Synthesis of Quaternary Stereocentres via Hydrogen Borrowing Catalysis

借氢催化是一种利用可逆氧化态变化形成C-C键的有效方法。我们已经证明，在过渡金属催化剂的存在下，五甲基苯基（Ph*）酮可以与醇烷基化，得到α和β支化产物。该过程通过从醇中提取氢来生成相应的羰基化合物和金属氢化物。反应性羰基化合物与Ph*酮发生醛醇缩合生成相应的烯酮，烯酮随后被金属氢化物还原生成烷基化产物，结束催化循环。因此，借氢方法将三个过程（氧化、缩合和还原）结合到一个锅中，从而说明了醇的合成效用。到目前为止，在所有的借氢反应中，催化循环的终止会导致一个氢原子被传递到-和-位置，从而阻止在这些位置合成季中心。由于它们在生物相关分子（如药物分子和天然产物）中普遍存在，因此具有很大的合成兴趣。因此，该项目的目的是研究利用借氢催化合成季中心的策略。我们将研究各种策略（包括位移和重排），在借氢歧管中产生α -和β -四元中心，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，我们将利用并扩展该小组开发的方法。我们还将研究四元产物中Ph*保护基团的裂解，并旨在开发温和的裂解条件，以允许合成一系列不同的α -四元功能。作为化学合成方法的延伸，我们将进一步研究产物α -季羰基化合物的反应，通过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。这种方法可以使药物分子中存在的关键基序的高度聚合合成得到发展。该项目预计将提供一个高影响力的研究项目，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.