Nitrogen- and Oxygen-Radicals-Based Strategies for the Divergent Assembly of Novel Building Blocks by Strain-Release

The invention of chemical reactions that form C-N and C-O bonds in novel ways is of strategic importance to discover and evolve molecules that impact our society. As the pharmaceutical and agrochemical sectors are now aware of the greater clinical success of sp3-rich molecules, developing methods to prepare 3D-shaped and saturated building blocks is fundamental to our well-being.

The small and strained bicyclo[1.1.1]pentyl motif has been identified as a powerful bioisostere to replace flat (2D) aromatics and improve the potency of lead molecules. However, difficulties in preparing and modifying this structural element have severely limited its use in biological and medicinal chemistry. There is an urgent need to develop novel methods that can effectively manipulate and introduce this motif into organic compounds.

The overarching aim of this project is to exploit the generation of nitrogen-radicals using the visible-light-mediated approach developed in our group and then use these species in "radical strain-release reactions". This reactivity mode will explore the ability of nitrogen-radicals to react with propellane (a highly strained hydrocarbon) by cleaving a strong sp3-sp3 C-C bond. This reactivity will then be harnessed as part of a radical multicomponent strategy to access poly-functionalised bicyclo[1.1.1]pentylamines and, using oxygen-radicals, bicyclo[1.1.1]penthanols.

In this way, we will provide unique reactions streamlining the synthesis of N- and O-containing sp3-rich molecules currently very difficult to prepare but highly sought after by pharmaceutical and agrochemical discovery programs.

The project is divided in three Aims that will address specific challenges relevant to the preparation of bioisosteres of anilines and phenols.

Aim 1. We will use our knowledge in nitrogen-radical generation using photocatalysis to develop unprecedented radical-strain-release cascades. The chemistry involves the generation of amidyl radicals, which subsequently react with propellane by strain-release and then are diversified by a final atom/group-transfer reaction with a broad range of radical trapping agents. We will evaluate the scope and limitations of this strategy and we will apply it to the preparation of novel and currently elusive bioisosteres of frequently prescribed drugs.

Aim 2. This photocatalytic strategy for nitrogen-radical strain-release will be expanded by merging it with nickel catalysis. Thus, we will provide an innovative dual photoredox-nickel platform for the preparation of valuable building blocks containing both N- and C-based substituents across the bicyclo[1.1.1]pentyl core.

Aim 3. The strategy for radical strain-release will then be extended to oxygen-radicals. This will enable fast and divergent access to a broad range of poly-functionalised bicyclo[1.1.1]penthanols. These molecules have application as phenol bioisosteres but they are currently very difficult to prepare even through lengthy synthetic sequences.

A relevant aspect of this research project will be investigating the scalability of these processes that we will develop. This will be evaluated through a collaboration with AstraZeneca (Macclesfield) that has agreed to host the PDRA associated to the project in their state-of-the-art flow-chemistry facilities.

Overall, this project will develop an innovative strategy for the fast, selective and divergent preparation of sp3-rich building blocks containing nitrogen- and oxygen-based functionalities. The possibility to access these high-value materials will facilitate the discovery, development and manufacture of therapeutic agents and agrochemicals with overall impact to the well-being of UK society.

A recent perspective by UK scientists from major pharma companies (Nat. Chem. 2018, 10, 383) has delineated the fundamental role of academic synthetic chemistry research in the discovery of novel drugs. An area of significant interest is the development of methodologies to access highly saturated (sp3-rich) molecules as they have increased changes of biological activity.
The research proposed here targets the development of novel strategies based on photocatalysis and radical chemistry to streamline access to these high-value materials. Therefore, this project is expected to generate the following types of impact.

Industry Impact. This project will develop innovative activation and reactivity modes for the fast, selective and divergent assembly of sp3-rich building blocks that are critical to the development of new bioactive compounds like drugs and agrochemicals. The research proposed here will therefore impact pharmaceutical, agrochemical and fine chemical industries in the UK. The collaboration with AstraZeneca will ensure that we tackle and address problems of great importance to industrial end-users.

Society Impact. We will provide new synthetic tools for the fast preparation of high-value building blocks which are sought after by the pharmaceutical and agrochemical sectors. This will find application and will facilitate the discovery of new therapeutic agents, biological probes and herbicides/pesticides thus impacting, in the log term, the health and wellbeing of the society as well as global food production.

Economic Impact. This impact will be generated by taking a proactive approach to IP by closely working with the University of Manchester Intellectual Property Ltd (the University's dedicated business support Department).

People Impact. The PDRA associated to this project will receive high-quality training and, by the end of the project, he/she will be able to embark in a high-profile independent career in academia or industry.

Public Impact. This impact will be achieved using the various outreach programs available at the University of Manchester to make the public aware of the fundamental role of synthetic chemistry in addressing social needs. Furthermore, the PI runs an annual outreach activity at the Manchester Grammar School where sixteen School pupils are involved in a real photo-chemistry research project.

Academic Impact. We plan to realise this impact by disseminating the results of the project at national and international conferences and by publication in high-profile journals.