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: EP/W007363/1
• 负责人: Stephen Fletcher
• 金额: $ 52.31万
• 依托单位: University of Oxford
• 依托单位国家: 英国
• 项目类别: Research Grant
• 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=EP%2FW007363%2F1
• 关键词: Catalytic; Asymmetric; Cross; Coupling; Approach

Cyclobutanes are an important class of compounds, which have a number of uses in the chemical industry. There are currently forty-three approved or candidate molecules in the drug discovery pipeline which contain the cyclobutane functionality. Cyclobutanes also appears in a number of natural products and fine chemicals. Methods to access this privileged class of compounds are however not very well developed and there is a pressing need to develop novel synthetic strategies, both to access novel cyclobutane scaffolds and to allow existing ones to be made more efficiently.An asymmetric metal-catalysed transformation is an efficient method to build a complex carbon skeleton from simple components, using only a very small quantity of metal and ligand. The successful development of such transformations revolutionises the molecules available to industry for the development of new medicines, new fragrances, new materials, and new catalysts. In building a complex carbon skeleton, we often come across difficulties in controlling the 3D arrangement. An enantioenriched product is a product in which only one, highly specific, 3D shape is selected for, and this represents a significant challenge to chemists in the production of pharmaceutical treatments and other complex molecules. This project aims to develop novel transformations which provide efficient access to a diverse array of enantioenriched cyclobutanes and other similar compounds, with focus on making the type of sp3-rich molecules that are essential for the development of new medicines.The objectives of this project are to develop technology to enable: i) the synthesis of chiral cyclobutane derivatives, similar to the structures found in a number of biologically active molecules and approved drugs; ii) a greater understanding of the mechanism by which this transformation is occurring, allowing us to further optimise and expand the reaction; iii) the synthesis of biologically active compounds, showcasing the utility of these novel methods and their applicability to medicine; iv) the synthesis of other enantioenriched scaffolds, including nitrogen heterocycles and multiple fused-ring systems, which would greatly expand the classes of 4 membered ring containing structures that can be easily prepared.The work develop a new strategy for the efficient preparation of cyclobutanes and then work will be conducted to increase our understanding of how the chemistry operates so that the reactions can be optimized and inspire us to tackle even more ambitious projects in the future. By developing and expanding the scope of this technology in this way, we significantly increase its value to the pharmaceutical industry and other end users of the technology. Finally, being able to access a diverse range of novel chiral materials will enable the discovery of new medicines, fragrances, materials and catalysts that would otherwise be inaccessible.

环丁烷是一类重要的化合物，在化学工业中有许多用途。目前在药物发现管道中有43种批准的或候选的分子含有环丁烷官能团。环丁烷也出现在许多天然产物和精细化学品中。然而，获得这类特权化合物的方法还没有得到很好的开发，迫切需要开发新的合成策略，既要获得新的环丁烷骨架，又要使现有的骨架更有效地制备。不对称金属催化转化是一种有效的方法，可以从简单的组分构建复杂的碳骨架，只需要非常少量的金属和配体。这种转化的成功开发彻底改变了工业界可用于开发新药、新香料、新材料和新催化剂的分子。在构建复杂的碳骨架时，我们经常遇到控制3D排列的困难。对映体富集的产物是其中仅选择一种高度特异性的3D形状的产物，这对药物治疗和其他复杂分子的生产中的化学家来说是一个重大挑战。该项目旨在开发新的转化方法，从而有效地获得各种对映体富集的环丁烷和其他类似化合物，重点是制造新药开发所必需的富含sp3的分子类型。该项目的目标是开发技术，以实现：i）手性环丁烷衍生物的合成，类似于在许多生物活性分子和批准的药物中发现的结构; ii）更好地理解这种转化发生的机制，使我们能够进一步优化和扩展反应; iii）生物活性化合物的合成，展示这些新方法的实用性及其对医学的适用性; iv）合成其他对映体富集的支架，包括氮杂环和多稠环体系，这将极大地扩展可容易制备的含4元环结构的种类。本工作为有效制备环丁烷开发了新的策略，然后将进行工作以提高我们的了解化学如何运作，使反应可以优化，并激励我们在未来处理更雄心勃勃的项目。通过以这种方式开发和扩大这项技术的范围，我们显著提高了其对制药行业和该技术的其他最终用户的价值。最后，能够获得各种各样的新型手性材料将能够发现新的药物，香料，材料和催化剂，否则将无法获得。

项目成果

Catalytic Enantioselective Synthesis of 3-Piperidines from Arylboronic Acids and Pyridine.

• DOI: 10.1021/jacs.3c05044
• 发表时间: 2023-07-05
• 期刊: JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
• 影响因子: 15
• 作者: Mishra, Sourabh;Karabiyikoglu, Sedef;Fletcher, Stephen P.
• 通讯作者: Fletcher, Stephen P.

Rhodium-Catalyzed Asymmetric Arylation of Cyclobutenone Ketals

• DOI: 10.1002/anie.202217381
• 发表时间: 2023-02-17
• 期刊: ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
• 影响因子: 16.6
• 作者: Egea-Arrebola, David;Goetzke, F. Wieland;Fletcher, Stephen P.
• 通讯作者: Fletcher, Stephen P.