Mild Functionalization Reactions of Prochiral Enolates

In this proposal, yet unprecedented enolate precursors i and ii and new functionalization methods thereof are presented. This allows for the elegant formation of all-carbon quaternary stereocenters, a motif which remains one of the most demanding challenges in synthetic organic chemistry. Prochiral enolates of type iii will be functionalized with different electrophiles in an enantioselective manner via palladium catalysis, transformations that are dramatically underdeveloped. Although the typical drawbacks of enolate formation either poor selectivity between the a and the a position or the need to install a blocking group that has to be removed again have been overcome with the developments in allylic alkylation chemistry, the installation of other groups other than allylic motifs remains difficult and largely unknown in an enantioselective manner. The key novelties of this proposal are 1) the synthesis of unknown precursors for prochiral enolates, 2) the mild formation of the latter and the 3) development of yet unknown transformations thereof. Developments from this project can be implemented in total syntheses of complex molecules bearing all-carbon quaternary stereocenters, a motif that is highly abundant in natural products and molecules of biological and medicinal interest.

The Schroedinger fellowship allowed Gerit Pototschnig to conduct her postdoctoral research in the group of Brian Stoltz at the california Institute of Technology in Pasadena, California. The plan she presented initially contained novel methods for the synthesis of quarternary carbohydrate centers in organic molecules. Methods of this kind are of extreme interest for the pharmaceutical industry. It became clear however, that the presented research program wouldn't be finished within the time constraints of the postdoc stay. G. Pototschnig shifted her focus to a high profile total synthesis project in the group which was very aligned with her expertise. The total synthesis and synthesis of medchem analogs of jorumycin, a natural compound isolated from the marine nudibranch jorunna funebris. In previous studies jorumycin had been shown to be extremely potent against a variety of cancer cells. The published synthetic routes at this point however didn't allow for the synthesis of analogs. In a team effort a new synthetic pathway towards jorumycin and analogs was developed that also contains a novel synthetic methodology for the stereoselective reduction of isoquinolines. A patent was filed, the work was published in Science and presented in numerous international conferences.