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Details of Grant 

EPSRC Reference: EP/T016019/1
Title: Nitrogen- and Oxygen-Radicals-Based Strategies for the Divergent Assembly of Novel Building Blocks by Strain-Release
Principal Investigator: Liddle, Professor ST
Other Investigators:
Researcher Co-Investigators:
Project Partners:
Department: Chemistry
Organisation: University of Manchester, The
Scheme: Standard Research
Starts: 10 February 2020 Ends: 09 February 2024 Value (£): 391,803
EPSRC Research Topic Classifications:
Catalysis & Applied Catalysis Chemical Synthetic Methodology
EPSRC Industrial Sector Classifications:
Chemicals Pharmaceuticals and Biotechnology
Related Grants:
Panel History:
Panel DatePanel NameOutcome
24 Oct 2019 EPSRC Physical Sciences - October 2019 Announced
Summary on Grant Application Form
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.
Key Findings
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Organisation Website: http://www.man.ac.uk