不对称Conia-ene反应构建高度官能团化环戊酮并应用于前列腺素的多样性合成研究

Prostaglandins (PGs), a kind of important endogenous natural products,possess multiple biological activities as well as widely used in medical treatment. PGs are mainly derived from total synthesis. Structurally, PGs possess a challenging five-membered ring system with several stereoegenic centers. Therefore, it is very significant to develop an efficient approach to construction of the chiral cyclopentanone framework, and achieve PGs' asymmetric diversity synthesis. We attempt to develop an approach to rapid construction of highly functionalized cyclopentanone, followed by a few simple transformations to achieve the diversity synthesis of PGs. A Conia-ene reaction has been proved to be an efficient method for construction of the five-membered ring systems.However, construction of the cyclopentanones has not been reported via an asymmetric Conia-ene reaction. We attempt to develop a Br?nsted base/Lewis acid co-catalyed Conia-ene reaction for construction of the highly functionalized cyclopentanones, so as to achieve the diversity synthesis of PGs and the natural product-like libraries which are able to provide lead compounds for drug discovery.

前列腺素是一类重要的，具有多重生物活性的内源性天然产物，在医药领域有广泛用途。PGs及其类似物目前主要是通过人工全合成方法制备。前列腺素的五元碳环上含有多个手性碳原子，立体选择性合成难度大。发展高效不对称方法构建手性环戊酮骨架，进而实现前列腺素化合物多样性合成具有重要意义。本项目拟通过发展不对称方法快速构建高度官能团化环戊酮结构，并经过简单官能团转化实现前列腺素化合物高效、多样性合成。Conia-ene 反应是高效的构建五元碳环的方法之一，然而对于不对称Conia-ene反应构建环戊酮，迄今为止没有报道。通过发展Brønsted base/Lewis acid联合催化的不对称Conia-ene反应构建手性高度官能团化环戊酮，进而实现前列腺素化合物的多样性不对称合成，同时运用此高效反应建立前列腺素类天然产物分子库，为前列腺素类药物研发提供研究基础。

前列腺素(prostaglandins，PGs)是一类重要的具有多重生物活性的内源性天然产物，在医药领域有广泛用途。PGs及其类似物从自然界来源缺乏，目前主要是通过人工全合成方法制备。前列腺素的高度官能团化的五元碳环结构给合成带来了挑战。本项目通过以廉价易得的β-酮酯为原料，合成了β-酮酯的关环前体。实现FeCl3促进的微波辅助的Conia-ene关环反应，一步快速高效合成多官能团取代的不饱和环戊酮结构。同时也发展了In(OTf)3与硫脲共同促进的不对称Conia-ene关环反应。为实现前列腺素化合物多样性的合成，我们研究了末端炔烃的反应，发展了钯/铜催化的甲基 2-(2’, 2’-二溴烯烃)苯酸盐与末端炔烃的串联反应，端炔的卤代反应，以及C-H官能团化反应。