Catalytic activation of oxygen-containing functional groups

化学合成是一个费力的实践，但在提供对社会有益的分子并帮助回答科学问题方面是无价的。虽然任何分子都可以用现有技术制备，但时间和资源的需求往往是不合理的。构建复杂性或将重要功能引入有机分子的化学反应是最理想的。相反，非建设性的氧化还原操作，官能团互变，和保护/脱保护步骤仅用于制备关键键形成的分子。为了使合成成为一种更有效和环保的实践，我们需要新的化学反应，这些反应能够直接利用在其天然氧化态的大量原料分子中普遍存在的未保护的官能团。过渡金属催化，特别是交叉偶联反应，已被证明是构建分子复杂性的有力工具，与更传统的亲核试剂/亲电试剂反应正交。因此，虽然格氏反应是用于形成C-C键的单一最常见的非催化方法，但它们的使用现在与Pd & Ni催化的偶联相比相形见绌。考虑到含氧官能团如醇、酚、酮和羧酸的丰度，在催化偶联反应中使用这些底物的策略令人惊讶地少。这项研究提案的总体目标是通过实施利用这些官能团的自然行为的激活策略来改变这一点。特别是，寻求“快捷”反应。这些直接的单步反应被设计为取代通常采用的需要非复杂性构建预活化步骤的多步合成程序。 这一研究目标将通过利用含碳氧键分子的动力学行为来实现。六名研究生和十名本科生HQP将通过三个目标解决这个问题。寻求原位削弱C-O键的活化途径以使醇、烯醇和羧酸能够像烷基卤化物、乙烯基三氟甲磺酸酯和酰氯一样容易地参与偶联化学。温和的方法来操纵醇/酮的氧化态（“借用氢”）将被利用在开发的Grignard样的1，2加成，而不需要化学计量的金属。最后，将探索使烯酮和非含氧π-系统瞬时亲核的策略，为正式的C-H官能化提供独特的方法。在解决这些问题的过程中，HQP将接受有机合成，催化和现代化学技术方面的世界级培训。沿着发现之路获得的见解将被推广到武装化学家的新工具，以更好地获得当前和未来的药物，材料和性能化学品加拿大人依赖于他们的生活质量。

Chemical synthesis is a laborious practice but is invaluable in providing access to molecules that provide benefits to society and help answer scientific questions. While any molecule can be prepared with existing technology, the demand of time and resources is often unreasonable. Chemical reactions that build complexity or introduce important functionality into an organic molecule are most desirable. In contrast, non-constructive redox manipulation, functional group interconversion, and protection/deprotection steps serve only to prepare a molecule for key bond formations. To make synthesis a more efficient and environmentally friendly practice, we need new chemical reactions that are able to directly harness the unprotected functional groups that are prevalent in abundant feedstock molecules in their native oxidation state. Transition metal catalysis, and cross-coupling reactions in particular, has proven itself to be powerful tool for building molecular complexity that is orthogonal to more traditional nucleophile/electrophile reactions. Thus, while Grignard reactions are the single most common non-catalytic method used to form C-C bonds, their use is now dwarfed by Pd & Ni-catalyzed couplings. Given the abundance of oxygen-containing functional groups like alcohols, phenols, ketones, and carboxylic acids, there are surprisingly few strategies for using these substrates in catalytic coupling reactions. The overarching goal of this research proposal is to change this by implementing activation strategies that exploit the natural behaviour of these functional groups. In particular, 'shortcut' reactions are sought. These direct, single step reactions are designed to replace commonly employed multi-step synthetic procedures that require non-complexity building pre-activation steps. This research goal will be achieved by exploiting the dynamic behaviour of carbon-oxygen bond containing molecules. Six graduate students and ten undergraduate HQP will tackle this problem across three objectives. Activation pathways that weaken C-O bonds in situ are sought to enable alcohols, enols, and carboxylic acids to participate in coupling chemistry as readily as alkyl halides, vinyl triflates, and acid chlorides. Mild methods to manipulate the alcohol/ketone oxidation state (`borrowing hydrogen') will be exploited in the development of Grignard-like 1,2 additions without the requirement of stoichiometric metals. Lastly, strategies to render enones and non-oxygenated pi-systems transiently nucleophilic will be explored, providing a unique approach to formal C-H functionalizations. In solving these problems, HQP will receive world-class training in organic synthesis, catalysis, and modern chemistry technologies. Insights gained along the path to discovery will be generalized to arm chemists with new tools to better access the current and future medicines, materials, and performance chemicals Canadians rely on for their quality of life.