Asymmetric a-Functionalization of Carboxylic Acids/Esters

The direct -functionalization of simple acyclic carboxylic acid derivatives is a challenging task and this project aims on the development of new strategies to carry out such reactions in an asymmetric fashion. We will hereby rely on the use of chiral Lewis base catalysts which provide a highly reactive chiral ammonium enolate intermediate upon reaction with simple starting materials. This intermediate will then undergo the targeted asymmetric -hetero- and carbofunctionalization reactions. The hereby accessed enantioenriched products are of high value for further applications and therefore this project will provide powerful tools to overcome challenging synthesis problem and will give access to a variety of interesting chiral small molecules in a so far unprecedented and highly efficient manner relying on simple starting materials.

The development of efficient methods to functionalise carboxylic acid derivatives in the a-position (the position next to the carboxylic acid) and to control the resulting stereocenter (i.e. the spatial arrangement) is of great importance. The use of chiral organocatalysts has proven to be very promising in this respect. In the course of this project, we succeeded in developing novel methods for asymmetric a-heterofunctionalisations and a-C-C bond formations by either using chiral Lewis base catalysts or chiral ion-pair catalysts. In the first case, the catalyst, in our case usually a chiral isothiourea, interacts covalently with the starting material allowing for high stereoselectivities. This was successfully established for e.g. a-chlorinations of esters, a-alkylations of amino acid derivatives, and the formation of chiral heterocycles. In addition, using non-covalent ion-pair catalysis, we were able to effectively prepare a variety of a-halogenated heterocycle-based amides and a-selenated and a-halogenated amino acid derivatives for the first time. Furthermore, we succeeded in introducing novel chiral Lewis base catalysts which proved to be very promising for future applications. In addition to these results, some of the observations made in the course of this project have led to interesting side projects and opened new avenues for future research.