Asymmetric Conjugated Additions of Exocyclic Enones with Alkylzirconocene Nucleophiles

不对称共轭加成反应是一种非常有趣的反应，在生物或药物合成中具有很大的应用潜力。由于有可能形成碳-碳键，产生手性产物，这些转化多年来已经被几个小组彻底研究。许多研究小组已经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。我们的小组已经开发了一种替代的铜催化的环状和线性基板利用烷基锆茂亲核试剂与亚磷酰胺手性配体的策略。通过将Schwartz试剂（Cp 2 ZrHCl）与烯烃混合，我们可以通过氢置换形成多功能的烷基锆茂亲核试剂。这是一个比较优势，因为它增加了可能的亲核试剂的种类，从而增加了所获得的产物的种类。在这个项目中，我的目标是适应环外底物的发展战略，以获得高对映体过量和产率的产品。尽管这种转变看起来很相似，但还有一些更复杂的问题。首先，在该反应中，在单一步骤中形成两个立体中心，导致非对映异构体。非对映体比率现在成为需要考虑的重要变量。此外，有相当少的文献关于这种转换相比，不对称共轭加成的环状或线性基板。这一事实表明，目前研究的反应是化学世界中相对未知的转化。本项目的第一个目标是开发（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，我将找到一个先导配体，它至少达到适度的对映体过量。在合成这种配体后，我将对其进行衍生化，并找到一个最佳的结构，实现高水平的产率和对映体过量。在为所研究的反应开发了最佳配体之后，我将使用一系列环外底物和不同的烯烃和炔来测试这种方法的稳健性。我将讨论这种化学的优点和缺点。此外，我将试图通过几种在机理研究中经常使用的技术来阐明这种反应的机理。这些技术可能包括动力学实验，如初始速率，可变时间归一化分析（VTNA）或动力学同位素效应和DFT计算之间的其他可能的技术。我将强调这种机制与该小组以前开发的线性烯酮的不对称共轭加成反应之间的相似性和差异。我正在研究的一个简单而通用的反应可以在一步中产生两个立体中心，这不仅在化学观点上非常吸引人，而且是非常有用的立体选择性sp3碳-碳键形成反应，可以帮助满足日益增长的合成工业的需求。该项目属于EPSRC物理科学领域的催化和合成有机化学领域的福尔斯。Vertex Pharmaceuticals参与了该项目。

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.