Diastereomeric Complexes Research Articles

Synthesis of a Chiral Palladacycle and Its Application in Asymmetric Hydrophosphanation Reactions

AbstractA novel amine ligand, 1‐(2,5‐dimethylphenyl)‐N,N,2,2‐tetramethylpropan‐1‐amine, was synthesized in six steps from commercially available p‐xylene. Direct ortho‐palladation of this amine ligand proceeded readily to form the racemic dimeric complex. The palladacycle structure and ring conformations of its triphenylphosphane derivative were thoroughly investigated by X‐ray structural analysis in the solid state and 2D 1H–1H ROESY NMR spectroscopy in solution. This racemic palladacycle was efficiently resolved through the formation of its (S)‐prolinato derivatives and an efficient separation of the resulting diastereomeric complexes was achieved by slow crystallization with the use of different solvent systems. The structure and absolute configuration of the two optically resolved palladium complexes were determined by X‐ray diffraction. Both the (R,R) and (S,S)‐di‐μ‐chlorido dimeric palladium complexes could be obtained chemoselectively by treating the corresponding prolinato derivatives with 1 M hydrochloric acid. The asymmetric hydrophosphanation reaction between diphenylphosphane and diethyl acetylenedicarboxylate was promoted by this newly synthesized palladacycle and resulted in the formation of a single isomer according to the 31P NMR spectrum. The amine auxiliary could be subsequently removed chemoselectively from the palladium center by treatment with concentrated HCl. An optically pure C2‐symmetrical diphosphane ligand containing two ester functional groups at the two chiral carbon stereogenic centers was prepared by ligand displacement.

Chiral trans-1,2-diaminocyclohexane derivatives as chiral solvating agents for carboxylic acids

Efficient use of the readily accessible chiral C 2-symmetric acyclic diamines (1–2) as well as macrocyclic amines (3–5) containing trans-1,2-diaminocyclohexyl moiety as chiral solvating agents (CSA) for the determination of enantiomeric excess of representative carboxylic acids (6–7) and an amino acid derivative (8) is illustrated. The enantiomeric composition of different carboxylic acids estimated here by the 1H NMR method, based on the integration of the corresponding methine proton signals are in good correlation with that determined using HPLC method. The data are in accordance with the formation of multimolecular diastereomeric complexes in solution, which render good splitting of NMR signals for the enantiomers of representative carboxylic acids as well as for N-Ts-phenylglycine (up to ΔΔδ = 0.295 ppm, 118 Hz).

Chiral discrimination between alanine enantiomers by field effect transistor with a homocysteine monolayer-modified gate

Abstract The application of field effect transistor (FET) to chiral discrimination was investigated. An Au film vapor-deposited on a self-assembled monolayer (SAM) of (3-mercaptopropyl)trimethoxysilane, which was formed on the SiO2 gate of FET as an adhesive and insulating layer, stabilizes the drain current–gate voltage (Id–Vg) property of FET. The modification by homocysteine (Hcy) SAM on the surface of Au-coated gate makes it possible for the FET to distinguish between the enantiomers of alanine (Ala). Namely, after the sequential addition of Ala and Cu(II) to a K2SO4 solution in this system, it was confirmed that the lateral shift of Id–Vg curves for the FET corresponded to the chirality of Ala. With the l -Hcy SAM-modified gate, a notable negative shift was observed for l -Ala, whereas the shift observed with d -Ala was much smaller. In contrast, opposite results were obtained with d -Hcy SAM. Results of quartz crystal microbalance measurement suggested that such an FET response was originated from the enantioselective formation of diastereomeric Cu complexes with Ala molecules on the Hcy SAM. This system was demonstrated to respond quantitatively to one enantiomeric form of Ala in mixed solutions of two enantiomers as well as in pure enantiomeric solutions.

Synthesis, characterization, and theoretical studies of metal complexes derived from the chiral tripyridyldiamine ligand Bn-CDPy3.

Synthesis and characterization of metal complexes of the chiral tripyridyldiamine ligand Bn-CDPy3 (1), derived from trans-1,2-diaminocyclohexane, are described, along with theoretical studies that support the experimental data. These studies confirm that a single coordination geometry, out of five possible, is favored for octahedral complexes of the type [M(Bn-CDPy3)Cl], where M equals Co(III), Fe(II), and Zn(II). A combination of X-ray crystallographic and NMR spectroscopic methods was used to define the structures of the complexes [Co(Bn-CDPy3)Cl]Cl(2) (5), [Fe(Bn-CDPy3)Cl]X (X = FeCl(4), Cl, ClO(4), 6-8), and [Zn(Bn-CDPy3)Cl](2)ZnCl(4) (9) in the solid state and in solution. Experimental and theoretical data indicate that the most stable coordination geometry for all complexes possesses the Cl group trans to a basic amine donor and three pyridyl donors adopting the mer geometry, with two pyridyl N-donors adopting a coplanar geometry with respect to the M-Cl bond and the third pyridyl donor perpendicular to that axis. Calculations indicate that the ability to favor a single geometry is born from the chiral ligand, which prefers to be in a single conformation in metal complexes due to steric interactions and electronic factors. Calculated structures of the complexes were used to locate key interactions among the various diastereomeric complexes that are proposed to create an energetic preference for the coordination geometry observed in the metal complexes of 1.

The absolute configuration of an inherently chiral phosphonatocavitand and its use toward the enantioselective recognition of l-adrenaline

An inherently chiral AB ii diphosphonato cavitand (±)- 4 bearing a single quinoxaline bridging moiety was synthesized and resolved by chiral HPLC. Its chiroptical properties were investigated and VCD experiments allowed the determination of its absolute configuration. Distinguishable diastereomeric complexes in solution with l-adrenaline were observed by 1H and 31P NMR together with a noticeable enantio-discrimination at 253 K (dr ∼2:1) in favor of the dextrorotatory cavitand (+)- 4.

Molecular modeling of complexes between two amino acids and copper(II): Correlation with Ligand Exchange Capillary Electrophoresis

The energies of various Cu(II) complexes have been computed at the MM and DFT levels of theory. These complexes are constituted of Cu(II) ion used as a central ion, an enantiomer of an amino acid and l-proline or trans-4- l-Hydroxy-proline (THLP) used as chiral selectors in Ligand Exchange Capillary Electrophoresis (LECE). The energy differences of the diastereomeric complexes containing implicit water molecules computed at the DFT/B3LYP/LANL2DZ level are in good agreement with the observed enantioseparations using LECE.

Ferrocenyl-Aryl Based trans-Chelating Diphosphine Ligands: Synthesis, Molecular Structure and Application in Enantioselective Hydrogenation

Potentially trans-chelating diphosphine ligands based on a ferrocenyl-aryl backbone were synthesised in a four-step sequence and the molecular structures in the solid state of two representatives were determined by X-ray diffraction. High throughput screening of these ligands in rhodium-, ruthenium- and iridium-mediated hydrogenations of a variety of alkenes and ketones revealed that these ligands can deliver high enantioselectivity for alkenes (up to 98% ee) but are less selective when ketones are used as the substrates. The coordination behaviour of one ligand in its square planar palladium and platinum dichloride complexes was studied by 31 P NMR and only trans-chelated complexes, together with oligomeric by-products, were observed. Reaction with the (p-cymene)ruthenium dichloride dimer, [RuCl 2 (p-cymene)] 2 , resulted in a mixture of diastereomeric complexes.

A practical and efficient method for the resolution of 3‐phospholene 1‐oxides via coordination complex formation1

A simple, efficient, and economical method based on the combination of the exceptional behavior of o,o'-dibenzoyl- or o,o'-di-p-toluyl-(2R,3R)-tartaric acid in chiral recognition processes, and the coordination ability of calcium or magnesium ion was developed for the resolution of phospholene oxides 1. The calcium or magnesium salt of (-)-o,o'-dibenzoyl-(2R,3R)-tartaric acid 2,4-6 or calcium hydrogen (-)-o,o'-di-p-toluyl-(2R,3R)-tartrate 3 may form crystalline diastereomeric coordination complexes with the appropriate antipode of substituted 3-phospholene oxides 1 that makes possible efficient resolutions. Optically active phospholene oxides 1 were prepared directly by simply crystallization and digestion of the corresponding diastereomeric complexes so formed. Thermal behavior of the crystalline diastereomeric complexes was studied by simultaneous TG/DTA. The novel method may be of more general value in respect of the resolution of tertiary phosphine oxides.

Diastereoselective Protonation, Substitution and Addition Reactions at Pseudotetrahedral Rhenium Complexes

AbstractThe chiral N,P ligand P(Me)(Ph)[8‐(2‐methylquinolinyl)] (3) was synthesized and separated into its enantiomers via diastereomeric palladium complexes. The reactions of 3 and (RP)‐3 with [CpRe(CO)(NO)(NCMe)]BF4 (7) gave thediastereomeric complexes [CpRe(CO)(NO){P(Me)(Ph)(C10H8N)}]BF4 [8 and (RRe,SP/SRe,SP)‐8], which, upon borohydride reduction, yielded the corresponding methyl complexes [CpRe(NO){P(Me)(Ph)(C10H8N)}(CH3)] [9 and (RRe,SP/SRe,SP)‐9]. Treatment of 9 with HBF4 under carefully controlled conditions gave the diastereomerically pure chelates [CpRe(NO){P(Me)(Ph)(C10H8N)}]BF4 [(RRe,SP/SRe,RP)‐10, (RRe,RP/SRe,SP)‐10 and (RRe,SP)‐10]. The chelate ring was opened with NaSH to produce the hydrosulfido complexes [CpRe(NO){P(Me)(Ph)(C10H8N)}(SH)] [(RRe,SP/SRe,RP)‐11, (RRe,RP/SRe,SP)‐11 and (RRe,SP)‐11]. Each step in this sequence proceeded with retention of configuration at rhenium. Complex 11 underwent acid‐promoted condensation with aldehydes to give thioaldehyde complexes [CpRe(NO){P(Me)(Ph)(C10H8N)}(S=CHR)]BF4 (12a–d, R = Ph, Me, 4‐C6H4OMe, C6F5). The addition of nucleophiles X– to 12a gave rhenium‐coordinated α‐chiral thiolate complexes [CpRe(NO){P(Me)(Ph)(C10H8N)}{SC(H)(Ph)(X)}] (13a–e, X = acac, PhCH2S, EtS, tBuS, CN) with 42–89 % de. The thiolate can readily be cleaved from the rhenium complex by a methylation/chelate ring‐closure strategy. The stereochemistry of the entire reaction sequence was corroborated for each step by X‐ray crystallography.

Enantiomeric discrimination of chiral crown ether ionophores containing phenazine subcyclic unit by ion-selective potentiometry

In this paper the enatiomeric selectivity of two chiral phenazino-18-crown-6 ether hosts ((R,R)-\textbf1 and (R,R)-\textbf2) is quantified. These hosts were incorporated into plasticized PVC membranes and used as recognition elements of ion-selective electrodes. The potentiometric response towards the two enantiomers of 1-phenylethylammonium ions (PEA+) was measured. Potentiometric selectivity coefficients were calculated which reflect the ratio of the stability constants of the diastereomeric complexes. Ligand (R,R)-\textbf1 does not show enantiomeric recognition, while ligand (R,R)-\textbf2 has a slight preference for the (S)-(-) enantiomer over the (R)-(+) enantiomer manifested by a selectivity coefficient of 0.77. The results were compared to enantioselectivity patterns of the ligands towards α -(1-naphthyl)ethyl ammonium perchlorate (NEA+ClO4-) enantiomers measured by circular dichroism and by 1H NMR titrations.

A facile circular dichroism protocol for rapid determination of enantiomeric excess and concentration of chiral primary amines.

A protocol for the rapid determination of the absolute configuration and enantiomeric excess (ee) of alpha-chiral primary amines with potential applications in asymmetric reaction discovery has been developed. The protocol requires derivatization of alpha-chiral primary amines through condensation with pyridine carboxaldehyde to quantitatively yield the corresponding imine. The Cu(I) complex with 2,2'-bis (diphenylphosphino)-1,1'-dinaphthyl (BINAP--Cu(I)) with the imine yields a metal-to-ligand charge-transfer (MLCT) band in the visible region of the circular dichroism (CD) spectrum upon binding. Diastereomeric host-guest complexes give CD signals of the same signs but different amplitudes, allowing for differentiation of enantiomers. Processing the primary optical data from the CD spectrum with linear discriminant analysis (LDA) allows for the determination of the absolute configuration and identification of the amines, and processing with a supervised multilayer perceptron artificial neural network (MLP-ANN) allows for the simultaneous determination of the ee and concentration. The primary optical data necessary to determine the ee of unknown samples is obtained in two minutes per sample. To demonstrate the utility of the protocol in asymmetric reaction discovery, the ee values and concentrations for an asymmetric metal-catalyzed reaction are determined. The potential of the application of this protocol in high-throughput screening (HTS) of ee is discussed.

Electrostatic chiral distinction: Tetrahedral model dimers

Although chiral distinction plays a pervasive role in chemistry, a complete understanding of how this takes place is still lacking. In this work, we expand the earlier described minimal requirement of so called four-point interactions (vide infra). We focus on chiral point charge model systems as a means to aid in the dissection of the underlying, operative principles. We also construct models with defined symmetry characteristics. By considering extensive constellations of diastereomeric complexes, we are able to identify emerging principles for chiral distinction. As previously postulated, all the diastereomeric complexes, regardless of their nominal contact-points, possess a chiral distinction energy. In the comparison of complexes, we find that, contrary to chemical intuition, the magnitude of chiral distinction does not correlate with the stability of the complexes, i.e., consideration of low energy complexes may not be an effective way to evaluate chiral distinction. Similarly, we do not find a correlation between the number of contact-points and chiral distinction. Moreover, favorable interactions and facile chiral distinction appear to be unrelated. We also see some tendency for greater chiral distinction in less symmetric systems, although this may not be general. These studies can now form the basis to fold in higher levels of complexity into the models so as to gain further insights into the nature of chiral distinction.

Enantiopure tert-butyl(phenyl)phosphine oxide. Chirality-recognition ability and mechanism

When enantiopure tert-butyl(phenyl)phosphine oxide 1 was used as a resolving agent, it showed an acceptable to good chirality-recognition ability for several kinds of racemic carboxylic acids 2. A study on a chirality-recognition mechanism based on X-ray crystallographic analyses of the diastereomeric complexes of 2 with 1 revealed that the complex crystals consisted of helical columns and that 1 was not responsible for the formation of the helical column and occupied a void between the columns; although 1 interacted with 2 via a hydrogen bond to primarily form a pair with 2, the complex crystals were mainly stabilized by the accumulation of weak interactions, such as CH/π, π/π and CH⋯O interactions, between 1/ 1, 1/ 2 and 2/ 2.

Kinetic Resolution of Aminoalkenes by Asymmetric Hydroamination: A Mechanistic Study

The kinetic resolution of chiral aminoalkenes by hydroamination-cyclization was studied by using 3,3'-bis(triarylsilyl)-substituted binaphtholate rare-earth-metal complexes. The resolution of 1-arylaminopentenes proceeds with high efficiency and high trans-diastereoselectivity, whereas the resolution process of 1-alkylaminopentenes suffers from decreasing resolution efficiency with increasing steric demand of the aliphatic substituent. Kinetic studies of the matching and mismatching substrate-catalyst pair by using enantiopure substrates and either the (R)- or (S)-binaphtholate catalysts revealed that the difference in resolution efficiency stems from a shift of the Curtin-Hammett pre-equilibrium. Although 1-arylaminopentenes favor the matching substrate-catalyst complex, preference for the mismatching substrate-catalyst complex for 1-alkylaminopentenes diminishes resolution efficiency. Nevertheless, the relative cyclization rate for the two diastereomeric substrate-catalyst complexes remains in a typical range of 7-10:1. Plausible attractive pi interactions between the aryl substituent and either the metal center or the aromatic system of the bis(triarylsilyl)-substituted binaphtholate ligand may explain increased stability of the matching substrate-catalyst complex. Incidentally, the methoxymethyl (MOM)-substituted aminopentene 3 g also exhibited a strong preference for the matching substrate-catalyst complex, possibly due to the chelating nature of the MOM substituent. The proximity of the stereocenter to the amino group in the aminoalkene substrate was crucial to achieve good kinetic resolution efficiency. The more remote beta-phenyl substituent in 2-phenylpent-4-en-1-amine (5) resulted in diminished discrimination of the substrate enantiomers with respect to the relative rate of cyclization of the two substrate-catalyst complexes and a Curtin-Hammett pre-equilibrium close to unity.

Asymmetric Twisting and Chirality Probing Properties of Quadruple-Stranded Helicates: Coordination Versatility and Chirality Response of Na+, Ca2+, and La3+ Complexes with Octadentate Cyclen Ligand

A series of Na(+), Ca(2+), and La(3+) complexes with octadentate cyclen ligand were prepared and structurally characterized in the crystal and solution states. The employed cyclen ligand formed 6-, 7-, and 9-coordinated, crystalline complexes with Na(+), Ca(2+), and La(3+) cations, respectively, in which the parent cyclen ring and quinoline-functionalized side arms were cooperatively coordinated. These three metal cations provided the quadruple-stranded helicates in CH(3)CN-C(2)H(5)OH solutions. In each helicate, four quinoline-functionalized side arms were arranged in a propeller-like fashion to yield an enantiomer-pair of Delta- and Lambda- forms. Addition of a chiral anion to the cyclen-Ca(2+) complex solution induced circular dichroism (CD) signals around the quinoline chromophore, which indicated that 1:1 diastereomeric complexation between the Ca(2+) complex and the chiral anion imposed the stereoisomeric equilibrium. The intensity and sign of the observed CD signal were significantly dependent on both the absolute configuration and the enantiomeric purity of the added anion. The corresponding cyclen-Na(+) complex rarely induced a CD signal, while the La(3+) complex exhibited complicated anion-induced spectral changes. Thus, the octadentate cyclen ligand employed was demonstrated to form the quadruple-stranded helicate with the Ca(2+) cation in the solution state, which functioned as an effective CD probe for the determination of enantiomer excess (ee%) of the chiral anions.

Towards Modular Design of Chiroptically Switchable Molecules Based on Formation and Cleavage of Metal-Ligand Coordination Bonds

The results presented in this paper demonstrate that the proposed design of C 2 -symmetric, pentadentate achiral or chiral ligands 8a-d and 15 allows to generate, upon coordination with Ni(II) and Pd(II), the corresponding diastereomeric complexes possessing three new elements of chirality: stereogenic axis, center, and helix. Of particular importance is that due to the specific steric characteristics of the designed ligands the formation of the corresponding diastereomeric products is highly stereoselective allowing preparation of only two out of four possible stereochemical combinations. For instance, each diastereoisomeric product (R a ',P h ',S c ')-9a and (R a ',M h ',R c ')-12a can be selectively prepared and characterized in solid state, simply by the choice of the chelating metal [Ni(II) or Pd(II)]. Furthermore, introduction of stereochemical information into the ligands design with application of a simple chiral 'Amine Module' allows for complete transfer of the corresponding stereochemistry to the newly generated axial, helical, and central chirality. For example, starting with chiral ligand (R)-15, out of eight possible products, only a single product of (R c ,R a ,P h ,S c ) absolute configuration was obtained in the solid state. Taking into account the modular nature of this design, one may agree that modification of the three major 'phenone', 'acid', and 'amine' modules, or application of different metals, will allow for virtually unlimited structural and functional flexibility in fine-tuning the diastereomeric relationships of this type of complexes making them more selective and controllable by an external stimulus.

The Significance of Degenerate Processes to Enantioselective Olefin Metathesis Reactions Promoted by Stereogenic-at-Mo Complexes

The present study provides spectroscopic and experimental evidence demonstrating that degenerate metathesis is critical to the effectiveness of this emerging class of chiral catalysts. Isolation and X-ray characterization of both diastereomeric complexes, as well as an examination of the reactivity and enantioselectivity patterns exhibited by such initiating neophylidenes in promoting ring-closing metathesis processes, are disclosed. Only when sufficient amounts of ethylene are generated and inversion at Mo through degenerate processes occurs at a sufficiently rapid rate is high enantioselectivity achieved, irrespective of the stereochemical identity of the initiating alkylidene (Curtin-Hammett kinetics). With diastereomeric metal complexes that undergo rapid interconversion, stereomutation at the metal center becomes inconsequential, and stereoselective synthesis of a chiral catalyst is not required.

Design, synthesis, resolution, and stereochemical assignment of a conformationally rigid chiral ligand derived from anthracene and a dienophile containing a pyridine moiety

The conformationally rigid chiral ligand, trans-12-(pyridin-2-yl)-9,10-dihydro-9,10-ethanoanthracene-11-carboxylic acid ethyl ester, 1, was designed and synthesized in racemic form. Both isomers were successfully obtained in enantiomerically pure form through classical resolution using l-(+)-tartaric acid in acetonitrile . The nature of the diastereomeric complex formed in this resolution was elucidated using single crystal X-ray crystallographic studies. The absolute configuration of (+)- 1 was unambiguously assigned as (11 S,12 S) by single crystal structural analysis of salt 5 formed from (+)- 1 and l-(+)-tartaric acid.

Supramolecular Complexation and Enantiodifferentiating Photocyclodimerization of 2-Anthracenecarboxylic Acid with 4-Aminoprolinol Derivatives as Chiral Hydrogen-Bonding Templates

The photochirogenesis of 2-anthracenecarboxylic acid (AC) complexed to a hydrogen-bonding template (TKS159) was investigated to obtain mechanistic information on how chirogenesis is achieved for the dimerization of AC. Complexation of AC to TKS159 leads to the shielding of one of the two surfaces of the prochiral AC molecule. The two diastereomeric AC-TKS complexes, i.e., re-AC-TKS and si-AC-TKS, were characterized by changes in the UV-vis, fluorescence, and circular dichroism spectra and excited-state lifetimes. The ee is not simply determined by the diastereomeric ratio of the re- and si-AC-TKS complexes but also depends on the relative lifetimes of the diastereomeric complexes. The relative population of the re and si complexes was calculated from the enantiomeric excess (ee) for the products, taking into account the relative lifetimes of the two complexes. These studies established a protocol that can be used to reveal the mechanism for photochirogenesis by investigating the ground state and the excited state behavior of supramolecular systems.

Use of (S)‐BINOL as NMR chiral solvating agent for the enantiodiscrimination of omeprazole and its analogs

The application of (S)-1,1'-binaphthyl-2,2'-diol as NMR chiral solvating agent (CSA) for omeprazole, and three of its analogs (lanso-, panto-, and rabe-prazole) was investigated. The formation of diastereomeric host-guest complexes in solution between the CSA and the racemic substrates produced sufficient NMR signal splitting for the determination of enantiomeric excesses by (1)H- or (19)F-NMR spectroscopy. Using of hydrophobic deuterated solvents was mandatory for obtaining good enantiodiscrimination, thus suggesting the importance of intermolecular hydrogen bonds in the stabilization of the complexes. The method was applied to the fast quantification of the enantiomeric purity of in-process samples of S-omeprazole.