Thiophene dioxides: Versatile tools for ring synthesis

The synthesis of ring-containing organic molecules is of fundamental importance in medicinal chemistry and agrochemistry, as such molecules are widespread in these fields. Methods that can achieve the synthesis of these compounds in a handful of steps, and also with high flexibility in the substituents on the rings, are of particular value as they offer a rapid entry to diversely functionalised molecules. This project seeks to develop new, highly modular methods for the synthesis of organic ring systems, using thiophene S,S-dioxides as the key building blocks.

Thiophene S,S-dioxides are easily prepared from the readily available sulfur-containing thiophene ring system in a single oxidation step, but have been largely ignored as tools for ring synthesis. We recognised their overlooked ability to undergo a 'cascade' process of cycloaddition and loss of SO2 to form a new organic ring. We propose to invent a number of methods to assemble the substrates for this cascade in a single reaction flask, in effect enabling a one-step 'tailored' synthesis of the organic ring targets. We will also explore ways to use this chemistry for the synthesis of bioactive natural products; in some cases, these molecules have previously required 10-20 step syntheses, but using our strategies these can be prepared in 2-5 synthetic transformations. This represents a major advance in the state-of-the-art, opening up new opportunities for the study of the biology of these molecules. Finally, we also plan to develop asymmetric versions of these cascades, such that chemists can prepare single 'hands' (enantiomers) of the product molecules. This is of key importance for medicinal chemistry applications, as different 'hands' of molecules can exhibit distinct biological properties.

In summary, this project will deliver many opportunities for the use of thiophene S,S-dioxides in the modular syntheses of important ring systems, as well as rapid entries to natural product scaffolds.