A Radical Approach to C-H Alkylation

有机化学改变了我们的生活方式。它使我们能够创造治疗疾病的分子，种植作物以维持我们的人口，并创造用于现代技术的高科技材料。有机分子本质上含有数十个C-H键，这些C-H键构成了它们的烃框架，但这些通常是“惰性”和不反应的。C-H功能化领域的目标是找到用其他化学基团选择性地取代一个或多个C-H键的方法，使化学家能够以更有效，更具成本效益和可持续的方式构建分子。考虑到化学和生物学性质的显著改变可以由简单的脂族基团（例如，Me，Et，i-Pr），C-H键的烷基化被认为是从结构多样化的观点来看最理想的取代之一。然而，尽管在这一领域取得了一些引人注目的进展，C-H烷基化仍然不是有机合成中的常规断开。在脂肪族化合物中的C（sp3）-H键的情况下，该问题的大多数解决方案依赖于氢原子提取以产生烷基自由基中间体，然后用烷基化剂捕获这些自由基。由于自由基本身不具有直接与饱和烷基亲电试剂结合的必要反应性，因此过渡金属如镍已被用于引导自由基中间体进入有机金属催化循环。然而，依赖于过渡金属催化剂来锻造C（sp3）-C（sp3）键可能导致药物开发环境中的问题，因为这些催化剂易于被“类药物”分子中通常遇到的基本官能团（例如，胺、某些杂芳族化合物）。此外，痕量金属污染是制药环境中的严重问题。由于这些原因，C（sp3）-H键烷基化的无金属方法可以证明在有机合成中具有变革性。在这个项目中，我们将开发一种概念上不同的方法来催化烷基化C（sp3）-H键-安装简单的烷基-不需要有机金属催化。考虑到最近工业上对“耐受氮杂原子和（未保护的）极性官能团”的方法的要求，我们的努力将主要集中在脂肪胺的C（sp3）-H烷基化上。用简单的烷基取代未保护的胺中的α-C-H键的温和的催化方案目前是未知的，并且实现这些转化的稳健程序的发明将构成小分子药物合成中的阶跃变化。毕竟，药物化学中十大最广泛使用的合成方法中有两种（即，N-烷基化和还原胺化）专门用于靶向取代的胺，但两者都依赖于C-N而不是C-C键的形成。显然，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），其本质上说明与未保护胺相容的合成方法的缺乏。鉴于超过80%的药物或候选药物含有胺官能团，很明显，以可扩展和可持续的方式获得复杂胺的新的和可行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.