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

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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.