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.

项目概要/摘要 有机化学和药物化学的现状集中于开发方法， 能够在一系列化学空间中精确安装广泛的功能。 在合成开始时安装不同功能的能力非常强大，因为面向多样性的合成 另一方面，后期的重要性。 多样化具有同等重要的意义，因为候选药物的理化特性可以很容易地被 调整以提供足够的细胞渗透性、寿命和效力 2012 年所有最畅销的药物。 含有硫官能团，并且根据他们的检查和其他已知的治疗剂掺入 硫通常缺乏立体化学信息。 含硫碳尤其是邻位立体中心缺乏立体化学，因为没有流线 目前有方法可以获取它们，因为硫功能通常是其关键组成部分。 治疗剂在该位置安装立体化学的能力非常重要，因为它可以 该提案计划的研究主题是显着改变其生物学特性。 开发一种偶联技术，可以快速获得高度多样化的对映体 含有邻位立体中心的硫醚支架具有同样重要的作用，即能够接触其他生物。 通过手性硫醚库的建设性阐述，获得了相关的硫骨架。 预计化学具有高度对映选择性，这使其更适合制药 因为基本上所有药物都必须制备成对映体纯产品才能实现这些目标。 我们的计划首先通过对以下方面进行初步调查来制定后期多元化协议 氧化硫醚支架“亚砜系统”，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获取硫醚 然后我们希望证明从三种市售试剂（醛、硫醇和烯烃）中得到的结果。 通过选择相关的技术，该技术在早期和后期药物发现中的通用性和稳健性 药物靶向和多样化其核心进入所描述的化学空间领域。 这种化学的成功预计将填补目前在两种领域获取此类化合物的空白 学术和工业环境都是如此。