Enantioselective C-H C-H Coupling of Alcohols with Heteroarenes

有机化学家的主要目标是构建分子，用于药物，新材料和生物分子等多种应用。在药物中反复出现的一种特殊的分子结构是杂芳环。这是一个平面结构，其表面上是一个离域电子环。它与普通芳环的区别在于它不仅由碳组成，而且有一个“杂原子”，通常是氮。这种氮在生物系统中特别有用，因为当碱性时，它允许与生物分子相互作用，这对新药的功效至关重要。想要合成这些有用分子的化学家面临的挑战是，由于碱性氮的碱性，通常会干扰化学方法。当在控制绝对立体化学（即产物的“手性”）的情况下在杂原子旁边形成立构中心时，该挑战尤其尖锐。由于单个氨基酸残基的点手性或DNA的螺旋手性，自然界本身就具有固有的手性或“手性”，因此控制这一因素在潜在药物中至关重要。我们最近开发了一种对映选择性反应，可以将前手性基团添加到最常用的碱性杂芳烃吡啶和喹啉中（Science，2018，360，419）。该反应在非对映体选择性意义上已经被了解了很多年，并且通常被描述为Minisci型加成，并且据我们所知，我们最近的贡献构成了这个非常重要的化学反应的第一个对映体选择性版本。然而，我们最初的方案仅允许获得手性胺，并且我们用于获得前手性基团的方法也具有许多实际缺点，这可能会限制其在合成社区中的更广泛使用。在这项研究中，我们将开发一种方法，从简单的醇开始，产生自由基，将添加到杂芳烃在Minisci型加成。这是具有挑战性的，原因有很多，在提案中详细列出了，但当成功时，回报将是巨大的，因为它将正式允许两个C-H键转化为C-C键，完全控制立体化学。此外，我们还将研究Minisci型加成的中断，其中中间体自由基被底物中的侧基官能团捕获，以生成独特的部分饱和杂环，这将在药物研究图书馆中引起极大兴趣。开发新药所需的时间和成本直接影响我们的社会。本文所提出的化学是药物开发的核心;加快这一进程对于更快地获得新的、负担得起的药物至关重要。在英国大学进行的世界领先的科学研究对增长和就业至关重要;这项研究将在催化剂的最前沿开展，我们的研究结果将加强这一关键领域。

A primary goal of organic chemists is the construction of molecules for applications as diverse as medicines, new materials and biomolecules. One particular molecular structure which crops up over and over again in medicines is the heteroaromatic ring. This is a planar structure over the surface of which is a ring of delocalised electrons. What differentiates this from a normal aromatic ring is that it is not just comprised of carbons but has a 'heteroatom', often a nitrogen. This nitrogen can be particularly useful in biological systems as, when basic, it allows for interaction with biomolecules which can be crucial to the efficacy of new medicines. The challenge for chemists who want to synthesise these useful molecules is that often the basic nitrogen may interfere with chemical methodology due to this basicity. This challenge is particularly acute when stereocentres are to be formed next to the heteroatom with control of absolute stereochemistry - ie the 'handedness' of the product. Control of this factor is essential in potential medicines since nature itself is inherently chiral or 'handed' due to the point chirality of individual amino acid residues, or the helical chirality of DNA.We have recently developed an enantioselective reaction which allows the addition of prochiral radicals to the most commonly used basic heteroarenes, pyridine and quinoline (Science, 2018, 360, 419). This reaction has been known in a non-enantioselective sense for many years and is typically described as a Minisci-type addition and to the best of our knowledge our recent contribution constitutes the first enantioselective version of this very important chemical reaction. However, our original protocol only allowed access to chiral amines and the method we used to obtain the prochiral radical also possessed a number of practical disadvantages that would likely limit its broader use within the synthetic community. In this research we will develop a method to start from simple alcohols to generate the radicals that will add to the heteroarenes in Minisci-type additions. This is challenging for a number of reasons, laid out in detail in the proposal, but when made successful the payoff will be substantial as it will formally allow two C-H bonds to be transformed into a C-C bond with full control of stereochemistry. Additionally we will also investigate the interruption of a Minisci type addition in which an intermediate radical is trapped by a pendent functional group in the substrate to generate unique partially saturated heterocycles that will be of great interest in library for pharmaceutical research.The time and cost required to develop new medicines directly impacts our society. Chemistry such as that proposed herein lies at the heart of drug development; expediting this is crucial for faster access to new, affordable medicines. The world-leading scientific research performed in UK universities is crucial to growth and jobs; this research will operate at the cutting edge of catalysis and our findings will strengthen this crucial sector.