Cooperative dual catalysis: application to the highly enantioselective conjugate cyanation of unsaturated imides

Cooperative heterobimetallic catalysis was used as a design principle to achieve a highly reactive system for the enantioselective conjugate addition of cyanide to alpha,beta-unsaturated imides. A dual-catalyst pathway involving chiral (salen)Al complex 1b and chiral (pybox)Er complex 4b provides measurable improvements in rates and enantioselectivities relative to single-catalyst systems. Mechanistic studies point to a cooperative bimetallic mechanism involving activation of the imide by the Al complex and activation of cyanide by the Er complex.     

Chirality induction of π-conjugated chains through chiral complexation

Chirality induction of π-conjugated polyanilines through chiral complexation with the chiral palladium(II) complexes was demonstrated to afford the chiral conjugated polymer complexes. Complexation of the emeraldine base of poly(o-toluidine) (POT) with the chiral palladium(II) complex bearing one labile coordination site led to the formation of the chiral conjugated polymer complex, which exhibited an induced circular dichroism (ICD) based on the chirality induction into a π-conjugated backbone. The mirror image of the CD signal was observed with the chiral conjugated polymer complex, which was obtained from the chiral palladium(II) complex possessing the opposite configuration. The chirality of the podand ligand moieties of the palladium complex is considered to induce a propeller twist of the π-conjugated molecular backbone. The crystal structure of the chiral conjugated complex of N-bis(4′-dimethylaminophenyl)-1,4-benzoquinonediimine (L³) as a model compound of the polyaniline revealed a chiral propeller twist conformation of the π-conjugated backbone. Furthermore, chiral complexation with the cationic palladium(II) complexes provided the ionic chiral conjugated complexes.     

Chiral recognition in association between antimony potassium tartrate and bis(L-alaninate)ethylenediamine cobalt(III) complexes using electrospray ionization mass spectrometry

The chiral recognition of metal complexes by a quick and sensitive mass spectrometric analysis was investigated. The principle is introduction of an external chiral standard compound and detection of the differential association with two optical isomers. Using electrospray ionization mass spectrometry we detected weak intermolecular association between the external chiral anion bis(mu-L-, D-tartrato)-diantimonate(III), [Sb2(L-, D-tart)2]2- and isomeric bis(L-alaninate) ethylenediamine cobalt(III) complex ions, [Co(L-ala)2(en)]+ in acetonitrile/water solution. The difference in the association with optical isomers of the Co complex was measured. The results were interpreted based on a model of intermolecular interaction involving hydrogen bonding. The prospects of the mass spectrometry method for chiral recognition using the external chiral negative ion [Sb2(L-, D-tart)2]2- was discussed.     

Nonenzymatic enantioselective monoacetylation of prochiral 2-protectedamino-2-alkyl-1,3-propanediols utilizing a chiral sulfonamide-Zn complex catalyst

[structure: see text] Treatment of a chiral sulfonamide with Et(2)Zn gave quantitatively its Zn complex and then the structure was determined by X-ray crystallographic analysis. Reaction of prochiral N-Boc-2-amino-2-alkyl-1,3-propanediols with Ac(2)O in the presence of 5 mol % of chiral sulfonamide-Zn complex catalyst afforded the corresponding chiral monoacetyl products in 70-92% yields with 70-88% ee values. The proposed mechanism for the catalytic monoacetylation of a prochiral 1,3-propanediol was presented on the basis of CSI-MS analysis.     

Di-n-amyl L-tartrate-boric acid complex chiral selector in situ synthesis and its application in chiral nonaqueous capillary electrophoresis

A chiral selector, di-n-amyl L-tartrate-boric acid complex, was in situ synthesized by the reaction of di-n-amyl L-tartrate with boric acid in a nonaqueous background electrolyte (BGE) using methanol as the medium. And a new method of chiral nonaqueous capillary electrophoresis (NACE) was developed with the complex as the chiral selector. It has been demonstrated that the chiral selector is suitable for the enantioseparation of some β-blockers and β-agonists in NACE. Some chiral analytes that could not be resolved in aqueous microemulsion electrokinetic chromatography (MEEKC) with the same chiral selector obtained baseline resolutions in the NACE system. The enantioseparation mechanism was considered to be ion-pair principle and the nonaqueous system was more favorable for the ion-pair formation which is quite useful for the chiral recognition. The addition of a proper concentration of triethylamine into the BGE to control the apparent pH (pH*) enhanced the enantiomeric discrimination. In order to achieve a good enantioseparation, the effects of di-n-amyl L-tartrate and boric acid concentration, triethylamine concentration, applied voltage, as well as capillary length were investigated. Under the optimum conditions, all of the tested chiral analytes including six β-blockers and five β-agonists were baseline resolved.     

New artificial host compounds containing galactose end groups for binding chiral organic amine guests: chiral discrimination and their complex structures

New linear host (1) and cyclic hosts (2 and 3), which have galactopyranose skeletons as chiral origins and oxyethylenes skeletons as binding sites, were designed based on the structural features extracted from the fructo-oligosaccharide derivatives, having a large chiral discrimination ability, and were then synthesized. These hosts showed chiral discrimination toward chiral organic ammonium salts. For example, the chiral discrimination ability (the ratio of association constants: K(R)/K(S)) of host 1, which has the highest value among them, was K(R)/K(S) = 3 for Trp-O-(i)Pr(+) and K(R)/K(S) = 0.7 for 1-(1-naphthyl)ethylammonium (NEA(+)) at 298 K in CHCl(3). It was clarified that host 1 changed the conformation from a linear structure to the pseudo-ring structure by complexation with cations such as alkali metallic ions and chiral organic ammonium ions. The (1)H NMR induced shifts of host 1 by adding the NEA(+) guests showed that the host-guest complex structures are clearly different, depending upon the chirality of the guest; in the complex with (R)-NEA(+), the naphthyl group of the guest is located above the oxyethylene skeleton of the host and in the complex with (S)-NEA(+), and the naphthyl group is located between the edges of the pseudo-ring of the host. The clearly different structure of the complex of host 1 with NEA(+) may be caused by the dynamic molecular recognition, thus the induced-fitting mechanism.     

Chiral imidates as a new class of nitrogen-based chiral ligands: synthesis and catalytic activity in asymmetric aziridinations and diethylzinc additions

Chiral imidates were efficiently synthesized in one step and with high yields (seven examples). These chiral imidates were used as ligands in the Cu(I)-catalyzed asymmetric aziridination of methyl cinnamate and in the asymmetric diethylzinc additions to benzaldehyde as a proof of principle. The imidate catalyst system showed high catalytic activities and induced encouraging selectivities. An X-ray structure analysis of an imidate-Cu(I) complex is included, showing a distorted tetrahedral arrangement with two bidentate ligand molecules surrounding the metal.     

Improvement of chiral stationary phases based on cinchona alkaloids bonded to crown ethers by chiral modification

To improve the chiral recognition capability of a cinchona alkaloid crown ether chiral stationary phase, the crown ether moiety was modified by the chiral group of (1S, 2S)‐2‐aminocyclohexyl phenylcarbamate. Both quinine and quinidine‐based stationary phases were evaluated by chiral acids, chiral primary amines and amino acids. The quinine/quinidine and crown ether provided ion‐exchange sites and complex interaction site for carboxyl group and primary amine group in amino acids, respectively, which were necessary for the chiral discrimination of amino acid enantiomers. The introduction of the chiral group greatly improved the chiral recognition for chiral primary amines. The structure of crown ether moiety was proved to play a dominant role in the chiral recognitions for chiral primary amines and amino acids.     

Chirality induction of polyaniline derivatives through chiral complexation

Chirality induction of π-conjugated polyaniline derivatives was achieved by chiral complexation with chiral palladium(II) complexes. The crystal structure of the chiral conjugated complex with a model compound of the polyaniline, N,N-bis(4^′-dimethylaminophenyl)-1,4-benzoquinonediimine, revealed a chiral propeller twist conformation of the π-conjugated moiety.     

一种新型手性席夫碱的合成及其在不对称环丙烷化反应中的催化性能

在不对称催化的发展过程中,设计与合成新的手性配体一直是人们所关注的热点,并已取得很大的进展[1].     

X-ray Crystallographic Evidence in Support of a Proposed Chiral Recognition Mechanism

A new family of pi-basic chiral selectors has been developed and employed in the separation of enantiomers by liquid chromatography. These chiral selectors, derived from (S)-proline and designed from mechanistic considerations, show high levels of discrimination between the enantiomers of N-(3,5-dinitrobenzoyl)amino acid esters and amides. A considerable amount of chromatographic data has been assembled, all of it consistent with the proposed chiral recognition mechanism. Moreover, this mechanism is supported by induced chemical shift differences and intermolecular NOE data previously obtained in solution with an equimolar mixture of (S)-1 and (S)-2. A crystalline 1:1 complex of (S)-1 and (S)-2 has been obtained and analyzed by X-ray crystallography. The structure of this complex in the solid state illustrates the essential features of the mechanism proposed to account for chiral recognition between chiral stationary phase (CSP) 3 and the enantiomers of 2 and related analytes. In addition, the orientation of the two components in the solid state is in close agreement with the structure of the more stable diastereomeric complex deduced from solution-state NMR evidence relating to the same system.     

Chiral separation of sympathomimetics by ligand exchange capillary electrophoresis.

A rapid and simple approach to the chiral separation of sympathomimetic drugs with amino alcohol structure by ligand exchange capillary electrophoresis is described. An N-(2-hydroxyoctyl)-L-4-hydroxyproline/copper(II) complex is used as chiral selector. Thirteen sympathomimetics were resolved, nine with baseline resolution. The influence of pH and composition of the electrolyte on resolution was investigated. The optimal pH for complexation of these amino alcohols was found to be 12.     

Evaluation of the interaction between sitagliptin and cyclodextrin derivatives by capillary electrophoresis and nuclear magnetic resonance spectroscopy

An aqueous capillary electrophoretic method was developed for chiral analysis of the novel anti-diabetic drug, sitagliptin. The acid-base profiling of the analyte was carried out using both capillary electrophoresis and nuclear magnetic resonance pH titrations. The apparent complex stability and chiral separation properties were investigated with 30 different cyclodextrins under acidic conditions. The effect of concentration and pH of the BGE, temperature of the capillary, and the type and concentration of the chiral selector on the enantiomer resolution were thoroughly investigated. The effects of dual cyclodextrin systems on separation were also extensively studied. Complete separation of racemic sitagliptin with good resolution (R(S)=2.24) was achieved within a short time (15 min) with optimized parameters (10°C, pH=4.4, 40 mM phosphate buffer) of a sulfobutylether-β-cyclodextrin (averaged degree of substitution ~4) and native β-cyclodextrin dual system. The averaged stoichiometry of the inclusion complex was determined using the Job plot method with both (1)H and (19)F NMR experiments and resulted in a 1:1 complex. The structure of the inclusion complex was elucidated using 2-D ROESY NMR experiments.     

Highly diastereoselective oxidative addition of methyl iodide to a chiral square-planar complex

Oxidative addition of methyl iodide to the chiral square-planar complex IrI(CO)(duphos) shows a high level of diastereoselectivity. The basis for the diastereoselectivity of the reaction is best explained based on the crystal structure of IrI(CO)(duphos) in which methyl iodide approach across the two faces is differentiated by the chiral ligand.     

In situ synthesis of di-n-butyl l-tartrate–boric acid complex chiral selector and its application in chiral microemulsion electrokinetic chromatography

A novel procedure for in situ assembling a complex chiral selector, di-n-butyl l-tartrate–boric acid complex, by the reaction of di-n-butyl l-tartrate with boric acid in a running buffer was reported and its application in the enantioseparation of β-blockers and structural related compounds by chiral microemulsion electrokinetic chromatography (MEEKC) has been demonstrated. In order to achieve a good enantioseparation, the effect of dibutyl l-tartrate and sodium tetraborate concentration, surfactant identity and concentration, cosurfactant, buffer pH and composition, organic modifiers, as well as applied voltage and capillary length were investigated. Ten pairs of enantiomers that could not be separated with only dibutyl l-tartrate, obtained good chiral separation using the complex chiral selector; among them, seven pairs could be baseline resolved under optimized experimental conditions. The fixation of chiral centers by the formation of five-membered rings, and being oppositely charged with basic analytes were thought to be the key factors giving the complex chiral selector a superior chiral recognition capability. The effect of the molecular structure of analytes on enantioseparation was discussed in terms of molecular interaction.     

高效液相色谱圆二色检测技术在手性化合物分析中的应用

对近年来高效液相色谱圆二色检测技术在手性化合物分析中的应用进展进行综述,简单介绍了高效液相色谱圆二色检测器的原理和特点,着重介绍了非手性色谱条件下圆二色检测技术在手性化合物对映体纯度测定、复杂基质中手性化合物分析以及在手性化合物绝对构型测定中的应用,并讨论了它的应用前景。     

Coordination-driven inversion of handedness in ligand-modified PNA

Peptide nucleic acid (PNA) is a synthetic analogue of DNA, which has the same nucleobases as DNA but typically has a backbone based on aminoethyl glycine (Aeg). PNA forms duplexes by Watson Crick hybridization. The Aeg-based PNA duplexes adopt a chiral helical structure but do not have a preferred handedness because they do not contain a chiral center. An L-lysine situated at the C-end of one or both strands of a PNA duplex causes the duplex to preferably adopt a left-handed structure. We have introduced into the PNA duplexes both a C-terminal L-lysine and one or two PNA monomers that have a γ-(S)-methyl-aminoethyl glycine backbone, which is known to induce a preference for a right-handed structure. Indeed, we found that in these duplexes the γ-methyl monomer exerts the dominant chiral induction effect causing the duplexes to adopt a right-handed structure. The chiral PNA monomer had a 2,2':6',2'-terpyridine (Tpy) ligand instead of a nucleobase and PNA duplexes that contained one or two Tpys formed [Cu(Tpy)(2)](2+) complexes in the presence of Cu(2+). The CD spectroscopy studies showed that these metal-coordinated duplexes were right-handed due to the chiral induction effect exerted by the S-Tpy PNA monomer(s) except for the cases when the [Cu(Tpy)(2)](2+) complex was formed with Tpy ligands from two different PNA duplexes. In the latter case, the metal complex bridged the two PNA duplexes and the duplexes were left-handed. The results of this study show that the preferred handedness of a ligand-modified PNA can be switched as a consequence of metal coordination to the ligand. This finding could be used as a tool in the design of functional nucleic-acid based nanostructures.     

Chemically modified chiral monolithic silica column prepared by a sol-gel process for enantiomeric separation by micro high-performance liquid chromatography

In this work a new type of chiral monolith silica column was developed for the chiral separation by micro high-performance liquid chromatography (micro-HPLC). The chiral monolith column with a continuous skeleton and a large through-pore structure was prepared inside a capillary of 100 microm I.D. by a sol-gel process, and chemically modified with chiral selectors, such as L-phenylalaninamide, L-alaninamide and L-prolinamide, on the surface of the monolithic silica column. Based on the principle of ligand exchange, these chiral monolithic columns were successfully used for the separation of dansyl amino acid enantiomers, as well as hydroxy acid enantiomers by micro-HPLC. The chromatographic conditions, the enantioselectivity and the performance of columns are discussed.     

Chiral self-dimerization of vanadium complexes on a SiO2 surface for asymmetric catalytic coupling of 2-naphthol: structure, performance, and mechanism

Vanadium monomers with chiral tridentate Schiff-base ligands were supported on SiO(2) through a chemical reaction with surface silanols, where we found a new chirality creation by the self-dimerization of the vanadyl complexes on the surface. The chiral self-dimerization and the role of surface silanols in the self-assembly were investigated by means of X-ray absorption near-edge structure (XANES), extended X-ray absorption fine structure (EXAFS), diffuse-reflectance ultraviolet/visible (DR-UV/VIS), X-ray photoelectron spectroscopy (XPS), Fourier transform infrared (FT-IR), electron spin resonance (ESR), and density functional theory (DFT) calculations. The surface vanadyl complexes had a distorted square-pyramidal conformation with a V=O bond. FT-IR spectra revealed that the Ph-O moiety of Schiff-base ligands was converted to Ph-OH by a surface-concerted reaction between the vanadium precursors and surface SiOH groups. The Ph-OH in an attached vanadyl complex interacted with a COO moiety of another vanadyl complex by hydrogen bonding to form a self-dimerized structure at the surface. The interatomic distance of V-V in the surface self-assembly was evaluated to be 0.40 +/- 0.05 nm by ESR after O(2) adsorption. The self-dimerized V structure on SiO(2) was modeled by DFT calculations, which demonstrated that two vanadium monomers with Ph-OH linked together by two hydrogen bonds and their V=O groups were directed opposite to each other. The surface self-dimerization of the vanadium precursors fixes the direction of the V=O bond and the plane of the Schiff-base ligand. Thus, a new chiral reaction field was created by two types of chirality: the chiral Schiff-base ligand and the chiral V center. We have also found that the chiral self-dimerized vanadyl complexes exhibit remarkable catalytic performance for the asymmetric oxidative coupling of 2-naphthol: 96% conversion, 100% selectivity to 1,1'-binaphthol (BINOL), and 90% enantiomeric excess (ee). Increasing the vanadium loading on SiO(2) caused a dramatic swell of enantioselectivity, and the maximum 90% ee was observed on the supported catalyst with the full coverage of the vanadyl complex (3.4 wt % vanadium). This value is equivalent to the maximum ee reported in homogeneous catalysis for the coupling reaction. Furthermore, the supported vanadium dimers were reusable without loss of the catalytic performance. To our knowledge, this is the first heterogeneous catalyst for the asymmetric oxidative coupling of 2-naphthol.     

Characterization of a chiral enolate aggregate and observation of 6Li-1H scalar coupling

A chiral enolate aggregate 1 containing a lithium enolate and a chiral lithium amide was systematically investigated by various NMR techniques. (1)H and (13)C DOSY at 25 and -78 degrees C provide its solution structure, aggregation number, and formula weight. Multiple 2D (6)Li NMR techniques, such as (6)Li-(6)Li EXSY, (6)Li-(1)H HOESY, were utilized to investigate its stereochemical structure. The configuration of the enolate in complex 1 was confirmed by (6)Li-(1)H HOESY and trapping with TMS-Cl. A unique (6)Li-(1)H coupling through the Li-N-C-H network was observed. This scalar coupling was corroborated by (6)Li-(1)H HMQC, deuterium labeling experiments, and selective (1)H decoupling (6)Li NMR. The stereostructure of 1 provides a model for the origin of enantioselectivity of chiral lithium amide-induced enolate addition reactions.