Development of diastereodivergent dynamic kinetic transformations

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.