Development of diastereodivergent dynamic kinetic transformations

高度期望开发用于医疗药物、农用化学品和香料的有机分子的立体选择性合成方法。弗莱彻小组最近表明，非稳定的sp 3烷基锆和sp 2硼酸亲核试剂可用于应用DYKAT的不对称烯丙基转化。现代不对称合成中的主要挑战之一是选择性地形成具有两个或更多个立体中心的所有非对映异构体产物（非对映异构体）中的每一种。在过去的十年中，这一领域的显着贡献已经取得了两个协同作用的催化剂的帮助下，每个控制的绝对立体化学的形成的立体中心之一。在2011年和2012年，Maulide及其同事将DYKAT概念扩展到钯催化的不对称烯丙基烷基化与稳定的亲核试剂。通过配体控制将4-氯环丁-2-烯-1-羧酸的所有四种立体异构体转化为所需产物的单一立体异构体。我们设想，非对映异构体DYKAT可以成为一个强大的战略，具有多个立体中心的手性化合物的合成。在这个博士项目中，Wieland计划在不对称烯丙基烷基化和芳基化中开发具有非稳定亲核试剂的立体分散DYKAT。他的第一次尝试将集中在我们组中已经建立的对映体分散的DYKAT的非对映体分散变体的开发上，以证明非对映体分散的DKYAT也可以用不稳定的亲核试剂实现的概念。如使用单取代的六元烯丙基化合物所讨论的，对此必须满足两个主要要求。首先，必须使用两种机理途径实现所有立体异构体之间的快速异构化：异构化可能发生在金属“π”-烯丙基络合物上（策略A），或者异构化也可能在添加剂或助催化剂的帮助下发生在起始材料的顺式和反式立体异构体之间（策略B）。第二，必须开发两种不同的催化体系，其显示相反的非对映选择性。配体控制、离去基团、反离子、溶剂、添加剂和不同的过渡金属可能是实现所需选择性的最有前途的策略。此外，该方法可应用于新型非稳定亲核试剂的DYKAT。希望该项目将找到新的方法，使更快速地获得高度复杂的手性分子。该项目属于EPSRC催化研究领域的福尔斯。

The development of methods for the stereoselective synthesis of organic molecules for medical drugs, agrochemicals and fragrances is highly desired. The Fletcher Group has recently shown that non-stabilized sp3 alkyl zirconium and sp2 boronic acid nucleophiles can be used for asymmetric allylic transformations applying DYKATs. One of the major challenges in modern asymmetric synthesis is the selective formation of each of all diastereomeric products that have two or more stereogenic centers (diastereodivergent). In the last decade, remarkable contributions to this field have been achieved with the help of two cooperatively acting catalysts each controlling the absolute stereochemistry of one of the formed stereogenic centers. In 2011 and 2012, Maulide and co-workers have extended the DYKAT concept to palladium catalyzed asymmetric allylic alkylation with stabilized nucleophiles. All four stereoisomers of 4-chlorocyclobut-2-ene-1-carboxylic acid were transformed by ligand control into a single stereoisomer of the desired product. We envision that diastereodivergent DYKATs could become a powerful strategy for the synthesis of chiral compounds that have multiple stereogenic centers. In this PhD project Wieland is planning to develop stereodivergent DYKATs with non-stabilized nucleophiles in asymmetric allylic alkylation and arylation. His first attempts will focus on the development of diastereodivergent variants of the already established enantiodivergent DYKATs in our group to prove the concept that diastereodivergent DKYATs can also be realized with nonstabilized nucleophiles. Two main requirements have to be fulfilled for this as discussed using a monosubstituted six-membered allylic compound. First, fast isomerization between all stereoisomers have to be enabled using two mechanistic pathways: The isomerization might occur on the metal 'pi'-allyl complex (Strategy A) or the isomerization might also occur between the syn and anti stereoisomers of the starting material with assistance of additives or a cocatalyst (Strategy B). Second, two distinct catalytic systems have to be developed, which show opposite diastereoselectivity. Ligand control, leaving group, counterions, solvent, additives and different transition metals might are the most promising strategies for achieving the desired selectivities. Furthermore, this methodology could be applied to novel non-stabilized nucleophiles for DYKATs. It is hoped that this project will find novel methods that enable a more rapid access to highly complex chiral molecules. This project falls within the EPSRC Catalysis research area.