Efficient Synthesis of New Chiral Synthons by Artificial Regulation of Biocatalysis and Development of Optically Active Drugs

人工调控生物催化高效合成新型手性合成子及光学活性药物的开发

• 批准号: 09555288
• 负责人: SAKAI Takashi
• 金额: $ 5.12万
• 依托单位: Okayama University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 1997
• 资助国家: 日本
• 起止时间: 1997 至 1999
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-09555288/
• 关键词: optically active; chiral; asymmetric synthesis; biocatalyst; lipase; subtilisin; reductase; bakers' yeast; アルコール; キラル; アジリン

1. Synthesis of Optically Active CompoundsWe designed and synthesized useful chiral synthetic intermediates having an azirine skeleton, a pentafluorophenyl group, a tetraphenylporphyrin moiety and so on. Optically active compounds of these molecules were prepared by lipase- and subtilisin-catalyzed kinetic resolutions or by asymmetric reductions using carbonyl reductases with high enantioselectivities. We found that the diastereofacial selectivity in the nucleophilic addition to azirine derivatives can be controlled by coordination and steric hindrance. We also synthesized new chiral 1, 2-diol and 1, 2 amino alcohol from 2-acyloxy-2-(pentafluorophenyl)acetonitrile.2. Lipase-catalyzed reactions at very low temperature(]SY.++.〔ィエD1) and △△SィイD1(〕SY.++.〔ィエD1) values were calculated according to a theoretical equation.3. Enantioselective reduction using bakers' yeast and purified reductaseAsymmetric reductions using bakers' yeast and carbonyl reductases afforded various optically active alcohols. In general, the reductases purified from bakers' yeast showed higher enantioselectivity than the whole cell of bakers' yeast.

1.光学活性化合物的合成我们设计并合成了具有氮丙啶骨架、五氟苯基、四苯基卟啉部分等的有用的手性合成中间体，这些分子的光学活性化合物通过脂肪酶和枯草杆菌蛋白酶催化的动力学拆分或通过不对称制备。使用具有高对映选择性的羰基还原酶进行还原，我们发现非对映选择性。氮丙啶衍生物的亲核加成可以通过配位和空间位阻来控制。我们还从2-酰氧基-2-(五氟苯基)乙腈合成了新的手性1, 2-二醇和1, 2氨基醇。2．低温(]SY.++.〔IED1) 和根据理论方程计算△△SiiD1(〕SY.++.〔IED1)值。3.使用面包酵母和纯化还原酶进行对映选择性还原，使用面包酵母和羰基还原酶进行不对称还原，得到光学活性醇。一般来说，从面包酵母中纯化的还原酶表现出比面包酵母全细胞更高的对映选择性。

项目成果

T.Sakai: "Enhancement of the Enantioselectivity in Lipase-Catalyzed Kinetic Resolutions of 2H-Azirine-2-methanol by Lowering the Temperature to -40℃." Journal of Organic Chemistry. 62・15. 4906-4907 (1997)

T.Sakai：“通过将温度降低至-40℃来提高脂肪酶催化的2H-氮丙啶-2-甲醇的对映选择性。”有机化学杂志62・15 4906-4907。

Jing-Nan Cui et al.: "Control of Enantioselectivity in the Bakers' Yeast Asymmetric Reduction of γ-Chloro β-Diketones to γ-Chloro(S)-β-Hydroxy Ketones"Tetrahedron : Asymmetry. 9(15). 2681-2692 (1998)

Jing-Nan Cui 等人：“面包酵母不对称还原 γ-氯 β-二酮对 γ-​​氯（S）-β-羟基酮的对映选择性的控制”四面体：不对称性 9(15)。 2692 (1998)

Jing-Nan Cui: "Control of Enantioselectivty in the Bakers Yeast Asymmetric Reduction of γ-Chloro β-Diketones to γ-Chloro (S)-β-Hydroxy Ketones"Tetrahedron : Asymmetry. 9 (15). 2681-2692 (1998)

Jing-Nan Cui：“面包酵母不对称还原 γ-氯 β-二酮至 γ-氯 (S)-β-羟基酮的对映选择性控制”四面体：不对称性 9 (15)。

T.Sakai: "Lipase-Catalyzed Efficient Kinetic Resolution of 3-Hydroxy-3-(pentafluoro-phenyl)propionitrile and Related Compounds." Tetrahedron Letters. 38・11. 1987-1990 (1997)

T.Sakai：“脂肪酶催化的 3-羟基-3-(五氟-苯基)丙腈及相关化合物的高效动力学拆分”。四面体快报 38・11 (1997)。

Tadashi Ema: "Highly Enantioselective Reduction of Carbonyl Compounds Using a Reductase Purified from Bakers' Yeast"The Journal of Organic Chemistry. 63 (15). 4996-5000 (1998)

Tadashi Ema：“使用从面包酵母中纯化的还原酶对羰基化合物进行高度对映选择性还原”有机化学杂志。