"Eeny, meeny, miny, moe": Selectivity-determining factors in asymmetric catalysis

Chemical reactions can often lead to the formation of multiple products. This is a problem for example in the production of pharmaceuticals. One possible solution is the use of metal-based catalysts that are selective for formation of only the desired product. Rational development and improvement of selective catalysts is dependent on a detailed knowledge about reaction mechanisms and selectivity-determining interactions between the substrate and the catalyst. The deFACTO project employs quantum chemical and experimental techniques to investigate different transition metal-catalyzed hydrogenation and hydrocarboxylation reactions. The studied catalysts include traditional precious metal complexes (based on e.g. iridium) as well as complexes based on cheaper and more abundant base metals (e.g. iron, cobalt, copper). deFACTO has proposed new mechanisms for several hydrogenation catalysts and has identified the factors that affect the stereo- and chemoselectivity in the studied systems. The results show that for stereoselective systems, the selectivity is often governed by weak non-covalent forces, in particular CH/pi interactions between substrate and ligands on the catalyst. This explains why systems, where the substrate does not interact with the metal centre, can display high stereoselectivity. For chemoselective systems, direct metal-substrate interactions are important in determining the preferred reaction path. deFACTO is occupied with developing strategies to improve the computational analysis of metal-catalyzed reactions. A variety of DFT methods has been analyzed and a straight-forward and fast protocol for accurate modelling of the reaction energies of iridium-mediated transformations has been proposed. deFACTO has also suggested a general concept, where known substrate preferences are employed as a diagnostic factor to evaluate the likelihood of mechanisms that are proposed on basis of computations. This implies that several real substrates are studied computationally to ensure that experimental selectivities are reproduced correctly. deFACTO employs the insights obtained through computational analysis in the development of novel selective reactions. For example, deFACTO has developed a selective iridium-catalyzed synthesis of pyrroles and indoles from cheap starting materials.

Many compounds utilized in industrial, agricultural, and pharmaceutical applications are chiral. A chiral molecule can exist in two enantiomeric forms (R or S), which are mirror images of each other. The two enantiomers interact differently with biologica l targets. For a pharmaceutical compound, one form might provide the therapeutic effect, whereas the other might be unreactive or harmful. Therefore, it is crucial to be able to produce only the desired enantiomer. Asymmetric catalysis relies on the use o f a chiral catalyst, which during the course of the reaction steers the substrate into a selective orientation, resulting in dominant formation of one enantiomer, ideally with a very large excess. The quest for the ideal catalyst can involve a time-consum ing trial-and-error approach. In order to improve the selectivity of chiral catalysts through a more efficient rational design approach, the factors governing the selectivity need to be understood. The main objective of deFACTO is to identify the selectiv ity-determining factors in asymmetric catalytic systems. This will be achieved through quantum chemical modeling of asymmetric reactions, also taking into account recent methodological developments. The deFACTO project will include studies of both traditi onal precious metal (e.g. iridium and rhodium) and novel base metal systems (e.g. iron or cobalt). Ongoing efforts in academia and in industry seek to replace established asymmetric catalytic systems with cheaper and more environmentally friendly base met al variants. The deFACTO project will be instrumental in this quest by providing insights into the selectivity-determining factors of asymmetric systems, and by proposing selectivity-enhancing modifications to the molecular structure of chiral catalysts, with experimental verification of the most promising alterations. The successful project will lead to more selective catalysts, and will be of high relevance for academic and industrial synthetic applications.