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

设计和制备新药的能力对英国经济和总体生活质量都至关重要。在这方面，有机化学家是设计最有可能作为特定疾病药物的分子，并设计如何制备这些潜在药物分子的科学家。因此，有机化学在药物发现过程中起着至关重要的作用。在农用化学工业和小分子构建块的制备（即在精细化学工业中）中也是如此，这些小分子构建块允许合成生物活性化合物。就有机化学而言，存在一个非常严重的复杂问题：许多有机分子可以以两种截然不同的镜像形式存在。这样的分子被称为显示手性，即它们是彼此的镜像。用来描述这些分子的术语是手性的。反过来，一个给定的药物分子有可能是手性分子，这就是潜在问题出现的地方。更具体地说，分子的一种镜像形式可以提供所需的类似药物的效果，并提供所需的健康益处，而另一种分子要么效果较弱（或没有），或者在最坏的情况下，可能导致严重的有害健康影响。在这方面，最广为人知的案例是1960年代的沙利度胺药物：人们认为，沙利度胺的一种镜像形式为孕妇提供了所需的健康益处，而另一种形式则会导致正在发育的胎儿出现缺陷。基于上述所有情况，现在至关重要的是将药物配制成单一镜像形式供患者使用。随着医学科学的发展，对药物的单一镜像形式的要求给有机化学家带来了越来越大的负担。有机分子的两种镜像形式称为对映体。因此，单对映体的合成称为对映选择性合成。可以进行对映异构体的分离，但通常困难且耗时，并且由于一半的材料被丢弃，因此在材料和资源方面是浪费的。从上面给出的细节来看，毫不奇怪，对各种对映选择合成方法的研究处于世界范围内有机化学活动的前沿。斯特拉斯克莱德大学最近的初步研究已经形成了新的金属基试剂，在对映选择性合成所需有机分子方面具有显著优势。这些新试剂本身是手性的，镁作为关键的金属成分，与含氮单元结合，可以制备出一种对映体比另一种对映体比例很高的分子。此外，所制备的分子是非常有用的构建块，用于以单一镜像形式合成更复杂的类药物材料。在这个研究项目中，通过仔细修改金属周围的成分，我们计划设计出更有效的镁基试剂，用于对映选择性合成。此外，我们将扩大使用我们的新试剂可以制备的有机分子的范围；这将允许在单一镜像形式中制备更多样化的有益产品。此外，我们将尝试仔细制定条件，只允许使用非常少量的含金属试剂，即我们将努力开发一个催化（回收）系统。因此，这将导致成本效益更高、能源和资源效率更高的方法，从而提高可持续性。因此，这项工作将对制药、农化和精细化工行业的研究人员以及整个国家的研究人员具有相当大的价值。

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.