Catalytic activation of oxygen-containing functional groups

化学合成是一项艰苦的实践，但在提供分子途径方面是无价的，这些分子可以为社会带来好处，并有助于回答科学问题。虽然现有技术可以制备任何分子，但对时间和资源的需求往往是不合理的。在有机分子中建立复杂性或引入重要功能的化学反应是最理想的。相比之下，非建设性氧化还原操作、官能团相互转换和保护/去保护步骤仅用于制备键形成的分子。为了使合成更加高效和环保，我们需要新的化学反应，能够直接利用在大量原料分子中普遍存在的处于天然氧化状态的未保护官能团。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/亲电反应正交。因此，虽然格氏反应是形成C-C键的最常见的非催化方法，但它们的使用现在与Pd和ni催化的偶联相比相形见绌。由于含有丰富的含氧官能团，如醇、酚、酮和羧酸，在催化偶联反应中使用这些底物的策略少得惊人。这项研究计划的总体目标是通过实施利用这些功能基团的自然行为的激活策略来改变这种情况。特别是寻找“捷径”反应。这些直接的单步反应旨在取代通常采用的需要非复杂构建预激活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态行为来实现。六名研究生和十名本科生HQP将跨越三个目标来解决这个问题。寻找原位削弱C-O键的激活途径，使醇、烯醇和羧酸能像烷基卤化物、三氟乙烯酯和酸氯化物一样容易地参与偶联化学。在不需要化学计量金属的情况下，将利用温和的方法来控制醇/酮的氧化态（“借氢”）。最后，将探讨使烯酮和非氧化pi系统具有瞬时亲核性的策略，为正式的碳氢官能化提供一种独特的方法。为了解决这些问题，HQP将在有机合成、催化和现代化学技术方面接受世界级的培训。沿着发现之路获得的见解将被推广到为化学家提供新的工具，以更好地获取加拿大人赖以提高生活质量的当前和未来的药物、材料和性能化学品。

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.