Catalytic Synthesis and Functionalisation of a Universal Aryl-Sulfur Intermediate

The ability of chemists to produce specific organic molecules on demand, at low cost and on scales ranging from milligrams to multi-tonnes, has been central to many of the advances on which our quality of life now relies. The UK's fine chemical industry - particularly within the pharmaceutical and agrochemical sectors - continually faces new synthetic challenges, and is under increasing pressure to reduce the environmental impact of its operations. As such, there is constant demand for new synthetic methods that either provide more efficient access to known classes of compounds, or that open up previously unexplored areas of chemical space.

Aryl-sulfur motifs feature in many societally-important molecules, including the sulfa drugs, anti-infectives that paved the way towards the modern healthcare we enjoy today. Formation of the C(aryl)-S linkage is often critical to the assembly of new aryl-sulfur-containing therapies, agrochemicals and materials, but - in many cases - is challenging to achieve in a mild and convenient fashion. Our research seeks to address these challenges through development of a robust and scalable method for C-S bond formation that avoids the malodorous, toxic and air sensitive intermediates that pervade organosulfur chemistry. The initial reaction products will then be exploited as a branching point from which to access all of the most important aryl-sulfur architectures, thereby demonstrating the ability of our methodology to deliver diverse, drug- and agrochemical-like scaffolds rapidly and under mild conditions. We will support this new methodology with detailed insight into how the system operates, and which variables are most critical for its successful application.

Ultimately, this project will provide new tools to aid synthetic chemists in the preparation of a more diverse range of sulfur-containing molecules, in a more efficient manner. Given the contribution of pharmaceutical and agrochemical companies to the UK economy, this increased capability will be of benefit to UK plc. In addition, this project will provide a wealth of useful information and fundamental academic understanding that could guide the future development of new synthetic methods.

This research will impact upon:

1. SMEs, national and multi-national companies within the pharmaceutical and agrochemical sectors. This programme will deliver a new and general method for the rapid assembly of aryl-sulfur motifs that are common to many biologically active molecules. As such, synthesis of the compound libraries required in the initial phases of drug / agrochemical discovery will be expedited, accelerating the progression of new compounds to market. In addition, the methodology will be applicable to large scales, potentially improving the efficiency and reducing the environmental impact of manufacture. This research will therefore directly impact industrial chemists, as well as those who utilise the chemists' output (e.g., biologists, chemical engineers etc.).

2. Chemical vendors. The availability of new synthetic methods will allow chemical vendors to increase the range of compounds for sale. Given the essential supporting role that such vendors play in the continued success of the pharmaceutical and agrochemical industries, an increased availability of new chemical building blocks could have significant benefits for said industries and the markets they serve.

3. The UK economy. More efficient synthesis will allow pharmaceutical, agrochemical and fine chemical companies to operate more profitably. Our methodology will enable efficiency by maximising yields, avoiding costly reagents and catalysts, and minimising waste. In addition, our methodology will be applicable to the entire product-development process, thereby reducing the investment of time and capital required to modify a synthetic route as a compound progresses from discovery to manufacture. Given that the UK chemical industry is worth ca £60M per day, any contribution to this area could have significant economic benefits. In addition to generating wealth for UK plc., the chemical industries are also major employers of skilled personnel, which directly benefits local communities.

4. The researchers on this project. A key part of this programme will be professional development of the researchers involved. This will go beyond an education in catalytic method development and physical organic chemistry - skills at the heart of the chemical industry - to include experience in scientific writing, communication and collaborative research. Nurturing the next generation of research-leaders in this way is vital if the vibrant scientific community if the UK is to be maintained.

5. Society. The UK's quality of life is built upon effective healthcare and food security, sectors that rely on the continued availability of new medicines and agrochemicals. The development of general methods for the synthesis of such molecules will allow pharmaceutical and agrochemical companies to increase their through-put and, ultimately, accelerate the progression of new products to market.