Catalytic C-H Activation of Aliphatic Amines

脂肪族胺是许多生物活性分子功能的核心，它们在大量药物制剂中的普遍存在证明了这一点。附加在这些氮原子上的基团对于决定胺的物理性质至关重要，并与它与生物靶标的相互作用有关。尽管脂肪胺基序明显简单，但用于合成这一重要特征的一般方法的数量却少得惊人。诸如还原胺化、烷基化、氢胺化和转胺化等方法已经满足了多年的需求，然而，开发新的直接合成复杂体系的方法对于合成的持续发展至关重要。合成复杂脂肪胺的系统方法对于药物发现的实践者来说是有价值的，并且这些分子的简化方法可能涉及一个催化过程，能够通过其C-H键的选择性功能化将简单，容易获得的脂肪胺转化为复杂的变体。使惰性脂肪族C-H键实现实用和选择性功能化的方法在从精细化工生产到药物发现等领域都有应用。过渡金属催化已经成为激活这些传统上不反应的碳氢键的有力工具。几种官能团可以通过称为环金属化的过程指导C-H活化；金属中心与近端路易斯碱原子的配位引导催化剂进入C-H键可以断裂的位置。生成的c -金属键与外部试剂的反应导致C-H键转化为通用基序的整体转变。环金属化导致了一些有用的催化C-H功能化过程，扩大了化学家可用反应的工具箱；通过调整定向官能团的电子特性，可以实现脂肪族碳氢化合物的环金属化，显示羧酸、羟基和这些基序的衍生物。尽管取得了这些进展，但脂肪胺的相关转化很少，成功的例子需要使用强吸电子磺酰或定制的定向基团来调节氮原子的金属配位能力。因此，它们的合成难解性常常阻碍了在脂肪胺系统中更广泛地应用战略性C-H键激活。本提案的总体目标是建立脂肪族胺作为可行的原料分子为C-H活化使用一种新的活化策略。这将提供不同的C-H断开，这将形成合成C-H激活路线图的一部分。脂肪胺基序在药学相关分子中无处不在，被认为是一种“特权”特征，因此我们将研究如何将多方面的C-H激活平台转化为影响药物发现和开发的可行应用。

Aliphatic amines are central to the function of many biologically active molecules as evidenced by their prevalence in a large number of pharmaceutical agents. The groups appended to these nitrogen atoms are crucial in determining the physical properties of the amine and are linked to how well it interacts with a biological target. Despite the apparent simplicity of the aliphatic amine motif, the number of general methods available for the synthesis of this important feature is surprisingly small. Methods such as reductive amination, alkylative tactics, hydroamination and transamination have met the demand for many years, however the development of new straightforward methods for the synthesis of complex systems is essential for the continued advance of synthesis. A systematic method for the synthesis of complex aliphatic amines would be valuable to practitioners of drug discovery, and a streamlined approach to these molecules could involve a catalytic process capable of transforming simple, readily available aliphatic amines into complex variants via selective functionalization of their C-H bonds.Methods that enable the practical and selective functionalization of inert aliphatic C-H bonds have applications in fields that range from fine chemical production to drug discovery. Transition metal catalysis has emerged as a powerful tool to activate these traditionally unreactive C-H bonds. Several classes of functional group can direct C-H activation via a process called cyclometallation; coordination of the metal centre to a proximal Lewis basic atom steers the catalyst into position where the C-H bond can be cleaved. Reaction of the resulting C-metal bond with an external reagent leads to an overall transformation that sees a C-H bond converted into a versatile motif. Cyclometallation has led to a number of useful catalytic C-H functionalization processes that have expanded the chemists toolbox of available reactions; tailoring the electronic properties of directing functionalities has enabled cyclometallation in aliphatic hydrocarbons displaying carboxylic acid, hydroxyl groups, and derivatives of these motifs. Despite these advances, related transformations on aliphatic amines are rare and successful examples require the use of strongly electron withdrawing sulfonyl or bespoke directing groups to modulate the metal coordinating power of the nitrogen atom. As such, their synthetic intractability frequently precludes the wider application of strategic C-H bond activation in aliphatic amine systems.The overarching aim of this proposal is to establish aliphatic amines as viable feedstock molecules for C-H activation using a novel activation strategy. This will provide distinct C-H disconnections that will form part of a C-H activation road map for synthesis. The aliphatic amine motif is so ubiquitous in pharmaceutically relevant molecules that it is considered a 'privileged' feature and so we will investigate how the multi-faceted C-H activation platform can be translated into viable applications that have impact drug discovery and development.