Asymmetric Conjugated Additions of Exocyclic Enones with Alkylzirconocene Nucleophiles

不对称共轭加成是一种非常有趣的转化，在合成生物或制药产品方面具有很大的潜力。这些转化具有形成碳-碳键产生手性产物的潜力，多年来已被几个研究小组进行了深入的研究。许多小组开发了不同的方法，涉及几种有机金属试剂（格氏试剂，三烷基铝和二烷基锌）。我们的团队已经开发了一种替代的铜催化策略，用于循环和线性底物，利用烷基锆新世亲核试剂和磷酰胺手性配体。通过将施瓦兹试剂（Cp2ZrHCl）与烯烃混合，通过金属加氢作用，我们可以得到多种多样的烷基锆新世亲核试剂。这是一种比较优势，因为它增加了可能的亲核试剂的种类，从而获得了产物。在这个项目中，我的目标是将开发的策略用于外环底物，以获得具有高对映体过剩和产量的产品。尽管转换看起来很相似，但还有一些进一步的复杂之处。首先，在这个反应中，两个立体中心在一个步骤中形成，导致非对映异构体。非对映比现在成为一个需要考虑的重要变量。此外，与循环或线性底物的非对称共轭添加相比，关于这种转换的文献相当少。这一事实表明，目前研究的反应在化学世界中是一种相对未知的转化。该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）一种手性配体，以实现高对映体过剩和产率。首先，我会找到一种铅配体它至少能达到适度的对映体过量。在合成了这样的配体之后，我将对其进行衍生化，找到一个最优的结构，从而达到高的产率和对映体的过剩。在为所研究的反应开发出最佳配体后，我将使用一系列外环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，我将试图阐明这一反应的机制，常用的几种技术在机制研究。这些技术可能包括动力学实验，如初始速率、变时间归一化分析（VTNA）或动力学同位素效应和其他可能技术之间的DFT计算。我将强调这种机制与之前由该小组开发的线性烯酮的不对称共轭加成反应之间的异同。一个简单而通用的反应，就像我正在研究的那样，可以一步生成两个立体中心，这不仅在化学角度上非常吸引人，而且是一个非常有用的立体选择性sp3碳碳键形成反应，可以帮助满足不断增长的合成工业的需求。该项目属于EPSRC在催化和合成有机化学领域的物理科学领域。Vertex制药公司参与了这个项目。

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.