STUDY ON THE EFFECTIVE APPEARANCE OF ENZYMATIC FUNCTION DIRECTED TOWARD THE ORGANIC SYNTHESIS

有机合成酶促功能有效发挥的研究

• 批准号: 06672115
• 负责人: AKITA Hiroyuki
• 金额: $ 1.15万
• 依托单位: Toho University, School of Pharmaceutical Science
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for General Scientific Research (C)
• 财政年份: 1994
• 资助国家: 日本
• 起止时间: 1994 至 1995
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-06672115/
• 关键词: lipid-lipase aggregate; water-insoluble substrate; enantioselective hydrolysis; X-ray diffraction; immobilized enzyme; lipase; 4,5-disubstituted-2E-hexenoate; X線回折; エポキシエステル

For the purpose of carrying out smoothly enzymatic reaction of water-insoluble substrates in organic solvents, a new type of immobilized enzyme, a lipid-lipase aggregate, was developed. In order to prepare various kinds of lipid-lipase aggregates, 27 kinds of dialkyl ether-type phospholipid analogues were newly synthesized and used for the preparation of aggregates with lipase. Thus obtained lipid-lipase aggregates catalyzed effectively an asymmetric hydrolysis of water-insoluble (<plus-minus>)-alpha-acyloxy ester in water-saturated isopropyl ether producing (S)-alpha-acyloxy ester, a key intermediate for medicinally active diltiazem hydrochloride, much more efficiently than lipase immobilized with synthetic prepolymer (ENTP-400) in water-saturated isopropyl ether. Namely, the reaction time became much shorter (2 to 3d for completion as compared with 21d) and the chemical and optical yields of the reaction products were found to be high. An ether-linked lipid-lipase aggregate obtained by sonication treatment was considered to have stacked bilayr structure of the lipid in the crystalline phase based on X-ray diffraction analysis. In addition, for the purpose of the synthesis of chiral synthon using lipase, a facile chemoenzymatic route to optically active 4,5-disubstituted-2E-hexenoate derivatives was achieve

为了使水不溶性底物在有机溶剂中顺利进行酶促反应，研制了一种新型的固定化酶--脂肪酶聚集体。为了制备各种类型的脂肪酶-磷脂复合物，合成了27种二烷基醚型磷脂类似物，并将其用于脂肪酶-磷脂复合物的制备。由此获得的脂质-脂肪酶聚集体有效地催化水不溶性（S<plus-minus>）-α-酰氧基酯在水饱和异丙醚中的不对称水解，产生（S）-α-酰氧基酯，其是具有药用活性的盐酸地尔硫卓的关键中间体，比用合成预聚物（ENTP-400）固定化的脂肪酶在水饱和异丙醚中的效率高得多。也就是说，反应时间变得更短（与21天相比，2 - 3天完成），并且发现反应产物的化学产率和光学产率高。基于X射线衍射分析，通过超声处理获得的醚连接的脂质-脂肪酶聚集体被认为在结晶相中具有脂质的堆叠双层结构。此外，为了利用脂肪酶合成手性合成子，我们还实现了一种简单的化学酶法合成光学活性的4，5-二取代-2E-己烯酸酯衍生物

项目成果

Shinji Nagumo,Isao Umezawa,Junko Akiyama and Hiroyuki Akita: "Formal Syntheses of N-Trifluoroacetyl-L-acosamine and N-Trifluoroacetyl-L-daunosamine from an Achiral Precursor, Methyl Sorbate" Chem.Pharm.Bull.43. 171-173 (1995)

Shinji Nagumo、Isao Umezawa、Junko Akiyama 和 Hiroyuki Akita：“从非手性前体山梨酸甲酯正式合成 N-三氟乙酰基-L-阿糖胺和 N-三氟乙酰基-L-道诺胺”Chem.Pharm.Bull.43。

Hiroyuki Akita, Isao Umezawa, Michika Takano and Takeshi Oishi: "A Facile Chemoenzymatic Route to Optically Active 4,5-Disubstituted -2E-hexenoate Derivatives. II" Chem.Pharm.Bull.41. 680-684 (1993)

Hiroyuki Akita、Isao Umezawa、Michika Takano 和 Takeshi Oishi：“光学活性 4,5-二取代 -2E-己烯酸酯衍生物的简便化学酶途径。II”Chem.Pharm.Bull.41。

Hiroyuki Akita,Isao Umezawa,Hiroko Matsukura,Takeshi Oishi: "A Lipid-Lipase Aggregate as a New Type of Immobilized Enzyme" Chem.Pharm.Bull.39. 1632-1633 (1991)

Hiroyuki Akita、Isao Umezawa、Hiroko Matsukura、Takeshi Oishi：“脂质-脂肪酶聚集体作为新型固定化酶”Chem.Pharm.Bull.39。

Hiroyuki Akita,Isao Umezawa,Djadjat Tisnadjaja,Hiroko Matsukura and Takeshi Oishi: "Enantioselective Acetylation of an α-Hydroxy Ester by Using Ether-Linked Lipid-Lipase Aggregates in Oraganic Solvents" Chem.Pharm.Bull.41. 16-20 (1993)

Hiroyuki Akita、Isao Umezawa、Djadjat Tisnadjaja、Hiroko Matsukura 和 Takeshi Oishi：“在有机溶剂中使用醚连接的脂质-脂肪酶聚集体对 α-羟基酯进行对映选择性乙酰化”Chem.Pharm.Bull.41（1993 年） ）

Hiroyuki Akita, Isao Umezawa, Ikuko Sakurai and Takeshi Oishi: "Strucural Characteristics of Lipid-Lipase Aggregates for Enantioselective Hydrolysis in Organic Solvents" Chem.Pharm.Bull.41. 12-15 (1993)

Hiroyuki Akita、Isao Umezawa、Ikuko Sakurai 和 Takeshi Oishi：“有机溶剂中对映选择性水解的脂质-脂肪酶聚集体的结构特征”Chem.Pharm.Bull.41。