A nitrenoid strategy to access sp3-rich nitrogen heterocycles

获取富含sp3氮杂环的氮烯类策略

• 批准号: EP/V061690/1
• 负责人: Paul Davies
• 金额: $ 56.67万
• 依托单位: University of Birmingham
• 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%2FV061690%2F1
• 关键词: nitrenoid; strategy; access; sp3; rich

Having 6-atoms linked together in a ring generates some of the most common structural motifs seen in chemistry and the fields that depend upon it. 'N-heterocycles' where five of the atoms are carbon, and one is nitrogen, are extremely important and the most common cyclic motif encountered in new pharmaceuticals in 2019. The nature of the N-heterocycle depends on the bonding within the ring and the positioning and types of atoms attached to it. Piperidine, pyridine, delta-lactams, cyclic amidines and hydroxypyridines are some of the most useful structures, found in bioactive designed or naturally occurring compounds. In the latter especially, metabolites that are potent starting points for drug discovery, these N-heterocycles are often embedded within complex polycyclic architectures. The N-heterocycles are found with different groups arranged around the ring: A huge number of molecular permutations are possible, even with the same groups, by changing their relative proximity to the nitrogen and relative 3D spatial arrangement. With different substituents the permutations are endless. As each permutation has different form and function, we need to be able to explore the chemical space around these N-heterocycles with great flexibility to enable most effective biomedical research. New synthesis strategies that are applicable to different types of N-heterocycles and accommodate significant changes in the groups and how they are arranged are needed to achieve this. With the appropriate tools, synthetic chemists will be more able to access and explore optimal molecule designs, rather than settle for the closest approximations available.In this project a unifying strategy will be explored for the preparation of varied N-heterocycles with diverse substitution patterns. Highly efficient transformations will be developed, delivering densely-functionalised core motifs to function as common intermediates on way to different N-heterocycles. Readily accessible starting materials (an alkyne and an acyl nitrenoid) will be used to deliver core structures surrounded by substantial structural and functional variety. These complexity-building catalytic methods employ one-pot sequences where several bonds, rings, stereogenic centres and functionalities are introduced and will enhance the sustainability of synthesis by minimising the amount of reagents and processing required. The project will study the development and applicability of these new transformations, examining how divergent pathways can be accessed from the same starting materials under catalyst or reactant control and how the polycyclic products can be converted into different N-heterocycles such as pyridines, piperidines, amidines, lactams or imides. The use of these methods to explore chemical space around these N-heterocycles and access structurally diverse compounds with desirable physicochemical properties for early stage drug discovery will be validated by the preparation of focused chemical libraries. In addition to these new tools enabling future research, the novel N-heterocycles from this study will be included within the Haworth Chemically-enabled Compound Collection (HC3), for access by researchers from the Schools of Biosciences and Pharmacy, the Medical School, Institute of Microbiology and Infection, and ultimately external academic and industrial parties looking for new hit molecules. The flexible nature of the strategy means that any hit arising is readily amenable to progression through structure-activity relationship studies.The advances and insights from these studies will be disseminated through publication in peer-reviewed internationally-leading journals, and publicised (inc. @SynCat_Bham, @chembham, https://syncatdavies.wordpress.com/). Data will be available in line with the RCUK Concordat on Open Research Data. Oral presentations and posters at international conferences and one-day meetings will be used to engage the community.

6个原子连接在一起形成一个环，产生了化学和依赖于它的领域中最常见的一些结构基序。其中5个原子是碳原子，1个是氮原子的“N-杂环”非常重要，也是2019年新药中最常见的环状基序。N-杂环的性质取决于环内的键合以及连接到其上的原子的位置和类型。N-杂环基嘧啶、吡啶、δ-内酰胺、环脒和羟基吡啶是在生物活性设计或天然存在的化合物中发现的一些最有用的结构。特别是在后者中，代谢物是药物发现的有效起点，这些N-杂环通常嵌入复杂的多环结构中。N-杂环被发现有不同的基团排列在环周围：通过改变它们与氮的相对接近度和相对的3D空间排列，即使是相同的基团，也可以进行大量的分子排列。随着取代基的不同，排列是无穷无尽的。由于每个排列都有不同的形式和功能，我们需要能够以极大的灵活性探索这些N-杂环周围的化学空间，以实现最有效的生物医学研究。为了实现这一目标，需要适用于不同类型的N-杂环并适应基团及其排列方式的显著变化的新合成策略。有了合适的工具，合成化学家将更能够访问和探索最佳的分子设计，而不是解决最接近的approximates.In本项目将探索一个统一的策略，用于制备不同的N-杂环与不同的取代模式。将开发高效的转化，提供密集官能化的核心基序，作为不同N-杂环的常见中间体。容易获得的起始材料（炔和酰基类氮杂环戊烯）将用于递送被大量结构和功能多样性包围的核心结构。这些复合物构建催化方法采用一锅法序列，其中引入了几个键、环、立体中心和官能团，并将通过最小化所需试剂和处理的量来增强合成的可持续性。该项目将研究这些新转化的发展和适用性，研究如何在催化剂或反应物控制下从相同的起始材料获得不同的途径，以及如何将多环产物转化为不同的N-杂环，如吡啶，哌啶，脒，内酰胺或酰亚胺。使用这些方法来探索这些N-杂环周围的化学空间，并获得具有所需物理化学性质的结构多样的化合物，用于早期药物发现，将通过制备集中的化学文库进行验证。除了这些新的工具，使未来的研究，从这项研究的新型N-杂环将被纳入Haworth化学启用化合物收藏（HC 3），由来自生物科学和药学学院，医学院，微生物学和感染研究所的研究人员访问，并最终外部学术和工业方寻找新的命中分子。该策略的灵活性意味着任何产生的命中很容易通过结构-活性关系研究进行进展。这些研究的进展和见解将通过在同行评审的国际领先期刊上发表来传播，并公开（inc. @SynCat_Bham，@chembham，https：//syncatdavies.wordpress.com/）。数据将根据RCUK开放研究数据协议提供。将在国际会议和为期一天的会议上进行口头介绍和张贴海报，以吸引社区参与。