Selective Nitrogen Atom Transfer for Applications in Biomedical Sciences

选择性氮原子转移在生物医学科学中的应用

• 批准号: 9018047
• 负责人: Hao Xu
• 金额: $ 28.12万
• 依托单位: GEORGIA STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-05-01 至 2019-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9018047
• 关键词: Alkenes; Amination; Amines; Amino Acids; Amino Alcohols; Biological; Biomedical Research; Clinical Research; Development; Foundations; Goals; Health; Hydrocarbons; Hydroxyl Radical; Indole Alkaloids; Indoles; Iron; Mediating; Metals; Methods; Nitrogen; Organic Synthesis; Pharmaceutical Chemistry; Pharmacologic Substance; Reaction; Research; Science; Series; Transition Elements; analog; base; drug discovery; functional group; innovation; method development; novel; small molecule; tool

DESCRIPTION (provided by applicant): Numerous pharmaceuticals contain at least one nitrogen atom and many of those nitrogen atoms are directly attached to stereogenic centers. Therefore, synthetic methods that incorporate selective nitrogen atom transfer to readily available hydrocarbons are important tools for the synthesis of these valuable molecules. While methods for selective olefin aziridination and direct C-H amination are well-established, methods for direct difunctionalization of olefins with a nitrogen atom and a range of heteroatom-based functional groups are less explored yet critically important to organic synthesis and its applications to the biomedical sciences. In particular, a general and selective nitrogen atom transfer approach that can achieve the aminohydroxylation, aminofluorination, and aminohalogenation of a wide variety of olefins has yet to be discovered. Our long-term goal is to develop selective and general nitrogen atom transfer methods that directly difunctionalize a wide variety of olefins with a nitrogen and a range of heteroatom-based functional groups. The objective of the proposed research is to develop a series of iron-catalyzed nitrogen atom transfer methods for direct olefin difunctionalization with an emphasis on aminohydroxylation, aminofluorination, and aminohalogenation. Based upon our preliminary discoveries, our underlying hypothesis is that a unique iron- nitrenoid can be modulated to mediate a range of olefin difunctionalization reactions rather than only precedent aziridination and C-H amination reactions. The proposed research will explore this hypothesis in the context of two Specific Aims. First, we plan to develop iron-catalyzed, selective aminohydroxylation methods that will incorporate a variety of olefin and heteroarene substrates for synthesis of amino alcohols and b-hydroxyl amino acids. Second, we will develop iron-catalyzed, selective aminofluorination and aminohalogenation methods for a range of olefins that will afford b-fluoro, chloro, and bromo amines as well as b-fluoro and chloro amino acids. The proposed approach is innovative because it explores the new reactivity of an iron-nitrenoid in a context that significantly departs from the established reactivity of metal-nitrenoids. The proposed research is significant because it will lay the foundation for the development of a wide range of methods for selective olefin difunctionalization from the same type of reactive intermediate generated from a first-row transition metal. Completion of the proposed research will provide an array of unique olefin difunctionalization methods that would become valuable tools for medicinal chemists. Furthermore, it will also produce a variety of valuable synthetic building blocks and biologically important molecules that will accelerate the basic biomedical and clinical research.

描述（由申请人提供）：许多药物至少包含一个氮原子，许多氮原子直接连接到立体中心。因此，将选择性氮原子转移到容易获得的碳氢化合物中的合成方法是合成这些有价值分子的重要工具。虽然选择性烯烃和直接的C-H氨基化的方法是建立的，但具有氮原子直接进行烯烃的直接化方法和一系列基于杂原子的官能团的方法对有机合成及其应用于生物学科学的应用非常重要。特别是，尚未发现一种可以实现氨基羟基化，氨基氟化和氨基化的一般和选择性的氮原子转移方法。 我们的长期目标是开发选择性和一般的氮原子转移方法，这些方法将各种氮和一系列基于异源的官能团直接扩散。拟议的研究的目的是开发一系列铁催化的氮原子转移方法，用于直接烯烃扩散化，重点是氨基羟基化，氨基氟化和氨基化。基于我们的初步发现，我们的基本假设是可以调节独特的铁硝酸铁，以介导一系列烯烃扩散反应，而不仅仅是先例的氮杂化反应和C-H胺化反应。拟议的研究将在两个具体目标的背景下探讨这一假设。首先，我们计划开发铁催化的选择性氨基羟基化方法，该方法将结合各种烯烃和杂种底物，以合成氨基醇和B-羟基氨基酸。其次，我们将开发一系列烯烃的铁催化，选择性的氨基氟化和氨基化方法，这些方法将负担得起B-fluoro，Chloro和Bromo胺以及B-氟氟胺和氯氯氨基酸。 提出的方法具有创新性，因为它探索了核酸铁的新反应性，在显着离开的情况下 来自金属硝酸盐的既定反应性。拟议的研究很重要，因为它将为从第一行转变金属产生的相同类型的反应性中间体提供多种方法为开发多种方法奠定基础。拟议的研究的完成将提供一系列独特的烯烃四功能化方法，这些方法将成为药物化学家的宝贵工具。此外，它还将产生各种有价值的合成构建块和生物学上重要的分子，这些构件将加速基本的生物医学和临床研究。