SciCombinator

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Concept: Enantiomer

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A new antibacterial chlorinated benzophenone derivative, (±)-pestalachloride D (1), along with a related analog, (±)-pestalachloride C (2), was recently isolated from the marine-derived fungus Pestalotiopsis sp. isolated from a soft coral Sarcophyton sp. collected from Yongxing Island in the South China Sea. Both chiral HPLC analysis and single-crystal X-ray data indicated that 1 is a racemic mixture. Interestingly, 1 did not exhibit any effect in the zebrafish embryo teratogenicity assay, while 2 led to abnormal growth. The potential impact on zebrafish embryo growth is discussed based on their crystal structures. The main difference of crystal structures between 1 and 2 is that the six-member non-aromatic ring (O4, C10, C9, C8, C2', and C3') in 1 exhibits a distorted chair conformation, while 2 shows a distorted boat conformation. Moreover, compounds 1 and 2 both exhibited moderate antibacterial activity.

Concepts: Stereochemistry, Enantiomer, Solid, South China Sea, Racemic mixture, Cyclohexane conformation, East China Sea, Adderall

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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

A convenient synthesis of natural and synthetic pterocarpans was achieved in three steps. Optical resolution of the respective enantiomers was accomplished by analytical and semi-preparative HPLC on a chiral stationary phase. For medicarpin and its synthetic derivative 9-demethoxymedicarpin, the absolute configuration was confirmed by a combination of experimental LC-ECD coupling and quantum-chemical ECD calculations. (-)-Medicarpin and (-)-9-demethoxymedicarpin are both 6aR,11aR-configured, and consequently the corresponding enantiomers, (+)-medicarpin and (+)-9-demethoxymedicarpin, possess the 6aS,11aS-configuration. A comparative mechanism study for osteogenic (bone forming) activity of medicarpin (racemic versus enantiomerically pure material) revealed that (+)-(6aS,11aS)-medicarpin (6a) significantly increased the bone morphogenetic protein-2 (BMP2) expression and the level of the bone-specific transcription factor Runx-2 mRNA, while the effect was opposite for the other enantiomer, (-)-(6aR,11aR)-medicarpin (6a), and for the racemate, (±)-medicarpin, the combined effect of both the enantiomers on transcription levels was observed.

Concepts: DNA, Genetics, Gene expression, Transcription, Stereochemistry, RNA polymerase, Enantiomer, Racemic mixture

28

Original mixed selectors were synthesized by coupling a single l-valine diamide moiety on permethylated β-cyclodextrin. The structures of the new selectors were designed to limit the interactions between the l-valine derivative and cyclodextrin by removing the amino acid moiety from the cyclodextrin cavity by means of an amide linkage on mono-6-amino permethylated β-CD or the insertion of a carboxymethyl group. The accessibility of the amino acid group moiety was thus facilitated. The new mixed selectors exhibited better enantioselectivity than Chirasil-l-Val for half (selector based on mono-6-amino permethylated β-CD) or more (selector with the carboxymethyl group) of the 41 amino acid derivatives. Molecular modeling confirmed that these results could be attributed to an increase in the distance between the chiral center of the amino acid and the cyclodextrin cavity allowing better access of the amino acid moiety. These new mixed chiral selectors demonstrated a novel enantioselective capability with the successful separation of more than 90 racemic mixtures among the 105 chiral compounds tested. These mixed selectors exhibited enhanced enantioselectivity in comparison to binary selectors previously described with respect to both enantiomer resolution and the number of separated chiral compounds. Moreover, an improvement of the enantioseparation factors compared to the corresponding ‘parent phases’ for the amino acid derivatives was observed in many cases. These mixed selectors should therefore be considered some of the most versatile selectors for chiral gas chromatography.

Concepts: Amino acid, Amine, Ammonia, Stereochemistry, Enantiomer, Chirality, Carboxylic acid, Racemic mixture

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

Efforts to substitute the cyclopropane ring in a series of aryl cyclopropylnitriles led to the discovery of an operationally simple one-pot method for Knoevenagel condensation and subsequent Corey-Chaykovsky cyclopropanation giving diastereomerically pure products as a racemic mixture of enantiomers. Method development and results for variably substituted aryl acetonitriles and aldehydes in the reaction are reported. A concise synthesis of (+/-)-bicifadine in two steps is provided to demonstrate the utility of the method.

Concepts: Stereochemistry, Enantiomer, Functional groups, Aldol condensation, Racemic mixture

28

Effusin A (1), a spirobicyclic N,O-acetal derivative with an unprecedented 3',3a',5',6'-tetrahydrospiro[piperazine-2,2'-pyrano[2,3,4-de]chromene] ring system, and a spiro-polyketide-diketopiperazine hybrid dihydrocryptoechinulin D (2) were isolated from a mangrove rhizosphere soil derived fungus, Aspergillus effuses H1-1. Their structures were determined by detailed spectroscopic analysis. Effusin A (1) and dihydrocryptoechinulin D (2) occurred as racemates, the enantiomers of which were separated and characterized by online HPLC-ECD analysis and their absolute configurations were determined by the solution TDDFT ECD calculation approach. The cytotoxic effects of 1 and 2 were preliminarily evaluated and 2 showed potent activity on P388 cells with an IC(50) value of 1.83 μM. The target of racemic 2 was also investigated and the (12R,28S,31S)-2 enantiomer showed selectivity against topoisomerase I.

Concepts: Spectroscopy, Function, Stereochemistry, Enantiomer, Physical chemistry, The Target, Aspergillus fumigatus, Racemic mixture

28

A highly diastereoselective (d.r. >99:1) and enantioselective (ee value up to 96 %) synthesis of trisubstituted cyclohexanols was achieved by using a one-pot sequential organocatalysis that involved a quinidine thiourea-catalyzed tandem Henry-Michael reaction between nitromethane and 7-oxo-hept-5-en-1-als followed by a tetramethyl guanidine (TMG)-catalyzed tandem retro-Henry-Henry reaction on the reaction products of the tandem Henry-Michael reaction. Through a mechanistic study, it has also been demonstrated that similar results may also be achieved with this one-pot sequential organocatalysis by using the racemic Henry product as the substrate.

Concepts: Product, Chemical reaction, Stereochemistry, Chemical synthesis, Enantiomer, Aldol reaction, Racemic mixture, Chiral resolution

28

Equal and opposite: A chiral surfactant molecule was used to induce high enantioselectivity in the transformation from the achiral phase of mercury sulfide, probably through binding of the surfactant thiolate groups to Hg ions in the forming crystal. The generation of truly chiral inorganic NCs of tailored size and shape should be useful for many applications, such as enantioselective catalysis and sensing.

Concepts: Electron, Chemistry, Atom, Chemical bond, Enantiomer, Chirality, Tartaric acid, Cinnabar

28

The ligand exchange reaction between racemic Au38(2-PET)24 (2-PET: 2-phenylethylthiolate) clusters and enantiopure 1,1'-binapththyl-2,2'-dithiol (BINAS) was monitored in situ using a chiral HPLC approach. In the first exchange step, a clear preference of R-BINAS towards the left-handed enantiomer of Au38(2-PET)24 is observed (about four times faster than reaction with the right-handed enantiomer). The second exchange step is drastically slowed compared to the first step. BINAS substitution deactivates the cluster for further exchange, which is attributed to (stereo)electronic effects. The results constitute the first example of a ligand exchange reaction in a thiolate-protected gold cluster with directed enrichment of a defined species in the product mixture. This may open new possibilities for the design of nanomaterials with tailored properties.

Concepts: Stereochemistry, Enantiomer, Chirality, In situ, Tartaric acid, Racemic mixture