Asymmetric arylation of racemic allylic halides

芳基硼酸与芳基卤化物之间的Csp2-Csp2交叉偶联反应在学术界和工业界都有广泛的应用，在新型农用化学品和药物的开发中具有重要的战略意义。Csp2-Csp3交叉偶联反应已经发展起来，但对映选择性的变化很少，简单地保持立体化学是一个问题。发展强大的和广泛适用的方法，形成单一的对映体产品是一个主要的当代研究目标。弗莱彻小组的研究重点是开发新的不对称合成方法。在此之前，该小组已经开发了一种新的反应-用硼酸亲核试剂和Rh催化剂对外消旋烯丙基卤化物进行动态动力学不对称烯丙基芳基化。它采用动态动力学分解（DKR）——一种将反应物的两种对映体转化为产物的单一对映体的简便方法。DKR利用一个特殊分子的中心，可以很容易地外聚，使对映体可以在整个反应过程中相互转化。此时，催化剂可以选择性地降低单个对映体的过渡态能量，从而使一种反应途径的产率几乎达到100%。在这种特殊情况下，环卤化物的每个对映体都与铑催化剂形成络合物。由于铑上存在手性配体，一种对映体的络合物立体特异性反应生成产物的速度比另一种快得多。铑中间体被认为在两种不同的烯丙基之间经历了表面的1,3异构化，如果还原消除是决定速率的，这将提供对映体选择的机制。该反应的优点包括催化剂负载低，为1 mol%（该反应可以很容易地放大到4.0 mmol）。该方法使用容易获得且价格低廉的构建块，例如芳基硼酸试剂，它在空气中相对稳定并且具有高原子经济性。此外，该反应条件温和，环烯丙基卤化物和芳基硼酸上的多种取代基均可耐受，因此该反应具有广泛的适用性。本项目的目的是将不对称烷基化方法应用于一组新的底物-线性烯丙基卤化物。首先，对称的烯丙基卤化物（两侧携带相同的取代基R）将测试烯丙基卤化物与铑催化剂、手性配体和苯硼酸的反应性。该反应将在溶剂、温度、催化剂负载和反应时间方面进行优化。接下来，将改变烯丙卤化物上的取代基，以确定任何反应性趋势。对称起始物质（在烯丙基卤化物的两侧携带相同的取代基R）将首先处理。然后测试两种不同基团的烯丙基卤化物。在这里，1,3移位的可能性可能导致更复杂的产品混合物。目标是确定哪些因素促进了这种转变，以及如何避免这种转变以获得单一的对映体产物。如果该项目成功，其影响将是巨大的，因为它将允许创建用于药物筛选的大量新化合物库，并为现有药物分子和其他具有生物学意义的目标提供更短、更有效的合成路线。该项目属于EPSRC物理科学研究领域。

Csp2-Csp2 cross-coupling reactions between arylboronic acid and aryl halides are widely used in both academia and industry and are strategically important in the development of new agrochemicals and pharmaceuticals. Csp2-Csp3 cross-coupling reactions have been developed, but enantioselective variations are rare and simply retaining the stereochemistry is a problem. The development of robust and widely applicable methods that form single enantiomer products is a major contemporary research goal. The research in Fletcher group focuses on the development of novel asymmetric synthesis methods. Previously the group has developed a novel reaction - dynamic kinetic asymmetric allylic arylation of racemic allylic halides using boronic acid nucleophiles and Rh catalysts. It employs dynamic kinetic resolution (DKR) - an elegant process to transform both enantiomers of reactant into a single enantiomer of product. DKR utilizes a centre of a particular molecule that can be easily epimerized so that the enantiomers can interconvert throughout the reaction process. At this point the catalyst can selectively lower the transition state energy of a single enantiomer, leading to almost 100% yield of one reaction pathway over the other. In this particular case, each of the enantiomers of the cyclic halide forms a complex with the rhodium catalyst. Due to presence of a chiral ligand on Rhodium, complex of one enantiomer reacts stereospecifically to give the product much faster than the other. The Rhodium intermediates are believed to undergo suprafacial 1,3-isomerisation between two different allyl species and if reductive elimination is rate-determining this would provide a mechanism for enantioselection. The advantages of the reaction include low catalyst loading of 1 mol% (the reaction can be easily scaled up to 4.0 mmol). The method uses readily available and inexpensive building blocks such as arylboronic acid reagents, which are relatively stable in air and have high atom economy. In addition, the reaction conditions are mild and a big variety of substituents on both cyclic allylic halides and arylboronic acids is tolerated hence the reaction is broadly applicable. The aim of my project is to apply the asymmetric alkylation method to a new set of substrates - linear allylic halides. Firstly, symmetrical (carrying the same substituent R on both sides of allylic halide) allylic halides will be tested for reactivity with Rhodium catalyst, chiral ligand and phenylboronic acid. The reaction will be optimised with respect to solvent, temperature, catalyst loading and reaction time. Next, substituents on allylic halide will be varied to determine any reactivity trends. Symmetrical starting materials (carrying the same substituent R on both sides of allylic halide) will be tackled first. Then allylic halides with two different groups will be tested. Here, the possibility of 1,3-shift could lead to a more complex mixture of products. The goal is to determine what factors facilitate the shift and how to avoid it to get a single enantiomer product. Provided the project is successful the impact would be immense as it would allow to create vast libraries of new compounds for drug screening and well as provide shorter and more efficient synthesis routes for existing drug molecules and other targets of biological significance. This project falls within the EPSRC Physical Sciences research area.