Cu-Catalysed Amination of Alkylboronic Esters

The more planar a drug candidate is, the more likely it is to show unwanted side effects and be rejected in clinical trials. It is therefore desirable to build more "3-dimensional" molecules where there are fewer aromatic rings and more alkyl groups. This concept is challenging as there are few general chemical coupling methods to build complex "3D" molecules in a predictable and reliable manner. An opportunity to achieve this is through the formation of amines, one of the most common functional groups found in medicinal drugs and agrochemicals. Traditional methods to make (chiral) alkyl amines, such as nucleophilic substitution and reductive amination, are often non-trivial. They suffer from poor control (e.g. over alkylation), require protecting groups to overcome issues of chemoselectivity, and are challenging reactions to control stereoselectively.

We aim to solve these difficulties by developing a Cu-catalysed amination of alkyl boronic esters, enabling access to complex "3D" amines. These organoboron reagents have several favourable properties which benefit this approach. They are air- and moisture-stable chemicals which tolerate a broad range of functional groups. They also show orthogonal reactivity to other common functionality, reducing the need for protecting groups. They can also be prepared stereoselectively, and typically do not racemise under conditions required for catalysis. These properties mean that formation of the key amine motif can be carried out at a late-stage in a synthetic sequence. This will enable the efficient preparation of diverse libraries of complex molecules from common boronic ester building blocks. Such technology will enable scientists in medicinal chemistry and agrochemical discovery to explore new chemical space, expediting the discovery of new medicines and crop protections.

In addition, we will apply our Cu-catalysed amination method to the intramolecular coupling of amine-containing diboronic esters. In this reaction, one boronic ester will react to form a saturated N-heterocycle, with the second boronic ester remaining as a handle for further functionalisation. This will allow access to complex saturated heterocyclic boronic ester building blocks, which currently have limited availability. These heterocyclic boronic esters are attractive scaffolds for medicinal chemistry and agrochemical discovery. By working with our industrial partner, Redbrick Molecular Ltd., these boron reagents will be made commercially available, providing direct impact for this grant.

1. Knowledge
This research will generate a significant amount of knowledge and data about Cu-catalysed transformations of alkylboron reagents. This will be primarily disseminated through publication in peer-reviewed journals and conference seminars. The new methods for amination shall be applied to the preparation of biologically active molecules. Such molecules will be used as probes for research in the biosciences or as molecules for biological testing in medicinal chemistry and agrochemical discovery. The data generated will also be invaluable for the development of new catalysts and catalytic reactions based on our findings.
In the short term, this research will have most impact on academic researchers. However, as the chemical methods become more mature, it is expected that it will be taken up by researchers in Industry, including medicinal chemists and agrochemical researchers, and manufacturers of chemical building blocks.

2. Society and Economy
In the long term, application of the chemistry has a likely impact in the discovery and manufacture of pharmaceuticals. As such, the research proposed may facilitate the discovery of new pharmaceutical treatments, and lead to more efficient manufacturing processes. This will have an impact on health care providers (e.g. NHS) and regulators, and patients, resulting in improved public health. Likewise, application in the agrochemical industry may lead to the development and manufacture of new crop treatments. This could lead to an increase in farming efficiency, resulting in impacts for agricultural businesses, supply chains including retailers, and the consumer.
The proposed research looks to increase the sustainability of chemical synthesis through using catalysis. In particular, we aim develop methods which lead to an increase in efficiency of synthesis of a target molecule, leading to lower amounts of waste, and reducing the use of highly toxic chemicals. As well as potential economic savings through efficiency savings, ultimately this will lower the environmental impact of chemical synthesis and manufacture. This will benefit chemical manufactures, as it will help chemical process to pass environmental guidelines and regulations more easily.
The potential commercialisation of catalysts, chemical building blocks and amine products developed through this research will also be investigated. This will be carried out in consultation with Research Services at the University of Sheffield and our industry partner, Redbrick Molecular Ltd.

3. People
In addition, this research will involve training researchers in synthetic chemistry and catalysis. These skills are widely utilised by a broad range of industries from pharmaceuticals to materials science to analytical chemistry. This will therefore help develop the pool of talent of potential employees for these key sectors in the UK economy. To maximise development, the PDRA working on this project will attend meetings such as the SCI Annual Review Meeting, which provides a series of review lectures covering a range of emerging concepts in organic synthesis. This will complement the development of science communication skills during our weekly group meetings and at conferences. Also, the PDRA will be actively encouraged to carry out personal development training throughout their contract. Courses will be primarily provided through the University of Sheffield's existing training programmes, for both general staff training and specific courses for researcher professional development (known as the Think Ahead programme).