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.

项目摘要/摘要 当前的有机化和医学化学状态集中在开发方法上 具有精确安装在一系列化学空间上的功能广度的能力。具体来说， 在综合开始时可以安装多样性功能的能力非常强大，因为以多样性为导向的综合 可以导致化学文库的快速形成。另一方面，晚期的重要性 多样化具有同等意义，因为候选药物的生理化学特性很容易被很容易 调整以提供足够的细胞渗透性，寿命和效力。 2012年，所有前10种销售毒品 包含硫功能，检查和其他已知的治疗剂编码 硫缺乏立体化学信息。具体而言，胸骨骨骼经常 由于没有流线，因此缺乏含碳的碳含碳的立体化学 当前可用于访问它们的方法。因为硫功能通常是 治疗剂能够在此位置安装立体化学的能力非常重要，因为它可以 动态改变其生物学特性。该提案计划的研究主题是 开发一种耦合技术，该技术可迅速访问高度潜水员的对照 含有替代立体中心的硫纤维支架。同等意义的是访问其他生物的能力 相关的硫骨骼通过手性硫醚库的建设性社论。此外，这个 预计化学是高度对映选择性的，这使其更适合于药物 行业是因为本质上必须将所有药物作为对映射产品制备。完成这些 目标我们的计划始于制定晚期多元化协议，通过对 氧化的硫醇支架“亚硫化氧化物系统”，可以优化反应参数。 其次，将开发早期方法以高度可编程的方式访问硫代 从三种市售试剂（醛，硫醇和烯烃）中。然后，我们希望证明 通过选择相关的早期和晚期药物发现，这项技术的一般性和鲁棒性 药物靶标并将其核心多样化为所描述的化学空间的领域。总体而言， 预计该化学的成功将填补当今的空隙，以获取这两种化合物 学术和工业环境。