Design and development of molecularly-defined catalysts for efficient synthesis of amino alcohol and amino acid precursors

SP1的主要目标是开发关键的合成方法和催化剂。以催化级联反应中的烯烃为原料，直接合成有价值的α-羟基酮。这种新转化的基础是多米诺骨牌氢甲酰化-Umpolung反应(或更好的骨牌氢甲酰化-交叉酰基-级联反应)，该反应将使用金属络合物(用于羰化步骤的催化剂)和卡宾(用于Umpolung步骤的催化剂)进行。根据这一概念，将对新的和现有的配体以及由此产生的催化剂进行测试。最初，将同时应用和测试两种催化系统的组合。然后，通过在卡宾取代的膦配体中引入催化性能，制备出集成的双功能催化剂。为了合理地设计合适的催化剂体系，将与SP6密切合作，使用一组用于实验应用的催化剂(Rh，Co)和磷配体的描述符来预测更好的性能。由易得的烯烃直接合成α-羟基酮和α-酮酸衍生物的创新催化方法为利用现代氧化和生物催化制备对映体β-氨基醇和α-氨基酸提供了基础。示例性地，将利用代表多种烯烃的两种基准烯烃(苯乙烯和1-辛烯)进行这种开发。为了实现这一目标，选定的基准产品的产率应该在WP 1和WP 2中进行优化，这些产品也将被所有其他Pi‘S用于各自的研究。在这里，催化剂体系的变化-包括金属和配体-将是中心焦点。除了筛选确定最佳催化剂体系的方法外，我们还希望对其机理有更深入的了解，以支持更合理的催化剂开发。将与战略规划编制局合作，进行机理和动力学研究，以便深入了解级联工艺步骤并对其建模。在这方面，还应该提到的是，在我们的优化研究中，我们的目标是获得高质量的数据，而不是简单地进行高通量实验。在选择合适的催化体系(这将是所有后续开发的基础)后，还将利用DOE优化关键反应参数，如温度、分压、溶剂系统等。下一步，将合成设计的双功能催化剂，所有必要的活性中心都集成在分子定义的结构中(WP3)。当然，催化剂设计的基础将从WP 1和WP 2中获得的结果开始，并与SP6合作选择改进的配体。

The main goal in SP1 is the development of key synthetic methodologies and catalysts. Starting from olefins in a catalytic cascade reaction valuable α-hydroxy ketones will be directly prepared. The basis of this novel transformation is a domino hydroformylation-Umpolung reaction (or better domino hydroformylation-cross acyloin-cascade), which will be performed using metal complexes (catalyst for the carbonylation step) and carbenes (catalyst for the Umpolung step). Following this concept, new and existing ligands and the resulting catalysts will be tested. Initially, a combination of the two catalytic systems will be applied and tested at the same time. Then, integrated bi-functional catalysts will be prepared by introducing catalytic properties in the phosphine ligands utilizing carbene-substituted phosphines. To rationally design a suitable catalyst system, a close cooperation with SP6 will be done, where a set of descriptors for the experimentally applied catalysts (Rh, Co) and phosphorus ligands is used to predict better performance. The innovative catalytic approach for the direct synthesis of α-hydroxy ketones and α-keto acid derivatives from easily available olefins provides the basis for the preparation of enantiopure β-aminoalcohols and α-amino acids utilizing modern oxidations (SP2) and biocatalysis (SP3). Exemplarily, this development will be performed utilizing two benchmark olefins (styrene and 1-octene) which are representative for a broad diversity of olefins. To achieve this goal, the yield of the selected benchmark products, which will be used also by all other PI´s for their respective investigations, should be optimized in WP 1 and WP 2. Here, specifically variations of the catalyst system – both metals and ligands – will be the central focus. Apart from screening approaches to identify the optimal catalyst system, we would like to obtain deeper insights into the mechanism to support a more rational catalyst development. In cooperation with SP5 mechanistic and kinetic studies for an in-depth understanding and modeling of the cascade process steps will be done. In this respect, it should be also mentioned that in our optimization studies, we aim to get high quality data, rather than simply doing high-throughput experimentation. After the selection of suitable catalytic systems, which will be the basis for all subsequent developments, critical reaction parameters such as temperature, partial pressures, solvent systems, etc. will be optimized also utilizing DOE. Next, designed bifunctional catalysts with all necessary active sites integrated in a molecularly defined structure will be synthesized (WP 3). Naturally, the basis for this catalyst design will start from results obtained in WP 1 and WP 2 and in cooperation with SP6 to select improved ligands.