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、副作用更少的药物的需求推动的。最近，人们的注意力转向了具有四个非等价碳取代基的四个立体中心的手性分子。这种三维性提供了许多已建立的、无手性的“平面”分子无法提供的优越特性。然而，获得这种不对称化合物的广泛适用的战略相对罕见，与建立四元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。在顶级药物中，没有一种是通过化学合成建立的四元立体中心。然而，使用具有预置的四元立体中心的生物合成天然起始材料。这一现状表明，手性化合物尚未开发的潜力和用于构建四元立体中心的合成方法缺乏之间存在着强烈的两极分化，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。人们计划开发一种合成三环萜类化合物的通用方法，该方法依赖于芳基硼酸与β取代的环烯酮的片段偶联共轭加成，然后是中心环完成。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调整。中心环的完成将通过开发创新的2-C双亲电环化来进行-这应该允许在一般意义上合成三环基元。为了举例说明这一一般方法，计划将这一策略应用于制备抗微生物松香烷衍生物Pisiferol和carnosol。此外，卡诺醇的抗癌和抗炎特性突出了其对药物治疗发展的潜在意义。与这个靶向驱动的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，这些新技术和反应方法对一系列应用有用，并获得与医学相关的新结构。