Nitrogen-Radical-Based Radical Strain-Release Strategies for the Divergent Assembly of Polyfunctionalized 3D-Building Blocks

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Nitrogen-containing compounds underpin every aspect of our life: they form the structural basis of almost all drugs, agrochemicals and materials. The invention of methods to form C–N bonds is of strategic importance to discover and evolve molecules with direct implications on our lives. Central to this quest is designing synthetic strategies able to explore novel areas of chemical space. As the pharmaceutical sector is now aware of the greater clinical success of molecules with 3D architectures, developing methods able to assemble 3D-shaped and saturated building blocks is a topic of continuous scientific endeavour. The small and strained bicyclo[1.1.1]pentyl motif has been identified as a valuable bioisoter 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 medicinal chemistry. There is an urgent need to develop novel methods that can effectively manipulate and introduce this motif into organic compounds. This project seeks to substantially expand the fields of photocatalysis and nitrogen-radicals by introducing the concept of “photoredox strain-release”: a novel reactivity that explores the ability of nitrogen-radicals to react with strained hydrocarbons (eg propellane) and enable a unique preparation of polyfunctionalized bicyclo[1.1.1]pentylamines. This research capitalizes on recent developments of the host group that has disclosed 2 novel ways to effectively generate nitrogen radicals. This reactivity will be integrated with other reaction platform allowing the divergent 1-step construction of many important nitrogenated 3D-building blocks that cannot be prepared by any other method. The development of such an innovative and ambitious project at the University of Manchester will be facilitated by generating, transferring, sharing and disseminating knowledge, and will enhance my future career following the training plan envisioned.