类天然产物丁烯酸内酯的催化不对称合成及其在多样性导向合成中的应用

Butenolides and its derivatives such as γ-butyrolactones constitutes the structural core shared by many naturally occurring products. The limitation posed on their synthetic methods impede the further applications. This project aims to carry out the systematic study towards the synthesis of butenolides through the Palladium-catalyzed asymmetric γ-allylation and the application of different butenolide regioisomers in the diversity-oriented synthesis. The proposal consists of the following three parts: Starting from simple silyl enol ether, we are planning to develop a highly regio- and stereoselective synthesis of various 5-substituted unsaturated furanones upon the choice of palladium catalyst and phosphinooxazoline ligands. To explore the reaction mechanism involving the palladium-catalyzed dienolate complex, the progress of the asymmetric γ-allylation will be monitored by 31P NMR. Rely on the strategy designed for the diversity-oriented synthesis, optical active 5- and 3-substituted furanones will be used as synthons to access the nature product-like library with structurally complex and diverse small molecules. The biological activity of those compounds will be further screened for the purpose of dissecting biological pathways and validating targets. This program will be extremely important to facilitate the discovery for the lead compound of novel heterocyclic drugs.

丁烯酸内酯和γ-丁内酯结构单元在自然界中普遍存在，但是制备方法的局限性却阻碍了其更广泛的应用。本项目从简单的烯醇硅醚原料出发，发展“金属钯-磷噁唑啉类配体催化的不对称γ位烯丙基化反应”和“基于手性丁烯酸内酯异构体的多样性导向合成”。主要内容包括：（1）从烯醇硅醚原料出发，利用金属钯-磷噁唑啉类配体催化不对称反应，高选择性制备多种不饱和2-呋喃酮区域异构体和立体异构体；（2）提出了钯-双烯醇络合物互变异构体的假设，利用磷-31核磁共振研究钯催化烯醇硅醚衍生物的γ位烯丙基化反应机理。（3）运用多样性导向合成策略，以光学活性的不饱和2-呋喃酮异构体为合成子，通过1,3-偶极环加成反应和Diels-Alder环加成反应，构建分子多样、结构新颖的γ-丁内酯核心结构的类天然产物化合物库。本项目的实施对杂环药物的先导化合物发现有重要意义。

丁烯酸内酯和γ-丁内酯结构单元在自然界中普遍存在，但是制备方法的局限性却阻碍了其更广泛的应用。本项目从简单的烯醇硅醚原料出发，发展“金属钯-磷噁唑啉类配体催化的不对称γ位烯丙基化反应”和“基于手性丁烯酸内酯异构体的多样性导向合成”。主要内容包括：（1）从烯醇硅醚原料出发，利用金属钯-磷噁唑啉类配体催化不对称反应，高选择性制备多种不饱和2-呋喃酮区域异构体和立体异构体；（2）提出了钯-双烯醇络合物互变异构体的假设，利用磷-31核磁共振研究钯催化烯醇硅醚衍生物的γ位烯丙基化反应机理。（3）运用多样性导向合成策略，以光学活性的不饱和2-呋喃酮异构体为合成子，通过1,3-偶极环加成反应和Diels-Alder环加成反应，构建分子多样、结构新颖的γ-丁内酯核心结构的类天然产物化合物库。本项目的实施对杂环药物的先导化合物发现有重要意义。