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

通过配体控制的化学选择性加氢反应，铜催化苯乙烯衍生的亲核试剂与硫碳鎓离子的对映选择性加成

• 批准号: 9395476
• 负责人: Andy Alexander Thomas
• 金额: $ 5.63万
• 依托单位: MASSACHUSETTS INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-15 至 2020-08-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9395476
• 关键词: Aldehydes; Alkenes; Area; Biological; Carbon; Cells; Chemicals; Chemistry; Complex; Copper; Coupling; Development; Discipline; Drug Industry; Employment; Estrogen Antagonists; FDA approved; Frequencies; Goals; Imines; In Situ; Industrialization; Intercept; Investigation; Ions; Lead; Libraries; Ligands; Location; Mediating; Methodology; Methods; Organic Chemistry; Oxides; Permeability; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacologic Substance; Process; Property; Protocols documentation; Reaction; Reagent; Recording of previous events; Research; Skeleton; Styrenes; Sulfhydryl Compounds; Sulfoxide; Sulfur; System; Tamoxifen; Technology; Therapeutic Agents; analog; catalyst; design; drug candidate; drug discovery; innovation; malignant breast neoplasm; novel therapeutics; pi bond; prevent; programs; scaffold; small molecule; small molecule libraries; stereochemistry; success; sulfa drug; thioether

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.

项目总结/摘要 有机化学和药物化学的现状是集中在开发方法， 具有在化学空间的范围内精确地安装广泛的功能的能力。具体而言是 在合成开始时安装不同功能的能力是非常强大的 可以快速形成化学文库。另一方面，后期的重要性 多样化具有同样的意义，因为候选药物的理化性质可以容易地被改变。 以提供足够的细胞渗透性、寿命和效力。2012年，所有十大销售药物 含有硫官能度，并且在检查它们和其它已知的结合有 观察到硫缺乏立体化学信息。具体地说，硫醚骨架通常 在含硫碳特别是邻位立体中心缺乏立体化学，因为没有流线 目前有方法可以访问它们。由于硫官能度通常是催化剂的关键组分， 治疗剂在该位置设置立体化学的能力是非常重要的， 显著改变了它的生物学特性本提案中计划的研究主题是 开发了一种偶联技术，可快速获得高度多样化的对映体富集的 含有邻位立构中心的硫醚支架。同样重要的是能够访问其他生物- 相关的硫骨架通过手性硫醚库的建设性阐述。而且这 预计化学是高度对映选择性的，这使得它甚至更适合于药物 因为基本上所有的药物必须制备为对映体纯的产品。完成这些 目标我们的计划从制定后期多元化协议开始，对以下方面进行初步调查： 氧化的硫醚支架“亚砜系统”，其允许优化反应参数。 第二，将开发早期方法，以高度可编程的方式获取硫醚 由三种市售试剂（醛、硫醇和烯烃）制得。然后，我们希望展示 在早期和晚期阶段的药物发现中，通过选择相关的 药物靶标，并将其核心多样化到所描述的化学空间的领域。总体看 这种化学的成功有望填补目前在两个领域获得此类化合物的空白， 学术界和工业界都一样。