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

新型镁基对映选择性去质子化方法：更环保的通用基础策略和催化方案的开发

• 批准号: EP/C548981/1
• 负责人: William Kerr
• 金额: $ 26.16万
• 依托单位: University of Strathclyde
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2006
• 资助国家: 英国
• 起止时间: 2006 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=EP%2FC548981%2F1
• 关键词: New; Magnesium; based; Enantioselective; Deprotonation

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.

设计和制备新药的能力对英国经济和一般生活质量都至关重要。在这方面，有机化学家是设计具有最大潜力作为特定疾病药物的分子的科学家，并设计如何制备这些潜在的药物分子。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结构单元的制备中（即在精细化学工业中）也是如此，这些小分子结构单元允许合成生物活性化合物。在有机化学方面，存在一个非常严重的复杂性：许多有机分子可以以两种不同的镜像形式存在。这样的分子被认为显示手性，即它们是彼此的镜像。用于描述这些分子的术语是手性的。反过来，给定的药物分子可能是手性分子，这就是可能出现潜在问题的地方。更具体地说，一种镜像形式的分子可以提供所需的药物样作用并提供所需的健康益处，而另一种分子可以具有减弱的（或没有）作用，或者在最坏的情况下，可以引起严重的有害健康影响。在这方面，最广为人知的案例是20世纪60年代的药物沙利度胺：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，而另一种形式导致了生长中的胎儿的缺陷。基于上述所有情况，现在至关重要的是，药物被制备成单一镜像形式用于给患者用药。随着对医学科学的需求不断增长，这种对药物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，单一对映异构体的合成被称为对映选择性合成。可以进行对映异构体的分离，但它通常是困难的、耗时的，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。根据以上的详细描述，对各种对映体选择性合成方法的研究已经成为世界范围内有机化学研究的前沿，这一点也不奇怪。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，这些试剂在对映体选择性合成所需有机分子方面具有显着的优势。这些新型试剂本身是手性的，具有镁作为关键金属组分，并且与含氮单元结合，可以允许制备具有非常高比例的一种对映异构体超过另一种对映异构体的分子。此外，所制备的分子是非常有用的构件，用于以单一镜像形式合成更精细的药物样材料。在这项研究计划中，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;这将允许以单一镜像形式制备更多样化的有益产品。此外，我们将尝试仔细制定仅允许使用非常少量的含金属试剂的条件，即我们将努力开发催化（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，农用化学品和精细化学品行业的研究人员以及整个国家具有相当大的价值。

项目成果

New C2-Symmetric and pseudo-C2-Symmetric Magnesium Amide Base Systems for Enantioselective Deprotonation Processes

用于对映选择性去质子化过程的新型 C2 对称和伪 C2 对称氨基镁基系统

• 发表时间: 2007
• 作者: N/a Kerr

Recyclable Supported Chiral Amines for use within Highly Efficient Asymmetric Mg-amide Base Processes

可回收的负载型手性胺，用于高效不对称镁酰胺基工艺

• 发表时间: 2008
• 作者: N/a Kerr