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Final Report Summary - ABC (Harnessing Carboxylic Acids via ABC – Asymmetric Boronic acid-based Catalysis)

Organic chemistry occupies a central, enabling position within the chemical disciplines. Through innovation in the science of making organic molecules, we create new systems and materials that are vital to the advancement of other sciences and ultimately the wellbeing of society. The ability to create carbon-nitrogen bonds is one of the most important goals in organic synthesis as nitrogen-containing compounds are widespread as therapeutic agents, agrochemicals, organic dyes and materials: as an example, the 20 top-selling drugs all contain C-N bonds. The invention of methods for the formation of C–N bonds is therefore of strategic importance for the discovery and evolution of molecules with direct implications on the quality of our lives.

From this perspective, it is now becoming increasingly important not just to be able to create new and complex molecules but also to identify novel methods that can access them in a more efficient, selective and sustainable way. In fact, factors such as cost, toxicity and waste production in chemical synthesis urgently needs to be addressed.

The overarching aim of this research project was to develop fundamentally novel catalytic methods for the direct functionalization of carboxylic acids and amines. The ability to modify these widely available feedstock chemicals in a simple, selective and efficient manner has the potential to streamline the preparation of many high-value materials.
Since the beginning of the Award, we have developed novel chemical reactions of carboxylic acid derivatives with the aid of abundant and benign Calcium-based catalysts.
We have also facilitated the formation of C–C bonds in complex molecular systems using boron-containing substrates in a novel way. This has enabled
More recently, we have developed a general catalysis concept where visible-light enables selective single-electron transfer processes from photo-excitable catalysts to simple organic molecules and, ultimately, allows access to nitrogen-radicals. These odd-electron species have remarkable potential in the assembly of N-containing compounds, but so far the scientific community has not taken advantage of their reactivity because of difficulties associated to their preparation – in a nutshell: if you cannot make them, you cannot use them.

Specifically, through this independent project at the University of Manchester we have reported two entirely novel ways of generating nitrogen-radicals from easy-to-make aryl oximes and aryloxyamides by using visible-light as the source of energy (ACIE 2015 and JACS 2016). We have developed a novel strategy for the assembly of small-nitrogen heterocycles by using an unprecedented approach relying on two consecutive visible-light-mediated single electron transfer events (CC 2016). More recently we have expanded this chemistry to the assembly of polyfunctnionalized nitrogen heterocycles (ACIE 2017) and the remote functionalization of complex organic molecules (ACIE 2018). Finally, we have developed a powerful method for the preparation of aryl amines, one of the most important class of organic molecules, and showcased the application of the methodology in the fast modification of many widely prescribed drugs (ACIE 2017). A key feature of this research is the combination of experimental and theoretical techniques belonging to different branches of chemistry, spanning synthetic organic, photochemistry, electrochemistry and spectroscopy. In this way we are creating a unified picture for the development of fundamentally novel methods to form C–N bonds. Furthermore, with this approach, we have simultaneously provided novel concepts in catalysis and novel synthetic approaches for the preparation of nitrogen heterocycles – the most abundant epitope in biologically active molecules. Overall, this work has been highly influential: the first two papers on nitrogen-radicals (ACIE 2015 and JACS 2016) have been highly cited and have inspired other researchers .

In recognition of the impact made by my work, I was the recipient of the 2015 UNESCO/IUPAC/PhosAgro Award in Green Chemistry, the 2016 Silver Medal at the 6th Young European Chemist Award and the 2017 Thieme Journal Award. The relevance of this approach and its potential in organic chemistry, catalysis and in the long-term society has been recognized by the recent award of an EPSRC Early Career Fellowship and the ERC Starting Grant as well as other research support from the Leverhulme Trust and the Marie Curie Actions.
My approach in forming C–N bonds has clear industrial implications and I am currently developing novel processes in partnership with AstraZeneca and Eli Lilly. I have also been recently approached by other companies that are planning to use my methods in their research programs.

Reported by

THE UNIVERSITY OF MANCHESTER
United Kingdom

Subjects

Life Sciences
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