Complex made simple: Enantioselective radical cascades mediated by SmI2

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Many of the molecules society needs for the medicines, agrochemicals and materials that will improve the quality of our lives have complicated chemical structures with intricately linked rings of atoms and elaborate 3D forms. For example, in drug discovery it is now recognised that complex 3D drug candidates do better than simple, 'flat' compounds in clinical trials en route to becoming new medicines. Unfortunately, building complex molecules using known chemical processes either takes a lot of time and money, or in some cases, simply can't be done: It is crucial that we build the structures precisely or we will not get the function we desire. Thus, inventing chemical reactions that allow scientists to rapidly and selectively construct complex molecules from simple starting materials is one of the major challenges in science.'Cascade reactions', chemical processes in which a molecule undergoes a number of reactions, one after the other, like toppling dominos, could provide the key to meeting this challenge. In particular, cascade reactions involving radicals hold particular promise. Radicals are highly reactive chemical species and are good at forming bonds in complex molecules when other chemistry fails. However, the high reactivity of radicals comes at a price: radicals are so reactive that they can be hard to control and their reactions often give rise to product mixtures. In fact, generations of chemists have struggled with the problem of how to harness the power of radicals for organic synthesis.Although there are many ways to form radicals for chemical reactions, the commercial reagent, samarium diiodide, is one of the most effective. However, until now, the reagent has a significant limitation. The complex molecules society needs often exist in both left and right-handed forms (enantiomers), however, only one enantiomer will exhibit the properties that we desire. Until a recent breakthrough in our laboratories, controlling chemical reactions using samarium diiodide, so that one enantiomer is obtained rather than a mixture, was thought to be impossible: In the forty years since samarium diiodide was first used in synthesis, and the thousands of publications that followed, no satisfactory enantioselective reactions have been reported until now.Our laboratory has recently invented the first enantiomer-selective reactions using samarium diiodide. The new chemical processes are controlled by a simple, recyclable chiral ligand - a single enantiomer molecule that binds to the samarium atom - and quickly convert simple chemicals to the products we need, possessing complex linked rings of atoms and 3D forms. Crucially, the complex products are formed as single enantiomers. We have also used computational studies to understand how the new chemical reactions work.We will now develop and exploit enantiomer selective radical cascades that allow one-step access to complex molecules that are currently made by laborious multi-step organic synthesis. Thus, we will provide new processes to help national and international scientists build complex molecules in a more streamlined fashion, saving time and money, and minimising the chemical waste generated. Building on our recent studies, we will work out precisely how the new chemical reactions work, so that we can develop even better processes, before showcasing the value of the new reactions by using them to build, in only a few steps, complex biologically-active compounds from Nature. We will also develop better computational methods that allow us to design new chemical reactions prior to testing the findings in the laboratory. Finally, we will look further into the future and explore the feasibility of enantiomer selective cascade reactions that use only a catalytic quantity of samarium diiiodide. Our expertise in the chemistry of samarium diiodide and our recent discovery means that we are the only team in the world who can meet these challenges.