A Catalytic Asymmetric Cross-Coupling Approach to the Synthesis of Cyclobutanes

环丁烷合成的催化不对称交叉偶联方法

• 批准号: 2758094
• 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: 2022
• 资助国家: 英国
• 起止时间: 2022 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-2758094
• 关键词: Catalytic; Asymmetric; Cross; Coupling; Approach

This project aims to expand on previous work by the Fletcher group which described a novel strategy for the formation of chiral cyclobutanes by an asymmetric Rh-catalysed Suzuki-Miyaura reaction between a cyclobutene and an arylboronic acid. Initially we seek to extend the strategy to 2-azetine substrates, enabling the formation of chiral azetidines. Further work may include the extension of the reaction strategy to ring-opening of spirocyclic acetals connected to cyclobutenes; and Rh-catalysed tandem reactions with bifunctional boronic acids. Azetidine motifs are found in marketed drugs, natural products and desirable synthetic intermediates, so the synthesis of chiral azetidines is relevant to both academic and industrial chemistry. However, the synthesis and functionalisation of azetidines are underexplored problems and few catalytic routes to chiral azetidines are known. This project aims to develop a convenient, enantioselective approach to azetidine synthesis, which may find applications in drug development and production as well as providing a useful tool for chemical synthesis.Fragment-based drug discovery is an established and effective approach for the discovery of small-molecule drug candidates, and usually involves screening of large libraries of molecules made by combinatorial chemistry methods. These methods traditionally rely on well-established sp2-sp2 coupling methods, so the compounds screened tend to be flat and sp2-rich. Due to the lack of simple, general and functional group tolerant methods for their formation, there has not been extensive screening of sp3-rich small molecules with complex, 3-dimensional structures although such molecules are known to have advantages as drug candidates. The methodology developed in this project would allow efficient access to a range of complex, chiral, sp3-rich small molecules based on azetidine scaffolds, enabling the synthesis of interesting candidates for fragment-based screening. The methodology may also be of use to pharmaceutical production due to its ability to form difficult motifs and increase structural complexity highly enantioselectively. This project falls within the ESPRC catalysis and synthetic organic chemistry research areas, under the physical sciences and healthcare technologies research themes. It is jointly funded by ESPRC and GSK through a UCASE studentship.

该项目旨在扩展 Fletcher 小组之前的工作，该小组描述了一种通过环丁烯和芳基硼酸之间的不对称 Rh 催化的 Suzuki-Miyaura 反应形成手性环丁烷的新策略。最初，我们寻求将该策略扩展到 2-氮杂环丁烷底物，从而能够形成手性氮杂环丁烷。进一步的工作可能包括将反应策略扩展到与环丁烯连接的螺环缩醛的开环； Rh 催化的双官能硼酸串联反应。氮杂环丁烷基序存在于市售药物、天然产物和理想的合成中间体中，因此手性氮杂环丁烷的合成与学术和工业化学相关。然而，氮杂环丁烷的合成和官能化是尚未充分研究的问题，并且已知的手性氮杂环丁烷的催化途径很少。该项目旨在开发一种方便的、对映选择性的氮杂环丁烷合成方法，该方法可能在药物开发和生产中得到应用，并为化学合成提供有用的工具。基于片段的药物发现是发现小分子的一种既定且有效的方法。 - 候选分子药物，通常涉及筛选通过组合化学方法制备的大型分子库。这些方法传统上依赖于完善的 sp2-sp2 偶联方法，因此筛选的化合物往往是平坦且富含 sp2 的。由于缺乏简单、通用和官能团耐受的形成方法，因此尚未对具有复杂、3维结构的富含sp3的小分子进行广泛的筛选，尽管已知此类分子作为候选药物具有优势。该项目开发的方法将允许有效地获得一系列基于氮杂环丁烷支架的复杂、手性、富含sp3的小分子，从而能够合成用于基于片段的筛选的有趣候选物。该方法也可用于药物生产，因为它能够形成困难的基序并高度对映选择性地增加结构复杂性。该项目属于 ESPRC 催化和合成有机化学研究领域，属于物理科学和医疗保健技术研究主题。它由 ESPRC 和 GSK 通过 UCASE 学生奖学金共同资助。