Ion-aggregation of chiral ionic liquids and its impact for asymmetric synthesis

To date, the synthesis of fine chemicals is mostly performed using conventional volatile organic sovlents; however this is always associated with the dangers of handling large volumes of volatile and combustible solvents, human risk and safety issues and poor environmental performance. Ionic Liquids (i.e. salts melting below 100 C) represent a class of solvents, as their tunable structure allows creating reaction media for a specific purposes. The combination of a constantly growing number of possible cations and anions permits the creation of tailor-made ionic liquids, including chiral species and it was early recognized that the properties of chiral ionic liquids might provide a new and attractive approach to asymmetric synthesis. This research project arising from a recent cooperation between Vienna University of Technology and the University of Vienna aims to develop novel chiral ionic that can be applied as ligands for the efficient production of enantiopure fine chemicals. I. The first part of this project addresses design, synthesis and characterization of a novel set of chiral ionic liquids based on chiral coordinating cations and structurally flexible anions. II. Synthetic efforts in this project will be accompanied by extensive theoretical and physico- chemical studies, able to rationalize ion aggregation in these ionic liquids and optimize their design toward their future application. III. In the last part of the project, the developed chiral ionic liquids, will be applied in transition- metal catalyzed asymmetric reactions, aiming to develop novel efficient catalytic processes. Successful completion of this task will pool the core competences of both involved institutions: On the one hand, novel chiral ionic liquids will be designed and applied; and on the other hand, the close cooperation between synthetic-organic and theoretical chemists will lead to a better understanding of the fundamental aspects of ion aggregation, thereby allowing to develop novel and efficient systems for the catalytic production of enantiopure fine chemicals.

In light of the growing awareness for economic and sustainable chemical transformations, the field of catalysis is of special interest. Given the high demand for enantiomerically pure products for pharmaceutical and agricultural applications, catalytic reactions involving chiral catalysts became particularly attractive in the last decades. This project was dedicated to the synthesis and application of new chiral catalysts for asymmetric transformations. In total, three different sub-projects were carried out. (1) The first sub-project focused on the application of ion-tagged chiral ligands for ruthenium-catalyzed asymmetric transfer hydrogenations (ATHs) in aqueous media. The fine tuning of the ligand structure together with the choice of anion resulted in water-soluble chiral ligands, which showed high catalytic activity and high enantioselectivity under environmentally benign aqueous conditions. A similar approach was investigated by using hydrophilically modified chiral ligands for Ru-catalyzed ATH reactions in ionic liquid-based thermomorphic microemulsion. As a result of the temperature-dependent multiphase behavior of such a microemulsion; not just high reactivities and selectivity but eventually also a rather simple product separation could be achieved. (2) The second sub-project part focused on the development of a new strategy for organocatalytic asymmetric transfer hydrogenations. Our novel concept of counterion enhanced catalysis relied on the ion-pairing of natural L-amino acids/amino acid derivatives - as source of chirality - in combination with either achiral or racemic phosphoric acids. These chiral frameworks were later found to be powerful tools for variable asymmetric transformations including organocatalytic transfer hydrogenations, epoxidations, aziridinations, as well as for different cyclisation reactions. Apart from providing highly enantioselective and metal-free alternatives, our catalyst frameworks could also give easy access to both product antipodes. Based on these findings, an additional project for the batchwise and continuous-flow synthesis of Warfarine-analogues is also ongoing the Research Group of Prof. Katharina Bica-Schröder. (3) The third sub-project aimed for designing new catalysts for asymmetric allylic alkylations (AAA reactions). At first, we focused on the application of Trost Modular Ligands with plausible P,O-binding motif for traditional AAA reactions. A small set of easily prepared carbamate-monophosphate ligands was applied for asymmetric allylic alkylations using activated allylic electrophiles with high yields and selectivity. Based on these findings, an additional project for the continuous-flow asymmetric allylic alkyliations with N-nucleophiles is currently ongoing the Research Group of Prof. Katharina Bica-Schröder. We then turned our attention to novel challenges by investigating the direct -allylation of -branched aldehydes with allylic alcohols. The three-component catalyst system comprising of a chiral amine, an atropoisomeric phosphoric acid and a palladium source enabled the smooth quaternization of aldehydes with poorly electrophilic, non-activated allylic alcohols via Pd/enamine dual activation, resulting in high isolated yields and excellent enantioselectivity.