Copper-Catalyzed Enantioselective Addition of Styrene-Derived Nucleophiles to Thiocarbenium Ions by Ligand-Controlled Chemoselective Hydrocupration

项目摘要/摘要 有机和药物化学的当前状态集中在开发 有能力在一系列化学空间内精确安装广泛的功能。具体地说， 与面向多样性的合成相比，在合成开始时安装多种功能的能力非常强大 可导致化学库的快速形成。另一方面，后期的重要性 多样化同样重要，因为候选药物的物理化学性质很容易 经过调整以提供足够的细胞渗透性、寿命和效力。2012年，前十大毒品销售量 含有硫官能团，并在检查后和其他已知的治疗药物结合 硫磺缺乏立体化学信息。具体地说，硫醚骨架往往 含硫碳缺乏立体化学，特别是邻近的立体中心，因为没有流线 目前有多种方法可以访问它们。因为硫的官能度通常是 治疗剂在这个位置安装立体化学的能力非常重要，因为它可以 戏剧性地改变了它的生物特性。这项建议计划的研究主题是 开发一种耦合技术，提供快速获得高度不同的对映体浓缩物的途径 含有邻近立体中心的硫醚支架。同样重要的是能够访问其他生物- 通过对手性硫醚文库的建设性阐述，得到了相关的硫骨架。此外，这一点 据预测，化学具有高度的对映选择性，这使得它更适合于药物 因为基本上所有药物都必须以对映体产品的形式制备。要实现这些目标 目标我们的计划从制定后期多样化协议开始，通过对以下方面进行初步调查 氧化硫醚支架“亚硫氧化物体系”，使反应参数得到优化。 其次，将开发早期方法，以高度可编程的方式获取硫醚 从三种商用试剂(醛、硫醇和烯烃)中提取。然后，我们希望演示 该技术在早期和晚期药物发现中的通用性和稳健性 药物目标，并使其核心多样化，进入所述化学空间领域。总体而言， 这种化学的成功有望填补目前在获取这类化合物方面的空白 学术界和工业界都是如此。

Project Summary/Abstract The current state of organic and medicinal chemistry is centered on developing methodologies that have the ability to precisely install a breadth of functionality over a range of chemical space. Specifically, the ability to install diverse functionality at the start of a synthesis is very powerful as diversity oriented synthesis can lead to the rapid formation of chemical libraries. On the other hand, the importance of late stage diversification is of equal significance because the physiochemical properties of a drug candidate can be easily tuned to provide adequate cell permeability, lifetimes and potency. In 2012, all of the top 10 selling drugs contained sulfur functionality and upon their examination and other known therapeutic agents incorporating sulfur a lack of stereochemical information was observed. Specifically, thioether skeletons more often than not lack stereochemistry at the sulfur bearing carbon especially vicinal stereogenic centers because no streamline methods are currently available to access them. As sulfur functionality is often the crucial component of the therapeutic agent the ability to install stereochemistry at this location is very significant because it could dramatically alter its biological properties. The theme of the research planned in this proposal is the development of a coupling technology that provides expeditious access to highly diverse enantioenriched thioether scaffolds containing vicinal stereocenters. Of equal significance is the ability to access other bio- relevant sulfur skeletons through the constructive elaboration of chiral thioether libraries. Furthermore, this chemistry is predicted to be highly enantioselective which makes it even more suitable for the pharmaceutical industry because essentially all medications must be prepared as enantiopure products. To accomplish these goals our plan starts with developing a late stage diversification protocol by performing initial investigations on oxidized thioether scaffold “sulfoxide system” that allows for the reaction parameters to be optimized. Secondly, early stage methodologies will be developed to access thioethers in a highly programmable manner from three commercially available reagents (aldehyde, thiol and alkene). We then wish to demonstrate the generality and robustness of this technology in both early and late stage drug discovery by selecting a relevant pharmaceutical target and diversifying its core into the realm of the described chemical space. Overall, the success of this chemistry is expected to fill the present-day void in accessing such compounds in both the academic and industrial settings alike.