Highly enantioselective kinetic resolution of primary alcohols of the type Ph-X-CH(CH3)-CH2OH by Pseudomonas cepacia lipase: effect of acyl chain length and solvent

Although lipase from Pseudomonas cepacia (PCL) shows high enantioselectivity towards many secondary alcohols, it usually exhibits only low to moderate enantioselectivity towards primary alcohols. To increase this enantioselectivity, we optimised the reaction conditions for the PCL-catalysed hydrolysis of esters of three chiral primary alcohols: 2-methyl-3-phenyl-1-propanol 1, 2-phenoxy-1-propanol 2 and solketal 3. The enantioselectivity towards 1-acetate increased from E=16 to 38 upon changing the solvent from ethyl ether/phosphate buffer to 30% n-propanol in phosphate buffer and increased again to E ≥190 upon changing the substrate from 1-acetate to 1-heptanoate. The same changes increased the enantioselectivity towards alcohol 2 from E=17 to 70, but did not significantly increase the enantioselectivity towards alcohol 3. The best solvent was similar to the solvent used to crystallise the open form of PCL and likely stabilises the open form of PCL. This stabilisation may increase the enantioselectivity by removing kinetic contributions from a non-enantioselective lid-opening step. We determined the kinetic contribution of the lid-opening step by measuring the interfacial activation of PCL. The activation energy for the PCL-catalysed hydrolysis of ethyl acetate was at least 2.6 kcal/mol lower in the presence of a water–organic solvent interface.     

Extraordinary chiral discrimination in inclusion gas chromatography. Thermodynamics of enantioselectivity between a racemic perfluorodiether and a modified γ-cyclodextrin

The enantiomers of the perfluorodiether “compound B” [2-(fluoromethoxy)-3-methoxy-1,1,1,3,3-pentafluoropropane], a decomposition product of the inhalational anesthetic sevoflurane [2-(fluoromethoxy)-1,1,1,3,3,3-hexafluoropropane], were separated by gas chromatography on octakis(3-O-butanoyl-2,6-di-O-n-pentyl)-γ-cyclodextrin (Lipodex E), dissolved in polysiloxane PS 255 (30% w/w), with an unexpectedly high separation factor of =10.6 at 26 °C. Using the concept of the retention increment R′, non-enantioselective and enantioselective contributions to retention were separated and thus reliable thermodynamic parameters of enantioselectivity, i.e. −Δ_S,R(ΔG)=5.7 (0.05) kJ/mol at 303 K, −Δ_S,R(ΔH)=20.1 (0.64) kJ/mol, Δ_S,R(ΔS)=−47.4 (2.0) J/K mol and T_isoenant=424 (30) K or 150 °C, were determined by temperature-dependent measurements. The enantiomeric bias represents the largest values ever measured in enantioselective gas chromatography. An equation is presented which allows calculation of the non-enantioselective contributions to retention from measurements at two arbitrary concentrations of Lipodex E in polysiloxane. Surprisingly, the enantioselectivity is greatly reduced when employing the β-cyclodextrin analogue and breaks down completely with the -cyclodextrin analogue of Lipodex E.     

6,6′-Bisperfluoroalkylated BINOLs promoted asymmetric allylation of aldehydes

6,6′-Bis(1H, 1H, 2H, 2H-perfluorooctyl)-1, 1′-bi-2-naphthol (Rf₆-BINOL) and 6,6′-bis(1H, 1H, 2H, 2H-perfluorodecyl)-1,1′-bi-2-naphthol (Rf₈-BINOL) were used in allylation of aldehydes in fluorous biphase system. Good enantioselectivity was obtained and the ligands could be recovered by continuos liquid–liquid extraction.     

Transformation of (+)-thiomicamine into a new ligand for the enantioselective addition of methyllithium to prochiral imines

A new ligand 2 was prepared from (+)-thiomicamine 1 and o-methoxyphenol, and its activity as an external controller of stereochemistry in enantioselective additions of methyllithium to prochiral imines 8–10 tested. The non-racemic secondary amines 11–13 were prepared in 60–90% chemical yield with the enantioselectivity ranging from 2 to 41%. 6,7-Dimethoxy-3,4-dihydroisoquinoline 8 was transformed into (+)-salsolidine 11 with an e.e. of 41%.     

Effectivity of solvents-A new approach in non-aqueous acid-base titrimetry

A new approach for selection of a suitable solvent system as a medium for non-aqueous acid—base titration is proposed. The essence of the approach is the development of a new criterion called “effectivity”. The latter is based on consequences of the Brønsted and Izmailov acid—base theories and represents a quantitative measure for improving or worsening the titration conditions of acids and bases in non-aqueous solvents as compared with water. The “effectivity” E is given by the relation E = ΔpK_s - ΔpK_s where ΔpK_s is the difference between the logarithmic values of the autoprotolysis constants of water and the solvent in question, and ΔpK is the so-called medium effect. The latter is a constant value which shows that acids and bases with the same charge alter their strength to the same extent when transferred from water into a non-aqueous solvent. The medium effect is calculated by statistical treatment of a great number of acid—base constants determined experimentally both in water and the non-aqueous solvent in question. The effectivity of the solvents most often used in non-aqueous acid—base titrimetry, determined by this approach, shows that in many cases these solvents offer significant advantages over water, but drawbacks are also observed. Some limitations of the approach are discussed. Special attention is paid to dimethylsulphoxide and its mixtures with water, which prove to be highly effective media for the acid—base titration of many substances.     

Catalytic and structural studies of Rh complexes of (−)-(2S,4S)-2,4-bis(diphenylphosphino)pentane. Asymmetric hydrogenation of acetophenonebenzylimine and acetophenone

Rhodium(I) complexes formed by (−)-(2S,4S)-2,4-bis(diphenylphosphino)pentane (BDPP) are efficient catalysts for the hydrogenation of acetophenone and acetophenonebenzylimine. The composition of the solvent mixture and the reaction temperature have a marked influenced on the enantioselectivity. These effects are thought to be related to the enhanced conformational flexibility of six-membered rings when simple substrates without functional groups are coordinated to the rhodium. X-ray crystallographic studies reveal that in [Rh((S,S)-BDPP)NBD]⁺ (1) the ligand is in a chair conformation, and that in [Rh((S,S)-BDPP)COD]⁺ (2) the chelate ring is in a δ-skew conformation. Studies of Rh((S,S)-BDPP)(NBD)Cl (3) in solution indicate a trigonal bipyramidal structure with a chair conformation of the ring in aromatic solvents and a conformationally labile ring in methanol.     

A convenient stereoselective synthesis of (R)-(−)-denopamine and (R)-(−)-salmeterol

β-Adrenoreceptor agonists (R)-(−)-denopamine (R)-1 and (R)-(−)-salmeterol (R)-2 have been prepared in good overall yield and high enantioselectivity through a biotransformative pathway.     

Chiral sulphonated phosphines : II. Influence of water on the enantioselectivity in the reduction of dehydro-aminoacids

For the reduction of dehydro aminoacids in various media with rhodium complexes containing chiral ligands, a linear correlation of log %S/%R with the solvophobicity parameter S_p has been observed. The decrease in enantioselectivity in water is due to the high interfacial energy of this solvent.     

The nature of the structure difference between light and heavy water and the origin of the solvent isotope effect—I

The observed differences in heat content, entropy and free energy of light and heavy liquid water can be calculated within experimental error from measured infrared frequencies, using a model for water with tetrahedral hydrogen bonding and treating the hindered rotations (librations) of the water molecules as three-dimensional isotropic harmonic oscillators. The origin of the solvent isotope effect for monatomic ions in light and heavy water is their effect on the structure difference between light and heavy water. The quantity Δθ = h Δν/k provides a measure of this structure difference, where Δν is ν−ν′, the difference in average values of the librational frequencies of H₂O and D₂O, and ν′=ν/1·3815. Differences in heat content, entropy and free energy for solution of monatomic ions in light and heavy water and individual ionic activity coefficients can be calculated from Δθ. Hydronium and hydroxide ions are also discussed.     

Asymmetric hydroformylation with Pt-phosphine-SnCl2 and Pt-bisphosphine-CuCl2 (or CuCl) catalytic systems

A study has been made of asymmetric hydroformylation of styrene with PtCl₂(PPh₃)₂ + bisphosphine + SnCl₂ (bisphosphine: BDPP = (−)-(2S,4S)-2,4-bis(diphenylphosphino)pentane or DIOP = (−)-(4R,5R)-2,2-dimethyl-4,5-bis(diphenylphosphinomethyl)-1,3-dioxolane) and PtCl₂(bisphosphine) + PPh₃ + SnCl₂ catalysts prepared “in situ”. The presence of an excess of the phosphine ligand slightly lowered the reaction rate, but the enantioselectivity of these systems is significantly higher than those involving PtCl(SnCl₃)(bisphosphine) catalysts. Under mild reaction conditions 88.8% enantiomeric excess was achieved. Replacing SnCl₂ in these catalysts by CuCl₂ or CuCl gave a new homogeneous catalytic system which is active at higher reaction temperature (> 100°C), but has a rather moderate enantioselectivity.     

Asymmetric hydrogenation - influence of the structure of carbohydrate derived catalysts on the relative enantioselectivity QH/Me regarding acid and ester substrates and its inversion - selectivity increase in water by amphiphiles

4,6-O-Benzylidene protected 2,3-bis(O-diphenylphosphino)-δ-glycopyranoside rhodium(I) chelate precatalysts 1-4 e,f showed for the hyrogenation of methyl (Z)-2-N-acylamidoacrylates 6-8 a stepwise decrease of the enantioselectivity with increasing number of axially oriented hexopyranoside substituents. The decrease is even stronger for the analogous substrate acids 6h-8h resulting in an unusual low relative enantioselectivity Q=q_H/q_Me of 0.3 for the precatalysts 4e and 4f. Deprotected, 4,6-OH-group bearing catalysts 1-4g,h generally show smaller differences of %ee in methanol or benzene, however, not in water. Under addition of amphiphiles a in comparison with blanks b the relative enantioselectivity Q=q_a/q_b clearly increases for both groups of catalysts - in most cases to Q-values between 3 up to 8 - independent of a neutral or ionic nature of the amphiphile.     

深共熔溶剂同步提取红景天中红景天苷和酪醇

采用深共熔溶剂(Deep eutectic solvents, DESs)法同步提取红景天中红景天苷和酪醇. 首先, 通过对氢键供体(HBD)、 氢键受体(HBA)及二者摩尔比和DESs含水量等因素的设计优化, 获得了同步提取红景天苷和酪醇的最佳DES为乙二醇-乙酰丙酸(摩尔比为1∶1), 含水质量分数为40%, 记为LAEG-40. 然后, 以LAEG-40作提取溶剂, 对提取方法、 料液比、 提取温度及提取时间等因素进行优化, 获得了最佳提取条件: 采用150 r/min搅拌速率提取, 料液比为1∶12.5(g/mL), 提取温度60 ℃, 提取时间65 min. 在此条件下LAEG-40对红景天苷的提取率可达(18.1268±0.1667) mg/g, 酪醇提取率可达(1.5608±0.0240) mg/g. 而在相同条件下, 以水和乙醇作为提取溶剂, 红景天苷提取率分别为(15.1221±0.1342)和(16.3425±0.0897) mg/g, 酪醇提取率分别为(1.1120±0.0389)和(1.1923±0.0423) mg/g, 可见LAEG-40的提取效果明显高于传统溶剂. 研究结果表明, LAEG-40是一种绿色、 高效的红景天苷和酪醇同步提取溶剂, 可用于替代传统溶剂.     

Liquid-phase fluorination of aromatic compounds by elemental fluorine

The fluorination of aromatic compounds (benzene, toluene, phenol and benzoic acid) by elemental fluorine diluted with nitrogen has been investigated in various solvents (Freon 11, chloroform, methanol, trifluoroacetic acid, 2,2,2-trifluoroethanol, water) in order to define the influence of the experimental conditions on the reaction. Experiments have been carried out by varying the temperature, the substrate concentration in solution, the molar ratio of fluorine to substrate, and the concentration of fluorine in the fluorine/nitrogen mixture. In all cases, the effects on the yield of fluorinated products were studied. Monofluorinated compounds were mainly found in the reaction mixture, the isomers formed being in accord with the mechanism for electrophilic substitution. The highest yield of monofluorinated products was obtained with polar solvents and the following order was found: CFCl₃ < CHCl₃ < CH₃OH < CF₃CH₂OH < CF₃COOH. Interesting results were also found using particular additives (for instance, KOH or C₄F₉SO₃Na in methanol) or water as the solvent. A direct relationship was observed between the yield of monofluorinated compounds and the molar ratio of fluorine to substrate, which has to be less than one in order to obtain high yields. In contrast, low selectivity, expressed as the yield ratio of ortho to para (or meta) isomers, was found.     

Enzyme catalytic promiscuity: asymmetric aldol addition reaction catalyzed by a novel thermophilic esterase in organic solvent

The asymmetric aldol addition of 2-butanone and 4-nitrobenzaldehyde catalyzed by a novel thermophilic esterase (APE1547) from the archaeon Aeropyrum pernix K1 was successfully conducted in organic solvents. APE1547 exhibited a good enzyme activity and enantioselectivity in the reaction. The effects of organic solvent, temperature, water content, and substrate concentration were investigated. The reaction provided optically active secondary alcohol with satisfying enantioselectivity (71.2 %ee) and enzyme activity (38.1 µmol/g/h) under the optimum conditions. A high yield (68.7%) could be obtained when the reaction time was approximately 120 h.     

Synthesis of enantiopure (R)-(−)-massoialactone through ruthenium-SYNPHOS asymmetric hydrogenation

Total synthesis of enantiopure (R)-(−)-massoialactone was achieved. The key step includes the asymmetric hydrogenation of an achiral β-keto ester using a ruthenium-SYNPHOS^® catalyst to set the hydroxyl function in a stereocontrolled manner with excellent enantioselectivity (>99% ee). Ring closing metathesis (RCM) in the presence of Grubbs’ catalyst allows the final construction of the six-membered lactone.     

有序介孔Ru-MgZr复合氧化物合成及催化亚油酸异构化性能

筛选高效、高选择性多相催化剂异构化亚油酸是共轭亚油酸(CLA)研究的重点。 本文采用溶剂挥发自组装改进的溶胶-凝胶法,合成有序介孔Ru掺杂的MgO-ZrO₂固体碱催化剂。 考察了催化剂中不同Mg物质的量对催化剂孔径、比表面积和表面碱性以及Ru等的结构和性能对催化性能的影响。 对比了催化剂的形貌、表面碱性及Ru组分对催化性能的影响程度。 结果表明,n(Zr)∶n(Mg)=3∶1时,Ru掺杂的MgO-ZrO₂固体碱催化剂具有高度有序的介孔结构和高的比表面积。 而n(Zr)∶n(Mg)=1∶1时, MgO-ZrO₂固体碱催化剂合成CLA产率较高,反应时间4 h,产率达到85%,催化效率为0.099 g(CLA)·L^-1(solvent)·min^-1,并且催化产物主要为具有生物活性的3种共轭亚油酸异构体。 催化剂的强碱性位点和晶格Ru是催化异构化反应的两个活性位点,强碱性位点是提高催化性能的关键。 固体碱复合氧化物催化效率高、制备方法简单、反应产物生物活性高等优点,具有较好的应用前景。     

Simultaneous separation of the enantiomers of cizolirtine and its degradation products by capillary electrophoresis

The simultaneous enantioselective separation of (±)-cizolirtine and its impurities: (±)-N-desmethylcizolirtine, (±)-cizolirtine-N-oxide and (±)-5-(-hydroxybenzyl)-1-methylpyrazole was investigated by capillary electrophoresis. Electrokinetic chromatography with carboxymethyl-β-CD (CM-β-CD) and sulfobutyl-ether-β-CD was tried, showing good enantioseparation but poor chemical selectivity. The four racemic pairs were baseline separated, in a single run, by cyclodextrin-modified micellar electrokinetic chromatography. The migration buffer composition was: (60 mM hydroxypropyl-β-cyclodextrin–150 mM sodium dodecyl sulfate–50 mM disodium tetraborate, pH 9.2, in water)–butanol (95:5, v/v). Work was done to determine the effect of buffer components and their optimal concentration on selectivity. The method was validated with respect to enantioselectivity of cizolirtine as well as its degradation products and separation selectivity between the different components. Linearity, limit of detection, limit of quantitation and precision were also determined. This method is suitable for the enantiomeric purity determination and stability control of cizolirtine (racemic mixture or enantiomers) and its degradation products. Examples of electropherograms of (R)-cizolirtine degraded under stressed conditions are shown.     

Surface charge and surface chemical characteristics of magnetites substituted with nickel, cobalt and chromium

Magnetite (MAG) and magnetites substituted with nickel, cobalt and chromium (NF, COF and CRF, respectively) have been prepared over the whole range of composition, Me_xFe_3−xO₄ (x=0–3, Me=Ni, Co or Cr) using the coprecipitation technique and have been characterized for their chemical composition, crystallinity and surface area. The types of sorption sites present in them were characterized by analysing the water sorption isotherms ultilizing the D'Arcy and Watt equation. Intrinsic dissociation constants, and point of zero charge, PZC, were evaluated by analysing the pH-titration curves in acid and alkaline media. A similarity in the trend was observed for the crystallinity, surface area, sorption sites and surface charge characteristics as a function of the composition of the substituted MAGs (i.e. x). The overall behaviour of the substituted MAGs could be grouped into two: mixed oxides having composition with x=0–1 and those in the composition region x=1–3. Those in the composition region x=0–1 were crystalline with a lower surface area, less hydrophilic in nature and have surface charge characteristics lower than that of MAG. Those mixed oxides in the composition region x=1–3 nearly had the opposite characteristics, with increasing value of x. The hydrophilicity of the substituted MAGs decreased in the sequence CRF>NFCOF, and the acidic nature decreased in the sequence NF>CRF>COF.     

Subcellular localization of docosahexaenoic acid and arachidonic acid ω-hydroxylation activity in the brain, liver and colonic adenocarcinoma

A homogenate of rat brain, rat liver or human colonic well differentiated adenocarcinoma was prepared in 250 mM sucrose isoosmolaric buffer (pH 7.6) and fractionated by differential centrifugation at 10³, 10⁴ and 10⁵ g. Each precipitate or supernatant was incubated with NADPH and docosahexaenoic acid or arachidonic acid as a substrate for 30 min at 37°C under aerobic conditions. ω-Hydroxydocosahexaenoic acid or ω-hydroxyeicosatetraenoic acid from an incubation mixture was detected by reversed-phase high-performance liquid chromatography-thermospray mass spectrometry with selected-ion monitoring. ω-Hydroxy polyunsaturated fatty acids were characterized by high intensity of the molecular ion (MH⁺) although common hydroxy polyunsaturated fatty acids were characterized by high intensity of the MH⁺ - H₂O ion. For the rat brain, ω-hydroxylation activity (the amount of ω-hydroxy product produced in 30 min) was concentrated to a 103 g precipitate although the specific activity (the activity per 1 mg of protein) in the 10³ g precipitate did not indicate superiority over other fractions. However, the specific activity of the rat brain increased on addition of a 10⁴ or 10⁵ g precipitate. For the rat liver, although ω-hydroxylation activity was concentrated to a 10³ g precipitate, the specific activity was concentrated to a 10⁵ g precipitate and the Subcellular localization differed from that of rat brain. In the human colonic well differentiated adenocarcinoma, although ω-hydroxylation activity was relatively high in the 10³ g supernatant, the specific activity was relatively high in the 10³ and 10⁵ g precipitates. These results suggest that there is a difference regarding subcellular localization of the ω-hydroxylation activity depending on the species of the organs.