水-离子液和水-有机溶剂体系中萘普生酶法拆分的比较研究

在水—有机溶剂和水—离子液两相体系中研究了脂肪酶催化的萘普生甲酯的立体选择性水解反应。考察了转化率，对映体过量值(eep)；(ees)与时间的关系。据此构建了一种可以进行萘普生甲酯立体选择性水解的水—离子液两相体系，在该水—离子液两相体系中酶的活性与传统的水—有机相两相体系相比没有明显的变化，但是酶的立体选择性却明显提高，同时也对水—离子液两相体系中水含量对萘普生甲酯立体选择性水解反应的影响进行了研究，发现在水：离子液(v／v)为1：1时酶的活性和立体选择性最好。     

Recyclable helical poly(phenylacetylene)‐supported catalyst for asymmetric aldol reaction in aqueous media

A novel one‐handed helical poly(phenylacetylene) bearing L‐hydroxyproline pendants (poly(PA‐P)) was synthesized as an eco‐friendly polymer‐supported catalyst for asymmetric reactions. The helical poly(PA‐P) catalyzed the asymmetric aldol reactions of cyclohexanone with p‐nitrobenzaldehyde, and showed good recyclability and higher enantiomeric excess (ee) in aqueous medias than that in organic medias. The one‐handed helicity of poly(PA‐P) was clearly affected by the water content in the aqueous media. The helical poly(PA‐P) showed the higher enantioselectivity (ee = 99%) than its monomer PA‐P (ee = 54%) in THF/H₂O (H₂O vol % = 25.0 vol %). After the one‐handed helical structure of poly(PA‐P) was destroyed by grinding treatment, the ee of the reaction clearly decreased from 99 to 49%. These indicate that the one‐handed helical structure of poly(PA‐P) played an important role in the high enantioselectivity of the asymmetric aldol reactions in the aqueous media. © 2019 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2019 , 57, 1024–1031     

脂肪酶催化一步酯化协同拆分合成S-萘普生淀粉酯前药

利用CRL脂肪酶选择性催化外消旋萘普生甲酯与玉米淀粉进行转酯化反应合成光学纯S-萘普生淀粉酯前药,同时达到拆分外消旋萘普生的目的。考察了有机溶剂、脂肪酶用量、底物浓度比、反应温度对酯化协同拆分反应的影响,结果表明在异辛烷中脂肪酶CRL可以催化S-萘普生甲酯与淀粉发生转酯化反应同时完成外消旋萘普生的拆分,并且在脂肪酶用量为10%、底物浓度比为1:3、异辛烷用量为15mL、反应温度为60℃的条件下反应6d,外消旋萘普生甲酯的转化率为27.2%,产物对应体过量值eep高达99.4%可以作为萘普生的前药进行应用。     

Enhancement of the Activity and Enantioselectivity of Lipase by Sol–Gel Encapsulation Immobilization onto β-cyclodextrin-Based Polymer

Candida rugosa lipase was encapsulated within a chemically inert sol–gel support prepared by polycondensation with tetraethoxysilane and octyltriethoxysilane in the presence of β-cyclodextrin-based polymer. The catalytic activity of the encapsulated lipases was evaluated both in the hydrolysis of p-nitrophenylpalmitate and the enantioselective hydrolysis of racemic Naproxen methyl ester. It has been observed that the percent activity yield of the encapsulated lipase was 65 U/g, which is 7.5 times higher than that of the covalently immobilized lipase. The β-cyclodextrin-based encapsulated lipases had higher conversion and enantioselectivity compared with covalently immobilized lipase. The study confirms an excellent enantioselectivity (E >300) for the encapsulated lipase with an enantiomeric excess value of 98% for S-naproxen.     

水饱和离子液体中脂肪酶催化萘普生甲酯对映选择性水解

 对比研究了水饱和异辛烷和水饱和离子液体1-正丁基-3甲基咪唑六氟磷酸盐([bmim]PF6)中脂肪酶催化萘普生甲酯不对称水解反应. 结果表明,由于离子液体[bmim]PF6同时具有极性和疏水性,因而成为萘普生甲酯不对称水解反应的理想介质. 与水饱和异辛烷相比,水饱和离子液体不仅明显降低了水解反应的平衡常数(K),增大了对映体比率(E),从而有效提高了水解反应的平衡转化率(ceq)和产物的对映体过量值(eep),而且由于离子液体对另一产物甲醇的溶解度高,还明显地提高了脂肪酶的操作稳定性.     

Calix[n]arene Carboxylic Acid Derivatives as Regulators of Enzymatic Reactions: Enhanced Enantioselectivity in Lipase-Catalyzed Hydrolysis of (R/S)-Naproxen Methyl Ester

Candida rugosa lipase was immobilized with a sol–gel encapsulation procedure in the presence and absence of a calix[n]arene carboxylic acid derivative grafted onto magnetic nanoparticles or in the presence of the calix[n]arene carboxylic acid derivative with Fe₃O₄ magnetic nanoparticles as an additive. Through the enantioselective hydrolysis of racemic naproxen methyl ester and the hydrolysis of p-nitrophenylpalmitate, the relative enzyme activity was evaluated and tested. These results show that the encapsulated lipase without supports has lower conversion and enantioselectivity compared to the Calix[n]COOH-based encapsulated lipase. It has also been observed that the Calix[4]COOH-based encapsulated lipase has excellent enantioselectivity (enantiomeric ratio (E)?>?400) as compared to encapsulated-free lipase enantioselectivity (E?=?137), and it also has an enantiomeric excess value of ~98 % for S-naproxen.     

Improvement of catalytic properties of Candida rugosa lipase by sol-gel encapsulation in the presence of magnetic calix[4]arene nanoparticles

Candida rugosa lipase (CRL) was encapsulated within a chemically inert sol-gel support prepared by polycondensation with tetraethoxysilane (TEOS) and octyltriethoxysilane (OTES) in the presence of N-methylglucamine based calix[4]arene magnetic nanoparticles. The results indicate that the magnetic calix[4]arene based encapsulated lipase particularly has shown high conversion and enantioselectivity. It has also been noticed that the magnetic calix[4]arene based encapsulated lipase has excellent enantioselectivity (E = 460) as compared to the free enzyme (E = 166) with an ee value of >98% for S-Naproxen.     

Access to a Key Building Block for the Prostaglandin Family via Stereocontrolled Organocatalytic Baeyer–Villiger Oxidation

A new protocol for the construction of a crucial bicyclic lactone of prostaglandins using a stereocontrolled organocatalytic Baeyer–Villiger (B‐V) oxidation was developed. The key B‐V oxidation of a racemic cyclobutanone derivative with aqueous hydrogen peroxide has enabled an early‐stage construction of a bicyclic lactone skeleton in high enantiomeric excess (up to 95 %). The generated bicyclic lactone is fully primed with two desired stereocenters and enabled the synthesis of the entire family of prostaglandins according to Corey′s route. Furthermore, the reactivity and enantioselectivity of B‐V oxidation of racemic bicyclic cyclobutanones were evaluated and 90–99 % ee was obtained, representing one of the most efficient routes to chiral lactones. This study further facilitates the synthesis of prostaglandins and chiral lactone‐containing natural products to promote drug discovery.     

Escherichia coli BioH: a highly enantioselective and organic solvent tolerant esterase for kinetic resolution of sec-alcohols

Escherichia coli BioH, which is obligatory for biotin synthesis, was found to be an organic solvent tolerant esterase with high enantioselectivity for the kinetic resolution of sec-alcohols using free enzyme powder. With this esterase, a variety of racemic sec-alcohols were efficiently resolved with ee values of up to 99%.     

Lipase-catalyzed enantioselective transesterification of 3-hydroxy-3-(2-thienyl) propanenitrile in liquid carbon dioxide

The transesterification of 3-hydroxy-3-(2-thienyl) propanenitrile catalyzed by Pseudomonas fluorescens lipase (PFL) in liquid carbon dioxide (CO₂) was reported. Compared with that in organic solvent (n-hexane), the catalytic performance of PFL was dramatically enhanced in liquid CO₂. Under the optimal reaction conditions, PFL exhibited an excellent enantioselectivity (E-value: 92.9) with a high enzyme activity (82.5?μmol/g/min). Besides, the remained (S)-3-hydroxy-3-(2-thienyl) propanenitrile with high enantiomeric purity (ee?>?99%) was obtained in 4?h when the conversion was about 52%.

Lipase-catalyzed transesterification of 3-hydroxy-3-(2-thienyl) propanenitrile in liquid CO₂     

Retention,enantioselectivity and enantiomeric elution order of propranolol and its ester derivatives on an alpha1-acid glycoprotein-bonded column

Summary The retention, enantionselectivity and enantiomeric elution order of racemic propranolol (PP) and its ester derivatives (O-acetyl,-propionyl,-butyrul and-valeryl PP) on an ₁-acid glycoprotein (AGP)-bonded column have been investigated by changing eluent composition (eluent pH, buffer concentration, type and content of organic modifier). The retention of these cationic solutes, PP and its ester derivatives, was influenced by eluent pH, ionic strength and organic modifier content. The enantioselectivity was dependent on eluent pH and type of organic modifier. Reversal of the enantiomeric elution order of ester derivatives of PP (O-propionyl-butyryl) and-valeryl PP) occurred around eluent pH 6–7. These results suggst that chiral recognition or binding properties may be altered by the change in eluent composition, espeically eluent pH and type of organic modifier.     

Efficient <Emphasis Type="Italic">Candida rugosa</Emphasis> lipase immobilization on Maghnite clay and application for the production of (<Emphasis Type="Italic">1R</Emphasis>)-(−)-Menthyl acetate

This work focused on the identification of natural, economical, and efficient supports for immobilization of Candida rugosa lipase (CRL) to catalyze the resolution of (±)-menthol. To this purpose, CRL has been immobilized on natural montmorillonite from Algeria (Maghnite-H), ion-exchange resins (Amberjet^®1200-H and Amberjet^®4200-Cl), and diatomaceous earth (Celite^®545). After a preliminary screening of supports, the immobilization of CRL led to a markedly improved enantioselectivity. Excellent enantioselectivity (E ≥ 134) was achieved by the four supported lipases (E = 68 for free enzyme). Compared to the three other supports tested, higher enantioselectivity was observed with Maghnite-H used as immobilization matrix. In this work, the effects of solvent, reaction time, and temperature, on the conversion as well as on enantioselectivity were investigated. The maximum of conversion (% C = 43%) with high enantiomeric excess of products (eep > 99) was obtained when the reaction is catalyzed by CRL immobilized on Maghnite-H at 30 °C for 24 h, and using toluene as selected solvent. Immobilized CRL on Maghnite-H exhibited good thermostability over a wide temperature range (30–90 °C) compared to the free one. These results suggest that CRL immobilized on Maghnite-H has good potential as biocatalyst for the production of (1R)-(?)-menthyl acetate.     

New chemical and chemo-enzymatic routes for the synthesis of (RS)- and (S)-enciprazine

The chemo-enzymatic synthesis of racemic and enantiopure (RS)- and (S)-enciprazine 1, a non-benzodiazepine anxiolytic drug, is described herein. The synthesis started from 1-(2-methoxyphenyl) piperazine 3, which was treated with 2-(chloromethyl) oxirane (RS)-4 using lithium bromide to afford a racemic alcohol, 1-chloro-3-(4-(2-methoxyphenyl) piperazin-1-yl) propan-2-ol (RS)-6 in 85% yield. Intermediate (S)-6 was synthesized from racemic alcohol (RS)-6 using Candida rugosa lipase (CRL) with vinyl acetate as the acyl donor. Various reaction parameters such as temperature, time, substrate, enzyme concentration, and the effect of the reaction medium on the conversion and enantiomeric excess for the transesterification of (RS)-6 by CRL were optimized. It was observed that 10 mM of (RS)-6, 50 mg/mL of CRL in 4.0 mL of toluene with vinyl acetate (5.4 mmol) as acyl donor at 30 °C gave good conversion (C = 49.4%) and enantiomeric excess (ee_P = 98.4% and ee_S = 96%) after 9 h of reaction. Compound (S)-6 is a key intermediate for the synthesis of enantiopure (S)-1. The (RS)- and (S)-enciprazine drug 1 was synthesized by treating (RS)- and (S)-6 with 3,4,5-trimethoxyphenol 5 using MeCN as a solvent and K₂CO₃ as a base.     

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.     

Efficient dynamic kinetic resolution of arylamines with Pd/layered double-hydroxide-dodecyl sulfate anion for racemization

A novel and efficient racemization catalyst, Pd/layered double-hydroxide-dodecyl sulfate anion, was prepared and used in the dynamic kinetic resolution (DKR) of arylamines. The undesired enantiomer was completely racemized at 55 °C, allowing the catalyst to be compatible with biocatalysts. DKR proceeded smoothly and showed a broad substrate scope, with good conversion and high product enantiomeric excesses (ee_p). The system could be reused more than 30 times without loss of conversion and ee_p value.     

Resolution of Racemic Ofloxacin Based on Co-Technology of Bubble Fractionation and Extraction

A method of bubble fractionation, with the help of solvent extraction, was developed for the resolution of racemic ofloxacin (rac OFLX). In this method, dibenzoyl-L-tartaric (L-DBTA), di-(2-ethylhexyl) phosphoric acid (D2EHPA) and sodium lauryl sulfate (SDS) were used as chiral collector, co-extractant and foamer, respectively. Several important parameters influencing the resolution performances, such as pH in aqueous phase, concentration of OFLX, concentration of L-DBTA, concentration of SDS and volume ratio of D2EHPA to n-octanol in solution, were investigated. The optimal resolution conditions were obtained with the aqueous phase pH 7, volume ratio of D2EHPA to n-octanol 6/14 in organic phase, concentration of SDS 0.42 mg mL^?1, concentration of OFLX 1.67 mg mL^?1, and concentration of L-DBTA 0.11 g mL^?1. Under the optimal extraction conditions, the enantiomeric excess value (e.e.%) was 60.08% and the enantioselectivity (??) was 5.58. It was found that the capacity of enantioselective separation can be greatly improved by the co-technology.     

水/有机溶剂双相中杏仁醇腈酶促不对称合成(R)-苯乙氰醇

 研究了水／有机溶剂双相中来源于杏仁的（R）－醇腈酶催化苯\r\n甲醛与HCN不对称合成（R）－苯乙氰醇,系统探讨了有机溶剂、水相与\r\n有机溶剂相体积比、水相pH值和反应温度对反应速度、转化率和产物光\r\n学纯度的影响．结果表明,上述因素对醇腈酶促不对称合成（R）－苯\r\n乙氰醇反应均有显著影响．异丙醚为该反应最好的有机溶剂,水相与有\r\n机溶剂相体积比以1／2为宜,适宜的pH值为3．4,最佳反应温度为0～\r\n5℃．在该优化反应条件下,反应转化率和产物的光学纯度均高达99％\r\n以上．     

Poly(styrene)‐Supported Co–Salen Complexes as Efficient Recyclable Catalysts for the Hydrolytic Kinetic Resolution of Epichlorohydrin

Here we describe an unprecedented synthetic approach to poly(styrene)‐supported chiral salen ligands by the free radical polymerization of an unsymmetrical styryl‐substituted salen monomer (H₂salen=bis(salicylidene)ethylenediamine). The new method allows for the attachment of salen moieties to the polymer main chain in a flexible, pendant fashion, avoiding grafting reactions that often introduce ill‐defined species on the polymers. Moreover, the loading of the salen is controlled by the copolymerization of the styryl‐substituted salen monomer with styrene in different ratios. The polymeric salen ligands are metallated with cobalt(II ) acetate to afford the corresponding supported Co–salen complexes, which are used in the hydrolytic kinetic resolution of racemic epichlorohydrin, exhibiting high reactivity and enantioselectivity. Remarkably, the copolymer‐supported Co–salen complexes showed a better catalytic performance (>99 % ee, 54 % conversion, one hour) in comparison to the homopolymeric analogues and the small molecule Co–salen complex. The soluble poly(styrene)‐supported catalysts were recovered by precipitation after the catalytic reactions and were recycled three times to afford almost identical enantiomeric excesses as the first run, with slightly reduced reaction rates.     

Effects of organic solvents and ionic liquids on the aminolysis of (RS)-methyl mandelate catalyzed by lipases

The enzymatic resolution of (RS)-methyl mandelate with n-butylamine using lipases in organic solvents (n-hexane, tert-butanol, and chloroform) and ionic liquids [BMIm][BF₄] and [BMIm][PF₆] is reported. The amide configuration is dependent on the organic solvent. When using mixtures of chloroform or tert-butanol/ionic liquids (10:1 v/v) with CAL-B as the catalyst, the amides were obtained in high enantiomeric excess (ee_p >99% and E >200).     

膜反应器中萘普生甲酯的动态拆分

在碱催化连续原位消旋条件下,利用CRL脂肪酶（Candida rugosa lipase）催化的萘普生甲酯立体选择性水解反应。动态拆分制备（S）－普生。使用硫水硅橡胶膜隔离生物催化拆分反应和碱催化消旋反应,解决了常规动态拆分反应中生物催化剂难以承受原位化学消旋苛刻反应条件的难题。为了利于从水－有机溶剂乳化体系中分离产物和克服产物抑制,将亲水半透膜引入搅拌罐反应器,在该膜反应器中进行动态拆分反应。当转化率超过60％时,产物（S）－萘普生的对映体过量值（eep)仍在96％以上,在反应过程中还发现CRL脂肪酶同工酶的转化。