Selective Functionalization of Aliphatic Amines

脂肪胺的选择性官能化

基本信息

批准号：
10442737
负责人：
Tomislav Rovis
金额：
$ 31.1万
依托单位：
COLUMBIA UNIV NEW YORK MORNINGSIDE
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-07-01 至 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10442737
关键词：
Alkenes Alkylation Amides Amines Automobile Driving Carboxylic Acids Catalysis Chemistry Cobalt Complex Copper Coupling Distal Drug Design FDA approved Funding Goals Health Hydrogen Bonding Imines Metals Methods Nickel Nitrogen Oxidation-Reduction Pharmaceutical Preparations Pharmacologic Substance Planet Earth Positioning Attribute Principal Investigator Protocols documentation Reaction Research Salts Site Sodium Chloride Sulfhydryl Compounds System Therapeutic Agents Uncertainty Work aryl halide catalyst chlorination dehydrogenation design drug discovery efficacious treatment functional group human disease interest programs scaffold small molecule success tertiary amine

Alkenes Alkylation Amides Amines Automobile Driving Carboxylic Acids Catalysis Chemistry Cobalt Complex Copper Coupling Distal Drug Design FDA approved Funding Goals Health Hydrogen Bonding Imines Metals Methods Nickel Nitrogen Oxidation-Reduction Pharmaceutical Preparations Pharmacologic Substance Planet Earth Positioning Attribute Principal Investigator Protocols documentation Reaction Research Salts Site Sodium Chloride Sulfhydryl Compounds System Therapeutic Agents Uncertainty Work aryl halide catalyst chlorination dehydrogenation design drug discovery efficacious treatment functional group human disease interest programs scaffold small molecule success tertiary amine

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项目摘要

Principal Investigator/Program Director (Last, First, Middle): Rovis, Tomislav Selective Functionalization of Aliphatic Amines and Derivatives Aliphatic amines are ubiquitous among pharmaceutical compounds, driving significant research into the synthesis and functionalization of molecules bearing nitrogen atoms. Traditional strategies use functional group handles to synthesize amines. We have been engaged in a research program that uses resident C-H bonds and transforms them directly into the functionality of interest. The central challenge to derivatizing amines, thus, was one of positional selectivity. A number of strategies were advanced in the previous funding period with broad success. In the next funding period, we will expand the repertoire of reactions, the positions of activation and the complementarity to existing methods. We will develop methods to arylate C-H bonds in aliphatic amines, to difunctionalize vicinal C-H bonds in analogy to olefin difunctionalization, again with complete positional selectivity and to use earth abundant metal salts to activate distal C-H bonds of amines. Complementary approaches will be aimed at providing a method to functionalize inaccessible C-H bonds on tertiary amines, common components of many FDA approved drugs. These will allow structural diversification of complex molecules as well as a structural editing approach to provide homologous scaffolds to bioactive molecules. Lastly, primary amines are surprisingly widely available, far more so than alkyl halides or even carboxylic acids, no doubt due to the ubiquity and importance of amide bond constructions. We will develop a complementary strategy that will use the C-N bond as a functional group handle in cross-coupling chemistry. All of these methods are designed to facilitate drug design and discovery in the pursuit of more efficacious treatments for human diseases. The specific goals of this research are as follows: 1) Site-Selective Remote Functionalization of Aliphatic Amines 2) Selective α-Functionalization of Tertiary Alkylamines 3) Deaminative Functionalization of Primary Amines PHS 398/2590 (Rev. 09/04) Page Continuation Format Page

首席调查员/计划总监（最后，第一，中间）：Rovis，Tomislav 脂肪族胺和衍生物的选择性功能化脂肪族胺在药物化合物中无处不在，推动了大量研究带有氮原子的分子的合成和功能化。传统策略使用功能组将胺化合物构成。我们已经参与了使用居民C-H债券的研究计划并将它们直接转化为感兴趣的功能。衍生胺的核心挑战，因此，是位置选择性之一。在上一个资金期间提出了许多策略取得了广泛的成功。在下一个资金期间，我们将扩大反应，激活的位置和现有方法的互补性。我们将开发用于在脂肪族胺中芳基芳烃键的方法，与烯烃双官能化类比，典型的C-H键同样具有完整的位置选择性并使用地球丰富的金属盐激活胺的远端C-H键。补充方法将旨在提供一种在第三级胺上官能化无法访问的C-H键的方法，许多FDA批准的药物的常见组成部分。这些将允许复杂的结构多样化分子以及一种结构编辑方法，可为生物活性分子提供同源支架。最后，初级胺可用，远比酸卤化物甚至羧基均多酸，毫无疑问，由于酰胺键构建的无处不在和重要性。我们将发展一个完全将C-N键用作交叉偶联化学的功能组手柄的策略。所有这些方法旨在促进药物设计和发现，以追求更高效的效率人类疾病的治疗方法。这项研究的具体目标如下： 1）脂族胺的位点选择性远程功能 2）选择性α官能化三级烷基胺 3）原代胺的脱氧功能 PHS 398/2590（修订版09/04）页面延续格式页面