Asymmetric Conjugated Additions of Exocyclic Enones with Alkylzirconocene Nucleophiles

环外烯酮与烷基锆茂亲核试剂的不对称共轭加成

• 批准号: 2446187
• 金额: --
• 依托单位: University of Oxford
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2020
• 资助国家: 英国
• 起止时间: 2020 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-2446187
• 关键词: Asymmetric; Conjugated; Additions; Exocyclic; Enones

Asymmetric conjugated additions are very intriguing transformations with great potential for synthesis of biological or pharmaceutical products. With the potential to form carbon-carbon bonds yielding chiral products these transformations have been thoroughly studied by several groups over the years. Many groups have developed different methodologies involving several organometallic reagents (Grignard reagents, trialkylaluminiums and dialkylzincs). Our group has developed an alternative copper catalysed strategy for cyclic and linear substrates utilizing alkylzirconocene nucleophiles with a phosphoramidite chiral ligand. By mixing the Schwartz reagent (Cp2ZrHCl) with an alkene, we can form a versatile range of alkylzirconocene nucleophiles by hydrometallation. This is a comparative advantage as it increases the variety of possible nucleophiles and therefore products obtained. In this project I will aim to adapt the developed strategy for exocyclic substrates in order to obtain products with high enantiomeric excess and yield. Even though the transformation is seemingly similar there are a few further complications. Firstly, in this reaction two stereocentres are formed in a single step leading to diastereoisomers. The diastereomeric ratio now becomes an important variable to consider. Furthermore, there is considerably less literature regarding this transformation when compared to asymmetric conjugate additions of cyclic or linear substrates. This fact presents the currently studied reaction as a relatively unknown transformation in the chemical world.The first objective in this project consists in developing (via ligand design and possibly statistical modelling) a chiral ligand to achieve high enantiomeric excess and yield. First, I will find a lead ligand which achieves at least moderate enantiomeric excess. After synthetizing such ligand, I will derivatize it and find an optimal structure which achieves high levels of yields and enantiomeric excess. After developing an optimal ligand for the studied reaction, I will be testing the robustness of this methodology using a scope of exocyclic substrates and different alkenes and alkynes. I will address on the strengths and weaknesses of this chemistry.Additionally, I will try to elucidate on the mechanism of this reaction by several techniques often used in mechanistic studies. These techniques might include kinetic experiments such as initial rates, Variable time normalisation analysis (VTNA) or kinetic isotope effects and DFT calculations between other possible techniques. I will be highlighting similarities and differences between this mechanism and the comparable reaction of asymmetric conjugated addition of linear enones, developed previously by the group.A simple and versatile reaction as the one I am studying can generate two stereo centres in one step, something not only very fascinating in a chemical standpoint but also a very useful stereoselective sp3 carbon-carbon bond formation reaction which could help meet the demands of an ever-growing synthetic industry.This project falls within the EPSRC field of physical sciences in the areas of catalysis and synthetic organic chemistry. Vertex Pharmaceuticals is involved in this project.

不对称共轭加成是非常有趣的转化，在生物或医药产品的合成方面具有巨大的潜力。由于形成碳-碳键并产生手性产物的潜力，这些转化多年来已被多个研究小组深入研究。许多小组开发了涉及几种有机金属试剂（格氏试剂、三烷基铝和二烷基锌）的不同方法。我们的小组开发了一种用于环状和线性底物的替代铜催化策略，利用烷基二茂锆亲核试剂和亚磷酰胺手性配体。通过将 Schwartz 试剂 (Cp2ZrHCl) 与烯烃混合，我们可以通过加氢金属化形成多种烷基锆茂亲核试剂。这是一个比较优势，因为它增加了可能的亲核试剂的种类，从而增加了获得的产品的种类。在这个项目中，我的目标是调整已开发的环外底物策略，以获得具有高对映体过量和产率的产品。尽管转变看似相似，但还有一些进一步的复杂性。首先，在该反应中一步形成两个立体中心，从而产生非对映异构体。非对映体比率现在成为需要考虑的重要变量。此外，与环状或线性底物的不对称共轭加成相比，关于这种转化的文献要少得多。这一事实表明，当前研究的反应是化学界中相对未知的转变。该项目的首要目标包括开发（通过配体设计和可能的统计建模）手性配体，以实现高对映体过量和产率。首先，我将找到一个至少实现适度对映体过量的先导配体。合成这样的配体后，我将对其进行衍生化并找到最佳结构，以实现高水平的产率和对映体过量。在为所研究的反应开发出最佳配体后，我将使用一系列环外底物和不同的烯烃和炔烃来测试该方法的稳健性。我将讨论这种化学的优点和缺点。此外，我将尝试通过机理研究中常用的几种技术来阐明该反应的机理。这些技术可能包括动力学实验，例如初始速率、可变时间归一化分析 (VTNA) 或动力学同位素效应以及其他可能技术之间的 DFT 计算。我将重点介绍这一机制与该小组之前开发的线性烯酮不对称共轭加成反应之间的异同。我正在研究的一种简单而通用的反应可以一步生成两个立体中心，这不仅从化学角度来看非常令人着迷，而且也是一种非常有用的立体选择性 sp3 碳-碳键形成反应，有助于满足不断增长的合成需求 该项目属于 EPSRC 物理科学领域的催化和合成有机化学领域。 Vertex Pharmaceuticals 参与了该项目。