微生物脂肪酶不对称拆分手性醇的研究
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摘要
本研究选择了来源于不同微生物的多种立体选择性脂肪酶,利用上述脂肪酶对手性伯醇-环氧丙醇及仲醇-α-苯乙醇进行不对称催化拆分反应,研究其催化反应规律。同时,构建了脂肪酶水相催化拆分体系、反胶束催化拆分体系及有机相催化拆分体系,并研究脂肪酶在不同反应体系中的催化特性,构建了高效的脂肪酶催化拆分手性醇体系,具体内容包括:
(1)在水相中,将来源于细菌、酵母、霉菌等3种微生物的15种脂肪酶对环氧丙醇进行不对称水解拆分反应,其中华根霉脂肪酶(RCL)对底物的立体选择性最高。以RCL为模式酶,环氧丙醇丁酸酯为模式底物,在水相中构建RCL不对称催化水解拆分环氧丙醇丁酸酯的反应体系。考察了温度、pH、酶浓度、底物浓度及时间等因素对RCL水解底物时立体选择性的影响。研究发现,RCL能够在pH 8.0的磷酸缓冲液体系中高效催化拆分环氧丙醇丁酸酯,当加酶量20 mg/g,40℃,反应时间6 h,转化率约50%时,产物(R)-环氧丙醇丁酸酯的光学纯度可达57.3%。
(2)在水相中RCL不对称拆分环氧丙醇达到的光学纯度较低,则本研究选择反胶束体系不对称拆分环氧丙醇,进一步提高RCL水解拆分时对底物的立体选择性。分别选取阴离子(CTAB、TBAB)、阳离子(AOT、SDS)及非离子(OP)等几种不同的反胶束,构建反胶束中不对称拆分环氧丙醇体系。经对比研究发现CTAB对RCL立体选择性影响较大,因此选择CTAB体系,进行RCL不对称水解拆分环氧丙醇丁酸酯的工艺优化,考察pH、Wo、底物浓度、温度等条件对RCL立体选择性的影响。实验结果显示,在CTAB中,pH 7.5,Wo为40,0.35 mol/L环氧丙醇丁酸酯,40℃条件下反应3 h,当底物转化率达50%时,R-环氧丙醇丁酸酯的ee值可达81.7%,较水相中显著提高。
(3)考察15种微生物脂肪酶有机相中不对称转酯化拆分α-苯乙醇。其中Lipase PS对底物的立体选择性最高,因此通过溶剂工程等手段进行拆分工艺的优化,包括对溶剂的筛选、底物浓度、温度、水活度等因素的考察。结果显示,底物醇浓度为0.3 mol/L,初始水活度为0.75,加酶量5 mg/ml,35°C,200 r/min,反应14 h后,(R,S)-α-苯乙醇的转化率达44.7%,产物R-乙酸苯乙酯的ee值为98.6%。另外,通过本研究可知,水活度对脂肪酶不对称拆分反应的催化效率及立体选择性具有显著的影响。
Fifteen stereoselective lipases from different microorganisms were applied to asymmetric resolve chiral alcohols such as glycidol,α-Phenylethanol and the mechanism of the reactions was investigated. The reactions in aqueous phase system, reverse micelle system and organic phase system was compared and the key factors that influence the chiral resolution was studied. In brief, an efficient lipase-catalyzed asymmetric resolution system was constructed which could be used for investigation of the properties of asymmetric resolution of chiral alcohol by lipases.
(1) The enantioselectivity of the 15 different microbial lipases were tested by the asymmetric hydrolysis of racemic glycidyl butyrate in aqueous medium. Among which the lipase from Rhizopus chinensis (RCL) exhibited higher activity and enantioselectivity. Then, RCL was applied as model enzyme and glycidyl butyrate as model substrate to conduct asymmetric hydrolysis reaction. We investigated the influence of temperature, pH, enzyme dosage, substrate concentration and reaction time on the enzymatic resolution of glycidyl butyrate in aqueous media. The results indicated that the optimal reaction conditions were 20mg/g RCL at 40℃for 6h. Under the optimal conditions, the RCL showed the best performance to produce R-enantiomers with 57.3% ee and 50% conversion of substrate.
(2) In order to obtain higher optically pure glycidyl butyrate, the hydrolysis of glycidyl butyrate was performed in reverse micelles system by RCL. Five different reverse micelles, based on cetyltrimethyl ammonium bromide (CTAB), Tetramethyl ammonium bromide (TBAB), sodium 2-ethylhexyl sulfosuccinate (AOT), sodium dodecylsulphonate (SDS) and Emulsifier OP-10(OP) were used as reaction media. The research discovered that CTAB had a great influence on the enantioselectivity of RCL. In the CTAB system the effect of pH, Wo, temperature, substrate concentration et al on the optical selectivity of RCL were investigated. The optimal resolution conditions were as follows: pH 7.5, Wo 40, 0.35 M substrate concentration, 40℃, 6 h under which RCL showed ee 81.7% of R-glycidol butyrate. Meanwhile, a clear trend was observed that the activity of RCL was greatly enhanced by the use of reverse micelles system in comparison with a classical aqueous media.
(3) After screening of 15 different microbial lipases for asymmetric resolution ofα-phenylethanol, Lipase PS from Burkholderia cepacia was chosen to asymmetric transesterification resolutionα-phenylethanol in organic solvent. We investigated the influence factors which played a crucial role on the enantioselectivity of Lipase PS , such as reaction medium, enzyme dosage, substrate concentration, temperature, and water activity et al. The optimal reaction conditions were as follows: 0.3 mol/L (R,S)-α-phenylethanol, and 0.6 mol/L vinyl acetate, 5 mg/mL lipase PS, under 35°C and 200 r/min with the initial water activity of 0.75 for 14 h. lipase PS exhibited the best performance to produce 98.6% ee of (R)-phenylethyl acetate and the substrate conversion reached at 44.7%.
(1)在水相中,将来源于细菌、酵母、霉菌等3种微生物的15种脂肪酶对环氧丙醇进行不对称水解拆分反应,其中华根霉脂肪酶(RCL)对底物的立体选择性最高。以RCL为模式酶,环氧丙醇丁酸酯为模式底物,在水相中构建RCL不对称催化水解拆分环氧丙醇丁酸酯的反应体系。考察了温度、pH、酶浓度、底物浓度及时间等因素对RCL水解底物时立体选择性的影响。研究发现,RCL能够在pH 8.0的磷酸缓冲液体系中高效催化拆分环氧丙醇丁酸酯,当加酶量20 mg/g,40℃,反应时间6 h,转化率约50%时,产物(R)-环氧丙醇丁酸酯的光学纯度可达57.3%。
(2)在水相中RCL不对称拆分环氧丙醇达到的光学纯度较低,则本研究选择反胶束体系不对称拆分环氧丙醇,进一步提高RCL水解拆分时对底物的立体选择性。分别选取阴离子(CTAB、TBAB)、阳离子(AOT、SDS)及非离子(OP)等几种不同的反胶束,构建反胶束中不对称拆分环氧丙醇体系。经对比研究发现CTAB对RCL立体选择性影响较大,因此选择CTAB体系,进行RCL不对称水解拆分环氧丙醇丁酸酯的工艺优化,考察pH、Wo、底物浓度、温度等条件对RCL立体选择性的影响。实验结果显示,在CTAB中,pH 7.5,Wo为40,0.35 mol/L环氧丙醇丁酸酯,40℃条件下反应3 h,当底物转化率达50%时,R-环氧丙醇丁酸酯的ee值可达81.7%,较水相中显著提高。
(3)考察15种微生物脂肪酶有机相中不对称转酯化拆分α-苯乙醇。其中Lipase PS对底物的立体选择性最高,因此通过溶剂工程等手段进行拆分工艺的优化,包括对溶剂的筛选、底物浓度、温度、水活度等因素的考察。结果显示,底物醇浓度为0.3 mol/L,初始水活度为0.75,加酶量5 mg/ml,35°C,200 r/min,反应14 h后,(R,S)-α-苯乙醇的转化率达44.7%,产物R-乙酸苯乙酯的ee值为98.6%。另外,通过本研究可知,水活度对脂肪酶不对称拆分反应的催化效率及立体选择性具有显著的影响。
Fifteen stereoselective lipases from different microorganisms were applied to asymmetric resolve chiral alcohols such as glycidol,α-Phenylethanol and the mechanism of the reactions was investigated. The reactions in aqueous phase system, reverse micelle system and organic phase system was compared and the key factors that influence the chiral resolution was studied. In brief, an efficient lipase-catalyzed asymmetric resolution system was constructed which could be used for investigation of the properties of asymmetric resolution of chiral alcohol by lipases.
(1) The enantioselectivity of the 15 different microbial lipases were tested by the asymmetric hydrolysis of racemic glycidyl butyrate in aqueous medium. Among which the lipase from Rhizopus chinensis (RCL) exhibited higher activity and enantioselectivity. Then, RCL was applied as model enzyme and glycidyl butyrate as model substrate to conduct asymmetric hydrolysis reaction. We investigated the influence of temperature, pH, enzyme dosage, substrate concentration and reaction time on the enzymatic resolution of glycidyl butyrate in aqueous media. The results indicated that the optimal reaction conditions were 20mg/g RCL at 40℃for 6h. Under the optimal conditions, the RCL showed the best performance to produce R-enantiomers with 57.3% ee and 50% conversion of substrate.
(2) In order to obtain higher optically pure glycidyl butyrate, the hydrolysis of glycidyl butyrate was performed in reverse micelles system by RCL. Five different reverse micelles, based on cetyltrimethyl ammonium bromide (CTAB), Tetramethyl ammonium bromide (TBAB), sodium 2-ethylhexyl sulfosuccinate (AOT), sodium dodecylsulphonate (SDS) and Emulsifier OP-10(OP) were used as reaction media. The research discovered that CTAB had a great influence on the enantioselectivity of RCL. In the CTAB system the effect of pH, Wo, temperature, substrate concentration et al on the optical selectivity of RCL were investigated. The optimal resolution conditions were as follows: pH 7.5, Wo 40, 0.35 M substrate concentration, 40℃, 6 h under which RCL showed ee 81.7% of R-glycidol butyrate. Meanwhile, a clear trend was observed that the activity of RCL was greatly enhanced by the use of reverse micelles system in comparison with a classical aqueous media.
(3) After screening of 15 different microbial lipases for asymmetric resolution ofα-phenylethanol, Lipase PS from Burkholderia cepacia was chosen to asymmetric transesterification resolutionα-phenylethanol in organic solvent. We investigated the influence factors which played a crucial role on the enantioselectivity of Lipase PS , such as reaction medium, enzyme dosage, substrate concentration, temperature, and water activity et al. The optimal reaction conditions were as follows: 0.3 mol/L (R,S)-α-phenylethanol, and 0.6 mol/L vinyl acetate, 5 mg/mL lipase PS, under 35°C and 200 r/min with the initial water activity of 0.75 for 14 h. lipase PS exhibited the best performance to produce 98.6% ee of (R)-phenylethyl acetate and the substrate conversion reached at 44.7%.
引文
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