Enantiomeric Ratio Research Articles

Catalytic Enantioselective Intramolecular Oxa-Michael Reaction to α,β-Unsaturated Esters and Amides.

A bifunctional iminophosphorane (BIMP)-catalyzed, enantioselective intramolecular oxa-Michael reaction of alcohols to tethered, low electrophilicity Michael acceptors is described. Improved reactivity over previous reports (1 day vs 7 days), excellent yields (up to 99%), and enantiomeric ratios (up to 99.5:0.5 er) are demonstrated. The broad reaction scope, enabled by catalyst modularity and tunability, includes substituted tetrahydrofurans (THFs) and tetrahydropyrans (THPs), oxaspirocycles, sugar and natural product derivatives, dihydro-(iso)-benzofurans, and iso-chromans. A state-of-the-art computational study revealed that the enantioselectivity originates from the presence of several favorable intermolecular hydrogen bonds between the BIMP catalyst and the substrate that induce stabilizing electrostatic and orbital interactions. The newly developed catalytic enantioselective approach was carried out on multigram scale, and multiple Michael adducts were further derivatized to an array of useful building blocks, providing access to enantioenriched biologically active molecules and natural products.

Organocatalytic Asymmetric Peroxidation of γ,δ-Unsaturated β-Keto Esters-A Novel Route to Chiral Cycloperoxides.

A methodology for the asymmetric peroxidation of γ,δ-unsaturated β-keto esters is presented. Using a cinchona-derived organocatalyst, the target δ-peroxy-β-keto esters were obtained in high enantiomeric ratios of up to 95:5. Additionally, these δ-peroxy esters can be readily reduced to chiral δ-hydroxy-β-keto esters without impacting the β-keto ester functionality. Importantly, this chemistry opens up a concise route to chiral 1,2-dioxolanes, a common motif in many bioactive natural products, via a novel P2O5-mediated cyclisation of the corresponding δ-peroxy-β-hydroxy esters.

Kinetic Resolution of 2-Aryldihydroquinolines Using Lithiation - Synthesis of Chiral 1,2- and 1,4-Dihydroquinolines.

Highly enantiomerically enriched dihydrohydroquinolines were prepared in two steps from quinoline. Addition of aryllithiums to quinoline with tert-butoxycarbonyl (Boc) protection gave N-Boc-2-aryl-1,2-dihydroquinolines. These were treated with n-butyllithium and electrophilic trapping occurred exclusively at C-4 of the dihydroquinoline, a result supported by DFT studies. Variable temperature NMR spectroscopy gave kinetic data for the barrier to rotation of the carbonyl group (ΔG≠ ≈49 kJ mol-1 , 195 K). Lithiation using the diamine sparteine allowed kinetic resolutions with high enantioselectivities (enantiomer ratio up to 99 : 1). The enantioenriched 1,2-dihydroquinolines could be converted to 1,4-dihydroquinolines with retention of stereochemistry. Further functionalisation led to trisubstituted products. Reduction provided enantioenriched tetrahydroquinolines, whereas acid-promoted removal of Boc led to quinolines, and this was applied to a synthesis of the antimalarial compound M5717.

Synergistic Li/Li Bimetallic System for the Asymmetric Synthesis of Antituberculosis Drug TBAJ-587.

TBAJ-587, an analogue of the antituberculosis drug bedaquiline (BDQ), bearing a diarylquinoline skeleton retains the high bacterial potency, is less toxic, and has a better pharmacokinetic profile than the parent molecule, which has entered phase I clinical trials. In contrast to its fascinating bioactivity, however, the highly efficient synthesis of this molecule is still an unsolved challenge. Herein, the first asymmetric synthesis of TBAJ-587 based on a synergistic Li/Li bimetallic system is reported. The product could be obtained in an excellent yield of 90% and an enantiomeric ratio (er) of 80:20. Furthermore, the reaction could be conducted on a 5 g scale, and the product was obtained with 99.9:0.1 er after a simple recrystallization. The realization of this protocol will greatly aid the demand for clinical drug production.

Enantiomeric separation and precise quantification of chiral volatiles in Wuyi rock teas using an efficient enantioselective GC × GC-TOFMS approach

Chiral volatiles play important roles in the formation of aroma quality of foods. To date, enantiomeric characteristics of chiral volatiles in Wuyi rock tea (WRT) and their aroma contributions are still unclear. In this study, an efficient enantioselective comprehensive two-dimensional gas chromatography-time-of-flight mass spectrometry (Es-GC × GC-TOFMS) approach to separate and precisely quantitate 24 pairs of chiral volatiles in WRTs was established, and the enantiomeric distribution and aroma contribution of chiral volatiles among WRTs from four representative cultivars were investigated. Enantiomeric ratio (ER) of R-α-ionone (80%) in Dahongpao (DHP), ER of S-α-terpineol (57%) in Jinfo (JF), ERs of R-γ-heptanolactone (69%), S-γ-nonanolactone (55%), (2R, 5S)-theaspirane B (91%), concentration of S-(E)-nerolidol (313.37 ng/mL) in Rougui (RG) and concentration of R-α-ionone (33.01 ng/mL) in Shuixian (SX) were unique from other types of WRTs, which were considered as the potential chemical markers to distinguish WRT cultivars. The OAV assessment determined 7 volatile enantiomers as the aroma-active compounds, especially R-α-ionone and R-δ-octanolactone in SX, as well as S-(E)-nerolidol and (1R, 2R)-methyl jasmonate in RG contribute much to aroma formation of the corresponding WRTs. The above results provide scientific references for discrimination of tea cultivars and directed improvement of the aroma quality of WRT.

Mechanistic Insights into the Stepwise (4+2) Cycloaddition toward Chiral Fused Uracil Derivatives

AbstractThe mechanism of the previously reported stereoselective (4+2) cycloaddition of N‐protected 6‐methyluracil‐5‐carbaldehydes and (E)‐β‐nitrostyrenes catalyzed by Takemoto's tertiary amine/thiourea organocatalyst was explored, using density functional theory (DFT) calculations on a model representative reaction. The cyclization reaction, which afforded notable enantioenriched carbocycle‐fused uracils embedding three contiguous stereocenters, was here proven to be the result of a four‐step sequence comprising a key stereo‐defining Michael addition, followed by a completely diastereoselective intramolecular Henry reaction. Going beyond the hitherto reported activation modes, a complex and unprecedented network of hydrogen‐bonding interactions between the chiral catalyst and the reaction partners has been disclosed, in which the protonated tertiary amine and the thiourea moiety of the catalyst simultaneously activate both the electrophile and the nucleophile components. By applying the Energetic Span Model (ESM) to four competitive energetic profiles, we unveiled the most plausible reaction pathways best fitting the experimental data, with close correlation with the observed enantiomeric ratio of the product.magnified image

Isothiourea-Catalyzed Acylative Desymmetrization of Silicon-Centered Bisphenols.

The preparation of optically pure organosilicon compounds bearing a stereogenic center at the silicon atom is an attractive but challenging enterprise. Herein we disclose an isothiourea (ITU)-catalyzed monoacylation reaction of silicon-centered bisphenols with 2,2-diphenylacetic pivalic anhydride, delivering tetrasubstituted organosilanes in moderate to excellent yields (36-91%) with moderate to excellent enantiomeric ratios (68:32-97.5:2.5). This organocatalytic desymmetrization approach can be performed on gram scale, and the products can be converted to other valuable compounds.

A Traceless Chiral Shift Reagent Based on Nonbonding Interactions with Single‐Handed Helical Poly(quinoxaline‐2,3‐diyl)

AbstractA single‐handed poly(quinoxaline‐2,3‐diyl) (PQX) has been found to serve as a new type of chiral shift reagent (CSR) for determining the enantiomeric ratio by NMR spectroscopy. Even though there is no specific binding site in the PQX, its nonbonding interaction with chiral analytes leads to a significant shift of the NMR chemical shift, allowing quantification of the enantiomeric ratio. The new type of CSR has the advantages of a wide scope of analytes including ethers, haloalkanes, and alkanes, easy tunability of the degree of chemical shifts by measurement temperature, and erasability of proton signals of CSR because of the short spin‐spin (T2) relaxation of the macromolecular scaffold.

Traceless Chiral Shift Reagent Based on Nonbonding Interaction with Single-Handed Helical Poly(quinoxaline-2,3-diyl).

Single-handed poly(quinoxaline-2,3-diyl)s (PQX) have been found to serve as a new chiral shift reagent (CSR) for determining the enantiomeric ratio by NMR. Even though there is no specific binding site in PQX, its nonbonding interaction with chiral analytes leads to a significant shift of the NMR chemical shift, allowing quantification of the enantiomeric ratio. The new CSR has the advantages of a wide scope of analytes including ethers, haloalkanes, and alkanes, easy tunability of the degree of chemical shifts by measurement temperature, and erasability of proton signals of CSR because of the short spin-spin (T2) relaxation of the macromolecular scaffold.

Cobalt‐Catalyzed Asymmetric Deuteration of α‐Amidoacrylates for Stereoselective Synthesis of α,β‐Dideuterated α‐Amino Acids

AbstractA cobalt‐catalyzed deuteration of amidoacrylates using deuterated methanol afforded α,β‐dideuterio‐α‐amino esters in excellent enantiomeric ratios (mostly >95 : 5) and almost complete deuteration (99 %). The new protocol was used to prepare dideuterio‐α‐amino acid fragments in some drugs. Furthermore, the stereoselective deuteration was applied in a concise synthesis of dideuterio l‐DOPA.

Cobalt-Catalyzed Asymmetric Deuteration of α-Amidoacrylates for Stereoselective Synthesis of α,β-Dideuterated α-Amino Acids.

A cobalt-catalyzed deuteration of amidoacrylates using deuterated methanol afforded α,β-dideuterio-α-amino esters in excellent enantiomeric ratios (mostly >95 : 5) and almost complete deuteration (99 %). The new protocol was used to prepare dideuterio-α-amino acid fragments in some drugs. Furthermore, the stereoselective deuteration was applied in a concise synthesis of dideuterio l-DOPA.

Toward in silico Catalyst Optimization.

In this minireview, we overview a computational pipeline developed within the framework of NCCRCatalysis that can be used to successfully reproduce the enantiomeric ratios of homogeneous catalytic reactions.At the core of this pipeline is the SCINE Molassembler module, a graph-based software that provides algorithmsfor molecular construction of all periodic table elements. With this pipeline, we are able to simultaneously functionalizenand generate ensembles of transition state conformers, which permits facile exploration of the influencenof various substituents on the overall enantiomeric ratio. This allows preconceived back-of-the-envelope designnmodels to be tested and subsequently refined by providing quick and reliable access to energetically low-lyingntransition states, which represents a key step in undertaking in silico catalyst optimization.

Detection and analysis of chiral molecules as disease biomarkers.

The chirality of small metabolic molecules is important in controlling physiological processes and indicating the health status of humans. Abnormal enantiomeric ratios of chiral molecules in biofluids and tissues occur in many diseases, including cancers and kidney and brain diseases. Thus, chiral small molecules are promising biomarkers for disease diagnosis, prognosis, adverse drug-effect monitoring, pharmacodynamic studies and personalized medicine. However, it remains difficult to achieve cost-effective and reliable analysis of small chiral molecules in clinical procedures, in part owing to their large variety and low concentration. In this Review, we describe current and emerging techniques that detect and quantify small-molecule enantiomers and their biological importance.

Dirigent gene editing of gossypol enantiomers for toxicity-depleted cotton seeds

Axial chirality of biaryls can generate varied bioactivities. Gossypol is a binaphthyl compound made by cotton plants. Of its two axially chiral isomers, (-)-gossypol is the bioactive form in mammals and has antispermatogenic activity, and its accumulation in cotton seeds poses health concerns. Here we identified two extracellular dirigent proteins (DIRs) from Gossypium hirsutum, GhDIR5 and GhDIR6, which impart the hemigossypol oxidative coupling into (-)- and (+)-gossypol, respectively. To reduce cotton seed toxicity, we disrupted GhDIR5 by genome editing, which eliminated (-)-gossypol but had no effects on other phytoalexins, including (+)-gossypol, that provide pest resistance. Reciprocal mutagenesis identified three residues responsible for enantioselectivity. The (-)-gossypol-forming DIRs emerged later than their enantiocomplementary counterparts, from tandem gene duplications that occurred shortly after the cotton genus diverged. Our study offers insight into how plants control enantiomeric ratios and how to selectively modify the chemical spectra of cotton plants and thereby improve crop quality.

Enantioselective Allylation of Stereogenic Nitrogen Centers.

Most tertiary amines with a stereogenic nitrogen center undergo rapid racemization at room temperature. Consequently, the quaternization of amines under dynamic kinetic resolution seems feasible. N-Methyl tetrahydroisoquinolines are converted into configurationally stable ammonium ions by Pd-catalyzed allylic alkylation. The optimization of conditions and the evaluation of the substrate scope enabled high conversions and an enantiomeric ratio of up to 10:90. We report here the first examples for the enantioselective catalytic synthesis of chiral ammonium ions.

Synthesis of amylose and cellulose derivatives bearing bulky pendants for high-efficient chiral fluorescent sensing

Three novel amylose and cellulose phenylcarbamate derivatives bearing bulky para-substituted benzothienyl or benzofuranyl pendants were successfully synthesized as chiral fluorescent sensors through carbamoylation followed by Suzuki-Miyaura coupling reactions. The bulky derivatives showed good enantioselective fluorescent sensing properties toward a total of eight chiral quenchers in this study. Especially, a high enantiomeric fluorescence difference ratio (ef = 164.35) was achieved on amylose benzofuranylphenylcarbamates (Amy-2) to the 3-amino-3-phenylpropan-1-ol (Q5), an important chiral drug intermediate. It indicated that a favorable chiral environment was effectively constructed by arrangement of bulky π-conjugated benzothienyl or benzofuranyl pendants on the phenylcarbamate moieties surrounding the helical backbone, which is crucial for high-efficient chiral fluorescent sensing. As chiral stationary phases for high-performance liquid chromatography, the bulky benzothienylphenylcarbamates of amylose and cellulose also showed good resolution powers to thirteen racemates, including metal tris(acetylacetonate) complexes, chiral drugs, analytes with axial chirality and chiral aromatic amines, which were difficult to be efficiently separated even on the popular Chiralpak AD and Chiralcel OD. The excitation-dependent chiral fluorescent sensing probably followed different mechanisms from that for chromatographic enantioseparation relying on the dynamic collision of molecules in the ground state. The structure of the bulky derivatives was also investigated by CD spectra and POM microscopy.

Multidimensional Gas Chromatography of Organosulfur Compounds in Coffee and Structure-Odor Analysis of 2-Methyltetrahydrothiophen-3-one.

Organosulfur compounds (OSCs) in coffee remain challenging to analyze by conventional gas chromatography (GC) due to their low concentrations amid coffee's complex matrix and susceptibility to chiral-odor influences. In this study, multidimensional GC (MDGC) methods were developed to profile OSCs in coffee. Conventional GC was compared to comprehensive GC (GC×GC) for untargeted OSC analysis in eight specialty coffees, and GC×GC was found to improve the fingerprinting of OSCs in coffee (50 vs 16 OSCs identified). Of the 50 OSCs, 2-methyltetrahydrothiophen-3-one (2-MTHT) was of high interest due to its chirality and known aroma contribution. Following that, a heart-cutting method for chiral GC (GC-GC) was developed, validated, and applied to the coffees. The mean enantiomer ratio of 2-MTHT was observed to be 1.56 (R/S) in brewed coffees. Overall, MDGC techniques allowed for more comprehensive analyses of coffee OSCs, from which (R)-2-MTHT was found to be the predominant enantiomer with the lower odor threshold.

Pseudomonas cepacia lipase immobilized on Zn2Al layered double hydroxides: Evaluation of different methods of immobilization for the kinetic resolution of (R,S)-1-phenylethanol

The present work deals with the preparation and characterization of Zn2Al layered double hydroxides (LDHs) intercalated with chloride and dodecyl sulfate ions and their use as supports for the immobilization of Pseudomonas cepacia lipase (LipPS). LipPS was immobilized on LDH by adsorption, in situ entrapment and delamination entrapment methods. The performance of free and immobilized LipPS in the transesterification of (R,S)-1-phenylethanol was compared. The immobilized derivatives prepared by adsorption gave the highest conversions (c = 50%), with an enantiomeric excess of the product (eep ) greater than 99% and a high enantiomeric ratio (E > 200). For immobilization by in situ entrapment (coprecipitation), a conversion of 31.5% and E > 200 were obtained. For immobilization by delamination entrapment, a conversion of 36% and E= 155 were obtained. Although the best results were obtained by adsorption, these results show that the delamination entrapment method can also be used to prepare bioinorganic-enzyme materials based on LDH. Our work therefore increases the range of methods that can be used to immobilize lipases for use in the production of optically pure secondary alcohols.

Semi-Preparative Separation, Absolute Configuration, Stereochemical Stability and Effects on Human Neuronal Cells of MDPV Enantiomers.

Synthetic cathinones, such as 3,4-methylenedioxypyrovalerone (MDPV), are widely abused due to their psychostimulant effects. As they are chiral molecules, studies of their stereochemical stability (racemization can occur in certain temperatures and acidic/basic environments) and of their biological and/or toxicity effects (enantiomers might display different properties) are of great relevance. In this study, the liquid chromatography (LC) semi-preparative enantioresolution of MDPV was optimized to collect both enantiomers with high recovery rates and enantiomeric ratio (e.r.) values. The absolute configuration of the MDPV enantiomers was determined by electronic circular dichroism (ECD) with the aid of theoretical calculations. The first eluted enantiomer was identified as S-(-)-MDPV and the second eluted enantiomer was identified as R-(+)-MDPV. A racemization study was performed by LC-UV, showing enantiomers' stability up to 48 h at room temperature and 24 h at 37 °C. Racemization was only affected by higher temperatures. The potential enantioselectivity of MDPV in cytotoxicity and in the expression of neuroplasticity-involved proteins-brain-derived neurotrophic factor (BDNF) and cyclin-dependent kinase 5 (Cdk5)-was also evaluated using SH-SY5Y neuroblastoma cells. No enantioselectivity was observed.

Chiral separation and quantitation of methylphenidate, ethylphenidate, and ritalinic acid in blood using supercritical fluid chromatography.

Supercritical fluid chromatography (SFC)is a technique that analyzes compounds that are temperature-labile, have moderately low weight, or are chiral compounds. Methylphenidate (MPH) is a chiral compound with two chiral centers. MPH has two chiral metabolites, ethylphenidate (EPH) and ritalinic acid (RA). MPH is sold as a racemic mixture. The d-enantiomer of threo-MPH is responsible for medicinal effects. Due to the differing effects of the enantiomers, it is important to analyze the enantiomers individually to better understand their effects. This method utilizes SFCand solid-phase extraction (SPE) to separate and analyze the enantiomers of MPH, EPH, and RA in postmortem blood. The objective of this method was to assess a unique approach with SFC for enantiomeric separation of MPH, EPH, and RA. A SPE method was developed and optimized to isolate the analytes in blood and validated as fit-for-purpose following international guidelines. The linear range for MPH and EPH was 0.25-25 and 10-1000 ng/mL for RA in blood. Bias was -8.6% to 0.8%, and precision was within 15.4% for all analytes. Following method validation, this technique was applied to the analysis of 49 authentic samples previously analyzed with an achiral method. Quantitative results for RA were comparable to achiral technique, whereas there was loss of MPH and EPH over time. The l:d enantiomer ratio was calculated, and MPH demonstrated greater abundance of the d-enantiomer. This is the first known method to separate and quantify the enantiomers of all three analytes utilizing SFC and SPE.