Development of a Catalytic Enantioselective Method for the Construction of All-Carbon Quaternary Stereocenters: The Asymmetric Palladium-Catalyzed Conjugate Addition of Alkyl-, Vinyl-, and Alkynylboron Nucleophiles to alpha, beta-Unsaturated Electrophiles

开发用于构建全碳四元立构中心的催化对映选择性方法：烷基-、乙烯基-和炔基硼亲核试剂与α、β-不饱和亲电子试剂的不对称钯催化共轭加成

• 批准号: 318856427
• 负责人: Dr. Denis Kröger
• 金额: --
• 依托单位: Division of Chemistry and Chemical Engineering
• 依托单位国家: 德国
• 项目类别: Research Fellowships
• 财政年份: 2016
• 资助国家: 德国
• 起止时间: 2015-12-31 至 2016-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/318856427?language=en
• 关键词: Development; Catalytic; Enantioselective; Method; Construction

The enantioselective construction of all-carbon quaternary stereocenters (carbon atoms to which four distinct carbon substituents are attached) is of significant interest for various fields of research. Due to its three-dimensionality, the underexplored chemical space is increased substantially. Associated therewith, new opportunities will be offered, which are not available in the case of broadly used achiral flat molecules. In spite of that, only a few of the drugs with the highest turnover have all-carbon quaternary stereocenters. None of these stereocenters have been constructed by chemical synthesis. In all cases, those structures are derived from natural products. Based on this situation, two main insights can be gained. On the one hand, the potential of such chiral molecules is largely underexplored, and on the other hand, there is a lack of broadly applicable synthetic strategies for its build-up. Thus, the objective of the research project is to develop and to establish a universal method for the construction of these kinds of stereocenters under easily practicable synthetic conditions and in an atom-economical manner. Inspired by a palladium-catalyzed asymmetric conjugate addition of arylboronic acids to beta-substituted cyclic enones, which is limited to arylboron nucleophiles, the research project will be taken up. This new method aims to overcome the limitations so far and will allow the implementation of numerous substituents. The project shall be realized by the use of new palladium based catalysts containing bi- or tridentate N-heterocyclic carbene (NHC) ligands together with stable alkyl, vinyl and alkynylboron nucleophiles with functionalized sidechains. Particularly due to the opportunity of using boron nucleophiles with functionalized sidechains (e.g. amino acids or heteroaromatic compounds), the proposed method will strongly contrast to former methods and will additionally provide the possibility for further multi-faceted reactions.

全碳四元立构中心（四个不同碳取代基连接的碳原子）的对映选择性构建对于各种研究领域具有重要意义。由于其三维性，未被探索的化学空间大大增加。与此相关，将提供新的机会，这是不可获得的情况下，广泛使用的非手性平面分子。尽管如此，只有少数具有最高周转率的药物具有全碳四元立体中心。这些立构中心都不是通过化学合成构建的。在所有情况下，这些结构都来自天然产物。基于这种情况，可以得到两个主要的见解。一方面，这种手性分子的潜力在很大程度上未被充分发掘，另一方面，缺乏广泛适用的合成策略。因此，该研究项目的目标是开发和建立一种通用的方法，用于在易于实施的合成条件下以原子经济的方式构建这些类型的立体中心。受钯催化的芳基硼酸与β-取代环烯酮的不对称共轭加成反应的启发，该反应仅限于芳基硼亲核试剂，该研究项目将被采纳。这种新方法旨在克服迄今为止的限制，并将允许实施许多取代基。该项目将通过使用新的钯基催化剂来实现，该催化剂含有二齿或三齿N-杂环卡宾（NHC）配体以及具有官能化侧链的稳定的烷基、乙烯基和炔基硼亲核试剂。特别是由于使用具有官能化侧链（例如氨基酸或杂芳族化合物）的硼亲核试剂的机会，所提出的方法将与以前的方法形成强烈对比，并且将另外提供进一步多方面反应的可能性。