几种结构刚性的二腈和二酰胺的去对称化生物转化反应和机理研究

Biotransformations have become an important method in organic synthesis owing to their high efficiency, excellent selectivity and mild reaction conditions. In contrast to the plethora of studies on the biotransformations of racemic nitriles and amides, enantioselective desymmetrization of prochiral and meso-dinitriles and diamides are very rare. And the mechanism of biocatalytic desymmetrization remains largely unexplored. In this project, we will design and synthesize novel prochiral and meso-dinitriles and diamides bearing rigid backbones, and develop their biotransformations under whole cell catalysis to synthesize highly enantiopure carboxylic acids and derivatives. The effects of electronic nature and steric hindrance of the substituents on efficiency and enantioselectivity of the biotransformations will be systematically investigated to find the rules of biocatalytic desymmetrization. On the base of the obtained gene sequence of the amidase, computational method will be applied to construct the protein domain, active center and study the enzyme-substrate interactions, in order to explore the enantioselective mechanism. Taking the enantiopure carboxylic acids and derivatives as the key starting materials, high efficient transformations will be developed to explore their applications in the synthesis of chiral drugs and bioactive compounds.

生物转化反应因其高效、高选择性和温和的反应条件已成为有机合成的重要方法，对各种外消旋腈和酰胺的动力学拆分生物转化反应已有大量报道，但是对于二腈和二酰胺的去对称化生物转化反应研究仍然较少，且对于酶催化去对称化生物转化反应的规律和机理的认识十分有限。本项目拟设计并合成新型的具有刚性结构的二腈和二酰胺底物，系统研究其去对称化生物转化反应，建立高效高选择性光学纯羧酸及其衍生物的合成方法学；考察底物结构中不同取代基的立体效应和电子效应对反应效率和选择性的影响，总结去对称化生物转化反应的规律，特别是手性识别规律；在获取酶的结构基因基础上，借助计算机辅助建模，阐释酶的结构域和活性中心，通过底物对接手段研究酶的催化机理和识别机制，并用来指导底物的分子设计；以所获得的光活性羧酸和酰胺为关键起始原料，发展高效生物催化-化学方法合成手性药物分子和生物活性分子。

本项目系统的考察了酰胺水解酶催化的内消旋环状二酰胺和前手性戊二酰胺类底物的去对称化生物转化反应并研究了酶-底物手性识别机理。取得了以下三方面进展：1) 设计并合成了内消旋环状二酰胺类底物，其去对称化生物转化反应具有较高的效率和对映选择性，能够以高达95%产率和大于99% ee值获得相应羧酸衍生物，并结合高效的化学转化合成了多种结构新颖且具有潜在应用价值的手性恶唑烷酮类化合物；2) 设计并合成了前手性戊二酰胺类底物，其去对称化生物转化反应可以得到相应手性羧酸衍生物，且该反应的效率和对映选择性受底物取代基的较大影响；3) 利用模拟计算和设计控制实验的方法研究了酶-底物手性识别机制以及酶高对映选择性的来源，并建立了底物与酶手性识别的模型。

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