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

该项目旨在扩展Fletcher小组先前的工作，该工作描述了一种通过环丁烯和芳基硼酸之间的不对称rh催化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-氮杂啶底物，使手性氮杂啶的形成成为可能。进一步的工作可能包括将反应策略扩展到与环丁烯相连的螺环缩醛的开环；以及铑催化双功能硼酸的串联反应。氮杂啶基序存在于上市的药物、天然产物和理想的合成中间体中，因此手性氮杂啶的合成与学术和工业化学都相关。然而，氮杂啶的合成和功能化是尚未充分探索的问题，很少有催化途径是已知的手性氮杂啶。本项目旨在开发一种方便、对映选择性的氮杂苷合成方法，为药物开发和生产以及化学合成提供一种有用的工具。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型分子文库。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、通用和功能基耐受的方法来形成sp3，尽管已知sp3小分子作为候选药物具有优势，但具有复杂三维结构的富含sp3的小分子尚未得到广泛的筛选。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的基于氮杂啶支架的小分子，使合成有趣的候选物用于基于片段的筛选。该方法也可用于制药生产，因为它能够形成困难的基序和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学生共同资助。

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.