Synthesis of Quaternary Stereocentres via Hydrogen Borrowing Catalysis

借氢催化是一种通过可逆的氧化状态变化来形成C-C键的有效方法。我们已经证明，在过渡金属催化剂存在下，五甲基苯基酮可以与醇发生烷基化反应，得到α-和β-支化产物。该方法的工作原理是从酒精中提取氢，生成相应的羰基化合物和一种金属氢化物。然后，反应性的羰基化合物可以与Ph*酮进行羟醛缩合得到相应的烯酮，该烯酮随后被金属氢化物还原得到烷基化产物并结束催化循环。因此，借氢方法将氧化、缩合和还原三个过程结合在一起，从而说明了醇的合成用途。在迄今为止的所有借氢反应中，催化循环的结束导致氢原子同时输送到α和β位置，从而排除了在这些位置合成四元中心的可能性。这类四元取代产物由于在药物分子和天然产物等生物相关分子中的广泛存在而引起了极大的合成兴趣。因此，本项目的目的是研究利用借氢催化合成四元中心的策略。我们将研究各种策略(包括置换和重排)，以使α-和β-四元中心同时位于借氢流形中，并通过借氢催化产生此类基序的第一个例子。为了实现这一雄心勃勃的目标，我们将利用和扩展该小组开发的方法。我们还将研究四元产品中Ph*保护基团的裂解，目标是开发温和的裂解条件，以合成一系列不同的α-季铵盐官能团。作为化学合成方法论的延伸，我们将研究产物α-季烷基化合物的进一步反应，利用它们的性质来获得以前通过借氢催化无法获得的其他功能。这种方法可能使药物分子中存在的关键基序的合成高度收敛。该项目预计将提供一个影响很大的研究方案，属于EPSRC物理科学研究领域。

Hydrogen borrowing catalysis is a powerful method for the formation of C-C bonds employing reversible oxidation state changes. We have shown that pentamethylphenyl (Ph*) ketones can be alkylated with alcohols in the presence of a transition metal catalyst to give both alpha- and beta- branched products. The process works by the abstraction of hydrogen from the alcohol to generate the corresponding carbonyl compound and a metal-hydride species. The reactive carbonyl compound can then undergo an aldol condensation with the Ph* ketone to give the corresponding enone, which is subsequently reduced by the metal-hydride species to give alkylated product and close the catalytic cycle. Therefore, hydrogen borrowing methodology combines three processes (oxidation, condensation and reduction) into one pot and consequently illustrates the synthetic utility of alcohols. In all hydrogen borrowing reactions to date, the termination of the catalytic cycle results in the delivery of a hydrogen atom to both the alpha- and beta- positions, precluding the synthesis of quaternary centres at these positions. Such quaternary-substituted products are of great synthetic interest due to their high prevalence in biologically relevant molecules, such as drug molecules and natural products. The aim of this project is therefore to investigate strategies to synthesise quaternary centres using hydrogen borrowing catalysis. We will investigate a variety of strategies (including displacement and rearrangement) to make both alpha- and beta- quaternary centres within the hydrogen borrowing manifold and produce the first examples of such motifs via hydrogen borrowing catalysis. In order to achieve this ambitious goal, we will both utilise and expand upon the methodology developed by the group. We will also investigate the cleavage of the Ph* protecting group in the quaternary products and aim to develop mild cleavage conditions to allow the synthesis of a range of different alpha-quaternary functionality. As an extension of the chemical synthesis methodology, we will investigate further reactions of the product alpha-quaternary carbonyl compounds, by exploiting their properties to gain access to other functionality previously inaccessible via hydrogen borrowing catalysis. This approach may allow the development of a highly convergent synthesis of key motifs which are present within drug molecules. This project is expected to provide a high impact programme of research and falls within the EPSRC Physical Sciences research area.