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Synthesis of Multi-functional Chiral Molecules by Developing the Function of Biocatalysts

开发生物催化剂功能合成多功能手性分子

基本信息

批准号：
07455362
负责人：
UTAKA Masanori
金额：
$ 4.16万
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：
1995
资助国家：
日本
起止时间：
1995 至 1997
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-07455362/
关键词：
bakers'yeast reductase asymmetric reduction biocatalyst lipase optically active 光学分割

项目摘要

1. Highly Stereoselective Synthesis of Polyfunctional Chiral Building BlocksA reductase that shows reducing activity toward 1-chloro-2-hexanone was purified from bakers'yeast cell-free extract by means of chromatographic separations in 4 steps. Reductants with high optical purity were obtained.Highly enantioselcective kinetic resolutions of several chiral building blocks were accomplished by the lipase-catalyzed transesterifications.2. Artificial Improvement of the EnantioselectivityWe incidentally discovered that a small amount of organic solvent can affect the enantioselectivity in the bakers'yeast reduction of 1-chloro-2,4-alkanediones. By using organic solvent, inhibitor, and heat treatment, the 6% ee was increased up to 94% ee.In the lipase-catalyzed transesterification in organic solvent, the acyl-enzyme intermediate is in situ formed. By changing the acyl donor, the structure of the acyl-enzyme is also changed, which is expected to change the enantioselectivity. Examination of this concept to 2-substituted cyclopentenols resulted in the change of the E values.The lipase-catalyzed transesterifications were performed at various temperatures ranging from 30 to -60ﾟC.As a result, the enantioselectivity was increased with decrease of the temperature. Plot of 1nE against 1/T afforded a straight line, from which DELTADELTAH^<<double plus>> and DELTADELTAS^<<double plus>> values were calculated according to a theoretical equation.3. Origin of the EnantioselectivityKinetic study revealed that chiral recognition in the binding step is unimportant for the enantioselectivity but that chiral discrimination operates at the transition state. Stereoelectronic theory was applied to the lipase-catalyzed reaction and molecular orbital calculations were performed on a model reaction. A transition -state model to rationalize the enantioselectivity was proposed.

1.高立体选择性合成多功能手性结构单元通过4步色谱分离从面包酵母无细胞提取物中纯化出对1-氯-2-己酮具有还原活性的还原酶。得到了高光学纯度的还原剂，并利用脂肪酶催化的反式异构化反应实现了几种手性结构单元的高对映选择性动力学拆分.对映体选择性的人为改进我们偶然发现，在面包酵母还原1-氯-2，4-烷二酮的反应中，少量有机溶剂会影响对映体选择性。通过使用有机溶剂、抑制剂和热处理，将6%ee提高到94%ee。在有机溶剂中脂肪酶催化酯交换反应中，酰基酶中间体原位形成。通过改变酰基供体，酰基-酶的结构也被改变，这有望改变对映体选择性。在30 ~-60 ℃的温度范围内，对脂肪酶催化的2-取代环戊烯醇的异构化反应进行了研究，结果表明，随着温度的降低，对映体选择性增加。1 nE对1/T的曲线提供了一条直线，根据理论方程计算出Δ Δ H ^<<double plus>>和Δ H ^<<double plus>>值。对映选择性的起源动力学研究表明，结合步骤中的手性识别对于对映选择性并不重要，但手性识别作用于过渡态。将立体电子理论应用于脂肪酶催化反应，并对模型反应进行了分子轨道计算。提出了一个过渡态模型来解释该反应的对映选择性.