A nitrenoid strategy to access sp3-rich nitrogen heterocycles

将6个原子连接在一个环中会产生一些在化学和依赖于此的场中看到的最常见的结构主题。“N-杂环”，其中五个原子是碳，一个是氮，是极其重要的，也是2019年新药物中遇到的最常见的循环基序。N-杂环的性质取决于环内的成键以及与之相连的原子的位置和类型。哌啶、吡啶、内酰胺、环胺和羟基吡啶是一些最有用的结构，存在于生物活性设计或天然存在的化合物中。在后者，尤其是作为药物发现的有效起点的代谢物中，这些N-杂环通常嵌入复杂的多环结构中。N-杂环以不同的基团排列在环的周围：通过改变它们与氮的相对接近程度和相对的3D空间排列，即使是相同的基团，也可能发生大量的分子排列。对于不同的取代基，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。为了实现这一点，需要新的合成策略，这些策略适用于不同类型的N-杂环，并适应基团及其排列方式的显著变化。有了合适的工具，合成化学家将能够更好地获得和探索最优的分子设计，而不是满足于可用的最接近的近似。在这个项目中，将探索一种统一的策略来制备具有不同取代模式的各种N-杂环。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-杂环的共同中间体。容易获得的起始材料(炔烃和酰基氮酮)将被用来提供核心结构，周围有大量的结构和功能变化。这些构建复杂性的催化方法使用一锅序列，其中引入了几个键、环、立体中心和官能团，并将通过最大限度地减少所需试剂和处理的数量来增强合成的可持续性。该项目将研究这些新转化的开发和适用性，研究如何在催化剂或反应物控制下从相同的起始物质获得不同的途径，以及如何将多环产物转化为不同的N-杂环，如吡啶、哌啶、酰胺、内酰胺或亚胺。使用这些方法探索这些N-杂环周围的化学空间，并获得具有理想物理化学性质的结构多样化的化合物以用于早期药物发现，将通过准备重点化学文库来验证。除了这些支持未来研究的新工具外，这项研究中的新型N-杂环将被包括在Haworth化学使能化合物集合(HC3)中，供来自生物科学和药学学院、医学院、微生物和感染研究所的研究人员访问，并最终由外部学术界和工业界寻找新的热门分子。这一策略的灵活性质意味着，任何产生的成功都很容易通过结构-活性关系研究进行进展。这些研究的进展和见解将通过发表在同行评议的国际领先期刊上传播，并公布(Inc.@Syncat_Bham，@Chembham，https://syncatdavies.wordpress.com/).数据将按照RCUK关于开放研究数据的协议书提供。将利用国际会议和为期一天的会议上的口头陈述和海报来吸引社区参与。

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.