海藻酸钠包埋面包酵母不对称催化合成（S）-（+）-1-苯基-2-丙醇
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摘要
(S)-(+)-1-苯基-2-丙醇是合成光学活性盐酸安非他明、(R)-司来吉兰、组织蛋白酶K(cathepsin K)抑制剂和苯并二氮类化合物等的重要中间体,目前(S)-(+)-1-苯基-2-丙醇的合成主要采用化学催化、酶催化还原、酶催化拆分法和微生物活细胞催化还原等方法,但很少有关于固定化面包酵母催化还原的方法报道。本论文采用海藻酸钠固定面包酵母催化还原苯基丙酮合成(S)-(+)-1-苯基-2-丙醇,主要研究内容和结果如下:
考察了面包酵母立体选择性催化苯基丙酮不对称还原反应的特性,建立了以气相色谱(GC)测定苯基丙酮转化率,IR和~1HMNR法对(S)-(+)-1-苯基-2-丙醇的结构进行表征以及(S)-(+)-1-苯基-2-丙醇的对映体过量值(e.e.)用比旋光度进行计算。
首先,以苯基丙酮为底物,研究了游离面包酵母不对称还原情况,考察了苯基丙酮浓度、反应时间、反应温度、pH值和葡萄糖浓度等因素对还原反应的影响。其优化条件:苯基丙酮浓度3.28g/L、反应时间22h、反应温度25℃、pH值6.5和葡萄糖浓度15g/L。其苯基丙酮转化率为61.6%,(S)-(+)-1-苯基-2-丙醇的e.e.值为90.4%。
其次,探讨了海藻酸钠固定化面包酵母的诸多条件,正交实验考察了海藻酸钠浓度、氯化钙浓度、固定化温度、酵母量和固定化时间对面包酵母固定化的影响,并且确定交联剂戊二醛浓度和交联时间。实验优化条件:海藻酸钠浓度3%、氯化钙浓度3%、酵母量20%、固定化时间4h、固定化温度30℃、戊二醛浓度1.5%和交联时间2h。
最后,以苯基丙酮为底物,研究了固定化面包酵母不对称还原情况,考察了苯基丙酮浓度、酵母量、固定化颗粒直径、摇床转速、反应pH值、反应温度和反应时间等反应条件对反应的影响。其优化条件:苯基丙酮浓度5.74g/L、酵母量1.5g、固定化颗粒直径1.5mm～2.0mm、摇床转速200r/min、pH值7.5、反应温度30℃和反应时间24h。其苯基丙酮转化率为62.5%,(S)-(+)-1-苯基-2-丙醇的e.e.值为90.7%。相同反应条件下,游离面包酵母不对称催化合成得到的苯基丙酮转化率为55.9%,(S)-(+)-1-苯基-2-丙醇的e.e.值为89.7%。由实验结果可知,固定化面包酵母与游离面包酵母相比,其苯基丙酮转化率和(S)-(+)-1-苯基-2-丙醇的e.e.值均有提高;固定化面包酵母重复利用三次后,仍然能保持较高的催化性能。
游离面包酵母和固定化面包酵母都能催化合成(S)-(+)-1-苯基-2-丙醇,但是固定化面包酵母催化合成得到的苯基丙酮转化率和产物的对映体过量值比游离面包酵母催化合成的稍高,且稳定性和耐底物浓度均有提高。
(S)-(+)-1-Phenyl-2-propanol can be used as building block for the synthesis of amphetamine hydrochloride,(R)-Selegiline,cathepsin K and Benzodiazepine.The reduction of phenylacetone or resolution of(R,S)-(+)-1-phenyl-2-propanol was catalyzed by chemical catalyst,enzyme and microorganism.But microbial reduction of phenylacetone by immobilized bake's yeast has been rarely mentioned in the literature.In this study,the asymmetric reduction of phenylacetone to(S)-(+)-Phenyl-2-propanol catalyzed by immobilized bake's yeast was studied.
Determing their appearance in the bioreduction of phenylacetone by bake's yeast.The gas chromatogram(GC)was applied to detect the conversion of phenylacetone.(S)-(+)-Phenyl-2-propanol was characterized by IR and ~1HMNR.Enantiomeric excess(e.e.)was determined by specific optical rotation.
At first,the asymmetric reduction of(S)-(+)-Phenyl-2-propanol by free bake's yeast was investigated when phenylacetone was chosen as the substrate.The effects of reaction conditions,such as substrate concentration,reaction time,reaction temperature,pH value and glucose concentration,on the reaction were investigated.The optimized reaction condition was as below:concentration of phenylacetone 3.28g/L,reaction time 22h,reaction temperature 25℃,pH 6.5 and glucose concentration 15g/L.The conversion of phenylacetone and e.e.of(S)-1-phenyl-2-propanol were 61.6%and 90.4%.
The immobilization conditions about the best technological parameters were studied such as the concentration of sodium alginate and calcium chloride,immobilized temperature,concentration of cells and so on.The concentration of glutaraldehyde and cross-link time were also studied.The results showed that sodium alginate and calcium chloride had the same the concentration of 3%,concentration of cells 20%,immobilized time 4h,temp.at 30℃,concentration of glutaraldehyde 1.5%and cross-link time 2h.
At last,the asymmetric reduction of(S)-(+)-Phenyl-2-propanol by immobilized bake's yeast was investigated when phenylacetone was chosen as the substrate.The effects of reaction conditions,such as substrate concentration,concentration of cells,bead diameter,shaker rotation,pH value,reaction temperature and reaction time,on the reaction were investigated.The optimized reaction condition was as below: concentration of phenylacetone 5.74g/L,concentration of cells 1.5g,bead diameter 1.5mm to 2.0mm,shaker rotation 200r/min,pH7.5,reaction temperature 30℃and reaction time 24h.The conversion of phenylacetone and e.e.of(S)-(+)-Phenyl-2-propanol were 62.5%and 90.7%.But the conversion of phenylacetone and e.e.of(S)-(+)- Phenyl -2-propanol were 55.9%and 89.7%by free bake's yeast.So immobilized bake's yeast had higher conversion of phenylacetone and e.e. of(S)-(+)-Phenyl-2-propanol than free bake's yeast.Immobilized bake's yeast maintains high catalysis after consecutive use 3 times.
It showed that the asymmetric reduction of phenylacetone to (S)-(+)-Phenyl-2-propanol can be catalyzed by free bake's yeast and immobilized bake's yeast.However,the conversion of phenylacetone and e.e.of(S)-(+)-Phenyl-2-propanol were higher when phenylacetone was catalyzed by immobilized bake's yeast.Moreover,it had higher stability and can stand higher concentration of phenylacetone.
考察了面包酵母立体选择性催化苯基丙酮不对称还原反应的特性,建立了以气相色谱(GC)测定苯基丙酮转化率,IR和~1HMNR法对(S)-(+)-1-苯基-2-丙醇的结构进行表征以及(S)-(+)-1-苯基-2-丙醇的对映体过量值(e.e.)用比旋光度进行计算。
首先,以苯基丙酮为底物,研究了游离面包酵母不对称还原情况,考察了苯基丙酮浓度、反应时间、反应温度、pH值和葡萄糖浓度等因素对还原反应的影响。其优化条件:苯基丙酮浓度3.28g/L、反应时间22h、反应温度25℃、pH值6.5和葡萄糖浓度15g/L。其苯基丙酮转化率为61.6%,(S)-(+)-1-苯基-2-丙醇的e.e.值为90.4%。
其次,探讨了海藻酸钠固定化面包酵母的诸多条件,正交实验考察了海藻酸钠浓度、氯化钙浓度、固定化温度、酵母量和固定化时间对面包酵母固定化的影响,并且确定交联剂戊二醛浓度和交联时间。实验优化条件:海藻酸钠浓度3%、氯化钙浓度3%、酵母量20%、固定化时间4h、固定化温度30℃、戊二醛浓度1.5%和交联时间2h。
最后,以苯基丙酮为底物,研究了固定化面包酵母不对称还原情况,考察了苯基丙酮浓度、酵母量、固定化颗粒直径、摇床转速、反应pH值、反应温度和反应时间等反应条件对反应的影响。其优化条件:苯基丙酮浓度5.74g/L、酵母量1.5g、固定化颗粒直径1.5mm～2.0mm、摇床转速200r/min、pH值7.5、反应温度30℃和反应时间24h。其苯基丙酮转化率为62.5%,(S)-(+)-1-苯基-2-丙醇的e.e.值为90.7%。相同反应条件下,游离面包酵母不对称催化合成得到的苯基丙酮转化率为55.9%,(S)-(+)-1-苯基-2-丙醇的e.e.值为89.7%。由实验结果可知,固定化面包酵母与游离面包酵母相比,其苯基丙酮转化率和(S)-(+)-1-苯基-2-丙醇的e.e.值均有提高;固定化面包酵母重复利用三次后,仍然能保持较高的催化性能。
游离面包酵母和固定化面包酵母都能催化合成(S)-(+)-1-苯基-2-丙醇,但是固定化面包酵母催化合成得到的苯基丙酮转化率和产物的对映体过量值比游离面包酵母催化合成的稍高,且稳定性和耐底物浓度均有提高。
(S)-(+)-1-Phenyl-2-propanol can be used as building block for the synthesis of amphetamine hydrochloride,(R)-Selegiline,cathepsin K and Benzodiazepine.The reduction of phenylacetone or resolution of(R,S)-(+)-1-phenyl-2-propanol was catalyzed by chemical catalyst,enzyme and microorganism.But microbial reduction of phenylacetone by immobilized bake's yeast has been rarely mentioned in the literature.In this study,the asymmetric reduction of phenylacetone to(S)-(+)-Phenyl-2-propanol catalyzed by immobilized bake's yeast was studied.
Determing their appearance in the bioreduction of phenylacetone by bake's yeast.The gas chromatogram(GC)was applied to detect the conversion of phenylacetone.(S)-(+)-Phenyl-2-propanol was characterized by IR and ~1HMNR.Enantiomeric excess(e.e.)was determined by specific optical rotation.
At first,the asymmetric reduction of(S)-(+)-Phenyl-2-propanol by free bake's yeast was investigated when phenylacetone was chosen as the substrate.The effects of reaction conditions,such as substrate concentration,reaction time,reaction temperature,pH value and glucose concentration,on the reaction were investigated.The optimized reaction condition was as below:concentration of phenylacetone 3.28g/L,reaction time 22h,reaction temperature 25℃,pH 6.5 and glucose concentration 15g/L.The conversion of phenylacetone and e.e.of(S)-1-phenyl-2-propanol were 61.6%and 90.4%.
The immobilization conditions about the best technological parameters were studied such as the concentration of sodium alginate and calcium chloride,immobilized temperature,concentration of cells and so on.The concentration of glutaraldehyde and cross-link time were also studied.The results showed that sodium alginate and calcium chloride had the same the concentration of 3%,concentration of cells 20%,immobilized time 4h,temp.at 30℃,concentration of glutaraldehyde 1.5%and cross-link time 2h.
At last,the asymmetric reduction of(S)-(+)-Phenyl-2-propanol by immobilized bake's yeast was investigated when phenylacetone was chosen as the substrate.The effects of reaction conditions,such as substrate concentration,concentration of cells,bead diameter,shaker rotation,pH value,reaction temperature and reaction time,on the reaction were investigated.The optimized reaction condition was as below: concentration of phenylacetone 5.74g/L,concentration of cells 1.5g,bead diameter 1.5mm to 2.0mm,shaker rotation 200r/min,pH7.5,reaction temperature 30℃and reaction time 24h.The conversion of phenylacetone and e.e.of(S)-(+)-Phenyl-2-propanol were 62.5%and 90.7%.But the conversion of phenylacetone and e.e.of(S)-(+)- Phenyl -2-propanol were 55.9%and 89.7%by free bake's yeast.So immobilized bake's yeast had higher conversion of phenylacetone and e.e. of(S)-(+)-Phenyl-2-propanol than free bake's yeast.Immobilized bake's yeast maintains high catalysis after consecutive use 3 times.
It showed that the asymmetric reduction of phenylacetone to (S)-(+)-Phenyl-2-propanol can be catalyzed by free bake's yeast and immobilized bake's yeast.However,the conversion of phenylacetone and e.e.of(S)-(+)-Phenyl-2-propanol were higher when phenylacetone was catalyzed by immobilized bake's yeast.Moreover,it had higher stability and can stand higher concentration of phenylacetone.
引文
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