Selective Nitrogen Atom Transfer for Applications in Biomedical Sciences

描述（由申请人提供）：许多药物含有至少一个氮原子，并且这些氮原子中的许多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烃的合成方法是合成这些有价值的分子的重要工具。虽然用于选择性烯烃氮丙啶化和直接C-H胺化的方法是完善的，但是用于具有氮原子和一系列基于杂原子的官能团的烯烃的直接双官能化的方法较少探索，但对于有机合成及其在生物医学科学中的应用至关重要。特别地，尚未发现可以实现多种烯烃的氨羟基化、氨取代和氨卤化的一般和选择性氮原子转移方法。 我们的长期目标是开发选择性和通用的氮原子转移方法，直接双官能化各种各样的烯烃与氮和一系列杂原子基官能团。提出的研究的目的是开发一系列的铁催化的氮原子转移方法直接烯烃双官能化，重点是氨羟基化，氨基取代，和氨基卤化。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-类氮杂环戊烯以介导一系列烯烃双官能化反应，而不仅仅是先前的氮丙啶化和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羟化方法，该方法将结合各种烯烃和杂芳烃底物用于合成氨基醇和b-羟基氨基酸。其次，我们将开发铁催化的，选择性的氨基化和氨基卤化方法，用于一系列烯烃，将提供b-氟，氯，溴胺以及b-氟和氯氨基酸。 所提出的方法是创新的，因为它探讨了新的反应性的铁氮类化合物的背景下，显着偏离 从金属-氮杂环戊烯的既定反应性。所提出的研究是有意义的，因为它将奠定基础的发展范围广泛的方法选择性烯烃双官能化从同一类型的反应中间体产生的第一行过渡金属。拟议研究的完成将提供一系列独特的烯烃双官能化方法，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结构单元和生物重要分子，这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.