Mechanistic study of enantiomeric recognition with native gamma-cyclodextrin by capillary electrophoresis,reversed-phase liquid chromatography,nuclear magnetic resonance spectroscopy,electrospray mass spectrometry and circular dichroism techniques

The possible mechanisms for the chiral recognition of 2(S)-(3,5-bis-trifluoromethyl-phenyl)-2-[3(S)-(4-fluorophenyl)-4-(1H-[1,2,4]triazol-3-ylmethyl)-morpholin-2(R)-yloxy]-ethanol (compound A) and its enantiomer with native gamma-cyclodextrin (gamma-CD) were investigated using capillary electrophoresis (CE), reversed-phase liquid chromatography (RPLC), proton (1H), fluorine (19F) and carbon (13C) nuclear magnetic resonance spectroscopy (NMR), electrospray mass spectrometry (ESI-MS) and circular dichroism (CD). All experiments provided clear evidence of the formation of diastereomeric complexes between the enantiomers and gamma-CD. Proton, fluorine and carbon NMR spectra suggested that both aromatic rings, with mono-fluoro and bis-tri-fluoro functional groups, on the guest molecule were partially included into the cavity of the gamma-CD. ESI-MS spectra indicated that the diastereomeric complexes have a 1:1 stoichiometric ratio. The binding constants of the diastereomeric complexes obtained by CE, RPLC and CD were compared. The effects of the gamma-CD concentration, organic modifiers and temperature on the CE-chiral separation were also investigated.     

Enantiomer separations by nonaqueous capillary electrophoresis using octakis(2,3-diacetyl-6-sulfato)-gamma-cyclodextrin

The newest member of the single-isomer isomer sulfated cyclodextrin family, octakis(2,3-diacetyl-6-sulfato)-gamma-cyclodextrin (ODAS-gamma-CD) was used for the first time as a resolving agent for the nonaqueous capillary electrophoretic separation of the enantiomers of 26 weak base pharmaceuticals in an acidic methanol background electrolyte. The solubility limit of ODAS-gamma-CD at room temperature proved to be 55 mM in this background electrolyte, which afforded good, fast enantiomer separations for most of the basic drugs tested. For all the bases studied, the effective mobilities and separation selectivities were found to follow the predictions of the charged resolving agent migration model of electrophoretic enantiomer separations. The effective mobilities of the weakly binding weak bases remained cationic throughout the entire 0 to 45 mM ODAS-gamma-CD concentration range; separation selectivities increased as the ODAS-gamma-CD concentration was increased. The effective mobilities of the moderately binding weak bases became anionic in the 2.5 to 45 mM ODAS-gamma-CD concentration range; separation selectivities first increased as the effective mobilities approached zero, then decreased again as the ODAS-gamma-CD concentration was increased further. The effective mobilities of the strongly binding weak bases became anionic in the 0 to 2.5 mM ODAS-gamma-CD concentration range; separation selectivities decreased as the ODAS-gamma-CD concentration was increased above 2.5 mM.     

Studies on the chiral recognition of peptide enantiomers by neutral and sulfated beta-cyclodextrin and heptakis-(2,3-di-O-acetyl)-beta-cyclodextrin using capillary electrophoresis and nuclear magnetic resonance

The separation of dipeptide and tripeptide enantiomers using a neutral single isomer cyclodextrin (CD) derivative, heptakis-(2,3-di-O-acetyl)-beta-CD (DIAC-beta-CD), was investigated with respect to the amino acid sequence applying standard separation conditions. With only one exception the DD-enantiomers migrated faster than the LL-stereoisomers. Separations obtained for the same set of peptides using beta-CD and the sulfated single isomer derivatives heptakis-(2,3-di-O-acetyl-6-sulfo)-beta-CD (HDAS-beta-CD) and heptakis-6-sulfo-beta-CD (HS-beta-CD) revealed identical enantiomer migration order in the presence of the 2,3-disubstituted derivatives DIAC-beta-CD and HDAS-beta-CD. In contrast, reversed migration sequence was found for beta-CD and HS-beta-CD compared to DIAC-beta CD and HDAS-beta-CD indicating the importance of the substitution pattern on the wider rim of the CD cavity on the chiral recognition of the peptide enantiomers by the CDs. Nuclear magnetic resonance (NMR) experiments indicated different complexation modes between the enantiomers and the CDs depending on the presence of acetyl substituents on the wider rim of the CD torus. Thus, the CD-induced chemical shifts observed in samples containing Ala-Phe or Ala-Tyr and beta-CD or HS-beta-CD were consistent with an inclusion of the aromatic moiety into the CD cavity. Although the CD-induced chemical shifts in the presence of DIAC-beta-CD and HDAS-beta-CD did not allow direct conclusions on the complexation mode they substantially differed from those observed in the presence of 2,3-unsubstituted CDs indicating different structures of the peptide-CD complexes.     

Characterization of sulfated beta-cyclodextrins and determination of enantiomeric purity of (1 R,2S)-ephedrine by capillary zone electrophoresis

Matrix-assisted laser-desorption ionization time-of-flight (MALDI-TOF) mass spectrometry (MS) and nuclear magnetic resonance (NMR) spectroscopy were employed to characterize two different sulfated beta-cyclodextrins (HS-beta-CD). It was found that the HS-beta-CDs have broad heterogeneity in terms of sulfation degree. The average sulfate contents were in the range of 6 to 8 per CD molecule. Furthermore the sugar moieties of both HS-beta-CDs were sulfated either at position 6 or at positions 2 and 6, but not at position 3. Enantiomeric separation by capillary zone electrophoresis (CZE) using the HS-beta-CDs as chiral selectors showed that these CDs exhibited similar chiral selectivity and resolution of the ephedrine enantiomers. One of the CDs was employed for the enantiomeric purity evaluation of (1R,2S)-ephedrine (or (-)-ephedrine) by capillary zone electrophoresis. Quantification was done by comparison between the corrected peak areas of the minor enantiomer and (-)-ephedrine.     

Study on the chiral recognition of the enantiomers of ephedrine derivatives with neutral and sulfated heptakis(2,3-O-diacetyl)-beta-cyclodextrins using capillary electrophoresis, UV, nuclear magnetic resonance spectroscopy and mass spectrometry

The enantiomers of methylephedrine, pseudoephedrine and ephedrine showed a different migration behavior in capillary electrophoresis in the presence of beta-cyclodextrin (beta-CD), heptakis(2,3-O-diacetyl)-beta-cyclodextrin and heptakis(2,3-O-diacetyl-6-sulfato)-beta-cyclodextrin (HDAS). Utilizing UV, MS and NMR spectroscopy, in particular rotating frame Overhauser experiments, an attempt was made to elucidate the chiral recognition mechanism. In the case of the neutral CDs 1:1 complexes were formed with ephedrine and methylephedrine characterized by the inclusion of the phenyl ring in the cavity and the side chain pointing out of the wider rim. In contrast, manifold complexes were formed with HDAS, which on average are characterized by an upside down inclusion of the phenyl ring in the cavity and the side chain pointing out of the narrow rim. This complex geometry is likely be stabilized by an ion-ion interaction between the positively charged nitrogens of the ephedrine derivatives and the negative charges of HDAS. In addition, an attachment of the ligand to the outside of HDAS and other complex stoichiometries are also possible.     

The CGC enantiomer separation of 2-arylcarboxylic acid esters by using β-cyclodextrin derivatives as chiral stationary phases

Chiral 2-arylcarboxylic acid esters are important intermediates in preparation of enantioenriched 2-arylpropionic acids type Non-steroidal anti-inflammatory drugs (NSAIDs). Enantiomer separation of 2-arylcarboxylic acid esters is crucial for evaluation of the asymmetric synthesis efficiency and the enantiomer excess of chiral 2-arylcarboxylic acid derivatives. The capillary gas chromatography (CGC) enantiomer separation of 17 pairs of 2-arylcarboxylic acid esters enantiomers was conducted by using seven different β-cyclodextrin derivatives (CDs) as chiral stationary phases. It was found that for the 7 pairs of 2-phenylpropionates enantiomers, CDs with both alkyl and acyl substituents especially 2,6-di-O-pentyl-3-O-butyryl-β-cyclodextrin exhibited better enantiomer separation abilities than the other CDs examined. For the 7 pairs of 2-(4-substituted phenyl)propionates enantiomers, 2,3,6-tri-O-methyl-β-cyclodextrin possessed better enantiomer separation abilities than the other CDs. Among the 3 pairs of 2-phenylbutyrates enantiomers examined, only methyl 2-phenylbutyrate enantiomers could be separated by three CDs among the 7 CDs tested, while enantiomers of ethyl 2-phenylbutyrate and isopropyl 2-phenylbutyrate couldn't be separated by any of the 7 CDs tested. Besides the structures of CDs, the structures of 2-arylcarboxylic acid esters including different ester moieties, substituents of phenyl, and different carboxylic acids moieties in 2-arylcarboxylic acid esters also affected the enantiomer separation results greatly. The CGC enantiomer separation results of 2-arylcarboxylic acid esters on different CDs are useful for solving the enantiomer separation problem of 2-arylcarboxylic acid esters.     

Palladium-catalyzed asymmetric phosphination. Scope, mechanism, and origin of enantioselectivity

Asymmetric cross-coupling of aryl iodides (ArI) with secondary arylphosphines (PHMe(Ar'), Ar' = (2,4,6)-R3C6H2; R = i-Pr (Is), Me (Mes), Ph (Phes)) in the presence of the base NaOSiMe3 and a chiral Pd catalyst precursor, such as Pd((R,R)-Me-Duphos)(trans-stilbene), gave the tertiary phosphines PMe(Ar')(Ar) in enantioenriched form. Sterically demanding secondary phosphine substituents (Ar') and aryl iodides with electron-donating para substituents resulted in the highest enantiomeric excess, up to 88%. Phosphination of ortho-substituted aryl iodides required a Pd(Et-FerroTANE) catalyst but gave low enantioselectivity. Observations during catalysis and stoichiometric studies of the individual steps suggested a mechanism for the cross-coupling of PhI and PHMe(Is) (1) initiated by oxidative addition to Pd(0) yielding Pd((R,R)-Me-Duphos)(Ph)(I) (3). Reversible displacement of iodide by PHMe(Is) gave the cation [Pd((R,R)-Me-Duphos)(Ph)(PHMe(Is))][I] (4), which was isolated as the triflate salt and crystallographically characterized. Deprotonation of 4-OTf with NaOSiMe3 gave the phosphido complex Pd((R,R)-Me-Duphos)(Ph)(PMeIs) (5); an equilibrium between its diastereomers was observed by low-temperature NMR spectroscopy. Reductive elimination of 5 yielded different products depending on the conditions. In the absence of a trap, the unstable three-coordinate phosphine complex Pd((R,R)-Me-Duphos)(PMeIs(Ph)) (6) was formed. Decomposition of 5 in the presence of PhI gave PMeIs(Ph) (2) and regenerated 3, while trapping with phosphine 1 during catalysis gave Pd((R,R)-Me-Duphos)(PHMe(Is))2 (7), which reacted with PhI to give 3. Deprotonation of 1:1 or 1.4:1 mixtures of cations 4-OTf gave the same 6:1 ratio of enantiomers of PMeIs(Ph) (2), suggesting that the rate of P inversion in 5 was greater than or equal to the rate of reductive elimination. Kinetic studies of the first-order reductive elimination of 5 were consistent with a Curtin-Hammett-Winstein-Holness (CHWH) scheme, in which pyramidal inversion at the phosphido ligand was much faster than P-C bond formation. The absolute configuration of the phosphine (SP)-PMeIs(p-MeOC6H4) was determined crystallographically; NMR studies and comparison to the stable complex 5-Pt were consistent with an RP-phosphido ligand in the major diastereomer of the intermediate Pd((R,R)-Me-Duphos)(Ph)(PMeIs) (5). Therefore, the favored enantiomer of phosphine 2 appeared to be formed from the major diastereomer of phosphido intermediate 5, although the minor intermediate diastereomer underwent P-C bond formation about three times more rapidly. The effects of the diphosphine ligand, the phosphido substituents, and the aryl group on the ratio of diastereomers of the phosphido intermediates Pd(diphos*)(Ar)(PMeAr'), their rates of reductive elimination, and the formation of three-coordinate complexes were probed by low-temperature 31P NMR spectroscopy; the results were also consistent with the CHWH scheme.     

Enantioseparation of solriamfetol and its major impurity phenylalaninol by capillary electrophoresis using sulfated gamma cyclodextrin

R-solriamfetol is a recently approved drug used for the treatment of excessive sleepiness associated with narcolepsy and sleep apnea. Herein, a capillary electrophoretic method was developed, enabling the simultaneous analysis of the API and its S-enantiomer in addition to the enantiomers of its major impurity phenylalaninol. Twenty-nine different cyclodextrins (CDs), including native, neutral, and charged ones were screened as potential chiral selectors, and the best results were obtained with sulfated CDs. Randomly sulfated-β-CD exhibited outstanding enantioresolution, the peaks of phenylalaninol enantiomers inserted between the two peaks of solriamfetol enantiomers, while sulfated-γ-CD (S-γ-CD) showed remarkable resolution values in a much shorter analysis time with the optimal enantiomer migration order. Among the single isomer sulfated CD derivatives, substituent dependent enantiomer migration order reversal could also be observed in the case of heptakis(6-O-sulfo)-β-CD (HS-β-CD) or heptakis(2,3-O-dimethyl-6-O-sulfo)-β-CD (HDMS-β-CD) with R-,S-solriamfetol, and heptakis(2,3-O-diacetyl-6-O-sulfo)-β-CD (HDAS-β-CD) resulting S-,R-solriamfetol migration order. The sulfated-γ-CD system was chosen for method optimization applying orthogonal experimental design. The optimized method (45 mM Tris-acetate buffer, pH 4.5, 4 mM S-γ-CD, 21°C, +19.5 kV) was capable for the baseline separation of solriamfetol and phenylalaninol enantiomers within 7 min. The optimized method was validated according to the ICH guidelines and successfully applied for the analysis of pharmaceutical preparation (Sunosi^® 75 mg tablet), thus it may serve as a routine procedure for the laboratories of regulatory authorities as well as in Pharmacopoeias.     

Determination of molecular structure using vibrational circular dichroism spectroscopy: the keto-lactone product of Baeyer-Villiger oxidation of (+)-(1R,5S)-bicyclo[3.3.1]nonane-2,7-dione

[reaction: see text] The Baeyer-Villiger oxidation of (+)-(1R,5S)-bicyclo[3.3.1]nonane-2,7-dione, 1, can lead to four keto-lactone products, 2a-d. A single isomer is obtained experimentally. We have used IR and VCD spectroscopies to identify the structure of this product. DFT calculations of the IR and VCD spectra of 2a-d show unambiguously that the experimental product is (+)-(1R,6R)-2a, and not the expected product 2b. NMR studies, including comparison of DFT and experimental 1H and 13C spectra, support this conclusion. This work provides the first example of the use of VCD spectroscopy to discriminate between structural isomers of a chiral molecule. The specific rotation of (+)-(1R,6R)-2a, predicted using TDDFT methods, is negative demonstrating that absolute configurations determined from TDDFT calculations of specific rotations are not 100% reliable.     

Comparative NMR and MS studies on the mechanism of enantioseparation of propranolol with heptakis(2,3-diacetyl-6-sulfo)-β-cyclodextrin in capillary electrophoresis with aqueous and non-aqueous electrolytes

In our recent studies, the reversal of the enantiomer migration order (EMO) was observed with heptakis (2,3-dimethyl-6-sulfo)-β-CD (HDMS-β-CD) when aqueous electrolyte was changed with nonaqueous electrolyte in CE. One-dimensional rotating frame nuclear Overhauser effect spectroscopy experiments prevailed that an inclusion complex was formed between the analyte and the chiral selector in the aqueous buffer, whereas an external complex resulted when a methanolic electrolyte was employed. In the case of the similarly substituted heptakis (2,3-diacetyl-6-sulfo)-β-CD (HDAS-β-CD), the external complex was observed in the aqueous buffer but an inclusion complex was formed in methanolic electrolyte. In contrast to heptakis (2,3-dimethyl-6-sulfo)-β-CD, no reversal of the enantiomer migration order was observed with HDAS-β-CD. In the present study, further mechanisms of enantioselective recognition and separation of propranolol enantiomers with HDAS-β-CD were investigated by using different techniques of nuclear magnetic resonance spectroscopy and high-resolution mass spectrometry. To the best of our knowledge, enantioselective nuclear Overhauser effect was observed for the first time in this study.     

Stereoisomeric separation of pharmaceutical compounds using CE with a chiral crown ether

Optical pure (+)-(18-crown-6)-2,3,11,12-tetracarboxylic acid, a chiral crown ether, was successfully used as a chiral selector for the stereoisomeric separation of numerous real pharmaceutical compounds. Both practical and mechanistic aspects were described. Effects of chiral selector concentration under different pH values of BGE were discussed. Chiral recognition for the enantiomeric compounds with (+)-(18-crown-6)-2,3,11,12-tetracarboxylic acid was investigated through model compounds using CE and infrared spectroscopic techniques. Relations between the enantioselectivity of the chiral crown ether and the structural features of the studied compounds were also investigated. Unusual resolutions of compound-p and its enantiomer as well as compound-o and its 2b epimer were described. These compounds contained only tertiary amine, believed to be nonbinding with crown ethers in general. The possible mechanisms for the interaction between compound-o and the chiral crown ether were investigated using CE, electrospray MS (ESI-MS), and proton ((1)H) NMR spectroscopy. All experiments provided clear evidence that binding between compound-o and the chiral crown ether had occurred. ESI-MS spectra indicated that the complexes had a 1:1 stoichiometric ratio. The advantages and disadvantages of using chiral crown ether for stereoisomeric separations were compared with those using sulfated CDs.     

Separation of enantiomers of ephedrine by capillary electrophoresis using cyclodextrins as chiral selectors: comparative CE, NMR and high resolution MS studies

The enantiomer migration order (EMO) of ephedrine was investigated in the presence of various CDs in CE. The molecular mechanisms of chiral recognition were followed for the ephedrine complexes with native α- and β-CD and heptakis(2,3-di-O-acetyl-6-O-sulfo)-β-CD (HDAS-β-CD) by CE, NMR spectroscopy and high-resolution MS. Minor structural differences were observed between the complexes of ephedrine with α- and β-CD although the migration order of enantiomers was opposite when these two CDs were applied as chiral selectors in CE. The EMO was also opposite between β-CD and HDAS-β-CD. Significant structural differences were observed between ephedrine complexes with the native CDs and HDAS-β-CD. The latter CD was advantageous as chiral CE selector not only due to its opposite electrophoretic mobility compared with that of the cationic chiral analyte, but also primarily due to its enhanced chiral recognition ability towards the enantiomers of ephedrine.     

Study on the inclusion behavior and solid inclusion complex of 5-amino-6-methyl-2-benzimidazolone with cyclodextrins

The inclusion behaviors of three native or modified CDs including p-CD,2-hydroxypropyl-β-CD(2-Hp-β-CD) and 2,6-dimethyl-β-CD(Me-β-CD) toward 5-amino-6-methyl-2-benzimidazolone(AMBI) were comparatively investigated by NMR and fluorescence titration in combination with IR spectra,X-ray diffractometry and scanning electron microphotographs.The experimental results jointly demonstrated that the phenyl ring of AMBI entered into the cavity of the CDs and located close to the narrow rims accompanied by the formation of the 1:1 inclusion complex with large stability constant in aqueous solution.The introduction of the hydroxypropyl unit to the host improved the solubility,ultimately effecting an obvious promoting in the fluorescence intensity and the stability constant     

Inclusion complexes of dihydroartemisinin with cyclodextrin and its derivatives: characterization,solubilization and inclusion mode

The characterization, inclusion complexation behavior and binding ability of the inclusion complexes of dihydroartemisinin with β-cyclodextrin and its derivatives, sulfobutyl ether β-cyclodextrin (SBE-β-CD), mono[6-(2-aminoethylamino)-6-deoxy]-β-cyclodextrin (en-β-CD) and mono{6-[2-(2-aminoethylamino)ethylamino]-6-deoxy}-β-cyclodextrin (dien-β-CD), were studied using phenolphthalein as a spectral probe. Spectral titration was performed in aqueous buffer solution (pH ca. 10.5) at 25 °C to determine the binding constants. The inclusion complexation behaviors were investigated in both solution and solid state by means of NMR, TG, XRD. The results showed that the water solubility and thermal stability of dihydroartemisinin were significantly increased in the inclusion complex with cyclodextrins (CDs). According to ¹H NMR and 2D NMR spectroscopy (ROESY), the A, B rings of dihydroartemisinin can be included into the cavity of CDs. The enhanced binding ability of CDs towards dihydroartemisinin was discussed from the viewpoint of the size/shape-fit concept and multiple recognition mechanism between host and guest.     

Host–guest complexation of omeprazole, pantoprazole and rabeprazole sodium salts with cyclodextrins: an NMR study on solution structures and enantiodiscrimination power

The application of different cyclodextrins (CDs) as NMR chiral solvating agents (CSAs) for the sodium salts of the proton-pump inhibitors omeprazole, pantoprazole (sesquihydrate) and rabeprazole was investigated. It was proved that the formation of diastereomeric host–guest complexes in D₂O solution between the CDs and those substrates permitted the direct ¹H NMR discrimination of the enantiomers of the sodium salts of these compounds without the need of previous working-up. Rotating frame nuclear overhauser effect spectroscopy (ROESY) was used to ascertain the solution geometries of the host–guest complexes. The results suggested a preferential binding of the benzimidazole moiety of the guest molecules within the macrocyclic cavity of α-CD, whereas the higher dimensions of β- and γ-CD also permitted the inclusion of the highly substituted pyridine moieties. Moreover, the solution stoichiometries and the binding constants of the complexes formed with pantoprazole at room temperature were determined by ¹H and ¹⁹F NMR titration. Diffusion-filtered Spectroscopy was applied to obtain clean spectra without the interference of the HOD signal.     

Study of the complexation of different methacrylates with cyclodextrins employing a combination of electrophoretic, chromatographic, and NMR-spectroscopic methods

The present study describes the application of capillary electromigration techniques; CEC and micellar EKC (MEKC), and the application of spectroscopic methods; 1H NMR and 1H NOESY spectroscopy to investigate interactions between CDs (alpha-CD, statistically methylated beta-CD, hydroxypropyl-beta-CD, and 2-hydroxypropyl-gamma-CD) and different methacrylates (adamantyl, isobornyl, cyclohexyl, and phenyl methacrylate). It is shown that these methods complement each other. While CD-mediated MEKC is a rapid screening technique for comparing complex stabilities in aqueous media, 1H NMR chemical shift analysis provides quantitative data for very strong methacrylate-CD complexes and CD-mediated CEC provides quantitative data for complexes with lower complex forming constants. CD-mediated MEKC did not prove to be suitable for the calculation of complex forming constants. Reasons are discussed. 1H NOESY spectra were used to study spatial relationships between host and guest atoms.     

Separation of brombuterol enantiomers in capillary electrophoresis with cyclodextrin‐type chiral selectors and investigation of structure of selector‐selectand complexes using nuclear magnetic resonance spectroscopy

The major goal of this study was to determine the affinity pattern of brombuterol (BB) enantiomers toward various cyclodextrins (CD) and to evaluate the potential of NMR spectroscopy for understanding fine mechanisms of interactions between CDs and BB enantiomers. Separation of BB enantiomers was performed in a fused‐silica capillary using a phosphate buffer, pH 2.5, at the room temperature in the normal polarity mode. It was shown once again that CE in combination with NMR spectroscopy represents a very sensitive tool for studies of affinity patterns and structure of CD complexes with chiral guests. Although opposite affinity patterns of BB enantiomers were observed toward native β‐ and γ‐CDs, no significant differences between the structures of the complexes of these two CDs with BB were detected by NMR spectroscopy. In contrary to this, the opposite affinity pattern of BB enantiomers toward β‐CD and its two sulfated derivatives, heptakis (2,3‐O‐diacetyl‐6‐sulfo)‐β‐CD (HDAS‐β‐CD) and heptakis (2‐O‐methyl‐3,6‐di‐O‐sulfo)‐β‐CD (HMDS‐β‐CD) was associated with major differences in the structure of the complexes. In addition, it was shown again that HMDS‐β‐CD provides separation of enantiomers without formation of inclusion‐type complex with the chiral analyte.     

Synthesis, Crystal, Calculated Structure and Biological Activity of N-（（6-bromo-2-methoxyquinolin-3-yl）（phenyl） methyl）-N-（1-adamantyl）-3-（dimethylamino） Propanamide

The halogenated hydrocarbon amination reaction between the original raw material N-((6-bromo-2-methoxyquinolin-3-yl)(phenyl)methyl)-3-chloro-N-(1-adamantyl) propanamide and dimethylamine hydrochloride produces the target molecule N-((6-bromo-2-methoxyquinolin-3- yl)(phenyl)methyl)-N-(1-adamantyl)-3-(dimethylamino) propanamide (C32H38BrN3O2, Mr = 576.56), and its structure was confirmed by elemental analysis, IR, 1H NMR, MS, and X-ray diffraction. This crystal is of monoclinic system, space group P21/c with a = 10.760(5), b = 14.768(5), c = 19.635(5), β = 113.969(16)°, V = 2851.0(18)3, Z = 4, Dc = 1.343 g/cm3, F(000) = 1208, μ(MoKα) = 1.475 mm-1, the final R = 0.0645 and wR = 0.2039. In total, 4681 independent reflections including 3164 observed ones with I > 2σ(I) were collected. The dihedral angle between substituted quinolyl and phenyl is 64.0°. Through C-H···O, C-H···N and C-H···Br weak hydrogen bonds among molecules, the whole molecule is stacked into a three-dimensional structure. The optimized geometric bond lengths and bond angles obtained by using density functional theory (DFT) have been compared with X-ray diffraction values. In addition, the preliminary biological test showed that the title compound has anti-Mycobacterium phlei 1180 activity.     

CpRu((R)-Binop-F)(H2O)][SbF6], a new fluxional chiral Lewis acid catalyst: synthesis, dynamic nmr, asymmetric catalysis, and theoretical studies

The C(2)-symmetric electron-poor ligand (R)-BINOP-F (4) was prepared by reaction of (R)-BINOL with bis(pentafluorophenyl)-phosphorus bromide in the presence of triethylamine. The iodo complex [CpRu((R)-BINOP-F)(I)] ((R)-6) was obtained by substitution of two carbonyl ligands by (R)-4 in the in situ-prepared [CpRu(CO)(2)H] complex followed by reaction with iodoform. Complex 6 was reacted with [Ag(SbF(6))] in acetone to yield [CpRu((R)-BINOP-F)(acetone)][SbF(6)] ((R)-7). X-ray structures were obtained for both (R)-6 and (R)-7. The chiral one-point binding Lewis acid [CpRu((R)-BINOP-F)][SbF(6)] derived from either (R)-7 or the corresponding aquo complex (R)-8 activates methacrolein and catalyzes the Diels-Alder reaction with cyclopentadiene to give the [4 + 2] cycloadduct with an exo/endo ratio of 99:1 and an ee of 92% of the exo product. Addition occurs predominantly to the methacrolein C(alpha)-Re face. In solution, water in (R)-8 exchanges readily. Moreover, a second exchange process renders the diastereotopic BINOP-F phosphorus atoms equivalent. These processes were studied by the application of variable-temperature (1)H, (31)P, and (17)O NMR spectroscopy, variable-pressure (31)P and(17)O NMR spectroscopy, and, using a simpler model complex, density functional theory (DFT) calculations. The results point to a dissociative mechanism of the aquo ligand and a pendular motion of the BINOP-F ligand. NMR experiments show an energy barrier of 50.7 kJ mol(-1) (12.2 kcal mol(-1)) for the inversion of the pseudo-chirality at the ruthenium center.     

Chromatographic resolution, solution and crystal phase conformations, and absolute configuration of tert-butyl(dimethylamino)phenylphosphine-borane complex

The enantiomers of tert-butyl(dimethylamino)phenylphosphine-borane complex 2 have been separated by HPLC using cellulose tris-p-methylbenzoate as chiral stationary phase. The borane protection could be removed without racemization and the P-configuration of the free aminophosphine 1 has shown to be stable in solution. Infrared (IR) and vibrational circular dichroism (VCD) spectra have been measured in CD2Cl2 solution for both enantiomers. B3LYP/6-31+G(d) DFT calculations allowed a prediction that complex (S)-2 exists as three conformers in equilibrium and computed population-weighted IR and VCD spectra. Predicted and experimental IR and VCD spectra compared very well and indicate that enantiomer (+)-2 has the S absolute configuration. This assignment has been confirmed by an X-ray diffraction study on a single crystal of (+)-2. The crystal structure of enantiomerically pure 2 appears to be very close to the most stable computed conformer which proved to be predominant in solution.