SciCombinator

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Concept: Enantiomeric excess

177

The enantioselective allylation of ketones is a problem of fundamental importance in asymmetric reaction design, especially given that only a very small number of methods can generate tertiary carbinols. Despite the vast amount of attention that synthetic chemists have given to this problem, success has generally been limited to just a few simple ketone types. A method for the selective allylation of functionally complex ketones would greatly increase the utility of ketone allylation methods in the chemical synthesis of important targets. Here we describe the operationally simple, direct, regioselective and enantioselective allylation of β-diketones. The strong tendency of β-diketones to act as nucleophilic species was overcome by using their enol form to provide the necessary Brønsted-acid activation. This reaction significantly expands the pool of enantiomerically enriched and functionally complex tertiary carbinols that may be easily accessed. It also overturns more than a century of received wisdom regarding the reactivity of β-diketones.

Concepts: Amino acid, Chemical reaction, Chemical synthesis, Carbonyl, Asymmetric induction, Asymmetric synthesis, Enantiomeric excess, Keto-enol tautomerism

28

A highly sensitive, specific and enantioselective assay has been developed and validated for the estimation of TAK-700 enantiomers [(+)-TAK-700 and (-)-TAK-700] in rat plasma on LC-MS/MS-ESI in the positive-ion mode. Liquid-liquid extraction was used to extract (±)-TAK-700 enantiomers and IS (phenacetin) from rat plasma. TAK-700 enantiomers were separated using methanol and 5 mm ammonium acetate (80:20, v/v) at a flow rate of 0.7 mL/min on a Chiralcel OJ-RH column. The total run time was 7.0 min and the elution of (+)-TAK-700, (-)-TAK-700 and IS occurred at 3.71, 4.45 and 4.33 min, respectively. The MS/MS ion transitions monitored were m/z 308.2 → 95.0 for TAK-700 and m/z 180.2 → 110.1 for IS. The standard curves for TAK-700 enantiomers were linear (r(2)  > 0.998) in the concentration range 2.01-2015 ng/mL for each enantiomer. The inter- and intra-day precisions were in the ranges 3.74-7.61 and 2.06-8.71% and 3.59-9.00 and 2.32-11.0% for (+)-TAK-700 and (-)-TAK-700, respectively. Both the enantiomers were found to be stable in a battery of stability studies. This novel method was applied to the study of stereoselective oral pharmacokinetics of (+)-TAK-700 and it was unequivocally demonstrated that (+)-TAK-700 does not undergo chiral inversion to its antipode in vivo. Copyright © 2012 John Wiley & Sons, Ltd.

Concepts: Stereochemistry, Enantiomer, Chirality, Tartaric acid, Enantiomeric excess

28

The first example of Ir-catalyzed asymmetric substitution reaction with vinyl trifluoroborates is described. The direct reaction between branched, racemic allylic alcohols and potassium alkenyltrifluoroborates proceeded with high site selectivity and excellent enantioselectivity (up to 99%) mediated by an Ir-(P,olefin) complex. This method allows rapid access to various 1,4-dienes or trienes including the biologically active natural products (-)-nyasol and (-)-hinokiresinol.

Concepts: Nucleophilic substitution, Stereochemistry, Enantiomer, Allyl alcohol, Organic chemistry, Asymmetric induction, Enantiomeric excess, Racemic mixture

28

We report the chiral diene ligated rhodium-catalyzed dynamic kinetic asymmetric transformation (DYKAT) of racemic secondary allylic trichloroacetimidates with a variety of N-methyl anilines, providing allylic N-methyl arylamines in high yields, regioselectivity, and enantiomeric excess. The rhodium-catalyzed DYKAT method addresses limitations previously associated with this particular class of aromatic nitrogen nucleophiles.

Concepts: Stereochemistry, Enantiomer, Chirality, Asymmetric induction, Tartaric acid, Asymmetric synthesis, Enantiomeric excess, Racemic mixture

28

All enantiopure atropisomeric (atropos) ligands essentially require enantiomeric resolution or synthetic transformation from a chiral pool. In sharp contrast, the use of tropos (chirally flexible) ligands, which are highly modular, versatile, and easy to synthesize without enantiomeric resolution, has recently been the topic of much interest in asymmetric catalysis. Racemic catalysts bearing tropos ligands can be applied to asymmetric catalysis through enantiomeric discrimination by the addition of a chiral source, which preferentially transforms one catalyst enantiomer into a highly activated catalyst enantiomer. Additionally, racemic catalysts bearing tropos ligands can also be utilized as atropos enantiopure catalysts obtained via the control of chirality by a chiral source followed by the memory of chirality. In this feature article, our results on the asymmetric catalysis via the combination of various central metals and tropos ligands are summarized.

Concepts: Amino acid, Stereochemistry, Hydrogenation, Enantiomer, Chirality, Tartaric acid, Enantiomeric excess, Racemic mixture

27

Fluoxetine is used clinically as a racemic mixture of (+)-(S) and (-)-® enantiomers for the treatment of depression. CYP2D6 catalyzes the metabolism of both fluoxetine enantiomers. We aimed to evaluate whether exposure to gasoline results in CYP2D inhibition. Male Wistar rats exposed to filtered air (n = 36; control group) or to 600 ppm of gasoline (n = 36) in a nose-only inhalation exposure chamber for 6 weeks (6 h/day, 5 days/week) received a single oral 10-mg/kg dose of racemic fluoxetine. Fluoxetine enantiomers in plasma samples were analyzed by a validated analytical method using LC-MS/MS. The separation of fluoxetine enantiomers was performed in a Chirobiotic V column using as the mobile phase a mixture of ethanol:ammonium acetate 15 mM. Higher plasma concentrations of the (+)-(S)-fluoxetine enantiomer were found in the control group (enantiomeric ratio AUC((+)-(S)/(-)-®)  = 1.68). In animals exposed to gasoline, we observed an increase in AUC(0-∞) for both enantiomers, with a sharper increase seen for the (-)-®-fluoxetine enantiomer (enantiomeric ratio AUC((+)-(S)/(-)-®)  = 1.07), resulting in a loss of enantioselectivity. Exposure to gasoline was found to result in the loss of enantioselectivity of fluoxetine, with the predominant reduction occurring in the clearance of the (-)-®-fluoxetine enantiomer (55% vs. 30%). Chirality, 2013. © 2013 Wiley Periodicals, Inc.

Concepts: Stereochemistry, Enantiomer, Chirality, Citalopram, Escitalopram, Enantiomeric excess, Racemic mixture, Enantiopure drug

27

The title compound, [Sn(CH(3))(2)(C(16)H(15)NO(3))], crystallized from one reaction batch with high enantiomeric excess as both a pure enantiomer and a racemate. The S enantiomer crystallizes in the chiral space group P3(2). The racemate crystallizes in the space group P-1 with R and S enantiomers in the crystal lattice; these form dimers about a crystallographic inversion centre.

Concepts: Crystal, Crystallography, Stereochemistry, Enantiomer, Chirality, Crystal system, Enantiomeric excess, Racemic mixture

25

An efficient, fully automated, enantioselective multi-step synthesis of no-carrier-added (nca) 6-[(18) F]fluoro-L-dopa ([(18) F]FDOPA) and 2-[(18) F]fluoro-L-tyrosine ([(18) F]FTYR) on a GE FASTlab synthesizer in conjunction with an additional high- performance liquid chromatography (HPLC) purification has been developed. A PTC (phase-transfer catalyst) strategy was used to synthesize these two important radiopharmaceuticals. According to recent chemistry improvements, automation of the whole process was implemented in a commercially available GE FASTlab module, with slight hardware modification using single use cassettes and stand-alone HPLC. [(18) F]FDOPA and [(18) F]FTYR were produced in 36.3 ± 3.0 % (n = 8) and 50.5 ± 2.7 % (n = 10) FASTlab radiochemical yield (decay corrected). The automated radiosynthesis on the FASTlab module requires about 52 min. Total synthesis time including HPLC purification and formulation was about 62 min. Enantiomeric excesses for these two aromatic amino acids were always >95 %, and the specific activity of was >740 GBq/µmol. This automated synthesis provides high amount of [(18) F]FDOPA and [(18) F]FTYR (>37 GBq end of synthesis (EOS)). The process, fully adaptable for reliable production across multiple PET sites, could be readily implemented into a clinical good manufacturing process (GMP) environment.

Concepts: Amino acid, Chemical synthesis, Chromatography, High performance liquid chromatography, Chirality, Aromatic L-amino acid decarboxylase, Tyrosine, Enantiomeric excess

23

The increasing demand for biocatalysts in synthesizing enantiomerically pure chiral alcohols results from the outstanding characteristics of biocatalysts in reaction, economic, ecological issues. Herein fifteen yeast strains belonging to three food originated yeast species Candida zeylanoides, Pichia fermentans and Saccharomyces uvarum were tested for their capability for asymmetric reduction of acetophenone to 1-phenylethanol as biocatalysts. Of these strains, Candida zeylanoides P1 showed an effective asymmetric reduction ability. Under optimized conditions, substituted acetophenones were converted to corresponding optically active secondary alcohols in up to 99% enantiomeric excess and at high yield. The preparative scale asymmetric bioreduction of 4-nitro acetophenone 1m by Candida zeylanoides P1 gave (S)-1-(4-nitrophenyl) ethanol 2m 89% yield, and >99% enantiomeric excess. Compound 2m has been obtained in an enantiomerically pure and inexpensive form. Additionally, these results indicate that Candida zeylanoides P1is a promising biocatalyst for the synthesis of chiral alcohols in industry. This article is protected by copyright. All rights reserved.

Concepts: Alcohol, Enzyme, Fungus, Yeast, Stereochemistry, Enantiomer, Tartaric acid, Enantiomeric excess

12

The steroidal neurotoxin (-)-batrachotoxin functions as a potent agonist of voltage-gated sodium ion channels (NaVs). Here we report concise asymmetric syntheses of the natural (-) and non-natural (+) antipodes of batrachotoxin, as well both enantiomers of a C-20 benzoate-modified derivative. Electrophysiological characterization of these molecules against NaV subtypes establishes the non-natural toxin enantiomer as a reversible antagonist of channel function, markedly different in activity from (-)-batrachotoxin. Protein mutagenesis experiments implicate a shared binding side for the enantiomers in the inner pore cavity of NaV These findings motivate and enable subsequent studies aimed at revealing how small molecules that target the channel inner pore modulate NaV dynamics.

Concepts: Protein, Chemistry, Action potential, Ion channel, Electrophysiology, Asymmetric induction, Enantiomeric excess, Neurotoxin