New Magnesium-based Enantioselective Deprotonation Methods: Greener General Base Strategies and the Development of a Catalytic Protocol

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The ability to design and prepare new medicines is of paramount importance both to the UK economy and to general quality of life. In this regard, organic chemists are the scientists who design the molecules which have the greatest potential of acting as medicines for specific diseases, and devise how these potential drug molecules can be prepared. As such, organic chemistry plays a crucial role in the drug discovery process. The same is true in relation to the agrochemical industry and in the preparation of the small molecular building blocks (i.e. within the fine chemicals industry) which allow biologically-active compounds to be synthesised.In terms of organic chemistry, one very serious complication exists: many organic molecules can exist in two distinct mirror image forms. Such molecules are said to display handedness , i.e. they are mirror images of each other. The term used to describe these molecules is chiral . In turn, there is a possibility that a given drug molecule can be a chiral molecule and this is where potential problems can arise. More specifically, one mirrorimage form of the molecule can provide the desired drug-like effect and deliver the required health benefits, whereas the other molecule can either have a lessened (or no) effect or, at worst, can cause severe detrimental health effects. In this regard, the most widely publicised case was that of the drug thalidomide in the 1960's: it is believed that one mirror-image form of thalidomide provided the desired health benefits to pregnant women, while the other form caused defects within the growing foetus.Based on all of above, it is now crucial that medicines are prepared as single mirror-image forms for administration to patients. With the burgeoning demands on medical science, this requirement for single mirror-image forms of drugs places an increasing burden on the organic chemist. The two mirror image forms of an organic molecule are called enantiomers . As such, the synthesis of single enantiomers is called enantioselective synthesis . Separation of enantiomers can be performed but it is often difficult, time-consuming, and, since half of the material is discarded, is wasteful in terms of materials and resources. Following on from the details given above, it is not surprising that research into various methods for enantioselective synthesis is at the forefront of world-wide activity in organic chemistry.Recent preliminary studies at the University of Strathclyde have resulted in the formation of new metal-based reagents that deliver significant advantages in the enantioselective synthesis of desired organic molecules. These novel reagents are themselves chiral, have magnesium as the key metallic component, and, in conjunction with a nitrogen containing unit, can allow the preparation of molecules with a very high proportion of one enantiomer over the other. Furthermore, the molecules that are prepared are very useful building blocks used in the synthesis of more elaborate druglike materials in a single mirror image form. In this programme of research, by carefully modifying the components around the metal, we plan to devise even more efficient magnesium-based reagents for use in enantioselective synthesis. Additionally, we will expand the range of organic molecules that can be prepared by using our new reagents; this will allow an even more diverse range of beneficial products to be prepared in a single mirror-image form. Furthermore, we will attempt to carefully formulate conditions that will allow the use of only very small amounts of our metal-containing reagent, i.e. we will strive to develop a catalytic (recycling) system. Consequently, this will lead to more cost-effective, and energy- and resource-efficient methods, which will lead to enhanced sustainability. As such, this work will be of considerable value to researchers in the pharmaceutical, agrochemical, and fine chemicals industries, and, in turn, the country as a whole.