Cyclizations and cyclization cascades triggered by new reductions

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Synthetic chemistry - construction at the molecular level - continues to make a major impact on global society through its crucial role in the work of millions of industrial and academic scientists who require new molecules and materials for their studies: if new molecules and materials can't be made, the advancement of science will slow and benefits for society may be lost. The discipline of synthetic chemistry is built on the manipulation of 'functional groups' that are present in starting materials. The carbonyl group, in which a carbon atom is doubly-bonded to oxygen, is arguably the most important of these functional groups and the reactions of this group form the bedrock of the discipline. For example, the reduction of carbonyl compounds to alcohols is a key process in industry. Methods that allow carbonyl groups to be manipulated in a fundamentally new way have the potential to make a major impact on the global scientific community in academia and industry.We have recently found that the carbonyl groups in carboxylic acid derivatives can be reduced using electrons supplied by the user-friendly, commercial reagent, SmI2. Crucially, the reagent can only carry out the reductions when it is mixed with activating additives. Traditionally, these kind of 'electron transfer' reductions required reducing agents such as Na, Li and K that ignite on contact with moisture. Our new discovery therefore provides an attractive, safer alternative reagent system for important chemical processes. Our new reduction works by pumping electrons from the metal - samarium (Sm) - into the carbonyl groups of carboxylic acid derivatives. The process results in reactive species called radicals and these species can be used to form carbon-carbon bonds. In this project we will use the radicals generated in our new reductions in new ring-forming reactions ('cyclizations'). Furthermore, we will use the radicals generated to trigger a chain of events we call 'cyclization cascades' that convert simple starting materials to complex polycyclic products in a single operation, using a single reagent, with control of the shape, or stereochemistry, of the molecule under construction. We will show the value of the new processes by using a cascade cyclization to rapidly build the complex molecular framework of the famous anticancer drug, Taxol.In the second phase of the project, we plan to activate the commercial SmI2 reagent using a 'chiral' additive. 'Chiral' compounds can exist in two forms - think of your left and right hand. Using a single-handed form of the chiral additive with SmI2, we plan to take simple, symmetrical starting materials (made from the inexpensive and renewable chemical feedstock, malonic acid) and convert them selectively into complex, unsymmetrical, high-value products using the new cyclization reactions. Using chiral ligands to control electron transfer is extremely challenging and our studies will make a major impact in synthesis laboratories around the world.