New Catalytic Reductive Functionalization Reactions of Carbonyl Derivatives

尽管在过去的7年中已经建立了一套新的叔酰胺的还原转化与Vaska的配合物，类似的应用Vaska型配合物的其他较低的刘易斯碱性官能团，如仲酰胺，酯，和氨基甲酸酯仍然基本上未开发。然而，新的计算机理的见解（见下文）到增强还原能力的Vaska型复合物，结合一个简单的和模块化的路线，以他们的合成，已经发现了丰富的未开发的潜力，在还原功能化的其他常见的羰基衍生物。这个博士项目旨在探索这些新的应用，并在药物样分子的后期功能化和复杂天然产物的合成中利用它们。将全面调查这些反应的范围、官能团耐受性和选择性。这种方法的发展可能会导致微不足道的化学修饰，允许获得复杂的化学图案的药物相关性，和广泛的潜在的工业应用。在该项目中，将探索一系列催化剂，允许微调反应性，以及还原官能化的区域选择性的调制。该项目属于EPSRC“制造未来”研究领域的福尔斯。新方法的开发对化学工业的未来至关重要，并帮助药物化学家获得新的工具来后期功能化药物以研究结构活性关系（SAR）。扩大合成化学家可用的化学工具箱可以使以前无法访问的基序，并简化现有的化学转化。传统上耗时的、需要资源的反应可以从容易获得的起始材料在单个步骤中进行，从而允许构建靶分子并降低多步反应的环境影响。该方法的应用旨在扩展到有价值的生物电子等排体的产生，这些生物电子等排体是模拟自然界中发现的那些官能团，允许调节DMPK和ADME性质，如结合强度、溶解度、稳定性、渗透性和其他可优化的参数。由于该项目具有广泛的工业应用潜力，因此该项目与EPSRC转变健康和医疗保健的战略优先事项保持一致。

Despite the suite of new reductive transformations of tertiary amides achievable with Vaska's complex that have been established over the past 7 years, the analogous application of Vaska-type complexes to other less Lewis basic functional groups such as secondary amides, esters, and carbamates has remained essentially unexplored. However, new computational mechanistic insight (vide infra) into enhanced reducing capability of Vaska-type complexes, combined with a simple and modular route to their synthesis, has uncovered a wealth of untapped potential in the reductive functionalization of other common carbonyl derivatives. This PhD project aims to explore these new applications and to and exploit them in late stage functionalisation of drug-like molecules and synthesis of complex natural products. Investigation into the scope, functional group tolerance, and selectivity of these reactions will be carried out in full. Development of this methodology may lead to trivial chemical modification allowing access to complex chemical motifs of pharmaceutical relevance, and wide potential industrial application. Within this project a range of catalysts will be explored allowing for fine tuning of reactivity, as well as modulation of regioselectivity of the reductive functionalisation. This project falls within the EPSRC "manufacturing the future" research area. The development of new methodology is imperative to the future of the chemical industry and help medicinal chemists to access new tools to late-stage functionalise drugs to study structure activity relationships (SAR). Expanding the chemical toolbox available to synthetic chemists can enable access to previously inaccessible motifs and simplify existing chemical transformations. Traditionally time consuming, resource demanding reactions can be carried out in a single step from readily available starting materials, allowing for the construction of target molecules and lowering the environmental impact of multi-step reactions. Applications of this methodology aims to extend to the generation of valuable bio-isosteres, functional groups which mimic those found in nature allowing the tuning tuning DMPK and ADME properties such as binding strength, solubility, stability, permeability and other optimisable parameters. This project aligns its self with the EPSRC strategic priority of transforming heath and healthcare due to the wide potential industrial applications of this project as outlined above.