists were identified based on the information provided by these two approaches. Their activity was studied in various bioassays, including measurement of cAMP levels, [Ca2+]i mobilization, TGF-α shedding and recruitment of arrestin 3. The in vivo effects of activating succinate receptors with these new agonists was evaluated on rat BP. Key Results: We identified cis-epoxysuccinic acid and cis-1,2-cyclopropanedicarboxylic acid as agonists with an efficacy similar to that of succinic acid. Interestingly, cis-epoxysuccinic acid was 10- to 20-fold more potent than succinic acid on succinate receptors. For example, cis-epoxysuccinic acid reduced cAMP levels with a pEC50?=?5.57?±?0.02 (EC50?=?2.7?μM), compared with succinate pEC50?=?4.54?±?0.08 (EC50?=?29?μM). The rank order of potency of the three agonists was the same in all in vitro assays. Both cis-epoxysuccinic and cis-1,2-cyclopropanedicarboxylic acid were as potent as succinate in increasing rat BP. Conclusions and Implications: We describe new agonists at succinate receptors that should facilitate further research on this understudied receptor.
Accessing Centnerszwer's quasiracemate-molecular shape controlled molecular recognition
Spaniol, Jacqueline M.,Wheeler, Kraig A.
, p. 64921 - 64929 (2016/07/21)
M. Centnerszwer's seminal 1899 report investigated the stereochemical relationship between optical antipodes of different substances using melting-point behavior. One intriguing melting-point phase diagram produced from this early investigation combined (+)-2-chlorosuccinic acid [(+)-1] and (-)-2-bromosuccinic acid [(-)-2]. While Centnerszwer's data clearly indicates the formation of a quasiracemic phase-i.e., materials constructed from pairs of isosteric molecules of opposite handedness-at the 1:1 component ratio, this material is energetically less favorable than the chiral counterparts. The consequence of this crystal instability is significant as evident by the absence of literature sited crystal structures for the quasiracemic phase (+)-1/(-)-2 and racemates (±)-1 and (±)-2. This study circumvented this challenge by generating multi-molecular assemblies using additional crystallizing agents capable of complementing the hydrogen-bond abilities of succinic acids 1 and 2. Both imidazole (Im) and 4,4′-bipyridyl-N,N′-dioxide (BPDO) served as tailor-made additives that effectively modified the crystal packing landscape of quasiracemate of (+)-1/(-)-2. Combining imidazole with the quasiracemate, racemate, and enantiopure forms of 1 and 2 resulted in crystal structures characterized as molecular salts with layered motifs formed from highly directional N+-H?carboxylate and carboxyl?carboxylate interactions. In contrast to the enantiopure [(+)-1·Im and (-)-2·Im] and racemic [(±)-1·Im and (±)-2·Im] systems, neighboring molecular layers observed in quasiracemate (+)-1/(-)-2·Im are organized by approximate inversion symmetry. Assessment of the crystal packing efficiency for this series of molecular salts via crystal densities and packing coefficients (Ck) indicates imidazole greatly alters the crystal landscape of the system in favor of racemic and quasiracemic crystal packing. A similar desymmetrized crystal environment was also realized for the ternary cocrystalline system of (+)-1/(-)-2·BPDO where the components organize via N+-O-?carboxyl contacts. This study underscores the importance of molecular shape to molecular recognition processes and the stabilizing effect of tailor-made additives for creating new crystalline phases of previously inaccessible crystalline materials.
Process for preparing R-(-) -carnitine from S-(-)-chlorosuccinic acid or from a derivative thereof
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Page column 9, (2008/06/13)
An inner salt of L-carnitine is prepared by reduction, with a suitable reducing agent, of a compound of formula (I): where X1and X2, which may be the same or different, are hydroxy, C1-C4alkoxy, phenoxy, halogen, or X1and X2, when taken together are an oxygen atom and the resulting compound is a derivative of succinic anhydride; Y is halogen, the mesyloxy or the tosyloxy group: and subsequent treatment with water, then with a base and then with trimethylamine.
Preparation of (S)-2-Substituted Succinates by Stereospecific Reductions of Fumarate and Derivatives with Resting Cells of Clostridium formicoaceticum
Eck, Richard,Simon, Helmut
, p. 13631 - 13640 (2007/10/02)
Fumarate derivatives have been reduced to (S)-2-methylsuccinate 2a, (S)-2-ethylsuccinate 3a and (S)-2-chlorosuccinate 4a in up to 1 M concentrations with Clostridium formicoaceticum.Formate was the electron donor and viologens or anthraquinone-2,6-disulphonate acted as artificial electron mediators.Reductions with freeze-dried cells in 2H2O-buffers led to the (2R,3S)--dideuterated succinate derivatives.The productivity numbers ranged from 450 to 5000 and the enantiomeric excess of all (S)-2-substituted succinates was >/= 99percent.
An efficient synthesis of enantiomerically pure (R)-(2-benzyloxyethyl)oxirane from (S)-aspartic acid
Frick,Klassen,Bathe,Abramson,Rapoport
, p. 621 - 623 (2007/10/02)
A 3-step synthesis of the title compound from (S)-aspartic acid is described. The overall yield of this process is 65% and the enantiomeric purity (ep) of the product is greater than 99%.
Application of (2)H N.M.R. Spectroscopy to Study the Incorporation of Enantiomeric -Labelled Putrescines into the Pyrrolizidine Alkaloid Retrorsine
Kunec, Ellen K.,Robins, David J.
, p. 1089 - 1094 (2007/10/02)
A sample of (2R)-putrescine (13) dihydrochloride was prepared from (2S)-aspartic acid (8), and (2S)-putrescine (15) dihydrochloride was synthesized from (2R)-aspartic acid.Feeding experiments carried out with these precursors on Senecio isatideus plants gave retrorsine (5) containing (2)H, and the distribution of (2)H from each experiment in retrorsine was determined by (2)H n.m.r. spectroscopy.All of the (2)H was confined to the base component of the alkaloid, retronecine (4).Retrorsine (14), derived biosynthetically from (2R)-putrescine (13) dihydrochloride was labelled with (2)H at C-2 and C-6α, while retrorsine (16), produced from (2S)-putrescine (15) dihydrochloride contained (2)H labels at C-6β and C-7α.These labelling patterns demonstrate that hydroxylation at C-7 of retronecine (4) proceeds with retention of configuration.In addition, the formation of the 1,2-double bond of retronecine involves removal of the pro-S hydrogen and retention of the pro-R hydrogen at the carbon atom which becomes C-2 of retronecine.
The Mechanism of Hydrogenation by Aqueous Chromium(II) Ion of the Carbon-Carbon Double Bond of Olefinic Compounds with Polar Substituents
Katakis, Dimitris,Vrachnou-Astra, Ersi,Konstantatos, John
, p. 1491 - 1498 (2007/10/02)
The kinetics of the reaction of Cr2+ with maleic acid, fumaric acid, methylmaleic acid, chloromaleic acid, dichloromaleic acid, and methylfumaric acid have been investigated over a wide range of chloromaleic > maleic methylmaleic > dichloromaleic > fumaric and maleic > dichloromaleic ligand is in excess.In excess of Cr2+ the rate law is as shown below and k3 follows the trend: chloromaleic > maleic > dichloromaleic > methylmaleic > methylfumaric.With excess ligand, L, the rate law has two terms (below) and the two rate constants, k3' and k2' follow the order: chloromaleic > maleic methylmaleic > dichloromaleic > fumaric and maleic > dichloromaleic methylmaleic > chloromaleic respectively.The kinetic data are supplemented by stoicheiometric data, by determinations of product distribution, and by spectroscopic data, and they are discussed in terms of a model involving at least partial attack by Cr2+ directly on the C=C double bonds.
TOTAL SYNTHESIS OF ANTITUMOR AGENT AT-125, (αS,5S)-α-AMINO-3-CHLORO-4,5-DIHYDRO-5-ISOXAZOLEACETIC ACID
Baldwin, Jack E.,Cha, Jin K.,Kruse, Lawrence I.
, p. 5241 - 5260 (2007/10/02)
A short and efficient total synthesis of racemic AT-125 and its racemic threo isomer proceeds via an intramolecular Michael cyclization of a protected α,β-dehydroglutamic acid γ-hydroxamate.Separation of diastereomers and deprotection to racemic AT-125 followed by enzymatic resolution of the N-chloroacetamide with hog-kidney acylase provides the natural αS,5S isomer.
Dianions Derived from α-Halo Acids. The Darzens Condensation Revisited
Johnson, Carl R.,Bade, Thomas R.
, p. 1205 - 1212 (2007/10/02)
The dianions of α-halo carboxylic acids are readily generated by the addition of the acids to 2 equiv of lithium diisopropylamide at low temperatures.When the mixture warms to room temperature dimeric products are formed.When aldehydes and ketones were added to the cooled solutions of the dianions and the reaction mixtures were allowed to warm to room temperature, followed by acid quench, glycidic acids were formed.The glycidic acids, per se, were often too unstable to be isolated and purified but could be analyzed by conversion to their methyl esters withdiazomethane.When the reactions were quenched prematurely, α-chloro-β-hydroxy carboxylic acids were isolated.Homologated aldehydes and ketones were obtained from the glycidic acids by catalytic and thermal decarboxylation methods.
