Development and evaluation of chiral catalysts for asymmetric C-C and C-H bond forming reactions

This work was dedicated to the development and evaluation of new chiral catalysts for asymmetric C-C and C-H bond forming reactions. In this context ESI-MS was used as a powerful tool for reactivity- and selectivity-studies.
In the first part an ESI-MS screening method is described, which allows the determination of the selectivity of a chiral catalyst in the palladium catalyzed asymmetric allylic alkylation by testing its racemic form. It was shown that, by reacting a racemic mixture of the with a scalemic mixture of quasi-enantiomeric mass-labeled substrates, the selectivity of the chiral catalyst can be calculated from the ratio of the formed mass-labeled reaction intermediates. The value of this new method was demonstrated when different new aryl-PHOX-type ligands, which are not easily accessible in enantiopure form, were synthesized and evaluated in the allylic alkylation reaction. In this way a more selective member of this class was found compared to the previously reported phenyl-PHOX ligand.
Since PHOX ligands are suitable ligands in the iridium-catalyzed asymmetric hydrogenation of C-C and C-N double bonds, the new PHOX ligands were then tested as well in the iridium-catalyzed asymmetric hydrogenation of different unsaturated compounds. Although low activities and selectivities were found in most cases, one ligand showed some promising results in the hydrogenation of allylic alcohols and imines.
Furthermore air- and moisture-stable secondary phosphine oxide (SPO) containing bidentate ligands were tested in the palladium-catalyzed asymmetric allylic alkylation reaction. SPO,N-ligands bearing a PHOX type backbone were inactive in this transformation as they tend to form inactive palladium-bis-ligand complexes stabilized by hydrogen-bonding between the two ligands. SPO,P ligands however, were able to promote the desired reaction in a highly selective fashion although only low activities were found.
During this work as well a new organo-catalyst, based on the structure of 2,3-dihydrobenzo[1,4]oxazine, was developed which allows for the asymmetric transfer-hydrogenation of alpha, beta-unsaturated aldehydes. Especially in the reduction of beta, beta-diaryl acrylaldehydes very good activities and high enantioselectivities were achieved. It was shown that for this particular substrate this catalyst outperformed the previously described ones. Thus it proved to be a useful extension to the limited known catalysts for this reaction and especially for this interesting class of products, which can act as precursors for many natural products or drugs.
Another organo-catalyzed reaction which was studied in this work was the conjugate addition reaction catalyzed by a tripeptidic organo-catalyst. As in the literature two different mechanistically pathways were hypothesized, via an enamine- or via an enol-intermediate, ESI-MS studies were carried out to clarify the actual mechanism for this transformation. All reaction intermediates which are postulated for the enamine-pathway could be found in both the forward- and the back-reaction. Furthermore the enantioselectivity of enamine-attack onto a nitroolefin was determined by an ESI-MS screening and it was shown that this enantioselectivity equals the selectivity of the preparative reaction. All of these findings strongly support the suggestion of an enamine-catalysis mechanism to be true in this reaction.
The last part of this work aimed for the asymmetric alpha-allylation of carbonyl compounds by a tandem-catalysis approach. An intensive screening of both the organo-catalyst and the palladium-ligand led to reaction conditions which allowed for the selective mono-allylation of ketones in high yields. The formation of a quaternary center by alpha-allylation of
alpha-branched aldehydes was also achieved. However, only low enantiomeric excesses were obtained in this transformation for the different catalyst systems tested.