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.

该项目旨在扩展弗莱彻小组以前的工作，该工作描述了一种新的策略，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。最初，我们试图将该策略扩展到2-氮杂环丁烷底物，从而形成手性氮杂环丁烷。进一步的工作可能包括反应策略的扩展到开环的螺环缩醛连接到环丁烯;和铑催化的串联反应与双官能硼酸。氮杂环丁烷基序广泛存在于市售药物、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都有关。然而，氮杂环丁烷的合成和官能化是未充分探索的问题，并且已知的手性氮杂环丁烷的催化途径很少。本项目旨在开发一种简便的、对映选择性的氮杂环丁烷合成方法，该方法可用于药物开发和生产，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候选药物的一种成熟而有效的方法，通常涉及通过组合化学方法筛选大分子库。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的和富含sp2的。由于缺乏简单的、通用的和官能团耐受的方法来形成它们，所以还没有广泛筛选具有复杂三维结构的富含sp3的小分子，尽管已知这些分子具有作为候选药物的优点。在这个项目中开发的方法将允许有效地获得一系列复杂的，手性的，富含sp3的小分子的氮杂环丁烷支架的基础上，使感兴趣的候选人的合成片段为基础的筛选。该方法也可以用于药物生产，因为它能够形成困难的基序，并增加结构的复杂性，高度对映选择性。该项目福尔斯属于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。它是由ESPRC和GSK通过UCASE助学金共同资助的。