Cyclizations and cyclization cascades triggered by new reductions

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.

Synthetic organic chemistry plays a crucial role in the advancement of science on many fronts as organic molecules and materials are vital to the work of millions of scientists around the world working in industry and academia.

The project will deliver new, reductive processes and innovative cyclizations and cyclization cascades triggered by the reductions. As functional group reductions and cyclization reactions are indispensible tools for scientists in established (pharmaceutical, agrochemical) and emerging (organic electronics, biotech/biopharmaceutical) industries in the UK (and beyond), our fundamental studies are aligned with the needs of UK industry (and academia) and will improve economic competitiveness and aid wealth creation in the UK. The selective reductive processes developed during this project will be valuable tools for synthetic chemists in their day-to-day work in academic and industrial laboratories and plants. The selective synthetic technology developed will allow chemists to streamline routes when designing future syntheses, thus shortening processes, minimising waste and avoiding potential hazardous reagents (e.g. alkali metals). Our preliminary results on the discovery of new organic reactions initiated by electron transfer mean that we are uniquely placed to meet the objectives of the project and thus deliver the predicted impact.

The proposed studies are also aligned with the EPSRC Portfolio. In the 'Healthcare Technologies' theme, reductive processes developed in this project will prove valuable tools in the battle against disease, allowing novel treatments and therapeutic technologies to be developed. The new synthetic methods will allow scientists working in 'Chemical biology and Biological chemistry' and 'Synthetic Organic Chemistry' to construct and modify molecules thus fine-tuning their therapeutic or diagnostic properties. Our studies on the synthesis of bioactive molecular architectures will be of particular benefit to members of the international research community working in pharmaceutical, biotech and biopharmaceutical companies. The new methods developed during the project could be used in the future to access natural product-inspired therapeutics, with new modes of action, and biological probes that could lead to improvements in the quality of life and patient health worldwide. In addition, the proposed studies address the goals of the Dial-A-Molecule Grand Challenge. Finally, the project may lead to future advances in Catalysis ('Manufacturing the Future' theme) and Sustainable Chemical Synthesis: the second phase of the work programme, involves the conversion of simple symmetrical substrates derived from the sustainable chemical feedstock malonic acid to high value, enantiomerically enriched molecular architectures using a new asymmetric reduction. Using chiral ligands to control electron transfer is extremely challenging and our studies will make a major impact in laboratories around the world.

Crucially, breakthroughs in industrial and academic research require skilled synthetic chemists. The project will provide a unique, interdisciplinary training for the postdoctoral researcher: the researcher will gain expertise in reaction development, radical and anionic mechanism, physical organic chemistry, multi-step synthesis, asymmetric synthesis and complex structure elucidation.