The on-off switch: Synthesis of functional heterocycles mediated by the capture and release of thiols

Organic compounds containing a cyclic arrangement of atoms, where at least one atom in the ring is an atom other than carbon, are refered to as heterocycles. Heterocyclic motifs are found in many natural and man-made biologically active compounds, for example drugs, and functional organic materials, such as organic semiconductors and liquid crystals. Whether these heterocyclic compounds are the constituents of new medicines or make up components of new electronic devices, this class of organic molecule has a tremendous impact on our quality of life. It is not surprising then that the development of new chemical processes that allow heterocyclic architectures to be constructed in a concise fashion is of major, international importance and is a highly competitive area of science. Recent discoveries in our research laboratories mean that we are uniquely placed to exploit our preliminary results in this area and to take a lead in the field.The grand challenge in organic synthesis - the construction of complex organic molecules from simple ones - is the development of efficient routes, using few chemical reactions, that produce the target compounds with minimum purification of intermediates. In this project we will develop strategies that allow important heterocyclic structures to be built quickly, using new chemical reactions, including 'cascade' reactions, and separation technology to reduce the need for traditional purification techniques such as chromatography. Cascade reactions are chemical reactions were a number of chemical changes happen in one reaction flask thus saving time and resources.The new chemical reactions we will use to form heterocycles are triggered by either the addition or the loss of a thiol - the sulfur analogue of an alcohol - from starting materials. We will 'couple' these new chemical reactions so that they work in a synergistic fashion and provide short routes to compounds that display either important biological activity (e.g. anti-tumour agents) or exhibit valuable physical properties (the constituents of semiconductor devices that show improved stability). When incorporated, the thiol unit will help us modify intermediates and will allows us to purify them quickly thus avoiding the expense of traditional chromatography.The project will feature the synthesis of analogues of two natural product families, the ecteinascidins and the spirotryprostatins. Natural products are, as the name suggest, naturally occuring organic molecules that often have important medicinal properties. One of the most famous examples is the natural product Taxol that was isolated from the bark of the Pacific Yew tree and is now a leading anti-cancer drug. The ecteinascidin and spirotryprostatin also have important anti-cancer activity and there is an urgent need for larger amounts of analogues of these scarce natural products for evaluation. We will also use our new strategies to make collections of indolocarbazoles, 'unnatural products' that have exciting semiconductor properties.Developing expedient routes to these natural and unnatural products is particularly timely as the link between the molecule's structure and its activity in these families is not clear. As existing access to these targets is limited, material for study is scarce. Ultimately, our research may lead to new heterocyclic drugs and organic electronic devices, and subsequently, to improvements in the quality of life, worldwide.