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: 8673127
• 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/8673127
• 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）：许多药物含有至少一个氮原子，其中许多氮原子直接附着在立体中心上。因此，将选择性氮原子转移到现成的碳氢化合物上的合成方法是合成这些有价值分子的重要工具。虽然选择性烯烃叠氮化和直接碳氢胺化的方法已经建立，但与氮原子和一系列杂原子官能团直接双官能团化烯烃的方法探索较少，但对有机合成及其在生物医学科学中的应用至关重要。特别是，一种通用的和选择性的氮原子转移方法，可以实现各种各样的烯烃的氨基羟基化，氨基氟化和氨基卤化尚未发现。我们的长期目标是开发选择性和通用的氮原子转移方法，直接用氮和一系列杂原子基官能团对各种烯烃进行双官能团化。本研究的目的是开发一系列铁催化氮原子转移的烯烃直接双功能化方法，重点是氨基羟基化、氨基氟化和氨基卤化。基于我们的初步发现，我们的基本假设是，一种独特的类氮铁可以被调节来介导一系列的烯烃双官能化反应，而不仅仅是先前的叠氮化和碳氢胺化反应。提出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芳烃底物来合成氨基醇和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氨基氟化和氨基卤化方法，这些方法将提供b-氟、氯和溴胺以及b-氟和氯氨基酸。所提出的方法是创新的，因为它探索了铁-硝基类铁在明显不同的环境中的新反应性