Towards Transition Metal Catalyzed Asymmetric C-H Activation

The present proposal is aiming at the development of asymmetric C-H activation reactions by means of transition metal catalysis. In this context, C-H activation reactions represent a methodology with great potential in synthesis since, if applicable, synthetic sequences can be shortened considerably. This was already demonstrated in innovative examples in the literature however, mainly in an asymmetric fashion. Most examples were reported for sp 2 C-H activation since the sp 2 C-H bond proved to be easier to activate and fewer side reactions are observed. In recent years also sp 3 C-H activation made considerable progress and also the first asymmetric versions were reported however, all of them had there own limitations. Therefore, further research in this area is needed and has the potential to improve on the efficiency of chemical synthesis. The current proposal tackles the problem of asymmetric C-H activation via two different approaches. The first one takes advantage of a directing group which shall be installed in the starting material with defined stereochemistry. This directing group shall then direct the transition metal catalyst to only one specific C-H bond of a CH 2 group leading finally to a diastereomerically-enriched or ideally diastereomerically-pure product. As starting materials compounds from the available chiral pool are envisioned such as carboxylic acids of pyrrolidine, piperidine, THF, THP, and others. Carboxylic acids were chosen as starting materials since they can be easily converted into a number of potential directing groups (esters, amides, oxazolines, etc.). Since the stereoinformation is already present in the substrates, achiral catalysts can be used even though chiral catalysts may lead to improved results (match - mismatch). The nature of the catalyst will be a main topic of investigation. As starting point for this research Pd, Rh, and Ru catalysts will be investigated since such systems were frequently used in the context of C- H activation chemistry. The second approach starts from achiral starting materials and it is aimed to introduce chirality into the products via the use of chiral catalysts. Ideally, the catalytic system will be formed in situ by the use of catalyst precursors and addition of chiral ligands. However, also pre-synthesized chiral catalysts will be tested in this transformation. Initially, the same transition metals as in the first approach will also be tested here. In this case, substrates carrying benzylic CH 2 groups are the first target systems since those CH 2 groups are believed to be quite reactive towards transition metal catalyzed C-H activation. Generally, no directing groups in the classical sense will be present in the starting materials. However, it is envisioned in one substrate class to have heteroatoms adjacent to the CH 2 group to be activated. Additionally, heterocycles such as pyridine can have a directing effect when located in a favorable distance to the CH 2 group in question and such compounds will be another class of substrates interesting for this project. Initially, arylation reactions will be investigated in both project parts. Therefore, suitable aryl donors have to be found. In later stages also alkylations, alkenylations, and carbonylations will be tested.

Efficiency is one of the most stressed terms in modern society and also in chemistry the trend to search more efficient processes is ubiquitous. In the field of organic chemistry (which is mainly the chemistry of carbon and only a few other elements) this is manifested by researchers trying to develop more efficient reactions, i.e. making bond forming processes better considering certain aspects. One of these aspects is minimization of waste, a goal which is sought after globally in all fields of our lives. Within this project it was tried to develop reactions which have the potential to fulfill this goal and indeed several transformations have evolved from this program. Additionally, in one of these methods has been applied to the synthesis of a compound class showing interesting biological properties. More specifically, the synthesized molecules were able to accelerate cell differentiation processes, which is the transformation of a less specialized cell to a more specialized cell. This is very interesting in the field of regenerative medicine and hence a hot topic of research worldwide.The synthesis of a complex organic molecule usually starts from small building blocks which are assembled to larger entities by bond forming processes. Usually, carbon-hydrogen (C-H) and carbon-carbon (C-C) bonds make up for most bonds in an organic molecule and hence C-C bond forming processes are of utmost importance in organic synthesis. One way to minimize waste in such a C-C bond forming process is to use reagents in catalytic amounts of only a few percent as compared to the building blocks connected to mediate the bond forming process. Here, metal catalysts have proved to be successful in the past decades. Methods were developed which enabled C-C bond formation between two molecules carrying suitable functional groups which specified the two carbons to be connected. However, these functional groups do not appear in the final molecule and have to be considered as waste in the end. Hence, in the past years it was the goal of chemists to avoid the usage of functional groups and rather use the omnipresent C-H bonds of a molecule for bond forming processes. However, omnipresence is of course problematic as well since a method should be selective for a specific C-H bond in order to make a single product and not mixtures of several compounds. Additionally, a typical C-H bond is also stronger compared to the usually applied C-(functional group) bond and hence also harder to break. Within this project different approaches have been investigated to realize the goals mentioned previously. Different types of C-H bonds (i.e. C-H bonds of different strength due to different neighboring groups) were successfully connected using different metal catalysts and reaction partners.