Selective Nitrogen Atom Transfer for Applications in Biomedical Sciences

描述(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连接到立体生成中心。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的分子的重要工具。虽然选择性烯烃氮杂化和直接C-H胺化的方法已经成熟，但烯烃与氮原子和一系列基于杂原子的官能团直接双官能化的方法探索得较少，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，还没有发现一种通用的、选择性的氮原子转移方法，可以实现多种烯烃的氨羟化、氨氟化和氨卤化反应。我们的长期目标是开发选择性和一般性的氮原子转移方法，使多种烯烃与氮和一系列基于杂原子的官能团直接去功能化。本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的双官能化，重点是氨羟化、氨氟化和氨卤化。根据我们的初步发现，我们的基本假设是，一种独特的铁-氮烯类化合物可以被调节来调节一系列的烯烃去功能化反应，而不仅仅是先例的氮杂环化和C-H胺化反应。这项拟议的研究将在两个具体目标的背景下探索这一假设。首先，我们计划开发铁催化的选择性氨羟化方法，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，我们将为一系列烯烃开发铁催化的选择性氨氟化和氨卤化方法，这些方法将产生b-氟、氯和溴胺以及b-氟和氯氨基酸。提出的方法是创新的，因为它探索了在一个显著不同的背景下类铁的新的反应性 从已建立的金属-硝基化合物的反应性。这项研究具有重要意义，因为它将为从第一排过渡金属生成的相同类型的反应中间体开发一系列选择性烯烃双官能化方法奠定基础。拟议研究的完成将提供一系列独特的烯烃去功能化方法，这些方法将成为药物化学家的宝贵工具。此外，它还将生产各种有价值的合成构件和具有生物重要性的分子，这些将加速基础生物医学和临床研究。

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.