Application of Palladium-Catalyzed Asymmetric Conjugate Addition Reactions of Arylboron Nucleophiles to α,β-Unsaturated Electrophiles as a Key-Step in Complex Bioactive Molecule Synthesis

钯催化的芳基硼亲核试剂与 α,β-不饱和亲电子试剂的不对称共轭加成反应作为复杂生物活性分子合成的关键步骤的应用

• 批准号: 399223652
• 负责人: Dr. Irina Geibel
• 金额: --
• 依托单位: Institut für Chemie (IfC)
• 依托单位国家: 德国
• 项目类别: Research Fellowships
• 财政年份: 2017
• 资助国家: 德国
• 起止时间: 2016-12-31 至 2018-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/399223652?language=en
• 关键词: Application; Palladium; Catalyzed; Asymmetric; Conjugate

The development of new synthetic methods is often driven by the demand for drugs with better efficacy and fewer side effects. Recently, attention has shifted toward chiral molecules with quaternary stereocenters, which are bound to four non-equivalent carbon substituents. The three-dimensionality offers a number of superior properties that established, achiral “flat” molecules cannot deliver. However, broadly applicable strategies to access such asymmetric compounds are relatively rare and the synthetic challenges associated with building quaternary stereocenters have largely prevented their implementation in drug discovery. Within the top pharmaceuticals, none have quaternary stereocenters build by chemical synthesis. However, biosynthetic natural starting materials with pre-built quaternary stereocenters are used. The status quo shows a strong dichotomy between the unexploited, promising potential of chiral compounds and the paucity of synthetic methods available for the construction of quaternary stereocenters and consequently the lack of their applications in drug discovery. The objective of the research stay is the application of a new palladium-catalyzed enantioselective conjugate addition reaction as a key step for the synthesis of complex bioactive molecules. It is planned to develop a general approach to tricyclic terpenoids that relies on fragment coupling conjugate addition of arylboronic acids to β-substituted cyclic enones followed by central ring completion. Importantly, the conjugate addition adducts will have enough functionality to address the final structural tailoring needed for multiple terpenoid families. The central ring completion will be pursued by the development of an innovative 2-C bis-electrophilic cyclization - this should allow the synthesis of tricyclic motifs in a general sense. To exemplify this general approach, the application of this strategy to the preparation of antimicrobial abietane derivatives pisiferol and carnosol is planned. Furthermore, the potential significance to the development of medicinal therapeutics is highlighted by the anti-cancer and anti-inflammatory properties of carnosol. Concurrent with this program of target-driven synthesis is a dedicated effort directed toward the development of new techniques and reaction methods that are useful for a range of applications and gain access to novel, medicinally relevant structures.

新的合成方法的发展往往是由对疗效更好、副作用更小的药物的需求驱动的。最近，人们的注意力转向了具有四元立体中心的手性分子，这些分子与四个不相等的碳取代基结合。这种三维结构提供了许多已建立的非手性“扁平”分子无法提供的优越特性。然而，广泛适用于获取此类不对称化合物的策略相对较少，并且与构建季立体中心相关的合成挑战在很大程度上阻碍了它们在药物发现中的实施。在顶级的药物中，没有一种是通过化学合成而形成的四元立体中心。然而，生物合成的天然起始材料与预先建立的四元立体中心被使用。目前的现状显示了一种强烈的二分法，一方面是手性化合物尚未开发的、有前景的潜力，另一方面是缺乏可用于构建四元立体中心的合成方法，因此缺乏它们在药物发现中的应用。本研究的目的是应用一种新的钯催化的对映选择性共轭加成反应作为合成复杂生物活性分子的关键步骤。计划开发一种三环萜类化合物的通用方法，该方法依赖于片段偶联-将芳基硼酸共轭加成到β-取代环烯酮上，然后进行中心环补全。重要的是，共轭加成加合物将具有足够的功能来解决多个萜类化合物家族所需的最终结构裁剪。中心环的完成将通过开发一种创新的2-C双亲电环来实现，这将允许在一般意义上合成三环基序。为了举例说明这种一般方法，计划将这种策略应用于制备抗菌枞烷衍生物pisiferol和carnosol。此外，油油醇的抗癌和抗炎特性突出了其在药物治疗学发展中的潜在意义。与这一目标驱动合成计划同时进行的是一项致力于开发新技术和反应方法的努力，这些技术和反应方法对一系列应用有用，并获得新颖的医学相关结构。