Synthesis of Quaternary Stereocentres via Hydrogen Borrowing Catalysis

借氢催化合成四元立构中心

• 批准号: 2417436
• 金额: --
• 依托单位: University of Oxford
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2020
• 资助国家: 英国
• 起止时间: 2020 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-2417436
• 关键词: Synthesis; Quaternary; Stereocentres; via; Hydrogen

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.

借氢催化是利用可逆氧化态变化形成C-C键的有力方法。我们已经表明，五甲基苯基（Ph*）酮可以在过渡金属催化剂的存在下与醇烷基化，得到α-和β-支化产物。该过程通过从醇中提取氢来产生相应的羰基化合物和金属氢化物物质。然后，反应性羰基化合物可以与Ph* 酮进行羟醛缩合，得到相应的烯酮，其随后被金属氢化物物质还原，得到烷基化产物并关闭催化循环。因此，氢借用方法将三个过程（氧化、缩合和还原）结合到一锅中，从而说明了醇的合成效用。在迄今为止的所有氢借用反应中，催化循环的终止导致氢原子传递到α-和β-位置，排除了在这些位置合成季中心。这种季铵取代的产物由于其在生物学相关分子如药物分子和天然产物中的高度普遍性而具有很大的合成兴趣。因此，本项目的目的是研究策略，利用氢借用催化合成季中心。我们将研究各种策略（包括置换和重排），使α-和β-四元中心内的氢借款歧管和生产的第一个例子，这样的图案通过氢借款催化。为了实现这一雄心勃勃的目标，我们将利用并扩展集团开发的方法。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，以合成一系列不同的α-四元官能团。作为化学合成方法的延伸，我们将研究产物α-季羰基化合物的进一步反应，通过利用它们的性质来获得以前通过氢借用催化无法获得的其他功能。这种方法可以允许开发药物分子内存在的关键基序的高度收敛合成。该项目预计将提供一个高影响力的研究方案，并属于EPSRC物理科学研究领域的福尔斯。