Chiral Compounds Research Articles

Rational Design of Multi‐color Phosphorescent Carbon Dots Based on Binaphthyldiamine with Chiral Signals

Comprehensive SummaryChiral phosphorescent materials have received extensive research owing to the unique properties of optical activity in recent years. Many phosphorescent carbon dots (CDs) materials have been reported, but the research on chiral phosphorescence is still in the exploratory stage. This work designs multi‐color room temperature phosphorescent (RTP) CDs with chiral signals, which are fully mixed with aromatic aldehyde precursors and chiral amino compounds precursors in a boric acid (BA) matrix and can be easily prepared by solvent‐free thermal method. The prepared (R)‐GCDs, (R)‐YCDs and (R)‐RCDs achieved phosphorescence emission at 545 nm, 582 nm, and 654 nm, respectively, and exhibited corresponding circular dichroism (CD) signals at 341 nm, 394 nm, 384 nm, and 380 nm, 448 nm, and 435 nm, respectively. The longest phosphorescence lifetime is up to 946 ms. Specifically, YCDs exhibit time‐dependent phosphorescence under UV excitation, and the afterglow time under white light excitation can reach 40 s. This article provides a new approach to the study of chiral phosphorescence.

Structural Elucidation and Absolute Stereochemistry for Pharma Compounds Using MicroED.

Microcrystal electron diffraction (microED) is an emerging technique for rapid crystallographic analysis of small molecule micro- and nanocrystals. In this report, we evaluate the applicability of microED to pharmaceutical compounds through the analysis of 30 samples obtained from the process and medicinal chemistry groups at Amgen Inc. Using only 40 h of microscope time, 15 of 30 crystal structures were elucidated. From these crystal structures, all chiral compounds had the correct absolute stereochemistry assigned by dynamical refinement of continuous rotation electron diffraction data, confirming dynamical refinement as a promising tool for the absolute stereochemistry determination of pharmaceutically relevant compounds.

Analysing the self-assembly modes in chiral multi-component gels based on donor and acceptor moieties

ABSTRACT The role of the structural similarity in the individual components on the self-assembly process of multi-component systems was studied by analysing the gelation properties of chiral multi-component gels with structurally similar (enantiomers) and non-similar donor or acceptor moieties. The gelation properties of the individual enantiomers, mixed enantiomers, and mixed chiral donor-acceptor compounds were analysed in various solvents. Analysis of the mechanical strength revealed that the mixed chiral gels were stronger compared to other gels in mesitylene; however, a reverse trend was observed for thermal stability. Scanning electron microscopy (SEM) of the dried gels of the mixed enantiomeric and mixed chiral donor-acceptor gels showed morphological changes indicating different self-assembly modes. Powder X-ray analysis revealed that a co-assembled mode was observed for the mixed gels with structurally similar components. However, a self-sorting nature was observed for the mixed chiral donor-acceptor gel, and the charge transfer interaction between the donor and acceptor played a major role in the self-assembly of these mixed gels. We performed computational studies to predict the electronic distribution in the individual chiral molecules. These results demonstrate that altering the structural features of the individual components is one of the key parameters that control the self-assembly modes of multi-component systems.

Heat of Dilution and Racemization of Chiral Amino Acid Solutions

Chiral interactions play a crucial role in both chemistry and biology. Understanding the behavior of chiral molecules and their interactions with other molecules is essential, and chiral interactions in solutions are particularly important for studying chiral compounds. Chirality influences the physical and chemical properties of molecules, including solubility, reactivity, and biological activity. In this work, we used isothermal titration calorimetry (ITC), a powerful technique for studying molecular interactions, including chiral interactions in solutions. We conducted a series of ITC measurements to investigate the heat of dilution and the heat of racemization of several amino acids (Asparagine, Histidine, Serine, Alanine, Methionine, and Phenylalanine). We also performed ITC measurements under different solute concentrations and temperatures to examine the effects of these parameters on chiral interactions, as well as the heat of dilution and racemization. The results of our measurements indicated that the heat of dilution, specifically the interactions between the solvent (water) and solute (chiral molecules), had a significant impact compared to the chiral interactions in the solution, which were found to be negligible. This suggests that the interactions between chiral molecules and the solvent play a more dominant role in determining the overall behavior and properties of the system. By studying chiral interactions in solutions, we can gain valuable insights into the behavior of chiral compounds, which can have implications in various fields, including drug design, chemical synthesis, and biological processes.

Beta2-adrenergic agonist salbutamol exhibits enantioselective disposition in skeletal muscle of lean young men following oral administration.

Salbutamol is a common short-acting beta2-adrenergic agonist used in treatment of asthma and exercise-induced bronchoconstriction but also possesses anabolic and metabolic actions in skeletal muscle. As a chiral compound, salbutamol is a racemic 1:1 mixture of two enantiomers, (R)-salbutamol and (S)-salbutamol, which exhibit divergent pharmacokinetic and pharmacodynamic actions. Despite salbutamol being available for decades, information on the enantioselective disposition of salbutamol enantiomers in human skeletal muscle is absent. In this study, we determined concentrations of (R)-salbutamol and (S)-salbutamol by UHPLC-MS/MS in arterial plasma and vastus lateralis muscle samples from 12 lean young men 2½ and 7 h following ingestion of 24 mg oral salbutamol. Mean (range) arterial plasma concentrations were 10-fold higher (p < 0.001) for (S)-salbutamol than (R)-salbutamol, being 33(9-62) and 49(30-84) ng·mL-1 for (S)-salbutamol and 4 (1-6) and 4 (2-5) ng·mL-1 for (R)-salbutamol 2½ and 7 h following administration, respectively, reflecting faster elimination of the (R)-enantiomer. Mean (range) muscle concentrations were higher (p < 0.001) for (S)-salbutamol than (R)-salbutamol 2½h (0.17 [0.1-0.26] vs. 0.04 [0.02-0.06]) and 7 h (0.31 [0.21-0.46] vs. 0.06 [0.04-0.12] ng·mgd.w. -1) after administration. However, muscle:plasma partition coefficient was two-fold higher (p < 0.001) for (R)-salbutamol than (S)-salbutamol 7 h following administration. These observations demonstrate that oral salbutamol exhibits enantioselective disposition in systemic circulation and muscle favoring the (S)-enantiomer but with higher relative partitioning of the (R)-enantiomer in skeletal muscle. Furthermore, the concentration-time profiles of salbutamol enantiomers are different in skeletal muscle and systemic circulation following oral ingestion. These findings have implications for the application of chiral switch (R)-salbutamol in doping control.

Structural Chemistry of C-N Axially Chiral Compounds.

In the last several years, atropisomers owing to the rotational restriction around a C-N single bond (C-N axially chiral compounds) have attracted significant attention in the field of synthetic organic chemistry. In particular, the highly enantioselective synthesis of various C-N axially chiral compounds and their application to asymmetric reactions have been reported by many groups. On the other hand, studies on the structural chemistry of C-N axially chiral compounds have attracted scant attention in comparison with synthetic studies. For over 25 years, our group has explored asymmetric synthesis of C-N axially chiral compounds and their synthetic application. In the course of these synthetic studies, we found several notable structural properties in relation to the C-N bond rotation and an association of enantiomers (the relationship between the rotational stability and the structure or electronic effect, the chirality-dependent halogen bond, and the self-disproportionation of enantiomers). Furthermore, on the basis of these structural properties, the development of acid-mediated molecular rotors and the synthesis of isotopic atropisomers possessing high stereochemical purity and rotational stability were achieved. Through this Perspective, I wish to make the chemistry community aware that C-N axially chiral compounds are attractive molecules from the viewpoints of both synthetic organic chemistry and structural chemistry.

Earth‐Abundant Nickel‐Catalyzed Asymmetric Hydrogenation†

Comprehensive SummaryTransition metal‐catalyzed asymmetric hydrogenation is an efficient and direct synthetic method to access chiral compounds, which features simplicity, easy working‐up process, and high atomic economy. It typically relies on precious transition metal catalytic systems, including ruthenium, rhodium, iridium and palladium, which always face the difficulties of limited resources, high cost, and environmental contamination. Therefore, great efforts were made to apply earth‐abundant, low (non‐)toxic, and environmentally friendly transition metals, such as iron, cobalt, nickel and copper, to the asymmetric hydrogenation in the past decades, and some considerable breakthroughs have been obtained. In this review, we mainly summarized some recent research progress of nickel‐catalyzed asymmetric hydrogenation of prochiral unsaturated molecules, including olefins, imines and ketones. And continuous development of chiral nickel catalytic systems and the application of them into challenging asymmetric hydrogenation is prospected in the future. Key ScientistsTransition metal‐catalyzed asymmetric hydrogenation has been regarded as an important and direct approach to access chiral molecules. The first example of homogeneous catalytic asymmetric hydrogenation was developed by Knowles and Horner in 1968, respectively. In 1971, Kagan developed privileged chiral DIOP ligand for asymmetric hydrogenation. Halpern and Brown made deep studies on the Rh‐catalyzed asymmetric hydrogenation in 1977, respectively. Noyori developed a powerful and privileged chiral BINAP ligand in 1980. Owing to Knowles and Noyori's great contribution in the field of catalytic asymmetric hydrogenation, they were awarded the Nobel Prize in Chemistry in 2001. In 1984, Ohkubo developed pioneering earth‐abundant transition metal Ni‐catalyzed asymmetric hydrogenation of ethyl α‐methylcrotonate. A great many scientists made tremendous contribution to the development of chiral privileged ligands, such as, Bosnich, Kumada, Giongo, Takaya, Miyashima, Achiwa, Burk, Pflaltz, Chan, X. Zhang, Imamoto, Zhou, Genet, Sannicolo, Ding, Hoge, W. Zhang, Z. Zhang, Tang, these ligands owned wide application in the catalytic asymmetric hydrogenation. In addition, Zhou, Fan made deep investigation on the asymmetric hydrogenation of challenging aromatic heterocyclic compounds. Owing to the great importance of the development of the asymmetric (transfer) hydrogenation promoted by cheap transition metal catalytic systems, some researchers, such as Hamada, Gao, J. S. Zhou, Chirik, X. Zhang, Y.‐G. Zhou, W. Zhang, Lv, Dong, Fu, Deng, and Hou, made great efforts to the development of earth‐abundant nickel‐catalyzed asymmetric hydrogenation of prochiral unsaturated molecules, including olefins, imines and ketones. In addition, there are some other scientists that have also made great contribution to the development of catalytic asymmetric hydrogenation and Ni‐catalyzed asymmetric transformation, with too limited space to list all of them.

(Invited) Synthesis and Optical Properties of Chiral Spiro π-Conjugated Compounds with Donor–Acceptor Structure

Chiral spiro π-conjugated compounds with donor–acceptor structures were synthesized. Carbazol-9-yl, 9,9-dimethylacridin-10-yl, phenoxazin-10-yl donor units were introduced on the spiro-fused acceptor unit with sulfonyl groups. The donor units were found to have great impact on the longest absorption maximum and emission maximum. The chiral spiro π-conjugated compounds with 9,9-dimethylacridin-10-yl or phenoxazin-10-yl donor units showed delayed fluorescence. All of three compounds exhibited circularly polarized luminescence both in solution and solid states.

(Invited) Stereoselective Synthesis of Molecular Nanographenes

Chirality is an important and fascinating concept which has not been properly addressed in carbon nanoscience [1]. We have previously reported the first inherently chiral bilayer nanographene with a helicene linker, both as the racemate and the M isomer [2,3]. Helical bilayer nanographenes (HBNGs) are chiral π-extended aromatic compounds consisting in two π-π stacked hexa-benzocoronenes (HBC) joined by a helicene, thus resembling van der Waals layered 2D materials. Recently, we have synthesized and compared [9]HBNG, [10]HBNG and [11]HBNG helical bilayers endowed with [9], [10] and [11]helicenes embedded in their structure, respectively. Interestingly, the helicene length defines the overlapping degree between the two HBCs (number of benzene rings involved in π-π interactions between the two layers), being of 26, 14 and 10 benzene rings, respectively, according to the X-ray analysis [4]. More interesting, this overlapping also controls the properties.Compounds constituted only by carbon atoms, such as optically active molecular nanographenes have, so far, been obtained as racemates followed by time-consuming chiral chromatographic separations. In this presentation, an enantioselective strategy of a new bilayer nanographene which uses two pivotal stereocontrolled key synthetic steps to introduce and extend stereogenic elements into a polycyclic aromatic Csp2-based structure will be discussed. The resulting helical core of six ortho-fused rings embedded in the nanographene ensures stereochemical stability and good chiroptic activity [5]. Acknowledgements : This work has been supported by the Ministerio de Educación, Cultura y Deporte of Spain (Grant PID2020-114653RB-100).

Brønsted Acid Catalyzed Asymmetric Synthesis of Cyclopentenones with C4-Quaternary Centers Starting from Vinyl Sulfoxides and Allenyl Ketones or Allenoates.

Starting with chiral vinyl sulfoxides and allenyl ketones or allenoates, a triflic acid-catalyzed asymmetric [3,3]-sigmatropic rearrangement of sulfoniums is reported to have a direct access to highly functionalized C4-chiral cyclopentenones (19 examples, up to 85% yield and >95% enantiomeric excesses). In addition to the use of these chiral compounds as key building blocks in organic synthesis, the antiproliferative activities of sulfoxide substrates and the corresponding cyclopentenones were evaluated, and promising cytotoxicity against the HL-60 human tumor cell line was found.

The series of L-lysine-derived gelators-modified multifunctional chromatography stationary phase for separation of chiral and achiral compounds

In this study, using chiral L-lysine as the molecular skeleton, three kinds of L-lysine-derived gelators (GBLB, GBLF and GFLF) were synthesized and then bonded to the surface of silica matrix (5 μm) by amide condensation to prepare a series of multifunctional chromatography stationary phases (GBLB-SiO2, GBLF-SiO2, and GFLF-SiO2) were prepared. The L-lysine-derived gelators not only possess chiral recognition ability, but also can spontaneously form oriented and ordered network structures in liquid medium through the interaction of non-covalent bonding forces such as hydrogen bonding, π-π stacking, and van der Waals forces. The comprehensive effect of multiple weak interaction sites enhances the molecular recognition ability and further improves the separation diversity of different types of compounds on stationary phases. The separation and evaluation of chiral compounds showed that benzoin, 1-phenyl-ethanol, 1-phenyl-propanol and 6-hydroxyflavanone could be separated in normal phase mode (NPLC). The separation of different types of non-chiral compounds, such as sulfonamides, nucleosides, nucleobases, polycyclic aromatic hydrocarbons (PAHs), anilines, and aromatic acids, were achieved in hydrophilic interaction/reversed-phase/ion-exchange mode (HILIC/RPLC/IEC), and the separation of polarized compounds could be performed under the condition of ultrapure water as the mobile phase, which has the typical retention characteristics of per aqueous liquid chromatography (PALC). The effects of organic solvent content, temperature, pH value, and buffer salt concentration on the retention and separation performance of the column were investigated. Comparison of the three prepared columns showed that the separation performance (such as aromatic selectivity) could be improved by increasing the types of functional groups on the surface of the stationary phase and the number of aromatic groups. In a word, the prepared stationary phase have multiple retention properties, can simultaneously separate chiral compounds and various types of achiral compounds. This work provides an idea for developing multifunctional liquid chromatography stationary phase materials, and further expands the application of gelators in separation science.

Asymmetric Synthesis and Applications of Chiral Organoselenium Compounds: A Review.

The synthesis and application of organoselenium compounds have developed rapidly, and chiral organoselenium compounds have become an important intermediate in the field of medicine, materials, organic synthesis. The strategy of developing a green economy is still a challenge in the synthesis of chiral organoselenium compounds with enantioselective properties. This review covers in detail the synthesis of chiral organoselenium compounds from 1979 to 2024 and their application in the fields of asymmetric synthesis and catalysis.

Room temperature synthesis of a chiral covalent organic framework core-shell composite for high-performance liquid chromatography enantioseparation.

In this article, chiral covalent organic framework core-shell composite CCOF-TpPa-Py@SiO2 was facilely synthesized by induction at room temperature. The CCOF-TpPa-Py@SiO2 core-shell composite was used as a chiral stationary phase for the separation of the racemates by high-performance liquid chromatography, which exhibits good separation performance for chiral compounds including ketones, alcohols, esters, epoxides, carboxylic acids, amides, and amines. The effects of analyte injection mass on the enantioseparation were studied. The reproducibility and stability of the CCOF-TpPa-Py@SiO2 chiral column were explored. The intra-day (n=5), inter-day (n=5), and inter-column (n=3) relative standard deviations for the migration times and resolution of benzoin were 0.32%-0.54%, 0.45%-0.61%, and 1.21%-1.53%, respectively. In addition, the chiral separation ability of the CCOF-TpPa-Py@SiO2 chiral column (column A) was compared with that of the MDI-β-CD-Modified COF@SiO2 (column B) as well as a commercial chiral column (Chiralpak AD-H). The chiral recognition ability of column A is complementary to that of column B and AD-H column. The resolution mechanism of CCOF-TpPa-Py@SiO2 stationary phase towards chiral analyte was explored. Hence, the synthesis of CCOF-TpPa-Py@SiO2 core-shell composite by induction at room temperature as chiral stationary phases for chromatographic separation has important research potential and application prospects.

Synthesis, crystal structures and fluorescence recognition properties of two novel chiral coordination compounds based on alanine derivate

Two novel chiral coordination compounds {[Cd(D-pmala)(2,2′-bipy)(H2O)]⋅1·25H2O}n (1), {[Pb4(D-pmala)4(5,5′-DM-2,2′-bipy)4(H2O)2]⋅7H2O}n (2) (D-pmala = N-(4-carboxyl) benzoyl-d-alanine, 2,2′-bipy = 2,2′-Bipyridine, 5,5′-DM-2,2′-bipy = 5,5′-Dimethyl-2,2′- Bipyridine) have been successfully synthesized under hydrothermal conditions. Their structures were identified using single-crystal X-ray crystallography and characterized by infrared spectroscopy, elemental analysis, thermogravimetric analysis, powder X-ray diffraction and solid-state circular dichroism spectra. Crystallographic analysis indicate that compound 1 features a "Z"-shaped one-dimensional chain structure, which further extends into three-dimensional supramolecular architectures through hydrogen-bonding interactions. Compound 2 displays a two-dimensional layer structure, a two-dimensional double-layer network structures is further formed through the hydrogen-bonding interactions. Moreover, The fluorescence recognition properties of compound 1 indicate that it is highly selective in detecting Cu2+ ions and tyrosine (Tyr) enantiomers in aqueous solutions, which indicates that compound 1 can be expected to be a bifunctional fluorescent recognition sensor to detect metal ions and amino acid enantiomers.

Unusual Cascade Reactions of 8-Acetoxy-6-hydroxymethyllimonene with Salicylic Aldehydes: Diverse Oxygen Heterocycles from Common Precursors.

Chiral oxygen-containing heterocyclic compounds are of great interest for the development of pharmaceuticals. Monoterpenes and their derivatives are naturally abundant precursors of novel synthetic chiral oxygen-containing heterocyclic compounds. In this study, acid catalyzed reactions of salicylic aldehydes with (-)-8-acetoxy-6-hydroxymethyllimonene, readily accessible from α-pinene, leads to the formation of chiral polycyclic products of various structural types. Three of the six isolated chiral heterocyclic products obtained from salicylic aldehyde contain previously unknown polycyclic ring types. Having carried out the reaction in the presence of Brønsted or Lewis acids (Amberlyst 15, trifluoromethanesulfonic acid, trifluoroacetic acid and boron trifluoride etherate) or aluminosilicates (montmorillonite K10, halloysite nanotubes), we found that the nature of products depends on the catalyst as well as the reaction conditions (reaction time, reactant ratio, presence or absence of solvent). Detailed mechanistic insight on the complex cascade reactions for product formation is provided with extensive experimental and quantum mechanical computational studies.

Identification of 3-hydroxyaspartate with two chiral centers by capillary electrophoresis-mass spectrometry and vibrational circular dichroism independent of single enantiomer standard

Background3-Hydroxyaspartate(3-HA) is a non-proteinaceous amino acid whose four stereoisomers have different biological functions, making it meaningful to separate and analyze them. A combination of capillary zone electrophoresis-mass spectrometry (CZE-MS) and electron circular dichroism enables the separation and analysis of the four stereoisomers of 3-HA, but relies on enantiomeric standards. In contrast, the new method based on vibrational circular dichroism (VCD) can successfully confirm the peak order of the four enantiomers simultaneously without a single enantiomeric standard. This method is suitable for molecules without UV absorption, as well as for molecules with polychiral centers, and does not require enantiomeric standards. ResultsWe present a new analytical method based on CZE-MS coupled with VCD for the simultaneous determination of four stereoisomers of 3-HA with two chiral centers (D-threo-3-hydroxyaspartate, D-THA; L-threo-3-hydroxyaspartate, L-THA; D-erythro-3-hydroxyaspartate, D-EHA; L-erythro-3-hydroxyaspartate, L-EHA) in the absence of an optically pure single enantiomeric standard. The semipreparations of the non-racemic mixtures of DL-THA and DL-EHA were performed using high performance liquid chromatography (HPLC), with enantiomeric excess values reaching 90 %. By comparing the experimental VCD spectra of the DL-THA/DL-EHA mixture with the theoretical VCD spectra of the single L-THA/L-EHA enantiomer, the configuration of the dominant enantiomer in the nonracemic mixture was determined, where the two characteristic peaks in the 1250-1750 cm−1 spectral range fitted well. Finally, combined with the comparison of CE peak areas, the four stereoisomers were identified successfully. SignificanceThis is the first combined CZE-MS and VCD method for the simultaneous separation and analysis of four stereoisomers of 3-HA without relying on enantiomeric standards. This method is simple and reliable, and provides a new idea for the separation and analysis of chiral compounds with polychiral centers, which are difficult to obtain from enantiomeric standards.

Optical Relay Sensing of Cryptochiral Alcohols Displaying α‐, β‐, γ‐ and δ‐Stereocenters or Chirality by Virtue of Isotopic Substitution

AbstractA reaction‐based optical relay sensing strategy that enables accurate determination of the concentration and enantiomeric ratio (er) of challenging chiral alcohols exhibiting stereocenters at the α‐, β‐, γ‐ or even δ‐position or hard‐to‐detect cryptochirality arising from H/D substitution is described. This unmatched application scope is achieved with a conceptually new sensing approach by which the alcohol moiety is replaced with an optimized achiral sulfonamide chromophore to minimize the distance between the covalently attached chiroptical reporter unit and the stereogenic center in the substrate. The result is a remarkably strong, red‐shifted CD induction that increases linearly with the sample er. The CD sensing part of the tandem assay is seamlessly coupled to a redox reaction with a quinone molecule to generate a characteristic UV response that is independent of the enantiopurity of the alcohol and thus allows determination of the total analyte concentration. The robustness and utility of the CD/UV relay are further verified by chromatography‐free asymmetric reaction analysis with small aliquots of crude product mixtures, paving the way toward high‐throughput chiral compound screening workflows which is a highly sought‐after goal in the pharmaceutical industry.

Optical Relay Sensing of Cryptochiral Alcohols Displaying α-, β-, γ- and δ-Stereocenters or Chirality by Virtue of Isotopic Substitution.

A reaction-based optical relay sensing strategy that enables accurate determination of the concentration and enantiomeric ratio (er) of challenging chiral alcohols exhibiting stereocenters at the α-, β-, γ- or even δ-position or hard-to-detect cryptochirality arising from H/D substitution is described. This unmatched application scope is achieved with a conceptually new sensing approach by which the alcohol moiety is replaced with an optimized achiral sulfonamide chromophore to minimize the distance between the covalently attached chiroptical reporter unit and the stereogenic center in the substrate. The result is a remarkably strong, red-shifted CD induction that increases linearly with the sample er. The CD sensing part of the tandem assay is seamlessly coupled to a redox reaction with a quinone molecule to generate a characteristic UV response that is independent of the enantiopurity of the alcohol and thus allows determination of the total analyte concentration. The robustness and utility of the CD/UV relay are further verified by chromatography-free asymmetric reaction analysis with small aliquots of crude product mixtures, paving the way toward high-throughput chiral compound screening workflows which is a highly sought-after goal in the pharmaceutical industry.

Direct Enantiomer Differentiation of Drugs and Drug-Like Compounds via Noncovalent Copper-Amino Acid Complexation and Ion Mobility-Mass Spectrometry.

Drug enantiomers can possess vastly different pharmacological properties, yet they are identical in their chemical composition and structural connectivity. Thus, resolving enantiomers poses a great challenge in the field of separation science. Enantiomer separations necessitate interaction of the analyte with a chiral environment─in mass spectrometry-based analysis, a common approach is through a three-point interaction with a chiral selector commonly introduced during sample preparation. In select cases, the structural difference imparted through noncovalent complexation results in enantiomer-specific structural differences, facilitating measurement using a structurally selective analytical technique such as ion mobility-mass spectrometry (IM-MS). In this work, we investigate the direct IM-MS differentiation of chiral drug compounds using mononuclear copper complexes incorporating an amino acid chiral selector. A panel of 20 chiral drugs and drug-like compounds were investigated for separation, and four l-amino acids (l-histidine, l-tryptophan, l-proline, and l-tyrosine) were evaluated as chiral selectors (CS) to provide the chiral environment necessary for differentiation. Enantiomer differentiation was achieved for four chiral molecule pairs (R/S-thalidomide, R/S-baclofen, R/S-metoprolol, and d/l-panthenol) with two-peak resolution (Rp-p) values ranging from 0.7 (>10% valley) to 1.5 (baseline separation). Calibration curves relating IM peak areas to enantiomeric concentrations enabled enantiomeric excess quantitation of racemic thalidomide and metoprolol with residuals of 5.7 and 2.5%, respectively. Theoretical models suggest that CuII and l-histidine complexation around the analyte chiral center is important for gas-phase stereoselectivity. This study demonstrates the potential of combining enantioselective noncovalent copper complexation with structurally selective IM-MS for differentiating chiral drugs and drug-like compounds.

Thermally Stable P-Chiral Supramolecular Phosphines, their Self-Assembly and Implication in Rh-Catalyzed Asymmetric Hydrogenation.

P-chiral supramolecular phosphine ligands are crucial for asymmetric transformations, but their synthesis is tedious. We report a one-step synthesis of thermally stable P-chiral supramolecular phosphines and their performance in the asymmetric hydrogenation of functionalized alkenes. A rational designing and synthesis of (R, R)-QuinoxP* ligated palladium complex (Pd-2) in excellent yield is reported. This Pd-2 catalyzed a direct P-C coupling of 2,3-dihydro-1-H-phosphindole (A1)/1,2,3,4-tetrahydrophosphindoline (A2) with 1-(3-iodophenyl)urea (B1)/2-iodo /6-hydroxy pyridine (B2) and,produced corresponding ligands L1-L3. The P-C coupling between A1 and B2 produced 6-(2,3-dihydro-1H-phosphindol-1-yl)pyridine-2(1H)-one (L2) with an excellent enantiomeric excess of up to 99 %. L2 was found to be remarkably stable even at 150 °C and did not oxidize/hydrolyze for at least 24 hours in open air. Such thermal stability and an impediment to oxidation are unprecedented. L2 self-assembled and produced L2-C1 (Pt), L2-C2(Pd), and L2-C3(Rh) assemblies. The utility of the self-assembled P-chiral ligand was demonstrated in the Rh-catalyzed asymmetric hydrogenation (AH) of functionalized olefins. The L2-C3 catalyzed AH of functionalized alkenes and delivered chiral products with excellent enantioselectivity of >99 %. A small library of 16 substrates was subjected to AH using L2-C3 to produce chiral compounds with excellent conversion and ee.