脂肪酶拆分环氧丙醇和2-辛醇
摘要
脂肪酶催化拆分于性化合物是研究小分子和生物大分子之间作用机理的重要内容之,也足‘绿色’化合成手性药物、坏保农药、高档液品和高级香料的理想途径之一。
本文以猪胰脂肪酶PPL生物催化剂、对脂肪酶水解环氧丙醇丁酸酯进行了探索,在最适反应条件下得到光学纯度超过98%的R型环氧丙醇丁酸酯。提出两步动力学拆分,在猪胰脂肪酶和Novozym 435共同催化下,同时得到两个高光学纯的环氧丙醇丁酸酯的异构体,总产率达到78%,极大的提高了底物的利用率。以固定化枯草杆菌脂肪酶PSL为催化剂,2-辛醇为底物、乙酸乙烯酯为酰化剂,钉复合物为消旋催化剂进行了动念动力学拆分的初步探索。在此基础上,模拟动态动力学拆分机制提出了在拆分的过程中同时引入固定酶,固定化氧化剂和固定化还原剂的方法,使底物得到充分的利用,并且把微波技术应用到该动态动力学拆分中,极大地提高了反应速率,得到99%ee的(s)-2-辛醇,总收率达到84%。
Enantiomerically pure alcohols and their derivatives are important synthetic intermediates, which have been widely used in many fields such as liquid crystals, medicaments, agricultural chemicals and organic non-linear materials. Kinetic resolution catalyzed by lipases which show high enantioselectivity for synthesizing these optically active compounds provides the most convenient methods. And many resolution methods had been wildly investigated by using lipases’transesterification and hydrolysis.
2,3-epoxy-1-propanol (glycidol) and 2-octanol were used as substrates in the lipase catalytic resolution in this thesis. Enhanced activity and enantioselectivity for the lipases were obtained by optimizing the reaction conditions. The immobilized lipase exhibited very good reusability and microwave irradiation was also introduced to increase the velocity of the reaction. The intrinsic limitation for classic resolution is that the theoretical maximum yield cannot exceed 50% for either enantiomer. But in our experiment, substrate was sufficiently used by using two step resolution and dynamic kinetic resolution (DKR) which employs a catalyst for the in situ racemization together with the enzymatic resolution to overcome the limitation, increasing the yield up to 100% in theory. The industry feasibility of these routes was also investigated.
There are three methods used for resolution of glycidol: 1. Hydrolysis of glycidyl butyrate by Porcine pancreatic lipase (PPL) (S-favored) with an E of 21 for production of (R)-glycidyl butyrate (13.2 mmol, 98% ee, 36% yield) under the optimal conditions. A rapid screening method for hydrolysis was found by using a water-soluble Quantum dot as luminescent pH probe. No product separation was needed and the probe also exhibited very high sensitivity. 2. The recovered (R)-enriched glycidol (19.8 mmol, 65% ee, 56% yield) from the first resolution was used as substrate for transesterification catalyzed by Novozym 435 (R-favored) with an E of 69 to obtain (S)-glycidyl butyrate (15.1 mmol, 98% ee, 42% yield) under the optimum conditions. 3. An efficient two-step enzymatic resolution process for production of both enantiomers of glycidyl butyrate was developed. Contrary to the transformations based on the classic kinetic resolution catalyzed by enzymes, where one enantiomer can be obtained with high enantiomeric excess, two-step enzymatic resolution is a method to obtain both enantionmers with high enantiomeric excess by subjecting the isolated enantiomerically enriched product of the first enzymatic resolution to the second, which results in the increase of the enantiomeric excess of the product in the second step. In the present study, an efficient method to produce (R)- and (S)-glycidyl butyrate with high enantiomeric purity is performed by using a two-step enzymatic resolution with sequential hydrolysis and transesterification by porcine pancreatic lipase (PPL) and the immobilized Candida antarctica lipase B (Novozym435) with the opposite enantioselectivity, respectively. The total yield of (R)- and (S)-glycidyl butyrate was 78% compared with the initial (R,S)-glycidyl butyrate added.
On the second part, Lipase from Pseudomonas sp. (PSL) was immobilized on SBA-15 (a highly ordered hexagonal array mesoporous silica molecular sieve) through physical adsorption and the immobilized PSL was used in resolution of (R,S)-2-octanol with vinyl acetate as acyl donor. Enhanced activity and enantioselectivity were observed for the immobilized PSL compared with those of the free one. The effects of reaction conditions, such as solvents, temperature, water activity and substrate ratio were investigated. Under the optimum conditions, the residual (S)-2-octanol was recovered with 99% enantiomeric excess at 52% conversion. The results also indicated that the immobilized PSL exhibited very good reusability. The Shvo’catalyst was synthesized and used in racemization. And dynamic kinetic resolution was also investigated by using both of the immobilized lipase and Shvo’catalyst, 62% (S)-octanol with 99% ee was obtained under the optimum condition. Microwave irradiation is widely used in organic chemistry while it is proved to be clean, fast, and convenient energy source. Traditionally, organic synthesis is carried out by conductive heating with an external heat source; this is comparatively slow and inefficient to transfer energy into the system, because it depends on the thermal conductivity that must be penetrated, resulting in the temperature of the reaction vessel being higher than that of the reaction mixture. In contrast, microwave irradiation produces efficient internal heating by direct coupling of microwave energy with the molecules (solvents, reagents, catalysts) in the reaction mixture, and it usually shortens the reaction time, but with a higher yield. Since lipase-catalyzed reactions are rather sluggish in non-aqueous media, the synergism with microwave could be expected to enhance the reaction rate. From our results, microwave irradiation can not only increase the velocity of lipase catalytic reaction, but also can highly increase the oxidation and reduction. A mimic dynamic kinetic resolution process was proposed based on this phenomenon by introducing the immobilized oxidant (Chromium trioxide) and reductant (Sodium borohydride) as racemization catalyst under microwave irradiation. Under the optimum conditions, (R)-2-octanol acetate was obtained at 99% enantiomeric excess with 84% yield in 2 h.
本文以猪胰脂肪酶PPL生物催化剂、对脂肪酶水解环氧丙醇丁酸酯进行了探索,在最适反应条件下得到光学纯度超过98%的R型环氧丙醇丁酸酯。提出两步动力学拆分,在猪胰脂肪酶和Novozym 435共同催化下,同时得到两个高光学纯的环氧丙醇丁酸酯的异构体,总产率达到78%,极大的提高了底物的利用率。以固定化枯草杆菌脂肪酶PSL为催化剂,2-辛醇为底物、乙酸乙烯酯为酰化剂,钉复合物为消旋催化剂进行了动念动力学拆分的初步探索。在此基础上,模拟动态动力学拆分机制提出了在拆分的过程中同时引入固定酶,固定化氧化剂和固定化还原剂的方法,使底物得到充分的利用,并且把微波技术应用到该动态动力学拆分中,极大地提高了反应速率,得到99%ee的(s)-2-辛醇,总收率达到84%。
Enantiomerically pure alcohols and their derivatives are important synthetic intermediates, which have been widely used in many fields such as liquid crystals, medicaments, agricultural chemicals and organic non-linear materials. Kinetic resolution catalyzed by lipases which show high enantioselectivity for synthesizing these optically active compounds provides the most convenient methods. And many resolution methods had been wildly investigated by using lipases’transesterification and hydrolysis.
2,3-epoxy-1-propanol (glycidol) and 2-octanol were used as substrates in the lipase catalytic resolution in this thesis. Enhanced activity and enantioselectivity for the lipases were obtained by optimizing the reaction conditions. The immobilized lipase exhibited very good reusability and microwave irradiation was also introduced to increase the velocity of the reaction. The intrinsic limitation for classic resolution is that the theoretical maximum yield cannot exceed 50% for either enantiomer. But in our experiment, substrate was sufficiently used by using two step resolution and dynamic kinetic resolution (DKR) which employs a catalyst for the in situ racemization together with the enzymatic resolution to overcome the limitation, increasing the yield up to 100% in theory. The industry feasibility of these routes was also investigated.
There are three methods used for resolution of glycidol: 1. Hydrolysis of glycidyl butyrate by Porcine pancreatic lipase (PPL) (S-favored) with an E of 21 for production of (R)-glycidyl butyrate (13.2 mmol, 98% ee, 36% yield) under the optimal conditions. A rapid screening method for hydrolysis was found by using a water-soluble Quantum dot as luminescent pH probe. No product separation was needed and the probe also exhibited very high sensitivity. 2. The recovered (R)-enriched glycidol (19.8 mmol, 65% ee, 56% yield) from the first resolution was used as substrate for transesterification catalyzed by Novozym 435 (R-favored) with an E of 69 to obtain (S)-glycidyl butyrate (15.1 mmol, 98% ee, 42% yield) under the optimum conditions. 3. An efficient two-step enzymatic resolution process for production of both enantiomers of glycidyl butyrate was developed. Contrary to the transformations based on the classic kinetic resolution catalyzed by enzymes, where one enantiomer can be obtained with high enantiomeric excess, two-step enzymatic resolution is a method to obtain both enantionmers with high enantiomeric excess by subjecting the isolated enantiomerically enriched product of the first enzymatic resolution to the second, which results in the increase of the enantiomeric excess of the product in the second step. In the present study, an efficient method to produce (R)- and (S)-glycidyl butyrate with high enantiomeric purity is performed by using a two-step enzymatic resolution with sequential hydrolysis and transesterification by porcine pancreatic lipase (PPL) and the immobilized Candida antarctica lipase B (Novozym435) with the opposite enantioselectivity, respectively. The total yield of (R)- and (S)-glycidyl butyrate was 78% compared with the initial (R,S)-glycidyl butyrate added.
On the second part, Lipase from Pseudomonas sp. (PSL) was immobilized on SBA-15 (a highly ordered hexagonal array mesoporous silica molecular sieve) through physical adsorption and the immobilized PSL was used in resolution of (R,S)-2-octanol with vinyl acetate as acyl donor. Enhanced activity and enantioselectivity were observed for the immobilized PSL compared with those of the free one. The effects of reaction conditions, such as solvents, temperature, water activity and substrate ratio were investigated. Under the optimum conditions, the residual (S)-2-octanol was recovered with 99% enantiomeric excess at 52% conversion. The results also indicated that the immobilized PSL exhibited very good reusability. The Shvo’catalyst was synthesized and used in racemization. And dynamic kinetic resolution was also investigated by using both of the immobilized lipase and Shvo’catalyst, 62% (S)-octanol with 99% ee was obtained under the optimum condition. Microwave irradiation is widely used in organic chemistry while it is proved to be clean, fast, and convenient energy source. Traditionally, organic synthesis is carried out by conductive heating with an external heat source; this is comparatively slow and inefficient to transfer energy into the system, because it depends on the thermal conductivity that must be penetrated, resulting in the temperature of the reaction vessel being higher than that of the reaction mixture. In contrast, microwave irradiation produces efficient internal heating by direct coupling of microwave energy with the molecules (solvents, reagents, catalysts) in the reaction mixture, and it usually shortens the reaction time, but with a higher yield. Since lipase-catalyzed reactions are rather sluggish in non-aqueous media, the synergism with microwave could be expected to enhance the reaction rate. From our results, microwave irradiation can not only increase the velocity of lipase catalytic reaction, but also can highly increase the oxidation and reduction. A mimic dynamic kinetic resolution process was proposed based on this phenomenon by introducing the immobilized oxidant (Chromium trioxide) and reductant (Sodium borohydride) as racemization catalyst under microwave irradiation. Under the optimum conditions, (R)-2-octanol acetate was obtained at 99% enantiomeric excess with 84% yield in 2 h.
引文
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