A Radical Approach to C-H Alkylation

有机化学改变了我们的生活方式。它使我们能够创造出治疗疾病的分子，种植农作物来养活我们的人口，并创造出用于现代技术的高科技材料。有机分子本身含有几十个C-H键，这些C-H键组成了它们的碳氢化合物骨架，但这些键通常是“惰性的”和不起反应的。C-H官能化领域的目标是找到有选择地用其他化学基团取代一个或多个这些C-H键的方法，使化学家能够以更有效、更具成本效益和更可持续的方式构建分子。考虑到简单脂肪族基团(如Me、Et、i-Pr)的引入会引起化学性质和生物学性质的巨大变化，从结构多样化的角度来看，C-H键的烷基化被认为是最理想的取代之一。然而，尽管在这一领域取得了一些令人瞩目的进展，C-H烷基化仍然不是有机合成中的常规断链。对于脂肪族化合物中的C(SP3)-H键，大多数解决方案依赖于氢原子的抽提来生成烷基中间体，然后用烷基化试剂捕获这些自由基。由于自由基本身并不具备与饱和的烷基亲电试剂直接接触所需的反应性，因此过渡金属如镍被用来将自由基中间体引入有机金属催化循环。然而，依赖过渡金属催化剂来建立C(SP3)-C(SP3)键可能会导致药物开发环境中的问题，因为这些催化剂容易被类药物分子(例如，胺、某些杂芳烃)中常见的基本官能团中毒。此外，微量金属污染在制药环境中是一个严重的问题。由于这些原因，无金属的C(SP3)-H键烷基化方法在有机合成中可能被证明是变革性的。在这个项目中，我们将开发一种概念上独特的方法来催化C(SP3)-H键的烷基化-安装简单的烷基-不需要有机金属催化。鉴于最近工业呼吁的方法“容忍氮杂原子和(无保护的)极性官能团”，我们的努力将主要集中在脂肪胺的C(SP3)-H烷基化。目前尚不清楚用简单的烷基取代未受保护的胺中的α-C-H键的温和催化方案，而发明强大的程序来实现这些转化将构成小分子药物合成的一步变化。毕竟，在药物化学中最广泛使用的十种合成方法中有两种(即N-烷基化和还原胺化)专门用于靶向取代胺，但这两种方法都依赖于C-N，而不是C-C键的形成。值得注意的是，制药工业中第三大最常用的反应是添加或去除胺N保护基团(即BOC)，这本身就说明与未保护的胺相兼容的合成方法很少。鉴于80%以上的药物或候选药物含有胺功能，显然，能够以可扩展和可持续的方式获得复合胺的新的合成方法将对我们社会的健康和福祉产生明显的影响。

Organic chemistry has transformed the way we live. It has allowed us to create molecules to treat disease, to grow crops to sustain our population, and to create high-tech materials used in modern technology. Organic molecules by their very nature contain dozens of C-H bonds which make up their hydrocarbon framework, but these are typically "inert" and unreactive. The field of C-H functionalisation aims to find ways of selectively replacing one or more of these C-H bonds with other chemical groups, allowing chemists to build up molecules in a much more efficient, cost-effective and sustainable fashion. Given the dramatic alterations of chemical and biological properties that can arise from the incorporation of simple aliphatic groups (e.g., Me, Et, i-Pr), the alkylation of C-H bonds is considered to be one of the most desirable substitutions from a structural-diversification viewpoint. However, despite some spectacular advances in this area, C-H alkylation is still not a routine disconnection in organic synthesis. In the case of C(sp3)-H bonds in aliphatic compounds, most solutions to the problem have relied upon hydrogen atom abstraction to generate alkyl radical intermediates, followed by trapping of these radicals with alkylating agents. As radicals alone do not possess the necessary reactivity to engage saturated alkyl electrophiles directly, transition metals such as nickel have been used to usher the radical intermediates into organometallic catalytic cycles. However, a reliance on transition metal catalysts to forge C(sp3)-C(sp3) linkages can lead to problems in a drug development setting, as these catalysts are prone to poisoning by the basic functionalities commonly encountered in 'drug-like' molecules (e.g., amines, certain heteroaromatics). Additionally, trace metal contamination is a serious concern in a pharmaceutical setting. For these reasons, a metal-free approach to C(sp3)-H bond alkylation could prove transformative in organic synthesis. In this project, we will develop a conceptually-distinct approach to the catalytic alkylation of C(sp3)-H bonds - to install simple alkyl groups - that does not require organometallic catalysis. Given the recent industry call for methods that "tolerate nitrogen heteroatoms and (unprotected) polar functional groups", our efforts will be focused primarily on the C(sp3)-H alkylation of aliphatic amines. Mild, catalytic protocols for the substitution of alpha-C-H bonds in unprotected amines with simple alkyl groups are currently unknown, and the invention of robust procedures to effect these transformations would constitute a step-change in the synthesis of small molecule drugs. After all, two of the top ten most widely-used synthetic methods in medicinal chemistry (i.e., N-alkylation and reductive amination) are specifically used to target substituted amines, but both rely on C-N as opposed to C-C bond formation. Tellingly, the third most utilised reaction in the pharmaceutical industry is addition or removal of amine N-protecting groups (i.e., Boc), which inherently speaks to a paucity of synthetic methods compatible with unprotected amines. Given that over 80% of drugs or drug candidates contain amine functionality, it is clear that new and enabling synthetic methods to access complex amines in a scalable and sustainable fashion would have demonstrable impact upon the health and wellbeing of our society.