Thiyl Radicals and Isocyanides: A New Approach Towards Biologically Active Heterocycles

The pharmaceutical industry is under intense pressure to improve the supply of new therapeutics whilst at the same time, reducing both cost and transition-time from discovery to application. This problem is hard to resolve without the development of new synthetic methodology or new technology and the proposed research will address both aspects of this.
Most medicines and agrochemicals are based on heterocycles and as a result, the search for new efficient methodology for their syntheses that avoids the use of protecting groups is essential. One key neglected class of reaction that is an obvious solution to this problem is radical chemistry, which uses mild conditions without the need for protecting groups. However, radical chemistry has received little attention from the pharmaceutical industry because the majority of reactions involve the use of organotin derivatives and are often carried out at high dilution. Whilst this is acceptable for the gram amounts required for medicinal chemistry, this is clearly impractical when moving to the kilogram quantities required in process chemistry. Synthetic routes are often redesigned and radical chemistry removed to minimise the purification steps required to remove the toxic by-products. To address this challenge, flow chemistry technology has emerged as a viable means for performing many types of chemical transformations as reactions can be run over time or in parallel, to produce either gram or kilogram quantities. Therefore, the transition from medicinal to process laboratories has become less cost-intensive and flow-chemistry has attracted considerable attention from the pharmaceutical industry.
Unfortunately, despite its potential, radical chemistry has not undergone the same transition in the pharmaceutical industry due to its reliance on organotin compounds. In preliminary studies, we have demonstrated that a non-toxic sulfur radical/ isocyanide based cyclisation of tricyclic heterocycles is viable and that it is a credible replacement for organotin derivatives. In the proposed research, we will explore the scope of this process to synthesise a range of key biologically active heterocycles, including anti-cancer compounds currently undergoing clinical trials. In conjunction with this, we will apply our chemistry to flow reactor technology to demonstrate that radical chemistry can be revisited as a method to produce larger scale quantities of material for the pharmaceutical industry.

This project has direct relevance to recent EPSRC priorities as illustrated by calls into the need for new methods for the synthesis of heterocycles as well as research into flow-based radical chemistry. Research outlined in the proposal will have a strong impact as it directly addresses these areas and will aid the development of the PI as an independent researcher. Initial results were obtained via support from the Royal Society to support a first grant application.
Key impacts that we expect to achieve at the end of this research are outlined below:
1) Advance knowledge in Organic Chemistry via fulfilment of EPSRC calls.
2) Provide a platform for the Principal Investigator to develop as an independent researcher.
3) Demonstrate advanced synthetic methodology at the School of Pharmacy.
4) Stimulate research into flow-based chemistry which will aid UK manufacturers of flow-reactor systems in subsequent years.
5) Reinvigorate research in the pharmaceutical industry into non-toxic radical chemistry, which will aid UK companies.
6) Demonstrate that radical chemistry can be carried out in an environmentally friendly process avoiding the use of tin compounds.
7) Develop new chemical entities (NCEs) that can be of benefit to cancer patients in the longer term.
8) Generate IP for the School via NCEs that can be exploited by the Commercial Development Office (CDO) to benefit the UK economy.
9) Raise the issue of the importance of science with MPs and Government at the annual SET for Britain event.
10) Promote science to Schools via outreach work with STEMNET to aid public perception and understanding of science.
11) Publish primary literature in journals and conference abstracts.
12) Generate expertise, data and methodology that will lead to new research projects in conjunction with biological scientists at the School and will have a future impact on public health.

In the first instance, the people that will benefit from this research will be the researcher and PI involved in this project. Both will use electronic laboratory notebooks as well as flow-chemistry, automatic purification and microwave synthesis in order to facilitate fast accurate recording of data and information sharing. As such, they will be able to transfer the knowledge gained to other academic groups in the UK or be employable in the Pharmaceutical industry. Following publication of our data, we intend to provide electronic access at the School to other researchers that will improve research and collaboration and enhance standards at the School. Longer term, this will impact on teaching of undergraduates and will also be of use in promoting science and the School to school children who visit as part of the PIs ongoing commitment to STEMNET.