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

新合成方法的开发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，人们的注意力已经转向具有四元立体中心的手性分子，其与四个非等价碳取代基结合。这种三维结构提供了许多上级性质，而这些性质是现有的非手性“扁平”分子所不能提供的。然而，获得这种不对称化合物的广泛适用的策略相对罕见，并且与构建四级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，没有一种药物具有通过化学合成构建的四级立体中心。然而，使用具有预构建的四元立体中心的生物合成天然起始材料。目前的现状表明，手性化合物的未开发的，有前途的潜力和缺乏合成方法可用于构建季立体中心，因此缺乏其在药物发现中的应用之间存在着强烈的二分法。本研究的目的是将一种新型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。计划开发三环萜类化合物的一般方法，其依赖于芳基硼酸与β-取代的环烯酮的片段偶联共辄加成，然后中心环完成。重要的是，共辄加成加合物将具有足够的官能度来解决多个萜类家族所需的最终结构调整。中心环的完成将通过创新的2-C双亲电环化的发展来追求-这应该允许在一般意义上合成三环基序。为了验证这种一般方法，计划将这种策略应用于制备抗微生物松香烷衍生物pisiferol和carnosol。此外，鼠尾草酚的抗癌和抗炎特性突出了其对药物治疗发展的潜在意义。与此目标驱动的合成计划同时进行的是致力于开发新技术和反应方法，这些技术和反应方法可用于一系列应用并获得新颖的医学相关结构。

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.