Development of Heterogeneous Transition Metal Catalysts

In the proposed work we aim to develop next-generation heterogeneous catalysts, - which include rigid (tripodal) tethers in order to control the distance of the catalytic moiety from the surface as well as the distance between the grafted complexes - which can be immobilized onto surfaces under controlled and mild conditions (no surface contamination with chemicals, immobilization at room temperature, etc.) - which show no or negligible metal leaching - which are highly active and selective for applications in the pharmaceutical industry and - which can be used as bifunctional catalysts, i.e., catalysts that feature two or more types of catalytic sites and are thus able to catalyze multistep reactions in a one-pot synthesis. The following five milestones are part of the proposed work: 1. The first milestone involves the preparation of heterogeneous metallocenes (titanocenes and zirconocenes). As a first step, we will synthesize tripodal tethers, i.e., tethers that bear three functionalities for the immobilization on the surface and a fourth functional group for further derivatization. Secondly, we will immobilize these tethers onto silica surfaces. The immobilization method is based on a UV-mediated hydrosilylation, which allows highly controlled grafting under mild conditions. Finally, the immobilized tethers will be coupled with ethylenebis(indenyl)-metallocenes, which include a terminal functional group at the indenyl backbone. 2. The second milestone is the preparation of heterogeneous palladium catalysts. For this purpose, different N- ligands will be immobilized on silica and will then be metalated with Pd-complexes. 3. Modern surface spectroscopic methods including single crystal studies as well as high-surface-area characterization methods will be used by us in order to investigate in detail the immobilization chemistry and the distribution and concentration of active sites on the surfaces. 4. The immobilized metallocenes will then be utilized for enantioselective reductions of imines, ketones and other prochiral unsaturated compounds using hydrosilylation and hydrogenation procedures. The heterogeneous palladium catalysts will be tested for Buchwald-Hartwig reactions to prepare arylpiperazines and other important pharmaceutical products. Kinetic and mechanistic investigations will help us to optimize the reaction parameters and to allow an easy reaction scale-up. 5. The ultimate goal of this project, however, is to combine the various methods to develop bi- and multifunctional catalysts with a spatial control of the catalytic sites, i.e., materials that feature two or more catalytic compounds. This technology may have significant impact on other fields, such as (micro-)reactor design, therapeutic devices and sensing applications. In summary, we intend to develop new and efficient catalysts for the preparation of pharmaceutical intermediates. Given the fact that the market for chiral drugs and fine chemicals is becoming increasingly important, this project will have significant impact and may lead to significant improvements in the field of pharmaceutical engineering.

The active pharmaceutical ingredients (APIs) developed today are usually complex molecules with several chiral centers. Such molecules are often enantiomers, which are chemical compounds that have an identical atom sequence in the molecule, however, the relative steric orientation of the atoms or functional groups differs so that the two molecules are like mirror images. Enantiomers have identical physical and chemical properties but they can act different in the human body. For example, one enantiomer of Thalidomide, the API in Contergan, acts against morning sickness whereas the other is teratogenic. In general, there are different possibilities to synthesize chiral molecules, such are chiral induction, asymmetric catalysis or synthesis of both enantiomers followed by separation of the mixture. Since this separation is costly in terms of time and money, chiral catalysis is the method of choice. In addition to biocatalytic transformations, many catalysts currently used in pharmaceutical processing today are homogeneous organometallic complexes or colloidal metals. These catalysts, despite their broad applicability, high selectivity and activity, have certain disadvantages, such as expensive removal from the product and they impede continuous processes. A straightforward method for overcoming the drawbacks of these homogeneous catalysts is to immobilize (or to heterogenize) the catalysts on solid support materials. Therefore, the goal of this project was the development and optimization of highly active heterogeneous catalysts, which can be used for the preparation of pharmaceutical intermediates. For this purpose we developed novel methods for catalyst immobilization that allow a precise molecular control of the location and dispersion of the catalytic sites on the surface of the solid materials. The novel heterogeneous catalysts were successfully used for the synthesis of amines and substituted biphenyls. Amines can be found in more than 85% of all APIs, substituted biphenyls are the structural motifs of, e.g., the family of Sartans, one of the most important APIs for the treatment of hypertension. The catalytic systems developed in this project are tethered group 4 metallocenes as well as Pd complexes. Metallocenes are organometallic compounds which include a metal atom surrounded by two aromatic ring systems. The modification of these ring systems can be used to tailor the properties of the novel catalysts. Both, the novel metallocenes as well as the Pd-based catalytic systems are attached to ligands, which can be used to control the distance of the catalytic active side to the surface and the distance between the catalysts in order to minimize undesired interactions which would lead to a decrase of the catalytic activity. Since the novel catalysts are chemically, i.e., covalently, attached to the solid supports, metal leaching and thus, the contamination of the product can be prevented. One method used for the immobilization of the catalysts is based on a UV-mediated reaction. This approach can be carried out at room temperature and prevents contamination of the surface with other chemicals. By implementation of a photolithographic mask in the UV-light beam highly controlled grafting of the surface could be carried out under mild conditions. This approach allowed us to develop bi- and multifunctional catalysts, i.e., materials that feature two or more catalytic compounds with a precise spatial control of the catalytic sites. This technology may have significant impact on other fields, such as (micro-)reactor design, therapeutic devices and sensing applications.