Chiral Reagent Research Articles

Structurally Defined α-Tetralol-Based Chiral Hypervalent Iodine Reagents.

A novel class of chiral hypervalent iodine reagents containing an α-tetralol scaffold is introduced. Iodine triacetate is employed in a key step as a highly selective and efficient iodinating reagent for a short and convenient synthesis of iodine(III) derivatives. Solid-state X-ray analyses offer valuable structural information, while reactivities and stereoselectivities are investigated in three model reactions.

Asymmetric syntheses and applications of planar chiral hypervalent iodine(V) reagents with crown ether backbones

Novel optically active hypervalent iodine(V) reagents with planar chiral crown ether backbones were synthesized using the intramolecular Huisgen reaction as a key step and l-methyl lactate as the source of chirality. The relative configurations of these reagents and stabilities of planar chiralities were determined by DFT calculations. These planar chiral reagents were applied to the hydroxylative dearomatization/[4 + 2]-dimerization reactions of phenols to afford bisthymol and biscarvacrol, a natural product, with moderate enantioselectivities.

A micellar electrokinetic chromatography approach using diastereomeric derivatization and a volatile surfactant for the enantioselective separation of selenomethionine.

A MEKC methodology with UV detection was developed for the enantioselective separation of selenomethionine (SeMet). The use of (+)-1-(9-fluorenyl)ethyl chloroformate (FLEC) as chiral derivatization reagent to form SeMet diastereomers enabled their subsequent separation using ammonium perfluorooctanoate (APFO) as a volatile pseudostationary phase. The effect of APFO concentration and pH, temperature, injection volume, and derivatization conditions (time and FLEC/SeMet ratio) were evaluated in order to select the best separation conditions. A chiral resolution of 4.4 for DL-SeMet was achieved in less than 6min using 100mM APFO at pH8.5 as electrophoretic buffer. Satisfactory results were obtained in terms of linearity, precision (RSD from 3.4 to 5.1% for migration times and from 1.8 to 4.6% for corrected peak areas), accuracy, and LODs (3.1×10-6 M and 3.7×10-6 M for d and l enantiomers, respectively). The method was successfully applied to the determination of l-SeMet in food supplements.

Sensitive enantioseparation and determination of isoprenaline in human plasma and pharmaceutical formulations.

A simple, sensitive and fast RPHPLC method was developed and validated for the enantioselective determination of (RS)-isoprenaline (Ipn) in human plasma. The enantiomers were converted to diastereomeric derivatives using s-triazine (cyanuric chloride) based chiral derivatizing reagents. l-isoleucine and l-methionine were introduced as chiral auxiliary in s-triazine and two new monochloro-s-triazine reagents were synthesized. These reagents were characterized and used for synthesis of diastereomeric derivatives of (RS)-Ipn spiked in human plasma. (RS)-Ipn was isolated (purified and characterized) from a commercial pharmaceutical formulation and was used as the standard racemic sample. Structures of the two diastereomeric derivatives were optimized for lowest energy using the Gaussian 09 Rev A. 02 program and hybrid density functional B3LYP with 6-31G* basis set which showed the spatial orientation of hydrophobic groups on stereogenic centers in the diastereomeric derivatives. The results were correlated with the mechanism of separation and elution order. Limit of detection values were found to be 24.6 and 26.8 ng mL-1 for the first and second eluting diastereomeric derivatives, respectively.

Novel chiral Oxa-bridged Calix[2]arene[2]triazine derivatives as NMR chiral reagents for enantioselective recognition of α-racemic carboxylic acids

A new family of chiral tetraoxacalix[2]arene[2]triazine receptors (2a–2c) have been synthesized efficiently in 69–73% yields. By 1H NMR spectroscopy, the chiral enantiodiscrimination ability of novel hosts against a series racemic carboxylic acids were examined. The chiral calix[2]arene[2]triazine-based compounds were found to have good enantiomeric recognition ability to racemic carboxylic acids. We also observed that the tetraoxacalix[2]arene[2]triazine derivative 2c is a more versatile chiral solvating agents than 2a and 2b, as 2c shows a better performance for the determination of the enantiomeric excess. The molar ratio of the each enantiomers of guest molecules with receptors were examined by using Job plots, respectively. The graphics show that the hosts form 1:1 complexes with all of the guests.

Potential for Underestimation of d-Methylphenidate Bioavailability Using Chiral Derivatization/Gas Chromatography.

A tenable hypothesis is presented which explains disparities between older oral dl-MPH bioavailability data generated using chiral derivatization-gas chromatography versus more recent findings using chiral liquid chromatography. These disparities persist in current literature. The gas chromatographic methods found that the absolute bioavailability of d-MPH is 23% and that of l-MPH is 5% (i.e., 82% as the active d-isomer), while liquid chromatographic methods consistently report that approximately 99% of circulating MPH is d-MPH. Older methods used perfluoroacylated S-prolyl derivatizing agents which have a history of imprecision due to the susceptibility of the prolyl S-configuration to isomerize to the R-enantiomer. Accordingly, any R-prolyl impurity in the chiral derivatization reagent yields the (R,R,R)-MPH-prolyl diastereomer which, in being related as the opposite enantiomer of (S,S,S)-prolyl-MPH, co-elutes with l-(S,S)-MPH. This results in overestimation of the percent l-MPH at the expense of underestimating d-MPH. Unless compelling reasons exist to justify use of any chiral discriminators, less complex and less costly achiral analysis of plasma MPH appears appropriate for d-MPH quantitation since 99% exists as d-MPH. However, simultaneous plasma monitoring of d-MPH and l-MPH may be warranted when alterations in first-pass hepatic metabolism by carboxylesterase 1 (CES1) occurs. For example, (a) with transdermal dl-MPH delivery; (b) in cases of concomitant dl-MPH and a CES1 inhibitor, e.g., ethanol, which elevates l-MPH and d-MPH concentrations; (d) in forensic studies of intravenous or intranasal dl-MPH abuse; (e) were dl-MPH to be formulated as a free base sublingual product; or (f) as emerging advances in dl-MPH gene-dose effects warrant isomer correlations.

The Preparation of Enantiopure [6]- and [7]Helicenes from Binaphthanol.

A general and efficient synthetic methodology for the preparation of enantio- and diastereopure [6]-, and [7]helicenes is developed. Commercially available chiral binaphthanols are utilized to generate the arylene-vinylene precursors, which undergo helical folding via photocyclization to give enantio- and diastereopure [6]-, and [7]helicenes. These optically pure helicenes could be easily obtained via silica gel column chromatography without the use of expensive HPLC or chiral resolution reagents. The configurations and structures of these helicenes are confirmed by CD spectra and X-ray crystallographic analysis. This work provides a new method for preparation of enantiopure helicenes.

Direct Enantioselective and Regioselective Alkylation of β,γ-Unsaturated Carboxylic Acids with Chiral Lithium Amides as Traceless Auxiliaries.

Efficient asymmetric alkylation of β,γ-unsaturated carboxylic acids without prior functionalization is enabled by chiral lithium amides. Enantioselectivity is imparted by a putative mixed lithium amide-enediolate aggregate that acts a traceless auxiliary formed in situ, allowing for a direct asymmetric alkylation and a simple recovery of the chiral reagent.

Absolute configuration determination of asarinin by synchrotron radiation with crystalline sponge method

The determination of the absolute configuration of natural products still faces many challenges, especially the active pharmaceutical ingredient which is trace, oily and novel structures. Currently, NMR requires chiral reagents in determining the absolute configuration; ECD involves theoretical calculations and requires chromophores. In this study, the absolute configuration of asarinin had successfully identified by using synchrotron radiation with crystalline sponge method and combining MS with NMR. This method could identifying the crystal structure of trace amorphous substances, resolving the problem of absolute configuration of multi-chiral central compounds, and hopefully providing a new idea and approach for structural elucidation of natural products.

Superiority of thin-layer chromatography over high-performance liquid chromatography in enantioseparation

The scientific development in the area of enantioseparation during the last few decades has centered on the production of new chiral stationary phases (CSPs) and new chiral derivatizing reagents (CDRs) for use in liquid chromatography, and in particular high-performance liquid chromatography (HPLC) only. Both CSPs and CDRs have several limitations which, in general, are ignored. Little attention has been paid to thin-layer chromatography (TLC) despite its many advantages compared to HPLC in pharmaceutical and drug analysis and the areas of natural products chemistry and organic synthesis, particularly enantioselective synthesis in purification of the product prior to establishing enantiomeric ratio by different method(s). TLC provides a rapid, easy, aff ordable, and simple approach in all these situations. The demonstrated capability and efficiency of TLC in direct resolution of the racemate clearly establish its superiority, and the methodology should allow its application in the resolution of several other racemates, irrespective of the functional group, in a very short time along with the recovery of native enantiomers (for further use).

Chiral Self-Assembly of Nanoparticles Induced by Polymers Synthesized via Reversible Addition-Fragmentation Chain Transfer Polymerization.

Chiral inorganic nanomaterials are of great interest because of their excellent optical properties. Most of the attention has been focused on the utilization of biomolecules or their derivatives as linkers or templates to control the chiral structure of assembled inorganic nanoparticles. Chiral polymers are promising synthetic materials that can be used to replace their biological counterparts. Here, by using poly(methacrylate hydroxyethyl-3-indole propionate) (PIPEMA) and poly(2-hydroxyethyl methacrylate) (PHEMA) synthesized via syndioselective reversible addition-fragmentation chain transfer polymerization, we successfully realized chiral self-assembly of gold nanorods with strong circular dichroism response in the vis-NIR region. Moreover, the intensity of the chiral signal of the assemblies can be regulated by the molecular weight of the polymers. Notably, although the monomers are achiral and no chiral reagents are involved in their synthesis, the main chains of PIPEMA and PHEMA exhibit a preferred-handed helical conformation, which is the origin of chirality of the nanorod assemblies. The preferred-handed helical conformation of polymers is attributed to their syndiotacticity and stabilized by the steric hindrance of the side groups. The addition of chiral carbon atoms at the side groups doesnot change the preferred-handedness of the polymer main chain, resulting in the assembled nanorod structures with the same chirality. This strategy provides inspiration for the rational design and synthesis of optically active functional synthetic polymers for the preparation of promising chiral nanomaterials.

Biaryl axially chiral derivatizing agent for simultaneous separation and sensitive detection of proteinogenic amino acid enantiomers using liquid chromatography–tandem mass spectrometry

Novel sophisticated derivatizing agents for the efficient enantioselective separation and mass spectrometric detection of d- and l-amino acids have been developed. Two new axially chiral reagents derived from 6,6′-dimethyl-2,2′-biphenyldiamine were synthesized. Their chiral separation and detection abilities were evaluated by derivatizing proteinogenic amino acid standards in reversed-phase liquid chromatography–tandem mass spectrometry (LC–MS/MS). The resulting diastereomers derived from the developed derivatizing agents and amino acids could be completely separated, because of the effective chiral environment constructed by the axially chiral biphenyl moiety. After optimizing the reactive group, (R)-4-nitrophenyl N-[2′-(diethylamino)-6,6′-dimethyl-[1,1′-biphenyl]-2-yl]carbamate hydrochloride ((R)-BiAC) was found to be the best reagent for highly sensitive simultaneous d,l-amino acid analysis. Using (R)-BiAC, the complete chiral separation of all derivatized proteinogenic amino acids was achieved within 11.5 min with Rs greater than 1.9, except for certain allo-isomers. An exceptional feature of this reagent was its control of elution order, i.e., it afforded elution of the diastereomers derived from d-amino acids before their l-amino acid counterparts for all 19 proteinogenic amino acids. Sensitive detection was also achieved by introducing a dialkyl amino group and selectively cleaving it at the binding site between the reagent and amino acid. Attomole (amol) detection limits (signal-to-noise ratio = 3) were obtained for the tested d,l-amino acids, in the range 7.0–127 amol. As an example of application, the method was applied to food sample analysis, and detected several d-amino acids. Consequently, the developed method seems likely to facilitate simultaneous determination of enantiomers, including the tiny amounts of d-amino acids found in nature.

Synthesis of [7]Helicene Enantiomers and Exploratory Study of Their Conversion into Helically Chiral Iodoarenes and Iodanes.

The facile and convenient preparation of both enantiomers of a [7]helicene scaffold from inexpensive (l)-(+)-tartaric acid and 4-methylstyrene is described. These helical structures were transformed into bis-iodinated ether derivatives in order to explore their potential as precursors of novel chiral organoiodane reagents or as iodoarene pre-catalysts. Promising results were obtained in hydroxylative phenol dearomatization/[4+2] cycloaddition cascade and dearomative spirolactonization reactions with encouraging enantiomeric excesses.

Development of Highly Enantioselective Catalysts for Asymmetric Copolymerization of meso-Epoxides and Cyclic Anhydrides: Subtle Modification Resulting in Superior Enantioselectivity

The asymmetric alternating copolymerization of meso-epoxides with cyclic anhydrides promoted by chiral catalysts or reagents is a powerful strategy for the synthesis of optically active polyesters ...

Selectivity evaluation of phenyl based stationary phases for the analysis of amino acid diastereomers by liquid chromatography coupled with mass spectrometry

D-amino acids (AA) analysis is becoming more and more relevant for metabolomics, therefore new analytical tools need to be developed. A common approach to achieve AA enantioseparation is chiral derivatization. Among the chiral derivatization reagents, (+) or (-)-1-(9-fluorenyl) ethyl chloroformate ((+) or (-)-FLEC) has proved to be one of the most versatile. Suitable chiral selectivity for FLEC derivatives of amino acids could be obtained in reversed-phase HPLC using nonpolar stationary phases (C4, C8 and C18) and tetrahydrofuran (THF) based mobile phases. This study is meant to provide alternatives to the use of THF as organic modifier by evaluating the selectivity obtained on two phenyl based stationary phases for 19 FLEC-DL-AA pairs of diastereomers using UHPLC-MS. Several mobile phases consisting of ammonium acetate and different common organic solvents (acetonitrile (ACN), methanol (MeOH), 2-propanol (IPA)) were tested using gradient elution. Experimental design was employed for the optimization of the separation conditions. In the optimized conditions, complete chiral separation can be achieved for 18 out of 19 FLEC-DL-AAs in less than 30 min.

Analysis and Enantioseparation of Amino Acids by Liquid Chromatography.

Enantioseparation studies of proteinogenic, non-proteinogenic, and dansyl amino acids are described herein by using liquid chromatographic techniques, i.e., HPLC and TLC. A researcher who wants to perform amino acid (AA) analysis or separate enantiomers of AAs by HPLC or TLC can follow the method. Figures included represent the actual experiments.Synthesis and application of chiral derivatizing reagents (CDRs) based on cyanuric chloride (CC) and difluorodinitrobenzene (DFDNB) have been described for AA analysis and enantioseparation by indirect approach. The methods represent pre-column derivatization of AAs and represent a good and less expensive substitute of AA analyzer. The application of commercial "Chiralplate" and use of erythromycin and L-tartaric acid have been described as chiral selector either as impregnating reagent in the stationary phase or as an additive in the mobile phase for direct enantioseparation by TLC. Application of the homemade TLC plates has also been described; the methods are successful in obtaining the native enantiomer as well.

Highly diastereoselective preparation of chiral NHC-boranes stereogenic at the boron atom.

Stereogenic main group elements are clearly generating interest in the enantioselective catalysis field. Surprisingly, while chiral organoboron reagents are very useful in stereoselective transformations, few scaffolds stereogenic at boron and configurationally stable have been reported to date. Herein, we describe an original library of chiral NHC-boranes, stereogenic at the boron atom, that has been prepared in only a few steps and in good yields (up to 93%). Key steps involve a chlorination/arylation sequence in the presence of simple Grignard reagents from bicyclic NHC-boranes. The high and unprecedented diastereoselectivity observed during the second step (up to 99 : 1 dr) has been rationalized through a plausible SRN1 mechanism thanks to EPR observations and DFT calculations.

DL-Amino Acid Analysis Based on Labeling with Light and Heavy Isotopic Reagents Followed by UPLC-ESI-MS/MS.

L-Pyroglutamic acid succinimidyl ester (L-PGA-OSu) and its isotopic variant (L-PGA[d5]-OSu) were synthesized and used as the chiral labeling reagents for the enantioseparation of amino acids by reversed-phase UPLC-ESI-MS/MS. The enantiomers of amino acids were labeled with the reagents at 60°C for 10min in an alkaline medium. The resulting diastereomers were well separated by the reversed-phase chromatography using an ODS column, packed with small particles (1.7μm) (Rs=1.95-8.05). A highly sensitive detection at a low-fmol level (0.5-3.2fmol) was obtained from the selected reaction monitoring (SRM) chromatograms. An isotope labeling strategy using light and heavy variants for the differential analysis of the DL-amino acids in different sample groups is also presented in this paper. The ratios of D/L-alanine in different yogurt products were successfully determined by the proposed method. The D/L ratios were almost comparable to those obtained from only using light reagent (i.e., L-PGA-OSu). Therefore, the proposed strategy seems to be useful for the differential analysis of DL-amino acids, not only in food products but also in biological samples.

Chiral Capillary Electrophoresis-Mass Spectrometry.

Capillary electrophoresis (CE) is a well-established and one of the most powerful separation techniques in the field of chiral separations. Its hyphenation with mass spectrometry (MS) combines both the high separation efficiency and low sample consumption of CE and the high sensitivity and structural information of MS. Thus, the outstanding chiral resolution power of CE along with the MS advantages makes CE-MS a perfect combination to achieve sensitive enantioseparations. This chapter describes three representative examples of different approaches used in the chiral analysis of amino acids in biological fluids by CE-MS. The first methodology uses the partial filling technique to avoid the entry of cyclodextrins in the MS source. The second method shows the possibility to carry out the direct coupling EKC-MS even when a relative high concentration of a native cyclodextrin is used as chiral selector. The last example illustrates an alternative strategy based on the formation of stable diastereomers between an enantiomerically pure chiral reagent and the amino acids enantiomers which can be separated in an achiral environment.

Enantioselective organocatalytic activation of vinylidene-quinone methides (VQMs).

Vinylidene-quinone methides (VQMs) are highly electrophilic chiral reagents that can be generated in situ from 2-(phenylethynyl)phenols. They were characterized for the first time in 2012 but their enantioselective organocatalytic activation was addressed only very recently. Their specific reactivity has revealed innovative strategies notably for the control of axial chirality.