New methodologies in enantioselective catalysis

在一个人口不断增加而资源有限的世界里，新的合成化学方法的发展将不仅取决于它们的总产率和产品选择性，而且还取决于它们的生态和经济足迹。催化提供了一种实现更高效和环境友好的过程的方法：反应加速，过程所需的能量减少，获得的浪费副产品更少。总体而言，催化在节省能源、时间和成本方面发挥着重要作用。此外，在对映体选择性催化的特殊情况下，催化剂还提供了选择性地合成产物的两个可能的不可重叠镜像之一--所谓的对映体--所需的不对称来源。对映体化合物的选择性合成在从医药和农产品到聚合物和智能材料等日常生活中的各种产品的制备中都是至关重要的。本建议的重点是开发一种强大的催化方法，用于从廉价和容易获得的原料制备对映体构建块。这一提议的主要主题是将有机金属试剂加到C=O键上。该反应是有机化学中创建新的C-C键的最有力的工具之一，并已被有机锌和有机硼试剂广泛研究。然而，有机镁和有机锂试剂的高反应性阻碍了它们在这一领域的应用。有机镁和有机锂试剂都是更容易获得和经济上可行的亲核试剂，这一事实推动了新的合适催化体系的发展，以满足科学、经济和环境的要求。我们实验室的最新发现提出了一种现成的催化剂，作为将有机镁和有机锂试剂添加到C=O键的杰出方法的一部分。这一最近建立的方法的机制尚不清楚，通过这里提出的研究，我们打算更好地了解这一过程--这将允许进一步改进方法(例如，通过解决目前关于底物范围的限制)。此外，我们还将研究这种新型催化体系在氟化分子生产中的应用，其独特的性质使其作为药物制剂和先进材料特别有吸引力。

In a world with increasing population and limited resources, the development of new synthetic chemical methods will be judged not only by their overall yield and product selectivity, but also by their ecological and economic footprint. Catalysis provides a means of achieving more efficient and environmentally friendly processes: the reaction is accelerated, the amount of energy required for the process is diminished and fewer wasteful by-products are obtained. Overall, catalysis plays an important role in saving energy, time and costs in chemical processes. Moreover, in the particular case of enantioselective catalysis, the catalyst also provides the source of asymmetry needed to selectively synthetise one of the two possible non-superimposable mirror images of the product - the so-called enantiomers. The selective synthesis of enantiopure compounds is of vital importance in the preparation of a myriad of products in daily life, from pharmaceutical and agricultural products to polymers and smart materials.This proposal focuses on the development of a robust catalytic methodology for the preparation of enantiopure building blocks from cheap and readily available starting materials. The chemical reaction that is the main subject of this proposal is the addition of an organometallic reagents to a C=O bond. This reaction is one of the most powerful tools in organic chemistry to create a new C-C bond and has been extensively studied with organozinc and organoboron reagents. However, the higher reactivity of organomagnesium and organolithium reagents has hampered their application in this field. The fact that both organomagnesium and organolithium reagents are more accessible and economically viable nucleophiles, drives the development of novel suitable catalytic systems to fulfil the scientific, economic and environmental demands. Recent discoveries in our laboratories have brought forward a readily available catalyst as part of an outstanding methodology for the addition of organomagnesium and organolithium reagents to C=O bonds. The mechanism of this recently established methodology is still unknown and, by means of the research proposed here, we intend to get a better understanding of the process - which will allow further improvements of the methodology (e.g. by resolving the current limitations regarding substrate scope). In addition, we will also investigate the use of this novel catalytic system in the production of fluorinated molecules, whose unique properties make them especially attractive as pharmaceutical agents and advanced materials.