New Catalytic Reductive Functionalization Reactions of Carbonyl Derivatives

尽管在过去的7年里，已经建立了一系列新的叔胺的还原转化，但瓦斯卡型络合物对其他不太路易斯的官能团，如仲酰胺、酯和氨基甲酸酯的类似应用基本上还没有被探索。然而，对Vaska类化合物增强还原能力的新的计算机理洞察(见下文)，结合其简单而模块化的合成路线，在其他常见的羰基衍生物的还原功能化中发现了大量尚未开发的潜力。这个博士项目旨在探索这些新的应用，并在药物类分子的后期功能化和复杂天然产品的合成中开发和利用它们。将对这些反应的范围、官能团耐受性和选择性进行全面的调查。这一方法学的发展可能导致微不足道的化学修饰，从而获得与药物相关的复杂化学基序，并具有广泛的工业应用潜力。在这个项目中，将探索一系列催化剂，允许微调反应活性，以及调节还原官能化的区域选择性。该项目属于EPSRC“制造未来”研究领域。新方法学的发展对化学工业的未来是势在必行的，并有助于药物化学家获得新的工具，使药物在后期功能化，以研究结构活性关系(SAR)。扩展合成化学家可用的化学工具箱可以使人们能够访问以前无法访问的基序，并简化现有的化学转化。传统上，耗时、耗费资源的反应可以从现成的起始材料一步完成，从而允许构建目标分子并降低多步反应对环境的影响。这种方法的应用旨在扩展到产生有价值的生物等位体，这些官能团模仿自然界中的官能团，允许调节DMPK和ADME的性质，如结合强度、溶解性、稳定性、渗透性和其他可优化的参数。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，因为如上所述，该项目具有广泛的潜在工业应用。

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.