酵母细胞催化的（S）-2-辛醇的不对称合成研究
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摘要
(S)-2-辛醇是合成铁电液晶材料和许多光学活性药物的重要中间体。目前(S)-2-辛醇的合成主要采用酶催化还原和酶催化拆分法。本工作采用酵母FD-12催化还原2-辛酮,合成(S)-2-辛醇。
从不同的酵母菌株筛选获得酵母菌株FD-12(Saccharomyces cerevisiae),对底物2-辛酮具有较高的催化还原活性和对映体选择性。还原产物主要是(S)-2-辛醇。
研究了纯水相反应体系中FD-12的生物还原特性。2-辛酮和2-辛醇在水相中的溶解度很低,在Tris-HCl缓冲液中2-辛酮和2-辛醇的溶解度约为2.01 mmol·L~(-1)和3.03 mmol·L~(-1)(32℃)。高浓度2-辛酮和2-辛醇对酵母FD-12有较大的毒性。当底物浓度高于15 mmol·L~(-1)时,存在底物的抑制作用。最优的反应条件为16%接种量,10g·L~(-1)葡萄糖,pH8.0,32℃,初始底物浓度10mmol·L~(-1)。在该反应条件下,反应96小时,产物得率达92.23%,ee(S)可达78.80%。
研究了高浓度底物2-辛酮时酵母FD-12的抑制效应,建立底物抑制动力学模型。采用最小二乘法和拟牛顿法进行参数估计,μpm=0.0346 mmol·h~(-1)·g~(-1) dcw,最适底物浓度为14.25mmol·L~(-1)。底物抑制数学模型可较好地拟合实验数据。
研究3种表面活性剂对2-辛酮还原反应的影响。SDS、OP和CTAB均能起到较好的助溶作用。在0.2mmol·L~(-1)浓度下对酵母催化的不对称还原反应表明OP和SDS有效地提高了产物得率和ee(S)。但仍无法减弱高浓度底物的抑制作用。
本工作重点研究了FD-12在水/有机溶剂两相体系中的生物转化。在所选择的6种有机溶剂中,酵母FD-12在水/正十二烷两相体系中的糖代谢活性保留值和细胞存活率最高达90%以上。对FD-12在水/正十二烷两相体系的生物催化活性进行了研究,最优的反应条件为水/正十二烷两相相比20/5,pH8.0,32℃。在2-辛酮初始浓度为50mmol·L~(-1),10g·L~(-1)葡萄糖为共底物,反应96h后,产物得率可达45.65%,ee(S)达90.23%;当以100mmol·L~(-1)甲醇为共底物时,产物得率可达46.11%,ee(S)达95.72%。水/正十二烷两相体系较好地解决了高浓度底物和产物对酵母细胞的毒害作用。在200mmol·L~(-1)2-辛酮时,反应96h, (S)-2-辛醇浓度可达63.98mmol·L~(-1),ee(S)达93.42%。
采用固定化细胞在水/正十二烷体系中进行2-辛酮的不对称还原反应。结果表明,固定化酵母细胞进一步提高了细胞对有机溶剂的耐受性,ee(S)提高至97%以上。
本工作关于水/正十二烷两相体系中酵母FD-12催化的(S)-2-辛醇不对称合成研究,提供了一种新型的(S)-2-辛醇的生物合成路线,具有潜在的应用价值。
(S)-2-octanol can be used as building block for the synthesis of FLCD(ferroelectricLCDs) and several optically active pharmaceutical intermediates. The reduction of 2-octanone or the resolution of (R,S)-2-octanol catalyzed by enzyme have been used for the synthesis of (S)-2-octanol. In this study the asymmetric reduction of 2-octanone to (S)-2-octanol catalyzed by FD-12 was studied.
FD-12(Saccharomyces cerevisiae) was screened from different strains of Saccharomyces cerevisiae, which showed a high bioreduction activity and enantioselectivity. The product of asymmetric reduction was mainly (S)-2-octanol.
FD-12’characteristic of the bioreduction was studied. The solubility of 2-octanone and 2-octanol in the aqueous phase was very low, with the value being 2.01 mmol·L~(-1) and 3.03 mmol·L~(-1) in the Tris-HCl buffer(32℃). The high concentrations of 2-octanone and 2-octanol showed a toxic damage to Yeast FD-12. The bioreduction activity of FD-12 was inhibited at the higher concentration of 2-octanone(>15 mmol·L~(-1)). At optimal conditions, pH8.0, 32℃, 16% inoculation, initial glucose concentration of 10g·L~(-1) and initial substrate of 10mmol·L~(-1) ,the yield of 2-octanol and the ee(S) value reached 92.23% and 78.80% respectively after 96h reaction.
Through parameter estimation with least squares fit method and Quasi-Newton algorithm, the model proposed can be fitted to the experimental data well.μpm was 0.0346 mmol·h~(-1)·g~(-1) dcw and the optimal concentration was 14.25mmol·L~(-1).
The influence of three kinds of surfactant on the reduction of 2-octanone by FD-12 was studied. The solubility of 2-octanone in aqueous phase was improved greatly in the presence of SDS、OP and CTAB. An increase of yield and ee(S) could be obtained with a concentration of 0.2mmol·L~(-1)SDS and OP. But the inhibition of the high concentration substrate would not be weakened.
The water/organic solvent biphasic system was employed to the reduction of 2-octanone. Yeast possessed the best tolerance in the water/n-dodecane biphasic system than in the other 5 biphasic systems assayed. The metabolic activity retention and livability were as high as 90% in the water/n-dodecane. Under the optimal conditions in water/n-dodecane biphasic system, Vaq/Vorg 20/5, pH8.0, 32℃, a yield of 45.65% and an ee(S) value of 90.23% could be obtained when the co-substrate 10g·L~(-1) glucose and substrate 2-octanone of 50mmol·L~(-1) were used after 96h reaction. A yield of 46.11% and an ee(S) value of 95.72% were obtained with
从不同的酵母菌株筛选获得酵母菌株FD-12(Saccharomyces cerevisiae),对底物2-辛酮具有较高的催化还原活性和对映体选择性。还原产物主要是(S)-2-辛醇。
研究了纯水相反应体系中FD-12的生物还原特性。2-辛酮和2-辛醇在水相中的溶解度很低,在Tris-HCl缓冲液中2-辛酮和2-辛醇的溶解度约为2.01 mmol·L~(-1)和3.03 mmol·L~(-1)(32℃)。高浓度2-辛酮和2-辛醇对酵母FD-12有较大的毒性。当底物浓度高于15 mmol·L~(-1)时,存在底物的抑制作用。最优的反应条件为16%接种量,10g·L~(-1)葡萄糖,pH8.0,32℃,初始底物浓度10mmol·L~(-1)。在该反应条件下,反应96小时,产物得率达92.23%,ee(S)可达78.80%。
研究了高浓度底物2-辛酮时酵母FD-12的抑制效应,建立底物抑制动力学模型。采用最小二乘法和拟牛顿法进行参数估计,μpm=0.0346 mmol·h~(-1)·g~(-1) dcw,最适底物浓度为14.25mmol·L~(-1)。底物抑制数学模型可较好地拟合实验数据。
研究3种表面活性剂对2-辛酮还原反应的影响。SDS、OP和CTAB均能起到较好的助溶作用。在0.2mmol·L~(-1)浓度下对酵母催化的不对称还原反应表明OP和SDS有效地提高了产物得率和ee(S)。但仍无法减弱高浓度底物的抑制作用。
本工作重点研究了FD-12在水/有机溶剂两相体系中的生物转化。在所选择的6种有机溶剂中,酵母FD-12在水/正十二烷两相体系中的糖代谢活性保留值和细胞存活率最高达90%以上。对FD-12在水/正十二烷两相体系的生物催化活性进行了研究,最优的反应条件为水/正十二烷两相相比20/5,pH8.0,32℃。在2-辛酮初始浓度为50mmol·L~(-1),10g·L~(-1)葡萄糖为共底物,反应96h后,产物得率可达45.65%,ee(S)达90.23%;当以100mmol·L~(-1)甲醇为共底物时,产物得率可达46.11%,ee(S)达95.72%。水/正十二烷两相体系较好地解决了高浓度底物和产物对酵母细胞的毒害作用。在200mmol·L~(-1)2-辛酮时,反应96h, (S)-2-辛醇浓度可达63.98mmol·L~(-1),ee(S)达93.42%。
采用固定化细胞在水/正十二烷体系中进行2-辛酮的不对称还原反应。结果表明,固定化酵母细胞进一步提高了细胞对有机溶剂的耐受性,ee(S)提高至97%以上。
本工作关于水/正十二烷两相体系中酵母FD-12催化的(S)-2-辛醇不对称合成研究,提供了一种新型的(S)-2-辛醇的生物合成路线,具有潜在的应用价值。
(S)-2-octanol can be used as building block for the synthesis of FLCD(ferroelectricLCDs) and several optically active pharmaceutical intermediates. The reduction of 2-octanone or the resolution of (R,S)-2-octanol catalyzed by enzyme have been used for the synthesis of (S)-2-octanol. In this study the asymmetric reduction of 2-octanone to (S)-2-octanol catalyzed by FD-12 was studied.
FD-12(Saccharomyces cerevisiae) was screened from different strains of Saccharomyces cerevisiae, which showed a high bioreduction activity and enantioselectivity. The product of asymmetric reduction was mainly (S)-2-octanol.
FD-12’characteristic of the bioreduction was studied. The solubility of 2-octanone and 2-octanol in the aqueous phase was very low, with the value being 2.01 mmol·L~(-1) and 3.03 mmol·L~(-1) in the Tris-HCl buffer(32℃). The high concentrations of 2-octanone and 2-octanol showed a toxic damage to Yeast FD-12. The bioreduction activity of FD-12 was inhibited at the higher concentration of 2-octanone(>15 mmol·L~(-1)). At optimal conditions, pH8.0, 32℃, 16% inoculation, initial glucose concentration of 10g·L~(-1) and initial substrate of 10mmol·L~(-1) ,the yield of 2-octanol and the ee(S) value reached 92.23% and 78.80% respectively after 96h reaction.
Through parameter estimation with least squares fit method and Quasi-Newton algorithm, the model proposed can be fitted to the experimental data well.μpm was 0.0346 mmol·h~(-1)·g~(-1) dcw and the optimal concentration was 14.25mmol·L~(-1).
The influence of three kinds of surfactant on the reduction of 2-octanone by FD-12 was studied. The solubility of 2-octanone in aqueous phase was improved greatly in the presence of SDS、OP and CTAB. An increase of yield and ee(S) could be obtained with a concentration of 0.2mmol·L~(-1)SDS and OP. But the inhibition of the high concentration substrate would not be weakened.
The water/organic solvent biphasic system was employed to the reduction of 2-octanone. Yeast possessed the best tolerance in the water/n-dodecane biphasic system than in the other 5 biphasic systems assayed. The metabolic activity retention and livability were as high as 90% in the water/n-dodecane. Under the optimal conditions in water/n-dodecane biphasic system, Vaq/Vorg 20/5, pH8.0, 32℃, a yield of 45.65% and an ee(S) value of 90.23% could be obtained when the co-substrate 10g·L~(-1) glucose and substrate 2-octanone of 50mmol·L~(-1) were used after 96h reaction. A yield of 46.11% and an ee(S) value of 95.72% were obtained with
引文
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