Gram-Scale Synthesis of Brevianamide Alkaloids.

With our rapidly increasing global population we must endeavor to reduce the economic and environmental cost associated with producing organic substances; our medicines, agrochemicals and high-tech materials. This project aims to mimic biological processes in an effort to improve the way in which we can make these highly important substances. This is akin to how engineers take inspiration from birds and other flying animals when developing better and more efficient planes. Through this "biomimetic" approach we will investigate and learn about the highly sophisticated way Nature utilizes predisposed, highly selective, chemical reactivity to rapidly construct complex molecules. We will demonstrate the power of this biomimetic strategy by synthesizing the brevianamide alkaloids, secondary metabolites isolated from various Aspergillus and Penicillium fungi. These alkaloids have only been isolated in milligram quantities, which has thus hampered full investigation into their biological function. The chemical syntheses proposed in this research project will produce gram-scale quantities of these highly important and complex molecules, which will enable further collaborative investigations into their biological profiles. Brevianamide S, for example, has been reported to exhibit selective antibacterial activity against Bacille Calmette-Guérin (a screening surrogate for Mycobacterium tuberculosis), suggestive of a new mechanism of action that could inform the development of next-generation TB drugs. Unfortunately, the quantity of natural brevianamide S that can be isolated from fermentation and extraction of Aspergillus versicolor has impeded greater investigation into this very promising biological activity. In summary, the expected outcome of this research will be uniquely efficient synthetic strategies that significantly surpass all previous approaches to this family of natural products, new synthetic methodology that will be of wider use in organic synthesis, and practical quantities of the target natural products for biological/medicinal research.

Total synthesis research, both in the UK and internationally, is undergoing a dramatic change in its perceived importance and its academic impact. Simply making a molecule, no matter how complex or useful, is not as impactful as it once was. The synthetic community is increasingly only recognising truly innovative approaches towards total synthesis research. This is because past generations of synthetic chemists have convincingly demonstrated that, given the required resources, it is indeed feasible to make almost any of Nature's most complex molecules. This total synthesis research proposal is, therefore, specifically focusing on the formidable challenge of efficiency, practicality and scalability in natural product synthesis. Yes, we can make complex natural products, but can we make useful quantities of them in a rapid and cost effective manner? We are also taking a more hypothesis-driven approach towards total synthesis research and hope to be able to better understand how and why Nature makes these molecules. The academic impact generated by this type of next-generation total synthesis research is very significant, with examples appearing in the very best peer-reviewed scientific journals (Nature, Science, Nature Chemistry, JACS, Angewandte, Chem Sci etc.). This project will result in the definitive synthetic strategy towards the brevianamide alkaloids, which have been 'hot-targets' for over three decades, and will allow for the production of previously unattainable quantities (i.e., grams instead of milligrams). When complete this total synthesis project will be considered a game-changer for these and similar natural products. The synthetic materials produced during this project will be screened for biological activity with our academic and industrial collaborators. This bio-activity data will then be used to direct a more 'function-orientated' synthetic programme. The identification and development of new lead-compounds could directly impact on the development of novel therapeutics. A particular focus of this research is to identify new natural product antibacterial agents that may help in the fight against drug resistant bacterial infections, a critical health issue facing the UK in the 21st century. We will explore all avenues for the benefit of the UK's economic competitiveness. The academic community will benefit from the tools developed in this programme and importantly the chemistry developed will be applicable across the life sciences. An important scientific skill is the ability to communicate and disseminate information: This project will also provide many opportunities for the PI and PDRA to have direct involvement in public engagement and dissemination, with a strong public interest in the process of developing new therapeutics from natural resources (more details in the 'Pathways to Impact' document).