A nitrenoid strategy to access sp3-rich nitrogen heterocycles

Lead Research Organisation: University of Birmingham
Department Name: School of Chemistry

Abstract

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.

Publications

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