Chiral Reagent Research Articles

Asymmetric Allenylation of Alkynes mediated by Chiral Organoselenated Reagents under Oxidative Conditions.

The reactivity of novel chiral lactamide-substituted diselenide-based reagents under oxidative conditions was exploited to develop a metal-free method for the preparation of enantioenriched allenylamides from simple alkynes in good yields, and with enantiomeric excesses up to 99 %. The key of the success in this method is attributed to the hydrogen-bonded lactamide appendages that ensure configurational stability of chiral vinyl selenoxide intermediates for an optimal enantiotopic β-syn-elimination step.

Helical dichroism in enantiomeric solutions.

A novel chiroptical sensing technique was recently introduced that utilized the helical phase of the structured light as a chiral reagent instead of polarization of light to differentiate enantiopure chiral liquids. The unique advantage of this non-resonant, nonlinear technique is that the chiral signal can be scaled and tuned. In this paper, we extend this technique to enantiopure powders of alanine and camphor by dissolving them in solvents of varying concentrations. We show the differential absorbance of helical light to be an order of magnitude higher relative to conventional resonant linear techniques and is comparable to nonlinear techniques that use circularly polarized light. The origin of helicity dependent absorption is discussed in terms of induced multipole moments in nonlinear light-matter interaction. These results opens up new opportunities in using helical light as a primary chiral reagent in nonlinear spectroscopic techniques.

Enantiomeric separation of ketoprofen using Frovatriptan as a chiral derivatizing reagent

AbstractWe established a validated high‐performance liquid chromatography method utilizing Frovatriptan as a chiral derivatizing agent to separate the enantiomers of ketoprofen from commercially available tablet formulations. The chiral derivatizing agent facilitated the synthesis of diastereomeric derivatives of ketoprofen, which were separated on a reversed‐phase C18 column using a mobile phase composed of acetonitrile and 0.1% trifluoroacetic acid under gradient elution from 30% to 70% of acetonitrile. The method demonstrated a limit of detection and quantitation of 2.52 and 8.31 ng/ml for the derivatives, respectively. Validation of the method was performed following the guidelines set by the International Council for Harmonisation to ensure accuracy, precision, and reliability, making it suitable for pharmaceutical industry applications. Notably, this study introduces the novel application of Frovatriptan as a chiral derivatizing agent in high‐performance liquid chromatography for the separation of ketoprofen enantiomers.

Enantioselective Bromination of Silyl Enol Ethers with Chiral Pentacarboxycyclopentadienyl Bromide

AbstractChiral pentacarboxycyclopentadienyl bromide reagents were synthesized to accomplish enantioselective bromination of silyl enol ethers to give corresponding α-bromoketone products in good yields and up to 77% ee. A catalytic version of this reaction was also demonstrated through the combination of Lewis acid activators and diethyl 2,2-dibromomalonate as stoichiometric achiral bromine source.

Stereoselective Hydrogen Atom Transfer in Free Radical Reactions

AbstractHydrogen atom transfer (HAT) is one of the important class of radical reactions. Although extensive research into this elementary step has resulted in the discovery of many compounds capable of functioning as HAT reagents, synthetic methods available to control the stereoselectivity of the HAT process remains challenging. This mini review outlines how small molecule chiral HAT reagents and catalysts were used to achieve stereoselectivity (diastereoselectivity and enantioselectivity) in free radical reactions. The review also focuses on the recent surge in photoenzymatic catalysis to achieve efficient HAT reactions.

Synthesis, crystal structure and DFT study of 1,1-dimethylethyl (2R)-2-(hydroxydiphenylmethyl)-1-pyrrolidinecarboxylate

During the asymmetric reduction process of Corey Bakshi Shibata chiral reagent, the target compound 1,1-dimethylethyl (2R)-2-(hydroxydiphenylmethyl)-1-pyrrolidine carboxylate was unexpectedly discovered. The structure was characterized by 1H NMR, 13C NMR, MS, and FT-IR. The crystal belongs to orthogonal crystal system, space group P212121, crystal cell parameters: a = 8.9941(8) Å, b = 9.8001(9) Å, c = 22.706(2) Å, α = 90°, β = 90°, γ = 90°, μ (MoKα) = 0.71073 Å mm−1. DFT further analyzed its structure. The frontier molecular orbital and molecular electrostatic potential of the target compound were further studied.

Spontaneous Chiral Resolution of a MnIII Spin-Crossover Complex with High Temperature 80 K Hysteresis.

Non-centrosymmetric spin-switchable systems are of interest for their prospective applications as magnetically active non-linear optical materials and in multiferroic devices. Chiral resolution of simple spin-crossover chelate complexes into the Δ and Λ forms offers a facile route to homochiral magnetic switches, which could be easily enantiomerically enriched. Here, we report the spontaneous resolution of a new hysteretic spin-crossover complex, [MnIII (sal2 323)]SCN ⋅ EtOH (1), into Δ and Λ forms, without the use of chiral reagents, where sal2 323 is a Schiff base resulting from condensation of 1,2-bis(3-aminopropylamino)ethane with 2-hydroxybenzaldehyde. The enantiopurity of the Δ and Λ isomers was confirmed by single crystal X-ray diffraction and circular dichroism. Quantum chemistry calculations were used to investigate the electronic structure. The opening of a wide 80 K thermal hysteresis window at high temperature highlights the potential for good magneto-optical function at ambient temperature for materials of this type.

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.

Stereospecific Transformations of Alkylboronic Esters Enabled by Direct Boron-to-Zinc Transmetalation.

Chiral secondary organoboronic esters, when activated with t-butyllithium, are shown to undergo efficient stereoretentive transmetalation with either zinc acetate or zinc chloride. This reaction provides chiral secondary alkylzinc reagents that are configurationally stable under practical experimental conditions. The organozinc compounds were found to engage in stereospecific reactions with difluorocarbene, catalytic cross-couplings with palladium-based catalysts, and trifluoromethylation with a copper(III) complex. Mechanistic and computational studies shed light on the inner workings of the transmetalation event.

N-Fluoro Ammonium Salts of Cinchona Alkaloids in Enantioselective Electrophilic Fluorination.

From 2000, our two research groups independently and simultaneously designed and developed a novel family of electrophilic fluorinating reagents based on the use of Cinchona alkaloids. The chiral N-fluoro ammonium salts demonstrated the highest efficiency compared to prior art in enantioselective electrophilic fluorination for a wide range of substrates. In this account, we tell our respective stories, how the same idea germinated in our laboratories, the characterization of the chiral reagents, the use in stoichiometric quantity then the development of a catalytic version, the application to the synthesis of chiral fluorinated molecules of pharmaceutical interest, and finally the exploitation of our reagents by other teams and for other applications.

Total Synthesis of Linear Coumarniolignoids (+) and (-)-Sapiumin C, (-)-Moluccanin, and (-)-Hemidesminine.

Coumarinolignoids (CLs) are a class of natural products isolated from a diverse range of plant species. Due to their unique structural scaffold, they exhibit a wide range of interesting biological activities including hepatoprotective, antitumor, anti-inflammatory, and antioxidant activities among others. In this research, key intermediate 10 was used to stereoselectively synthesize CLs (7'S,8'S)- and (7'R,8'R)-sapiumin C 1 and 2, (7'S,8'S)-moluccanin 3, and (7'S,8'S) hemidesminine 4 for the first time, establishing a versatile synthetic method for the stereoselective synthesis of linear CLs. The developed method includes a Mitsunobu coupling, a modified Miyaura arylation via a rhodium catalyst, and an acid-catalyzed cyclization in key bond-forming steps. The developed synthetic route allows the synthesis of both enantiomers of a given natural product from the same chiral pool reagent (S)-solketal while allowing easy variation of aromatic substitution and hydroxymethyl/allylhydroxymethyl moieties that are common in this class of natural products.

Iodine(III)-Mediated Enantioselective Oxidative Contraction of Dihydropyranones.

The γ-butyrolactone motif is promising in pharmaceuticals and natural products with various biological activities. The oxidative contraction of dihydropyranones mediated by hypervalent iodine (HVI) reagents is an efficient approach of preparing this motif. We show that, using readily available chiral HVI reagents, numerous enantioenriched γ-butyrolactones are accessible. The method provides generally high enantioselectivities and modest to high yields. The resulting chiral iodoarene is easily recovered and reused for the reaction multiple times, without loss of yield or enantioselectivities.

Simultaneous measurement of amino acid enantiomers in the serum of late-life depression patients using convenient LC–MS/MS method with Nα-(5-fluoro-2,4-dinitrophenyl)-l-leucinamide Derivatization

D-amino acids may be indicators of late-life depression but separation and quantification of enantiomers which differ only by optical rotation sign remain challenging due to their identical physical and chemical properties. A convenient LC-MS/MS method was developed for the simultaneous measurement of l- and d-amino acids based on the chiral derivatization reagent, Nα-(5-fluoro-2,4-dinitrophenyl)-L-leucinamide, and conventional octadecylsilane reversed-phase column. Methanol was used as the extraction solvent and a single-step derivatization reaction using volatile triethylamine eliminated the requirement for desalination prior to LC-MS/MS. Simultaneous separation and identification of 21 amino acids and the enantiomeric compositions of the 18 chiral proteogenic entities were achieved. Low limits of detection (0.03–4.0 nM), wide linear range (0.01–20 μM), good precision (RSDs < 10 %) and negligible matrix effects indicated the suitability of the method. Application of the method to the quantification of serum chiral amino acids in late-life depression patients (n = 40) and controls (n = 35) found a total of 17 L-amino acids, 14 D-amino acids, DL-asparagine, glycine and γ-aminobutyric acid. The statistical evaluation showed significant differences of glycine, L-threonine and D-methionine between late-life depression patients and controls, indicating that these are potential biomarkers of late-life depression.

A chiral metal-organic framework {(HQA)(ZnCl2)(2.5H2O)}n for the enantioseparation of chiral amino acids and drugs

Chiral metal-organic frameworks (CMOFs) with enantiomeric subunits have been employed in chiral chemistry. In this study, a CMOF formed from 6-methoxyl-(8S,9R)-cinchonan-9-ol-3-carboxylic acid (HQA) and ZnCl2, {(HQA)(ZnCl2)(2.5H2O)}n, was constructed as a chiral stationary phase (CSP) via an in situ fabrication approach and used for chiral amino acid and drug analyses for the first time. The {(HQA)(ZnCl2)(2.5H2O)}n nanocrystal and the corresponding chiral stationary phase were systematically characterised using a series of analytical techniques including scanning electron microscopy, X-ray diffraction, Fourier transform infrared spectroscopy, circular dichroism, X-ray photoelectron spectroscopy, thermogravimetric analysis, and Brunauer-Emmett-Teller surface area measurements. In open-tubular capillary electrochromatography (CEC), the novel chiral column exhibited strong and broad enantioselectivity toward a variety of chiral analytes, including 19 racemic dansyl amino acids and several model chiral drugs (both acidic and basic). The chiral CEC conditions were optimised, and the enantioseparation mechanisms are discussed. This study not only introduces a new high-efficiency member of the MOF-type CSP family but also demonstrates the potential of improving the enantioselectivities of traditional chiral recognition reagents by fully using the inherent characteristics of porous organic frameworks.

Simultaneous determination of all aminobutyric acids by chiral derivatization and liquid chromatography-tandem mass spectrometry.

Aminobutyric acids include eight structural or stereoisomers that exhibit a wide range of biological activities. Recent evidence on some low abundant isomers have increased the demand for highly selective analysis of all the isomers; however, simultaneous separation of all the aminobutyric acid isomers has not been successful yet, except for a specialized method that uses multiple separation columns and a split of samples. In this study, we developed a new analytical method using chiral derivatization and liquid chromatography-tandem mass spectrometry to separate all the aminobutyric acid isomers in a single separation column. All the diastereomeric derivatives were resolved in a C18 column, and the derivatives showed characteristic fragmentation patterns in tandem mass spectrometry. By using the method, we analyzed the isomers in the Arabidopsis thaliana seeds and revealed the existence of three low abundant isomers, i.e., D-, L-β-aminoisobutyric acid, and D-β-aminobutyric acid. The proposed method uses a commercially available chiral derivatizing reagent and a broadly used column; therefore, it can be widely used in biological and food analyses.

Development and Application of Analytical Methods for Chiral Amino Acids and Related Metabolites

Three different types of analytical methods for D,L-amino acid were developed. First, a method for simultaneous analysis of D,L-amino acids in food was constructed by combining pre-column derivatization with 4-fluoro-7-nitro-2,1,3-benzoxadiazole (NBD-F), UHPLC separation, and UV and circular dichroism (CD) detection. Using this method, D,L-amino acids in food samples was determined at a very short time of 5.5 minutes. Second, a pre-column derivatization LC/MS method (direct method) for D-alanine, D-serine, and D-aspartic acid and L-isomers in biological samples was developed. In this method, D,L-amino acids were derivatized with an achiral reagent, p-N,N,N-trimethylammonioanilyl N′-hydroxysuccinimidyl carbamate iodide (TAHS), separated with a chiral column, and detected using mass spectrometry (MS). Third, a pre-column derivatization LC/MS method (indirect method) for highly sensitive and selective analysis of 20 D,L-amino acids using a chiral derivatization reagent, (R)-4-nitrophenyl-N-[2-(diethylamino)-6,6-dimethyl-[1,1-biphenyl]-2-yl] carbamate hydrochloride ((R)-BiAC), was developed. The unique structure of the (R)-BiAC reagent, which has a biaryl axially chiral structure, allowed for higher resolution and a high sensitive analysis of the 20 D,L-amino acids within 12 minutes. This method has been applied to various D-amino acid research studies, and it can be applied to a wide range of analyses from food to biological samples. Lastly, an LC/MS method was established that simultaneously analyzes tryptophan and 15 of its metabolites, which is involved in neurotransmission and immunity in vivo.

Praseodymium Metallacrown-Based NMR Probe for Enantioselective Discrimination of Mandelate Anions in Water.

Recently, the enhanced interest in water-soluble aminohydroximate Ln(III)-Cu(II) metallacrowns (MC) is largely due to their fascinating structural chemistry, diverse properties and ease of synthesis. We examined the water-soluble praseodymium(III) alaninehydroximate complex Pr(H2O)4[15-MCCu(II)Alaha-5]·3Cl (1) as a highly effective chiral lanthanide shift reagent for NMR analysis of the biologically relevant (R/S)-mandelate (MA) anions in aqueous media. The R-MA and S-MA enantiomers can be easily discriminated in the presence of small (1.2-6.2 mol %) amounts of MC 1 by the 1H NMR signals of multiple protons exhibiting an enantiomeric shift difference (ΔΔδ) of 0.06 ppm up to 0.31 ppm. Additionally, a possibility of coordination of MA to the metallacrown was investigated by the ESI-MS technique and a Density Functional Theory modeling of the molecular electrostatic potential and noncovalent interactions.

Determination of d- and l-Amino Acids in Garlic Foodstuffs by Liquid Chromatography–Tandem Mass Spectrometry

Black garlic is currently attracting interest as a health food and constituent of commercial supplements; however, no data regarding the d-amino acids within black garlic have been reported. Therefore, the amino acid compositions of methanol extracts from fresh and black garlic were compared herein. We investigated the contents of the d- and l-forms of amino acids in commercial fresh, black, and freeze-dried garlic foodstuffs by liquid chromatography-tandem mass spectrometry (LC-MS/MS) using a pre-column chiral derivatization reagent, succinimidyl 2-(3-((benzyloxy)carbonyl)-1-methyl-5-oxoimidazolidin-4-yl) acetate. Several d-amino acids, namely, the d-forms of Asn, Ala, Ser, Thr, Glu, Asp, Pro, Arg, Phe, Orn, Lys, and Tyr, were observed in the methanol extract of black garlic, whereas only d-Ala was detected in that of fresh garlic foodstuffs. These data suggest that several d-amino acids can be produced during fermentation for preparing black garlic.

Mechanistic Features of Asymmetric Vinylidene ortho-Quinone Methide Construction and Subsequent Transformations

Vinylidene ortho-quinone methide (VQM), an elusive dearomatized intermediate, is widely used in asymmetric catalysis. Due to its transient nature, the current understanding of VQM was largely acquired based on computational studies and trapping experiments. Herein, the enantioselective construction of stable VQM intermediates by an organocatalyzed bromination was achieved. Kinetic studies, control experiments, and nonlinear effects were realized to obtain insights into the two sequential mechanistic events in VQM-involved reactions. The results elucidated that the stereocontrol was enforced by one catalyst molecule in the generation of the axially chiral VQM, but the subsequent transformation was independent of the catalyst. The efficiency of the VQM as axially chiral synthetic reagents was demonstrated by its reactions with carboxylic acids, cyclo-1,3-diones, and nitrone. In all cases, the VQM reacted smoothly to provide the axially chiral esters and ethers via an axial-to-axial chirality transfer, as well as the chiral α-bromo ketones through an axial-to-central chirality conversion. The properties of the isolated VQM exhibited its high potential in organic chemistry.