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General and Convergent Strategy for Asymmetric Synthesis

不对称合成的通用和收敛策略

基本信息

批准号：
EP/E052185/1
负责人：
Varinder Aggarwal
金额：
$ 125.48万
依托单位：
University of Bristol
依托单位国家：
英国
项目类别：
Fellowship
财政年份：
2007
资助国家：
英国
起止时间：
2007 至无数据
项目状态：
已结题

来源：
https://gtr.ukri.org/projects?ref=EP%2FE052185%2F1
关键词：
General Convergent Strategy Asymmetric Synthesis

项目摘要

Many important molecules required for life exist in two forms that are mirror images of each other. They are related like our left and right hands, but they are not the same. This property is called chirality, from the Greek word for hand, and the two forms are called enantiomers, from the Greek word for opposite. Perhaps surprisingly, Nature mainly uses only one of the two enantiomers available. Many drugs consist of chiral molecules and in the past a mixture of the two enantiomers was routinely employed since it is much easier to produce than the single more effective enantiomer. Since the catastrophic case of thalidomide, this scenario has changed and now two enantiomers of a chiral compound have to be treated as different products and are required to be tested separately. Consequently, it is vital to be able to produce the two chiral forms separately, particularly because they cannot easily be separated from a mixture. Thus, there is a strong industrial need fuelled by the pharma and agrochemical industries to be able to produce single enantiomers for testing and ultimately marketing. These large industries clearly impact on our every day lives: we need to eat, and need help to fight off disease. But chirality also has a major impact in biology. Anyone studying biological processes needs to make small molecules with the correct chirality to interact appropriately with the natural host. Chirality is also important in materials. The properties of polymers and liquid crystals are directly related to how they align (conformation) and stereogenic centres along the polymer chain can force the chain to turn right/left or go straight on (depending on whether it is a right or left handed centre). Thus, from medicine to materials, chirality is important. It spans all the scientific disciplines because it is a fundamental property of matter. Clearly, chemical processes that create chirality are extremely important. Chemical processes (synthesis) that create new C-C bonds from simpler molecules are also hugely important as this is how chemical complexity is built up. In a synthesis starting molecules are used to build new molecules by means of various chemical reactions. Organic synthesis generally involves the reaction between two molecules a nucleophile and an electrophile. These are attracted to each other rather like opposite poles of a magnet and a chemical bond is created between them. One class of useful nucleophiles are organometallic reagents as they readily react with electrophiles to make new bonds. However, chiral organometallic reagents are very rare, but clearly if they could be easily prepared they would be extremely useful as they would provide a direct synthesis of a broad range of chiral molecules. We propose a unique method for generating configurationally stable chiral organometallics and then we will explore what classes of electrophiles they react with. With this information we will then apply the new chemistry in the synthesis of biologically important molecules that are otherwise difficult to make. This will particularly highlight the power of the new methodology.A range of methodologies and their applications in synthesis are proposed in this proposal with common themes of synthesis and chirality. They are all linked together in that each methodology involves a nucleophile bearing a group that makes it behave as a nucleophiles but also leaves during the course of the reaction. We believe that reactions of this class of nucleophiles with conventional and non- conventional electrophiles will open up a whole new area of synthesis and provide a step change in asymmetric synthesis that could have far reaching consequences.

生命所需的许多重要分子以两种互为镜像的形式存在。它们就像我们的左手和右手一样相关，但它们并不相同。这种性质被称为手性，来自希腊语的手，这两种形式被称为对映体，来自希腊语的相反。也许令人惊讶的是，自然主要使用两种对映体中的一种。许多药物由手性分子组成，过去通常使用两种对映体的混合物，因为它比单一更有效的对映体更容易生产。自从沙利度胺的灾难性案例以来，这种情况已经改变，现在手性化合物的两种对映异构体必须被视为不同的产品，并需要分别进行测试。因此，能够分别产生两种手性形式是至关重要的，特别是因为它们不能容易地从混合物中分离。因此，在制药和农业化学工业的推动下，存在强烈的工业需求，以能够生产用于测试和最终销售的单一对映异构体。这些大型工业显然影响着我们的日常生活：我们需要吃饭，需要帮助来抵御疾病。但手性在生物学中也有重大影响。任何研究生物过程的人都需要制造具有正确手性的小分子，以便与天然宿主适当地相互作用。手性在材料中也很重要。聚合物和液晶的性质与它们如何排列（构象）直接相关，并且沿着聚合物链的立体中心沿着可以迫使链向右/向左转或直行（取决于它是右手中心还是左手中心）。因此，从药物到材料，手性都很重要。它跨越了所有的科学学科，因为它是物质的基本属性。显然，产生手性的化学过程是极其重要的。从简单分子中产生新的C-C键的化学过程（合成）也非常重要，因为这是化学复杂性的建立方式。在合成中，起始分子通过各种化学反应被用于构建新分子。有机合成通常涉及两个分子之间的反应，亲核试剂和亲电试剂。它们相互吸引，就像磁铁的两极，它们之间产生了化学键。一类有用的亲核试剂是有机金属试剂，因为它们容易与亲电试剂反应以形成新的键。然而，手性有机金属试剂是非常罕见的，但显然，如果它们可以容易地制备，它们将是非常有用的，因为它们将提供广泛的手性分子的直接合成。我们提出了一种独特的方法来产生构型稳定的手性有机金属化合物，然后我们将探讨它们与哪类亲电试剂反应。有了这些信息，我们将应用新的化学方法合成生物学上重要的分子，否则很难制造。这将特别突出新方法的力量。一系列的方法及其在合成中的应用提出了在这个建议与合成和手性的共同主题。它们都是联系在一起的，因为每种方法都涉及一个亲核试剂，该试剂带有一个基团，使其表现为亲核试剂，但在反应过程中也会离开。我们相信，这类亲核试剂与常规和非常规亲电试剂的反应将开辟一个全新的合成领域，并在不对称合成中提供一个可能具有深远影响的步骤变化。