General and Convergent Strategy for Asymmetric Synthesis

生命所必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有联系，但它们并不相同。这种性质被称为手性，来自希腊语“手”的意思，这两种形式被称为对映体，来自希腊语“相反”的意思。也许令人惊讶的是，《自然》主要只使用两种对映体中的一种。许多药物由手性分子组成，过去通常采用两种对映体的混合物，因为它比单一的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，这种情况发生了变化，现在一种手性化合物的两种对映体必须被视为不同的产品，并要求分别进行测试。因此，能够分别生产这两种手性形式是至关重要的，特别是因为它们不容易从混合物中分离。因此，在制药和农用化学工业的推动下，有强烈的工业需求，能够生产用于测试和最终销售的单一对映体。这些大型产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要影响。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来与自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，聚合物链上的立体中心可以迫使链向右/左或直转（取决于它是右中心还是左中心）。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非常重要。从更简单的分子中产生新的碳-碳键的化学过程（合成）也非常重要，因为这是化学复杂性建立的方式。在合成过程中，起始分子通过各种化学反应生成新的分子。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，就像磁铁的两极一样，在它们之间形成了化学键。一类有用的亲核试剂是有机金属试剂，因为它们很容易与亲电试剂反应形成新的化学键。然而，手性有机金属试剂非常罕见，但很明显，如果它们可以很容易地制备出来，它们将非常有用，因为它们可以直接合成各种手性分子。我们提出了一种独特的方法来生成构型稳定的手性有机金属，然后我们将探索它们与哪类亲电试剂反应。有了这些信息，我们将把新的化学应用于合成生物学上重要的分子，否则这些分子很难合成。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，在这个建议中提出了合成和手性的共同主题。它们都是联系在一起的，因为每种方法都包含一个亲核试剂，它带有一个基团，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，并为不对称合成提供一个台阶，可能会产生深远的影响。

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.