微水相中改性Ultrastable-Y分子筛固定化脂肪酶拆分(R,S)-2-辛醇

采用改性Ultrastable-Y分子筛固定化P. expansum PED-03脂肪酶(PEL), 利用固定化PEL在微水相中对(R,S)-2-辛醇进行拆分. 结果表明, 改性Ultrastable-Y分子筛固定化PEL所催化的拆分反应的转化率(c)和对映体过量值(e.e.)以及对映体选择性(E)均得到大幅度提高. 介质类型和体系含水量对酶促拆分反应有较大的影响. 在以正己烷为溶剂, 含水量为0.8%的体系中, 于50 ℃反应24 h的转化率(c)可达到理论值的97.68%, 对映体过量值(e.e.)可达到98.75%. 改性Ultrastable-Y分子筛固定化PEL催化效率高、立体选择性强, 且催化性能稳定, 在(R,S)-2-辛醇的酶法拆分方面具有良好的应用前景.     

ENZYME CATALYSIS IN DIFFERENT GELATIN GELS

Enzymes in microemulsions, liposomes, aqueous monomer surfactant solutions or pure water have been entrapped in gelatin-based gels. These gels have been used as minireactors for stereoselective resolution of racemic 2-octanol in esterifications with alkanoic acids or in transesterifications with vinyl butyrate. The microstructures were stabilized by the anionic surfactant sodium 1,4-bis(2-ethylhexyl) sulfosuccinate (AOT) or the zwitterionic surfactant soybean lecithin. The enzymes used were commercial lipases from Chromobacterium viscosum or Candida antarctica (SP 525). The incubation temperature was 298.2 K. The enantiomeric excess (e.e.) values were high in all systems studied, but the reaction rates depended on the gel used. In AOT-stabilized and in ethanol-free lecithin-stabilized gels the conversion was close to 0.45. However, in the ethanol-containing lecithin gels, the conversion was lower and decreased with increased ethanol content, due to competing reactions. In the hydrogels, the conversion and e.e. values were high, but the reaction rates were low.     

Biphasic asymmetric hydroformylation and hydrogenation by water-soluble rhodium and ruthenium complexes of sulfonated (R)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl in ionic liquids

A biphasic catalytic system with water-soluble rhodium complexes of sulfonated (R)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (labeled as (R)-BINAPS) in ionic liquid BMI·BF₄ has been developed for the asymmetric hydroformylation of vinyl acetate under mild conditions. The corresponding ruthenium complexes have been investigated for the biphasic asymmetric hydrogenation of dimethyl itaconate. The biphasic asymmetric hydroformylation of vinyl acetate provided 28.2% conversion and 55.2% enantiomeric excess when BMI·BF₄–toluene was used as the reaction medium at 333 K and 1.0 MPa for 24 h. The biphasic asymmetric hydrogenation of dimethyl itaconate in BMI·BF₄–ⁱPrOH at 333 K and 2.0 MPa afforded 65% enantiomeric excess with an activity similar to the homogenous analogs. Both biphasic catalytic systems with (R)-BINAPS ligand could be reused several times without significantly decrease in the activity, enantio- and regio-selectivities. The effects of properties of ionic liquid, molar ratio of ligand to rhodium, temperature, pressure and reaction time have been discussed.     

Lipase-catalyzed kinetic resolution of cis-1-diethylphosphonomethyl-2-hydroxymethylcyclohexane. Application to enantioselective synthesis of 1-diethylphosphonomethyl-2-(5′-hydantoinyl)cyclohexane

A kinetic resolution of cis-1-diethylphosphonomethyl-2-hydroxymethylcyclohexane1 by lipase has been developed. The transesterification of (±)−1 with vinyl acetate in the presence of Lipase AK without solvent proceeded to give (+)−1 and the corresponding acetate (+)−5 in good yield and high enantiomeric ratio. The alcohol (+)−1 was transformed to the optically active hydantoins 12 and 13, possible intermediates for the synthesis of conformational constrained analogues of AP-5.     

Reactivity and enantioselectivity in the reactions of scalemic stereogenic alpha-(N-carbamoyl)alkylcuprates

Stereogenic 2-(N-carbamoyl)pyrrolidinylcuprates prepared from scalemic (i.e., enantioenriched) N-Boc-2-lithiopyrrolidine and THF soluble CuCN.2LiCl react with vinyl iodides, vinyl triflates, beta-iodo-alpha,beta-enoates, propargyl mesylates, and allyl bromide to afford the substitution products with excellent enantioselectivity. Excellent enantiomeric ratios are obtained in the conjugate addition reactions with methyl vinyl ketone while low enantiomeric ratios can be achieved with acrylate esters using HMPA/TMSCl activation. Enantiomeric ratios vary with substrate substitution patterns and the observed enantioselectivities appear to be more a function of cuprate-electrophile reactivities than of the reaction type (e.g., substitution, conjugate addition). Low enantiomeric ratios are obtained with the alpha-(N-carbamoyl)benzylcuprates. The lithium-copper transmetalation and cuprate vinylation reactions proceed with retention of configuration.     

`Watching' lipase-catalyzed acylations using 1H NMR: competing hydrolysis of vinyl acetate in dry organic solvents

Lipase-catalyzed acetylations of 1-phenylethanol with vinyl acetate were monitored in situ by ¹H NMR spectroscopy. Surprisingly, even under dry conditions (no added water) the major reaction was hydrolysis of the vinyl acetate, not acetylation of the substrate. Because this competing hydrolysis consumes water and releases acetic acid, the reaction conditions in lipase-catalyzed acylations are not constant, but vary with the reaction time. Addition of a chiral shift reagent reveals the enantiomeric purity of the starting alcohol and allows calculation of the enantiomeric ratio, E, for the reaction.     

Enzymatic desymmetrization of a meso polyol corresponding to the C(19)-C(27) segment of rifamycin S

The stereoselective acylation of meso polyol 2 by vinyl acetate (solvent and acyl donor) in the presence of porcine pancreas lipase gave the corresponding monoester 5 in good yield (76%) and high enantiomeric purity (ee > 98%). The enzymatic reaction was also highly regioselective for a primary alcohol end group, and the two unprotected secondary alcohols were not involved. Compound 5 corresponds to the C(19)-C(27) fragment of rifamycin S.     

Chiral synthesis of functionalized tetrahydropyridines: gamma-aminobutyric acid uptake inhibitor analogues

[Chemical reaction: See text] A convenient preparation of functionalized chiral tetrahydropyridine-3-carboxylates from nitriles in 68-90% enantiomeric excess (ee) via allylboration, followed by a conjugate addition-elimination and ring-closing metathesis, has been developed. Thus, the treatment of the acetate derived from vinylalumination of formaldehyde by use of [alpha-(ethoxycarbonyl)vinyl]diisobutylaluminum with chiral beta-substituted and beta-unsubstituted homoallylic amines, prepared in >98% diastereomeric excess (de) and 68-90% ee via allylboration of the corresponding N-aluminoimines, furnished functionalized aminodienes, which underwent ring-closing metathesis to provide chiral C5-C6 disubstituted tetrahydropyridine-3-carboxylates. This methodology has been applied for the synthesis of a chiral C6-substituted tetrahydropyridine with known GABA-inhibiting properties at low concentrations.     

Lipase-catalyzed kinetic resolution approach toward enantiomerically enriched 1-(β-hydroxypropyl)indoles

In a route towards enantiomerically enriched 1-(β-hydroxypropyl)indoles, which are potentially useful building blocks for high value-added chemicals synthesis, a kinetic resolution approach by means of lipase-catalyzed enantioselective acylation as well as hydrolysis/methanolysis has been elaborated for the first time. The enzymatic resolution of chiral N-substituted indole-based sec-alcohols was successfully accomplished, yielding both enantiomeric forms of the employed derivatives with up to >99% enantiomeric purity via an enantioselective transesterification under mild reaction conditions. The most selective resolutions were obtained using fungal (CAL-B and TLL) and bacterial (PFL and BCL) lipases and vinyl acetate as the acyl?group donor. The synthetic protocol described herein is very simple, user-friendly and efficient, thus paving the way for future access towards more complex compounds of this type. The absolute configurations of novel enantiomeric derivatives, and thus stereoselectivity of the described enzymatic reactions were confirmed by application of CDA-based NMR methodology and single-crystal X-ray diffraction analysis.     

Macrocycles with sulfide and amine binding sites as chiral ligands for nickel catalyzed cross coupling of a grignard reagent with vinyl bromide

Synthetic routes to macrocycles derived from (S)-phenyl alanine and (S)-cysteine have been developed. The catalyzed coupling of the Grignard reagent of 1-chloro-1-phenylethane and vinyl bromide in the presence of these ligands proceeds usually in good yields and in enantiomeric excesses (e.e.) of up to 46%.     

Enantiomeric analysis of chiral compounds using phosphorus acid chlorides

New achiral separating bifunctional reagents, dichlorides of methylphosphonic and O-ethyl-thiophophoric acids, have been used for the quantitative determination of the enantiomeric composition of α-amino acids (alanine, valine, proline), secondary alcohols (2-octanol, 2-pentanol, 1-methoxy-2-propanol) and α-phenylethylamine. The determination of the enantiomeric composition of optically active α-amino acids, secondary alcohols, and amines is based on the transformation of compounds into symmetric diastereometers using organophosphorous achiral bifunctional reagents followed by the determination of the derivatives by gas chromatography with a mass spectral detector.     

Formal enantioselective synthesis of tacamonine starting from asymmetrized 2-substituted propane-1,3-diols

2-Substituted propanediols monoacetates, derived from enzymatic asymmetrization of the corresponding diols, have been obtained in high yields and enantiomeric excesses by using lipases and vinyl acetate as both solvent and acylating agent. These chiral building blocks have been transformed into the advanced intermediate 3, useful for the enantioselective synthesis of tacamane alkaloids.     

Enzymatic desymmetrization of meso cis,cis-2,4,6-substituted tetrahydropyrans

The stereoselective acylation of meso-tetrahydropyrans 6 and 7 by enol esters (vinyl acetate or isopropenyl acetate) in the presence of Candida antarctica lipase in organic media gave the corresponding (2R,4S,6S)-monoesters 10 and 11 in high enantiomeric purity. The hydrolysis of the corresponding diacetate derivatives 8 and 9 in the presence of the same enzyme provided the opposite enantiomers, (2S,4R,6R)-monoesters 10 and 11.     

Enantioselectivity of enzymatic acylation of some structurally various racemic alcohols in anhydrous aprotic media

Partial acylation of (R,S)-3,7-dimethyloctan-1-ol (1) and (R,S)-7-methoxy-3,7-dimethyloctan-1-ol (2) with vinyl acetate catalyzed by the lipase fromCandida cylindracea affords in good yields the correspondingS-configured acetates with 92–98% enantiomeric excess (ee). Under similar conditions, racemic α-cyclogeraniol (3), drim-7-en-11-ol, methyl 4-(3-hydroxy-2-methylpropyl)benzoate, and its η⁶-chromium(tricarbonyl) complex (6) are acylated with rather poor (and, for the two latter, opposite) enantioselectivity, whereas (R,S)-2,4∶3,5-di-O-benzylidenexylitol remains unaffected. Racemic isoborneol (8) and 2-nitro-1-phenylethanol also remain almost or completely unconverted. Attempts to perform enantioselective acylation of alcohols 3 and 8 with Ac₂O in the presence of porcine pancreatic lipase (PPL) proved equally unsuccessful. By contrast, the PPL-catalyzed acylation of alcohol 6 with vinyl acetate at 17% conversion affords the levorotatory acetate (S)-6a withca. 100%ee. PPL-Mediated partial acylation of (R,S)-pantolactone with Ac₂O, followed by mild deacylation of the resultingR acetate, gives (R)-(-)-pantolactone of 97% enantiomeric purity in 60% overall yield. Translated fromIzvestiya Akademii Nauk. Seriya Khimicheskaya, No. 1, pp. 175–186, January, 1997.     

Polymer particle formation in suspension polymerization of vinyl chloride and vinyl acetate

Equipment has been designed and assembled in such a way that direct microscopic observation of polymer particle formation in suspension polymerization of vinyl chloride and vinyl acetate is possible. The apparent mode of transformation from monomer droplets into polymer particles has thus been studied under two sets of conditions: (1) with agitation and (2) without agitation. In both cases, as the initial vinyl acetate/vinyl chloride ratio was raised, the apparent change in the shape and transparency of particles occurring during the course of polymerization became less evident. In vinyl chloride homopolymerization and vinyl acetate–vinyl chloride copolymerization with relatively high vinyl chloride concentrations, the polymer particles burst during the course of polymerization. Some factors which affect the change in the size of particles are also discussed.     

Dynamic kinetic resolution of secondary alcohols combining enzyme-catalyzed transesterification and zeolite-catalyzed racemization

Hydrophobic zeolite beta containing low concentrations of Zr or Al was found to be a good catalyst for the racemization of 1-phenylethanol. The formation of styrene as a side product could be minimized by reducing the metal concentration in the zeolite beta. Combined with an immobilized lipase from Candida antarctica, the dynamic kinetic resolution of 1-phenylethanol to the (R)-phenylethylester can be achieved with high yield and selectivity. The reaction was best conducted in toluene as solvent at 60 degrees C, with higher temperatures leading to a loss in the enantioselectivity of the formed ester. By using high-molecular-weight acyl-transfer reagents, such as vinyl butyrate or vinyl octanoate, a high enantiomeric excess of the product esters of 92 and 98 %, respectively, could be achieved. This is attributed to a steric effect: the bulky ester is less able to enter the pore space of the zeolite catalyst where the active sites for racemization are localized. Close to 100 % conversion of the alcohol was achieved within 2 h. If the more common acyl donor, isopropenyl acetate, was used, the enantiomeric excess (ee) of the formed ester was only 67 %, and the reaction was considerably slower.     

Immobilization of Pseudomonas fluorescens Lipase onto Magnetic Nanoparticles for Resolution of 2-Octanol

The lipase from Pseudomonas fluorescens (Lipase AK, AKL) was immobilized onto the magnetic Fe₃O₄ nanoparticles via hydrophobic interaction. Enzyme loading and immobilization yield were determined as 21.4?±?0.5?mg/g and 49.2?±?1.8?%, respectively. The immobilized AKL was successfully used for resolution of 2-octanol with vinyl acetate used as acyl donor. Effects of organic solvent, water activity, substrate ratio, and temperature were investigated. Under the optimum conditions, the preferred isomer for AKL is the (R)-2-octanol and the highest enantioselectivity (E?=?71.5?±?2.2) was obtained with a higher enzyme activity (0.197?±?0.01???mol/mg/min). The results also showed that the immobilized lipase could be easily separated from reaction media by the magnetic steel and remained 89?% of its initial activity as well as the nearly unchanged enantioselectivity after five consecutive cycles, indicating a high stability in practical operation.     

Enzymatic preparation of (1S,2R)- and (1R,2S)-stereoisomers of 2-halocycloalkanols

The stereoisomers of cis-2-halocycloalkanols were resolved by a kinetically controlled transesterification with vinyl acetate in the presence of lipases in organic media. High enantioselectivities (ee >98%) and good isolated yields were obtained for all substrates using the appropriate lipase. Burkholderia cepacia lipase was the most efficient enzyme for the resolution of these substrates. The enantiomeric purities of the compounds were defined by derivatization with Mosher’s acid and the absolute configurations were determined by chemical correlation.     

Lipase-catalyzed kinetic resolution of α-hydroxymethylcycloalkanones with a quaternary carbon center. Chemoenzymatic synthesis of chiral pseudoiridolactones

The resolution of α-alkyl-α-hydroxymethylcyclopentanones 1 and cyclohexanones 3 has been efficiently achieved by using lipase-catalyzed transesterification reactions with vinyl acetate as the acylating agent. The enantiomeric selectivities were dependent on both the ring size of the cycloalkanone and the bulk of the carbon group located at the stereogenic quaternary center. The resolved α-alkyl-α-hydroxymethylcyclopentanones 1 were used as enantiopure (or enantioenriched) precursors for the synthesis of the optically active pseudoiridolactones 6–7.     

Kinetic resolution of fluorinated propargyl alcohols by lipase-catalyzed enantioselective transesterification

In order to obtain optically active fluorinated propargyl alcohols, a lipase-catalyzed kinetic resolution has been carried out. The effect of lipase types, organic solvents, reaction temperature, and acyl donors was examined in the lipase-catalyzed transesterification of 1,1,1-trifluoro-4-phenyl-3-butyn-2-ol. Various enantiomerically pure fluorinated propargyl alcohols have been successfully prepared in good enantiomeric excess (>84%) by Novozym 435-catalyzed transesterification with vinyl butanoate at 60 °C in n-hexane. In some cases, the enantiomeric purities were excellent (>99% ee).