Development of diastereodivergent dynamic kinetic transformations

开发用于医药、农用化学品和香料的有机分子的立体选择性合成方法是非常必要的。Fletcher集团最近发现，非稳定的SP3烷基锆基和SP2硼酸亲核试剂可用于DYKATs的不对称烯丙基转化。现代不对称合成的主要挑战之一是选择性地形成具有两个或更多立体中心(非对映发散)的所有非对映异构体产物。在过去的十年里，通过两个协同作用的催化剂的帮助，这一领域取得了显著的贡献，每个催化剂都控制了一个形成的立体产生中心的绝对立体化学。2011年和2012年，Maulide和他的同事将DYKAT的概念扩展到钯催化的与稳定的亲核试剂的不对称烯丙基烷基化反应。4-氯环丁-2-烯-1-羧酸的四种立体异构体都通过配体控制转化为目标产物的单一立体异构体。我们预见，非对映发散的DYKATs可能成为合成具有多个立体生成中心的手性化合物的有效策略。在这个博士项目中，威兰德正计划开发立体发散的DYKATs，在不对称烯丙基烷基化和芳基化中具有不稳定的亲核剂。他的第一次尝试将集中在我们小组已经建立的对映发散DYKATs的非对映发散变体的开发上，以证明非对映发散DKYATs也可以用不稳定的亲核试剂实现的概念。如使用单取代六元烯丙基化合物所讨论的那样，必须满足两个主要要求。首先，所有立体异构体之间的快速异构化必须使用两种机械途径：异构化可能发生在金属‘pi’-烯丙基络合物上(策略A)，或者异构化也可能发生在原料的正反立体异构体之间，借助添加剂或辅助催化剂(策略B)。其次，必须开发两种不同的催化体系，它们表现出相反的非对映选择性。配体控制、离开基团、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，该方法还可应用于DYKATs的新型非稳定亲核试剂。人们希望这个项目能够找到新的方法，使人们能够更快地获得高度复杂的手性分子。该项目属于EPSRC催化研究领域。

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.