New Strategies to Nitrogen Heterocycles by Alkyne Functionalisation/6pi-Electrocyclisation

Aromatic compounds play a leading role in all aspects of the chemical sciences, and are found as core molecular fragments in a wide range of areas from coordination complexes to bioactive molecules and smart materials. Their application in these areas is dependent on our ability to design and tailor-make bespoke variants that will participate in further chemical modifications towards specific and intended target compounds. We have developed a way to make these compounds in a predictable manner, that controls the incorporation of functionalisable groups at specific positions on the aromatic ring. These functionalisable groups are based on boron, a privileged group in organic chemistry that mediates a very broad range of reactions. Using our approach, we will exploit borylated starting materials by showing how they can (1) play a key role in taking the starting materials to products by reacting with an alkyne unit in the substrates; (2) by forming a handle for further chemical modifications. We are only just beginning to understand the scope of this process, but we believe that it will represent a general method for preparing these important compounds. The requested grant will allow us to demonstrate the potential of the methodology, and will show that we can use it to access a very broad range of high value chemicals.

The proposed programme of research will deliver novel heteroaromatic boronic acid derivatives, an important class of small molecules, which provides access to a broad range of compounds. The continued development of novel aromatic and heteroaromatic scaffolds is crucial for a range of sectors. Moreover, the versatility of boronic esters has led to the uptake of these compounds in fine chemicals industries such as the pharmaceutical, agrochemical and electronic sectors.
Academics and researchers studying the assembly of bioactive molecules will benefit from the proposed research programme which has the potential to broaden the range of chemical intermediates and scaffolds available. Moreover, Industries involved in the synthesis of bioactive molecules including Fine Chemicals, Pharmaceuticals and Custom Research Organisations (CRO's) will also be able to take advantage of the new ring forming strategies proposed here.
Heteroaromatic motifs are widespread in small molecule drug therapies, with 11 out of the top 20 prescription drugs containing these building blocks. Interest in boronic esters is driven by the demand for novel molecular scaffolds which can be used as intermediates to generate active pharmaceutical ingredients. However, the chemical targets that can be accessed by pharma are often limited by the availability and diversity of existing chemical intermediates. Emerging challenges associated with maintaining a healthy drug discovery pipeline means that there is a growing need for chemistries that allow access to more diverse compounds and previously inaccessible structures. The proposed research programme would generate new compounds that may find application as new pharmaceuticals, intermediates towards new drugs or as tool compounds to further the understanding of disease conditions. Thereby this research has the potential to benefit the health of the population through the introduction of new treatments and also contribute to the economy through sales of new drugs and also by reducing the loss to the economy through ill health.
Heteroaromatic and aromatic compounds are also common structures in small molecule crop protection agents. The need for crop protection is becoming increasingly important as the demand for food crops rises due to the increase in the world population and also as the demand for non-food crops grows as the market for biofuels and industrial biotechnologies develops. Annual sales of crop protection agents are $8 billion. However, many fungal pathogens are becoming resistant to existing fungicides and therefore developing new, safe compounds with novel mechanisms of action is increasingly important.
The proposed research programme has the potential to deliver cleaner, more sustainable routes to not only novel compounds but also compounds that are already used on an industrial scale. The introduction of this methodology also has the potential to reduce the environmental impact of producing aromatic and heteroaromatic compounds on scale.