Automating the Synthetic Chemistry Landscape in Bristol: Accelerating Impact and Application

In universities across the UK, research devoted to chemical synthesis is traditionally pursued one reaction at a time leading to an average of one reaction being conducted per day per person. Therefore, an unacceptably large portion of time, manpower and consumables is devoted to the routine yet necessary tasks of reaction optimisation, the exploration of substrate scope and the synthesis of molecular libraries. A large and disproportionate amount of time is spent low-value activities such as handling, preparation and data collection rather than on high-value activities such as the actual reaction and the subsequent analysis and interpretation of results. Access to an automated workstation would significantly increase the efficiency, output and quality of these tasks thus allowing valuable resource to be reallocated to problem-solving, innovation and application.

The development of simple and robust automated methods for peptide and oligonucleotide (and to some extent oligosaccharide) synthesis revolutionised the field enabling complex proteins and DNA/RNA oligomers to be prepared routinely and studied. These types of methodology were so useful that they were recognised by the award of Nobel prizes to the discoverers (Merrifield, 1984; Todd, 1957, Khorana 1968). We plan to employ recently created robust methodology that has been created in the UK and world-wide and adapt its employment on an ISYNTH Automated Workstation. This fully automated and programmable workstation can setup (dispense solids and liquids), run, and workup as many as 96 reactions at a time (up to an 8 mL volume for each vessel). The workstation can then purify products (through an aqueous extraction module or through a filtration module) and subject them as starting materials for further reactions (through automated evaporation and dissolution in fresh solvent), thus enabling multistep synthesis of libraries of molecules. The reactions can be set up under an inert atmosphere, under high pressure of reactive gases, at any temperatures from -70 C to +200 C and will be interfaced with an ultra-high-performance liquid chromatography/mass spectrometry (UHPLC-MS) for rapid and high-throughput in-line (online) analysis of reaction mixtures. The envisaged set-up is thus capable of automating most types of reactions that are employed in modern synthesis. For the user, it involves just loading raw materials, keying in a set of commands and walking away. If, even a fraction of organic synthesis can be conducted in this way it could have as big an impact as automated peptide and oligonucleotide synthesis.

Automating the optimisation of organic reactions and automating the synthesis of compound libraries will improve efficiency and throughput dramatically. Furthermore, the increased high-quality data that will emerge from optimisation reactions will feed into multi dimension computations that ultimately will be used to design and predict reaction outcomes. The synergy between high-quality reaction setup, data collection, analysis and computation, which will be key components of our facility, will enable such predictions to become meaningful.

There are four broad areas where this research will have an impact:

1. Academic. Automating organic synthesis will be truly transformative - it would create the biggest change to how we do organic synthesis that has taken place for over 50 years and give UK leadership on how molecules are made world-wide. It would foster closer relationships with other disciplines that need organic molecules and so result in greater academic growth not just in chemistry but in their own science. More rapid and efficient synthesis will have a major effect on academic biological research dependent on small molecules. It has been stated that the provision of molecules is often the rate limiting step in many of these pursuits. Indeed, molecules are often selected on the basis of what can be made easily. Removal of these constraints will allow faster progress and the selection of molecules that provide optimal function, not ease of access.

2. Providing well-trained scientists with enhanced skills. Students trained to doctoral level are highly employable in a variety of industries including those based on pharma, biotech, fine chemicals and petrochemicals. The increasing popularity of outsourcing, particularly in respect to chemical synthesis, has led to a marked increase in opportunities for employment in SMEs and the number of such companies is clearly on the increase. Investment in automation will provide further opportunities for intensive training for early career researchers and doctoral students, putting them in an ideal position to develop future careers in industry. Importantly, these early career researchers will be trained to have an open mindset where automation is a key opportunity to enhance synthetic endeavors and improve efficiency, thus making them indispensable to the search for solutions to important technical and societal challenges.

3. Economic benefit to the Pharmaceutical, Agrochemical and Fine Chemicals Industries. The UK chemical industry has a turnover in excess of £50 billion and provides an annual trade surplus of £5 billion, making it one of the most important industries and creator of wealth for the UK. In order to retain this position, it is essential that the UK remains competitive with cutting edge research that maintains our position as one of the most creative scientific nations. Investing in the technology will provide the UK with a world-leading position on how molecules are made more rapidly, how processes are optimized more quickly, greater insight into selecting the correct process at the outset, faster routes to compound libraries and greater imagination in compound selection. Each of these features will make UK chemical industry more competitive, which is essential in the face of growing pressures from competitors in the emerging economies. Chemistry also underpins many other industries, estimated to contribute 21% of the U.K. economy (£258 billion in global sales and employing over 6 million people). Thus, supporting innovative chemistry has far-reaching and major impact in the UK

4. Societal benefit through the promotion and use of new science by researchers in the UK and internationally. The solutions to a number of societal challenges (Energy, Food, Human Health, Lifestyle & Recreation) can be addressed through innovations in chemistry. Such innovations requires the synthesis of new molecules and to deliver the necessary solutions for society in a useful timeframe requires a step change in chemical efficiency. Automated methods for chemical synthesis will deliver such a step-change. Automated methods can deliver a range of outcomes depending on the goal targeted. It can focus on the highest yield (robust methodology for process chemistry and manufacture), the greatest diversity of molecules created (new medicines or agrochemicals), or the lowest Sheldon E environmental impact. Thus, it can also deliver on minimizing waste by simply selecting this aspect as the most important factor.